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FORMATION OF THE AZIRIDINE RING
FORMATION OF THE AZIRIDINE RING
Historica l Backgroun d The earliest assignment of an aziridine structure to a compound was by Sabaneyev (3084) in 1875. He believed that the crystalline compound obtained from 1,1,2,2-tetrabromoethane, aniline, and alcoholic alkali was 2,3-dianilino1-phenylaziridine (1). However, it was later shown to have the isomeric form P h N H C H C ( = N P h ) N H P h , an acetamidine derivative. In 1881 Lehrfeld (2287) warmed ethyl 2,3-dibromosuccinate with alcoholic ammonia and obtained what he considered was probably ethyl 3-carbamoylaziridine-2-carboxylate (2), and thence made other aziridine derivatives. His observations have been confirmed (1677), but it still remains uncertain whether he had aziridines or the isomeric enamines, e.g., 3. 2
^.NHP h PhNH^~~ / Í
^C0 E t 2
Ç ÍèË~~ /
Et0 C-C-NH
2
O N I
2
2
H NCO—C— Ç 2
I
Ph
Ç
1
2
3
Apparently without knowledge of the earlier work, Ladenburg (2253) conceived and pointed out the probable existence of ethylenimine (EI) and homologous imines. He predicted that they should be obtainable from diamines by loss of ammonia. With this idea he tried for several years to prepare EI (2252). In 1888 he and Abel (2251) reported pyrolysis of ethylenediamine dihydrochloride to give small yields of the hydrochloride of a base believed to be EI, although its vapor density indicated that it was the dimer, piperazine. Preparation and properties of authentic piperazine led Sieber (3260) and von Hofmann (1748) to think that this was different from Ladenburg and Abel's product; but Majert and Schmidt (2398) soon showed that this product was indeed piperazine, and von Hofmann (1749) agreed. 1
2
1. FORMATIO N OF TH E AZIRIDIN E RIN G
In the meantime Gabriel had prepared and characterized what he considered t o be vinylamine, by the rearrangement of 2-bromoethylamine t o "vinylamine" hydrobromide and liberation of the free base with silver oxide (1385) or potassium hydroxide (1391). This preparation was improved (1392) and applied to 2-bromopropylamine (1388, 1723) and 2-chloro-3-camphanamine (1006). However, the insolubility of the benzenesulfonyl derivative of "vinylamine" in aqueous alkali and the failure of the free base t o react rapidly with aqueous potassium permanganate led Marckwald (1771, 2429) to conclude that it was really E I . The further evidence for the E I structure adduced by Marckwald and Frobenius (2428) pretty well settled the question, although some uneasiness about whether 2-phenylaziridine was really 2-phenylvinylamine was expressed in 1934 (1340), and vinylamine structures were written for what were surely aziridines as recently as 1939 (381) and 1949 (2265). Intramolecula r Displacemen t by th e Amin o Grou p INTRODUCTIO N
The most general method of generating an aziridine ring is the unimolecular rearrangement of a vicinally substituted amine ( 4 ) to an iminium salt ( 5 ) . This intramolecular alkylation occurs more or less readily depending on the structure of the substituted amine and the nature of the solvent. The reaction has both theoretical and preparative importance; these will be discussed in that order. I I -c—c-
\ I
Í / \
L-
N+
/\ -
( L - leavin g group )
Kinetics of the cyclization were first studied by Freundlich and his students (1338-1344, 3092, 3093, 3095). The investigation of the mode of physiological action of nitrogen mustards during World W a r I I soon was concerned with the rate of formation a n d decomposition of quaternary aziridinium intermediates of type 5 (1473). Since then, interest in such ions has been maintained by their connection with 2-haloalkylamines as antitumor drugs and as sympatholytic agents (744,3647). The cyclization also represents an interesting example of those nucleophilic displacements on carbon that involve neighboring group participation (1720, 2364, 3395, 3397). The first postulation of a quaternary aziridinium salt was by Marckwald and Frobenius (2428) in 1901; the salt was considered t o be the spiro salt 6 , presumably formed from l-(2-chloroethyl)piperidine.
INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P
3
This structural assignment was rejected by K n o r r (2118, 2119) and definitely disproved recently (2294, 2295), the compound being the dimeric
Ï
- Ï
a-
CH CH C 1 2
2
piperazine. The next, and more acceptable, suggestions were that such quaternary salts constitute reactive intermediates, such as 7 and 8 , in many
Br -
CHPhCHBrA c
(786, 787,2620, 2621)
Ph ,
*Ac 7
Et NCH CH C l 2
2
2
>
\
/
CI"
(1479)
/ \ Et Et
of the reactions of (2-haloalkyl)dialkylamines. This theme was expanded rapidly when it was found that toxicity of the nitrogen mustards could be correlated with the extent to which they had so cyclized (490, 1355-1357, 1489-1492, 1556, 1557). It was also reassuring that the aziridinium ions, though unstable, could be isolated as the insoluble picrylsulfonates (1355, 1490-1492). Association of other physiological effects of nitrogen mustards with their aziridinium forms soon followed. The antitumor action of such alkylating agents has had major study (139, 744, 2870), and many cyclizations, including those of N,Ar -bis(2-chloroethyl)amino acids (1941, 2966), Ar,AT -bis(2-chloroethyl)amino sugars (3687), and i^,A -bis(2-chloroethyl)purines (2377, 3190), have been noted. 3-Carbamoyl-l-(2-chloroethyl)pyridinium chloride cannot thus cyclize, but its reduction with sodium hyposulfite yields a 1,4-dihydropyridine derivative (9) that can do so (Eq 1) (1349). Indeed many aziridines have antitumor action (see Chapter 6). However, there is n o clear correspondence of such action in nitrogen mustards to their rate or extent of cyclization. Such correlation has also been sought in the mutagenic effects of r
4
1. FORMATIO N OF TH E AZIRIDIN E RIN G
CONH
CONH
2
2
0) CH CH C 1 2
2
9
these mustards (2918, 3269-3271, 3347). The case for aziridinium ion intermediates as active agents in the sympatholytic action of the mustards is much better (744, 3647). The pressor action of adrenaline and noradrenaline is counteracted by "one-armed" nitrogen mustards such as dibenamine [ ( P h C h ) N C H C H C l ] and dibenzyline [ P h O C H C H M e N ( C H P h ) C H CH C1] and good, though inexact, correlation between their existence in aziridinium form and their blocking potency has repeatedly been demonstrated (64, 65, 317-319, 642-644, 1056, 1442, 1514, 1515, 1517, 1518, 1620, 1764,2073,2075,2695,2696,2698, 2918,3145). 2
2
2
2
2
2
2
2
RATE S OF REACTIO N
Analytical Methods. Since compounds containing aziridinium nitrogen atoms are as a rule difficult to isolate, much of the work just discussed has had to develop and rely on analytical methods for following the rate of the cyclization forming 5 . 1. Determination of L " formed. This is very simple and common, at least when L " is a halide and an argentometric method can be used. It is untrustworthy if any other L"-forming process is significant, e.g., displacement of L~ by a solvent molecule, usually water, or by a second molecule of substituted amine. If no substantial buildup of acidity accompanies formation of L~, direct hydrolysis (Eq 2) can be ruled o u t ; if the reaction is first order in amine, L I
I
(2)
—C—C — + H 0 2
Í / \
OH
Í / \
attack by a second molecule of amine is excluded. If hydrogen ions do form, a correction for the extent of direct hydrolysis can be made (7555,1620,3647). In the cyclization of JV-(2-bromoethyl)aniline a second-order reaction with base can compete significantly with intramolecular displacement of the halogen (1668). The reversal of the cyclization, to form the substituted amine, is likely to be kinetically significant as the concentration of L~ builds u p .
5
INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P
2. Determination of aziridinium ion with thiosulfate ion. The aziridinium ring is quantitatively opened by thiosulfate, and excess thiosulfate can readily be determined {1492, 1602, 1802). However, the ring opening is sometimes too slow to be satisfactory for rate studies (280, 3269, 3270). One technique is to have thiosulfate present continuously during the cyclization, to trap the aziridinium ions (1442, 2343, 2426). The method assumes that no direct displacement of L~ by thiosulfate occurs. Recent work (2109) shows that this is an unsafe assumption, especially for primary halides, but the validity of the method can be established by showing the rate of reaction independent of thiosulfate concentration. Complete reaction of thiosulfate with a nitrogen mustard uses u p one equivalent of thiosulfate per - C H C H C 1 group except for that part of the chloro amine that undergoes direct hydrolysis; the extent of the latter can thus be estimated. Because of the consecutive ring openings and recyclizations that can occur with bis- and tris(2-haloalkyl)amines, the thiosulfate method is less reliable in application to them except to measure total cyclization. 3. Determination of unreacted amine by titration with standard acid. This has been used but little (1639, 3540). 4. In a tertiary amine, the protonated form (e.g., L C H C H N H R ) cannot cyclize, but in solution the aminium ion is in equilibrium with the free base, which can undergo cyclization. Titration of hydrogen ions to keep the p H near the pK permits calculation or at least estimation of the a m o u n t of amine that has cyclized (281, 1607, 3670). 5. The direct polarographic reduction of aziridinium intermediates has been shown suitable for their determination (2427) and used in rate studies (3869). 6. Other instrumental methods can be specific for determination of aziridinium ions: ultraviolet spectrophotometry (3345,3670) and nuclear magnetic resonance spectrometry (2310, 3347). Observed Rates of Cyclization. The interest in studying correlation between sympatholytic effect and aziridinium ion content led to a series of measurements of the maximum concentrations of such ions attained in solutions of appropriate 2-haloalkylamines. While the data are the resultants of the rate of formation of the ring and the rates of destruction of the ring, and therefore essentially empirical, they are reproduced in Table 1-1. It will be noted that maximum concentration of aziridinium ions is usually found for bromides; the corresponding fluorides do not cyclize at measurable rates, the chlorides cyclize so slowly that the rings are exposed to various nucleophilic attacks, and the iodides necessarily give the very nucleophilic iodide ion which keeps the "steady state" concentration of aziridinium ions low. As a unimolecular reaction, the formation of aziridinium ions by ring closure follows a very simple rate law, and many such rate constants have 2
2
+
2
a
2
2
2
2
2
2
2
Me CH CH F CH CH C I Et Me Me Me c-QH „ CH P h CH P h CH P h CH P h CH P h CH P h
Me Me or Et Me Et Me Me Me c-C H CH P h CH P h CH P h CH P h CH P h CH P h
Ç Me Ç Ç Ph Ph Ph Ç Ç Ç Ç Ç Ç Ç
CI CI CI CI CI CI Br Br Br Br Br Br Br Br
2
CH CH Br
Ç
Ç
Br
n
CH CH Br
Ç
Ç
Br
6
CH CH C 1
Ç
Ç
Br
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
CH CH C 1
2
Ç
3
Ç
2
R
Br
2
CH CH C 1
R
Ç
1
Ç
R
Amin e
CI
X
1
2
2
2
2
2
2
2
2
2
s
3
0.2M phosphat e p H 7.3 0.2M phosphat e p H 7.3 0.2M phosphat e p H 6.0 0.2M phosphat e pH7. 3 0.2M phosphat e p H 6.0 D 0 , excess N a Aq. buffer lMNa CO D 0 , excess N a 0.16MNaHCO H 0 50% Me C O 70% EtO H 67% Me C O 67% Me C O 70% EtO H 70% EtO H 70% EtO H 70% EtO H
Solvent
2
2
C0
C0
3
3
buffer , 27 36.7 30 0 37 37 31 27 30 30 4 27 37 37
37
37
37
buffer , buffer ,
37
37
buffer ,
buffer ,
Temp . (°Q
— —
—
—
— —
—
—
5 — 20 35 0 0
20
3
30
15
90
Tim e (min )
3
22 Some 57 * 100 98 96 92 » 50 0 2 « 50 4-10 15 2-8
« 80
* 95
« 80
« 90
« 80
Ion forme d (% of theory)
MAXIMU M CONCENTRATION S OF AZIRIDINIU M ION S FRO M 2-HALOALKYLAMINES , X C H R C H N R R
Tabl e 1-1
0
3347 2691 3347 3347 1286 1286 645 1620 641 642 1620 642 1620 642
2988
2988
2988
2988
2988
Referen c
6 1. FORMATIO N OF THE AZIRIDIN E RING
Ç Br Ç Br Ç I Me CI CI, Br , I Ç Ç F Ç CI Ç CI Ç Br Ç I Ç F Ç CI Ç Br Ç I Ç F Ç CI Ç Br Ç I Ç F Ç CI Ç Br Ç I Ç CI Ç Br Ç I Ç CI Ç Br Ç I Ç CI Ç Br Ç I Ç CI
2
2
2
2
2
2
CH P h CH P h CH P h CH P h Ph Et Et Et Et Et Me Me Me Me Et Et Et Et Me Me Me Me Et Et Et Et Et Et Et Et Et CH CH C 1 6
6
2
2
2
6
6
6
2
2
6
2
2
6
6
2
2
6
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
4
4
4
4
4
4
4
4
4
CH P h CH P h CH P h CH P h CH P h CH -l-CioH 7 CH -l-CioH 7 CH -l-CioH 7 CH -l-CioH 7 CH -l-CioH 7 CH -1-CiqH 7 CH -1-CioH 7 CH -l-CioH 7 CH -l-CioH 7 CH -2-CioH 7 CH -2-CioH 7 CH -2-C10H7 CH -2-CioH 7 CH -2-CioH 7 CH -2-CioH 7 CH -2-CioH 7 CH -2-CioH 7 CH C H Cl- p CH C H Cl- p CH C H C1-/? CH C H Cl-/ w CH C H Cl- m CH C H Cl- m CH C H Cl- o CH C H Cl- o CH C H Cl- o CH P h 2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
70%EtO H + KHCO 67%Me C O 67% Me C O 70% EtO H + KHCO 3 67%Me C O 67%Me C O 67% Me C O 67%Me C O 67%Me C O 67%Me C O 67%Me C O 67%Me C O 67% Me C O 67%Me C O 67%Me C O 67%Me C O 67%Me C O 67% Me C O 67% Me C O 67%Me C O 67%Me C O 67%Me C O 67%Me C O 67%Me C O 67% Me C O 67%Me C O 67%Me C O 67%Me C O 67%Me C O 67%Me C O 67%Me C O 50% EtO H
37 30 30 37 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 25
15
20
— —
30
—
—
30
—
—
—
—
—
— — —
— — —
— — — — —
—
—
—
—
—
10
—
—
5 16 4.5 7 0 0 34 86 86 100 0 18 100 47 0 47 96 79 0 15 72 52 36 81 60 26 75 52 22-23 75 52 61* 318, 3647 642 642 3647 641, 644 641, 644 641, 644 642 641, 644 644 641, 644 641, 644 644 641, 644 644 641, 644 641, 644 644 644 641, 644 641, 644 644 65, 1517 65 65 65, 1517 65 65 65, 1517 65 65 2851a INTRAMOLECULA R DISPLACEMEN T BY THE AMIN O GROU P 7
Ç Ç Ç Ç Ç Ç Ç Ç Ç Ç Ç Ç Ç Ç Ç Ç Ç Ç Ç Ç Ç Me Me Ç
CI CI CI CI CI CI CI CI CI CI CI CI CI CI Br
CI Br CI Br CI
I
CI Br
I
R
X
1
2
CH CH CH CH CH CH CH CH CH CH CH CH CH Et Et Et Et Et Et CH CH Et Et Et
R
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
Ph Ph
CH CH CH CH CH CH CH CH CH CH CH CH CH
2
2
2
2
2
2
2
2
2
2
2
2
2
C1 C1 C1 C1 C1 C1 C1 C1 C1 C1 C1 C1 C1
Amin e 3
2
2
2
6
6
6
6
2
2
6
6
2
6
2
2
6
6
2
2
6
6
2
2
4
4
4
3
3
3
4
4
4
4
4
2
2
2
4
5
7
CH C H Me -i7 CH C H -iso-Pr- p CH C H OMe-< ? CH C H OMe- m CH C H OMe-/ > CH C H OEt- p CH C H OPr-; ? CH C H OBu-/ > CH C H (OMe) -3,4 CH C H -3-N0 -4-OM e 5,6,7,8-H -2-CioH CH C H [(CH ) ]-3,4 CH -5-indany l 9-Fluoreny l 9-Fluoreny l 9-Fluoreny l 9-Fluoreny l 9-Fluoreny l 9-Fluoreny l 9-Fluoreny l 9-Fluoreny l 9-Fluoreny l 9-Fluoreny l Benzo [6]then-3-ylmethy l
R
2
2
2
2
2
2
2
2
2
2
2
50%EtO H 50%EtO H 50% EtO H 50% EtO H 50% EtO H 50% EtO H 50% EtO H 50% EtO H 50% EtO H 50% EtO H 50% EtO H 50% EtO H 50% EtO H 67% Me C O 67%Me C O 67%Me C O 67%Me C O 67% Me C O 67% Me C O 67% Me C O 67%Me C O 67%Me C O 67%Me C O 67% Me C O
Solvent 20 20 20 20 20 20 20 20 20 20 20 20 20 15 15 15 15 0.5
25 25 25 25 25 25 25 25 25 25 25 25 25 30 30 30 30 30 30 30 30 30 30 30
—
—
—
— — —
Tim e (min )
Temp . CO
3
67* 71* 92* 52* 77* 70* 79* 73* 74* 31* 63* 59* 62* 7 36-40 14 7 36-40 14 1 4 4 31 22
0
2851a 2851a 2851a 2851a 2851a 2851a 2851a 2851a 2851a 2851a 2851a 2851a 2851a 642, 1517 642, 1517 642 642, 1517 642, 1517 642 642 642 642 642 642
Reference s
—continue d
Ion forme d (% of theory)
MAXIMU M CONCENTRATION S OF AZIRIDINIU M ION S FRO M 2-HALOALKYLAMINES , XCHR'CHiNR^
Tabl e 1-1
8 1. FORMATIO N OF TH E AZIRIDIN E RIN G
4
6
6
6
6
2
2
2
Ç Ç Ç Ç Ç Ç Ç Ç Ç Ç />-MeC H /7-ClC H />-ClC H 3,4-Br C H 3,4-Cl C H 3,4-Cl C H
CI Br I CI Br I CI Br CI CI Br Br CI Br Br CI
4
Ç
CI
4
Ç
CI
6
Ç
CI
6
Ç Ç Ç Ç Ç
Br I CI Br I
3
3
3
Q
6
H
-)
2
2
2
2
2
2
2
2
2
2
-
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
6
6
6
6
6
4
4
4
4
4
CH CH OP h CH CH OP h CH CH OP h CH CH OC H Me- o CH CH OC H Me- o CH CH OC H Me- 0 CH CH OC H Me-/ > CH CH OC H Me-/ > CHMeCH OP h CHMeCH OP h Me Me Me Me Me Me
^CH2CH2CH2 —
4
2
^CH -
2
2
^CH CH —
2
Benzo [6]then-3-ylmethy l Benzo [Z>]then-3-ylmethy l 2-Theny l 2-Theny l 2-Theny l
/CH —
3
O-C H :
°-
2
(R + R
CH P h CH P h CH P h CH P h CH P h CH P h CH P h CH P h CH P h Et Me Me Me Me Me Me
Et Et Et Et Et
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
67% Me C O 67%Me C O 67%Me C O 67% Me C O 67%Me C O 67% Me C O 67% Me C O 67% Me C O 70%EtO H + KHCO 70%EtO H + K C O 40% Me C O 40% Me C O 40% Me C O 40% Me C O 40% Me C O 40% Me C O
2
3
67% Me C O + K C 0
2
2
67% Me C O + K H C 0
2
67%Me C O + K H C 0
2
2
2
2
2
67% Me C O 67% Me C O 67%Me C O 67% Me C O 67% Me C O
3
3
30 30 30 30 30 30 30 30 37 37 37 37 37 37 37 37
37
37
37
30 30 30 30 30
5 3 5 5 5 5 5 5
8.5
« 15
—
—
6 33 7 4 21 3 6 27 21 83 67 83 83 88 87 79
60
1
0
72 56 1.5 10 4
64 64 64 64 64 64 64 64 3647 3647 640 640 640 640 640 640
318
318
318
642, 1518 642 642 642 642 INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P 9
Me Et Pr Me
Ph Ph Ph
b
a
R
Ar
X
Amin e
2
2
2
2
2
2
2
2
2
2
40% Me C O 0.01 Ì phosphat e buffer , p H 7.3 0.01 Ì phosphat e buffer , pH 7.3 67%Me C O
Solvent
2
R
3
50% 50% 50% 50%
Me Me Me Me 2
2
2
2
CO CO CO CO
Solvent
31 31 31 31
C O
Temp .
2
30
37
37 23
Temp . (°Q
For a few 2-haloethylamine s of typ e BrCRArCH NMe
2
2
CH CH 0 CCPh O H
2
CH CH 0 CCPh O H
2
3
Me CH CH 0 CCPh O H
R
On th e basi s of reactio n of only one haloalky l group . Not necessaril y th e maximu m yield.
I-C10H7
Me
Ç
Me Me
CI
3
Me
6
2
Ç
2
R
CI
1
3,4-Me C H Ç
R
CI CI
X
1
2
2
3
— — —
Tim e (min )
« 60
10
5 20
Tim e (min )
0 0 0 0
Io n forme d (% of theory) "
<30
83
78 82
645
645
645
645
Reference s
1470
1470
1470
640
Ion forme d (% of theory) * Reference s
MAXIMU M CONCENTRATION S OF AZIRIDINIU M ION S FRO M 2-HALOALKYLAMINES , X C H R C H N R R — c o n t i n u e d
Tabl e 1-1
10 1. FORMATIO N OF THE AZIRIDIN E RIN G
11
INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P
been measured. In some instances values have also been obtained for the frequency factor and the energy of activation for the cyclization. Such data are presented in Table l-II, which considerably extends the compilation n o w available (2677). Factors Affecting Rate of Cyclization. 1. Solvent. Since initially neutral parts of the molecule must come into a transition state which involves some separation of charge, solvents of high dielectric constant favor the reaction. There has been n o systematic comparison of many solvents in the cyclization, b u t the higher rates of 2-haloalkylamines in water compared t o methanol (Table l-II, entries for 2-bromoethylamine hydrobromide) and acetone [entries for ( C l C H C H ) N H E t C r ] illustrate the effect. While both E, the energy of activation, and A, the frequency factor, are decreased in nonaqueous solvents, the effect of the change in A is the greater a n d the cyclization is retarded. 2. N a t u r e of L. The most familiar leaving groups are seen here, and the rates of leaving are in the order t o be expected: 0 S R (1056,1442,1764) > Br > C 1 > F , O S 0 " (896). Similar displacement occurs spontaneously in 2aminoethyl diethyl phosphate ( 1 0 ) and 2-aminoethyl diphenyl phosphate (498) and in 2-dimethylaminoethyl diphenyl phosphate (1013). +
2
2
2
3
3
10
/ Ç
\ Ç
Phosphatidyiethanolamines, R C 0 C H C H ( 0 C R ) C H O P ( 0 ) ( O H ) O C H C H N H , u p o n exhaustive treatment with diazomethane lose their nitrogen (243), probably as EI (498), and it is likely that .merely treating a phosphatidylethanolamine with strong base, t o which it is reported very sensitive (1540), will cause such elimination. However, 2-aminoethyl dihydrogen phosphate is undecomposed by boiling for 24 hours with 1 JVNaOH (2895); evidently the displacement of the highly charged phosphate ion is virtually impossible. 2-Aminoalkyl nitrates would probably cyclize t o form aziridinium ions. This path has been suggested for the dimerization of the trinitric ester of triethanolamine, N ( C H C H O N 0 ) , t o 1,1,4,4-tetrakis(nitroxyethyl)piperazinium dinitrate (1010). The mechanism of the conversion of 2-(dialkylamino)alkyl halides by silver perchlorate t o aziridinium perchlorates (1306a, 2294,2295) has not been directly investigated. The path might 2
2
2
2
2
2
2
2
R NCH CH2C 1 2
2
A g C 1
4
° >
R NCH CH OC10 3 2
2
2
2
2
3
\
/ / \ R R
C10 " 4
(3)
3
3
3
3
+
+
3
Cl Cl Cl Cl + picrate -
D D H H H D H
2
2
2
3
3
3
3
2
2
2
3
2
2
3
2
3
3
3
2
3
3
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0
H H H H H H H H H H
2
MeCHClCH NH + Cl" MeCHClCH NH + Cl~ ClCH CHPhNH +Cl PhCHClCH NH + Cl" PhCHClCH NH + Cl~ PhCHClCH NH + Cl~ PhCHClCH NH + Cl~ PhCHClCH NH + Cl~ PhCHClCH NH + Cl" MeCHClCH NHMe + Cl~
2
2
2
H 0 H 0
2
2
2
2
2
2
2
2
2
2
Solvent
ClCH CHMeNH + Cl~ MeCHClCH NH + picrate -
2
FCH CH NH (FCH CH ) NH C1CH CH NH C1CH CH NH C1CH CH NH + C1CH CH NH + ClCH CHMeNH
Amin e salt or free bas e
2
4
+ AcO H or K H P 0 + NaO H
II
« 0.07,
KCIO4 , ì
II II II II II II II II II II II
2
I I II II II I II
0
Analytica l method
NaO H NaO H NaO H NaO H NaO H NaO H NaO H Non e Non e
NaO H Ba(OH)
2
0.2MNaO H 0.2MNaO H NaO H NaO H NaO H 0.3MNaO H Ba(OH)
Adden d
5 5 6 4 3 2
— 3 3 3
— « 1 « 5 1.63
— 82 100 25
4 3
5 5 7 6 5 5 3
ç
3 3.44 w 5 3.0 7.0 2.0
2.5 1.13
1.6 7.5 2 8 1.56 1.3 8.2
k°
-1
0
25 31 25 0 25 37
25 25
90 80 0 25 31 50 25
Temp . (°C)
n
k (= 10- A: ), (sec )
RATE S OF CYCLIZATIO N OF 2-SUBSTITUTE D AMINE S TO AZIRIDINIU M SALT S
Tabl e 1-Ð
—
— —
— —
14
—
—
—
ç
—
—
—
—
— — —
6 1
19.1 20.6
—
— — — —
—
—
—
— 11 13
—
(But considere d 2nd order ) — — — — — — « 27 — —
—
— (But considere d 2nd order )
9
—
—
—
A°
27.5
—
—
—
Å (kcal )
-1
A (= 10M°), (sec )
1341 620 1341 1341 1341 1341 3095 3095 3095 1605
1341 3301
2310 2310 1344 3095 620 2310 3301
Reference s
12 1. FORMATION OF THE AZIRIDINE RING
2
2
+
2
H 0
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
+
+
+
+
+
+
2
2
2
2
2
2
2
2
2
2
2
2
2
2
0 0 0 0 0 0 0 0 0 0 0
D H H H H H H H H H H
2
2
2
2
(C1CH CH ) NH + Cl (C1CH CH ) NH Cl (C1CH CH ) NH + Cl (ClCH CH ) NHMe + Cl~ (ClCH CH ) NHMe Cl" (ClCH CH ) NHMe Cl~ (ClCH CH ) NHMe + Cl" (ClCH CH ) NHMe Cl~ (ClCH CH ) NHMe + Cl~ (ClCH CH ) NHMe Cl~ (ClCH CH ) NHMe Cl~
2
2
67%Me C O H 0
+
ClCH CH NHEt + Cl" (C1CH CH ) NH + Cl -
2
2
2
2
2
H 0
2
2
2
2
ClCH CH NHEt + Cl~
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
H 0 ClCH CH NHMe + Cl" H 0 ClCH CH NHMe + Cl~ H 0 C l C H C H N H M e Cl~ ClCH CH NH (CH CH OH) Cl" H 0 ClCH CH NH (CH CH OH) + Cl~ H 0 H 0 ClCH CH NHMe(CH CH OH) + Cl H 0 ClCH CH NHMe(CH CH OH) + Cl H 0 ClCH CH NHEt + Cl" H 0 ClCH CH NHEt + Cl" H 0 ClCH CH NHEt + C\~
2
ClCH CHMeNHMe + Cl~
2
2
2
2
2
2
2
3
3
4
+ AcO H or K H P 0 + NaO H II NaHC0 + N a C 0 , pH 10.7 Non e II Borat e buffer , VI p H 7.36 I NaOH , 0.2M II NaOH , pH 7.2 NaOH , pH 6.0 II NaOH , p H 8.0 II , NaOH , pH 8.0 II , NaOH , pH 8.0 II , Ba(OH) 11, Ba(OH) ð, II Ba(OH) Ba(OH) II Ba(OH) II
4
KC10 ,/x«
0.07,
IV? , V? IV? , V? IV? , V? í í
II , IV? , V? II , IV? , V? Il l
NaOH , p H 8 NaOH , pH 8
37 37 37 0 15 30 10 25 15 25 35
25 25
25
0 15 25
15
4
11, iv, í
2
NaOH , pH 7.9
25
18 25 35 37 37 0
II
+ AcO H or K H P 0 + NaO H II + II I NaO H NaO H II + II I NaO H II + II I NaOH , pH 7.2 II II NaOH , pH 6.0 NaOH , pH 7.9 Ð, IV, V
KCIO4 , ì « 0.07,
6.2 5.00 7.01 3.84 4.00 3.25 1.87 1.61 3.7 1.3 3.7
3.4 5.5
4.17
2.64 2.42 9.3
3.84
1.1 3 1 1.01 1.06 4.50
1.6
5 4 5 5 4 3 4 3 4 3 3
3 5
3
4 3 3
4
4 3 2 4 5 5
2
—
—
— —
— —
— —
—
14
— —
— —
—
— 8
— — —
—
— —
—
— —
—
—
—
—
—
—
—
14
—
24
—
—
—
—
28.7 28.9
—
— —
—
8
—
—
23
13
— 1.6
—
—
—
—
—
—
—
—
— —
—
—
—
—
22
— —
á 22 32.1
— —
—
2310 2985,2986 2985,2986 726 726 726 1602 1602 3270 3270 3270
279 3869
2919
726 726 1605
726
1605 1605 3269 2985 2985 726
1605
INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P 13
+
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
+
+
2
2
2
2
(ClCH CH ) NHMe + Cl~ (ClCH CH ) NHMe Cl" (ClCH CH ) NHMe + Cl~ (ClCH CH ) NHMe + Cl~ (ClCH CH ) NHMe + Cl" (ClCH CH ) NHMe + Cl~ (ClCH CH ) NHEt + Cl" (ClCH CH ) NHEt + Cl" (ClCH CH ) NHEt + Cl~ (ClCH CH ) NHEt + Cl~ (ClCH CH ) NHEt + Cl~ (ClCH CH ) NHPr + Cl" (ClCH CH ) NHPr + Cl~ (ClCH CH ) NHPr + Cl" (ClCH CH ) NH-iso-Pr + Cl" (ClCH CH ) NH-iso-Pr + Cl~ (ClCH CH ) NH-iso-Pr + Cl~ (ClCH CH ) NHBu Cl" (ClCH CH ) NHBu + Cl" (C1CH CH ) NHCH CH 0 M e Cl (C1CH CH ) NHCH CH 0 Me+ Cl (C1CH CH ) NH + Cl -
Amin e salt or free bas e
2
NaOH , pH ~ 8
2
H 0
pH ~ 8 pH ~ 8 pH ~ 8
pH 7.4 pH 7.4
pH « 8 pH « 8
pH 9.1 pH 9.1
pH 7.2 pH 6.0
NaOH , pH ~ 8
2
2
2
2
NaOH , NaOH , Non e Non e Non e Non e NaOH , NaOH , Non e Non e Non e NaOH , NaOH , Non e NaOH , NaOH , Non e NaOH , NaOH , NaOH ,
Adden d
H 0
2
2
H 0
2
2
2
2
2
2
2
2
2
2
2
2
H 0 H 0 50% Me C O 67% Me C O MeO H MeO H H 0 H 0 H 0 25%Me C O 67%Me C O H 0 H 0 H 0 H 0 H 0 H 0 H 0 H 0
Solvent
IV? , IV? , V II I II I IV? , IV? , í IV? , IV? , í IV? , IV? , IV? , V? V? V?
V? V?
V? V?
V? V?
II , IV? , V?
II , IV? , V?
II II II II II II II , II , Ð, II , II , II , II , ð, II , II , II , II , II , II ,
Analytica l method "
Tabl e 1-Зcontinue d
0
15
37 37 25 25 0 25 0 15 25 25 25 0 15 25 0 15 25 0 15 0
Temp . (°C)
1.15
8.67
6.91 1.78 4.7 « 3 « 2.3 6.1 1.95 2.14 1.37 4 1.42 3.37 3.62 1.81 9.20 8.16 2.61 2.57 2.57 8.16
k°
-1
Å (kcal )
-1
4
4
3 3 5 4 6 5 4 3 5 3 3 4 3 5 4 3 5 4 3 5
ç
5
—
17.9
—
— —
—
25
—
—
4
4
24
—
—
— 2
— — —
23
— —
25
— 2
2
25
—
—
—
—
4
19.6
—
—
— —
—
24.8
A°
726
726
—
726
726
726
1602
726
726
1602
726
726
279
279
1602
726
726
1639
1639
279
3540
2985
2985
Reference s
15
15
15
16
16
—
13
11
ç
A (= 10M°) (sec )
n
k (= 10- £°), (sec )
14 1. FORMATIO N OF THE AZIRIDIN E RING
10
10
10
1 0
10
7
2
2
2
2
2
2
6
6
2
6
4
2
4
4
2
2
+
2
2
2
2
2
2
2
2
2
+
2
7
7
7
7
2
2
2
2
2
2
+
2
+
+
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
70%EtO H
2
2
2
ClCH CH NHEt(CH -lC H )+ Cl ClCH CH NHEt(CH -lC H ) Cl ClCH CH NHEt(CH -lC H )+ Cl ClCH CH NHEt(CH -lC H )+ Cl ClCH CH NHEt(CH -lC H )+ Cl ClCH CH NHEt(CH CH OPh) + Cl ClCH CH NHEt(CH CH OC H N0 -/>) Cl ClCH CH NHEt(CH CH OC H OMe-p) Cl ClCH CH NHEt(CH CH OC H C1-/0+ Cl ClCH CH NHEt(CH CH CH Ph) Cl ClCH CH NHEt(CH CH SPh) Cl ClCH CH NHEt(CH CH OCH Ph) + Cl -
2
2
70%EtO H 60%EtO H
2
2
ClCH CH NH(CH Ph) + Cl" MeCHClCH NH(CH Ph) + Cl"
2
3
3
70% EtO H
70% EtO H
70% EtO H
70% EtO H
70% EtO H
2
0.1MinK CO
2
O.lMi n K C 0
2
0.1MinK CO
2
3
3
3
3
3
O.lMi n K C 0
2
0.1MinK CO
3
II
2
0.1MinK CO
II
II
II
II
II
IV
IV
IV
70% EtO H
2
H 0
2
H 0
2
H 0
37
37
37
37
37
37
37
25
25
25
25
3.5
3.7
5.8
2.9
3.1
2.0
2.7
9.43
5.56
2.4
2.4
2
37
IV IV
2.8 8.8
37 25
11 + I V IV
3
3
3
3
3
3
3
5
5
5
4
3
4 5
4
1.55
25
IV
II
3
s
3 5 3
1.22 9.2 5.2
15 25 25
II , IV? , V? II VI
70% EtO H
NaOH , p H ~ 8 Non e Borat e buffer , p H 7.3 Acetat e buffer , pH~ 7 O.lMi n KHCO Acetat e buffer , pH 7 NaHCO , Acetat e buffer , pH 7 Phosphat e buffer , p H 5.9 Phosphat e buffer , p H 7.4 Phosphat e buffer , pH 9.3 0.1MinKHCO
60% EtO H
2
2
50%EtO H
2
2
2
2
ClCH CH NH(CH Ph) + Cl"
2
2
3
H 0 67%Me C O H 0
2
2
(C1CH CH ) NH + Cl (C1CH CH ) NH + Cl (C1CH CH ) NH + Cl -
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
7 —
25
15
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
317
317
317
317
317
317
317
2343
2343
2343
2426
1442
318 2426
2426
726 279 2427
INTRAMOLECULA R DISPLACEMEN T BY THE AMINO GROU P 15
2
2
Ç
2
2
2
\ ^
2
2
2
2
_
2
2
2
2
(aCH CH ) NHCH —
2
2
+
+
C
I
I
+
ci-
ci-
a-
^Me _
Ã
2
CH OM e
(C1CH CH ) N(CH C0 H)
2
C1CH CH —
2
C1CH CH ^
2
ClCH CH NH(CH Ph ) (CHMeCH OPh) + ci-
Amin e salt or free bas e
ci-
+
2
H 0
2
H 0
2
H 0
2
H 0
2
H 0?
2
H 0
Solvent
Borat e buffer , pH 7.36
Borat e buffer , pH 7.36
KHCO 3
KHCO 3
KHCO 3
Buffer
Adden d
VI
VI
11 + I V
11 + I V
25
25
37
37
37
3
3
9.7
4.0
3
4
5
4
ç
3.4
2.5
6.8
3.6
25
IV
11 + I V
k°
0
Temp . (°C)
n
k (= 10- k°), (sec~ Analytica l method
Tabl e 1-Зcontinue d
—
—
—
—
—
—
—
—
0
A
Å (kcal ) ç
—
—
—
—
-1
A (= WA°) (sec )
3869
3869
318
318
318
2426
Reference s
16 1. FORMATIO N OF THE AZIRIDIN E RIN G
2
2
2
2
2
2
2
2
2
2
2
2
2
N0
2
2
+
4
2
2
2
2
2
4
2
2
2
2
2
2
4
2
2
2
2
2
2
2
2
2
3
3
2
ClCH(C0 Et)CH NH BrCH CH NH + Br ~ BrCH CH NH + Br~
2
2
C1CH CH (C0 H)NH
6
C H N 0 - J C + Cl -
6
2
2
2
2
2
2
(C1CH CH ) NHCH CH 0 C C H N 0 - x + CI (C1CH CH ) NHCH CH 0 C
6
C H N0 -JC + Cl -
2
(C1CH CH ) NHCH CH 0 C
2
2
— ^ ^ ^ " ^ ^
2
C1CH(C0 H)CH NH
2
C1CH CH —r /
2
3
3
2
2
2
N—CH CH CI
—
2
2
3
2
2
EtO H H 0 H 0
2
H 0
2
80% Me C O
2
80% Me C O
80% Me C O
2
2
3
0.03-0.05M in NaO H N(CH CH OH) 0.12M in NaO H 0.12M in NaO H
3
Variou s R N
3
Variou s R N
0.03-0.05M in NaO H Variou s R N
H 0
2
pH 9
2
1,4-Diazabi cyclo[2.2.2]octan e
Borat e buffer , p H 7.36 Borat e buffer , pH 7.2 Borat e buffer , pH 6.0 pH 7.0 pH 7.0 pH 7:0
H 0
2
2
2
2
2
H 0
2
H 0
2
H 0
MeC N
2
2
C H
2
2
2
2
2
2
2
C 1 C H
2
2
2
2
2
2
2
2
2
2
H 0 H 0 H 0
2
2
2
C1CH CH NH CH(CH C1 ) CH CH CH CH C1 + Cl~ (C1CH CH ) NP(0)(0")(0CH CH CH NH )+ (C1CH CH ) NP(0)(0")(0CH CH CH NH )+ C1CH CH -NH(CH CH ) 0+ Cl~ C 1 C H C H - N H ( C H C H ) 0 Cl" C1CH CH -NH(CH CH ) 0+ Cl~
20
II
35.5 25? 0 9.7
II II II
20
II
II
20
35.5
II
II
« 25
50.8
17.5 30.0 45.0
37
37
25
?
II
II II II
II
II
VI
« 2 1.5 . 6.0
4.28
1.28
1.38
0.96
1.29
« 8
2.3
1.42 2.48 7.6
2.03
2.21
1.5
6 5 5
-1
3
3
3
-2
4
5
4 4 4
5
5
4
—
—
—
25.8
25.8
—
—
—
—
—
—
—
—
1553 1338 1338
1553
689
689
689
1553
3079; cf. 2919
3066
2919 2919 2919
2985
2985
3869
INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P 17
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
+
+
+
+
CH NH CH NH + CH NH CH NH CH NH + CH NH + CH NH + CH NH
2
Br Br Br Br Br Br Br Br
2
3
2
3
-
-
-
-
-
-
-
-
-
-
2
2
2
2
3
2
2
BrCH CH NHMe
2
2
+
-
Br
MeCHBrCH NH + B r
2
BrCH CH NH Me + B r
2
BrCH CH NH Me + B r
2
BrCH CH NH + B r
2
BrCH CH NH + B r
BrCH BrCH BrCH BrCH BrCH BrCH BrCH BrCH
-
-
-
Amin e salt or free bas e
2
2
H 0
2
25% HCONMe H 0
2
25% H°CONMe H 0
2
H 0
2
2
2
H 0 H 0 H 0 MeO H MeO H MeO H MeO H H 0
Solvent
2
2
2
2
2
2
4
3
4
4
0.12MinNaO H 11 0.12MinNaO H II NaO H II 0.12MinNaO H II 0.12MinNaO H II 0.12MinNaO H II 0.12MinNaO H II KC10 , ì * 0.07, II I + AcO H or K H P 0 +NaO H ì « 0.3, buffer II to pH 8 ì « 0.3, buffer II to pH 8 ì * 0.3, buffer II to pH 8 ì w 0.3, buffer II to p H 8 Na S 0 , 1 I equiv . (2M) KCIO4 , ì « 0.07, II I + AcO H or K H P 0 + NaO H
Adden d
0
Analytica l method
Tabl e l-II— continue d
1.14 1
25
3.4
1.4
8.3
3.7
5.6
—
6.0 1.1 0.96 3 1.2 2
k°
36.5
35
35
35
35
25.1 30 0 0 25 30 30 25
Temp . (°C)
n
-1
2
5
3
3
4
4
4 3 5 6 4 4 — 4
ç
k (= \0- k°), (sec )
—
—
—
—
—
—
—
—
—
—
—
12
—
—
—
—
—
—
—
— 9
—
—
— 23 20.2
— 14 — 2 —
ç
—
0
A
-1
— 24 — —
Å (kcal )
n
A ( = 10 A°) (sec )
1607
2109
27
27
27
27
1338 1338 620 1338 1338 1338 3095 1607
Reference s
18 1. FORMATIO N OF THE AZIRIDIN E RIN G
2
Br~
2
2
H 0
2
2
2
2
é
3
2
2
3
2
2
BrCH CH —Í H\
2
2
2
2
2
2
2
2
2
2
2
2
2
+
+
2
2
1
/
2
Br
2
2
H 0
2
2
2
2
2
2
2
2
H 0
2
+
BrCH CH —Í H \ _
2
2
H 0
70% EtO H H 0 H 0 H 0 H 0 H 0 H 0 H 0
2
Br~
2
BrCH CH NH Ph + Br~ PhCHBrCH NH Br~ PhCHBrCH NH Br~ BrCH CH NHCH CH C l (ClCH CH )(BrCH CH )NH (ClCH CH )(BrCH CH )NH (BrCH CH ) NH (BrCH CH ) NH
2
BrCH CH NHEt
2
MeCHBrCH NHMe
2
2
+
BrCH CH NH(iso-Pr) + Br~
2
2
2
H 0
BrCH CH NHMe(iso-Pr) + Br~
2
2
25% HCONMe H 0
Br -
2
BrCH CH NHMe
+
2
H 0
Br -
+
2
2
2
BrCH CH NHMe
2
4
KCIO4 , ì « 0.07, etc.
2
4
II I
KCIO4 , ì « 0.07, II I + AcO H or K H P 0 + NaO H
2
ì « 0.3, buffer II to pH 8 ì • «· 0.3, buffer II to p H 8 KCIO4 , ì « 0.07, II I + AcO H or K H P 0 + NaO H II I KCIO4 , ì « 0.07, etc. II I KCIO4 , ì « 0.07, etc. II I KCIO4 , ì « 0.07, etc. NaO H II NaO H II NaO H II II pH 6.2 p H 6.0 II p H 7.2 II pH 6.0 II pH 7.2 II
25
25
8
2
9.4 1.7 ð 6 « 6 2.5 1.28 6.46 3.90
4
25 30 « 25 25 37 37 37 37 37
2
8
25
2
2
3 1 0 0 3 2 3 2
1
1
1
2
3
3
4
3.8
9.6
25
25
35
35
_
26.8 26.5 28.4 28.0
— — — —
—
—
—
—
—
—
— — — — — — — —
—
—
—
—
—
—
—
— — — — — — —
—
—
—
—
—
—
1607
1607
1668 1341 3095 3095 2984 2984 2984 2984
1607
1607
1607
1607
27
27
INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P 19
2 CIO4 -
2
y
3
3
2
2
3
-OS0 CH CH NH +
2
H
H N ^ N H
3
2
H 0
2
H 0
2
H 0
0.13, p H 4.80 0.5N in NaO H
/*« 0.10, p H 10.85
NaO H
EtO H
erythro
BrCH CH(NH )-7
NaO H
EtO H
threo
V-CHB z
V
II I
75
25
25 .
25
II I
25
VII
25
25
Temp . (°C)
VII
VII
NaO H
EtO H
erythro
VII
Analytica l method "
NaO H
Adden d
EtO H
Solvent
threo
\—CHP h
BrCH CH{NH )-y 1 2 CIO4 - H N ^ ^ N
Ï
Ï
Amin e salt or free bas e
Tabl e 1 - Ð --continued
k -1
0
1.931.98*' 8.0
4.83*
1.26
c
6
5
3
4
3
3
1.5
3.53
4
ç
1
k°
(= 10-"A: ), (sec )
Å -
—
—
—
—
—
—
—
—
—
A°
—
(kcal )
ç
0
—
—
—
—
—
—
-1
A (= 10M ) (sec )
896, 897
3670
3670
3345
3345
3345
3345
Reference s
20 1. FORMATIO N OF THE AZIRIDIN E RIN G
2
2
2
2
2
2
2
2
+
2
2
2
1
2
3
3
3
3
+
2
+
+
2
+
2
3
3
+
3
3
+
3
3
OSO3 -
3
3
3
3
+
2
3
2
2
2
2
2
2
+
+
2
Ç
/v_ y
OSO3CH2CH2- Í
2
2
3
2
3
3
2
3
2
\
n=3 n=A n=5 n=6 -OS0 CH CH NH + -OS0 CH CH NH Me + -OS0 CH CH NHMe -OS0 CH CH NHEt ~OS0 CH CH NH(CH CH OH)
2
(CH ),,
3
3
3
3
3
3
3
3
3
3
3
3
3
2
-OS0 CH CHMeNH -OS0 CHMeCH NH -OS0 CH CMe NH -OS0 CHMeCHMeNH (threo) -OS0 CHMeCHMeNH + (erythro) -OS0 CH CHEtNH + -OS0 CHEtCH NH -OS0 CH CH(iso-Pr)NH + -OS0 CH(iso-Pr)CH NH -OS0 CH(terf-Bu)CH NH + -OS0 CH CHPhNH + -OS0 CHPhCH NH + -OS0 CH(CH Ph)CH NH
2
2
2
2
2
2
2
2
2
0 0 0 0 0 0 0 0 0
2
2
2
2
2
2
2
2
2
0 0 0 0 0 0 0 0 0 0 0 0 0
2
2
2
2
2
H 0
H H H H H H H H H
H H H H H H H H H H H H H
4 5 5 5 5 4 3 3 3 4 3.9 100 II
IN in NaO H
5 5 4 4 4 5 5 5 6 7 6 4 6
1.75 1.9 6.8 2.2 7.1 3.7 1.1 5 1.9
5.2 1.6 3.3 1.07 1.36 7.4 1.6 9.2 8.3 5.7 9.8 4.8 4.0
75 75 75 75 100 100 100 100 100
75 75 75 75 75 75 75 75 75 75 75 75 75
V V V V II II II II II
V V V V V V V V V V V V V
0.5W in NaO H 0.5N in NaO H 0.5N in NaO H 0.5ËÃ in NaO H IN in NaO H liV in NaO H IN in NaO H I N in NaO H liVinNaO H
0.5N in NaO H 0.5N in NaO H 0.5N in NaO H 0.5N in NaO H 0.5N in NaO H 0.5N in NaO H 0.5ËÔ in NaO H 0.5Ë^ in NaO H 0.5N in NaO H 0.5N in NaO H 0.5N in NaO H 0.5N in NaO H 0.57V in NaO H
—
—
— —
— —
— — —
—
—
—
— — —
— —
— — — — — —
—
— — — — — —
— —
— — — — — — — — — —
—
— —
—
—
—
— — —
— — —
—
— — — — — — — — —
668
896, 897 897 897 897 668, 4022 668 668 668 668
896, 897 896, 897 896, 897 896, 897 896, 897 896, 897 897 897 896, 897 897 897 897 896, 897 INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P 21
a
+
2
2
3
2
10
3
2
2
2
4
2
4
2
4
2
2
6
6
6
2
2
2
7
2
2
2
2
3
3
2
7
2
2
2
2
2
4
10
2
2
2
2
2
2
7
2
2
25% EtO H 25% EtO H
70% EtO H
70% EtO H
70% EtO H
70% EtO H 70% EtO H
Solvent
Non e Non e
NaHC0 3
NaHCO ,
NaHCO ,
NaHCO , NaHCO ,
Adden d
IV IV
IV
IV
IV
IV IV
37.1 37.1
37
37
2 2.7
2
2
1.5
3.2 2
37 37 37
k°
Temp . (°Q
(sec )
-1
2
2
2
6 2
4 7
ç
k (= 10-"k°),
— —
—
—
—
— —
—
—
—
Reference s
— 1375 — 1375
— 1442
— 1442
— 1442
— 1442 — 1442
(sec ) — A° ç
— —
Å (kcal )
n
-1
A ( = 10 A°)
c
b
I: determinatio n of aziridiniu m ions by nuclea r magneti c resonance . II : determinatio n of X formed . Ill : determinatio n of hydroge n ions formed . IV: determinatio n of aziridiniu m ions with thiosulfate . V: determinatio n of residua l amin e by titratio n with acid . VI : polarographi c determinatio n of aziridiniu m ions. VII : determinatio n of aziridiniu m ions by ultraviole t spectrophotometry . Additiona l value s of k at intermediat e pH value s ar e also reporte d (3670). Thes e an d othe r value s of k for thi s system at low pH value s ar e in fact composit e rat e constant s for th e cyclizatio n of th e imidazoliu m an d th e unprotonate d form .
10
3
3
2
3
-OS0 CH CH NH(CH Ph) + PhS0 OCH CH NH(CH Ph) + -0 SP h /?-CH C H S0 OCH CH NH (CH Ph) - 0 S Q H M e - ^ p-CH C H S0 OCH CH NHE t (CH CH -1-C H )+ -0 SC H Me-/ ? 2-C H SO OCH CH NH (CH Ph) + -O S-2-C H (EtO) P(S)OCH CH NEt (EtO) P(S)OCH CH NEt
Amin e salt or free bas e
Analytica l method "
Tabl e 1-Зcontinue d
22 1. FORMATIO N OF THE AZIRIDIN E RIN G
23
INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P
conceivably involve mainly metathesis first, then cyclization (Eq 3) (rather than these steps in reverse order), b u t this is unlikely. The path by which /V-(2-fluoroethyl)-/8, 8-difluoroborazane, F C H C H N H B F , is converted to EI by aqueous alkali (3712) is not clear, but in any case is of theoretical interest only. Benzoate ion is not displaced thus from 2-aminoalkyl benzoates (1442, 1606) but in the sterically favorable case of L (+)-2-tropanol acetate ( 1 1 ) , the acetate ion and an unstable intermediate aziridinium ion are believed formed (Eq 4) (128). J
i
2
2
2
Ac Ï ->·
OAcr
racemize d acetat e
(4)
11
Perhaps formulation of the process via a more symmetrical transition state ( 1 2 ) , similar to that suggested for the thermal ring expansion of 2-(chloromethyl)pyrrolidines ( 1 3 ) (476), would be preferable. The ready dimerization ...CI ACO :
Í Ç 13
of 2-dialkylaminoalkyl perfluoroalkanoates to piperazine salts (Eq 5) indicates that the perfluorinated anion is a good leaving group (1637) and the reaction involves an aziridinium ion. R R \ /
o
-C^ftuCOz C F n
2 n + 1
C0 CH CH NR 2
2
2
2 +
N / \ R R
(5)
/ \ R R
The possibility of cyclization of allylamines to aziridinium dipolar ions has been mentioned (3627) but there is at present no evidence that such a reaction as shown in E q 6 occurs. H
2
/ \ R N 2
-CH 2
CH / CH 2
(6) N / R
+
\ R
24
1. FORMATIO N OF TH E AZIRIDIN E RIN G
The same comment applies to the hypothetical tautomerization of á -amino ketones (Eq 7) (2813). NH OH
(7)
There are two examples only of an aziridine-forming reaction in which the leaving group is trimethylamine (but compare the preparation of azirines, p. 63). The quaternary hydrazonium salts 1 4 when heated with alcoholic sodium methoxide gave 2-substituted aziridines as shown in Eq 8 (4071).
P h
N-C-CH CH NHNMe 2
I
R
2
3
P
I"
h
N
II
R
f ^ \ O
Ï
/
(8)
N I
14
Ç R = Me, 35% yield R = iso-Pr , 57% yield
Ordinarily, 2-amino alcohols cannot be dehydrated to aziridines, the reaction giving almost entirely acyclic imines and other products. Ethylenimine was suggested as an intermediate in the catalytic dehydration of 2-aminoethanol (2271) and heterogeneous catalysts, such as silica gel, were reported to convert this alcohol mainly into EI and derived products (256); it is tempting to postulate esterification at the acid surface, displacement to give EI, and immediate polymerization at the surface. 1-Amino-1-cyclohexanemethanol over hot alumina does yield a little of the spiro aziridine 1 5 (202) and 2-hydrazinoethanol gives 1-aminoaziridine (1513). The mechanism of such processes is obscure. NH
j
2
CH O H 2
>
í V V ^ H 15
3. The effect of p H on the rate of cyclization is easily stated. Since the amino group must be free, and not protonated, to accomplish the internal displacement the p H must be high enough to establish this condition. Buffers at p H 7-8 are often used in studies of such rates. Higher alkalinity has essentially no effect on the cyclization, but tends to stabilize the aziridine formed by deprotonating the aziridinium ion. The ring closure may be retarded by lowering the p H (345). The same effect is produced by cupric ions, which also combine with and reduce the reactivity of the amino groups; the retardation has been measured and interpreted (3671).
25
INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P
4. Clearly the nucleophilicity of the amino nitrogen atom is a major factor in fixing the rate of cyclization. However, there is close correspondence of base strength and rate of cyclization (proportionality of pK t o log k) only when compounds of very similar structure are compared, e.g., E t N ( C H C H C 1 ) , P r N ( C H C H C l ) , and B u N ( C H C H C l ) (726), and compounds of structure / ? - X C H Y C H C H N E t ( C H C H C l ) , where X and Y are various groups (317). Qualitatively the picture is better: as would be expected, rates of cyclization are in the order M e N C H C H B r > M e N H C H C H B r > H N C H C H B r (27); M e N C H C H B r M e > H N C H C H B r M e (643); a n d E t N C H C H C l > E t N ( C H C H C l ) > N ( C H C H C 1 ) (280, 726). T h e failure of arylbis(2-chloroethyl)amines t o hydrolyze via aziridinium intermediates (3067) must be due t o their low basicity. 5. The rate of cyclization involved in neighboring group effects depends on ring size (573,3397). F o r three-membered rings, the entropy decrease required to achieve the transition state is less than for larger ones, b u t the ring strain is greater and the mutual effects of the leaving group and the nucleophile are more detrimental. F o r two classes of compounds, the balance of these factors yields the relative rates of ring closure shown in Table l-III. a
2
2
2
2
2
6
4
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
Tabl e l-II I RELATIV E RATE S OF RIN G CLOSUR E OF L ( C H ) „ N H 2
L = -OS0
= Br
L
(in H 0 , 2
25°C )
(in IN NaOH , 1 0 0 ° C )
(897)
(668)
2
1.0
1.0
3 4
0.014
0.08
5
» 800 14
6
0.02
L = -OSO3
3
(in 0.57V NaOH , 7 5 ° C )
(3093, 3095)
ç
2
1.0 0.028 >27
443
— —
8.2 0.03
6. As for many ring closures, the reaction is facilitated by the presence of small alkyl groups on the ring-forming atoms. Some relative rates are C 1 C H C H N H , 0.8; C l C H C H M e N H , 2 5 ; C l C H C M e N H , 750 (573); -OS0 CH CHEtNH ,7.6; -OS0 CH CHMeNH ,5.2; -OS0 CH CH NH , 0.8 (896, 897); a n d M e N ( C H C H C l ) C H C H C l M e > M e N ( C H C H C l ) (2966). While some of these differences may be due t o different nucleophilicities of the nitrogen atoms, most of them are attributable t o steric effects (897,1605,1607). These are most likely the improvement of the driving force of the reaction, —Ä G, by the alkyl substituent (72,573) but the alteration of bond angles in favor of cyclization m a y also play a part (1605, 1607). A sufficiently bulky group, as in ~ O S 0 C H ( t e r / - B u ) C H N H , depresses the 2
3
2
2
2
2
2
2
3
2
2
2
2
2
2
2
3
2
2
2
+
3
2
2
3
2
2
2
26
1. FORMATIO N OF TH E AZIRIDIN E RIN G
rate of cyclization (897). The small but recurrent difference in rates between amines with primary and secondary leaving groups (L) [ C l C H C H M e N H , 2 5 ; C l C H M e C H N H , 3 (1341); C l C H C H M e N M e , 1 6 0 0 ; C l C H M e C H N M e , 163 (1605)] is consistent with the idea that these cyclizations are of S 2 type (albeit intramolecular), in which primary halides react faster t h a n secondary ones. This order is decisively reversed by the presence of the phenyl group [ C l C H C H P h N H , 0.5; C l C H P h C H N H , 700 (1344, 1387); and - O S 0 C H C H P h N H , 1.22; - O S 0 C H P h C H N H , 59.2 (897)] and barely so by that of the carboxyl group [ C 1 C H C H ( C 0 H ) N H , 4.28; C 1 C H = ( C 0 H ) C H N H , 12.9 (1554)] or when L is sulfate [ - O S 0 C H C H M e N H , 5.2; - O S 0 C H M e C H N H , 1.6 (896)]. Equilibrium constants for processes of the type of Eq 9 2
2
2
2
2
2
2
2
N
2
2
2
2
+
3
2
+
3
3
2
2
2
2
3
3
2
2
2
3
2
2
2
2
are rarely measurable because too many other nucleophiles compete with L~ to open the ring (1339). Nevertheless the rate of reaction of the cyclic ion with L~ can be measured, and the equilibrium constant Ê calculated as the ratio of the rate constants. Thus for cyclization of P h C H C l C H N H , K= 16.7 at 0°C and 4 at 24.6°C (1341). F o r B r C H C H N H , Ê is shifted from about 9 in aqueous solution to about 2 in presence of blood charcoal, presumably because of preferential absorption and stabilization of the b r o m o amine on the charcoal surface (1343). A similar shift was observed for P h C H C l C H N H (1340, 1342). F o r M e N ( C H C H C l ) in dilute aqueous solution at 37°C, AT was calculated as 3.68, whence the amine was 99.86 % cyclized at equilbrium (728). 2
2
2
2
2
2
2
2
2
2
STEREOCHEMISTR Y OF R I N G CLOSUR E
It was early shown (3763) that (+)- and ( - ) - P h C H C l C H P h N H of m.p. 127°C give (+)- and (—)-irfl«5 -2,3-diphenylaziridine, and that the corresponding dl isomer of m.p. 59°C gives the cw-2,3-diphenylaziridine; but n o conclusions could be drawn about the steric course of the reaction. The trans closing of the aziridine ring (which helped classify the reaction as an internal nucleophilic displacement) was firmly established (910) by the demonstration that pairs of Walden inversions are involved in converting m&sO -2,3-epoxybutane via i/zra?-3-amino-2-butanol to raesO -2,3-dimethylaziridine, and D(+)-2,3-epoxybutane ( 1 6 ) via the L ( + ) erythro-zmino alcohol ( 1 7 ) to L(—)-2,3dimethylaziridine ( 1 8 ) . 2
,
27
INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P
Me
Ç
Me H S0 2
4
-03S0
Me
Ç V
Ç
base
I X NH + H^^M e 3
Ç
16
17
Ç
18
This inversion during the cyclization was immediately confirmed when cyclohexenimine was obtained from i//-/m^-2-aminocyclohexyl hydrogen sulfate but not from i//-m-2-chlorocyclohexylamine, in which intramolecular displacement of the chlorine with inversion would generate only the sterically impossible ira/w-cyclohexenimine (2813, 2820, 3456, 3463, 3817). Still further verification came from similar preparations of N-rnethylcyclohexenimine (2627, 3457, 3814), cyclopentenimine (1098), cycloheptenimine (3483), cyclooctenimine (2047), and cyclodecenimine [from the trans- but not the cw-amino alcohol (1101)]. Only when the cyclododecenimines are reached are both the cis- and ira/w-aziridines capable of isolation (1102). The fact of inversion on closure of the aziridinium ring is now so well established that it is used to deduce the configuration of the parent chloro amine as trans (2517). When inversion is not possible because the amino group and leaving group are cis (128) or otherwise constrained from interaction (1321, 2296, 3026), the cyclization fails. Interest in the stereochemistry of the long-known interconversion of ephedrine and pseudoephedrine has led to detailed examination of the related chloro compounds and aziridines. Piecing together the evidence shows once more that each cyclization of the chloro amine or sulfuric ester corresponding to a normal (threo) ephedrine or ephedrine analog proceeds with inversion to yield a cis (erythro) 2,3-disubstituted aziridine. This upon ring opening undergoes inversion again to give the normal (threo) alcohol or its derivative. Pseudoephedrine types in the same steps go via a trans -dizmaint to pseudoephedrine (erythro) analogs (1572, 2130, 2131, 2636, 2708, 3464, 3479, 3489, 3490). Contrary to earlier belief (1048), the conversion of L(—)-ephedrine and D(+)-pseudoephedrine to the alkyl hydrogen sulfates occurs with retention of configuration if minimum temperatures are used (443, 493, 1015). A series of papers, mostly by Cromwell and his students, has dealt with the cyclization of a,j8-dibromo ketones upon treatment with primary or secondary amines (Eq 10). RCHBrCHBrCOR / + R"NH
2
>
(10)
28
1. FORMATIO N OF TH E AZIRIDIN E RIN G
This was independently shown to proceed with a Walden inversion at the carbon atom from which the amino group displaces bromide (804). The ratios of isomers produced have been reported in a number of these papers (784, 790, 792, 793, 795, 796, 800, 802, 803, 805, 806, 2087, 2088, 3344), but of course these cis-trans ratios merely reflect the threo-erythro ratios in the bromo amines undergoing cyclization (795). The threo-erythro ratios are explained in terms of either steric factors (803, 3886) or chelation in the transition state (3344, 3346). The configurations of the stereoisomeric aziridinium salts have been verified by the N M R spectra of the isolated prechlorates (2299).
REARRANGEMENT S PROCEEDIN G THROUG H AZIRIDINIU M ION S
Some reactions of 2-aminoalkyl halides, especially alkylations, do not produce the products to be expected by direct replacement of the halogen. Since 1947 it has been recognized that this is well explained on the basis of intermediate cyclization. In every case of rearrangement the intermediate aziridinium ion is an unsymmetrical one, in which the ring may be opened in two ways (Eq 11) or at least in the way that gives the product not derivable by simple displacement. Â
R'
(Ð) N+ /\
Thus alkylation of diphenylacetonitrile carbanion (401, 3175-3177) with (2-chloropropyl)dimethylamine was observed to yield a mixture of isomers, and (2-chloro-l-methylethyl)dimethylamine gives the same mixture (Eq 12) (491). ClCH CHMeNMe 2
:
Ph CC N or
— •a-^r
ClCHMeCH NMe 2
N+
Ph C(CN)CHMeCH NMe + Ph C(CN)CH CHMeNMe 2
>
2
2
2
2
Further instances of such rearrangements are shown in Table 1-IV.
2
2
(12)
29
INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P
The anomalous alkaline hydrolysis of l-(2-chloroethyl)-2,2,5,5-tetramethylpiperazine (19), while not involving a rearrangement, gives mostly polymers by way of an aziridinium ion (Eq 13) (2501). MewM e
Ç
Me Me
Me Me
-ci-
Me •N^ "M e
Me Me
Ho 2
Ç
Í
Í—CH CH — OH 2
2
/^M e Me
I
CH CH C 1 2
2
(13)
19
The formation of polymers from ( P h O ) P ( 0 ) O C H C H N ( C H C H O H ) (1296) is attributable to a similar intermediate aziridinium ion. Involving the same principles, but more complex, is the set of transformations shown in Eq 14 (1993, 2699, 2700); some difference of opinion exists about the mechanism. 2
2
2
2
2
2
B - = H" , CI" , OEt "
In reactions of 19A and 19B, which may be interconvertible, stabilized carbonium ions appear to be more probable intermediates than the bicyclic aziridinium ion 19C (903a, 1395a).
CH2X
V^ I
Bu-tert 19A
l Bu-tert 19C
A similar bicyclic aziridinium ion was a useful participant in the recent synthesis of a j8-benzomorphan (1359). N o comparable reaction occurs for 8-(chloromethyl)pyrrolizidine ( 2 0 ) because formation of the aziridinium ion
1 . FORMATIO N OF TH E AZIRIDIN E RIN G
30
is sterically impossible (2296), and n o rearrangement (and hence no aziridinium intermediate) was observed u p o n treatment of phenyl-l,2,3,6-tetrahydropyridine
l-methyl-3-halo-4-
( 2 1 ) with base, presumably because of
conformational preferences (2374).
20
Tabl e 1-IV REARRANGEMENT S VIA AZIRIDINIU M ION S
Nucleophil e
Origina l hal o amin e ClCH CHMeNEt HOCH CMe NMe + a carbodiimid e ClCH CHMeN(CH Ph) ClCH CHEtN(CH Ph) BrCHMeCH NH ClCHMeCH NEt ClCHEtCH NEt C1CH CHNH C0 H C1CH(C0 H)CH NH ClCHMeCH NMe ClCHMeCH NMe ClCHMeCH NMe ClCHMeCH NH R (R = c - C H or iso-Pr ) ClCHEtCH NH R (R = c - C H or iso-Pr ) ClCH CHClCH NMe N,N-MQ -1 -ClCH -cyclohexylamin e N,N-Me -4-Br-cyclopent-2-enylamin e (cis or trans) 2-ClCH -l-Et-PY 2-ClCH , or 2-RC0 CH -l-Me-PY l-ClCHMeCH^PP " 3-Cl-l-Me - or -l-Et-PP 3-Cl-l-Me-PP 2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
6
ci-
H 0/OH AlH H O H O Ph CH" 3-Indoly l carbanio n Phenothiazin e anio n 6-MeO-8-H N-quinolin e
2074 164b 2074 2074 3074a 3065 2683 1551, 1553 1551, 1553 401 1404 646 757
6-MeO-8-H N-quinolin e
757
RS~ Ph C(CN)" Me NH
2724a 401 758
/?-0 NC H 02
6
4
ciciso — 3
2
fl
4
a
2
fl
2
a
2
2
n
2
6
2
n
2
2
2
2
2
2
c
2
c
2
2
2
d
d
C
2-BCH -l-R-PY [L(-)] 3-B-l-R-PP [D(+)] 2
D
Reference s
E
l-Et^-HOCHa-PY' ^
E
e
2
5
2
cici-
e
Ph C(CN)N H or amine s N H , Me N(CH ) NH B~(?) B-(?) RC0 " 2
3
2
4
2
a
a
2
2
3
2
1379 460a 401 3024a 369 1601 1601 3288
INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P
31
Tabl e 1-IV—continued Nucleophil e
Origina l hal o amin e
Reference s
d
3-X-l-R-PP 3-Cl-l-Me-PP 3-Cl-l-Et-PP 3-Cl-l-Et-PP 2-ClCH -l-Me-PY 3-Cl-l-Me-PP 3-Cl-l-Et-PP 3-Cl-l-Et-PP 3-Cl-l-Me-PP l-Et-3-tosyl-0-PP 4-(BzOCH CHICH )-morpholin e l-ClCMe CH -2,2,4-Me -piperazin e 3,7-Cl -l,5-OMeC H S0 ) -l,5-diazocin e (EtO) P(S)OCH CH NR Mesylat e of a u/c-amin o alcoho l derive d fro m thebain e d
d
d
c
2
d
d
d
d
d
2
2
2
2
3
2
6
2
a
b
c
d
e
f
9
ff
2
4
2
2
2
2
HO" , PhCH 0~, NC ~ EtO~ NC " RC0 RC0 ~ AcO" PhCH(CN)Ph C(CN)" H 0 BzO H 0/HO" 2
e
f l
2
a
2
e
fl
e
2
2
e
2
ci —
A1H4-
1601 460a 2834 2834 460a, 2834 460a, 2834 3288 2852 368 3288 1287 2500 2808 1375, 3484 2586
Unrearrange d amin e also found . Allylic rearrangemen t involved . P Y = pyrrolidine . PP = piperidine . Â is undefined ; R is alkyl . N o halid e involved ; ester exchang e gave l-Et-3-HO-PP . N o halid e involved ; produc t was l-Et-2-HOCH -PY . 2
Pyrolysis of the hydrochlorides of sterically crowded amines and hydrolysis of the reaction products yield a mixture of allylamines, ketones, and saturated amines in varying p r o p o r t i o n s (Eq 15). A n aziridinium ion ( 2 2 ) is probably intermediate (1695). R' RCH ^ /CHClM e 2
RCH
c
,M e -H
2
+
RCH=CR'CHMeNR " 2
N+ / \ R" R" 22 (15) RCH CR'=CMeNR "
[RCH CHR'CMe=NR " l 2
2
2
,H o
H Oy
2
2
RCH CHR'A c + R / N H 2
2
32
1. FORMATIO N OF TH E AZIRIDIN E RIN G
PREPARATIV E METHOD S
By far the commonest type of organic intermediates for the preparation of aziridines are the vicinal amino alcohols. These in turn are usually prepared by the well-known addition of ammonia or primary or secondary amines to epoxides (Eq 16) (3063).
+ H — N <
—C
C—
OH
(16)
Í
A Alternative routes to the amino alcohols are the reduction of esters of aamino acids with lithium aluminum hydride (447, 2576, 3471, 3632) and the hydrolysis of oxazolines (1430). Conversion of a protonated amino alcohol to a corresponding protonated halo amine is also a familiar operation in synthesis. Thionyl chloride is the most used for the conversion, but occasionally recourse is had to phosphorus pentachloride; direct esterification with hydrogen chloride or hydrogen bromide is feasible but requires forcing conditions (Eq 17). —C
C—
I OH
I Í
SOCI , PClj , HX
— C—C—
2
-
-
•
I
I
×
Í
.etc.
(17)
A A Handling of the 2-chloroethylammonium chloride thus formed is facilitated by using chlorobenzene as a diluent, etc. (1180). Amino alcohols of the type R C ( O H ) C H N H can be converted to the desired chlorides R C C 1 C H N H only with great difficulty if at all (724, 2101, 2519); the reaction also fails for 3a-amino-2jS-cholestanol (1622) and for 2-hydrazinoethanol (1085). It was pointed out by Wenker (3769) that conversion of 2-aminoethanol to 2-aminoethyl hydrogen sulfate offers some advantage in preparing EI. The esterification step is very simple, requiring only heating an equimolar mixture of the amino alcohol and concentrated sulfuric acid to about 250°C. Moreover, since the ester is nonvolatile, unlike the halo amine, there is no danger of distilling unreacted starting material along with the EI and exposing the latter to the considerable hazard of polymerization catalyzed by the halo amine. Hence the method has been used frequently. An important improvement was effecting the esterification-dehydration under reduced pressure to minimize charring (492,1484, 2255, 2290, 3422, 4022); other variations in this step are also claimed (214,237,1308,1313, 2890,3052,3229) and even sulfur trioxide (321a , 1432) also has some advantages. The Wenker esterification step, like conversion to a halo amine, usually fails when the alcohol is tertiary, dehydration to an olefinic compound (sometimes 2
2
2
2
2
2
33
INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P
an enamine) then taking precedence (12, 2170); but 2-amino-l-methylcyclohexanol did give some of an aziridine along with the unsaturated amine (3814). 3a-Amino-2j8-cholestanol, a secondary alcohol, was not esterified by sulfuric acid (1622), and 2-amino-2-methyl-l-tridecanol was merely charred (2883). Failure of the method applied to 2-anilinoethanol was attributed to sulfonation of the ring instead of esterification of the alcohol function (1377), but later work met no such difficulty (492). A quite different synthesis of 2-aminoalkyl hydrogen sulfates involves the Ritter reaction; an ally lie halide such as methallyl chloride treated with hydrogen cyanide or acetonitrile and concentrated sulfuric acid, then with water, yields a 2-aminopropyl ester such as ~ O S 0 C H C M e N H (1430). The process may be formulated, somewhat speculatively, as in Eq 18. +
3
CH =CMeCH C l 2
H z S
CH ==CMeCH +
2
2
2
4
° >
2
2
3
CH =CMeCH OS0 H 2
2
3
H +
(18)
Y +
H NCMe CH OS0 3
2
2
HG=NCMe CH OS0 H
3
2
2
Me CCH OS0 H
3
2
2
3
+ HC0 H T o return to the preparation of vicinal halo amines: most of the routes not yet discussed depend in principle u p o n addition to an olefinic b o n d at one stage. Thus the product of addition of bromine to ethylene, 1,2-dibromoethane, can be caused to react in excess with a primary (or secondary) aromatic amine to yield the "one-ended" displacement product, A r N H C H C H B r (461, 462); some advantage is claimed in having the halogen atoms dissimilar, and a tertiary amine present to serve as acid acceptor (1290). Although no intermediate is claimed or isolated, this one-ended displacement must operate in the recent process (119, 731,921,2561) for producing aziridines from vicinal dihalides or alkylene sulfates or disulfonates and ammonia or primary amines (Eq 19). The acid acceptor may be either calcium hydroxide, excess nitrogenous base, or an ion-exchange resin (3563a). The process is improved by 2
2
XCH CH X 2
2
-22L>
XCH CH NH + 2
2
XCH CH NH
3
羂
2
A
2
\7 +
N / \ Ç Ç
2
2
(19) X-
operation at high pressures (119). A more laborious path is the one-ended reaction of a 1,2-dihaloethane in the Gabriel synthesis using phthalimide,
34
1. FORMATIO N OF TH E AZIRIDIN E RIN G
then hydrolysis to the halo amine (3353). It has been suggested that one of the unidentified products of reaction of 1,2-dibromoethane and hydrazine is 1-aminoaziridine, isolated as the benzal derivative (3391), but no indication of formation of that aziridine from 1,2-dichloroethane in ethanol could be obtained (1084). It has been obtained by the Wenker method (202,1513,1765), as has l-amino-2-phenylaziridine in 6 0 - 7 0 % yield from the dimesyl ester of 1-phenyl-1,2-ethanediol and hydrazine (1284c). An old observation that dibromides of 2-bromoanethole and 2,x-dibromoanethole with excess aniline yield products that probably have the aziridine structure is also to be cited (1676), but should be confirmed. Less acceptable are the aziridine structures attributed to the products of reaction of potassium anilide with the dibromides of oleic and ricinoleic acids (1757a), which are not classified as aziridines in Beilstein and need reinvestigation. The reaction of dibromides derived from á,â-unsaturate d ketones ( 2 3 ) with ammonia and primary and secondary amines has already been mentioned (p. 27); secondary amines can of course yield only quaternary aziridinium compounds. While the process was at first formulated as yielding piperazine dimers (3784) or enamines (46, 2622, 3073), the assignment of aziridine structures to the products (786) has been amply confirmed. However, the reaction proceeds not by displacement, but by elimination to give the a-bromo-á,â unsaturated ketone ( 2 4 ) . Michael addition of a molecule of the nitrogenous base then yields the a-amino-/?-bromo ketone ( 2 5 ) , which cyclizes. The similar RCHBrCHBrCOR '
RCH=CBrCOR '
reaction of dibromides of á,â-unsaturate d acids and their derivatives takes the same course (1364). The nature of the amine can be influential: 2,3dibromopropionitrile with most primary amines yields aziridines but benzylamine produces enamines also (1553), and aziridine-2-carbonitrile could not be isolated as a product (1552). In 2 3 , when R is aroyl and R ' is aryl, the product of reaction with ammonia is more often an enamine than an aziridine (2360). The concurrent reaction of iodine and amines with á,â-unsaturate d ketones is a convenient route to substituted aziridines (795, 802, 806, 2799, 3343), but it involves addition of an iodine-amine complex to the olefinic bond and then elimination, and not the formation of a diiodide (3343).
35
INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P
Dibromides from allylic amines present difficulties in this reaction, because aziridine ring closure must yield a 2-(a-bromoalkyl)aziridine, in which the bromine function will tend to quaternize and activate the ring (intermolecularly) toward polymerization. 2,3-Dibromo-l-methylpropylamine thus gave a rapidly polymerizing aziridine (3702), and 2,3-dibromopropylamine has been found not to yield an aziridine at all by reaction with ammonia (3071) or aqueous sodium hydroxide (1449). The well-known addition of hypochlorous acid to olefins for chlorohydrin preparation suggests an analogous preparation of chloro amines. Passing nitrogen-diluted chlorine into liquid ammonia containing styrene causes only oxidation of the ammonia, and no involvement of the olefin (963). However, the preparation of 2-chloroalkylamines by addition of 7V-chloro amines to olefins is well authenticated (2564-2566, 2680-2684). The process is believed to involve aminium radicals (2683) in which each of the nitrogen atoms bears either a proton or a transition metal chloride; a chain reaction may prevail (Eq 20). \
1 1
+
+
R NH + / C = C ^
>
2
R NH—C—C 2
1
+
1
1
+
+
R NH—C—C - + R NH—C I 2
1
•
2
(20) I
I
R NH—C—C—C I + R NH + 2
2
I I
I I
In a different reaction, JV-bromo secondary amines have been shown to add to á,â-unsaturate d ketones and thus lead to aziridinium ions (3342, 3344, 3346). The addition of nitrogen trichloride to olefins succeeds and the hydrolysis of the resultant /?,7V,iV-trichloro amines yields â-chlor o amines (735), but this is not an attractive route to these intermediates. The addition of iodine isocyanate, I N C O , to olefins stereospecifically yields 2-iodoalkyl isocyanates ( 2 6 ) hydrolyzable to 2-iodoalkylamines, which may spontaneously cyclize to aziridines (Eq 21) (984, 1622, 1623); the reaction is useful in laboratory application to complex olefins, such as unsaturated steroids. NC O \
^
INC O + ^ c = c f ^
I >
I
—C—C— I I é
NH HO
I
2
>
2
I
—C—C—
(21)
I I é
26
A somewhat similar route involves reducing a vicinal chloronitrosoalkane, ^ C C I C ( N O ) ^ , t o the vicinal chloro amine; stannous chloride is preferred as the reducing agent (1006,2517,3703). Whereas highly substituted aziridines are probably best made by this route, simple ones cannot be so made. Just the
36
1. FORMATIO N OF TH E AZIRIDIN E RIN G
reverse situation sometimes prevails for the amino alcohol route to aziridines. Another predictable reduction, this one of á -chloro nitriles with lithium aluminum hydride, produces chloro amines cyclizable to aziridines. The following aziridines have been so prepared in the yields shown: 2-Pr, 8 2 % ; 2-iso-Pr, 7 2 % ; 2 - n - C H , 6 2 % ; 2-Ph, 4 6 % ; and 2 - P h C H , 5 8 % ( / * « ) ; 2 7 , 8 9 % , and 2 8 , 8 6 % (2175). F o r the preparation of 2-fluoroethylamines from fluoroacetamides (2811) or 2-iodoalkylamines from 2-azidoalkyl iodides (1310, 1626), reduction with diborane is particularly recommended. 6
13
2
?
PhNH -
\
N—Ph /
Cl NH
\
NH
27
Ï
28
29
A different reduction—that of a 2-azidoalkyl methanesulfonate ( 3 0 ) , with hydrazine and Raney nickel—forms an amino ester that immediately undergoes ring closure by expulsion of the mesylate ion (Eq 22). MeS0 0
MeS0 0
2
2
I I —c—c— I I
N
3
[H]
-0 SMe (22) 3
NH
2
N+ H 2
30
The reaction was used first for sugars and then for steroids (1561, 2908). Lithium aluminum hydride can also serve similarly as the reducing agent (2907), and 2-azido-3-cycloocten-l-yl iodide as the substrate for reduction and cyclization (1310). Some failures of the conversion of vicinal haloalkyl amines may be noted. 2-Anilino-1 -chloro- 1,1,2-triphenylethane could not be made to yield an aziridine (3506), nor could triphenylmethylamine and methyl 2,3-dibromopropionate (3310); steric factors are surely implicated. A failure to obtain 1phenylaziridine from JV-(2-bromoethyl)aniline (1378) is unaccountable since the preparation in fact succeeds very well (see Table I-V). l-Anilino-2-chloroN-phenylsuccinimide ( 2 9 ) yields only the enamine and not the aziridine (162), probably because elimination in this case is faster than displacement by the weakly basic anilino nitrogen atom. Somewhat similarly, l-(aminomethyl)cycloheptyl hydrogen sulfate gives only l-(aminomethyl)cycloheptene (4064). iV-(2-Bromoethyl)-l,5-pentanediamine has been reported (463) to be dehydrobrominated to the JV-vinyl diamine (Eq 23), b u t the product may in fact have been l-(5-aminopentyl)aziridine ( 3 1 ) (2002).
INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P
37
Tabl e 1-V PREPARATIO N OF AZIRIDINE S BY INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P
Aziridin e made , or substituent s therei n
Method "
% Yield*
Reference s
Aziridines Containing No Functional Groups N o substituent s
I
—
I
>70-75 >62 51.7 62 up t o 85 71.6 26.5 « 70-80
I I I I I II II II
1-Me
II II II II II II II II II II I I
2-Me
II II II II I I I II II II II
30-32 up to 85 70-76 34-37 83 81-83 80-84 50-91 77
47 40 26
80 19 65 60-63 50
57, 325, 464, 1182, 1385, 1391, 1392, 2091, 2117, 2125, 2440, 4034 325 1480 2440 470 1199 1180 3769 3651 525,1011,1083, 1430, 1742, 2177, 2254, 3052,3546 1996, 1997 1199 3841 61 3007 1252, 2090 1501 1308 176 921 2117, 2428 1742, 3185 3500 3044 333 406,1383,1388, 1723, 3302 3128 2576 1996, 1997 321a, 447, 2576 525 4022
38
1. FORMATIO N OF TH E AZIRIDIN E RIN G
Tabl e 1-V—continue d Aziridin e made , or substituent s therei n
Method "
% Yield"
Aziridines Containing No Functional Groups—continued I 7 I 35 II — II « 70 II 34 II 55
1-Et
c
2-Et
1,2-Me 1,2-Me 2,2-Me
2,3-Me
2
2
2
2
2-CH =C H 1-iso-Pr 2
2-Et-l-M e 1,2,2-Me 1,2,3-Me 2,2,3-Me 3
3
3
l-iso-Pr-2-CH = 1-Bu 2
\-sec-Bu \-tert-Bu 2-iso-Bu
—
II II II II II II I II II
46 50 — 68 65 55-89 20 30-35
II II I II II II II II II II II II II II II II II I, II I II II II I II II II
68 45-51
— 47 48-95 82
— 49 40-43 34 38
— — 19 45 65 >50
— « 70-80 74 54 72 35-40 27 45
Referenc e
2269 885 525 1043 333 2793 2662 1997 1466 525, 3651 2793 270 3629 2576 2576 518, 525,560, 1431, 1432, 2043 1997 565 3166 1997 910, 1466 333 288 3389 469 2883 2883 1976b, 2337 1680 1997 333 270 443 963 3651 1043 3796 470 469, 470 453 3471, 3631, 3632
39
INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P
Tabl e 1-V—continue d Aziridin e made , or substituent s therei n
Method "
% Yield
ft
Reference s
Aziridines Containing No Functional Groups—continued 1,2-Et 2-Me-2-P r 2-iso-Pr-2-M e l-Et-2,3-Me 2
2
2,2,3,3-Me 2,3-(CH =CH) (trans) l-(PrCHMe ) 2-Bu~2-Me 2GS>iso-Bu-l-M e 2-iso-Bu-2-M e l-iso-Pr-2,3-Me 4
2
2
2
l-Et-2,2,3-Me l-Ethyl-2(S)-iso-B u 2,2-Me -3-Pr 3-Et-2,2,3-Me 2,2,3-Me -3-Pr l-Bu-2-E t l-Bu-2,2-Me l-ter/-Bu-2,3-Me l-iso-Pr-2,2,3-Me l-c-C H „ l-Et-2,3-(CH =CH) 2-tf-C H -2-M e l-/^-Bu-2,2,3-Me 2-Et-l-iso-Pr-2,3-Me l-tert-C H 2-Me-l-/ert-C H 1-Ph 3
2
3
3
2
2
3
6
2
6
2
13
3
s
17
8
2-Ph
l-o-MeC H 6
4
17
2
(trans)
II II II II II 11 I II II II II II II II I II II I I II II II I II II II I I II II I I I I I I I II II I I I II I
60 47 39 — 72-73 >50 79 28.6 33-39 53 40 31 — >50 69 48 57 71 84 70 80 > 50 73 32 ð 21 51 69 73 41 76 * 40 68 85 61 60 — 56 High 81 — 66 80 90 57
1466 2883 2883 1680 1466 443 724 3389 469 2883 3631 2883 446, 1680 443 1694 3631 1997 724 724 1043 1043 443 1694 453 3388 2883 1694 1694 435 435 80 1658 1668 1290 453 2745 4018 3651 492 1387, 3824 3889 2564 492 1661
40
1. FORMATIO N OF TH E AZIRIDIN E RIN G
Tabl e 1-V—continue d Aziridin e made , or substituent s therei n
Method
0
% Yield
6
Reference s
Aziridines Containing No Functional Groups—continued l-m-MeC H l-/?-MeC H 6
6
I I I I I I I I II II II I I I II I II II I II II I
4
4
1-O-C1C H 6
4
l-m-ClQH l-m-FC H l-/>-FC H l-PhCH 6
4
4
6
4
2
2-PhCH l-Me-2-P h 2-Me-l-P h 2-Me-2-P h 3-Me-2-P h 2
l-PhCH -2-M e 2-PhCH -3-M e l-Et-2-P h 2-Et-2-P h 3-Et-2-P h l-PhCH CH l,3-Me -2-P h 2
2
2
2
2
2,2-Me -3-Ph l-iso-Pr-2-P h l-PhCH -2-(5)-iso-Bu l-G?-PhC H ) 2,3-Ph 2
2
6
4
2
2,3-(/?-ClC H ) l,2-Ph -3-M e 2,3-Ph -l-M e 2,2-Ph -3-Me 3,3-Me -2,2-Ph l-PhCH CH -2-P h 1,2,3-Ph 1-(1-C H ) l-iso-Pr-2-(2-C H ) l-iso-Pr-2-(l-C H OCH ) 1,2-[(CH ) ] 6
4
2
2
2
2
2
2
2
2
3
10
7
2
3
2,3-[(CH ) ] 2
3
l0
7
10
7
2
71 65 52 62 59.5 57.5
— 24 65 76 32
— — — 84
— 60 32 Poor 88 28
—
II
—
II II II I I I I I I I II II II II I I I II II
83 52 46 93
— 80-96
— — — Low Low 34
— 75
— — 20-25 Trac e to 40* 61-75
1661 1661 1661 1661 558 558 1389 1550 453 2046 3765 1290 2564 2130 492 3390 3601 3765 568 492 3765 2636, 2637 2708, 346 3479, 348 493,1015, 1572 492 3765 3631 302 853, 3762 3763 1630 903 3490 566 2101 3765 3506 3770 1773 1773 552 1419 1098, 1104
41
INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P
Tabl e 1-V—continue d Aziridin e made , or substituent s therei n
Method
Aziridines Containing No Functional I 2,3-Me -2,3-[(CH ) ] II 1,2-[(CH ) ] e 2,2-[(CH ) ] II 2,2-[(CH ) ] II I 2,3-[(CH ) ] II 2
2
2
2
4
4
2
4
l-Me-2,3-[(CH ) ] 2
4
2,3-(CH CHMeCH CH ) 2-Me-2,3-[(CH ) ] l-Et-2,3-[(CH ) ] 2,3-Me -2,3-[(CH ) ] l-Pr-2,3-[(CH ) ] l-C H -2,3-[(CH ) ] l-C H -2,3-[(CH ) ] l-Ph-2,3-[(CH ) ] l-PhCH -2,3-[(CH ) ] 2,2-[(CH ) ] 2
2
2
2
4
4
2
2
2
4
4
6
n
2
4
8
17
2
4
2
4
2
2
2
2
4
5
2,3-[(CH ) ] l-iso-Pr-2,2-[(CH ) ]-3-M e l-ter/-Bu-2,2-[(CH ) ]-3-Me 2,3-[(CH ) ] 2,3-[(CH ) ] 2,3-[(CH ) ] 2,3-(CH=CHCH CH CH CH ) l-(7-Cl-4-quinolyl ) 1 -(6-Cl-2-MeO-9-acridinyl ) 1-Adamanty l 2,3-Epimino-l,2,3,4-H -naphthalen e 1,2; 3,4-Diepimino-l,2,3,4-H naphthalen e (trans) 4a,8a-Epimino-l,4,4a,5,8,8a-H naphthalen e 4a, 8a-Epimino-H ! -naphthalen e 2,3-Epimino-7,7-Me -norbornane 27 (see p. 36) 28 (see p. 36) 9,10-Epimino- l ,5-cyclododecadien e 2
5
2
5
2
2
5
6
2
8
2
10
2
2
2
6
Referenc e
Groups—continued 73 — — 66 63 — —
II II II I
— —
I
—
1021
I I I I I I
— 78 42 89 86 —
3703 2517 1006 2175 2175 1623
II II II II
82.5 28 70 —
II II II II I II II II II II II II II I I II II II
77.5 — —
— 76 63.5 73 65 — 72 57 68 78 59 56 33 13 30-50
/
2
4
% Yield
724 3458, 3854 202 3482 2883 3456 1435, 3463, 3814 3151a 2820 3456 2627, 3457, 3814 3151 1436, 3151 3814 2131 724 3151 3151 3151 1685 3151 3151 1099 2883 3483 1694 1694 2047 1101 1102 1310 2837 2837 991, 994 984
3
4
2
e
— 38 15
9
4
6
0
g
2
42
1. FORMATIO N OF TH E AZIRIDIN E RIN G
Tabl e 1-V—continue d
Aziridin e made , or substituent s therei n
Method
0
% Yield"
Reference s
Aziridines Containing No Functional Groups—continued 5,6-Epiminodibenzo[tf,c]cycloheptan e 2,3-Epiminosqualen e 2a, 3a-Epiminocholestan e 2â, 3^-Epiminocholestan e 2â, 3j3-Epiminocholestan e 2â, 3^-Epiminocholestan e ÇÍ / í NH É ×
×
É
I — — I I —
h
1
1
II
— — ^ 100 75 « 70 « 100
3240 759 2907 1622 2906 2907
46
2883
30 68 36
1905 1905 1905 46, 789, 2622, 3073 3343 796 3184 1905 798 796 3784 801 4075 795 2360 3638 796 803 2360 796 789 796 3343 788 2799 3344 802 800 3344 805 3638
Aziridinyl Ketones 2-Bz-l-M e 2-Bz-l,3-Me 2-Ac-l-Me-3-P h 2-Bz-3-Ph
II I II I II I II I
2
2-Bz-l-c-C H n 2-Bz-l-c-C H -3-M e 2-Bz-l-Me-3-P h 6
6
n
3-Ph-2pC/?-MeC H CO ) 2-Bz-3-(/?-0 NC H ) 6
2
4
6
4
2-(p-0 NC H CO)-3-P h 1,3-Me -2-(^-PhC H CO ) 2,3-Bz -l-M e 2
6
4
2
6
4
2
l-Me-3-Ph-2-(^-MeC H CO ) 6
4
2,3-Bza-l-E t 1-c-QH i -2-(;7-PhC H CO ) 2-Bz-l-c-C H -3-P h 1
6
6
4
n
2-Bz-l-c-C H -3-(/7-MeOC H ) 2-Bz-l-c-C H -3-(/7-0 NC H ) 2-Bz-l-c-QH ! 3 - ( p - 0 N C H ) 2-Ac-3-(p-PhC H )-l-c-C H l-c-C Hn-2,3-Bz 6
11
6
6
n
2
r
2
6
6
6
2
2
6
6
4
4
4
11
II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I
— 57 80
— 57 26 61
— 78
— 84.6 43 50 40
High — 80
— 78 46 50-54
— 97-100
— 89 60-90 » 68 65
43
INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P
Tabl e 1-V—continue d
Aziridin e made , or substituent s therei n
Method "
% Yield"
Reference s
Aziridines Containing No Functional Groups—continued 2-Bz-l-PhCH -3-P h 2
2-Bz-l-PhCH -3-(m-0 NC H ) l-c-C H -3-Me-2-(p-PhC H CO ) l-c-C H ! 3-Ph-2-(/?-MeC H CO ) 2,3-Bz -l-P h 1 -Me-3-Ph-2-(/?-PhC H CO ) 2
6
2
6
n
6
6
r
4
4
6
4
2
6
2
l-PhCH -2,3-Bz 1 -PhC H -3-Ph-2-(/?-MeC H CO ) 2
2
2
6
4
l-c-C H -3-Ph-2-(^-PhC H CO ) 6
n
6
4
2-(/>-BrC H CO)-l-c-C H 3 - P h 8,9-(N-Cyclohexylepimino)perinaphthan 7-one 6
4
6
1 r
Hi II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I
— 35 73 52 46 20 92 77 31 74 92 71 74 20 91 94 89
789 796 3343 788 793 785 806 796 2360 795 803 3638 796 785 790 795 2898
II I
—
4031
Aziridines Containing Other Functional Groups 1-H N 2
2-H NCH 1-H NCH CH 2-H NCH -2-M e l-R-2-Ph-2,3-(0-QH C- ) II NR (R = Me or c - C H ) l-(2-C!CH CH ) 2-ClCH -3-M e (or 2-MeCHCl? ) 2-BrCH -3-Me 1 -p-(4-H NC H S0 C H ) 2-Me0 C 2-Et0 C 2
2
2
2
2
2
2
II
35
II II II
42.7 16 29
202,1513, 1765 3354 1996 3354
4
6
2
II I
4116
n
2
2
2
2
6
2
2
2-Pr0 C 2-iso-Pr0 C 2-Bu0 C l-Me-2-Me0 C 2
2
2
2
4
2
6
4
II I
80 7.6 20 50 38 55 25 76 44 49
161b, 891 3702 1942 1364, 1551 1553 1364, 433 2215 1364, 1364, 124
2987a
2215
2215
2215 2215
44
1. FORMATIO N OF TH E AZIRIDIN E RIN G
Tabl e 1-V—continue d Aziridin e made , or substituent s therei n
Method "
% Yield*
Reference s
Aziridines Containing Other Functional Groups—continued l,3-Me -2-Me0 C 2-Et0 C-3-M e l-Bu-2-Me0 C l-Et-2-Me0 C-3-M e l-CH =CHCH -2-Me0 C-3-M e 1 -EtOCH CH -2-Me0 C-3-M e l-(3-HOCH CH CH )-2-Me0 C-3-M e l-(3-Me NCH CH CH )-2-Me0 C-3-M e l-Bu-2-Me0 C-3-M e l-«-C H -2-Me0 C-3"M e l-Bu-2-Me0 C-3-P r l-C H -2-Me0 C l-C H -2-Me0 C-3-M e PhCH 0 C l-PhCH -2-Me0 C 2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
6
13
2
2
6
n
6
2
n
2
2
2
2
2
l-PhCH -2-Me0 C-3-M e 2
2
1 -0?-ClC H CH )-2-MeO C-3-M e 1 -0?-MeOC H CH )-2-MeO C-3-M e 2-Me0 C-l-PhCH CH 2-MeO C-l -0?-MeOC H ) 2-Et0 C-l-PhCH -3-M e 2-Me0 C-3-Me-l-PhCH CH l-PhCH -2-iso-Pr0 C-3-M e 6
4
2
6
2
4
2
2
2
2
2
2
6
2
4
2
2
2
2
2
2
l-(c-C H , NHCH CH )-2-Me0 C l-(2-Furylmethyl)-2-Me0 C l-(2-Furylmethyl)-2-Et0 C-3-M e 2-Me0 C-3-Me-l-(l-methylpiperid-4-yl ) 3-AcO-l-PhCH -2-Me0 C 2-Et0 C-l-Et-3-P h l-C H -2-Et0 C-3-P h l-PhCH -2-Et0 C-3-P h l-Ph CH-2-Me0 C l-(Ph CHCH )-2-Me0 C 2-Me0 C-l-Ph C 6
1
2
2
2
2
2
2
2
2
2
6
n
2
2
2
2
2
2
2
2
2
II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I k
3
l,2,2-(o-MeC H NH) l,2,2-(/?-MeC H NH) 2-NC-l-M e 2-NC-l-P r 2-NC-l-iso-P r l-Bu-2-NC 6
6
4
4
3
3
II I II I II I II I II I II I
33.8 44 76.9 40.4 61.3 49.2 26.3 24.5 73.0 71.4 41.5 85 78.4 34 74 —
50 71.2 91.2 62.8 21 36 20 51.9 64 65-85 13 68 Poor 17.2 Poor 62 99 19 78-94 « 30 80 — —
34.5 —
59 77
3720 2215 3720 3720 3720 3720 3720 3720 3720 3720 3720 572 3720 1684 572, 3390 2078, 3310 572, 3390 3720 3720 3720 572, 2078 572 572 3720 572 2928 572 572 572 3720 572 2624 2624 2624 3310 572 3310, 3311, 3315 2656 2656 125 3721 125 1553
45
INTRAMOLECULA R DISPLACEMEN T BY THE AMINO GROU P
Tabl e 1-V—continue d Aziridin e made , or substituent s therei n
Method "
% Yield*
Reference s
Aziridines Containing Other Functional Groups—continued 2-NC-l-Me CCH 2-NC-l-c-C H 3
6
2
n
l-PhCH -2-NC 2
l-(/?-ClQH CH )-2-NC 2-NC-l-0-MeOC H CH ) l-PhCH -2-NC-3-M e 2-NC-l-c-C H -3-P h 2,3-(Me0 C) 2,3-(Et0 C) 2,3-(Pr0 C) l-(R-MeOC H )-2,3-(Me0 C) 2-H NC O 2-Et0 C-3-H NC O 2-H NCO-3-P h 2-H NCO-3-(/?-0 NC H ) 2,3-(H NCO) 2,3-(Et0 CCH CH ) -2-M e l-Bz-2-NC 1,2-(CMe N=CPh)-3-(>0 NC H ) 2,3-(CH OCH ) l-Me-2,3-(CH OCH ) 1,2-(CH CH NHCO)-3-P h 1,2-(CMe=CHCHOEt)-2-Me-3-C l l,2-[C(te^Bu)==CHCHOEt]-2-Me-3-C l 2,5-Az -hydroquinone 2-AzCH CH NH-quinolin e JV,iV'-Methylenebis(l-R-aziridine-2 carboxamide ) (R = Me, Et , Bu, or PhCH ) 4-(MeN=)-l-Ph- l ,2-(AT-Me-epimino) 1,2,3,4-H -naphthalen e 4-(PhN=)-l-Ph-l,2-(A^-Ph-epimino) 1,2,3,4-H -naphthalen e Variou s dyes containin g th e CH Az' grou p TE M [2,4,6-tris( l -aziridinyl)-5-triazine ] Methy l 4,6-Obenzylidene-2,3-dideoxy 2,3-epimino-a-D-mannosid e Methy l 4,6-0-benzylidene-2,3-dideoxy 2,3-epimino-a-D-allosid e 1-(H or PhCH )-2-EtO C-3-(tetra-0-acetyl L-arabinobuty\) 4
2
6
4
2
2
6
n
2
2
2
2
2
2
6
4
2
2
2
2
2
2
2
2
2
6
4
2
2
2
2
2
2
2
2
6
4
2
2
2
2
2
i
2
2
2
2
4
4
II I II I II I II I II I II I II I II I in II I II I II I II I II I II I II I II I II I I II I II I II II II I I I I I
67 51 59
55
7555 125 3721 1553, 3721 125 1553 1553 1553 2856a 3798 3798 3798 3798 2215 1677, 2287 3862 2087, 2088 1677 1065 150 4074 1095 1095 2623 2699 2700 2453 2921
II I
—
152
II I
70-77
797
II I
73-81
797
II II
— —
2970 4210
I
83
1561
I
48-100
1561
II I
up to 25
924a
—
39.5 66
—
—
99 « 28 30-45 « 50 <5 — — —
56-80 — — —
72 49 58 16 — — —
2
2
2
1. FORMATIO N OF THE AZIRIDIN E RING
46
Tabl e 1-V—continue d Aziridin e made , or substituent s therei n
Method "
% Yield"
Reference s
Aziridines Containing Other Functional Groups—continued 5-Cl-la-R-l,la-H -3-Ph-azirino[l,2-tf] quinazolin e 2-oxide (R = Ç or C1CH ) 6a , 7a-Epiminocholestanol-(3j8 ) 3-acetat e 6â, 7j8-Epiminocholestanol-(3/? ) 3-acetat e 5a , 6a-Epiminocholestanol-(3/? ) 3-acetat e 4a , 5a-Epiminoandrostanediol-(3j8, 1 ºâ) 4á , 5a-Epiminoandrostanediol-(3/8, 1 ºâ) 17-propionat e 2
80 80 85
1287b, 1744 2908 2908 2908 979a
90
979a
94 98 40 42 24
2294 2294 2295 1905 1905
64
13
61
2299
79 >50
2299 2299
2
Aziridinium Salts 1,1-Et (perchlorate ) 1,1,2,2-Me (perchlorate ) 2,2-[(CH ) ]-l,1-[(CH ) ] (perchlorate ) 2-Bz-l,l-Me (bromide ) 2-Bz-l,l,3-Me (bromide ) 2-H0 C-l,l-(CH CH CH CH CO) (bromide ) 2-Ac-l,l-[(CH ) ]-3-P h (dl-cis) (perchlorate ) 2-Bz-l,l-(CH CH OCH CH )-3-P h (perchlorate ) dl-cis for m dl-trans for m (1 -Et- 1 -azoniabicycl o [3.1.0]hexane ) (perchlorate ) (6-PhCH -4-Br-l,4,5-Me -l-azoniabi cyclo [3.1.0]hexane ) (perchlorate ) (l-Azoniatetracyclo^^^.O ' . 0 · ] tetradecane ) (perchlorate ) 1,1 - ( C H C H N H M e C H C H ) (dipicrate ) 2
4
2
5
2
4
2
3
m
2
2
2
2
2
2
5
2
2
2
2
2
1601
3
1
1 3
5
+
2
2
2
14
1359
39
2295 825
1 3
2
a
l = hal o amin e + stron g base ; II = aminoalky l hydroge n sulfat e + stron g base ; II I = hal o amin e + N H or amine , or olefinic compoun d + haloge n + excess amine . Whe n a paten t claim s a genera l proces s bu t gives no yields, only th e simples t aziridin e mentione d is tabulate d here . By pyrolysi s of H O C H C H N H E t Cl~. Trac e fro m 3-piperidino l bu t 40% fro m 3-pyrrolidinemethanol . By dehydratio n of th e amin o alcoho l over hot alumina . Fro m th e vicina l azid o halid e by reductio n with LiAlH an d displacemen t of halide . Structur e uncertain ; formulate d as an enamin e in th e literature . Fro m th e vicina l azid o tosylat e by reductio n with LiAlH an d concomitan t displace men t of th e tosylat e group . Fro m th e vicina l azid o mesylat e as in h. 3
b
c
+
2
2
2
d
e
f
4
9
Ë
4
1
INTRAMOLECULA R DISPLACEMEN T BY THE AMINO GROU P
BrCH CH NH(CH ) NH ->CH =CHNH(CH ) NH 2
2
2
5
2
2
2
5
2
or
47
Az(CH ) NH 31 2
5
2
(23)
The actual cyclization step has been most studied preparatively for EI, partly because among all the aziridines it is most important commercially and at the same time one of those most easily destroyed in the preparation and isolation. Wenker's suggestion for use of 2-aminoethyl hydrogen sulfate (3769) appeared at nearly the same time that a general method was patented (3651). The major advances since then have been the realization that rapid removal of alkylenimine from the hot alkaline reaction mixture is essential to good yields, and development of ways to accomplish this. The halo amine salt or sodium aminoalkyl sulfate solution is dropped into boiling aqueous alkali, whence the imine is immediately steam-distilled out (304, 325, 1011, 1199, 3007, 3008, 3841). In continuous processes operated at 50-80 atmospheres and 220°-250°C, all EI may be produced in 4-10 seconds in 8 0 % yield (176, 1252, 2090). Ethylenimine is separable from mixtures by distillation as an azeotrope, preferably with hexane (725). Table 1-V presents results of preparations on aziridines and aziridinium salts by intramolecular displacements. A discussion of quaternary aziridinium salts, including review of their preparation, is given by Leonard (2292). The structures assigned to those derived from 2-pyridone (75) appear very improbable in view of the reactivity of activated aziridines in the presence of acid (see p. 248). If valid, these structures represent the only known stable activated aziridines containing tetracovalent nitrogen. In a good many instances of preparative work a 2haloalkylamine or 2-aminoethyl hydrogen sulfate has been treated with aqueous alkali and a nucleophilic reagent simultaneously. Whether such reactions proceed by way of aziridines that undergo ring opening, or whether direct displacement occurs, is not usually clear, and can only be surmised for each individual reaction mixture. Since, as has been noted, 2-bromoethylamine cyclizes much faster than 2-chloroethylamine or 2-aminoethyl hydrogen sulfate (see p. 11 and Table l-II), the arbitrary decision has been made for present purposes to regard use of a 2-bromoalkylamine in alkaline solution as an in situ preparation of an aziridine, whereas such reactions of the others are considered not to proceed via aziridines and are not reviewed here. 2-Bromoethylamine has thus been used to make methyl Af-(2-mercaptoethyl)dithiocarbamate (2943), 2-aminothiazolines, 2-aminooxazolines, and 3
Claime d forme d (bu t as a distillabl e product , which appear s extremel y unlikely ) fro m 1,2,3-trichlorobutan e an d ammoni a autoclave d together . By intramolecula r displacemen t of a sulfonat e group . Fro m th e vicina l azid o halide , mesylate , or tosylat e by reductio n with Rane y nicke l an d hydrazin e an d concomitan t displacement . Structur e is in doubt ; see above . k
1
m
48
1. FORMATIO N OF THE AZIRIDIN E RING
2-mercaptothiazolines (1386), substituted thiazolidines from xanthates (2395), H N C H C H S C S - (4153), 2-aminoethanethiol (3622), 2-(alkylthio)ethylamines (166, 723, 3622), 2-(arylthio)ethylamines (2205), polyamines (2752), and aminated dextran (3695). 2-Bromobutylamine similarly gave a mercaptothiazoline (418) and an aminated dextrin (3695). A curiosity of some biological interest is the detection of l-(2-chloroethyl)aziridine in the air exhaled by rats to which Endoxan had been administered; evidently hydrolysis and cyclization are involved (4157). +
3
2
2
2
X
N(CH CH C1) 2
2
2
Endoxa n
Intramolecula r Displacemen t by Amid e Anion s
L = leavin g group ; A = acyl or like grou p
This method of obtaining aziridines is very like the one already discussed, in stereochemistry, variability of L, order of reaction, etc. However, it succeeds only in solution alkaline enough to produce the requisite concentration of amide anions; the statement (1444) that it can proceed with elimination of H L appears unfounded. Sulfonamides are more readily converted to such anions than are carboxamides; their cyclization is reviewed first, in Tables 1-VI and 1-VII. N o doubt diethyl A^-(2-chloroalkyl)phosphoramidates (3902) can be cyclized similarly. Tabl e 1-VI PREPARATIO N OF 1-ARYLSULFONYLAZIRIDINE S BY CYCLIZATIO N
L
Aziridin e substituent s
CI
l-PhS0
CI
1-OFC H S0 )
2
6
4
2
% Yield 90 94 70 92
Reference s 1848 3183 1979 3183
INTRAMOLECULA R DISPLACEMEN T BY AMIDE ANIONS
49
Tabl e 1-VI—continue d Aziridin e substituent s
L
l-(m-H NC H S0 ) l-(/7-H NC H S0 ) l-(/?-MeC H S0 ) l-(m-0 NC H S0 ) l-(/>-0 NC H S0 ) l-(p-MeOC H S0 ) l-(3-H N-4-MeOC H S0 ) l-PhS0 -2-ClCH l-PhS0 -2-ClCH l-(/?-ClC H S0 )-2-ClCH l-0>-BrC H SO )-2-ClCH 1 -0?-MeC H SO )-2-ClCH l-PhS0 -2-BrCH l-PhS0 -2-BrCH
CI CI CI Br Br Br CI Br Br Br CI Br CI Br Br CI CI CI Br
l-PhS0 -2-E t l-ArS0 -2,2-Me l-PhS0 -2,3-Me (cis an d trans) l-PhS0 -2,3-Me l-PhS0 -2-BrCH -2-M e 1 -(/?-ClC H S0 )-2-BrCH -2-M e l-(/?-BrC H S0 )-2,2-Me l-(/?-BrC H S0 )-2-BrCH -2-M e l-(p-MeC H S0 )-2-BrCH -2-M e l-(p-AcNHC H S0 ) l-PhS0 -2-P h l-PhS0 -2-P h l-(p-MeC H S0 )-2-P h l-( p-MeC H S0 )-2-P h l-PhS0 -2-PhCH l-PhS0 -2-Bz l-ArS0 -2-Me-2-Cl C l-(/?-MeC H S0 )-2,3-Ph (cis an d trans) l-PhS0 -2,3-[(CH ) ] (CH CMe) «
2
6
4
6
2
4
6
2
4
2
6
2
6
2
4
2
4
6
2
4
2
2
6
2
4
2
2
2
2
6
4
6
4
2
2
2
6
2
4
2
2
2
2
2
2
56
—
2660
— —
1366 1366
—
1366 3185a 542a
— 70-81
2
2
— —
2
2
82-93
2
2
2
2
2
6
4
2
6
4
2
6
4
2
6
4
2
2
2
2
2
6
4
2
2
2
6
4
2
6
4
2
j
2
2
2
2
3
6
4
2
2
2
2
4
Reference s 1979 1979 3183 3183 3183 3183 1979 2058 1453 2058 2058 2058 1453 7, 1449, 1450, 2124 2322 2439 852a, 2322 2323 541 541 12 541 541 1480 3185a 519, 3479a 3185a 2077 1454 2551 2059 3185a 4185
64 65 94 81 75 98 82 65 85 50 70 61
CI CI CI CI CI CI CI CI Br CI CI CI CI Br
2
% Yield
— 96 95 46 97 83
— —
— —
> 95 81 60-80 0
—
2
I
CI CI CI CI CI Br
1 l-/>-0 SC H CON H 1 - [3-(l -Hydroxy-2-naphthoylamino) 4-methoxyphenylsulfonyl ] l-[4-(^_Anisoylacetylamino)phenylsulfonyl ] 1 - [4-(5-Oxo-l -phenyl-2-pyrazoline-3 carboxamido)phenylsulfonyl ] l-(/?-MeC H S0 )-2,3-(CH C H -i? ) l-PhSQ -2-NC 2
6
4
6
2
4
2
2
6
4
—
—
2
2
2
2
2
2
ClCH CH NHS0 P h
2
(ClCH ) CHNHS0 P h
2
ClCH CHMeNHS0 P h
Benzenesulfonamid e
95% 95% 95% 95% 95% 95% 95% 95% 95% 95% 95% 95%
EtO H EtO H EtO H EtO H EtO H EtO H EtO H EtO H EtO H EtO H EtO H EtO H
Solvent
6
NaOH , NaOH , NaOH , NaOH , NaOH , NaOH , NaOH , NaOH , Alkali, NaOH , NaOH , NaOH ,
2 2 2 2 2 2 2 2 1-2 2 2 2
2
Addend , M x 10 0.04 10.30 15.10 21.0 0.04 10.30 15.10 21.0 0.04 10.30 15.10 21.0
Temp . (°C) 3.74 11.09 25.03 61.17 2.75 10.26 23.18 43.03 2.46-2.56 10.79 22.54 40.23
k°
-1
k (= k° ÷ 10-" ) (sec )
4 4 4 4 4 4 4 4 5 5 5 5
ç
0
—
—
— —
— 7.4
—
— 21.65
—
1.59
—
—
— 13
— 1.88
— — 21.54
— —
—
—
— — — 21.42 — —
— 12
—
— 12 —
ç
-1
A (= A° ÷ 10") (sec ) A°
Å (kcal )
RAT E OF CYCLIZATIO N OF SUBSTITUTE D BENZENESULFONAMIDE S TO AZIRIDINES
Tabl e 1-VH
1448 1448 1448 1448 1448 1448 1448 1448 1448 1448 1448 1448
Refer ences
50 1. FORMATIO N OF THE AZIRIDIN E RIN G
a
2
2
6
6
4
NaOH , 2 NaOH , 2 NaOH , 2 NaOH , 2 NaOH , 2 NaOEt , 0.8-6.2 NaOEt , 0.9-6.7 NaOEt , 1.8-6.7 NaOEt , 1.5-6.7 NaOEt , 1.1-6.7 NaOEt , 1.0-6.7 NaOH , excess NaOH , excess
— — —
— — — —
— — — —
4 4 4 5
0.97-0.81 0.88-0.80 6.24 8.37
25.0 25.0 60 60
—
3183
— —
—
4
25.0
3183
—
—
3.8-3.1
8.1-7.2
25.0
2111 2111
3183
3183
3183
—
—
—
12
— — — —
1448 1448 1448 1448 1448 3183
— —
—
4
6.8-5.9
25.0
—
— —
8.3
—
— —
22.01
— — —
4
5 5 5 5 2 4
5.61 20.2 49.4 95.1 « 5 5.6-4.5
0.04 10.30 15.10 21.0 0.04 25.0
Exceptin g for th e last two sulfonamides , all rate s wer e followed by determinatio n of chloride . * LiOH , NaOH , KOH , CsOH ; adde d NaC10 ha d littl e effect.
2
4
70% MeO H 70% MeO H
3
3
2
6
4
4
H0 SOCH CHMeNHS0 C H Cl -/7 H0 SOCHMeCH NHS0 C H Cl-/ ?
2
2
6
2
EtO H
2
2
2
6
2
ClCH CH NHS0 C H N0 -w
2
2
2
6
4
ClCH CH NHS0 C H N0 -i7
2
2
2
2
6
EtO H
ClCH CH NHS0 C H F-/ >
2
2
2
2
2
EtO H
ClCH CH NHS0 C H OMe -/7
2
2
4
EtO H
ClCH CH NHS0 C H Me- p
2
2
2
4
EtO H
(BrCH ) CHNHS0 P h ClCH CH NHS0 P h
2
4
47.5% EtO H 47.5% EtO H 47.5% EtO H 47.5% EtO H 95% EtO H EtO H
2
ClCH CH NHS0 P h
INTRAMOLECULA R DISPLACEMEN T BY AMID E ANIONS 51
52
1. FORMATIO N OF THE AZIRIDIN E RING
W h a t has been called "methylenation" of Schiff bases by sulfonium ylides, though only a few examples are known, may be classified here mechanistically. Trimethylsulfonium methylide (32) adds to the ^ C = N - group and then intromolecular displacement of dimethyl sulfide closes the ring (Eq 24) (760,1326). ArCH=NA r + -CH SMe + 2
•
2
+Me SCH CHArNAr 2
_
M C z S
2
>
\
/
A
r
Í
32
I
Ar
(24)
Similar reactions occur, although more slowly, with dimethyloxosulfonium methylide, ~ C H S ( 0 ) M e (760, 1800, 2126,2536), dimethyl sulfoxide being eliminated; the most striking example is the conversion of 3-phenyl-2i/-azirine to the bicyclic compound 33 (1763). Carbonyl-stabilized sulfonium ylides, " R C O C H S M e , ultimately yield not the aziridine 34 but its isomer R C O C H = C A r N H A r (3352). +
2
2
+
2
^A r RC 7 11
XT
Ï
Í Ar 34
33
It might be supposed that cyclization of iV-(2-substituted alkyl)carboxamides would yield 1-acylaziridines (Eq 25), but it has long been known and L '
I
I
stron g base Â
_C_C I I
I
\
*
/
\ / Í I CO R
NHCO R
,_
+ L - + BH
(25)
often redemonstrated that the usual course of the reaction (Eq 26) leads to an oxazoline (35). I
I
J + + L+H
I
I
R
R 35
(26)
While 1-acylaziridines can be rearranged to oxazolines (1656), it is not likely that oxazoline formation proceeds by way of aziridine intermediates as a
INTRAMOLECULA R DISPLACEMEN T BY AMIDE ANIONS
53
rule (1667). Those few instances in which aziridines are formed rather than oxazolines will now be discussed. Possibly because of decreased resonance stabilization of the anion 36 resulting from removal of a proton from a mono-7V-substituted urethan (Eq 27), stron g bas e
RNHC0 R ' 2
•
-
RNC0 R '
(27)
2
36
which is apparently less than for other carboxamide anions, internal displacement of halide by the amide nitrogen atom to give aziridines occurs (Eq 28) instead of the displacement by amide oxygen to give oxazolines (Table 1-VIII).
NHC0 R
I C0 R
2
2
Since the iodo urethans can be made readily, and stereospecifically trans, by the addition of iodine isocyanate to olefins (see p. 35) and addition of alcohol to the product, the synthesis is an attractive one for laboratory use. In one example only, a mesylate anion, M e S 0 0 ~ , is displaced instead of halide, to produce a biaziridine (1275). Occasionally a competing elimination leads to the enamides, ^ C = C R — N H C 0 R , which tautomerize and hydrolyze to ketones (1624). The l-(alkoxycarbonyl)aziridines, however, are as unusually susceptible to hydrolysis as a urethan is resistant, and normally the final product is an aziridine without the 1-substituents (Eq 29) (see p. 253). 2
2
Threo iodo carbamates yield aziridines (cis) more smoothly than the erythro forms do (to give ira«,y-aziridines) (1433). This is attributed to steric impedance of formation of the transition state yielding the trans form; moreover, also for steric reasons, the hydrolysis of methyl frafl.y-2,3-dialkyl-l-aziridinecarboxylates is much slower than that of the cis isomers. Nearly all examples of this kind of aziridine formation remaining for discussion are facilitated by the presence of very effective leaving groups, tosylate or mesylate. They also all involve trans groups on six-membered rings. Thus
1. FORMATIO N OF THE AZIRIDIN E RING
54
DL-iraAW -2-benzamidocyclohexyl tosylate (3459) and DL -ira«s-2-benzamidocyclohexyl-S,S-dimethylsulfonium iodide (37) (3465) with hot alcoholic sodium ethoxide each yield an aziridine and an oxazoline in about 4 : 1 ratio (Eq 30).
Tabl e 1-VII I PREPARATIO N OF AZIRIDINE S FRO M JV-(2-HALOETHYL)CARBAMI C ESTERS "
Aziridine , or substituent s therei n 2-tert-Bu 2,3-Et (trans) 3-Me-2-iso-P r (trans) 3-Me-2-iso-P r (cis) 2-("-C H ) 2-(n-C H ) 2-(«-C H ) 3-(«-C H )-2-[R(CH ) ] 2
8
n
10
21
16
x
33
2x+1
X
2
R Me Me HO HO Me Me HO HO Me0 C
5-8 8 5-8 8 5-8 8 5-8 8 8
2
2-Ac 2-Cl CC H 2 2-Ph 2-Ph 2-Ph-3-r f 2,3-Ph (cis) 2,3-[(CH ) ] 2,3-[(CH ) l 3
2
2
4
2
4
% Yield
Reference s
60 45 33 32 75* 65* 70"
4056 3448 3448 3448 1305 1305 1305
30-43 47 35-50 70 49-65 19 30-58 53-58 51-97
4115 1433 4115 1433 4115 1433 4115 1433 1433
0 0 60 61-88 — 45 55 52
4056 4056 1305 1624 1625 1305 1305 1624,
y
y
Configuratio n
7-11 7 7-11 8 7-11 7 7-11 8 7
cis cis cis cis trans trans trans trans cis
b
c
INTRAMOLECULA R DISPLACEMEN T BY AMIDE ANIONS
55
Tabl e 1-VII I —continued Aziridine , or substituent s therei n
% Yield
Reference s
70* 60 65 64 56 65 — — 56-70'
3167 3448 1623 1623 1623 1624 4140 4140 1624, 1627 3165 1624, 1627, 3167 433 2837
2,3-[(CH ) ] 2,3-[(CH ) ] 2,3-[(CH ) ] 2,2-[(CH ) ] 2,3-[(CH ) ] 1,2-Epiminoinda n 2,3-(CH CMe=CHCH ) 2,3-(CH CH=CHCH )-2-M e 1,2-Epimino- l ,2,3,4-H -naphthalen e 2,3-Epiminonorbornan e Cholesten(2j8,3j3)imine '
88-90
3,4-Epiminotetrahydrofura n 5,6-Epiminodibenzo[fl,c]cycloheptadien e
54 Goo d
2
4
2
4
2
4
2
5
2
5
2
d
e
d
2
2
2
4
—
g fc
a
Haloge n = iodin e except as noted . Haloge n = chlorine . In aqueou s solutio n 0.01-0.001Mi n carbamat e an d 0.01-0.15Mi n KOH , at 24° ± 0.5°C; rat e of cyclization , k, = 2.69-3.78 ÷ 10" sec" . Via th e sodiu m bisulfit e adduc t of th e isocyanat e instea d of th e alcoho l adduct . Produc t isolate d as th e pheny l isocyanat e adduct . For th e methy l ester , for which rat e (as before ) = 12.1 ÷ 1 0 s e c . Othe r rates : ethy l ester , 10.05 ÷ 1 0 s e c ; isopropy l ester , 7.32 ÷ 1 0 s e c . By mild treatmen t th e methoxycarbony l derivativ e could be isolate d in 64 % yield (1627). Rat e of cyclizatio n for th e methy l ester = 16.9 ÷ 1 0 s e c . b
c
5
1
d
e
f
- 5
- 5
-1
- 5
-1
-1
9
h
- 5
-1
+
In contrast, B z N H C H M e C H P h S M e I " gives only the oxazoline (3465). The products of acetolysis of either 2-benzyl-3-oxo-2-azabicyclo[2.2.2]octan-ewifo-6-ol tosylate or 2-benzyl-3-oxo-2-azabicyclo[3.2.1]octan-e«ifo-7-ol tosylate are best explained by postulating the acylaziridinium ion 3 8 as an intermediate (1792). 2
CH P h 2
Desire for possible antitumor drugs and intermediates for synthesis of various amino sugars has motivated related research. Various methylpyranosides, but not furanosides (549), having appropriate groups in the 2- and 3-
D-Altros e D-Altros e D-Altros e D-Altros e D-Altros e D-Altros e D-Altros e D-Altros e
D-Altros e D-Altros e D-Altros e D-Altros e D-Altros e D-Altros e D-Altros e D-Altrose D-Altros e
e
fl
Paren t suga r (as Me glucoside)
OM s OM s OM s OM s NHB z NHB z NHB z NHTo s
OM s OM s OM s OM s OM s OM s OM s OM s OM s 2
2
2
2
NHC N NHCONH NHC(=NOH)NH N=CHP h OM s OM s OM s OTo s
2
2
NHCS M e NHB z NHB z NHB z NHA c NHC(=NN0 )NH NHCSNH NHCSNH NHC N
Substituents *
2
2
d
2
2
2
3
4
Base
NaOMe , 1.1 eq. NaOE t NaOEt , 0.2ºÍ LiAlH NaOE t NaOMe , 0.13 Í NaOMe , 0.3iV NaOMe , 0.1JV NaOM e or NaOH , resp . EtO H or H 0 N H EtO H NaOM e EtO H NaOMe , 0Ë Í H 0 NaOH , 0.2N EtO H NaOE t EtO H NaOEt , 0.2ºÍ HCONMe KC N MeO H NaOMe , 0.6N
Mixed ales. EtO H EtO H THF EtO H EtO H EtO H EtO H EtO H or H 0
Solvent 60 25 B.p. B.p. B.p. 25 B.p. 40 25 or b.p. , resp . — B.p. 50 B.p. 25 B.p. 100 25
(°Q
Temp .
Reactio n condition s
PREPARATIO N OF 2,3-EPIMIN O SUGAR DERIVATIVE S
Tabl e 1-IX
c
c
c
c
32 38 56 * 49* 78
/
61 68-73
— 60 Few 120 45 30 120 60
—
88-90
—
65 29 72 53 53 76 85
Yield (% )
—
4-5 90 30 180 20 1080 10 Few
Tim e (min. )
9
9
249 248 249 248 551 1562 551 2539 252
685 551 551 551 551 246 247 247 248
Refer ences
56 1. FORMATIO N OF TH E AZIRIDIN E RIN G
]
J
3
OTo s NHTo s OM s OTo s OM s NHCSNH NHC N OM s OM s OM s OM s NHM s NHM s N 2
d
2
d
d
THF MeO H EtO H MeO H EtO H MeO H MeO H THF EtO H THF HCONMe H 0 HGONMe THF ? 2
2
L1AIH 4
KC N NaOH , 17V BzONa
L1AIH 4
NaOMe , 0.37V
L1AIH 4
NaOMe , 0.17V NaOEt , 0.147V NaOMe , 0.1 TV NaOM e NaOMe , 0.27V NaOMe , 0.27V
L1AIH 4
—
B.p. B.p. B.p. B.p. War m B.p. B.p. B.p. B.p. B.p. 100 25 90-100
— 45 40 120 — 240 120 270 10 60 300 (3 days ) 540 —
c
k
c
100 0* 0 92 44 85 — 17" 90 56 61
c,h
60-66 79
551 252 551 250 247 251 251 1467 1467 47a, 1467 2538a 253 253 722b
1
J
1
h
0
f
e
d
c
b
Th e á-glucosid e was used unles s otherwis e noted . Th e acylamin o substituen t is understoo d t o be on a deoxy carbo n atom , an d a 4,6-benzyliden e grou p presen t unles s otherwis e noted . As th e free epimine . TH F = tetrahydrofuran . N o benzyliden e grou p present . Of th e benzylidenebis(aziridine) . Along with 25 % of th e oxazoline . Oxazolin e also formed . In othe r cases, not cited here , th e â-hexos e derivativ e gave only th e oxazoline , etc. No benzyliden e grou p present , bu t a 5-mesyl was. * Th e 5-Ms grou p was displace d by th e 5-Bz grou p in th e product . No benzyliden e grou p present , bu t a 5-azid o grou p was. Th e produc t was isolate d as th e dibenzoy l derivative .
a
1
1
2
NHTo s D-Altros e OTo s D-Altros e NHA c D-Altros e NHCONH D-Altros e NHCONH 2 D-Altros e (â) OM s D-Glucos e OM s D-Glucos e NHB z D-Glucos e NHB z D-Glucos e NHA c D-Glucos e NHB z D-Glucos e (â) D-Arabinos e (fi) OM s D-Arabinos e (â) OM s OT s D-Xylose (â)
INTRAMOLECULA R DISPLACEMEN T BY AMID E ANION S 57
58
1. FORMATIO N OF THE AZIRIDIN E RING
positions have been found to yield epimino sugar derivatives (aziridines) with bases (Eq 31). °~1
. /
„
ÐË
base
/ Ms6\ w
^OM e
(Ms = MeS0 )'
Ph- X
2
k
A
\ Y y O M e , etc.
31
( )
0
acyl-NH
V I
.
acyl
The reaction requires careful choice of base and conditions. Results are given in Table 1-IX. A 3,4-epimino sugar derivative was suggested as an intermediate (3741) and subsequently one was prepared by similar reactions (273). Still more recently, reduction of /ra?i y-(4iS-azido-3S-tosyloxy)-2£'-benzoyloxymethyltetrahydrofuran with either lithium aluminum hydride or hydrogen and catalyst has produced the aziridine 3 9 A (4027) (see p . 36); 3 9 B was made i
~
R
Ç /Í ,
39A, R = CH OB z 39B, R = CH O 2
very similarly (722a). 3-O-Benzyl-l,2-0-isopropylidene-5,6-di-0-mesyl-Dglucofuranose ( 4 0 ) with hydrazine, by displacement of the primary mesyloxy group and ring closure, yields the JV-aminoaziridine 4 1 (4145). The reaction succeeds for other similar furanoses, but not for pyranoses in which the vicinal mesyloxy groups are attached to the ring. Other 5,6-epimino sugar derivatives have been made from the 5-0-tosyl-6-azido-6-deoxy derivatives by treatment with lithium aluminum hydride (3088a). MsOCH
2
H N—Í
MsOC H
2
N H ,J 2
40
4
41
The formation of an N-diazonium aziridine intermediate has been suggested to explain the steric course of the acetolysis of /raH ^-azidocyclohexyl tosylate (Eq 32)· (3396), but an alternative rationalization by way of 1-azidocyclohexene (Eq 33) may be preferable (3448).
INTRAMOLECULA R DISPLACEMEN T BY CARBANION S
59
A recent claim that iV-(2-chloroethyl)-j8-ethoxyacrylamide ( 4 2 ) is converted by strong alkali to the aziridine derivative (2135) is of doubtful validity; the EtOCH==CHCONHCH CH C l 2
EtOCH=CHCOA z
2
(?)
42
product was probably the oxazoline. The brief statement (732) that N-(2chloro-l,2-diphenylethyl)benzamide, B z N H C H P h C H C l P h (the original name a,j8-diphenyl-j8-chloroethylamine is a misprint), yields l-benzoyl-2,3-diphenylaziridine when heated with alcoholic sodium ethoxide has been verified (1670).
Intramolecula r Displacemen t by Carbanion s This class of reactions may be represented by Eq 34. L
L S t r
RCOC-C-N -
°
n 8 b a S e
>
I
RCOC-C-N -
Ç
•
R
'
I + L"
(34)
O N
It is, of course, also possible that some such reactions proceed by a concerted mechanism instead of by the steps shown. The reaction has been reported only once for an ordinary value of L, the leaving group, which in this case was chloride (Eq 35) (2527). CO E t z
tert-BuOCl ^ Ç
^/\^C0 Ã J
2
Et
/~x.C0 E t à 2
NaQMe ^
^
I
CI
Nevertheless it appears to be the best mechanism (784) for explaining the formation of aziridines from JV-alkoxyamino ketones in alkaline solution. The
1. FORMATIO N OF THE AZIRIDIN E RING
60
first examples (381) of the reaction (Eq 36) are represented by the equation shown although the products were not then so formulated.
ArCOCH CHP h 2
+ base , Â
>
Arc\/
NHOM e
Ï
+ OMe "
(36)
J Ç
Applications of the synthesis are shown in Table 1-X. Tabl e 1-X PREPARATIO N OF AZIRIDINE S FROM 2-(ALKOXYAMINO)ETHY L KETONE S Aziridin e made , or substituent s therei n 2-Bz-3-Ph 3-Ph-2-(p-MeC H CO ) 3-Ph-2-(/?-MeC H CO ) 2-(/>-ClC H CO)-3-P h 2-Bz-3-(/?-ClC H ) 2-(p-BrC H CO)-3-P h 2-Bz-3-(p-BrC H CO ) 2-Q?-MeOC H CO)-3-P h 3j8-Hydroxy-16á , 17a-epimino-5-pregnen-20-on e 6
4
6
4
6
6
4
6
4
6
4
6
4
% Yield 94 64 61 66 80 83 90 65 78-82
4
Reference s 381, 980 381 796 381 381 381, 980 381 980 985
Intramolecular displacement reactions similar to the Favorskii rearrangement can also lead to the formation of aziridinones (á-lactams ) (4110) ( 4 3 ) , sometimes only as reactive intermediates but capable of isolation under favorable circumstances. Two routes have been used (Eqs 37 and 38). CI I
-c—c=o I
stron g base
I NH R
CI I
-c—c=o I
Ï
—ci -
I NI R
(37) Í I R 43 -á -
-C—C—N R I I Ç Ç
ROC l
Ï I II -C—C—N R I I Ç CI
stron g base
Ï ,R I II -C—C—N C CI
(38)
61
ELIMINATION-ADDITIO N REACTION S
Cyclizations of type 37 have been suggested and discussed for P h C H C l C O N H P h (3116, 3118) and P h C C l C O N H P h (3117, 3225) but demonstrated for Me CBrCONH-ter*-Bu (3224), ter^BuCHBrCONH-ter/-Bu (3222), Ph CClCONH-terf-Bu (2650), several l-(l-adamantyl)aziridinones (440a, 3481), and several ring compounds (2651,3223). Those of type 38 were indicated by infrared spectra for N-ter^butylphenylacetamide, iV-teri-butylacetamide, and iV-teri-butylpropionamide (298), and products that pretty surely have the l-teri-butyl-3-phenylaziridinone structure have been isolated and examined (296,300,1362). Products of the reaction of P h C C l C O N H with primary and secondary amines indicate that even with these weak bases the aziridinone is an intermediate (3119). A reaction noted here in the absence of more information on mechanism is the conversion of erjtfAr0 -l-azido-2-iodo-l,2-diphenylethane ( 4 4 ) (but not the threo isomer) by alcoholic base to 2-ethoxy-2,3-diphenylaziridine (Eq 39) (1628) (compare the Neber rearrangement, p. 63). 2
2
2
2
2
Et O
I
n
u
P
h
Ç
N V
Ê
-H I
X Ç
^P h
I
3
J^L ^
r
™_^
™ ^
[PhCH=CPhN ] T T
T
1
3
EtO H
—
^
P h \ /
2
Ph
(39)
g
Ç
44
Elimination-Additio n Reaction s This very small class of reactions, discovered recently, is given only by 2-bromoallylamines, which are converted by alkali amides in liquid ammonia to 2-methyleneaziridines (= allenimines) (Eq 40) (Table 1-XI). CH =CBrCH NH R 2
2
Of the several paths that can be conceived, only that one is acceptable that involves formation of an allenamine, its conversion to an anion, cyclization, and protonation (Eq 41) (444). CH =CBrCH NH R 2
2
> CH =C=CHNH R
*
2
CH =^ CH \ / Í 2
CH =C=CHN R 2
>
CH =^ 7 \ / Í 2
•
I
I
R
R
( 4 1 )
62
1. FORMATIO N OF THE AZIRIDIN E RING
An unfailing side reaction, and indeed the only one that occurs with 2-chloroallylamines, is formation of the isomeric propargylamines, H C = C C H N H R . Proof of structure of these aziridines, which were first regarded as allylidenamines (2905), was supplied by infrared (1081) and N M R (449) data. 2
Tabl e 1-XI PREPARATIO N OF 2-METHYLENEAZIRIDINE S
CH ==CBrCH NHR , 2
% Yield of
2
R =
Í
Reference s
R « 50
Me Et
— « 45 48-55 68
iso-Pr
— Propyl-3- / Bu tert-Bu teri-BuCH CHMeCH CH (+)-CH =CHCHOHCH (_)_CH =CHCHOHCH 2
2
2
2
2
2
2
« 40 74.5 « 25 « 50 45 40-50 « 45
450 449 450 441 2905 450 444 2905 450 450 2905 448 448
Preparatio n via Azirine s In all intramolecular displacements discussed up to this point, a saturated (aziridine) ring is formed. There is a small class of reactions, however, in which internal displacement yields an unsaturated (2//-azirine) ring. Inasmuch as the azirine often undergoes reduction to an aziridine, this family of reactions is reviewed here. In one subfamily, aziridines are formed by the action of excess Grignard reagent on á-chlor o nitriles. While a somewhat different mechanism has been written (1094), the one in Eq 42, involving intramolecular displacement of chloride by imine anion, seems preferable. The last step, addition of the Grignard reagent to an azirine, is known separately (1025, 4057). It would be desirable to effect the reaction of an achloro alkanenitrile with a Grignard reagent in 1:1 ratio, to see whether an azirine intermediate could be isolated. The reaction with excess Grignard re-
63
PREPARATIO N VIA AZIRINE S
agent is known to produce 2,2,3-triethylaziridine (863), 3,3-diethyl-2-propylaziridine (3525), and 2-isobutyl-3,3-diethylaziridine (3525). Chloroacetonitrile gave no aziridine (2471). á-Chlor o nitriles with lithium aluminum hydride also produce aziridines (see p. 36) (1883, 2175); the mechanism is doubtless similar to that when Grignard reagents are used. R'
R'
I
RCHC N + R'Mg X Cl
,
> RCHC=NMg X
I
„
RCHC=N " + XMg+
á
CI CI I RC— I Ç
R' I C II Í -
-R ' -á -
(42)
Í
an azirin e R' R'
+ R'Mg X Í
Í
I Ç
Another class of reactions yielding azirines by intramolecular displacement is the Neber rearrangement (Eq 43) (1769, 2739, 3027). base
RCH CR ' 2
— NOS0 R"
RCHCR '
- ii
A
R
/
> R \ Í/
+ R*so o2
NOSOzR '
2
(43)
HO + H+ z
RCH—CR ' I +NH
3
II Ï
Reduction of the unstable intermediate azirine to an aziridine with lithium aluminum hydride (777,1630) helped establish the course of the reaction. In a closely related process, JV,iV-dichloro .seoalkylamines with alkali yield azirines and then, by acid hydrolysis, á-amin o ketones (Eq 44) (73, 294, 297, 299, 2736). r— R CH CH R 3
NC1
2
CH CR 3
NCI
\ j T
>
p r o d u c t s
( 4 4 )
Í
The azirine was again reducible to an aziridine (294), as was the one made from the isolated N-chloro imine (295). Another variation is the generation of the azirine from a quaternized hydrazone (45) (1919, 2616, 2818, 3304). In the reaction illustrated by Eq 45
1. FORMATIO N OF THE AZIRIDIN E RING
64
Me -Ph +
Me CHCPh=NNMe 2
IS
3
Pr
°" ° >
M e
'
\ /
+ Me N 3
N
45
it was possible to isolate an alkoxyaziridine adduct (46) in high yield, and to convert it either back to the azirine or, by hydrolysis, to the amino ketone (1768, 2818, 4072). Me M e ' \ y
-Ph +
i
s
o
. p
r
0
H ^ ^ >
Me
Ph
é
é
Me^/^O-iso-P r
Í
(
4
5
)
Í I
Ç 46
In contrast, 2-aryl-2-anilinoaziridines could not be isolated though they were postulated as intermediates in reactions of azirines (3307). Azirines add alcohols to form 2-alkoxyaziridines in the presence of acids also, preferably perchloric acid, though the aziridine ring does not then survive; but pyridine and perchloric acid with 3,3-dimethyl-2-phenyl-l-azirine gave the crystalline adduct 47 (2302), and the reaction of this azirine with primary aromatic amines is believed to involve similar aziridines as intermediates (4112). Me
V
Me l
—Ph
N
+ C H NH + C10 5
5
4
>
Ph + 4—NC H 5
u / \
/
5
CIO4 -
Í I
Ç 47
The rearrangement of 2-acylcoumarone oxime /?-toluenesulfonates is more complex but probably involves azirine and aziridine intermediates (1441). Presumably by reason of steric effects, neither the Neber nor the quaternized hydrazone route could be made to yield the fused aziridine ring system characteristic of mitomycins (3026). A n isolable azirine proved to be intermediate in the photochemical rearrangement of a substituted isoxazole to an oxazole (3272), and several azirines have been shown to add arenesulfinic acids to produce C-arylsulfonylaziridines (2510a). The reactions just discussed would scarcely be chosen as preparative routes to aziridines. The action of 3 moles of a Grignard reagent on a ketoxime, however, does have utility for laboratory synthesis (Eq 46). The recorded examples of application of the ketoxime-Grignard and the ketoxime-lithium aluminum hydride reactions are listed in Table 1-XII,
65
PREPARATIO N VIA AZIRINE S
excepting some in very recent papers (2103, 2165, 2165a). That the reaction is thus related to the Neber reaction has been well established (1025,1619,1697, 1917), the evidence again including trapping of the azirine intermediate with lithium aluminum hydride to form the less alkylated aziridine (1025), and also such reduction of the authentic azirine otherwise prepared. The reduction gives cw-aziridines stereospecifically (1626). Catalytic reduction of azirinecarboxylic esters, however, yields acyclic enamines and not aziridines (1619).
RCH CR'=NO H 2
2 R
M g X
>
[RCH(MgX)CR'=NOMgX ]
F o r preparative use the oxime-Grignard reaction works best when the ketoxime is not wholly aliphatic. It occurs when cyclooctanone oxime tosylate is treated with phenyllithium (1382), but methyllithium gives a different kind of product (1382), as does a Grignard reagent with the tosylate of at least 4-tertbutylcyclohexanone oxime (2841). Evidently similar is the production of aziridines by reduction of ketoximes with lithium aluminum hydride (2103, 3211), although, unlike the Neber rearrangement, the reaction is stereochemically sensitive to the configuration of the oximes used (2165,4091). It is applicable to a variety of ketoximes and aldoximes (2165a, 2165b). Azirines in general yield rather unstable but isolable adducts, l-benzoyl-2chloroaziridines (e.g., 4 8 and 4 9 ) , with benzoyl chloride in benzene; the isomer 4 9 predominates (4072). Me
Me
Me
48
49
The remarkable change in reactivity of organic compounds effected by perfluorination extends to azirines. Perfluoro-3-methylazirine (50) and perfluoro-2-methylazirine (51) are polymerized by catalytic amounts of bases to polyaziridines. Similarly, hydrogen fluoride causes isomerization of the
66
1. FORMATIO N OF THE AZIRIDIN E RING
Tabl e 1-XII PREPARATIO N OF AZIRIDINE S FRO M KETOXIME S AND GRIGNAR D REAGENT S OR META L HYDRIDE S
From Grignard Reagents Group s in Grignar d reagen t
Group s in ketoxim e Me, Me Et , Et Me, Me Pr , Pr Me, Et0 CCH CH CH 2
2
2
Bu Et «-C H Pr 5
2
Aziridin e produced , or substituent s therei n 2-Bu-2-M e 2,2-Et -3-Me 2-0i-C H )-2-M e 3-Et-2,2-Pr
17 14 — 37
2
n
Me
5
n
2
2,2-Me -3-HOCMe CH CH and/o r 2-Me-2-HOCMe CH CH CH 2-Et-2-P h 2-Et-2-P h 2,3-Me -2-Ph 2-Ph-2-P r 2-Et-3-Me-2-P h 2-Et-3-Me-2-P h 3-Me-2-Ph-2-P r 3-Et-2-Ph-2-P r 3-Me-2,2-Ph 3,3-Me -2,2-Ph 3,3-Me -2,2-Ph 2
2
2
Ph , Ph , Ph , Ph , Ph , Ph , Ph , Ph , Ph , Ph , Ph ,
Me Me Et Me Et Et Et Pr Et iso-Pr iso-Pr
/o
Yield
Et Et Me Pr Et Et Pr Pr Ph Ph —
2
2
2
2
40 20-60 40-64 64 25-35 — 50 — 43
2
a
2
2
2
1697 1697 1697 1697
2
2
2
Reference s
— 24
3487a 568 1025, 1917 1025, 1917 568 1697,1725 568 1697 1697 1725 1773 1773
From Lithium Aluminum Hydride Aziridin e produced , or substituent s therei n
Oxim e PhC(=NOH)E t or PhCH C(=NOH)M e PhC(=NOH)M e or PhCH CH=NO H /?-ClC H C(==NOH)M e or />-ClC H CH CH=NO H /?-MeOC H C(=NOH)M e or />-MeOC H CH CH=NO H PhC(=NOH)E t PhCH C(=NOH)M e PhC(=NOH)CH=CH
/o Yield
3-Me-2-P h
Reference s 3245
2
2-Ph
—
3245
—
3245
2-(/>-MeOC H )
—
3245
3-Me-2-P h 3-Me-2-P h 3-Me-2-P h
—
3245 2103, 3245 3211
2
6
4
6
4
6
4
6
2-0?-ClC H ) 6
4
2
4
6
4
2
2
2
34' 50
PREPARATIO N VIA AZIRINE S
67
Tabl e 1-XII —continued From Lithium Aluminum Hydride Aziridin e produced , or substituent s therei n
Oxim e PhCH (=NOH)P h PhCH (=NOH)P h />-ClC H C(MNOH)CH C H Cl-/ ? 2,4-(0 N) C H CH C(=NOH)M e ( P h C H ) C = N O H , or its acetate , tosylate , or methy l ethe r PhCH=CHC(=NOH)P h l-C H C(=NOH)M e 2-C H C(=NOH)M e PhCHMeC(=NOH)M e PhCHEtC(=NOH)M e Ph CHC(==NOH)M e 9-Phenanthryl-C(=NOH)M e l-C H CH C(=NOH)M e 1-Tetralon e oxime 2-Tetralon e oxime 2-C H NCH C(=NOH)P h 2-(HON=)- l ,2,3,4-H -l ,4methanonaphthalen e 2-(HON=)-1,2,3,4-H -l ,4ethanonaphthalen e 2
2
6
4
2
2
2
2
10
7
10
7
6
3
6
4
2
2
2
10
5
7
2
4
2
4
4
1,4-Ethano-2-cyclohexanon e oxime 1-Me-l ,4-isopropylidene-2 cyclohexanon e oxime 2-syn, 3 - ^ - ( M e 0 C ) - 9 (HON=)-l,2,3,4-H -l,4ethanonaphthalen e 11-(HON=)-9,10-H -9,10ethanoanthracen e 6-(HON=)-dibenz o [tf ,c]cycloheptadien e 10-5^-(MeONHCO)-7-(HON=) 5,6,7,8-H -6,9-methano-9# benzocyclohepten e 2
2
4
2
4
1 -(HON=)-dibenz o [c,e]cyclooctan e a
Phenyllithiu m was used .
2,3-Ph 2,3-Ph 2,3-(/>-ClC H ) 3,Me-2-[2,4-(0 N) C H ] 2-PhCH -3-Ph
% Yield
2
2
6
4
2
2
2
6
3
2
2-PhCH -3-Ph 2-(l-C H ) 2-(2-C H ) 2-[Ph(Me)CH ] 2-[Ph(Et)CH ] 2-Ph C H 2-(9-Phenanthryl ) 3-Me-2-(l-C H ) 1,2-Epiminotetrali n 1,2-Epiminotetrali n 3-Ph-2-(2-C H N) 2,3-Epimino-l,2,3,4-H -l,3methanonaphthalen e 2,3-Epimino- l ,2,3,4-H -l ,4ethanonaphthalen e 2
10
7
10
7
2
10
5
7
4
4
25-33
— — 36-94
— 64 16 47 43 41
— 32 100? 41
— —
Reference s 1630 2103, 3245 1630 777 2103, 3245 2103, 3245 3245 3245 3245 3245 3245 3245 3245 3245 3245 3245 3245
50 (cis + trans)
2103, 3245
2,3-Epimino- l ,4-ethanocyclo — hexan e 2,3-Epimino- l -methyl-1,4 — isopropylidenecyclohexan e 2-syn, 3-5^-(HOCH ) -9,1014 tf/!//-epimino-1,2,3,4-H -l ,4ethanonaphthalen e ll,12-Epimino-9,10-H -9,1032-46 ethanoanthracen e 5,6-Epimino-dibenzo[a,c] 70-96 cycloheptadien e 10-syn-(HOCU )-7,S-syn- an d 58 tf«//-epimino-5,6,7,8-H 6,9-methano-9#-benzo cyclohepten e 1,2-Epiminodibenzo[c,e] 70 cyclooctan e
2103, 3245
4
2
2
3245 3245
4
2
2
2103, 3245 3245, 4097 3245
4
2103
68
1. FORMATIO N OF THE AZIRIDIN E RING
3-trifluoromethyl- to the 2-trifluoromethylazirine by way of the unstable aziridine 52 (252, 727, 722).
Í
Addition s to Olefini c Bond s The direct "epimination" of carbon-carbon double bonds is by no means so easy and useful as epoxidation of such structures, but it is of theoretical interest and perhaps occasionally of preparative value. Recent reviews (2373, 2634a, 3367a, 4103) deal in part with many such reactions. With only two exceptions (2365, 2460), the nitrogen which thus becomes part of an aziridine ring is the substituted one in an azide, - N = N = N ~ . The formation of the aziridine may be by way of a J M ^ - t r i a z o l i n e adduct (53) which is pyrolyzed or photolyzed; +
the pyrolysis may proceed via a dipolar-ion intermediate +
I
I
N=N-C-C-NR I
I
(2340, 2747, 2748), or a nitrene (6, 1761), which adds to the double bond (Eq 48).
Í I
R
ADDITION S TO OLEFINI C BONDS
69
Besides these paths, there is possible a concerted mechanism, in which the aziridine is formed as the nitrogen escapes from a complex ( 5 4 ) . Í
V\ ' / C
ú
V
ill
r<
+ é — • li
N*
+
.-x? -
—
N-
> N
/ \
/\
R
R
54
Both the direct and the sensitized photolysis of triazolines show high efficiency, insensitivity to nature of the solvent, and much retention of configuration. These results suggest participation of an excited singlet state and a short-lived 1,3-diradical in the reaction (3132). It is known that the formation of an isolable triazoline is favored by mild conditions, by absence of strongly electronegative groups in the azide, and by strain or other activation of the double bond. Indeed phenyl azide has often been used to establish the reactivity of olefins by their tendency to form adducts of triazoline structure. Olefinic azides can undergo the process intramolecularly (Eq 49) (2340, 4209). CH=CH CH
2
CH
2
2
(49)
\
,
CMe N 2
3
Me
,
Me
However, the pyrolysis of the phenyltriazolines usually gives some anil along with the aziridine, and sometimes only anil (Eq 50) (3133). Photolysis
Ph
instead of pyrolysis gives clean conversions of the triazolines to aziridines (3133, 3135). The preparation of aziridines by decomposition of 1,2,3triazolines is summarized here, Table 1-XIII presenting preparations from isolated triazolines, and Table 1-XIV those without isolation of the intermediate. That cyanogen azide reacts by the triazoline path rather than the nitrene path at 0°C has been proved by use of the N-labeled form, N * = N = N * — C N , in which the nitrene becomes symmetrical, · Í * = 0 = Í · , and must therefore give some unlabeled nitrogen in the aziridine ring; none is found (95). On the other hand, reactions of this azide with olefins above about 40°C go by way of cyanonitrene; thus cyclooctatetraene and cyanogen azide 15
70
1. FORMATIO N OF THE AZIRIDIN E RING
Tabl e 1-XHI PREPARATIO N OF AZIRIDINE S BY DECOMPOSITIO N OF ISOLATE D TRIAZOLINE S
Aziridin e made , or substituent s therei n
% Yield
Reference s
—
1659 2014 4163 4163 587 587 1795, 3451
By Pyrolysis l-(m-ClC H ) 1,2-Ph l-(/?-BrC H )-2,2,3-Me l-(/>-BrC H )-2-Bu l-PhCH -2,2,3-F -2-F C l-PhCH -2,3-F -2,3-(F C) 2-MeO C-l -0?-RC H ) (R = H, Me, MeO , CI, Bz, 0 N ) l-PhCH -2,3-(Me0 C) 2,3-(Me0 C) -l-(/?-MeOC H ) H/?-BrC H )-2-MeC(=CH ) 2-H NCO-l-P h 2-NC-l-P h 6
4
2
6
4
6
4
69 64 74 80 —
3
2
3
2
3
2
3
2
6
2
4
2
2
2
2
2
6
— 81 — — —
2
6
4
4
2
2
1-OBrC H )-2-(2-pyridyl ) 1,2-[(CH ) ] l,2-(CHMeCH CH ) l,2-(CMe CH CH ) l,2-(CHMeCH CHMe ) l-(/>-BrC H )-2,3-[(CH ) ] l-(p-BrC H )-2,3-(CH OCH ) l-(/>-BrC H )-2,3-(CH NHCH ) M/?-BrC H )-2,3-(CH==CHCH CH ) l-(/?-BrC H )-2,3-[(CH ) ] l-(j>-BrC H )-2,3-[(CH ) ] l-(/7-BrC H )-2,2-[(CH ) ] 1 -PhS0 -2,3-(OCH CH CH ) 6
4
2
3
2
2
2
2
2
2
6
4
6
2
4
6
3
2
4
2
2
2
6
4
6
4
2
2
6
4
2
6
4
6
2
2
2
5
s
2
2
2
1,2-Epiminoindan e 2,3-Epiminonorbornane, ' substituent s in: ËÃ-Ph N-Bz 7V-C0 Me iV-C0 Et J -W-C0 E t 5,6-Benzo-JV-C0 Et W-OBrC H ) W-P(0)R (R = Ph or OEt ) 5,6-[(CH ) ]-N-Ph (cis an d trans) 5,6-(Me0 C) -AT-P h (cis an d trans) 5-NC-W-P h 5,6-(NC) -7V-Ph l,5,6-(Me0 C) -W-P h 7-Oxa-5,6-(Me0 C) -W-P h
— — 100 100 — 21 47 61 — 54 64 — 0 0
1795, 3451 1795, 3451 3137a 3137a 1795, 3451, 4163 3137a 2340 2340 2340 2340 4163 4163 4163 4163 4163 4163 4163 2998; cf. 1323, 3135 1978
i
2
2
5
2
2
6
4
2
2
3
2
2
2
2
3
2
2
c — 40 87 60 97 53 — —
— 78 75.5
— 71
38, 1797, 1798 1794 1795, 2747 3243, 3491 3243, 3491 3243, 3491 3133 341, 2496a 38 38 3134 3134 39 3872
71
ADDITION S TO OLEFINI C BONDS
Tabl e 1-×ÉЗcontinue d Aziridin e made , or substituent s therei n
% Yield
Reference s
By Pyrolysis 7-Oxa-5,6-(Me0 C) -W-CH P h 5,6-[C(0)OC(0)]-AT-P h (cis) 7-Oxa-5,6-[C(0)OC(0)]-W-P h 2,3-[Epiminobicyclo(2.2.2)octane] , endo an d exo A/-(/7-MeC H S0 )-epiminoisodrin N-(tert Bu0 C)-epiminoisodrin 2
2
2
d
6
4
2
3872a 38 3872 3578 3370, 4175 3370, 4175
0
38 93 48
2
Í—A r
R— Í
40
1573b
— —
861 861 162,2647,2754 162, 2647 2647 162 162 162 162 162 162 2647 2647 2647 2647 2647 2647 2647 2647 2647 2647
as follows:
Ar Ç Ç Ph /7-ClC H />-0 NC H /?-MeC H /?-MeOC H Ph P-C1C H /?-MeC H /?-MeOQH Ph /?-ClC H /7-0 NC H Ph /7-ClC H /7-0 NC H Ph />-ClC H p-0 NC H Ph 6
6
4
6
4
6
6
6
4
4
4
6
6
2
2
4
6
4
4
6
4
2,2-(F C) 2,2,3-Me 2,3-Et (trans) 2-Bu 3
2
3
2
6
4
6
2
4
6
2
4
4
6
2
2
4
2
Ph />-0 NC H Ph Ph Ph Ph Ph /7-0 NC H p-0 NC H /7-0 NC H /7-0 NC H /?-MeC H /?-MeC H p-MeC H /?-MeOC H /?-MeOC H /?-MeOC H /?-EtOC H /?-EtOC H /?-EtOC H 2,4-Me C H By Photolysis 4
6
4
2
6
4
2
6
4
6
4
6
4
6
4
6
4
6
4
6
4
6
4
6
4
6
2
4
6
3
91 77-94 58 80 83 73 90 90 91 86 84 81 71 65 58 61 64 65 92 84 83 84 88
.
2121 4163 4163 4163
72
1. FORMATIO N OF THE AZIRIDIN E RING Tabl e 1-×ÐÉ— continued Aziridin e made , or substituent s therei n
% Yield
Reference s
By Photolysis l-(/?-BrC H )-2-CH ==CM e 2,3-Ph 3-Me-l,2-Ph (cis an d trans) 2-H NCO-l-P h 2-NC-l-P h l-(p-BrC H )-2,3-[(CH ) ] l-(/7-BrC H )-2,3-(CH OCH ) l-(/)-BrC H )-2,3-(CH=CHCH CH ) l-(/7-BrC H )-2,3-(OCH CH CH ) l-(^-BrC H )-2,3-[(CH ) ] l-(i>-BrC H )-2,3-[(CH ) ] l-Bu-2,3-(CONPhCO ) 2-(Me C=)-3,3-Me -l-picry l A steroida l aziridiniu m salt 2,3-Epiminonorbornane, substituent s in : W-Ph AT-C H Me-m W-C H Me-/? 6
4
2
2
2
2
6
4
2
6
4
6
4
6
4
6
2
2
2
4
6
3
2
4
2
2
5
2
6
2
2
2
2
e
100
— Variou s
— — 86-94 96
— 67 89 88
— 0
—
3137 3133 3132, 3136 4163 3133 3133, 4163 4163 4163 3135 4163 4163 3133 4013 3644
b
6
4
6
4
N-C U C\-m N-C H C\-p 6
4
6
4
JV-C H Br- m N-C U Bt-p iV-C H OMe- m 6
6
4
4
6
4
N-C U OMQ-P 6
4
JV-C H N0 -m AT-C H N0 -/? AT-CH Ph W-CPh=CH iV-P(0)(OEt) AT-C0 Et JV-SiMe JV-Ph-2,3-[C(0)OC(0) ] 2,3; 5,6-(A^-Et0 C-epimino) -norbornan e 6
4
6
4
2
2
2
2
2
2
3
2
a
c
d
e
2
94 90 92 90 92 90 100 90 90 0 18 53
— > 90 95
— — —
In spit e of th e suggestion s of earlie r worker s (38, 3822).
6 2 Sometime s not isolate d bu t hydrolyze d to th e anilin o alcohol . Isodri n = th e adduc t of hexachlorocyclopentadien e an d norbornadiene . Not isolate d bu t postulate d as an intermediate .
1798 4163 1798, 4163 3137a, 4163 1798 3137a, 4163 3133 4163 4163 4163 4163 558a, 3866 4163 2496a 3133, 4163 4163 3133 4163
73
ADDITION S TO OLEFINI C BONDS Tabl e 1-XIV PREPARATIO N OF AZIRIDINE S FRO M OLEFINI C COMPOUND S AND AZIDE S VIA UNISOLATE D TRIAZOLINE S
Azide, R N R =
Olefini c compoun d
% Yield of aziridin e
3
Reference s
Cyclohexen e Cycloalkene s (C , C ) Cyclohexen e 1-Octen e Cycloocten e (cis) Cycloocten e (trans) Inden e 2-Norbornen e
Ç Ph Ph Ph Ph Ph Ph Ph
1.5 Low or zer o 79 63 0 85 0 64
2,5-Norbornadien e Methy l methacrylat e Methy l crotonat e CH =CHSiMe(OSiMe ) Vinylheptamethylcyclotetrasiloxan e Allylheptamethylcyclotetrasiloxan e 5-Norbornene-2,3-dicarboxyli c anhydrid e (exo or endo) 7-tert-Butoxy-2,5-norbornadiene 7-PhNH-2,3-(CH=CHCH )-5norbornane CH =CHSiMe(OSiMe ) /7-Benzoquinon e 5-Norbornene-2,3-dicarboxyli c anhydrid e /7-Benzoquinon e an d its 2-methy l derivativ e Inden e Cyclopenten e Cyclohexen e Cyclohepten e Cycloocten e 1 -Methylcyclopenten e Inden e 2-Norbornen e a-Pinen e Dicyclopentadien e 3a,4,7,7a-Tetrahydro 4,7-methanoinden e endo-cis-Bicyc\o [2.2.1 ]hept-5-ene-2,3 dicarboxyli c anhydrid e  enzo-2,5-norbornadien e Dimethy l 5-norbornene-2,3 dicarboxylat e
Ph Ph Ph Ph Ph Ph
— 10.6 10 0
2926 717, 1685 717, 1685 717, 1685 1685 1685 1685 1322, 1324. 3867 2749 1796 3451 101 101 101
Ph Ph
— —
1325, 3868 2114
Ph PhCH Ar , variou s
— — —
1375a 100 648
p-MeC H
64.6
1322
— —
— —
584 3728 245 245 245 245 245 245 245 245 245
—
245
—
245 2443b
5
2
7
3
2
70
—
2
c
2
3
2
2
6
4
/>-0 NC H /?-MeOC H 2,4,6-(0 N)^C 2,4,6-(0 N) C 2,4,6-(0 N) C 2,4,6-(0 N) C 2,4,6-(0 N) C 2,4,6-(0 N) C 2,4,6-(0 N) C 2,4,6-(0 N) C 2,4,6-(0 N) C 2
6
4
6
4
2
2
3
H H H H H H H H H
6
2
6
2
2
3
6
2
3
6
2
3
6
2
3
6
2
3
6
2
3
6
2
3
6
2
2
2
2
2
2
2
2,4,6-(0 N) C H
3
2,4,6-(0 N) C H 2,4,6-(0 N) C H
2
3
6
2
3
6
3
2
3
6
3
4,6-Me -2-C H N 2
5
2
70 20 58 68 70 60 90
70 (exo)
—
1794
74
1. FORMATIO N OF THE AZIRIDIN E RING
Tabl e 1-XIV —continued Azide, R N R =
Olefini c compoun d
3
% Yield aziridin e
Reference s 998 998 998, 2442
Ethylen e Propylen e Isobutylen e 1-Butene , 2-butene , 2-methylbutene , 1-hexen e 3,3-Dimethyl-l-buten e Methylenecyclohexan e Cyclooctatetraen e 2-Norbornen e
NC NC NC
15 19-57 33
NC NC NC NC NC
0 20 18 48 80
2,5-Norbornadien e 3-Methyl-y4-nor-3-cholesten e 3j8-Chloro-5-cholesten e Norcholestery l acetat e Cholestery l acetat e Cholestero l Variou s steroi d alcohol s Diethy l fumarat e Diethy l maleat e Cyclohexen e
NC NC NC NC NC NC NC H NC O H NC O Et0 C
Cycloocten e Anthracen e 2-Norbornen e J -Dihydropyra n Cyclohexen e 2-Norbornen e 2-Norbornen e Diethy l fumarat e 2-Norbornen e 2-Norbornen e Cyclohexen e 2-Norbornen e Dicyclopentadien e
Et0 C Et0 C Et0 C Et0 C tert-B\\0 C Bz /?-0 NC H C O /?-0 NC H C O MeS0 Et NS0 PhS0 PhS0 PhS0
2,5-Norbornadien e 7-Oxa-5-norbornene-2,3-dicarboxyli c anhydrid e
PhS0
2
PhS0
2
c/s-e/2i/o-5-Norbornene-2,3 dicarboxyli c anhydrid e
PhS0
2
2
c/s-e*0-5-Norbornene-2,3 dicarboxyli c anhydrid e
á
41 — 37 35 — 24-40 10-15 —
2
2
2
2
— a
2
2
2
2
2
6
4
2
6
4
2
2
2
2
2
2
PhSQ
45 63-79 100 0 — — 15-17 — — a
2
998 998 998 96 93, 95, 397, 997, 998 92 4168 998 4169 998 998, 2442 440 821 821 2060, 2365, 2366, 2371 4064 305 344 506 3554 558a, 1798 1325, 1798 3798 1325 1325 2214 1325, 2748 1325, 2748, 3866 2749 1325
60 endo, 19 exo
2750
74 endo, 22 exo
2750
75
ADDITION S TO OLEFINI C BONDS
Tabl e 1-XIV—continue d Azide, R N R=
Olefini c compoun d Me 5,6-benzonorborn-2-ene-l carboxylat e Dicyclopentadien e 2-Norbornen e Diethy l 2,3-diazabicyclo[2.2.1] 5-heptene-2,3-dicarboxylat e Benzo-2,5-norbornadien e 2-Norbornen e 2-Norbornen e 2-Norbornen e 2-Norbornen e 2,5-Norbornadien e 2-Norbornen e Isodrin * Dicyclopentadien e Cyclohexen e Trimethylvinylsilan e a
b
c
PhS0 /?-MeC H S0 />-MeC H S0
% Yield of aziridin e
3
83
2
6
4
2
6
4
2
6
4
2
6
4
2
4
100
2
6
4
6
4
3
74 45 (exo) 83 79 75
2
6
2
4
2
2
6
4
6
4
2
39 48 Smal l 13 20
2
6
4
6
4
1798 2443b 558a 558a 558a 1325 1325 3255 3370 398 4049 4049
— —
2
2
4205 1325 1325, 1798
—
/?-MeC H S0 /?-MeC H S0 /?-BrC H S0 /?-MeOC H S0 />-0 NC H S0 0(C H S0 -/7) /7-N 0 SC H C H S0 PhN(CHO)S0 /?-MeC H S0 />-MeC H N=PPh Me Si Me Si 6
Reference s
2
2
3
3
Immediatel y rearrange s with rin g expansio n or destruction . Adduc t of hexachlorocyclopentadien e an d 2,5-norbornadiene . Reactin g at th e olefinic bon d on th e 5-ring .
in boiling ethyl acetate yield 56 (p. 76) a m o n g other products, although the aziridine does not then survive long (4003). It seems likely that photolysis of an azide-olefin mixture always bypasses triazoline formation, and indeed this has been proved in some cases. T h u s either ethyl azidoformate or JV-(/?-nitrobenzenesulfonyloxy)urethan, the latter incapable of reacting via a triazoline, photolyzed in liquid cyclohexene yields the cyclohexenimine derivative ethyl 7-azabicyclo[4.1.0]heptane-7-carboxylate (55) via a nitrene (Eq 51) (2365, 2366, 2371). N3C0 E t 2
—í
cyclohexene
ZZ N C 0 E t 2
•
N—CO,E t
/>-0 NC H S0 ONHC0 E t 2
6
4
2
2
55 (51) T h e vapor-phase reaction gives the same product (344, 762), and so does the base-induced decomposition of the urethan (2367\ cf. 2493, 3088b).
76
1. FORMATIO N OF THE AZIRIDIN E RING
Photolysis of methyl azidoformate in cis- or trans-l-buttns followed by saponification of the products yields mainly cis- and ira«5 -2,3-dimethylaziridine, respectively, showing that the nitrene adds stereospecifically cis (1576). Similar selectivity has been observed for the addition of ethoxycarbonylnitrene to pure 4-methyl-2-pentenes and to isoprene, but the selectivity decreases with dilution of the olefins, and with temperature. This probably means that the nitrene as generated reacts in the singlet state, but has time to change to the triplet when dilution has slowed the reaction (94, 305, 2369, 2370,2493,4010,4128). Ethoxycarbonylnitrene from photolysis of ethyl azidoformate is exceptional in giving about 30 % nonstereospecific addition even (by extrapolation) at infinite olefin concentration; this and other evidence indicate that about one-third of such nitrene production yields the triplet form directly (2494). The multiplicity of cyanonitrene, N C N , is dependent on concentration in the same way, and on the nature of the solvent. Singlet N C N , favored in acetonitrile or cyclohexane and in concentrated solution, yields more 1,2-adduct 56 with cyclooctatetraene; triplet N C N , formed in dilute solutions in ethyl acetate or methylene bromide, undergoes 1,4-addition to the polyene (4003). The high (>95 %) stereospecificity of the addition of the complex nitrene 57 to olefins indicates that it reacts exclusively in the singlet state (4006). ,
Í
56
57
Except for cyanonitrene, addition of substituted nitrenes to conjugated dienes has proved to be exclusively 1,2- (1576, 4006, 4128); sometimes the aziridines produced are partly rearranged (4128). Photolysis of acyl azides in the presence of olefinic compounds has produced 2-acetyl-l-ethoxycarbonyl2-methylaziridine and a cyclic analog 58 (2060), iV-(trimethylacetyl)cyclohexenimine (2368), and other complex aziridines 59 (506) and 60 (3866).
Carbethoxynitrene from iV-(/?-nitrobenzenesulfonyloxy)urethan added to cyclopentadiene and 1,3-cyclohexadiene to give the expected aziridines and their rearrangement products (4128).
ADDITION S TO OLEFINI C BONDS
77
The products ot photolyzing 2,3-diphenyl-2-cyclopropenylcarbonyl azide (61) (or the isocyanate formed from it by pyrolysis) are consistent with the suggestion that the reaction proceeds by an intramolecular addition to yield 62 as an intermediate (603). Pyrolysis of the vinylic azides P h C ( N ) = C H 3
2
(3308), P h C ( N ) = C H P h (1310), and F C ( N ) = C F C F (262), the latter two at room temperature, yields azirines; photolysis is also effective (1626). However, the photolysis, at least for P h C ( N ) = C H , also gives some dimer 63 that has an aziridine structure (4207). 3
3
3
3
Ph
2
NP h
N63
Also a bit difficult to classify is the photolytic rearrangement of 64 to 56, presumably by a Q - C 5 bridge migration (97).
hv
56
N—C N
1
2
64
Photoisomerization of 37/-pyrazoles 64A at low temperatures yields the tricyclic aziridines 64B, but these upon warming revert very readily to the 3/i-pyrazoles (724a). MeyM e (CH ) 2
64A
n
64B
1. FORMATIO N OF THE AZIRIDIN E RING
78
It has even been possible to trap imidogen, N H , generated by photolysis of hydrazoic acid at 4°K in an argon matrix, by reaction with ethylene to give recognizable EI (1956). However, there was no sign, even for microseconds, of aziridines produced from imidogen and olefin vapors (761). Thus the suggestion that 65 may be an intermediate in the reaction of active nitrogen with propylene is admittedly only speculation (3609). The oxidation of ä,â -unsaturated primary amines 66 to highly strained bridged aziridines 67 is a recent novelty; the oxidation may be effected with iV-chlorosuccinimide, lead tetraacetate, or mercuric oxide (2655). The preliminary report available does not establish whether the reaction proceeds by a nitrene or a radical mechanism.
Me'
H N 2
Í
66
65
This section will be closed by citation of those references that have postulated nitrene addition to aromatic nuclei to produce intermediates such as 68 (Eqs 52 and 53). In the beginning the suggestion of such structures was purely speculative, to help account for formation of nitrogenous bases from arenes and sulfuryl azide or carbonyl azide (346, 822, 823, 3156). More recent proposals are based on the known tendency of analogous norcaradienes to undergo ring expansion. It is probably only the singlet ethoxycarbonylnitrene that gives this reaction (2372).
PhN
—N 3
2
Ph N
PhNH ^ 2
NHP h
NHP h
NH
(52) (1793)
N—R
R N or RNHOS0 Ar + 3
2
68
R = Me, C 0 E t , or C N 2
(767, 1574,2367, 2394, 2441)
Aromatic substitution by nitrenes is also still regarded as involving the bicyclic aziridines 68 as intermediates (257,305, 1575, 2367, 3285, 3551).
79
ADDITION S TO CARBON-NITROGE N DOUBLE BONDS
The reactions of 2-phenylazirine with anilines have been interpreted as proceeding by way of the adduct 69, although formation of the observed product benzanilide thence (after hydrolysis), like the ring expansion noted above, requires an unusual but not unprecedented rupture of the carbon-carbon bond in the aziridine ring (3307). NHA r
Í Ç 69
Addition s t o Carbon-Nitroge n Doubl e Bond s This small group of additions, usually to acyclic imines (Schiff bases), is of theoretical rather than preparative interest. Analogy with addition to c a r b o n carbon double bonds suggests that an alkylidenimine might yield an aziridine either by way of a triazoline (Eq 54)
+
N
* N
—• 1
1 Í
+
—Í
t
V
Í
(54)
+Nz
Í
1
1
or by direct bridging of the Schiff base by a carbene (Eq 55). \ / C
X:+
||
•
\ /
Í
(55)
Í
The second step of Eq 54 is not observable for triazolines made from diazomethane and ordinary Schiif bases (2014), but Eq 54 is followed by diazomethane and (methoxyimino)bis(methylsulfonyl)methane (69) (Eq 56) (165). MeS0
2
S0 M e
/ ^ N - O M e CH N + (MeS0 ) G=NOM e 2
2
2
2
>
I
N = N
S0 M e
2
I
2
_
N
^>
\
/
S
° 2
M
E
Í
é OM e
(56)
80
1. FORMATIO N OF THE AZIRIDIN E RING
The initial ^ C = N — compound without the 0-methyl group also yields an aziridine, probably by way of a less stable triazoline (165). There is no evidence of triazoline intermediates in the preparation of aziridines from diazomethane and polyfluorinated Schiff bases (2339, 3775) or 7V-arenesulfonyl imines, C l C C H = N S 0 A r (2439a) or from various diazoalkanes and ternary iminium perchlorates (70) or fluoroborates in the cold (Eq 57) (2062, 2292, 2300, 2301, 4165). 3
2
70
71
The cyclopentylidene iminium salt homologous with 70 gives not only 72 in this reaction but also 7 1 ; by homocyclic ring enlargement and then formation of the aziridinium ion (2062).
72 Tabl e 1-XV PREPARATIO N OF AZIRIDINE S FRO M DICHLOROCARBEN E
Sourc e of carbene "
PhC R = N R
Ç Ç Ç Ç Ç Ph Ph Ph Ph Ph
A
 C D D D D D D D A = CHC1 + NaOMe ; KO-tert-Bu . a
3
/
R =
% Yield of aziridin e
Ph Ph Ph i7-ClC H /?-MeOC H Ph /?-MeC H />-ClC H m-MeC H m-ClC H
55 61 — 68 91 63 66 77 — —
R =
6
4
6
6
6
4
4
6
6
4
4
4
Reference s 1288, 3104 2013 1655 753, 3104 753, 3104 902, 4079 4079 4079 4079 4079
 = (Cl C) C O + NaOMe ; C = unspecified ; D = CHCI 3 + 3
2
ADDITION S TO CARBON-NITROGE N DOUBLE BONDS
Formation of the aziridine ring in such reactions occurs essentially with retention of configuration at the nitrogen atom (3865a). Clear-cut examples of the addition of dichlorocarbene to Schiff bases, mostly benzalanilines, are available (Table 1-XV). The fact that P h C ( C C l ) N H P h yields an aziridine with potassium ter/-butoxide alone but not with the strong base in the presence of 2,3-dimethyl-2-butene indicates that the starting material does not react by way of P h C ( C C l ) N P h ~ and internal displacement, but by dissociation and dichlorocarbene formation (902). At low temperatures chlorocarbene (from L i C H C l ) is stereospecifically trapped by benzalaniline to give c/5 -l,2-diphenyl-3-chloroaziridine in high yield (902, 903); cw-3-chloro-3-methyl-l,2-diphenylaziridine is formed similarly (903). The reaction of dichlorocarbene from sodium trichloroacetate with 70 p r o b ably yields an aziridine, but the ring does not survive nucleophilic attack by the trichloroacetate anion (Eq 58) (753). 2
2
3
3
2
,
7 0 + :CC1
CI
ci cco -H o 3
2
2
2
I^0 CCC 1
v
2
3
> o=c
(58)
LJ Similar difficulty is encountered with dichlorocarbene generated with ethylene oxide as acid acceptor; the intermediate dichloroaziridine 73 from benzophenone anil ends u p as l-(2-chloroethyl)-3,3-diphenyloxindole (74) (2106).
I CH CH C1
Ph
2
73
2
74
Difluorocarbene is considered to be the intermediate whereby pyrolysis of difluorodiazirine yields complex aziridines (Eq 59) (2579). Í
F CN 2
F C ./ 2
||
heat , — N ^ 2
[F C: ] 2
2
F C=N—N=CF 2
2
(59)
Í F
F
F:CF F C=N—N=CF 2
2
2
> - N = C F
2
i^L >
N—N: F-
82
1. FORMATIO N OF THE AZIRIDIN E RING
By similar dissociation and recombination, fluorodifluoraminocarbene and thence 75.
fluorodifluoroaminoazirine
-NF
2
-NF
2
gives
F NCF=N—Í ' 2
75
A reaction in atisine chemistry is supposed to yield an aziridine ring in an unprecedented way, presumably because of the unusual rigidity of the molecule. Heating polycyclic Schiff bases with acetic anhydride is believed to produce complex iV-acetylaziridines (Eq 60) (1024, 2839).
Ac-.-N
\
Ac^ Ç
Ac
X
/°·.
C
.- \
->
Ac—Ê .
I
+ AcOH
(60) In a very different addition to Schiff bases, carbon vapor at — 196°C yields new aziridines (76) of remarkable structure (Eq 61) (878b). RCH=NR ' + C
(61)
3
R'— Í 76
A related reaction is that of benzophenone azine with diphenylmethyl radicals from pyrolysis of P h C H N = N C H P h to give 2,2,3,3-tetraphenylaziridine (Eq 62) (3737); the addition could be extended to only two analogous compounds (3739). 2
2
Ph 2Ph CH - + P h C = N — N = C P h 2
2
Ph
2 Ph '
2
Ph
(62)
Í Ç 50% yield
An isocyanide is capable of adding a complexed carbene 77 to give the complexed aziridine (4008). OM e (CO) Cr-- ^ ~k \ / OM e 5
(MeOCH)(CO) Cr + c - C H N C 77 5
6
n
>
ø c-C«H
tl
(63)
INTRAMOLECULA R INSERTIO N REACTIO N
83 5
Recently reported are additions of nitronic esters (78, R = OMe) and nitrones (78, R = alkyl or aryl) to acetylenes to yield aziridines; isoxazolines 79 were first postulated (3501) and then demonstrated (257a) to be intermediates (Eq 64). 5
R R
RifeCR
2
T/ / C = XN .
+ _
2
\
··
X â
R 1
A
78 1
3
R
2
R
>
N C K
X
RiC' \
R
4
2
4
/ R
ï
I
Rs
79
3
3
L- R 4
5
R , R , an d R = alky l groups , R = H, R = OM e
(3501)
(64)
1
R i = R 2 = C 0 M e , R3 = R4 = H , R5 = mesityl ; or R = CMe OH , 2
R2
=
R
3= 4 R
2
H , R5 = ^r/-B u (257a)
=
Intramolecula r Insertio n Reaction s This class of aziridine ring formation is very little known. It was surmised (2283) and later confirmed (1438, 2926) that the vapor-phase pyrolysis of ethyl azide yields some E I ; isobutyl and tert-buty\ azides likewise give 2,2-dimethylaziridine, but in even lower yield (2926). Photolysis of liquid ter/-butyl azide is similar (Eq 65) (282). Me Me CN 3
M , 3
'~
N 2
>
[Me CN ] 3
>
M t \ / Í Ç
(12% yield)
(65)
It has been suggested that the decomposition of 4-azido-2-butanone in acid solution goes by way of an aziridinium salt (Eq 66) (931). H+,—N
AcCH CH N 2
2
3
2
•
Ac
AcCMe=NH
H o, 2
2
A c + NH + 2
4
+
N / \ Ç Ç
(66)
Degradativ e Route s Some reactions that might be reviewed here have already been discussed, e.g., the decomposition of 1,2,3-triazolines. The principal pyrolysis yet needing attention is that of 2-oxazolidinones (Eq 67) (3387).
1. FORMATIO N OF THE AZIRIDIN E RING
84
I
I
ç*
AzH + CQ
(67)
2
Ô Ï
Ordinarily this is a source of polyethylenimine (PEI) instead of the monomer shown, because the carbon dioxide concurrently produced catalyzes the polymerization (808, 2002, 3336, 3561). In the absence of additives, the polymer chain has 2-imidazolidinone end groups, and indeed a little l-[2-(l-aziridinyl)ethyl]-2-imidazolidinone (80) can be isolated from the product mixture (2744). HN
—CH CH —Az
S
2
2
Ô Ï 80
The process is catalyzed by both the EI and PEI produced (autocatalysis) and by added amines (2745) as well as by imidazolidinones (3734). The claim (3387) that monomeric EI can be obtained if a stronger base, such as triethanolamine, is present to remove the carbon dioxide seems reasonable. The pyrolysis of 3-amino-2-oxazolidinone in the same way gives polymeric poly(l-aminoaziridine), useful in rocket fuels (Eq 68) (1085, 1711).
HNJTT>
(68)
(-CH.CH.N-) .
2
I
NH
2
Ï
Three unrelated pyrolyses remain to be cited. The pyrolysis of some 2oxazolines (3753) did not yield the 1-acylaziridines sought, but these may possibly have been intermediates (Eq 69). Me
Me
Me i
é
RCONHCH CMe=CH
Me
2
2
(69)
Í I
RC= 0
Heating Ë^-vinylphthalamid e produces a little EI and phthalimide (Eq 70) (2051), most likely by way of the intermediate 81. Ï „CONH
'
2
^"^CONHCH=CH
2
-
y
N
H
NH
DEGRADATIV E ROUTE S
85
Diphenylketene and JV,a-diphenylnitrone yield a cyclic adduct which upon pyrolysis gives carbon dioxide and 1,2,2,3-tetraphenylaziridine (Eq 71) (3506), Ph
Ph
Ph-
—co
Ph C=C= 0 + PhCH=N(0)P h 2
Ph-
-N—Ph \ Ï
2
Ph
Ph Í I
Ph (71)
but the reaction could not be extended even to closely related ketenes and nitrones (Eq 71). Ethylenimine has been observed among the products of photolysis (2542) and pyrolysis (98) of methylamine, and is in fact initially the major product of decomposition of dimethylamine in a hydrogen atmosphere at low pressure and high temperature on an evaporated tungsten film (98). 1,2,2-Trifluoroaziridine is formed during fluorination of the acetonitrile-boron trifluoride adduct (1057). Intermediates with aziridine structure have been suggested to explain the course of alkaline cleavage of 2,2-dithiobis(ethylamine) (2134) and the hydrogenation of dimethyl l,2,7-trimethylazepine-3,6-dicarboxylate (82) (which gave dimethyl 2,3-dimethylterephthalate) (675).
2,2,5,5-Tetramethyl-3,6-dipropylpiperazine partly decomposes upon distillation at 252°-256°C and 1 atmosphere, yielding a lower-boiling product which was supposed to be 2,2-dimethyl-3-propylaziridine (3525); but so extraordinary a dissociation should be verified before it is believed. Long ago several authors (1319, 1320, 3200) surmised that the compounds obtained by the intramolecular dehydration of 2-(hydroxyamino)alkyl ketones in the presence of hot concentrated acids were aziridine derivatives (Eq 72). R' RCOCHR'CNHO H
-)(-•
RCA ü
Ë
(72)
Í Ç
In fact, the products were surely isoxazolines (83); the mode of preparation and reported properties are consistent with this interpretation.
1. FORMATIO N OF THE AZIRIDIN E RING
86
Similarly, a few workers have written the outdated aziridinone structures (84) for the products of reaction of acetic anhydride and an amino acid, etc. (1408, 1678, 2245, 3764). These compounds are in fact the well-known azlactones (oxazolinones) (85) (589). -
RCH
JO
RCH ^
^.O
é Ã H
83
I
CO R 84
R 85
Historica l Backgroun d The earliest assignment of an aziridine structure to a compound was by Sabaneyev (3084) in 1875. He believed that the crystalline compound obtained from 1,1,2,2-tetrabromoethane, aniline, and alcoholic alkali was 2,3-dianilino1-phenylaziridine (1). However, it was later shown to have the isomeric form P h N H C H C ( = N P h ) N H P h , an acetamidine derivative. In 1881 Lehrfeld (2287) warmed ethyl 2,3-dibromosuccinate with alcoholic ammonia and obtained what he considered was probably ethyl 3-carbamoylaziridine-2-carboxylate (2), and thence made other aziridine derivatives. His observations have been confirmed (1677), but it still remains uncertain whether he had aziridines or the isomeric enamines, e.g., 3. 2
^.NHP h PhNH^~~ / Í
^C0 E t 2
Ç ÍèË~~ /
Et0 C-C-NH
2
O N I
2
2
H NCO—C— Ç 2
I
Ph
Ç
1
2
3
Apparently without knowledge of the earlier work, Ladenburg (2253) conceived and pointed out the probable existence of ethylenimine (EI) and homologous imines. He predicted that they should be obtainable from diamines by loss of ammonia. With this idea he tried for several years to prepare EI (2252). In 1888 he and Abel (2251) reported pyrolysis of ethylenediamine dihydrochloride to give small yields of the hydrochloride of a base believed to be EI, although its vapor density indicated that it was the dimer, piperazine. Preparation and properties of authentic piperazine led Sieber (3260) and von Hofmann (1748) to think that this was different from Ladenburg and Abel's product; but Majert and Schmidt (2398) soon showed that this product was indeed piperazine, and von Hofmann (1749) agreed. 1
2
1. FORMATIO N OF TH E AZIRIDIN E RIN G
In the meantime Gabriel had prepared and characterized what he considered t o be vinylamine, by the rearrangement of 2-bromoethylamine t o "vinylamine" hydrobromide and liberation of the free base with silver oxide (1385) or potassium hydroxide (1391). This preparation was improved (1392) and applied to 2-bromopropylamine (1388, 1723) and 2-chloro-3-camphanamine (1006). However, the insolubility of the benzenesulfonyl derivative of "vinylamine" in aqueous alkali and the failure of the free base t o react rapidly with aqueous potassium permanganate led Marckwald (1771, 2429) to conclude that it was really E I . The further evidence for the E I structure adduced by Marckwald and Frobenius (2428) pretty well settled the question, although some uneasiness about whether 2-phenylaziridine was really 2-phenylvinylamine was expressed in 1934 (1340), and vinylamine structures were written for what were surely aziridines as recently as 1939 (381) and 1949 (2265). Intramolecula r Displacemen t by th e Amin o Grou p INTRODUCTIO N
The most general method of generating an aziridine ring is the unimolecular rearrangement of a vicinally substituted amine ( 4 ) to an iminium salt ( 5 ) . This intramolecular alkylation occurs more or less readily depending on the structure of the substituted amine and the nature of the solvent. The reaction has both theoretical and preparative importance; these will be discussed in that order. I I -c—c-
\ I
Í / \
L-
N+
/\ -
( L - leavin g group )
Kinetics of the cyclization were first studied by Freundlich and his students (1338-1344, 3092, 3093, 3095). The investigation of the mode of physiological action of nitrogen mustards during World W a r I I soon was concerned with the rate of formation a n d decomposition of quaternary aziridinium intermediates of type 5 (1473). Since then, interest in such ions has been maintained by their connection with 2-haloalkylamines as antitumor drugs and as sympatholytic agents (744,3647). The cyclization also represents an interesting example of those nucleophilic displacements on carbon that involve neighboring group participation (1720, 2364, 3395, 3397). The first postulation of a quaternary aziridinium salt was by Marckwald and Frobenius (2428) in 1901; the salt was considered t o be the spiro salt 6 , presumably formed from l-(2-chloroethyl)piperidine.
INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P
3
This structural assignment was rejected by K n o r r (2118, 2119) and definitely disproved recently (2294, 2295), the compound being the dimeric
Ï
- Ï
a-
CH CH C 1 2
2
piperazine. The next, and more acceptable, suggestions were that such quaternary salts constitute reactive intermediates, such as 7 and 8 , in many
Br -
CHPhCHBrA c
(786, 787,2620, 2621)
Ph ,
*Ac 7
Et NCH CH C l 2
2
2
>
\
/
CI"
(1479)
/ \ Et Et
of the reactions of (2-haloalkyl)dialkylamines. This theme was expanded rapidly when it was found that toxicity of the nitrogen mustards could be correlated with the extent to which they had so cyclized (490, 1355-1357, 1489-1492, 1556, 1557). It was also reassuring that the aziridinium ions, though unstable, could be isolated as the insoluble picrylsulfonates (1355, 1490-1492). Association of other physiological effects of nitrogen mustards with their aziridinium forms soon followed. The antitumor action of such alkylating agents has had major study (139, 744, 2870), and many cyclizations, including those of N,Ar -bis(2-chloroethyl)amino acids (1941, 2966), Ar,AT -bis(2-chloroethyl)amino sugars (3687), and i^,A -bis(2-chloroethyl)purines (2377, 3190), have been noted. 3-Carbamoyl-l-(2-chloroethyl)pyridinium chloride cannot thus cyclize, but its reduction with sodium hyposulfite yields a 1,4-dihydropyridine derivative (9) that can do so (Eq 1) (1349). Indeed many aziridines have antitumor action (see Chapter 6). However, there is n o clear correspondence of such action in nitrogen mustards to their rate or extent of cyclization. Such correlation has also been sought in the mutagenic effects of r
4
1. FORMATIO N OF TH E AZIRIDIN E RIN G
CONH
CONH
2
2
0) CH CH C 1 2
2
9
these mustards (2918, 3269-3271, 3347). The case for aziridinium ion intermediates as active agents in the sympatholytic action of the mustards is much better (744, 3647). The pressor action of adrenaline and noradrenaline is counteracted by "one-armed" nitrogen mustards such as dibenamine [ ( P h C h ) N C H C H C l ] and dibenzyline [ P h O C H C H M e N ( C H P h ) C H CH C1] and good, though inexact, correlation between their existence in aziridinium form and their blocking potency has repeatedly been demonstrated (64, 65, 317-319, 642-644, 1056, 1442, 1514, 1515, 1517, 1518, 1620, 1764,2073,2075,2695,2696,2698, 2918,3145). 2
2
2
2
2
2
2
2
RATE S OF REACTIO N
Analytical Methods. Since compounds containing aziridinium nitrogen atoms are as a rule difficult to isolate, much of the work just discussed has had to develop and rely on analytical methods for following the rate of the cyclization forming 5 . 1. Determination of L " formed. This is very simple and common, at least when L " is a halide and an argentometric method can be used. It is untrustworthy if any other L"-forming process is significant, e.g., displacement of L~ by a solvent molecule, usually water, or by a second molecule of substituted amine. If no substantial buildup of acidity accompanies formation of L~, direct hydrolysis (Eq 2) can be ruled o u t ; if the reaction is first order in amine, L I
I
(2)
—C—C — + H 0 2
Í / \
OH
Í / \
attack by a second molecule of amine is excluded. If hydrogen ions do form, a correction for the extent of direct hydrolysis can be made (7555,1620,3647). In the cyclization of JV-(2-bromoethyl)aniline a second-order reaction with base can compete significantly with intramolecular displacement of the halogen (1668). The reversal of the cyclization, to form the substituted amine, is likely to be kinetically significant as the concentration of L~ builds u p .
5
INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P
2. Determination of aziridinium ion with thiosulfate ion. The aziridinium ring is quantitatively opened by thiosulfate, and excess thiosulfate can readily be determined {1492, 1602, 1802). However, the ring opening is sometimes too slow to be satisfactory for rate studies (280, 3269, 3270). One technique is to have thiosulfate present continuously during the cyclization, to trap the aziridinium ions (1442, 2343, 2426). The method assumes that no direct displacement of L~ by thiosulfate occurs. Recent work (2109) shows that this is an unsafe assumption, especially for primary halides, but the validity of the method can be established by showing the rate of reaction independent of thiosulfate concentration. Complete reaction of thiosulfate with a nitrogen mustard uses u p one equivalent of thiosulfate per - C H C H C 1 group except for that part of the chloro amine that undergoes direct hydrolysis; the extent of the latter can thus be estimated. Because of the consecutive ring openings and recyclizations that can occur with bis- and tris(2-haloalkyl)amines, the thiosulfate method is less reliable in application to them except to measure total cyclization. 3. Determination of unreacted amine by titration with standard acid. This has been used but little (1639, 3540). 4. In a tertiary amine, the protonated form (e.g., L C H C H N H R ) cannot cyclize, but in solution the aminium ion is in equilibrium with the free base, which can undergo cyclization. Titration of hydrogen ions to keep the p H near the pK permits calculation or at least estimation of the a m o u n t of amine that has cyclized (281, 1607, 3670). 5. The direct polarographic reduction of aziridinium intermediates has been shown suitable for their determination (2427) and used in rate studies (3869). 6. Other instrumental methods can be specific for determination of aziridinium ions: ultraviolet spectrophotometry (3345,3670) and nuclear magnetic resonance spectrometry (2310, 3347). Observed Rates of Cyclization. The interest in studying correlation between sympatholytic effect and aziridinium ion content led to a series of measurements of the maximum concentrations of such ions attained in solutions of appropriate 2-haloalkylamines. While the data are the resultants of the rate of formation of the ring and the rates of destruction of the ring, and therefore essentially empirical, they are reproduced in Table 1-1. It will be noted that maximum concentration of aziridinium ions is usually found for bromides; the corresponding fluorides do not cyclize at measurable rates, the chlorides cyclize so slowly that the rings are exposed to various nucleophilic attacks, and the iodides necessarily give the very nucleophilic iodide ion which keeps the "steady state" concentration of aziridinium ions low. As a unimolecular reaction, the formation of aziridinium ions by ring closure follows a very simple rate law, and many such rate constants have 2
2
+
2
a
2
2
2
2
2
2
2
Me CH CH F CH CH C I Et Me Me Me c-QH „ CH P h CH P h CH P h CH P h CH P h CH P h
Me Me or Et Me Et Me Me Me c-C H CH P h CH P h CH P h CH P h CH P h CH P h
Ç Me Ç Ç Ph Ph Ph Ç Ç Ç Ç Ç Ç Ç
CI CI CI CI CI CI Br Br Br Br Br Br Br Br
2
CH CH Br
Ç
Ç
Br
n
CH CH Br
Ç
Ç
Br
6
CH CH C 1
Ç
Ç
Br
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
CH CH C 1
2
Ç
3
Ç
2
R
Br
2
CH CH C 1
R
Ç
1
Ç
R
Amin e
CI
X
1
2
2
2
2
2
2
2
2
2
s
3
0.2M phosphat e p H 7.3 0.2M phosphat e p H 7.3 0.2M phosphat e p H 6.0 0.2M phosphat e pH7. 3 0.2M phosphat e p H 6.0 D 0 , excess N a Aq. buffer lMNa CO D 0 , excess N a 0.16MNaHCO H 0 50% Me C O 70% EtO H 67% Me C O 67% Me C O 70% EtO H 70% EtO H 70% EtO H 70% EtO H
Solvent
2
2
C0
C0
3
3
buffer , 27 36.7 30 0 37 37 31 27 30 30 4 27 37 37
37
37
37
buffer , buffer ,
37
37
buffer ,
buffer ,
Temp . (°Q
— —
—
—
— —
—
—
5 — 20 35 0 0
20
3
30
15
90
Tim e (min )
3
22 Some 57 * 100 98 96 92 » 50 0 2 « 50 4-10 15 2-8
« 80
* 95
« 80
« 90
« 80
Ion forme d (% of theory)
MAXIMU M CONCENTRATION S OF AZIRIDINIU M ION S FRO M 2-HALOALKYLAMINES , X C H R C H N R R
Tabl e 1-1
0
3347 2691 3347 3347 1286 1286 645 1620 641 642 1620 642 1620 642
2988
2988
2988
2988
2988
Referen c
6 1. FORMATIO N OF THE AZIRIDIN E RING
Ç Br Ç Br Ç I Me CI CI, Br , I Ç Ç F Ç CI Ç CI Ç Br Ç I Ç F Ç CI Ç Br Ç I Ç F Ç CI Ç Br Ç I Ç F Ç CI Ç Br Ç I Ç CI Ç Br Ç I Ç CI Ç Br Ç I Ç CI Ç Br Ç I Ç CI
2
2
2
2
2
2
CH P h CH P h CH P h CH P h Ph Et Et Et Et Et Me Me Me Me Et Et Et Et Me Me Me Me Et Et Et Et Et Et Et Et Et CH CH C 1 6
6
2
2
2
6
6
6
2
2
6
2
2
6
6
2
2
6
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
4
4
4
4
4
4
4
4
4
CH P h CH P h CH P h CH P h CH P h CH -l-CioH 7 CH -l-CioH 7 CH -l-CioH 7 CH -l-CioH 7 CH -l-CioH 7 CH -1-CiqH 7 CH -1-CioH 7 CH -l-CioH 7 CH -l-CioH 7 CH -2-CioH 7 CH -2-CioH 7 CH -2-C10H7 CH -2-CioH 7 CH -2-CioH 7 CH -2-CioH 7 CH -2-CioH 7 CH -2-CioH 7 CH C H Cl- p CH C H Cl- p CH C H C1-/? CH C H Cl-/ w CH C H Cl- m CH C H Cl- m CH C H Cl- o CH C H Cl- o CH C H Cl- o CH P h 2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
70%EtO H + KHCO 67%Me C O 67% Me C O 70% EtO H + KHCO 3 67%Me C O 67%Me C O 67% Me C O 67%Me C O 67%Me C O 67%Me C O 67%Me C O 67%Me C O 67% Me C O 67%Me C O 67%Me C O 67%Me C O 67%Me C O 67% Me C O 67% Me C O 67%Me C O 67%Me C O 67%Me C O 67%Me C O 67%Me C O 67% Me C O 67%Me C O 67%Me C O 67%Me C O 67%Me C O 67%Me C O 67%Me C O 50% EtO H
37 30 30 37 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 25
15
20
— —
30
—
—
30
—
—
—
—
—
— — —
— — —
— — — — —
—
—
—
—
—
10
—
—
5 16 4.5 7 0 0 34 86 86 100 0 18 100 47 0 47 96 79 0 15 72 52 36 81 60 26 75 52 22-23 75 52 61* 318, 3647 642 642 3647 641, 644 641, 644 641, 644 642 641, 644 644 641, 644 641, 644 644 641, 644 644 641, 644 641, 644 644 644 641, 644 641, 644 644 65, 1517 65 65 65, 1517 65 65 65, 1517 65 65 2851a INTRAMOLECULA R DISPLACEMEN T BY THE AMIN O GROU P 7
Ç Ç Ç Ç Ç Ç Ç Ç Ç Ç Ç Ç Ç Ç Ç Ç Ç Ç Ç Ç Ç Me Me Ç
CI CI CI CI CI CI CI CI CI CI CI CI CI CI Br
CI Br CI Br CI
I
CI Br
I
R
X
1
2
CH CH CH CH CH CH CH CH CH CH CH CH CH Et Et Et Et Et Et CH CH Et Et Et
R
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
Ph Ph
CH CH CH CH CH CH CH CH CH CH CH CH CH
2
2
2
2
2
2
2
2
2
2
2
2
2
C1 C1 C1 C1 C1 C1 C1 C1 C1 C1 C1 C1 C1
Amin e 3
2
2
2
6
6
6
6
2
2
6
6
2
6
2
2
6
6
2
2
6
6
2
2
4
4
4
3
3
3
4
4
4
4
4
2
2
2
4
5
7
CH C H Me -i7 CH C H -iso-Pr- p CH C H OMe-< ? CH C H OMe- m CH C H OMe-/ > CH C H OEt- p CH C H OPr-; ? CH C H OBu-/ > CH C H (OMe) -3,4 CH C H -3-N0 -4-OM e 5,6,7,8-H -2-CioH CH C H [(CH ) ]-3,4 CH -5-indany l 9-Fluoreny l 9-Fluoreny l 9-Fluoreny l 9-Fluoreny l 9-Fluoreny l 9-Fluoreny l 9-Fluoreny l 9-Fluoreny l 9-Fluoreny l 9-Fluoreny l Benzo [6]then-3-ylmethy l
R
2
2
2
2
2
2
2
2
2
2
2
50%EtO H 50%EtO H 50% EtO H 50% EtO H 50% EtO H 50% EtO H 50% EtO H 50% EtO H 50% EtO H 50% EtO H 50% EtO H 50% EtO H 50% EtO H 67% Me C O 67%Me C O 67%Me C O 67%Me C O 67% Me C O 67% Me C O 67% Me C O 67%Me C O 67%Me C O 67%Me C O 67% Me C O
Solvent 20 20 20 20 20 20 20 20 20 20 20 20 20 15 15 15 15 0.5
25 25 25 25 25 25 25 25 25 25 25 25 25 30 30 30 30 30 30 30 30 30 30 30
—
—
—
— — —
Tim e (min )
Temp . CO
3
67* 71* 92* 52* 77* 70* 79* 73* 74* 31* 63* 59* 62* 7 36-40 14 7 36-40 14 1 4 4 31 22
0
2851a 2851a 2851a 2851a 2851a 2851a 2851a 2851a 2851a 2851a 2851a 2851a 2851a 642, 1517 642, 1517 642 642, 1517 642, 1517 642 642 642 642 642 642
Reference s
—continue d
Ion forme d (% of theory)
MAXIMU M CONCENTRATION S OF AZIRIDINIU M ION S FRO M 2-HALOALKYLAMINES , XCHR'CHiNR^
Tabl e 1-1
8 1. FORMATIO N OF TH E AZIRIDIN E RIN G
4
6
6
6
6
2
2
2
Ç Ç Ç Ç Ç Ç Ç Ç Ç Ç />-MeC H /7-ClC H />-ClC H 3,4-Br C H 3,4-Cl C H 3,4-Cl C H
CI Br I CI Br I CI Br CI CI Br Br CI Br Br CI
4
Ç
CI
4
Ç
CI
6
Ç
CI
6
Ç Ç Ç Ç Ç
Br I CI Br I
3
3
3
Q
6
H
-)
2
2
2
2
2
2
2
2
2
2
-
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
6
6
6
6
6
4
4
4
4
4
CH CH OP h CH CH OP h CH CH OP h CH CH OC H Me- o CH CH OC H Me- o CH CH OC H Me- 0 CH CH OC H Me-/ > CH CH OC H Me-/ > CHMeCH OP h CHMeCH OP h Me Me Me Me Me Me
^CH2CH2CH2 —
4
2
^CH -
2
2
^CH CH —
2
Benzo [6]then-3-ylmethy l Benzo [Z>]then-3-ylmethy l 2-Theny l 2-Theny l 2-Theny l
/CH —
3
O-C H :
°-
2
(R + R
CH P h CH P h CH P h CH P h CH P h CH P h CH P h CH P h CH P h Et Me Me Me Me Me Me
Et Et Et Et Et
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
67% Me C O 67%Me C O 67%Me C O 67% Me C O 67%Me C O 67% Me C O 67% Me C O 67% Me C O 70%EtO H + KHCO 70%EtO H + K C O 40% Me C O 40% Me C O 40% Me C O 40% Me C O 40% Me C O 40% Me C O
2
3
67% Me C O + K C 0
2
2
67% Me C O + K H C 0
2
67%Me C O + K H C 0
2
2
2
2
2
67% Me C O 67% Me C O 67%Me C O 67% Me C O 67% Me C O
3
3
30 30 30 30 30 30 30 30 37 37 37 37 37 37 37 37
37
37
37
30 30 30 30 30
5 3 5 5 5 5 5 5
8.5
« 15
—
—
6 33 7 4 21 3 6 27 21 83 67 83 83 88 87 79
60
1
0
72 56 1.5 10 4
64 64 64 64 64 64 64 64 3647 3647 640 640 640 640 640 640
318
318
318
642, 1518 642 642 642 642 INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P 9
Me Et Pr Me
Ph Ph Ph
b
a
R
Ar
X
Amin e
2
2
2
2
2
2
2
2
2
2
40% Me C O 0.01 Ì phosphat e buffer , p H 7.3 0.01 Ì phosphat e buffer , pH 7.3 67%Me C O
Solvent
2
R
3
50% 50% 50% 50%
Me Me Me Me 2
2
2
2
CO CO CO CO
Solvent
31 31 31 31
C O
Temp .
2
30
37
37 23
Temp . (°Q
For a few 2-haloethylamine s of typ e BrCRArCH NMe
2
2
CH CH 0 CCPh O H
2
CH CH 0 CCPh O H
2
3
Me CH CH 0 CCPh O H
R
On th e basi s of reactio n of only one haloalky l group . Not necessaril y th e maximu m yield.
I-C10H7
Me
Ç
Me Me
CI
3
Me
6
2
Ç
2
R
CI
1
3,4-Me C H Ç
R
CI CI
X
1
2
2
3
— — —
Tim e (min )
« 60
10
5 20
Tim e (min )
0 0 0 0
Io n forme d (% of theory) "
<30
83
78 82
645
645
645
645
Reference s
1470
1470
1470
640
Ion forme d (% of theory) * Reference s
MAXIMU M CONCENTRATION S OF AZIRIDINIU M ION S FRO M 2-HALOALKYLAMINES , X C H R C H N R R — c o n t i n u e d
Tabl e 1-1
10 1. FORMATIO N OF THE AZIRIDIN E RIN G
11
INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P
been measured. In some instances values have also been obtained for the frequency factor and the energy of activation for the cyclization. Such data are presented in Table l-II, which considerably extends the compilation n o w available (2677). Factors Affecting Rate of Cyclization. 1. Solvent. Since initially neutral parts of the molecule must come into a transition state which involves some separation of charge, solvents of high dielectric constant favor the reaction. There has been n o systematic comparison of many solvents in the cyclization, b u t the higher rates of 2-haloalkylamines in water compared t o methanol (Table l-II, entries for 2-bromoethylamine hydrobromide) and acetone [entries for ( C l C H C H ) N H E t C r ] illustrate the effect. While both E, the energy of activation, and A, the frequency factor, are decreased in nonaqueous solvents, the effect of the change in A is the greater a n d the cyclization is retarded. 2. N a t u r e of L. The most familiar leaving groups are seen here, and the rates of leaving are in the order t o be expected: 0 S R (1056,1442,1764) > Br > C 1 > F , O S 0 " (896). Similar displacement occurs spontaneously in 2aminoethyl diethyl phosphate ( 1 0 ) and 2-aminoethyl diphenyl phosphate (498) and in 2-dimethylaminoethyl diphenyl phosphate (1013). +
2
2
2
3
3
10
/ Ç
\ Ç
Phosphatidyiethanolamines, R C 0 C H C H ( 0 C R ) C H O P ( 0 ) ( O H ) O C H C H N H , u p o n exhaustive treatment with diazomethane lose their nitrogen (243), probably as EI (498), and it is likely that .merely treating a phosphatidylethanolamine with strong base, t o which it is reported very sensitive (1540), will cause such elimination. However, 2-aminoethyl dihydrogen phosphate is undecomposed by boiling for 24 hours with 1 JVNaOH (2895); evidently the displacement of the highly charged phosphate ion is virtually impossible. 2-Aminoalkyl nitrates would probably cyclize t o form aziridinium ions. This path has been suggested for the dimerization of the trinitric ester of triethanolamine, N ( C H C H O N 0 ) , t o 1,1,4,4-tetrakis(nitroxyethyl)piperazinium dinitrate (1010). The mechanism of the conversion of 2-(dialkylamino)alkyl halides by silver perchlorate t o aziridinium perchlorates (1306a, 2294,2295) has not been directly investigated. The path might 2
2
2
2
2
2
2
2
R NCH CH2C 1 2
2
A g C 1
4
° >
R NCH CH OC10 3 2
2
2
2
2
3
\
/ / \ R R
C10 " 4
(3)
3
3
3
3
+
+
3
Cl Cl Cl Cl + picrate -
D D H H H D H
2
2
2
3
3
3
3
2
2
2
3
2
2
3
2
3
3
3
2
3
3
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0
H H H H H H H H H H
2
MeCHClCH NH + Cl" MeCHClCH NH + Cl~ ClCH CHPhNH +Cl PhCHClCH NH + Cl" PhCHClCH NH + Cl~ PhCHClCH NH + Cl~ PhCHClCH NH + Cl~ PhCHClCH NH + Cl~ PhCHClCH NH + Cl" MeCHClCH NHMe + Cl~
2
2
2
H 0 H 0
2
2
2
2
2
2
2
2
2
2
Solvent
ClCH CHMeNH + Cl~ MeCHClCH NH + picrate -
2
FCH CH NH (FCH CH ) NH C1CH CH NH C1CH CH NH C1CH CH NH + C1CH CH NH + ClCH CHMeNH
Amin e salt or free bas e
2
4
+ AcO H or K H P 0 + NaO H
II
« 0.07,
KCIO4 , ì
II II II II II II II II II II II
2
I I II II II I II
0
Analytica l method
NaO H NaO H NaO H NaO H NaO H NaO H NaO H Non e Non e
NaO H Ba(OH)
2
0.2MNaO H 0.2MNaO H NaO H NaO H NaO H 0.3MNaO H Ba(OH)
Adden d
5 5 6 4 3 2
— 3 3 3
— « 1 « 5 1.63
— 82 100 25
4 3
5 5 7 6 5 5 3
ç
3 3.44 w 5 3.0 7.0 2.0
2.5 1.13
1.6 7.5 2 8 1.56 1.3 8.2
k°
-1
0
25 31 25 0 25 37
25 25
90 80 0 25 31 50 25
Temp . (°C)
n
k (= 10- A: ), (sec )
RATE S OF CYCLIZATIO N OF 2-SUBSTITUTE D AMINE S TO AZIRIDINIU M SALT S
Tabl e 1-Ð
—
— —
— —
14
—
—
—
ç
—
—
—
—
— — —
6 1
19.1 20.6
—
— — — —
—
—
—
— 11 13
—
(But considere d 2nd order ) — — — — — — « 27 — —
—
— (But considere d 2nd order )
9
—
—
—
A°
27.5
—
—
—
Å (kcal )
-1
A (= 10M°), (sec )
1341 620 1341 1341 1341 1341 3095 3095 3095 1605
1341 3301
2310 2310 1344 3095 620 2310 3301
Reference s
12 1. FORMATION OF THE AZIRIDINE RING
2
2
+
2
H 0
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
+
+
+
+
+
+
2
2
2
2
2
2
2
2
2
2
2
2
2
2
0 0 0 0 0 0 0 0 0 0 0
D H H H H H H H H H H
2
2
2
2
(C1CH CH ) NH + Cl (C1CH CH ) NH Cl (C1CH CH ) NH + Cl (ClCH CH ) NHMe + Cl~ (ClCH CH ) NHMe Cl" (ClCH CH ) NHMe Cl~ (ClCH CH ) NHMe + Cl" (ClCH CH ) NHMe Cl~ (ClCH CH ) NHMe + Cl~ (ClCH CH ) NHMe Cl~ (ClCH CH ) NHMe Cl~
2
2
67%Me C O H 0
+
ClCH CH NHEt + Cl" (C1CH CH ) NH + Cl -
2
2
2
2
2
H 0
2
2
2
2
ClCH CH NHEt + Cl~
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
H 0 ClCH CH NHMe + Cl" H 0 ClCH CH NHMe + Cl~ H 0 C l C H C H N H M e Cl~ ClCH CH NH (CH CH OH) Cl" H 0 ClCH CH NH (CH CH OH) + Cl~ H 0 H 0 ClCH CH NHMe(CH CH OH) + Cl H 0 ClCH CH NHMe(CH CH OH) + Cl H 0 ClCH CH NHEt + Cl" H 0 ClCH CH NHEt + Cl" H 0 ClCH CH NHEt + C\~
2
ClCH CHMeNHMe + Cl~
2
2
2
2
2
2
2
3
3
4
+ AcO H or K H P 0 + NaO H II NaHC0 + N a C 0 , pH 10.7 Non e II Borat e buffer , VI p H 7.36 I NaOH , 0.2M II NaOH , pH 7.2 NaOH , pH 6.0 II NaOH , p H 8.0 II , NaOH , pH 8.0 II , NaOH , pH 8.0 II , Ba(OH) 11, Ba(OH) ð, II Ba(OH) Ba(OH) II Ba(OH) II
4
KC10 ,/x«
0.07,
IV? , V? IV? , V? IV? , V? í í
II , IV? , V? II , IV? , V? Il l
NaOH , p H 8 NaOH , pH 8
37 37 37 0 15 30 10 25 15 25 35
25 25
25
0 15 25
15
4
11, iv, í
2
NaOH , pH 7.9
25
18 25 35 37 37 0
II
+ AcO H or K H P 0 + NaO H II + II I NaO H NaO H II + II I NaO H II + II I NaOH , pH 7.2 II II NaOH , pH 6.0 NaOH , pH 7.9 Ð, IV, V
KCIO4 , ì « 0.07,
6.2 5.00 7.01 3.84 4.00 3.25 1.87 1.61 3.7 1.3 3.7
3.4 5.5
4.17
2.64 2.42 9.3
3.84
1.1 3 1 1.01 1.06 4.50
1.6
5 4 5 5 4 3 4 3 4 3 3
3 5
3
4 3 3
4
4 3 2 4 5 5
2
—
—
— —
— —
— —
—
14
— —
— —
—
— 8
— — —
—
— —
—
— —
—
—
—
—
—
—
—
14
—
24
—
—
—
—
28.7 28.9
—
— —
—
8
—
—
23
13
— 1.6
—
—
—
—
—
—
—
—
— —
—
—
—
—
22
— —
á 22 32.1
— —
—
2310 2985,2986 2985,2986 726 726 726 1602 1602 3270 3270 3270
279 3869
2919
726 726 1605
726
1605 1605 3269 2985 2985 726
1605
INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P 13
+
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
+
+
2
2
2
2
(ClCH CH ) NHMe + Cl~ (ClCH CH ) NHMe Cl" (ClCH CH ) NHMe + Cl~ (ClCH CH ) NHMe + Cl~ (ClCH CH ) NHMe + Cl" (ClCH CH ) NHMe + Cl~ (ClCH CH ) NHEt + Cl" (ClCH CH ) NHEt + Cl" (ClCH CH ) NHEt + Cl~ (ClCH CH ) NHEt + Cl~ (ClCH CH ) NHEt + Cl~ (ClCH CH ) NHPr + Cl" (ClCH CH ) NHPr + Cl~ (ClCH CH ) NHPr + Cl" (ClCH CH ) NH-iso-Pr + Cl" (ClCH CH ) NH-iso-Pr + Cl~ (ClCH CH ) NH-iso-Pr + Cl~ (ClCH CH ) NHBu Cl" (ClCH CH ) NHBu + Cl" (C1CH CH ) NHCH CH 0 M e Cl (C1CH CH ) NHCH CH 0 Me+ Cl (C1CH CH ) NH + Cl -
Amin e salt or free bas e
2
NaOH , pH ~ 8
2
H 0
pH ~ 8 pH ~ 8 pH ~ 8
pH 7.4 pH 7.4
pH « 8 pH « 8
pH 9.1 pH 9.1
pH 7.2 pH 6.0
NaOH , pH ~ 8
2
2
2
2
NaOH , NaOH , Non e Non e Non e Non e NaOH , NaOH , Non e Non e Non e NaOH , NaOH , Non e NaOH , NaOH , Non e NaOH , NaOH , NaOH ,
Adden d
H 0
2
2
H 0
2
2
2
2
2
2
2
2
2
2
2
2
H 0 H 0 50% Me C O 67% Me C O MeO H MeO H H 0 H 0 H 0 25%Me C O 67%Me C O H 0 H 0 H 0 H 0 H 0 H 0 H 0 H 0
Solvent
IV? , IV? , V II I II I IV? , IV? , í IV? , IV? , í IV? , IV? , IV? , V? V? V?
V? V?
V? V?
V? V?
II , IV? , V?
II , IV? , V?
II II II II II II II , II , Ð, II , II , II , II , ð, II , II , II , II , II , II ,
Analytica l method "
Tabl e 1-Зcontinue d
0
15
37 37 25 25 0 25 0 15 25 25 25 0 15 25 0 15 25 0 15 0
Temp . (°C)
1.15
8.67
6.91 1.78 4.7 « 3 « 2.3 6.1 1.95 2.14 1.37 4 1.42 3.37 3.62 1.81 9.20 8.16 2.61 2.57 2.57 8.16
k°
-1
Å (kcal )
-1
4
4
3 3 5 4 6 5 4 3 5 3 3 4 3 5 4 3 5 4 3 5
ç
5
—
17.9
—
— —
—
25
—
—
4
4
24
—
—
— 2
— — —
23
— —
25
— 2
2
25
—
—
—
—
4
19.6
—
—
— —
—
24.8
A°
726
726
—
726
726
726
1602
726
726
1602
726
726
279
279
1602
726
726
1639
1639
279
3540
2985
2985
Reference s
15
15
15
16
16
—
13
11
ç
A (= 10M°) (sec )
n
k (= 10- £°), (sec )
14 1. FORMATIO N OF THE AZIRIDIN E RING
10
10
10
1 0
10
7
2
2
2
2
2
2
6
6
2
6
4
2
4
4
2
2
+
2
2
2
2
2
2
2
2
2
+
2
7
7
7
7
2
2
2
2
2
2
+
2
+
+
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
70%EtO H
2
2
2
ClCH CH NHEt(CH -lC H )+ Cl ClCH CH NHEt(CH -lC H ) Cl ClCH CH NHEt(CH -lC H )+ Cl ClCH CH NHEt(CH -lC H )+ Cl ClCH CH NHEt(CH -lC H )+ Cl ClCH CH NHEt(CH CH OPh) + Cl ClCH CH NHEt(CH CH OC H N0 -/>) Cl ClCH CH NHEt(CH CH OC H OMe-p) Cl ClCH CH NHEt(CH CH OC H C1-/0+ Cl ClCH CH NHEt(CH CH CH Ph) Cl ClCH CH NHEt(CH CH SPh) Cl ClCH CH NHEt(CH CH OCH Ph) + Cl -
2
2
70%EtO H 60%EtO H
2
2
ClCH CH NH(CH Ph) + Cl" MeCHClCH NH(CH Ph) + Cl"
2
3
3
70% EtO H
70% EtO H
70% EtO H
70% EtO H
70% EtO H
2
0.1MinK CO
2
O.lMi n K C 0
2
0.1MinK CO
2
3
3
3
3
3
O.lMi n K C 0
2
0.1MinK CO
3
II
2
0.1MinK CO
II
II
II
II
II
IV
IV
IV
70% EtO H
2
H 0
2
H 0
2
H 0
37
37
37
37
37
37
37
25
25
25
25
3.5
3.7
5.8
2.9
3.1
2.0
2.7
9.43
5.56
2.4
2.4
2
37
IV IV
2.8 8.8
37 25
11 + I V IV
3
3
3
3
3
3
3
5
5
5
4
3
4 5
4
1.55
25
IV
II
3
s
3 5 3
1.22 9.2 5.2
15 25 25
II , IV? , V? II VI
70% EtO H
NaOH , p H ~ 8 Non e Borat e buffer , p H 7.3 Acetat e buffer , pH~ 7 O.lMi n KHCO Acetat e buffer , pH 7 NaHCO , Acetat e buffer , pH 7 Phosphat e buffer , p H 5.9 Phosphat e buffer , p H 7.4 Phosphat e buffer , pH 9.3 0.1MinKHCO
60% EtO H
2
2
50%EtO H
2
2
2
2
ClCH CH NH(CH Ph) + Cl"
2
2
3
H 0 67%Me C O H 0
2
2
(C1CH CH ) NH + Cl (C1CH CH ) NH + Cl (C1CH CH ) NH + Cl -
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
7 —
25
15
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
317
317
317
317
317
317
317
2343
2343
2343
2426
1442
318 2426
2426
726 279 2427
INTRAMOLECULA R DISPLACEMEN T BY THE AMINO GROU P 15
2
2
Ç
2
2
2
\ ^
2
2
2
2
_
2
2
2
2
(aCH CH ) NHCH —
2
2
+
+
C
I
I
+
ci-
ci-
a-
^Me _
Ã
2
CH OM e
(C1CH CH ) N(CH C0 H)
2
C1CH CH —
2
C1CH CH ^
2
ClCH CH NH(CH Ph ) (CHMeCH OPh) + ci-
Amin e salt or free bas e
ci-
+
2
H 0
2
H 0
2
H 0
2
H 0
2
H 0?
2
H 0
Solvent
Borat e buffer , pH 7.36
Borat e buffer , pH 7.36
KHCO 3
KHCO 3
KHCO 3
Buffer
Adden d
VI
VI
11 + I V
11 + I V
25
25
37
37
37
3
3
9.7
4.0
3
4
5
4
ç
3.4
2.5
6.8
3.6
25
IV
11 + I V
k°
0
Temp . (°C)
n
k (= 10- k°), (sec~ Analytica l method
Tabl e 1-Зcontinue d
—
—
—
—
—
—
—
—
0
A
Å (kcal ) ç
—
—
—
—
-1
A (= WA°) (sec )
3869
3869
318
318
318
2426
Reference s
16 1. FORMATIO N OF THE AZIRIDIN E RIN G
2
2
2
2
2
2
2
2
2
2
2
2
2
N0
2
2
+
4
2
2
2
2
2
4
2
2
2
2
2
2
4
2
2
2
2
2
2
2
2
2
3
3
2
ClCH(C0 Et)CH NH BrCH CH NH + Br ~ BrCH CH NH + Br~
2
2
C1CH CH (C0 H)NH
6
C H N 0 - J C + Cl -
6
2
2
2
2
2
2
(C1CH CH ) NHCH CH 0 C C H N 0 - x + CI (C1CH CH ) NHCH CH 0 C
6
C H N0 -JC + Cl -
2
(C1CH CH ) NHCH CH 0 C
2
2
— ^ ^ ^ " ^ ^
2
C1CH(C0 H)CH NH
2
C1CH CH —r /
2
3
3
2
2
2
N—CH CH CI
—
2
2
3
2
2
EtO H H 0 H 0
2
H 0
2
80% Me C O
2
80% Me C O
80% Me C O
2
2
3
0.03-0.05M in NaO H N(CH CH OH) 0.12M in NaO H 0.12M in NaO H
3
Variou s R N
3
Variou s R N
0.03-0.05M in NaO H Variou s R N
H 0
2
pH 9
2
1,4-Diazabi cyclo[2.2.2]octan e
Borat e buffer , p H 7.36 Borat e buffer , pH 7.2 Borat e buffer , pH 6.0 pH 7.0 pH 7.0 pH 7:0
H 0
2
2
2
2
2
H 0
2
H 0
2
H 0
MeC N
2
2
C H
2
2
2
2
2
2
2
C 1 C H
2
2
2
2
2
2
2
2
2
2
H 0 H 0 H 0
2
2
2
C1CH CH NH CH(CH C1 ) CH CH CH CH C1 + Cl~ (C1CH CH ) NP(0)(0")(0CH CH CH NH )+ (C1CH CH ) NP(0)(0")(0CH CH CH NH )+ C1CH CH -NH(CH CH ) 0+ Cl~ C 1 C H C H - N H ( C H C H ) 0 Cl" C1CH CH -NH(CH CH ) 0+ Cl~
20
II
35.5 25? 0 9.7
II II II
20
II
II
20
35.5
II
II
« 25
50.8
17.5 30.0 45.0
37
37
25
?
II
II II II
II
II
VI
« 2 1.5 . 6.0
4.28
1.28
1.38
0.96
1.29
« 8
2.3
1.42 2.48 7.6
2.03
2.21
1.5
6 5 5
-1
3
3
3
-2
4
5
4 4 4
5
5
4
—
—
—
25.8
25.8
—
—
—
—
—
—
—
—
1553 1338 1338
1553
689
689
689
1553
3079; cf. 2919
3066
2919 2919 2919
2985
2985
3869
INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P 17
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
+
+
+
+
CH NH CH NH + CH NH CH NH CH NH + CH NH + CH NH + CH NH
2
Br Br Br Br Br Br Br Br
2
3
2
3
-
-
-
-
-
-
-
-
-
-
2
2
2
2
3
2
2
BrCH CH NHMe
2
2
+
-
Br
MeCHBrCH NH + B r
2
BrCH CH NH Me + B r
2
BrCH CH NH Me + B r
2
BrCH CH NH + B r
2
BrCH CH NH + B r
BrCH BrCH BrCH BrCH BrCH BrCH BrCH BrCH
-
-
-
Amin e salt or free bas e
2
2
H 0
2
25% HCONMe H 0
2
25% H°CONMe H 0
2
H 0
2
2
2
H 0 H 0 H 0 MeO H MeO H MeO H MeO H H 0
Solvent
2
2
2
2
2
2
4
3
4
4
0.12MinNaO H 11 0.12MinNaO H II NaO H II 0.12MinNaO H II 0.12MinNaO H II 0.12MinNaO H II 0.12MinNaO H II KC10 , ì * 0.07, II I + AcO H or K H P 0 +NaO H ì « 0.3, buffer II to pH 8 ì « 0.3, buffer II to pH 8 ì * 0.3, buffer II to pH 8 ì w 0.3, buffer II to p H 8 Na S 0 , 1 I equiv . (2M) KCIO4 , ì « 0.07, II I + AcO H or K H P 0 + NaO H
Adden d
0
Analytica l method
Tabl e l-II— continue d
1.14 1
25
3.4
1.4
8.3
3.7
5.6
—
6.0 1.1 0.96 3 1.2 2
k°
36.5
35
35
35
35
25.1 30 0 0 25 30 30 25
Temp . (°C)
n
-1
2
5
3
3
4
4
4 3 5 6 4 4 — 4
ç
k (= \0- k°), (sec )
—
—
—
—
—
—
—
—
—
—
—
12
—
—
—
—
—
—
—
— 9
—
—
— 23 20.2
— 14 — 2 —
ç
—
0
A
-1
— 24 — —
Å (kcal )
n
A ( = 10 A°) (sec )
1607
2109
27
27
27
27
1338 1338 620 1338 1338 1338 3095 1607
Reference s
18 1. FORMATIO N OF THE AZIRIDIN E RIN G
2
Br~
2
2
H 0
2
2
2
2
é
3
2
2
3
2
2
BrCH CH —Í H\
2
2
2
2
2
2
2
2
2
2
2
2
2
+
+
2
2
1
/
2
Br
2
2
H 0
2
2
2
2
2
2
2
2
H 0
2
+
BrCH CH —Í H \ _
2
2
H 0
70% EtO H H 0 H 0 H 0 H 0 H 0 H 0 H 0
2
Br~
2
BrCH CH NH Ph + Br~ PhCHBrCH NH Br~ PhCHBrCH NH Br~ BrCH CH NHCH CH C l (ClCH CH )(BrCH CH )NH (ClCH CH )(BrCH CH )NH (BrCH CH ) NH (BrCH CH ) NH
2
BrCH CH NHEt
2
MeCHBrCH NHMe
2
2
+
BrCH CH NH(iso-Pr) + Br~
2
2
2
H 0
BrCH CH NHMe(iso-Pr) + Br~
2
2
25% HCONMe H 0
Br -
2
BrCH CH NHMe
+
2
H 0
Br -
+
2
2
2
BrCH CH NHMe
2
4
KCIO4 , ì « 0.07, etc.
2
4
II I
KCIO4 , ì « 0.07, II I + AcO H or K H P 0 + NaO H
2
ì « 0.3, buffer II to pH 8 ì • «· 0.3, buffer II to p H 8 KCIO4 , ì « 0.07, II I + AcO H or K H P 0 + NaO H II I KCIO4 , ì « 0.07, etc. II I KCIO4 , ì « 0.07, etc. II I KCIO4 , ì « 0.07, etc. NaO H II NaO H II NaO H II II pH 6.2 p H 6.0 II p H 7.2 II pH 6.0 II pH 7.2 II
25
25
8
2
9.4 1.7 ð 6 « 6 2.5 1.28 6.46 3.90
4
25 30 « 25 25 37 37 37 37 37
2
8
25
2
2
3 1 0 0 3 2 3 2
1
1
1
2
3
3
4
3.8
9.6
25
25
35
35
_
26.8 26.5 28.4 28.0
— — — —
—
—
—
—
—
—
— — — — — — — —
—
—
—
—
—
—
—
— — — — — — —
—
—
—
—
—
—
1607
1607
1668 1341 3095 3095 2984 2984 2984 2984
1607
1607
1607
1607
27
27
INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P 19
2 CIO4 -
2
y
3
3
2
2
3
-OS0 CH CH NH +
2
H
H N ^ N H
3
2
H 0
2
H 0
2
H 0
0.13, p H 4.80 0.5N in NaO H
/*« 0.10, p H 10.85
NaO H
EtO H
erythro
BrCH CH(NH )-7
NaO H
EtO H
threo
V-CHB z
V
II I
75
25
25 .
25
II I
25
VII
25
25
Temp . (°C)
VII
VII
NaO H
EtO H
erythro
VII
Analytica l method "
NaO H
Adden d
EtO H
Solvent
threo
\—CHP h
BrCH CH{NH )-y 1 2 CIO4 - H N ^ ^ N
Ï
Ï
Amin e salt or free bas e
Tabl e 1 - Ð --continued
k -1
0
1.931.98*' 8.0
4.83*
1.26
c
6
5
3
4
3
3
1.5
3.53
4
ç
1
k°
(= 10-"A: ), (sec )
Å -
—
—
—
—
—
—
—
—
—
A°
—
(kcal )
ç
0
—
—
—
—
—
—
-1
A (= 10M ) (sec )
896, 897
3670
3670
3345
3345
3345
3345
Reference s
20 1. FORMATIO N OF THE AZIRIDIN E RIN G
2
2
2
2
2
2
2
2
+
2
2
2
1
2
3
3
3
3
+
2
+
+
2
+
2
3
3
+
3
3
+
3
3
OSO3 -
3
3
3
3
+
2
3
2
2
2
2
2
2
+
+
2
Ç
/v_ y
OSO3CH2CH2- Í
2
2
3
2
3
3
2
3
2
\
n=3 n=A n=5 n=6 -OS0 CH CH NH + -OS0 CH CH NH Me + -OS0 CH CH NHMe -OS0 CH CH NHEt ~OS0 CH CH NH(CH CH OH)
2
(CH ),,
3
3
3
3
3
3
3
3
3
3
3
3
3
2
-OS0 CH CHMeNH -OS0 CHMeCH NH -OS0 CH CMe NH -OS0 CHMeCHMeNH (threo) -OS0 CHMeCHMeNH + (erythro) -OS0 CH CHEtNH + -OS0 CHEtCH NH -OS0 CH CH(iso-Pr)NH + -OS0 CH(iso-Pr)CH NH -OS0 CH(terf-Bu)CH NH + -OS0 CH CHPhNH + -OS0 CHPhCH NH + -OS0 CH(CH Ph)CH NH
2
2
2
2
2
2
2
2
2
0 0 0 0 0 0 0 0 0
2
2
2
2
2
2
2
2
2
0 0 0 0 0 0 0 0 0 0 0 0 0
2
2
2
2
2
H 0
H H H H H H H H H
H H H H H H H H H H H H H
4 5 5 5 5 4 3 3 3 4 3.9 100 II
IN in NaO H
5 5 4 4 4 5 5 5 6 7 6 4 6
1.75 1.9 6.8 2.2 7.1 3.7 1.1 5 1.9
5.2 1.6 3.3 1.07 1.36 7.4 1.6 9.2 8.3 5.7 9.8 4.8 4.0
75 75 75 75 100 100 100 100 100
75 75 75 75 75 75 75 75 75 75 75 75 75
V V V V II II II II II
V V V V V V V V V V V V V
0.5W in NaO H 0.5N in NaO H 0.5N in NaO H 0.5ËÃ in NaO H IN in NaO H liV in NaO H IN in NaO H I N in NaO H liVinNaO H
0.5N in NaO H 0.5N in NaO H 0.5N in NaO H 0.5N in NaO H 0.5N in NaO H 0.5N in NaO H 0.5ËÔ in NaO H 0.5Ë^ in NaO H 0.5N in NaO H 0.5N in NaO H 0.5N in NaO H 0.5N in NaO H 0.57V in NaO H
—
—
— —
— —
— — —
—
—
—
— — —
— —
— — — — — —
—
— — — — — —
— —
— — — — — — — — — —
—
— —
—
—
—
— — —
— — —
—
— — — — — — — — —
668
896, 897 897 897 897 668, 4022 668 668 668 668
896, 897 896, 897 896, 897 896, 897 896, 897 896, 897 897 897 896, 897 897 897 897 896, 897 INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P 21
a
+
2
2
3
2
10
3
2
2
2
4
2
4
2
4
2
2
6
6
6
2
2
2
7
2
2
2
2
3
3
2
7
2
2
2
2
2
4
10
2
2
2
2
2
2
7
2
2
25% EtO H 25% EtO H
70% EtO H
70% EtO H
70% EtO H
70% EtO H 70% EtO H
Solvent
Non e Non e
NaHC0 3
NaHCO ,
NaHCO ,
NaHCO , NaHCO ,
Adden d
IV IV
IV
IV
IV
IV IV
37.1 37.1
37
37
2 2.7
2
2
1.5
3.2 2
37 37 37
k°
Temp . (°Q
(sec )
-1
2
2
2
6 2
4 7
ç
k (= 10-"k°),
— —
—
—
—
— —
—
—
—
Reference s
— 1375 — 1375
— 1442
— 1442
— 1442
— 1442 — 1442
(sec ) — A° ç
— —
Å (kcal )
n
-1
A ( = 10 A°)
c
b
I: determinatio n of aziridiniu m ions by nuclea r magneti c resonance . II : determinatio n of X formed . Ill : determinatio n of hydroge n ions formed . IV: determinatio n of aziridiniu m ions with thiosulfate . V: determinatio n of residua l amin e by titratio n with acid . VI : polarographi c determinatio n of aziridiniu m ions. VII : determinatio n of aziridiniu m ions by ultraviole t spectrophotometry . Additiona l value s of k at intermediat e pH value s ar e also reporte d (3670). Thes e an d othe r value s of k for thi s system at low pH value s ar e in fact composit e rat e constant s for th e cyclizatio n of th e imidazoliu m an d th e unprotonate d form .
10
3
3
2
3
-OS0 CH CH NH(CH Ph) + PhS0 OCH CH NH(CH Ph) + -0 SP h /?-CH C H S0 OCH CH NH (CH Ph) - 0 S Q H M e - ^ p-CH C H S0 OCH CH NHE t (CH CH -1-C H )+ -0 SC H Me-/ ? 2-C H SO OCH CH NH (CH Ph) + -O S-2-C H (EtO) P(S)OCH CH NEt (EtO) P(S)OCH CH NEt
Amin e salt or free bas e
Analytica l method "
Tabl e 1-Зcontinue d
22 1. FORMATIO N OF THE AZIRIDIN E RIN G
23
INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P
conceivably involve mainly metathesis first, then cyclization (Eq 3) (rather than these steps in reverse order), b u t this is unlikely. The path by which /V-(2-fluoroethyl)-/8, 8-difluoroborazane, F C H C H N H B F , is converted to EI by aqueous alkali (3712) is not clear, but in any case is of theoretical interest only. Benzoate ion is not displaced thus from 2-aminoalkyl benzoates (1442, 1606) but in the sterically favorable case of L (+)-2-tropanol acetate ( 1 1 ) , the acetate ion and an unstable intermediate aziridinium ion are believed formed (Eq 4) (128). J
i
2
2
2
Ac Ï ->·
OAcr
racemize d acetat e
(4)
11
Perhaps formulation of the process via a more symmetrical transition state ( 1 2 ) , similar to that suggested for the thermal ring expansion of 2-(chloromethyl)pyrrolidines ( 1 3 ) (476), would be preferable. The ready dimerization ...CI ACO :
Í Ç 13
of 2-dialkylaminoalkyl perfluoroalkanoates to piperazine salts (Eq 5) indicates that the perfluorinated anion is a good leaving group (1637) and the reaction involves an aziridinium ion. R R \ /
o
-C^ftuCOz C F n
2 n + 1
C0 CH CH NR 2
2
2
2 +
N / \ R R
(5)
/ \ R R
The possibility of cyclization of allylamines to aziridinium dipolar ions has been mentioned (3627) but there is at present no evidence that such a reaction as shown in E q 6 occurs. H
2
/ \ R N 2
-CH 2
CH / CH 2
(6) N / R
+
\ R
24
1. FORMATIO N OF TH E AZIRIDIN E RIN G
The same comment applies to the hypothetical tautomerization of á -amino ketones (Eq 7) (2813). NH OH
(7)
There are two examples only of an aziridine-forming reaction in which the leaving group is trimethylamine (but compare the preparation of azirines, p. 63). The quaternary hydrazonium salts 1 4 when heated with alcoholic sodium methoxide gave 2-substituted aziridines as shown in Eq 8 (4071).
P h
N-C-CH CH NHNMe 2
I
R
2
3
P
I"
h
N
II
R
f ^ \ O
Ï
/
(8)
N I
14
Ç R = Me, 35% yield R = iso-Pr , 57% yield
Ordinarily, 2-amino alcohols cannot be dehydrated to aziridines, the reaction giving almost entirely acyclic imines and other products. Ethylenimine was suggested as an intermediate in the catalytic dehydration of 2-aminoethanol (2271) and heterogeneous catalysts, such as silica gel, were reported to convert this alcohol mainly into EI and derived products (256); it is tempting to postulate esterification at the acid surface, displacement to give EI, and immediate polymerization at the surface. 1-Amino-1-cyclohexanemethanol over hot alumina does yield a little of the spiro aziridine 1 5 (202) and 2-hydrazinoethanol gives 1-aminoaziridine (1513). The mechanism of such processes is obscure. NH
j
2
CH O H 2
>
í V V ^ H 15
3. The effect of p H on the rate of cyclization is easily stated. Since the amino group must be free, and not protonated, to accomplish the internal displacement the p H must be high enough to establish this condition. Buffers at p H 7-8 are often used in studies of such rates. Higher alkalinity has essentially no effect on the cyclization, but tends to stabilize the aziridine formed by deprotonating the aziridinium ion. The ring closure may be retarded by lowering the p H (345). The same effect is produced by cupric ions, which also combine with and reduce the reactivity of the amino groups; the retardation has been measured and interpreted (3671).
25
INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P
4. Clearly the nucleophilicity of the amino nitrogen atom is a major factor in fixing the rate of cyclization. However, there is close correspondence of base strength and rate of cyclization (proportionality of pK t o log k) only when compounds of very similar structure are compared, e.g., E t N ( C H C H C 1 ) , P r N ( C H C H C l ) , and B u N ( C H C H C l ) (726), and compounds of structure / ? - X C H Y C H C H N E t ( C H C H C l ) , where X and Y are various groups (317). Qualitatively the picture is better: as would be expected, rates of cyclization are in the order M e N C H C H B r > M e N H C H C H B r > H N C H C H B r (27); M e N C H C H B r M e > H N C H C H B r M e (643); a n d E t N C H C H C l > E t N ( C H C H C l ) > N ( C H C H C 1 ) (280, 726). T h e failure of arylbis(2-chloroethyl)amines t o hydrolyze via aziridinium intermediates (3067) must be due t o their low basicity. 5. The rate of cyclization involved in neighboring group effects depends on ring size (573,3397). F o r three-membered rings, the entropy decrease required to achieve the transition state is less than for larger ones, b u t the ring strain is greater and the mutual effects of the leaving group and the nucleophile are more detrimental. F o r two classes of compounds, the balance of these factors yields the relative rates of ring closure shown in Table l-III. a
2
2
2
2
2
6
4
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
Tabl e l-II I RELATIV E RATE S OF RIN G CLOSUR E OF L ( C H ) „ N H 2
L = -OS0
= Br
L
(in H 0 , 2
25°C )
(in IN NaOH , 1 0 0 ° C )
(897)
(668)
2
1.0
1.0
3 4
0.014
0.08
5
» 800 14
6
0.02
L = -OSO3
3
(in 0.57V NaOH , 7 5 ° C )
(3093, 3095)
ç
2
1.0 0.028 >27
443
— —
8.2 0.03
6. As for many ring closures, the reaction is facilitated by the presence of small alkyl groups on the ring-forming atoms. Some relative rates are C 1 C H C H N H , 0.8; C l C H C H M e N H , 2 5 ; C l C H C M e N H , 750 (573); -OS0 CH CHEtNH ,7.6; -OS0 CH CHMeNH ,5.2; -OS0 CH CH NH , 0.8 (896, 897); a n d M e N ( C H C H C l ) C H C H C l M e > M e N ( C H C H C l ) (2966). While some of these differences may be due t o different nucleophilicities of the nitrogen atoms, most of them are attributable t o steric effects (897,1605,1607). These are most likely the improvement of the driving force of the reaction, —Ä G, by the alkyl substituent (72,573) but the alteration of bond angles in favor of cyclization m a y also play a part (1605, 1607). A sufficiently bulky group, as in ~ O S 0 C H ( t e r / - B u ) C H N H , depresses the 2
3
2
2
2
2
2
2
3
2
2
2
2
2
2
2
3
2
2
2
+
3
2
2
3
2
2
2
26
1. FORMATIO N OF TH E AZIRIDIN E RIN G
rate of cyclization (897). The small but recurrent difference in rates between amines with primary and secondary leaving groups (L) [ C l C H C H M e N H , 2 5 ; C l C H M e C H N H , 3 (1341); C l C H C H M e N M e , 1 6 0 0 ; C l C H M e C H N M e , 163 (1605)] is consistent with the idea that these cyclizations are of S 2 type (albeit intramolecular), in which primary halides react faster t h a n secondary ones. This order is decisively reversed by the presence of the phenyl group [ C l C H C H P h N H , 0.5; C l C H P h C H N H , 700 (1344, 1387); and - O S 0 C H C H P h N H , 1.22; - O S 0 C H P h C H N H , 59.2 (897)] and barely so by that of the carboxyl group [ C 1 C H C H ( C 0 H ) N H , 4.28; C 1 C H = ( C 0 H ) C H N H , 12.9 (1554)] or when L is sulfate [ - O S 0 C H C H M e N H , 5.2; - O S 0 C H M e C H N H , 1.6 (896)]. Equilibrium constants for processes of the type of Eq 9 2
2
2
2
2
2
2
2
N
2
2
2
2
+
3
2
+
3
3
2
2
2
2
3
3
2
2
2
3
2
2
2
2
are rarely measurable because too many other nucleophiles compete with L~ to open the ring (1339). Nevertheless the rate of reaction of the cyclic ion with L~ can be measured, and the equilibrium constant Ê calculated as the ratio of the rate constants. Thus for cyclization of P h C H C l C H N H , K= 16.7 at 0°C and 4 at 24.6°C (1341). F o r B r C H C H N H , Ê is shifted from about 9 in aqueous solution to about 2 in presence of blood charcoal, presumably because of preferential absorption and stabilization of the b r o m o amine on the charcoal surface (1343). A similar shift was observed for P h C H C l C H N H (1340, 1342). F o r M e N ( C H C H C l ) in dilute aqueous solution at 37°C, AT was calculated as 3.68, whence the amine was 99.86 % cyclized at equilbrium (728). 2
2
2
2
2
2
2
2
2
2
STEREOCHEMISTR Y OF R I N G CLOSUR E
It was early shown (3763) that (+)- and ( - ) - P h C H C l C H P h N H of m.p. 127°C give (+)- and (—)-irfl«5 -2,3-diphenylaziridine, and that the corresponding dl isomer of m.p. 59°C gives the cw-2,3-diphenylaziridine; but n o conclusions could be drawn about the steric course of the reaction. The trans closing of the aziridine ring (which helped classify the reaction as an internal nucleophilic displacement) was firmly established (910) by the demonstration that pairs of Walden inversions are involved in converting m&sO -2,3-epoxybutane via i/zra?-3-amino-2-butanol to raesO -2,3-dimethylaziridine, and D(+)-2,3-epoxybutane ( 1 6 ) via the L ( + ) erythro-zmino alcohol ( 1 7 ) to L(—)-2,3dimethylaziridine ( 1 8 ) . 2
,
27
INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P
Me
Ç
Me H S0 2
4
-03S0
Me
Ç V
Ç
base
I X NH + H^^M e 3
Ç
16
17
Ç
18
This inversion during the cyclization was immediately confirmed when cyclohexenimine was obtained from i//-/m^-2-aminocyclohexyl hydrogen sulfate but not from i//-m-2-chlorocyclohexylamine, in which intramolecular displacement of the chlorine with inversion would generate only the sterically impossible ira/w-cyclohexenimine (2813, 2820, 3456, 3463, 3817). Still further verification came from similar preparations of N-rnethylcyclohexenimine (2627, 3457, 3814), cyclopentenimine (1098), cycloheptenimine (3483), cyclooctenimine (2047), and cyclodecenimine [from the trans- but not the cw-amino alcohol (1101)]. Only when the cyclododecenimines are reached are both the cis- and ira/w-aziridines capable of isolation (1102). The fact of inversion on closure of the aziridinium ring is now so well established that it is used to deduce the configuration of the parent chloro amine as trans (2517). When inversion is not possible because the amino group and leaving group are cis (128) or otherwise constrained from interaction (1321, 2296, 3026), the cyclization fails. Interest in the stereochemistry of the long-known interconversion of ephedrine and pseudoephedrine has led to detailed examination of the related chloro compounds and aziridines. Piecing together the evidence shows once more that each cyclization of the chloro amine or sulfuric ester corresponding to a normal (threo) ephedrine or ephedrine analog proceeds with inversion to yield a cis (erythro) 2,3-disubstituted aziridine. This upon ring opening undergoes inversion again to give the normal (threo) alcohol or its derivative. Pseudoephedrine types in the same steps go via a trans -dizmaint to pseudoephedrine (erythro) analogs (1572, 2130, 2131, 2636, 2708, 3464, 3479, 3489, 3490). Contrary to earlier belief (1048), the conversion of L(—)-ephedrine and D(+)-pseudoephedrine to the alkyl hydrogen sulfates occurs with retention of configuration if minimum temperatures are used (443, 493, 1015). A series of papers, mostly by Cromwell and his students, has dealt with the cyclization of a,j8-dibromo ketones upon treatment with primary or secondary amines (Eq 10). RCHBrCHBrCOR / + R"NH
2
>
(10)
28
1. FORMATIO N OF TH E AZIRIDIN E RIN G
This was independently shown to proceed with a Walden inversion at the carbon atom from which the amino group displaces bromide (804). The ratios of isomers produced have been reported in a number of these papers (784, 790, 792, 793, 795, 796, 800, 802, 803, 805, 806, 2087, 2088, 3344), but of course these cis-trans ratios merely reflect the threo-erythro ratios in the bromo amines undergoing cyclization (795). The threo-erythro ratios are explained in terms of either steric factors (803, 3886) or chelation in the transition state (3344, 3346). The configurations of the stereoisomeric aziridinium salts have been verified by the N M R spectra of the isolated prechlorates (2299).
REARRANGEMENT S PROCEEDIN G THROUG H AZIRIDINIU M ION S
Some reactions of 2-aminoalkyl halides, especially alkylations, do not produce the products to be expected by direct replacement of the halogen. Since 1947 it has been recognized that this is well explained on the basis of intermediate cyclization. In every case of rearrangement the intermediate aziridinium ion is an unsymmetrical one, in which the ring may be opened in two ways (Eq 11) or at least in the way that gives the product not derivable by simple displacement. Â
R'
(Ð) N+ /\
Thus alkylation of diphenylacetonitrile carbanion (401, 3175-3177) with (2-chloropropyl)dimethylamine was observed to yield a mixture of isomers, and (2-chloro-l-methylethyl)dimethylamine gives the same mixture (Eq 12) (491). ClCH CHMeNMe 2
:
Ph CC N or
— •a-^r
ClCHMeCH NMe 2
N+
Ph C(CN)CHMeCH NMe + Ph C(CN)CH CHMeNMe 2
>
2
2
2
2
Further instances of such rearrangements are shown in Table 1-IV.
2
2
(12)
29
INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P
The anomalous alkaline hydrolysis of l-(2-chloroethyl)-2,2,5,5-tetramethylpiperazine (19), while not involving a rearrangement, gives mostly polymers by way of an aziridinium ion (Eq 13) (2501). MewM e
Ç
Me Me
Me Me
-ci-
Me •N^ "M e
Me Me
Ho 2
Ç
Í
Í—CH CH — OH 2
2
/^M e Me
I
CH CH C 1 2
2
(13)
19
The formation of polymers from ( P h O ) P ( 0 ) O C H C H N ( C H C H O H ) (1296) is attributable to a similar intermediate aziridinium ion. Involving the same principles, but more complex, is the set of transformations shown in Eq 14 (1993, 2699, 2700); some difference of opinion exists about the mechanism. 2
2
2
2
2
2
B - = H" , CI" , OEt "
In reactions of 19A and 19B, which may be interconvertible, stabilized carbonium ions appear to be more probable intermediates than the bicyclic aziridinium ion 19C (903a, 1395a).
CH2X
V^ I
Bu-tert 19A
l Bu-tert 19C
A similar bicyclic aziridinium ion was a useful participant in the recent synthesis of a j8-benzomorphan (1359). N o comparable reaction occurs for 8-(chloromethyl)pyrrolizidine ( 2 0 ) because formation of the aziridinium ion
1 . FORMATIO N OF TH E AZIRIDIN E RIN G
30
is sterically impossible (2296), and n o rearrangement (and hence no aziridinium intermediate) was observed u p o n treatment of phenyl-l,2,3,6-tetrahydropyridine
l-methyl-3-halo-4-
( 2 1 ) with base, presumably because of
conformational preferences (2374).
20
Tabl e 1-IV REARRANGEMENT S VIA AZIRIDINIU M ION S
Nucleophil e
Origina l hal o amin e ClCH CHMeNEt HOCH CMe NMe + a carbodiimid e ClCH CHMeN(CH Ph) ClCH CHEtN(CH Ph) BrCHMeCH NH ClCHMeCH NEt ClCHEtCH NEt C1CH CHNH C0 H C1CH(C0 H)CH NH ClCHMeCH NMe ClCHMeCH NMe ClCHMeCH NMe ClCHMeCH NH R (R = c - C H or iso-Pr ) ClCHEtCH NH R (R = c - C H or iso-Pr ) ClCH CHClCH NMe N,N-MQ -1 -ClCH -cyclohexylamin e N,N-Me -4-Br-cyclopent-2-enylamin e (cis or trans) 2-ClCH -l-Et-PY 2-ClCH , or 2-RC0 CH -l-Me-PY l-ClCHMeCH^PP " 3-Cl-l-Me - or -l-Et-PP 3-Cl-l-Me-PP 2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
6
ci-
H 0/OH AlH H O H O Ph CH" 3-Indoly l carbanio n Phenothiazin e anio n 6-MeO-8-H N-quinolin e
2074 164b 2074 2074 3074a 3065 2683 1551, 1553 1551, 1553 401 1404 646 757
6-MeO-8-H N-quinolin e
757
RS~ Ph C(CN)" Me NH
2724a 401 758
/?-0 NC H 02
6
4
ciciso — 3
2
fl
4
a
2
fl
2
a
2
2
n
2
6
2
n
2
2
2
2
2
2
c
2
c
2
2
2
d
d
C
2-BCH -l-R-PY [L(-)] 3-B-l-R-PP [D(+)] 2
D
Reference s
E
l-Et^-HOCHa-PY' ^
E
e
2
5
2
cici-
e
Ph C(CN)N H or amine s N H , Me N(CH ) NH B~(?) B-(?) RC0 " 2
3
2
4
2
a
a
2
2
3
2
1379 460a 401 3024a 369 1601 1601 3288
INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P
31
Tabl e 1-IV—continued Nucleophil e
Origina l hal o amin e
Reference s
d
3-X-l-R-PP 3-Cl-l-Me-PP 3-Cl-l-Et-PP 3-Cl-l-Et-PP 2-ClCH -l-Me-PY 3-Cl-l-Me-PP 3-Cl-l-Et-PP 3-Cl-l-Et-PP 3-Cl-l-Me-PP l-Et-3-tosyl-0-PP 4-(BzOCH CHICH )-morpholin e l-ClCMe CH -2,2,4-Me -piperazin e 3,7-Cl -l,5-OMeC H S0 ) -l,5-diazocin e (EtO) P(S)OCH CH NR Mesylat e of a u/c-amin o alcoho l derive d fro m thebain e d
d
d
c
2
d
d
d
d
d
2
2
2
2
3
2
6
2
a
b
c
d
e
f
9
ff
2
4
2
2
2
2
HO" , PhCH 0~, NC ~ EtO~ NC " RC0 RC0 ~ AcO" PhCH(CN)Ph C(CN)" H 0 BzO H 0/HO" 2
e
f l
2
a
2
e
fl
e
2
2
e
2
ci —
A1H4-
1601 460a 2834 2834 460a, 2834 460a, 2834 3288 2852 368 3288 1287 2500 2808 1375, 3484 2586
Unrearrange d amin e also found . Allylic rearrangemen t involved . P Y = pyrrolidine . PP = piperidine . Â is undefined ; R is alkyl . N o halid e involved ; ester exchang e gave l-Et-3-HO-PP . N o halid e involved ; produc t was l-Et-2-HOCH -PY . 2
Pyrolysis of the hydrochlorides of sterically crowded amines and hydrolysis of the reaction products yield a mixture of allylamines, ketones, and saturated amines in varying p r o p o r t i o n s (Eq 15). A n aziridinium ion ( 2 2 ) is probably intermediate (1695). R' RCH ^ /CHClM e 2
RCH
c
,M e -H
2
+
RCH=CR'CHMeNR " 2
N+ / \ R" R" 22 (15) RCH CR'=CMeNR "
[RCH CHR'CMe=NR " l 2
2
2
,H o
H Oy
2
2
RCH CHR'A c + R / N H 2
2
32
1. FORMATIO N OF TH E AZIRIDIN E RIN G
PREPARATIV E METHOD S
By far the commonest type of organic intermediates for the preparation of aziridines are the vicinal amino alcohols. These in turn are usually prepared by the well-known addition of ammonia or primary or secondary amines to epoxides (Eq 16) (3063).
+ H — N <
—C
C—
OH
(16)
Í
A Alternative routes to the amino alcohols are the reduction of esters of aamino acids with lithium aluminum hydride (447, 2576, 3471, 3632) and the hydrolysis of oxazolines (1430). Conversion of a protonated amino alcohol to a corresponding protonated halo amine is also a familiar operation in synthesis. Thionyl chloride is the most used for the conversion, but occasionally recourse is had to phosphorus pentachloride; direct esterification with hydrogen chloride or hydrogen bromide is feasible but requires forcing conditions (Eq 17). —C
C—
I OH
I Í
SOCI , PClj , HX
— C—C—
2
-
-
•
I
I
×
Í
.etc.
(17)
A A Handling of the 2-chloroethylammonium chloride thus formed is facilitated by using chlorobenzene as a diluent, etc. (1180). Amino alcohols of the type R C ( O H ) C H N H can be converted to the desired chlorides R C C 1 C H N H only with great difficulty if at all (724, 2101, 2519); the reaction also fails for 3a-amino-2jS-cholestanol (1622) and for 2-hydrazinoethanol (1085). It was pointed out by Wenker (3769) that conversion of 2-aminoethanol to 2-aminoethyl hydrogen sulfate offers some advantage in preparing EI. The esterification step is very simple, requiring only heating an equimolar mixture of the amino alcohol and concentrated sulfuric acid to about 250°C. Moreover, since the ester is nonvolatile, unlike the halo amine, there is no danger of distilling unreacted starting material along with the EI and exposing the latter to the considerable hazard of polymerization catalyzed by the halo amine. Hence the method has been used frequently. An important improvement was effecting the esterification-dehydration under reduced pressure to minimize charring (492,1484, 2255, 2290, 3422, 4022); other variations in this step are also claimed (214,237,1308,1313, 2890,3052,3229) and even sulfur trioxide (321a , 1432) also has some advantages. The Wenker esterification step, like conversion to a halo amine, usually fails when the alcohol is tertiary, dehydration to an olefinic compound (sometimes 2
2
2
2
2
2
33
INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P
an enamine) then taking precedence (12, 2170); but 2-amino-l-methylcyclohexanol did give some of an aziridine along with the unsaturated amine (3814). 3a-Amino-2j8-cholestanol, a secondary alcohol, was not esterified by sulfuric acid (1622), and 2-amino-2-methyl-l-tridecanol was merely charred (2883). Failure of the method applied to 2-anilinoethanol was attributed to sulfonation of the ring instead of esterification of the alcohol function (1377), but later work met no such difficulty (492). A quite different synthesis of 2-aminoalkyl hydrogen sulfates involves the Ritter reaction; an ally lie halide such as methallyl chloride treated with hydrogen cyanide or acetonitrile and concentrated sulfuric acid, then with water, yields a 2-aminopropyl ester such as ~ O S 0 C H C M e N H (1430). The process may be formulated, somewhat speculatively, as in Eq 18. +
3
CH =CMeCH C l 2
H z S
CH ==CMeCH +
2
2
2
4
° >
2
2
3
CH =CMeCH OS0 H 2
2
3
H +
(18)
Y +
H NCMe CH OS0 3
2
2
HG=NCMe CH OS0 H
3
2
2
Me CCH OS0 H
3
2
2
3
+ HC0 H T o return to the preparation of vicinal halo amines: most of the routes not yet discussed depend in principle u p o n addition to an olefinic b o n d at one stage. Thus the product of addition of bromine to ethylene, 1,2-dibromoethane, can be caused to react in excess with a primary (or secondary) aromatic amine to yield the "one-ended" displacement product, A r N H C H C H B r (461, 462); some advantage is claimed in having the halogen atoms dissimilar, and a tertiary amine present to serve as acid acceptor (1290). Although no intermediate is claimed or isolated, this one-ended displacement must operate in the recent process (119, 731,921,2561) for producing aziridines from vicinal dihalides or alkylene sulfates or disulfonates and ammonia or primary amines (Eq 19). The acid acceptor may be either calcium hydroxide, excess nitrogenous base, or an ion-exchange resin (3563a). The process is improved by 2
2
XCH CH X 2
2
-22L>
XCH CH NH + 2
2
XCH CH NH
3
羂
2
A
2
\7 +
N / \ Ç Ç
2
2
(19) X-
operation at high pressures (119). A more laborious path is the one-ended reaction of a 1,2-dihaloethane in the Gabriel synthesis using phthalimide,
34
1. FORMATIO N OF TH E AZIRIDIN E RIN G
then hydrolysis to the halo amine (3353). It has been suggested that one of the unidentified products of reaction of 1,2-dibromoethane and hydrazine is 1-aminoaziridine, isolated as the benzal derivative (3391), but no indication of formation of that aziridine from 1,2-dichloroethane in ethanol could be obtained (1084). It has been obtained by the Wenker method (202,1513,1765), as has l-amino-2-phenylaziridine in 6 0 - 7 0 % yield from the dimesyl ester of 1-phenyl-1,2-ethanediol and hydrazine (1284c). An old observation that dibromides of 2-bromoanethole and 2,x-dibromoanethole with excess aniline yield products that probably have the aziridine structure is also to be cited (1676), but should be confirmed. Less acceptable are the aziridine structures attributed to the products of reaction of potassium anilide with the dibromides of oleic and ricinoleic acids (1757a), which are not classified as aziridines in Beilstein and need reinvestigation. The reaction of dibromides derived from á,â-unsaturate d ketones ( 2 3 ) with ammonia and primary and secondary amines has already been mentioned (p. 27); secondary amines can of course yield only quaternary aziridinium compounds. While the process was at first formulated as yielding piperazine dimers (3784) or enamines (46, 2622, 3073), the assignment of aziridine structures to the products (786) has been amply confirmed. However, the reaction proceeds not by displacement, but by elimination to give the a-bromo-á,â unsaturated ketone ( 2 4 ) . Michael addition of a molecule of the nitrogenous base then yields the a-amino-/?-bromo ketone ( 2 5 ) , which cyclizes. The similar RCHBrCHBrCOR '
RCH=CBrCOR '
reaction of dibromides of á,â-unsaturate d acids and their derivatives takes the same course (1364). The nature of the amine can be influential: 2,3dibromopropionitrile with most primary amines yields aziridines but benzylamine produces enamines also (1553), and aziridine-2-carbonitrile could not be isolated as a product (1552). In 2 3 , when R is aroyl and R ' is aryl, the product of reaction with ammonia is more often an enamine than an aziridine (2360). The concurrent reaction of iodine and amines with á,â-unsaturate d ketones is a convenient route to substituted aziridines (795, 802, 806, 2799, 3343), but it involves addition of an iodine-amine complex to the olefinic bond and then elimination, and not the formation of a diiodide (3343).
35
INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P
Dibromides from allylic amines present difficulties in this reaction, because aziridine ring closure must yield a 2-(a-bromoalkyl)aziridine, in which the bromine function will tend to quaternize and activate the ring (intermolecularly) toward polymerization. 2,3-Dibromo-l-methylpropylamine thus gave a rapidly polymerizing aziridine (3702), and 2,3-dibromopropylamine has been found not to yield an aziridine at all by reaction with ammonia (3071) or aqueous sodium hydroxide (1449). The well-known addition of hypochlorous acid to olefins for chlorohydrin preparation suggests an analogous preparation of chloro amines. Passing nitrogen-diluted chlorine into liquid ammonia containing styrene causes only oxidation of the ammonia, and no involvement of the olefin (963). However, the preparation of 2-chloroalkylamines by addition of 7V-chloro amines to olefins is well authenticated (2564-2566, 2680-2684). The process is believed to involve aminium radicals (2683) in which each of the nitrogen atoms bears either a proton or a transition metal chloride; a chain reaction may prevail (Eq 20). \
1 1
+
+
R NH + / C = C ^
>
2
R NH—C—C 2
1
+
1
1
+
+
R NH—C—C - + R NH—C I 2
1
•
2
(20) I
I
R NH—C—C—C I + R NH + 2
2
I I
I I
In a different reaction, JV-bromo secondary amines have been shown to add to á,â-unsaturate d ketones and thus lead to aziridinium ions (3342, 3344, 3346). The addition of nitrogen trichloride to olefins succeeds and the hydrolysis of the resultant /?,7V,iV-trichloro amines yields â-chlor o amines (735), but this is not an attractive route to these intermediates. The addition of iodine isocyanate, I N C O , to olefins stereospecifically yields 2-iodoalkyl isocyanates ( 2 6 ) hydrolyzable to 2-iodoalkylamines, which may spontaneously cyclize to aziridines (Eq 21) (984, 1622, 1623); the reaction is useful in laboratory application to complex olefins, such as unsaturated steroids. NC O \
^
INC O + ^ c = c f ^
I >
I
—C—C— I I é
NH HO
I
2
>
2
I
—C—C—
(21)
I I é
26
A somewhat similar route involves reducing a vicinal chloronitrosoalkane, ^ C C I C ( N O ) ^ , t o the vicinal chloro amine; stannous chloride is preferred as the reducing agent (1006,2517,3703). Whereas highly substituted aziridines are probably best made by this route, simple ones cannot be so made. Just the
36
1. FORMATIO N OF TH E AZIRIDIN E RIN G
reverse situation sometimes prevails for the amino alcohol route to aziridines. Another predictable reduction, this one of á -chloro nitriles with lithium aluminum hydride, produces chloro amines cyclizable to aziridines. The following aziridines have been so prepared in the yields shown: 2-Pr, 8 2 % ; 2-iso-Pr, 7 2 % ; 2 - n - C H , 6 2 % ; 2-Ph, 4 6 % ; and 2 - P h C H , 5 8 % ( / * « ) ; 2 7 , 8 9 % , and 2 8 , 8 6 % (2175). F o r the preparation of 2-fluoroethylamines from fluoroacetamides (2811) or 2-iodoalkylamines from 2-azidoalkyl iodides (1310, 1626), reduction with diborane is particularly recommended. 6
13
2
?
PhNH -
\
N—Ph /
Cl NH
\
NH
27
Ï
28
29
A different reduction—that of a 2-azidoalkyl methanesulfonate ( 3 0 ) , with hydrazine and Raney nickel—forms an amino ester that immediately undergoes ring closure by expulsion of the mesylate ion (Eq 22). MeS0 0
MeS0 0
2
2
I I —c—c— I I
N
3
[H]
-0 SMe (22) 3
NH
2
N+ H 2
30
The reaction was used first for sugars and then for steroids (1561, 2908). Lithium aluminum hydride can also serve similarly as the reducing agent (2907), and 2-azido-3-cycloocten-l-yl iodide as the substrate for reduction and cyclization (1310). Some failures of the conversion of vicinal haloalkyl amines may be noted. 2-Anilino-1 -chloro- 1,1,2-triphenylethane could not be made to yield an aziridine (3506), nor could triphenylmethylamine and methyl 2,3-dibromopropionate (3310); steric factors are surely implicated. A failure to obtain 1phenylaziridine from JV-(2-bromoethyl)aniline (1378) is unaccountable since the preparation in fact succeeds very well (see Table I-V). l-Anilino-2-chloroN-phenylsuccinimide ( 2 9 ) yields only the enamine and not the aziridine (162), probably because elimination in this case is faster than displacement by the weakly basic anilino nitrogen atom. Somewhat similarly, l-(aminomethyl)cycloheptyl hydrogen sulfate gives only l-(aminomethyl)cycloheptene (4064). iV-(2-Bromoethyl)-l,5-pentanediamine has been reported (463) to be dehydrobrominated to the JV-vinyl diamine (Eq 23), b u t the product may in fact have been l-(5-aminopentyl)aziridine ( 3 1 ) (2002).
INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P
37
Tabl e 1-V PREPARATIO N OF AZIRIDINE S BY INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P
Aziridin e made , or substituent s therei n
Method "
% Yield*
Reference s
Aziridines Containing No Functional Groups N o substituent s
I
—
I
>70-75 >62 51.7 62 up t o 85 71.6 26.5 « 70-80
I I I I I II II II
1-Me
II II II II II II II II II II I I
2-Me
II II II II I I I II II II II
30-32 up to 85 70-76 34-37 83 81-83 80-84 50-91 77
47 40 26
80 19 65 60-63 50
57, 325, 464, 1182, 1385, 1391, 1392, 2091, 2117, 2125, 2440, 4034 325 1480 2440 470 1199 1180 3769 3651 525,1011,1083, 1430, 1742, 2177, 2254, 3052,3546 1996, 1997 1199 3841 61 3007 1252, 2090 1501 1308 176 921 2117, 2428 1742, 3185 3500 3044 333 406,1383,1388, 1723, 3302 3128 2576 1996, 1997 321a, 447, 2576 525 4022
38
1. FORMATIO N OF TH E AZIRIDIN E RIN G
Tabl e 1-V—continue d Aziridin e made , or substituent s therei n
Method "
% Yield"
Aziridines Containing No Functional Groups—continued I 7 I 35 II — II « 70 II 34 II 55
1-Et
c
2-Et
1,2-Me 1,2-Me 2,2-Me
2,3-Me
2
2
2
2
2-CH =C H 1-iso-Pr 2
2-Et-l-M e 1,2,2-Me 1,2,3-Me 2,2,3-Me 3
3
3
l-iso-Pr-2-CH = 1-Bu 2
\-sec-Bu \-tert-Bu 2-iso-Bu
—
II II II II II II I II II
46 50 — 68 65 55-89 20 30-35
II II I II II II II II II II II II II II II II II I, II I II II II I II II II
68 45-51
— 47 48-95 82
— 49 40-43 34 38
— — 19 45 65 >50
— « 70-80 74 54 72 35-40 27 45
Referenc e
2269 885 525 1043 333 2793 2662 1997 1466 525, 3651 2793 270 3629 2576 2576 518, 525,560, 1431, 1432, 2043 1997 565 3166 1997 910, 1466 333 288 3389 469 2883 2883 1976b, 2337 1680 1997 333 270 443 963 3651 1043 3796 470 469, 470 453 3471, 3631, 3632
39
INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P
Tabl e 1-V—continue d Aziridin e made , or substituent s therei n
Method "
% Yield
ft
Reference s
Aziridines Containing No Functional Groups—continued 1,2-Et 2-Me-2-P r 2-iso-Pr-2-M e l-Et-2,3-Me 2
2
2,2,3,3-Me 2,3-(CH =CH) (trans) l-(PrCHMe ) 2-Bu~2-Me 2GS>iso-Bu-l-M e 2-iso-Bu-2-M e l-iso-Pr-2,3-Me 4
2
2
2
l-Et-2,2,3-Me l-Ethyl-2(S)-iso-B u 2,2-Me -3-Pr 3-Et-2,2,3-Me 2,2,3-Me -3-Pr l-Bu-2-E t l-Bu-2,2-Me l-ter/-Bu-2,3-Me l-iso-Pr-2,2,3-Me l-c-C H „ l-Et-2,3-(CH =CH) 2-tf-C H -2-M e l-/^-Bu-2,2,3-Me 2-Et-l-iso-Pr-2,3-Me l-tert-C H 2-Me-l-/ert-C H 1-Ph 3
2
3
3
2
2
3
6
2
6
2
13
3
s
17
8
2-Ph
l-o-MeC H 6
4
17
2
(trans)
II II II II II 11 I II II II II II II II I II II I I II II II I II II II I I II II I I I I I I I II II I I I II I
60 47 39 — 72-73 >50 79 28.6 33-39 53 40 31 — >50 69 48 57 71 84 70 80 > 50 73 32 ð 21 51 69 73 41 76 * 40 68 85 61 60 — 56 High 81 — 66 80 90 57
1466 2883 2883 1680 1466 443 724 3389 469 2883 3631 2883 446, 1680 443 1694 3631 1997 724 724 1043 1043 443 1694 453 3388 2883 1694 1694 435 435 80 1658 1668 1290 453 2745 4018 3651 492 1387, 3824 3889 2564 492 1661
40
1. FORMATIO N OF TH E AZIRIDIN E RIN G
Tabl e 1-V—continue d Aziridin e made , or substituent s therei n
Method
0
% Yield
6
Reference s
Aziridines Containing No Functional Groups—continued l-m-MeC H l-/?-MeC H 6
6
I I I I I I I I II II II I I I II I II II I II II I
4
4
1-O-C1C H 6
4
l-m-ClQH l-m-FC H l-/>-FC H l-PhCH 6
4
4
6
4
2
2-PhCH l-Me-2-P h 2-Me-l-P h 2-Me-2-P h 3-Me-2-P h 2
l-PhCH -2-M e 2-PhCH -3-M e l-Et-2-P h 2-Et-2-P h 3-Et-2-P h l-PhCH CH l,3-Me -2-P h 2
2
2
2
2
2,2-Me -3-Ph l-iso-Pr-2-P h l-PhCH -2-(5)-iso-Bu l-G?-PhC H ) 2,3-Ph 2
2
6
4
2
2,3-(/?-ClC H ) l,2-Ph -3-M e 2,3-Ph -l-M e 2,2-Ph -3-Me 3,3-Me -2,2-Ph l-PhCH CH -2-P h 1,2,3-Ph 1-(1-C H ) l-iso-Pr-2-(2-C H ) l-iso-Pr-2-(l-C H OCH ) 1,2-[(CH ) ] 6
4
2
2
2
2
2
2
2
2
3
10
7
2
3
2,3-[(CH ) ] 2
3
l0
7
10
7
2
71 65 52 62 59.5 57.5
— 24 65 76 32
— — — 84
— 60 32 Poor 88 28
—
II
—
II II II I I I I I I I II II II II I I I II II
83 52 46 93
— 80-96
— — — Low Low 34
— 75
— — 20-25 Trac e to 40* 61-75
1661 1661 1661 1661 558 558 1389 1550 453 2046 3765 1290 2564 2130 492 3390 3601 3765 568 492 3765 2636, 2637 2708, 346 3479, 348 493,1015, 1572 492 3765 3631 302 853, 3762 3763 1630 903 3490 566 2101 3765 3506 3770 1773 1773 552 1419 1098, 1104
41
INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P
Tabl e 1-V—continue d Aziridin e made , or substituent s therei n
Method
Aziridines Containing No Functional I 2,3-Me -2,3-[(CH ) ] II 1,2-[(CH ) ] e 2,2-[(CH ) ] II 2,2-[(CH ) ] II I 2,3-[(CH ) ] II 2
2
2
2
4
4
2
4
l-Me-2,3-[(CH ) ] 2
4
2,3-(CH CHMeCH CH ) 2-Me-2,3-[(CH ) ] l-Et-2,3-[(CH ) ] 2,3-Me -2,3-[(CH ) ] l-Pr-2,3-[(CH ) ] l-C H -2,3-[(CH ) ] l-C H -2,3-[(CH ) ] l-Ph-2,3-[(CH ) ] l-PhCH -2,3-[(CH ) ] 2,2-[(CH ) ] 2
2
2
2
4
4
2
2
2
4
4
6
n
2
4
8
17
2
4
2
4
2
2
2
2
4
5
2,3-[(CH ) ] l-iso-Pr-2,2-[(CH ) ]-3-M e l-ter/-Bu-2,2-[(CH ) ]-3-Me 2,3-[(CH ) ] 2,3-[(CH ) ] 2,3-[(CH ) ] 2,3-(CH=CHCH CH CH CH ) l-(7-Cl-4-quinolyl ) 1 -(6-Cl-2-MeO-9-acridinyl ) 1-Adamanty l 2,3-Epimino-l,2,3,4-H -naphthalen e 1,2; 3,4-Diepimino-l,2,3,4-H naphthalen e (trans) 4a,8a-Epimino-l,4,4a,5,8,8a-H naphthalen e 4a, 8a-Epimino-H ! -naphthalen e 2,3-Epimino-7,7-Me -norbornane 27 (see p. 36) 28 (see p. 36) 9,10-Epimino- l ,5-cyclododecadien e 2
5
2
5
2
2
5
6
2
8
2
10
2
2
2
6
Referenc e
Groups—continued 73 — — 66 63 — —
II II II I
— —
I
—
1021
I I I I I I
— 78 42 89 86 —
3703 2517 1006 2175 2175 1623
II II II II
82.5 28 70 —
II II II II I II II II II II II II II I I II II II
77.5 — —
— 76 63.5 73 65 — 72 57 68 78 59 56 33 13 30-50
/
2
4
% Yield
724 3458, 3854 202 3482 2883 3456 1435, 3463, 3814 3151a 2820 3456 2627, 3457, 3814 3151 1436, 3151 3814 2131 724 3151 3151 3151 1685 3151 3151 1099 2883 3483 1694 1694 2047 1101 1102 1310 2837 2837 991, 994 984
3
4
2
e
— 38 15
9
4
6
0
g
2
42
1. FORMATIO N OF TH E AZIRIDIN E RIN G
Tabl e 1-V—continue d
Aziridin e made , or substituent s therei n
Method
0
% Yield"
Reference s
Aziridines Containing No Functional Groups—continued 5,6-Epiminodibenzo[tf,c]cycloheptan e 2,3-Epiminosqualen e 2a, 3a-Epiminocholestan e 2â, 3^-Epiminocholestan e 2â, 3j3-Epiminocholestan e 2â, 3^-Epiminocholestan e ÇÍ / í NH É ×
×
É
I — — I I —
h
1
1
II
— — ^ 100 75 « 70 « 100
3240 759 2907 1622 2906 2907
46
2883
30 68 36
1905 1905 1905 46, 789, 2622, 3073 3343 796 3184 1905 798 796 3784 801 4075 795 2360 3638 796 803 2360 796 789 796 3343 788 2799 3344 802 800 3344 805 3638
Aziridinyl Ketones 2-Bz-l-M e 2-Bz-l,3-Me 2-Ac-l-Me-3-P h 2-Bz-3-Ph
II I II I II I II I
2
2-Bz-l-c-C H n 2-Bz-l-c-C H -3-M e 2-Bz-l-Me-3-P h 6
6
n
3-Ph-2pC/?-MeC H CO ) 2-Bz-3-(/?-0 NC H ) 6
2
4
6
4
2-(p-0 NC H CO)-3-P h 1,3-Me -2-(^-PhC H CO ) 2,3-Bz -l-M e 2
6
4
2
6
4
2
l-Me-3-Ph-2-(^-MeC H CO ) 6
4
2,3-Bza-l-E t 1-c-QH i -2-(;7-PhC H CO ) 2-Bz-l-c-C H -3-P h 1
6
6
4
n
2-Bz-l-c-C H -3-(/7-MeOC H ) 2-Bz-l-c-C H -3-(/7-0 NC H ) 2-Bz-l-c-QH ! 3 - ( p - 0 N C H ) 2-Ac-3-(p-PhC H )-l-c-C H l-c-C Hn-2,3-Bz 6
11
6
6
n
2
r
2
6
6
6
2
2
6
6
4
4
4
11
II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I
— 57 80
— 57 26 61
— 78
— 84.6 43 50 40
High — 80
— 78 46 50-54
— 97-100
— 89 60-90 » 68 65
43
INTRAMOLECULA R DISPLACEMEN T BY TH E AMIN O GROU P
Tabl e 1-V—continue d
Aziridin e made , or substituent s therei n
Method "
% Yield"
Reference s
Aziridines Containing No Functional Groups—continued 2-Bz-l-PhCH -3-P h 2
2-Bz-l-PhCH -3-(m-0 NC H ) l-c-C H -3-Me-2-(p-PhC H CO ) l-c-C H ! 3-Ph-2-(/?-MeC H CO ) 2,3-Bz -l-P h 1 -Me-3-Ph-2-(/?-PhC H CO ) 2
6
2
6
n
6
6
r
4
4
6
4
2
6
2
l-PhCH -2,3-Bz 1 -PhC H -3-Ph-2-(/?-MeC H CO ) 2
2
2
6
4
l-c-C H -3-Ph-2-(^-PhC H CO ) 6
n
6
4
2-(/>-BrC H CO)-l-c-C H 3 - P h 8,9-(N-Cyclohexylepimino)perinaphthan 7-one 6
4
6
1 r
Hi II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I
— 35 73 52 46 20 92 77 31 74 92 71 74 20 91 94 89
789 796 3343 788 793 785 806 796 2360 795 803 3638 796 785 790 795 2898
II I
—
4031
Aziridines Containing Other Functional Groups 1-H N 2
2-H NCH 1-H NCH CH 2-H NCH -2-M e l-R-2-Ph-2,3-(0-QH C- ) II NR (R = Me or c - C H ) l-(2-C!CH CH ) 2-ClCH -3-M e (or 2-MeCHCl? ) 2-BrCH -3-Me 1 -p-(4-H NC H S0 C H ) 2-Me0 C 2-Et0 C 2
2
2
2
2
2
2
II
35
II II II
42.7 16 29
202,1513, 1765 3354 1996 3354
4
6
2
II I
4116
n
2
2
2
2
6
2
2
2-Pr0 C 2-iso-Pr0 C 2-Bu0 C l-Me-2-Me0 C 2
2
2
2
4
2
6
4
II I
80 7.6 20 50 38 55 25 76 44 49
161b, 891 3702 1942 1364, 1551 1553 1364, 433 2215 1364, 1364, 124
2987a
2215
2215
2215 2215
44
1. FORMATIO N OF TH E AZIRIDIN E RIN G
Tabl e 1-V—continue d Aziridin e made , or substituent s therei n
Method "
% Yield*
Reference s
Aziridines Containing Other Functional Groups—continued l,3-Me -2-Me0 C 2-Et0 C-3-M e l-Bu-2-Me0 C l-Et-2-Me0 C-3-M e l-CH =CHCH -2-Me0 C-3-M e 1 -EtOCH CH -2-Me0 C-3-M e l-(3-HOCH CH CH )-2-Me0 C-3-M e l-(3-Me NCH CH CH )-2-Me0 C-3-M e l-Bu-2-Me0 C-3-M e l-«-C H -2-Me0 C-3"M e l-Bu-2-Me0 C-3-P r l-C H -2-Me0 C l-C H -2-Me0 C-3-M e PhCH 0 C l-PhCH -2-Me0 C 2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
6
13
2
2
6
n
6
2
n
2
2
2
2
2
l-PhCH -2-Me0 C-3-M e 2
2
1 -0?-ClC H CH )-2-MeO C-3-M e 1 -0?-MeOC H CH )-2-MeO C-3-M e 2-Me0 C-l-PhCH CH 2-MeO C-l -0?-MeOC H ) 2-Et0 C-l-PhCH -3-M e 2-Me0 C-3-Me-l-PhCH CH l-PhCH -2-iso-Pr0 C-3-M e 6
4
2
6
2
4
2
2
2
2
2
2
6
2
4
2
2
2
2
2
2
l-(c-C H , NHCH CH )-2-Me0 C l-(2-Furylmethyl)-2-Me0 C l-(2-Furylmethyl)-2-Et0 C-3-M e 2-Me0 C-3-Me-l-(l-methylpiperid-4-yl ) 3-AcO-l-PhCH -2-Me0 C 2-Et0 C-l-Et-3-P h l-C H -2-Et0 C-3-P h l-PhCH -2-Et0 C-3-P h l-Ph CH-2-Me0 C l-(Ph CHCH )-2-Me0 C 2-Me0 C-l-Ph C 6
1
2
2
2
2
2
2
2
2
2
6
n
2
2
2
2
2
2
2
2
2
II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I II I k
3
l,2,2-(o-MeC H NH) l,2,2-(/?-MeC H NH) 2-NC-l-M e 2-NC-l-P r 2-NC-l-iso-P r l-Bu-2-NC 6
6
4
4
3
3
II I II I II I II I II I II I
33.8 44 76.9 40.4 61.3 49.2 26.3 24.5 73.0 71.4 41.5 85 78.4 34 74 —
50 71.2 91.2 62.8 21 36 20 51.9 64 65-85 13 68 Poor 17.2 Poor 62 99 19 78-94 « 30 80 — —
34.5 —
59 77
3720 2215 3720 3720 3720 3720 3720 3720 3720 3720 3720 572 3720 1684 572, 3390 2078, 3310 572, 3390 3720 3720 3720 572, 2078 572 572 3720 572 2928 572 572 572 3720 572 2624 2624 2624 3310 572 3310, 3311, 3315 2656 2656 125 3721 125 1553
45
INTRAMOLECULA R DISPLACEMEN T BY THE AMINO GROU P
Tabl e 1-V—continue d Aziridin e made , or substituent s therei n
Method "
% Yield*
Reference s
Aziridines Containing Other Functional Groups—continued 2-NC-l-Me CCH 2-NC-l-c-C H 3
6
2
n
l-PhCH -2-NC 2
l-(/?-ClQH CH )-2-NC 2-NC-l-0-MeOC H CH ) l-PhCH -2-NC-3-M e 2-NC-l-c-C H -3-P h 2,3-(Me0 C) 2,3-(Et0 C) 2,3-(Pr0 C) l-(R-MeOC H )-2,3-(Me0 C) 2-H NC O 2-Et0 C-3-H NC O 2-H NCO-3-P h 2-H NCO-3-(/?-0 NC H ) 2,3-(H NCO) 2,3-(Et0 CCH CH ) -2-M e l-Bz-2-NC 1,2-(CMe N=CPh)-3-(>0 NC H ) 2,3-(CH OCH ) l-Me-2,3-(CH OCH ) 1,2-(CH CH NHCO)-3-P h 1,2-(CMe=CHCHOEt)-2-Me-3-C l l,2-[C(te^Bu)==CHCHOEt]-2-Me-3-C l 2,5-Az -hydroquinone 2-AzCH CH NH-quinolin e JV,iV'-Methylenebis(l-R-aziridine-2 carboxamide ) (R = Me, Et , Bu, or PhCH ) 4-(MeN=)-l-Ph- l ,2-(AT-Me-epimino) 1,2,3,4-H -naphthalen e 4-(PhN=)-l-Ph-l,2-(A^-Ph-epimino) 1,2,3,4-H -naphthalen e Variou s dyes containin g th e CH Az' grou p TE M [2,4,6-tris( l -aziridinyl)-5-triazine ] Methy l 4,6-Obenzylidene-2,3-dideoxy 2,3-epimino-a-D-mannosid e Methy l 4,6-0-benzylidene-2,3-dideoxy 2,3-epimino-a-D-allosid e 1-(H or PhCH )-2-EtO C-3-(tetra-0-acetyl L-arabinobuty\) 4
2
6
4
2
2
6
n
2
2
2
2
2
2
6
4
2
2
2
2
2
2
2
2
2
6
4
2
2
2
2
2
2
2
2
6
4
2
2
2
2
2
i
2
2
2
2
4
4
II I II I II I II I II I II I II I II I in II I II I II I II I II I II I II I II I II I I II I II I II II II I I I I I
67 51 59
55
7555 125 3721 1553, 3721 125 1553 1553 1553 2856a 3798 3798 3798 3798 2215 1677, 2287 3862 2087, 2088 1677 1065 150 4074 1095 1095 2623 2699 2700 2453 2921
II I
—
152
II I
70-77
797
II I
73-81
797
II II
— —
2970 4210
I
83
1561
I
48-100
1561
II I
up to 25
924a
—
39.5 66
—
—
99 « 28 30-45 « 50 <5 — — —
56-80 — — —
72 49 58 16 — — —
2
2
2
1. FORMATIO N OF THE AZIRIDIN E RING
46
Tabl e 1-V—continue d Aziridin e made , or substituent s therei n
Method "
% Yield"
Reference s
Aziridines Containing Other Functional Groups—continued 5-Cl-la-R-l,la-H -3-Ph-azirino[l,2-tf] quinazolin e 2-oxide (R = Ç or C1CH ) 6a , 7a-Epiminocholestanol-(3j8 ) 3-acetat e 6â, 7j8-Epiminocholestanol-(3/? ) 3-acetat e 5a , 6a-Epiminocholestanol-(3/? ) 3-acetat e 4a , 5a-Epiminoandrostanediol-(3j8, 1 ºâ) 4á , 5a-Epiminoandrostanediol-(3/8, 1 ºâ) 17-propionat e 2
80 80 85
1287b, 1744 2908 2908 2908 979a
90
979a
94 98 40 42 24
2294 2294 2295 1905 1905
64
13
61
2299
79 >50
2299 2299
2
Aziridinium Salts 1,1-Et (perchlorate ) 1,1,2,2-Me (perchlorate ) 2,2-[(CH ) ]-l,1-[(CH ) ] (perchlorate ) 2-Bz-l,l-Me (bromide ) 2-Bz-l,l,3-Me (bromide ) 2-H0 C-l,l-(CH CH CH CH CO) (bromide ) 2-Ac-l,l-[(CH ) ]-3-P h (dl-cis) (perchlorate ) 2-Bz-l,l-(CH CH OCH CH )-3-P h (perchlorate ) dl-cis for m dl-trans for m (1 -Et- 1 -azoniabicycl o [3.1.0]hexane ) (perchlorate ) (6-PhCH -4-Br-l,4,5-Me -l-azoniabi cyclo [3.1.0]hexane ) (perchlorate ) (l-Azoniatetracyclo^^^.O ' . 0 · ] tetradecane ) (perchlorate ) 1,1 - ( C H C H N H M e C H C H ) (dipicrate ) 2
4
2
5
2
4
2
3
m
2
2
2
2
2
2
5
2
2
2
2
2
1601
3
1
1 3
5
+
2
2
2
14
1359
39
2295 825
1 3
2
a
l = hal o amin e + stron g base ; II = aminoalky l hydroge n sulfat e + stron g base ; II I = hal o amin e + N H or amine , or olefinic compoun d + haloge n + excess amine . Whe n a paten t claim s a genera l proces s bu t gives no yields, only th e simples t aziridin e mentione d is tabulate d here . By pyrolysi s of H O C H C H N H E t Cl~. Trac e fro m 3-piperidino l bu t 40% fro m 3-pyrrolidinemethanol . By dehydratio n of th e amin o alcoho l over hot alumina . Fro m th e vicina l azid o halid e by reductio n with LiAlH an d displacemen t of halide . Structur e uncertain ; formulate d as an enamin e in th e literature . Fro m th e vicina l azid o tosylat e by reductio n with LiAlH an d concomitan t displace men t of th e tosylat e group . Fro m th e vicina l azid o mesylat e as in h. 3
b
c
+
2
2
2
d
e
f
4
9
Ë
4
1
INTRAMOLECULA R DISPLACEMEN T BY THE AMINO GROU P
BrCH CH NH(CH ) NH ->CH =CHNH(CH ) NH 2
2
2
5
2
2
2
5
2
or
47
Az(CH ) NH 31 2
5
2
(23)
The actual cyclization step has been most studied preparatively for EI, partly because among all the aziridines it is most important commercially and at the same time one of those most easily destroyed in the preparation and isolation. Wenker's suggestion for use of 2-aminoethyl hydrogen sulfate (3769) appeared at nearly the same time that a general method was patented (3651). The major advances since then have been the realization that rapid removal of alkylenimine from the hot alkaline reaction mixture is essential to good yields, and development of ways to accomplish this. The halo amine salt or sodium aminoalkyl sulfate solution is dropped into boiling aqueous alkali, whence the imine is immediately steam-distilled out (304, 325, 1011, 1199, 3007, 3008, 3841). In continuous processes operated at 50-80 atmospheres and 220°-250°C, all EI may be produced in 4-10 seconds in 8 0 % yield (176, 1252, 2090). Ethylenimine is separable from mixtures by distillation as an azeotrope, preferably with hexane (725). Table 1-V presents results of preparations on aziridines and aziridinium salts by intramolecular displacements. A discussion of quaternary aziridinium salts, including review of their preparation, is given by Leonard (2292). The structures assigned to those derived from 2-pyridone (75) appear very improbable in view of the reactivity of activated aziridines in the presence of acid (see p. 248). If valid, these structures represent the only known stable activated aziridines containing tetracovalent nitrogen. In a good many instances of preparative work a 2haloalkylamine or 2-aminoethyl hydrogen sulfate has been treated with aqueous alkali and a nucleophilic reagent simultaneously. Whether such reactions proceed by way of aziridines that undergo ring opening, or whether direct displacement occurs, is not usually clear, and can only be surmised for each individual reaction mixture. Since, as has been noted, 2-bromoethylamine cyclizes much faster than 2-chloroethylamine or 2-aminoethyl hydrogen sulfate (see p. 11 and Table l-II), the arbitrary decision has been made for present purposes to regard use of a 2-bromoalkylamine in alkaline solution as an in situ preparation of an aziridine, whereas such reactions of the others are considered not to proceed via aziridines and are not reviewed here. 2-Bromoethylamine has thus been used to make methyl Af-(2-mercaptoethyl)dithiocarbamate (2943), 2-aminothiazolines, 2-aminooxazolines, and 3
Claime d forme d (bu t as a distillabl e product , which appear s extremel y unlikely ) fro m 1,2,3-trichlorobutan e an d ammoni a autoclave d together . By intramolecula r displacemen t of a sulfonat e group . Fro m th e vicina l azid o halide , mesylate , or tosylat e by reductio n with Rane y nicke l an d hydrazin e an d concomitan t displacement . Structur e is in doubt ; see above . k
1
m
48
1. FORMATIO N OF THE AZIRIDIN E RING
2-mercaptothiazolines (1386), substituted thiazolidines from xanthates (2395), H N C H C H S C S - (4153), 2-aminoethanethiol (3622), 2-(alkylthio)ethylamines (166, 723, 3622), 2-(arylthio)ethylamines (2205), polyamines (2752), and aminated dextran (3695). 2-Bromobutylamine similarly gave a mercaptothiazoline (418) and an aminated dextrin (3695). A curiosity of some biological interest is the detection of l-(2-chloroethyl)aziridine in the air exhaled by rats to which Endoxan had been administered; evidently hydrolysis and cyclization are involved (4157). +
3
2
2
2
X
N(CH CH C1) 2
2
2
Endoxa n
Intramolecula r Displacemen t by Amid e Anion s
L = leavin g group ; A = acyl or like grou p
This method of obtaining aziridines is very like the one already discussed, in stereochemistry, variability of L, order of reaction, etc. However, it succeeds only in solution alkaline enough to produce the requisite concentration of amide anions; the statement (1444) that it can proceed with elimination of H L appears unfounded. Sulfonamides are more readily converted to such anions than are carboxamides; their cyclization is reviewed first, in Tables 1-VI and 1-VII. N o doubt diethyl A^-(2-chloroalkyl)phosphoramidates (3902) can be cyclized similarly. Tabl e 1-VI PREPARATIO N OF 1-ARYLSULFONYLAZIRIDINE S BY CYCLIZATIO N
L
Aziridin e substituent s
CI
l-PhS0
CI
1-OFC H S0 )
2
6
4
2
% Yield 90 94 70 92
Reference s 1848 3183 1979 3183
INTRAMOLECULA R DISPLACEMEN T BY AMIDE ANIONS
49
Tabl e 1-VI—continue d Aziridin e substituent s
L
l-(m-H NC H S0 ) l-(/7-H NC H S0 ) l-(/?-MeC H S0 ) l-(m-0 NC H S0 ) l-(/>-0 NC H S0 ) l-(p-MeOC H S0 ) l-(3-H N-4-MeOC H S0 ) l-PhS0 -2-ClCH l-PhS0 -2-ClCH l-(/?-ClC H S0 )-2-ClCH l-0>-BrC H SO )-2-ClCH 1 -0?-MeC H SO )-2-ClCH l-PhS0 -2-BrCH l-PhS0 -2-BrCH
CI CI CI Br Br Br CI Br Br Br CI Br CI Br Br CI CI CI Br
l-PhS0 -2-E t l-ArS0 -2,2-Me l-PhS0 -2,3-Me (cis an d trans) l-PhS0 -2,3-Me l-PhS0 -2-BrCH -2-M e 1 -(/?-ClC H S0 )-2-BrCH -2-M e l-(/?-BrC H S0 )-2,2-Me l-(/?-BrC H S0 )-2-BrCH -2-M e l-(p-MeC H S0 )-2-BrCH -2-M e l-(p-AcNHC H S0 ) l-PhS0 -2-P h l-PhS0 -2-P h l-(p-MeC H S0 )-2-P h l-( p-MeC H S0 )-2-P h l-PhS0 -2-PhCH l-PhS0 -2-Bz l-ArS0 -2-Me-2-Cl C l-(/?-MeC H S0 )-2,3-Ph (cis an d trans) l-PhS0 -2,3-[(CH ) ] (CH CMe) «
2
6
4
6
2
4
6
2
4
2
6
2
6
2
4
2
4
6
2
4
2
2
6
2
4
2
2
2
2
6
4
6
4
2
2
2
6
2
4
2
2
2
2
2
2
56
—
2660
— —
1366 1366
—
1366 3185a 542a
— 70-81
2
2
— —
2
2
82-93
2
2
2
2
2
6
4
2
6
4
2
6
4
2
6
4
2
2
2
2
2
6
4
2
2
2
6
4
2
6
4
2
j
2
2
2
2
3
6
4
2
2
2
2
4
Reference s 1979 1979 3183 3183 3183 3183 1979 2058 1453 2058 2058 2058 1453 7, 1449, 1450, 2124 2322 2439 852a, 2322 2323 541 541 12 541 541 1480 3185a 519, 3479a 3185a 2077 1454 2551 2059 3185a 4185
64 65 94 81 75 98 82 65 85 50 70 61
CI CI CI CI CI CI CI CI Br CI CI CI CI Br
2
% Yield
— 96 95 46 97 83
— —
— —
> 95 81 60-80 0
—
2
I
CI CI CI CI CI Br
1 l-/>-0 SC H CON H 1 - [3-(l -Hydroxy-2-naphthoylamino) 4-methoxyphenylsulfonyl ] l-[4-(^_Anisoylacetylamino)phenylsulfonyl ] 1 - [4-(5-Oxo-l -phenyl-2-pyrazoline-3 carboxamido)phenylsulfonyl ] l-(/?-MeC H S0 )-2,3-(CH C H -i? ) l-PhSQ -2-NC 2
6
4
6
2
4
2
2
6
4
—
—
2
2
2
2
2
2
ClCH CH NHS0 P h
2
(ClCH ) CHNHS0 P h
2
ClCH CHMeNHS0 P h
Benzenesulfonamid e
95% 95% 95% 95% 95% 95% 95% 95% 95% 95% 95% 95%
EtO H EtO H EtO H EtO H EtO H EtO H EtO H EtO H EtO H EtO H EtO H EtO H
Solvent
6
NaOH , NaOH , NaOH , NaOH , NaOH , NaOH , NaOH , NaOH , Alkali, NaOH , NaOH , NaOH ,
2 2 2 2 2 2 2 2 1-2 2 2 2
2
Addend , M x 10 0.04 10.30 15.10 21.0 0.04 10.30 15.10 21.0 0.04 10.30 15.10 21.0
Temp . (°C) 3.74 11.09 25.03 61.17 2.75 10.26 23.18 43.03 2.46-2.56 10.79 22.54 40.23
k°
-1
k (= k° ÷ 10-" ) (sec )
4 4 4 4 4 4 4 4 5 5 5 5
ç
0
—
—
— —
— 7.4
—
— 21.65
—
1.59
—
—
— 13
— 1.88
— — 21.54
— —
—
—
— — — 21.42 — —
— 12
—
— 12 —
ç
-1
A (= A° ÷ 10") (sec ) A°
Å (kcal )
RAT E OF CYCLIZATIO N OF SUBSTITUTE D BENZENESULFONAMIDE S TO AZIRIDINES
Tabl e 1-VH
1448 1448 1448 1448 1448 1448 1448 1448 1448 1448 1448 1448
Refer ences
50 1. FORMATIO N OF THE AZIRIDIN E RIN G
a
2
2
6
6
4
NaOH , 2 NaOH , 2 NaOH , 2 NaOH , 2 NaOH , 2 NaOEt , 0.8-6.2 NaOEt , 0.9-6.7 NaOEt , 1.8-6.7 NaOEt , 1.5-6.7 NaOEt , 1.1-6.7 NaOEt , 1.0-6.7 NaOH , excess NaOH , excess
— — —
— — — —
— — — —
4 4 4 5
0.97-0.81 0.88-0.80 6.24 8.37
25.0 25.0 60 60
—
3183
— —
—
4
25.0
3183
—
—
3.8-3.1
8.1-7.2
25.0
2111 2111
3183
3183
3183
—
—
—
12
— — — —
1448 1448 1448 1448 1448 3183
— —
—
4
6.8-5.9
25.0
—
— —
8.3
—
— —
22.01
— — —
4
5 5 5 5 2 4
5.61 20.2 49.4 95.1 « 5 5.6-4.5
0.04 10.30 15.10 21.0 0.04 25.0
Exceptin g for th e last two sulfonamides , all rate s wer e followed by determinatio n of chloride . * LiOH , NaOH , KOH , CsOH ; adde d NaC10 ha d littl e effect.
2
4
70% MeO H 70% MeO H
3
3
2
6
4
4
H0 SOCH CHMeNHS0 C H Cl -/7 H0 SOCHMeCH NHS0 C H Cl-/ ?
2
2
6
2
EtO H
2
2
2
6
2
ClCH CH NHS0 C H N0 -w
2
2
2
6
4
ClCH CH NHS0 C H N0 -i7
2
2
2
2
6
EtO H
ClCH CH NHS0 C H F-/ >
2
2
2
2
2
EtO H
ClCH CH NHS0 C H OMe -/7
2
2
4
EtO H
ClCH CH NHS0 C H Me- p
2
2
2
4
EtO H
(BrCH ) CHNHS0 P h ClCH CH NHS0 P h
2
4
47.5% EtO H 47.5% EtO H 47.5% EtO H 47.5% EtO H 95% EtO H EtO H
2
ClCH CH NHS0 P h
INTRAMOLECULA R DISPLACEMEN T BY AMID E ANIONS 51
52
1. FORMATIO N OF THE AZIRIDIN E RING
W h a t has been called "methylenation" of Schiff bases by sulfonium ylides, though only a few examples are known, may be classified here mechanistically. Trimethylsulfonium methylide (32) adds to the ^ C = N - group and then intromolecular displacement of dimethyl sulfide closes the ring (Eq 24) (760,1326). ArCH=NA r + -CH SMe + 2
•
2
+Me SCH CHArNAr 2
_
M C z S
2
>
\
/
A
r
Í
32
I
Ar
(24)
Similar reactions occur, although more slowly, with dimethyloxosulfonium methylide, ~ C H S ( 0 ) M e (760, 1800, 2126,2536), dimethyl sulfoxide being eliminated; the most striking example is the conversion of 3-phenyl-2i/-azirine to the bicyclic compound 33 (1763). Carbonyl-stabilized sulfonium ylides, " R C O C H S M e , ultimately yield not the aziridine 34 but its isomer R C O C H = C A r N H A r (3352). +
2
2
+
2
^A r RC 7 11
XT
Ï
Í Ar 34
33
It might be supposed that cyclization of iV-(2-substituted alkyl)carboxamides would yield 1-acylaziridines (Eq 25), but it has long been known and L '
I
I
stron g base Â
_C_C I I
I
\
*
/
\ / Í I CO R
NHCO R
,_
+ L - + BH
(25)
often redemonstrated that the usual course of the reaction (Eq 26) leads to an oxazoline (35). I
I
J + + L+H
I
I
R
R 35
(26)
While 1-acylaziridines can be rearranged to oxazolines (1656), it is not likely that oxazoline formation proceeds by way of aziridine intermediates as a
INTRAMOLECULA R DISPLACEMEN T BY AMIDE ANIONS
53
rule (1667). Those few instances in which aziridines are formed rather than oxazolines will now be discussed. Possibly because of decreased resonance stabilization of the anion 36 resulting from removal of a proton from a mono-7V-substituted urethan (Eq 27), stron g bas e
RNHC0 R ' 2
•
-
RNC0 R '
(27)
2
36
which is apparently less than for other carboxamide anions, internal displacement of halide by the amide nitrogen atom to give aziridines occurs (Eq 28) instead of the displacement by amide oxygen to give oxazolines (Table 1-VIII).
NHC0 R
I C0 R
2
2
Since the iodo urethans can be made readily, and stereospecifically trans, by the addition of iodine isocyanate to olefins (see p. 35) and addition of alcohol to the product, the synthesis is an attractive one for laboratory use. In one example only, a mesylate anion, M e S 0 0 ~ , is displaced instead of halide, to produce a biaziridine (1275). Occasionally a competing elimination leads to the enamides, ^ C = C R — N H C 0 R , which tautomerize and hydrolyze to ketones (1624). The l-(alkoxycarbonyl)aziridines, however, are as unusually susceptible to hydrolysis as a urethan is resistant, and normally the final product is an aziridine without the 1-substituents (Eq 29) (see p. 253). 2
2
Threo iodo carbamates yield aziridines (cis) more smoothly than the erythro forms do (to give ira«,y-aziridines) (1433). This is attributed to steric impedance of formation of the transition state yielding the trans form; moreover, also for steric reasons, the hydrolysis of methyl frafl.y-2,3-dialkyl-l-aziridinecarboxylates is much slower than that of the cis isomers. Nearly all examples of this kind of aziridine formation remaining for discussion are facilitated by the presence of very effective leaving groups, tosylate or mesylate. They also all involve trans groups on six-membered rings. Thus
1. FORMATIO N OF THE AZIRIDIN E RING
54
DL-iraAW -2-benzamidocyclohexyl tosylate (3459) and DL -ira«s-2-benzamidocyclohexyl-S,S-dimethylsulfonium iodide (37) (3465) with hot alcoholic sodium ethoxide each yield an aziridine and an oxazoline in about 4 : 1 ratio (Eq 30).
Tabl e 1-VII I PREPARATIO N OF AZIRIDINE S FRO M JV-(2-HALOETHYL)CARBAMI C ESTERS "
Aziridine , or substituent s therei n 2-tert-Bu 2,3-Et (trans) 3-Me-2-iso-P r (trans) 3-Me-2-iso-P r (cis) 2-("-C H ) 2-(n-C H ) 2-(«-C H ) 3-(«-C H )-2-[R(CH ) ] 2
8
n
10
21
16
x
33
2x+1
X
2
R Me Me HO HO Me Me HO HO Me0 C
5-8 8 5-8 8 5-8 8 5-8 8 8
2
2-Ac 2-Cl CC H 2 2-Ph 2-Ph 2-Ph-3-r f 2,3-Ph (cis) 2,3-[(CH ) ] 2,3-[(CH ) l 3
2
2
4
2
4
% Yield
Reference s
60 45 33 32 75* 65* 70"
4056 3448 3448 3448 1305 1305 1305
30-43 47 35-50 70 49-65 19 30-58 53-58 51-97
4115 1433 4115 1433 4115 1433 4115 1433 1433
0 0 60 61-88 — 45 55 52
4056 4056 1305 1624 1625 1305 1305 1624,
y
y
Configuratio n
7-11 7 7-11 8 7-11 7 7-11 8 7
cis cis cis cis trans trans trans trans cis
b
c
INTRAMOLECULA R DISPLACEMEN T BY AMIDE ANIONS
55
Tabl e 1-VII I —continued Aziridine , or substituent s therei n
% Yield
Reference s
70* 60 65 64 56 65 — — 56-70'
3167 3448 1623 1623 1623 1624 4140 4140 1624, 1627 3165 1624, 1627, 3167 433 2837
2,3-[(CH ) ] 2,3-[(CH ) ] 2,3-[(CH ) ] 2,2-[(CH ) ] 2,3-[(CH ) ] 1,2-Epiminoinda n 2,3-(CH CMe=CHCH ) 2,3-(CH CH=CHCH )-2-M e 1,2-Epimino- l ,2,3,4-H -naphthalen e 2,3-Epiminonorbornan e Cholesten(2j8,3j3)imine '
88-90
3,4-Epiminotetrahydrofura n 5,6-Epiminodibenzo[fl,c]cycloheptadien e
54 Goo d
2
4
2
4
2
4
2
5
2
5
2
d
e
d
2
2
2
4
—
g fc
a
Haloge n = iodin e except as noted . Haloge n = chlorine . In aqueou s solutio n 0.01-0.001Mi n carbamat e an d 0.01-0.15Mi n KOH , at 24° ± 0.5°C; rat e of cyclization , k, = 2.69-3.78 ÷ 10" sec" . Via th e sodiu m bisulfit e adduc t of th e isocyanat e instea d of th e alcoho l adduct . Produc t isolate d as th e pheny l isocyanat e adduct . For th e methy l ester , for which rat e (as before ) = 12.1 ÷ 1 0 s e c . Othe r rates : ethy l ester , 10.05 ÷ 1 0 s e c ; isopropy l ester , 7.32 ÷ 1 0 s e c . By mild treatmen t th e methoxycarbony l derivativ e could be isolate d in 64 % yield (1627). Rat e of cyclizatio n for th e methy l ester = 16.9 ÷ 1 0 s e c . b
c
5
1
d
e
f
- 5
- 5
-1
- 5
-1
-1
9
h
- 5
-1
+
In contrast, B z N H C H M e C H P h S M e I " gives only the oxazoline (3465). The products of acetolysis of either 2-benzyl-3-oxo-2-azabicyclo[2.2.2]octan-ewifo-6-ol tosylate or 2-benzyl-3-oxo-2-azabicyclo[3.2.1]octan-e«ifo-7-ol tosylate are best explained by postulating the acylaziridinium ion 3 8 as an intermediate (1792). 2
CH P h 2
Desire for possible antitumor drugs and intermediates for synthesis of various amino sugars has motivated related research. Various methylpyranosides, but not furanosides (549), having appropriate groups in the 2- and 3-
D-Altros e D-Altros e D-Altros e D-Altros e D-Altros e D-Altros e D-Altros e D-Altros e
D-Altros e D-Altros e D-Altros e D-Altros e D-Altros e D-Altros e D-Altros e D-Altrose D-Altros e
e
fl
Paren t suga r (as Me glucoside)
OM s OM s OM s OM s NHB z NHB z NHB z NHTo s
OM s OM s OM s OM s OM s OM s OM s OM s OM s 2
2
2
2
NHC N NHCONH NHC(=NOH)NH N=CHP h OM s OM s OM s OTo s
2
2
NHCS M e NHB z NHB z NHB z NHA c NHC(=NN0 )NH NHCSNH NHCSNH NHC N
Substituents *
2
2
d
2
2
2
3
4
Base
NaOMe , 1.1 eq. NaOE t NaOEt , 0.2ºÍ LiAlH NaOE t NaOMe , 0.13 Í NaOMe , 0.3iV NaOMe , 0.1JV NaOM e or NaOH , resp . EtO H or H 0 N H EtO H NaOM e EtO H NaOMe , 0Ë Í H 0 NaOH , 0.2N EtO H NaOE t EtO H NaOEt , 0.2ºÍ HCONMe KC N MeO H NaOMe , 0.6N
Mixed ales. EtO H EtO H THF EtO H EtO H EtO H EtO H EtO H or H 0
Solvent 60 25 B.p. B.p. B.p. 25 B.p. 40 25 or b.p. , resp . — B.p. 50 B.p. 25 B.p. 100 25
(°Q
Temp .
Reactio n condition s
PREPARATIO N OF 2,3-EPIMIN O SUGAR DERIVATIVE S
Tabl e 1-IX
c
c
c
c
32 38 56 * 49* 78
/
61 68-73
— 60 Few 120 45 30 120 60
—
88-90
—
65 29 72 53 53 76 85
Yield (% )
—
4-5 90 30 180 20 1080 10 Few
Tim e (min. )
9
9
249 248 249 248 551 1562 551 2539 252
685 551 551 551 551 246 247 247 248
Refer ences
56 1. FORMATIO N OF TH E AZIRIDIN E RIN G
]
J
3
OTo s NHTo s OM s OTo s OM s NHCSNH NHC N OM s OM s OM s OM s NHM s NHM s N 2
d
2
d
d
THF MeO H EtO H MeO H EtO H MeO H MeO H THF EtO H THF HCONMe H 0 HGONMe THF ? 2
2
L1AIH 4
KC N NaOH , 17V BzONa
L1AIH 4
NaOMe , 0.37V
L1AIH 4
NaOMe , 0.17V NaOEt , 0.147V NaOMe , 0.1 TV NaOM e NaOMe , 0.27V NaOMe , 0.27V
L1AIH 4
—
B.p. B.p. B.p. B.p. War m B.p. B.p. B.p. B.p. B.p. 100 25 90-100
— 45 40 120 — 240 120 270 10 60 300 (3 days ) 540 —
c
k
c
100 0* 0 92 44 85 — 17" 90 56 61
c,h
60-66 79
551 252 551 250 247 251 251 1467 1467 47a, 1467 2538a 253 253 722b
1
J
1
h
0
f
e
d
c
b
Th e á-glucosid e was used unles s otherwis e noted . Th e acylamin o substituen t is understoo d t o be on a deoxy carbo n atom , an d a 4,6-benzyliden e grou p presen t unles s otherwis e noted . As th e free epimine . TH F = tetrahydrofuran . N o benzyliden e grou p present . Of th e benzylidenebis(aziridine) . Along with 25 % of th e oxazoline . Oxazolin e also formed . In othe r cases, not cited here , th e â-hexos e derivativ e gave only th e oxazoline , etc. No benzyliden e grou p present , bu t a 5-mesyl was. * Th e 5-Ms grou p was displace d by th e 5-Bz grou p in th e product . No benzyliden e grou p present , bu t a 5-azid o grou p was. Th e produc t was isolate d as th e dibenzoy l derivative .
a
1
1
2
NHTo s D-Altros e OTo s D-Altros e NHA c D-Altros e NHCONH D-Altros e NHCONH 2 D-Altros e (â) OM s D-Glucos e OM s D-Glucos e NHB z D-Glucos e NHB z D-Glucos e NHA c D-Glucos e NHB z D-Glucos e (â) D-Arabinos e (fi) OM s D-Arabinos e (â) OM s OT s D-Xylose (â)
INTRAMOLECULA R DISPLACEMEN T BY AMID E ANION S 57
58
1. FORMATIO N OF THE AZIRIDIN E RING
positions have been found to yield epimino sugar derivatives (aziridines) with bases (Eq 31). °~1
. /
„
ÐË
base
/ Ms6\ w
^OM e
(Ms = MeS0 )'
Ph- X
2
k
A
\ Y y O M e , etc.
31
( )
0
acyl-NH
V I
.
acyl
The reaction requires careful choice of base and conditions. Results are given in Table 1-IX. A 3,4-epimino sugar derivative was suggested as an intermediate (3741) and subsequently one was prepared by similar reactions (273). Still more recently, reduction of /ra?i y-(4iS-azido-3S-tosyloxy)-2£'-benzoyloxymethyltetrahydrofuran with either lithium aluminum hydride or hydrogen and catalyst has produced the aziridine 3 9 A (4027) (see p . 36); 3 9 B was made i
~
R
Ç /Í ,
39A, R = CH OB z 39B, R = CH O 2
very similarly (722a). 3-O-Benzyl-l,2-0-isopropylidene-5,6-di-0-mesyl-Dglucofuranose ( 4 0 ) with hydrazine, by displacement of the primary mesyloxy group and ring closure, yields the JV-aminoaziridine 4 1 (4145). The reaction succeeds for other similar furanoses, but not for pyranoses in which the vicinal mesyloxy groups are attached to the ring. Other 5,6-epimino sugar derivatives have been made from the 5-0-tosyl-6-azido-6-deoxy derivatives by treatment with lithium aluminum hydride (3088a). MsOCH
2
H N—Í
MsOC H
2
N H ,J 2
40
4
41
The formation of an N-diazonium aziridine intermediate has been suggested to explain the steric course of the acetolysis of /raH ^-azidocyclohexyl tosylate (Eq 32)· (3396), but an alternative rationalization by way of 1-azidocyclohexene (Eq 33) may be preferable (3448).
INTRAMOLECULA R DISPLACEMEN T BY CARBANION S
59
A recent claim that iV-(2-chloroethyl)-j8-ethoxyacrylamide ( 4 2 ) is converted by strong alkali to the aziridine derivative (2135) is of doubtful validity; the EtOCH==CHCONHCH CH C l 2
EtOCH=CHCOA z
2
(?)
42
product was probably the oxazoline. The brief statement (732) that N-(2chloro-l,2-diphenylethyl)benzamide, B z N H C H P h C H C l P h (the original name a,j8-diphenyl-j8-chloroethylamine is a misprint), yields l-benzoyl-2,3-diphenylaziridine when heated with alcoholic sodium ethoxide has been verified (1670).
Intramolecula r Displacemen t by Carbanion s This class of reactions may be represented by Eq 34. L
L S t r
RCOC-C-N -
°
n 8 b a S e
>
I
RCOC-C-N -
Ç
•
R
'
I + L"
(34)
O N
It is, of course, also possible that some such reactions proceed by a concerted mechanism instead of by the steps shown. The reaction has been reported only once for an ordinary value of L, the leaving group, which in this case was chloride (Eq 35) (2527). CO E t z
tert-BuOCl ^ Ç
^/\^C0 Ã J
2
Et
/~x.C0 E t à 2
NaQMe ^
^
I
CI
Nevertheless it appears to be the best mechanism (784) for explaining the formation of aziridines from JV-alkoxyamino ketones in alkaline solution. The
1. FORMATIO N OF THE AZIRIDIN E RING
60
first examples (381) of the reaction (Eq 36) are represented by the equation shown although the products were not then so formulated.
ArCOCH CHP h 2
+ base , Â
>
Arc\/
NHOM e
Ï
+ OMe "
(36)
J Ç
Applications of the synthesis are shown in Table 1-X. Tabl e 1-X PREPARATIO N OF AZIRIDINE S FROM 2-(ALKOXYAMINO)ETHY L KETONE S Aziridin e made , or substituent s therei n 2-Bz-3-Ph 3-Ph-2-(p-MeC H CO ) 3-Ph-2-(/?-MeC H CO ) 2-(/>-ClC H CO)-3-P h 2-Bz-3-(/?-ClC H ) 2-(p-BrC H CO)-3-P h 2-Bz-3-(p-BrC H CO ) 2-Q?-MeOC H CO)-3-P h 3j8-Hydroxy-16á , 17a-epimino-5-pregnen-20-on e 6
4
6
4
6
6
4
6
4
6
4
6
4
% Yield 94 64 61 66 80 83 90 65 78-82
4
Reference s 381, 980 381 796 381 381 381, 980 381 980 985
Intramolecular displacement reactions similar to the Favorskii rearrangement can also lead to the formation of aziridinones (á-lactams ) (4110) ( 4 3 ) , sometimes only as reactive intermediates but capable of isolation under favorable circumstances. Two routes have been used (Eqs 37 and 38). CI I
-c—c=o I
stron g base
I NH R
CI I
-c—c=o I
Ï
—ci -
I NI R
(37) Í I R 43 -á -
-C—C—N R I I Ç Ç
ROC l
Ï I II -C—C—N R I I Ç CI
stron g base
Ï ,R I II -C—C—N C CI
(38)
61
ELIMINATION-ADDITIO N REACTION S
Cyclizations of type 37 have been suggested and discussed for P h C H C l C O N H P h (3116, 3118) and P h C C l C O N H P h (3117, 3225) but demonstrated for Me CBrCONH-ter*-Bu (3224), ter^BuCHBrCONH-ter/-Bu (3222), Ph CClCONH-terf-Bu (2650), several l-(l-adamantyl)aziridinones (440a, 3481), and several ring compounds (2651,3223). Those of type 38 were indicated by infrared spectra for N-ter^butylphenylacetamide, iV-teri-butylacetamide, and iV-teri-butylpropionamide (298), and products that pretty surely have the l-teri-butyl-3-phenylaziridinone structure have been isolated and examined (296,300,1362). Products of the reaction of P h C C l C O N H with primary and secondary amines indicate that even with these weak bases the aziridinone is an intermediate (3119). A reaction noted here in the absence of more information on mechanism is the conversion of erjtfAr0 -l-azido-2-iodo-l,2-diphenylethane ( 4 4 ) (but not the threo isomer) by alcoholic base to 2-ethoxy-2,3-diphenylaziridine (Eq 39) (1628) (compare the Neber rearrangement, p. 63). 2
2
2
2
2
Et O
I
n
u
P
h
Ç
N V
Ê
-H I
X Ç
^P h
I
3
J^L ^
r
™_^
™ ^
[PhCH=CPhN ] T T
T
1
3
EtO H
—
^
P h \ /
2
Ph
(39)
g
Ç
44
Elimination-Additio n Reaction s This very small class of reactions, discovered recently, is given only by 2-bromoallylamines, which are converted by alkali amides in liquid ammonia to 2-methyleneaziridines (= allenimines) (Eq 40) (Table 1-XI). CH =CBrCH NH R 2
2
Of the several paths that can be conceived, only that one is acceptable that involves formation of an allenamine, its conversion to an anion, cyclization, and protonation (Eq 41) (444). CH =CBrCH NH R 2
2
> CH =C=CHNH R
*
2
CH =^ CH \ / Í 2
CH =C=CHN R 2
>
CH =^ 7 \ / Í 2
•
I
I
R
R
( 4 1 )
62
1. FORMATIO N OF THE AZIRIDIN E RING
An unfailing side reaction, and indeed the only one that occurs with 2-chloroallylamines, is formation of the isomeric propargylamines, H C = C C H N H R . Proof of structure of these aziridines, which were first regarded as allylidenamines (2905), was supplied by infrared (1081) and N M R (449) data. 2
Tabl e 1-XI PREPARATIO N OF 2-METHYLENEAZIRIDINE S
CH ==CBrCH NHR , 2
% Yield of
2
R =
Í
Reference s
R « 50
Me Et
— « 45 48-55 68
iso-Pr
— Propyl-3- / Bu tert-Bu teri-BuCH CHMeCH CH (+)-CH =CHCHOHCH (_)_CH =CHCHOHCH 2
2
2
2
2
2
2
« 40 74.5 « 25 « 50 45 40-50 « 45
450 449 450 441 2905 450 444 2905 450 450 2905 448 448
Preparatio n via Azirine s In all intramolecular displacements discussed up to this point, a saturated (aziridine) ring is formed. There is a small class of reactions, however, in which internal displacement yields an unsaturated (2//-azirine) ring. Inasmuch as the azirine often undergoes reduction to an aziridine, this family of reactions is reviewed here. In one subfamily, aziridines are formed by the action of excess Grignard reagent on á-chlor o nitriles. While a somewhat different mechanism has been written (1094), the one in Eq 42, involving intramolecular displacement of chloride by imine anion, seems preferable. The last step, addition of the Grignard reagent to an azirine, is known separately (1025, 4057). It would be desirable to effect the reaction of an achloro alkanenitrile with a Grignard reagent in 1:1 ratio, to see whether an azirine intermediate could be isolated. The reaction with excess Grignard re-
63
PREPARATIO N VIA AZIRINE S
agent is known to produce 2,2,3-triethylaziridine (863), 3,3-diethyl-2-propylaziridine (3525), and 2-isobutyl-3,3-diethylaziridine (3525). Chloroacetonitrile gave no aziridine (2471). á-Chlor o nitriles with lithium aluminum hydride also produce aziridines (see p. 36) (1883, 2175); the mechanism is doubtless similar to that when Grignard reagents are used. R'
R'
I
RCHC N + R'Mg X Cl
,
> RCHC=NMg X
I
„
RCHC=N " + XMg+
á
CI CI I RC— I Ç
R' I C II Í -
-R ' -á -
(42)
Í
an azirin e R' R'
+ R'Mg X Í
Í
I Ç
Another class of reactions yielding azirines by intramolecular displacement is the Neber rearrangement (Eq 43) (1769, 2739, 3027). base
RCH CR ' 2
— NOS0 R"
RCHCR '
- ii
A
R
/
> R \ Í/
+ R*so o2
NOSOzR '
2
(43)
HO + H+ z
RCH—CR ' I +NH
3
II Ï
Reduction of the unstable intermediate azirine to an aziridine with lithium aluminum hydride (777,1630) helped establish the course of the reaction. In a closely related process, JV,iV-dichloro .seoalkylamines with alkali yield azirines and then, by acid hydrolysis, á-amin o ketones (Eq 44) (73, 294, 297, 299, 2736). r— R CH CH R 3
NC1
2
CH CR 3
NCI
\ j T
>
p r o d u c t s
( 4 4 )
Í
The azirine was again reducible to an aziridine (294), as was the one made from the isolated N-chloro imine (295). Another variation is the generation of the azirine from a quaternized hydrazone (45) (1919, 2616, 2818, 3304). In the reaction illustrated by Eq 45
1. FORMATIO N OF THE AZIRIDIN E RING
64
Me -Ph +
Me CHCPh=NNMe 2
IS
3
Pr
°" ° >
M e
'
\ /
+ Me N 3
N
45
it was possible to isolate an alkoxyaziridine adduct (46) in high yield, and to convert it either back to the azirine or, by hydrolysis, to the amino ketone (1768, 2818, 4072). Me M e ' \ y
-Ph +
i
s
o
. p
r
0
H ^ ^ >
Me
Ph
é
é
Me^/^O-iso-P r
Í
(
4
5
)
Í I
Ç 46
In contrast, 2-aryl-2-anilinoaziridines could not be isolated though they were postulated as intermediates in reactions of azirines (3307). Azirines add alcohols to form 2-alkoxyaziridines in the presence of acids also, preferably perchloric acid, though the aziridine ring does not then survive; but pyridine and perchloric acid with 3,3-dimethyl-2-phenyl-l-azirine gave the crystalline adduct 47 (2302), and the reaction of this azirine with primary aromatic amines is believed to involve similar aziridines as intermediates (4112). Me
V
Me l
—Ph
N
+ C H NH + C10 5
5
4
>
Ph + 4—NC H 5
u / \
/
5
CIO4 -
Í I
Ç 47
The rearrangement of 2-acylcoumarone oxime /?-toluenesulfonates is more complex but probably involves azirine and aziridine intermediates (1441). Presumably by reason of steric effects, neither the Neber nor the quaternized hydrazone route could be made to yield the fused aziridine ring system characteristic of mitomycins (3026). A n isolable azirine proved to be intermediate in the photochemical rearrangement of a substituted isoxazole to an oxazole (3272), and several azirines have been shown to add arenesulfinic acids to produce C-arylsulfonylaziridines (2510a). The reactions just discussed would scarcely be chosen as preparative routes to aziridines. The action of 3 moles of a Grignard reagent on a ketoxime, however, does have utility for laboratory synthesis (Eq 46). The recorded examples of application of the ketoxime-Grignard and the ketoxime-lithium aluminum hydride reactions are listed in Table 1-XII,
65
PREPARATIO N VIA AZIRINE S
excepting some in very recent papers (2103, 2165, 2165a). That the reaction is thus related to the Neber reaction has been well established (1025,1619,1697, 1917), the evidence again including trapping of the azirine intermediate with lithium aluminum hydride to form the less alkylated aziridine (1025), and also such reduction of the authentic azirine otherwise prepared. The reduction gives cw-aziridines stereospecifically (1626). Catalytic reduction of azirinecarboxylic esters, however, yields acyclic enamines and not aziridines (1619).
RCH CR'=NO H 2
2 R
M g X
>
[RCH(MgX)CR'=NOMgX ]
F o r preparative use the oxime-Grignard reaction works best when the ketoxime is not wholly aliphatic. It occurs when cyclooctanone oxime tosylate is treated with phenyllithium (1382), but methyllithium gives a different kind of product (1382), as does a Grignard reagent with the tosylate of at least 4-tertbutylcyclohexanone oxime (2841). Evidently similar is the production of aziridines by reduction of ketoximes with lithium aluminum hydride (2103, 3211), although, unlike the Neber rearrangement, the reaction is stereochemically sensitive to the configuration of the oximes used (2165,4091). It is applicable to a variety of ketoximes and aldoximes (2165a, 2165b). Azirines in general yield rather unstable but isolable adducts, l-benzoyl-2chloroaziridines (e.g., 4 8 and 4 9 ) , with benzoyl chloride in benzene; the isomer 4 9 predominates (4072). Me
Me
Me
48
49
The remarkable change in reactivity of organic compounds effected by perfluorination extends to azirines. Perfluoro-3-methylazirine (50) and perfluoro-2-methylazirine (51) are polymerized by catalytic amounts of bases to polyaziridines. Similarly, hydrogen fluoride causes isomerization of the
66
1. FORMATIO N OF THE AZIRIDIN E RING
Tabl e 1-XII PREPARATIO N OF AZIRIDINE S FRO M KETOXIME S AND GRIGNAR D REAGENT S OR META L HYDRIDE S
From Grignard Reagents Group s in Grignar d reagen t
Group s in ketoxim e Me, Me Et , Et Me, Me Pr , Pr Me, Et0 CCH CH CH 2
2
2
Bu Et «-C H Pr 5
2
Aziridin e produced , or substituent s therei n 2-Bu-2-M e 2,2-Et -3-Me 2-0i-C H )-2-M e 3-Et-2,2-Pr
17 14 — 37
2
n
Me
5
n
2
2,2-Me -3-HOCMe CH CH and/o r 2-Me-2-HOCMe CH CH CH 2-Et-2-P h 2-Et-2-P h 2,3-Me -2-Ph 2-Ph-2-P r 2-Et-3-Me-2-P h 2-Et-3-Me-2-P h 3-Me-2-Ph-2-P r 3-Et-2-Ph-2-P r 3-Me-2,2-Ph 3,3-Me -2,2-Ph 3,3-Me -2,2-Ph 2
2
2
Ph , Ph , Ph , Ph , Ph , Ph , Ph , Ph , Ph , Ph , Ph ,
Me Me Et Me Et Et Et Pr Et iso-Pr iso-Pr
/o
Yield
Et Et Me Pr Et Et Pr Pr Ph Ph —
2
2
2
2
40 20-60 40-64 64 25-35 — 50 — 43
2
a
2
2
2
1697 1697 1697 1697
2
2
2
Reference s
— 24
3487a 568 1025, 1917 1025, 1917 568 1697,1725 568 1697 1697 1725 1773 1773
From Lithium Aluminum Hydride Aziridin e produced , or substituent s therei n
Oxim e PhC(=NOH)E t or PhCH C(=NOH)M e PhC(=NOH)M e or PhCH CH=NO H /?-ClC H C(==NOH)M e or />-ClC H CH CH=NO H /?-MeOC H C(=NOH)M e or />-MeOC H CH CH=NO H PhC(=NOH)E t PhCH C(=NOH)M e PhC(=NOH)CH=CH
/o Yield
3-Me-2-P h
Reference s 3245
2
2-Ph
—
3245
—
3245
2-(/>-MeOC H )
—
3245
3-Me-2-P h 3-Me-2-P h 3-Me-2-P h
—
3245 2103, 3245 3211
2
6
4
6
4
6
4
6
2-0?-ClC H ) 6
4
2
4
6
4
2
2
2
34' 50
PREPARATIO N VIA AZIRINE S
67
Tabl e 1-XII —continued From Lithium Aluminum Hydride Aziridin e produced , or substituent s therei n
Oxim e PhCH (=NOH)P h PhCH (=NOH)P h />-ClC H C(MNOH)CH C H Cl-/ ? 2,4-(0 N) C H CH C(=NOH)M e ( P h C H ) C = N O H , or its acetate , tosylate , or methy l ethe r PhCH=CHC(=NOH)P h l-C H C(=NOH)M e 2-C H C(=NOH)M e PhCHMeC(=NOH)M e PhCHEtC(=NOH)M e Ph CHC(==NOH)M e 9-Phenanthryl-C(=NOH)M e l-C H CH C(=NOH)M e 1-Tetralon e oxime 2-Tetralon e oxime 2-C H NCH C(=NOH)P h 2-(HON=)- l ,2,3,4-H -l ,4methanonaphthalen e 2-(HON=)-1,2,3,4-H -l ,4ethanonaphthalen e 2
2
6
4
2
2
2
2
10
7
10
7
6
3
6
4
2
2
2
10
5
7
2
4
2
4
4
1,4-Ethano-2-cyclohexanon e oxime 1-Me-l ,4-isopropylidene-2 cyclohexanon e oxime 2-syn, 3 - ^ - ( M e 0 C ) - 9 (HON=)-l,2,3,4-H -l,4ethanonaphthalen e 11-(HON=)-9,10-H -9,10ethanoanthracen e 6-(HON=)-dibenz o [tf ,c]cycloheptadien e 10-5^-(MeONHCO)-7-(HON=) 5,6,7,8-H -6,9-methano-9# benzocyclohepten e 2
2
4
2
4
1 -(HON=)-dibenz o [c,e]cyclooctan e a
Phenyllithiu m was used .
2,3-Ph 2,3-Ph 2,3-(/>-ClC H ) 3,Me-2-[2,4-(0 N) C H ] 2-PhCH -3-Ph
% Yield
2
2
6
4
2
2
2
6
3
2
2-PhCH -3-Ph 2-(l-C H ) 2-(2-C H ) 2-[Ph(Me)CH ] 2-[Ph(Et)CH ] 2-Ph C H 2-(9-Phenanthryl ) 3-Me-2-(l-C H ) 1,2-Epiminotetrali n 1,2-Epiminotetrali n 3-Ph-2-(2-C H N) 2,3-Epimino-l,2,3,4-H -l,3methanonaphthalen e 2,3-Epimino- l ,2,3,4-H -l ,4ethanonaphthalen e 2
10
7
10
7
2
10
5
7
4
4
25-33
— — 36-94
— 64 16 47 43 41
— 32 100? 41
— —
Reference s 1630 2103, 3245 1630 777 2103, 3245 2103, 3245 3245 3245 3245 3245 3245 3245 3245 3245 3245 3245 3245
50 (cis + trans)
2103, 3245
2,3-Epimino- l ,4-ethanocyclo — hexan e 2,3-Epimino- l -methyl-1,4 — isopropylidenecyclohexan e 2-syn, 3-5^-(HOCH ) -9,1014 tf/!//-epimino-1,2,3,4-H -l ,4ethanonaphthalen e ll,12-Epimino-9,10-H -9,1032-46 ethanoanthracen e 5,6-Epimino-dibenzo[a,c] 70-96 cycloheptadien e 10-syn-(HOCU )-7,S-syn- an d 58 tf«//-epimino-5,6,7,8-H 6,9-methano-9#-benzo cyclohepten e 1,2-Epiminodibenzo[c,e] 70 cyclooctan e
2103, 3245
4
2
2
3245 3245
4
2
2
2103, 3245 3245, 4097 3245
4
2103
68
1. FORMATIO N OF THE AZIRIDIN E RING
3-trifluoromethyl- to the 2-trifluoromethylazirine by way of the unstable aziridine 52 (252, 727, 722).
Í
Addition s to Olefini c Bond s The direct "epimination" of carbon-carbon double bonds is by no means so easy and useful as epoxidation of such structures, but it is of theoretical interest and perhaps occasionally of preparative value. Recent reviews (2373, 2634a, 3367a, 4103) deal in part with many such reactions. With only two exceptions (2365, 2460), the nitrogen which thus becomes part of an aziridine ring is the substituted one in an azide, - N = N = N ~ . The formation of the aziridine may be by way of a J M ^ - t r i a z o l i n e adduct (53) which is pyrolyzed or photolyzed; +
the pyrolysis may proceed via a dipolar-ion intermediate +
I
I
N=N-C-C-NR I
I
(2340, 2747, 2748), or a nitrene (6, 1761), which adds to the double bond (Eq 48).
Í I
R
ADDITION S TO OLEFINI C BONDS
69
Besides these paths, there is possible a concerted mechanism, in which the aziridine is formed as the nitrogen escapes from a complex ( 5 4 ) . Í
V\ ' / C
ú
V
ill
r<
+ é — • li
N*
+
.-x? -
—
N-
> N
/ \
/\
R
R
54
Both the direct and the sensitized photolysis of triazolines show high efficiency, insensitivity to nature of the solvent, and much retention of configuration. These results suggest participation of an excited singlet state and a short-lived 1,3-diradical in the reaction (3132). It is known that the formation of an isolable triazoline is favored by mild conditions, by absence of strongly electronegative groups in the azide, and by strain or other activation of the double bond. Indeed phenyl azide has often been used to establish the reactivity of olefins by their tendency to form adducts of triazoline structure. Olefinic azides can undergo the process intramolecularly (Eq 49) (2340, 4209). CH=CH CH
2
CH
2
2
(49)
\
,
CMe N 2
3
Me
,
Me
However, the pyrolysis of the phenyltriazolines usually gives some anil along with the aziridine, and sometimes only anil (Eq 50) (3133). Photolysis
Ph
instead of pyrolysis gives clean conversions of the triazolines to aziridines (3133, 3135). The preparation of aziridines by decomposition of 1,2,3triazolines is summarized here, Table 1-XIII presenting preparations from isolated triazolines, and Table 1-XIV those without isolation of the intermediate. That cyanogen azide reacts by the triazoline path rather than the nitrene path at 0°C has been proved by use of the N-labeled form, N * = N = N * — C N , in which the nitrene becomes symmetrical, · Í * = 0 = Í · , and must therefore give some unlabeled nitrogen in the aziridine ring; none is found (95). On the other hand, reactions of this azide with olefins above about 40°C go by way of cyanonitrene; thus cyclooctatetraene and cyanogen azide 15
70
1. FORMATIO N OF THE AZIRIDIN E RING
Tabl e 1-XHI PREPARATIO N OF AZIRIDINE S BY DECOMPOSITIO N OF ISOLATE D TRIAZOLINE S
Aziridin e made , or substituent s therei n
% Yield
Reference s
—
1659 2014 4163 4163 587 587 1795, 3451
By Pyrolysis l-(m-ClC H ) 1,2-Ph l-(/?-BrC H )-2,2,3-Me l-(/>-BrC H )-2-Bu l-PhCH -2,2,3-F -2-F C l-PhCH -2,3-F -2,3-(F C) 2-MeO C-l -0?-RC H ) (R = H, Me, MeO , CI, Bz, 0 N ) l-PhCH -2,3-(Me0 C) 2,3-(Me0 C) -l-(/?-MeOC H ) H/?-BrC H )-2-MeC(=CH ) 2-H NCO-l-P h 2-NC-l-P h 6
4
2
6
4
6
4
69 64 74 80 —
3
2
3
2
3
2
3
2
6
2
4
2
2
2
2
2
6
— 81 — — —
2
6
4
4
2
2
1-OBrC H )-2-(2-pyridyl ) 1,2-[(CH ) ] l,2-(CHMeCH CH ) l,2-(CMe CH CH ) l,2-(CHMeCH CHMe ) l-(/>-BrC H )-2,3-[(CH ) ] l-(p-BrC H )-2,3-(CH OCH ) l-(/>-BrC H )-2,3-(CH NHCH ) M/?-BrC H )-2,3-(CH==CHCH CH ) l-(/?-BrC H )-2,3-[(CH ) ] l-(j>-BrC H )-2,3-[(CH ) ] l-(/7-BrC H )-2,2-[(CH ) ] 1 -PhS0 -2,3-(OCH CH CH ) 6
4
2
3
2
2
2
2
2
2
6
4
6
2
4
6
3
2
4
2
2
2
6
4
6
4
2
2
6
4
2
6
4
6
2
2
2
5
s
2
2
2
1,2-Epiminoindan e 2,3-Epiminonorbornane, ' substituent s in: ËÃ-Ph N-Bz 7V-C0 Me iV-C0 Et J -W-C0 E t 5,6-Benzo-JV-C0 Et W-OBrC H ) W-P(0)R (R = Ph or OEt ) 5,6-[(CH ) ]-N-Ph (cis an d trans) 5,6-(Me0 C) -AT-P h (cis an d trans) 5-NC-W-P h 5,6-(NC) -7V-Ph l,5,6-(Me0 C) -W-P h 7-Oxa-5,6-(Me0 C) -W-P h
— — 100 100 — 21 47 61 — 54 64 — 0 0
1795, 3451 1795, 3451 3137a 3137a 1795, 3451, 4163 3137a 2340 2340 2340 2340 4163 4163 4163 4163 4163 4163 4163 2998; cf. 1323, 3135 1978
i
2
2
5
2
2
6
4
2
2
3
2
2
2
2
3
2
2
c — 40 87 60 97 53 — —
— 78 75.5
— 71
38, 1797, 1798 1794 1795, 2747 3243, 3491 3243, 3491 3243, 3491 3133 341, 2496a 38 38 3134 3134 39 3872
71
ADDITION S TO OLEFINI C BONDS
Tabl e 1-×ÉЗcontinue d Aziridin e made , or substituent s therei n
% Yield
Reference s
By Pyrolysis 7-Oxa-5,6-(Me0 C) -W-CH P h 5,6-[C(0)OC(0)]-AT-P h (cis) 7-Oxa-5,6-[C(0)OC(0)]-W-P h 2,3-[Epiminobicyclo(2.2.2)octane] , endo an d exo A/-(/7-MeC H S0 )-epiminoisodrin N-(tert Bu0 C)-epiminoisodrin 2
2
2
d
6
4
2
3872a 38 3872 3578 3370, 4175 3370, 4175
0
38 93 48
2
Í—A r
R— Í
40
1573b
— —
861 861 162,2647,2754 162, 2647 2647 162 162 162 162 162 162 2647 2647 2647 2647 2647 2647 2647 2647 2647 2647
as follows:
Ar Ç Ç Ph /7-ClC H />-0 NC H /?-MeC H /?-MeOC H Ph P-C1C H /?-MeC H /?-MeOQH Ph /?-ClC H /7-0 NC H Ph /7-ClC H /7-0 NC H Ph />-ClC H p-0 NC H Ph 6
6
4
6
4
6
6
6
4
4
4
6
6
2
2
4
6
4
4
6
4
2,2-(F C) 2,2,3-Me 2,3-Et (trans) 2-Bu 3
2
3
2
6
4
6
2
4
6
2
4
4
6
2
2
4
2
Ph />-0 NC H Ph Ph Ph Ph Ph /7-0 NC H p-0 NC H /7-0 NC H /7-0 NC H /?-MeC H /?-MeC H p-MeC H /?-MeOC H /?-MeOC H /?-MeOC H /?-EtOC H /?-EtOC H /?-EtOC H 2,4-Me C H By Photolysis 4
6
4
2
6
4
2
6
4
6
4
6
4
6
4
6
4
6
4
6
4
6
4
6
4
6
2
4
6
3
91 77-94 58 80 83 73 90 90 91 86 84 81 71 65 58 61 64 65 92 84 83 84 88
.
2121 4163 4163 4163
72
1. FORMATIO N OF THE AZIRIDIN E RING Tabl e 1-×ÐÉ— continued Aziridin e made , or substituent s therei n
% Yield
Reference s
By Photolysis l-(/?-BrC H )-2-CH ==CM e 2,3-Ph 3-Me-l,2-Ph (cis an d trans) 2-H NCO-l-P h 2-NC-l-P h l-(p-BrC H )-2,3-[(CH ) ] l-(/7-BrC H )-2,3-(CH OCH ) l-(/)-BrC H )-2,3-(CH=CHCH CH ) l-(/7-BrC H )-2,3-(OCH CH CH ) l-(^-BrC H )-2,3-[(CH ) ] l-(i>-BrC H )-2,3-[(CH ) ] l-Bu-2,3-(CONPhCO ) 2-(Me C=)-3,3-Me -l-picry l A steroida l aziridiniu m salt 2,3-Epiminonorbornane, substituent s in : W-Ph AT-C H Me-m W-C H Me-/? 6
4
2
2
2
2
6
4
2
6
4
6
4
6
4
6
2
2
2
4
6
3
2
4
2
2
5
2
6
2
2
2
2
e
100
— Variou s
— — 86-94 96
— 67 89 88
— 0
—
3137 3133 3132, 3136 4163 3133 3133, 4163 4163 4163 3135 4163 4163 3133 4013 3644
b
6
4
6
4
N-C U C\-m N-C H C\-p 6
4
6
4
JV-C H Br- m N-C U Bt-p iV-C H OMe- m 6
6
4
4
6
4
N-C U OMQ-P 6
4
JV-C H N0 -m AT-C H N0 -/? AT-CH Ph W-CPh=CH iV-P(0)(OEt) AT-C0 Et JV-SiMe JV-Ph-2,3-[C(0)OC(0) ] 2,3; 5,6-(A^-Et0 C-epimino) -norbornan e 6
4
6
4
2
2
2
2
2
2
3
2
a
c
d
e
2
94 90 92 90 92 90 100 90 90 0 18 53
— > 90 95
— — —
In spit e of th e suggestion s of earlie r worker s (38, 3822).
6 2 Sometime s not isolate d bu t hydrolyze d to th e anilin o alcohol . Isodri n = th e adduc t of hexachlorocyclopentadien e an d norbornadiene . Not isolate d bu t postulate d as an intermediate .
1798 4163 1798, 4163 3137a, 4163 1798 3137a, 4163 3133 4163 4163 4163 4163 558a, 3866 4163 2496a 3133, 4163 4163 3133 4163
73
ADDITION S TO OLEFINI C BONDS Tabl e 1-XIV PREPARATIO N OF AZIRIDINE S FRO M OLEFINI C COMPOUND S AND AZIDE S VIA UNISOLATE D TRIAZOLINE S
Azide, R N R =
Olefini c compoun d
% Yield of aziridin e
3
Reference s
Cyclohexen e Cycloalkene s (C , C ) Cyclohexen e 1-Octen e Cycloocten e (cis) Cycloocten e (trans) Inden e 2-Norbornen e
Ç Ph Ph Ph Ph Ph Ph Ph
1.5 Low or zer o 79 63 0 85 0 64
2,5-Norbornadien e Methy l methacrylat e Methy l crotonat e CH =CHSiMe(OSiMe ) Vinylheptamethylcyclotetrasiloxan e Allylheptamethylcyclotetrasiloxan e 5-Norbornene-2,3-dicarboxyli c anhydrid e (exo or endo) 7-tert-Butoxy-2,5-norbornadiene 7-PhNH-2,3-(CH=CHCH )-5norbornane CH =CHSiMe(OSiMe ) /7-Benzoquinon e 5-Norbornene-2,3-dicarboxyli c anhydrid e /7-Benzoquinon e an d its 2-methy l derivativ e Inden e Cyclopenten e Cyclohexen e Cyclohepten e Cycloocten e 1 -Methylcyclopenten e Inden e 2-Norbornen e a-Pinen e Dicyclopentadien e 3a,4,7,7a-Tetrahydro 4,7-methanoinden e endo-cis-Bicyc\o [2.2.1 ]hept-5-ene-2,3 dicarboxyli c anhydrid e  enzo-2,5-norbornadien e Dimethy l 5-norbornene-2,3 dicarboxylat e
Ph Ph Ph Ph Ph Ph
— 10.6 10 0
2926 717, 1685 717, 1685 717, 1685 1685 1685 1685 1322, 1324. 3867 2749 1796 3451 101 101 101
Ph Ph
— —
1325, 3868 2114
Ph PhCH Ar , variou s
— — —
1375a 100 648
p-MeC H
64.6
1322
— —
— —
584 3728 245 245 245 245 245 245 245 245 245
—
245
—
245 2443b
5
2
7
3
2
70
—
2
c
2
3
2
2
6
4
/>-0 NC H /?-MeOC H 2,4,6-(0 N)^C 2,4,6-(0 N) C 2,4,6-(0 N) C 2,4,6-(0 N) C 2,4,6-(0 N) C 2,4,6-(0 N) C 2,4,6-(0 N) C 2,4,6-(0 N) C 2,4,6-(0 N) C 2
6
4
6
4
2
2
3
H H H H H H H H H
6
2
6
2
2
3
6
2
3
6
2
3
6
2
3
6
2
3
6
2
3
6
2
3
6
2
2
2
2
2
2
2
2,4,6-(0 N) C H
3
2,4,6-(0 N) C H 2,4,6-(0 N) C H
2
3
6
2
3
6
3
2
3
6
3
4,6-Me -2-C H N 2
5
2
70 20 58 68 70 60 90
70 (exo)
—
1794
74
1. FORMATIO N OF THE AZIRIDIN E RING
Tabl e 1-XIV —continued Azide, R N R =
Olefini c compoun d
3
% Yield aziridin e
Reference s 998 998 998, 2442
Ethylen e Propylen e Isobutylen e 1-Butene , 2-butene , 2-methylbutene , 1-hexen e 3,3-Dimethyl-l-buten e Methylenecyclohexan e Cyclooctatetraen e 2-Norbornen e
NC NC NC
15 19-57 33
NC NC NC NC NC
0 20 18 48 80
2,5-Norbornadien e 3-Methyl-y4-nor-3-cholesten e 3j8-Chloro-5-cholesten e Norcholestery l acetat e Cholestery l acetat e Cholestero l Variou s steroi d alcohol s Diethy l fumarat e Diethy l maleat e Cyclohexen e
NC NC NC NC NC NC NC H NC O H NC O Et0 C
Cycloocten e Anthracen e 2-Norbornen e J -Dihydropyra n Cyclohexen e 2-Norbornen e 2-Norbornen e Diethy l fumarat e 2-Norbornen e 2-Norbornen e Cyclohexen e 2-Norbornen e Dicyclopentadien e
Et0 C Et0 C Et0 C Et0 C tert-B\\0 C Bz /?-0 NC H C O /?-0 NC H C O MeS0 Et NS0 PhS0 PhS0 PhS0
2,5-Norbornadien e 7-Oxa-5-norbornene-2,3-dicarboxyli c anhydrid e
PhS0
2
PhS0
2
c/s-e/2i/o-5-Norbornene-2,3 dicarboxyli c anhydrid e
PhS0
2
2
c/s-e*0-5-Norbornene-2,3 dicarboxyli c anhydrid e
á
41 — 37 35 — 24-40 10-15 —
2
2
2
2
— a
2
2
2
2
2
6
4
2
6
4
2
2
2
2
2
2
PhSQ
45 63-79 100 0 — — 15-17 — — a
2
998 998 998 96 93, 95, 397, 997, 998 92 4168 998 4169 998 998, 2442 440 821 821 2060, 2365, 2366, 2371 4064 305 344 506 3554 558a, 1798 1325, 1798 3798 1325 1325 2214 1325, 2748 1325, 2748, 3866 2749 1325
60 endo, 19 exo
2750
74 endo, 22 exo
2750
75
ADDITION S TO OLEFINI C BONDS
Tabl e 1-XIV—continue d Azide, R N R=
Olefini c compoun d Me 5,6-benzonorborn-2-ene-l carboxylat e Dicyclopentadien e 2-Norbornen e Diethy l 2,3-diazabicyclo[2.2.1] 5-heptene-2,3-dicarboxylat e Benzo-2,5-norbornadien e 2-Norbornen e 2-Norbornen e 2-Norbornen e 2-Norbornen e 2,5-Norbornadien e 2-Norbornen e Isodrin * Dicyclopentadien e Cyclohexen e Trimethylvinylsilan e a
b
c
PhS0 /?-MeC H S0 />-MeC H S0
% Yield of aziridin e
3
83
2
6
4
2
6
4
2
6
4
2
6
4
2
4
100
2
6
4
6
4
3
74 45 (exo) 83 79 75
2
6
2
4
2
2
6
4
6
4
2
39 48 Smal l 13 20
2
6
4
6
4
1798 2443b 558a 558a 558a 1325 1325 3255 3370 398 4049 4049
— —
2
2
4205 1325 1325, 1798
—
/?-MeC H S0 /?-MeC H S0 /?-BrC H S0 /?-MeOC H S0 />-0 NC H S0 0(C H S0 -/7) /7-N 0 SC H C H S0 PhN(CHO)S0 /?-MeC H S0 />-MeC H N=PPh Me Si Me Si 6
Reference s
2
2
3
3
Immediatel y rearrange s with rin g expansio n or destruction . Adduc t of hexachlorocyclopentadien e an d 2,5-norbornadiene . Reactin g at th e olefinic bon d on th e 5-ring .
in boiling ethyl acetate yield 56 (p. 76) a m o n g other products, although the aziridine does not then survive long (4003). It seems likely that photolysis of an azide-olefin mixture always bypasses triazoline formation, and indeed this has been proved in some cases. T h u s either ethyl azidoformate or JV-(/?-nitrobenzenesulfonyloxy)urethan, the latter incapable of reacting via a triazoline, photolyzed in liquid cyclohexene yields the cyclohexenimine derivative ethyl 7-azabicyclo[4.1.0]heptane-7-carboxylate (55) via a nitrene (Eq 51) (2365, 2366, 2371). N3C0 E t 2
—í
cyclohexene
ZZ N C 0 E t 2
•
N—CO,E t
/>-0 NC H S0 ONHC0 E t 2
6
4
2
2
55 (51) T h e vapor-phase reaction gives the same product (344, 762), and so does the base-induced decomposition of the urethan (2367\ cf. 2493, 3088b).
76
1. FORMATIO N OF THE AZIRIDIN E RING
Photolysis of methyl azidoformate in cis- or trans-l-buttns followed by saponification of the products yields mainly cis- and ira«5 -2,3-dimethylaziridine, respectively, showing that the nitrene adds stereospecifically cis (1576). Similar selectivity has been observed for the addition of ethoxycarbonylnitrene to pure 4-methyl-2-pentenes and to isoprene, but the selectivity decreases with dilution of the olefins, and with temperature. This probably means that the nitrene as generated reacts in the singlet state, but has time to change to the triplet when dilution has slowed the reaction (94, 305, 2369, 2370,2493,4010,4128). Ethoxycarbonylnitrene from photolysis of ethyl azidoformate is exceptional in giving about 30 % nonstereospecific addition even (by extrapolation) at infinite olefin concentration; this and other evidence indicate that about one-third of such nitrene production yields the triplet form directly (2494). The multiplicity of cyanonitrene, N C N , is dependent on concentration in the same way, and on the nature of the solvent. Singlet N C N , favored in acetonitrile or cyclohexane and in concentrated solution, yields more 1,2-adduct 56 with cyclooctatetraene; triplet N C N , formed in dilute solutions in ethyl acetate or methylene bromide, undergoes 1,4-addition to the polyene (4003). The high (>95 %) stereospecificity of the addition of the complex nitrene 57 to olefins indicates that it reacts exclusively in the singlet state (4006). ,
Í
56
57
Except for cyanonitrene, addition of substituted nitrenes to conjugated dienes has proved to be exclusively 1,2- (1576, 4006, 4128); sometimes the aziridines produced are partly rearranged (4128). Photolysis of acyl azides in the presence of olefinic compounds has produced 2-acetyl-l-ethoxycarbonyl2-methylaziridine and a cyclic analog 58 (2060), iV-(trimethylacetyl)cyclohexenimine (2368), and other complex aziridines 59 (506) and 60 (3866).
Carbethoxynitrene from iV-(/?-nitrobenzenesulfonyloxy)urethan added to cyclopentadiene and 1,3-cyclohexadiene to give the expected aziridines and their rearrangement products (4128).
ADDITION S TO OLEFINI C BONDS
77
The products ot photolyzing 2,3-diphenyl-2-cyclopropenylcarbonyl azide (61) (or the isocyanate formed from it by pyrolysis) are consistent with the suggestion that the reaction proceeds by an intramolecular addition to yield 62 as an intermediate (603). Pyrolysis of the vinylic azides P h C ( N ) = C H 3
2
(3308), P h C ( N ) = C H P h (1310), and F C ( N ) = C F C F (262), the latter two at room temperature, yields azirines; photolysis is also effective (1626). However, the photolysis, at least for P h C ( N ) = C H , also gives some dimer 63 that has an aziridine structure (4207). 3
3
3
3
Ph
2
NP h
N63
Also a bit difficult to classify is the photolytic rearrangement of 64 to 56, presumably by a Q - C 5 bridge migration (97).
hv
56
N—C N
1
2
64
Photoisomerization of 37/-pyrazoles 64A at low temperatures yields the tricyclic aziridines 64B, but these upon warming revert very readily to the 3/i-pyrazoles (724a). MeyM e (CH ) 2
64A
n
64B
1. FORMATIO N OF THE AZIRIDIN E RING
78
It has even been possible to trap imidogen, N H , generated by photolysis of hydrazoic acid at 4°K in an argon matrix, by reaction with ethylene to give recognizable EI (1956). However, there was no sign, even for microseconds, of aziridines produced from imidogen and olefin vapors (761). Thus the suggestion that 65 may be an intermediate in the reaction of active nitrogen with propylene is admittedly only speculation (3609). The oxidation of ä,â -unsaturated primary amines 66 to highly strained bridged aziridines 67 is a recent novelty; the oxidation may be effected with iV-chlorosuccinimide, lead tetraacetate, or mercuric oxide (2655). The preliminary report available does not establish whether the reaction proceeds by a nitrene or a radical mechanism.
Me'
H N 2
Í
66
65
This section will be closed by citation of those references that have postulated nitrene addition to aromatic nuclei to produce intermediates such as 68 (Eqs 52 and 53). In the beginning the suggestion of such structures was purely speculative, to help account for formation of nitrogenous bases from arenes and sulfuryl azide or carbonyl azide (346, 822, 823, 3156). More recent proposals are based on the known tendency of analogous norcaradienes to undergo ring expansion. It is probably only the singlet ethoxycarbonylnitrene that gives this reaction (2372).
PhN
—N 3
2
Ph N
PhNH ^ 2
NHP h
NHP h
NH
(52) (1793)
N—R
R N or RNHOS0 Ar + 3
2
68
R = Me, C 0 E t , or C N 2
(767, 1574,2367, 2394, 2441)
Aromatic substitution by nitrenes is also still regarded as involving the bicyclic aziridines 68 as intermediates (257,305, 1575, 2367, 3285, 3551).
79
ADDITION S TO CARBON-NITROGE N DOUBLE BONDS
The reactions of 2-phenylazirine with anilines have been interpreted as proceeding by way of the adduct 69, although formation of the observed product benzanilide thence (after hydrolysis), like the ring expansion noted above, requires an unusual but not unprecedented rupture of the carbon-carbon bond in the aziridine ring (3307). NHA r
Í Ç 69
Addition s t o Carbon-Nitroge n Doubl e Bond s This small group of additions, usually to acyclic imines (Schiff bases), is of theoretical rather than preparative interest. Analogy with addition to c a r b o n carbon double bonds suggests that an alkylidenimine might yield an aziridine either by way of a triazoline (Eq 54)
+
N
* N
—• 1
1 Í
+
—Í
t
V
Í
(54)
+Nz
Í
1
1
or by direct bridging of the Schiff base by a carbene (Eq 55). \ / C
X:+
||
•
\ /
Í
(55)
Í
The second step of Eq 54 is not observable for triazolines made from diazomethane and ordinary Schiif bases (2014), but Eq 54 is followed by diazomethane and (methoxyimino)bis(methylsulfonyl)methane (69) (Eq 56) (165). MeS0
2
S0 M e
/ ^ N - O M e CH N + (MeS0 ) G=NOM e 2
2
2
2
>
I
N = N
S0 M e
2
I
2
_
N
^>
\
/
S
° 2
M
E
Í
é OM e
(56)
80
1. FORMATIO N OF THE AZIRIDIN E RING
The initial ^ C = N — compound without the 0-methyl group also yields an aziridine, probably by way of a less stable triazoline (165). There is no evidence of triazoline intermediates in the preparation of aziridines from diazomethane and polyfluorinated Schiff bases (2339, 3775) or 7V-arenesulfonyl imines, C l C C H = N S 0 A r (2439a) or from various diazoalkanes and ternary iminium perchlorates (70) or fluoroborates in the cold (Eq 57) (2062, 2292, 2300, 2301, 4165). 3
2
70
71
The cyclopentylidene iminium salt homologous with 70 gives not only 72 in this reaction but also 7 1 ; by homocyclic ring enlargement and then formation of the aziridinium ion (2062).
72 Tabl e 1-XV PREPARATIO N OF AZIRIDINE S FRO M DICHLOROCARBEN E
Sourc e of carbene "
PhC R = N R
Ç Ç Ç Ç Ç Ph Ph Ph Ph Ph
A
 C D D D D D D D A = CHC1 + NaOMe ; KO-tert-Bu . a
3
/
R =
% Yield of aziridin e
Ph Ph Ph i7-ClC H /?-MeOC H Ph /?-MeC H />-ClC H m-MeC H m-ClC H
55 61 — 68 91 63 66 77 — —
R =
6
4
6
6
6
4
4
6
6
4
4
4
Reference s 1288, 3104 2013 1655 753, 3104 753, 3104 902, 4079 4079 4079 4079 4079
 = (Cl C) C O + NaOMe ; C = unspecified ; D = CHCI 3 + 3
2
ADDITION S TO CARBON-NITROGE N DOUBLE BONDS
Formation of the aziridine ring in such reactions occurs essentially with retention of configuration at the nitrogen atom (3865a). Clear-cut examples of the addition of dichlorocarbene to Schiff bases, mostly benzalanilines, are available (Table 1-XV). The fact that P h C ( C C l ) N H P h yields an aziridine with potassium ter/-butoxide alone but not with the strong base in the presence of 2,3-dimethyl-2-butene indicates that the starting material does not react by way of P h C ( C C l ) N P h ~ and internal displacement, but by dissociation and dichlorocarbene formation (902). At low temperatures chlorocarbene (from L i C H C l ) is stereospecifically trapped by benzalaniline to give c/5 -l,2-diphenyl-3-chloroaziridine in high yield (902, 903); cw-3-chloro-3-methyl-l,2-diphenylaziridine is formed similarly (903). The reaction of dichlorocarbene from sodium trichloroacetate with 70 p r o b ably yields an aziridine, but the ring does not survive nucleophilic attack by the trichloroacetate anion (Eq 58) (753). 2
2
3
3
2
,
7 0 + :CC1
CI
ci cco -H o 3
2
2
2
I^0 CCC 1
v
2
3
> o=c
(58)
LJ Similar difficulty is encountered with dichlorocarbene generated with ethylene oxide as acid acceptor; the intermediate dichloroaziridine 73 from benzophenone anil ends u p as l-(2-chloroethyl)-3,3-diphenyloxindole (74) (2106).
I CH CH C1
Ph
2
73
2
74
Difluorocarbene is considered to be the intermediate whereby pyrolysis of difluorodiazirine yields complex aziridines (Eq 59) (2579). Í
F CN 2
F C ./ 2
||
heat , — N ^ 2
[F C: ] 2
2
F C=N—N=CF 2
2
(59)
Í F
F
F:CF F C=N—N=CF 2
2
2
> - N = C F
2
i^L >
N—N: F-
82
1. FORMATIO N OF THE AZIRIDIN E RING
By similar dissociation and recombination, fluorodifluoraminocarbene and thence 75.
fluorodifluoroaminoazirine
-NF
2
-NF
2
gives
F NCF=N—Í ' 2
75
A reaction in atisine chemistry is supposed to yield an aziridine ring in an unprecedented way, presumably because of the unusual rigidity of the molecule. Heating polycyclic Schiff bases with acetic anhydride is believed to produce complex iV-acetylaziridines (Eq 60) (1024, 2839).
Ac-.-N
\
Ac^ Ç
Ac
X
/°·.
C
.- \
->
Ac—Ê .
I
+ AcOH
(60) In a very different addition to Schiff bases, carbon vapor at — 196°C yields new aziridines (76) of remarkable structure (Eq 61) (878b). RCH=NR ' + C
(61)
3
R'— Í 76
A related reaction is that of benzophenone azine with diphenylmethyl radicals from pyrolysis of P h C H N = N C H P h to give 2,2,3,3-tetraphenylaziridine (Eq 62) (3737); the addition could be extended to only two analogous compounds (3739). 2
2
Ph 2Ph CH - + P h C = N — N = C P h 2
2
Ph
2 Ph '
2
Ph
(62)
Í Ç 50% yield
An isocyanide is capable of adding a complexed carbene 77 to give the complexed aziridine (4008). OM e (CO) Cr-- ^ ~k \ / OM e 5
(MeOCH)(CO) Cr + c - C H N C 77 5
6
n
>
ø c-C«H
tl
(63)
INTRAMOLECULA R INSERTIO N REACTIO N
83 5
Recently reported are additions of nitronic esters (78, R = OMe) and nitrones (78, R = alkyl or aryl) to acetylenes to yield aziridines; isoxazolines 79 were first postulated (3501) and then demonstrated (257a) to be intermediates (Eq 64). 5
R R
RifeCR
2
T/ / C = XN .
+ _
2
\
··
X â
R 1
A
78 1
3
R
2
R
>
N C K
X
RiC' \
R
4
2
4
/ R
ï
I
Rs
79
3
3
L- R 4
5
R , R , an d R = alky l groups , R = H, R = OM e
(3501)
(64)
1
R i = R 2 = C 0 M e , R3 = R4 = H , R5 = mesityl ; or R = CMe OH , 2
R2
=
R
3= 4 R
2
H , R5 = ^r/-B u (257a)
=
Intramolecula r Insertio n Reaction s This class of aziridine ring formation is very little known. It was surmised (2283) and later confirmed (1438, 2926) that the vapor-phase pyrolysis of ethyl azide yields some E I ; isobutyl and tert-buty\ azides likewise give 2,2-dimethylaziridine, but in even lower yield (2926). Photolysis of liquid ter/-butyl azide is similar (Eq 65) (282). Me Me CN 3
M , 3
'~
N 2
>
[Me CN ] 3
>
M t \ / Í Ç
(12% yield)
(65)
It has been suggested that the decomposition of 4-azido-2-butanone in acid solution goes by way of an aziridinium salt (Eq 66) (931). H+,—N
AcCH CH N 2
2
3
2
•
Ac
AcCMe=NH
H o, 2
2
A c + NH + 2
4
+
N / \ Ç Ç
(66)
Degradativ e Route s Some reactions that might be reviewed here have already been discussed, e.g., the decomposition of 1,2,3-triazolines. The principal pyrolysis yet needing attention is that of 2-oxazolidinones (Eq 67) (3387).
1. FORMATIO N OF THE AZIRIDIN E RING
84
I
I
ç*
AzH + CQ
(67)
2
Ô Ï
Ordinarily this is a source of polyethylenimine (PEI) instead of the monomer shown, because the carbon dioxide concurrently produced catalyzes the polymerization (808, 2002, 3336, 3561). In the absence of additives, the polymer chain has 2-imidazolidinone end groups, and indeed a little l-[2-(l-aziridinyl)ethyl]-2-imidazolidinone (80) can be isolated from the product mixture (2744). HN
—CH CH —Az
S
2
2
Ô Ï 80
The process is catalyzed by both the EI and PEI produced (autocatalysis) and by added amines (2745) as well as by imidazolidinones (3734). The claim (3387) that monomeric EI can be obtained if a stronger base, such as triethanolamine, is present to remove the carbon dioxide seems reasonable. The pyrolysis of 3-amino-2-oxazolidinone in the same way gives polymeric poly(l-aminoaziridine), useful in rocket fuels (Eq 68) (1085, 1711).
HNJTT>
(68)
(-CH.CH.N-) .
2
I
NH
2
Ï
Three unrelated pyrolyses remain to be cited. The pyrolysis of some 2oxazolines (3753) did not yield the 1-acylaziridines sought, but these may possibly have been intermediates (Eq 69). Me
Me
Me i
é
RCONHCH CMe=CH
Me
2
2
(69)
Í I
RC= 0
Heating Ë^-vinylphthalamid e produces a little EI and phthalimide (Eq 70) (2051), most likely by way of the intermediate 81. Ï „CONH
'
2
^"^CONHCH=CH
2
-
y
N
H
NH
DEGRADATIV E ROUTE S
85
Diphenylketene and JV,a-diphenylnitrone yield a cyclic adduct which upon pyrolysis gives carbon dioxide and 1,2,2,3-tetraphenylaziridine (Eq 71) (3506), Ph
Ph
Ph-
—co
Ph C=C= 0 + PhCH=N(0)P h 2
Ph-
-N—Ph \ Ï
2
Ph
Ph Í I
Ph (71)
but the reaction could not be extended even to closely related ketenes and nitrones (Eq 71). Ethylenimine has been observed among the products of photolysis (2542) and pyrolysis (98) of methylamine, and is in fact initially the major product of decomposition of dimethylamine in a hydrogen atmosphere at low pressure and high temperature on an evaporated tungsten film (98). 1,2,2-Trifluoroaziridine is formed during fluorination of the acetonitrile-boron trifluoride adduct (1057). Intermediates with aziridine structure have been suggested to explain the course of alkaline cleavage of 2,2-dithiobis(ethylamine) (2134) and the hydrogenation of dimethyl l,2,7-trimethylazepine-3,6-dicarboxylate (82) (which gave dimethyl 2,3-dimethylterephthalate) (675).
2,2,5,5-Tetramethyl-3,6-dipropylpiperazine partly decomposes upon distillation at 252°-256°C and 1 atmosphere, yielding a lower-boiling product which was supposed to be 2,2-dimethyl-3-propylaziridine (3525); but so extraordinary a dissociation should be verified before it is believed. Long ago several authors (1319, 1320, 3200) surmised that the compounds obtained by the intramolecular dehydration of 2-(hydroxyamino)alkyl ketones in the presence of hot concentrated acids were aziridine derivatives (Eq 72). R' RCOCHR'CNHO H
-)(-•
RCA ü
Ë
(72)
Í Ç
In fact, the products were surely isoxazolines (83); the mode of preparation and reported properties are consistent with this interpretation.
1. FORMATIO N OF THE AZIRIDIN E RING
86
Similarly, a few workers have written the outdated aziridinone structures (84) for the products of reaction of acetic anhydride and an amino acid, etc. (1408, 1678, 2245, 3764). These compounds are in fact the well-known azlactones (oxazolinones) (85) (589). -
RCH
JO
RCH ^
^.O
é Ã H
83
I
CO R 84
R 85