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Bicyclic 5-6 Systems with One Ring Junction Nitrogen Atom: Three Extra Heteroatoms 1:2
8,17 Bicyclic 5-6 Systems with One Ring Junction Nitrogen Atom: Three Extra Heteroatoms 1:2 GYORGY HAJOS Hungarian Academy of Sciences, Budapest, Hungary 8.17.1 INTRODUCTION
445
8.17.2 THEORETICAL METHODS
447
8.17.3 EXPERIMENTAL STRUCTURAL METHODS
447
8.17.3.1 8.17.3.2 8.17.3.3 8.17.3.4 8.17.3.5
Proton NMR Results Carbon-13 NMR Measurements UV Investigations Mass Spectral Studies X-ray Elucidations
447 447 449 AA9 449
8.17.4
THERMODYNAMIC ASPECTS
451
8.17.5
REACTIVITY
451
8.17.5.1 8.17.5.2 8.17.5.3 8.17.5.4 8.17.5.5 8.17.5.6 8.17.5.7 8.17.5.8
Ring-opening Reactions Ring Transformations Ring Contraction Reactions Formation of Further Condensed Rings Electrophilic Reactions Reductions Alkylation and Realkylation Reactions Transformations of Substituents of the Various Ring Systems
451 452 452 452 453 453 453 453
8.17.6 RING SYNTHESES CLASSIFIED BY RING SYSTEMS 8.17.6.1 Synthesis of Fused Oxadiazines and Thiadiazines 8.17.6.2 Synthesis of Oxazolo- and Isoxazolo[1,3,5)'triazines 8.17.6.3 Synthesis of Thiazolo[3,2-a][ 1,3,5]triazines 8.17.6.4 Synthesis of Imidazo- and Pyrazolo[ 1,3,5 [triazines 8.17.6.5 Synthesis of Fused [1,2,4 ]Triazines 8.17.6.5.1 b-Fused [1,2,4] triazines 8.17.6.5.2 c-Fused[ 1,2,4] triazines 8.17.6.5.3 f-Fused [1,2,4 [triazines 8.17.6.5.4 d-Fused[ 1,2,4 [triazines
454 454 457 458 458 459 459 460 462 462
8.17.7
464
8.17.1
IMPORTANT COMPOUNDS AND APPLICATIONS
INTRODUCTION
Due to the wide variation which is possible, the structure, reactivity, and syntheses of 33 different ring systems of which new literature records have been found will be discussed here. These ring 445
446
Bicyclic 5-6 Systems, One Ring Junction N: Three Extra Heteroatoms 1:2
systems are depicted in Figure 1. Some of these have been mentioned in the first edition of Comprehensive Heterocyclic Chemistry (CHEC-I): imidazo[2,l-Z>][l,3,5]thiadiazine (2) (84CHECI(5)667>, imidazo [2,l-6][l,3,4]thiadiazine (5) <84CHEC-I(5)666>, oxazolo[3,2-, thiazolo[3,2-tf][l,3,5]triazine (14) <84CHEC-I(6)671>, imidazo[l,2-a][l,3,5]triazine (15) <84CHEC-I(5)63i>, imidazo[l,5-a][l,3,5]triazine (16) <84CHEC-I(5)659>, pyrazolo[l,5-a][l,3,5]triazine (17) <84CHEC-l(5)320>, imidazo[l,2-Z>][l,2,4]triazine (20) <84CHEC-I(5)630>, thiazolo[2,3-c] [l,2,4]triazine (22) <84CHEC-i(6)l0l9>, imidazo[2,l-c][l,2,4]triazine (24) <84CHEC-l(5)630>, imidazo[5,l-c][l,2,4]triazine (25) <84CHEC-I(5)656>, imidazo[l,2-, imidazo[l,5-, pyrazolo[l,5-G?][l,2,4]triazine (33) <84CHEC-I(5)273>. The following 19 ring systems, however, have been reported only since 1985 for the first time in the literature: viz. (1), (3), (4), (6), (7), (8), (9), (10), (11), (13), (18), (19), (21), (23), (26), (27), (28), (29), (30), and these will be discussed in more detail (see Section 8.17.6).
s N
(3)
(1)
x>
N
(4)
(5)
(9)
(10)
(12)
(14)
(16)
r O (13)
rNr (17)
(20)
N'
J
N
(23)
(21) N'
N'
.N
(24)
O
^\
k- ,NN (28)
(27)
(25) N
N
(29)
(31) N' I
(33)
Figure 1 Ring systems discussed in this chapter.
N
(32)
Bicyclic 5-6 Systems, One Ring Junction N: Three Extra Heteroatoms 1:2 8.17.2
447
THEORETICAL METHODS
The aromaticity index of the ring system (20) has been calculated and compared with related systems <87T4725>. Quantum chemical calculation for the formation of some derivatives of ring system (24) (e.g., (130), see 8.17.6.5.2) suggested that the cyclization is quite asynchronous and can be regarded as a Diels-Alder reaction of inverse electron demand <90JCS(P2)1943>.
8.17.3 EXPERIMENTAL STRUCTURAL METHODS 8.17.3.1
Proton NMR Results
Besides routine 'H NMR spectra, compounds shown in Figure 2 were studied in more detail. The most characteristic chemical shifts of these compounds are summarized in Table 1. For the sake of comparison of values of related protons, a common arbitrary numbering has been applied which is shown in structure (a) in Figure 2. Additional studies have been published of derivatives of the following ring systems: (9) <90T4353>, (26) <89JHC869>, (28) <93LA367>, and (33) <92CPBi4ll>.
C1O 4 -
(D
(e)
Me
MeO
OMe
OMe (h)
Me
JJ
- N *_-N N
0
Ci)
(i)
(k)
Me
Me. >
O
(1)
Me
O
Q
(m)
(n)
i
o
(o)
Figure 2 Compounds studied in detail by proton NMR spectroscopy (see Table 1).
8.17.3.2
Carbon-13 NMR Measurements
Compounds listed in Figure 3 have been investigated by 13C NMR spectroscopy, and the assignments are summarized in Table 2. An arbitrary numbering, similar to that used in the previous section, has been applied as shown in structure (a) in order to obtain an easy comparison of values of the related carbon atoms. Additional studies have been published for the ring systems (9) <90T4353> and (16) <83JOC3>.
Table 1 Compound (a)a 2 (b)R = R3 = Ph Ph /j-Cl-Ph />-Cl-Ph (c) (d)R == Ph R=/7-tolyl (e)b R6 = H Ph Ph Me Me Me 2 (f)R == H,R 6 = H H, Me H, Ph Ph, Me c (g)
H-l R6 = Ph Me Ph Ph
R7 = Ph Me H H Me Ph 7 R =H Me Ph Me
H-2
H-3
7.07
8.12
6.24 3.42 3.43
4.59 4.59
H-6
H-7
NH
N-Me
2-Me
6-Me
7-Me
a) (k) 6.53 6.67 6.75
* OMe protons where indicated by asterisk. •in DMSO-d6.
8.3
8.25 8.05 8.27 4.66 5.17 6.96 7.74 7.76 7.70 7.93
7.04 8.03 7.40 7.70 7.79 8.05 8.32 8.17 "in TFA.
c
in (CD3)2CO.
2.28 2.28 2.20
2.57 2.50 2.57 2.55 2.54 2.48
rs
2.60
2.61
2.50
2.50 91CC924
12.5
3.21* 4.30* 3.98 3.78 4.28 3.94 4.27 4.23
V1
85KGS498
89JHC1109
8.41
10.1 6.56 8.50 7.56 8.00 8.06 7.57 8.02 7.95
g.
82CCC1229 92T1953
2.08
8.60 8.06
Ref. 85CCC2170 82H(19)2119
2.23
6.87 6.63 6.88 7.00 3.86
S-Me*
3.91
6.87 3.94 3.44 4.00 3.94
8.67
(h)
(1) (m) (n) (o)
to
Proton NMR shifts of selected compounds (Figure 2) in CDC13 (unless otherwise indicated).
86CC1127
I
Bicyclic 5-6 Systems, One Ring Junction N: Three Extra Heteroatoms 1:2 Ph
449
,N N'
-N
Me^ 6 " Y 4 ~3 S
MeO
(a)
(b)
Me
OMe
OMe
(d)
(c)
Me
Me
l
I
.N N'
N
,N
O
O
O
(0
(e)
O (h)
(g) CN N'
Me
O (i)
^S
"
o (J)
Ph N
NH2 (k)
CO2Me
s>»H
O
(1)
Figure 3
8.17.3.3
Compounds investigated by carbon-13 NMR spectroscopy (see Table 2).
UV Investigations
Detailed UV spectroscopic studies on the deep colored dimers (34) and related compounds have been published. The visible and UV absorptions of derivatives with various ethylene chains have been compared <86KGS1693, 88KGS418).
8.17.3.4
Mass Spectral Studies
Such studies have appeared for the derivatives of six different ring systems: (12), (14), (15), (18), (20), (21). These are listed in Table 3.
8.17.3.5
X-ray Elucidations
X-ray structure determinations of derivatives of ring systems of this chapter have been carried out in several cases. The most significant and interesting structures are (35)-(40). The salt (35) was found to contain dimers held together by N H * " O = C hydrogen bonds <90T4353>. The oxazolotriazinedione derivative (36) showed a nearly planar fused bicycle with a dihedral angle of 0.9° between the oxazole and triazine rings <82CPB412>. Study of the partly reduced imidazotriazinethione
450 Table 2
Bicyclic 5-6 Systems, One Ring Junction N: Three Extra Heteroatoms 1:2 Carbon-13 NMR shifts of selected compounds (Figure 3) in DMSO-d 6 (unless otherwise indicated).
Compound (a) (b)a (c)a (d)« (e) (f> (g) (h) (i)
G) (k)
C-1
C-2
C-3
C-5
C-6
121.88 97.8 107.8 106.2 109.1 105.4 108.5
172.72
89.2 94.9 96.7 79.3
129.2 142.8 126.7 137.8 131.0 123.1 136.2 144.4 140.5 145.5 156.3
63.28 136.5 140.9 127.0 115.0 126.6 133.9 118.3 127.4 134.8 119.5 110.4 144.52 159.25 153.27 159.80 159.21 158.91
(1) R = H R = Me R = CH 2 Ph R = Ph (m) R' = H R' = H R'=H R' = H R1 = OMe R1 = OMe R1 = OMe R1 = OMe R' = C1 R' = C1 R' = C1 R'=C1 (n) R' = H R' = OMe R' = C1
R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2
= = = = = = = = = = = = = = =
H Me Et Ph H Me Et Ph H Me Et Ph H H H
35.6 35.4 35.1 36.0 35.8 35.5 35.4 36.1 35.6 35.3 35.2 36.0 102.6 102.0 102.7
158.03 136.35 158.04 136.39 158.11 136.30 158.07 153.4 152.5 152.4 151.7 153.2 154.1 152.4 151.6 152.4 151.7 151.5 150.8 154.3 154.3 153.2
100.9 152.3 150.6 148.6 152.0 148.8 151.5 150.9 142.9
C-7
135.3 143.1 147.2 144.3 135.4 144.1 147.1 144.4 135.2 143.1 147.1 144.2 130.3 130.2 130.2
C-8
C-8a
C-Me
162.3 162.6 162.8 162.8 163.8 162.2 162.3 162.9 162.3 162.7 162.9 163.7 154.4 154.4 154.2
43.35 85CCC2170 89JHC1109 141.7 51.7 86CC1127 143.7 147.0 57.6 40.9 88JOC887 142.8 145.8 32.0 149.6 51.2 42.9 143.5 39.8 147.9 51.5 149.3 151.4 88AP(321)851 166.24 84JCS(P 1)2707 165.97 166.10 165.00 91JHC769 56.5 56.6 56.7 56.7 56.3 56.4 56.6 56.6 56.7 56.7 56.9 56.5 135.4 135.4 135.5
Ref.
"in CDC1,.
Table 3 Studies on mass spectral fragmentations of derivatives of various ring systems. Ring system
Ref.
(12) (14) (15) (18) (20) (21)
82KGS124 82KGS124 81KGS1689 84JCS(P1)27O7 86JFC(32)299 86S71
(37) revealed that the [l,3,5]triazine ring is essentially planar, whereas the dihydroimidazole moiety adopts a flattened halfchair conformation <87LA72l>. An additional interesting feature of this structure is that the length of the S—C single bond is 1.739 A, which is significantly shorter than an ordinary S—C(arom.) bond (177.6 pm). Elucidation of the structure of compound (38) unambiguously showed that in the ring closure reaction leading to this product (see 8.17.6.5.2) retention of the configuration occurred, which observation allowed some valuable conclusions to be drawn concerning the reaction mechanism <91CC924>. In the 2-substituted imidazotriazinone molecule (39), only a small deviation from the co-planar arrangement of the aromatic and heterocyclic rings (9°) was found; this has been correlated with the biological effect of this and related compounds <89JCR(S)206>. The partially reduced bicyclic compound (40) was found to be composed of a planar imidazole ring fused to the puckered as-triazine with a torsion angle of C(4)—N(3)—N(2)—C(l) = 50° <91MI353>. On the other hand, the two bonds extending from the ring junction (i.e., C(8a)—C(8) and N(5)—C(6)) are nearly planar with the imidazole ring. Derivatives of the ring systems (3) and (21) (one of each, <90H(3l)6ll> and <89JHCllO9>, respectively) have also been investigated by x-ray diffraction.
451
Bicyclic 5-6 Systems, One Ring Junction N: Three Extra Heteroatoms 1:2 NHMe C3H7S
N
N
v
MeHN
S
SMe (36)
(35)
(37)
MeO
H CO2Me N
NO2 OMe
(39)
(40)
8.17.4 THERMODYNAMIC ASPECTS Protonation equilibria of imidazo[l,2-&][l,2,4]triazines (20) have been studied and the pKa values (found between 0.35 and 2.53) have been determined <87UKZ325>. Tautomeric equilibria of pyrazolo[5,l-c][l,2,4]triazin-4-ones (i.e., derivatives of (26)) and related compounds have also been investigated <89JHC869>.
8.17.5 8.17.5.1
REACTIVITY Ring-opening Reactions
Ring opening reactions of two different ring systems should be mentioned in this chapter. The substituted 5,7-diamino-l,2-dihydrooxazolo[l,5-fl][l,3,5]triazinium salt (41) undergoes hydrolytic cleavage under basic conditions and affords the hydroxyethyltriazinone compound (42) (Equation (1)). Reductive ring opening of the triazine ring of the pyrazolotriazine compound (43) was observed upon reaction with sodium borohydride, leading to the pyrazole derivative (44). The tetramethyl compound (45), obtained from (43) with methyl tosylate, also underwent ring cleavage (splitting off of acetone) when treated with acid to give the product (46) (Scheme 1) <89JHC1O45>. R2N
N
O HO
N
N
NH2
(1)
cr
(41)
NaBH4
(44)
(43) TsOMe
Me
HC1
(46)
(45) Scheme 1
452 8.17.5.2
Bicyclic 5-6 Systems, One Ring Junction N: Three Extra Heteroatoms 1:2 Ring Transformations
Ring transformation of (47) was reported to result in the imidazotriazinone derivative (48) (Equation (2)) <81KGS1689>. An unexpected ring transformation was observed with the attempted substitution of the methylthio group of (49) by amines. Instead of the expected product, a formal substitution of the 4-amino group was found which was explained by supposing a ring opening to (51) followed by an addition reaction to give (52) and ring closure to the final product (Scheme 2) <92JCS(P1)2789>. NHCOR
•W-o
Y
(2)
V
NNHCOR
O
(47)
(48)
MeS
MeS N
RNH2
NH2 (49)
MeS
N
N
NHR (50)
N
MeS N
N
RNH2
RHN
N N
N
C II
H2N
HN
(52)
(51) Scheme 2
8.17.5.3
Ring Contraction Reactions
Ring contraction of (53) under basic conditions has been reported to result in the thiazolo[3,2 &]pyrazole compound (54) (Equation (3)) <88S729>. o 1
K 2 CO 3 , CH 2 C1 2 , H 2 O
Ar
Ar
(3)
N Ph (53)
8.17.5.4
(54)
Formation of Further Condensed Rings
The reaction of the substituted 4-aminoimidazo[l,2-&][l,3,5]triazine (55) with ethoxymethylene malonate afforded ethyl 4-oxo-4#-imidazo[3,4-c]pyrimido [l,2-a][l,3,5]triazine-3-carboxylate (56) (Equation (4)) <92JCS(P1)2789>.
Bicyclic 5-6 Systems, One Ring Junction N: Three Extra Heteroatoms 1:2 R1
N
453
N N
N
(4) NH2
N
EtO2C
(55)
(56)
8.17.5.5 Electrophilic Reactions In the case of the imidazo[l,2-6][l,2,4]triazine ring system (20), brominations, nitrations, and hydroxymethylations have been reported. Compound (57) reacted with bromine at position 2, i.e., (58) was formed, (Equation (5)), and the nitration of the same starting compound showed similar selectivity <84KGS413>. Hydroxymethylation of the isomeric diphenyl derivative (59) was found to take place at positions 3 and 7 <84KGS1565>. Br-
Ph
N
N
Br Ph
(5)
N (58)
(57)
Ph
N
N
Ph
(59)
8.17.5.6
Reductions
Reduction of the N(l)—C(2) bond in the derivative (60) was reported in the reaction with sodium borohydride to yield the JV-hydroxy product (61) (Equation (6)) <87KGS554>.
NaBH 4
(60)
8.17.5.7
(6)
(61)
Alkylation and Realkylation Reactions
Alkylation and realkylation reactions have been reported for derivatives of five different ring systems. These are summarized in Table 4.
8.17.5.8 Transformations of Substituents of the Various Ring Systems Several functional group transformations have been published which are summarized in Table 5.
454
Bicyclic 5-6 Systems, One Ring Junction N: Three Extra Heteroatoms 1:2 Table 4 Alkylations of derivatives of the various ring systems. Ring system
Reactant NHR
NHR
O
N-Ph
(9)
Ref.
Product
MeN
MeHN
X.J N H
N-Ph
90T4353
SMe O
AcHlN
1S
(15)
AcHN
o
(15)
TS
OBn OBn
85JHC1137
O
N
HN
N
v
V ^
N
RS. -N
§
v
N
87LA721
s
H N
N
N
(24)
Mixture of methylated products
88JOC887
O
(32)
85JMC1704 Sw
SR
(32)
85JMC1704
EtO2C
(33)
92CPB1411 N R
R
8.17.6 RING SYNTHESES CLASSIFIED BY RING SYSTEMS 8.17.6.1
Synthesis of Fused Oxadiazines and Thiadiazines
Compound (63) represents the first example of the imidazo[l,5-d][l,3,4]oxadiazine ring system (1) which was obtained by the reaction of (62) with isocyanates (Equation (7)) <90T4353>. A simple route to (65) was found by the cyclization of vinylene diisothiocyanate with AT-benzylidenemethylamine (Equation (8)) <85CCC217O>. Compound (67) is the first representative of the imidazo[5,l&][l,3,5]thiadiazine ring system (3). This was obtained by reaction of ethyl isocyanoacetate (66) and arylsulfenylthiocyanates followed by treatment with triethylamine (Equation (9)) <90H(3l)6ll>. The structure of the product was verified by x ray (see Section 8.17.3.5).
Bicyclic 5-6 Systems, One Ring Junction N: Three Extra Heteroatoms 1:2
455
Table 5 Functional group transformations of derivatives of the various ring systems Ring system
Reactant
Ref.
Transformation
r°
(14)
92T1953
Ph
CN
(14)
Me .N
OMe
N
\
Me
\ N-Me
(15)
85KGS1125
OMe Cl
o HS (16)
87KGS978
CN
o R.
CO2H
N SH
HN
H
87MI 817-01
HO
OH
(16)
87MI 817-01
N
NMe2
NH2
(16)
92 JCS(P 1)2789
N
NH2
CN MeS R
(17)
SMe
NRR"
88T7155
Me
88KGS418
NH 2 Ph SMe
(19) N +
A-
SMe
H
O
(20)
Ph
N
N
r°
R R (32)
8
N
R1 N
I
SR
86KGS981 ^
Cl
R3
SR
NRR"
85JMC1704
456
Bicyclic 5-6 Systems, One Ring Junction N: Three Extra Heteroatoms 1:2 NHR
O RNCO
N-Ph Ph 3 P^
N
O
N-Ph
,N
(7)
RHN
(62)
(63) Ph
NCS
N
Ph
N
Me
(8)
NCS S (64)
(65) CO2Et i, ArSSCN
Et3NH+
N
N
(9)
ii, Et3N
EtO2C (66)
SAr
N (67)
Positively charged derivatives of the ring system (4) have been reported <87H(26)1323,88S729). In these syntheses, Af-amino-4-phenylthiazol-2(3//)thione (68) was reacted with phenacyl bromide derivatives to yield the products (69) as bromide salts (Equation (10)). The same ring closure principle was applied for the l,2,6,7-tetrahydroimidazo[5,l-6][l,3,4]thiadiazine (71)—ring system (5)—which was obtained from the dihydroimidazole derivative (70) (Equation (11)) <90JCS(Pl)3003>. The derivative of the same ring system with an aromatic imidazole ring (73) was prepared by treatment of (72) with hydrazine hydrate (Equation (12)) <82H(19)2119>.
i, ArCOCH2Br
N
(10)
Ph
ii, Et3N
H2N (68)
(69)
i, ArCOCH2Br
(11)
ii, H+
H2N (70)
(71)
N
O
R
2
R1
N
R1
N2H4xH2O
R1
R1 (72)
(12)
(73)
The totally saturated compound (75) represents the first example of the thiazolo[2,3-c] [l,2,4]thiadiazine ring system (6). This compound was obtained as a ring enlargement product in the reaction of (74) with ammonia (Equation (13)) <89CL89>. Reaction of 2-ethyloxazoline (76; X = O) or 2-ethylthiazoline (76; X = S) with chlorosulfonyl isocyanate followed by treatment with triethylamine led to the ring closed products (77; X = O or S), derivatives of ring systems (7) and (8), respectively (Equation (14)) <93SC121>.
Bicyclic 5-6 Systems, One Ring Junction N: Three Extra Heteroatoms 1:2
457
N
NH4OH
(13) (74)
(75)
O
Et
X
i,CSI ii, Et3N
N
w
HN
T
(14)
N
o
(77)
(76)
Reaction of the phosphinimine derivative (78) with isothiocyanates also resulted in formation of a derivative of a hitherto unknown ring system: imidazo[l,5-. Both the reaction of (80) with carbon disulfide to give (81) (Equation (16)) <90JHC775> and the ring closure of (82) to the sulfone (83) (Equation (17)) <89SC302l> represent synthetic pathways to two new ring systems (i.e., derivatives of pyrazolo[l,5c][l,3,5]thiadiazine (10) and imidazo[l,2-£][l,2,6]thiadiazine (11), respectively). RHN
O
N-Ph
O
R-NCS
N-Ph
(15)
N
(78)
(79)
R
MeS SMe
i, KOH, CS2
SMe
(16)
ii, Mel
(80)
(81)
NO2
R N
i,CSI
(17) ii, Pr^NH
HN
(82)
(83)
8.17.6.2 Synthesis of Oxazolo- and Isoxazolo[l,3,5]triazines Synthesis of derivatives of the two isomeric ring systems (12) and (13) are discussed in this section. An example of the ring system (12) in unsaturated form was obtained by the dimerization reaction of oxazoloisocyanate (84), which afforded (85) (Equation (18)) <82CPB412, 82CPB4195), whereas derivatives with a saturated oxazole ring for example, the salt (87) prepared from (86) (Equation (19)) <92KGS228>—have also been reported (see also <81KGS1689>). o OCN (18)
(84)
(85)
458
Bicyclic 5-6 Systems, One Ring Junction N: Three Extra Heteroatoms 1:2
(19) R" A (86)
(87)
Compound (89), the first representative of the ring system isoxazolo[2,3-tf][l,3,5]triazine (13)? w a s obtained by the reaction of (88) with phenoxycarbonylisocyanate (Equation (20)) <87JHC50l>. Other derivatives of this ring system have also been described <9OUC(B)182>. o
X NCO PhO
H2N
(20)
(88)
8.17.6.3
Synthesis of Thiazolo[3,2-a][ 1,3,5)triazines
Principally, two approaches have been applied for the synthesis of these ring systems: (i) closure of the triazine ring as shown by the reaction of aminothiazoline (90) with aroylisothiocyanate to give (91) (Equation (21)) <83MI 817-01 >, or (ii) closure of the thiazole ring as realized in the transformation of (92) to (93) followed by cyclization to (94) (Scheme 3) <87KGS978>. Several other examples of related ring closures have been published <82AP(315)791,82CCC1229,82CPB4195,82KGS124, 87LA65, 87MI 817-02, 91SC319>. O
X NCS Ar
H2N
(21)
N (90) Cl
R2N
N
SH
CN
(92)
(93)
(94)
Scheme 3
8.17.6.4
Synthesis of Imidazo- and Pyrazolo[l,3,5]triazines
Three ring systems—(15), (16), (17)—belonging to this section were reported in CHEC-I (see Section 8.17.1). Some more important new applications are as follows; (i) Ring system imidazo[l,2-tf][l,3,5]triazine (15). The hydroxyethylamino compound (95) when heated underwent ring closure to (96) (Equation (22)) <87NKK40, 88NKK236) and formation of the related 7V-cyano product (98) by cyclization of (97) was also reported (Equation (23)). Also a partially reduced derivative (100) was obtained by the reaction of 2-chloroimidazoline hydrochloride (99) with ammonium thiocyanate (Equation (24)) <87LA72i>. Other syntheses (mostly applications of well-established methods) have also been published <81MI 817-01, 85KGS1125, 87NKK40, 88NKK236, 92KGS228). The ring closure of (101) led to formation of the benzologue (102) (Equation (25)) <82AP(315)791, 93MI 817-01, 94MI 817-01 >. H
Y Y
N
ArN OH
r
Y R
R (95)
(96)
H N (22)
Bicyclic 5-6 Systems, One Ring Junction N: Three Extra Heteroatoms 1:2 R2N
N.
459
CN
.NHCN
N
110°C
(23)
V o
(97)
(98) H N
H N
N NH4SCN
Cl
HN N H
T
(24)
N
s
(99)
(100)
R-N =
(25)
OEt (101)
Y (102)
(ii) Ring system imidazo[l,5-tf][l,3,5]triazine (16). Synthesis of derivatives of this ring system using translocative rearrangements has been published (82JA235, 83JOC3): reaction of (103) with formamidine gave (105) via formation of intermediate (104) (Equation (26)). Syntheses of other representatives of this ring system have also been reported <87MI 817-01,92JCS(Pl)2789>. R NC H2N
H2N
/=NH
N
H2N
R R
N
N N
(103)
f
N
N
N N
N NH2
N
(26)
R
(105)
(104)
(iii) Ring system pyrazolo[2,3-tf][l,3,5]triazine (17). Ring closure of the open chain compound (106) to (107) under basic conditions (Equation (27)) <85LA1962>, and conversion of (108) into (109) (Equation (28)) <88T7155> are two important new routes to these compounds. Other approaches have also been published <84JHC389, 86JHC349, 89AP(322)557>.
o
S KOH
N"% H
H
(27)
CN O (107)
(106) NC
SMe
MeS SMe
(28) NH2
(108)
(109)
8.17.6.5 Synthesis of Fused [l,2,4]Triazines 8.17.6.5.1 b-Fused [l>2,4]triazines Two thiazolo-fused ((18) and (19)), one imidazo-fused (20), and one pyrazolo-fused ring (21) belong to this category of systems. Compound (111), a representative of the new ring system
460
Bicyclic 5-6 Systems, One Ring Junction N: Three Extra Heteroatoms 1:2
thiazolo[3,2-6][l,2,4]triazine (18), has been obtained by reaction of (110) with DMAD (Equation (29)) <84JCS(P1)27O7>. CO2Me
DMAD
R
(29)
NH
N (110)
(111)
Several syntheses have been described for the isomeric ring system thiazolo[3,4-6][l,2,4]triazine (19). The heteroaromatic system (114) has been obtained by the reaction of (112) with O-benzenesulfonyl a-cyanobenzylalcohol through the intermediate (113) (Equation (30)) <85KGS498, 85KGS1497). The partially saturated derivative (116) of the same ring system was prepared by the treatment of (115) with diacetyl (Equation (31)) <87KGS554>. NC ) - OSO2Ph Ph
R1
H2N O
R"
N
Ph (30)
N R"
N
+
A"
SMe (112)
N
R
SMe (114)
(113) R HOHN
diacetyl
(31) H2N (116)
(115)
Various syntheses have been published earlier for the ring system (20). The reaction of triazine diester (117) with propargylamine gave (118) (Equation (32)). Numerous other works have also appeared in this field (84KGS413, 84MI 817-01, 86JFC(32)299, 87UKZ1095, 88JMC2221). Two major routes
to the new ring system pyrazolo[l,5-6][l,2,4]triazine (21) have been described: reaction of the zwitterion (119) with DMAD to yield (120) (Equation (33)) <83CPB3759>, for which reaction two possible mechanisms have been proposed, and a condensation reaction of (121) with dioxo reagents to give (122) (Equation (34)) <89JHC11O9>. MeO2C . ^ N
SMe
NH2
MeO2C (32)
MeO2C
MeO2C
N
(118)
(117)
DMAD
MeO2C (33)
MeO2C (119)
(120)
H2N (34)
HoN (121)
8.17.6.5.2
(122)
c-Fused fl ,2>4]triazines
Two thiazolo-fused ((22) and (23)), two imidazo-fused ((24) and (25)), and a pyrazolo-fused ring (26) are discussed here. While (22) has already been described in CHEC-I, a novel approach to its
Bicyclic 5-6 Systems, One Ring Junction N: Three Extra Heteroatoms 1:2
461
synthesis should be mentioned here: the reaction of the diazonium salt (123) with malononitrile to give (124) (Equation (35)) (87SUL125, 89MI 817-01, 9lPS(60)ll9>. Other reports have also appeared <84AQ232, 87MI 817-03>. +
N2 A"
CO2Et
N
CO2Et
CH2(CN)2
(123)
(35)
(124)
Ring closure of (125) to (126) under basic conditions (Equation (36)) <91CC924>, as well as reaction of (127) with phenacyl bromide to yield (128) (Equation (37)), are the first examples of synthesis of the thiazolo[4,3-c][l,2,4]triazine ring system (23) (86PHA101). Derivatives of both imidazo-fused systems (24) and (25) can be synthesized by reactions of diazoimidazoles (129) or (132) with alkenes or reagents containing active methylene groups. Thus, reaction of 2-diazoimidazole (129) with 1,2dimethoxyethene gave (130) <9OJCS(P2)1943>, whereas 1,1-dimethoxyethene yielded (131) (Scheme 4) <86CC1127>. Compound (129) was also cyclized with active methylene reagents <88JOC887>. 4Diazoimidazole (132), similarly, was cyclized to (133) and (134) by using substituted acetonitriles or substituted acetic esters (Scheme 4) <87JCS(Pl)665>. H CO2Me N NEt3, MeOH
(36)
(125)
PhHN
N
N
PhCOCH2Br
N (37) Ph
(127)
(128)
MeO MeO
OMe
R
N
N
MeO
N
MeO R
OMe
MeO
(129)
(130)
N2 N
NH 2 (133)
N
RCH2CO2Et
AcOH
R
OMe R (131)
R1 RCH2CN
H N
pyridine
H N
R' N
R O
(132)
(134)
Scheme 4
The synthesis of pyrazolo[5,l-c][l,2,4]triazines (derivatives of (26)) was also accomplished by an analogous method: the diazo compound (135) was reacted with ynamines to give (136), or with enamines to yield (137) after elimination of one molecule of amine (Scheme 5) <83JOC2330). Numerous applications of this very straightforward method have been described <84JHC945,84M431,85JHC453, 85LA1962, 87AP(320)850, 88AP(321)851, 88JOC887, 89AP(322)557, 90CCC2790, 91JPR(333)333>. The
intra-
462
Bicyclic 5-6 Systems, One Ring Junction N: Three Extra Heteroatoms 1:2
molecular condensation of (138) led to a derivative of the benzologue of system (26); pyrazolo[5,l c]benzo[l,2,4]triazine-5-oxide (139) (Equation (38)) <82MI 817-01 >. NEt2
NEt2
N (137)
(135) Scheme 5 H2N base
(38)
N
(139)
(138)
8.17.6.5.3 f-Fused [1,2,4]triazines Formation of the oxazolo[3,4-&][l,2,4]triazine ring system (27) was first observed in the phototransformation of (140) with ketene which gave the product (141) (Equation (39)) <88CPB3354>. The proposed mechanism involves formation of the biradical (142), its cyclization to the fused aziridine (143), ring opening of the three-membered ring to give the zwitterion (144), which upon reaction with a further molecule of ketene affords the final product (141). o Me
CF
N
R
/iv,H2C = C =
(39) N
N
(140)
(141) /JV,H 2 C = C =
/iv,H2C = C =
oii
/CF 3
Me. -CO
JL R
N
>1
+
(144)
(143)
(142)
'N
The first representative of the ring system (28), the pyrazolo[l,5-6][l,2,4]triazin-l(2//)one (146), has been synthesized by condensation of (145) with triethyl orthoformate (Equation (40)) <93LA367>.
i, HC(OEt)3
MeO
(40) ii, NH3
H2N (145)
(146)
8.17.6.5.4 d-Fused /1,2,4Jtriazines Partially saturated derivatives of two of the ring systems belonging to this section (oxazolo[3,2d][l,2,4]triazine (29) and thiazolo[3,2-d?][l,2,4]triazine (30)) have been prepared since 1985 for the
Bicyclic 5-6 Systems, One Ring Junction N: Three Extra Heteroatoms 1:2
463
first time. Both the oxazoline compound (147) and the analogous thiazoline derivative (149) were reacted with tetrazines. These Diels-Alder reactions with inverse electron demand yielded the ringclosed products (148) and (150) (Equations (41) and (42)), respectively <84AP(3l7)237>. R ii
R (162)
(41)
(147)
(148) CF
CF3
II
f
CF3
N I
(42)
N
N
CF3 (149)
(150)
A novel synthesis of imidazo[l,2-d][l,2,4]triazines has been realized by the ring closure of the imidazole compound (151) with urethane to yield the fused triazinone (152) (Equation (43)) <89JCR(S)206>. Other approaches to this ring system have also been published <84CCC275,88JIC784). Eto
N
N EtO2CNHNH2
EtO
AcOH
HN
HN
Ar
To
N
(43)
(152)
(151)
Condensation reactions of (153) and related compounds provided a route to derivatives of the ring system (32): reaction of (153) with acetone yielded (154) (Equation (44)). Another analogous ring closure has also been reported <85JMC17O4>. The Diels-Alder reaction between (155) and terazine diester afforded the pyrazole-fused product (156) (Equation (45)) <84AP(3l 7)237 >. A similar condensation reaction as above was also applied for the ring closure to derivatives of (33): treatment of (157) with ethyl orthoformate yielded (158) (Equation (46)) <9UHC769>. Another related case has also been reported <89JHC1O45>. The reaction path from (159) to (160) involving ring transformation has been described (Equation (47)) <82JHC817>.
acetone
(153)
(44)
(154) CO2Me n
N
CO2Me
CO2Me
(45)
N Me CO2Me
(155)
(156)
464
Bicyclic 5-6 Systems, One Ring Junction N: Three Extra Heteroatoms 1:2 HC(OEt)3
(46)
(157)
(158)
KOH
(47) EtOH
(159)
8.17.7
(160) X = H, Br
IMPORTANT COMPOUNDS AND APPLICATIONS
Four particular derivatives are worth mentioning in this section for their practical applications. The imidazothiadiazine compound (161) proved to possess marked antihypertensive and diuretic properties <87GEP3 542662). The derivative (162) was tested for calcium channel blocking <88JMC222l >. Compound (163) was found to be a potential antiasthma agent <85JMC17O4>, and the derivative (164) showed significant aldose reductase inhibitory effect <92CPBl4ll). CONRR"
HfNBu: (162)
(161)
HO2C
(163)
Copyright © 1996 Elsevier Ltd.
Comprehensive Heterocyclic Chemistry II
445
8.17.2 THEORETICAL METHODS
447
8.17.3 EXPERIMENTAL STRUCTURAL METHODS
447
8.17.3.1 8.17.3.2 8.17.3.3 8.17.3.4 8.17.3.5
Proton NMR Results Carbon-13 NMR Measurements UV Investigations Mass Spectral Studies X-ray Elucidations
447 447 449 AA9 449
8.17.4
THERMODYNAMIC ASPECTS
451
8.17.5
REACTIVITY
451
8.17.5.1 8.17.5.2 8.17.5.3 8.17.5.4 8.17.5.5 8.17.5.6 8.17.5.7 8.17.5.8
Ring-opening Reactions Ring Transformations Ring Contraction Reactions Formation of Further Condensed Rings Electrophilic Reactions Reductions Alkylation and Realkylation Reactions Transformations of Substituents of the Various Ring Systems
451 452 452 452 453 453 453 453
8.17.6 RING SYNTHESES CLASSIFIED BY RING SYSTEMS 8.17.6.1 Synthesis of Fused Oxadiazines and Thiadiazines 8.17.6.2 Synthesis of Oxazolo- and Isoxazolo[1,3,5)'triazines 8.17.6.3 Synthesis of Thiazolo[3,2-a][ 1,3,5]triazines 8.17.6.4 Synthesis of Imidazo- and Pyrazolo[ 1,3,5 [triazines 8.17.6.5 Synthesis of Fused [1,2,4 ]Triazines 8.17.6.5.1 b-Fused [1,2,4] triazines 8.17.6.5.2 c-Fused[ 1,2,4] triazines 8.17.6.5.3 f-Fused [1,2,4 [triazines 8.17.6.5.4 d-Fused[ 1,2,4 [triazines
454 454 457 458 458 459 459 460 462 462
8.17.7
464
8.17.1
IMPORTANT COMPOUNDS AND APPLICATIONS
INTRODUCTION
Due to the wide variation which is possible, the structure, reactivity, and syntheses of 33 different ring systems of which new literature records have been found will be discussed here. These ring 445
446
Bicyclic 5-6 Systems, One Ring Junction N: Three Extra Heteroatoms 1:2
systems are depicted in Figure 1. Some of these have been mentioned in the first edition of Comprehensive Heterocyclic Chemistry (CHEC-I): imidazo[2,l-Z>][l,3,5]thiadiazine (2) (84CHECI(5)667>, imidazo [2,l-6][l,3,4]thiadiazine (5) <84CHEC-I(5)666>, oxazolo[3,2-
s N
(3)
(1)
x>
N
(4)
(5)
(9)
(10)
(12)
(14)
(16)
r O (13)
rNr (17)
(20)
N'
J
N
(23)
(21) N'
N'
.N
(24)
O
^\
k- ,NN (28)
(27)
(25) N
N
(29)
(31) N' I
(33)
Figure 1 Ring systems discussed in this chapter.
N
(32)
Bicyclic 5-6 Systems, One Ring Junction N: Three Extra Heteroatoms 1:2 8.17.2
447
THEORETICAL METHODS
The aromaticity index of the ring system (20) has been calculated and compared with related systems <87T4725>. Quantum chemical calculation for the formation of some derivatives of ring system (24) (e.g., (130), see 8.17.6.5.2) suggested that the cyclization is quite asynchronous and can be regarded as a Diels-Alder reaction of inverse electron demand <90JCS(P2)1943>.
8.17.3 EXPERIMENTAL STRUCTURAL METHODS 8.17.3.1
Proton NMR Results
Besides routine 'H NMR spectra, compounds shown in Figure 2 were studied in more detail. The most characteristic chemical shifts of these compounds are summarized in Table 1. For the sake of comparison of values of related protons, a common arbitrary numbering has been applied which is shown in structure (a) in Figure 2. Additional studies have been published of derivatives of the following ring systems: (9) <90T4353>, (26) <89JHC869>, (28) <93LA367>, and (33) <92CPBi4ll>.
C1O 4 -
(D
(e)
Me
MeO
OMe
OMe (h)
Me
JJ
- N *_-N N
0
Ci)
(i)
(k)
Me
Me. >
O
(1)
Me
O
Q
(m)
(n)
i
o
(o)
Figure 2 Compounds studied in detail by proton NMR spectroscopy (see Table 1).
8.17.3.2
Carbon-13 NMR Measurements
Compounds listed in Figure 3 have been investigated by 13C NMR spectroscopy, and the assignments are summarized in Table 2. An arbitrary numbering, similar to that used in the previous section, has been applied as shown in structure (a) in order to obtain an easy comparison of values of the related carbon atoms. Additional studies have been published for the ring systems (9) <90T4353> and (16) <83JOC3>.
Table 1 Compound (a)a 2 (b)R = R3 = Ph Ph /j-Cl-Ph />-Cl-Ph (c) (d)R == Ph R=/7-tolyl (e)b R6 = H Ph Ph Me Me Me 2 (f)R == H,R 6 = H H, Me H, Ph Ph, Me c (g)
H-l R6 = Ph Me Ph Ph
R7 = Ph Me H H Me Ph 7 R =H Me Ph Me
H-2
H-3
7.07
8.12
6.24 3.42 3.43
4.59 4.59
H-6
H-7
NH
N-Me
2-Me
6-Me
7-Me
a) (k) 6.53 6.67 6.75
* OMe protons where indicated by asterisk. •in DMSO-d6.
8.3
8.25 8.05 8.27 4.66 5.17 6.96 7.74 7.76 7.70 7.93
7.04 8.03 7.40 7.70 7.79 8.05 8.32 8.17 "in TFA.
c
in (CD3)2CO.
2.28 2.28 2.20
2.57 2.50 2.57 2.55 2.54 2.48
rs
2.60
2.61
2.50
2.50 91CC924
12.5
3.21* 4.30* 3.98 3.78 4.28 3.94 4.27 4.23
V1
85KGS498
89JHC1109
8.41
10.1 6.56 8.50 7.56 8.00 8.06 7.57 8.02 7.95
g.
82CCC1229 92T1953
2.08
8.60 8.06
Ref. 85CCC2170 82H(19)2119
2.23
6.87 6.63 6.88 7.00 3.86
S-Me*
3.91
6.87 3.94 3.44 4.00 3.94
8.67
(h)
(1) (m) (n) (o)
to
Proton NMR shifts of selected compounds (Figure 2) in CDC13 (unless otherwise indicated).
86CC1127
I
Bicyclic 5-6 Systems, One Ring Junction N: Three Extra Heteroatoms 1:2 Ph
449
,N N'
-N
Me^ 6 " Y 4 ~3 S
MeO
(a)
(b)
Me
OMe
OMe
(d)
(c)
Me
Me
l
I
.N N'
N
,N
O
O
O
(0
(e)
O (h)
(g) CN N'
Me
O (i)
^S
"
o (J)
Ph N
NH2 (k)
CO2Me
s>»H
O
(1)
Figure 3
8.17.3.3
Compounds investigated by carbon-13 NMR spectroscopy (see Table 2).
UV Investigations
Detailed UV spectroscopic studies on the deep colored dimers (34) and related compounds have been published. The visible and UV absorptions of derivatives with various ethylene chains have been compared <86KGS1693, 88KGS418).
8.17.3.4
Mass Spectral Studies
Such studies have appeared for the derivatives of six different ring systems: (12), (14), (15), (18), (20), (21). These are listed in Table 3.
8.17.3.5
X-ray Elucidations
X-ray structure determinations of derivatives of ring systems of this chapter have been carried out in several cases. The most significant and interesting structures are (35)-(40). The salt (35) was found to contain dimers held together by N H * " O = C hydrogen bonds <90T4353>. The oxazolotriazinedione derivative (36) showed a nearly planar fused bicycle with a dihedral angle of 0.9° between the oxazole and triazine rings <82CPB412>. Study of the partly reduced imidazotriazinethione
450 Table 2
Bicyclic 5-6 Systems, One Ring Junction N: Three Extra Heteroatoms 1:2 Carbon-13 NMR shifts of selected compounds (Figure 3) in DMSO-d 6 (unless otherwise indicated).
Compound (a) (b)a (c)a (d)« (e) (f> (g) (h) (i)
G) (k)
C-1
C-2
C-3
C-5
C-6
121.88 97.8 107.8 106.2 109.1 105.4 108.5
172.72
89.2 94.9 96.7 79.3
129.2 142.8 126.7 137.8 131.0 123.1 136.2 144.4 140.5 145.5 156.3
63.28 136.5 140.9 127.0 115.0 126.6 133.9 118.3 127.4 134.8 119.5 110.4 144.52 159.25 153.27 159.80 159.21 158.91
(1) R = H R = Me R = CH 2 Ph R = Ph (m) R' = H R' = H R'=H R' = H R1 = OMe R1 = OMe R1 = OMe R1 = OMe R' = C1 R' = C1 R' = C1 R'=C1 (n) R' = H R' = OMe R' = C1
R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2
= = = = = = = = = = = = = = =
H Me Et Ph H Me Et Ph H Me Et Ph H H H
35.6 35.4 35.1 36.0 35.8 35.5 35.4 36.1 35.6 35.3 35.2 36.0 102.6 102.0 102.7
158.03 136.35 158.04 136.39 158.11 136.30 158.07 153.4 152.5 152.4 151.7 153.2 154.1 152.4 151.6 152.4 151.7 151.5 150.8 154.3 154.3 153.2
100.9 152.3 150.6 148.6 152.0 148.8 151.5 150.9 142.9
C-7
135.3 143.1 147.2 144.3 135.4 144.1 147.1 144.4 135.2 143.1 147.1 144.2 130.3 130.2 130.2
C-8
C-8a
C-Me
162.3 162.6 162.8 162.8 163.8 162.2 162.3 162.9 162.3 162.7 162.9 163.7 154.4 154.4 154.2
43.35 85CCC2170 89JHC1109 141.7 51.7 86CC1127 143.7 147.0 57.6 40.9 88JOC887 142.8 145.8 32.0 149.6 51.2 42.9 143.5 39.8 147.9 51.5 149.3 151.4 88AP(321)851 166.24 84JCS(P 1)2707 165.97 166.10 165.00 91JHC769 56.5 56.6 56.7 56.7 56.3 56.4 56.6 56.6 56.7 56.7 56.9 56.5 135.4 135.4 135.5
Ref.
"in CDC1,.
Table 3 Studies on mass spectral fragmentations of derivatives of various ring systems. Ring system
Ref.
(12) (14) (15) (18) (20) (21)
82KGS124 82KGS124 81KGS1689 84JCS(P1)27O7 86JFC(32)299 86S71
(37) revealed that the [l,3,5]triazine ring is essentially planar, whereas the dihydroimidazole moiety adopts a flattened halfchair conformation <87LA72l>. An additional interesting feature of this structure is that the length of the S—C single bond is 1.739 A, which is significantly shorter than an ordinary S—C(arom.) bond (177.6 pm). Elucidation of the structure of compound (38) unambiguously showed that in the ring closure reaction leading to this product (see 8.17.6.5.2) retention of the configuration occurred, which observation allowed some valuable conclusions to be drawn concerning the reaction mechanism <91CC924>. In the 2-substituted imidazotriazinone molecule (39), only a small deviation from the co-planar arrangement of the aromatic and heterocyclic rings (9°) was found; this has been correlated with the biological effect of this and related compounds <89JCR(S)206>. The partially reduced bicyclic compound (40) was found to be composed of a planar imidazole ring fused to the puckered as-triazine with a torsion angle of C(4)—N(3)—N(2)—C(l) = 50° <91MI353>. On the other hand, the two bonds extending from the ring junction (i.e., C(8a)—C(8) and N(5)—C(6)) are nearly planar with the imidazole ring. Derivatives of the ring systems (3) and (21) (one of each, <90H(3l)6ll> and <89JHCllO9>, respectively) have also been investigated by x-ray diffraction.
451
Bicyclic 5-6 Systems, One Ring Junction N: Three Extra Heteroatoms 1:2 NHMe C3H7S
N
N
v
MeHN
S
SMe (36)
(35)
(37)
MeO
H CO2Me N
NO2 OMe
(39)
(40)
8.17.4 THERMODYNAMIC ASPECTS Protonation equilibria of imidazo[l,2-&][l,2,4]triazines (20) have been studied and the pKa values (found between 0.35 and 2.53) have been determined <87UKZ325>. Tautomeric equilibria of pyrazolo[5,l-c][l,2,4]triazin-4-ones (i.e., derivatives of (26)) and related compounds have also been investigated <89JHC869>.
8.17.5 8.17.5.1
REACTIVITY Ring-opening Reactions
Ring opening reactions of two different ring systems should be mentioned in this chapter. The substituted 5,7-diamino-l,2-dihydrooxazolo[l,5-fl][l,3,5]triazinium salt (41) undergoes hydrolytic cleavage under basic conditions and affords the hydroxyethyltriazinone compound (42) (Equation (1)). Reductive ring opening of the triazine ring of the pyrazolotriazine compound (43) was observed upon reaction with sodium borohydride, leading to the pyrazole derivative (44). The tetramethyl compound (45), obtained from (43) with methyl tosylate, also underwent ring cleavage (splitting off of acetone) when treated with acid to give the product (46) (Scheme 1) <89JHC1O45>. R2N
N
O HO
N
N
NH2
(1)
cr
(41)
NaBH4
(44)
(43) TsOMe
Me
HC1
(46)
(45) Scheme 1
452 8.17.5.2
Bicyclic 5-6 Systems, One Ring Junction N: Three Extra Heteroatoms 1:2 Ring Transformations
Ring transformation of (47) was reported to result in the imidazotriazinone derivative (48) (Equation (2)) <81KGS1689>. An unexpected ring transformation was observed with the attempted substitution of the methylthio group of (49) by amines. Instead of the expected product, a formal substitution of the 4-amino group was found which was explained by supposing a ring opening to (51) followed by an addition reaction to give (52) and ring closure to the final product (Scheme 2) <92JCS(P1)2789>. NHCOR
•W-o
Y
(2)
V
NNHCOR
O
(47)
(48)
MeS
MeS N
RNH2
NH2 (49)
MeS
N
N
NHR (50)
N
MeS N
N
RNH2
RHN
N N
N
C II
H2N
HN
(52)
(51) Scheme 2
8.17.5.3
Ring Contraction Reactions
Ring contraction of (53) under basic conditions has been reported to result in the thiazolo[3,2 &]pyrazole compound (54) (Equation (3)) <88S729>. o 1
K 2 CO 3 , CH 2 C1 2 , H 2 O
Ar
Ar
(3)
N Ph (53)
8.17.5.4
(54)
Formation of Further Condensed Rings
The reaction of the substituted 4-aminoimidazo[l,2-&][l,3,5]triazine (55) with ethoxymethylene malonate afforded ethyl 4-oxo-4#-imidazo[3,4-c]pyrimido [l,2-a][l,3,5]triazine-3-carboxylate (56) (Equation (4)) <92JCS(P1)2789>.
Bicyclic 5-6 Systems, One Ring Junction N: Three Extra Heteroatoms 1:2 R1
N
453
N N
N
(4) NH2
N
EtO2C
(55)
(56)
8.17.5.5 Electrophilic Reactions In the case of the imidazo[l,2-6][l,2,4]triazine ring system (20), brominations, nitrations, and hydroxymethylations have been reported. Compound (57) reacted with bromine at position 2, i.e., (58) was formed, (Equation (5)), and the nitration of the same starting compound showed similar selectivity <84KGS413>. Hydroxymethylation of the isomeric diphenyl derivative (59) was found to take place at positions 3 and 7 <84KGS1565>. Br-
Ph
N
N
Br Ph
(5)
N (58)
(57)
Ph
N
N
Ph
(59)
8.17.5.6
Reductions
Reduction of the N(l)—C(2) bond in the derivative (60) was reported in the reaction with sodium borohydride to yield the JV-hydroxy product (61) (Equation (6)) <87KGS554>.
NaBH 4
(60)
8.17.5.7
(6)
(61)
Alkylation and Realkylation Reactions
Alkylation and realkylation reactions have been reported for derivatives of five different ring systems. These are summarized in Table 4.
8.17.5.8 Transformations of Substituents of the Various Ring Systems Several functional group transformations have been published which are summarized in Table 5.
454
Bicyclic 5-6 Systems, One Ring Junction N: Three Extra Heteroatoms 1:2 Table 4 Alkylations of derivatives of the various ring systems. Ring system
Reactant NHR
NHR
O
N-Ph
(9)
Ref.
Product
MeN
MeHN
X.J N H
N-Ph
90T4353
SMe O
AcHlN
1S
(15)
AcHN
o
(15)
TS
OBn OBn
85JHC1137
O
N
HN
N
v
V ^
N
RS. -N
§
v
N
87LA721
s
H N
N
N
(24)
Mixture of methylated products
88JOC887
O
(32)
85JMC1704 Sw
SR
(32)
85JMC1704
EtO2C
(33)
92CPB1411 N R
R
8.17.6 RING SYNTHESES CLASSIFIED BY RING SYSTEMS 8.17.6.1
Synthesis of Fused Oxadiazines and Thiadiazines
Compound (63) represents the first example of the imidazo[l,5-d][l,3,4]oxadiazine ring system (1) which was obtained by the reaction of (62) with isocyanates (Equation (7)) <90T4353>. A simple route to (65) was found by the cyclization of vinylene diisothiocyanate with AT-benzylidenemethylamine (Equation (8)) <85CCC217O>. Compound (67) is the first representative of the imidazo[5,l&][l,3,5]thiadiazine ring system (3). This was obtained by reaction of ethyl isocyanoacetate (66) and arylsulfenylthiocyanates followed by treatment with triethylamine (Equation (9)) <90H(3l)6ll>. The structure of the product was verified by x ray (see Section 8.17.3.5).
Bicyclic 5-6 Systems, One Ring Junction N: Three Extra Heteroatoms 1:2
455
Table 5 Functional group transformations of derivatives of the various ring systems Ring system
Reactant
Ref.
Transformation
r°
(14)
92T1953
Ph
CN
(14)
Me .N
OMe
N
\
Me
\ N-Me
(15)
85KGS1125
OMe Cl
o HS (16)
87KGS978
CN
o R.
CO2H
N SH
HN
H
87MI 817-01
HO
OH
(16)
87MI 817-01
N
NMe2
NH2
(16)
92 JCS(P 1)2789
N
NH2
CN MeS R
(17)
SMe
NRR"
88T7155
Me
88KGS418
NH 2 Ph SMe
(19) N +
A-
SMe
H
O
(20)
Ph
N
N
r°
R R (32)
8
N
R1 N
I
SR
86KGS981 ^
Cl
R3
SR
NRR"
85JMC1704
456
Bicyclic 5-6 Systems, One Ring Junction N: Three Extra Heteroatoms 1:2 NHR
O RNCO
N-Ph Ph 3 P^
N
O
N-Ph
,N
(7)
RHN
(62)
(63) Ph
NCS
N
Ph
N
Me
(8)
NCS S (64)
(65) CO2Et i, ArSSCN
Et3NH+
N
N
(9)
ii, Et3N
EtO2C (66)
SAr
N (67)
Positively charged derivatives of the ring system (4) have been reported <87H(26)1323,88S729). In these syntheses, Af-amino-4-phenylthiazol-2(3//)thione (68) was reacted with phenacyl bromide derivatives to yield the products (69) as bromide salts (Equation (10)). The same ring closure principle was applied for the l,2,6,7-tetrahydroimidazo[5,l-6][l,3,4]thiadiazine (71)—ring system (5)—which was obtained from the dihydroimidazole derivative (70) (Equation (11)) <90JCS(Pl)3003>. The derivative of the same ring system with an aromatic imidazole ring (73) was prepared by treatment of (72) with hydrazine hydrate (Equation (12)) <82H(19)2119>.
i, ArCOCH2Br
N
(10)
Ph
ii, Et3N
H2N (68)
(69)
i, ArCOCH2Br
(11)
ii, H+
H2N (70)
(71)
N
O
R
2
R1
N
R1
N2H4xH2O
R1
R1 (72)
(12)
(73)
The totally saturated compound (75) represents the first example of the thiazolo[2,3-c] [l,2,4]thiadiazine ring system (6). This compound was obtained as a ring enlargement product in the reaction of (74) with ammonia (Equation (13)) <89CL89>. Reaction of 2-ethyloxazoline (76; X = O) or 2-ethylthiazoline (76; X = S) with chlorosulfonyl isocyanate followed by treatment with triethylamine led to the ring closed products (77; X = O or S), derivatives of ring systems (7) and (8), respectively (Equation (14)) <93SC121>.
Bicyclic 5-6 Systems, One Ring Junction N: Three Extra Heteroatoms 1:2
457
N
NH4OH
(13) (74)
(75)
O
Et
X
i,CSI ii, Et3N
N
w
HN
T
(14)
N
o
(77)
(76)
Reaction of the phosphinimine derivative (78) with isothiocyanates also resulted in formation of a derivative of a hitherto unknown ring system: imidazo[l,5-. Both the reaction of (80) with carbon disulfide to give (81) (Equation (16)) <90JHC775> and the ring closure of (82) to the sulfone (83) (Equation (17)) <89SC302l> represent synthetic pathways to two new ring systems (i.e., derivatives of pyrazolo[l,5c][l,3,5]thiadiazine (10) and imidazo[l,2-£][l,2,6]thiadiazine (11), respectively). RHN
O
N-Ph
O
R-NCS
N-Ph
(15)
N
(78)
(79)
R
MeS SMe
i, KOH, CS2
SMe
(16)
ii, Mel
(80)
(81)
NO2
R N
i,CSI
(17) ii, Pr^NH
HN
(82)
(83)
8.17.6.2 Synthesis of Oxazolo- and Isoxazolo[l,3,5]triazines Synthesis of derivatives of the two isomeric ring systems (12) and (13) are discussed in this section. An example of the ring system (12) in unsaturated form was obtained by the dimerization reaction of oxazoloisocyanate (84), which afforded (85) (Equation (18)) <82CPB412, 82CPB4195), whereas derivatives with a saturated oxazole ring for example, the salt (87) prepared from (86) (Equation (19)) <92KGS228>—have also been reported (see also <81KGS1689>). o OCN (18)
(84)
(85)
458
Bicyclic 5-6 Systems, One Ring Junction N: Three Extra Heteroatoms 1:2
(19) R" A (86)
(87)
Compound (89), the first representative of the ring system isoxazolo[2,3-tf][l,3,5]triazine (13)? w a s obtained by the reaction of (88) with phenoxycarbonylisocyanate (Equation (20)) <87JHC50l>. Other derivatives of this ring system have also been described <9OUC(B)182>. o
X NCO PhO
H2N
(20)
(88)
8.17.6.3
Synthesis of Thiazolo[3,2-a][ 1,3,5)triazines
Principally, two approaches have been applied for the synthesis of these ring systems: (i) closure of the triazine ring as shown by the reaction of aminothiazoline (90) with aroylisothiocyanate to give (91) (Equation (21)) <83MI 817-01 >, or (ii) closure of the thiazole ring as realized in the transformation of (92) to (93) followed by cyclization to (94) (Scheme 3) <87KGS978>. Several other examples of related ring closures have been published <82AP(315)791,82CCC1229,82CPB4195,82KGS124, 87LA65, 87MI 817-02, 91SC319>. O
X NCS Ar
H2N
(21)
N (90) Cl
R2N
N
SH
CN
(92)
(93)
(94)
Scheme 3
8.17.6.4
Synthesis of Imidazo- and Pyrazolo[l,3,5]triazines
Three ring systems—(15), (16), (17)—belonging to this section were reported in CHEC-I (see Section 8.17.1). Some more important new applications are as follows; (i) Ring system imidazo[l,2-tf][l,3,5]triazine (15). The hydroxyethylamino compound (95) when heated underwent ring closure to (96) (Equation (22)) <87NKK40, 88NKK236) and formation of the related 7V-cyano product (98) by cyclization of (97) was also reported (Equation (23)). Also a partially reduced derivative (100) was obtained by the reaction of 2-chloroimidazoline hydrochloride (99) with ammonium thiocyanate (Equation (24)) <87LA72i>. Other syntheses (mostly applications of well-established methods) have also been published <81MI 817-01, 85KGS1125, 87NKK40, 88NKK236, 92KGS228). The ring closure of (101) led to formation of the benzologue (102) (Equation (25)) <82AP(315)791, 93MI 817-01, 94MI 817-01 >. H
Y Y
N
ArN OH
r
Y R
R (95)
(96)
H N (22)
Bicyclic 5-6 Systems, One Ring Junction N: Three Extra Heteroatoms 1:2 R2N
N.
459
CN
.NHCN
N
110°C
(23)
V o
(97)
(98) H N
H N
N NH4SCN
Cl
HN N H
T
(24)
N
s
(99)
(100)
R-N =
(25)
OEt (101)
Y (102)
(ii) Ring system imidazo[l,5-tf][l,3,5]triazine (16). Synthesis of derivatives of this ring system using translocative rearrangements has been published (82JA235, 83JOC3): reaction of (103) with formamidine gave (105) via formation of intermediate (104) (Equation (26)). Syntheses of other representatives of this ring system have also been reported <87MI 817-01,92JCS(Pl)2789>. R NC H2N
H2N
/=NH
N
H2N
R R
N
N N
(103)
f
N
N
N N
N NH2
N
(26)
R
(105)
(104)
(iii) Ring system pyrazolo[2,3-tf][l,3,5]triazine (17). Ring closure of the open chain compound (106) to (107) under basic conditions (Equation (27)) <85LA1962>, and conversion of (108) into (109) (Equation (28)) <88T7155> are two important new routes to these compounds. Other approaches have also been published <84JHC389, 86JHC349, 89AP(322)557>.
o
S KOH
N"% H
H
(27)
CN O (107)
(106) NC
SMe
MeS SMe
(28) NH2
(108)
(109)
8.17.6.5 Synthesis of Fused [l,2,4]Triazines 8.17.6.5.1 b-Fused [l>2,4]triazines Two thiazolo-fused ((18) and (19)), one imidazo-fused (20), and one pyrazolo-fused ring (21) belong to this category of systems. Compound (111), a representative of the new ring system
460
Bicyclic 5-6 Systems, One Ring Junction N: Three Extra Heteroatoms 1:2
thiazolo[3,2-6][l,2,4]triazine (18), has been obtained by reaction of (110) with DMAD (Equation (29)) <84JCS(P1)27O7>. CO2Me
DMAD
R
(29)
NH
N (110)
(111)
Several syntheses have been described for the isomeric ring system thiazolo[3,4-6][l,2,4]triazine (19). The heteroaromatic system (114) has been obtained by the reaction of (112) with O-benzenesulfonyl a-cyanobenzylalcohol through the intermediate (113) (Equation (30)) <85KGS498, 85KGS1497). The partially saturated derivative (116) of the same ring system was prepared by the treatment of (115) with diacetyl (Equation (31)) <87KGS554>. NC ) - OSO2Ph Ph
R1
H2N O
R"
N
Ph (30)
N R"
N
+
A"
SMe (112)
N
R
SMe (114)
(113) R HOHN
diacetyl
(31) H2N (116)
(115)
Various syntheses have been published earlier for the ring system (20). The reaction of triazine diester (117) with propargylamine gave (118) (Equation (32)). Numerous other works have also appeared in this field (84KGS413, 84MI 817-01, 86JFC(32)299, 87UKZ1095, 88JMC2221). Two major routes
to the new ring system pyrazolo[l,5-6][l,2,4]triazine (21) have been described: reaction of the zwitterion (119) with DMAD to yield (120) (Equation (33)) <83CPB3759>, for which reaction two possible mechanisms have been proposed, and a condensation reaction of (121) with dioxo reagents to give (122) (Equation (34)) <89JHC11O9>. MeO2C . ^ N
SMe
NH2
MeO2C (32)
MeO2C
MeO2C
N
(118)
(117)
DMAD
MeO2C (33)
MeO2C (119)
(120)
H2N (34)
HoN (121)
8.17.6.5.2
(122)
c-Fused fl ,2>4]triazines
Two thiazolo-fused ((22) and (23)), two imidazo-fused ((24) and (25)), and a pyrazolo-fused ring (26) are discussed here. While (22) has already been described in CHEC-I, a novel approach to its
Bicyclic 5-6 Systems, One Ring Junction N: Three Extra Heteroatoms 1:2
461
synthesis should be mentioned here: the reaction of the diazonium salt (123) with malononitrile to give (124) (Equation (35)) (87SUL125, 89MI 817-01, 9lPS(60)ll9>. Other reports have also appeared <84AQ232, 87MI 817-03>. +
N2 A"
CO2Et
N
CO2Et
CH2(CN)2
(123)
(35)
(124)
Ring closure of (125) to (126) under basic conditions (Equation (36)) <91CC924>, as well as reaction of (127) with phenacyl bromide to yield (128) (Equation (37)), are the first examples of synthesis of the thiazolo[4,3-c][l,2,4]triazine ring system (23) (86PHA101). Derivatives of both imidazo-fused systems (24) and (25) can be synthesized by reactions of diazoimidazoles (129) or (132) with alkenes or reagents containing active methylene groups. Thus, reaction of 2-diazoimidazole (129) with 1,2dimethoxyethene gave (130) <9OJCS(P2)1943>, whereas 1,1-dimethoxyethene yielded (131) (Scheme 4) <86CC1127>. Compound (129) was also cyclized with active methylene reagents <88JOC887>. 4Diazoimidazole (132), similarly, was cyclized to (133) and (134) by using substituted acetonitriles or substituted acetic esters (Scheme 4) <87JCS(Pl)665>. H CO2Me N NEt3, MeOH
(36)
(125)
PhHN
N
N
PhCOCH2Br
N (37) Ph
(127)
(128)
MeO MeO
OMe
R
N
N
MeO
N
MeO R
OMe
MeO
(129)
(130)
N2 N
NH 2 (133)
N
RCH2CO2Et
AcOH
R
OMe R (131)
R1 RCH2CN
H N
pyridine
H N
R' N
R O
(132)
(134)
Scheme 4
The synthesis of pyrazolo[5,l-c][l,2,4]triazines (derivatives of (26)) was also accomplished by an analogous method: the diazo compound (135) was reacted with ynamines to give (136), or with enamines to yield (137) after elimination of one molecule of amine (Scheme 5) <83JOC2330). Numerous applications of this very straightforward method have been described <84JHC945,84M431,85JHC453, 85LA1962, 87AP(320)850, 88AP(321)851, 88JOC887, 89AP(322)557, 90CCC2790, 91JPR(333)333>. The
intra-
462
Bicyclic 5-6 Systems, One Ring Junction N: Three Extra Heteroatoms 1:2
molecular condensation of (138) led to a derivative of the benzologue of system (26); pyrazolo[5,l c]benzo[l,2,4]triazine-5-oxide (139) (Equation (38)) <82MI 817-01 >. NEt2
NEt2
N (137)
(135) Scheme 5 H2N base
(38)
N
(139)
(138)
8.17.6.5.3 f-Fused [1,2,4]triazines Formation of the oxazolo[3,4-&][l,2,4]triazine ring system (27) was first observed in the phototransformation of (140) with ketene which gave the product (141) (Equation (39)) <88CPB3354>. The proposed mechanism involves formation of the biradical (142), its cyclization to the fused aziridine (143), ring opening of the three-membered ring to give the zwitterion (144), which upon reaction with a further molecule of ketene affords the final product (141). o Me
CF
N
R
/iv,H2C = C =
(39) N
N
(140)
(141) /JV,H 2 C = C =
/iv,H2C = C =
oii
/CF 3
Me. -CO
JL R
N
>1
+
(144)
(143)
(142)
'N
The first representative of the ring system (28), the pyrazolo[l,5-6][l,2,4]triazin-l(2//)one (146), has been synthesized by condensation of (145) with triethyl orthoformate (Equation (40)) <93LA367>.
i, HC(OEt)3
MeO
(40) ii, NH3
H2N (145)
(146)
8.17.6.5.4 d-Fused /1,2,4Jtriazines Partially saturated derivatives of two of the ring systems belonging to this section (oxazolo[3,2d][l,2,4]triazine (29) and thiazolo[3,2-d?][l,2,4]triazine (30)) have been prepared since 1985 for the
Bicyclic 5-6 Systems, One Ring Junction N: Three Extra Heteroatoms 1:2
463
first time. Both the oxazoline compound (147) and the analogous thiazoline derivative (149) were reacted with tetrazines. These Diels-Alder reactions with inverse electron demand yielded the ringclosed products (148) and (150) (Equations (41) and (42)), respectively <84AP(3l7)237>. R ii
R (162)
(41)
(147)
(148) CF
CF3
II
f
CF3
N I
(42)
N
N
CF3 (149)
(150)
A novel synthesis of imidazo[l,2-d][l,2,4]triazines has been realized by the ring closure of the imidazole compound (151) with urethane to yield the fused triazinone (152) (Equation (43)) <89JCR(S)206>. Other approaches to this ring system have also been published <84CCC275,88JIC784). Eto
N
N EtO2CNHNH2
EtO
AcOH
HN
HN
Ar
To
N
(43)
(152)
(151)
Condensation reactions of (153) and related compounds provided a route to derivatives of the ring system (32): reaction of (153) with acetone yielded (154) (Equation (44)). Another analogous ring closure has also been reported <85JMC17O4>. The Diels-Alder reaction between (155) and terazine diester afforded the pyrazole-fused product (156) (Equation (45)) <84AP(3l 7)237 >. A similar condensation reaction as above was also applied for the ring closure to derivatives of (33): treatment of (157) with ethyl orthoformate yielded (158) (Equation (46)) <9UHC769>. Another related case has also been reported <89JHC1O45>. The reaction path from (159) to (160) involving ring transformation has been described (Equation (47)) <82JHC817>.
acetone
(153)
(44)
(154) CO2Me n
N
CO2Me
CO2Me
(45)
N Me CO2Me
(155)
(156)
464
Bicyclic 5-6 Systems, One Ring Junction N: Three Extra Heteroatoms 1:2 HC(OEt)3
(46)
(157)
(158)
KOH
(47) EtOH
(159)
8.17.7
(160) X = H, Br
IMPORTANT COMPOUNDS AND APPLICATIONS
Four particular derivatives are worth mentioning in this section for their practical applications. The imidazothiadiazine compound (161) proved to possess marked antihypertensive and diuretic properties <87GEP3 542662). The derivative (162) was tested for calcium channel blocking <88JMC222l >. Compound (163) was found to be a potential antiasthma agent <85JMC17O4>, and the derivative (164) showed significant aldose reductase inhibitory effect <92CPBl4ll). CONRR"
HfNBu: (162)
(161)
HO2C
(163)
Copyright © 1996 Elsevier Ltd.
Comprehensive Heterocyclic Chemistry II