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The Reduction of Nitrogen Heterocycles with Complex Metal Hydrides
ADVANCES IN HETEROCYCLIC CHEMISTRY. VOL . 39
The Reduction of Nitrogen Heterocycles with Complex Metal Hydrides JAMES G. KEAY
Reilly Tar & Chemical Corporation. Indianapolis. Indiana 46204 1. Scope of Review . . . . . . . . . . . . . . . . . I1. Introduction . . . . . . . . . . . . . . . . . . . I11. Reduction of Heterocycles Containing One Nitrogen Atom . . A . Pyridines . . . . . . . . . . . . . . . . . . 1. With Borohydride . . . . . . . . . . . . . . 2. With Aluminurn Hydrides . . . . . . . . . . . 3. Other Hydrides . . . . . . . . . . . . . . . B. Pyridones . . . . . . . . . . . . . . . . . . 1. With Aluminum Hydrides . . . . . . . . . . . C . Pyridinium Salts . . . . . . . . . . . . . . . . I . With Borohydrides . . . . . . . . . . . . . . 2 . With Aluminum Hydrides . . . . . . . . . . . D. I-Alkoxypyridinium Salts and Pyridine I-Oxides . . . . E . Cyclic lmines . . . . . . . . . . . . . . . . . F. Quinolines . . . . . . . . . . . . . . . . . . 1. With Borohydrides . . . . . . . . . . . . . . 2 . With Aluminum Hydrides . . . . . . . . . . . G. Quinolinium Salts . . . . . . . . . . . . . . . I . With Borohydride . . . . . . . . . . . . . . 2. With Aluminum Hydndes . . . . . . . . . . . H . Isoquinolines . . . . . . . . . . . . . . . . . I . With Borohydrides . . . . . . . . . . . . . . 2 . With Aluminum Hydrides . . . . . . . . . . . I . lsoquinolinium Salts . . . . . . . . . . . . . . I . With Borohydride . . . . . . . . . . . . . . 2. With Aluminum Hydrides . . . . . . . . . . . J . Indoles . . . . . . . . . . . . . . . . . . . K . 1, 2-Oxazoles . . . . . . . . . . . . . . . . . L . 1, 3-Oxazoles . . . . . . . . . . . . . . . . . M . I ,3-Thiazoles . . . . . . . . . . . . . . . . . N . 1, 3-Thiazines . . . . . . . . . . . . . . . . . IV . Reductions of Heterocycles Containing Two Nitrogen Atoms . A. Pyrazoles . . . . . . . . . . . . . . . . . . B. Imidazoles . . . . . . . . . . . . . . . . . . C . Benzimidazoles . . . . . . . . . . . . . . . . D. I ,2,4-Oxadiazoles . . . . . . . . . . . . . . . 1
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6 6 6 10 12 12 12 13 13 23 24 25 25 25 28 30 30 32 32 32 33 33 33 35 35 38 40 40 41 42 42 44 46 46
Copyright 0 1986 by Academic Press. Inc. All rights of reproduction in any form rcservcd .
JAMES G. KEAY
2
[Sec. I
E . Pyridazines . . . . . . . . . . . . . . . . . . . . . . . . F. Pyrimidines . . . . . . . . . . . . . . . . . . . . . . . G . Pyrazines . . . . . . . . . . . . . . . . . . . . . . . . H . Cinnolines . . . . . . . . . . . . . . . . . . . . . . . . I. Quinazolines . . . . . . . . . . . . . . . . . . . . . . . J . Quinoxalines . . . . . . . . . . . . . . . . . . . . . . . K . 1,2-Diazepines . . . . . . . . . . . . . . . . . . . . . . L . I , 4-Diazepines . . . . . . . . . . . . . . . . . . . . . . M. I 5.Benzodiazepines . . . . . . . . . . . . . . . . . . . . V . Reductions of Heterocycles Containing Three Nitrogen Atoms . . . . . . . A . 1.2.3.Triazoles . . . . . . . . . . . . . . . . . . . . . . B. 1.2.4.Triazoles . . . . . . . . . . . . . . . . . . . . . . C. Benzotriazoles. . . . . . . . . . . . . . . . . . . . . . . D. 1.2.3.Triazines . . . . . . . . . . . . . . . . . . . . . . E . 1.2.4.Triazines . . . . . . . . . . . . . . . . . . . . . . F. 1.3.5.Triazines . . . . . . . . . . . . . . . . . . . . . . VI . Reduction of Heterocycles Containing Four Nitrogen Atoms . . . . . . . A . Tetrazoles . . . . . . . . . . . . . . . . . . . . . . . . VII . Reduction of Fused Heterocycles . . . . . . . . . . . . . . . . . A . Quinolizines . . . . . . . . . . . . . . . . . . . . . . . B. Azolopyridazines. . . . . . . . . . . . . . . . . . . . . . C. Azolopyrimidines . . . . . . . . . . . . . . . . . . . . . 1. 1.2.5.0xadiazolo[3. 4-dlpyrimidine . . . . . . . . . . . . . . 2. Imidazolo[4.5.d]pyrimidine. . . . . . . . . . . . . . . . . 3. Pyrazolo[1. 5.alpyrimidine . . . . . . . . . . . . . . . . . D. Thieno[Z.3.dlpyrimidine . . . . . . . . . . . . . . . . . . . E . Thienopyridines . . . . . . . . . . . . . . . . . . . . . . I . Thieno[3.2.c 1. and Thieno[2.3-c]pyridines. . . . . . . . . . . . F. Azoloazepines. . . . . . . . . . . . . . . . . . . . . . . I . Pyrazolo[3.4.b].l. 4-diazepine . . . . . . . . . . . . . . . . G . Azanaphthalenes. . . . . . . . . . . . . . . . . . . . . . 1 . Pyrido[3.2.e 1. and Pyrido[3.4.e].l.2. 4.triazines . . . . . . . . . . 2. Pyrazino[2.3.dlpyrimidine . . . . . . . . . . . . . . . . . 3. Pyrimidino[4.5.dlpyridazine . . . . . . . . . . . . . . . . 4. Pyrido[3.4-dlpyrimidine . . . . . . . . . . . . . . . . . . 5. Pyrido[2.3.blpyrazine . . . . . . . . . . . . . . . . . . . 6. Pyrido[2.3.dlpyridazine . . . . . . . . . . . . . . . . . . 7. Pyrido[4.3-blpyridine . . . . . . . . . . . . . . . . . . . H . Azoloindoles . . . . . . . . . . . . . . . . . . . . . . . I . Pyrido(2.3.bJ.. .[3.4.b 1. and .[4. 3.bIindoles . . . . . . . . . . . I . 1.3.Thiazolo[2. 3.a]isoquinoline . . . . . . . . . . . . . . . . J . 1.4.Thiazeno[4. 5.alquinoline and .[4. 5.a]quinazoline . . . . . . . . K . Benzo[d.elquinazoline . . . . . . . . . . . . . . . . . . . . L. Indolo[2.3.a]quinolizine . . . . . . . . . . . . . . . . . . . M . Pyrido[3.2. I.k, llphenothiazines . . . . . . . . . . . . . . . .
.
46 48 50 51
52 53 54 55 55 56 56 56 57 58 59 60 60 60 61 61 62 63 63 63 66 67 67 67 68 68 68 68 69 70 70 71 71 72 72 72 74 74 75 76 76
I . Scope of Review This article covers the literature published between the years 1965 and 1983 and that contained in ChemicalAbstracts. Volumes 64-99 inclusive.
Sec. 111
REDUCTION OF NITROGEN HETEROCYCLES
3
Pertinent 1984 literature is also included. It serves to update the review of Lyle and Anderson, which covered the earlier literature. Substrates covered are listed in the index page. Most investigators have worked with the complex hydrides of boron and aluminum; therefore reactions with these form the principal part of the discussion. Some work with other organometallic hydrides and complex hydrides of some transition metals is also described.
11. Introduction The previous review on this subject was published in 1966.’ Though the number of reagents and systems investigated has been greatly expanded since that time, this review is structured after the Lyle and Anderson document. Some of the earlier observations regarding general reactivity principles deserve restatement. Complex metal hydrides are nucleophilic reagents that formally add hydride to polarized carbon - carbon or carbon - heteroatom double bonds. The two best known reagents of this type are lithium aluminum hydride (LAH) and sodium borohydride (NBH). The former is moisture sensitive and generally used in ethers; the latter is milder and is most often employed in hydroxylic solvents. The efficacy and selectivity ofthese reagents is greatly affected by structural modifications [e.g., LiAlH,(O-t-Bu),], for instance, the addition of Lewis acids and mixed hydride formation. Solvents can also affect the power of the reducing agent; this is particularly so with sodium borohydride. Many modified complex metal hydrides are now known. A comprehensive review on complex metal hydrides was published in 1979., Those heterocyclic systems attacked by complex metal hydrides are required to be relatively electron deficient. Nitrogen heterocycles in which the heteroatom contributes a single electron to the K system are considered electron deficient (e.g., 1). However, systems where the nitrogen atom contributes two electrons are considered electron rich (e.g., 2) and are not normally attacked by metal hydrides. Aromatic species that contain both a “pyridine-like” (1) and a “pyrrole-like” (2) heteroatom (e.g., 3) exhibit be-
X
=
N,O, S
P. S. Anderson and R. E. Lyle, Adv. Heterocycl. Chem. 6,45 (1966).
A. Hajos, “Complex Hydrides and Related Reducing Agents in Organic Synthesis.” Am.
Elsevier, New York, 1979.
4
JAMES G . KEAY
[Sec. I1
havior due to each atom and are generally capable of being attacked by these reagents. Traditionally, the mechanism by which complex metal hydrides reduce unsaturated compounds has been viewed as nucleophilic and regarded as a direct hydride transfer from reagent to ~ubstrate.~ However, in the last few years this view has been radically challenged amid reports of the operation of single-electron transfer (SET) processes. Ashby and co-workers have shown that such mechanisms do occur in the reaction of both organometallic compounds or simple metal hydrides with a variety of substrate^.^" The first suggestion that an alternative radical mechanism may operate in the borohydride reduction of pyridinium ions was put forward by Uzienko and Yasnikov in 1972 during investigation of 1-benzyl-3-carboxamidopyridinium chloride (4).6
C3
CONH 2
I
ci
CH,Ph
(4) Conclusive evidence for the formation of radical intermediates in the reaction of pyridine with LAH’ itself has not been forthcoming to date. This is due to the short lifetime of such radicals and their propensity toward coupling with hydrogen or other pyridine radicals. However, the use of substrates that generate radicals with a greater steric requirement (e.g., 1,lOphenanthroline, 2,2-bipyridine, isoquinoline) has allowed detection of radicals by ESR spectrometry. Much stronger signals were observed with the less reactive hydrides, lithium di- and lithium tri-tert-butoxyaluminum hydride. Much higher radical concentrations, up to 27%, were observed. Electronspin resonance signals were still detectable one month later in some cases.’ In the absence of more readily attacked species, excess pyridine is known to form lithium tetra(dihydropyridiny1)aluminates with LAH.* Such intermediate complexes react with heterocyclesat much slower rates and allow observation of the radical intermediates. Indeed, ratios of substrate to hydride such that the available hydrogens could be involved in intermediate heterocyclic hydride complexes (e.g., 5) resulted in the highest
’E. C. Ashby, A. B. Goel, R. N. DePriest,and H. S.Prasad,J. Am. Chem. SOC.103,973 (198 I). ’
E. C. Ashby, A. B. Goel, and R. N. DePnest, J. Am. Chem. SOC. 102,7779 (1980). E. C. Ashby and J. R. Bowers,Jr., J. Am. Chem. SOC. 103,2242 (I98 I). A. B. Uzienko and A. A. Yasnikov, Ukr. Khim. Zh. (Russ.Ed.) 38, 1289 (1972). E. C. Ashby and A. B. Goel, TefrahedronLett., 4783 (1981). P. T. Lansbury and J. 0. Peterson, J. Am. Chem. SOC.85,2236 (1963).
Sec. 11)
5
REDUCTION OF NITROGEN HETEROCYCLES
concentration of observable radical intermediates. It was suggested that the initial radical pair that was formed (7) underwent not only further reaction to the reduced product 8 but also dissociation to the free radical anion 9.'
ArH'
+
Li** H
+
AIH(Ot-Bu),
(9)
ArH,
+
LiOH
AI(OH),
+
t-BuOH
H,
00)
Sosonkin and co-workers have recently shown that the ESR signal obtained on reduction of 9-cyano- 10-methylacridinium perchlorate (1 1) with NBH was identical with that produced by electrochemical (one-electron) reduction of the same cation in dimethylf~rmamide.~
1. M. Sosonkin, A. 1. Matern, and 0. N. Chupakhin, Khim. Geferofsikl.Soedin. 10, 1377 (1983).
6
JAMES G . KEAY
[Sec. 1II.A
111. Reduction of Heterocycles Containing One Nitrogen Atom A. PYRIDINES 1. With Borohydride The reduction of pyridines with NBH occurs only if they carry electronwithdrawing substituents. Most pyridines containing a single electron-withdrawing substituent in the 2 or 4 position are unaffected by NBH. Reaction, if any, occurs at the substituent.lo However, a single electron-withdrawing group in the 3 position can lead to ring reduction.ll 3,5-Dicyano-(14)12and 3,5-diethoxycarbonylpyridine(15) were among the first to be studied in detail.13 Reduction leads mainly to mixtures of the 1,2- and 1,Cdihydro species. In pyridine, the 1,Cdihydropyridinesare favored.l4 Sodium cyanoborohydride affordsthe 1,Cdihydropyridine 18in high yield (- 80%),essentially free from the 1,2-dihydro analog. Reduction of 3,5-diacetylpyridine (16)with NBH and LAH gives the 3,5-diol19 in 98% yield. A small amount of nuclear reduction is observed (- 2%),of which the major component was determined spectrophotometrically to be the the 1,Cdihydro isomer.15
NcocN EtOg
,
RO
64)
lo
C02Et
H & O C U O C H ,
R
(15)
66)
Y. Kikugawa, M. Kuramoto, I. Saito, and S . 4 . Yamada, Chem. Pharm. Bull. 21, 1927
(1973). 'I
Y. Kikugawa, M. Kuramoto, I. Saito, and S . 4 . Yamada, Chem. Pharm. Bull. 21, 1914
(1973).
J. Kuthan and E. Janeckova, Collect. Czech. Chem. Commun. 29, 1654 (1964). P. J. Brignell, U. Eisner, and P. G. Farrell, J. Chem. SOC.B, 1083 (1966). I4 E. Booker and U. Eisner, J. C. S. Perkin I, 929 (1975). IJJ. Palecek, L. Vavruska, and J. Kuthan, Collect. Czech. Chem. Commun.37,2764 (1972). I2
l3
Sec. III.A]
REDUCTION OF NITROGEN HETEROCYCLES
7
The reduction of 3-cyanopyridine (20) in ethanol leads mainly to the tetrahydropyridine 22.16Reduction in pyridine or diglyme however, produces 1,Cdihydropyridine (21)as the major product. Minor amounts of the 3-pyridylmethylamine 23 are also obtained with ethanol, and the aprotic solvents prevent further ring reduction.
I''I
Reduction of 2- and 4-cyanopyridines with NBH in pyridine or diglyme might be expected to give the aminomethyl compounds. However, 2-cyanopyridine (24)gives in diglyme a 20% yield of 2,4,5-tris-2-pyridylimidaole (26).164-Cyanopyridine (25)on reduction in pyridine gave low yields of 2,4,5-tris-4-pyridylimidazole(27)and 1,l -bis-4-pyridylmethylamine (28). The formation of such products possibly involves a benzoin type coupling of the initially formed aldimine, which can then undergo further reaction with another molecule of cyanopyridine. In ethanol, substituent reactions predominate on NBH reduction. 2-Cyanopyridine gives the amine 29 and amidine 30.4-Cyanopyridine gives the amine 29 in 53% yield.'O The reduction of nicotinamide (31)with NBH in diglyme at 140°Cgave a low yield of tetrahydropyridine (22) and the piperidine 32. Addition of ethanol as a proton source raised the yield of 22 to 42%."J7 The dehydration of primary amides with borohydride is known to occur in moderate yield.'* The reduction of 2-alkylamino- and 2-arylamino-3,5-dinitropyridines (33)in water leads to the tetrahydropyridines 34 in high yield^.'^.^^ The I6
l9 Zo
S . 4 . Yarnada, M. Kurarnoto, and Y. Kikugawa, Tetrahedron Lett., 3101 (1969). Y. Kikugawa, S. Ikegami, and S.-I. Yarnada, Chem. Pharm. Bull. 17,98 (1969). V. M. Micovic and M. L. J. Mihailovic, J. Org. Chem. 18, 1190 (1953). A. Signor, A. Orio, and A. Marzotto, Atti Accad. Peloritana Pericolanti, CI. Sci. Fis., Mat. Naf.50, 85 (1970). A. Signor and E. Bordignon, Tetrahedron 24,6995 (1968).
8
JAMES G . KEAY
NaB/ Pyror Diglyme
(24) ; 2-CN (25); 4-CN
\
[Sec. 1II.A
(26) ; 2-Pyridinyl
(27):
4-Pyridinyl
OCN H
(22)
(32)
precise nature of the products was confirmed, and the mechanism was proposed on the basis of experiments using deuterated reagents.213-Nitropyri21
E. Bordignon, A. Signor, I. J. Fletcher,A. R. Katritzky, and J. R. Lea, J. Chem. Soc. B, I567 (1970).
Sec. III.A]
9
REDUCTION OF NITROGEN HETEROCYCLES
dine (35)was reduced to the piperidine 36 with borohydride, an indication that initial attack occurs at the 4 position." Pyridine 3-carboxylic acid derivatives and 3-halopyridines are normally unreactive toward borohydride.'l NaBH, NHR
H2
0
* O Z N a N NHR o z U ..
(33)
(34)
NaBH, b
EtOH
(3 5)
H
(36)
42
%
An interesting occurrence is the complete reduction of the pyridine ring in 5,6-dihydro-l lH-benzo[5,6]cyclohepta[1,2-b]pyridin-ll-one (37) to the piperidine 38 in 2-propanol with NBH.22 The cis isomer was favored (- 9 : 1). This is a rare example of deactivated pyridine undergoing borohydride reduction. The answer lies in the carbonyl group, which undoubtedly undergoes reduction to give the borate ester 39. This boron complex will have a significant steric requirement. It is known that increasing the size of the 1 substituent increases the proportion of hydride attack at the 4 position, and hence formation of piperidine, in pyridinium salts.23 Likewise, initial hydride attack will now be directed toward the 4 position, and subsequently the piperidine 38 will be formed.
($I NaBH, i-PrOH
Yo
I
qp
23
1
HO
(38) 22
23
J. A, Bristol and C. Puchalski, J. Org. Chem. 45,4206 ( I 980). P. S. Anderson, W. E. Krueger, and R. E. Lyle, Tetrahedron Letf.,401 1 (1965).
10
JAMES G. KEAY
[Sec. 1II.A
2. With Aluminum Hydrides Lithium aluminum hydride (LAH) reductions are camed out in aprotic solvents and give rise to the dihydro- and tetrahydropyridine derivatives. LAH reacts with both pyridines and pyridinium salts.’ It has been known for some time that aged (- 24 h) pyridine and LAH solutions form complexes of lithium tetrakis(N-dihydropyridiny1)aluminate (40, LDPA),z40z5which is believed to consist of a mixture of the 1,2- and 1,Cdihydropyridines (by NMR). Indeed, LDPA itself has been used as a selective reducing agent for ketonesz4and affords 3-substituted pyridines (41) on reaction with alkyl halides.z6 2,5-Dihydropyridines have been identified as intermediates in similar reactions.27Kuthan and co-workers have shown that for 3,Sdicyan-
r
1-
I_ RX
% Yield
R
X
Me
I
86
Et
I
89
PhCH,
CI
63
Br
Br
41
QrR (41)
opyndine (14) the rate of reduction was faster in ether than in THF, but the ratio of isomers was not altered.28For lithium and sodium aluminum hydrides and sodium diethoxyaluminum hydride, NaA1Hz(OEt)2, approxi24
C. S . Giam and S. D. Abbott, J. Am. Chern. SOC.93, 1294 (197 I).
’’P. T. Lansbury and J. 0. Peterson, J. Am. Chem. SOC.84, 1756 (1962).
R. F. Francis, C. D. Crews, and B. S . Scott, J. Org. Chem. 43, 3227 (1978). R. F. Francis, W. Davis, and J. T. Wisener, J. Org. Chem. 39, 59 (1 974). laJ. Kuthan, J. Prochazkova, and E. Janeckova, Collect. Czech. Chem. Cornmiin. 33, 3558 (1968). 26 27
11
REDUCTION OF NITROGEN HETEROCYCLES
Sec. III.A]
mately 1 : 1 mixtures of 1,2- and 1,4-dihydro-3,5-dicyanopyridines(42 and 17) are isolated. When sodium bis-( I ,4-dioxapentyl)aluminum hydride [ NaAIH2(OCH2CH20CH3),]was used, only the 1,4-dihydro compound 17 was isolated in low yield.28This can be explained by the formation of an initial coordination complex between the hydride reagent and the pyridine 43. Attack at the 2 position is favored for X = H, but when X = OCH2CH20CH3,steric effects make this more difficult, and reduction occurs at the 4 position. N
C
~
C
M'AIH~X, N
*N lC l U
h
N
NCy-JCN H
(2)
14)
(1 7)
NCnC
M = Na,Li
N'
X = H, OEt ,OCH,CH,OMe
X'
H'
f
Al
x,
H '
(43)
The preference for a attack occurs due to the N- A1 interaction, aided by the metal dorbitals from which hydride transfer can be considered as occurring favorably to these positions.28 Pentachloropyridine (44) gives mainly 2,3,6-trichloropyridine (45) on ~ ~products ,~~ of ring reduction treatment with LAH at room t e r n p e r a t ~ r e .No are observed, and the reactions are believed to proceed via an additionelimination mechanism. The chlorine atom prevents additions at the 1,2
cl&lN' CI
LiAIH,-
Et,O
*
fJC'
clrJ;
I cyJcl &; CI
16h, 2 5 'C
CI
(44)
(45)
LiAlH,-
(46)
2 5 OIo
Et,O
3h. 0 OC
CI
CI
(47)
29
CI 7 5 yo
8O0li
+(45)
CI N '
(!q
12 96
8 yo
F. Binns, S. M. Roberts, and H. Suschitzky, J. C. S. Chem. Commun., 121 1 (1969). F. Binns, S. M. Roberts, and H. Suschitzky, J. Chem. SOC.C, 1375 (1970).
12
JAMES G. KEAY
ISec. 1II.B
and 1,4 positions. 4-Substituted tetrachloropyridines (49) give different products (50, 51, 52) at different temperature^.^^ LiAIH,
- 20-0 Qc
CI
+
25-35 ‘C
D,O
35-55
Qc
CI
(50) R=OMe, NHEt, C5H,,N
3 . Other Hydrides Magnesium3’and zinc hydridesg2have both been reported to form bis(dihydropyridinyl) complexeswhen dissolved in pyridine. Both have been used as reducing agents for ketones, nitnles, and heterocyclic systems.” Nuclear magnetic resonance studies on these complexes have shown only signalsdue to 1,4-dihydropyridine~.~~ The formation of 1,2-dihydropyridines,obtained on dissolvingMgHzin ~yridine,’~ was attributed to contamination by aluminum h~dride.’~ Cyclic trimeric structures for these magnesium and zinc hydride complexes have been proposed in agreement with spectral data.32
B. PYRIDONES 1. With Aluminum Hydrides
Most of the work concerning the reduction of pyridones has been carried out by Ferles and Holik, using 1,X-dimethyl-2-pyridones. Reaction of 1A. J. de Koning, P. H. M. Budzelaar, B. G .K. van Aarssen, J. Boersma, and G. J. M. van der Kerk, J. Organomet.Chem. 217, CI (1981). 32 A. J. de Koning, J. Boersma, and G . J. M. van der Kerk, Tetrahedron Lett., 2547 (1977). 33 E. C. Ashby and A. B. Goel, J. Organomet.Chem. 204, 139 (1981). 34 G . D. Barbaras, C. Dillard, A. E. Finholt, T. Wartik, K. E. Wilzbach, and H. I. Schlesinger,J. Am. Chem. Soc. 73,4585 (195 1). ’I
Sec. III.C]
13
REDUCTION OF NITROGEN HETEROCYCLES
methyl-2-pyridones (53) with LAH/aluminum chloride mixtures gives isomeric piperidienes (54) in admixture with the fully saturated piperidines (55).35 - 37 LiAIH4 Me0
0
I
AICI,
Me
(53
1
D
Me
I Me
(54
I Me
90%
1
(55
10%
1
C. PYRIDINIUM SALTS 1. With Borohydrides The reduction of pyridinium salts to dihydro- and tetrahydropyridines continues to attract much attention. Readers with a particular interest in dihydropyridines are directed to the excellent reviews by Eisner and K ~ t h a nKuthan , ~ ~ and K u r f u r ~ tand , ~ ~Stout and Meyema The ability of coenzyme NAD(P)+ (57, R = sugar) and its mimics to accept and deliver hydride ion stereoselectively via 1,Cdihydropyridine intermediates has spurred much intere~t.~' Much work involving NAD( P)+ and its simpler derivatives (56; R = PhCH,, BNAH; R = C12H25, DNAH) as chiral reducing agents has been r e p ~ r t e d . ~ '
R (57)
Pyridinium salts may also be reduced to dihydropyridines with sodium dithionite; although not clearly understood, the 1,4 isomer is very often the sole product obtained when electron-withdrawing groups in the 3 position are present.41Reductions with NAD(P)+ models have indicated that these M. Ferles and M. Holik, Collect. Czech. Chem. Commun. 31,2416 (1966). M. Holik, A. Tesarova, and M. Ferles, Collect. Czech. Chem. Commun. 32, 1730 (1967). 37 M. Holik and M. Ferles, Collect. Czech. Chem. Commun. 32, 2288 (1967). 38 U. Eisner and J. Kuthan, Chem. Rev. 72, 1 (1972). 39 J. Kuthan and A. Kurfurst, Ind. Eng. Chem. Prod. Rex Dev. 21, 191 (1982). 40 D. M. Stout and A. 1. Meyers, Chem. Rev. 82,223 (1982). B. J . van Keulen and R. M. Kellog, J. Am. Chem. Soc. 106,6029 ( 1 984). 35
36
14
JAMES G. KEAY
[Sec. II1.C
reactions occur initially by single-electron transfer followed by proton tran~fer.~~.~~ Pyridinium salts can initially give three different products on borohydride attack, the 1,2-, 1,4-, and 1,6-dihydropyridines. Invariably, mixtures are obtained, and it should be noted that in some of the early literature incorrect assignments have been made. The use of IR, UV, and high-power NMR spectroscopyhas simplified the task of identification, but care should still be exercised. Initially formed adducts may also rearrange in the presence of pyridinium salts; an internal oxidation - reduction may occur affording the thermodynamically stable 1,4 i s ~ m e rFowler . ~ ~ ~showed ~ ~ in a quantitative study that 1,4-dihydropyridines are generally some 2 kcal/mol more stable than their 1,2-dihydro c o ~ n t e r p a r t s .The ~ ~ ~dihydropyridines ~.~~ formed by hydride reduction possess either an enamine or a dienamine structure. Such systems are well known to undergo attack by electrophilic reagents.48 For 1,2(6)-dihydropyridines this can occur at two positions. Lyle has shown that protonation of the dienamine system occurs at the central atom, giving the kinetically controlled product 59.49This has been described as following Ingold’s rule50951in that the solvents employed, water or alcohols,
0 I
R
(5
*I
D+
QD
Thermodynamic
I R (60)
F. M. Martens and J. W. Verhoeven, Red. Truv. Chim. Pays-Bus 100,228 (181). S. Yasui, K. Nakamura, and A. Ohno, J. Org. Chem. 49, 878 (1984). 44 U. Eisner and M. M. Sadeghi, Tetrahedron Lett., 299 (1978). 45 R. E. Lyle and S. E. Mallet, Ann. N. Y.Acad. Sci. 145, 83 (1967). 46 F. W. Fowler, J. Am. Chem. SOC. 94, 5926 (1 972). 47 N. C. Cook and J. E. Lyons, J. Am. Chem. SOC. 87,3283 (1965). ‘* A. G . Cook, “Enamines: Synthesis, Structure and Reactions.” Dekker, New York, 1969. 49 P. S. Anderson and R. E. Lyle, Tetrahedron Lett., 153 (1964). N. Bodor, E. Shek, and T. Higuchi, J. Med. Chem. 19, 102 (1976). 5I C. K. Ingold, “Structure and Mechanism in Organic Chemistry,” p. 565. Cornell Univ. Press, Ithaca, New York, 1953. 42
43
Sec. III.C]
REDUCTION OF NITROGEN HETEROCYCLES
15
are weak acids. Strong acids allow formation of the thermodynamic product 60, i.e., protonation at the terminal carbon. Invariably the iminium salt is reduced to the tetrahydropyridine. Isomeric mixtures can result, and considerable effort has gone into the analysis and predication of the particular tetrahydropyridine f ~ r m e d . ~ ~ . ~ ~ Dihydropyridines can be isolated under appropriate sets of conditions. Use of aprotic solvents, or aqueous systems at high pH when protonation of the enamine system is less likely, favors dihydropyridine isolation. Precipitation of the dihydropyridine, or its removal from the reaction medium using two-phase systems, have been employed as techniques for their isolation. Reductions carried out with NBH in the presence of a large excess of cyanide ion result in the formation of the 2-cyano- 1,2,3,6-tetrahydropyridine 64.54The 1,2-dihydropyridine 62 is regenerated on treatment with ethoxide ion. This solution to the problem of overreduction has been employed in improved syntheses of some strychnos-group alkaloid^.^' NaBH,
'
C
Me
(61
1-
1
Me
"P
/// KCN
O
I
C
N
Me
(64
1
Bulky substituents attached to the ring nitrogen have been found to direct Subsehydride attack to the 4 position, giving the 1,4-dihydr0pyridine.~~ quent attack would lead to the piperidine, but often p - R interactions between the pyridine nitrogen atom and the substituent deactivate the J. Bosch, J. Canals, E. Giralt, and R. Granados, J. Heterocycl. Chem. 13, 305 (1976). J. Bosch, R. Granados, R. Llobera, D. Mauleon, and J. Tur, An. Quim. 77C, 166 (1981). 54 E. M.Fry, J. Org. Chem. 29, 1647 (1964). 55 J. P. Kutney, Hererocycles 7, 593 ( I 977), and see Ref 78. 56 R. E. Lyle and C. B. Boyce, J. Org. Chem. 39, 3708 (1974). 52
53
16
JAMES G. KEAY
(Sec. 1II.C
enamine system, and dihydropyridines are i ~ o l a t e d . ~N-Triphenylmeth~*~' ylpyridinium salts (65) give rise to this type of behavior.
0
4)
NaBH,
CPh,
(65
+
I
I
BF,-
CPh,
1
(66
77'23
1
Q I
CPh,
(67
1
Dihydropyridines generated from pyridinium salts carrying electronwithdrawing substituents at the 3 position by borohydride reduction are generally resistant to further reduction.' The dihydro derivatives of 1methyl-3-cyanopyridine, 68,69, and 70, were recovered unchanged when treated with borohydride in water.s8 Only 1,2-dihydro-I-methyl-3-cyanopyridine (68) was converted to the tetrahydropyridine 71 when trimethyl borate was added to the reaction medium. Diboranelwater achieved the same conversion, while added boric acid returned the starting rnaterial~.~~ QCN
H 4;;
I Me
B(OMe),
(
y I
Me
(711
(6*)
N
QCN
QCN
I Me
I Me
(69)
(70)
The reduction of 1-methyl-4-cyanopyridinium iodide (72) in aqueous However, in methanol/ methanol gave solely the tetrahydropyridine 73.59.60 sodium hydroxide two different temperature-dependent products could be isolated. The [4 21 product 74 predominated above -2O"C, whereas the [2 21 adduct 75 was the sole product at or below -45 "C. Similar behavior is observed with the 2-cyano derivative 76 (R = H); again, the initially formed [2 21 adduct 79 (R = H) thermally rearranges to the [4 21 product 80 (R = H). In this case pH and temperature control are not as important because enamine reactivity is diminished by the presence of the cyano group. Other pyridinium salts behave similarly in strong base.61.62 Reduction
+
+
+
57
+
A. R. Katritzky, M. H. Ibrahim, J.-Y. Valnot, and M. P. Sammes, J. Chem. Res., Synop.. 70 (1981).
Liberatore, V. Carelli, and M. Cardellini, Tetrahedron Lett., 4735 (1968). F. Liberatre, A. Casini, V. Carelli, A. Amone, and R. Mondelli, Tetrahedron Lett., 238 1
93 F. 59
(197 1).
60 F. Liberatore, A.
(1971). 61 62
Casini, V. Carelli, A. Amone, and R. Mondelli, Tetrahedron Lett., 3829
P. P. Zarin, E. S. Lavrinovich, and A. K. Aren, Khim. Geterotsikl. Soedin.. 104 (1974). P. P. Zann, E. E. Liepin, E. S. Lavrinovich,and A. K. Aren, Khim. Geterotsikl.Soedin., 115 (1974).
Sec. 1II.C]
/;- \\\-\\6
17
REDUCTION OF NITROGEN HETEROCYCLES
'
NaBH4 H,O- MeOH *
NaBH,
-20 OC
I
I-
H,O-
- NaOH MeOH
- 45 OC
Me' CN (74
R = Ph MeOH
Me
(75
1
\Me
18
JAMES G . KEAY
[Sec. 1II.C
of 1-benzyl-2-cyano pyridinium salts (76, R = Ph) with 1-benzyl-1,2-dihydroisonicotinamide (81) in methanol affords the similar dimeric dihydropyridine 80, (R = Ph).63 The propensity of 1,2-dihydropyridinesto undergo the Diels- Alder reaction has been used to separate mixtures of 1,2 and 1,4 isomer^.^^^^^ Fowler separated out 1,Cdihydropyridines by reaction of the 1,2 isomer 82 with maleic anhydride (85).66Other workers have utilized the Diels- Alder adducts 84 in the synthesis of isoquin~clidines.~~
(84)
The reduction of pyridinium salts 86 with borohydride in methanolic sodium hydroxide gives mixtures of di- and tetrahydropyridines (87- 9 1 y 8 Over time, the dimeric species 91 increased, while 87 decreased.
''A. Nuvole, G. Paglietti, P. Sanna, and R. M. Acheson, J. Chem. Rex, Synop., 356 ( I 984). 64
E. E. Knaus, F. M. Pasutto, and C. S. Giam, J. Heterocyl. Chem. 11,843 (1974).
'' E. E. Knaus, F. M. Pasutto, C. S. Giam, and E. A. Swinyard,J. Heterocycl. Chem. 13,48 I 66
''
(1976). F. W. Fowler, J. Org. Chem. 37, 1321 (1972). G. R. Krow, J. T. Carey, D. E. Zacharias,and E. E. Knaus, J. Org. Chem. 47,1989 (1982). A. Casini, B. Di Rienzo, F. M. Moracci, S. Tortorella, F. Liberatore, and A. Arnone, Tetrahedron Lett., 2 I39 ( 1 978).
19
REDUCTION OF NITROGEN HETEROCYCLES
Sec. IKC]
X = H,D
X Me
I
(90)
(91) Me
The reduction of 1-methyl-3-ethylpyridinium iodide (92) in the presence of a large excess (10 equiv) of benzyl bromide led to a moderate yield of 1-methyl-3-ethyl-5-benzyl-1,2,5,6-tetrahydropyriidine(94),69,70 presumably via the 1,2-dihydropyridine. 1,6-Dimethy1-3-hydroxypyridinium iodide (95) undergoes reduction with NBH and sodium hydroxide to the 3-piperidinol 96.71
flEt .N
I
Me
l.NaBH, 2. PhCH2Br
( 10 eqs)
(92)
PhCH(
M ‘,
I
1.PrSH 2. LiH-HMPA
Me
( 93)
(94
40 %
1
NaBH,
1
NaOH
I
Me
Me
(95)
(96)
R - H , R’zMe R z Me, R’:H
Comins reported the regiospecific addition ofhydride ion to the 4 position of 1-acylpyridinium salts in moderate yields, but with high selectivity (>90%).72The copper hydride reagent used was prepared in situ from lithium tri-tert-butoxyaluminum hydride and cuprous bromide. 1-( Phenoxycarbony1)pyridinium chloride (97) gave the 1,Cdihydropyridine 98 exclu69
J . P. Kutney, M. Noda, and B. R. Worth, Heterocycles 12, 1269 (1979). P. Kutney, R. Greenhouse, and V. E. Ridaura, J. Am. Chem. SOC.96, 7364 (1974).
70 J. 71
’2
M. A. Iorio, F. Gatto, and H. Michalek, Eur. J. Med. Chem. 15, 165 (1980). D. L. Cornins and A. H. Abdullah, J. Org. Chem. 49, 3392 (1984).
20
[Sec. 1II.C
JAMES G. KEAY
aR
sively. Previous work had shown that reduction with NBH and sodium and lithium copper hydndes yields mixtures of 1,2- and 1,4-dihydropyridine~.~~ Li(t-BuO),AIH
-OR
- CuBr
a COOPh
I
I
COO Ph
(97)
(94
Selectivity = 90- 100 OIo Yield 5 40-65 YO
R = H , Me, E t ,Cl, C0,Me
The acid-induced cyclization of 2-(arylmethyl)tetrahydropyridines (100) has been used as a general method for the preparation of b e n z ~ m o r p h a n s ~ ~ (101) and their heterocyclic counterparts. Similar behavior is used in the
-
NaBH,
I Me (99
i
Rb C H 2 P h
I
Me
1
Me ('01)
formation of the indole alkaloid (+)-dasycarpidone (103).75-77 Preparation of these tetracyclic substrates can be achieved more conveniently via 2cyano-l,2,3,6-tetrahydropyridines (105 4107), which are masked 2,5-dihydropyridinium salts as discovered by Fry.54,78 R. J. Sundberg and J. D. Bloom, J. Org. Chem. 46,4836 (198 1). J. Bosch, D. Mauleon, F. Boncompte, and R. Granados, J. Heterocycl. Chem. 18, 263 (1981). 7J A. Jackson, A. J. Gaskell, N. D. V. Wilson, and J. A. Joule, J. C. S.Chem. Commun.. 364 (1968). 76 M. S . Allen, A. J. Gaskell, and J. A. Joule, J. Chem. SOC. C, 736 (1971). 77 A. Jackson, N. D. V. Wilson, A. J. Gaskell, and J. A. Joule, J. Chem. SOC.C, 2738 (1969). 78 M. Feliz, J. Bosch, D. Mauleon, M. Amat, and A. DomingoJ. Org. Chem. 47,2435 (1982). 73 74
Sec. 111.C]
REDUCTION OF NITROGEN HETEROCYCLES
7 C
O
e - +N
-Me H
I
Q
CH(OEt),
I
Me
* b CH(OEt),
NaBH.,
i
21
NaCN
NC
I
Me
(105)
(104
OEt
0
CH(OEt),
3- indolylMgBr
1
Often indol0[2,3-~]quinolizines(e.g., 109)form the skeletal basis for work in the indole and oxindole alkaloid field.79These are most often prepared from pyridinyl- (108) or quinolinylindolethanes via reduction with metal h y d r i d e ~The . ~ ~tetrahydropyridines ~~~ then undergo acid-catalyzed ring closure, often giving mixtures of several compounds (109, 110, 111). The reduction of N-iminopyridinium salts and their ylides (112) has been studied and found to parallel the behavior of N-alkylpyridinium Salks1In protic solvents reduction leads to the formation of 1,2,3,6-tetrahydroderiva79
M. Lounasmaa and M. Puhakka, Acfa Chem. Scand., Ser. B B32,216 (1978). W. R. Ashcroft and J. A. Joule, Tetrahedron Left.,2341 (1980). E. E. Knaus and K. Redda, J. Heleroc.vc1. Chem. 13, 1237 (1976).
22
JAMES G . KEAY
(Sec. 1II.C
- MeOH NaBH4 - H' NaOH
H
H
30 %
tives (113).A probable intermediate is the 1,2-dihydrospecies, which, when it bears suitable substituents, may be isolated.82Products of this type have shown analgesic and antiinflammatory activity.
0 I
-N
'R
NaBH, EtOH
* I
HN\R
('12)
The in situ preparation of N-sulfonylpyridinium salts and their concomitant reduction in the presence ofNBH has been studied. Using both sulfonyl chlorides and sulfonic acid anhydrides, Knaus and Redda obtained mixtures of both the 1,2- (114) and 1,4-dihydropyridines(115). The 1,Cdihydropyridine was favored (15 :8 by NMR) at 25°C in pyridine; the 1,Zdihydro product was the major isomer (29 :4 by NMR) at - 65 "C in methanol.83
a2 83
Y. Tamura and M. Ikeda, Adv. Heterocycl. Chem. 29,71 (1981). E. E. Knaus and K. Redda, Can. J. Chem. 55, 1788 (1977).
Sec. III.C]
REDUCTION O F NITROGEN HETEROCYCLES
23
Sodium cyanoborohydride is a more selective reducing agent than boroh ~ d r i d eAn . ~ investigation ~ into the reduction of 4-substituted pyridinium salts (1 16) would seem to bear this out. With these the 4 substituent directs hydride attack to the a positions, and in protic solvents the tetrahydropyridines 117 are isolated. Thus a variety of sensitive substituents can be carried through a synthetic sequence without redu~tion.~’ However, raising the temperature is known in one instance (4-carboxamido) to cause concomitant reduction of the ketone carbonyl group.
&
NaBH3CN
b&
+LaBr NflB 250c
0
0
(117)
(116)
2 . With Aluminum Hydrides Pyridinium salts react more readily with LAH than do pyridines, affording mixtures of di- and tetrahydropyridines. However, prolonged heating of alkylpyridinium salts with excess sodium aluminum hydride in tetrahydrofuran generates 3-piperidienes (120) with 5-alkylamino-1,3-pentadiene (121) as the major products. Small amounts of the piperidines (119) were also obtained. Similar behavior has been noticed with other alkylpyridinium saltsE6 Attempts to add one equivalent of hydrogen to the 3-oxidopyridinium salts 122 led to a mixture of products, the main component being the tetrahydro derivative 123 (R = Ph, indolyl-3-ethyl) or the dimer 124 (R = Me).*’
THF-POh
R
1
Et,Pr,Bu, Am.
C. F. Lane, Synthesis, 135 (1975). R. 0. Hutchins and N. R. Natale, Synthesis, 281 (1979). 86 M. Ferles, 0.Kocian, and A. Silhankova, Collect. Czech. Chem. Commun. 39,3532 (1974). 87 W. R. Ashcroft and J. A. Joule, Heterocycles 16, 1883 (1981). 84
24
[Sec. 1II.D
JAMES G. KEAY
Ph
""?yJ
N
Me
I
R
I
Me
(123) (124)
D. 1 -ALKOXYPYRIDINIUM SALTSAND PYRIDINE O OXIDES The reduction of pyridine N-oxide (1 25) and 1 -alkoxypyridinium salts (126) with a variety of reducing agents, including NBH, LAH, and sodium bis(2-methoxyethyl)aluminum hydride, gives a mixture of products. The mixtures contained pyridines (1 29), 3-piperidiene (1 28), and piperidines (127). The major product was dependent on the nature of the substituents
Sec. III.F]
REDUCTION OF NITROGEN HETEROCYCLES
25
present and the reducing agent employed.88Titanium tetrachloride and NBH mixtures have been employed for the deoxygenation of heteroaromatic amine oxides.89
E. CYCLIC IMINES Cyclic imines will not be dealt with in this review as the conversion is often simply achieved.' Mention will be made to the stereoselective reduction involved in the preparation of Solenopsin A and B (131), two naturally occurring piperidine alkaloids isolated from the venom of the fire ant. The desired trans isomer 131 was obtained with >%yo selectivity,using LAH (7 equiv) and trimethylaluminum (7 equiv) in THF. This selectivity could be reversed by using LAH (7 equiv) and NaOMe (14 equi~).~O LiAlHd Me(CHJnC G
M
*
e
Solenopsin A , n z 10 Solenopsin B , nz 12
F. QUINOLINES 1. With Borohydrides
Quinolines are expected to be reduced much more readily than pyridines. This is borne out when quinoline (133) is heated in ethanol with excess NBH to give mixtures of the 1,2-di- 134 and 1,2,3,4-tetrahydroquinolines135.'O Treatment of the 1,2-dihydroquinoline 134 with NBH in diglyme or diglyme/ethanol mixtures gave conversion to the tetrahydroquinoline 135. Migration of the 3,4 double bond to the enamine has been proposed to account for this reduction.l' With electron-withdrawing groups in the 3 position, 1,4-dihydroquinolines 137 were obtained in high yields. 3-Haloquinolines, on the other hand, gave low yields of the 1,2-dihydro adducts 89
M. Jankovsky and M. Ferles, Collect. Czech. Chem. Commun. 35, 2802 (1970). S. Kano, Y. Tanaka, and S. Hibino, Heterocycles 14, 39 (1980). Y. Matsumura, K. Maruoka, and H. Yamamoto, Tetrahedron Lett., 1929 (1982).
26
JAMES G.W A Y
[Sec. 1II.F
138.'Os1 3-Dimethylaminoquinolinewas recovered unchanged under these conditions. NaBH,
I
EtOHNaBH, 5h
diglyme
*a+ a /
('33)
(13 t
NaBH,
ax
(y-J
H
H
%Yield
1
X = 86
86
95
I Br
%Yield I40
(134 F 40
NMe, 0
2-Cyanoquinoline and the + isomer afforded different products when reduced in ethanol or pyridine. In hot ethanol the amidine 141 was the major product, whereas in pyridine the tetrahydroquinoline 142 was favored. The latter compound occurred with an increase in tar formation. 4-Cyanoquinoline (140) was reduced to give the tetrahydro derivative 143 and the product of reductive decyanation 144.10J1 Reduction of 5-, 6-, 7-, and 8-nitroquinolines (145) with NRH in acetic acid proceeds smoothly to the 1,2-dihydro derivatives 146.91Gribble and 91
K. V. Rao and D. Jackman, J. Heterocycl. Chem. 10,213 (1973).
Sec. III.F]
27
REDUCTION OF NITROGEN HETEROCYCLES
CN b39)
NaBH, EtOH or
1
Pyr
(141)
(144
FN
H (143)
Heald repeated the same reduction of 6-nitroquinoline (147) at a higher temperature and isolated 1-ethyl- 1,2-dihydro-6-nitroquinoline(148), the . ~ ~ quinoline and NBH in carboxylic product of reductive a l k y l a t i ~ nWith acids the N-alkyl- 1,2,3,4-tetrahydroquinoline149 is obtained. Use of sodium cyanoborohydride gives reduction but no alkylation (150). In the presence of acetone, 1-isopropyl-1,2,3,4-tetrahydroquinoline(151) is the predominant compound.92 Quinoline N-oxides undergo deoxygenation, and some ring reduction with NBH.93 92
G . W. Gribble and P. W. Heald, Synthesis, 650 (1975). Kawazoe and M. Tachibana, Chem. Pharm. Bull. 13, 1103 (1965).
93 Y.
28
JAMES G.KEAY
[Sec. II1.F
NaBH, AcOH 0 %
O2N
(146r71-90%
(145)
NaBH, AcOH 50%
P9 NaBH, RCOOH
03 I
CH,R (149 52-60%
NaBH,, Me,CO RCOOH
I
H
(13
71 %
6.Pr (151) 59%
2. With Aluminum Hydrides The 2-, 3-, 4-, and 6-trifluoromethyl derivatives ofquinoline on treatment with LAH give a variety of products that depend on the position of the substituent. Only the 3 isomer 152 leads to anything other than dehalogenation, giving 3-(difluoromethy1)-1,2-dihydroquinoline (153).94On the other hand, with sodium borohydride, only 152 undergoes complete dehalogenation (154). This is believed to proceed via ring attack and the involvement of a 1,4-dihydroquinoline (155). 94
Y. Kobayashi, 1. Kumadaki, and S. Taguchi, Chem. Pharm. Bull. 20,823 (1972).
Sec. III.F]
29
REDUCTION OF NITROGEN HETEROCYCLES
t
H (154)
(155)
t
f
WCF2 \
N+ H F
Generally, quinolines are reduced to their 1,2-dihydro derivatives with LAH. Use of diisobutylaluminum hydride and sodium bis(2-methoxyethoxy)aluminum hydride with quinoline (133) has shown that 1,2-dihydroquinolines (160) can be conveniently and cleanly generated at low temperaDibal
* I
-
(~.BU),AIH
(14 I
30
JAMES G . KEAY
[Sec. 1II.G
tures in high ~ i e l d .Tetrahydroquinolines ~~.~~ via 1,4-dihydro intermediates (thermodynamic control) are formed at higher temperatures, when prolonged reaction times are employed or when a 2 substituent is present.96
G. QUINOLINIUM SALTS 1. With Borohydride Like pyridinium salts, initial hydride attack can occur at either the 2 or 4 position. That the 2 position is generally favored is borne out by the isolation of 1 ,Zdihydroquinolines (162) as the usual products of these reductions. 1,CDihydro- (163) and 1,2,3,4-tetrahydroquinolines (164) formed by 4 attack are isolated as minor products.
a
NaBH,
I
*a' I
R
R
(164
(161)
NaBH,
I
Me
R=
IH
i
Me I
CN
C02Et
I
9J 96
%Yield(164
87
87
23
%Yield(167)
-
-
72
I
Me (163
D. E. Minter and P. L. Stotter, J. Org. Chem. 46, 3965 (1981). B. K. Blackburn, J. F. Frysinger, and D. E. Minter, Tetrahedron Lett., 4913 (1984).
Sec. III.G]
31
REDUCTION OF NITROGEN HETEROCYCLES
Similar to the pyridinium salt series, the position and nature of substituents attached to the heteroaromatic ring can affect the position of initial attack. 1-Methylquinolinium iodide (165, R = H) gives the 1,2-dihydro adduct 166 after 10 min at O'C, as does the 3-cyano derivative 165, (R = CN). I I However, under similar conditions the ethoxycarbonyl derivative 165 (R = C0,Et) affords mixtures of both 1,2- (166) and 1,Cdihydroquinolines (167)." However, 1-benzyl-3-cyanoquinoliniumbromide (168) gives a 759/0yield of the 1,4-dihydro adduct 169 when reduced with NBH and allowed to equilibrate in the presence of the parent quinolinium salt.971,4-Dimethyl-2methylaminoquinolinium iodide (170) undergoes hydride attack at the 2 position with borohydride to give the product 171as an unstable yellow Alstonilin or benz[g]indolo[2,3-a]chinolizidine-typealkaloids (173) have been successfully prepared in high yields from the isoquinolinium salt 172 via hydride reduction.99
J Q . 4
NaBH4
I
B;
D
WCN
+ (168)
1
CH,Ph
CH,Ph
(168)
(169)
NaBH,
Me
1
NHMe
he
I
(170)
(171)
NaBH,-HCl
Me0
Me0
(174
(173)
66%
M. M. Kreevoy, R. M. G . Roberts, D. Ostovic, and A. D. Binder, Ventron Alembic 28,2 (1982) [CA 98, 125838j (1983)l. 98 N. D. Sharma, V. K. Goyal, and B. C. Joshi, Croat. Chem. Acfa 48,3 17 (1976). 99 J. A. Beisler, Chem. Eer. 103, 3360 (1970).
97
32
JAMES G.KEAY
[Sec. 1II.H
2. With Aluminum Hydrides 1,2-Dihydroquinolines predominate as the major reduction product of quinolinium salts with LAH. As in the pyridine series, preferred attack occurs at the 2 position.
H. ISOQUINOLINES 1. With Borohydrides Isoquinolines usually do not undergo reduction with NBH in ethanol or pyridine unless they bear an electron-withdrawing 4 substituent.'l In this case 1,2-dihydroisoquinolines175 are formed. In water or aqueous solvent mixtures isoquinoline (176) is converted to the tetrahydroisoquinoline 177.Il In the case of 1-cyanoisoquinoline (178), both ring and substituent were reduced by borohydride in pyridine or diglyme.I0 With 3-cyanoisoquinoline (180) the major products are derived from substituent reaction to form amides (181) and amidines (182). Some 1,2,3,4-tetrahydroisoquinoline(1 77) is also isolated.10Mixtures of alcohols are obtained upon reduction of ethyl isoquinoline-2- and 3-carboxylate.l o
d
dNH
NaBH, EtOH
(14
(174
X
37-86%
= CN, CONH ,,CO,Et
NaBH, D
Pyr or Diglyrne
CN (178)
CONH, 674
Sec. 111.11
REDUCTION OF NITROGEN HETEROCYCLES
33
Isoquinoline (176), as in the case of quinoline, undergoes reductive alkylation with NBH in the presence of carboxylic acids, affording the amine 184.92Sodium cyanoborohydride under these conditions gave the unalkylated product 177. Under similar conditions, but at lower temperature, h i troisoquinoline affords the tetrahydrois~quinoline.~~ NaBH,
(176)
2. With Aluminum Hydrides As with the milder borohydride, isoquinolines are reduced to 1,2-dihydro derivatives 185 with LAH and subsequently to the tetrahydroisoquinoline 177.
I. ISOQUINOLINIUM SALTS 1. With Borohydride
Isoquinolinium salts (186) are readily reduced with NBH to the 1,2-dihydro- (187) or I ,2,3,4-tetrahydroisoquinolines(188). Initial attack occurs at
34
JAMES G.KEAY
[Sec. 111.1
the 1 position and subsequent reduction of the enamine system is determined by the nature and position of ring substituents. Generally, tetrahydro adducts are formed.
Certain 1-benzylisoquinolinium salts (189) undergo C-C bond cleavage on reduction with borohydride.'''Jol The benzyl group must contain a nitro group in order to weaken the ring-substituent D bond. M Me
e
m
'
M
e
NaBH4
M Me
e
3
+'
M Me e S N 0 2
Me Me
Reaction of the isoquinolinium salt 191 with NBH gave the 1,2-dihydroisoquinoline 192 in high yield. Subsequent treatment of 192 with bromine and heating gave 4-bromoisoquinoline (193)?' J. L. Neumeyer, M. McCarthy, K. K. Winhardt, and P. L. Levins, J. Org. Chem. 33,2890 (1968). J. L. Neumeyer, M. McCarthy, and K. K. Weinhardt, Tetrahedron Leff.,1095 (1967).
lM
lo'
Sec. III.J]
REDUCTION OF NITROGEN HETEROCYCLES
Br,
Br
35
I.
AcOH
2. With Aluminum Hydrides The reduction of isoquinolinium salts in aprotic solvents with LAH leads to the formation of I ,2-dihydroisoquinolines (195), in which the enamine system can undergo subsequent reaction with electrophiles. This type of reactivity has been exploited in the synthesis of alkaloids.55 Intermediates of the types 196 and 197 have been used in synthetic approaches to the pavinane and isopavinane alkaloids.lo2
LiAIH,
'R
LiAIH,
Ph
'Me Ph
J. INDOLES Although indoles are not normally reduced under neutral conditions with LAH or NBH, tetra-n-butylammonium borohydnde has recently been apIo2S.
F. Dyke, R. G. Kinsman, P. Warren, and A. W. C. White, Tetrahedron34,241 (1978).
36
JAMES G. W A Y
[Sec. 1II.J
plied successfully in the reduction of the indoles 198 - 200 to indolines 201 203.Io33-Methylindole was reduced to the indoline in only 6% yield.Io3 The observation that enamines may be reduced by NBH in acetic acid/ THFIM and sodium cyanoborohydridelos coupled with the tendency for indoles to protonate at the 3-position enabled Gribble and co-workers to reduce indoles to indolines (201,205)in high yield.lMN-Alkyl indoles (204) were also reduced, as was 3-methylindole. The use of formic acid favored the formation of 1-methyl-3-[2-(2-dimethylaminophenyl)ethyl]indoline(207) via an intermeuiate 3,2 dimer (206).lo7 Borohydride reduction of indole (198) in the presence of trifluoroacetic acid (TFA) gave the indoline 201 without alkylation but in low yield. The yield of 201 can be increased when carried out with sodium cyanoborohydride in acetic acid at 15°C. This eliminates the isolation of any N-alkyl indolines.lo* The reaction clearly proceeds via reduction of the iminium salt 208 produced on protonation, and as such the method is limited to indoles suffil1 ciently basic to be protonated by acetic or trifluroacetic The reduction of indole (198) has also been achieved with sodium borohydride-aluminum chloride mixtures ( 5 :3) in pyridine at room temperature.l12The pyridine serves to moderate the reducing agent and a 68Yo yield of indoline (201)was obtained along with unchanged starting material. When 2-methylpyridine replaced pyridine, no reduction was observed. W
R H
m.-Bu,N*BH,
CH,CI, 36'C 1Oh
(198-204
R=
'ol
Io5 Io6 'ol Io8
Io9 'lo
WR H
(201 - 203)
H , 2-Me, 2,3-(CHZ),-
T. Wakamatsu, H. Inaki, A. Ogawa, M. Watanabe, and Y. Ban, Heterocycles 14, 1441
(1980). IM
*
J. A. Marshall and W. S. Johnson, J. Org. Chem. 28,421 (1963). R. F. Borch, M. D. Bernstein, and H. D. Durst, J. Am. Chem. Soc. 93,2897 (1971). G. W. Gribble, P. D. Lord, J. Skotnicki, S. E. Dietz, J. T. Eaton, and J. L. Johnson, J. Am. Chem. Soc. 96,78 12 (1974). G. W. Gribble and S. W. Wright, Heterocycles 19,229 (1982). G. W. Gribble and J. H. Hoffman, Synthesis, 859 (1977). J. G. Berger, F. Davidson, and G. E. Langford, J. Med. Chem. 20,600 ( 1 977). N. Umino, T. Iwakuma, and N. Itoh, Tetrahedron Lett., 763 (1976). G. W. Gribble, C. F. Nutaitis, and R. M. Leese, Heterocycles 22, 379 (1984). Y. Kikugawa, Chem. Pharm. Bull. 26, 108 (1978).
Sec. III.J]
37
REDUCTION OF NITROGEN HETEROCYCLES NaBH,CN AcOH
94%
H
NaBH,
NaBH,
AcOH 86%
88 %
t
NaBH, AcOH
AcOH
86%
I
Et
--
NaBH,
HCOOH
H
Me
NaBH,
H' H
H
(208)
(13
AICI,- Pyr
H (201)
The reduction of the indolinones 209 with NBH in methanol leads readily to the indoles 210 in 56-96% yield. Intermediacy of the corresponding alcohols has been propo~ed."~ The reduction of indoles and related compounds has been the subject of a previous review.'I4 Oxindoles (211) are reduced with LAH to indoles (212)but in low yields.Il4Small amounts ofthe indolines 213 are also obtained. Dimerization on hydride reduction has also been recorded.II5 M. Hooper and W. M. Pitkethly, J. C. S.Perkin I . 1607 (1972). B. Robinson, Chem. Rev. 69, 785 (1969). H. J. Roth and H. H. Lausen, Arch. Pharm. (Weinheim, Ger.)306,775 (1973).
38
[ Sec. 1II.K
JAMES G. KEAY
R = Aryl R'= H , M e LiAIH,
I
wd+d /
\
I
R
I
R
(211)
R
(212)
(213)
R = Alkyl
K.
1,2-OXAZOLES
3-Aminopropanols (217, 218) can be prepared from alkenes and nitrile oxides via the LAH reduction of the isoxazoline intermediate 216.IL6The stereospecificity of the reaction is surprisingly high. 1,3-Asymmetricinduction leads to ratios of 1 : 19 for 217 and 218, respectively (R = Ph) and
1
LiAIH,
HO
NH,
HO
(217) Il6
V. Jager, V. Buss,and W. Schwab, Liebigs Ann. Chem., 122 (1980).
NH,
39
REDUCTION OF NITROGEN HETEROCYCLES
Sec. III.K]
slightly less (3: 17) when R = Me.117Li-0 complexation during hydride transfer is probably responsible for this selectivity. Acylic products are the normal result of reductions on dihydroisoxazoles with metal hydrides. However, some tetrahydro derivatives (220) have been produced stereoselectivelyupon treatment with NBH. Sodium cyanoborohydride gave cis-and trans-1,2-oxazolidines(222)from 3,5-diphenyl-4,5dihydro-1,2-oxazole (22l).Il7 3,5-Dialkylisoxazoles with electron-withdrawing groups at C-4 can be reduced by LAH/ether and NBH/ethanol to give 4-functionalized 2-isoxazolines in 7 - 70% yield.' 17* Interestingly, alkyl- 1 ,Loxazoles (223) on reduction with LAH give aziridines 224 and 225.lI9Preparative chromatographywas used to separate one major (224,40-5090) and two minor (225, 226) components. Most likely, the reaction proceeds through a hydroxyazirine intermediate (227). Me-'(
Rq NaBH,
t
100% stereosel. 00% yield
NaBH3CN
* P h a P h
P h a p h
LiAIH,
R
MeHRM e + ' ' d , r y M e YaMe
(24
I R = H , Me Il7 II8
119
THF 40 h
';I
7'
(224 OH I
t 'e+CHMe
+
Me'"'
RE^ ..
+
M e A O H
H
NH, h e
(24
(23
I
@4OAiH3
V. Jager and V. Buss, Liebigs Ann. Chem., 101 (1980). A. Alberola, A. M. Gonzalez, M. A. Laguna, and F. J. Pulido, Synthesis, 413 (1983). A. Cem, C. De Micheli, and R. Gandolfi, Synfhesis. 710 (1974). A. L. Khurana and A. M. Unrau, Can. J. Chem. 53,301 1 (1975).
40
[Sec. 1:I.M
JAMES G . KEAY
L.
1,3-OXAZOLES
The reduction of 2-oxazolin-5-ones(228)with excess NBH results in the cleavage of a C-0 bond to afford the amides 229.120By contrast, the oxazoline moiety itself (230)is stable to reduction by LAH and serves as a protecting group for the carboxylic acid function.lZ1 However, 2,2'-bis(oxazolines) (232)have been recorded in the patent literature as precursors to the amino alcohols 233.122
R = Me, R'=Me,CH,Ph
LiAIH,
MeLJGo2Me Me
Me
M. 1 ,%THIAZOLES 3-Benzyl-4-methylthiazolium chloride (234)is reduced in water by excess NBH to the fully saturated 1,3-thiazolidine237 via the thiazoline 235.lz3A diastereoisomeric mixture is obtained in more highly substituted cases.124 121
Iz2
Iz4
P. Truitt and J. Chakravarty, J. Org. Chem. 35, 864 (1970). D. Haidukewych and A. 1. Meyers, Tetrahedron Leff.,3031 (1972). Pliva Tvornica Farmaceut., Fr. Demande 2,187,761 (1974) [CA 81, 13101f(1974)]. G . M. Clarke and P. Sykes, J. C. S.Chem. Commun., 370 (1965). G . M. Clarke and P. Sykes, J. Chem SOC.C. 141 1 (1967).
Sec. III.N]
REDUCTION OF NITROGEN HETEROCYCLES
41
Although, in principle, the 4-alkylidene-l,3-thiazolin-5-ones (238)can undergo initial attack at C=O, C=O or C=N, in practice only the exocyclic double bond is attacked and reduced by NBH.lZ5 1,3-Thiazoles containing 2-amino functionalities (239) are, not surprisingly, resistant to ring reduction with NBH.lZ6Thiamine is reduced to the tetrahydro derivative 240.124
\s’
c,
H*O
S ‘’
RWC 0
$a, b i
N. 1,STHIAZINES Little work has been carried out on the selective reduction of the imine bond present in 1,3-thiazine~.’~’ Concomitant ring opening normally occurs M.D. Bachi, J. C. S. Perkin I , 310 (1972).
126 12’
D. S u c k J. Prakt. Chem. 314,961 (1972). J.-L. Pradere, J.-C. Roze, and G . Duguay, J. Chem. Res., Synop., 72 (1982).
42
JAMES G.KEAY
[Sec. 1V.A
in such systems. However, sodium cyanoborohydride will selectivelyreduce the imine bond in 2-phenyl-6H-l,3-thiazines (241) in acidic media.Iz7This results partially from the bond polarization effects of the phenyl group and partially from protonation. More powerful reducing agents affordring cleavage. 2-Phenyl-4-oxobenzo-1,3-thiazine(243) gives 2-mercaptobenzylamine (244) as the major product when treated with LAH.lZ8The isolation of the benzothiazole 245 as a minor product points to C-2-S rupture prior to reduction of the imine.
DcoR NaBH,CN
Ph
H,O'
*
HDcoR
Ph
(241)
(242)
IV. Reductions of Heterocycles Containing Two Nitrogen Atoms A. PYRAZOLES The LAH reduction of alkyl- and arylpyrazolium salts (246) has been investigated and leads to a mixture of the 3- (247) and 4-pyrazolines (248), along with the fully saturated pyrazolidine 249 in some cases.129,130 The exact nature of the mixture is dependent on the substituents and the amount of reducing agent employed. The 3- and 4-pyrazolinesgenerally predominate. Overreduction with formation of acyclic hydrazines is also observed.129Pyrazolidines(249) may be produced from pyrazolines (247 and 248) by reduction with LAH.I3' Elguero and co-workers also report the NBH and LAH reduction of 128
IM I3l
D. Bourgoin-Lagay and R. Boudet, C.R. Acad. Sci.,Paris, Ser. C 264, 1304 (1967). J. Elguero, R. Jacquier, and D. Tizane, Bull. SOC.Chim.Fr., 1121 (1970). J. Elguero, R. Jacquier, and D. Tizane, Bull. Soc. Chim. Fr., 3866 (1968). J. Elguero, R. Jacquier, and D. Tizane, Bull. SOC.Chim. Fr., 1129 (1970).
Sec. IV.A]
43
REDUCTION OF NITROGEN HETEROCYCLES R\
R ,'
R5 q
R R4
R ;
LiAIH, 3I
R ,'
THF or E t 2 0
R5vR3 R5qR R1
RZ
R'
RZ
+
R4
R4
(24
(24
3-(disubstituted amino)-l,5-dimethyl-2-phenylpyrazoliumsalts (250), affording the hydrazines 251 and 253 as the major products.132
(4
P h A M Me e
2.
H,O
@54
@51)
+ 1
+
R' R ~ N
(24
Reductant
-C H,C H,OC H,C H,Me
Ph
-C H,C H,OC H,CH,Me 132
I
Ph
(=. Product (96)
LiAIH,
251 (SO), 252 (15)
LiAIH,
251 (95)
LiAIH,
251 (95)
NaBH,
53 (60),254(40)
NaBH,
5 3 (go), 254(10)
J. Elguero, R. Jacquier, and S. Mignonac-Mondon, Bull. SOC.Chirn. Fr., 2807 (1972).
44
JAMES G. KEAY
[Sec. 1V.B
Increasing the polarization of the imine double bond by complexation of l-acetyl-3,5,5-trimethylpyrazoline(255) with Lewis acids is an effective method of inducing C-3 nucleophilic attack.133LAH Reduction of 255 in acetic anhydride has the overall effect of a reductive alkylation to give l-acetyl-2-ethyl-3,5,5-trimethylpyrazolidine (256). Similar behavior has been ob,COMe
Et,
Me
Ac 2O
Lewis Acid (255)
served with the hydrochloride salts of 1-phenyl- and 1,5-diphenyl-3-methyl2-pyraz01ines.l~~
B. IMIDAZOLES The reaction of several simple imidazolium salts (257) in 95% ethanol, employing a large excess of NBH, led to reductive ring cleavage to the diamines 258 and 259.135The major product was 258 (77-9390) and the minor product, 259 (3 -22%). Thus the predominant cleavage is between C-2 and N-benzyl. Similar reduction of 1-methyl-3-(2-phenylethyl)imidazolium iodide (260) gave 262 as the major product (9290).'~~
I
CH,Ph (253
I
I
CH,Ph
CH,Ph (254
(259
Me
Me
L. A. Sviridova, G.A. Golubeva, A. V. Dovgilevich, and A. N. Kost, Khim. Geterotsikl. Soedin. 9, 1239 (1980). G. A. Golubeva, L. A. Sviridova, N. Y. Lebedenko, and A. N. Kost, Khim. Geterotsikl. Soedin. 4, 541 (1973). E. F. Godefroi, J. Org. Chem. 33, 860 (1968).
REDUCTION OF NITROGEN HETEROCYCLES
Sec. IV.B]
45
NHMe
I
CH,CH,Ph (24
I
I
C H,C H,P h
I?@
(26’)
,
C H,C H P h
Treatment of the long-chain imidazolium salts 263 with potassium, sodium, and tetra-n-butylammonium borohydrides affords the acyclic diamines 264 and 265. The isomer ratio was not reported.136Sodium cyanoborohydride failed to reduce the same salt under a variety of conditions. The imidazoline 266 reacts with LAH in THF above - 10°Cto give the 1,2-diaminoethane 267.136Sodium borohydride is a less effective reducing agent in this reaction, achieving the same conversion over a longer period of time. Other less reactive hydrides [ LiBH,, NaBH,CN, LiAlH(0-t-Bu),] do not react.
CH,Ph (263)
CH,Ph (266)
CH,Ph
CH,Ph
(4
(263
CH,Ph (267)
Reductive ring cleavage of the tetrahydroimidazole 268 has been recorded with LAH in ether.’,’ Formation of the isoindolone 269 is in contrast with earlier reports in which ring expansion to the diazocine 270 was r e ~ 0 r t e d . l ~ ~
13’
M. W. Anderson, R. C. F. Jones, and J. Saunders, J. C. S. Chem. Commun. 282 (1982). P. Aeberli, G. Cooke, W. J. Houlihan, and W. G. Salmond, J. Org. Chem. 40,382 (1975).
46
JAMES G . KEAY
[Sec. 1V.E
C. BENZIMIDAZOLES The reduction of the benzimidazolium salts 271 under controlled conditions with LAH in THF has been described.138The resulting benzimidazolines 272 may be similarly prepared, using LAH in ether139or NBH in water.'@
a$R QJPR LiAIH, - THF
*
I
I
Me
Me
(27')
(272)
D.
1,2,4-OXADIAZOLES
A variety of ureas and oximes can result from the reduction of lY2,4-oxadiazoles with LAH. The nature and position of substituents will determine the position of the attack and hence, the product. However, the majority of products arise from cleavage of the C-5-0 bond via chelation-assistance (273 + 274).141 LIAIH,
Ph w
YdfP;
k73)
H,O'
NHMe H,CO
N
'OH (2741
E. PYRIDAZINES Simple dihydropyridazines have been obtained by reduction of the parent pyridazine after initial alky1ati0n.l~~ Sodium borohydride reduced the 1methylpyridazinium salts in water to the corresponding lY6-dihydropyridazine 276 in 40-60% yield. In some instances (276c,e,f)the 1,4,5,6-tetrahy13* 139
la
J-L. Aubagnac, J. Elguero, R. Jacquier, and R. Robert, Bull. SOC.Chim. Fr., 2 184 (197 1). A. V. El'tsov, J. Org. Chem. USSR (Engl. Transl.) 1, I121 (1965). J. W. Clark-Lewis, J. A. Edgar, J. S. Shannon, and M. J. Thompson, Aust. J. Chem. 17,877 (1964).
142
Y . Royer, M. Selim, and P. Rumpf, Bull. Soc. Chim. Fr., 1060 (1973). C. Kaneko, T. Tsuchiya, and H. Igeta, Chem. Pharm. Bull. 22,2894 (1974).
Sec. IV.E]
47
REDUCTION OF NITROGEN HETEROCYCLES
dropyridazines 277 were also isolated. The phenyl derivatives 276e,fwere the most stable, but all gradually decomposed when exposed to the atmosphere. 1,3,4,6-Tetraalkyl-1,6-dihydropyridazinesare also available by this route.143Reduction of 275 with NBH in the presence of methyl chloroformate gave the 1,6-dihydro derivatives 278 in 30- 50% yield along with small amounts of the 1,4 isomer 279.These were more stable than their N-methyl counterparts (276).The presence of a phenyl group favored the 1,6-dihydropyridazines 278 and in its absence the 1,4 isomers 279a p r e d ~ m i n a t e d . ' ~ ~ . ' ~ ~ Dihydropyridazine (276a)was also obtained by treatment of l-methyl-6pyridazinone (280)or 278a with LAH in THF.Iu
(277)
(275)
L NaBH,
R'
LiAIH, Me
,";L\"/'
LIAIH,
(me.)
(276a)
f Me
Ph
Hexahydro derivatives 283 are favored when 3 mol of LAH are allowed to (281).144 Use of less reducing react with 2,3,4,5-tetrahydropyridazin-3-ones 143
la
Y. Zenichi, Jpn. Kokai 78/44,580 (1978). J-L. Aubagnac, J. Elguero, R. Jacquier, and R. Robert, Bull. SOC.Chirn. Fr., 2859 (1 972).
48
JAMES G . KEAY
[Sec. 1V.F
agent leads to a time-dependent mixture of products (282 - 284). Other substituted and dipyridazinones146yield hexahydropyridazines with LAH.
Do
R3
I
R’
(281)
LIAIH,
*
Rh +
\N
.
R3Q
HN,
I
RQN--N
I
I
R’
R’
R’
(284
(4
(284)
R’= H,Me,Ph; RJ= Me,Ph
F. PYRIMIDINES The reduction of pyrimidin-2( 1H)-ones (285) or their sulfur analogs occurs readily with NBH to give mixtures of products (286-288).147The ratio of these products varies markedly, depending on the presence of sodium hydroxide. The use of methanol/NBH favored 286 and 287 over 288 possibly as a result of the in situ formation of trimethyl borate.147The presence of sodium hydroxide retards formation of trimethyl borate, and a large increase in the proportion of 286 and 287 is now observed. In some cases, products 286/287 or 288 could be obtained exclusively by judicious choice of reaction conditions. Earlier reports by other workerPJ4*prompted these authors to attempt reductions of 285 with NBH in acetic acid. This led to either the exclusive formation of the 3,4,5,6-tetrahydropyrimidin-2(1H)-ones288 ( X = 0)and thiones 288 ( X = S) or isolation in admixtures with 286 and 287.*49 Reduc1H)-ones 288 ( X = 0) with tion of the 3,4,5,6-tetrahydropyrimidin-2-( LAH gives the diaminopropanes 289 by reductive ring ~1eavage.l~~ The thione derivatives 288 ( X = S) did not react under these conditionsand were RZ
R2
RZ
I R’ (285)
(2%)
(287)
P. Aeberli and W. J. Houlihan, J. Org. Chem. 34,2720 (1969). M. Tisler and B. Stanovnik, Adv. Heterocycl. Chem. 24,42 I ( 1979). 14’ C. Kashima, A. Katoh, Y. Yokota, and Y. Omote, J. C. S. Perkin I, 1622 (1981). 14* J. A. Marshall and W. S. Johnson, J. Org. Chem. 28,421 (1963). 149 C. Kashima, A. Katoh, N. Yoshiwara, and Y. Omote,J. Heterocycl.Chem. 18,1595 (198 1). 145
Sec. IV.F]
49
REDUCTION OF NITROGEN HETEROCYCLES
tXX
R
I
LiAlH,
TH F
R'
b R
H
M
e
NHR'
(24
(288) X = O , S ; R'=Me,Aryl; RZ= H , M e , Pr,Ph; R3=H,Me,Ph
recovered. Earlier, it had been found that ethyl 4-hydroxyiminomethyl-2methylthiopyrimidine-5-carboxylate(290a), and subsequently other pyrimidines, underwent preferential ring reduction. Lithium aluminum hydride in pyridine, lithium borohydride in THF, and sodium borohydride in ethanol all reduced 290 to ethyl 4-substituted-2-methylthio- I ,6-dihydropyrimidines (291). When R = SMe, NHMe, or NHNH,, reduction of the carboxylic acid ester occurs.15o R
R LiAlH4
MeS
or M+BH,
H
N-Substituted dihydropyrimidines on reaction with a large excess of NBH in ethanol at room temperature give rise to ring-opened products (e.g., 294).I5lThe intermediacy of the hexahydro derivative 293 was proved by its isolation from the reaction mixture and subsequent conversion to 294 with (292) additional borohydride. l-Phenyl-4,4,6-trimethyldihydropyrimidine may ring open via N-1 -C-2 or C-2-N-3 cleavage. In fact, only the former is observed, presumably a result of the increased stability of the N- I -phenyl anion. This is in agreement with the observation that 1-benzyl-4,4,6-trimethyl-1,4-dihydropyrimidine (296) gave only the hexahydro derivative in 70%yield.lsl Surprisingly,LAH left the imine bond intact prior to ring cleavage, whereas borohydride had been demonstrated to saturate all bonds prior to opening. Alkylation and subsequent reduction of the dihydropyrimidinium salts affords mixtures of the cyclic and acyclic diamines lSo Is'
R. S. Shadbolt and T. L. V. Ulbricht, J. Chem. Soc. C, 733 (1968). C. Kashima, M. Shimizu, A. Katoh, and Y. Omote, J. Heterocycl. Chem. 21,441 (1984).
50
JAMES G. KEAY
[Sec. 1V.G
298 and 299.lS1Ring opening has also been observed in the reduction of certain 2,4,6-(1H,3H,5H)-pyrimidinetrione (barbituric acid) derivatives. 152,153 NaBH,
Me Me O Me
LiAIH,
Me Me
H Y Y L - C H M e I Ph
P93)
5
Me Me
MeC N H M e
I Ph
I Ph
(294)
Q95)
JO Me Me
I CH,Ph
w
a , R’=Ph; R2,R:R4,R5=Me
b, R’=Ph; R2,R3,R4=Me;R5=Et
G. PYRAZINES The successful trapping of the valence-bond isomer, induced during the UV irradiation of pyridine,ls4with NBH led to the application of this technique to 2,3,5,6-tetramethylpyrazine(300) Although no valence-bond iso15*
Iu
M.Rautio, Acta Chem. Scand., Ser. B B33, 770 (1979).
M. Rautio and K. Vuon, Acta Chem. Scand., Ser. B B34,llO (1980). K. E. Wilzbach and D. J. Rausch, J. Am. Chem. SOC.92,2178 (1970).
51
REDUCTION OF NITROGEN HETEROCYCLES
Sec. IV.H]
merization was observed, hexahydropyrazine (301) was isolated. 155 The reduction of tetrachloropyrazine (302) with LAH affords the dehalogenated product 303.ls6 NaBH,
*
Me
Mea: Me
H
LiAIH,
H. CINNOLINES On reduction with LAH, cinnolines generally yield di- and tetrahydro
derivative^.^^'^' The LAH reduction of 5,6,7,8-tetrahydro-3-cinnolinones
(304)in THF leads to mixtures of the dihydrocinnolines 305, the decahydro The ratio cinnolines 306 and the deoxygenated tetrahydrocinnolines 307.158 of products is dependent on the substituents and the amount of LAH used.15s
& \“\R‘
R
LiAIH, THF
(304) R
=
H, M e , P h ;
R’
=
H, Ph.
O$!N,R:
@N,
H
(0s)
(305)
(XiRl (307)
ls5
Is6
Is*
D. J. Bell, I. R. Brown, R. Cocks, R. F. Evans, G. A. Macfarlane, K. N. Mewett, and A. V. Robertson, Aust. J. Chem. 32, 1281 (1979). R. D. Chambers, W. K. R. Musgrave, and P. G.Urben, J. C. S.Perkin I, 2584 (1974). L. S. Besford, G . Allen, and J. M. Bruce, J. Chem. Soc., 2867 (1 963). J. Daunis, M. Guerret-Rigail, and R. Jacquier, Bull. Soc. Chim. Fr., 1994 (1972).
52
[Sec. IV.1
JAMES G. KEAY
I. QUINAZOLINES The reductive ring cleavage that prevails with 4-quinazolinone and LAH has been the subject of several reports.159-162 Interest was first shown after the (308, abnormal reaction of the alkaloid 1-methyl-2-benzyl-4-quinazolinone asborine) was found to give the 2,3-dihydro derivative 309 with the carbonyl function still intact.159However, a different orientation of the same substituents leads to the ring-opened product 311, with cleavage occurring between C-2 and N-3 when LAH is used. In methanol, NBH gives 3-methyl-4-quinazolinone (312), the product of reductive debenzylation, albeit in low yield.159,162- 164 The position and nature of the substituents has been shown to affect the reaction markedly; for instance, NBH and LAH both generate 2-phenyl-3(314) from the parent heterocycle 313. methyl- 1,2-dihydro-4-quinazolinone This compound may then be converted to the ring-cleaved product 315 on further heating with NBH in ethanol. The 2-methyl-3-phenyl derivative with LAH gives the aniline 316 by C-2-NN-3 cleavage. In the absence of the phenyl group, this cleavage occurs preferentially along the N-1-C-2 bond (317, 84%) along with a small amount of that derived from C-2-N-3 cleavage (318, 5%).160 LiAIH, d
C
H Me z
P
25 OC
h
d
x
H 2 Me
p
h
(309)
(34
55% (311) 0
(313)
NaBH. or
0
(314)
0
(315)
S. C. Pakrashi and A. K. Chakravarty, J. Org. Chem. 31, 3143 (1972). I. R. Gelling, W. J. Irwin, and D. G. Wibberley, J. C. S. Chern. Cornmun., 1 1 38 (1969). W. J. Irwin, J. C. S. Perkin I, 353 (1972). 162 S. C. Pakrashi and A. K. Chakravarty, Indian J. Chem. 11, 122 (1973). S. C. Pakrashi and A. K. Chakravarty, J. C. S. Chem. Cornmun., 1443 (1969). N. Finch, and H. W. Gschwend, J. Org. Chem. 36, 1463 (1971). 159
I6O
Sec. IV.J]
53
REDUCTION OF NITROGEN HETEROCYCLES
Monosubstituted 4-quinazolines, with the exception of the 1and 3 - p h e n ~ l derivatives, '~~ do not undergo this ring opening reaction. The 2-phenyl derivative 319 leads to the product of carbonyl reduction 320 in 46% yield.'61 0
The ring cleavage presumably occurs via the dihydro derivative; earlier work'65had shown this ring opening to be facilitated when the reduction is camed out on the dihydro derivative. Failure of the carbonyl function to be reduced may be a result of the formation of a complex between it and the metal of the hydride reagent.
J. QUINOXALINES Quinoxaline (321)was reductively alkylated with potassium borohydride in acetic acid by the method of Gribble and co-workers to give 1,Cdiethyl1,2,3,4-tetrahydroquinoxaline(322).166 The use of formic instead of acetic acid gave mixtures of 323 and 324. Quinoxalines 325 containing electronwithdrawing groups on the benzene ring can be efficiently reduced to the 1,2,3,4-tetrahydroquinoxalines326 in high yield with NBH.91No substituent reduction is observed.
I Et
(322)
165
(3231
I CHO (324)
K. Okumura, T. Oine, Y. Yamada, G . Hayashi, and M. Nakama, J. Med. Chem. 11,348
(1968). 166
I
me
J. M. Cosmao, N. Collignon, and G . Queguiner, J. Heterocycl. Chem. 16,973 (1979).
54
(Sec. 1V.K
JAMES G. KEAY
The NBH reduction of 1,4-quinoxaline di-N-oxide (327) in alcohols has been shown to produce the cis-tetrahydroquinoxalines328 as the predominant product.167The product 328 was identical to that obtained from the reduction of 2,3-dimethylquinoxaline with LAH. 16* 0-
ax: I
0I -
NaBH, ROH
(yy H
(324
(327)
K. 1,2-DIAZEPINES The NBH reduction of 1-acetyl- and 1-carbethoxy-1,2( IN)-diazepines (329) leads to the 2,3-dihydro-1,2(1H)-diazepines 330 in high yield.169J70 The dienamine system produced is resistant to further reduction under these conditions. That only single products were obtained was verified by preparing dihydro- 1,2(1H)-diazepines labeled with methyl groups. Treatment of 330 (R'= Ac) with base generates the unstable 3,Cdihydro- 1,2(2H>diazepines 331. Analagous reduction is also observed with lithium disobutylaluminum hydride ( DIBAL).169
M. J. Haddadin, H. N. Alkaysi, and S . E. Saheb, Tetrahedron 26, 11 15 (1970). J. Figueras, J. Org.Chem. 31,803 (1966). 169 J. Streith and B. Willig, Bull. SOC.Chim. Fr., 2847 (1973). T. Tsuchiya and V. Snieckus, Can. J. Chem. 53,5 19 (1975). 167
Sec. IV.M]
R
55
REDUCTION OF NITROGEN HETEROCYCLES a
b
C
d
e
H
3-Me
5-Me
4,6 -di- Me
3,7-di -Me
L. 1,4-DIAZEPINES Most of the work on the 1,4-diazepines has been directed toward the reduction of 0x0 derivatives and other functionalities. These reactions will not be covered here, and interested readers are encouraged to refer to the appropriate sources.1 7 1 ~ 1 7 2
M. Iy5-BENZODIAZEPINES 6,7-Benzo-1,2,4,5-tetrahydro-l,5-diazepines (333) may be obtained by the NBH reduction of the benzo-l,5-diazepinium chloride precursors 332. Yields in excess of 90% are ~1airned.l~~ When the reduction was carried out in dimethylformamide, 2,4-dimethyl-1,5-dihydro-6,7-benzo-1,5-diazepine (334) was obtained. Additional work has shown that this reduction occurs stereoselectively, giving cis-tetrahydro-1,5-diazepine~.'~~
aye ggMe _NaBH,, R=MeDMF
N
95%EtOH NaBH,
Me05%
(334)
(332)
R
ci
*eMJf (
H
R
(333)
R = M e , Aryl
F. D. Popp and A. C. Noble, Adv. Heterocycl. Chem. 8, 52 (1967). D. Lloyd and H. P. Cleghorn, Adv. Heterocycl. Chem. 17,2 (1974). N. M. Omar, Indian J. Chem. 12,498 (1974). N. M. Omar, A. F. Youssef, and M. A. El-Gendy, Arch. Pharm. Chemi. Sci. Ed. 3, 89
(1975).
56
JAMES G. KEAY
[Sec. V.B
V. Reductions of Heterocycles Containing Three Nitrogen Atoms A. 1,2,3-TRIAZOLES 1,2,3-Triazolium salts (335) are not readily reduced by NBH. Indeed, 4-phenyl- and 4,5-diphenyl-1,3-dimethyl-1,2,3-triazolium iodides do not undergo reduction, yet 1-methyl-2-phenyl-1,2,3-triazolium triflate (336) is reduced to the 4-triazoline 337.17sThis reactivity pattern is explained by the need for an immonium ion for successful reaction. The presence of a C-2 substituent in 336 makes this possible; the lack ofsuch a substituent localizes the double bond joining C-4 and C-5.
:$t
NaBH,
Ph Me’
e...
Me’
Me -
I R = H,Ph
\Q
M e - Ph . q L -
I Ph
(336)
($4
B. 1,2,4-TRIAZOLES 1,2,4-Triazoliumsalts (338)are readily reduced to the dihydro derivatives 339, (triazolines) by aqueous NBH. Similarly, borohydride attack occurs exclusively at the 5 position of 5-substituted-1,4-diphenyl-3-methylthio1,2,4-triazoliumsalts (340) to give the triazolines 341 in high yield.176Acid hydrolysis of the triazolines leads to the aldehydes 342 in 40- 80%yield. Lithium aluminum hydride has been used to convert the triazol-5-ones 343 to both triazoles (345)and triazolines (346).The yields of the former are low ( 15- 30%) by this method, triazoline formation being preferred.177 R , +N-N meX&Me I
-
1
NaBH,
X$
R, Me
I
R
Ph,
me
NaBH,
R4iXs=es4iXR I I Ph (341) Ph
(4
/Ph
H,O’ -RCHO
(.14
(33.9
T. Isida, T. Akiyama, N. Mihara, S. Kozima, and K. Sisido, Bull. Chem. SOC.Jpn. 46,1250 (1973). 176 G. Doleschall, Tetrahedron 32, 2549 ( 1 976). J. Daunis, Y. Guindo, R. Jacquier, and P. Viallefont, Bull. SOC.Chim.Fr., 3296 (1971). 17J
57
REDUCTION OF NITROGEN HETEROCYCLES
Sec. V.C]
C . BENZOTRIAZOLES Attempts have been made to reduce 1,2- (347) and 1,3-benzotriazolium salts (350) both with potassium and sodium borohydride and LAH.175*178 The 1,2-dimethylderivative yielded mainly 1-methylbenzotriazole (348) on heating with borohydride in water and probably results from base-controlled dealkylation. Small amounts of 349 were also detected. No reaction was observed in the cold with the iodides of 347 or 350*751,3-Dimethylbenzotriazolium methosulfate (350) gave 1,2-di(rnethylamino)benzene (351); heating at reflux produced intractable materials. The more reactive LAH, in ether, gave high yields of the ring-cleaved products 349 and351, respectively. Me
Me
KBH,
'
H2O
eM- +b j Q MeSO,
6 h 100°C
32%
+
(348)
m Me
I
Me
K BH,
*
H,O
24%
20 "C
MeSO, (351
'NHMe
(349)
P47)
I
QNH2
1
L. 1. Rudaya and A. V. El'tsov, Zh. Org. Khim. 10,2142 (1970).
58
JAMES G. KEAY
[Sec. V.D
D. 1,2,3-TRIAZINES The election-deficient triazine ring 352 is readily attacked by sodium borohydride in methanol to give the 2,Sdihydro- 1,2,3-triazines 353 in quantitative yield.179~180Under similar conditions 4,6-dimethyl- 1,2,3-triazine 1-oxide (354) gave the same compound (353, R = Me) in 85% yield, along with 352 (R = Me).179However, reduction of the 1,2,3-triazine 2oxides 355 left the N-oxide functionality intact for the most part, giving the 1,4,5,6-tetrahydro-1,2,3-triazine 2-oxides 356 as the major products. 179 Both cis and trans isomers of 356 were detected, the former predominating. These results were confirmed by carrying out the reduction with sodium borodeuteride and deuteromethanol. The C-5 proton originates from the
NaBH,
R = P h , 62%
35 %
R = M e , 03%
5%
MeOH
R
*
a
M
I
-0 (357)
(355)
NaBH, MeOH
@54
I OH (354
e
I -0
(34
H b54
(353)
H. Arai, A. Ohsawa, H. Ohnishi, and H. Igeta, Heterocycles 17, 317 (1982). A. Ohsawa, H. Arai, H. Ohnishi, and H. Igeta, J. C. S.Chem. Commun. 1174 (1981).
Sec. V.E]
REDUCTION OF NITROGEN HETEROCYCLES
59
solvent whereas the C-4 and C-6 protons are from the reducing agent. The implication is that 356 arises from an initial 1,6-dihydrotriazine, whereas 353 forms from the 2,5-dihydro derivative 359. The triazines 352 were detected in the product m i ~ t u r e . ” ~
E. I ,2,4-TRIAZINES 5,6-Diaryl-1,2,4-triazines(360), containing a 3-methoxy or 3-methylthio substituent, give rise to the formation of the 2,5-dihydro derivatives 361 on treatment with NBH181J82 These dihydro species, trapped with dimethylacetylenedicarboxylate, were assigned structures by NMR spectroscopy, which were confirmed by X-ray analysis. 3-Methylthio- and 3-methoxy-5-phenylThe 2,5- and 4,5-dihydro- 1,2,4-triatriazines (362) behaved zines may be differentiated by NMR s p e c t r o ~ c o p yThe . ~ ~ ~1,Caddition of hydrogen is explained by initial hydride attack at C-5 followed by N-2 protonation by the solvent. MeXCJAr Ar
N%MeX THF/MeOH
rAr
N
Ar
x = 0,s A report on the reaction of NBH with 5-methylthio-l,2,4-triazin-3(2H)-
ones (363) claims demethiolation in methanol to 4,Sdihydro- 1,2,4-triazin3(2H)-ones (364)in good yield.185The same workers extended this study and described a similar reaction occumng on 3-methylthio- 1,2,4-triazin-5(222)Conducting the reaction in methanol led to ones (365) in DMF at 70°C.186 substantial amounts of 367 being isolated.
SMe
(4
b S 9
T. Sasaki, K. Minamoto, and K. Harada, J. Org.Chem. 45,4587 (1980). H. Neunhoeffer and P. F. Wiley, eds., “Chemistry of 1,2,3-Tnazines and 1,2,4-Triazines, Tetrazines and Pentazines.” Wiley (Interscience), New York, 1978. In3T. Sasaki, K. Minamoto, and K. Harada, J. Org.Chem. 45,4594 (1980). Ia4 J. Daunis and C. Pigiere, Bull. Soc. Chirn. Fr., 2493 ( I 973). InsY. Nakayama, Y. Sanemitsu, M. Mizutani, and K. Yoshioka, J. Heterocycl. Chem. 18,63 I (1 98 1). Ia6 Y. Sanemitsu, Y. Nakayama, and M. Shiroshita, J. Heterocycl. Chem. 18, 1053 (1981).
Ia2
60
JAMES G . KEAY Me
Me
Me
NaBH4 Hc.)lR
[Sec. V1.A
XT-
NaBH, MeOH
___)
R
“‘o@.*
366
0
0
0
(34
(34
(367)
R = alkyl, Ph
F. 1,3,5-TRIAZINES Studies on the stability of 1,2-dihydro-2,4,6-triphenyl1,3,5-triazine(369) included its synthesis from the aromatic 1,3,5-triazine368. However, in the presence of aluminum chloride rearrangement occurs to give a 16Y0yield of 2,4,5-triphenylimidazole(370).lE7A suggested mechanism proposed that the unstable dihydrotriazine undergoes a radical-induced ring opening and contraction to 37O.lE7
VI. Reduction of Heterocycles Containing Four Nitrogen Atoms A. TETRAZOLES
The action of NBH on some tetrazolium iodides has been ~tudied.”~ The positions of the substituents determined whether or not reduction occurred. 1,4,5-Trisubstituted tetrazolium iodides (371) were reduced to the 2-tetrazolines 372, whereas under the same conditions the 1,3,5-trisubstituted tetrazolium iodide 373 remained unchanged. The ring carbon is insufficiently electrophilic to induce attack.
I*’
H.L. Nyquist, J. Org. Chem. 31, 784 (1966).
Sec. VII.A]
61
REDUCTION OF NITROGEN HETEROCYCLES
VII. Reduction of Fused Heterocycles A. QUINOLIZINES The reduction of quinolizinium bromide (374) with NBH and LAH has been the subject of a series of publications by Miyadera and coworker^.^^*-^^^ Hydride reduction with LAH (in THF) leads to ring cleavage to 1-(2-pyridy1)- 1,3-butadiene (375), whereas NBH (in THF) gave 1-(2-pyridyl)-2-butene (376) in low yield. Studies of the reaction of 374 with Grignard reagent^'^^^^^ and MO calcul a t i o n ~indicate ' ~ ~ that the preferred site for nucleophilic attack of the quinolizinium ion is C-4. Thus the intermediacy of the unstable 4H-quinolizine 377, formed directly or by isomerization, has been suggested. Reduction of 374 with NBH ( 1 : 1) in water gave a four-component mixture, which was shown by gas chromotography to contain the quinolizines 378-381. Catalytic hydrogenation of the mixture gave quinolizidine (392). Conducting the reduction in deuterium oxide or deuterated ethanol led to incorporation of deuterium in the product. The different products obtained in aprotic solvents reflects the possibility of ring opening and reestablishment of aromaticity to the pyridine ring. In water or ethanol the proposed intermediate 377 may undergo a variety of protonations and equilibrations prior to further reduction.189The reduction NaB"4
J )ft
fJJE!?a N
Br
(375)
(374)
~ (378)
/
(376)
\ N
(377)
c (379)
(380)
g (4
(382)
of benzo[b]quinolizinium bromide (383) in ethanol with NBH led to the formation of 1,6,11,1la-tetrahydrobenzo[b]quinolizine(384) as the major product.lg3 In boiling water, only the 1,3,4,6,11,1la-hexahydro-2Hbenzo[b]quinolizine 386 was obtained. T. Miyadera and Y. Kishida, Tetrahedron 25,209 (1969). T. Miyadera and Y. Kishida, Tetrahedron 25, 397 (1969). I W T. Miyadera and Y. Kishida, Tetrahedron Lett., 905 (1965). I g 1 C. K. Bradsher and J. H. Jones, J. Am. Chem. Suc. 81, 1938 (1959). 192 R. M. Acheson and D. M. Goodall, J. Chem. Suc., 3225 (1964). 193 T. Miyadera and R. Tachikawa, Tetrahedron 25,5 I89 ( I 969).
IE9
62
[Sec. VI1.B
JAMES G.KEAY NaBH, EtOH
BF
(383)
(386
B. AZOLOPYRIDAZINES The reduction of simple pyridazines normally occurs only after quaternization and leads to mixtures of di- and tetrahydropyridazines (see Section IV,E). However, bicyclic azolopyridazines containing a bridgehead nitrogen (387-389) readily undergo reduction of the pyridazine ring with NBH in ethan01.I~~ Thus tetrazolo[ 1,5-b]- (387), 1,2,4-triazol0[4,3-b]- (388), and imidazolo[ 1,2-b]pyridazines (389) are reduced to the corresponding tetrahydro derivatives 390-392. The reduction of 388 in deuterium oxide led to deuterium incorporation at C-3,N-5, and C-7 in 391. Hydrogen -deuterium exchange will occur at C-3 in both 388 and 391 and at N-5 in 391. Deuterium incorporation at C-7 can be seen as occurring via the intermediate 393.Ig4
a)
194
NaBH,
-
a3 H
(=3;
X=N
Y=N
(34
91%
(389) ;
X =CH
Y =CH
b92)
72%
P. K. Kadaba, B. Stanovnik, and M. Tisler, J. Heterocycl. Chem. 13,835 (1976).
Sec. VII.C]
REDUCTION OF NITROGEN HETEROCYCLES
63
C. AZOLOPYRIMIDINES 1. 1,2,5-Oxadiazolo[3,4-d]pyrimidine Previous work on this system by Taylor et al.195has illustrated the facile nucleophilic attack that occurs at C-7. Reduction of the 5-phenyl-7-substituted derivatives with NBH in THF has been shown to be substituent dependent.196Amino substituents (394a, 394b) inhibit reduction, whereas the thioester 394e gives the product of reductive cleavage 396. The 6,7-dihydro derivative is obtained from the acetamido compound 394c. However, the benzamido analog 394d gives 396 and benzamide in 60% yield. NaBH, THF
(394)
a
b
C
d
e
2. Imidazolo[4,5-d]pyrimidine The purine ring system has been the subject ofconsiderable study, which is a reflection of its biological importance. Reduction of the imidazole or pyrimidine ring is controlled by the nature and position of substituents; for instance, 1-methyladenosine (397) undergoes ready reduction with NBH to 9-Benzyladenine (399a)and its N-benzoyl the 1,6-dihydroderivative 398.197 derivative 399b remained unchanged on treatment with NBH in alcohols.198 Reduction of399b with NBH in acetic acid gave reduction in the imidazole ring to afford the 7,8-dihydro compound 400b, (759/0)but without the Nethylation previously observed with this method. A similar reduction of the N-acetyl derivative has been observed, but the product was not isolated. The 19)
196 '91 19*
E. C. Taylor, S. F. Martin, Y. Maki, and G. P. Beardsley, J. Org. Chem. 38,2238 (1973). Y. Maki, Chem. Pharm. Bull. 24,235 (1976). J. B. Bacon and R. Wolfenden, Biochemistry 7, 3453 (1968). Y. Maki, M. Suzuki, and K. Ozeki, Tetrahedron Lett., 1199 (1976).
64
JAMES G. KEAY
[Sec. VI1.C
adenine 399a was recovered unchanged under these conditions. Reductive sites were determined by deuterium labeling. The site ofreduction appears to be the enamine system, which can generate an imminium ion in a protic solvent. 3-Benzyl derivatives (401) were used in order to confer the required *
NaBH,
Me,$y
6 N
pH 8.2
(397)
4
2
(IN/
H
CH,Ph
(394 (399)
stability to the dihydro derivatives 402.19*3,9-Dimethyladeninium perNHCOPh
N (N
2 y
I
CH,Ph
(44
&! . N
I
NaBH, MeOH
CH,Ph (401)
(;I;:
1
~
H
N
5
LN
I
CH,Ph (402)
b COPh Ac
chlorate (403) undergoes reduction with NBH in methanol to give the 2,3dihydro compound 404.199 The purine derivatives 405 and 407 undergo reduction in the pyrimidinium and imidazolium rings, respectively.200Studies on the reduction of 2,8-dioxo- and 2,8-diaminopurines were carried out in order to study the simpler chemical derivatives of saxitoxin.201Attempts to reduce 1,7-dihydro-9H-purine-2,8-dione (409) with NBH were unsuccessful. Reduction of 3,7,8,9-tetrahydro- 1,3,9-trimethyl-2,8-dioxo-2H-purinium iodide (410, R = H) under the same conditions gave spectral evidence for generation of the hexahydro derivative. However, on attempted isolation, facile hydrolytic C-4 -C-9 ring cleavage occurred, and the uracil 41 1 (R = 199T. Fujii, T. Saito, T. Nakasaka, and K. Kim,Heferocycles 14, 1729 (1980). 2wZ. Neiman, J. Chem. SOC.C, 91 (1970). 201 W. L. F. Armarego and P. A. Reece, J. C. S.Perkin I, 1414 (1976).
f
m 2
/
r"
I
0
I.
0
f-A-r"
oa
r
I' 2 z
66
JAMES G. KEAY
[Sec. V1I.C
H) was produced. In methanol, at pH 9 and with excess NBH, the perhydro compound 412 (R = H) was formed in high yield. This was shown by 'H NMR to be the cis fused product.201Similarly, the reduction of the 1,3,7,9tetramethyl derivative 410 (R = CHJ provided the cis product 412 (R = CHq). InD,O, NBH gave incorporation of a deuterium atom at C-5, suggesting that hydride attack occurs at C-4 in generating the hexahydro and at C-4 and C-6 in formation of the perhydro species. The reduction of 3,7,8,9-tetrahydro-l,3,6,9-tetramethyl-2,8-dioxo-2H-purinium iodide (413) with NBH proceeds more slowly to the perhydro derivative 415 but via a different hexahydro intermediate (414). The reduction of 1,7,9-trimethyl-2,8-diaminopurinium diiodide (416, R = H) gave only one product with NBH, the 2,8-diamino-4,5,6,9-tetrahydro- 1,7,9-trimethyl-1H-purine cation (417, R = H).zo'The 1,6,7,9-tetramethylpurine 416 (R = Me) similarly gave the tetrahydro product 417 (R = Me). Both of these products were isolated as the dihydrochlorides in high yield and contained a cis-ring junction.20'
R = H,Me
3. Pyrazolo[l,5-a]pyrirnidine Ethyl 2-phenylpyrazolo[1,5-~]pyrimidinecarboxylates(418) are converted to the dihydro derivatives 419 on treatment with NBH.Z02 202
G . Auzzi, L. Cecchi, A. Costanzo, P. L. Vettori, and F. Bruni, Farmaco, Ed. Sci. 34,75 1
(1979).
67
REDUCTION OF NITROGEN HETEROCYCLES
Sec. VII.E]
R‘
R’ “
“
“
~
~
~ NaBH, h
“ “ “ fN ~ ~ h
H
R
(418
1
R
(419)
R = H,Br,CI R’= Me,CH,Br,CH,CI
D.
THIENO[2,3-d]PYRIMIDINE
2-Chloro-3,4-dihydrothieno[2,3-d]pyrimidines (421) are prepared when the aromatic precursors 420 are treated with excess NBH over an 8-h period at room temperaturea203 NaBH,
E. THIENOPYRIDINES 1. Thieno/3,2-c]-and Thieno/2,3-c]pyridines N-Alkylation and subsequent reduction of both thieno[3,2-c]- (422) and thieno[2,3-c]pyridines (424) give predictably the 4,5,6,7-tetrahydrothienopyridines 423 and 425, respectively. Large excesses of borohydride were used, and the reductions were carried out in ethanol over 4-h periods at reflux temperatures. Yields of 57 -78% are obtained.2@’ The relatively electron-rich thiophene ring resists reduction.
X. (424
203 *04
Daiichi Seiyaku Co., Ltd., Jpn. Kokai Tokkyo Koho 82/77,687 (1982). F. Eloy and A. Deryckere, Bull. SOC.Chim. Belg. 79,415 (1970).
68
JAMES G. KEAY
[Sec. V1I.G
F. AZOLOAZEPINES
I. Pyrazolo[3,4-b]-1,4-diazepine 3,5-Dimethyl-7-oxo- 1-phenyl-6,8-dihydro-7H-pyrazolo[ 3,441- 1,4-diazepine (426)gave a mixture of three products on reduction with LAH. After heating at reflux for 6 h in ether, the ratio of 427 :428:429 was 5 :4 :8; after 24 h only 429 was found. Reduction of 1-phenyl-3,5,7-trimethylpyrazolo[3,4-b]-1,4-diazepine(430)under similar conditions led to the tetrahydro derivative 431205in 80% yield after 12 h. 7,8-Dihydro derivatives of 430 were isolated on catalytic hydrogenation and could be subsequently converted to 431 with LAH.ZoS
(-JpJe. M&y
+:je - @;je Ah
Me
Me
Me
LiAIH,
*
H
Ph
c224
(427)
Q:je
Me
Me
&ye
*
I
Ph
Ph
6130)
Ph I
H
0
(428)
I
Ph
H 6129)
Me
LiAIH,
I
OH
H
Me
(4311
G . AZANAPHTHALENES 1 . Pyrido[3,2-e]-andPyrido[3,4-e]-l,2,4-triazines The addition of LAH to a solution of 3-phenylpyrido[3,2-e]-1,2,4-triazine (432a)in THF gave the tetrahydro derivative 433a. Likewise with the unsubstituted analog 432b,reduction occurred in the pyridine ring affording 433b.3-Phenylpyrido[3,4-e]-1,2,4-triazine (434),however, undergoes hydride reduction in both rings to give the 4,5,6,10-tetrahydro derivative
435.206 The reason for this disparity is not obvious. Theoretical studies do
not resolve the issue. One study indicates that in pyrido-l,2,4-triazines and pyridopyridazines the pyridine-ring nitrogen is the most basic.207However, 20J
J.-P. Affane-Nguema, J.-P. Lavergne, and P. Viallefont, J. Heterocycl. Chem. 14, 1013 ( 1977).
206 207
J. Armand, K. Chekir, N. Ple, G. Queguiner, and M. P. Simonnin, J. Org. Chem. 45,4754 (1981). S. C. Wait, Jr. and J. W. Wesley, J. Mol. Spectrosc. 19,25 (1966).
69
REDUCTION OF NITROGEN HETEROCYCLES
Sec. VII.G]
Dinya208in a CNDO study concluded that this is not so in every case. The pyridine N atom in pyrido[2,3-e]- (436) and pyrido[3,2-e]-1,2,4-triazines (432) carries the largest negative charge and indicates that reduction should occur in the triazine ring for the [3,4-el (434) and [4,3-el (437) analogs. Previous work on other azanaphthalene systems suggests that reduction should occur in the triazine ring. LiAIH, R
2. Pyrazino[2,3-d]pyrirnidine The reduction of pyrazine[2,3-d]pyrimidines,the pteridine ring system, usually occurs in the pyrazine ring to yield dihydro and tetrahydro derivat i v e ~The .~~ reduction ~ of 1- and 3-methyl-6,7-diphenylpteridin-4-one with NBH gves no isolable products, whereas 3,4-dihydro- 1,3-dimethyl-6,7-diphenyl-4-oxopteridinium iodide (438) gives the 1,2,3,4-tetrahydro product 439.200The reduction of pteridine (440) itself with NBH occurs readily in trifluoroacetic acid, giving two products in 94% overall yield. 1,2,3,4-(441) and 5,6,7,8-tetrahydropteridine(442) were obtained in 38 and 58% yields, respectively.z10The pyrazine ring is preferentially reduced.
M e \ h 1 P h
I
Me
(434
MeOH NaBH,
Ph
I
*Me
y5fJ
Ph
I
Me
(439)
Z. Dinya and P. Benko, Acta Chim. Acad. Sci. H u g . 96,61 (1978). E. C. Taylor, M. J. Thompson, and W. Pfleider, Pteridine Chem.. Proc. Int. Symp., 3rd, lY62, 181 (1964). 210 R. C. Bugle and R. A. Osteryoung, J . Org. Chem. 44, 1719 (1979). 208
209
70
[Sec. V1I.G
JAMES G. KEAY
(444
(441)
(44
3. Pyrimidino[4,5-d]pyridazine Reduction of 2-aryl-5,8-dialkylaminepyrimido[4,5-d]pyridazines (443) with NBH, LAH, and catalytic hydrogenation gives the 3,4-dihydropyrimidopyridazines 444.21I
Ary‘w NaBH,
LiAIH,
(44;
or
m
H
/N
64;
R = b-PrNH, PhNH , PhCH,NH, C,H,,N , morphilino
4. Pyrido[3,4-d]pyrimidine The expected product of reduction of the pyrido[3,4-d]pyrimid-4(3H)one 445 with LAH is the 1,2,3,4-tetrahydropyndo[3,4-d]pyrimidine 446. However, the product obtained (447) resulted from cleavage at the 2,3 position.212High yields of the pyridine 447 were obtained after 1-h at room temperature with excess LAH. Reductive ring closures of fused pyrimidines and pyrimidin-4(3H)-ones has been reported previously to occur at the 1,2 2 L 3and the 2,3 bond214(see also Section IV,F) but under much more vigorous conditions. More vigorous conditions are required when the pyrido[ 3,4-d]pyrimidin-4(3H)-onesdo not possess a 3-aryl substituent. The substrate 448 required 3 days at room temperature to give 1,2,3,4-tetrahydro-3,6,8-trimethylpyrido[3,4-d]pyrimidine (449) in 92%yield. Heating the pyridopyrimidone 448 at reflux in THF for 6 h was required to convert this to the pyridine 450.212Compounds without 3 substituents led to specific S . Yurugi, T. Fushimi, and M. Hieda, Yukuguku Zusshi 92, I3 16 (1972). I. R. Gelling and D. G. Wibberley, J. Chem. Soc. C,780 (1971). 213 R. F. Smith, P. C. Bnggs, R. A. Kent, J. A. Albright, and E. J. Walsh, J. Heterocycl. Chem. 2, 157 (1965). 214 H. Ott and M. Denzer, J. Org. Chem. 33,4263 (1968). 212
71
REDUCTION OF NITROGEN HETEROCYCLES
Sec. VII.G]
2,3-bond fission but with more difficulty (boiling ether, 7 days). Use of less reducing agent and lower temperatures gave mixtures of products, starting materials, and 3,4-dihydro derivatives. The latter are likely intermediates in the reduction, although initial 1,2 attack has also been ~ u g g e s t e d . ’ ~ J ~ ~ , ~ ~ ~
LIAIH,, &HMe
T H F , 67 “C, NHEt
Me
*
6h
Me
LiAIH, Me
@5d
Me
,
25°C w
72h
Me
Me
0
0
6244
(444
5. Pyrido[L?,S-b]pyrazine Pyrido[2,3-b]pyrazine (451) is reduced rapidly and regiospecifically by NBH in trifluoroacetic acid to the 1,2,3,4-tetrahydropyrazine452.210No reduction of the pyridine ring was observed. Reduction with LAH on this and pyrido[ 3,441pyrazines leads to tetrahydropyrazines.206
a> (451)
NaBH, C F,COOH
a> 75%
(452)
6, Pyrido[2,3-d]pyridazine Calculations of the n-electron density2I5of pyrido[2,3-d]pyridazine (453) suggests that the nucleophilic attack is favored at C-2, C-5, and C-8. Studies of the reaction of 453 with LAH in THF gave 5,6- and 7,8-dihydro compounds in 35 : 65 ratio and 75%overall yield. The preferred site ofattack is at 2’5
M. Tisler and B. Stanovnich, “The Chemistry of Heterocyclic Compounds,” Vol. 27, p. 989. Wiley (Interscience), New York, 1973.
12
JAMES G . W A Y
[Sec. V1I.H
C-8 as a result of the greater deactivation of the pyridazine ring and the proximity of the pyridine
7. Pyrido[4,3-b]pyridine The tetrahydro derivatives 455 are conveniently prepared in aqueous methanol, using NBH.217Quaternization of the parent heterocycle gives the precursor 454. NaBH,
R = MeCEC-
*
, alkyl
H. AZOLOINDOLES 1. Pyrido-[2,3-b]-, -[3,4-b]-, and -[4,3-b]indoles The reduction of the 1,2,3,4-tetrahydropyrido[4,3-b]indolinium salts (456) proceeds stereospecifically with NBH to give the trans-ring junction (457).2'8Pyridine-borane yields the cis product. A deep orange color is generated from the pyrido[3,4-b]indolinium salt 458 on treatment with NBH. This suggests the formation of the anhydro base 459 (R = H), the color of which dissipates as the 1,2,3,4-tetrahydro derivative 460 is formed.219The pyrido[2,3-b]indole461 (R = -) is reportedly not affected by NBH. The salt 461 ( R = CH, +) is, however, reduced.220 D. Marchand, A. Turck, G . Queguiner, and P. Pastour, Bull. SOC.Chim. Fr. 9 19 ( 1 977). Nippon Kayaku Co., Ltd., Jpn. Kokai Tokkyo Koho 81 135,848 (1980). V. A. Zagorevskii,S. G . Rozenberg,N. M. Sipilina, L. U. Bykova, and A. P. Rodiono, Zh. Vses. Khim.0-va 21, 102 (1982). 219 I. W. Elliott, J. Efeterocycl. Chem. 3, 36 I ( 1 966). 220 B. Witkop and J. B. Patrick, J. Am. Chem. SOC.IS, 4475 (1953). 216
217
Sec. VII.H]
73
REDUCTION OF NITROGEN HETEROCYCLES Me
R
'
d
I
Me
"
NaBH,
Ci
diglyme
b
R&I
I
R
R (457)
(456)
r
R = H,Ph; R'= H,Me
L
R (458)
-
-
659)
The reduction of the pyrrolo[3,4-b]indol-3(2H)-ones 462 with LAH in toluene at reflux temperatures gave the expected 1,2,3,4-tetrahydro derivative 463 in 4590 yield. However, the dihydropyrrolo[3,4-b]indole464 was also isolated. The yield of this latter product was increased from 27 to 429/0 when the reduction was carried out in the presence of 1-ethylpiperidine.221 This was interpreted as increasing the propensity toward C- 1 proton extraction from the aluminum-oxygen complex 465.
flo ,CH,Ph
N
LiAIH, PhMe
I
Ph (462)
221
W. M. Welch, J . Org. Chern. 41,2031 (1976).
,CH,Ph
-@ N I
Ph
(463)
74
JAMES G . KEAY
[Sec. V1I.J
Ph
I. 1,3-THIAZOLO[2,3-U]ISOQUINOLINE The reduction of 3-methylthiazolo[2,3-a]isoquinoliniumperchlorate (466) and its 2,3-dihydro derivative (467) led to the same three products with both NBH and LAH.222The formation of469 was favored with borohydride, whereas 468 and 470 were the major product with LAH. Reductive ring cleavage of thiazoles is known and has been reported
@64
J.
NaBH,/LiAIH,
1,4-THIAZENO[4,5-U]QUINOLINEAND -[4,5-U]QUINAZOLINE
Reduction with NBH leads to cleavage of the thiazine ring of 471 and produces the quinoline derivative 472. The driving force for such a reaction 222 223
H. Sin& and K. Lal, J . C. S.Perkin I, I799 (1972). A. D. Clarke and P. Sykes, J. Chern. SOC.C.103 (1971).
75
REDUCTION OF NITROGEN HETEROCYCLES
Sec. VII.K]
is rearomatization of the pyridine ring.224Likewise, NBH in ethanol at reflux converts the thiazenoquinazoline 473 to the quinazoline 474.224
&
NaBH, OH
E tOH
(471)
(473)
NaEH, CI
Ph
Ph (474)
(473)
K. BENZO[d,e]QUINAZOLINE 1-Substituted benzo[d,e]quinazolines (475, the perimidine ring system) are unaffected by NBH but are readily reduced to the 2,3-dihydro derivatives with LAH, yielding the 2,3-dihydroperimidines 476. The perimidones and thiones 477 are readily reduced to 478 on treatment with LAH.225The
67,.
H
LiAlH,
R=alkyl
\
Me
‘R
*
Me
I
NaBH, or Me
LiAIH,
LiAIH,
Me
Me
\
(479)
(478)
(477)
x = 0,s 224
P. Neelakantan, N. Rao, U.T. Bhalerao, and G. Thyagarajan, Indian J. Chem. 11, 105 1
(1973). 225 A. F. Pozhankii and I. S . Kashparov, Khim. Geterotsikl. Soedin. 2, 860 (1972).
76
[Sec. VI1.M
JAMES G . KEAY
1,3-substituted quaternary salts 479 undergo facile reduction to 478 with both of the above metal hydrides.226
L. INDOLo[2,3-a]QUINOLIZINE Using NBH in trifluoroacetic acid has been shown to possess great utility for the reduction of indoles to indolines.lMThis ability has also been applied to the reduction of indole alkaloid^.^^^.^^^ Studies on the alkaloid I ,2,3,4,6,7,I2,12b-octahydroindolo[2,3-a]quinolizine(480) gave the 1,2,3,4,6,7,7a,12,12a,12b-decahydro derivative 481.229Preparation of the deuterated derivatives enabled the stereochemistry of the ring junction to be determined as cis from the coupling constants observed in the undeuterated sample. This is in agreement with the proposed intermediacy of a bis- or tris(trifluoroacetoxy)borohydride species (484, 485). These have a greater steric requirement than the monoacetate 483, which is generated when the reaction is conducted in THF,230giving a 20% yield of 481 along with a number of other stereo isomers (i.e., 482).
CF,COOBH,
(C F,COO),BH,
(44
(44
(C F,COO) ,BH (485)
M. PYRID0[3,2,1-k,/]PHENOTHIAZINES The reduction of the pyridophenothiazinium salts 486 in aprotic solvents leads to the I ,Zdihydro compounds 487, which are relatively unstable. In
226
V. I. Sokolov, A. F. Pozharskii, I. S. Kashparov, A. G . Ivanov, and B. 1. Ardashev, Khim. Geterotsikl. Soedin. 4, 558 (1974).
D. Herlern and F. K-Huu, Tetrahedron 35,633 (1979). J. Le Men, L. Le Men-Oliver, J. Levy, and M. C. Levy-Appert-Colin, German Patent 2,410,651 [CA 8 2 , 4 3 6 4 0 ~(1975)l. 22q G. W. Gribble, J. L. Johnson, and M. G. Saulnier, Heterocycles 16, 2109 (1981). 2M G. W. Gribble, W. J. Kelly, and S. E. Emery, Synthesis. 763 (1978). 227
228
REDUCTION OF NITROGEN HETEROCYCLES
Sec. VKM]
77
protic solvents with NBH the tetrahydro derivative 488 is formed.231Reduction of the 3-chloro derivative 486, (R = C1) gave the products 487 (R = H) and 488 ( R = H) when conducted in different solvents. This probably results from the formation of the dihydro intermediate 489 ( R = Cl), which rearomatizes with expulsion of the halogen. The reduction then continues as before.
a:2 +'
/
NaBH,
THF
(44
I
NaBH, EtOH
U
(487)
R
(488)
R = H,CI,Ph
R =CI
ACKNOWLEDGMENTS
The author is most grateful to Dr. Eric F. V. Scriven for his continuous advice and support during the preparation of this manuscript. Dr. Robert E. Lyle generously supplied many references and undertook the reading of an early draft. Mr. Don Galow assisted with electronic data retrieval and the task of typing the manuscript was completed by Ms. Anita Brown. Indulgence by Reilly Tar & Chemical Corporation is deeply appreciated, along with that of my colleagues, in particular, Ms. Cheryl Huss. A debt of gratitude is also due my wife, Debi. The author remains solely responsible for errors and omissions.
231
A. R. Martin, S. H. Kim, G. W. Peng, G. V. Siegel, and T. J. Yale, J. Heterocycl. Chem. 15, 1331 (1978).
The Reduction of Nitrogen Heterocycles with Complex Metal Hydrides JAMES G. KEAY
Reilly Tar & Chemical Corporation. Indianapolis. Indiana 46204 1. Scope of Review . . . . . . . . . . . . . . . . . I1. Introduction . . . . . . . . . . . . . . . . . . . I11. Reduction of Heterocycles Containing One Nitrogen Atom . . A . Pyridines . . . . . . . . . . . . . . . . . . 1. With Borohydride . . . . . . . . . . . . . . 2. With Aluminurn Hydrides . . . . . . . . . . . 3. Other Hydrides . . . . . . . . . . . . . . . B. Pyridones . . . . . . . . . . . . . . . . . . 1. With Aluminum Hydrides . . . . . . . . . . . C . Pyridinium Salts . . . . . . . . . . . . . . . . I . With Borohydrides . . . . . . . . . . . . . . 2 . With Aluminum Hydrides . . . . . . . . . . . D. I-Alkoxypyridinium Salts and Pyridine I-Oxides . . . . E . Cyclic lmines . . . . . . . . . . . . . . . . . F. Quinolines . . . . . . . . . . . . . . . . . . 1. With Borohydrides . . . . . . . . . . . . . . 2 . With Aluminum Hydrides . . . . . . . . . . . G. Quinolinium Salts . . . . . . . . . . . . . . . I . With Borohydride . . . . . . . . . . . . . . 2. With Aluminum Hydndes . . . . . . . . . . . H . Isoquinolines . . . . . . . . . . . . . . . . . I . With Borohydrides . . . . . . . . . . . . . . 2 . With Aluminum Hydrides . . . . . . . . . . . I . lsoquinolinium Salts . . . . . . . . . . . . . . I . With Borohydride . . . . . . . . . . . . . . 2. With Aluminum Hydrides . . . . . . . . . . . J . Indoles . . . . . . . . . . . . . . . . . . . K . 1, 2-Oxazoles . . . . . . . . . . . . . . . . . L . 1, 3-Oxazoles . . . . . . . . . . . . . . . . . M . I ,3-Thiazoles . . . . . . . . . . . . . . . . . N . 1, 3-Thiazines . . . . . . . . . . . . . . . . . IV . Reductions of Heterocycles Containing Two Nitrogen Atoms . A. Pyrazoles . . . . . . . . . . . . . . . . . . B. Imidazoles . . . . . . . . . . . . . . . . . . C . Benzimidazoles . . . . . . . . . . . . . . . . D. I ,2,4-Oxadiazoles . . . . . . . . . . . . . . . 1
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Copyright 0 1986 by Academic Press. Inc. All rights of reproduction in any form rcservcd .
JAMES G. KEAY
2
[Sec. I
E . Pyridazines . . . . . . . . . . . . . . . . . . . . . . . . F. Pyrimidines . . . . . . . . . . . . . . . . . . . . . . . G . Pyrazines . . . . . . . . . . . . . . . . . . . . . . . . H . Cinnolines . . . . . . . . . . . . . . . . . . . . . . . . I. Quinazolines . . . . . . . . . . . . . . . . . . . . . . . J . Quinoxalines . . . . . . . . . . . . . . . . . . . . . . . K . 1,2-Diazepines . . . . . . . . . . . . . . . . . . . . . . L . I , 4-Diazepines . . . . . . . . . . . . . . . . . . . . . . M. I 5.Benzodiazepines . . . . . . . . . . . . . . . . . . . . V . Reductions of Heterocycles Containing Three Nitrogen Atoms . . . . . . . A . 1.2.3.Triazoles . . . . . . . . . . . . . . . . . . . . . . B. 1.2.4.Triazoles . . . . . . . . . . . . . . . . . . . . . . C. Benzotriazoles. . . . . . . . . . . . . . . . . . . . . . . D. 1.2.3.Triazines . . . . . . . . . . . . . . . . . . . . . . E . 1.2.4.Triazines . . . . . . . . . . . . . . . . . . . . . . F. 1.3.5.Triazines . . . . . . . . . . . . . . . . . . . . . . VI . Reduction of Heterocycles Containing Four Nitrogen Atoms . . . . . . . A . Tetrazoles . . . . . . . . . . . . . . . . . . . . . . . . VII . Reduction of Fused Heterocycles . . . . . . . . . . . . . . . . . A . Quinolizines . . . . . . . . . . . . . . . . . . . . . . . B. Azolopyridazines. . . . . . . . . . . . . . . . . . . . . . C. Azolopyrimidines . . . . . . . . . . . . . . . . . . . . . 1. 1.2.5.0xadiazolo[3. 4-dlpyrimidine . . . . . . . . . . . . . . 2. Imidazolo[4.5.d]pyrimidine. . . . . . . . . . . . . . . . . 3. Pyrazolo[1. 5.alpyrimidine . . . . . . . . . . . . . . . . . D. Thieno[Z.3.dlpyrimidine . . . . . . . . . . . . . . . . . . . E . Thienopyridines . . . . . . . . . . . . . . . . . . . . . . I . Thieno[3.2.c 1. and Thieno[2.3-c]pyridines. . . . . . . . . . . . F. Azoloazepines. . . . . . . . . . . . . . . . . . . . . . . I . Pyrazolo[3.4.b].l. 4-diazepine . . . . . . . . . . . . . . . . G . Azanaphthalenes. . . . . . . . . . . . . . . . . . . . . . 1 . Pyrido[3.2.e 1. and Pyrido[3.4.e].l.2. 4.triazines . . . . . . . . . . 2. Pyrazino[2.3.dlpyrimidine . . . . . . . . . . . . . . . . . 3. Pyrimidino[4.5.dlpyridazine . . . . . . . . . . . . . . . . 4. Pyrido[3.4-dlpyrimidine . . . . . . . . . . . . . . . . . . 5. Pyrido[2.3.blpyrazine . . . . . . . . . . . . . . . . . . . 6. Pyrido[2.3.dlpyridazine . . . . . . . . . . . . . . . . . . 7. Pyrido[4.3-blpyridine . . . . . . . . . . . . . . . . . . . H . Azoloindoles . . . . . . . . . . . . . . . . . . . . . . . I . Pyrido(2.3.bJ.. .[3.4.b 1. and .[4. 3.bIindoles . . . . . . . . . . . I . 1.3.Thiazolo[2. 3.a]isoquinoline . . . . . . . . . . . . . . . . J . 1.4.Thiazeno[4. 5.alquinoline and .[4. 5.a]quinazoline . . . . . . . . K . Benzo[d.elquinazoline . . . . . . . . . . . . . . . . . . . . L. Indolo[2.3.a]quinolizine . . . . . . . . . . . . . . . . . . . M . Pyrido[3.2. I.k, llphenothiazines . . . . . . . . . . . . . . . .
.
46 48 50 51
52 53 54 55 55 56 56 56 57 58 59 60 60 60 61 61 62 63 63 63 66 67 67 67 68 68 68 68 69 70 70 71 71 72 72 72 74 74 75 76 76
I . Scope of Review This article covers the literature published between the years 1965 and 1983 and that contained in ChemicalAbstracts. Volumes 64-99 inclusive.
Sec. 111
REDUCTION OF NITROGEN HETEROCYCLES
3
Pertinent 1984 literature is also included. It serves to update the review of Lyle and Anderson, which covered the earlier literature. Substrates covered are listed in the index page. Most investigators have worked with the complex hydrides of boron and aluminum; therefore reactions with these form the principal part of the discussion. Some work with other organometallic hydrides and complex hydrides of some transition metals is also described.
11. Introduction The previous review on this subject was published in 1966.’ Though the number of reagents and systems investigated has been greatly expanded since that time, this review is structured after the Lyle and Anderson document. Some of the earlier observations regarding general reactivity principles deserve restatement. Complex metal hydrides are nucleophilic reagents that formally add hydride to polarized carbon - carbon or carbon - heteroatom double bonds. The two best known reagents of this type are lithium aluminum hydride (LAH) and sodium borohydride (NBH). The former is moisture sensitive and generally used in ethers; the latter is milder and is most often employed in hydroxylic solvents. The efficacy and selectivity ofthese reagents is greatly affected by structural modifications [e.g., LiAlH,(O-t-Bu),], for instance, the addition of Lewis acids and mixed hydride formation. Solvents can also affect the power of the reducing agent; this is particularly so with sodium borohydride. Many modified complex metal hydrides are now known. A comprehensive review on complex metal hydrides was published in 1979., Those heterocyclic systems attacked by complex metal hydrides are required to be relatively electron deficient. Nitrogen heterocycles in which the heteroatom contributes a single electron to the K system are considered electron deficient (e.g., 1). However, systems where the nitrogen atom contributes two electrons are considered electron rich (e.g., 2) and are not normally attacked by metal hydrides. Aromatic species that contain both a “pyridine-like” (1) and a “pyrrole-like” (2) heteroatom (e.g., 3) exhibit be-
X
=
N,O, S
P. S. Anderson and R. E. Lyle, Adv. Heterocycl. Chem. 6,45 (1966).
A. Hajos, “Complex Hydrides and Related Reducing Agents in Organic Synthesis.” Am.
Elsevier, New York, 1979.
4
JAMES G . KEAY
[Sec. I1
havior due to each atom and are generally capable of being attacked by these reagents. Traditionally, the mechanism by which complex metal hydrides reduce unsaturated compounds has been viewed as nucleophilic and regarded as a direct hydride transfer from reagent to ~ubstrate.~ However, in the last few years this view has been radically challenged amid reports of the operation of single-electron transfer (SET) processes. Ashby and co-workers have shown that such mechanisms do occur in the reaction of both organometallic compounds or simple metal hydrides with a variety of substrate^.^" The first suggestion that an alternative radical mechanism may operate in the borohydride reduction of pyridinium ions was put forward by Uzienko and Yasnikov in 1972 during investigation of 1-benzyl-3-carboxamidopyridinium chloride (4).6
C3
CONH 2
I
ci
CH,Ph
(4) Conclusive evidence for the formation of radical intermediates in the reaction of pyridine with LAH’ itself has not been forthcoming to date. This is due to the short lifetime of such radicals and their propensity toward coupling with hydrogen or other pyridine radicals. However, the use of substrates that generate radicals with a greater steric requirement (e.g., 1,lOphenanthroline, 2,2-bipyridine, isoquinoline) has allowed detection of radicals by ESR spectrometry. Much stronger signals were observed with the less reactive hydrides, lithium di- and lithium tri-tert-butoxyaluminum hydride. Much higher radical concentrations, up to 27%, were observed. Electronspin resonance signals were still detectable one month later in some cases.’ In the absence of more readily attacked species, excess pyridine is known to form lithium tetra(dihydropyridiny1)aluminates with LAH.* Such intermediate complexes react with heterocyclesat much slower rates and allow observation of the radical intermediates. Indeed, ratios of substrate to hydride such that the available hydrogens could be involved in intermediate heterocyclic hydride complexes (e.g., 5) resulted in the highest
’E. C. Ashby, A. B. Goel, R. N. DePriest,and H. S.Prasad,J. Am. Chem. SOC.103,973 (198 I). ’
E. C. Ashby, A. B. Goel, and R. N. DePnest, J. Am. Chem. SOC. 102,7779 (1980). E. C. Ashby and J. R. Bowers,Jr., J. Am. Chem. SOC. 103,2242 (I98 I). A. B. Uzienko and A. A. Yasnikov, Ukr. Khim. Zh. (Russ.Ed.) 38, 1289 (1972). E. C. Ashby and A. B. Goel, TefrahedronLett., 4783 (1981). P. T. Lansbury and J. 0. Peterson, J. Am. Chem. SOC.85,2236 (1963).
Sec. 11)
5
REDUCTION OF NITROGEN HETEROCYCLES
concentration of observable radical intermediates. It was suggested that the initial radical pair that was formed (7) underwent not only further reaction to the reduced product 8 but also dissociation to the free radical anion 9.'
ArH'
+
Li** H
+
AIH(Ot-Bu),
(9)
ArH,
+
LiOH
AI(OH),
+
t-BuOH
H,
00)
Sosonkin and co-workers have recently shown that the ESR signal obtained on reduction of 9-cyano- 10-methylacridinium perchlorate (1 1) with NBH was identical with that produced by electrochemical (one-electron) reduction of the same cation in dimethylf~rmamide.~
1. M. Sosonkin, A. 1. Matern, and 0. N. Chupakhin, Khim. Geferofsikl.Soedin. 10, 1377 (1983).
6
JAMES G . KEAY
[Sec. 1II.A
111. Reduction of Heterocycles Containing One Nitrogen Atom A. PYRIDINES 1. With Borohydride The reduction of pyridines with NBH occurs only if they carry electronwithdrawing substituents. Most pyridines containing a single electron-withdrawing substituent in the 2 or 4 position are unaffected by NBH. Reaction, if any, occurs at the substituent.lo However, a single electron-withdrawing group in the 3 position can lead to ring reduction.ll 3,5-Dicyano-(14)12and 3,5-diethoxycarbonylpyridine(15) were among the first to be studied in detail.13 Reduction leads mainly to mixtures of the 1,2- and 1,Cdihydro species. In pyridine, the 1,Cdihydropyridinesare favored.l4 Sodium cyanoborohydride affordsthe 1,Cdihydropyridine 18in high yield (- 80%),essentially free from the 1,2-dihydro analog. Reduction of 3,5-diacetylpyridine (16)with NBH and LAH gives the 3,5-diol19 in 98% yield. A small amount of nuclear reduction is observed (- 2%),of which the major component was determined spectrophotometrically to be the the 1,Cdihydro isomer.15
NcocN EtOg
,
RO
64)
lo
C02Et
H & O C U O C H ,
R
(15)
66)
Y. Kikugawa, M. Kuramoto, I. Saito, and S . 4 . Yamada, Chem. Pharm. Bull. 21, 1927
(1973). 'I
Y. Kikugawa, M. Kuramoto, I. Saito, and S . 4 . Yamada, Chem. Pharm. Bull. 21, 1914
(1973).
J. Kuthan and E. Janeckova, Collect. Czech. Chem. Commun. 29, 1654 (1964). P. J. Brignell, U. Eisner, and P. G. Farrell, J. Chem. SOC.B, 1083 (1966). I4 E. Booker and U. Eisner, J. C. S. Perkin I, 929 (1975). IJJ. Palecek, L. Vavruska, and J. Kuthan, Collect. Czech. Chem. Commun.37,2764 (1972). I2
l3
Sec. III.A]
REDUCTION OF NITROGEN HETEROCYCLES
7
The reduction of 3-cyanopyridine (20) in ethanol leads mainly to the tetrahydropyridine 22.16Reduction in pyridine or diglyme however, produces 1,Cdihydropyridine (21)as the major product. Minor amounts of the 3-pyridylmethylamine 23 are also obtained with ethanol, and the aprotic solvents prevent further ring reduction.
I''I
Reduction of 2- and 4-cyanopyridines with NBH in pyridine or diglyme might be expected to give the aminomethyl compounds. However, 2-cyanopyridine (24)gives in diglyme a 20% yield of 2,4,5-tris-2-pyridylimidaole (26).164-Cyanopyridine (25)on reduction in pyridine gave low yields of 2,4,5-tris-4-pyridylimidazole(27)and 1,l -bis-4-pyridylmethylamine (28). The formation of such products possibly involves a benzoin type coupling of the initially formed aldimine, which can then undergo further reaction with another molecule of cyanopyridine. In ethanol, substituent reactions predominate on NBH reduction. 2-Cyanopyridine gives the amine 29 and amidine 30.4-Cyanopyridine gives the amine 29 in 53% yield.'O The reduction of nicotinamide (31)with NBH in diglyme at 140°Cgave a low yield of tetrahydropyridine (22) and the piperidine 32. Addition of ethanol as a proton source raised the yield of 22 to 42%."J7 The dehydration of primary amides with borohydride is known to occur in moderate yield.'* The reduction of 2-alkylamino- and 2-arylamino-3,5-dinitropyridines (33)in water leads to the tetrahydropyridines 34 in high yield^.'^.^^ The I6
l9 Zo
S . 4 . Yarnada, M. Kurarnoto, and Y. Kikugawa, Tetrahedron Lett., 3101 (1969). Y. Kikugawa, S. Ikegami, and S.-I. Yarnada, Chem. Pharm. Bull. 17,98 (1969). V. M. Micovic and M. L. J. Mihailovic, J. Org. Chem. 18, 1190 (1953). A. Signor, A. Orio, and A. Marzotto, Atti Accad. Peloritana Pericolanti, CI. Sci. Fis., Mat. Naf.50, 85 (1970). A. Signor and E. Bordignon, Tetrahedron 24,6995 (1968).
8
JAMES G . KEAY
NaB/ Pyror Diglyme
(24) ; 2-CN (25); 4-CN
\
[Sec. 1II.A
(26) ; 2-Pyridinyl
(27):
4-Pyridinyl
OCN H
(22)
(32)
precise nature of the products was confirmed, and the mechanism was proposed on the basis of experiments using deuterated reagents.213-Nitropyri21
E. Bordignon, A. Signor, I. J. Fletcher,A. R. Katritzky, and J. R. Lea, J. Chem. Soc. B, I567 (1970).
Sec. III.A]
9
REDUCTION OF NITROGEN HETEROCYCLES
dine (35)was reduced to the piperidine 36 with borohydride, an indication that initial attack occurs at the 4 position." Pyridine 3-carboxylic acid derivatives and 3-halopyridines are normally unreactive toward borohydride.'l NaBH, NHR
H2
0
* O Z N a N NHR o z U ..
(33)
(34)
NaBH, b
EtOH
(3 5)
H
(36)
42
%
An interesting occurrence is the complete reduction of the pyridine ring in 5,6-dihydro-l lH-benzo[5,6]cyclohepta[1,2-b]pyridin-ll-one (37) to the piperidine 38 in 2-propanol with NBH.22 The cis isomer was favored (- 9 : 1). This is a rare example of deactivated pyridine undergoing borohydride reduction. The answer lies in the carbonyl group, which undoubtedly undergoes reduction to give the borate ester 39. This boron complex will have a significant steric requirement. It is known that increasing the size of the 1 substituent increases the proportion of hydride attack at the 4 position, and hence formation of piperidine, in pyridinium salts.23 Likewise, initial hydride attack will now be directed toward the 4 position, and subsequently the piperidine 38 will be formed.
($I NaBH, i-PrOH
Yo
I
qp
23
1
HO
(38) 22
23
J. A, Bristol and C. Puchalski, J. Org. Chem. 45,4206 ( I 980). P. S. Anderson, W. E. Krueger, and R. E. Lyle, Tetrahedron Letf.,401 1 (1965).
10
JAMES G. KEAY
[Sec. 1II.A
2. With Aluminum Hydrides Lithium aluminum hydride (LAH) reductions are camed out in aprotic solvents and give rise to the dihydro- and tetrahydropyridine derivatives. LAH reacts with both pyridines and pyridinium salts.’ It has been known for some time that aged (- 24 h) pyridine and LAH solutions form complexes of lithium tetrakis(N-dihydropyridiny1)aluminate (40, LDPA),z40z5which is believed to consist of a mixture of the 1,2- and 1,Cdihydropyridines (by NMR). Indeed, LDPA itself has been used as a selective reducing agent for ketonesz4and affords 3-substituted pyridines (41) on reaction with alkyl halides.z6 2,5-Dihydropyridines have been identified as intermediates in similar reactions.27Kuthan and co-workers have shown that for 3,Sdicyan-
r
1-
I_ RX
% Yield
R
X
Me
I
86
Et
I
89
PhCH,
CI
63
Br
Br
41
QrR (41)
opyndine (14) the rate of reduction was faster in ether than in THF, but the ratio of isomers was not altered.28For lithium and sodium aluminum hydrides and sodium diethoxyaluminum hydride, NaA1Hz(OEt)2, approxi24
C. S . Giam and S. D. Abbott, J. Am. Chern. SOC.93, 1294 (197 I).
’’P. T. Lansbury and J. 0. Peterson, J. Am. Chem. SOC.84, 1756 (1962).
R. F. Francis, C. D. Crews, and B. S . Scott, J. Org. Chem. 43, 3227 (1978). R. F. Francis, W. Davis, and J. T. Wisener, J. Org. Chem. 39, 59 (1 974). laJ. Kuthan, J. Prochazkova, and E. Janeckova, Collect. Czech. Chem. Cornmiin. 33, 3558 (1968). 26 27
11
REDUCTION OF NITROGEN HETEROCYCLES
Sec. III.A]
mately 1 : 1 mixtures of 1,2- and 1,4-dihydro-3,5-dicyanopyridines(42 and 17) are isolated. When sodium bis-( I ,4-dioxapentyl)aluminum hydride [ NaAIH2(OCH2CH20CH3),]was used, only the 1,4-dihydro compound 17 was isolated in low yield.28This can be explained by the formation of an initial coordination complex between the hydride reagent and the pyridine 43. Attack at the 2 position is favored for X = H, but when X = OCH2CH20CH3,steric effects make this more difficult, and reduction occurs at the 4 position. N
C
~
C
M'AIH~X, N
*N lC l U
h
N
NCy-JCN H
(2)
14)
(1 7)
NCnC
M = Na,Li
N'
X = H, OEt ,OCH,CH,OMe
X'
H'
f
Al
x,
H '
(43)
The preference for a attack occurs due to the N- A1 interaction, aided by the metal dorbitals from which hydride transfer can be considered as occurring favorably to these positions.28 Pentachloropyridine (44) gives mainly 2,3,6-trichloropyridine (45) on ~ ~products ,~~ of ring reduction treatment with LAH at room t e r n p e r a t ~ r e .No are observed, and the reactions are believed to proceed via an additionelimination mechanism. The chlorine atom prevents additions at the 1,2
cl&lN' CI
LiAIH,-
Et,O
*
fJC'
clrJ;
I cyJcl &; CI
16h, 2 5 'C
CI
(44)
(45)
LiAlH,-
(46)
2 5 OIo
Et,O
3h. 0 OC
CI
CI
(47)
29
CI 7 5 yo
8O0li
+(45)
CI N '
(!q
12 96
8 yo
F. Binns, S. M. Roberts, and H. Suschitzky, J. C. S. Chem. Commun., 121 1 (1969). F. Binns, S. M. Roberts, and H. Suschitzky, J. Chem. SOC.C, 1375 (1970).
12
JAMES G. KEAY
ISec. 1II.B
and 1,4 positions. 4-Substituted tetrachloropyridines (49) give different products (50, 51, 52) at different temperature^.^^ LiAIH,
- 20-0 Qc
CI
+
25-35 ‘C
D,O
35-55
Qc
CI
(50) R=OMe, NHEt, C5H,,N
3 . Other Hydrides Magnesium3’and zinc hydridesg2have both been reported to form bis(dihydropyridinyl) complexeswhen dissolved in pyridine. Both have been used as reducing agents for ketones, nitnles, and heterocyclic systems.” Nuclear magnetic resonance studies on these complexes have shown only signalsdue to 1,4-dihydropyridine~.~~ The formation of 1,2-dihydropyridines,obtained on dissolvingMgHzin ~yridine,’~ was attributed to contamination by aluminum h~dride.’~ Cyclic trimeric structures for these magnesium and zinc hydride complexes have been proposed in agreement with spectral data.32
B. PYRIDONES 1. With Aluminum Hydrides
Most of the work concerning the reduction of pyridones has been carried out by Ferles and Holik, using 1,X-dimethyl-2-pyridones. Reaction of 1A. J. de Koning, P. H. M. Budzelaar, B. G .K. van Aarssen, J. Boersma, and G. J. M. van der Kerk, J. Organomet.Chem. 217, CI (1981). 32 A. J. de Koning, J. Boersma, and G . J. M. van der Kerk, Tetrahedron Lett., 2547 (1977). 33 E. C. Ashby and A. B. Goel, J. Organomet.Chem. 204, 139 (1981). 34 G . D. Barbaras, C. Dillard, A. E. Finholt, T. Wartik, K. E. Wilzbach, and H. I. Schlesinger,J. Am. Chem. Soc. 73,4585 (195 1). ’I
Sec. III.C]
13
REDUCTION OF NITROGEN HETEROCYCLES
methyl-2-pyridones (53) with LAH/aluminum chloride mixtures gives isomeric piperidienes (54) in admixture with the fully saturated piperidines (55).35 - 37 LiAIH4 Me0
0
I
AICI,
Me
(53
1
D
Me
I Me
(54
I Me
90%
1
(55
10%
1
C. PYRIDINIUM SALTS 1. With Borohydrides The reduction of pyridinium salts to dihydro- and tetrahydropyridines continues to attract much attention. Readers with a particular interest in dihydropyridines are directed to the excellent reviews by Eisner and K ~ t h a nKuthan , ~ ~ and K u r f u r ~ tand , ~ ~Stout and Meyema The ability of coenzyme NAD(P)+ (57, R = sugar) and its mimics to accept and deliver hydride ion stereoselectively via 1,Cdihydropyridine intermediates has spurred much intere~t.~' Much work involving NAD( P)+ and its simpler derivatives (56; R = PhCH,, BNAH; R = C12H25, DNAH) as chiral reducing agents has been r e p ~ r t e d . ~ '
R (57)
Pyridinium salts may also be reduced to dihydropyridines with sodium dithionite; although not clearly understood, the 1,4 isomer is very often the sole product obtained when electron-withdrawing groups in the 3 position are present.41Reductions with NAD(P)+ models have indicated that these M. Ferles and M. Holik, Collect. Czech. Chem. Commun. 31,2416 (1966). M. Holik, A. Tesarova, and M. Ferles, Collect. Czech. Chem. Commun. 32, 1730 (1967). 37 M. Holik and M. Ferles, Collect. Czech. Chem. Commun. 32, 2288 (1967). 38 U. Eisner and J. Kuthan, Chem. Rev. 72, 1 (1972). 39 J. Kuthan and A. Kurfurst, Ind. Eng. Chem. Prod. Rex Dev. 21, 191 (1982). 40 D. M. Stout and A. 1. Meyers, Chem. Rev. 82,223 (1982). B. J . van Keulen and R. M. Kellog, J. Am. Chem. Soc. 106,6029 ( 1 984). 35
36
14
JAMES G. KEAY
[Sec. II1.C
reactions occur initially by single-electron transfer followed by proton tran~fer.~~.~~ Pyridinium salts can initially give three different products on borohydride attack, the 1,2-, 1,4-, and 1,6-dihydropyridines. Invariably, mixtures are obtained, and it should be noted that in some of the early literature incorrect assignments have been made. The use of IR, UV, and high-power NMR spectroscopyhas simplified the task of identification, but care should still be exercised. Initially formed adducts may also rearrange in the presence of pyridinium salts; an internal oxidation - reduction may occur affording the thermodynamically stable 1,4 i s ~ m e rFowler . ~ ~ ~showed ~ ~ in a quantitative study that 1,4-dihydropyridines are generally some 2 kcal/mol more stable than their 1,2-dihydro c o ~ n t e r p a r t s .The ~ ~ ~dihydropyridines ~.~~ formed by hydride reduction possess either an enamine or a dienamine structure. Such systems are well known to undergo attack by electrophilic reagents.48 For 1,2(6)-dihydropyridines this can occur at two positions. Lyle has shown that protonation of the dienamine system occurs at the central atom, giving the kinetically controlled product 59.49This has been described as following Ingold’s rule50951in that the solvents employed, water or alcohols,
0 I
R
(5
*I
D+
QD
Thermodynamic
I R (60)
F. M. Martens and J. W. Verhoeven, Red. Truv. Chim. Pays-Bus 100,228 (181). S. Yasui, K. Nakamura, and A. Ohno, J. Org. Chem. 49, 878 (1984). 44 U. Eisner and M. M. Sadeghi, Tetrahedron Lett., 299 (1978). 45 R. E. Lyle and S. E. Mallet, Ann. N. Y.Acad. Sci. 145, 83 (1967). 46 F. W. Fowler, J. Am. Chem. SOC. 94, 5926 (1 972). 47 N. C. Cook and J. E. Lyons, J. Am. Chem. SOC. 87,3283 (1965). ‘* A. G . Cook, “Enamines: Synthesis, Structure and Reactions.” Dekker, New York, 1969. 49 P. S. Anderson and R. E. Lyle, Tetrahedron Lett., 153 (1964). N. Bodor, E. Shek, and T. Higuchi, J. Med. Chem. 19, 102 (1976). 5I C. K. Ingold, “Structure and Mechanism in Organic Chemistry,” p. 565. Cornell Univ. Press, Ithaca, New York, 1953. 42
43
Sec. III.C]
REDUCTION OF NITROGEN HETEROCYCLES
15
are weak acids. Strong acids allow formation of the thermodynamic product 60, i.e., protonation at the terminal carbon. Invariably the iminium salt is reduced to the tetrahydropyridine. Isomeric mixtures can result, and considerable effort has gone into the analysis and predication of the particular tetrahydropyridine f ~ r m e d . ~ ~ . ~ ~ Dihydropyridines can be isolated under appropriate sets of conditions. Use of aprotic solvents, or aqueous systems at high pH when protonation of the enamine system is less likely, favors dihydropyridine isolation. Precipitation of the dihydropyridine, or its removal from the reaction medium using two-phase systems, have been employed as techniques for their isolation. Reductions carried out with NBH in the presence of a large excess of cyanide ion result in the formation of the 2-cyano- 1,2,3,6-tetrahydropyridine 64.54The 1,2-dihydropyridine 62 is regenerated on treatment with ethoxide ion. This solution to the problem of overreduction has been employed in improved syntheses of some strychnos-group alkaloid^.^' NaBH,
'
C
Me
(61
1-
1
Me
"P
/// KCN
O
I
C
N
Me
(64
1
Bulky substituents attached to the ring nitrogen have been found to direct Subsehydride attack to the 4 position, giving the 1,4-dihydr0pyridine.~~ quent attack would lead to the piperidine, but often p - R interactions between the pyridine nitrogen atom and the substituent deactivate the J. Bosch, J. Canals, E. Giralt, and R. Granados, J. Heterocycl. Chem. 13, 305 (1976). J. Bosch, R. Granados, R. Llobera, D. Mauleon, and J. Tur, An. Quim. 77C, 166 (1981). 54 E. M.Fry, J. Org. Chem. 29, 1647 (1964). 55 J. P. Kutney, Hererocycles 7, 593 ( I 977), and see Ref 78. 56 R. E. Lyle and C. B. Boyce, J. Org. Chem. 39, 3708 (1974). 52
53
16
JAMES G. KEAY
(Sec. 1II.C
enamine system, and dihydropyridines are i ~ o l a t e d . ~N-Triphenylmeth~*~' ylpyridinium salts (65) give rise to this type of behavior.
0
4)
NaBH,
CPh,
(65
+
I
I
BF,-
CPh,
1
(66
77'23
1
Q I
CPh,
(67
1
Dihydropyridines generated from pyridinium salts carrying electronwithdrawing substituents at the 3 position by borohydride reduction are generally resistant to further reduction.' The dihydro derivatives of 1methyl-3-cyanopyridine, 68,69, and 70, were recovered unchanged when treated with borohydride in water.s8 Only 1,2-dihydro-I-methyl-3-cyanopyridine (68) was converted to the tetrahydropyridine 71 when trimethyl borate was added to the reaction medium. Diboranelwater achieved the same conversion, while added boric acid returned the starting rnaterial~.~~ QCN
H 4;;
I Me
B(OMe),
(
y I
Me
(711
(6*)
N
QCN
QCN
I Me
I Me
(69)
(70)
The reduction of 1-methyl-4-cyanopyridinium iodide (72) in aqueous However, in methanol/ methanol gave solely the tetrahydropyridine 73.59.60 sodium hydroxide two different temperature-dependent products could be isolated. The [4 21 product 74 predominated above -2O"C, whereas the [2 21 adduct 75 was the sole product at or below -45 "C. Similar behavior is observed with the 2-cyano derivative 76 (R = H); again, the initially formed [2 21 adduct 79 (R = H) thermally rearranges to the [4 21 product 80 (R = H). In this case pH and temperature control are not as important because enamine reactivity is diminished by the presence of the cyano group. Other pyridinium salts behave similarly in strong base.61.62 Reduction
+
+
+
57
+
A. R. Katritzky, M. H. Ibrahim, J.-Y. Valnot, and M. P. Sammes, J. Chem. Res., Synop.. 70 (1981).
Liberatore, V. Carelli, and M. Cardellini, Tetrahedron Lett., 4735 (1968). F. Liberatre, A. Casini, V. Carelli, A. Amone, and R. Mondelli, Tetrahedron Lett., 238 1
93 F. 59
(197 1).
60 F. Liberatore, A.
(1971). 61 62
Casini, V. Carelli, A. Amone, and R. Mondelli, Tetrahedron Lett., 3829
P. P. Zarin, E. S. Lavrinovich, and A. K. Aren, Khim. Geterotsikl. Soedin.. 104 (1974). P. P. Zann, E. E. Liepin, E. S. Lavrinovich,and A. K. Aren, Khim. Geterotsikl.Soedin., 115 (1974).
Sec. 1II.C]
/;- \\\-\\6
17
REDUCTION OF NITROGEN HETEROCYCLES
'
NaBH4 H,O- MeOH *
NaBH,
-20 OC
I
I-
H,O-
- NaOH MeOH
- 45 OC
Me' CN (74
R = Ph MeOH
Me
(75
1
\Me
18
JAMES G . KEAY
[Sec. 1II.C
of 1-benzyl-2-cyano pyridinium salts (76, R = Ph) with 1-benzyl-1,2-dihydroisonicotinamide (81) in methanol affords the similar dimeric dihydropyridine 80, (R = Ph).63 The propensity of 1,2-dihydropyridinesto undergo the Diels- Alder reaction has been used to separate mixtures of 1,2 and 1,4 isomer^.^^^^^ Fowler separated out 1,Cdihydropyridines by reaction of the 1,2 isomer 82 with maleic anhydride (85).66Other workers have utilized the Diels- Alder adducts 84 in the synthesis of isoquin~clidines.~~
(84)
The reduction of pyridinium salts 86 with borohydride in methanolic sodium hydroxide gives mixtures of di- and tetrahydropyridines (87- 9 1 y 8 Over time, the dimeric species 91 increased, while 87 decreased.
''A. Nuvole, G. Paglietti, P. Sanna, and R. M. Acheson, J. Chem. Rex, Synop., 356 ( I 984). 64
E. E. Knaus, F. M. Pasutto, and C. S. Giam, J. Heterocyl. Chem. 11,843 (1974).
'' E. E. Knaus, F. M. Pasutto, C. S. Giam, and E. A. Swinyard,J. Heterocycl. Chem. 13,48 I 66
''
(1976). F. W. Fowler, J. Org. Chem. 37, 1321 (1972). G. R. Krow, J. T. Carey, D. E. Zacharias,and E. E. Knaus, J. Org. Chem. 47,1989 (1982). A. Casini, B. Di Rienzo, F. M. Moracci, S. Tortorella, F. Liberatore, and A. Arnone, Tetrahedron Lett., 2 I39 ( 1 978).
19
REDUCTION OF NITROGEN HETEROCYCLES
Sec. IKC]
X = H,D
X Me
I
(90)
(91) Me
The reduction of 1-methyl-3-ethylpyridinium iodide (92) in the presence of a large excess (10 equiv) of benzyl bromide led to a moderate yield of 1-methyl-3-ethyl-5-benzyl-1,2,5,6-tetrahydropyriidine(94),69,70 presumably via the 1,2-dihydropyridine. 1,6-Dimethy1-3-hydroxypyridinium iodide (95) undergoes reduction with NBH and sodium hydroxide to the 3-piperidinol 96.71
flEt .N
I
Me
l.NaBH, 2. PhCH2Br
( 10 eqs)
(92)
PhCH(
M ‘,
I
1.PrSH 2. LiH-HMPA
Me
( 93)
(94
40 %
1
NaBH,
1
NaOH
I
Me
Me
(95)
(96)
R - H , R’zMe R z Me, R’:H
Comins reported the regiospecific addition ofhydride ion to the 4 position of 1-acylpyridinium salts in moderate yields, but with high selectivity (>90%).72The copper hydride reagent used was prepared in situ from lithium tri-tert-butoxyaluminum hydride and cuprous bromide. 1-( Phenoxycarbony1)pyridinium chloride (97) gave the 1,Cdihydropyridine 98 exclu69
J . P. Kutney, M. Noda, and B. R. Worth, Heterocycles 12, 1269 (1979). P. Kutney, R. Greenhouse, and V. E. Ridaura, J. Am. Chem. SOC.96, 7364 (1974).
70 J. 71
’2
M. A. Iorio, F. Gatto, and H. Michalek, Eur. J. Med. Chem. 15, 165 (1980). D. L. Cornins and A. H. Abdullah, J. Org. Chem. 49, 3392 (1984).
20
[Sec. 1II.C
JAMES G. KEAY
aR
sively. Previous work had shown that reduction with NBH and sodium and lithium copper hydndes yields mixtures of 1,2- and 1,4-dihydropyridine~.~~ Li(t-BuO),AIH
-OR
- CuBr
a COOPh
I
I
COO Ph
(97)
(94
Selectivity = 90- 100 OIo Yield 5 40-65 YO
R = H , Me, E t ,Cl, C0,Me
The acid-induced cyclization of 2-(arylmethyl)tetrahydropyridines (100) has been used as a general method for the preparation of b e n z ~ m o r p h a n s ~ ~ (101) and their heterocyclic counterparts. Similar behavior is used in the
-
NaBH,
I Me (99
i
Rb C H 2 P h
I
Me
1
Me ('01)
formation of the indole alkaloid (+)-dasycarpidone (103).75-77 Preparation of these tetracyclic substrates can be achieved more conveniently via 2cyano-l,2,3,6-tetrahydropyridines (105 4107), which are masked 2,5-dihydropyridinium salts as discovered by Fry.54,78 R. J. Sundberg and J. D. Bloom, J. Org. Chem. 46,4836 (198 1). J. Bosch, D. Mauleon, F. Boncompte, and R. Granados, J. Heterocycl. Chem. 18, 263 (1981). 7J A. Jackson, A. J. Gaskell, N. D. V. Wilson, and J. A. Joule, J. C. S.Chem. Commun.. 364 (1968). 76 M. S . Allen, A. J. Gaskell, and J. A. Joule, J. Chem. SOC. C, 736 (1971). 77 A. Jackson, N. D. V. Wilson, A. J. Gaskell, and J. A. Joule, J. Chem. SOC.C, 2738 (1969). 78 M. Feliz, J. Bosch, D. Mauleon, M. Amat, and A. DomingoJ. Org. Chem. 47,2435 (1982). 73 74
Sec. 111.C]
REDUCTION OF NITROGEN HETEROCYCLES
7 C
O
e - +N
-Me H
I
Q
CH(OEt),
I
Me
* b CH(OEt),
NaBH.,
i
21
NaCN
NC
I
Me
(105)
(104
OEt
0
CH(OEt),
3- indolylMgBr
1
Often indol0[2,3-~]quinolizines(e.g., 109)form the skeletal basis for work in the indole and oxindole alkaloid field.79These are most often prepared from pyridinyl- (108) or quinolinylindolethanes via reduction with metal h y d r i d e ~The . ~ ~tetrahydropyridines ~~~ then undergo acid-catalyzed ring closure, often giving mixtures of several compounds (109, 110, 111). The reduction of N-iminopyridinium salts and their ylides (112) has been studied and found to parallel the behavior of N-alkylpyridinium Salks1In protic solvents reduction leads to the formation of 1,2,3,6-tetrahydroderiva79
M. Lounasmaa and M. Puhakka, Acfa Chem. Scand., Ser. B B32,216 (1978). W. R. Ashcroft and J. A. Joule, Tetrahedron Left.,2341 (1980). E. E. Knaus and K. Redda, J. Heleroc.vc1. Chem. 13, 1237 (1976).
22
JAMES G . KEAY
(Sec. 1II.C
- MeOH NaBH4 - H' NaOH
H
H
30 %
tives (113).A probable intermediate is the 1,2-dihydrospecies, which, when it bears suitable substituents, may be isolated.82Products of this type have shown analgesic and antiinflammatory activity.
0 I
-N
'R
NaBH, EtOH
* I
HN\R
('12)
The in situ preparation of N-sulfonylpyridinium salts and their concomitant reduction in the presence ofNBH has been studied. Using both sulfonyl chlorides and sulfonic acid anhydrides, Knaus and Redda obtained mixtures of both the 1,2- (114) and 1,4-dihydropyridines(115). The 1,Cdihydropyridine was favored (15 :8 by NMR) at 25°C in pyridine; the 1,Zdihydro product was the major isomer (29 :4 by NMR) at - 65 "C in methanol.83
a2 83
Y. Tamura and M. Ikeda, Adv. Heterocycl. Chem. 29,71 (1981). E. E. Knaus and K. Redda, Can. J. Chem. 55, 1788 (1977).
Sec. III.C]
REDUCTION O F NITROGEN HETEROCYCLES
23
Sodium cyanoborohydride is a more selective reducing agent than boroh ~ d r i d eAn . ~ investigation ~ into the reduction of 4-substituted pyridinium salts (1 16) would seem to bear this out. With these the 4 substituent directs hydride attack to the a positions, and in protic solvents the tetrahydropyridines 117 are isolated. Thus a variety of sensitive substituents can be carried through a synthetic sequence without redu~tion.~’ However, raising the temperature is known in one instance (4-carboxamido) to cause concomitant reduction of the ketone carbonyl group.
&
NaBH3CN
b&
+LaBr NflB 250c
0
0
(117)
(116)
2 . With Aluminum Hydrides Pyridinium salts react more readily with LAH than do pyridines, affording mixtures of di- and tetrahydropyridines. However, prolonged heating of alkylpyridinium salts with excess sodium aluminum hydride in tetrahydrofuran generates 3-piperidienes (120) with 5-alkylamino-1,3-pentadiene (121) as the major products. Small amounts of the piperidines (119) were also obtained. Similar behavior has been noticed with other alkylpyridinium saltsE6 Attempts to add one equivalent of hydrogen to the 3-oxidopyridinium salts 122 led to a mixture of products, the main component being the tetrahydro derivative 123 (R = Ph, indolyl-3-ethyl) or the dimer 124 (R = Me).*’
THF-POh
R
1
Et,Pr,Bu, Am.
C. F. Lane, Synthesis, 135 (1975). R. 0. Hutchins and N. R. Natale, Synthesis, 281 (1979). 86 M. Ferles, 0.Kocian, and A. Silhankova, Collect. Czech. Chem. Commun. 39,3532 (1974). 87 W. R. Ashcroft and J. A. Joule, Heterocycles 16, 1883 (1981). 84
24
[Sec. 1II.D
JAMES G. KEAY
Ph
""?yJ
N
Me
I
R
I
Me
(123) (124)
D. 1 -ALKOXYPYRIDINIUM SALTSAND PYRIDINE O OXIDES The reduction of pyridine N-oxide (1 25) and 1 -alkoxypyridinium salts (126) with a variety of reducing agents, including NBH, LAH, and sodium bis(2-methoxyethyl)aluminum hydride, gives a mixture of products. The mixtures contained pyridines (1 29), 3-piperidiene (1 28), and piperidines (127). The major product was dependent on the nature of the substituents
Sec. III.F]
REDUCTION OF NITROGEN HETEROCYCLES
25
present and the reducing agent employed.88Titanium tetrachloride and NBH mixtures have been employed for the deoxygenation of heteroaromatic amine oxides.89
E. CYCLIC IMINES Cyclic imines will not be dealt with in this review as the conversion is often simply achieved.' Mention will be made to the stereoselective reduction involved in the preparation of Solenopsin A and B (131), two naturally occurring piperidine alkaloids isolated from the venom of the fire ant. The desired trans isomer 131 was obtained with >%yo selectivity,using LAH (7 equiv) and trimethylaluminum (7 equiv) in THF. This selectivity could be reversed by using LAH (7 equiv) and NaOMe (14 equi~).~O LiAlHd Me(CHJnC G
M
*
e
Solenopsin A , n z 10 Solenopsin B , nz 12
F. QUINOLINES 1. With Borohydrides
Quinolines are expected to be reduced much more readily than pyridines. This is borne out when quinoline (133) is heated in ethanol with excess NBH to give mixtures of the 1,2-di- 134 and 1,2,3,4-tetrahydroquinolines135.'O Treatment of the 1,2-dihydroquinoline 134 with NBH in diglyme or diglyme/ethanol mixtures gave conversion to the tetrahydroquinoline 135. Migration of the 3,4 double bond to the enamine has been proposed to account for this reduction.l' With electron-withdrawing groups in the 3 position, 1,4-dihydroquinolines 137 were obtained in high yields. 3-Haloquinolines, on the other hand, gave low yields of the 1,2-dihydro adducts 89
M. Jankovsky and M. Ferles, Collect. Czech. Chem. Commun. 35, 2802 (1970). S. Kano, Y. Tanaka, and S. Hibino, Heterocycles 14, 39 (1980). Y. Matsumura, K. Maruoka, and H. Yamamoto, Tetrahedron Lett., 1929 (1982).
26
JAMES G.W A Y
[Sec. 1II.F
138.'Os1 3-Dimethylaminoquinolinewas recovered unchanged under these conditions. NaBH,
I
EtOHNaBH, 5h
diglyme
*a+ a /
('33)
(13 t
NaBH,
ax
(y-J
H
H
%Yield
1
X = 86
86
95
I Br
%Yield I40
(134 F 40
NMe, 0
2-Cyanoquinoline and the + isomer afforded different products when reduced in ethanol or pyridine. In hot ethanol the amidine 141 was the major product, whereas in pyridine the tetrahydroquinoline 142 was favored. The latter compound occurred with an increase in tar formation. 4-Cyanoquinoline (140) was reduced to give the tetrahydro derivative 143 and the product of reductive decyanation 144.10J1 Reduction of 5-, 6-, 7-, and 8-nitroquinolines (145) with NRH in acetic acid proceeds smoothly to the 1,2-dihydro derivatives 146.91Gribble and 91
K. V. Rao and D. Jackman, J. Heterocycl. Chem. 10,213 (1973).
Sec. III.F]
27
REDUCTION OF NITROGEN HETEROCYCLES
CN b39)
NaBH, EtOH or
1
Pyr
(141)
(144
FN
H (143)
Heald repeated the same reduction of 6-nitroquinoline (147) at a higher temperature and isolated 1-ethyl- 1,2-dihydro-6-nitroquinoline(148), the . ~ ~ quinoline and NBH in carboxylic product of reductive a l k y l a t i ~ nWith acids the N-alkyl- 1,2,3,4-tetrahydroquinoline149 is obtained. Use of sodium cyanoborohydride gives reduction but no alkylation (150). In the presence of acetone, 1-isopropyl-1,2,3,4-tetrahydroquinoline(151) is the predominant compound.92 Quinoline N-oxides undergo deoxygenation, and some ring reduction with NBH.93 92
G . W. Gribble and P. W. Heald, Synthesis, 650 (1975). Kawazoe and M. Tachibana, Chem. Pharm. Bull. 13, 1103 (1965).
93 Y.
28
JAMES G.KEAY
[Sec. II1.F
NaBH, AcOH 0 %
O2N
(146r71-90%
(145)
NaBH, AcOH 50%
P9 NaBH, RCOOH
03 I
CH,R (149 52-60%
NaBH,, Me,CO RCOOH
I
H
(13
71 %
6.Pr (151) 59%
2. With Aluminum Hydrides The 2-, 3-, 4-, and 6-trifluoromethyl derivatives ofquinoline on treatment with LAH give a variety of products that depend on the position of the substituent. Only the 3 isomer 152 leads to anything other than dehalogenation, giving 3-(difluoromethy1)-1,2-dihydroquinoline (153).94On the other hand, with sodium borohydride, only 152 undergoes complete dehalogenation (154). This is believed to proceed via ring attack and the involvement of a 1,4-dihydroquinoline (155). 94
Y. Kobayashi, 1. Kumadaki, and S. Taguchi, Chem. Pharm. Bull. 20,823 (1972).
Sec. III.F]
29
REDUCTION OF NITROGEN HETEROCYCLES
t
H (154)
(155)
t
f
WCF2 \
N+ H F
Generally, quinolines are reduced to their 1,2-dihydro derivatives with LAH. Use of diisobutylaluminum hydride and sodium bis(2-methoxyethoxy)aluminum hydride with quinoline (133) has shown that 1,2-dihydroquinolines (160) can be conveniently and cleanly generated at low temperaDibal
* I
-
(~.BU),AIH
(14 I
30
JAMES G . KEAY
[Sec. 1II.G
tures in high ~ i e l d .Tetrahydroquinolines ~~.~~ via 1,4-dihydro intermediates (thermodynamic control) are formed at higher temperatures, when prolonged reaction times are employed or when a 2 substituent is present.96
G. QUINOLINIUM SALTS 1. With Borohydride Like pyridinium salts, initial hydride attack can occur at either the 2 or 4 position. That the 2 position is generally favored is borne out by the isolation of 1 ,Zdihydroquinolines (162) as the usual products of these reductions. 1,CDihydro- (163) and 1,2,3,4-tetrahydroquinolines (164) formed by 4 attack are isolated as minor products.
a
NaBH,
I
*a' I
R
R
(164
(161)
NaBH,
I
Me
R=
IH
i
Me I
CN
C02Et
I
9J 96
%Yield(164
87
87
23
%Yield(167)
-
-
72
I
Me (163
D. E. Minter and P. L. Stotter, J. Org. Chem. 46, 3965 (1981). B. K. Blackburn, J. F. Frysinger, and D. E. Minter, Tetrahedron Lett., 4913 (1984).
Sec. III.G]
31
REDUCTION OF NITROGEN HETEROCYCLES
Similar to the pyridinium salt series, the position and nature of substituents attached to the heteroaromatic ring can affect the position of initial attack. 1-Methylquinolinium iodide (165, R = H) gives the 1,2-dihydro adduct 166 after 10 min at O'C, as does the 3-cyano derivative 165, (R = CN). I I However, under similar conditions the ethoxycarbonyl derivative 165 (R = C0,Et) affords mixtures of both 1,2- (166) and 1,Cdihydroquinolines (167)." However, 1-benzyl-3-cyanoquinoliniumbromide (168) gives a 759/0yield of the 1,4-dihydro adduct 169 when reduced with NBH and allowed to equilibrate in the presence of the parent quinolinium salt.971,4-Dimethyl-2methylaminoquinolinium iodide (170) undergoes hydride attack at the 2 position with borohydride to give the product 171as an unstable yellow Alstonilin or benz[g]indolo[2,3-a]chinolizidine-typealkaloids (173) have been successfully prepared in high yields from the isoquinolinium salt 172 via hydride reduction.99
J Q . 4
NaBH4
I
B;
D
WCN
+ (168)
1
CH,Ph
CH,Ph
(168)
(169)
NaBH,
Me
1
NHMe
he
I
(170)
(171)
NaBH,-HCl
Me0
Me0
(174
(173)
66%
M. M. Kreevoy, R. M. G . Roberts, D. Ostovic, and A. D. Binder, Ventron Alembic 28,2 (1982) [CA 98, 125838j (1983)l. 98 N. D. Sharma, V. K. Goyal, and B. C. Joshi, Croat. Chem. Acfa 48,3 17 (1976). 99 J. A. Beisler, Chem. Eer. 103, 3360 (1970).
97
32
JAMES G.KEAY
[Sec. 1II.H
2. With Aluminum Hydrides 1,2-Dihydroquinolines predominate as the major reduction product of quinolinium salts with LAH. As in the pyridine series, preferred attack occurs at the 2 position.
H. ISOQUINOLINES 1. With Borohydrides Isoquinolines usually do not undergo reduction with NBH in ethanol or pyridine unless they bear an electron-withdrawing 4 substituent.'l In this case 1,2-dihydroisoquinolines175 are formed. In water or aqueous solvent mixtures isoquinoline (176) is converted to the tetrahydroisoquinoline 177.Il In the case of 1-cyanoisoquinoline (178), both ring and substituent were reduced by borohydride in pyridine or diglyme.I0 With 3-cyanoisoquinoline (180) the major products are derived from substituent reaction to form amides (181) and amidines (182). Some 1,2,3,4-tetrahydroisoquinoline(1 77) is also isolated.10Mixtures of alcohols are obtained upon reduction of ethyl isoquinoline-2- and 3-carboxylate.l o
d
dNH
NaBH, EtOH
(14
(174
X
37-86%
= CN, CONH ,,CO,Et
NaBH, D
Pyr or Diglyrne
CN (178)
CONH, 674
Sec. 111.11
REDUCTION OF NITROGEN HETEROCYCLES
33
Isoquinoline (176), as in the case of quinoline, undergoes reductive alkylation with NBH in the presence of carboxylic acids, affording the amine 184.92Sodium cyanoborohydride under these conditions gave the unalkylated product 177. Under similar conditions, but at lower temperature, h i troisoquinoline affords the tetrahydrois~quinoline.~~ NaBH,
(176)
2. With Aluminum Hydrides As with the milder borohydride, isoquinolines are reduced to 1,2-dihydro derivatives 185 with LAH and subsequently to the tetrahydroisoquinoline 177.
I. ISOQUINOLINIUM SALTS 1. With Borohydride
Isoquinolinium salts (186) are readily reduced with NBH to the 1,2-dihydro- (187) or I ,2,3,4-tetrahydroisoquinolines(188). Initial attack occurs at
34
JAMES G.KEAY
[Sec. 111.1
the 1 position and subsequent reduction of the enamine system is determined by the nature and position of ring substituents. Generally, tetrahydro adducts are formed.
Certain 1-benzylisoquinolinium salts (189) undergo C-C bond cleavage on reduction with borohydride.'''Jol The benzyl group must contain a nitro group in order to weaken the ring-substituent D bond. M Me
e
m
'
M
e
NaBH4
M Me
e
3
+'
M Me e S N 0 2
Me Me
Reaction of the isoquinolinium salt 191 with NBH gave the 1,2-dihydroisoquinoline 192 in high yield. Subsequent treatment of 192 with bromine and heating gave 4-bromoisoquinoline (193)?' J. L. Neumeyer, M. McCarthy, K. K. Winhardt, and P. L. Levins, J. Org. Chem. 33,2890 (1968). J. L. Neumeyer, M. McCarthy, and K. K. Weinhardt, Tetrahedron Leff.,1095 (1967).
lM
lo'
Sec. III.J]
REDUCTION OF NITROGEN HETEROCYCLES
Br,
Br
35
I.
AcOH
2. With Aluminum Hydrides The reduction of isoquinolinium salts in aprotic solvents with LAH leads to the formation of I ,2-dihydroisoquinolines (195), in which the enamine system can undergo subsequent reaction with electrophiles. This type of reactivity has been exploited in the synthesis of alkaloids.55 Intermediates of the types 196 and 197 have been used in synthetic approaches to the pavinane and isopavinane alkaloids.lo2
LiAIH,
'R
LiAIH,
Ph
'Me Ph
J. INDOLES Although indoles are not normally reduced under neutral conditions with LAH or NBH, tetra-n-butylammonium borohydnde has recently been apIo2S.
F. Dyke, R. G. Kinsman, P. Warren, and A. W. C. White, Tetrahedron34,241 (1978).
36
JAMES G. W A Y
[Sec. 1II.J
plied successfully in the reduction of the indoles 198 - 200 to indolines 201 203.Io33-Methylindole was reduced to the indoline in only 6% yield.Io3 The observation that enamines may be reduced by NBH in acetic acid/ THFIM and sodium cyanoborohydridelos coupled with the tendency for indoles to protonate at the 3-position enabled Gribble and co-workers to reduce indoles to indolines (201,205)in high yield.lMN-Alkyl indoles (204) were also reduced, as was 3-methylindole. The use of formic acid favored the formation of 1-methyl-3-[2-(2-dimethylaminophenyl)ethyl]indoline(207) via an intermeuiate 3,2 dimer (206).lo7 Borohydride reduction of indole (198) in the presence of trifluoroacetic acid (TFA) gave the indoline 201 without alkylation but in low yield. The yield of 201 can be increased when carried out with sodium cyanoborohydride in acetic acid at 15°C. This eliminates the isolation of any N-alkyl indolines.lo* The reaction clearly proceeds via reduction of the iminium salt 208 produced on protonation, and as such the method is limited to indoles suffil1 ciently basic to be protonated by acetic or trifluroacetic The reduction of indole (198) has also been achieved with sodium borohydride-aluminum chloride mixtures ( 5 :3) in pyridine at room temperature.l12The pyridine serves to moderate the reducing agent and a 68Yo yield of indoline (201)was obtained along with unchanged starting material. When 2-methylpyridine replaced pyridine, no reduction was observed. W
R H
m.-Bu,N*BH,
CH,CI, 36'C 1Oh
(198-204
R=
'ol
Io5 Io6 'ol Io8
Io9 'lo
WR H
(201 - 203)
H , 2-Me, 2,3-(CHZ),-
T. Wakamatsu, H. Inaki, A. Ogawa, M. Watanabe, and Y. Ban, Heterocycles 14, 1441
(1980). IM
*
J. A. Marshall and W. S. Johnson, J. Org. Chem. 28,421 (1963). R. F. Borch, M. D. Bernstein, and H. D. Durst, J. Am. Chem. Soc. 93,2897 (1971). G. W. Gribble, P. D. Lord, J. Skotnicki, S. E. Dietz, J. T. Eaton, and J. L. Johnson, J. Am. Chem. Soc. 96,78 12 (1974). G. W. Gribble and S. W. Wright, Heterocycles 19,229 (1982). G. W. Gribble and J. H. Hoffman, Synthesis, 859 (1977). J. G. Berger, F. Davidson, and G. E. Langford, J. Med. Chem. 20,600 ( 1 977). N. Umino, T. Iwakuma, and N. Itoh, Tetrahedron Lett., 763 (1976). G. W. Gribble, C. F. Nutaitis, and R. M. Leese, Heterocycles 22, 379 (1984). Y. Kikugawa, Chem. Pharm. Bull. 26, 108 (1978).
Sec. III.J]
37
REDUCTION OF NITROGEN HETEROCYCLES NaBH,CN AcOH
94%
H
NaBH,
NaBH,
AcOH 86%
88 %
t
NaBH, AcOH
AcOH
86%
I
Et
--
NaBH,
HCOOH
H
Me
NaBH,
H' H
H
(208)
(13
AICI,- Pyr
H (201)
The reduction of the indolinones 209 with NBH in methanol leads readily to the indoles 210 in 56-96% yield. Intermediacy of the corresponding alcohols has been propo~ed."~ The reduction of indoles and related compounds has been the subject of a previous review.'I4 Oxindoles (211) are reduced with LAH to indoles (212)but in low yields.Il4Small amounts ofthe indolines 213 are also obtained. Dimerization on hydride reduction has also been recorded.II5 M. Hooper and W. M. Pitkethly, J. C. S.Perkin I . 1607 (1972). B. Robinson, Chem. Rev. 69, 785 (1969). H. J. Roth and H. H. Lausen, Arch. Pharm. (Weinheim, Ger.)306,775 (1973).
38
[ Sec. 1II.K
JAMES G. KEAY
R = Aryl R'= H , M e LiAIH,
I
wd+d /
\
I
R
I
R
(211)
R
(212)
(213)
R = Alkyl
K.
1,2-OXAZOLES
3-Aminopropanols (217, 218) can be prepared from alkenes and nitrile oxides via the LAH reduction of the isoxazoline intermediate 216.IL6The stereospecificity of the reaction is surprisingly high. 1,3-Asymmetricinduction leads to ratios of 1 : 19 for 217 and 218, respectively (R = Ph) and
1
LiAIH,
HO
NH,
HO
(217) Il6
V. Jager, V. Buss,and W. Schwab, Liebigs Ann. Chem., 122 (1980).
NH,
39
REDUCTION OF NITROGEN HETEROCYCLES
Sec. III.K]
slightly less (3: 17) when R = Me.117Li-0 complexation during hydride transfer is probably responsible for this selectivity. Acylic products are the normal result of reductions on dihydroisoxazoles with metal hydrides. However, some tetrahydro derivatives (220) have been produced stereoselectivelyupon treatment with NBH. Sodium cyanoborohydride gave cis-and trans-1,2-oxazolidines(222)from 3,5-diphenyl-4,5dihydro-1,2-oxazole (22l).Il7 3,5-Dialkylisoxazoles with electron-withdrawing groups at C-4 can be reduced by LAH/ether and NBH/ethanol to give 4-functionalized 2-isoxazolines in 7 - 70% yield.' 17* Interestingly, alkyl- 1 ,Loxazoles (223) on reduction with LAH give aziridines 224 and 225.lI9Preparative chromatographywas used to separate one major (224,40-5090) and two minor (225, 226) components. Most likely, the reaction proceeds through a hydroxyazirine intermediate (227). Me-'(
Rq NaBH,
t
100% stereosel. 00% yield
NaBH3CN
* P h a P h
P h a p h
LiAIH,
R
MeHRM e + ' ' d , r y M e YaMe
(24
I R = H , Me Il7 II8
119
THF 40 h
';I
7'
(224 OH I
t 'e+CHMe
+
Me'"'
RE^ ..
+
M e A O H
H
NH, h e
(24
(23
I
@4OAiH3
V. Jager and V. Buss, Liebigs Ann. Chem., 101 (1980). A. Alberola, A. M. Gonzalez, M. A. Laguna, and F. J. Pulido, Synthesis, 413 (1983). A. Cem, C. De Micheli, and R. Gandolfi, Synfhesis. 710 (1974). A. L. Khurana and A. M. Unrau, Can. J. Chem. 53,301 1 (1975).
40
[Sec. 1:I.M
JAMES G . KEAY
L.
1,3-OXAZOLES
The reduction of 2-oxazolin-5-ones(228)with excess NBH results in the cleavage of a C-0 bond to afford the amides 229.120By contrast, the oxazoline moiety itself (230)is stable to reduction by LAH and serves as a protecting group for the carboxylic acid function.lZ1 However, 2,2'-bis(oxazolines) (232)have been recorded in the patent literature as precursors to the amino alcohols 233.122
R = Me, R'=Me,CH,Ph
LiAIH,
MeLJGo2Me Me
Me
M. 1 ,%THIAZOLES 3-Benzyl-4-methylthiazolium chloride (234)is reduced in water by excess NBH to the fully saturated 1,3-thiazolidine237 via the thiazoline 235.lz3A diastereoisomeric mixture is obtained in more highly substituted cases.124 121
Iz2
Iz4
P. Truitt and J. Chakravarty, J. Org. Chem. 35, 864 (1970). D. Haidukewych and A. 1. Meyers, Tetrahedron Leff.,3031 (1972). Pliva Tvornica Farmaceut., Fr. Demande 2,187,761 (1974) [CA 81, 13101f(1974)]. G . M. Clarke and P. Sykes, J. C. S.Chem. Commun., 370 (1965). G . M. Clarke and P. Sykes, J. Chem SOC.C. 141 1 (1967).
Sec. III.N]
REDUCTION OF NITROGEN HETEROCYCLES
41
Although, in principle, the 4-alkylidene-l,3-thiazolin-5-ones (238)can undergo initial attack at C=O, C=O or C=N, in practice only the exocyclic double bond is attacked and reduced by NBH.lZ5 1,3-Thiazoles containing 2-amino functionalities (239) are, not surprisingly, resistant to ring reduction with NBH.lZ6Thiamine is reduced to the tetrahydro derivative 240.124
\s’
c,
H*O
S ‘’
RWC 0
$a, b i
N. 1,STHIAZINES Little work has been carried out on the selective reduction of the imine bond present in 1,3-thiazine~.’~’ Concomitant ring opening normally occurs M.D. Bachi, J. C. S. Perkin I , 310 (1972).
126 12’
D. S u c k J. Prakt. Chem. 314,961 (1972). J.-L. Pradere, J.-C. Roze, and G . Duguay, J. Chem. Res., Synop., 72 (1982).
42
JAMES G.KEAY
[Sec. 1V.A
in such systems. However, sodium cyanoborohydride will selectivelyreduce the imine bond in 2-phenyl-6H-l,3-thiazines (241) in acidic media.Iz7This results partially from the bond polarization effects of the phenyl group and partially from protonation. More powerful reducing agents affordring cleavage. 2-Phenyl-4-oxobenzo-1,3-thiazine(243) gives 2-mercaptobenzylamine (244) as the major product when treated with LAH.lZ8The isolation of the benzothiazole 245 as a minor product points to C-2-S rupture prior to reduction of the imine.
DcoR NaBH,CN
Ph
H,O'
*
HDcoR
Ph
(241)
(242)
IV. Reductions of Heterocycles Containing Two Nitrogen Atoms A. PYRAZOLES The LAH reduction of alkyl- and arylpyrazolium salts (246) has been investigated and leads to a mixture of the 3- (247) and 4-pyrazolines (248), along with the fully saturated pyrazolidine 249 in some cases.129,130 The exact nature of the mixture is dependent on the substituents and the amount of reducing agent employed. The 3- and 4-pyrazolinesgenerally predominate. Overreduction with formation of acyclic hydrazines is also observed.129Pyrazolidines(249) may be produced from pyrazolines (247 and 248) by reduction with LAH.I3' Elguero and co-workers also report the NBH and LAH reduction of 128
IM I3l
D. Bourgoin-Lagay and R. Boudet, C.R. Acad. Sci.,Paris, Ser. C 264, 1304 (1967). J. Elguero, R. Jacquier, and D. Tizane, Bull. SOC.Chim.Fr., 1121 (1970). J. Elguero, R. Jacquier, and D. Tizane, Bull. Soc. Chim. Fr., 3866 (1968). J. Elguero, R. Jacquier, and D. Tizane, Bull. SOC.Chim. Fr., 1129 (1970).
Sec. IV.A]
43
REDUCTION OF NITROGEN HETEROCYCLES R\
R ,'
R5 q
R R4
R ;
LiAIH, 3I
R ,'
THF or E t 2 0
R5vR3 R5qR R1
RZ
R'
RZ
+
R4
R4
(24
(24
3-(disubstituted amino)-l,5-dimethyl-2-phenylpyrazoliumsalts (250), affording the hydrazines 251 and 253 as the major products.132
(4
P h A M Me e
2.
H,O
@54
@51)
+ 1
+
R' R ~ N
(24
Reductant
-C H,C H,OC H,C H,Me
Ph
-C H,C H,OC H,CH,Me 132
I
Ph
(=. Product (96)
LiAIH,
251 (SO), 252 (15)
LiAIH,
251 (95)
LiAIH,
251 (95)
NaBH,
53 (60),254(40)
NaBH,
5 3 (go), 254(10)
J. Elguero, R. Jacquier, and S. Mignonac-Mondon, Bull. SOC.Chirn. Fr., 2807 (1972).
44
JAMES G. KEAY
[Sec. 1V.B
Increasing the polarization of the imine double bond by complexation of l-acetyl-3,5,5-trimethylpyrazoline(255) with Lewis acids is an effective method of inducing C-3 nucleophilic attack.133LAH Reduction of 255 in acetic anhydride has the overall effect of a reductive alkylation to give l-acetyl-2-ethyl-3,5,5-trimethylpyrazolidine (256). Similar behavior has been ob,COMe
Et,
Me
Ac 2O
Lewis Acid (255)
served with the hydrochloride salts of 1-phenyl- and 1,5-diphenyl-3-methyl2-pyraz01ines.l~~
B. IMIDAZOLES The reaction of several simple imidazolium salts (257) in 95% ethanol, employing a large excess of NBH, led to reductive ring cleavage to the diamines 258 and 259.135The major product was 258 (77-9390) and the minor product, 259 (3 -22%). Thus the predominant cleavage is between C-2 and N-benzyl. Similar reduction of 1-methyl-3-(2-phenylethyl)imidazolium iodide (260) gave 262 as the major product (9290).'~~
I
CH,Ph (253
I
I
CH,Ph
CH,Ph (254
(259
Me
Me
L. A. Sviridova, G.A. Golubeva, A. V. Dovgilevich, and A. N. Kost, Khim. Geterotsikl. Soedin. 9, 1239 (1980). G. A. Golubeva, L. A. Sviridova, N. Y. Lebedenko, and A. N. Kost, Khim. Geterotsikl. Soedin. 4, 541 (1973). E. F. Godefroi, J. Org. Chem. 33, 860 (1968).
REDUCTION OF NITROGEN HETEROCYCLES
Sec. IV.B]
45
NHMe
I
CH,CH,Ph (24
I
I
C H,C H,P h
I?@
(26’)
,
C H,C H P h
Treatment of the long-chain imidazolium salts 263 with potassium, sodium, and tetra-n-butylammonium borohydrides affords the acyclic diamines 264 and 265. The isomer ratio was not reported.136Sodium cyanoborohydride failed to reduce the same salt under a variety of conditions. The imidazoline 266 reacts with LAH in THF above - 10°Cto give the 1,2-diaminoethane 267.136Sodium borohydride is a less effective reducing agent in this reaction, achieving the same conversion over a longer period of time. Other less reactive hydrides [ LiBH,, NaBH,CN, LiAlH(0-t-Bu),] do not react.
CH,Ph (263)
CH,Ph (266)
CH,Ph
CH,Ph
(4
(263
CH,Ph (267)
Reductive ring cleavage of the tetrahydroimidazole 268 has been recorded with LAH in ether.’,’ Formation of the isoindolone 269 is in contrast with earlier reports in which ring expansion to the diazocine 270 was r e ~ 0 r t e d . l ~ ~
13’
M. W. Anderson, R. C. F. Jones, and J. Saunders, J. C. S. Chem. Commun. 282 (1982). P. Aeberli, G. Cooke, W. J. Houlihan, and W. G. Salmond, J. Org. Chem. 40,382 (1975).
46
JAMES G . KEAY
[Sec. 1V.E
C. BENZIMIDAZOLES The reduction of the benzimidazolium salts 271 under controlled conditions with LAH in THF has been described.138The resulting benzimidazolines 272 may be similarly prepared, using LAH in ether139or NBH in water.'@
a$R QJPR LiAIH, - THF
*
I
I
Me
Me
(27')
(272)
D.
1,2,4-OXADIAZOLES
A variety of ureas and oximes can result from the reduction of lY2,4-oxadiazoles with LAH. The nature and position of substituents will determine the position of the attack and hence, the product. However, the majority of products arise from cleavage of the C-5-0 bond via chelation-assistance (273 + 274).141 LIAIH,
Ph w
YdfP;
k73)
H,O'
NHMe H,CO
N
'OH (2741
E. PYRIDAZINES Simple dihydropyridazines have been obtained by reduction of the parent pyridazine after initial alky1ati0n.l~~ Sodium borohydride reduced the 1methylpyridazinium salts in water to the corresponding lY6-dihydropyridazine 276 in 40-60% yield. In some instances (276c,e,f)the 1,4,5,6-tetrahy13* 139
la
J-L. Aubagnac, J. Elguero, R. Jacquier, and R. Robert, Bull. SOC.Chim. Fr., 2 184 (197 1). A. V. El'tsov, J. Org. Chem. USSR (Engl. Transl.) 1, I121 (1965). J. W. Clark-Lewis, J. A. Edgar, J. S. Shannon, and M. J. Thompson, Aust. J. Chem. 17,877 (1964).
142
Y . Royer, M. Selim, and P. Rumpf, Bull. Soc. Chim. Fr., 1060 (1973). C. Kaneko, T. Tsuchiya, and H. Igeta, Chem. Pharm. Bull. 22,2894 (1974).
Sec. IV.E]
47
REDUCTION OF NITROGEN HETEROCYCLES
dropyridazines 277 were also isolated. The phenyl derivatives 276e,fwere the most stable, but all gradually decomposed when exposed to the atmosphere. 1,3,4,6-Tetraalkyl-1,6-dihydropyridazinesare also available by this route.143Reduction of 275 with NBH in the presence of methyl chloroformate gave the 1,6-dihydro derivatives 278 in 30- 50% yield along with small amounts of the 1,4 isomer 279.These were more stable than their N-methyl counterparts (276).The presence of a phenyl group favored the 1,6-dihydropyridazines 278 and in its absence the 1,4 isomers 279a p r e d ~ m i n a t e d . ' ~ ~ . ' ~ ~ Dihydropyridazine (276a)was also obtained by treatment of l-methyl-6pyridazinone (280)or 278a with LAH in THF.Iu
(277)
(275)
L NaBH,
R'
LiAIH, Me
,";L\"/'
LIAIH,
(me.)
(276a)
f Me
Ph
Hexahydro derivatives 283 are favored when 3 mol of LAH are allowed to (281).144 Use of less reducing react with 2,3,4,5-tetrahydropyridazin-3-ones 143
la
Y. Zenichi, Jpn. Kokai 78/44,580 (1978). J-L. Aubagnac, J. Elguero, R. Jacquier, and R. Robert, Bull. SOC.Chirn. Fr., 2859 (1 972).
48
JAMES G . KEAY
[Sec. 1V.F
agent leads to a time-dependent mixture of products (282 - 284). Other substituted and dipyridazinones146yield hexahydropyridazines with LAH.
Do
R3
I
R’
(281)
LIAIH,
*
Rh +
\N
.
R3Q
HN,
I
RQN--N
I
I
R’
R’
R’
(284
(4
(284)
R’= H,Me,Ph; RJ= Me,Ph
F. PYRIMIDINES The reduction of pyrimidin-2( 1H)-ones (285) or their sulfur analogs occurs readily with NBH to give mixtures of products (286-288).147The ratio of these products varies markedly, depending on the presence of sodium hydroxide. The use of methanol/NBH favored 286 and 287 over 288 possibly as a result of the in situ formation of trimethyl borate.147The presence of sodium hydroxide retards formation of trimethyl borate, and a large increase in the proportion of 286 and 287 is now observed. In some cases, products 286/287 or 288 could be obtained exclusively by judicious choice of reaction conditions. Earlier reports by other workerPJ4*prompted these authors to attempt reductions of 285 with NBH in acetic acid. This led to either the exclusive formation of the 3,4,5,6-tetrahydropyrimidin-2(1H)-ones288 ( X = 0)and thiones 288 ( X = S) or isolation in admixtures with 286 and 287.*49 Reduc1H)-ones 288 ( X = 0) with tion of the 3,4,5,6-tetrahydropyrimidin-2-( LAH gives the diaminopropanes 289 by reductive ring ~1eavage.l~~ The thione derivatives 288 ( X = S) did not react under these conditionsand were RZ
R2
RZ
I R’ (285)
(2%)
(287)
P. Aeberli and W. J. Houlihan, J. Org. Chem. 34,2720 (1969). M. Tisler and B. Stanovnik, Adv. Heterocycl. Chem. 24,42 I ( 1979). 14’ C. Kashima, A. Katoh, Y. Yokota, and Y. Omote, J. C. S. Perkin I, 1622 (1981). 14* J. A. Marshall and W. S. Johnson, J. Org. Chem. 28,421 (1963). 149 C. Kashima, A. Katoh, N. Yoshiwara, and Y. Omote,J. Heterocycl.Chem. 18,1595 (198 1). 145
Sec. IV.F]
49
REDUCTION OF NITROGEN HETEROCYCLES
tXX
R
I
LiAlH,
TH F
R'
b R
H
M
e
NHR'
(24
(288) X = O , S ; R'=Me,Aryl; RZ= H , M e , Pr,Ph; R3=H,Me,Ph
recovered. Earlier, it had been found that ethyl 4-hydroxyiminomethyl-2methylthiopyrimidine-5-carboxylate(290a), and subsequently other pyrimidines, underwent preferential ring reduction. Lithium aluminum hydride in pyridine, lithium borohydride in THF, and sodium borohydride in ethanol all reduced 290 to ethyl 4-substituted-2-methylthio- I ,6-dihydropyrimidines (291). When R = SMe, NHMe, or NHNH,, reduction of the carboxylic acid ester occurs.15o R
R LiAlH4
MeS
or M+BH,
H
N-Substituted dihydropyrimidines on reaction with a large excess of NBH in ethanol at room temperature give rise to ring-opened products (e.g., 294).I5lThe intermediacy of the hexahydro derivative 293 was proved by its isolation from the reaction mixture and subsequent conversion to 294 with (292) additional borohydride. l-Phenyl-4,4,6-trimethyldihydropyrimidine may ring open via N-1 -C-2 or C-2-N-3 cleavage. In fact, only the former is observed, presumably a result of the increased stability of the N- I -phenyl anion. This is in agreement with the observation that 1-benzyl-4,4,6-trimethyl-1,4-dihydropyrimidine (296) gave only the hexahydro derivative in 70%yield.lsl Surprisingly,LAH left the imine bond intact prior to ring cleavage, whereas borohydride had been demonstrated to saturate all bonds prior to opening. Alkylation and subsequent reduction of the dihydropyrimidinium salts affords mixtures of the cyclic and acyclic diamines lSo Is'
R. S. Shadbolt and T. L. V. Ulbricht, J. Chem. Soc. C, 733 (1968). C. Kashima, M. Shimizu, A. Katoh, and Y. Omote, J. Heterocycl. Chem. 21,441 (1984).
50
JAMES G. KEAY
[Sec. 1V.G
298 and 299.lS1Ring opening has also been observed in the reduction of certain 2,4,6-(1H,3H,5H)-pyrimidinetrione (barbituric acid) derivatives. 152,153 NaBH,
Me Me O Me
LiAIH,
Me Me
H Y Y L - C H M e I Ph
P93)
5
Me Me
MeC N H M e
I Ph
I Ph
(294)
Q95)
JO Me Me
I CH,Ph
w
a , R’=Ph; R2,R:R4,R5=Me
b, R’=Ph; R2,R3,R4=Me;R5=Et
G. PYRAZINES The successful trapping of the valence-bond isomer, induced during the UV irradiation of pyridine,ls4with NBH led to the application of this technique to 2,3,5,6-tetramethylpyrazine(300) Although no valence-bond iso15*
Iu
M.Rautio, Acta Chem. Scand., Ser. B B33, 770 (1979).
M. Rautio and K. Vuon, Acta Chem. Scand., Ser. B B34,llO (1980). K. E. Wilzbach and D. J. Rausch, J. Am. Chem. SOC.92,2178 (1970).
51
REDUCTION OF NITROGEN HETEROCYCLES
Sec. IV.H]
merization was observed, hexahydropyrazine (301) was isolated. 155 The reduction of tetrachloropyrazine (302) with LAH affords the dehalogenated product 303.ls6 NaBH,
*
Me
Mea: Me
H
LiAIH,
H. CINNOLINES On reduction with LAH, cinnolines generally yield di- and tetrahydro
derivative^.^^'^' The LAH reduction of 5,6,7,8-tetrahydro-3-cinnolinones
(304)in THF leads to mixtures of the dihydrocinnolines 305, the decahydro The ratio cinnolines 306 and the deoxygenated tetrahydrocinnolines 307.158 of products is dependent on the substituents and the amount of LAH used.15s
& \“\R‘
R
LiAIH, THF
(304) R
=
H, M e , P h ;
R’
=
H, Ph.
O$!N,R:
@N,
H
(0s)
(305)
(XiRl (307)
ls5
Is6
Is*
D. J. Bell, I. R. Brown, R. Cocks, R. F. Evans, G. A. Macfarlane, K. N. Mewett, and A. V. Robertson, Aust. J. Chem. 32, 1281 (1979). R. D. Chambers, W. K. R. Musgrave, and P. G.Urben, J. C. S.Perkin I, 2584 (1974). L. S. Besford, G . Allen, and J. M. Bruce, J. Chem. Soc., 2867 (1 963). J. Daunis, M. Guerret-Rigail, and R. Jacquier, Bull. Soc. Chim. Fr., 1994 (1972).
52
[Sec. IV.1
JAMES G. KEAY
I. QUINAZOLINES The reductive ring cleavage that prevails with 4-quinazolinone and LAH has been the subject of several reports.159-162 Interest was first shown after the (308, abnormal reaction of the alkaloid 1-methyl-2-benzyl-4-quinazolinone asborine) was found to give the 2,3-dihydro derivative 309 with the carbonyl function still intact.159However, a different orientation of the same substituents leads to the ring-opened product 311, with cleavage occurring between C-2 and N-3 when LAH is used. In methanol, NBH gives 3-methyl-4-quinazolinone (312), the product of reductive debenzylation, albeit in low yield.159,162- 164 The position and nature of the substituents has been shown to affect the reaction markedly; for instance, NBH and LAH both generate 2-phenyl-3(314) from the parent heterocycle 313. methyl- 1,2-dihydro-4-quinazolinone This compound may then be converted to the ring-cleaved product 315 on further heating with NBH in ethanol. The 2-methyl-3-phenyl derivative with LAH gives the aniline 316 by C-2-NN-3 cleavage. In the absence of the phenyl group, this cleavage occurs preferentially along the N-1-C-2 bond (317, 84%) along with a small amount of that derived from C-2-N-3 cleavage (318, 5%).160 LiAIH, d
C
H Me z
P
25 OC
h
d
x
H 2 Me
p
h
(309)
(34
55% (311) 0
(313)
NaBH. or
0
(314)
0
(315)
S. C. Pakrashi and A. K. Chakravarty, J. Org. Chem. 31, 3143 (1972). I. R. Gelling, W. J. Irwin, and D. G. Wibberley, J. C. S. Chern. Cornmun., 1 1 38 (1969). W. J. Irwin, J. C. S. Perkin I, 353 (1972). 162 S. C. Pakrashi and A. K. Chakravarty, Indian J. Chem. 11, 122 (1973). S. C. Pakrashi and A. K. Chakravarty, J. C. S. Chem. Cornmun., 1443 (1969). N. Finch, and H. W. Gschwend, J. Org. Chem. 36, 1463 (1971). 159
I6O
Sec. IV.J]
53
REDUCTION OF NITROGEN HETEROCYCLES
Monosubstituted 4-quinazolines, with the exception of the 1and 3 - p h e n ~ l derivatives, '~~ do not undergo this ring opening reaction. The 2-phenyl derivative 319 leads to the product of carbonyl reduction 320 in 46% yield.'61 0
The ring cleavage presumably occurs via the dihydro derivative; earlier work'65had shown this ring opening to be facilitated when the reduction is camed out on the dihydro derivative. Failure of the carbonyl function to be reduced may be a result of the formation of a complex between it and the metal of the hydride reagent.
J. QUINOXALINES Quinoxaline (321)was reductively alkylated with potassium borohydride in acetic acid by the method of Gribble and co-workers to give 1,Cdiethyl1,2,3,4-tetrahydroquinoxaline(322).166 The use of formic instead of acetic acid gave mixtures of 323 and 324. Quinoxalines 325 containing electronwithdrawing groups on the benzene ring can be efficiently reduced to the 1,2,3,4-tetrahydroquinoxalines326 in high yield with NBH.91No substituent reduction is observed.
I Et
(322)
165
(3231
I CHO (324)
K. Okumura, T. Oine, Y. Yamada, G . Hayashi, and M. Nakama, J. Med. Chem. 11,348
(1968). 166
I
me
J. M. Cosmao, N. Collignon, and G . Queguiner, J. Heterocycl. Chem. 16,973 (1979).
54
(Sec. 1V.K
JAMES G. KEAY
The NBH reduction of 1,4-quinoxaline di-N-oxide (327) in alcohols has been shown to produce the cis-tetrahydroquinoxalines328 as the predominant product.167The product 328 was identical to that obtained from the reduction of 2,3-dimethylquinoxaline with LAH. 16* 0-
ax: I
0I -
NaBH, ROH
(yy H
(324
(327)
K. 1,2-DIAZEPINES The NBH reduction of 1-acetyl- and 1-carbethoxy-1,2( IN)-diazepines (329) leads to the 2,3-dihydro-1,2(1H)-diazepines 330 in high yield.169J70 The dienamine system produced is resistant to further reduction under these conditions. That only single products were obtained was verified by preparing dihydro- 1,2(1H)-diazepines labeled with methyl groups. Treatment of 330 (R'= Ac) with base generates the unstable 3,Cdihydro- 1,2(2H>diazepines 331. Analagous reduction is also observed with lithium disobutylaluminum hydride ( DIBAL).169
M. J. Haddadin, H. N. Alkaysi, and S . E. Saheb, Tetrahedron 26, 11 15 (1970). J. Figueras, J. Org.Chem. 31,803 (1966). 169 J. Streith and B. Willig, Bull. SOC.Chim. Fr., 2847 (1973). T. Tsuchiya and V. Snieckus, Can. J. Chem. 53,5 19 (1975). 167
Sec. IV.M]
R
55
REDUCTION OF NITROGEN HETEROCYCLES a
b
C
d
e
H
3-Me
5-Me
4,6 -di- Me
3,7-di -Me
L. 1,4-DIAZEPINES Most of the work on the 1,4-diazepines has been directed toward the reduction of 0x0 derivatives and other functionalities. These reactions will not be covered here, and interested readers are encouraged to refer to the appropriate sources.1 7 1 ~ 1 7 2
M. Iy5-BENZODIAZEPINES 6,7-Benzo-1,2,4,5-tetrahydro-l,5-diazepines (333) may be obtained by the NBH reduction of the benzo-l,5-diazepinium chloride precursors 332. Yields in excess of 90% are ~1airned.l~~ When the reduction was carried out in dimethylformamide, 2,4-dimethyl-1,5-dihydro-6,7-benzo-1,5-diazepine (334) was obtained. Additional work has shown that this reduction occurs stereoselectively, giving cis-tetrahydro-1,5-diazepine~.'~~
aye ggMe _NaBH,, R=MeDMF
N
95%EtOH NaBH,
Me05%
(334)
(332)
R
ci
*eMJf (
H
R
(333)
R = M e , Aryl
F. D. Popp and A. C. Noble, Adv. Heterocycl. Chem. 8, 52 (1967). D. Lloyd and H. P. Cleghorn, Adv. Heterocycl. Chem. 17,2 (1974). N. M. Omar, Indian J. Chem. 12,498 (1974). N. M. Omar, A. F. Youssef, and M. A. El-Gendy, Arch. Pharm. Chemi. Sci. Ed. 3, 89
(1975).
56
JAMES G. KEAY
[Sec. V.B
V. Reductions of Heterocycles Containing Three Nitrogen Atoms A. 1,2,3-TRIAZOLES 1,2,3-Triazolium salts (335) are not readily reduced by NBH. Indeed, 4-phenyl- and 4,5-diphenyl-1,3-dimethyl-1,2,3-triazolium iodides do not undergo reduction, yet 1-methyl-2-phenyl-1,2,3-triazolium triflate (336) is reduced to the 4-triazoline 337.17sThis reactivity pattern is explained by the need for an immonium ion for successful reaction. The presence of a C-2 substituent in 336 makes this possible; the lack ofsuch a substituent localizes the double bond joining C-4 and C-5.
:$t
NaBH,
Ph Me’
e...
Me’
Me -
I R = H,Ph
\Q
M e - Ph . q L -
I Ph
(336)
($4
B. 1,2,4-TRIAZOLES 1,2,4-Triazoliumsalts (338)are readily reduced to the dihydro derivatives 339, (triazolines) by aqueous NBH. Similarly, borohydride attack occurs exclusively at the 5 position of 5-substituted-1,4-diphenyl-3-methylthio1,2,4-triazoliumsalts (340) to give the triazolines 341 in high yield.176Acid hydrolysis of the triazolines leads to the aldehydes 342 in 40- 80%yield. Lithium aluminum hydride has been used to convert the triazol-5-ones 343 to both triazoles (345)and triazolines (346).The yields of the former are low ( 15- 30%) by this method, triazoline formation being preferred.177 R , +N-N meX&Me I
-
1
NaBH,
X$
R, Me
I
R
Ph,
me
NaBH,
R4iXs=es4iXR I I Ph (341) Ph
(4
/Ph
H,O’ -RCHO
(.14
(33.9
T. Isida, T. Akiyama, N. Mihara, S. Kozima, and K. Sisido, Bull. Chem. SOC.Jpn. 46,1250 (1973). 176 G. Doleschall, Tetrahedron 32, 2549 ( 1 976). J. Daunis, Y. Guindo, R. Jacquier, and P. Viallefont, Bull. SOC.Chim.Fr., 3296 (1971). 17J
57
REDUCTION OF NITROGEN HETEROCYCLES
Sec. V.C]
C . BENZOTRIAZOLES Attempts have been made to reduce 1,2- (347) and 1,3-benzotriazolium salts (350) both with potassium and sodium borohydride and LAH.175*178 The 1,2-dimethylderivative yielded mainly 1-methylbenzotriazole (348) on heating with borohydride in water and probably results from base-controlled dealkylation. Small amounts of 349 were also detected. No reaction was observed in the cold with the iodides of 347 or 350*751,3-Dimethylbenzotriazolium methosulfate (350) gave 1,2-di(rnethylamino)benzene (351); heating at reflux produced intractable materials. The more reactive LAH, in ether, gave high yields of the ring-cleaved products 349 and351, respectively. Me
Me
KBH,
'
H2O
eM- +b j Q MeSO,
6 h 100°C
32%
+
(348)
m Me
I
Me
K BH,
*
H,O
24%
20 "C
MeSO, (351
'NHMe
(349)
P47)
I
QNH2
1
L. 1. Rudaya and A. V. El'tsov, Zh. Org. Khim. 10,2142 (1970).
58
JAMES G. KEAY
[Sec. V.D
D. 1,2,3-TRIAZINES The election-deficient triazine ring 352 is readily attacked by sodium borohydride in methanol to give the 2,Sdihydro- 1,2,3-triazines 353 in quantitative yield.179~180Under similar conditions 4,6-dimethyl- 1,2,3-triazine 1-oxide (354) gave the same compound (353, R = Me) in 85% yield, along with 352 (R = Me).179However, reduction of the 1,2,3-triazine 2oxides 355 left the N-oxide functionality intact for the most part, giving the 1,4,5,6-tetrahydro-1,2,3-triazine 2-oxides 356 as the major products. 179 Both cis and trans isomers of 356 were detected, the former predominating. These results were confirmed by carrying out the reduction with sodium borodeuteride and deuteromethanol. The C-5 proton originates from the
NaBH,
R = P h , 62%
35 %
R = M e , 03%
5%
MeOH
R
*
a
M
I
-0 (357)
(355)
NaBH, MeOH
@54
I OH (354
e
I -0
(34
H b54
(353)
H. Arai, A. Ohsawa, H. Ohnishi, and H. Igeta, Heterocycles 17, 317 (1982). A. Ohsawa, H. Arai, H. Ohnishi, and H. Igeta, J. C. S.Chem. Commun. 1174 (1981).
Sec. V.E]
REDUCTION OF NITROGEN HETEROCYCLES
59
solvent whereas the C-4 and C-6 protons are from the reducing agent. The implication is that 356 arises from an initial 1,6-dihydrotriazine, whereas 353 forms from the 2,5-dihydro derivative 359. The triazines 352 were detected in the product m i ~ t u r e . ” ~
E. I ,2,4-TRIAZINES 5,6-Diaryl-1,2,4-triazines(360), containing a 3-methoxy or 3-methylthio substituent, give rise to the formation of the 2,5-dihydro derivatives 361 on treatment with NBH181J82 These dihydro species, trapped with dimethylacetylenedicarboxylate, were assigned structures by NMR spectroscopy, which were confirmed by X-ray analysis. 3-Methylthio- and 3-methoxy-5-phenylThe 2,5- and 4,5-dihydro- 1,2,4-triatriazines (362) behaved zines may be differentiated by NMR s p e c t r o ~ c o p yThe . ~ ~ ~1,Caddition of hydrogen is explained by initial hydride attack at C-5 followed by N-2 protonation by the solvent. MeXCJAr Ar
N%MeX THF/MeOH
rAr
N
Ar
x = 0,s A report on the reaction of NBH with 5-methylthio-l,2,4-triazin-3(2H)-
ones (363) claims demethiolation in methanol to 4,Sdihydro- 1,2,4-triazin3(2H)-ones (364)in good yield.185The same workers extended this study and described a similar reaction occumng on 3-methylthio- 1,2,4-triazin-5(222)Conducting the reaction in methanol led to ones (365) in DMF at 70°C.186 substantial amounts of 367 being isolated.
SMe
(4
b S 9
T. Sasaki, K. Minamoto, and K. Harada, J. Org.Chem. 45,4587 (1980). H. Neunhoeffer and P. F. Wiley, eds., “Chemistry of 1,2,3-Tnazines and 1,2,4-Triazines, Tetrazines and Pentazines.” Wiley (Interscience), New York, 1978. In3T. Sasaki, K. Minamoto, and K. Harada, J. Org.Chem. 45,4594 (1980). Ia4 J. Daunis and C. Pigiere, Bull. Soc. Chirn. Fr., 2493 ( I 973). InsY. Nakayama, Y. Sanemitsu, M. Mizutani, and K. Yoshioka, J. Heterocycl. Chem. 18,63 I (1 98 1). Ia6 Y. Sanemitsu, Y. Nakayama, and M. Shiroshita, J. Heterocycl. Chem. 18, 1053 (1981).
Ia2
60
JAMES G . KEAY Me
Me
Me
NaBH4 Hc.)lR
[Sec. V1.A
XT-
NaBH, MeOH
___)
R
“‘o@.*
366
0
0
0
(34
(34
(367)
R = alkyl, Ph
F. 1,3,5-TRIAZINES Studies on the stability of 1,2-dihydro-2,4,6-triphenyl1,3,5-triazine(369) included its synthesis from the aromatic 1,3,5-triazine368. However, in the presence of aluminum chloride rearrangement occurs to give a 16Y0yield of 2,4,5-triphenylimidazole(370).lE7A suggested mechanism proposed that the unstable dihydrotriazine undergoes a radical-induced ring opening and contraction to 37O.lE7
VI. Reduction of Heterocycles Containing Four Nitrogen Atoms A. TETRAZOLES
The action of NBH on some tetrazolium iodides has been ~tudied.”~ The positions of the substituents determined whether or not reduction occurred. 1,4,5-Trisubstituted tetrazolium iodides (371) were reduced to the 2-tetrazolines 372, whereas under the same conditions the 1,3,5-trisubstituted tetrazolium iodide 373 remained unchanged. The ring carbon is insufficiently electrophilic to induce attack.
I*’
H.L. Nyquist, J. Org. Chem. 31, 784 (1966).
Sec. VII.A]
61
REDUCTION OF NITROGEN HETEROCYCLES
VII. Reduction of Fused Heterocycles A. QUINOLIZINES The reduction of quinolizinium bromide (374) with NBH and LAH has been the subject of a series of publications by Miyadera and coworker^.^^*-^^^ Hydride reduction with LAH (in THF) leads to ring cleavage to 1-(2-pyridy1)- 1,3-butadiene (375), whereas NBH (in THF) gave 1-(2-pyridyl)-2-butene (376) in low yield. Studies of the reaction of 374 with Grignard reagent^'^^^^^ and MO calcul a t i o n ~indicate ' ~ ~ that the preferred site for nucleophilic attack of the quinolizinium ion is C-4. Thus the intermediacy of the unstable 4H-quinolizine 377, formed directly or by isomerization, has been suggested. Reduction of 374 with NBH ( 1 : 1) in water gave a four-component mixture, which was shown by gas chromotography to contain the quinolizines 378-381. Catalytic hydrogenation of the mixture gave quinolizidine (392). Conducting the reduction in deuterium oxide or deuterated ethanol led to incorporation of deuterium in the product. The different products obtained in aprotic solvents reflects the possibility of ring opening and reestablishment of aromaticity to the pyridine ring. In water or ethanol the proposed intermediate 377 may undergo a variety of protonations and equilibrations prior to further reduction.189The reduction NaB"4
J )ft
fJJE!?a N
Br
(375)
(374)
~ (378)
/
(376)
\ N
(377)
c (379)
(380)
g (4
(382)
of benzo[b]quinolizinium bromide (383) in ethanol with NBH led to the formation of 1,6,11,1la-tetrahydrobenzo[b]quinolizine(384) as the major product.lg3 In boiling water, only the 1,3,4,6,11,1la-hexahydro-2Hbenzo[b]quinolizine 386 was obtained. T. Miyadera and Y. Kishida, Tetrahedron 25,209 (1969). T. Miyadera and Y. Kishida, Tetrahedron 25, 397 (1969). I W T. Miyadera and Y. Kishida, Tetrahedron Lett., 905 (1965). I g 1 C. K. Bradsher and J. H. Jones, J. Am. Chem. Suc. 81, 1938 (1959). 192 R. M. Acheson and D. M. Goodall, J. Chem. Suc., 3225 (1964). 193 T. Miyadera and R. Tachikawa, Tetrahedron 25,5 I89 ( I 969).
IE9
62
[Sec. VI1.B
JAMES G.KEAY NaBH, EtOH
BF
(383)
(386
B. AZOLOPYRIDAZINES The reduction of simple pyridazines normally occurs only after quaternization and leads to mixtures of di- and tetrahydropyridazines (see Section IV,E). However, bicyclic azolopyridazines containing a bridgehead nitrogen (387-389) readily undergo reduction of the pyridazine ring with NBH in ethan01.I~~ Thus tetrazolo[ 1,5-b]- (387), 1,2,4-triazol0[4,3-b]- (388), and imidazolo[ 1,2-b]pyridazines (389) are reduced to the corresponding tetrahydro derivatives 390-392. The reduction of 388 in deuterium oxide led to deuterium incorporation at C-3,N-5, and C-7 in 391. Hydrogen -deuterium exchange will occur at C-3 in both 388 and 391 and at N-5 in 391. Deuterium incorporation at C-7 can be seen as occurring via the intermediate 393.Ig4
a)
194
NaBH,
-
a3 H
(=3;
X=N
Y=N
(34
91%
(389) ;
X =CH
Y =CH
b92)
72%
P. K. Kadaba, B. Stanovnik, and M. Tisler, J. Heterocycl. Chem. 13,835 (1976).
Sec. VII.C]
REDUCTION OF NITROGEN HETEROCYCLES
63
C. AZOLOPYRIMIDINES 1. 1,2,5-Oxadiazolo[3,4-d]pyrimidine Previous work on this system by Taylor et al.195has illustrated the facile nucleophilic attack that occurs at C-7. Reduction of the 5-phenyl-7-substituted derivatives with NBH in THF has been shown to be substituent dependent.196Amino substituents (394a, 394b) inhibit reduction, whereas the thioester 394e gives the product of reductive cleavage 396. The 6,7-dihydro derivative is obtained from the acetamido compound 394c. However, the benzamido analog 394d gives 396 and benzamide in 60% yield. NaBH, THF
(394)
a
b
C
d
e
2. Imidazolo[4,5-d]pyrimidine The purine ring system has been the subject ofconsiderable study, which is a reflection of its biological importance. Reduction of the imidazole or pyrimidine ring is controlled by the nature and position of substituents; for instance, 1-methyladenosine (397) undergoes ready reduction with NBH to 9-Benzyladenine (399a)and its N-benzoyl the 1,6-dihydroderivative 398.197 derivative 399b remained unchanged on treatment with NBH in alcohols.198 Reduction of399b with NBH in acetic acid gave reduction in the imidazole ring to afford the 7,8-dihydro compound 400b, (759/0)but without the Nethylation previously observed with this method. A similar reduction of the N-acetyl derivative has been observed, but the product was not isolated. The 19)
196 '91 19*
E. C. Taylor, S. F. Martin, Y. Maki, and G. P. Beardsley, J. Org. Chem. 38,2238 (1973). Y. Maki, Chem. Pharm. Bull. 24,235 (1976). J. B. Bacon and R. Wolfenden, Biochemistry 7, 3453 (1968). Y. Maki, M. Suzuki, and K. Ozeki, Tetrahedron Lett., 1199 (1976).
64
JAMES G. KEAY
[Sec. VI1.C
adenine 399a was recovered unchanged under these conditions. Reductive sites were determined by deuterium labeling. The site ofreduction appears to be the enamine system, which can generate an imminium ion in a protic solvent. 3-Benzyl derivatives (401) were used in order to confer the required *
NaBH,
Me,$y
6 N
pH 8.2
(397)
4
2
(IN/
H
CH,Ph
(394 (399)
stability to the dihydro derivatives 402.19*3,9-Dimethyladeninium perNHCOPh
N (N
2 y
I
CH,Ph
(44
&! . N
I
NaBH, MeOH
CH,Ph (401)
(;I;:
1
~
H
N
5
LN
I
CH,Ph (402)
b COPh Ac
chlorate (403) undergoes reduction with NBH in methanol to give the 2,3dihydro compound 404.199 The purine derivatives 405 and 407 undergo reduction in the pyrimidinium and imidazolium rings, respectively.200Studies on the reduction of 2,8-dioxo- and 2,8-diaminopurines were carried out in order to study the simpler chemical derivatives of saxitoxin.201Attempts to reduce 1,7-dihydro-9H-purine-2,8-dione (409) with NBH were unsuccessful. Reduction of 3,7,8,9-tetrahydro- 1,3,9-trimethyl-2,8-dioxo-2H-purinium iodide (410, R = H) under the same conditions gave spectral evidence for generation of the hexahydro derivative. However, on attempted isolation, facile hydrolytic C-4 -C-9 ring cleavage occurred, and the uracil 41 1 (R = 199T. Fujii, T. Saito, T. Nakasaka, and K. Kim,Heferocycles 14, 1729 (1980). 2wZ. Neiman, J. Chem. SOC.C, 91 (1970). 201 W. L. F. Armarego and P. A. Reece, J. C. S.Perkin I, 1414 (1976).
f
m 2
/
r"
I
0
I.
0
f-A-r"
oa
r
I' 2 z
66
JAMES G. KEAY
[Sec. V1I.C
H) was produced. In methanol, at pH 9 and with excess NBH, the perhydro compound 412 (R = H) was formed in high yield. This was shown by 'H NMR to be the cis fused product.201Similarly, the reduction of the 1,3,7,9tetramethyl derivative 410 (R = CHJ provided the cis product 412 (R = CHq). InD,O, NBH gave incorporation of a deuterium atom at C-5, suggesting that hydride attack occurs at C-4 in generating the hexahydro and at C-4 and C-6 in formation of the perhydro species. The reduction of 3,7,8,9-tetrahydro-l,3,6,9-tetramethyl-2,8-dioxo-2H-purinium iodide (413) with NBH proceeds more slowly to the perhydro derivative 415 but via a different hexahydro intermediate (414). The reduction of 1,7,9-trimethyl-2,8-diaminopurinium diiodide (416, R = H) gave only one product with NBH, the 2,8-diamino-4,5,6,9-tetrahydro- 1,7,9-trimethyl-1H-purine cation (417, R = H).zo'The 1,6,7,9-tetramethylpurine 416 (R = Me) similarly gave the tetrahydro product 417 (R = Me). Both of these products were isolated as the dihydrochlorides in high yield and contained a cis-ring junction.20'
R = H,Me
3. Pyrazolo[l,5-a]pyrirnidine Ethyl 2-phenylpyrazolo[1,5-~]pyrimidinecarboxylates(418) are converted to the dihydro derivatives 419 on treatment with NBH.Z02 202
G . Auzzi, L. Cecchi, A. Costanzo, P. L. Vettori, and F. Bruni, Farmaco, Ed. Sci. 34,75 1
(1979).
67
REDUCTION OF NITROGEN HETEROCYCLES
Sec. VII.E]
R‘
R’ “
“
“
~
~
~ NaBH, h
“ “ “ fN ~ ~ h
H
R
(418
1
R
(419)
R = H,Br,CI R’= Me,CH,Br,CH,CI
D.
THIENO[2,3-d]PYRIMIDINE
2-Chloro-3,4-dihydrothieno[2,3-d]pyrimidines (421) are prepared when the aromatic precursors 420 are treated with excess NBH over an 8-h period at room temperaturea203 NaBH,
E. THIENOPYRIDINES 1. Thieno/3,2-c]-and Thieno/2,3-c]pyridines N-Alkylation and subsequent reduction of both thieno[3,2-c]- (422) and thieno[2,3-c]pyridines (424) give predictably the 4,5,6,7-tetrahydrothienopyridines 423 and 425, respectively. Large excesses of borohydride were used, and the reductions were carried out in ethanol over 4-h periods at reflux temperatures. Yields of 57 -78% are obtained.2@’ The relatively electron-rich thiophene ring resists reduction.
X. (424
203 *04
Daiichi Seiyaku Co., Ltd., Jpn. Kokai Tokkyo Koho 82/77,687 (1982). F. Eloy and A. Deryckere, Bull. SOC.Chim. Belg. 79,415 (1970).
68
JAMES G. KEAY
[Sec. V1I.G
F. AZOLOAZEPINES
I. Pyrazolo[3,4-b]-1,4-diazepine 3,5-Dimethyl-7-oxo- 1-phenyl-6,8-dihydro-7H-pyrazolo[ 3,441- 1,4-diazepine (426)gave a mixture of three products on reduction with LAH. After heating at reflux for 6 h in ether, the ratio of 427 :428:429 was 5 :4 :8; after 24 h only 429 was found. Reduction of 1-phenyl-3,5,7-trimethylpyrazolo[3,4-b]-1,4-diazepine(430)under similar conditions led to the tetrahydro derivative 431205in 80% yield after 12 h. 7,8-Dihydro derivatives of 430 were isolated on catalytic hydrogenation and could be subsequently converted to 431 with LAH.ZoS
(-JpJe. M&y
+:je - @;je Ah
Me
Me
Me
LiAIH,
*
H
Ph
c224
(427)
Q:je
Me
Me
&ye
*
I
Ph
Ph
6130)
Ph I
H
0
(428)
I
Ph
H 6129)
Me
LiAIH,
I
OH
H
Me
(4311
G . AZANAPHTHALENES 1 . Pyrido[3,2-e]-andPyrido[3,4-e]-l,2,4-triazines The addition of LAH to a solution of 3-phenylpyrido[3,2-e]-1,2,4-triazine (432a)in THF gave the tetrahydro derivative 433a. Likewise with the unsubstituted analog 432b,reduction occurred in the pyridine ring affording 433b.3-Phenylpyrido[3,4-e]-1,2,4-triazine (434),however, undergoes hydride reduction in both rings to give the 4,5,6,10-tetrahydro derivative
435.206 The reason for this disparity is not obvious. Theoretical studies do
not resolve the issue. One study indicates that in pyrido-l,2,4-triazines and pyridopyridazines the pyridine-ring nitrogen is the most basic.207However, 20J
J.-P. Affane-Nguema, J.-P. Lavergne, and P. Viallefont, J. Heterocycl. Chem. 14, 1013 ( 1977).
206 207
J. Armand, K. Chekir, N. Ple, G. Queguiner, and M. P. Simonnin, J. Org. Chem. 45,4754 (1981). S. C. Wait, Jr. and J. W. Wesley, J. Mol. Spectrosc. 19,25 (1966).
69
REDUCTION OF NITROGEN HETEROCYCLES
Sec. VII.G]
Dinya208in a CNDO study concluded that this is not so in every case. The pyridine N atom in pyrido[2,3-e]- (436) and pyrido[3,2-e]-1,2,4-triazines (432) carries the largest negative charge and indicates that reduction should occur in the triazine ring for the [3,4-el (434) and [4,3-el (437) analogs. Previous work on other azanaphthalene systems suggests that reduction should occur in the triazine ring. LiAIH, R
2. Pyrazino[2,3-d]pyrirnidine The reduction of pyrazine[2,3-d]pyrimidines,the pteridine ring system, usually occurs in the pyrazine ring to yield dihydro and tetrahydro derivat i v e ~The .~~ reduction ~ of 1- and 3-methyl-6,7-diphenylpteridin-4-one with NBH gves no isolable products, whereas 3,4-dihydro- 1,3-dimethyl-6,7-diphenyl-4-oxopteridinium iodide (438) gives the 1,2,3,4-tetrahydro product 439.200The reduction of pteridine (440) itself with NBH occurs readily in trifluoroacetic acid, giving two products in 94% overall yield. 1,2,3,4-(441) and 5,6,7,8-tetrahydropteridine(442) were obtained in 38 and 58% yields, respectively.z10The pyrazine ring is preferentially reduced.
M e \ h 1 P h
I
Me
(434
MeOH NaBH,
Ph
I
*Me
y5fJ
Ph
I
Me
(439)
Z. Dinya and P. Benko, Acta Chim. Acad. Sci. H u g . 96,61 (1978). E. C. Taylor, M. J. Thompson, and W. Pfleider, Pteridine Chem.. Proc. Int. Symp., 3rd, lY62, 181 (1964). 210 R. C. Bugle and R. A. Osteryoung, J . Org. Chem. 44, 1719 (1979). 208
209
70
[Sec. V1I.G
JAMES G. KEAY
(444
(441)
(44
3. Pyrimidino[4,5-d]pyridazine Reduction of 2-aryl-5,8-dialkylaminepyrimido[4,5-d]pyridazines (443) with NBH, LAH, and catalytic hydrogenation gives the 3,4-dihydropyrimidopyridazines 444.21I
Ary‘w NaBH,
LiAIH,
(44;
or
m
H
/N
64;
R = b-PrNH, PhNH , PhCH,NH, C,H,,N , morphilino
4. Pyrido[3,4-d]pyrimidine The expected product of reduction of the pyrido[3,4-d]pyrimid-4(3H)one 445 with LAH is the 1,2,3,4-tetrahydropyndo[3,4-d]pyrimidine 446. However, the product obtained (447) resulted from cleavage at the 2,3 position.212High yields of the pyridine 447 were obtained after 1-h at room temperature with excess LAH. Reductive ring closures of fused pyrimidines and pyrimidin-4(3H)-ones has been reported previously to occur at the 1,2 2 L 3and the 2,3 bond214(see also Section IV,F) but under much more vigorous conditions. More vigorous conditions are required when the pyrido[ 3,4-d]pyrimidin-4(3H)-onesdo not possess a 3-aryl substituent. The substrate 448 required 3 days at room temperature to give 1,2,3,4-tetrahydro-3,6,8-trimethylpyrido[3,4-d]pyrimidine (449) in 92%yield. Heating the pyridopyrimidone 448 at reflux in THF for 6 h was required to convert this to the pyridine 450.212Compounds without 3 substituents led to specific S . Yurugi, T. Fushimi, and M. Hieda, Yukuguku Zusshi 92, I3 16 (1972). I. R. Gelling and D. G. Wibberley, J. Chem. Soc. C,780 (1971). 213 R. F. Smith, P. C. Bnggs, R. A. Kent, J. A. Albright, and E. J. Walsh, J. Heterocycl. Chem. 2, 157 (1965). 214 H. Ott and M. Denzer, J. Org. Chem. 33,4263 (1968). 212
71
REDUCTION OF NITROGEN HETEROCYCLES
Sec. VII.G]
2,3-bond fission but with more difficulty (boiling ether, 7 days). Use of less reducing agent and lower temperatures gave mixtures of products, starting materials, and 3,4-dihydro derivatives. The latter are likely intermediates in the reduction, although initial 1,2 attack has also been ~ u g g e s t e d . ’ ~ J ~ ~ , ~ ~ ~
LIAIH,, &HMe
T H F , 67 “C, NHEt
Me
*
6h
Me
LiAIH, Me
@5d
Me
,
25°C w
72h
Me
Me
0
0
6244
(444
5. Pyrido[L?,S-b]pyrazine Pyrido[2,3-b]pyrazine (451) is reduced rapidly and regiospecifically by NBH in trifluoroacetic acid to the 1,2,3,4-tetrahydropyrazine452.210No reduction of the pyridine ring was observed. Reduction with LAH on this and pyrido[ 3,441pyrazines leads to tetrahydropyrazines.206
a> (451)
NaBH, C F,COOH
a> 75%
(452)
6, Pyrido[2,3-d]pyridazine Calculations of the n-electron density2I5of pyrido[2,3-d]pyridazine (453) suggests that the nucleophilic attack is favored at C-2, C-5, and C-8. Studies of the reaction of 453 with LAH in THF gave 5,6- and 7,8-dihydro compounds in 35 : 65 ratio and 75%overall yield. The preferred site ofattack is at 2’5
M. Tisler and B. Stanovnich, “The Chemistry of Heterocyclic Compounds,” Vol. 27, p. 989. Wiley (Interscience), New York, 1973.
12
JAMES G . W A Y
[Sec. V1I.H
C-8 as a result of the greater deactivation of the pyridazine ring and the proximity of the pyridine
7. Pyrido[4,3-b]pyridine The tetrahydro derivatives 455 are conveniently prepared in aqueous methanol, using NBH.217Quaternization of the parent heterocycle gives the precursor 454. NaBH,
R = MeCEC-
*
, alkyl
H. AZOLOINDOLES 1. Pyrido-[2,3-b]-, -[3,4-b]-, and -[4,3-b]indoles The reduction of the 1,2,3,4-tetrahydropyrido[4,3-b]indolinium salts (456) proceeds stereospecifically with NBH to give the trans-ring junction (457).2'8Pyridine-borane yields the cis product. A deep orange color is generated from the pyrido[3,4-b]indolinium salt 458 on treatment with NBH. This suggests the formation of the anhydro base 459 (R = H), the color of which dissipates as the 1,2,3,4-tetrahydro derivative 460 is formed.219The pyrido[2,3-b]indole461 (R = -) is reportedly not affected by NBH. The salt 461 ( R = CH, +) is, however, reduced.220 D. Marchand, A. Turck, G . Queguiner, and P. Pastour, Bull. SOC.Chim. Fr. 9 19 ( 1 977). Nippon Kayaku Co., Ltd., Jpn. Kokai Tokkyo Koho 81 135,848 (1980). V. A. Zagorevskii,S. G . Rozenberg,N. M. Sipilina, L. U. Bykova, and A. P. Rodiono, Zh. Vses. Khim.0-va 21, 102 (1982). 219 I. W. Elliott, J. Efeterocycl. Chem. 3, 36 I ( 1 966). 220 B. Witkop and J. B. Patrick, J. Am. Chem. SOC.IS, 4475 (1953). 216
217
Sec. VII.H]
73
REDUCTION OF NITROGEN HETEROCYCLES Me
R
'
d
I
Me
"
NaBH,
Ci
diglyme
b
R&I
I
R
R (457)
(456)
r
R = H,Ph; R'= H,Me
L
R (458)
-
-
659)
The reduction of the pyrrolo[3,4-b]indol-3(2H)-ones 462 with LAH in toluene at reflux temperatures gave the expected 1,2,3,4-tetrahydro derivative 463 in 4590 yield. However, the dihydropyrrolo[3,4-b]indole464 was also isolated. The yield of this latter product was increased from 27 to 429/0 when the reduction was carried out in the presence of 1-ethylpiperidine.221 This was interpreted as increasing the propensity toward C- 1 proton extraction from the aluminum-oxygen complex 465.
flo ,CH,Ph
N
LiAIH, PhMe
I
Ph (462)
221
W. M. Welch, J . Org. Chern. 41,2031 (1976).
,CH,Ph
-@ N I
Ph
(463)
74
JAMES G . KEAY
[Sec. V1I.J
Ph
I. 1,3-THIAZOLO[2,3-U]ISOQUINOLINE The reduction of 3-methylthiazolo[2,3-a]isoquinoliniumperchlorate (466) and its 2,3-dihydro derivative (467) led to the same three products with both NBH and LAH.222The formation of469 was favored with borohydride, whereas 468 and 470 were the major product with LAH. Reductive ring cleavage of thiazoles is known and has been reported
@64
J.
NaBH,/LiAIH,
1,4-THIAZENO[4,5-U]QUINOLINEAND -[4,5-U]QUINAZOLINE
Reduction with NBH leads to cleavage of the thiazine ring of 471 and produces the quinoline derivative 472. The driving force for such a reaction 222 223
H. Sin& and K. Lal, J . C. S.Perkin I, I799 (1972). A. D. Clarke and P. Sykes, J. Chern. SOC.C.103 (1971).
75
REDUCTION OF NITROGEN HETEROCYCLES
Sec. VII.K]
is rearomatization of the pyridine ring.224Likewise, NBH in ethanol at reflux converts the thiazenoquinazoline 473 to the quinazoline 474.224
&
NaBH, OH
E tOH
(471)
(473)
NaEH, CI
Ph
Ph (474)
(473)
K. BENZO[d,e]QUINAZOLINE 1-Substituted benzo[d,e]quinazolines (475, the perimidine ring system) are unaffected by NBH but are readily reduced to the 2,3-dihydro derivatives with LAH, yielding the 2,3-dihydroperimidines 476. The perimidones and thiones 477 are readily reduced to 478 on treatment with LAH.225The
67,.
H
LiAlH,
R=alkyl
\
Me
‘R
*
Me
I
NaBH, or Me
LiAIH,
LiAIH,
Me
Me
\
(479)
(478)
(477)
x = 0,s 224
P. Neelakantan, N. Rao, U.T. Bhalerao, and G. Thyagarajan, Indian J. Chem. 11, 105 1
(1973). 225 A. F. Pozhankii and I. S . Kashparov, Khim. Geterotsikl. Soedin. 2, 860 (1972).
76
[Sec. VI1.M
JAMES G . KEAY
1,3-substituted quaternary salts 479 undergo facile reduction to 478 with both of the above metal hydrides.226
L. INDOLo[2,3-a]QUINOLIZINE Using NBH in trifluoroacetic acid has been shown to possess great utility for the reduction of indoles to indolines.lMThis ability has also been applied to the reduction of indole alkaloid^.^^^.^^^ Studies on the alkaloid I ,2,3,4,6,7,I2,12b-octahydroindolo[2,3-a]quinolizine(480) gave the 1,2,3,4,6,7,7a,12,12a,12b-decahydro derivative 481.229Preparation of the deuterated derivatives enabled the stereochemistry of the ring junction to be determined as cis from the coupling constants observed in the undeuterated sample. This is in agreement with the proposed intermediacy of a bis- or tris(trifluoroacetoxy)borohydride species (484, 485). These have a greater steric requirement than the monoacetate 483, which is generated when the reaction is conducted in THF,230giving a 20% yield of 481 along with a number of other stereo isomers (i.e., 482).
CF,COOBH,
(C F,COO),BH,
(44
(44
(C F,COO) ,BH (485)
M. PYRID0[3,2,1-k,/]PHENOTHIAZINES The reduction of the pyridophenothiazinium salts 486 in aprotic solvents leads to the I ,Zdihydro compounds 487, which are relatively unstable. In
226
V. I. Sokolov, A. F. Pozharskii, I. S. Kashparov, A. G . Ivanov, and B. 1. Ardashev, Khim. Geterotsikl. Soedin. 4, 558 (1974).
D. Herlern and F. K-Huu, Tetrahedron 35,633 (1979). J. Le Men, L. Le Men-Oliver, J. Levy, and M. C. Levy-Appert-Colin, German Patent 2,410,651 [CA 8 2 , 4 3 6 4 0 ~(1975)l. 22q G. W. Gribble, J. L. Johnson, and M. G. Saulnier, Heterocycles 16, 2109 (1981). 2M G. W. Gribble, W. J. Kelly, and S. E. Emery, Synthesis. 763 (1978). 227
228
REDUCTION OF NITROGEN HETEROCYCLES
Sec. VKM]
77
protic solvents with NBH the tetrahydro derivative 488 is formed.231Reduction of the 3-chloro derivative 486, (R = C1) gave the products 487 (R = H) and 488 ( R = H) when conducted in different solvents. This probably results from the formation of the dihydro intermediate 489 ( R = Cl), which rearomatizes with expulsion of the halogen. The reduction then continues as before.
a:2 +'
/
NaBH,
THF
(44
I
NaBH, EtOH
U
(487)
R
(488)
R = H,CI,Ph
R =CI
ACKNOWLEDGMENTS
The author is most grateful to Dr. Eric F. V. Scriven for his continuous advice and support during the preparation of this manuscript. Dr. Robert E. Lyle generously supplied many references and undertook the reading of an early draft. Mr. Don Galow assisted with electronic data retrieval and the task of typing the manuscript was completed by Ms. Anita Brown. Indulgence by Reilly Tar & Chemical Corporation is deeply appreciated, along with that of my colleagues, in particular, Ms. Cheryl Huss. A debt of gratitude is also due my wife, Debi. The author remains solely responsible for errors and omissions.
231
A. R. Martin, S. H. Kim, G. W. Peng, G. V. Siegel, and T. J. Yale, J. Heterocycl. Chem. 15, 1331 (1978).