First direct reductive amination of mucochloric acid: a simple and efficient method for preparing highly functionalized alpha,beta-unsaturated gamma-butyrolactams.

Article abstract of DOI:10.1021/ol0274662

[reaction: see text] The first direct reductive amination of mucochloric acid (1) has been accomplished. Reaction of 1 with various alkyl, aryl, and benzylamines, followed by reduction in the same pot, provides an efficient method of obtaining N-benzyl-3,4-dichloro-1,5-dihydro-pyrrol-2-one and N-aryl (or alkyl)-3,4-dichloro-1,5-dihydro-pyrrol-2-ones.

Full text of DOI:10.1021/ol0274662

ORGANIC
LETTERS
2003
Vol. 5, No. 4
553-556
First Direct Reductive Amination of
Mucochloric Acid: A Simple and
Efficient Method for Preparing Highly
Functionalized r,â-Unsaturated
γ-Butyrolactams
Ji Zhang,* Peter G. Blazecka, and James G. Davidson
Chemical Research and DeVelopment, Pfizer Global Research & DeVelopment,
Ann Arbor Laboratories, Pfizer, Inc., 2800 Plymouth Road,
Ann Arbor, Michigan 48105
ji.zhang@pfizer.com
Received December 13, 2002
ABSTRACT
The first direct reductive amination of mucochloric acid (1) has been accomplished. Reaction of 1 with various alkyl, aryl, and benzylamines,
followed by reduction in the same pot, provides an efficient method of obtaining N-benzyl-3,4-dichloro-1,5-dihydro-pyrrol-2-one and N-aryl (or
alkyl)-3,4-dichloro-1,5-dihydro-pyrrol-2-ones.
The γ-butyrolactam (pyrrolidinone or γ-lactam) skeleton
exists throughout nature and is present in many bioactive
natural products;1 it also serves as a key intermediate in the
synthesis of biologically and pharmaceutically useful mol-
ecules.2 For example, Ennis and co-workers3 used a chiral
polycyclic lactam to prepare cis-fused bicyclic pyrrolidine
U-93385, a potent serotonin 1A agonist. Recently, Snider
and his team4 finished the total synthesis of racemic
martinellic acid, a novel non-peptide antagonist for the
bradykinin (BK) B1 and B2 receptor. Reduction of the
pyrrolidinone to an amino alcohol, a key step, was achieved
by careful selection of the reducing agent. A short time ago,
Duan and co-workers5 reported development of a new series
of selective TACE inhibitors based on a γ-lactam scaffold.
These compounds may have potential use in the treatment
of rheumatoid arthritis.
The γ-butyrolactam skeleton can be viewed as the
dehydration product of γ-aminobutyric acid (GABA),6 one
of the most abundant inhibitory neurotransmitters. Several
successful pharmaceutical products and drug candidates such
as Neurontin, (R)-Baclofen, and CI-1008 (Pregabalin) are
γ-amino acids.7 The γ-lactams Rolipram and Rolicyprine are
antidepressant agents.8 Generally speaking, γ-amino acids
(1) (a) Corey, E. J.; Li, W.-D. Chem. Pharm. Bull. 1999, 47, 1. (b)
Baldwin, J. E.; Lynch, G. P.; Pitlik, J. J. Antibiot. 1991, 44, 1.
(2) (a) Yee, N. K.; Dong, Y.; Kapadia, S. R.; Song, J. J. J. Org. Chem.
2002, 67, 8688. (b) Xie, X.; Lu, X.; Liu, Y.; Xu, W. J. Org. Chem. 2001,
66, 6545.
(3) Ennis, M. D.; Hoffman, R. L.; Ghazal, N. B.; Old, D. W.; Mooney,
P. A. J. Org. Chem. 1996, 61, 5813.
(5) Duan, J. J.-W.; Chen, L.; Wasserman, Z. R.; Lu, Z.; Liu, R.-Q.;
Covington, M. B.; Qian, M.; Hardman, K. D.; Magolda, R. L.; Newton, R.
C.; Christ, D. D.; Wexler, R. R.; Decicco, C. P. J. Med. Chem. 2002, 45,
4954.
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Am. Chem. Soc. 1999, 121, 7751. (b) Silverman, R. B.; Bichler, K. A.;
Leon, A. J. J. Am. Chem. Soc. 1996, 118, 1253. (c) Silverman, R. B.; Bichler,
K. A.; Leon, A. J. J. Am. Chem. Soc. 1996, 118, 1241.
(4) Snider, B. B.; Ahn, Y.; O’Hare, S. M. Org. Lett. 2001, 3, 4217.
10.1021/ol0274662 CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/28/2003

serve as precursors to γ-lactams,9 but in some cases γ-lactams
can be transformed into the corresponding γ-amino acid.10
Furthermore, the γ-butyrolactam can be converted to
pyrrolidine by reduction.11 Pyrrolidines are ubiquitous struc-
tural motifs in drugs and potential drug candidates such as
antidepressants,12 antimicrobials,13 antihypertensives,14 an-
tiarthritics,15 antivirals,16 and antinociceptive agents.17 Sin-
garam and co-workers recently reported the facile reduction
of N-alkyl lactams to the corresponding pyrrolidines in
excellent yields using lithium aminoborohydrides.18
and has attracted our attention recently.20 It has one carbon-
carbon double bond with (Z)-configuration, two halogen
atoms, and two carbonyl groups possessing different reactiv-
ity. Surprisingly, this C-4 building block is not often used
in organic synthesis, presumably for reasons of its many
reactive sites, poor stability under basic conditions, and
assumed difficulty in the selective manipulation of its halogen
atoms. Therefore, we sought to develop a manifold for
selective manipulation of this densely functionalized mol-
ecule.
It has long been known that 1 and 2 (mucobromic acid)
react with hydrazine (3) or arylhydrazines 4 to form
pyridazinones 5 in acetic acid medium (Figure 1).21 This
Considering the close relationship among γ-lactams,
γ-amino acids, and pyrrolidine and their potential benefit in
drug discovery and development, we set out to develop a
method for preparing highly functionalized R,â-unsaturated
γ-butyrolactams.19 Mucochloric acid (1, 3,4-dichloro-5-
hydroxy-5H-furan-2-one) is a commercially available and
inexpensive starting material with multiple functional groups
(7) (a) Warner-Lambert; Neurontin (gabapentin). U.S. Patent 4,024,175,
1977. (b) Doyle, M. P.; Hu, W. Chirality 2002, 14, 169. Carpes, M. J. S.;
Correia, C. R. D. Tetrahedron Lett. 2002, 43, 741. Corey, E. J.; Zhang,
F.-Y. Org. Lett. 2000, 2, 4257. (c) Hoekstra, M. S.; Sobieray, D. M.;
Schwindt, M. A.; Mulhern, T. A.; Grote, T. M.; Huckabee, B. K.;
Hendrickson, V. S.; Franklin, L. C.; Granger, E. J.; Karrick, G. L. Org.
Process Res. DeV. 1997, 1, 26.
Figure 1. Condensation of mucohalic acids with hydrazines.
(8) (a) Itoh, K.; Kanemasa, S. J. Am. Chem. Soc. 2002, 124, 13394. (b)
Barnes, D. M.; Ji, J.; Fickes, M. G.; Fitzgerald, M. A.; King, S. A.; Morton,
H. E.; Plagge, F. A.; Preskill, M.; Wagaw, S. H.; Wittenberger, S. J.; Zhang,
J. J. Am. Chem. Soc. 2002, 124, 13097. (c) Anada, M.; Mita, O.; Watanabe,
H.; Kitagaki, S.; Hashimoto, S. Synlett 1999, 1775. (d) Diaz, A.; Siro, J.
G.; Garcia-Navio, J. L.; Vaquero, J. J.; Alvarez-Builla, J. Synthesis 1997,
559. (e) Meyers, A. I.; Snyder, L. J. Org. Chem. 1993, 58, 36. (f) Mulzer,
J.; Zuhse, R.; Schmiechen, R. Angew. Chem., Int. Ed. Engl., 1992, 31, 870.
(g) Goldenthal, E. I. Toxicol. Appl. Pharmacol. 1971, 18, 185.
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Lett. 1997, 38, 5503.
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1999, 40, 3233. (c) Galeazzi, R.; Mobbili, G.; Orena, M. Tetrahedron:
Asymmetry 1997, 8, 133. (d) Nebois, P.; Greene, A. E. J. Org. Chem. 1996,
61, 5210. (e) Gennari, C.; Pain, G.; Moresca, D. J. Org. Chem. 1995, 60,
6248. (f) Wei, Z.-Y.; Knaus, E. E. Tetrahedron 1994, 50, 5569.
(11) Collins, C. J.; Lanz, M.; Singaram, B. Tetrahedron Lett. 1999, 40,
3673 and references therein.
prompted us to investigate the reactions of 1 or 2 with aniline
or benzylamine in acetic acid, including reductive amination.
The reaction products would be useful as intermediates in
organic synthesis, especially in the synthesis of many
biologically active heterocycles such as substituted 1,5-
dihydro-pyrrol-2-ones,22 other γ-lactams,23 and pyrrolidines.24
Herein we report the first direct reductive amination of
mucochloric acid (1).
The reaction between 1 and benzylamine (6) was selected
initially (Table 1). A 1:1 v/v mixture of dichloromethane
(12) Nagai, Y.; Uno, H.; Umemoto, S. Chem. Pharm. Bull. 1977, 25,
1911.
Table 1. Reductive Amination in Different Solventsa
(13) (a) Ma, Z.; Chu, D. T. W.; Cooper, C. S.; Li, Q.; Fung, A. K. L.;
Wang, S.; Shen, L. L.; Flamm, R. K.; Nilius, A. M.; Alder, J. D.; Meulbroek,
J. A.; Or, Y. S. J. Med. Chem. 1999, 42, 4202. (b) Hong, C. Y.; Kim, Y.
K.; Chang, J. H.; Kim, S. H.; Choi, H.; Nam, D. H.; Kim, Y. Z.; Kwak, J.
H. J. Med. Chem. 1997, 40, 3584.
(14) (a) Hanessian, S.; Claridge, S.; Johnstone, S. J. Org. Chem. 2002,
67, 4261. (b) Das, J.; Floyd, D. M.; Kimball, S. D.; Duff, K. J.; Lago, M.
W.; Krapcho, J.; White, R. E.; Ridgewell, R. E.; Obermeier, M. T.; et al.
J. Med. Chem. 1992, 35, 2610.
entry
solvent
yield (%)b
(15) (a) Lee, D.; Long, S. A.; Murray, J. H.; Adams, J. L.; Nuttall, M.
E.; Nadeau, D. P.; Kikly, K.; Winkler, J. D.; Sung, C.-M.; Ryan, M. D.;
Levy, M. A.; Keller, P. M.; DeWolf, W. E., Jr. J. Med. Chem. 2001, 44,
2015. (b) Chang, A.-C.; Cowan, A.; Takemori, A. E.; Portoghese, P. S. J.
Med. Chem. 1996, 39, 4478.
(16) (a) Andrews, D. M.; Chaignot, H.; Coomber, B. A.; Good, A. C.;
Hind, S. L.; Johnson, M. R.; Jones, P. S.; Mills, G.; Robinson, J. E.;
Skarzynski, T.; Slater, M. J.; Somers, D. O. Org. Lett. 2002, 4, 4479. (b)
Andrews, D. M.; Carey, S. J.; Chaignot, H.; Coomber, B. A.; Gray, N. M.;
Hind, S. L.; Jones, P. S.; Mills, G.; Robinson, J. E.; Slater, M. J. Org. Lett.
2002, 4, 4475.
1
2
3
4
5
6
7
8
1:1 CH2Cl2/HOAc
1,4-dioxane
THF
CH3CN
DCE
CHCl3
CH3NO2
CHCl3
46
48
52
49
68
66
35
76
a Reaction conditions: 1 equiv of 1, 1.1 equiv of 6, 1.5 equiv of
NaBH(OAc)3, 24 h at room temperature. A catalytic amount of HOAc was
used in entries 2-8. The reaction time was not optimized. A reaction time
of 48 h and 1.5 equiv of 6 was used in entry 8. b Products were isolated
and purified by silica gel chromatography and/or crystallization. Isolated
yields are averages of two runs, and products are estimated to be >95%
pure by 1H NMR and elemental analysis. All compounds gave satisfactory
elemental analysis data.
(17) (a) Vecchietti, V.; Clarke, G. D.; Colle, R.; Dondio, G.; Giardina,
G.; Petrone, G.; Sbacchi, M. J. Med. Chem. 1992, 35, 2970. (b) Vecchietti,
V.; Clarke, G. D.; Colle, R.; Giardina, G.; Petrone, G.; Sbacchi, M. J. Med.
Chem. 1991, 34, 2624.
(18) Flaniken, J. M.; Collins, C. J.; Lanz, M.; Singaram, B. Org. Lett.
1999, 1, 799.
(19) Chatani, N.; Kamitani, A.; Murai, S. J. Org. Chem. 2002, 67, 7014.
(20) Zhang, J.; Blazecka, P. G.; Belmont, D.; Davidson, J. G. Org. Lett.
2002, 4, 4559.
554
Org. Lett., Vol. 5, No. 4, 2003

but a solvent screen revealed that 7 could be obtained in
66-76% yield once the amount of acetic acid was reduced.
The reaction has been further extended to anilines, with
electron-donating, electron-withdrawing, and neutral sub-
stituents (Table 2).26 Electron-deficient (entries 2, 3, and 7)
and electron-rich (entries 1, 4, and 5) anilines reacted with
almost equal facility.
Table 2. Reductive Amination with Different Anilinesa
Mucochloric acid (1) can exist as the open or cyclic form
(Figure 2).27 However, the ultraviolet spectrum in CHCl3
indicates that 1 exists predominantly in the lactone form.28
Figure 2. Equilibria of mucochloric and mucobromic acids.
Additional spectral data, i.e., vibrational (IR, Raman)29 and
others (NMR and NQR)30 suggest that the lactone is the
dominant form in both the liquid and solid states. Experi-
(21) (a) Koenig, H. Angew. Chem. GE 1980, 92, 802. (b) Bistrzycki, H.
Chem. Ber. 1901, 34, 1014.
(22) (a) Bandini, E.; Martelli, G.; Spunta, G.; Bongini, A.; Panunzio,
M.; Piersanti, G. Tetrahedron: Asymmetry 1999, 10, 1445. (b) Giambastiani,
G.; Pacini, B.; Porcelloni, M.; Poli, G. J. Org. Chem. 1998, 63, 804 and
references therein.
(23) (a) Yoon, C. H.; Zaworotko, M. J.; Moulton, B.; Jung, K. W. Org.
Lett. 2001, 3, 3539 and references therein. (b) Boivin, J.; Yousfi, M.; Zard,
S. Z. Tetrahedron Lett. 1994, 35, 5629. (c) Chatterjee, B. G.; Sahu, D. P.
J. Org. Chem. 1977, 42, 3162. (d) Giering, W. P.; Raghu, S.; Rosenblum,
M.; Cutler, A.; Ehtholt, D.; Fish, R. W. J. Am. Chem. 1972, 94, 8251.
(24) (a) Dieter, R. K.; Lu, K.; J. Org. Chem. 2002, 67, 847. (b) Dieter,
R. K.; Lu, K. Tetrahedron Lett. 1999, 40, 4011. (c) Katritzky, A. R.; Cui,
X.-L.; Yang, B.; Steel, P. J. J. Org. Chem. 1999, 64, 1979. (d) Katritzky,
A. R.; Cui, X.-L.; Yang, B.; Steel, P. J. Tetrahedron Lett. 1998, 39, 1698.
(e) Pearson, W, W. H.; Clark, R. B. Tetrahedron Lett. 1997, 38, 7669. (f)
Denmark, S. E.; Marcin, L. R. J. Org. Chem. 1995, 60, 3221. (g) Larock,
R. C.; Yang, H.; Weinreb, S. M.; Herr, R. J. J. Org. Chem. 1994, 59, 4172.
(h) Zhou, J. Q.; Alper, H. J. Org. Chem. 1992, 57, 3328. (i) Padwa, A.;
Nimmesgern, H.; Wong, G. S. K. Tetrahedron Lett. 1985, 26, 957. (j)
Overman, L. E.; Kakimoto, M.; Okazaki, M. E.; Meier, G. P. J. Am. Chem.
Soc. 1983, 105, 6622. (k) Padwa, A.; Chen, Y. Y. Tetrahedron Lett. 1983,
24, 3447.
(25) (a) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff,
C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849. (b) Abdel-Magid, A. F.;
Maryanoff, C. A.; Carson, K. G. Tetrahedron Lett. 1990, 31, 5595.
(26) For another method of preparing N-aryl heterocycles, see: (a)
Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
7421. (b) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am.
Chem. Soc. 2001, 123, 7727.
(27) It is interesting to note that several fine chemical manufacturers’
catalogs list 1 only as the open form, whereas The Merck Index suggests
the existence of an equilibrium between the open and cyclic forms: (a)
The Merck Index, 12th ed.; Merck & Co., Inc.: Whitehouse, NJ, 1996; p
1079. (b) 2003-2004 Aldrich Handbook of Fine Chemicals and Laboratory
Equipment; Aldrich Chemical Co., Inc.: Milwaukee, WI, 2003; p 1313.
(c) Acros Organics 2002/03 Catalog of Organics and Fine Chemicals; Fisher
Scientific Company, L.L.C.: Pittsburgh, PA, 2002; p 1523. (d) Lancaster
2002-3 Research Chemicals Catalog; Lancaster Synthesis, Inc.: Windham,
NH, 2002; p 1304.
a Reaction conditions (except for entry 1): 1 equiv of 1, 1.0 equiv of
aniline, 3.0 equiv of NaBH(OAc)3, 5:3 v/v CH2Cl2/HOAc, 24 h at room
temperature. Reaction conditions for entry 1: 1 equiv of 1, 1.1 equiv of
aniline, 1.5 equiv of NaBH(OAc)3, CHCl3 (cat. HOAc), 24 h at room
temperature. The reaction time was not optimized. b Products were isolated
and purified by silica gel chromatography and/or crystallization. Products
are estimated to be >95% pure by 1H NMR and elemental analysis. All
compounds gave satisfactory elemental analysis data.
and acetic acid was chosen as the solvent to maintain the
stability and solubility of both starting materials. A mild
reductive amination reagent, sodium triacetoxyborohydride,25
was used, and the reactions were conducted at room
temperature. Initially γ-lactam 7 was isolated in 46% yield,
(28) (a) Wasserman, H. H.; Precopio, F. M. J. Am. Chem. Soc. 1952,
74, 326. (b) Mowry, D. T. J. Am. Chem. Soc. 1950, 72, 2535.
(29) Moore, R. D.; Katon, J. E. Appl. Spectrosc. 1978, 32, 145.
(30) Valente, E. J.; Fuller, J. F.; Ball, J. D. Acta Crystallogr., Sect. B.
Struct. Sci. 1998, B54, 162.
Org. Lett., Vol. 5, No. 4, 2003
555

mental results further support these observations. Thus, a
possible mechanism for forming lactam 7 is proposed in
Scheme 1.
Table 3. Reductive Amination with Different Aminesa
Scheme 1. Proposed mechanism of reductive amination
In accordance with the proposed mechanism, removing
water will favor formation of the desired lactams. Therefore,
4 Å molecular sieves were added to the reaction mixture
and the chemical yield was increased from 76 to 85% (Table
1, entry 8; Table 3, entry 2). We also successfully introduced
chirality into the lactam system by using chiral amines 21-
24.
a Reaction conditions: 1 equiv of 1, 1.1 equiv of amine, 1.5 equiv of
NaBH(OAc)3, CHCl3 (cat. HOAc), 24 h at room temperature. The reaction
time was not optimized. b Products were isolated and purified by silica gel
chromatography and/or crystallization. Products are estimated to be >95%
pure by 1H NMR and elemental analysis. All compounds gave satisfactory
elemental analysis data. c Used 4 Å molecular sieves.
In summary, we have developed a simple, efficient, and
selective method for preparing N-benzyl-3,4-dichloro-1,5-
dihydro-pyrrol-2-one and N-aryl (or alkyl)-3,4-dichloro-1,5-
dihydro-pyrrol-2-ones.31 These products possess a geometri-
cally defined tetrasubstituted olefin and two differentiated
vinyl halides, and could be used in the synthesis of a variety
of compounds. Further investigations, including extension
of the use of these building blocks, will be reported in due
course.
Acknowledgment. We thank Dr. Derek Pflum and Dr.
Thomas Mulhern for reviewing this manuscript and providing
valuable suggestions.
Supporting Information Available: Experimental pro-
cedures, spectral and analytical data for all products, and
additional structures. This material is available free of charge
via the Internet at http://pubs.acs.org.
(31) Mucobromic acid (2) gave the corresponding bromides when
subjected to similar reaction conditions. Unpublished results.
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