NaBH4-InCl3-mediated one-pot chemo- and stereoselective decarboxylative reduction of α-aza gem-dicarboxylic esters to monoalcohols

Article abstract of DOI:10.1021/ol051453h

(Chemical Equation Presented) The combination of NaBH₄ and a catalytic amount of InCl₃ provides a one-pot method for chemo- and stereoselective decarboxylative reduction of gem-dicarboxylic esters 1 to monoalcohols 2 in the presence

Full text of DOI:10.1021/ol051453h

ORGANIC
LETTERS
2005
Vol. 7, No. 20
4341-4343
NaBH4
and Stereoselective Decarboxylative
Reduction of -Aza gem-Dicarboxylic
−InCl3-Mediated One-Pot Chemo-
r
Esters to Monoalcohols
Pranab Haldar and Jayanta K. Ray*
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
jkray@chem.iitkgp.ernet.in
Received June 22, 2005
ABSTRACT
The combination of NaBH4 and a catalytic amount of InCl3 provides a one-pot method for chemo- and stereoselective decarboxylative reduction
of gem-dicarboxylic esters 1 to monoalcohols 2 in the presence of the lactam carbonyl in refluxing acetonitrile under inert atmosphere.
The reduction of carboxylic esters to monoalcohols in the
γ-lactam moiety is an important multistep transformation in
synthetic organic chemistry.1 This type of transformation has
traditionally been accomplished with lithium borohydride2
(LiBH4), but the reduction is often accompanied by the
cleavage of lactam ring via carbon-nitrogen bond fissions.3
Due to the lack of a proper reducing agent, the selective
decarboxylative reduction of gem-dicarboxylic esters to
monoalcohols in a single step is a challenging problem in
synthetic organic chemistry.
To the best of our knowledge, to date there is no report
of single-step chemo- and stereoselective decarboxylative
reduction of gem-dicarboxylic esters to monoalcohols in the
presence of a lactam, though this one-pot transformation
would be very useful for the synthesis of various bioactive
compounds.1,2,4
Recently, we reported a chemoselective reduction of
γ-butyrolactams to tetrahydro pyrroles with NaBH4-I2 in
the presence of geminal dicarboxylic esters.5 Herein we are
eager to report on our study to explore a reagent system that
could chemoselectively as well as stereoselectively reduce
the gem-dicarboxylic esters of various 1,4-diarylpyrrolidin-
2-one-5,5-dicarboxylic esters to the corresponding 5-hy-
droxymethyl derivatives in one step, keeping the lactam
carbonyl intact.
A literature survey shows that dichloroindium hydride6
(Cl2InH), generated in situ from sodium borohydride and a
catalytic amount of indium trichloride, is a very good re-
agent system for the dehalogenation of alkyl halides,6 radi-
cal cyclization,6 selective reduction of Vic-dibromides,7
reductive cleavage of the C-O bond8 in 2,3-epoxy bro-
mides, and the selective reduction of carbon-carbon double
bonds.9
In view of the novel pattern of reactivity of NaBH4-InCl3
reagent system, we became interested in exploring its
reactivity toward the reduction of γ-lactam-5,5-dicarboxylic
(1) (a) Hartwig, W.; Benz, U. Ger. Offen. 1988, 3624102. (b) Hartwig,
W. Ger. Offen. 1987, 3632589. (c) Hartwig, W. Ger. Offen. 1987, 3537075.
(2) Silverman, R. B.; Nanavati, S. M. J. Med. Chem. 1990, 33, 931.
(3) (a) Soai, K.; Ookawa, A. J. Org. Chem. 1986, 51, 4000. (b) Penning,
T. D.; Djuric, S. W.; Haack, R. A.; Kalish, V. J.; Miyashiro, J. M.; Rowell,
B. W.; Yu, S. S. Synth. Commun. 1990, 20, 307. (c) Snider, B. B.; Ahn,
Y.; Foxman, B. M. Tetrahedron Lett. 1999, 40, 3339.
(4) (a) Atigadda, V. R.; Brouillette, W. J.; Duarte, F.; Ali, S. M.; Babu,
Y. S.; Bantia, S.; Chand, P.; Chu, N.; Montgomery, J. A.; Walsh, D. A.;
Sudbeck, E. A.; Finley, J.; Luo, M.; Air, G. M.; Laver, G. W. J. Med.
Chem. 1999, 42, 2332. (b) Barco, A.; Benetti, S.; Pollini, G. P.; Baraldi, P.
G.; Guarneri, M.; Gandolfi, C.; Ceserani, R.; Longiave, D. J. Med. Chem.
1981, 24, 625.
(5) Haldar, P.; Ray, J. K. Tetrahedron Lett. 2003, 44, 8229.
(6) Inoue, K.; Sawada, A.; Shibata, I.; Baba, A. J. Am. Chem. Soc. 2002,
124, 906.
(7) Ranu, B. C.; Das, A.; Hajra, A. Synthesis 2003, 7, 1012.
(8) Ranu, B. C.; Banerjee, S.; Das, A. Tetrahedron Lett. 2004, 45, 8579.
(9) (a) Ranu, B. C.; Samanta, S. Tetrahedron Lett. 2002, 43, 7405. (b)
Ranu, B. C.; Samanta, S. Tetrahedron 2003, 59, 7901. (c) Ranu, B. C.;
Samanta, S. J. Org. Chem. 2003, 68, 7130.
10.1021/ol051453h CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/03/2005

esters, and herein we are gratified to report an exclusively
novel and efficient method for the chemo- and stereoselective
reduction of gem-diesters to monoalcohols by using the
NaBH4-InCl3 reagent system. The ultimate utility of that
system extends to unexpected applications that were not
initially envisioned.
of 1c with KOH-H2O, EtOH, followed by in situ stereo-
selective decarboxylation.
Though the mechanism of the reaction is still uncertain,
but as the γ-lactam diester 1c and γ-lactam monoester 3 gave
the same reduced product 2c, we speculated that the
decarboxylative reduction to alcohols proceeds via an initial
stereoselective radical decarboxylation mediated by HInCl2
followed by chemoselective reduction of the ester functional-
ity. A plausible mechanism for the radical decarboxylation
is depicted in Scheme 3.
The starting materials for this study, 1,4-diarylpyrrolidin-
2-one-5,5-dicarboxylic esters 1, were synthesized following
the general method5,10 developed in our laboratory. Chemose-
lective and in situ stereoselective decarboxylative reduction
of these dicarboxylic esters with sodium borohydride and
catalytic indium trichloride in dry acetonitrile at reflux
temperature for 8-11 h, furnished exclusively trans-1,4-
diaryl-5-hydroxymethyl-pyrrolidin-2-ones 2 (Scheme 1) in
Scheme 3. Plausible Mechanism of Decarboxylation of
gem-Dicarboxylic Ester by HinCl2
Scheme 1. Reduction of γ-Lactam-5,5-dicarboxylic Esters 1
to Alcohols 2
high yields (Table 1). The trans geometry of the product
has been elucidated by single-crystal-X-ray11 and also by
Table 1. Synthesis of 5-Hydroxymethyl γ-Lactams 2 from
γ-Lactam 5,5-Dicarboxylic Esters 1
Alternatively the first carbon radical may easily break into
carbon monoxide and EtOInCl2.
The pleasing outcome of the above reaction prompted us
to extend this method to include other substrates. We selected
the amine derivatives diethyl 1-(4-fluorophenyl)-4-phenyl-
pyrrolidine-2,2-dicarboxylate 45 (Scheme 4) and diethyl 2-(4-
substrate
Ar
Ar′
product yield (%)
1a
1b
1c
1d
1e
1f
phenyl
phenyl
phenyl
phenyl
2- furyl
2-thienyl
2a
2b
2c
2d
2e
2f
84
81
83
79
77
79
82
80
4-Cl-C6H4
4-F-C6H4
4-F-C6H4
4-F-C6H4
3,5-dichlorophenyl phenyl
3,4- difluorophenyl phenyl
1g
1h
2g
2h
Scheme 4. Reduction of Pyrrolidine-2,2-dicarboxylic Ester 4
by NaBH4-InCl3
3-Cl,4-F-C6H3
2-thienyl
matching the NMR spectra of product 2c obtained indepen-
dently from reductive decarboxylation of 1c (Table 1) and
the NaBH4-InCl3-mediated reduction of trans-monoester 3
(Scheme 2). Compound 3 was synthesized from the corre-
fluorophenylamino)malonate 6 (Scheme 5) to study the effect
of the amide (lactam) carbonyl on the outcome of the reac-
tion. While the reaction was successful, it was much slower
than those reported in Table 1; it took nearly 15 h for the
conversion of 4 to provide 5 in 62% yield and 6 to afford 7
in 38% yield.
Scheme 2. Reduction of γ-Lactam Monoester 3 to Alcohol 2c
(10) (a) Kar, G. K.; Ramesh, D.; Chatterjee, B. G.; Ray, J. K. J. Chem.
Res., Miniprint 1997, 568 and J. Chem. Res., Synop. 1997, 80. (b) Ray, J.
K.; Sami, I.; Kar, G. K.; Roy, B. C.; Brahma, N. K. Bioorg. Med. Chem.
1994, 2, 1417. (c) Kar, G. K.; Roy, B. C.; Adhikari, S. D.; Ray, J. K.;
Brahma, N. K. Bioorg. Med. Chem. 1998, 6, 2397.
sponding trans-1-(4-fluorophenyl)-4-phenylpyrrolidin-2-one-
5-carboxylic acid. The latter was synthesized by hydrolysis
(11) Haldar, P.; Ray, J. K. Unpublished data.
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Org. Lett., Vol. 7, No. 20, 2005

that a substrate “N” is essential for insitu dealkylative-
decarboxylation.
Scheme 5. Reduction of Diethyl Arylaminomalonate 6 by
NaBH4-InCl3
In conclusion, we have developed a novel and simple
method for the chemo- and stereoselective decarboxylative
reduction of gem-diesters to monoalcohols in the presence
of lactam carbonyls in one step with good yields. Certainly,
this demonstrates the potential of the NaBH4-InCl3 reagent
system as a stereoselective decarboxylative agent under
refluxing acetonitrile. To the best of our knowledge, this
constitutes the first efficient method of such selective
reduction of gem-diesters by NaBH4-InCl3, which is not
achievable by any other conventional reducing agents.
Furthermore, the reagent system used is safe and easy to
handle. The operational simplicity and selectivity of this one-
pot process probably opens up new opportunities for the use
of this transformation in synthetic industrial procesess by
reducing the number of steps in multistep synthetic proce-
dures, and definitely it broadens the preview of further
research in this area. Studies on the mechanistic aspects of
the reaction, in particular structural requirements of the
substrates, are underway.
To further test the generality of this reduction, and assess
the effect of NH on the reaction, we investigated the reduc-
tion of diethyl 2-benzylmalonate 812 as a substrate wherein
there is no N-atom R to the dicarboxylic esters. Under the
same reaction condition as before, the compound 8 under-
went reduction (Scheme 6) in much more slower rate, and
Scheme 6. Reduction of Diethyl 2-Benzylmalonate 8 by
NaBH4-InCl3
Acknowledgment. Financial support from DST (New
Delhi) and CSIR (New Delhi) (for a fellowship to P.H.) is
gratefully acknowledged. We are thankful to Prof. D. Mal,
IIT-Kharagpur, for helpful discussions.
after 20 h it was converted to 2-benzylpropane-1,3-diol 913
in 14% yield. Increase in the reaction time up to 42 h
increased the yield of the product 9 to 32%. So, it is apparent
Supporting Information Available: Analytical and
spectroscopic data of compounds 2a-h, 5, and 7. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(12) Wu, Z.; Minhas, G. S.; Wen, D.; Jiang, H.; Chen, K.; Zimniank,
P.; Zheng, J. J. Med. Chem. 2004, 47, 3282.
(13) (a) Perlman, N.; Livneh, M.; Albeck, A. Tetrahedron 2000, 56, 1505.
(b) Itoh, T.; Chika, J.; Takagi, Y.; Nishiyama, S. J. Org. Chem. 1993, 58,
5717. (c) Mori, I.; Ishihara, K.; Flippin, L. A.; Nozaki, K.; Yamamoto, H.;
Bartlett, P. A.; Heathcock, C. H. J. Org. Chem. 1990, 55, 6107.
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