Chemoselective reduction of a lactam carbonyl group in the presence of a gem-dicarboxylate by sodium borohydride and iodine: A facile entry to N-aryl trisubstituted pyrroles

Article abstract of DOI:10.1016/j.tetlet.2003.09.085

Several N-aryl γ-lactam gem dicarboxylates were chemoselectively reduced to cyclic amine diesters by using sodium borohydride-iodine system. The reduction in all cases was completed within 2.5 h after refluxing in THF. The cyclic amine products were isolated after aqueous (acidic) workup in good yields. Hydrolytic decarboxylation followed by dehydrogenation produced N-aryl carboethoxy pyrroles.

Full text of DOI:10.1016/j.tetlet.2003.09.085

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8229–8231
Chemoselective reduction of a lactam carbonyl group in the
presence of a gem-dicarboxylate by sodium borohydride and
iodine: a facile entry to N-aryl trisubstituted pyrroles
Pranab Haldar and Jayanta K. Ray*
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
Received 31 July 2003; revised 2 September 2003; accepted 11 September 2003
Abstract—Several N-aryl g-lactam gem dicarboxylates were chemoselectively reduced to cyclic amine diesters by using sodium
borohydride–iodine system. The reduction in all cases was completed within 2.5 h after refluxing in THF. The cyclic amine
products were isolated after aqueous (acidic) workup in good yields. Hydrolytic decarboxylation followed by dehydrogenation
produced N-aryl carboethoxy pyrroles.
© 2003 Elsevier Ltd. All rights reserved.
The reduction of a tertiary lactam to the corresponding
cyclic tertiary amine is of interest in both natural
products1 and synthetic chemistry.2 In order to utilize
synthetic g-lactams having two functional groups, viz.
lactam carbonyl and ester carbonyl groups, we were
eager to develop a methodology which could chemose-
lectively reduce the carbonyl group of a lactam in the
presence of two or more other carbonyl groups preserv-
ing the integrity of stereogenic centers in the substrate.
plished with diborane,6 9-BBN (for N-alkyl lactams)7
and LiEt3BH/Et3SiH-Et2O·BF3 (for N-Boc protected
lactams).8 The use of a large excess of BH3·SMe2 is
9
reported to reduce lactams in the presence of both
esters and carbamates. Various five- and six-membered
N-alkyl lactams have been reduced (nonselectively) to
the corresponding cyclic amines by using lithium N,N-
dialkylaminoborohydrides,10 but these reagents suffer
from disadvantages of cost, inflammability and tedious
isolation procedures.
The selectively reduced products were to be utilized for
the synthesis of poly substituted pyrrole derivatives
which constitute an important class of synthetic
pharmaceuticals3 and natural products with fungicidal
and insecticidal activities and which also constitute the
building blocks for porphyrin ring systems present in
chlorophyll, heme, Vitamin B12 and the bile pigments.4
Additionally, there are a number of pyrrole containing
small molecules that exhibit useful biological activities.5
It has been reported that carboxylic acid esters and
amides are reduced to the corresponding alcohols and
amines using NaBH4/ZnCl2 in THF11 in the presence of
a tertiary amine and also with NaBH4–I2 in dry THF12
under refluxing conditions. The NaBH4–I2 system is
also useful for the chemoselective reduction of lactams
in the presence of urethane functionality but with
higher reduction times.13
Selective reductions of lactam carbonyls in the presence
of other reducible groups have usually been accom-
In our present work we have synthesized N-aryl-3-aryl/
heteroaryl-2,2-dicarbethoxypyrrolidines through the
Scheme 1.
Keywords: chemoselective; lactam; reduction; pyrrole.
* Corresponding author. Tel.: +91-3222-283326; fax: +91-3222-282252; e-mail: jkray@chem.iitkgp.ernet.in
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.085

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P. Haldar, J. K. Ray / Tetrahedron Letters 44 (2003) 8229–8231
monoester 3, which was converted to the substituted
pyrrole derivative 417b by dehydrogenation using DDQ
(Scheme 3).
In conclusion, we have developed a novel method16 for
the chemoselective reduction of lactam carbonyl groups
in presence of geminal diesters, in one step, with good
yields that will provide a simple and novel approach for
the conversion of g-lactam derivatives to tri-substituted
pyrroles.
Scheme 2.
highly chemoselective reduction of lactam carbonyls in
the presence of geminal diester groups by sodium boro-
hydride and iodine. This serves as a very simple and
novel methodology to synthesize bioactive substituted
pyrrole derivatives starting from g-lactam derivatives.
The reagent system used is safe, simple and inexpensive.
Acknowledgements
We are thankful to CSIR and DRDO (New Delhi) for
financial assistance and Mr. Sujit Thakur for some
preliminary work on this project.
The g-lactam diesters 1a–e were prepared following the
general method14,15 developed in our laboratory. The
novel fluoro analogs 1f–j were synthesized following the
same protocol starting from 4-fluoroanilinomalonates
and 3,4-difluoroanilinomalonate through intermolecu-
lar Michael reactions, followed by intramolecular
amide formation (Scheme 1).
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Table 1. Synthesis of pyrrolidines (2a–j) from pyrrolidin-2-ones (1a–j)
Pyrrolidin-2-one
Ar
Ar1
Pyrrolidine
Yield (%)
1a
1b
1c
1d
1e
1f
1g
1h
1i
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-CH3-C6H4
4-CH3-C6H4
4-F-C6H4
4-F-C6H4
4-F-C6H4
4-F-C6H4
3,4-Difluorophenyl
Phenyl
2a
2b
2c
2d
2e
2f
2g
2h
2i
84
81
80
83
77
83
78
78
79
82
2-Thienyl
2-Naphthyl
Phenyl
2-Thienyl
Phenyl
2-Furyl
2-Thienyl
2-Napthyl
Phenyl
1j
2j
Scheme 3.

P. Haldar, J. K. Ray / Tetrahedron Letters 44 (2003) 8229–8231
8231
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mmol) in dry THF (20 ml) a solution of iodine (3 mmol)
in dry THF (5 ml) was added dropwise under an argon
atmosphere at 0°C over 45 min. Next lactamdiester (1
mmol) in dry THF (5 ml) was added to the reagent mixture,
which was stirred at 25–30°C for 2 h. Then the mixture was
refluxed for 20 min, cooled to 0°C and the excess hydride
was carefully destroyed with 3N HCl, neutralized with 3N
NaOH. The organic layer was separated and the aqueous
layer was extracted with ether. The combined organic
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a.
1-(4-Chlorophenyl)-2,2-dicarbethoxy-3-phenylpyrro-
1
lidine (2a): H NMR (200 MHz, CDCl3): l 0.87 (t, 3H,
Jꢀ7.2 Hz), 1.16 (t, 3H, Jꢀ7.2 Hz), 2.38–2.57 (m, 2H),
3.64–3.91 (m, 4H), 4.14–4.24 (m, 3H), 6.54–6.62 (m, 2H),
7.09–7.17 (m, 2H), 7.21–7.34 (m, 5H). 13C NMR (50 MHz,
CDCl3): l 13.49, 13.97, 28.94, 50.07, 55.06, 61.37, 61.84,
115.47, 122.78, 128.22, 128.30, 128.46, 137.88, 144.31,
167.87, 169.40
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b. 1-(4-Chlorophenyl)-2-carbethoxy-3-phenyl-1H-pyrrole
(4): 1H NMR (200 MHz, CDCl3): l 0.95 (t, 3H, Jꢀ7.1 Hz),
4.00–4.04 (m, 2H), 6.37–6.38 (d, 1H, Jꢀ2.6 Hz), 6.89–6.91
(d, 1H, Jꢀ2.7 Hz), 7.18–7.20 (d, 2H, Jꢀ2.45 Hz), 7.22–
7.24 (d, 2H, Jꢀ2.45 Hz), 7.30–7.53 (m, 5H). 13C NMR (50
MHz, CDCl3): l 13.63, 60.24, 111.78, 112.19, 125.55,
127.09, 127.31, 127.64, 127.81, 128.05, 128.87, 129.54,
130.26, 131.90, 132.57, 135.02, 135.56, 140.31, 160.82.