Simple and efficient synthesis of substituted 2-pyrrolidinones, 2-pyrrolones, and pyrrolidines from enaminones of Baylis-Hillman derivatives of 3-isoxazolecarbaldehydes

Article abstract of DOI:10.1021/jo048411b

(Chemical Equation Presented). The enaminones, generated from derivatives of appropriately substituted Baylis-Hillman adducts of 3-isoxazolecarbaldehydes, undergo intramolecular ring-closure reactions to afford substituted 2-pyrrolidinones, 1,5-dihydro-2-

Full text of DOI:10.1021/jo048411b

simple and efficient synthesis of pyrrolidinone and pyr-
rolidine derivatives exists.
Simple and Efficient Synthesis of
Substituted 2-Pyrrolidinones, 2-Pyrrolones,
and Pyrrolidines from Enaminones of
Baylis-Hillman Derivatives of
The facile cleavage of the N-O bond experienced by
the isoxazole nucleus under simple reaction conditions
makes it an important synthetic intermediate for the
construction of arrays of molecular assemblies including
different heterocycles and natural products.12 As a part
of our ongoing research program for studying the syn-
thetic utility of the isoxazole derivatives, obtained as
products of Baylis-Hillman reaction of different isox-
azolecarbaldehydes,13 we envisioned the synthesis of
2-pyrrolidinones from derivatives of the Baylis-Hillman
adducts of 3-isoxazolecarbaldehydes. The details of this
study are presented here.
3-Isoxazolecarbaldehydes§,‡
Vijay Singh, Rashmi Saxena, and Sanjay Batra*
Medicinal Chemistry Division, Central Drug Research
Institute, Lucknow 226 001, India
batra_san@yahoo.co.uk
Received September 9, 2004
During the studies on the synthesis of the corrin
frameworks, Stevens14 reported that an appropriately
substituted isoxazole derivative upon hydrogenolysis led
to the formation of the 2-pyrrolidinone derivative. Simi-
larly, Jones et al.15 reported that the appropriately
substituted isoxazole derivative under Pd/C-promoted
hydrogenation affords the 2-pyrrolidinone derivative in
good yield, but both these reports dealt with only limited
substrates. On the basis of these reports, we have
reasoned that derivatives of the Baylis-Hillman adduct,
obtained by reacting substituted 3-isoxazolecarbalde-
hydes with acrylates, upon hydrogenolysis, would lead
to enaminones which could undergo intramolecular cy-
clization involving the amino and the ester groups to yield
substituted 2-pyrrolidinone derivatives. However, during
the detailed catalytic hydrogenation studies of Baylis-
Hillman derivatives reported recently by us we were
unsuccessful in this direction.16 Attempts with the Pd/
C-promoted hydrogenolysis followed by cyclization as
reported by Jones et al. also failed to work with these
derivatives. However, this impediment has now been
removed by carrying out Raney-Ni-promoted hydro-
genolyses of Baylis-Hillman derivatives 4a-e and
5a-e. The synthesis of starting substrates (4a-e and
The enaminones, generated from derivatives of appropriately
substituted Baylis-Hillman adducts of 3-isoxazolecarbal-
dehydes, undergo intramolecular ring-closure reactions to
afford substituted 2-pyrrolidinones, 1,5-dihydro-2-pyrrolo-
nes, and N-substituted pyrrolidines in good yields.
The five-membered nitrogen-containing heterocycles
are ubiquitously present in natural products and are
components of several compounds with medicinal proper-
ties. Among these heterocycles 2-pyrrolidinone, pyrrolone,
and pyrrolidine have special significance because they
represent an integral part of different alkaloids and
toxins such as epolactaene,1 preussin,2 cylindricine,3
lepadiformine,4 etc. A few of the recently reported ex-
amples of 2-pyrrolidinone and pyrrolidine derivatives
exhibiting promising bioactivity are Piracetam as a
nootropic,5 Levetiracetam and its analogues as an
antiepileptic,6-8 8-aza-11-deoxyPGE1 9 as an EP4 agonist,
DM 232 as a cognition enhancer,10 and 3,5-disubstituted-
2-pyrrolidinones as inhibitors of collagen-induced throm-
bocyte aggregation for treatment of inflammation.11 In
light of these observations, the interest and need for
(6) Grant, R.; Shorvon, S. D. Epilepsy Res. 2000, 42, 89-95.
(7) Shorvon, S. D.; Lowenthal, A.; Janz, D.; Bielen, E.; Loiseau, P.
Epilepsia 2000, 41, 1179-1186.
(8) Kenda, B. M.; Matagne, A. C.; Talaga, P. E.; Pasau, P. M.;
Differding, E.; Lallemand, B. I.; Frycia, A. M.; Moureau, F. G.;
Klitgaard, H. V.; Gillard, M. R.; Fuks, B.; Michel P. J. Med. Chem.
2004, 47, 530-549.
(9) Elworthy, T. R.; Kertesz, D. J.; Kim, W.; Roepel, M. G.; Quat-
trocchio-Setti, L.; Smith, D. B.; Tracy, J. L.; Chow, A.; Li, F.; Brill, E.
R.; Lach, L. K.; McGee, D.; Yang, D. S.; Chiou, S.-S. Bioorg. Med. Chem.
Lett. 2004, 14, 1655-1659.
(10) Manetti, D.; Ghelardini, C.; Bartolini, A.; Bellucci, C.; Dei, S.;
Galeotti, N.; Gualtieri, F.; Romanelli, M. N.; Scapecchi, S.; Teodori, E.
J. Med. Chem. 2000, 43, 1969-1974.
(11) (a) Austel, V.; Eisert, W.; Himmelsbach, F.; Linz, G.; Mueller,
T.; Pieper, H.; Weisenberger, J. U.S. Patent 5,455,348, Oct 2, 1995.
(b) Himmelsbach, F.; Austel, V.; Pieper, H.; Eisert, W.; Mueller, T.;
Weisenberger, J.; Linz, G.; Krueger, G. U.S. Patent 5,591,769, Jan 7,
1997.
(12) Baraldi, P. G.; Barco, A.; Benetti, S.; Pollini, G. P.; Simoni, D.
Synthesis 1987, 857-869.
* Address correspondence to this author. Phone: +91-0522-2212411-
18, ext 4368. Fax: +91-0522-2223405, +91-0522-2223938.
§ CDRI Communication No. 6651.
‡ This paper is dedicated to Dr. C. M. Gupta, Director, CDRI on his
60th birthday.
(1) Hayashi, Y.; Kanayama, J.; Yamaguchi, J.; Shoji, M. J. Org.
Chem. 2002, 67, 9443-9448.
(2) (a) Johnson, J. H.; Phillipson, D. W.; Kahle, A. D. J. Antibiot.
1989, 42, 1184-1185. (b) Schwartz, R. E.; Liesch, J.; Hensens, O.;
Zitano, L.; Honeycutt, S.; Garrity, G.; Fromtling, R. A.; Onishi, J.;
Monaghan, R. J. Antibiot. 1988, 41, 1774-1779.
(13) (a) Patra, A.; Batra, S.; Kundu, B.; Joshi, B. S.; Roy, R.; Bhaduri,
A. P. Synthesis 2001, 276-281. (b) Roy, A. K.; Batra, S. Synthesis 2003,
1347-1356. (c) Roy, A. K.; Batra, S. Synthesis 2003, 2325-2330.
(14) Stevens, R. V. Tetrahedron 1976, 32, 1599-1612.
(15) Jones, R. C. F.; Dunn, S. H.; Duller, K. A. M. J. Chem. Soc.,
Perkin Trans. 1 1996, 1319-1321.
(3) (a) Arai, T.; Abe, H.; Aoyagi, S.; Kibayashi, C. Tetrahedron Lett.
2004, 45, 5921-5924. (b) Li, C. C.; Blackman, A. J. Aust. J. Chem.
1994, 47, 1355-1361.
(4) Biard, J. F.; Guyot, S.; Roussakis, C.; Verbist, J. F.; Vercauteren,
J.; Weber, J. F.; Boukef, K. Tetrahedron Lett. 1994, 35, 2691-2694.
(5) Shorvon, S. Lancet 2001, 358, 1885-1892.
(16) Saxena, R.; Singh, V.; Batra, S. Tetrahedron 2004, 60, 10311-
10320.
10.1021/jo048411b CCC: $30.25 © 2005 American Chemical Society
Published on Web 12/02/2004
J. Org. Chem. 2005, 70, 353-356
353

SCHEME 1a
a Reagents and conditions: (a) CH2dCHCO2Me, DABCO, 10 min, rt. (b) AcCl, pyridine, CH2Cl2, 0 °C to rt, 3 h. (c) NaBH4, MeOH, 2
h, rt. (d) DABCO, NaBH4, THF:H2O, 15 min, rt. (e) Raney-Ni, H2, 30 psi, 2 h, rt. (f) 10% Pd/C, H2, 30 psi, 3 h, rt. (g) NaH, toluene, 10 min,
rt or DBU, THF, 30 min, rt. (h) 24 h at rt followed by a silica gel column.
SCHEME 2a
5a-e) for the present study is outlined in Scheme 1. The
substituted 3-isoxazolecarbaldehydes (1a-e) were sub-
jected to Baylis-Hillman reaction to afford adducts 2a-e
in excellent yields. Subsequent acetylation of adducts
2a-e furnished the acetates 3a-e, which reacted with
sodium borohydride under different reaction conditions
to afford products 4a-e and 5a-e.17,18 These substrates
(4a-e or 5a-e) were subjected to hydrogenolysis in the
presence of Raney-Ni to yield enaminones 7a-e, which
on overnight storage at room temperature yielded a
mixture of compounds based on the TLC analysis.
Purification by column chromatography on silica gel led
to isolation of a less polar product as compared to the
enaminone 7a-e. This product was assigned the struc-
ture 8a-e. The stereochemistry across the exocyclic
double bond in compounds 8a-e was assigned as Z on
a Reagents and conditions: (a) RH, MeOH, 8 h, rt. (b) Raney-
the basis of NOE experiments. In a subsequent attempt
Ni, H2, 30 psi, 2 h, rt. (c) Silica gel column chromatography or rt
for 48 h.
to obtain the optimal yields of 2-pyrrolidinones (8a-e)
through a one-pot procedure, the hydrogenation reaction
was carried out under different conditions and even
allowed to continue for longer periods, but the attempts
were unsuccessful. Interestingly however, if the hydro-
therefore it was considered that if the double bond in
compounds 5a-e was appropriately substituted, similar
hydrogenation followed by ring closure of the resulting
genation was run for long durations then two products
product should produce 2-pyrrolidinones with substitu-
were isolated during chromatography. The major com-
tion at position-3 of the heterocyclic ring. To evaluate the
ponent was the 2-pyrrolidinone (8d-e) while the minor
feasibility of this approach, compounds 10a-e were
polar product was identified as the hydroxy derivative
prepared by reacting compounds 5a-e with N-meth-
ylpiperazine. These compounds (10a-e) were then sub-
(9d-e). The failure of the enaminones 7a-e to cyclize
upon hydrogenation may be due to poor nucleophilicity
jected to hydrogenation in the presence of Raney-Ni
of the eneamine and therefore it was desired to identify
(Scheme 2).
an appropriate base to facilitate the cyclization proce-
The hydrogenations furnished enaminones 13a-e (on
dure. It was found that the enaminones 7a-e upon
the basis of the polarity of spot on the TLC and 1H NMR
reaction with a catalytic amount of NaH in toluene at
analysis of the crude product) but during purification on
room temperature almost instantaneously yielded the
a silica gel column, these compounds completely trans-
desired cyclized derivatives (8a-e) in good yields. In
formed to yield a less-polar derivative compared to the
addition, DBU was also found to be suitable to affect the
enaminone. On the basis of spectroscopic evidence the
cyclization though the reaction time was slightly higher.
structure of these compounds was identified as 1,5-
A series of 3,5-susbstituted-2-pyrrolidinones were re-
dihydro-2-pyrrolones (17a-e) instead of the expected
ported to be pharmacologically active compounds,19 and
products 16a-e. It was also observed that if these
hydrogenation products were allowed to stand at room
temperature for 48 h, then also the 1,5-dihydro-2-
(17) Patra, A.; Batra, S.; Bhaduri, A. P.; Khanna, A.; Chander, R.;
Dikshit, M. Bioorg. Med. Chem. 2003, 11, 2269-2276.
(18) Batra, S.; Roy, A. K.; Patra, A.; Bhaduri, A. P.; Surin, W. S.;
Raghvan, S. A. V.; Sharma, P.; Kapoor, K.; Dikshit, M. Bioorg. Med.
Chem. 2004, 12, 2059-2077.
(19) Yee, N. K.; Dong, Y.; Kapadia, S. R.; Song J. J. J. Org. Chem.
2002, 67, 8688-8691.
354 J. Org. Chem., Vol. 70, No. 1, 2005

FIGURE 2. Mechanism for the formation of pyrrolidines.
FIGURE 1. Mechanism for the formation of 1,5-dihydro-2-
pyrrolones.
SCHEME 4a
SCHEME 3a
a Reagents and conditions: (a) N-methylpiperazine, MeOH, 8
h, rt. (b) Raney-Ni, H2, 30 psi, 3 h, rt. (c) 24 h at rt followed by
silica gel chromatography. (d) PhCH2NH2, MeOH, 8 h, rt. (e)
Raney-Ni, H2, 30 psi, 3 h, rt.
a Reagents and conditions: (a) RNH2, MeOH, 8 h, rt. (b) Raney-
Ni, H2, 30 psi, 3 h, rt.
protocol described in this paper is simple and convenient,
involves the use of inexpensive reagents, and is amenable
to parallel synthesis. The facile nucleophilic substitution
of amines in the Baylis-Hillman derivatives provides the
opportunity to easily obtain the desired substitution on
the heterocyclic nitrogen atom in the N-substituted
pyrrolidine derivatives.
pyrrolone derivatives were obtained in good yields.
Similarly to compounds 7a-e these compounds (13a-
e) too, upon treatment with NaH, are cyclized to afford
the products 17a-e within a short period. The stereo-
chemistry across the exocyclic double bond was assigned
as Z on the basis of results of the NOE experiments.
Similar to compounds 10a-e, derivatives 11d-12a,d led
to the formation of 1,5-dihydro-2-pyrrolone rather than
the desired products. The formation of the 1,5-dihydro-
2-pyrrolone is explained on the basis of deamination as
shown in Figure 1.
Mechanistic considerations generated interest in study-
ing the fate of ring closure reactions in amino derivatives
18-20, which were easily obtained from compound 5a-e
(Scheme 3). Interestingly the hydrogenolysis of com-
pounds 18-20a-e in the presence of Raney-Ni gave
pyrrolidines 24-26a-e instead of the expected enami-
nones 21-23a-e. The stereochemistry across the exo-
cyclic double bond was assigned as Z. These results
therefore indicated that the elimination of a secondary
base was favored in ring closure of enaminones 13-15
but elimination of ammonia was favored in the ring
closure reactions of compounds 18-20 (Figure 2).
Since compounds 4a-e led to 2-pyrrolidinones (8a-
e), we envisioned that the amino derivatives 27 and 29
could be utilized for obtaining 1,5-dihydro-2-pyrrolone
(17) and the pyrrolidines (24-26) thereby reducing the
number of synthetic steps involved in the synthesis of
these heterocycles. Thus in a model study compounds 27a
and 29b were generated and subjected to hydrogenolysis
in the presence of Raney-Ni. As expected, compounds 27a
and 29b afforded the corresponding compounds 17a and
24b, respectively, in good yields (Scheme 4).
Experimental Section
General Considerations. See the Supporting Information.
General Procedure for Compounds 2a-e. See ref 13c.
General Procedure for Compounds 3a-e As Exempli-
fied for 3b. To the stirred solution of compound 2b (0.89 g, 3.25
mmol) in dry dichloromethane (5 mL) was added pyridine (0.48
mL, 6.0 mmol) followed by dropwise addition of a solution of
acetyl chloride (0.46 mL, 6.5 mmol) in dry dichloromethane (3
mL) at 0 °C. After the addition was complete, the reaction was
continued at room temperature for 3 h. The reaction mixture
was extracted with dichloromethane (2 × 25 mL) and water (40
mL). The combined organic layer was washed with brine, dried
over anhydrous Na2SO4, and evaporated to obtain an oily
residue. The residue was purified through column chromatog-
raphy over silica gel with hexane:ethyl acetate (85:15, v/v) as
eluent to obtain 0.88 g (86%) of 3b as a white solid.
2-[Acetoxy-(5-p-tolylisoxazol-3-yl)methyl]acrylic acid
methyl ester (3b): mp 86-88 °C; νmax (KBr) 1706 (CO2Me),
1742 (OCOMe) cm-1; 1H NMR (CDCl3, 200 MHz) δ 2.17 (s, 3H),
2.39 (s, 3H), 3.78 (s, 3H), 6.06 (d, 1H, J ) 0.74 Hz), 6.48 (s, 1H),
6.53 (s, 1H), 6.84 (s, 1H), 7.25 (d, 2H, J ) 8.0 Hz), 7.64 (d, 2H,
J ) 8.0 Hz); 13C NMR (CDCl3, 50.32 MHz) δ 21.2, 52.6, 66.55,
99.1, 126.2, 127.5, 128.2, 129.4, 130.7, 137.3, 141.1, 162.6, 165.3,
169.6, 170.8; mass (ES+) m/z 338.33 (M+ + Na). Anal. Calcd for
C
17H17NO5: C, 64.75, H, 5.43, N, 4.44. Found: C, 65.02, H, 5.33,
N, 4.57.
General Procedure for Compounds 4a-e As Exempli-
fied for 4d. To the solution of 3d (1.34 g, 4.0 mmol) in methanol
(5 mL) was added NaBH4 (0.76 g, 8.0 mmol) with stirring at
0-5 °C. After 15 min the reaction was decomposed with water
and extracted with ethyl acetate (2 × 30 mL). The organic phase
was separated and washed with brine (40 mL), dried (Na2SO4),
and concentrated in vacuo. The residue upon column chroma-
In conclusion, the present study reveals easy access
to substituted 2-pyrrolidinones, 1,5-dihydro-2-pyrrolones,
and N-substituted pyrrolidine derivatives. The synthetic
J. Org. Chem, Vol. 70, No. 1, 2005 355

tography over silica gel with hexane:ethyl acetate (85:15, v/v)
furnished 0.85 g (77%) of pure 4d as a white solid.
3-Methyl-5-(2-oxo-2-phenylethylidene)pyrrolidin-2-
one (8a): mp 162-163 °C; νmax (KBr) 1650 (CONH), 1737 (Cd
O), 3450 (br, NH) cm-1 1H NMR (CDCl3, 200 MHz) δ 1.34 (d,
;
3-[5-(4-Chlorophenyl)isoxazol-3-yl]-2-methylacrylic acid
methyl ester (4d): mp 153-154 °C; νmax (KBr) 1712 (CO2Me)
3H, J ) 7.1 Hz), 2.55-2.75 (m, 2H), 3.16-3.25 (m, 1H), 6.18 (s,
1H), 7.42-7.57 (m, 3H), 7.87-7.98 (m, 2H), 11.01 (br s, 1H); 13
NMR (CDCl3, 50.32 MHz) δ 16.9, 34.1, 35.7, 95.6, 128.1, 129.8,
cm-1 1H NMR (CDCl3, 200 MHz) δ 2.29 (s, 3H), 3.85 (s, 3H),
;
C
6.64 (s, 1H), 7.46 (d, 2H, J ) 8.6 Hz), 7.52 (d, 1H, J ) 1.4 Hz),
7.74 (m, 2H, J ) 8.6 Hz); 13C NMR (CDCl3, 50.32 MHz) δ 15.4,
52.8, 72.7, 101.0, 125.6, 127.5, 129.8, 135.1, 136.9, 160.3, 168.4,
132.3, 132.7, 159.1, 181.5, 190.7; mass (ES+) m/z 216.47 (M+
+
1), 248.60 (M+ + Na). Anal. Calcd for C13H13NO2: C, C, 72.54;
169.4; mass (ES+) m/z 278.56 (M+ + 1). Anal. Calcd for C14H12
-
H, 6.09; N, 6.51. Found: C, 72.59, H, 5.83, N, 6.54.
ClNO3: C, 60.55, H, 4.36, N, 5.04. Found: C, 60.45, H, 4.49, N,
5.36.
General Procedure for the Cyclization in the Presence
of DBU As Exemplified for 8b. To the stirred solution of 7b
(0.52 g, 2.0 mmol) was added DBU (0.36 mL, 2.4 mmol) and the
reaction mixture was continued at ambient temperature. After
completion (30 min) the reaction mixture was extracted with
ethyl acetate (25 mL) and water (20 mL). The organic layer was
separated, dried over anhydrous Na2SO4, and evaporated to
afford crude product, which was purified through column chro-
matography over silica gel. Elution with hexane:ethyl acetate
(85:15, v/v) yielded 0.43 g (95%) of product 8b as a white solid.
General Procedure for Compounds 5a-e As Exempli-
fied for 5e. To the solution of acetate 3e (0.64 g, 2.0 mmol) in
THF:water (3 mL, 1:1, v/v) was added DABCO (0.22 g, 2.0 mmol)
and the reaction was allowed to proceed at room temperature.
As soon as the solution became clear (ca. 15 min), NaBH4 (0.08
g, 2.0 mmol) was added with stirring. The reaction was complete
in 15 min, after which the reaction mixture was extracted with
ethyl acetate (2 × 30 mL). The organic layers were combined,
dried over anhydrous Na2SO4, and evaporated to obtain a residue
that after chromatography on silica gel with hexane:ethyl acetate
(90:10, v/v) as eluent afforded 0.43 g (83%) of 5e as pale yellow
oil (approximately as in ref 18).
3-Methyl-5-(2-oxo-2-p-tolylethylidene)pyrrolidin-2-one
(8b): mp 156-158 °C; νmax (KBr) 1655 (CONH), 1736 (CdO),
1
3429 (br, NH) cm-1; H NMR (CDCl3, 200 MHz) δ 1.33 (d, 3H,
J ) 7.1 Hz), 2.41 (s, 3H), 2.53-2.74 (m, 2H), 3.13-3.21 (m, 1H),
6.17 (s, 1H), 7.25 (d, 2H, J ) 8.0 Hz), 7.82 (d, 2H, J ) 8.0 Hz),
10.93 (br s, 1H); 13C NMR (CDCl3, 50.32 MHz) δ 16.9, 21.9, 34.1,
35.7, 95.6, 128.3, 129.6, 136.3, 143.8, 158.6, 181.5, 190.4; mass
(ES+) m/z 230 (M+ + 1). Anal. Calcd for C14H15NO2‚H2O: C,
68.00; H, 6.93; N, 5.66. Found: C, 67.88; H, 7.11; N, 5.70.
2-[5-(4-Fluorophenyl)isoxazol-3-ylmethyl]acrylic acid
methyl ester (5e): νmax (neat) 1722 (CO2Me) cm-1 1H NMR
;
(CDCl3, 200 MHz) δ 3.74 (s, 2H), 3.79 (s, 3H), 5.75 (d, 1H, J )
1.0 Hz), 6.35 (s, 2H), 6.36 (s, 1H, CH), 7.09-7.17 (m, 2H), 7.70,
7.77 (m, 2H); 13C NMR (CDCl3, 50.32 MHz) δ 29.2, 52.5, 99.7,
116.7, 128.3, 128.2, 136.9, 162.7, 166.6, 167.1, 169.3; mass (ES+)
m/z 262.33 (M+ + 1), 284.60 (M+ + Na). Anal. Calcd for C14H12
-
General Procedure for the Reaction of Amines As
Exemplified for 10a. To the solution of compound 5a (1.33 g,
5.0 mmol) in methanol (4 mL) was added the desired N-
methylpiperazine (0.67 mL, 6.0 mmol) and the mixture was
stirred at room temperature from 14 to 20 h (preferentially
overnight). On completion, the excess solvent was evaporated
and the residue was filtered from a small band of basic alumina
with chloroform or chloroform:methanol (99.5:0.5, v/v). The
eluent was evaporated to obtain 1.45 g (78%) of amine as a pale
yellow oil (approximately as in ref 18).
2-(4-Methylpiperazin-1-ylmethyl)-3-(5-phenylisoxazol-3-
yl)propionic acid methyl ester (10a): νmax (neat) 1734 (CO2-
Me) cm-1; 1H NMR (CDCl3, 200 MHz) δ 2.27 (s, 3H), 2.30-2.76
(m, 10H), 2.98-3.10 (m, 3H), 3.69 (s, 3H), 6.36 (s, 1H), 7.42-
7.48 (m, 3H), 7.72-7.77 (m, 2H); 13C NMR (CDCl3, 50.32 MHz)
δ 27.2, 43.3, 46.2, 52.2, 53.4, 55.4, 60.1, 99.9, 126.2, 127.9, 129.3,
130.5, 162.6, 170.2, 175.1; mass (ES+) m/z 344 (M+ + 1). Anal.
Calcd for C19H25NO3‚H2O: C, 63.14; H, 7.53; N, 11.63. Found:
C, 62.91; H, 7.33; N, 11.66.
FNO3: C, 64.36, H, 4.63, N, 5.36. Found: C, 64.74, H, 4.66, N,
5.44.
General Procedure for Compounds 6a-e. See ref 16.
General Procedure for the Hydrogenation in the Pres-
ence of Raney-Ni As Exemplified for 24c. A mixture of
compound 18c (0.85 g, 2.0 mmol) and Raney-Ni (100 mg in
ethanol) in methanol (10 mL) was subjected to hydrogenation
in the Parr assembly at 35 psi at room temperature. The reaction
was allowed to continue for 3 h. Thereafter, the catalyst was
removed by vacuum filtering the reaction mixture through a
Celite bed with methanol. The filtrate was evaporated to obtain
an oily residue, which was taken up in ethyl acetate (2 × 20
mL) and washed with water (20 mL). The organic layers were
pooled and dried over anhydrous Na2SO4 and the solvent was
evaporated in vacuo to obtain the crude oil. Purification of the
crude product by column chromatography over silica gel with
hexane:ethyl acetate (60:40, v/v) as the eluent furnished 0.54 g
(65%) of 24c as a white solid.
1-Benzyl-5-[2-(4-bromophenyl)-2-oxoethylidene]pyrro-
lidine-3-carboxylic acid methyl ester (24c): mp 95-98 °C;
1
νmax (KBr) 1736 (CdO and CO2Me) cm-1; H NMR (CDCl3, 200
Acknowledgment. Two of the authors (V.S. and
R.S.) acknowledge the financial support from DST and
CSIR, respectively, in the form of fellowships. This work
was supported by a financial grant under DST Project
no. SR/SI/OC-04/2003.
MHz) δ 3.26-3.30 (m, 1H), 3.62-3.84 (m, 7H), 4.53 (s, 2H), 5.91
(s, 1H), 7.23-7.41 (m, 7H), 7.78-7.83 (m, 2H, J ) 8.6 Hz); 13C
NMR (CDCl3, 50.32 MHz) δ 37.8, 39.4, 50.7, 52.7, 54.7, 87.8,
127.7, 128.3, 128.5, 129.4, 130.9, 131.6, 135.5, 141.9, 165.2, 173.9,
188.6; mass (FAB+) m/z 336 (M+ + 1 - Br). Anal. Calcd for
C21H20BrNO3: C, 60.88, H, 4.87, N, 3.38. Found: C, 60.70, H,
5.20, N, 3.66.
Supporting Information Available: General experimen-
tal information and spectroscopic details for all compounds,
1H NMR spectra for compounds 3b,d, 4d, 5b,d, 6e, 7e, 8b,d,
10a,d-e, 11d, 12a,d, 17d,e, 18b,c,e, 19b,c,d-e, 20a,c,e,
24a-e, 25a,d-e, 26a,d-e, 27a, 29b, 13C NMR spectra for
8b,d, 10a, 24b,c,e, 25a,e, 26a,e, and mass spectra of 8b, 10e,
12a, 18c,e, 19e, 20a,c,e, 24c, 25a,d-e, and 26a,e. This
material is available free of charge via the Internet at
http://pubs.acs.org.
General Procedure for the Cyclization in the Presence
of NaH As Exemplified for 8a. To the stirred suspension of
NaH (0.0345 g in 60% oil, 1.5 mmol) in anhydrous toluene (2
mL) was added a solution of compound 7a (0.37 g, 1.5 mmol) in
toluene (5 mL) at ambient temperature. After 10 min the
reaction mixture was quenched with water and extracted with
ethyl acetate (15 mL). The organic layer was dried over Na2SO4
and evaporated to obtain a residue that was subjected to column
chromatography over silica gel to yield 0.31 g (96%) of 8a as a
white solid.
JO048411B
356 J. Org. Chem., Vol. 70, No. 1, 2005