Cerium(III) chloride heptahydrate-lithium iodide: A novel reagent system for the synthesis of N-arylpyrrolidines

Article abstract of DOI:10.1055/s-0029-1216970

Aldimines, generated in situ from arylamines and aryl aldehydes, undergo smooth cycloaddition with cyclopropane-1,1-dicarboxylate in the presence of the cerium(III) chloride heptahydrate-lithium iodide reagent system in refluxing acetonitrile under neutral conditions to produce the corresponding Narylpyrrolidines in good yields with high selectivity.

Full text of DOI:10.1055/s-0029-1216970

PAPER
3443
Cerium(III) Chloride Heptahydrate–Lithium Iodide: A Novel Reagent System
for the Synthesis of N-Arylpyrrolidines
C
erium(II
.
I)
C
hloride
H
S
eptahydrate–L
.
ithium Iodid
Y
e
adav,* B. V. Subba Reddy, G. Narasimhulu, D. Chandrakanth, G. Satheesh
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27193535; E-mail: yadavpub@iict.res.in
Received 25 May 2009; revised 6 June 2009
propanedicarboxylates9 have been used. Various Lewis
acids such as magnesium iodide, diethylaluminum iodide,
scandium(III) trifluoromethanesulfonate, and ytterbi-
um(III) trifluoromethanesulfonate have been utilized for
Abstract: Aldimines, generated in situ from arylamines and aryl al-
dehydes, undergo smooth cycloaddition with cyclopropane-1,1-di-
carboxylate in the presence of the cerium(III) chloride
heptahydrate–lithium iodide reagent system in refluxing acetoni-
trile under neutral conditions to produce the corresponding N- the annulation of imines and nitrones with activated cy-
clopropanes.6–9 The coupling of aldehydes with activated
arylpyrrolidines in good yields with high selectivity.
cyclopropanes in the presence of tin(II) trifluoromethane-
sulfonate has also been reported to produce highly substi-
tuted tetrahydrofurans.10 However, the development of a
simple and convenient protocol using inexpensive, readily
available, and efficient reagents would extend the scope
of this reaction.
Key words: cerium(III) reagents, aldimines, cyclopropanedicar-
boxylate, pyrrolidines, cycloadditions, ring expansion
The pyrrolidine ring represents one of the most ubiquitous
heterocyclic motifs found in naturally occurring com-
pounds.1 Several substituted pyrrolidines are known to ex-
hibit potent biological activities as enzyme inhibitors and
agonists or antagonists of receptors.2 Furthermore, the ad-
vanced progress achieved in genomic research increases
the demand for identification of small molecules that are
active and selective against a broader range of therapeutic
targets. In view of more biologically interesting targets
becoming available, the efficient synthesis and yield opti-
mization of new drug-like chemical entities actually con-
stitutes the bottleneck in medicinal chemistry.3
Lanthanide salts are unique Lewis acids that are currently
of great research interest.11 Of various lanthanide salts, ce-
rium(III) chloride is relatively nontoxic, readily available
at low cost as an easy-to-handle neutral catalyst, and fairly
stable to water.12
In light of our previous work on the use of cerium(III)
chloride heptahydrate–sodium iodide,13 we herein report
an efficient and practical method for the preparation of N-
arylpyrrolidines via the cycloaddition of imines with cy-
clopropane-1,1-dicarboxylate. First, we attempted a novel
three-component reaction of benzaldehyde (1a), aniline
(2a), and diethyl cyclopropane-1,1-dicarboxylate (3a).
The reaction proceeded smoothly in the presence of 20
mol% cerium(III) chloride heptahydrate and a stoichio-
metric amount of lithium iodide in refluxing acetonitrile
to furnish diethyl 1,2-diphenylpyrrolidine-3,3-dicarboxy-
late (4a) in 80% yield (Scheme 1).
The generation of a bifunctional intermediate via ring
opening of a highly strained and activated three-mem-
bered carbocycle is a synthetically useful tool for the con-
struction of expanded ring systems.4 Therefore, the ring
expansion reactions of highly strained rings such as cyclo-
propanes constitute an efficient method for the construc-
tion of cyclic compounds. One useful approach to ring
expansion involves the ring opening of a monoactivated
or doubly activated cyclopropane, where the enolate or
enol intermediate generated in situ acts as a nucleophile in
cyclization.5 A variety of activated cyclopropanes such as
This result provided incentive for further study. Interest-
ingly, several substituted aryl aldehydes and arylamines
participated in this reaction (Table 1). Both electron-rich
and electron-deficient substrates underwent smooth cy-
cloaddition with diethyl cyclopropane-1,1-dicarboxylate
to produce a wide range of N-arylpyrrolidines 4 in good
spirocyclopropyl-2-oxindoles,6
amides,7 cyclopropylmethyl ketone,8 and cyclo-
methylenecyclopropyl
CO2Et
CHO
NH2
CO2Et
CO2Et
CO2Et
Ph
CeCl3⋅7H2O, LiI
+
+
MeCN, reflux
N
Ph
1a
2a
3a
4a 80%
Scheme 1
SYNTHESIS 2009, No. 20, pp 3443–3448
x
x.
x
x
.
2
0
0
9
Advanced online publication: 28.08.2009
DOI: 10.1055/s-0029-1216970; Art ID: Z16709SS
© Georg Thieme Verlag Stuttgart · New York

3444
J. S. Yadav et al.
PAPER
yields. The arylimine derived from thiophene-2-carboxal- Initially, we performed this three-component reaction us-
dehyde also participated effectively in this cycloaddition, ing one equivalent of cerium(III) chloride heptahydrate
providing 4n.
and one equivalent of lithium iodide. Later, we observed
that there was no considerable decrease in yield even
when the amount of cerium(III) chloride heptahydrate
was decreased to 0.2 equivalents, albeit with long reaction
times. However, decreasing the amount of lithium iodide
to 0.2 equivalents slowed the reaction and stopped it be-
fore completion. Increasing the amount of cerium(III)
chloride heptahydrate to 1.5 equivalents gave no improve-
ment compared to 0.2 equivalents. Therefore, a substoi-
chiometric amount of cerium(III) chloride heptahydrate
(0.2 equiv) and stoichiometric amount of lithium iodide (1
equiv) are optimal for this conversion. The reactions were
carried out by combining equimolar amounts of the aryl
aldehyde 1 and arylamine 2 and stirring to allow forma-
tion of the imine. Then the catalyst and diethyl cyclopro-
pane-1,1-dicarboxylate (3a) were added to accomplish the
cycloaddition. The scope and generality of this cycloaddi-
tion are illustrated with respect to various aldehydes 1 and
arylamines 2, and the results are presented in Table 1.
The combination of various Lewis acids including ytterbi-
um(III) chloride, yttrium(III) chloride, indium(III) chlo-
ride, iron(III) chloride, and zinc(II) chloride with lithium
iodide was tested for this conversion. Of these, cerium(III)
chloride–lithium iodide performed the best, giving gener-
ally higher yields. On the other hand, metal iodides such
as aluminum(III) iodide, gallium(III) iodide, indium(III)
iodide, and zinc(II) iodide were also not so effective.
The reaction seems to be sensitive to electronic effects.
Generally, electron-rich aldehydes gave slightly higher
yields than their electron-deficient counterparts. Under
the described conditions, both electron-rich and electron-
deficient aldehydes gave the products in good yields
whereas previously reported methods failed to produce
the desired product from p-nitrobenzaldehyde.9a Disap-
pointingly, aliphatic substrates (both aldehydes and
amines) gave a sluggish reaction under the optimal reac-
tion conditions.
Table 1 Cerium(III) Chloride Heptahydrate–Lithium Iodide Mediated Synthesis of N-Substituted Pyrrolidine-3,3-dicarboxylates 4
Aldehyde
Amine
Cyclopropyl diester Producta
4
Reaction time (h)
Yield (%)b
CO2Et
CHO
NH2
CO2Et
CO2Et
CO2Et
Ph
4a
5.5
80
N
Ph
CO2Et
CO2Et
CHO
NH2
CO2Et
CO2Et
4b
4c
5.0
5.0
83
85
N
Me
Ph
Me
CO2Et
CO2Et
CHO
NH2
CO2Et
CO2Et
N
MeO
Ph
OMe
CO2Et
CO2Et
MeO
MeO
CHO
NH2
CO2Et
CO2Et
OMe
OMe
4d
5.0
90
N
Ph
OMe
OMe
CO2Et
CO2Et
CHO
NH2
CO2Et
CO2Et
4e
4f
6.5
7.0
78
76
N
Br
Cl
Ph
Br
Cl
CO2Et
CO2Et
CHO
NH2
CO2Et
CO2Et
N
Ph
Synthesis 2009, No. 20, 3443–3448 © Thieme Stuttgart · New York

PAPER
Cerium(III) Chloride Heptahydrate–Lithium Iodide
3445
Table 1 Cerium(III) Chloride Heptahydrate–Lithium Iodide Mediated Synthesis of N-Substituted Pyrrolidine-3,3-dicarboxylates 4 (continued)
Aldehyde
Amine
Cyclopropyl diester Producta
4
Reaction time (h)
6.0
Yield (%)b
72
CO2Et
CHO
CO2Et
NH2
CO2Et
CO2Et
4g
NO2
N
NO2
Ph
CO2Et
CO2Et
NH2
Ph
CHO
CHO
CHO
CHO
CHO
N
CO2Et
CO2Et
4h
5.5
6.0
6.5
6.0
6.0
5.0
82
84
78
81
75
85
Me
MeO
Br
Me
N
CO2Et
CO2Et
NH2
Ph
CO2Et
CO2Et
4i
OMe
CO2Et
CO2Et
NH2
Ph
N
CO2Et
CO2Et
4j
Br
CO2Et
CO2Et
Me
Ph
N
CO2Et
CO2Et
NH2
4k
Me
Br
Br
CO2Et
CO2Et
Cl
Ph
N
CO2Et
CO2Et
NH2
4l
Cl
Cl
Cl
CO2Et
CO2Et
CHO
NH2
N
CO2Et
CO2Et
4m
OMe
MeO
MeO
OMe
Synthesis 2009, No. 20, 3443–3448 © Thieme Stuttgart · New York

3446
J. S. Yadav et al.
PAPER
Table 1 Cerium(III) Chloride Heptahydrate–Lithium Iodide Mediated Synthesis of N-Substituted Pyrrolidine-3,3-dicarboxylates 4 (continued)
Aldehyde
Amine
Cyclopropyl diester Producta
4
Reaction time (h)
6.0
Yield (%)b
78
CO2Et
CO2Et
Cl
CO2Et
CO2Et
NH2
4n
CHO
S
N
Cl
S
Ph
a Products were characterized by 1H NMR, IR, and MS.
b Yields of pure products after chromatography.
H), 3.21–3.26 (m, 1 H), 3.62–3.86 (m, 3 H), 4.16–4.36 (m, 2 H),
5.38 (s, 1 H), 6.41 (d, J = 7.5 Hz, 2 H, Ar-H), 6.59 (t, J = 7.5 Hz, 1
H, Ar-H), 7.01–7.17 (m, 6 H, Ar-H).
ESI-MS: m/z = 382 [M + H]+, 336, 320.
HRMS (EI): m/z [M + H]+ calcd for C23H28NO4: 382.2018; found:
382.2014.
In conclusion, we have developed an efficient three-com-
ponent reaction for the cycloaddition of aldimines with
cyclopropane-1,1-dicarboxylate to produce N-arylpyrro-
lidines. The conditions include the utilization of the mild
Lewis acid cerium(III) chloride, and the substrate scope
appears to be quite general. The present method is practi-
cal and efficient and is therefore readily amenable to
scale-up.
Diethyl 2-(4-Methoxyphenyl)-1-phenylpyrrolidine-3,3-dicar-
boxylate (4c)
Liquid.
Melting points were recorded on a Buchi R-535 apparatus and are
uncorrected. IR spectra were recorded on a Perkin-Elmer FT-IR
240-c spectrophotometer using KBr optics. 1H NMR and 13C NMR
spectra were recorded on a Gemini-200 and a Varian Bruker-300
spectrometer of samples prepared in CDCl3 using TMS as internal
standard. Mass spectra were recorded on a Finnigan MAT 1020
mass spectrometer operating at 70 eV.
IR (KBr): 3446, 2903, 1730, 1681, 1476, 1439, 1249, 1171, 1071,
863 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.06 (t, J = 7.1 Hz, 3 H), 1.24 (t,
J = 7.1 Hz, 3 H), 2.38–2.48 (m, 1 H), 2.85–2.97 (m, 1 H), 3.21–3.32
(m, 1 H), 3.65–3.87 (m, 6 H), 4.13–4.29 (m, 2 H), 5.35 (s, 1 H),
6.38–6.44 (m, 2 H, Ar-H), 6.56–6.63 (m, 1 H, Ar-H), 6.76 (t, J = 8.6
Hz, 2 H, Ar-H), 7.02–7.18 (m, 4 H).
ESI-MS: m/z = 398 [M+], 352, 280.
Pyrrolidine-3,3-dicarboxylates 4; General Procedure
A mixture of the appropriate aldehyde 1 (1 mmol) and aniline 2 (1
mmol) was stirred in MeCN (5 mL) before diethyl cyclopropane-
1,1-dicarboxylate (3a; 1 mmol), CeCl3 7 H2O (20 mol%), and LiI (1
mmol) were added; the mixture was then stirred at reflux tempera-
ture for the time required to complete the reaction (see Table 1). Af-
ter complete conversion, as indicated by TLC, the reaction mixture
was diluted with H2O (10 mL) and extracted with CH2Cl2 (2 × 10
mL). The combined organic layers were dried (Na2SO4), concen-
trated in vacuo, and purified by column chromatography (silica gel,
Merck, 100–200 mesh, EtOAc–hexane, 2:8); this afforded the cor-
responding pure N-arylpyrrolidines 4.
HRMS (EI): m/z [M+] calcd for C23H28NO5: 398.1967; found:
398.1956.
Diethyl 1-Phenyl-2-(3,4,5-trimethoxyphenyl)pyrrolidine-3,3-di-
carboxylate (4d)
Solid; mp 132–134 °C.
IR (KBr): 3460, 2964, 2934, 2826, 1728, 1591, 1507, 1476, 1355,
1265, 858, 830 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.01 (t, J = 7.1 Hz, 3 H), 1.25 (t,
J = 7.1 Hz, 3 H), 2.38–2.49 (m, 1 H), 2.82–2.96 (m, 1 H), 3.20–3.32
(m, 1 H), 3.65–3.74 (m, 1 H), 3.76 (s, 3 H), 3.80 (s, 6 H), 3.82–3.94
(m, 2 H), 4.12–4.30 (m, 2 H), 5.32 (s, 1 H), 6.40–6.50 (m, 4 H, Ar-
H), 6.62 (t, J = 7.3 Hz, 1 H, Ar-H), 7.06–7.14 (m, 2 H, Ar-H).
Diethyl 1,2-Diphenylpyrrolidine-3,3-dicarboxylate (4a)
Solid; mp 94–96 °C.
ESI-MS: m/z = 458 [M + H]+, 177, 161, 147, 131, 117.
HRMS (EI): m/z [M + H]+ calcd for C25H32NO7: 458.2178; found:
IR (KBr): 3461, 2978, 2924, 2843, 1729, 1597, 1504, 1452, 1365,
1255, 1168, 1100, 1068, 881, 850, 799, 744, 693 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.02 (t, J = 7.5 Hz, 3 H), 1.25 (t,
J = 6.7 Hz, 3 H), 2.42–2.50 (m, 1 H), 2.86–2.99 (m, 1 H), 3.21–3.34
(m, 1 H), 3.62–3.89 (m, 3 H), 4.12–4.32 (m, 2 H), 5.41 (s, 1 H), 6.42
(d, J = 7.5 Hz, 2 H, Ar-H), 6.59 (t, J = 7.5 Hz, 1 H), 7.06 (t, J = 7.5
Hz, 2 H), 7.17–7.27 (m, 5 H).
ESI-MS: m/z = 368 [M + H]+, 322.
HRMS (EI): m/z [M + H]+ calcd for C22H26NO4: 368.1861; found:
458.2158.
Diethyl 2-(4-Bromophenyl)-1-phenylpyrrolidine-3,3-dicarbox-
ylate (4e)
Semisolid.
IR (KBr): 3476, 2981, 2926, 2850, 1734, 1597, 1505, 1484, 1363,
1257, 1227, 1171, 1103, 1072, 1012 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.08 (t, J = 7.0 Hz, 3 H), 1.27 (t,
J = 7.0 Hz, 3 H), 2.41–2.54 (m, 1 H), 2.80–2.98 (m, 1 H), 3.23–3.38
(m, 1 H), 3.65–3.87 (m, 3 H), 4.15–4.34 (m, 2 H), 5.40 (s, 1 H), 6.43
(d, J = 7.8 Hz, 2 H, Ar-H), 6.65 (t, J = 7.0 Hz, 1 H, Ar-H), 7.04–
7.22 (m, 4 H), 7.38–7.45 (m, 2 H).
368.1851.
Diethyl 2-(4-Methylphenyl)-1-phenylpyrrolidine-3,3-dicarbox-
ylate (4b)
Solid; mp 84–86 °C.
ESI-MS: m/z = 446 [M + H]+, 433, 417, 400.
HRMS (EI): m/z [M + H]+ calcd for C22H25NO4Br: 446.0966;
IR (KBr): 3446, 2923, 2852, 1735, 1599, 1505, 1458, 1255, 1171,
1072 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.06 (t, J = 7.5 Hz, 3 H), 1.24 (t,
J = 7.5 Hz, 3 H), 2.30 (s, 3 H), 2.3–2.49 (m, 1 H), 2.82–2.98 (m, 1
found: 446.0985.
Synthesis 2009, No. 20, 3443–3448 © Thieme Stuttgart · New York

PAPER
Cerium(III) Chloride Heptahydrate–Lithium Iodide
3447
Diethyl 2-(4-Chlorophenyl)-1-phenylpyrrolidine-3,3-dicarbox-
ylate (4f)
IR (KBr): 3470, 2983, 2898, 2832, 1960, 1733, 1594, 1496, 1478,
1362, 1273, 1170, 1108, 1070, 918, 851, 801, 748, 704 cm–1.
Semisolid.
1H NMR (200 MHz, CDCl3): d = 1.02 (t, J = 7.5 Hz, 3 H), 1.25 (t,
J = 6.7 Hz, 3 H), 2.41–2.49 (m, 1 H), 2.86–2.99 (m, 1 H), 3.20–3.30
(m, 1 H), 3.62–3.89 (m, 3 H), 4.14–4.32 (m, 2 H), 5.35 (s, 1 H), 6.30
(d, J = 9.0 Hz, 2 H, Ar-H), 7.12–7.28 (m, 7 H).
ESI-MS: m/z = 446 [M+], 402, 390, 368, 328, 322, 256, 203.
HRMS (EI): m/z [M+] calcd for C22H24NO4Br: 446.0966; found:
IR (KBr): 3464, 2982, 2932, 2847, 1734, 1598, 1505, 1363, 1257,
1226, 1174, 1103, 1071, 1017 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.04 (t, J = 7.3 Hz, 3 H), 1.23 (t,
J = 7.3 Hz, 3 H), 2.25–2.55 (m, 1 H), 2.80–2.99 (m, 1 H), 3.21–3.38
(m, 1 H), 3.58–3.98 (m, 2 H), 4.10–4.33 (m, 3 H), 5.40 (s, 1 H), 6.40
(d, J = 7.3 Hz, 2 H, Ar-H), 6.64 (t, J = 6.5 Hz, 1 H, Ar-H), 7.06 (t,
J = 7.3 Hz, 2 H, Ar-H), 7.22–7.28 (m, 4 H).
446.0962.
ESI-MS: m/z = 402 [M + H]+, 286, 250, 209, 187, 143, 102.
Diethyl 1-(4-Bromo-2-methylphenyl)-2-phenylpyrrolidine-3,3-
dicarboxylate (4k)
Liquid.
HRMS (EI): m/z [M + H]+ calcd for C22H25NO4Cl: 402.1472; found:
402.1476.
IR (KBr): 3461, 2983, 2835, 1725, 1627, 1485, 1450, 12758, 1231,
1183, 1106, 1072, 870, 807, 750 cm–1.
Diethyl 2-(3-Nitrophenyl)-1-phenylpyrrolidine-3,3-dicarboxy-
late (4g)
Solid; mp 106–108 °C.
1H NMR (200 MHz, CDCl3): d = 0.75 (t, J = 7.0 Hz, 3 H), 1.27 (t,
J = 7.0 Hz, 3 H), 2.15–2.23 (m, 1 H), 2.23 (s, 3 H), 2.57–3.05 (m, 2
H), 3.21–3.40 (m, 1 H), 3.65–3.90 (m, 2 H), 4.12–4.39 (m, 2 H),
5.42 (s, 1 H), 6.84 (d, J = 8.5 Hz, 2 H, Ar-H), 6.98–7.20 (m, 5 H,
Ar-H), 7.28 (dd, J = 2.3, 7.8 Hz, 2 H, Ar-H).
ESI-MS: m/z = 460 [M+], 462 (M+2), 414, 382, 336, 203.
HRMS (EI): m/z [M+] calcd for C23H27NO4Br: 460.1123; found:
IR (KBr): 3478, 2984, 2930, 1736, 1598, 1479, 1448, 1260, 1167,
1076, 855 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.12 (t, J = 7.3 Hz, 3 H), 1.28 (t,
J = 7.3 Hz, 3 H), 2.43–2.58 (m, 1 H), 2.80–2.98 (m, 1 H), 3.23–3.42
(m, 1 H), 3.65–3.98 (m, 3 H), 4.15–4.39 (m, 2 H), 5.52 (s, 1 H),
6.38–6.48 (m, 2 H, Ar-H), 6.67 (t, J = 7.3 Hz, 1 H, Ar-H), 7.10 (t,
J = 7.3 Hz, 2 H, Ar-H), 7.46 (t, J = 8.0 Hz, 1 H, Ar-H), 7.60 (d,
J = 8.0 Hz, 1 H, Ar-H), 8.08–8.24 (m, 2 H, Ar-H).
460.1133.
Diethyl 1-(2,4-Dichlorophenyl)-2-phenylpyrrolidine-3,3-dicar-
boxylate (4l)
ESI-MS: m/z = 413 [M + H]+, 355, 353, 271, 248, 220.
Solid; mp 76–78 °C.
HRMS (EI): m/z [M + H]+ calcd for C22H25N2O6: 413.1712; found:
413.1702.
IR (KBr): 3456, 3067, 2976, 2931, 1729, 1585, 1480, 1265, 1229,
1101, 1064, 862, 806, 697 cm–1.
Diethyl 1-(4-Methylphenyl)-2-phenylpyrrolidine-3,3-dicarbox-
ylate (4h)
Solid; mp 95–98 °C.
1H NMR (300 MHz, CDCl3): d = 0.78 (t, J = 6.8 Hz, 3 H), 1.26 (t,
J = 6.8 Hz, 3 H), 2.21–2.30 (m, 1 H), 2.88–2.99 (m, 2 H), 3.30–3.42
(m, 1 H), 3.67–3.79 (m, 1 H), 4.15–4.37 (m, 3 H), 5.58 (s, 1 H),
6.90–6.95 (m, 2 H, Ar-H), 7.10–7.36 (m, 6 H).
ESI-MS: m/z = 436 [M + H]+, 390, 331, 209.
HRMS (EI): m/z [M + H]+ calcd for C22H24NO4Cl2: 436.1082;
IR (KBr): 3466, 3062, 2988, 2929, 2845, 1855, 1731, 1619, 1521,
1492, 1451, 1364, 1254, 1227, 1170, 1066, 880, 852, 796, 697 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.01 (t, J = 6.7 Hz, 3 H), 1.24 (t,
J = 6.7 Hz, 3 H), 2.17 (s, 3 H), 2.44 (dd, J = 5.2, 13.5 Hz, 1 H),
2.84–2.98 (m, 1 H), 3.20–3.32 (m, 1 H), 3.60–3.72 (m, 1 H), 3.76–
3.88 (m, 2 H), 4.12–4.30 (m, 2 H), 5.38 (s, 1 H), 6.33 (d, J = 9.0 Hz,
2 H, Ar-H), 6.86 (d, J = 8.3 Hz, 2 H, Ar-H), 7.16–7.28 (m, 5 H).
found: 436.1084.
Diethyl 1,2-Bis(4-methoxyphenyl)pyrrolidine-3,3-dicarboxy-
late (4m)
Solid; mp 84–86 °C.
ESI-MS: m/z = 404 [M + Na]+, 382, 336, 304, 265, 258, 209.
HRMS (EI): m/z [M + Na]+ calcd for C23H27NO4Na: 404.1837;
found: 404.1837.
IR (KBr): 3447, 2925, 2837, 1733, 1611, 1512, 1460, 1245, 1171,
1072 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.04 (t, J = 6.7 Hz, 3 H), 1.24 (t,
J = 6.7 Hz, 3 H), 2.36–2.45 (m, 1 H), 2.84–2.96 (m, 1 H), 3.14–3.25
(m, 1 H), 3.65 (s, 3 H), 3.67–3.90 (m, 3 H), 3.75 (s, 3 H), 4.14–4.28
(m, 2 H), 5.26 (s, 1 H), 6.36 (d, J = 9.0 Hz, 2 H, Ar-H), 6.66 (d,
J = 9.0 Hz, 2 H, Ar-H), 6.75 (d, J = 9.0 Hz, 2 H, Ar-H), 7.16 (d,
J = 9.0 Hz, 2 H, Ar-H).
Diethyl 1-(4-Methoxyphenyl)-2-phenylpyrrolidine-3,3-dicar-
boxylate (4i)
Solid; mp 86–88 °C.
IR (KBr): 3448, 2982, 2928, 1733, 1643, 1512, 1455, 1365, 1246,
1175, 1072, 812 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.00 (t, J = 6.7 Hz, 3 H), 1.24 (t,
J = 6.7 Hz, 3 H), 2.36–2.46 (m, 1 H), 2.83–2.98 (m, 1 H), 3.16–3.28
(m, 1 H), 3.58–3.70 (m, 4 H), 3.74–3.88 (m, 2 H), 4.12–4.30 (m, 2
H), 5.32 (s, 1 H), 6.34–6.40 (m, 2 H, Ar-H), 6.62–6.68 (m, 2 H, Ar-
H), 7.15–7.28 (m, 5 H).
ESI-MS: m/z = 428 [M + H]+, 382, 308.
HRMS (EI): m/z [M + H]+ calcd for C24H30NO6: 428.2073; found:
428.2071.
Diethyl 1-Phenyl-2-(2-thienyl)pyrrolidine-3,3-dicarboxylate
(4n)
ESI-MS: m/z = 398 [M+], 382.
Semisolid.
HRMS (EI): m/z [M+] calcd for C23H28NO5: 398.1967; found:
398.1959.
IR (KBr): 3452, 2981, 2932, 2847, 1735, 1599, 1504, 1363, 1256,
1171, 1101, 1072, 1018 cm–1.
Diethyl 1-(4-Bromophenyl)-2-phenylpyrrolidine-3,3-dicarbox-
ylate (4j)
Solid; mp 103–105 °C.
1H NMR (200 MHz, CDCl3): d = 1.06–1.42 (m, 6 H), 2.49 (dd,
J = 5.4, 12.5 Hz, 1 H), 2.86–3.24 (m, 2 H), 3.58–4.38 (m, 5 H), 5.65
(s, 1 H), 6.52 (d, J = 7.8 Hz, 2 H, Ar-H), 6.66 (t, J = 7.8 Hz, 1 H, Ar-
H), 6.88–6.96 (m, 2 H), 7.05–7.16 (m, 3 H).
Synthesis 2009, No. 20, 3443–3448 © Thieme Stuttgart · New York

3448
J. S. Yadav et al.
PAPER
(6) (a) Alper, P. B.; Meyers, C.; Lerchner, A.; Siegel, D. R.;
ESI-MS: m/z = 374 [M + H]+, 345, 328.
Carreira, E. M. Angew. Chem. Int. Ed. 1999, 38, 3186.
(b) Fischer, C.; Meyers, C.; Carreira, E. M. Helv. Chim. Acta
2000, 83, 1175. (c) Meyers, C.; Carreira, E. M. Angew.
Chem. Int. Ed. 2003, 42, 694. (d) Lerchner, A.; Carreira, E.
M. J. Am. Chem. Soc. 2002, 124, 14826.
HRMS (EI): m/z [M + H]+ calcd for C20H24NO4S: 374.1426; found:
374.1414.
Acknowledgment
(7) (a) Lautens, M.; Han, W. J. Am. Chem. Soc. 2002, 124,
6312. (b) Lautens, M.; Han, W.; Liu, J. H.-C. J. Am. Chem.
Soc. 2003, 125, 4028.
G.N.L., D.C.K., and G.S. thank CSIR, New Delhi, for the award of
fellowships.
(8) Bertozzi, F.; Gustafsson, M.; Olsson, R. Org. Lett. 2002, 4,
3147.
(9) (a) Carson, C. A.; Kerr, M. A. J. Org. Chem. 2005, 70, 8242.
(b) Kang, Y.-B.; Tang, Y.; Sun, X.-L. Org. Biomol. Chem.
2006, 4, 299.
(10) Pohlhaus, P. D.; Johnson, J. S. J. Org. Chem. 2005, 70, 1057.
(11) Imamoto, T. Lanthanides in Organic Synthesis; Academic
Press: New York, 1994.
(12) (a) Cappa, A.; Marcantoni, E.; Torregiani, E.; Bartoli, G.;
Bellucci, M. C.; Bosco, M.; Sambri, L. J. Org. Chem. 1999,
64, 5696. (b) Marcantoni, E.; Nobili, F.; Bartoli, G.; Bosco,
M.; Sambri, L.; Torregiani, E. J. Org. Chem. 1997, 62,
4183. (c) Di Dea, M.; Marcantoni, E.; Torregiani, E.;
Bartoli, G.; Bellucci, M. C.; Bosco, M.; Sambri, L. J. Org.
Chem. 2000, 65, 2830.
(13) (a) Yadav, J. S.; Reddy, B. V. S. Synlett 2000, 1275.
(b) Yadav, J. S.; Reddy, B. V. S.; Bhaskar Reddy, K.;
Satyanarayana, M. Tetrahedron Lett. 2002, 43, 7009.
(c) Yadav, J. S.; Reddy, B. V. S.; Sathaiah, K.;
Vishnumurthy, P. Synlett 2005, 2811. (d) Yadav, J. S.;
Reddy, B. V. S.; Srinivas, M.; Padmavani, B. Tetrahedron
2004, 60, 3261.
References
(1) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435; and previous
reports in this series.
(2) (a) Bhagwat, S. S.; Gude, C.; Chan, K. Tetrahedron Lett.
1996, 37, 4627. (b) Hanessian, S.; Reinhold, U.; Saulnier,
M.; Claridge, S. Bioorg. Med. Chem. Lett. 1998, 8, 2123.
(c) Hansen, J. J.; Krogsgaard-Larsen, P. Med. Res. Rev.
1990, 10, 55. (d) Murphy, M. M.; Schullek, J. R.; Gordon, E.
M.; Gallop, M. A. J. Am. Chem. Soc. 1995, 117, 7029.
(e) Shi, Z.-C.; Zeng, C.-M.; Lin, G.-Q. Heterocycles 1995,
41, 277. (f) Cushman, D. W.; Ondetti, M. A. Prog. Med.
Chem. 1980, 17, 41.
(3) Wess, G.; Urmann, M.; Sickenberger, B. Angew. Chem. Int.
Ed. 2001, 40, 3341.
(4) (a) Kantorowsk, E. J.; Kurth, M. J. Tetrahedron 2000, 56,
4317. (b) Kim, S.; Yoon, J.-Y. Synthesis 2000, 1622.
(c) Hoberg, J. O. Tetrahedron 1998, 54, 12631.
(5) (a) Wong, H. N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C.;
Tanko, J.; Hudlicky, T. Chem. Rev. 1989, 89, 165.
(b) Danishefsky, S. Acc. Chem. Res. 1979, 12, 66.
Synthesis 2009, No. 20, 3443–3448 © Thieme Stuttgart · New York