Gadolinium triflate catalyzed alkylation of pyrroles: efficient synthesis of 3-oxo-2,3-dihydro-1H-pyrrolizine derivatives

Article abstract of DOI:10.1016/j.tet.2007.04.018

Novel 2-alkylated pyrrole derivatives were synthesized regioselectively by Gd(OTf)₃ catalyzed addition reactions of pyrrole to?substituted dimethyl 2-benzylidenemalonate derivatives under mild reaction conditions. 2-Alkylated pyrrole derivative

Full text of DOI:10.1016/j.tet.2007.04.018

Tetrahedron 63 (2007) 5608–5613
Gadolinium triflate catalyzed alkylation of pyrroles: efficient
synthesis of 3-oxo-2,3-dihydro-1H-pyrrolizine derivatives
*
Canan Unaleroglu and Arife Yazici
Hacettepe University, Department of Chemistry, Beytepe Campus, 06532 Ankara, Turkey
Received 25 December 2006; revised 15 March 2007; accepted 5 April 2007
Available online 14 April 2007
Abstract—Novel 2-alkylated pyrrole derivatives were synthesized regioselectively by Gd(OTf)3 catalyzed addition reactions of pyrrole
to substituted dimethyl 2-benzylidenemalonate derivatives under mild reaction conditions. 2-Alkylated pyrrole derivatives are used for the
construction of the 3-oxo pyrrolizine skeleton. Intramolecular cyclization of alkylated pyrrole derivatives afforded new diastereoselective
3-oxo-2,3-dihydro-1H-pyrrolizine derivatives with good to high yields.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
A previously published method for the synthesis of pyrro-
lizine-3-ones involves the cyclization of the condensation
product of pyrrole 2-carboxyaldehyde and malonic acid
in very low yield.7 The formation of pyrrolizine-3-one by
flash vacuum pyrolysis of the condensation product of
pyrrole 2-carboxyaldehyde with Meldrum’s acid at 600 ꢀC
with high yield has been reported by McNab.8 The prod-
ucts were further used in the synthesis of 1,2-dihydropyrro-
lizine-3-one derivatives.9 Recently, the alkylation product
of pyrrole with a,b-unsaturated 2-acyl imidazole10 and a
radical reaction product of pyrrole and a-haloesters11 were
used in the synthesis of oxo-2,3-dihydro-1H-pyrrolizine
derivatives.
The Friedel–Crafts alkylation reaction is a powerful C–C
bond-forming process in organic synthesis.1 Recently,
M(OTf)x (M¼Yb, Sc, Cu, Zn, Dy, etc.) have been used in
this transformation as mild, water tolerant, high yielding
and environmentally benign Lewis acid catalysts.2
Synthesis of pyrrole derivatives and bridgehead nitrogen
heterocycles are of interest because they often display
biological activity and are important as precursors in the
synthesis of many biologically active compounds.3 Avariety
of methods have been developed for the alkylation of
pyrrole4 and to generate bicyclic [5-5] systems with one
ring junction nitrogen atom.5 Consequently, interest has
been ongoing in the synthesis of pyrrole and pyrrolizine
derivatives.
In this work, we describe the gadolinium triflate catalyzed
regioselective addition of pyrrole to substituted dimethyl
2-benzylidenemalonates and their intramolecular cycliza-
tion affording 3-oxo-2,3-dihydro-1H-pyrrolizine derivatives
(Scheme 1).
Recently our studies have revealed that metal triflates are
very suitable Lewis acids for the direct alkylation of
pyrrole compounds. We have reported that the metal triflate
catalyzed conjugate addition of pyrrole to a,b-unsaturated
esters and N-tosyl imines proceeded in good yields.6
With our ongoing research, we have become interested in
the construction of the 3-oxo pyrrolizine skeleton from
alkylated pyrroles themselves obtained from the addition
of pyrrole to electron-deficient alkenes with a metal triflate
catalyst.
R
+
10% Gd(OTf)3
N
H
CO2CH3
R
N
H
H3CO2C
CO2CH3
H3CO2C
NaH
R= H, 4-NO2, 4-F, 4-CH3, 4-OCH3
4-CF3, 4-Br, 4-OH, 2-OCH3
R
N
O
Keywords: 3-Oxo-pyrrolizine derivatives; Pyrrolizine derivatives; Metal
triflate; Pyrrole derivatives; Lewis acid catalysis.
* Corresponding author. Tel.: +90 312 297 7962; fax: +90 312 299 2163;
e-mail: canan@hacettepe.edu.tr
CO2CH3
Scheme 1.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.04.018

C. Unaleroglu, A. Yazici / Tetrahedron 63 (2007) 5608–5613
5609
2. Results and discussion
The addition reactions of pyrrole with 2a in the presence of
various metal triflates in THF at rt were subsequently inves-
tigated (Table 1). The addition reaction regioselectively
provided dimethyl 2-(phenyl(1H-pyrroyl)methyl)malonate
(3a) as product in 80% yield with Gd(OTf)3 (Table 1, entry
7). Cu(OTf)2, Yb(OTf)3, Nd(OTf)3 and La(OTf)3 catalyzed
the addition reaction with 50–70% yields (Table 1, entries
1, 4–6). Zn(OTf)2 and Y(OTf)3 were found to be inefficient
in improving the yield (Table 1, entries 2 and 3). Of the var-
ious organic solvents examined (THF, CH2Cl2, toluene and
acetone) in the presence of 10 mol % Gd(OTf)3 at rt, the
best chemical yield (80%) was obtained in THF.
Dimethyl 2-benzylidenemalonate (2a) was synthesized
from benzaldehyde and dimethylmalonate, via the classic
Knoevenagel condensation, with piperidine as a catalyst in
toluene at reflux. It is known that the high reactivity of
pyrrole allows addition to electron-deficient alkenes.
Dimethyl 2-benzylidinemalonate (2a) seems to be a good
acceptor for the addition reactions of pyrrole (1) (Scheme 2).
+
10% Gd(OTf)3
N
H
CO2CH3
N
H
Substituted dimethyl 2-benzylidenemalonates 2b–i were
synthesized to examine the effect of substituents on the addi-
tion reaction. Employing Gd(OTf)3 in THF at rt, the influence
of the substituent on the alkylation efficiency was examined
(Table 2). Addition reactions of pyrrole to 2g, 2h and 2i with
electron donating substituents gave the product with low
yield (37–55%) (Table 2, entries 7–9). Weakly electron dona-
ting methyl substituted 2f yielded 3f in 74% yield (Table 2,
entry 6). Electron-withdrawing substituents improved the
efficiency of the alkylation reaction, and 3b, 3d and 3e were
obtained in high yields (83%, 81% and 84%, respectively)
(Table 2, entries 2, 4 and 5). Compound 2c with CF3 gave
the addition product 3c with the highest yield (92%). The
structure of 3a–i was identified by 1H NMR, 13C NMR and
elemental analysis. The position of the substituent was
H3CO2C
CO2CH3
3a
H3CO2C
1
2a
Scheme 2.
Table 1. Effect of catalyst on the alkylation reaction of pyrrolea
Entry
Catalyst
Yieldb (%)
1
2
3
4
5
6
7
Cu(OTf)2
Zn(OTf)2
Y(OTf)3
Yb(OTf)3
Nd(OTf)3
La(OTf)3
Gd(OTf)3
50
20
40
65
50
70
80
a
1
Reactions were carried out in THF at rt.
Yield refers to pure product after column chromatography.
assigned by COSY spectra and by comparing the H NMR
spectra with those of the known 2-alkylated pyrroles.4a,12
b
The following reaction mechanism is proposed for Gd(OTf)3
catalyzed addition reaction of pyrrole to substituted di-
methyl 2-benzylidenemalonates (Scheme 3). Coordination
of Gd(OTf)3 activates the structure of 2-benzylidenemalo-
nate, then addition of pyrrole to activated dimethyl 2-benzyl-
idenemalonate affords 3a through the intermediate 4. When
the reaction was performed without Gd(OTf)3, the addition
product was not obtained. Consequently, Gd(OTf)3 has a cru-
cial function in the addition reaction of pyrrole to dimethyl
2-benzylidenemalonate.
Table 2. Effect of substituent on the alkylation reaction of pyrrolea
R
+
R
10% Gd(OTf)3
N
H
CO2CH3
N
H
THF, rt
H3CO2C
CO2CH3
H3CO2C
1a-i
2a-i
3a-i
Entry
R
3
Yieldb (%)
1
2
3
4
5
6
7
8
9
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
80
83
92
81
84
74
50
37
55
4-NO2
4-CF3
4-F
For the synthesis of the [5-5] membered ring system of pyr-
rolizine, alkylated novel pyrrole derivatives 3a–i are suitable
functional five-membered ring equivalents. Intramolecular
cyclizations of 3a were carried out in the presence of NaH
in dry THF under argon (Scheme 4). The reaction mixture
was stirred at 0 ꢀC and monitored by TLC. Intramolecular
cyclization of dimethyl 2-benzylidenemalonate (3a) dia-
stereoselectively furnished lactam product 5a in 74% yield
(Table 3, entry 1). The same method was applied to
4-Br
4-CH3
4-OCH3
4-OH
2-OCH3
a
Reactions were carried out in THF at rt.
Yield refers to pure product after column chromatography.
b
Gd(OTf)3
O
-2Gd(OTf)3
+
OCH3
OCH3
N
H
H
O
N
O
N
H
H3CO
O
Gd(OTf)3
OCH3
O
H
O
OCH3
Gd(OTf)3
H3CO
Gd(OTf)3
4
3a
Scheme 3.

5610
C. Unaleroglu, A. Yazici / Tetrahedron 63 (2007) 5608–5613
used for intramolecular cyclization was freshly distilled
from sodium benzophenone. H NMR (400 MHz) and 13C
1
NaH
N
N
H
NMR (100 MHz) spectra were recorded on a Brucker ultra
shield FT NMR spectrometer using CDCl3 and DMSO-d6
as solvents and SiMe4 as an internal standard. Chemical
shifts (parts per million) were reported relative to SiMe4.
Coupling constants are expressed as J values in hertz. Infra-
red spectra were recorded on a Unicam Mattson 1000 FTIR
spectrometer. Melting points were measured on a Gallen-
kamp capillary melting point apparatus and are uncorrected.
Reactions were monitored by thin layer chromatography
using precoated silica plates (Kiesel 60, F254, E. Merck),
visualized with UV light (l¼254 nm). Flash column chro-
matography was performed on silica gel (230–400 mesh,
E. Merck).
THF, 0 °C
CO2CH3
H3CO2C
O
CO2CH3
3a
5a
Scheme 4.
Table 3. Intramolecular cyclization products 5a–i of 3a–i
R
R
NaH
THF, 0 °C
N
N
H
CO2CH3
H3CO2C
O
CO2CH3
4.2. General procedure for the synthesis of
compounds 3a–i
3a-i
5a-i
Entry
R
H
5
Yielda (%)
A mixture of dimethyl benzylidenemalonate derivatives
(0.5 mmol) and Gd(OTf)3 (0.03 g, 0.05 mmol) in THF (5 mL)
was stirred for 0.5 h at rt. Pyrrole (0.33 g, 5.0 mmol) was
added instantly via syringe pump. The resulting mixture
was stirred for 12 h at rt and monitored by TLC. Five
millilitres of water was added to the solution and the mixture
was then extracted with diethylether (3ꢁ10 mL). The com-
bined organic layers were dried over MgSO4 and the solvent
was removed under reduced pressure. The crude product was
purified by flash silica gel column chromatography.
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5h
5i
74
78
68
70
77
76
73
76
65
4-NO2
4-CF3
4-F
4-Br
4-CH3
4-OCH3
4-OH
2-OCH3
a
Yield refers to pure product after column chromatography.
intramolecular cyclization of 3b–i. Alkylated pyrrole deri-
vatives 3b, 3e, 3f and 3h gave, respectively, the cyclization
products 5b (78%), 5e (77%), 5f (76%) and 5h (76%) with
comparable yields (Table 3, entries 2, 5, 6 and 8). Compound
5d was obtained with 70% yield (Table 3, entry 4). Com-
pounds 5c and 5i were formed in 68% and 65% yield,
respectively (Table 3, entries 3 and 9). 3-Oxo-2,3-dihydro-
1H-pyrrolizine derivatives 5a–i formed diastereoselectively.
4.2.1. Dimethyl 2-(phenyl(1H-pyrrol-2-yl)methyl)malo-
nate (3a). White tiny prisms; mp: 112–113 ꢀC; Rf 0.38
(1:3 EtOAc/hexane); IR (KBr): 3379, 2952, 1744, 1601,
1
1558, 1508, 1432, 1258, 1148 cmꢂ1; H NMR (400 MHz,
CDCl3): d 3.49 (s, 3H, OCH3), 3.71 (s, 3H, OCH3), 4.19
(d, 1H, J¼10.4, CH), 4.82 (d, 1H, J¼10.4, CH), 5.95 (br s,
1H, C3-H), 6.05–6.08 (m, 1H, C4-H), 6.63 (br s, 1H, C5-
H), 7.21–7.32 (m, 5H, Ar-H), 8.52 (br s, 1H, NH); 13C
NMR (100 MHz, CDCl3): d 44.4, 52.3, 52.7, 57.6, 106.5,
108.2, 117.6, 127.2, 128.2, 128.5, 130.6, 139.8, 167.7,
168.9. Anal. Calcd for C16H17NO4: C, 66.89; H, 5.96; N,
4.88. Found: C, 67.17; H, 5.82; N, 4.52.
3. Conclusion
In summary, we report that addition reaction of pyrrole to
dimethyl 2-benzylidenemalonate derivatives regioselectively
produced novel 2-alkylated pyrrole derivatives 3a–i in the
presence of Gd(OTf)3 under mild reaction conditions. The
isolated yields are highly dependent on the substituent.
The products are almost formed with high yield excepting
the OH and OCH3 substituents. 2-Alkylated pyrrole deriva-
tives 3a–i are convenient precursors for the synthesis of
3-oxo-2,3-dihydro-1H-pyrrolizine derivatives. The synthe-
sis of these heterocycles can be achieved by intramolecular
cyclization of 2-alkylated pyrrole derivatives 3a–i. Novel
diastereoselective 3-oxo-2,3-dihydro-1H-pyrrolizine deriva-
tives are obtained in good to high yield.
4.2.2. Dimethyl 2-((4-nitrophenyl)(1H-pyrrol-2-yl)-
methyl)malonate (3b). Pale yellow powder; mp: 170–
171 ꢀC; Rf 0.33 (1:3 EtOAc/hexane); IR (KBr): 3370,
2951, 1739, 1559, 1509, 1434, 1299, 1256, 1173 cmꢂ1; 1H
NMR (400 MHz, CDCl3): d 3.55 (s, 3H, OCH3), 3.73 (s,
3H, OCH3), 4.19 (d, 1H, J¼9.8, CH), 4.92 (d, 1H, J¼9.8,
CH), 5.90 (br s, 1H, C3-H), 6.06–6.09 (m, 1H, C4-H),
6.69 (br s, 1H, C5-H), 7.45 (d, 2H, J¼8.7, Ar-H), 8.17
(d, 2H, J¼8.7, Ar-H), 8.74 (br s, 1H, NH); 13C NMR
(100 MHz, CDCl3): d 44.0, 52,8, 53.0, 57.2, 107.6, 108.8,
118.4, 123.8, 128.8, 129.1, 147.2, 147.3, 167.4, 168.6.
Anal. Calcd for C16H16N2O6: C, 57.83; H, 4.85; N, 8.43.
Found: C, 58.10; H, 4.87; N, 8.25.
4. Experimental
4.1. General
4.2.3. Dimethyl 2-((1H-pyrrol-2-yl)(4-(trifluoromethyl)-
phenyl)methyl)malonate (3c). White powder; mp: 94–
95 ꢀC; Rf 0.45 (1:3 EtOAc/hexane); IR (KBr): 3380, 2955,
1747, 1617, 1432, 1331, 1260, 1153 cmꢂ1 1H NMR
;
Commercially available reagents and solvents were used
without further purification. Anhydrous tetrahydrofuran
(400 MHz, CDCl3): d 3.54 (s, 3H, OCH3), 3.73 (s, 3H,
OCH3), 4.18 (d, 1H, J¼10.0, CH), 4.87 (d, 1H, J¼10.0,

C. Unaleroglu, A. Yazici / Tetrahedron 63 (2007) 5608–5613
5611
CH), 5.91 (br s, 1H, C3-H), 6.07 (br s, 1H, C4-H), 6.67 (br s,
1H, C5-H), 7.40 (d, 2H, J¼8.0, Ar-H), 7.57 (d, 2H, J¼8.0,
Ar-H), 8.56 (br s, 1H, NH); 13C NMR (100 MHz, CDCl3):
4.2.8. Dimethyl 2-((4-hydroxyphenyl)(1H-pyrrol-2-yl)-
methyl)malonate (3h). White powder; mp: 164–165 ꢀC;
Rf 0.30 (1:3 EtOAc/hexane); IR (KBr): 3378, 2952, 1746,
d 44.1, 52.6, 52.9, 57.3, 107.3, 108.6, 118.1, 124.1 (q, 1JC–F
¼
1432, 1215, 1258, 1146 cmꢂ1 1H NMR (400 MHz,
;
3
270.2), 125.5 (q, JC–F¼3.7), 128.6, 129.6 (q, 2JC–F¼32.2),
129.9, 144.0, 167.5, 168.7. Anal. Calcd for C17H16F3NO4:
C, 57.47; H, 4.54; N, 3.94. Found: C, 57.21; H, 4.64; N, 3.92.
DMSO-d6): d 3.41 (s, 3H, OCH3), 3.52 (s, 3H, OCH3),
4.25 (d, J¼12.0, 1H, CH), 4.52 (d, J¼12.0, 1H, CH), 5.84
(br s, 1H, C3-H), 5.92 (s, 1H, C4-H), 6.53 (br s, 1H, C5-
H), 6.62 (d, J¼8.5, 2H, Ar-H), 7.06 (d, J¼8.5, 2H, Ar-H),
9.27 (s, 1H, OH), 10.58 (br s, 1H, NH); 13C NMR
(100 MHz, DMSO-d6): d 44.0, 52.7, 52.8, 57.3, 104.3,
107.6, 115.3, 117.2, 129.3, 131.7, 132.4, 156.4, 165.2,
168.0. Anal. Calcd for C16H17NO5: C, 63.36; H, 5.65; N,
4.62. Found: C, 63.47; H, 5.64; N, 4.54.
4.2.4. Dimethyl 2-((4-fluorophenyl)(1H-pyrrol-2-yl)-
methyl)malonate (3d). White powder; mp: 131–132 ꢀC;
Rf 0.43 (1:3 EtOAc/hexane); IR (KBr): 3378, 2955, 1739,
1507, 1429, 1296, 1250 cmꢂ1
;
1H NMR (400 MHz,
CDCl3): d 3.52 (s, 3H, OCH3), 3.71 (s, 3H, OCH3), 4.13
(d, 1H, J¼10.4, CH), 4.80 (d, 1H, J¼10.4, CH), 5.92 (br s,
1H, C3-H), 6.07 (br s, 1H, C4-H), 6.65 (br s, 1H, C5-H),
6.96–7.01 (m, 2H, Ar-H), 7.23–7.26 (m, 2H, Ar-H), 8.67
(br s, 1H, NH); 13C NMR (100 MHz, CDCl3): d 43.7,
4.2.9. Dimethyl 2-((2-methoxyphenyl)(1H-pyrrol-2-yl)-
methyl)malonate (3i). White powder; mp: 85–86 ꢀC; Rf
0.30 (1:3 EtOAc/hexane); IR (KBr): 3339, 2954, 1720,
2
1
52.4, 52.8, 57.7, 106.6, 108.4, 115.4 (d, JC–F¼21.2),
1512, 1437, 1320, 1240, 1157 cmꢂ1; H NMR (400 MHz,
3
4
117.8, 129.8 (d, JC–F¼7.9), 130.5, 135.6 (d, JC–F¼3.3),
CDCl3): d 3.51 (s, 3H, OCH3), 3.65 (s, 3H, OCH3), 3.90
(s, 3H, OCH3), 4.51 (d, J¼10.8, 1H, CH), 5.13 (J¼10.4,
1H, CH), 5.95 (br s, 1H, C3-H), 6.03–6.05 (m, 1H, C4-H),
6.63 (br s, 1H, C5-H), 6.90–6.93 (m, 2H, Ar-H), 7.19–7.23
(m, 2H, Ar-H), 9.12 (br s, 1H, NH); 13C NMR (100 MHz,
CDCl3): d 39.8, 52.3, 52.9, 55.5, 55.6, 107.8, 108.1, 111.0,
116.8, 121.1, 128.1, 128.9, 129.6, 130.3, 156.5, 167.8,
169.0. Anal. Calcd for C17H19NO5: C, 64.34; H, 6.03; N,
4.41. Found: C, 64.62; H, 6.09; N, 4.53.
1
161.9 (d, JC–F¼244.8), 167.7, 168.8. Anal. Calcd for
C16H16FNO4: C, 62.94; H, 5.28; N, 4.59. Found: C, 62.65;
H, 5.40; N, 4.70.
4.2.5. Dimethyl 2-((4-bromophenyl)(1H-pyrrol-2-yl)-
methyl)malonate (3e). White powder; mp: 158–160 ꢀC;
Rf 0.35 (1:3 EtOAc/hexane); IR (KBr): 3385, 2952, 1752,
1
1436, 1352, 1307, 1256, 1142 cmꢂ1; H NMR (400 MHz,
CDCl3): d 3.54 (s, 3H, OCH3), 3.71 (s, 3H, OCH3), 4.13
(d, J¼10.2, 1H, CH), 4.77 (d, J¼10.2, 1H, CH), 5.90 (br s,
1H, C3-H), 6.05–6.07 (m, 1H, C4-H), 6.65 (br s, 1H, C5-
H), 7.15 (d, J¼8.4, 2H, Ar-H), 7.42 (d, J¼8.4, 2H, Ar-H),
8.53 (br s, 1H, NH); 13C NMR (100 MHz, CDCl3): d 43.8,
52.6, 52.9, 57.4, 106.9, 108.4, 117.9, 121.3, 130.0, 131.7,
139.0, 167.6, 168.8. Anal. Calcd for C16H16BrNO4: C,
52.48; H, 4.40; N, 3.82. Found: C, 52.21; H, 4.20; N, 3.89.
4.3. General procedure for the synthesis of 5a–i
The following process was used for the synthesis of the
above-mentioned compounds. Dimethyl 2-(phenyl(1H-
pyrrol-2-yl)methyl)malonate (3a) (0.29 g, 1.00 mmol) was
dissolved in THF (3 mL) under argon and cooled to 0 ꢀC.
Sodium hydride (0.04 g, 1.5 mmol) was added to the solu-
tion and the mixture was stirred at 0 ꢀC for 8 h and moni-
tored by TLC. The mixture was then poured into pH 7
phosphate buffer (5 mL) and the product was extracted
with EtOAc (3ꢁ10 mL). After removal of the solvents under
reduced pressure, the residue was purified by flash silica gel
column chromatography.
4.2.6. Dimethyl 2-((1H-pyrrol-2-yl)(p-tolyl)methyl)malo-
nate (3f). White powder; mp: 133–134 ꢀC; Rf 0.46 (1:3
EtOAc/hexane); IR (KBr): 3381, 2936, 1739, 1632, 1558,
1509, 1432, 1252 cmꢂ1 1H NMR (400 MHz, CDCl3):
;
d 2.34 (s, 3H, CH3), 3.52 (s, 3H, OCH3), 3.71 (s, 3H,
OCH3), 4.16 (d, 1H, J¼10.6, CH), 4.78 (d, 1H, J¼10.6,
CH), 5.93 (br s, 1H, C3-H), 6.04–6.06 (m, 1H, C4-H),
6.62 (br s, 1H, C5-H), 7.06–7.16 (m, 4H, Ar-H), 8.58
(br s, 1H, NH); 13C NMR (100 MHz, CDCl3): d 21.1,
44.0, 52.3, 52.6, 57.7, 106.4, 108.2, 117.5, 128.0, 129.2,
130.9, 136.5, 136.8, 167.7, 168.9. Anal. Calcd for
C17H19NO4: C, 67.76; H, 6.36; N, 4.65. Found: C, 67.50;
H, 6.42; N, 4.50.
4.3.1. Methyl 3-oxo-1-phenyl-2,3-dihydro-1H-pyrrol-
izine-2-carboxylate (5a). Viscous oil; Rf 0.48 (1:3 EtOAc/
hexane); IR (KBr): 2952, 1762, 1571, 1455, 1398, 1289,
1251, 1164, 1082 cmꢂ1 1H NMR (400 MHz, CDCl3):
;
d 3.88 (s, 3H, OCH3), 3.94 (d, 1H, J¼5.1, CH), 4.92 (d,
1H, J¼4.6, CH), 6.00 (br s, 1H, Pyr-H), 6.53 (t, 1H,
J¼3.2, Pyr-H), 7.11 (d, 1H, J¼3.2, Pyr-H), 7.27–7.34 (m,
5H, Ar-H). 13C NMR (100 MHz, CDCl3): 43.0, 53.1, 62.3,
106.3, 111.9, 119.8, 127.3, 127.9, 128.9, 129.2, 140.1,
165.0, 167.6. Anal. Calcd for C15H13NO3: C, 70.58; H,
5.13; N, 5.49. Found: C, 70.36; H, 5.10; N, 5.16.
4.2.7. Dimethyl 2-((4-methoxyphenyl)(1H-pyrrol-2-yl)-
methyl)malonate (3g). White block crystals; mp: 112–
113 ꢀC; Rf 0.27 (1:3 EtOAc/hexane); IR (KBr): 3381,
2952, 1747, 1609, 1512, 1431, 1307, 1257, 1142 cmꢂ1; 1H
NMR (400 MHz, CDCl3): d 3.51 (s, 3H, OCH3), 3.70 (s,
3H, OCH3), 3.78 (s, 3H, OCH3), 4.12 (d, 1H, J¼10.6,
CH), 4.76 (d, 1H, J¼10.6, CH), 5.92 (br s, 1H, C3-H),
6.03–6.06 (m, 1H, C4-H), 6.61 (br s, 1H, C5-H), 6.81 (d,
2H, J¼8.7, Ar-H), 7.18 (d, 2H, J¼8.7, Ar-H), 8.48 (br s,
1H, NH); 13C NMR (100 MHz, CDCl3): d 43.6, 52.3, 52.7,
55.0, 57.8, 106.2, 108.2, 113.9, 116.1, 117.5, 129.2, 131.1,
131.8, 158.6, 167.8, 168.9. Anal. Calcd for C17H19NO5: C,
64.34; H, 6.03; N, 4.41. Found: C, 64.52; H, 6.13; N, 4.60.
4.3.2. Methyl 1-(4-nitrophenyl)-3-oxo-2,3-dihydro-1H-
pyrrolizine-2-carboxylate (5b). Viscous oil; Rf 0.54 (1:3
EtOAc/hexane); IR (KBr): 2866, 1732, 1641, 1517, 1461,
1397, 1344, 1287, 1124 cmꢂ1
;
1H NMR (400 MHz,
CDCl3): d 3.91 (br s, 4H, OCH3, CH), 5.07 (d, 1H, J¼5.2,
CH), 6.04 (br s, 1H, Pyr-H), 6.58 (t, 1H, J¼3.2, Pyr-H),
7.15 (br s, 1H, Pyr-H), 7.47 (d, 2H, J¼8.7, Ar-H), 8.24 (d,
2H, J¼8.7, Ar-H); 13C NMR (100 MHz, CDCl3): d 42.5,
53.4, 61.7, 106.8, 112.6, 119.9, 120.1, 124.5, 128.4, 138.3,

5612
C. Unaleroglu, A. Yazici / Tetrahedron 63 (2007) 5608–5613
147.1, 147.9, 162.0, 167.6. Anal. Calcd for C15H12N2O5: C,
60.00; H, 4.03; N, 9.33. Found: C, 60.17; H, 4.05; N, 9.12.
(d, 2H, J¼8.6, Ar-H), 7.09 (br s, 1H, Pyr-H), 7.16 (d, 2H,
J¼8.6, Ar-H); 13C NMR (100 MHz, CDCl3): d 42.4, 53.0,
55.2, 62.5, 106.1, 111.7, 114.5, 119.8, 128.4, 132.0, 140.5,
159.3, 165.1, 167.6. Anal. Calcd for C16H15NO4: C, 67.36;
H, 5.30; N, 4.91. Found: C, 66.97; H, 5.29; N, 4.91.
4.3.3. Methyl 3-oxo-1-(4-(trifluoromethyl)phenyl)-2,3-di-
hydro-1H-pyrrolizine-2-carboxylate (5c). Viscous oil; Rf
0.71 (1:3 EtOAc/hexane); IR (KBr): 2957, 1760, 1653,
1
1618, 1404, 1324, 1165, 1068 cmꢂ1; H NMR (400 MHz,
4.3.8. Methyl 1-(4-hydroxyphenyl)-3-oxo-2,3-dihydro-
1H-pyrrolizine-2-carboxylate (5h). Viscous oil; Rf 0.61
(1:3 EtOAc/hexane); IR (KBr): 2955, 1771, 1571, 1474,
CDCl3): d 3.86 (s, 3H, OCH3), 3.91 (d, 1H, J¼5.2, CH),
4.99 (d, 1H, J¼5.2, CH), 6.01 (br s, 1H, Pyr-H), 6.55 (t,
1H, J¼3.2, Pyr-H), 7.14 (d, 1H, J¼3.2, Pyr-H), 7.41 (d,
2H, J¼8.1, Ar-H), 7.63 (d, 2H, J¼8.1, Ar-H); 13C NMR
(100 MHz, CDCl3): d 42.6, 53.3, 61.9, 106.6, 112.3, 120.1,
;
1398, 1292, 1165, 1080 cmꢂ1 1H NMR (400 MHz,
CDCl3): d 3.86 (s, 3H, OCH3), 3.89 (d, 1H, J¼5.2, CH),
4.86 (d, 1H, J¼4.9, CH), 5.74 (br s, 1H, Pyr-H), 5.97 (br s,
1H, Pyr-H), 6.52 (t, 1H, J¼3.2, Pyr-H), 6.78 (d, 2H,
J¼8.6, Ar-H), 7.10 (d, 2H, J¼8.5, Ar-H); 13C NMR
(100 MHz, CDCl3): d 42.4, 53.2, 62.6, 106.3, 111.8, 115.3,
120.1, 128.5, 131.8, 140.5, 155.7, 165.6, 167.8. Anal. Calcd
for C15H13NO4: C, 66.41; H, 4.83; N, 5.16. Found: C, 66.20;
H, 5.10; N, 5.08.
3
1
126.1 (q, JC–F¼3.7), 126.6 (q, JC–F¼270.3), 127.8, 130.4
2
(q, JC–F¼32.3), 139.0, 144.1, 164.4, 167.2. Anal. Calcd
for C16H12F3NO3: C, 59.45; H, 3.74; N, 4.33. Found: C,
59.48; H, 4.01; N, 4.44.
4.3.4. Methyl 1-(4-fluorophenyl)-3-oxo-2,3-dihydro-1H-
pyrrolizine-2-carboxylate (5d). Viscous oil; Rf 0.60 (1:3
EtOAc/hexane); IR (KBr): 2953, 1760, 1605, 1570, 1508,
4.3.9. Methyl 1-(2-methoxyphenyl)-3-oxo-2,3-dihydro-
1H-pyrrolizine-2-carboxylate (5i). Viscous oil; Rf 0.65
(1:3 EtOAc/hexane); IR (KBr): 2951, 1631, 1584, 1399,
1464, 1231, 1162 cmꢂ1 1H NMR (400 MHz, CDCl3):
;
d 3.87 (br s, 4H, OCH3, CH), 4.91 (d, 1H, J¼4.9, CH),
5.99 (br s, 1H, Pyr-H), 6.52 (t, 1H, J¼3.2, Pyr-H), 7.01–
7.05 (m, 2H, Ar-H), 7.10 (br s, 1H, Pyr-H), 7.22–7.26
(m, 2H, Ar-H); 13C NMR (100 MHz, CDCl3): d 42.3,
;
1292, 1247, 1160, 1085 cmꢂ1 1H NMR (400 MHz,
CDCl3): d 3.77 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 3.90
(d, 1H, J¼4.2, CH), 5.01 (d, 1H, J¼4.0, CH), 5.99–6.01
(m, 1H, Pyr-H), 6.52 (t, 1H, J¼3.2, Pyr-H), 6.87–6.93 (m,
2H, Ar-H), 7.10 (br s, Pyr-H), 7.25–7.28 (m, 2H, Ar-H);
13C NMR (100 MHz, CDCl3): 39.2, 52.8, 55.3, 61.0,
106.0, 110.0, 111.7, 119.7, 120.8, 128.0, 128.2, 129.1,
140.0, 157.2, 166.0, 168.3. Anal. Calcd for C16H15NO4: C,
67.36; H, 5.30; N, 4.91. Found: C, 67.10; H, 5.25; N, 4.98.
2
53.1, 62.3, 106.4, 112.0, 116.1 (d, JC–F¼21.3), 119.8,
3
4
129.0 (d, JC–F¼8,1), 135.8 (d, JC–F¼3.4), 139.8, 162.4
1
(d, JC–F¼245.9), 164.7, 167.4. Anal. Calcd for C15H12
FNO3: C, 65.93; H, 4.43; N, 5.13. Found: C, 65.60; H,
4.47; N, 5.24.
4.3.5. Methyl 1-(4-bromophenyl)-3-oxo-2,3-dihydro-1H-
pyrrolizine-2-carboxylate (5e). White tiny prisms; mp:
66–68 ꢀC; Rf 0.63 (1:3 EtOAc/hexane); IR (KBr): 2966,
1754, 1612, 1512, 1454, 1401, 1254, 1168, 1118 cmꢂ1; 1H
NMR (400 MHz, CDCl3): d 3.87 (br s, 4H, OCH3, CH),
4.89 (d, 1H, J¼4.9, CH), 5.98 (br s, 1H, Pyr-H), 6.55 (t,
1H, J¼3.2, Pyr-H), 7.09 (br s, 1H, Pyr-H), 7.15 (d, 2H,
J¼8.5, Ar-H), 7.46 (d, 2H, J¼8.5, Ar-H); 13C NMR
(100 MHz, CDCl3): d 42.4, 53.1, 61.9, 106.3, 112.0, 119.9,
121.9, 129.0, 132.2, 139.0, 139.3, 164.5, 167.2. Anal. Calcd
for C15H12BrNO3: C, 53.91; H, 3.62; N, 4.19. Found: C,
53.54; H, 3.56; N, 4.17.
Acknowledgements
The authors thank Hacettepe University for financial support
(BAP Project 0302601004).
References and notes
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1
1400, 1088 cmꢂ1; H NMR (400 MHz, CDCl3): d 2.37 (s,
3H, CH3), 3.87 (s, 3H, OCH3), 3.91 (d, 1H, J¼5.1, CH),
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;
(400 MHz, CDCl3): d 3.81 (s, 3H, OCH3), 3.87 (s, 3H,
OCH3), 3.89 (d, 1H, J¼5.2, CH), 4.87 (d, 1H, J¼5.0, CH),
5.96–5.98 (m, 1H, Pyr-H), 6.52 (t, 1H, J¼3.2, Pyr-H), 6.85

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