Copper triflate catalyzed regioselective alkylation of pyrrole: Conversion of 2-alkylated pyrroles to novel pyrrolizine derivatives by self-cyclization

Article abstract of DOI:10.3987/COM-07-11137

Metal triflate catalyzed addition reaction of pyrrole to methyl 2-oxo-4-phenylbut-3-enoate and substituted derivatives generated the related novel alkylated pyrroles regioselectively at C(2) of pyrrole. Among the studied metal triflates, Cu(OTf)₂

Full text of DOI:10.3987/COM-07-11137

HETEROCYCLES, Vol. 71, No. 11, 2007
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HETEROCYCLES, Vol. 71, No. 11, 2007, pp. 2427 - 2440. © The Japan Institute of Heterocyclic Chemistry
Received, 11th June, 2007, Accepted, 20th July, 2007, Published online, 31st July, 2007. COM-07-11137
COPPER TRIFLATE CATALYZED REGIOSELECTIVE
ALKYLATION OF PYRROLE: CONVERSION OF 2-ALKYLATED
PYRROLES TO NOVEL PYRROLIZINE DERIVATIVES BY
SELF-CYCLIZATION
Canan Unaleroglu,* Sertan Aytac, and Baris Temelli
Hacettepe University, Department of Chemistry, 06800 Ankara, Turkey.
Fax: +90 (312) 299 2163, E-mail: canan@hacettepe.edu.tr
Abstract – Metal triflate catalyzed addition reaction of pyrrole to methyl
2-oxo-4-phenylbut-3-enoate and substituted derivatives generated the related
novel alkylated pyrroles regioselectively at C(2) of pyrrole. Among the studied
metal triflates, Cu(OTf)2 was found to be more effective in the addition reaction.
The synthesized methyl 2-oxo-4-phenyl-4-(1H-pyrrole-2-yl)butanoate esters
underwent self-cyclization by heating and yielded the corresponding methyl
3-hydroxy-1-phenyl-2,3-dihydro-1H-pyrrolizine-3-carboxylate and substituted
derivatives. This reaction procedure allowed easy access to pyrrolizine structure
in mild reaction conditions.
INTRODUCTION
Pyrrole and many of its derivatives are very important units in many naturally occurring compounds,
because of a wide variety of their pharmaceutical and biological properties.1 Therefore, many synthetic
methods have been reported in the literature for the preparation of pyrrole derivatives.2 2- and
N-substituted pyrroles have been used as a synthon for the synthesis of pyrrolizines3 and indolizines4 that
constitute a very large family of natural products having a wide range of biological activities.5 Synthesis
of these heterocycles is an important area of heterocyclic chemistry.
The Michael addition reaction is a fundamental C-C bond forming reaction in organic synthesis. In recent
years, metal triflates have been used in the Michael addition of pyrrole and indole to various enones.6 In

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HETEROCYCLES, Vol. 71, No. 11, 2007
our previous work, we reported
the addition reaction of pyrrole to N-tosyl imines7 and
N-substituted pyrroles8 by using metal triflates providing the alkylated pyrrole with good to high yields.
In this work, we have chosen methyl 2-oxo-4-phenylbut-3-enoate, as a suitable polyfunctional substituent,
for the alkylation of pyrrole to obtain the intramolecular cyclization product from the alkylated pyrrole.
We present here the regioselective, Cu(OTf)2 catalyzed Michael addition of pyrrole to substituted
methyl 2-oxo-4-phenylbut-3-enoate esters and their self-cyclization reactions (Scheme 1).
R
O
10%M(OTf)x
CO2Me
+
rt
N
N
H
R
H
O
CO2Me
heat
R=H, 4-Me, 4-OMe, 2-OMe,
4-F, 4-Cl, 4-Br, 4-NO2
R
N
HO
CO2Me
Scheme 1
2-Oxo-4-phenylbut-3-enoate esters have been used in catalytic enantioselective Friedel-Crafts alkylation
reactions of indole and furan by using various metal complexes. These heteroaromatic compounds
are known to give the Friedel-Crafts alkylation products with 2-oxo-4-phenylbut-3-enoate esters in very
high yields.6c, 6d We previously indicated that methyl 2-oxo-4-phenylbut-3-enoate (2a) is also a
good acceptor for the 1,4- addition reaction of N- and C(2)-substituted pyrroles.8
RESULTS AND DISCUSSION
We used the electron deficient 2a-h in the 1,4-addition of pyrrole (1) to obtain 3a-h as precursors to
synthesize the bicyclic systems with nitrogen at bridgehead position. Addition reaction was tested with 2a
in order to optimize the reaction conditions (Scheme 2). We first performed the addition reactions of
pyrrole to 2a in THF at rt by using various metal triflates (Table 1). The addition product, methyl
2-oxo-4-phenyl-4-(1H-pyrrole-2-yl)butanoate (3a), formed regioselectively at C(2) of pyrrole. The
results in Table 1 show that Y(OTf)3, Yb(OTf)3, Gd(OTf)3, Zn(OTf)2, La(OTf)3 and Nd(OTf)3 furnished
the product with 50-67% yields (Enteries 2-7, Table 1). Cu(OTf)2 provided 3a with the highest yield
(83%) in THF at rt (Entry 1, Table 1).

HETEROCYCLES, Vol. 71, No. 11, 2007
2429
O
10%M(OTf)x
CO2Me
+
N
rt
N
H
1
H
O
3a
2a
CO2Me
Scheme 2
Table 1. The effect of metal triflates on the addition of
pyrrole to methyl 2-oxo-4-phenylbut-3-enoate at rt
Entry
M(OTf)x
Cu(OTf)2
Y(OTf)3
Solvent
THF
THF
THF
THF
THF
THF
THF
Yield (%)a
1
2
3
4
5
6
7
83
67
65
60
50
58
56
Yb(OTf)3
Gd(OTf)3
Zn(OTf)2
La(OTf)3
Nd(OTf)3
a isolated yield after purification.
We continued to examine the effect of the solvent and temperature on the reaction. The solvents,
CH2Cl2, toluene, Et2O, acetone, MeCN and THF:H2O (1:1), all gave the product with lower yields
(15-36%) in the presence of 10 mol % Cu(OTf)2 (Entries 4-9, Table 2). The best chemical yield (83%)
was obtained with 10 mol % Cu(OTf)2 in THF at rt (Entry 3, Table 2). To examine the effect of
temperature on the addition reaction, the reactions were repeated using THF and 10% Cu(OTf)2 at 0 °C
and -20 °C. The reaction was monitored with TLC. 50% and 20% chemical yields were obtained at 0 °C
and -20 °C, respectively (Entries 1 and 2, Table 2). Lowering the reaction temperature increased the
reaction time and decreased the chemical yield.
Substituted derivatives of methyl 2-oxo-4-phenylbut-3-enoate, 2b-h, gave the addition product with
45-70 % yield (Enteries 2-8, Table 3). 2-OMe substituted 2d gave the lowest yield (45%) while 4-OMe
substituted 2c yielded the product with 65%. 2f with 4-Cl gave the product with lower yield (49%) than
1
halogen substituted 2e and 2g. The structures of 3a-h were identified by H NMR, 13C NMR and
elementel analysis. The position of the substituent was assigned by COSY spectra.

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HETEROCYCLES, Vol. 71, No. 11, 2007
Table 2. The effect of solvent and temperature on the addition reaction of pyrrole to methyl
2-oxo-4-phenylbut-3-enoate
Entry
M(OTf)x
Solvent
Time(h)a
Yied (%)b
Temperature (°C)
1
2
3
4
5
6
7
8
9
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
THF
THF
-20
0
12
20
50
83
36
30
28
20
15
30
12
THF
rt
0.25
0.25
0.25
0.25
0.25
0.25
0.25
CH2Cl2
toluene
Et2O
rt
rt
rt
acetone
MeCN
rt
rt
Cu(OTf)2 THF:H2O (1:1)
rt
a all reactions were monitored by TLC.
b Isolated yield after purification.
Table 3. Addition of the pyrrole to β,γ-unsaturated α-keto esters in the presence of Cu(OTf)2 in THF at rt
R
O
R
10%Cu(OTf)2
CO2Me
+
N
THF, rt
N
H
H
O
3a-h
2a-h
1
CO2Me
Entry
R
3
Yield (%)a
1
2
3
4
5
6
7
8
H
3a
3b
3c
3d
3e
3f
83
65
65
45
58
49
63
70
4-Me
4-OMe
2-OMe
4-F
4-Cl
4-Br
3g
3h
4-NO2
a isolated yield after purification.
The synthesized novel alkylated pyrroles 3a-h with α-ketoester on alkyl group are convenient
precursors for investigating intramolecular cyclization reaction. We have recently synthesized the
3-oxo-2,3-dihydro-1H-pyrrolizine derivatives from intramolecular cyclization of dimethyl

HETEROCYCLES, Vol. 71, No. 11, 2007
2431
2-(phenyl(1H-pyrrol-2-yl)methyl)malonate esters.9 Ester functional groups bearing diethyl
2-(1H-pyrrol-2-yl)butanedioate with Na2CO3 in toluene and dimethyl 2-(1H-pyrrol-2-yl)pentanedioate
with K2CO3 in DMF also gave the corresponding bicyclic pyrroles by the intramolecular cyclization
reactions.10 Such reactions proceed through the intramolecular cyclization of pyrrole nitrogen and ester
functional group upon treatment with a base. 3a-h, with α-ketoester functionalized alkyl group at C(2) of
pyrrole, readily gave the intramolecular self-cyclization reaction between the keto group and pyrrole
nitrogen. Alkylated pyrroles 3a-h completely converted to the self-cyclization products 4a-h by heating
in CCl4 at 75 °C (Scheme 3). Formation of self-cyclization products were monitored by TLC and checked
1
1
by H NMR after the heating process. H NMR spectra of 4a-h indicated that the cyclization products
were formed as diastreoisomeric mixtures in 1:1 ratio. Diastereomers were separated by column
chromatagrophy and denoted as 4a and 4a′ according to their Rf values. The structures of 4a-h were
1
13
identified by H NMR, C NMR and elementel analysis although their stereochemistries have remained
undetermined.
R
R
heat
N
N
H
HO
O
R=H, 4-Me, 4-OMe, 2-OMe,
4-F, 4-Cl, 4-Br, 4-NO2
CO2Me
CO2Me
3a-h
4a-h
Scheme 3
CONCLUSION
In summary, we have developed a catalytic addition reaction of pyrrole to substituted methyl
2-oxo-4-phenylbut-3-enoate for the synthesis of novel alkylated pyrrole derivatives. Metal triflate
catalyzed addition products formed regioselectively at C(2) of pyrrole. C(2) alkylated pyrrole derivatives
3a-h gave the self-cyclization products 4a-h by heating. Consequently, novel pyrrolizine structures
have been synthesized from easily available starting materials and in mild reaction conditions.
EXPERIMENTAL
General. Solvents were of the highest commercial quality and used without further purification.
β,γ-Unsaturated α-keto esters 2a-g11 and 2h12 were prepared according to literature procedures. Reactions
were monitored by thin layer chromatography plates (Kieselgel 60, F254, E.Merck) and visualized with

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HETEROCYCLES, Vol. 71, No. 11, 2007
UV-light or phosphomolybdic acid in methanol or anisaldehyde in methanol. Flash column
chromatography was carried out using silica gel (0.05-0.63 nm. 230-400 mesh ASTM, Merck). 1H NMR
13
and C NMR spectra were recorded by a Bruker DPX-400, Ultrashield, 400 MHz high performance
digital FT-NMR spectrometer using CDCl3 as the solvent and tetramethylsilane (TMS) as the internal
standard. Spin multiplicities were mentioned as s (singlet), d (doublet), dd (doublet of doublet), t (triplet),
q (quartet), m (multiplet), bs (broad singlet). Infrared spectra were taken by 2000 Perkin-Elmer FTIR
Spectrophotometer. Melting points were measured by Gallenkamp capillary melting point apparatus and
were uncorrected. Elementel analyses were performed by LECO CHNS system.
General Procedure for the 1,4 -Addition Reaction of Pyrrole to β,γ-Unsaturated α-Keto Esters: A
mixture of β,γ-unsaturated α-keto esters 2a-h (1 mmol) and Cu(OTf)2 (36 mg, 0.1 mmol) was stirred in
THF (5 mL) at rt for 30 min. The solution of pyrrole (134 mg, 2 mmol) in THF (2 mL) was added
dropwise into the reaction mixture. The pale yellow colour of the mixture turned black and the reaction
was monitored by TLC. After the consumption of reactants, the reaction was quenched by the addition of
2 mL of water and extracted with Et2O (2 x 10 mL). The organic layer was dried with anhydrous MgSO4.
The solvent was then removed under reduced pressure and the residue was purified by flash column
chromatography.
Methyl 2-oxo-4-phenyl-4-(1H-pyrrole-2-yl)butanoate (3a): Yield: 0.214g (83%); light brown solid; mp
1
76-77 °C ; Rf 0.44 (EtOAc:hexane, 1:3). IR (KBr): 3426, 2978, 2865, 1636, 1360, 1125 cm-1. H NMR
(400 MHz, CDCl3) (δ ppm): 3.45 (dd, J=18.4 and J=6.8 Hz, 1H, CHH), 3.67 (dd, J=18.4 and J=8.0
Hz, 1H, CHH), 3.84 (s, 3H, OCH3), 4.62 (t, J=7.2 Hz, 1H, CH), 5.94 (bs, 1H, C(3)H), 6.08 (dd, J=6.0 and
13
J=2.8 Hz, 1H, C(4)H), 6.61(bs, 1H, C(5)H), 7.24-7.34 (m, 5H, ArH), 7.95 (bs, 1H, NH). C NMR (100
MHz, CDCl3) (δ ppm): 39.06, 45.56, 52.81, 105.78, 108.33, 117.41, 127.12, 127.95, 128.80, 133.02,
142.15, 161.10, 192.21. Anal. Calcd for C15H15NO3 (257.28): C 70.02, H 5.88, N 5.44. Found: C 69.87, H
5.83, N 5.43.
Methyl 2-oxo-4-(1H-pyrrol-2-yl)-4-p-tolylbutanoate (3b): Yield: 0.176 g (65%); orange viscous oil; Rf
0.32 (EtOAc:hexane, 1:3). IR (KBr): 3421, 3098, 3022, 2954, 2923, 1730, 1563, 1513, 1438, 1272, 1076,
1041 cm-1. 1H NMR (400 MHz, CDCl3) (δ ppm): 2.36 (s, 3H, CH3), 3.44 (dd, J=18.0 and J=6.8 Hz, 1H,
CHH), 3.65 (dd, J=18.0 and J=7.6 Hz, 1H, CHH), 3.84 (s, 3H, OCH3), 4.58 (t, J=7.2 Hz, 1H, CH), 5.94
(bs, 1H, C(3)H), 6.08 (dd, J=5.6 and J=2.8 Hz, 1H, C(4)H), 6.60 (bs, 1H, C(5)H), 7.11-7.21 (m, 4H, ArH),
7.95 (bs, 1H, NH). 13C NMR (100 MHz, CDCl3) (δ ppm): 21.07, 38.65, 45.56, 52.76, 105.58, 108.25,

HETEROCYCLES, Vol. 71, No. 11, 2007
2433
117.27, 127.82, 129.43, 133.24, 136.49, 139.10, 161.10, 192.25. Anal. Calcd for C16H17NO3 (271.31): C
70.83, H 6.32, N 5.16. Found: C 70.67, H 6.18, N 4.77.
Methyl 4-(4-methoxyphenyl)-2-oxo-4-(1H-pyrrol-2-yl)butanoate (3c): Yield: 0.187 g (65%); light
brown viscous oil; Rf 0.43 (EtOAc:hexane, 1:3). IR (KBr): 3442, 2977, 2863, 1636, 1505, 1451, 1381,
1250, 1123, 1012 cm-1. 1H NMR (400 MHz, CDCl3) (δ ppm): 3.43 (dd, J=18.0 and J=7.2 Hz, 1H, CHH),
3.62 (dd, J=18.0 and J=7.6 Hz, 1H, CHH), 3.80 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 4.56 (t, J=7.3 Hz,
1H, CH), 5.93 (bs, 1H, C(3)H), 6.08 (bs, 1H, C(4)H), 6.60 (bs, 1H, C(5)H), 6.82-6.87 (m, 2H, ArH),
13
7.14-7.16 (m, 2H, ArH), 7.96 (bs, 1H, NH). C NMR (100 MHz, CDCl3) (δ ppm): 38.28, 45.68, 52.77,
55.08, 105.53, 108.26, 114.05, 117.28, 128.60, 133.41, 134.13, 158.62, 161.12, 192.30. Anal. Calcd for
C16H17NO4 (287.31): C 66.89, H 5.96, N 4.88. Found: C 66.59, H 5.83, N 4.71.
Methyl-4-(2-methoxyphenyl)-2-oxo-4-(1H-pyrrol-2-yl)butanoate (3d): Yield: 0.129 g (45%); white
solid; mp 119-120 °C; Rf 0.38 (EtOAc:hexane, 1:3). IR (KBr): 3426, 2980, 2865, 1634, 1382, 1127, 1046
cm-1. 1H NMR (400 MHz, CDCl3) (δ ppm): 3.38 (dd, J=17.2 and J=6.4, 1H, CHH), 3.73 (dd, J=17.2 and
J=8.4 Hz, 1H, CHH), 3.85 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 5.00 (t, J=7.2 Hz, 1H, CH), 5.97 (bs, 1H,
C(3)H), 6.09 (bs, 1H, C(4)H), 6.64 (bs, 1H, C(5)H), 6.89-6.93 (m, 2H, ArH), 7.09 (d, J=7.6 Hz, 1H, ArH),
13
7.20-7.24 (m, 1H, ArH), 8.25 (bs, 1H, NH). C NMR (100 MHz, CDCl3) (δ ppm): 33.23, 44.12, 52.83,
55.33, 105.40, 108.08, 111.03, 117.00, 121.16, 128.13, 128.58, 130.52, 133.05, 156.44, 161.25, 192.41.
Anal. Calcd for C16H17NO4 (287.31): C 66.89, H 5.96, N 4.88. Found: C 66.61, H 5.93, N 4.52.
Methyl 4-(4-flourophenyl)-2-oxo-4-(1H-pyrrol-2-yl)butanoate (3e): Yield: 0.160 g (58%); light yellow
viscous oil; Rf 0.37 (EtOAc:hexane, 1:3). IR (KBr):3452, 2976, 2862, 1636, 1504, 1446, 1379, 1121, 991
cm-1. 1H NMR (400 MHz, CDCl3) (δ ppm): 3.43 (dd, J=18.0 and J=6.8 Hz, 1H, CHH), 3.65 (dd, J=18.0
and J=7.6 Hz, 1H, CHH), 3.87 (s, 3H, OCH3), 4.60 (t, J=7.2 Hz, 1H, CH), 5.92 (bs, 1H, C(3)H), 6.08 (bs,
1H, C(4)H), 6.63 (bs, 1H, C(5)H), 6.98-7.03 (m, 2H, ArH), 7.20-7.24 (m, 2H, ArH), 7.95 (bs, 1H, NH).
13C NMR (100 MHz, CDCl3) (δ ppm): 38.34, 45.66, 52.89, 105.88, 108.45, 115.67(d, JCF=21.3 Hz),
117.59, 129.49(d, JCF=7.9 Hz), 132.84, 137.88, 161.07, 161.90(d, JCF=245.0 Hz), 192.07. Anal. Calcd
for C15H14FNO3 (275.27): C 65.45, H 5.13, N 5.09. Found: C 65.22, H 5.18, N 5.12.
Methyl 4-(4-chlorophenyl)-2-oxo-4-(1H-pyrrol-2-yl)butanoate (3f): Yield: 0.143 g (49%); light brown
viscous oil; Rf 0.35 (EtOAc:hexane, 1:3). IR (KBr): 3403, 2965, 2929, 2862, 1729, 1644, 1487, 1443,
1257, 1091 cm-1. 1H NMR (400 MHz, CDCl3) (δ ppm): 3.42 (dd, J=18.4 and J=6.8 Hz, 1H, CHH), 3.64
(dd, J=18.0 and J=7.6 Hz, 1H, CHH), 3.84 (s, 3H, OCH3), 4.58 (t, J=7.2 Hz, 1H, CH), 5.94 (bs, 1H,
C(3)H), 6.09 (bs, 1H, C(4)H), 6.60 (bs, 1H, C(5)H), 7.18 (d, J=8.4 Hz, 2H, ArH), 7.27-7.30 (m, 2H,

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HETEROCYCLES, Vol. 71, No. 11, 2007
ArH), 8.03 (bs, 1H, NH).13C NMR (100 MHz, CDCl3) (δ ppm): 38.38, 45.39, 52.88, 105.87, 108.38,
117.64, 128.74, 128.88, 132.45, 132.93, 140.71, 160.95, 191.94. Anal. Calcd for C15H14ClNO3 (291.73):
calcd. C 61.76, H 4.84, N 4.80. Found: C 61.93, H 4.83, N 4.65.
Methyl 4-(4-bromophenyl)-2-oxo-4-(1H-pyrrol-2-yl)butanoate (3g): Yield: 0.212 g (63%); light brown
solid; mp 126 °C; Rf 0.46 (EtOAc:hexane, 1:3). IR (KBr): 3424, 2976, 2863, 1636, 1379, 1261, 1122
cm-1. 1H NMR (400 MHz, CDCl3) (δ ppm): 3.43 (dd, J=18.0 and J=6.8 Hz, 1H, CHH), 3.65 (dd, J=18.0
and J=7.6 Hz, 1H, CHH), 3.86 (s, 3H, OCH3), 4.58 (t, J=7.2 Hz, 1H, CH), 5.93 (bs, 1H, C(3)H), 6.08 (dd,
J=6.0 and J=2.8 Hz, 1H, C(4)H), 6.63 (bs, 1H, C(5)H), 7.13 (d, J=8.4 Hz, 2H, ArH), 7.44 (d, J=8.4 Hz,
2H, ArH), 7.94 (bs, 1H, NH).13C NMR (100 MHz, CDCl3) (δ ppm): 38.53, 45.40, 52.94, 106.03, 108.52,
117.70, 121.14, 129.70, 131.95, 132.41, 141.19, 161.02, 191.94. Anal. Calcd for C15H14BrNO3 (336.18):
C 53.59, H 4.20, N 4.17. Found: C 53.98, H 4.01, N 4.06.
Methyl 4-(4-nitrophenyl)-2-oxo-4-(1H-pyrrol-2-yl)butanoate (3h): Yield: 0.212 g (70%); brown
viscous oil; Rf 0.33 (EtOAc:hexane, 1:2). IR (KBr): 3401, 2956, 2866, 1733, 1605, 1519, 1438, 1348,
1277, 1076 cm-1. 1H NMR (400 MHz, CDCl3) (δ ppm): 3.47 (dd, J= 18.6 and J=7.1 Hz, 1H, CHH), 3.69
(dd, J=18.6 and J=7.3 Hz, 1H, CHH), 3.82 (s, 3H, OCH3 ), 4.70 (t, J=7.2 Hz, 1H, CH), 5.95 (bs, 1H,
C(3)H), 6.06 (d, J=3.1 Hz, 1H, C(4)H), 6.62 (bs, 1H, C(5)H), 7.36 (d, J= 8.7 Hz, 2H, ArH), 8.03 (d,
13
J=8.7 Hz, 2H, ArH), 8.46 (bs, 1H, NH). C NMR (100 MHz, CDCl3) (δ ppm): 38.57, 44.86, 52.90,
105.93, 108.34, 118.04, 123.66, 128.63, 131.24, 146.62, 149.95, 160.67, 191.48. Anal. Calcd for
C15H14N2O5 (302.28): calcd. C 59.60, H 4.67, N 9.27. Found C 59.27, H 4.97, N 9.12.
General Procedure for the Cyclisation Reactions: 2-Substituted pyrrole derivatives 3a-h were refluxed
ο
1
in CCl4 for 6 hours at 75 C and the reaction was monitored by TLC. H NMR spectra of cyclization
products indicated that all C(2)-substituted pyrrole derivatives 3a-h were converted to 4a-h
quantatively in 1:1 ratio of diastereomers. To identify the diastereomers, the solvent was removed under
reduced pressure and the residue was separated by flash column chromatography (EtOAc:hexane, 1:4).
Methyl 3-hydroxy-1-phenyl-2,3-dihydro-1H-pyrrolizine-3-carboxylate (4a): Light brown solid; mp
64 °C; Rf 0.33 (EtOAc:hexane, 1:3). IR (KBr): 3455, 3030, 2955, 2871, 1740, 1659, 1495, 1453, 1270,
1146, 1068 cm-1. 1H NMR (400 MHz, CDCl3) (δ ppm): 2.64 (dd, J=13.6 and J=7.7 Hz, 1H, CHH), 3.39
(dd, J=13.6 and J=8.4 Hz, 1H, CHH), 3.88 (s, 3H, OCH3), 4.48 (t, J=8.0 Hz, 1H, CH), 4.64 (bs, 1H, OH),
13
5,75 (bs, 1H, pyrH), 6.31 (bs, 1H, pyrH), 6.62 (bs, 1H, pyrH), 7.24-7.37 (m, 5H, ArH). C NMR (100
MHz, CDCl3) (δ ppm): 42.08, 50.14, 53.73, 87.18, 101.20, 110.70, 115.00, 126.93, 127.65, 128.65,

HETEROCYCLES, Vol. 71, No. 11, 2007
2435
139.16, 142.72, 172.02. Anal. Calcd for C15H15NO3 (257.28): C 70.02 , H 5.88, N 5.44. Found: C 69.72,
H 5.86, N 5.44.
Methyl 3-hydroxy-1-phenyl-2,3-dihydro-1H-pyrrolizine-3-carboxylate (4a′): Light brown solid; mp
96-97 °C; Rf 0.27 (EtOAc:hexane, 1:3). IR (KBr): 3460, 3100, 3024, 2955, 2911, 1733, 1493, 1275,
1202, 1115, 1069, 1041 cm-1. 1H NMR (400 MHz, CDCl3) (δ ppm): 3.00-3.08 (m, 2H, CH2), 3.89 (s, 3H,
OCH3), 4.32 (bs, 1H, OH), 4.65 (t, J=8.1 Hz, 1H, CH), 5,78 (bs, 1H, pyrH), 6.31 (bs, 1H, pyrH), 6.59 (bs,
13
1H, pyrH), 7.24-7.34 (m, 5H, ArH). C NMR (100 MHz, CDCl3) (δ ppm): 41.60, 50.82, 53.68, 86.93,
101.58, 110.99, 115.04, 126.94, 127.71, 128.62, 139.81, 142.46, 171.39.
Methyl 3-hydroxy-1-p-tolyl-2,3-dihydro-1H-pyrrolizine-3-carboxylate (4b): Light brown solid; mp
111-111.5 °C; Rf 0.49 (EtOAc:hexane, 1:3). IR (KBr): 3446, 3004, 2953, 2923, 1738, 1513, 1454,
1
1268, 1180, 1146, 1103, 1069 cm-1. H NMR (400 MHz, CDCl3) (δ ppm): 2.37 (s, 3H, CH3), 2.59 (dd,
J=13.6 and J=8.0 Hz, 1H, CHH), 3.33 (dd, J=13.6 and J=8.4 Hz, 1H, CHH), 3.88 (s, 3H, OCH3), 4.42 (t,
J=8.0 Hz, 1H, CH), 4.49 (bs, 1H, OH), 5.71 (bs, 1H, pyrH), 6.29 (bs, 1H, pyrH), 6.58 (bs, 1H, pyrH),
7.12 (d, J=8.0 Hz, 2H, ArH), 7.23 (d, J=8.0 Hz, 2H, ArH). 13C NMR (100 MHz, CDCl3) (δ ppm): 21.10,
42.68, 50.16, 53.70, 87.04, 101.03, 110.49, 114.90, 127.49, 129.27, 136.22, 139.34, 139.64, 172.07. Anal.
Calcd for C16H17NO3 (271.31): C 70.83, H 6.32, N 5.16. Found: C 70.48, H 6.03, N 4.76.
Methyl 3-hydroxy-1-p-tolyl-2,3-dihydro-1H-pyrrolizine-3-carboxylate (4b′): Light brown viscous oil;
Rf 0.41 (EtOAc:hexane, 1:3). IR (KBr): 3455, 2977, 2917, 2869, 1740, 1658, 1513, 1455, 1262, 1206,
1098, 1073 cm-1. 1H NMR (400 MHz, CDCl3) (δ ppm): 2.38 (s, 3H, CH3), 2.97-3.03 (m, 2H, CH2), 3.88
(s, 3H, OCH3), 4.21 (bs, 1H, OH), 4.60 (t, J=8.1 Hz, 1H, CH), 5.75 (bs, 1H, pyrH), 6.29 (bs, 1H, pyrH),
6.56 (bs, 1H, pyrH), 7.13 (d, J=7.9 Hz, 2H, ArH), 7.22 (d, J=8.0 Hz, 2H, ArH). 13C NMR (100 MHz,
CDCl3) (δ ppm): 21.10, 41.16, 50.81, 53.62, 86.82, 101.35, 110.77, 114.92, 127.51, 129.21, 136.21,
139.33, 140.02, 171.37.
Methyl 3-hydroxy-1-(4-methoxyphenyl)-2,3-dihydro-1H-pyrrolizine-3-carboxylate (4c): Light brown
solid; mp 116.5-117.5 °C; Rf 0.33 (EtOAc:hexane, 1:3). IR (KBr): 3479, 3008, 2954, 2841, 1738, 1615,
1
1513, 1455, 1251, 1190, 1109, 1035 cm-1. H NMR (400 MHz, CDCl3) (δ ppm): 2.58 (dd, J=13.6 and
J=7.6 Hz, 1H, CHH), 3.34 (dd, J=13.6 and J=8.4 Hz, 1H, CHH), 3.82 (s, 3H, OCH3), 3.88 (s, 3H, OCH3),
4.42 (t, J=8.0 Hz, 1H, CH), 4.52 (bs, 1H, OH), 5.71 (bs, 1H, pyrH), 6.29 (bs, 1H, pyrH), 6.59 (bs, 1H,
pyrH), 6.85 (d, J=8.6 Hz, 2H, ArH), 7.26 (d, J=8.6 Hz, 2H, ArH). 13C NMR (100 MHz, CDCl3) (δ ppm):
41.39, 50.35, 53.57, 55.11, 87.14, 101.04, 110.60, 114.08, 114.96, 128.62, 134.77, 139.58, 158.66, 172.10.
Anal. Calcd for C16H17NO4 (287.31): C 66.89, H 5.96, N 4.88. Found: C 67.12, H 6.33, N 4.56.

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HETEROCYCLES, Vol. 71, No. 11, 2007
Methyl 3-hydroxy-1-(4-methoxyphenyl)-2,3-dihydro-1H-pyrrolizine-3-carboxylate (4c′): Light
brown viscous oil; Rf 0.28 (EtOAc:hexane, 1:3).IR (KBr): 3441, 2977, 2866, 1743, 1613, 1512, 1447,
1
1383, 1252, 1179, 1118, 1036, 939 cm-1. H NMR (400 MHz, CDCl3) (δ ppm): 2.98-3.01 (m, 2H, CH2),
3.81 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 4.23 (bs, 1H, OH), 4.59 (t, J=8.4 Hz, 1H, CH), 5.74 (bs, 1H,
pyrH), 6.29 (bs, 1H, pyrH), 6.56 (bs, 1H, pyrH), 6.85 (d, J=8.4 Hz, 2H, ArH), 7.23-7.28 (m, 2H, ArH).
13C NMR (100 MHz, CDCl3) (δ ppm): 40.90, 51.02, 53.73, 55.16, 86.92, 101.41, 110.89, 114.06, 115.00,
128.67, 134.44, 140.27,158.70, 171.47.
Methyl 3-hydroxy-1-(2-methoxyphenyl)-2,3-dihydro-1H-pyrrolizine-3-carboxylate (4d): Light brown
solid; mp 111-111.5 °C; Rf 0.49 (EtOAc:hexane, 1:3). IR (KBr): 3470, 2954, 2872, 1740, 1625, 1492,
1
1459, 1385, 1289, 1245, 1146, 1108, 1049 cm-1. H NMR (400 MHz, CDCl3) (δ ppm): 2.21 (dd, J=12.8
and J=9.1 Hz, 1H, CHH), 3.48 (dd, J=13.8 and J=8.7 Hz, 1H, CHH), 3.89 (bs, 6H, OCH3), 4.45 (s, 1H,
OH), 4.77 (t, J=7.7 Hz, 1H, CH), 5.78 (bs, 1H, pyrH), 6.32 (bs, 1H, pyrH), 6.61 (bs, 1H, pyrH), 6.87-6.91
13
(m, 2H, ArH), 7.22-7.36 (m, 1H, ArH), 7.34 (d, J=7.5 Hz, 1H, ArH). C NMR (100 MHz, CDCl3) (δ
ppm): 35.73, 48.63, 53.65, 55.35, 87.26, 101.16, 110.32, 110.73, 114.81, 120.89, 127.84, 128.01, 131.18,
138.50, 156.92, 172.05. Anal. Calcd for C16H17NO4 (287.31): C 66.89, H 5.96, N 4.88. Found: C 66.49,
H 5.72, N 4.94.
Methyl 3-hydroxy-1-(2-methoxyphenyl)-2,3-dihydro-1H-pyrrolizine-3-carboxylate (4d′): Light
brown viscous oil; Rf 0.41 (EtOAc:hexane, 1:3). IR (KBr): 3442, 2955, 2869, 1739, 1599, 1492, 1459,
1439, 1245, 1107, 1050, 1027 cm-1. 1H NMR (400 MHz, CDCl3) (δ ppm): 2.84 (dd, J=13.5 and J=7.2 Hz,
1H, CHH), 3.17 (dd, J=13.6 and J=8.3Hz, 1H, CHH), 3.80 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 4.21 (bs,
1H, OH), 4.95 (t, J=7.7 Hz, 1H, CH), 5.82 (bs, 1H, pyrH), 6.33 (bs, 1H, pyrH), 6.60 (bs, 1H, pyrH),
13
6.87-6.91 (m, 2H, ArH), 7.19-7.24 (m, 1H, ArH), 7.32 (d, J=7.6 Hz, 1H, ArH). C NMR (100 MHz,
CDCl3) (δ ppm): 35.73, 48.63, 53.65, 55.35, 87.26, 101.70, 110.07, 110.84, 114.96, 120.58, 127.77,
127.84, 130.83, 138.88, 157.35, 171.75.
Methyl 1-(4-flourophenyl)-3-hydroxy-2,3-dihydro-1H-pyrrolizine-3 carboxylate (4e): Light brown
solid; mp 121-122 °C; Rf 0.45 (EtOAc:hexane, 1:3). IR (KBr): 3447, 2978, 2871, 2361 1741, 1604,
1510, 1456, 1270, 1223, 1148, 1100, 1067, 1013 cm-1. 1H NMR (400 MHz, CDCl3) (δ ppm): 2.57 (dd,
J=13.6 and J=6.2 Hz, 1H, CHH), 3.39 (dd, J=13.6 and J=8.4 Hz, 1H, CHH), 3.88 (s, 3H, OCH3), 4.45 (t,
J=7.9 Hz, 1H, CH), 4.60 (bs, 1H, OH), 5.72 (bs, 1H, pyrH), 6.30 (bs, 1H, pyrH), 6.60 (bs, 1H, pyrH),
13
6.99-7.04 (m, 2H, ArH), 7.30-7.34 (m, 2H, ArH). C NMR (100 MHz, CDCl3) (δ ppm): 41.39, 50.20,
53.85, 87.11, 101.23, 110.80, 115.14, 115.52 (d, JCF=21.3 Hz), 129.15 (d, JCF=7.9 Hz), 138.51, 139.06,

HETEROCYCLES, Vol. 71, No. 11, 2007
2437
161.86 (d, JCF=244.1 Hz), 171.97. Anal. Calcd for C15H14FNO3 (275.27): C 65.45, H 5.13, N 5.09.
Found: C 65.10, H 5.23, N 5.29.
Methyl 1-(4-flourophenyl)-3-hydroxy-2,3-dihydro-1H-pyrrolizine-3 carboxylate (4e′): Light brown
solid; mp 78-79 °C; Rf 0.38 (EtOAc:hexane, 1:3). IR (KBr): 3400, 2977, 2871, 1743, 1663, 1510, 1263,
1
1223, 1121, 1074, 1014 cm-1. H NMR (400 MHz, CDCl3) (δ ppm): 2.98 (dd, J=13.4 and J=8.0 Hz, 1H,
CHH), 3.05 (dd, J=13.4 and J=8.0 Hz, 1H, CHH), 3.88 (s, 3H, OCH3), 4.29 (bs, 1H, OH), 4.62 (t, J=8.0
Hz, 1H, CH), 5.75 (bs, 1H, pyrH), 6.30 (bs, 1H, pyrH), 6.57 (bs, 1H, pyrH), 6.99-7.04 (m, 2H, ArH),
7.28-7.32 (m, 2H, ArH).13C NMR (100 MHz, CDCl3) (δ ppm): 40.80, 50.81, 53.67, 86.78, 101.47, 111.01,
115.27, 115.38 (d, JCF=21.1 Hz), 129.06 (d, JCF=7.7 Hz), 138.07, 139.54, 161.85 (d, JCF=244.4 Hz),
171.18.
Methyl 1-(4-chlorophenyl)-3-hydroxy-2,3-dihydro-1H-pyrrolizine-3-carboxylate (4f): Light brown
viscous oil; Rf 0.39 (EtOAc:hexane, 1:3). IR (KBr): 3459, 3100, 2977, 2955, 2873, 1741, 1659, 1491,
1
1456, 1410, 1266, 1203, 1148, 1092, 1014 cm-1. H NMR (400 MHz, CDCl3) (δ ppm): 2.57 (dd, J=13.7
and J=7.4 Hz, 1H, CHH), 3.39 (dd, J=13.6 and J=8.4 Hz, 1H, CHH), 3.87 (s, 3H, OCH3), 4.45 (t, J=7.9
Hz, 1H, CH), 4.71 (bs, 1H, OH), 5.73 (bs, 1H, pyrH), 6.31 (bs, 1H, pyrH), 6.62 (bs, 1H, pyrH), 7.27-7.30
(m, 4H, ArH). 13C NMR (100 MHz, CDCl3) (δ ppm): 41.42, 50.70, 53.78, 87.10, 101.23, 110.88, 115.08,
128.42, 128.98, 132.77, 138.67, 141.26, 171.80. Anal. Calcd for C15H14ClNO3 (291.73): calcd. C 61.76, H
4.84, N 4.80. Found: C 61.44 , H 4.75, N 4.73.
Methyl 1-(4-chlorophenyl)-3-hydroxy-2,3-dihydro-1H-pyrrolizine-3-carboxylate (4f′): Light brown
viscous oil; Rf 0.34 (EtOAc:hexane, 1:3). IR (KBr): 3443, 2978, 2872, 1743, 1657, 1491, 1455, 1409,
1263, 1208, 1121, 1092, 1014 cm-1. 1H NMR (400 MHz, CDCl3) (δ ppm): 2.97 (dd, J=13.4 and J=8.0 Hz,
1H, CHH), 3.05 (dd, J=13.4 and J=8.1 Hz, 1H, CHH), 3.88 (s, 3H, OCH3), 4.29 (bs, 1H, OH), 4.61 (t,
J=8.0 Hz, 1H, CH), 5.75 (bs, 1H, pyrH), 6.30 (bs, 1H, pyrH), 6.57 (bs, 1H, pyrH), 7.26-7.30 (m, 4H,
ArH). 13C NMR (100 MHz, CDCl3) (δ ppm): 41.03, 50.77, 53.82, 86.89, 101.67, 111.19, 115.20, 128.83,
129.18, 132.89, 139.29, 141.03, 171.26.
Methyl 1-(4-bromophenyl)-3-hydroxy-2,3-dihydro-1H-pyrrolizine-3-carboxylate (4g): Light brown
solid; mp 80-81 °C; Rf 0.49 (EtOAc:hexane, 1:3). IR (KBr): 3474, 2949, 1721, 1458, 1284, 1200, 1147,
1098, 1054 cm-1. 1H NMR (400 MHz, CDCl3) (δ ppm): 2.58 (dd, J=13.6 and J=8.4 Hz, 1H, CHH), 3.41
(dd, J=13.6 and J=8.4 Hz, 1H, CHH), 3.88 (s, 3H, OCH3), 4.46 (t, J=8.0 Hz, 1H, CH), 4.57 (bs, 1H, OH),
5.76 (bs, 1H, pyrH), 6.35 (bs, 1H, pyrH), 6.65 (bs, 1H, pyrH), 7.25 (d, J=8.8, 2H, ArH), 7.46 (d, J=8.4 Hz,
2H, ArH). 13C NMR (100 MHz, CDCl3) (δ ppm): 41.46, 49.91, 53.90, 87.03, 101.21, 110.85, 115.05,

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HETEROCYCLES, Vol. 71, No. 11, 2007
120.83, 129.33, 131.74, 138.63, 141.74, 171.86.Anal. Calcd for C15H14BrNO3(336.18): C 53.59, H 4.20,
N 4.17. Found: C 53.32, H 4.07, N 4.15.
Methyl 1-(4-bromophenyl)-3-hydroxy-2,3-dihydro-1H-pyrrolizine-3-carboxylate (4g′): Light brown
1
viscous oil; Rf 0.44 (EtOAc:hekzan, 1:3). IR (KBr): 3497, 2949, 1738, 1476, 1265, 1085, 1023 cm-1. H
NMR (400 MHz, CDCl3) (δ ppm): 2.99 (dd, J=13.6 and J=8.0 Hz, 1H, CHH), 3.07 (dd, J=13.6 and J=8.0
Hz, 1H, CHH), 3.87 (s, 3H, OCH3), 4.39 (bs, 1H, OH), 4.62 (t, J=8.0 Hz, 1H, CH), 5.79 (bs, 1H, pyrH),
6.35 (bs, 1H, pyrH), 6.64 (bs, 1H, pyrH), 7.22 (d, J=8.4 Hz, 2H, ArH), 7.47 (d, J=8.4 Hz, 2H, ArH). 13C
NMR (100 MHz, CDCl3) (δ ppm): 40.97, 50.63, 53.80, 86.84, 101.53, 111.18, 115.03, 120.78, 129.36,
131.74, 139.19, 141.45, 171.17.
Methyl 1-(4-nitrophenyl)-3-hydroxy-2,3-dihydro-1H-pyrrolizine-3-carboxylate (4h): Light brown
solid; mp 111.5-112.5 °C; Rf 0.36 (EtOAc:hexane, 1:2). IR (KBr): 3448, 2978, 2869, 1736, 1648, 1518,
1
1456, 1348, 1267, 1109, 1072, 1014 cm-1. H NMR (400 MHz, CDCl3) (δ ppm): 2.59 (dd, J=14.0 and
J=7.2 Hz, 1H, CHH,), 3.47 (dd, J=13.6 and J=8.4 Hz, 1H, CHH), 3.90 (s, 3H, OCH3 ), 4.57 (t, J=7.6 Hz,
1H, CH), 4.66 (bs, 1H, OH), 5.74 (bs, 1H, pyrH), 6.32 (t, J=2.8 Hz, 1H, pyrH), 6.63 (bs, 1H, pyrH), 7.52
13
(d, J=8.7 Hz, 2H, ArH), 8.19 (d, J=9.1 Hz, 2H, ArH). C NMR (100 MHz, CDCl3) (δ ppm): 41.74,
49.60, 54.01, 87.11, 101.65, 111.33, 115.41, 124.00, 128.53, 137.71, 147.20, 150.38, 171.55. Anal. Calcd
for C15H14N2O5 (302.28): C 59.60, H 4.67, N 9.27. Found: C 59.14, H 4.81, N 8.90.
(Methyl 1-(4-nitrophenyl)-3-hydroxy-2,3-dihydro-1H-pyrrolizine-3-carboxylate (4h′): Light brown
solid; mp 97.5-98.5 °C; Rf 0.31 (EtOAc:hexane, 1:2). IR (KBr): 3394, 2900, 1743, 1637, 1518, 1473,
1348, 1263, 1121 cm-1. 1H NMR (400 MHz, CDCl3) (δ ppm): 3.02 (dd, J=13.6 and J=7.6 Hz, 1H, CHH),
3.13 (dd, J=13.6 and J=8.4 Hz, 1H, CHH), 3.90 (s, 3H, OCH3 ), 4.36 (bs, 1H, OH), 5.78 (bs, 1H, pyrH),
6.33 (bs, 1H, pyrH), 6.61 (bs, 1H, pyrH), 7.51 (d, J=8,7 Hz, 2H, ArH), 8.21(d, J=8.7 Hz, 2H, ArH). 13C
NMR(100 MHz, CDCl3) (δ ppm): 41.37, 51.41, 53.95, 86.88, 101.99, 111.59, 115.46, 123.96, 128.56,
138.15, 147.28, 150.13, 170.96.
ACKNOWLEDGEMENTS
This work is granted by Hacettepe University ( Grant No. BAP Project 0302601004).
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