An efficient synthetic route for pyrrolizinone synthesis through functionalized c-alkylpyrroles

Article abstract of DOI:10.1055/s-0029-1216951

Regioselective addition of pyrrole to methyl 3-aryl-2-cyanoacrylates was achieved, in high yields, with copper(II) triflate as the catalyst in toluene. C-Alkylated pyrroles afforded novel pyrrolizin-3-ones, in good to high yields and high diastereomeric r

Full text of DOI:10.1055/s-0029-1216951

PAPER
3243
An Efficient Synthetic Route for Pyrrolizinone Synthesis through
Functionalized C-Alkylpyrroles
An
E
fficient Syn
a
n
for Pyrroliz
a
inone Synt
n
Hacettepe University, Department of Chemistry, 06800 Ankara, Turkey
Fax +90(312)2992163; E-mail: canan@hacettepe.edu.tr
Received 21 January 2009; revised 19 May 2009
We previously demonstrated that metal triflates are very
efficient catalysts for the addition of pyrrole to a,b-unsat-
urated carbonyl compounds under mild reaction condi-
tions.8 This methodology allows direct alkylation of
Abstract: Regioselective addition of pyrrole to methyl 3-aryl-2-cy-
anoacrylates was achieved, in high yields, with copper(II) triflate as
the catalyst in toluene. C-Alkylated pyrroles afforded novel pyr-
rolizin-3-ones, in good to high yields and high diastereomeric ratio
by an intramolecular cyclization reaction under mild reaction con- pyrroles in high yields. Alkylated products, especially
ditions.
with carbonyl or ester functionalities, have been demon-
strated to be convenient precursors for the synthesis of
pyrrolizine structures by their intramolecular cycliza-
tion.9,10
Key words: pyrrole, pyrrolizine, cyclizations, Michael additions,
metal triflates
As an extension of these studies, we report herein the di-
rect alkylation of pyrrole and subsequent intramolecular
cyclization reactions providing novel cyano-substituted
Bridgehead-nitrogen-containing heterocycles constitute a
very large family of natural products. Pyrrolizine alka-
loids are of interest among heterocyclic compounds since
they have a wide range of biological activity.1 Therefore,
the development of efficient and simple synthetic meth-
ods for heterocyclic compounds occupy a broad area in
organic synthesis.
pyrrolizin-3-ones
(Scheme 2).
with
high
diastereoselectivity
Electron-deficient enones are suitable acceptors for addi-
tion reactions of heterocyclic aromatic compounds. Metal
triflate catalyzed addition of pyrrole to methyl 3-aryl-2-
cyanoacrylates has not been previously reported. We in-
tended to use this enone as an acceptor for the addition re-
action of pyrrole. These addition products are capable of
undergoing intramolecular cyclizations to give novel ex-
amples of pyrrolizin-3-ones bearing cyano and variously
substituted phenyl groups. Methyl 3-aryl-2-cyanoacry-
lates 1a–l were obtained readily via Knovenagel conden-
sation of methyl 2-cyanoacetate with substituted
benzaldehydes.
In several previously published works, different synthetic
approaches have been used to construct the pyrrolizin-3-
one structure (Scheme 1). Cyclization of the condensation
product of pyrrole-2-carbaldehyde and malonic acid
yielded pyrrolizin-3-one in very low yields.2 It was report-
ed that the reaction of 2-[(dimethylamino)methyl]pyrrole
and diethyl acetamidomalonate in basic medium directly
produced the bicyclic pyrrolizin-3-one structure (Scheme
1, eq. 1).3 McNab was the first to generate 3H-pyrrolizin-
3-one by flash vacuum pyrolysis (FVP) of the condensa-
tion product of pyrrole-2-carbaldehyde with Meldrum’s
acid (Scheme 1, eq. 2).4 Pinho e Melo and co-workers lat-
er obtained pyrrolizin-3-ones by FVP of N-vinyl- and C-
vinylpyrroles generated by the thermal extrusion of sulfur
dioxide from pyrrolo[1,2-c]thiazole 2,2-dioxides
(Scheme 1, eqs. 3 and 4).5 Recently, pyrrolizin-3-one de-
rivatives were synthesized from the alkylation products of
pyrrole with a,b-unsaturated 2-acylimidazoles by Evans
and Fandrick (Scheme 1, eq. 5)6 and from the cyclization
of the radical reaction product of pyrrole and a-halo esters
by Byers and co-workers (Scheme 1, eq. 6).7
Using methyl 2-cyano-3-phenylacrylate (1a) as a model
reaction, we identified the optimum conditions for the ad-
dition reaction with pyrrole; the catalytic efficiency of
metal triflates depends on many parameters such as the
structure of the reactants, the solvent, and the type of met-
al in the catalyst.11 In our previous study,9 we showed that
gadolinium(III) triflate is the most efficient catalyst in the
addition of pyrrole to substituted dimethyl 2-benzylene-
malonates. Nevertheless, this catalyst did not work with
methyl 2-cyano-3-phenylacrylate (1a) (Table 1, entry 1).
Attempted addition reactions using ytterbium, lanthanum,
neodymium, and yttrium triflates (10 mol%) in toluene at
room temperature also failed (Table 1, entries 2–5). Zinc
triflate catalyzed the reaction, but gave 2a in low yield
(30%) while copper(II) triflate efficiently catalyzed the
addition reaction and formed the product 2a in 90% yield.
The effect of catalyst loading (5–15 mol%) was examined
and the best chemical yield, 90%, was obtained with 10
mol% of copper(II) triflate in toluene (Table 1, entry 7).
The effect of solvent on the addition reaction was investi-
gated by using various organic solvents (Table 1, entries
Despite the existence of different synthetic approaches for
the synthesis of the pyrrolizin-3-one structure with differ-
ent substituents, there remains a need for efficient and
simple synthetic methods that provide substituted pyr-
rolizine structures under mild reaction conditions.
SYNTHESIS 2009, No. 19, pp 3243–3250
x
x.
x
x
.
2
0
0
9
Advanced online publication: 21.08.2009
DOI: 10.1055/s-0029-1216951; Art ID: T01509SS
© Georg Thieme Verlag Stuttgart · New York

3244
C. Unaleroglu et al.
PAPER
CO2C2H5
NHCOMe
CO2C2H5
toluene, NaOH
reflux
NMe2
H
C
+
N
(1)
(2)
N
H
CO2C2H5
NHCOMe
O
70–80% yield
O
O
FVP
O
N
N
H
O
O
MeO2C
Me
CO2Me
FVP
MeO2C
Me
Me
MeO2C
O2S
CO2Me
Me
– SO2
(3)
Me
N
N
N
Me
O
78% yield
MeO2C
Me
Me
MeO2C
CO2Me
Me
MeO2C
Me
CO2Me
FVP
Me
+
Me
Me
N
N
(4)
N
– SO2
O2S
Me
O
54–70% yield
5–17% yield
Me
N
i) MeOTf (1.1 equiv)
N
MeCN, 4 Å MS
ii) Hünig's base
i-Pr
N
N
H
(5)
O
Me
O
99%
Na2CO3
toluene
CO2Et
CO2Et
N
H
CO2Et
N
O
(6)
43% yield
Scheme 1
R2
R1
R1
1) pyrrole, M(OTf)x, toluene
2) NaH, 50 °C
N
CO2Me
R2
NC
O
CN
Scheme 2
7–10). No addition product was formed in acetone and 4 and 6). A moderate yield (50%) was obtained for 2e
copper(II) triflate catalyzed the reaction in 10% and 56% (Table 2, entry 5) and more sterically encumbered sub-
yields in dichloromethane and tetrahydrofuran, respec- strates 1k and 1l did not undergo the addition reaction
tively.
(Table 2, entries 11 and 12). The addition of pyrrole to
1a–j formed novel addition products 2a–j, regioselective-
ly. Diastereomeric ratios of 2a,c–j were found to be 1:1.
For 2b, a 7:3 diastereomeric ratio was obtained. The struc-
We continued the addition reactions of pyrrole to methyl
2-cyano-3-phenylacrylates with different substituents un-
der the optimized reaction conditions. Addition products
2a–j were obtained in 50–95% yield (Table 2, entries 1–
10). Strongly electron-withdrawing groups, nitro and tri-
fluoromethyl, and halogens gave the products with the
1
tures of these novel products were identified by H and
13C NMR and elemental analysis and the position of the
substituent on pyrrole was assigned by COSY spectra.
highest yields (89–95%) (Table 2, entries 2, 3, 7–9). Elec- After the synthesis of the novel pyrrole derivatives 2a–j,
tron-donating methyl and methoxy group bearing prod- our interest in the use of these compounds to construct
ucts 2d and 2f were formed in high yields (Table 2, entries pyrrolizinone structures led us to consider their cycliza-
Synthesis 2009, No. 19, 3243–3250 © Thieme Stuttgart · New York

PAPER
An Efficient Synthetic Route for Pyrrolizinone Synthesis
3245
Table 1 The Effect of Metal Triflates, Solvent, and Amount of Cat-
alyst on the Addition Reaction of Pyrrole to Methyl 2-Cyano-3-phe-
nylacrylate (1a)
Table 2 Alkylation Reactions of Pyrrole with 1a–l
R1
R3
R3
Cu(OTf)2
R1
(10 mol%)
+
CO2Me
toluene, r.t.
N
N
M(OTf)x, solvent
R2
CO2Me
H
CO Me
+
H
2
R2 CN
N
N
NC
r.t.
H
NC
H
CN
O
1a–l
2a–j
OMe
1a
2a
Entry
1
R1
R2
H
R3
Product
Yielda (%)
Entry M(OTf)x
Solvent M(OTf)x (mol%) Yielda (%)
H
H
2a
2b
2c
2d
2e
2f
90
89
95
79
50
83
94
94
92
60
1
2
Gd(OTf)3 toluene
Yb(OTf)3 toluene
La(OTf)3 toluene
Nd(OTf)3 toluene
10
10
10
10
10
10
10
–
2
NO2
CF3
Me
OMe
H
H
H
–
3
H
H
3
–
4
H
H
4
–
5
H
H
5
Y(OTf)3
toluene
toluene
toluene
–
6
OMe
H
H
6
Zn(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
30
90
10
56
–
7
F
H
2g
2h
2i
7
8
Cl
H
H
8
CH2Cl2 10
THF 10
acetone 10
9
Br
H
H
9
10
11
12
CN
Me
OMe
H
H
2j
10
11
12
b
Me
OMe
Me
OMe
2k
2l
–
toluene
toluene
5
59
85
b
–
15
a Isolated yield after column chromatography.
b Compounds 1k and 1l did not give addition products.
a Isolated yield after column chromatography.
tion reactions. Firstly, intramolecular cyclization of 3a mophenyl)-3-oxo-2,3-dihydro-1H-pyrrolizine-2-carboni-
was tested in tetrahydrofuran at 0 °C using a 1:1 molar ra- trile (3i). The 1H NMR peak of H1 at d = 4.80 is a doublet
tio of 2a to sodium hydride, which gave 3a in 25% yield. (Figure 1). When this peak was irradiated, a NOE effect
The yield of 3a increased to 47% with a 1:1.5 molar ratio appeared only with phenyl protons. Irradiation of H7
of 2a to sodium hydride. A significant improvement in demonstrated a strong NOE effect with H6 and very weak
yield (63%) was obtained in the case of a 1:1.5 molar ratio NOE effect with H1. In addition, an NOE effect was not
of 2a to sodium hydride and performing the reaction at 50 observed between H1 at d = 4.80 and H2 at d = 3.95 when
°C (Table 3, entry 3). These reaction conditions were then H2 was irradiated. Thus, the major diastereomer of com-
applied to the intramolecular cyclization reaction of 2b–j. pound 3i was determined to be the trans-isomer. The vic-
Pyrrolizin-3-ones 3c–j were obtained with the yields inal coupling constants of H1 and H2 (3J1,2) of the major
ranging from 43–89%. Substrates 2d and 2j gave the and minor diastereomers of 3i are 6.3 Hz and 8.7 Hz, re-
products 3d (46%) and 3j (43%) with moderate yields spectively. These vicinal coupling constants were further
(Table 3, entries 6 and 12). Compound 2b did not undergo correlated with the values of vicinal coupling of 3c–j, 4.8–
the cyclization reaction. Intramolecular cyclization of 2a, 6.4 Hz for major diastereomers and 8.2–8.8 Hz for minor
2c, 2e, and 2f formed, respectively, 3a (63%), 3c (64%), diastereomers, to assign their configurations. These fine
3e (64%), and 3f (60%) with comparable yields (Table 3, correlations between vicinal coupling constants enabled
entries 3, 5, 7 and 8). The compounds 3g and 3h were the configuration of the major diastereomers of 3a,c–j to
formed in 71% and 75% yield, respectively (Table 3, en- be assigned as trans and the minor diastereomers of 3a,c–j
tries, 9 and 10). Pyrrolizin-3-one 3i was obtained with the as cis.
best chemical yield (89%) (Table 3, entry 11). All of the
In conclusion, we described here the regioselective addi-
cyclization products were formed with high diastereose-
tion reaction of pyrrole to methyl 2-cyano-3-phenylacry-
1
lectivity. The structures of 3a,c–j were identified by H
late derivatives in the presence of copper(II) triflate in
and 13C NMR and elemental analysis.
high yields. The obtained novel addition products 2a–j
NOE difference experiments were performed to deter- were then used for the synthesis of pyrrolizin-3-one com-
mine the configuration of major diastereomer of 1-(4-bro- pounds. The intramolecular cyclization reaction of 2a,c–j
Synthesis 2009, No. 19, 3243–3250 © Thieme Stuttgart · New York

3246
C. Unaleroglu et al.
PAPER
Table 3 Intramolecular Cyclization Reaction of 2a–j
R1
R1
NaH, THF
N
N
R2
H
R2
CO2Me
NC
CN
3a–j
O
2a–j
Entry
R1
R2
H
Time (h) Temp. (°C) Ratio 2a–j/NaH
Product
3a
dra
Yieldb (%)
1
2
H
6
0
1:1
85:15
86:14
87:13
–
25
47
63
H
H
6
0
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
3a
3
H
H
2
50
50
50
50
50
50
50
50
50
50
3a
c
4
NO2
CF3
Me
OMe
H
H
10
2
3b
3c
–
5
H
84:16
83:17
85:15
71:29
79:21
82:18
83:17
83:17
64
46
64
60
71
75
89
43
6
H
2.5
3
3d
3e
7
H
8
OMe
H
2
3f
9
F
2.5
2
3g
10
11
12
Cl
H
3h
3i
Br
H
3
CN
H
2.5
3j
a Determined by 1H NMR (400 MHz) spectroscopic analysis of the isolated product.
b Isolated yield after column chromatography.
c Compound 2b did not give a cyclization product.
corded on a system 2000 Perkin-Elmer spectrophotometer. Reac-
tions were monitored by TLC using precoated silica plates
(Kieselgel 60, F254, E. Merck), visualized with UV light. Flash col-
umn chromatography was performed by using silica gel (0.05–0.63
mm, 230–400 mesh ASTM, E. Merck). All melting points were
measured in sealed tubes using an electrothermal digital melting
apparatus (Gallenkamp). All chemicals were purchased from
E. Merck, Aldrich, and Sigma. Solvents were either reagent or tech-
nical grade and when necessary they were purified and dried by dis-
tillation from an appropriate desiccant.
H
(6)H
(7)H
H
Br
H(1)
= NOE
N
CN
O
H(2)
Figure 1 NOE correlation pattern for 3i
provided the corresponding pyrrolizin-3-ones 3a,c–j with
high diastereoselectivity and with the trans-isomers as the
major diastereomers. Novel 3-oxo-1-phenyl-2,3-dihydro-
1H-pyrrolizine-2-carbonitrile derivatives were obtained
in good to high yields. This work provides an efficient
synthetic route to access pyrrolizinone structure from
functionalized C-alkylpyrroles using mild reaction condi-
tions.
Methyl 3-Aryl-2-cyano-3-(1H-pyrrol-2-yl)propanoates 2a–j;
General Procedure
Methyl 3-aryl-2-cyanoacrylate 1a–l (1.88 mmol) and Cu(OTf)2 (68
mg, 0.188 mmol) were stirred in toluene (10 mL) at r.t. for 0.5 h.
Pyrrole (1.3 mL, 18.8 mmol) was added instantly via syringe pump.
The resulting mixture was stirred at r.t. for 24 h (TLC monitoring).
Metal triflate was removed from the reaction medium by subjecting
the mixture to a short flash chromatography (silica gel, EtOAc). The
eluent was removed under reduced pressure and residue was puri-
fied by flash chromatography (silica gel, EtOAc–hexane, 1:5).
1H and 13C NMR spectra were recorded with a Brucker DPX-400,
ultra shield, 400 MHz high performance digital FT-NMR spectrom-
eter using CDCl3 as solvent and TMS as an internal standard. Peaks
that represent both the major and the minor diastereomers are denot-
ed by ‘*’. Square brackets indicate peaks arising from the minor dia-
stereomer, where applicable. Elemental analyses (C, H, N) were
performed with a LECO CHNS-932 analyzer. IR spectra were re-
Methyl 2-Cyano-3-phenyl-3-(1H-pyrrol-2-yl)propanoate (2a)
Viscous oil; yield: 430 mg (90%); dr 50:50; Rf = 0.36 (EtOAc–
hexane, 1:3).
IR (KBr): 3418, 3105, 3031, 2975, 2876, 2252, 1957, 1743, 1565,
1436, 1100, 1031, 724 cm–1.
Synthesis 2009, No. 19, 3243–3250 © Thieme Stuttgart · New York

PAPER
An Efficient Synthetic Route for Pyrrolizinone Synthesis
3247
1H NMR (400 MHz, CDCl3): d = 3.71 (s, 3 H, OCH3), [3.73 (s, 3 H,
OCH3)], 4.11 (d, J = 6.4 Hz, 1 H, CH), [4.27 (d, J = 7.2 Hz, 1 H,
CH)], [4.79 (d, J = 7.2 Hz, 1 H, CH)], 4.84 (d, J = 6.0 Hz, 1 H, CH),
6.19–6.20 (m, 2 H, Hpyrrole)*, 6.23 (br s, 1 H, Hpyrrole), [6.32 (br s, 1
H, Hpyrrole)], 6.68 (br s, 1 H, Hpyrrole), [6.71 (br s, 1 H, Hpyrrole)], 7.34–
7.39 (m, 10 H, ArH)*, 8.12 (br s, 1 H, NH), [8.27 (br s, 1 H, NH)].
13C NMR (100 MHz, CDCl3): d = 43.6, [44.0], 44.7, [44.8], 53.6,
[53.7], 106.8, [107.8], 108.5, [108.6], 115.5, [116.0], 118.44,
[118.5], 127.9, [128.0], 128.1, [128.2], 128.3, [128.4], 128.8,
[129.0], 137.6, [138.4], 165.6, [165.7].
H, Hpyrrole), 6.65 (br s, 1 H, Hpyrrole), [6.69 (br s, 1 H, Hpyrrole)], 7.17–
7.23 (m, 8 H, ArH)*, 8.01 (br s, 1 H, NH), [8.21 (br s, 1 H, NH)].
13C NMR (100 MHz, CDCl3): d = 20.8, [20.8], 43.3, [43.7], 44.0,
[44.1], 53.1, [53.2], 106.3, [107.1], 108.1, [108.2], 115.3, [115.7],
118.0, [118.1], 127.6, [127.9], 128.1, [128.9], 129.3, [129.4], 129.5,
134.5*, [135.3], 137.3, [137.5], 165.4*.
Anal. Calcd for C16H16N2O2: C, 71.62; H, 6.01; N, 10.44. Found: C,
71.29; H, 6.13; N, 10.53.
Methyl 2-Cyano-3-(4-methoxyphenyl)-3-(1H-pyrrol-2-yl)pro-
Anal. Calcd for C15H14N2O2: C, 70.85; H, 5.55; N, 11.02. Found: C,
70.72; H, 5.50; N, 11.00.
panoate (2e)
Viscous oil; yield: 265 mg (50%); dr 50:50; Rf = 0.27 (EtOAc–
hexane, 1:3).
Methyl 2-Cyano-3-(4-nitrophenyl)-3-(1H-pyrrol-2-yl)pro-
panoate (2b)
Viscous oil; yield: 501 mg (89%); dr 70:30; Rf = 0.13 (EtOAc–
hexane, 1:3).
IR (KBr): 3393, 3009, 2956, 2839, 2252, 1746, 1610, 1512, 1436,
1251, 1178, 1098, 1030, 726 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.74 (s, 3 H, OCH3), [3.76 (s, 3 H,
OCH3)], 3.82 (s, 3 H, OCH3), [3.82 (s, 3 H, OCH3)], 4.02 (d, J = 6.0
Hz, 1 H, CH), [4.18 (d, J = 6.8 Hz, 1 H, CH)], [4.72 (d, J = 6.8 Hz,
1 H, CH)], 4.77 (d, J = 6.0 Hz, 1 H, CH), 6.14–6.16 (m, 3 H,
IR (KBr): 3403, 3109, 2958, 2252, 1749, 1606, 1520, 1436, 1349,
1258, 1111, 1015, 856, 728 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.80 (s, 3 H, OCH3), [3.82 (s, 3 H,
OCH3)], 4.15 (d, J = 5.7 Hz, 1 H, CH), [4.31 (d, J = 6.8 Hz, 1 H,
CH)], [4.93 (d, J = 6.8 Hz, 1 H, CH)], 4.96 (d, J = 5.7 Hz, 1 H, CH),
6.22 (br s, 2 H, Hpyrrole)*, 6.27 (br s, 2 H, Hpyrrole)*, [6.80 (br s, 1 H,
Hpyrrole)], 6.81 (br s, 1 H, Hpyrrole), 7.53 (d, J = 8.8 Hz, 4 H, ArH)*,
[8.05 (br s, 1 H, NH)], 8.25 (d, J = 8.7 Hz, 4 H, ArH)*, 8.32 (br s, 1
H, NH)
13C NMR (100 MHz, CDCl3): d = 43.0, [43.5], 44.0, [44.2], 54.0*,
107.5, [108.5], 108.9, [109.0], 114.9, [115.3], 119.1, [119.2], 124.1,
[124.2], 126.3, [127.4], 128.9, [129.6], 144.9, [145.6], 147.6,
[147.7], 165.1*.
Hpyrrole)*, 6.17 (br s, 1 H, Hpyrrole), 6.66 (br s, 1 H, Hpyrrole), [6.67 (br
s, 1 H, Hpyrrole)], 6.87–6.90 (m, 4 H, ArH), [7.24–7.26 (m, 4 H,
ArH)], 7.93 (br s, 1 H, NH), [8.17 (br s, 1 H, NH)].
13C NMR (100 MHz, CDCl3): d = 43.7, [44.0], 44.2, [44.2], 53.5,
[53.5], 55.2, [55.2], 106.7, [108.0], 108.8, [108.9], 114.4*, 115.2,
[115.7], 118.2, [118.4], 128.3, [129.1], 129.4, [129.7], 130.4*,
159.4, [159.7], 165.6*.
Anal. Calcd for C16H16N2O3: C, 7.59; H, 5.67; N, 9.85. Found: C,
67.72; H, 5.32; N, 9.47.
Methyl 2-Cyano-3-(2-methoxyphenyl)-3-(1H-pyrrol-2-yl)pro-
panoate (2f)
Yellow solid; yield: 444 mg (83%); dr 50:50; mp 89–90 °C; Rf =
Anal. Calcd for C15H13N3O4: C, 60.20; H, 4.38; N, 14.04. Found: C,
60.42; H, 4.35; N, 13.87.
0.26 (EtOAc–hexane, 1:3).
Methyl 2-Cyano-3-(1H-pyrrol-2-yl)-3-[4-(trifluoromethyl)phe-
nyl]propanoate (2c)
Viscous oil; yield: 576 mg (95%); dr 50:50; Rf = 0.32 (EtOAc–
hexane, 1:3).
IR (KBr): 3407, 3104, 2973, 2251, 1748, 1600, 1491, 1437, 1250,
1026, 926, 757 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.71 (s, 3 H, OCH3), [3.72 (s, 3 H,
OCH3)], 3.95 (s, 3 H, OCH3), [3.96 (s, 3 H, OCH3)], 4.44 (d, J = 6.6
Hz, 1 H, CH), [4.49 (d, J = 9.5 Hz, 1 H, CH)], [5.00 (d, J = 9.4 Hz,
1 H, CH)], 5.13 (d, J = 6.5 Hz, 1 H, CH), 6.11 (br s, 2 H, Hpyrrole)*,
6.19 (br s, 1 H, Hpyrrole), [6.38 (br s, 1 H, Hpyrrole)], 6.70 (br s, 1 H,
IR (KBr): 3400, 2959, 2253, 1748, 1620, 1422, 1325, 1166, 1123,
1069, 1018, 728 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.76 (s, 3 H, OCH3), [3.78 (s, 3 H,
OCH3)], 4.10 (d, J = 6.0 Hz, 1 H, CH), [4.24 (d, J = 7.2 Hz, 1 H,
CH)], [4.85 (d, J = 7.2 Hz, 1 H, CH)], 4.89 (d, J = 5.6 Hz, 1 H, CH),
6.17 (br s, 2 H, Hpyrrole)*, 6.21 (br s, 2 H, Hpyrrole)*, 6.70 (br s, 1 H,
Hpyrrole), [6.76 (br s, 1 H, Hpyrrole)], 6.94–6.99 (m, 4 H, ArH), [7.28–
7.32 (m, 4 H, ArH)], 8.28 (br s, 1 H, NH), [8.58 (br s, 1 H, NH)].
13C NMR (100 MHz, CDCl3): d = 39.9*, 41.4, [42.0], 42.1, [42.2],
53.4*, 55.6, [55.7], 107.2, [108.2], 108.3, [108.5], 110.6, [111.4],
116.1, [116.2], 118.0, [118.1], 121.3, [121.5], 126.3, [126.5], 127.6,
[128.9], 129.3, [129.5], 129.9, [130.2], 156.2, [156.7], 165.7,
[166.1].
Hpyrrole), [6.74 (br s, 1 H, Hpyrrole)], 7.45–7.49 (m, 4 H, ArH)*, 7.65
(d, J = 8.4 Hz, 4 H, ArH)*, 8.06 (br s, 1 H, NH), [8.30 (br s, 1 H,
NH)].
13C NMR (100 MHz, CDCl3): d = 43.1, [43.6], 44.2, [44.5], 53.7,
[53.8], 107.4, [108.6], 109.0*, 114.9, [115.3], 118.8, [119.0], 123.8
Anal. Calcd for C16H16N2O3: C, 67.59; H, 5.67; N, 9.85. Found: C,
67.38; H, 5.60; N, 9.80.
1
3
(q, JC-F = 270.5 Hz)*, 126.0 (q, JC-F = 3.8 Hz)*, 126.9, [128.0],
2
2
128.4, [129.3], 130.6 (q, JC-F = 32.5 Hz), [130.8 (q, JC-F = 32.4
Hz)], 141.7, [142.5], 165.2, [165.3].
Methyl 2-Cyano-3-(4-fluorophenyl)-3-(1H-pyrrol-2-yl)pro-
Anal. Calcd for C16H13F3N2O2: C, 59.63; H, 4.07; N, 8.69. Found:
C, 59.40; H, 4.38; N, 8.55.
panoate (2g)
Viscous oil; yield: 481 mg (94%); dr 50:50; Rf = 0.24 (EtOAc–
hexane, 1:3).
Methyl 2-Cyano-3-(1H-pyrrol-2-yl)-3-(4-tolyl)propanoate (2d)
Viscous oil; yield: 398 mg (79%); dr 50:50; Rf = 0.30 (EtOAc–
hexane, 1:3).
IR (KBr): 3394, 3106, 2957, 2897, 2252, 1747, 1605, 1509, 1436,
1225, 1098, 1015, 842, 729 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.69 (s, 3 H, OCH3), [3.72 (s, 3 H,
OCH3)], 4.06 (d, J = 6.4 Hz, 1 H, CH), [4.22 (d, J = 6.9 Hz, 1 H,
CH)], [4.75 (d, J = 6.9 Hz, 1 H, CH)], 4.79 (d, J = 6.5 Hz, 1 H, CH),
6.13–6.16 (m, 2 H, Hpyrrole)*, 6.17 (br s, 1 H, Hpyrrole), [6.24 (br s, 1
H, Hpyrrole)], 6.65 (br s, 1 H, Hpyrrole), [6.68 (br s, 1 H, Hpyrrole)], 7.03
(t, J = 8.3 Hz, 4 H, ArH)*, 7.25–7.32 (m, 4 H, ArH)*, 8.26 (br s, 1
H, NH), [8.40 (br s, 1 H, NH)].
IR (KBr): 3400, 3103, 3025, 2955, 2904, 2251, 1740, 1513, 1436,
1259, 1118, 1098, 1021, 728 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.38 (s, 6 H, 2 CH3)*, 3.73 (s, 3
H, OCH3), [3.74 (s, 3 H, OCH3)], 4.04 (d, J = 6.2 Hz, 1 H, CH),
[4.19 (d, J = 7.1 Hz, 1 H, CH)], [4.72 (d, J = 7.0 Hz, 1 H, CH)], 4.78
(d, J = 6.2 Hz, 1 H, CH), 6.14–6.17 (m, 3 H, Hpyrrole)*, 6.22 (br s, 1
Synthesis 2009, No. 19, 3243–3250 © Thieme Stuttgart · New York

3248
C. Unaleroglu et al.
PAPER
13C NMR (100 MHz, CDCl3): d = 43.3, [43.5], 43.7, [43.8], 53.3*,
106.5, [107.2], 108.2, [108.3], 115.3*, 115.8 (d, 2JC-F = 21.1 Hz)*,
13C NMR (100 MHz, CDCl3): d = 43.0, [43.4], 44.3, [44.6], 53.9*,
107.6, [108.9], 109.1, [109.2], 112.5, [112.7], 114.7, [115.1], 117.9,
[118.0], 119.0, [119.8], 126.3, [127.6], 128.3, [128.8], 129.1,
[129.5], 132.7, [132.8], 142.7, [143.7], 165.1*.
3
118.3, [118.3], 127.5, [128.5], 129.8 (d, JC-F = 8.1 Hz), [130.4 (d,
4
4
3JC-F = 8.1 Hz)], 133.7 (d, JC-F = 3.2 Hz), [134.5 (d, JC-F = 3.1
1
1
Hz)], 162.5 (d, JC-F = 245.7 Hz), [162.3 (d, JC-F = 245.7 Hz)],
Anal. Calcd for C16H13N3O2: C, 68.81; H, 4.69; N, 15.05. Found: C,
69.05; H, 4.60; N, 15.31.
165.3, [165.4].
Anal. Calcd for C15H13FN2O2: C, 66.17; H, 4.81; N, 10.29. Found:
C, 66.05; H, 4.58; N, 9.91.
1-Aryl-3-oxo-2,3-dihydro-1H-pyrrolizine-2-carbonitriles 3a–j;
General Procedure
Methyl 3-(4-Chlorophenyl)-2-cyano-3-(1H-pyrrol-2-yl)pro-
panoate (2h)
Viscous oil; yield: 510 mg (94%); dr 50:50; Rf = 0.35 (EtOAc–
hexane, 1:3).
Methyl 3-aryl-2-cyano-3-(1H-pyrrol-2-yl)propanoate 2a–j (0.6
mmol) was dissolved in anhyd THF (3 mL) under an argon atmo-
sphere at 0 °C. NaH (22 mg, 0.9 mmol) was added to the mixture
and the mixture was stirred at 0 °C for 0.5 h. Then the mixture was
heated to 50 °C (TLC monitoring). When the reaction was com-
plete, the mixture was poured into pH 7 phosphate buffer (10 mL)
and the product was extracted with EtOAc (3 × 10 mL) and dried
(MgSO4). The solvent was removed under reduced pressure and
residue was purified by flash chromatography (silica gel, EtOAc–
hexane 1:7).
IR (KBr): 3385, 2957, 2253, 1748, 1593, 1491, 1436, 1260, 1091,
1035, 1014, 799, 731 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.74 (s, 3 H, OCH3), [3.76 (s, 3 H,
OCH3)], 4.04 (d, J = 6.0 Hz, 1 H, CH), [4.20 (d, J = 6.8 Hz, 1 H,
CH)], [4.75 (d, J = 6.8 Hz, 1 H, CH)], 4.79 (d, J = 6.0 Hz, 1 H, CH),
6.15 (br s, 2 H, Hpyrrole)*, 6.17 (br s, 1 H, Hpyrrole), [6.20 (br s, 1 H,
H
pyrrole)], 6.67 (br s, 1 H, Hpyrrole), [6.71 (br s, 1 H, Hpyrrole)], 7.28 (d,
3-Oxo-1-phenyl-2,3-dihydro-1H-pyrrolizine-2-carbonitrile (3a)
Light brown solid; yield: 84 mg (63%); dr 87:13; mp 130–131 °C;
Rf = 0.56 (EtOAc–hexane, 1:3).
J = 8.4 Hz, 4 H, ArH)*, 7.33–7.35 (m, 4 H, ArH)*, 8.16 (br s, 1 H,
NH), [8.36 (br s, 1 H, NH)].
13C NMR (100 MHz, CDCl3): d = 43.3, [43.8], 44.0, [44.2], 53.6*,
107.1, [107.8], 108.3, [108.9], 114.9, [115.4], 118.6, [118.7], 127.3,
[128.5], 129.2, [129.3], 130.0*, 134.2, [134.5], 136.2, [137.0],
165.4*.
IR (KBr): 3138, 3098, 2923, 2248, 1758, 1578, 1469, 1457, 1401,
1264, 1095, 745 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.98 (d, J = 6.0 Hz, 1 H, CH),
[4.62 (d, J = 8.8 Hz, 1 H, CH)], 4.84 (d, J = 6.0 Hz, 1 H, CH), [4.99
(d, J = 8.4 Hz, 1 H, CH)], 6.10, (br s, 2 H, Hpyrrole)*, 6.63–6.61 (m,
2 H, Hpyrrole)*, 7.17 (br s, 2 H, Hpyrrole)*, 7.35–7.46 (m, 10 H, ArH)*.
Anal. Calcd for C15H13ClN2O2: C, 62.40; H, 4.54; N, 9.70. Found:
C, 62.70; H, 4.53; N, 9.65.
13C NMR (100 MHz, CDCl3): d = [41.8], 45.0, [45.8], 47.1, [107.5],
107.6, [112.6], 112.9, 114.5*, 120.8, [120.9], 127.1, [128.0], 128.8,
[128.9], [129.2], 129.5, [137.3], 137.6, 138.1*, 161.6*.
Methyl 3-(4-Bromophenyl)-2-cyano-3-(1H-pyrrol-2-yl)pro-
panoate (2i)
Viscous oil; yield: 574 mg (92%); dr 50:50; Rf = 0.30 (EtOAc–
hexane, 1:3).
Anal. Calcd for C14H10N2O: C, 75.66; H, 4.54; N, 12.60. Found: C,
75.48; H, 4.69; N, 12.43.
IR (KBr): 3392, 3054, 2955, 2310, 1745, 1488, 1435, 1259, 1073,
1010, 727 cm–1.
3-Oxo-1-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1H-pyrroliz-
ine-2-carbonitrile (3c)
Light brown solid; yield: 111 mg (64%); dr 84:16; mp 132–133 °C;
1H NMR (400 MHz, CDCl3): d = 3.76 (s, 3 H, OCH3), [3.78 (s, 3 H,
OCH3)], 4.05 (d, J = 6.0 Hz, 1 H, CH), [4.21 (d, J = 6.8 Hz, 1 H,
CH)], [4.75 (d, J = 6.8 Hz, 1 H, CH)], 4.79 (d, J = 6.0 Hz, 1 H, CH),
6.16–6.19 (m, 2 H, Hpyrrole)*, 6.20 (br s, 2 H, Hpyrrole)*, 6.70 (br s, 1
H, Hpyrrole), [6.74 (br s, 1 H, Hpyrrole)], 7.21–7.24 (m, 4 H, ArH),
[7.50–7.53 (m, 4 H, ArH)], 7.96 (br s, 1 H, NH), [8.22 (br s, 1 H,
NH)].
13C NMR (100 MHz, CDCl3): d = 43.2, [43.7], 44.0, [44.2], 53.6,
[53.7], 107.0*, 108.3, [108.8], 115.0, [115.5], 118.6, [118.7], 122.2,
[122.6], 127.2, [128.4], 129.6, [130.3], 132.2*, 136.6, [137.5],
165.3, [165.4].
Rf = 0.50 (EtOAc–hexane, 1:3).
IR (KBr): 3138, 2911, 2261, 1760, 1620, 1578, 1410, 1330, 1137,
1068, 852, 726 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.13 (d, J = 6.4 Hz, 1 H, CH),
[4.61 (d, J = 8.4 Hz, 1 H, CH)], 4.90 (d, J = 6.4 Hz, 2 H, CH)*, 6.11
(br s, 2 H, Hpyrrole)*, 6.63 (br s, 2 H, Hpyrrole)*, 7.22 (br s, 2 H,
Hpyrrole)*, 7.53 (d, J = 8.4 Hz, 4 H, ArH)*, 7.72 (d, J = 8.4 Hz, 4 H,
ArH)*.
13C NMR (100 MHz, CDCl3): d = [40.4], 44.3, [45.2], 46.6, 107.8*,
[112.9], 113.1, 113.9*, 120.7, [120.9], [126.0], 126.3, 127.5,
[128.4], 136.8*, 141.2*, 160.8*.
Anal. Calcd for C15H13BrN2O2: C, 54.07; H, 3.93; N, 8.41. Found:
C, 53.87; H, 3.93; N, 8.36.
Methyl-2-Cyano-3-(4-cyanophenyl)-3-(1H-pyrrol-2-yl)pro-
panoate (2j)
Anal. Calcd for C15H9F3N2O: C, 62.07; H, 3.13; N, 9.65. Found: C,
62.11; H, 3.41; N, 9.37.
Viscous oil; yield: 315 mg (60%); dr 50:50; Rf = 0.11 (EtOAc–
hexane, 1:3).
3-Oxo-1-(4-tolyl)-2,3-dihydro-1H-pyrrolizine-2-carbonitrile
(3d)
IR (KBr): 3386, 3104, 2958, 2930, 2230, 1749, 1608, 1436, 1259,
1117, 1020, 846, 730 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.77 (s, 3 H, OCH3), [3.80 (s, 3 H,
OCH3)], 4.08 (d, J = 5.6 Hz, 1 H, CH), [4.22 (d, J = 6.8 Hz, 1 H,
CH)], [4.84 (d, J = 6.8 Hz, 1 H, CH)], 4.88 (d, J = 5.6 Hz, 1 H, CH),
6.17 (br s, 2 H, Hpyrrole)*, 6.21 (br s, 2 H, Hpyrrole)*, 6.72 (br s, 1 H,
Viscous oil; yield: 65 mg (46%); dr 83:17; Rf = 0.54 (EtOAc–
hexane, 1:3).
IR (KBr): 2922, 2252, 1766, 1577, 1470, 1404, 1285, 1092, 818,
725 cm–1.
1H NMR (400 MHz, CDCl3): d = [2.37 (s, 3 H, CH3)], 2.40 (s, 3 H,
CH3), 3.96 (d, J = 6.2 Hz, 1 H, CH), [4.59 (d, J = 8.6 Hz, 1 H, CH)],
4.80 (d, J = 6.0 Hz, 1 H, CH), [4.85 (d, J = 8.4 Hz, 1 H, CH)], 6.08
(br s, 2 H, Hpyrrole)*, 6.61 (br s, 2 H, Hpyrrole)*, [7.05 (d, J = 8.1 Hz,
1 H, Hpyrrole)], 7.18 (br s, 1 H, Hpyrrole), 7.24 (br s, 8 H, ArH)*.
Hpyrrole), [6.76 (br s, 1 H, Hpyrrole)], 7.45–7.48 (m, 4 H, ArH)*, 7.67
(d, J = 8.0 Hz, 4 H, ArH)*, 8.07 (br s, 1 H, NH), [8.33 (br s, 1 H,
NH)].
Synthesis 2009, No. 19, 3243–3250 © Thieme Stuttgart · New York

PAPER
An Efficient Synthetic Route for Pyrrolizinone Synthesis
3249
13C NMR (100 MHz, CDCl3): d = 21.1*, [41.5], 44.6, [45.9], 47.2,
[107.4], 107.5, [112.6], 112.8, 114.6*, 120.7, [120.9], 127.0,
[127.9], [129.8], 130.1, 134.6*, 138.4*, 138.6*, 161.7*.
1-(4-Chlorophenyl)-3-oxo-2,3-dihydro-1H-pyrrolizine-2-carbo-
nitrile (3h)
Viscous oil; yield: 116 mg (75%); dr 82:18; Rf = 0.54 (EtOAc–
hexane, 1:3).
Anal. Calcd for C15H12N2O: C, 76.25; H, 5.12; N, 11.86. Found: C,
75.94; H, 5.10; N, 11.72.
IR (KBr): 2925, 2253, 1765, 1578, 1492, 1405, 1282, 1092, 1014,
840, 727 cm–1.
1-(4-Methoxyphenyl)-3-oxo-2,3-dihydro-1H-pyrrolizine-2-car-
bonitrile (3e)
Light brown solid; yield: 97 mg (64%); dr 85:15; mp 103–104 °C;
Rf = 0.39 (EtOAc–hexane, 1:3).
1H NMR: (400 MHz, CDCl3): d = 3.96 (d, J = 5.8 Hz, 1 H, CH),
[4.61 (d, J = 8.7 Hz, 1 H, CH)], 4.82 (d, J = 6.0 Hz, 1 H, CH), [4.87
(d, J = 8.4 Hz, 1 H, CH)], 6.10 (br s, 2 H, Hpyrrole)*, 6.62 (br s, 2 H,
Hpyrrole)*, [7.05 (d, J = 7.5 Hz, 2 H, ArH)], 7.20 (br s, 2 H, Hpyrrole)*,
IR (KBr): 3137, 3104, 2922, 2849, 2253, 1757, 1518, 1400, 1269,
1167, 845 cm–1.
7.29 (d, J = 8.4 Hz, 2 H, ArH), 7.39 (d, J = 8.6 Hz, 2 H, ArH), [7.49
(d, J = 8.6 Hz, 2 H, ArH)].
1H NMR (400 MHz, CDCl3): d = [3.83 (s, 3 H, OCH3)], 3.84 (s, 3
H, OCH3), 3.89 (d, J = 6.3 Hz, 1 H, CH), [4.54 (d, J = 8.6 Hz, 1 H,
CH)], 4.78 (d, J = 6.1 Hz, 1 H, CH), [4.82 (d, J = 8.4 Hz, 1 H, CH)],
6.06 (br s, 2 H, Hpyrrole)*, 6.59 (br s, 2 H, Hpyrrole)*, 6.92 (d, J = 8.6
Hz, 2 H, ArH), [7.05 (d, J = 8.6 Hz, 2 H, ArH)], 7.17 (br s, 2 H,
Hpyrrole)*, 7.27 (d, J = 9.4 Hz, 4 H, ArH)*.
13C NMR (100 MHz, CDCl3): d = [41.1], 44.3, [45.6], 47.0, [107.7],
107.8, [112.9], 113.1, 114.3*, 120.8, [121.0], 128.5, [128.7],
[129.4], 129.7, 134.9*, 136.0*, 137.5*, 161.2*.
Anal. Calcd for C14H9ClN2O: C, 65.51; H, 3.53; N, 10.91. Found:
C, 65.42; H, 3.51; N, 10.87.
13C NMR (100 MHz, CDCl3): d = [41.3], 44.5, [46.0], 47.4, [55.1],
55.3, [107.3], 107.4, [112.6], 112.8, 114.3*, [114.5], 114.9, 120.6,
[120.7], 128.3, [129.2], 129.5*, 138.5*, [159.9], 160.0, 161.5*.
1-(4-Bromophenyl)-3-oxo-2,3-dihydro-1H-pyrrolizine-2-carbo-
nitrile (3i)
Viscous oil; yield: 160 mg (89%); dr 83:17; Rf = 0.61 (EtOAc–
hexane, 1:3).
Anal. Calcd for C15H12N2O2: C, 71.42; H, 4.79; N, 11.10. Found: C,
71.21; H, 5.09; N, 10.92.
IR (KBr): 3140, 3063, 2973, 2903, 2252, 1770, 1577, 1489, 1470,
1406, 1297, 1124, 1091, 1010, 893, 848, 723 cm–1.
1-(2-Methoxyphenyl)-3-oxo-2,3-dihydro-1H-pyrrolizine-2-car-
bonitrile (3f)
Viscous oil; yield: 91 mg (60%); dr 71:29; Rf = 0.50 (EtOAc–
hexane, 1:3).
1H NMR (400 MHz, CDCl3): d = 3.95 (d, J = 6.3 Hz, 1 H, CH),
[4.61 (d, J = 8.7 Hz, 1 H, CH)], 4.80 (d, J = 6.2 Hz, 1 H, CH), [4.86
(d, J = 8.6 Hz, 1 H, CH)], 6.10 (br s, 2 H, Hpyrrole)*, 6.62 (br s, 2 H,
Hpyrrole)*, [7.04 (d, J = 8.3 Hz, 2 H, ArH)], 7.20 (br s, 2 H, Hpyrrole)*,
7.25 (d, J = 8.3 Hz, 2 H, ArH), [7.52 (d, J = 7.1 Hz, 2 H, ArH)], 7.57
(d, J = 8.2 Hz, 2 H, ArH).
IR (KBr): 3115, 3040, 2942, 2839, 2252, 1770, 1575, 1493, 1465,
1405, 1294, 1248, 1105, 1025, 894, 757 cm–1.
1H NMR (400 MHz, CDCl3): d = [3.82 (s, 3 H, OCH3)], 3.85, (s, 3
H, OCH3), 4.07 (d, J = 4.9 Hz, 1 H, CH), [4.62 (d, J = 8.6 Hz, 1 H,
CH)], 5.00 (d, J = 4.8 Hz, 2 H, CH)*, 6.05 (br s, 2 H, Hpyrrole)*, [6.56
(br s, 1 H, Hpyrrole)], 6.59 (br s, 1 H, Hpyrrole), 6.95 (br s, 2 H, Hpyrrole)*,
6.98 (br s, 2 H, ArH)*, 7.17 (br s, 2 H, ArH)*, 7.26 (d, J = 7.6 Hz,
2 H, ArH)*, 7.37 (t, J = 7.9 Hz, 2 H, ArH)*.
13C NMR (100 MHz, CDCl3): d = [41.2], 44.4, [45.5], 46.9, [107.7],
107.8, [112.9], 113.1, 114.3*, 120.9, [121.0], 122.9*, 128.8,
[129.0], [132.4], 132.7, 136.5*, 137.4*, 161.2*.
Anal. Calcd for C14H9BrN2O: C, 55.84; H, 3.01; N, 9.30. Found: C,
55.67; H, 3.12; N, 9.10.
13C NMR (100 MHz, CDCl3): d = 40.6*, [44.3], 45.1, 55.3*,
[106.9], 107.0, [111.0], 111.1, [112.3], 112.5, [113.6], 115.5,
[120.2], 120.5, [120.8], 120.9, [125.1], 126.0, 128.0, [128.8], 129.9,
[130.1], 138.3, [138.7], 157.2, [157.3], 162.5, [163.1].
1-(4-Cyanophenyl)-3-oxo-2,3-dihydro-1H-pyrrolizine-2-carbo-
nitrile (3j)
Light brown solid; yield: 64 mg (43%); dr 83:17; mp 161–163 °C;
Rf = 0.28 (EtOAc–hexane, 1:3).
Anal. Calcd for C15H12N2O2: C, 71.42; H, 4.79; N, 11.10. Found: C,
71.33; H, 5.00; N, 10.86.
IR (KBr): 3146, 2924, 2225, 1762, 1467, 1404, 1269, 1093, 838,
745 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.97 (d, J = 6.0 Hz, 1 H, CH),
[4.65 (d, J = 8.7 Hz, 1 H, CH)], 4.91 (d, J = 5.9 Hz, 1 H, CH), [4.95
(d, J = 8.8 Hz, 1 H, CH)], 6.13 (br s, 2 H, Hpyrrole)*, 6.65 (br s, 2 H,
Hpyrrole)*, 7.23 (br s, 2 H, Hpyrrole)*, 7.52 (d, J = 8.2 Hz, 4 H, ArH)*,
7.75 (d, J = 8.3 Hz, 4 H, ArH)*.
1-(4-Fluorophenyl)-3-oxo-2,3-dihydro-1H-pyrrolizine-2-carbo-
nitrile (3g)
Light brown solid; yield: 102 mg (71%); dr 79:21; mp 124–126 °C;
Rf = 0.50 (EtOAc–hexane, 1:3).
IR (KBr): 3138, 3105, 2922, 2853, 2257, 1758, 1513, 1399, 1263,
1158, 849 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.95 (d, J = 6.2 Hz, 1 H, CH),
[4.60 (d, J = 8.6 Hz, 1 H, CH)], 4.83 (d, J = 5.9 Hz, 1 H, CH), [4.89
(d, J = 8.2 Hz, 1 H, CH)], 6.10 (br s, 2 H, Hpyrrole)*, 6.63 (br s, 2 H,
13C NMR (100 MHz, CDCl3): d = [41.5], 44.6, [45.2], 46.5, 108.2*,
[113.2], 113.5, 114.0*, 117.9*, 121.0, [121.1], 128.2, [129.0],
[133.0], 133.3*, 137.0*, 142.6*, 161.4*.
Anal. Calcd for C15H9N3O: C, 72.87; H, 3.67; N, 16.99. Found: C,
73.01; H, 4.00; N, 16.89.
Hpyrrole)*, 7.13 (t, J = 8.3 Hz, 4 H, ArH)*, 7.20 (br s, 2 H, Hpyrrole)*,
7.34–7.37 (m, 4 H, ArH)*.
13C NMR (100 MHz, CDCl3): d = [41.2], 44.3, [45.8], 47.2, 107.7*,
Acknowledgment
[112.9], 113.1, 114.3*, [116.3 (d, 2JC-F = 21.6 Hz)], 116.6 (d, 2JC-F
21.7 Hz), 120.8, [120.9], 128.9 (d, 3JC-F = 8.3 Hz), [129.9 (d, 3JC-F
8.1 Hz)], 133.4*, 137.9*, 161.3*, 162.9 (d, 1JC-F = 247.4 Hz)*.
=
=
This project was supported by the Scientific and Technological
Research Council of Turkey (No. 105T163). We thank Assoc.
Prof. Dr. Cavit Kazaz for NOE experiments.
Anal. Calcd for C14H9FN2O: C, 66.99; H, 3.78; N, 11.66. Found: C,
67.18; H, 3.82; N, 11.43.
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C. Unaleroglu et al.
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Synthesis 2009, No. 19, 3243–3250 © Thieme Stuttgart · New York