1,3-dipolar cycloaddition on baylis-hillman adducts: Novel synthesis of pyrrolidines, spiropyrrolidines, and spiropyrrolizidines

Article abstract of DOI:10.1055/s-0030-1260053

A facile regio- and stereoselective synthesis of functionalized pyrrolidines, spiropyrrolidines, and spiropyrrolizidines using the Baylis-Hillman adducts derived from nitroolefins via intermolecular [3+2]-cycloaddition reaction is reported. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0030-1260053

2136
PAPER
1,3-Dipolar Cycloaddition on Baylis–Hillman Adducts: Novel Synthesis of
Pyrrolidines, Spiropyrrolidines, and Spiropyrrolizidines
N
ovel Synthesis of Pyr
a
rolidines,
S
n
piropyrrolid
i
ines,
a
n
c
d Spiropyr
k
a
Dept. of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, India
Fax +91(44)22352494; E-mail: bhakthadoss@yahoo.com
b
Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai 600 020, Tamil Nadu, India
Received 12 February 2011; revised 7 April 2011
many natural products such as horsfiline (1),11a pteropo-
dine (2),11b strychnofoline (3),11c spirotryprostatin A
(4),11d gelsemine (5),11e alstonisine (6),11f etc. (Figure 1).
In addition, oxindoles derivatives, in particular 3-spiroox-
indoles, are the central skeleton of numerous alkaloids
and are elegant targets in organic synthesis due to their
significant biological activity.12 The spiropyrrolidines
also possess anticancer, antimicrobial, antibiotic, and an-
tineoplastic properties.13–15
Abstract: A facile regio- and stereoselective synthesis of function-
alized pyrrolidines, spiropyrrolidines, and spiropyrrolizidines using
the Baylis–Hillman adducts derived from nitroolefins via intermo-
lecular [3+2]-cycloaddition reaction is reported.
Key words: Baylis–Hillman reaction, intermolecular [3+2] cy-
cloaddition, azomethine ylides, 1,3-dipolar cycloaddition, pyrro-
lidines, spiro compounds
The Baylis–Hillman reaction has become a useful and
popular synthetic tool for obtaining diverse classes of
densely functionalized molecules usually referred to as
the Baylis–Hillman (BH) adducts; the reaction occurs
through an atom-economical carbon–carbon bond-form-
ing reaction which involves coupling of the a-position of
an activated alkene with an electrophile under the influ-
ence of a catalyst/catalytic system.1,2 Due to the multi-
functionality of Baylis–Hillman adducts they represent
valuable starting materials for a variety of novel classes of
organic compounds. Applications of Baylis–Hillman ad-
ducts in a variety of organic transformations and also in
the synthesis of natural products and unnatural bioactive
skeletons have been well documented over the last few
years.3,4
Me
NMe
MeO
O
H
N
H
O
H
N
H
O
COOMe
horsfiline (1)
N
H
pteropodine (2)
N
HO
H
H
O
H
H
N
N
O
N
MeN
H
H
N
O
strychnofoline (3)
MeO
N
O
H
H
N
The synthesis of nitrogen- and oxygen-containing hetero-
cycles continues to be an important and challenging area
in the field of organic chemistry.5–8 The 1,3-dipolar cy-
cloaddition reaction is one of the most important and use-
ful methods for the preparation of five-membered
heterocycles. Though various methods9 are available, the
1,3-dipolar cycloaddition of azomethine ylides to alkenes
is one of the most efficient and expedient synthetic proto-
cols for the construction of highly substituted pyrrolidine
and spiropyrrolidine rings.
O
spirotryprostatin A (4)
O
H
N
H
Me
COMe
NH
H
O
H
gelsemlne (5)
N
O
Me
alstonisine (6)
Figure 1
The synthesis of pyrrolidine-based heterocycles has been
the center of attraction for the past several decades be-
cause it constitutes an important class of substances with
highly pronounced biological activity.9 Nitropyrrolidines
are effective precursors for the synthesis of cephalotaxus
alkaloids and potentially useful as sources of conforma-
tionally restricted analogues of dopamine.10 The pyrroli-
dine and spiropyrrolidine frameworks are integral part of
Utilizing the azomethine ylide based [3+2]-cycloaddition
reaction, a variety of spiropyrrolidines have been reported
in the literature.16 In the Baylis–Hillman reaction, elec-
tron-deficient olefins are utilized although nitroolefins
have only been used as the activated olefinic component
in a couple of reports.17
We envisaged that the novel class of b-substituted Baylis–
Hillman adducts 7 derived from b-aryl nitroolefins would
be a useful starting material for the construction of
pyrrolidine, spiropyrrolidine, and spiropyrrolizidine
compounds via an azomethine ylide based [3+2] cycload-
SYNTHESIS 2011, No. 13, pp 2136–2146
x
x.
x
x
.
2
0
1
1
Advanced online publication: 19.05.2011
DOI: 10.1055/s-0030-1260053; Art ID: Z19011SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Novel Synthesis of Pyrrolidines, Spiropyrrolidines, and Spiropyrrolizidines
2137
dition. It is well documented in the literature that Baylis– Encouraged by this result, we prepared a variety of (E)-3-
Hillman adducts have been utilized for the synthesis of aryl-2-nitroprop-2-en-1-ols 7b,d,e,g–i,o as starting mate-
various heterocycles.1–4 Even though various reports are rials for the preparation of various pyrrolidine com-
available, the synthesis of heterocyclic spiro compounds pounds. Treatment of these Baylis–Hillman adducts with
using Baylis–Hillman adducts derived from nitroolefins paraformaldehyde and sarcosine in acetonitrile for eight
was not known to date with the exception of our initial re- hours at reflux temperature led to the desired pyrrolidine
port.18d
compounds 8b,e,g–i,o in 69–80% yields (Scheme 2). The
results are summarized in Table 1.
In continuation of our interest in the field of Baylis–
Hillman chemistry,18 we herein report a simple and con-
venient route for the regio- and stereoselective synthesis
of pyrrolidine, spiropyrrolidine, and spiropyrrolizidine
frameworks using the Baylis–Hillman adducts derived
from nitroolefins with sarcosine/proline-based dipoles
generated via in situ imine formation, decarboxylation,
and intermolecular [3+2] cycloaddition as shown below in
the retrosynthetic strategy (Scheme 1).
Table 1 Synthesis of Pyrrolidine Compounds from Baylis–Hillman
Adducts 8a,b,d,e,g–i,o
BH adduct
R
Producta,b
Yieldc (%)
7a
7b
7d
7e
7g
7h
7i
Ph
8a
8b
8dd
8e
8g
8h
8i
76
74
80
70
75
73
69
75
2-naphthyl
4-MeC6H4
4-EtC6H4
2-MeOC6H4
4-MeOC6H4
3,4-(MeO)2C6H3
2-thienyl
O
NO2
R
N
N
H
R
NH
OH
O
O2N
HO
[3+2] cycloaddition
N
H
7o
8o
decarboxylation
a Reaction conditions: Baylis–Hillman alcohol 7a,b,d,e,g–i,o (2
mmol), sarcosine (3 equiv), paraformaldehyde (6 equiv), MeCN (8
mL), reflux, 8 h.
O
O
O
imine
formation
N
b All products gave satisfactory IR, 1H (300 MHz) and 13C NMR (75
MHz), MS, and elemental analyses.
O +
HOOC
N
N
H
O
H
c Yields of the pure products 8a,b,e,g–i,o obtained after column chro-
matography (silica gel, 20% EtOAc–hexanes).
formaldehyde or isatin sarcosine or proline
N
H
d Structure was further confirmed by single-crystal X-ray analysis.
Scheme 1
The 1H NMR spectrum of compound 8a showed a singlet
for NCH3 proton at d = 2.49 ppm and the hydroxy proton
showed a broad singlet at d = 2.85 ppm. The two Hb pro-
tons of pyrrolidine ring appeared as triplets at d = 2.93 and
3.27 ppm. The two Ha protons of pyrrolidine ring ap-
peared as doublets at d = 3.65 and 3.70 ppm. The benzylic
proton (Hc) was observed as a triplet at d = 4.20 ppm. The
CH2OH protons appeared as doublets at d = 2.99 and 3.55
ppm. The aromatic protons appeared in the region d =
7.31–7.35 ppm.
(E)-2-Nitro-3-phenylprop-2-en-1-ol (7a),
a
Baylis–
Hillman adduct derived from nitrostyrene, was used as a
starting material for the [3+2]-cycloaddition reaction with
dipoles generated from sarcosine (N-methylglycine) with
paraformaldehyde. Best results were obtained when 7a
was treated with paraformaldehyde and sarcosine without
a catalyst with acetonitrile as the solvent for eight hours at
reflux temperature, which successfully provided the de-
sired pyrrolidine compound 8a in very good yield (76%)
after the usual workup followed by column chromatogra-
phy. Compound 8a was characterized by IR, H and 13C
NMR, mass spectrometry, and elemental analyses
(Scheme 2).
1
The X-ray crystal structure analysis of compound 8d
showed that the relative stereochemistry (Figure 2) of the
phenyl group and CH2OH group in the vicinal positions is
cis. Similarly the NO2 group and benzylic proton also
have a cis orientation.
Hb
Me
Hb
Hc
O
N
Ha
Ha
H
To check the generality of the reaction we treated the nitro
alcohols, i.e. (E)-3-aryl-2-nitroprop-2-en-1-ols 7a,c–f,h–
n, as starting materials for [3+2]-cycloaddition reactions
with dipoles generated from sarcosine and isatin. Treat-
ment of 7a,c–f,h–n with isatin and sarcosine without a
catalyst with acetonitrile as the solvent for five hours at re-
flux temperature provided the desired 3-spiropyrrolidine
compounds 9a,c–f,h–n in very good yields (60–82%) af-
ter usual workup followed by column chromatography
(Table 2).
NO2
OH
N
R
HO
Me
+
(CH2O)n
R
NO2
MeCN
reflux, 8 h
OH
7a,b,d,e,g–i,o
8a,b,d,e,g–i,o
R = Ph, 2-naphthyl, 4-MeC6H4, 4-EtC6H4, 2-MeOC6H4,
4-MeOC6H4, 3,4-(MeO)2C6H3, 2-thienyl
Scheme 2
Synthesis 2011, No. 13, 2136–2146 © Thieme Stuttgart · New York

2138
M. Bakthadoss et al.
PAPER
observe in any of the cases (9a,c–f,h–n). Comparison of
the 1H NMR spectra of the crude and recrystallized prod-
ucts showed them to be identical which confirm the ste-
reoselective nature of the reaction. Furthermore the
structure 9a was confirmed by X-ray crystallographic
analysis.
The X-ray crystal structure analysis of compound 9a
showed that the relative stereochemistry (Figure 3) of the
phenyl group and CH2OH group in the vicinal positions is
cis. Similarly the NO2 group and benzylic proton also
have a cis orientation.
Figure 2 ORTEP diagram of 8d
Table 2 Synthesis of 3-Spiropyrrolidine Compounds from the
Baylis–Hillman Adducts 9a,c–f,h–n
BH adduct
R
Producta,b
Yieldc (%)
7a
7c
7d
7e
7f
H
9ad
9b
9c
9e
9f
82
75
76
77
60
61
62
60
64
80
64
70
2-Me
4-Me
4-Et
Figure 3 ORTEP diagram of 9a
4-i-Pr
4-OMe
3,4-(OMe)2
3,4-OCH2O
4-F
7h
7i
9h
9i
To probe further the generality of the reaction, we subject-
ed various Baylis–Hillman adducts 7a,c–e,l,n with the di-
pole generated from isatin and proline. Treatment of 7a,c–
e,l,n with isatin and proline without a catalyst with aceto-
nitrile as the solvent for two hours at reflux temperature,
provided the desired 3-spiropyrrolizidine compounds
10a,c–e,l,n in good yields (52–65%) along with the minor
regioisomers 11a,c–e,l,n in 20–37% yields (Scheme 3).
Compounds 10a,c–e,l,n and 11a,c–e,l,n were character-
ized by IR, 1H and 13C NMR, mass spectrometry, and ele-
mental analyses (Scheme 4). The results are summarized
in Table 3.
7j
9j
7k
7l
9k
9l
2-Cl
7m
7n
3-Cl
9m
9n
4-Cl
a Reaction conditions: Baylis–Hillman alcohol 7a,c–f,h–n (2 mmol),
sarcosine (2 mmol), isatin (2 mmol), MeCN (8 mL), reflux, 5 h.
b All products gave satisfactory IR, 1H (300 MHz) and 13C NMR (75
MHz), MS, and elemental analyses.
NO2
c Yields of the pure products 9a,c–f,h–n obtained after column chro-
matography (silica gel, 20% EtOAc–hexanes).
Me
N
O
R
O
OH
d Structure was further confirmed by single-crystal X-ray analysis.
H
H
NH
7a,c–f,h–n
N
HO
Me
+
R
MeCN
reflux, 5 h
It is important to mention here that the high regio- and ste-
reoselectivity obtained in each case was clearly evidenced
O2N
HO
9a,c–f,h–n
H
N
by H NMR data and X-ray crystal analysis.19 The H
NMR spectrum of compound 9a showed a singlet for the
NCH3 protons at d = 2.18 ppm and a triplet for the benzylic
proton at d = 4.97 ppm. The NCH2 protons of the pyrroli-
dine ring appeared as two triplets at d = 3.53 and 4.04
ppm. The CH2OH protons appeared as a multiplet in the
region d = 3.78–3.99 ppm. The NH proton of the oxindole
ring appeared at d = 7.74 ppm and the aromatic protons
appeared in the region d = 6.82–7.57 ppm.
1
1
O
R = H, 2-Me, 4-Me, 4-Et, 4-i-Pr, 4-MeO, 3,4-(MeO)2,
3,4-OCH2O-, 4-F, 2-Cl, 3-Cl, 4-Cl
O
Scheme 3
The NMR data and X-ray crystal structure analysis19
showed that the proline and isatin based [3+2]-cycloaddi-
tion reaction with the Baylis–Hillman adducts yielded re-
gioisomeric compounds which were separated by column
Had the other regioisomer been formed, the benzylic pro-
ton should have been appeared as singlet which we did not
1
chromatography. The H NMR spectrum of compound
Synthesis 2011, No. 13, 2136–2146 © Thieme Stuttgart · New York

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Novel Synthesis of Pyrrolidines, Spiropyrrolidines, and Spiropyrrolizidines
2139
orientation. The benzylic proton (Ha) and pyrrolidizine
proton (Hb) at the ring junction are in a trans orientation
as shown in Scheme 4.
O
Hb
Ha
N
NH
NO2
OH
R
R
O2N
HO
10a,c–e,l,n
HOOC
7a,c–e,l,n
major
N
H
+
+
MeCN
reflux, 2 h
H
N
O
O
Hb
N
NH
O2N
O
Ha
HO
R = H, 2-Me, 4-Me, 4-Et, 2-Cl, 4-Cl
R
11a,c–e,l,n
minor
Scheme 4
Table 3 Synthesis of 3-Spiropyrrolizidine Compounds from the
Baylis–Hillman Adducts 10a,c–e,l,n and 11a,c–e,l,n
BH ad- R
duct
Producta,b Yieldc Producta,b Yieldc Yield (%)
(%)
52
65
59
52
60
62
(%)
33
25
35
37
20
31
(10 + 11)
7a
7c
7d
7e
7l
H
10a
10c
10d
10ed
10l
11ad
11c
11d
11e
11l
85
90
94
89
80
93
2-Me
4-Me
4-Et
2-Cl
4-Cl
Figure 4 ORTEP diagram of 10e
The X-ray crystal structure analysis of compound 11a
showed that the relative stereochemistry (Figure 5) of the
phenyl group and CH2OH group in the vicinal positions is
cis. Similarly the NO2 group and benzylic proton also
have a cis orientation.
7n
10n
11n
a Reaction conditions: Baylis–Hillman alcohol 7a,c–e,l,n (2 mmol),
proline (2 mmol), isatin (2 mmol), MeCN (8 mL), reflux, 2 h.
b All products gave satisfactory IR, 1H (300 MHz) and 13C NMR (75
MHz), MS, and elemental analyses.
c Yields of the pure products 10a,c–e,l,n and 11a,c–e,l,n obtained af-
ter column chromatography [silica gel, 30% EtOAc–hexanes (10a,c–
e,l,n), 40% EtOAc–hexanes (11a,c–e,l,n)].
d Structure was further confirmed by single-crystal X-ray analysis.
10a showed a doublet for the Ha proton at d = 4.29 ppm.
The Hb proton and one of the CH2OH protons appeared as
a multiplet in the region d = 4.39–4.53 ppm. The other
CH2OH proton appeared as a doublet of doublets at d =
4.95 ppm. The pyrrolidine ring protons appeared as mul-
tiplets in the region d = 1.51–2.74 ppm, and the aromatic
protons appeared in the region δ = 6.87–7.81 ppm.
1
The H NMR spectrum of compound 11a showed a sin-
glet for the Ha proton (benzylic proton) at d = 5.29 ppm
and the Hb proton appeared as a doublet of doublets at d =
4.78 ppm. The pyrrolidine ring protons appeared as mul-
tiplets in the region d = 1.41–3.37 ppm. The CH2OH pro-
tons appeared as two doublet of doublets at d = 4.15 and
4.49 ppm. The aromatic protons appeared in the region of
d = 6.72–7.52 ppm. The X-ray crystal structure of the
compound 10e showed that the relative stereochemistry
(Figure 4) of the aryl and CH2OH groups to be cis. Simi-
larly the NO2 group and benzylic proton also have a cis
Figure 5 ORTEP diagram of 11a
In conclusion, we have successfully developed a simple
and novel protocol for the facile synthesis of pyrrolidines
and functionalized spiropyrrolidines with high regio- and
stereoselectivity. We have also demonstrated that this
method is useful for making novel spiropyrrolizidine
Synthesis 2011, No. 13, 2136–2146 © Thieme Stuttgart · New York

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M. Bakthadoss et al.
PAPER
(E)-2-Nitro-3-(4-tolyl)prop-2-en-1-ol (7d)
Yield: 0.80 g (42%); mp 49–52 °C.
IR (KBr): 3436, 1648, 1521, 1460, 1021, 702 cm–1.
frameworks using Baylis–Hillman adducts derived from
nitroolefins.
1H NMR (300 MHz, CDCl3): d = 2.42 (s, 3 H), 2.57 (t, J = 7.2 Hz,
1 H), 4.71 (d, J = 7.2 Hz, 2 H), 7.26–7.48 (m, 4 H), 8.20 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 21.55, 56.76, 128.44, 129.92,
130.38, 137.92, 141.83, 148.67.
All reagents were purchased from commercial sources and used
without further purification. Solvents were distilled prior to use.
Column chromatography was performed on silica gel. IR spectra
1
were recorded on an FTIR-8300 Shimadzu spectrophotometer. H
(300 MHz) and 13C NMR (75 MHz) were recorded on Bruker spec-
trometer using CDCl3 as solvent and TMS as an internal standard.
Mass spectra were recorded on a Jeol-JMS-DX 303 HF mass spec-
trometer. Elemental analyses were recorded on a Perkin-Elmer
240C-CHN analyzer. Melting points are uncorrected. TLC was per-
formed using glass plates coated with silica gel (ACME, 254F);
spots were visualized using I2 vapor and a UV lamp.
MS: m/z = 193 (M+).
Anal. Calcd for C10H11NO3: C, 62.17; H, 5.74; N, 7.25. Found: C,
62.22; H, 5.78; N, 7.19.
(E)-3-(4-Ethylphenyl)-2-nitroprop-2-en-1-ol (7e)
Yellow oil; yield: 0.95 g (46%).
IR (KBr): 3233, 1643, 1590, 1321, 1093, 723 cm–1.
(E)-2-Nitro-3-phenylprop-2-en-1-ol (7a); Typical Procedure for
the Synthesis of Baylis–Hillman Adducts According to the Lit-
erature Procedure17b
1H NMR (300 MHz, CDCl3): d = 1.27 (t, J = 7.5 Hz, 3 H), 2.72 (q,
J = 7.5 Hz, 2 H), 2.78 (s, 1 H), 4.74 (s, 2 H), 7.26–7.82 (m, 4 H),
8.20 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 15.17, 28.83, 56.53, 128.70,
130.05, 130.55, 137.92, 147.98, 148.75.
To a stirred soln of nitrostyrene (1.50 g, 10 mmol) in THF (20 mL)
at r.t. was added imidazole (0.68 g, 1 equiv) followed by anthranilic
acid (0.14 g, 10 mol%). 38% Aq formaldehyde (20 mL, excess) was
then added and the mixture was stirred at r.t. for a period of 24 h.
After completion of the reaction (TLC analysis), the mixture was
acidified with 5 M HCl (20 mL) and the aqueous layer was extracted
with EtOAc (3 × 25 mL). The combined organic layers were
washed with brine (50 mL), dried (anhyd Na2SO4) and concentrated
in vacuo. The residue was purified by column chromatography (sil-
ica gel, 0–25% EtOAc–hexanes) to afford pure 7a as a yellow oil;
yield: 0.90 g (50%).
MS: m/z = 207 (M+).
Anal. Calcd for C11H13NO3: C, 63.76; H, 6.32; N, 6.76. Found: C,
63.82; H, 6.36; N, 6.67.
(E)-3-(4-Isopropylphenyl)-2-nitroprop-2-en-1-ol (7f)
Yellow oil; yield: 1.15 g (52%).
IR (KBr): 3300, 1651, 1590, 1310, 1093, 715 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.28 (d, J = 6.9 Hz, 6 H), 2.68 (s,
1 H), 2.96 (sept, J = 6.9 Hz, 1 H), 4.72 (s, 2 H), 7.26–7.52 (m, 4 H),
8.20 (s, 1 H).
IR (KBr): 3423, 1653, 1522, 1326, 1023, 695 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.61 (s, 1 H), 4.71 (d, J = 4.2 Hz,
2 H), 7.48–7.58 (m, 5 H), 8.22 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 23.68, 34.16, 56.77, 127.32,
128.79, 130.52, 137.87, 148.74, 152.60.
13C NMR (75 MHz, CDCl3): d = 56.62, 129.14, 130.19, 130.96,
131.31, 137.67, 149.44.
MS: m/z = 221 (M+).
MS: m/z = 179 (M+).
Anal. Calcd for C12H15NO3: C, 65.14; H, 6.83; N, 6.33. Found: C,
65.19; H, 6.87; N, 6.25.
Anal. Calcd for C9H9NO3: C, 60.33; H, 5.06; N, 7.82. Found: C,
60.37; H, 5.08; N, 7.80.
(E)-3-(2-Methoxyphenyl)-2-nitroprop-2-en-1-ol (7g)
Yellow oil; yield: 1.05 g (52%).
(E)-3-(Naphthalen-2-yl)-2-nitroprop-2-en-1-ol (7b)
Yield: 1.60 g (70%); mp 80–82 °C.
IR (KBr): 3430, 1643, 1512, 1305, 1025, 705 cm–1.
IR (KBr): 3425, 1652, 1517, 1339, 1218, 704 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.92 (t, J = 6.6 Hz, 1 H), 3.89 (s,
3 H), 4.66 (d, J = 6.6 Hz, 2 H), 6.94–7.55 (m, 4 H), 8.43 (s, 1 H).
1H NMR (300 MHz, CDCl3): d = 2.47 (s, 1 H), 4.67 (s, 2 H), 7.53–
8.00 (m, 7 H), 8.81 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 55.67, 56.72, 110.85, 120.44,
13C NMR (75 MHz, CDCl3): d = 56.88, 123.94, 125.50, 126.82,
127.47, 128.29, 128.47, 128.92, 131.38, 131.52, 133.40, 135.72,
150.58.
120.95, 130.70, 132.81, 133.90, 148.96, 158.38.
MS: m/z = 209 (M+).
MS: m/z = 229 (M+).
Anal. Calcd for C10H11NO4: C, 57.41; H, 5.30; N, 6.70. Found: C,
57.39; H, 5.24; N, 6.76.
Anal. Calcd for C13H11NO3: C, 68.11; H, 4.84; N, 6.11. Found: C,
68.13; H, 4.87; N, 6.18.
(E)-3-(4-Methoxyphenyl)-2-nitroprop-2-en-1-ol (7h)
Yield: 1.17 g (56%); mp 75–77 °C.
(E)-2-Nitro-3-(2-tolyl)prop-2-en-1-ol (7c)
Yellow oil; yield: 0.96 g (52%).
IR (KBr): 3445, 1653, 1528, 1338, 1023, 695 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.38 (s, 3 H), 2.68 (s, 1 H), 4.62
(s, 2 H), 7.26–7.46 (m, 4 H), 8.33 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 19.99, 56.54, 126.48, 129.45,
130.55, 130.59, 130.76, 136.32, 138.19, 149.80.
MS: m/z = 193 (M+).
IR (KBr): 3427, 1643, 1512, 1460, 1025, 715 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.25 (s, 1 H), 3.85 (s, 3 H), 4.72
(s, 2 H), 6.96–7.58 (m, 4 H), 8.15 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 55.49, 56.69, 114.72, 123.67,
132.62, 137.98, 147.37, 162.12.
MS: m/z = 209 (M+).
Anal. Calcd for C10H11NO4: C, 57.41; H, 5.30; N, 6.70. Found: C,
57.46; H, 5.33; N, 6.64.
Anal. Calcd for C10H11NO3: C, 62.17; H, 5.74; N, 7.25. Found: C,
62.23; H, 5.71; N, 7.30.
Synthesis 2011, No. 13, 2136–2146 © Thieme Stuttgart · New York

PAPER
Novel Synthesis of Pyrrolidines, Spiropyrrolidines, and Spiropyrrolizidines
2141
(E)-3-(3,4-Dimethoxyphenyl)-2-nitroprop-2-en-1-ol (7i)
Yield: 1.05 g (44%); mp 100–102 °C.
1H NMR (300 MHz, CDCl3): d = 2.60 (s, 1 H), 4.67 (s, 2 H), 7.42–
7.54 (m, 4 H), 8.16 (s, 1 H).
IR (KBr): 3430, 1660, 1528, 1478, 1022, 720 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.05 (s, 1 H), 3.92 (s, 3 H), 3.94
(s, 3 H), 4.75 (s, 2 H), 6.94–7.25 (m, 3 H), 8.17 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 56.51, 128.85, 129.03, 131.49,
136.44, 137.37, 149.65.
MS: m/z = 213 (M+), 215 (M+ + 2).
13C NMR (75 MHz, CDCl3): d = 55.96, 56.01, 56.79, 111.31,
112.95, 123.95, 124.88, 130.30, 147.55, 149.24, 151.77.
Anal. Calcd for C9H8ClNO3: C, 50.60; H, 3.77; N, 6.56. Found: C,
50.63; H, 3.75; N, 6.58.
MS: m/z = 239 (M+).
(E)-2-Nitro-3-(thiophen-2-yl)prop-2-en-1-ol (7o)
Yield: 1.11 g (60%); mp 104–106 °C.
IR (KBr): 3335, 1643, 1518, 1338, 1023, 715 cm–1.
Anal. Calcd for C11H13NO5: C, 55.23; H, 5.48; N, 5.86. Found: C,
55.27; H, 5.51; N, 5.81.
(E)-3-[3,4-(Methylenedioxy)phenyl]-2-nitroprop-2-en-1-ol (7j)
Yield: 1.12 g (50%); mp 96–98 °C.
1H NMR (300 MHz, CDCl3): d = 2.74 (t, J = 6.9 Hz, 1 H), 4.91 (d,
J = 6.9 Hz, 2 H), 7.18–7.72 (m, 3 H), 8.31 (s, 1 H).
IR (KBr): 3420, 2949, 1643, 1512, 1305, 1025, 705 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.54 (t, J = 6.9 Hz, 1 H), 4.71 (d,
J = 7.2 Hz, 2 H), 6.07 (s, 2 H), 6.90–7.15 (m, 3 H), 8.13 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 56.72, 128.65, 130.39, 133.50,
133.55, 136.27, 146.18.
MS: m/z = 185 (M+).
13C NMR (75 MHz, CDCl3): d = 56.74, 63.15, 101.94, 109.04,
109.80, 125.16, 126.56, 128.54, 137.92, 147.85.
Anal. Calcd for C7H7NO3S: C, 45.40; H, 3.81; N, 7.56. Found: C,
45.45; H, 3.76; N, 7.59.
MS: m/z = 223 (M+).
(1-Methyl-3-nitro-4-phenylpyrrolidin-3-yl)methanol (8a); Typ-
ical Procedure
Anal. Calcd for C10H9NO5: C, 53.82; H, 4.06; N, 6.28. Found: C,
53.87; H, 4.09; N, 6.30.
A mixture of (E)-2-nitro-3-phenylprop-2-en-1-ol (7a, 0.36 g, 2
mmol), paraformaldehyde (0.36 g, 12 mmol), and sarcosine (0.53 g,
6 mmol) in MeCN (8 mL) was refluxed for 8 h. After completion of
the reaction (TLC), the mixture was concentrated and the resulting
crude mass was diluted with H2O (20 mL) and extracted with
EtOAc (3 × 10 mL). The combined organic layers were washed
with brine (3 × 10 mL) and dried (anhyd Na2SO4). The organic lay-
er was concentrated and purified by column chromatography (silica
gel, Acme 100–200 mesh, EtOAc–hexanes, 3:7) to provide 8a as a
colorless solid; yield: 0.36 g (76%); mp 104–106 °C.
(E)-3-(4-Fluorophenyl)-2-nitroprop-2-en-1-ol (7k)
Yield: 0.59 g (30%); mp 54–56 °C.
IR (KBr): 3458, 1653, 1560, 1394, 1053, 755 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.64 (s, 1 H), 4.68 (s, 2 H), 7.15–
7.62 (m, 4 H), 8.18 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 56.48, 116.32, 116.61, 127.43,
127.45, 132.48, 132.59, 136.69, 149.17, 162.58, 165.94.
MS: m/z = 197 (M+).
IR (KBr): 3373, 3073, 1525, 1349 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.49 (s, 3 H), 2.85 (br s, 1 H), 2.93
(t, J = 8.7 Hz, 1 H), 2.99 (d, J = 11.4 Hz, 1 H), 3.27 (t, J = 8.4 Hz,
1 H), 3.55 (d, J = 12.3 Hz, 1 H), 3.65 (d, J = 11.4 Hz, 1 H), 3.70 (d,
J = 12.6 Hz, 1 H), 4.20 (t, J = 7.4 Hz, 1 H), 7.31–7.35 (m, 5 H).
Anal. Calcd for C9H8FNO3: C, 54.83; H, 4.09; N, 7.10. Found: C,
54.88; H, 4.12; N, 7.07.
(E)-3-(2-Chlorophenyl)-2-nitroprop-2-en-1-ol (7l)
Yellow oil; yield: 1.17 g (55%).
IR (KBr): 3448, 1643, 1528, 1368, 1033, 715 cm–1.
13C NMR (75 MHz, CDCl3): d = 41.75, 51.57, 60.67, 62.71, 65.51,
98.98, 128.15, 128.28, 128.80, 128.88.
1H NMR (300 MHz, CDCl3): d = 3.40 (s, 1 H), 4.67 (s, 2 H), 7.27–
MS: m/z = 237 (M+ + 1).
7.85 (m, 4 H), 8.11 (s, 1 H).
Anal. Calcd for C12H16N2O3: C, 61.00; H, 6.83; N, 11.86. Found: C,
60.97; H, 6.91; N, 11.88.
13C NMR (75 MHz, CDCl3): d = 56.30, 128.17, 129.82, 129.87,
130.42, 130.88, 134.49, 135.52, 136.10.
[1-Methyl-4-(naphthalen-2-yl)-3-nitropyrrolidin-3-yl]metha-
nol (8b)
Yield: 0.42 g (74%); mp 115–117 °C.
IR (KBr): 3364, 3065, 1530, 1356 cm–1.
MS: m/z = 213 (M+), 215 (M+ + 2).
Anal. Calcd for C9H8ClNO3: C, 50.60; H, 3.77; N, 6.56. Found: C,
50.65; H, 3.70; N, 6.58.
1H NMR (300 MHz, CDCl3): d = 2.45 (s, 3 H), 2.56 (s, 1 H), 3.05
(t, J = 6.6 Hz, 1 H), 3.11 (d, J = 11.1 Hz, 1 H), 3.24 (t, J = 9.3 Hz,
1 H), 3.40 (d, J = 12.9 Hz, 1 H), 3.49 (d, J = 13.2 Hz, 2 H), 4.97 (t,
J = 6.9 Hz, 1 H), 7.35–7.93 (m, 7 H).
13C NMR (75 MHz, CDCl3): d = 41.75, 46.46, 62.54, 63.90, 64.79,
99.91, 122.96, 125.20, 125.92, 126.08, 127.07, 128.66, 129.04,
132.48, 133.01, 133.83.
(E)-3-(3-Chlorophenyl)-2-nitroprop-2-en-1-ol (7m)
Yellow oil; yield: 0.85 g (43%).
IR (KBr): 3442, 1647, 1530, 1363, 1036, 720 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.40 (s, 1 H), 4.62 (s, 2 H), 7.35–
8.01 (m, 4 H), 8.36 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 56.60, 126.70, 127.40, 130.01,
130.94, 131.44, 131.95, 132.37, 133.44.
MS: m/z = 287 (M+ + 1).
MS: m/z = 213 (M+), 215 (M+ + 2).
Anal. Calcd for C16H18N2O3: C, 67.12; H, 6.34; N, 9.78. Found: C,
67.14; H, 6.35; N, 9.76.
Anal. Calcd for C9H8ClNO3: C, 50.60; H, 3.77; N, 6.56. Found: C,
50.67; H, 3.72; N, 6.62.
[1-Methyl-3-nitro-4-(4-tolyl)pyrrolidin-3-yl]methanol (8d)
Yield: 0.40 g (80%); mp 106–108 °C.
IR (KBr): 3374, 3069, 1532, 1351 cm–1.
(E)-3-(4-Chlorophenyl)-2-nitroprop-2-en-1-ol (7n)
Yellow oil; yield: 0.64 g (30%).
IR (KBr): 3432, 1649, 1536, 1360, 1039, 715 cm–1.
Synthesis 2011, No. 13, 2136–2146 © Thieme Stuttgart · New York

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M. Bakthadoss et al.
PAPER
1H NMR (300 MHz, CDCl3): d = 2.02 (s, 1 H), 2.34 (s, 3 H), 2.44
(s, 3 H), 2.80 (d, J = 9.00 Hz, 1 H), 2.86 (d, J = 10.8 Hz, 1 H), 3.20
(t, J = 9 Hz, 1 H), 3.51 (d, J = 12.3 Hz, 1 H), 3.62 (d, J = 11.4 Hz, 1
H), 3.68 (d, J = 12.6 Hz, 1 H), 4.11 (t, J = 7.2 Hz, 1 H), 7.15 (d,
J = 7.2 Hz, 2 H), 7.24 (d, J = 11.1 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 21.05, 41.74, 51.34, 61.17, 63.21,
65.69, 99.29, 128.74, 129.48, 132.74, 137.84.
1H NMR (300 MHz, CDCl3): d = 2.49 (s, 3 H), 2.89 (t, J = 9.3 Hz,
1 H), 2.96 (d, J = 11.7 Hz, 1 H), 3.26 (t, J = 8.4 Hz, 1 H), 3.55 (d,
J = 12.3 Hz, 1 H), 3.72 (d, J = 12.6 Hz, 2 H), 3.88 (s, 6 H), 3.95 (s,
1 H), 4.10 (t, J = 8.1 Hz, 1 H), 6.81–6.88 (m, 3 H).
13C NMR (75 MHz, CDCl3): d = 41.74, 51.33, 55.90, 56.01, 60.76,
62.66, 65.52, 99.04, 111.18, 112.29, 120.73, 127.65, 148.87,
149.06.
MS: m/z = 251 (M+ + 1).
MS: m/z = 297 (M+ + 1).
Anal. Calcd for C13H18N2O3: C, 62.38; H, 7.25; N, 11.19. Found: C,
62.40; H, 7.24; N, 11.22.
Anal. Calcd for C14H20N2O5: C, 56.75; H, 6.80; N, 9.45. Found: C,
56.77; H, 6.78; N, 9.47.
[4-(4-Ethylphenyl)-1-methyl-3-nitropyrrolidin-3-yl]methanol
(8e)
[1-Methyl-3-nitro-4-(thiophen-2-yl)pyrrolidin-3-yl]methanol
(8o)
Yield: 0.37 g (70%); mp 110–112 °C.
Yield: 0.36 g (75%); mp 92–94 °C.
IR (KBr): 3366, 3063, 1529, 1343 cm–1.
IR (KBr): 3362, 3076, 1530, 1352 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.15 (t, J = 8.7 Hz, 3 H), 2.38 (s,
3 H), 2.57 (q, J = 9.6 Hz, 2 H), 2.66 (s, 1 H), 2.73 (d, J = 7.5 Hz, 1
H), 2.80 (d, J = 8.4 Hz, 1 H), 3.14 (t, J = 12.30 Hz, 1 H), 3.43 (d,
J = 12.3 Hz, 1 H), 3.60 (d, J = 13.2 Hz, 2 H), 4.03 (t, J = 11.1 Hz, 1
H), 7.09 (d, J = 7.8 Hz, 2 H), 7.18 (d, J = 7.5 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 15.45, 28.44, 41.78, 51.77, 60.93,
62.82, 65.80, 99.27, 128.16, 128.91, 132.49, 144.10.
1H NMR (300 MHz, CDCl3): d = 2.45 (s, 3 H), 2.49 (s, 1 H), 2.71
(t, J = 9.3 Hz, 1 H), 2.79 (d, J = 11.7 Hz, 1 H), 3.36 (t, J = 7.5 Hz,
1 H), 3.64 (d, J = 12.6 Hz, 1 H), 3.77 (d, J = 12 Hz, 1 H), 3.86 (d,
J = 12.3 Hz, 1 H), 4.48 (t, J = 8.7 Hz, 1 H), 7.00–7.29 (m, 3 H).
13C NMR (75 MHz, CDCl3): d = 41.48, 47.11, 62.24, 62.64, 65.65,
99.03, 125.55, 127.17, 127.29, 137.97.
MS: m/z = 243 (M+ + 1).
MS: m/z = 265 (M+ + 1).
Anal. Calcd for C10H14N2O3S: C, 49.57; H, 5.82; N, 11.56. Found:
C, 49.60; H, 5.85; N, 11.58.
Anal. Calcd for C14H20N2O3: C, 63.62; H, 7.63; N, 10.60. Found: C,
63.65; H, 7.62; N, 10.59.
3¢-(Hydroxymethyl)-1¢-methyl-3¢-nitro-4¢-phenylspiro[indole-
3,2¢-pyrrolidin]-2(1H)-one (9a); Typical Procedure
[4-(2-Methoxyphenyl)-1-methyl-3-nitropyrrolidin-3-yl]metha-
nol (8g)
Yield: 0.40 g (75%); mp 121–123 °C.
IR (KBr): 3364, 3065, 1527, 1344 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.05 (s, 1 H), 2.51 (s, 3 H), 2.93
(t, J = 9.3 Hz, 1 H), 3.04 (d, J = 11.4 Hz, 1 H), 3.25 (d, J = 13.2 Hz,
1 H), 3.33 (t, J = 8.4 Hz, 1 H), 3.43 (d, J = 11.1 Hz, 2 H), 3.72 (s, 3
H), 4.57 (t, J = 7.8 Hz, 1 H), 6.83–7.31 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 41.90, 46.82, 54.93, 59.30, 63.98,
64.48, 97.31, 110.24, 120.74, 123.80, 127.65, 129.07, 157.46.
A mixture of (E)-2-nitro-3-phenylprop-2-en-1-ol (7a, 0.36 g, 2
mmol), isatin (0.29 g, 2 mmol), and sarcosine (0.18 g, 2 mmol) in
MeCN (8 mL) was refluxed for 5 h. After completion of the reaction
(TLC), the mixture was concentrated and the resulting crude mass
was diluted with H2O (10 mL) and extracted with EtOAc (3 × 10
mL). The combined organic layers were washed with brine (2 × 10
mL) and dried (anhyd Na2SO4). The organic layer was concentrated
and the residue purified by column chromatography (silica gel,
Acme 100–200 mesh, EtOAc–hexanes, 2:8) to afford 9a as a color-
less solid; yield: 0.58 g (82%); mp 160–162 °C.
IR (KBr): 3484, 3227, 1717, 1544, 1337 cm–1.
MS: m/z = 267 (M+ + 1).
1H NMR (300 MHz, CDCl3): d = 2.18 (s, 3 H), 2.87 (dd, J = 2.7,
11.7 Hz, 1 H), 3.53 (t, J = 9.0 Hz, 1 H), 3.78–3.99 (m, 2 H), 4.04 (t,
J = 9.6 Hz, 1 H), 4.97 (t, J = 9.0 Hz, 1 H), 6.82–7.57 (m, 9 H), 7.74
(s, 1 H).
13C NMR (75 MHz, CDCl3): d = 34.77, 49.40, 56.78, 64.17, 77.23,
105.05, 110.15, 123.38, 124.46, 125.20, 128.18, 128.78, 129.99,
130.48, 134.75, 141.55, 176.06.
Anal. Calcd for C13H18N2O4: C, 58.63; H, 6.81; N, 10.52. Found: C,
58.60; H, 6.83; N, 10.55.
[4-(4-Methoxyphenyl)-1-methyl-3-nitropyrrolidin-3-yl]metha-
nol (8h)
Yield: 0.39 g (73%); mp 129–131 °C.
IR (KBr): 3367, 3064, 1531, 1343 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.15 (s, 1 H), 2.45 (s, 3 H), 2.80
(t, J = 9.00 Hz, 1 H), 2.86 (d, J = 11.4 Hz, 1 H), 3.20 (t, J = 8.4 Hz,
1 H), 3.51 (d, J = 12.6 Hz, 1 H), 3.63 (d, J = 11.4 Hz, 1 H), 3.69 (d,
J = 12.3 Hz, 1 H), 3.81 (s, 3 H), 4.10 (t, J = 8.1 Hz, 1 H), 6.88 (d,
J = 8.4 Hz, 2 H), 7.27 (d, J = 8.4 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 41.77, 51.10, 55.33, 61.31, 63.17,
65.77, 99.30, 114.16, 127.72, 129.95, 159.30.
MS: m/z = 354 (M+ + 1).
Anal. Calcd for C19H19N3O4: C, 64.58; H, 5.42; N, 11.89. Found: C,
64.56; H, 5.39; N, 11.94.
3¢-(Hydroxymethyl)-1¢-methyl-3¢-nitro-4¢-(2-tolyl)spiro[indole-
3,2¢-pyrrolidin]-2(1H)-one (9c)
Yield: 0.55 g (75%); mp 98–100 °C.
IR (KBr): 3429, 3176, 1716, 1541, 1346 cm–1.
MS: m/z = 267 (M+ + 1).
1H NMR (300 MHz, CDCl3): d = 2.19 (s, 3 H), 2.14 (s, 3 H), 2.52
(dd, J = 3.3, 11.7 Hz, 1 H), 3.52 (t, J = 9 Hz, 1 H), 3.62 (dd, J = 3.6,
13.8 Hz, 1 H), 3.94 (t, J = 12 Hz, 1 H), 4.13 (t, J = 9.6 Hz, 1 H), 5.14
(t, J = 9.6 Hz, 1 Hz), 6.79–7.89 (m, 9 H).
13C NMR (75 MHz, CDCl3): d = 20.37, 34.50, 45.40, 56.95, 63.68,
77.28, 105.62, 110.05, 123.50, 124.24, 125.15, 126.56, 127.90,
129.27, 130.49, 130.67, 133.39, 137.68, 142.00, 175.89.
Anal. Calcd for C13H18N2O4: C, 58.63; H, 6.81; N, 10.52. Found: C,
58.65; H, 6.80; N, 10.54.
[4-(3,4-Dimethoxyphenyl)-1-methyl-3-nitropyrrolidin-3-
yl]methanol (8i)
Yield: 0.41 g (69%); mp 130–132 °C.
IR (KBr): 3363, 3060, 1529, 1338 cm–1.
MS: m/z = 367 (M+ + 1).
Synthesis 2011, No. 13, 2136–2146 © Thieme Stuttgart · New York

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Novel Synthesis of Pyrrolidines, Spiropyrrolidines, and Spiropyrrolizidines
2143
Anal. Calcd for C20H21N3O4: C, 65.38; H, 5.76; N, 11.44. Found: C,
65.40; H, 5.70; N, 11.42.
Anal. Calcd for C20H21N3O5: C, 62.65; H, 5.52; N, 10.96. Found: C,
62.68; H, 5.50; N, 10.96.
3¢-(Hydroxymethyl)-1¢-methyl-3¢-nitro-4¢-(4-tolyl)spiro[indole-
3,2¢-pyrrolidin]-2(1H)-one (9d)
Yield: 0.56 g (76%); mp 122–124 °C.
4¢-(3,4-Dimethoxyphenyl)-3¢-(hydroxymethyl)-1¢-methyl-3¢-ni-
trospiro[indole-3,2¢-pyrrolidin]-2(1H)-one (9i)
Yield: 0.51 g (62%); mp 112–114 °C.
IR (KBr): 3564, 3151, 1710, 1550, 1331 cm–1.
IR (KBr): 3446, 3085, 1717, 1545, 1347 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.17 (s, 3 H), 2.35 (s, 3 H), 2.81
(dd, J = 3.6, 11.7 Hz, 1 H), 3.50 (t, J = 9 Hz, 1 H), 3.78 (dd, J = 3.3,
13.5 Hz, 1 H), 3.91–4.03 (m, 2 H), 4.93 (t, J = 9.3 Hz, 1 H), 6.81–
7.45 (m, 8 H), 7.67 (s, 1 H).
1H NMR (300 MHz, CDCl3): d = 2.17 (s, 3 H), 2.84 (d, J = 9 Hz, 1
H), 3.49 (t, J = 6.9 Hz, 1 H), 3.56 (d, J = 9.3 Hz, 1 H), 3.83 (d,
J = 10.8 Hz, 1 H), 3.89 (s, 3 H), 3.92 (s, 3 H), 3.97 (t, J = 5.4 Hz, 1
H), 4.88 (t, J = 9.3 Hz, 1 H), 6.81–7.33 (m, 7 H), 7.67 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 21.08, 34.78, 49.07, 56.86, 64.17,
77.23, 105.07, 110.09, 123.38, 124.47, 125.24, 129.49, 129.83,
130.44, 131.59, 137.98, 141.50, 175.98.
13C NMR (75 MHz, CDCl3): d = 34.77, 49.15, 55.89, 55.98, 57.37,
64.04, 76.66, 105.06, 110.06, 111.13, 112.97, 122.49, 123.42,
124.48, 125.16, 127.08, 130.45, 141.37, 148.87, 149.08, 175.85.
MS: m/z = 367 (M+ + 1).
MS: m/z = 414 (M+ + 1).
Anal. Calcd for C20H21N3O4: C, 65.38; H, 5.76; N, 11.44. Found: C,
65.43; H, 5.74; N, 11.49.
Anal. Calcd for C21H23N3O6: C, 61.01; H, 5.61; N, 10.16. Found: C,
61.05; H, 5.62; N, 10.24.
4¢-(4-Ethylphenyl)-3¢-(hydroxymethyl)-1¢-methyl-3¢-nitro-
spiro[indole-3,2¢-pyrrolidin]-2(1H)-one (9e)
Yield: 0.59 g (77%); mp 134–136 °C.
3¢-(Hydroxymethyl)-1¢-methyl-4¢-[3,4-(methylenedioxy)phe-
nyl]-3¢-nitrospiro[indole-3,2¢-pyrrolidin]-2(1H)-one (9j)
Yield: 0.48 g (60%); mp 117–119 °C.
IR (KBr): 3489, 3217, 1746, 1532, 1347 cm–1.
IR (KBr): 3515, 3305, 1721, 1543, 1356 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.23 (t, J = 7.5 Hz, 3 H), 2.17 (s,
3 H), 2.64 (q, J = 7.5 Hz, 2 H), 2.82 (dd, J = 3.0, 11.4 Hz, 1 H), 3.50
(t, J = 9 Hz, 1 H), 3.79 (dd, J = 3.3, 13.5 Hz, 1 H), 3.91–4.04 (m, 2
H), 4.94 (t, J = 9.3 Hz, 1 H), 6.81–7.48 (m, 8 H), 7.69 (s, 1 H).
1H NMR (300 MHz, CDCl3): d = 2.16 (s, 3 H), 2.90 (dd, J = 3.3,
11.4 Hz, 1 H), 3.50 (t, J = 9 Hz, 1 H), 3.83 (dd, J = 3.3, 13.5 Hz, 1
H), 3.89–4.02 (m, 2 H), 4.88 (t, J = 9.3 Hz, 1 H), 5.97 (s, 2 H), 6.77–
7.32 (m, 7 H), 7.74 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 15.44, 28.47, 34.78, 49.14, 56.81,
64.17, 77.64, 105.04, 110.24, 123.34, 124.43, 125.25, 128.28,
129.89, 130.44, 131.83, 141.71, 144.31, 176.29.
13C NMR (75 MHz, CDCl3): d = 34.73, 49.17, 57.09, 64.03, 76.51,
101.24, 105.05, 108.35, 110.05, 110.12, 123.42, 123.56, 124.47,
125.15, 128.23, 130.47, 141.36, 147.43, 148.04, 175.80.
MS: m/z = 381 (M+ + 1).
MS: m/z = 398 (M+ + 1).
Anal. Calcd for C21H23N3O4: C, 66.13; H, 6.08; N, 11.02. Found,
66.17; H, 6.10; N, 11.07.
Anal. Calcd for C20H19N3O6: C, 60.45; H, 4.82; N, 10.57. Found: C,
60.40; H, 4.88; N, 10.54.
3¢-(Hydroxymethyl)-4¢-(4-isopropylphenyl)-1¢-methyl-3¢-nitro-
spiro[indole-3,2¢-pyrrolidin]-2(1H)-one (9f)
Yield: 0.47 g (60%); mp 127–129 °C.
4¢-(4-Fluorophenyl)-3¢-(hydroxymethyl)-1¢-methyl-3¢-nitro-
spiro[indole-3,2¢-pyrrolidin]-2(1H)-one (9k)
Yield: 0.47 g (64%); mp 154–156 °C.
IR (KBr): 3435, 3213, 1711, 1541, 1330 cm–1.
IR (KBr): 3203, 3145, 1749, 1509, 1327 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.24 (d, J = 6.9 Hz, 6 H), 2.17 (s,
3 H), 2.80 (dd, J = 3, 11.7 Hz, 1 H), 2.88 (sept, J = 6.9 Hz, 1 H),
3.50 (t, J = 9 Hz, 1 H), 3.79 (dd, J = 3.3, 13.2 Hz, 1 H), 3.90–4.04
(m, 2 H), 4.94 (t, J = 9.3 Hz, 1 H), 6.81–7.49 (m, 8 H), 7.58 (s, 1 H).
1H NMR (300 MHz, CDCl3): d = 2.17 (s, 3 H), 3.07 (dd, J = 3.3,
10.8 Hz, 1 H), 3.53 (t, J = 9.3 Hz, 1 H), 3.81 (dd, J = 3.9, 13.5 Hz,
1 H), 3.86 (d, J = 11.4 Hz, 1 H), 3.96 (t, J = 9.3 Hz, 1 H), 4.94 (t,
J = 9.3 Hz, 1 H), 6.82–7.59 (m, 8 H), 7.81 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 23.90, 33.76, 34.79, 49.06, 56.84,
64.23, 77.21, 105.07, 110.01, 123.39, 124.52, 125.24, 126.83,
129.89, 130.42, 131.90, 141.41, 148.94, 175.90.
13C NMR (75 MHz, CDCl3): d = 34.79, 48.64, 57.19, 64.14, 76.71,
104.60, 110.25, 115.49, 115.78, 123.44, 124.46, 125.01, 130.50,
130.55, 131.72, 131.83, 141.47, 176.14.
MS: m/z = 395 (M+ + 1).
MS: m/z = 372 (M+ + 1).
Anal. Calcd for C22H25N3O4: C, 66.82; H, 6.37; N, 10.63. Found:
C, 66.80; H, 6.33; N, 10.65.
Anal. Calcd for C19H18FN3O4: C, 61.45; H, 4.89; N, 11.32. Found:
C, 61.47; H, 4.87; N, 11.38.
3¢-(Hydroxymethyl)-4¢-(4-methoxyphenyl)-1¢-methyl-3¢-nitro-
spiro[indole-3,2¢-pyrrolidin]-2(1H)-one (9h)
Yield: 0.47 g (61%); mp 143–145 °C.
4¢-(2-Chlorophenyl)-3¢-(hydroxymethyl)-1¢-methyl-3¢-nitro-
spiro[indole-3,2¢-pyrrolidin]-2(1H)-one (9l)
Yield: 0.62 g (80%); mp 116–118 °C.
IR (KBr): 3199, 3176, 1731, 1538, 1328 cm–1.
IR (KBr): 3421, 3157, 1712, 1546, 1337 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.16 (s, 3 H), 2.91 (d, J = 2.7 Hz,
1 H), 3.51 (t, J = 9 Hz, 1 H), 3.81 (s, 3 H), 3.81–4.00 (m, 3 H), 4.91
(t, J = 9 Hz, 1 H), 6.81–7.50 (m, 8 H), 7.85 (s, 1 H).
1H NMR (300 MHz, CDCl3): d = 2.89 (s, 3 H), 2.76 (dd, J = 6.3, 9.0
Hz, 1 H), 3.54 (t, J = 9 Hz, 1 H), 3.72 (t, J = 6 Hz, 2 H), 4.14 (t,
J = 9.6 Hz, 1 H), 5.30 (t, J = 9 Hz, 1 H), 6.77–7.93 (m, 9 H).
13C NMR (75 MHz, CDCl3): d = 34.79, 48.77, 55.29, 57.06, 64.17,
77.24, 104.97, 110.15, 114.14, 123.37, 124.45, 125.20, 126.52,
130.45, 131.09, 141.53, 159.39, 179.08.
13C NMR (75 MHz, CDCl3): d = 34.42, 45.86, 55.61, 63.51, 76.51,
104.38, 109.99, 123.55, 124.26, 124.93, 127.33, 129.23, 129.60,
130.47, 130.62, 132.96, 135.65, 142.02, 175.72.
MS: m/z = 383 (M+ + 1).
MS: m/z = 389 (M+ + 2).
Synthesis 2011, No. 13, 2136–2146 © Thieme Stuttgart · New York

2144
M. Bakthadoss et al.
PAPER
Anal. Calcd for C19H18ClN3O4: C, 58.84; H, 4.68; N, 10.84. Found:
C, 58.83; H, 4.70; N, 10.86.
Compound 11a
Mp 170–172 °C.
IR (KBr): 3467, 3185, 1709, 1535, 1345 cm–1.
4¢-(3-Chlorophenyl)-3¢-(hydroxymethyl)-1¢-methyl-3¢-nitro-
spiro[indole-3,2¢-pyrrolidin]-2(1H)-one (9m)
Yield: 0.50 g (64%); mp 122–124 °C.
IR (KBr): 3216, 3097, 1714, 1540, 1330 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.17 (s, 3 H), 3.10 (dd, J = 3.3,
10.8 Hz, 1 H), 3.52 (t, J = 9.3 Hz, 1 H), 3.82 (dd, J = 3.0, 12.9 Hz,
1 H), 3.89 (d, J = 10.8 Hz, 1 H), 3.98 (t, J = 9.3 Hz, 1 H), 4.92 (t,
J = 9.3 Hz, 1 H), 6.83–7.59 (m, 8 H), 8.08 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 34.75, 48.98, 56.83, 64.05, 76.69,
104.60, 110.38, 123.44, 124.39, 124.94, 128.34, 128.40, 129.93,
130.18, 130.61, 134.64, 136.97, 141.56, 176.25.
1H NMR (300 MHz, CDCl3): d = 1.41–1.47 (m, 1 H), 1.86–2.00 (m,
2 H), 2.17–2.22 (m, 2 H), 2.64 (td, J = 2.1, 5.4 Hz, 1 H), 3.22–3.27
(m, 1 H), 4.15 (dd, J = 4.2, 13.2 Hz, 1 H), 4.49 (dd, J = 10.5, 13.2
Hz, 1 H), 4.78 (dd, J = 5.4, 8.1 Hz, 1 H), 5.29 (s, 1 H), 6.72–7.52
(m, 10 H).
13C NMR (75 MHz, CDCl3): d = 25.04, 27.69, 48.50, 59.23, 65.28,
69.60, 73.67, 104.73, 110.22, 122.73, 125.31, 126.25, 128.33,
128.96, 129.43, 130.01, 131.79, 141.40, 178.87.
MS: m/z = 380 (M+ + 1).
Anal. Calcd for C21H21N3O4: C, 66.48; H, 5.58; N, 11.08. Found: C,
66.42; H, 5.49; N, 11.16.
MS: m/z = 389 (M+ + 2).
Anal. Calcd for C19H18ClN3O4: C, 58.84; H, 4.68; N, 10.84. Found:
C, 58.80; H, 4.65; N, 10.82.
2¢-(Hydroxymethyl)-2¢-nitro-1¢-(2-tolyl)-1¢,2¢,5¢,6¢,7¢,7a¢-
hexahydrospiro[indole-3,3¢-pyrrolizin]-2(1H)-one (10c)
Yield: 0.51 g (65%); mp 160–162 °C.
4¢-(4-Chlorophenyl)-3¢-(hydroxymethyl)-1¢-methyl-3¢-nitro-
spiro[indole-3,2¢-pyrrolidin]-2(1H)-one (9n)
Yield: 0.54 g (70%); mp 143–145 °C.
IR (KBr): 3421, 3156, 1712, 1546, 1337 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.19 (s, 3 H), 2.68 (dd, J = 5.7, 9.6
Hz, 1 H), 3.55 (t, J = 9 Hz, 1 H), 3.72 (t, J = 5.7 Hz, 2 H), 4.14 (t,
J = 9.3 Hz, 1 H), 5.30 (t, J = 9.3 Hz, 1 H), 6.78–7.93 (m, 9 H).
13C NMR (75 MHz, CDCl3): d = 34.41, 45.82, 55.64, 63.54, 76.42,
104.51, 109.80, 123.58, 124.33, 127.35, 129.20, 129.57, 130.47,
130.64, 132.95, 141.76, 175.27.
IR (KBr): 3255, 3075, 1712, 1543, 1333 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.52–1.59 (m, 1 H), 1.83–2.09 (m,
3 H), 2.58 (s, 3 H), 2.63–2.77 (m, 2 H), 4.15 (t, J = 12.0 Hz, 1 H),
4.31–4.89 (m, 2 H), 4.65 (d, J = 10.2 Hz, 1 H), 4.77 (s, 1 H), 6.90–
8.02 (m, 8 H), 8.34 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 20.60, 27.31, 31.76, 47.88, 51.82,
64.74, 70.91, 77.79, 106.56, 111.19, 123.08, 125.11, 125.26,
126.46, 127.48, 129.52, 130.64, 130.96, 133.18, 138.38, 141.26,
179.36.
MS: m/z = 394 (M+ + 1).
MS: m/z = 389 (M+ + 2).
Anal. Calcd for C22H23N3O4: C, 67.16; H, 5.89; N, 10.68. Found: C,
67.20; H, 5.91; N, 10.65.
Anal. Calcd for C19H18ClN3O4: C, 58.84; H, 4.68; N, 10.84. Found:
C, 58.83; H, 4.64; N, 10.83.
1¢-(Hydroxymethyl)-1¢-nitro-2¢-(2-tolyl)-1¢,2¢,5¢,6¢,7¢,7a¢-
hexahydrospiro[indole-3,3¢-pyrrolizin]-2(1H)-one (11c)
Yield: 0.20 g (25%); mp 168–170 °C.
IR (KBr): 3457, 3185, 1709, 1535, 1345 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.36–1.49 (m, 1 H), 1.86–2.18 (m,
3 H), 2.20 (s, 3 H), 2.21–2.25 (m, 1 H), 2.68 (dt, J = 2.7, 3.0 Hz, 1
H), 3.33 (q, J = 8.1 Hz, 1 H), 4.03 (d, J = 13 Hz, 1 H), 4.51 (t,
J = 10.5 Hz, 1 H), 4.82 (q, J = 5.7 Hz, 1 H), 5.71 (s, 1 H), 6.69 (d,
J = 7.5 Hz, 1 H), 7.02–7.63 (m, 8 H).
13C NMR (75 MHz, CDCl3): d = 20.37, 25.03, 27.13, 47.40, 54.99,
65.11, 70.60, 74.42, 103.79, 110.10, 122.57, 125.16, 126.44,
126.62, 128.09, 128.66, 129.95, 130.43, 131.27, 138.18, 141.19,
178.79.
2¢-(Hydroxymethyl)-2¢-nitro-1¢-phenyl-1¢,2¢,5¢,6¢,7¢,7a¢-hexa-
hydrospiro[indole-3,3¢-pyrrolizin]-2(1H)-one (10a) and
1¢-(Hydroxymethyl)-1¢-nitro-2¢-phenyl-1¢,2¢,5¢,6¢,7¢,7a¢-hexa-
hydrospiro[indole-3,3¢-pyrrolizin]-2(1H)-one (11a); Typical
Procedure
A mixture of (E)-2-nitro-3-phenylprop-2-en-1-ol (7a, 0.36 g, 2
mmol), isatin (0.29 g, 2 mmol), and L-proline (0.23 g, 2 mmol) in
MeCN (8 mL) was refluxed for 2 h. After completion of the reaction
(TLC), the mixture was concentrated and the resulting crude mass
was diluted with H2O (20 mL) and extracted with EtOAc (3 × 10
mL). The combined organic layers were washed with brine (3 × 10
mL) and dried (anhyd Na2SO4). The organic layer was concentrated
and purified by column chromatography (silica gel, Acme 100–200
mesh, EtOAc–hexanes, 3:7 to give 10a followed by 4:6 to give 11a)
to provide 10a (0.39 g, 52%) as a colorless solid and 11a (0.25 g,
33%) as a colorless solid.
MS: m/z = 394 (M+ + 1).
Anal. Calcd for C22H23N3O4: C, 67.16; H, 5.89; N, 10.68. Found: C,
67.20; H, 5.92; N, 10.72.
Compound 10a
Mp 148–150 °C.
IR (KBr): 3463, 3197, 1709, 1540, 1336 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.51–1.55 (m, 1 H), 1.92–2.08 (m,
3 H), 2.50–2.56 (m, 1 H), 2.69–2.74 (m, 1 H), 3.88 (t, J = 12.3 Hz,
1 H), 4.29 (d, J = 10.2 Hz, 1 H), 4.39–4.53 (m, 2 H), 4.95 (dd,
J = 3.6, 12.0 Hz, 1 H), 6.87–7.81 (m, 10 H).
13C NMR (75 MHz, CDCl3): d = 27.88, 32.74, 47.89, 56.59, 64.51,
69.88, 78.03, 105.54, 111.22, 122.96, 124.98, 125.52, 127.99,
128.56, 130.70, 130.88, 134.19, 140.86, 179.78.
2¢-(Hydroxymethyl)-2¢-nitro-1¢-(4-tolyl)-1¢,2¢,5¢,6¢,7¢,7a¢-
hexahydrospiro[indole-3,3¢-pyrrolizin]-2(1H)-one (10d)
Yield: 0.46 g (59%); mp 193–195 °C.
IR (KBr): 3461, 3173, 1714, 1535, 1343 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.51–1.61 (m, 1 H), 1.92–2.11 (m,
3 H), 2.36 (s, 3 H), 2.48–2.56 (m, 1 H), 2.70–2.76 (m, 1 H), 3.90 (t,
J = 12.0 Hz, 1 H), 4.27 (d, J = 10.2 Hz, 1 H), 4.40–4.55 (m, 2 H),
4.92 (dd, J = 3.6, 12.0 Hz, 1 H), 6.90 (d, J = 7.5 Hz, 1 H), 7.07–7.81
(m, 7 H), 8.29 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 21.11, 27.88, 32.71, 47.97, 56.23,
64.51, 69.82, 78.11, 105.50, 111.33, 122.97, 125.03, 125.54,
129.33, 130.73, 131.09, 132.67, 137.76, 140.95, 180.08.
MS: m/z = 380 (M+ + 1).
Anal. Calcd for C21H21N3O4: C, 66.48; H, 5.58; N, 11.08. Found: C,
66.41; H, 5.46; N, 11.14.
MS: m/z = 394 (M+ + 1).
Synthesis 2011, No. 13, 2136–2146 © Thieme Stuttgart · New York

PAPER
Novel Synthesis of Pyrrolidines, Spiropyrrolidines, and Spiropyrrolizidines
2145
Anal. Calcd for C22H23N3O4: C, 67.16; H, 5.89; N, 10.68. Found: C,
67.20; H, 5.86; N, 10.65.
129.83, 130.00, 130.60, 130.93, 132.73, 136.32, 141.32, 179.09.
MS: m/z = 414 (M+ + 1), 415 (M+ + 2).
Anal. Calcd for C21H20ClN3O4: C, 60.95; H, 4.87; N, 10.15. Found:
C, 60.92; H, 4.90; N, 10.12.
1¢-(Hydroxymethyl)-1¢-nitro-2¢-(4-tolyl)-1¢,2¢,5¢,6¢,7¢,7a¢-
hexahydrospiro[indole-3,3¢-pyrrolizin]-2(1H)-one (11d)
Yield: 0.27 g (35%); mp 178–180 °C.
IR (KBr): 3453, 3182, 1709, 1532, 1342 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.42–1.57 (m, 1 H), 1.86–1.99 (m,
2 H), 2.19 (s, 3 H), 2.27–2.42 (m, 2 H), 2.68 (dt, J = 1.8, 2.1 Hz, 1
H), 3.27 (dd, J = 8.1, 16.2 Hz, 1 H), 4.15 (d, J = 13.2 Hz, 1 H), 4.50
(d, J = 11.7 Hz, 1 H), 4.79 (dd, J = 5.4, 8.4 Hz, 1 H), 5.25 (s, 1 H),
6.75–7.51 (m, 8 H), 8.40 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 20.91, 25.01, 27.66, 48.47, 58.92,
65.32, 69.56, 73.70, 104.69, 110.21, 122.71, 125.30, 126.36,
128.58, 129.30, 129.69, 129.95, 138.13, 141.42, 179.00.
2¢-(2-Chlorophenyl)-1¢-(hydroxymethyl)-1¢-nitro-
1¢,2¢,5¢,6¢,7¢,7a¢-hexahydrospiro[indole-3,3¢-pyrrolizin]-2(1H)-
one (11l)
Yield: 0.16 g (20%); mp 165–167 °C.
IR (KBr): 3461, 3175, 1759, 1538, 1342 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.43–1.52 (m, 1 H), 1.86–2.33 (m,
4 H), 2.69 (t, J = 7.8 Hz, 1 H), 3.47 (dd, J = 8.1, 16.8 Hz, 1 H), 4.04
(d, J = 13.2 Hz, 1 H), 4.46 (d, J = 12.0 Hz, 1 H), 4.91 (dd, J = 4.8,
8.4 Hz, 1 H), 6.01 (s, 1 H), 6.75 (d, J = 7.8 Hz, 1 H), 7.03–7.66 (m,
7 H), 8.01 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 24.88, 27.24, 48.23, 54.57, 65.00,
70.77, 74.67, 77.20, 103.52, 109.96, 122.77, 125.80, 125.91,
127.04, 129.35, 129.92, 130.10, 130.19, 135.99, 141.07, 178.41.
MS: m/z = 394 (M+ + 1).
Anal. Calcd for C22H23N3O4: C, 67.16; H, 5.89; N, 10.68. Found: C,
67.20; H, 5.87; N, 10.71.
MS: m/z = 414 (M+ + 1), 415 (M+ + 2).
1¢-(4-Ethylphenyl)-2¢-(hydroxymethyl)-2¢-nitro-1¢,2¢,5¢,6¢,7¢,7a¢-
hexahydrospiro[indole-3,3¢-pyrrolizin]-2(1H)-one (10e)
Yield: 0.42 g (52%); mp 153–155 °C.
Anal. Calcd for C21H20ClN3O4: C, 60.95; H, 4.87; N, 10.15. Found:
C, 60.98; H, 4.83; N, 10.13.
IR (KBr): 3462, 2963, 1723, 1508, 1346 cm–1.
1¢-(4-Chlorophenyl)-2¢-(hydroxymethyl)-2¢-nitro-
1¢,2¢,5¢,6¢,7¢,7a¢-hexahydrospiro[indole-3,3¢-pyrrolizin]-2(1H)-
one (10n)
Yield: 0.51 g (62%); mp 160–162 °C.
IR (KBr): 3244, 2960, 1711, 1543, 1337 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.68–2.05 (m, 4 H), 2.70–2.74 (m,
2 H), 4.04 (t, J = 12.3 Hz, 1 H), 4.29–4.46 (m, 3 H), 5.04 (d, J = 10.2
Hz, 1 H), 6.88–8.08 (m, 8 H), 8.17 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 27.08, 31.29, 47.88, 52.17, 64.75,
70.13, 106.04, 110.98, 123.25, 125.22, 127.25, 128.82, 129.99,
130.58, 130.93, 132.72, 136.32, 141.19, 178.93.
1H NMR (300 MHz, CDCl3): d = 1.25 (t, J = 7.5 Hz, 3 H), 1.43–1.55
(m, 1 H), 1.92–2.12 (m, 3 H), 2.47–2.76 (m, 4 H), 3.89 (t, J = 12.0
Hz, 1 H), 4.25 (d, J = 11.3 Hz, 1 H), 4.38–4.54 (m, 2 H), 4.89 (dd,
J = 3.9, 12.3 Hz, 1 H), 6.86–7.68 (m, 8 H), 7.71 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 15.35, 27.88, 28.47, 32.75, 47.90,
56.24, 64.50, 69.81, 78.02, 105.54, 111.16, 122.95, 125.04, 125.57,
128.05, 130.67, 130.76, 131.27, 140.82, 143.98, 179.82.
MS: m/z = 408 (M+ + 1).
Anal. Calcd for C23H25N3O4: C, 67.80; H, 6.18; N, 10.31. Found: C,
67.78; H, 6.20; N, 10.29.
MS: m/z = 414 (M+ + 1), 415 (M+ + 2).
2¢-(4-Ethylphenyl)-1¢-(hydroxymethyl)-1¢-nitro-1¢,2¢,5¢,6¢,7¢,7a¢-
hexahydrospiro[indole-3,3¢-pyrrolizin]-2(1H)-one (11e)
Yield: 0.30 g (37%); mp 163–165 °C.
Anal. Calcd for C21H20ClN3O4: C, 60.95; H, 4.87; N, 10.15. Found:
C, 60.90; H, 4.83; N, 10.17.
IR (KBr): 3461, 3165, 1732, 1537, 1342 cm–1.
2¢-(4-Chlorophenyl)-1¢-(hydroxymethyl)-1¢-nitro-
1¢,2¢,5¢,6¢,7¢,7a¢-hexahydrospiro[indole-3,3¢-pyrrolizin]-2(1H)-
one (11n)
Yield: 0.26 g (31%); mp 168–170 °C.
IR (KBr): 3473, 3162, 1723, 1572, 1342 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.45–1.49 (m, 1 H), 1.84–2.29 (m,
3 H), 2.52 (s, 1 H), 2.69 (dt, J = 1.8, 2.1 Hz, 1 H), 3.45 (dd, J = 3.3,
12.9 Hz, 1 H), 4.03 (d, J = 13.2 Hz, 1 H), 4.46 (d, J = 5.4 Hz, 1 H),
4.90 (dd, J = 4.8, 8.4 Hz, 1 H), 6.01 (s, 1 H), 6.74 (d, J = 7.5 Hz, 1
H), 7.03–7.65 (m, 7 H), 8.05 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 24.87, 27.25, 48.26, 54.55, 64.99,
70.76, 74.69, 103.53, 109.98, 122.77, 125.79, 125.91, 127.04,
129.35, 129.91, 130.18, 130.98, 141.10, 178.44.
1H NMR (300 MHz, CDCl3): d = 1.13 (t, J = 7.5 Hz, 3 H), 1.39–1.50
(m, 2 H), 1.93–2.00 (m, 1 H), 2.17–2.26 (m, 2 H), 2.51 (q, J = 7.5
Hz, 2 H), 2.66 (dt, J = 2.4, 2.4 Hz, 1 H), 3.26 (q, J = 8.4 Hz, 1 H),
4.27 (d, J = 12.9 Hz, 1 H), 4.48 (dd, J = 9.9, 11.7 Hz, 1 H), 4.77 (dd,
J = 5.4, 8.1 Hz, 1 H), 5.27 (s, 1 H), 6.75 (d, J = 7.5 Hz, 1 H), 6.97–
7.52 (m, 7 H), 7.73 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 25.03, 27.60, 28.22, 29.68, 48.25,
59.01, 65.63, 69.55, 73.48, 104.06, 109.98, 122.71, 125.36, 126.44,
128.44, 128.83, 129.38, 129.88, 141.26, 144.31, 178.48.
MS: m/z = 408 (M+ + 1).
Anal. Calcd for C23H25N3O4: C, 67.80; H, 6.18; N, 10.31. Found: C,
67.86; H, 6.15; N, 10.33.
MS: m/z = 414 (M+ + 1), 415 (M+ + 2).
1¢-(2-Chlorophenyl)-2¢-(hydroxymethyl)-2¢-nitro-
1¢,2¢,5¢,6¢,7¢,7a¢-hexahydrospiro[indole-3,3¢-pyrrolizin]-2(1H)-
one (10l)
Anal. Calcd for C21H20ClN3O4: C, 60.95; H, 4.87; N, 10.15. Found:
C, 60.93; H, 4.89; N, 10.14.
Yield: 0.50 g (60%); mp 178–180 °C.
IR (KBr): 3253, 3182, 1710, 1543, 1335 cm–1.
Acknowledgment
1H NMR (300 MHz, CDCl3): d = 1.69–2.06 (m, 4 H), 2.70–2.74 (m,
2 H), 4.04 (t, J = 12.3 Hz, 1 H), 4.30–4.47 (m, 3 H), 5.04 (d, J = 10.2
Hz, 1 H), 6.89–8.09 (m, 8 H), 8.50 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 27.07, 31.29, 47.91, 52.20, 64.74,
70.12, 77.48, 106.03, 11.08, 123.23, 125.18, 127.26, 128.84,
We thank CSIR and UGC (New Delhi) for the financial support. We
also thank DST-FIST for the NMR facility. N.S. thanks CSIR for
his SRF and A.D. thanks UGC for his fellowship. D.S.S. thanks
DST for her research grant.
Synthesis 2011, No. 13, 2136–2146 © Thieme Stuttgart · New York

2146
M. Bakthadoss et al.
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