Novel synthesis of N-methyl spiropyrrolidines by 1,3-dipolar cycloaddition reaction of azomethine ylides

Article abstract of DOI:10.1080/00397910500182572

A series of novel N-methyl spiropyrrolidines have been synthesized in good yield by the cycloaddition reaction of azomethine ylides generated by a decarboxylative route from sarcosine and paraformaldehyde with conformationally locked s-trans enone functionality present in the (E)-3-arylidene-4-chromanone as dipolarophiles. The structure of the title compound was established by spectroscopic techniques. Copyright Taylor & Francis, Inc.

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Novel Synthesis of N‐Methyl
Spiropyrrolidines by
1,3‐Dipolar Cycloaddition
Reaction of Azomethine Ylides
G. Subramaniyan a , J. Jayashankaran a & R.
Raghunathan a
a Department of Organic Chemistry , University of
Madras , Chennai, India
Published online: 18 Aug 2006.
To cite this article: G. Subramaniyan , J. Jayashankaran & R. Raghunathan (2005)
Novel Synthesis of N‐Methyl Spiropyrrolidines by 1,3‐Dipolar Cycloaddition Reaction
of Azomethine Ylides, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 35:16, 2189-2193
To link to this article: http://dx.doi.org/10.1080/00397910500182572
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Synthetic Communicationsw, 35: 2189–2193, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500182572
Novel Synthesis of N-Methyl
Spiropyrrolidines by 1,3-Dipolar
Cycloaddition Reaction of
Azomethine Ylides
G. Subramaniyan, J. Jayashankaran, and R. Raghunathan
Department of Organic Chemistry, University of Madras, Chennai, India
Abstract: A series of novel N-methyl spiropyrrolidines have been synthesized in good
yield by the cycloaddition reaction of azomethine ylides generated by a decarboxyla-
tive route from sarcosine and paraformaldehyde with conformationally locked s-trans
enone functionality present in the (E)-3-arylidene-4-chromanone as dipolarophiles.
The structure of the title compound was established by spectroscopic techniques.
Keywords: 1,3-dipole, azomethine, ylide, spiropyrrolidines
INTRODUCTION
The intermolecular 1,3-dipolar cycloaddition reaction of azomethine ylides
with olefins represents an efficient and convergent method for the construction
of the pyrrolidine structural unit.[1–3] Their ease of generation coupled with
the highly regio- and stereoselective nature of their cycloaddition has
resulted in a number of syntheses that utilize such a reaction as the key step.
This method is widely used in the synthesis of natural products such as
alkaloids and pharmacologically active compounds.[4] Spiro compounds
represent an important class of naturally occurring substances characterized
by highly pronounced biological properties.[5–7] 4-Chromanones are
versatile intermediates for the synthesis of many natural products such as
Received in India March 31, 2005
Address correspondence to R. Raghunathan, Department of Organic Chemistry,
University of Madras, Guindy Campus, Chennai 600 025, India. Tel.: þ91-44-
22351269; Fax: þ91-44-22352494; E-mail: ragharaghunathan@yahoo.com
2189

2190
G. Subramaniyan, J. Jayashankaran, and R. Raghunathan
brazilin, hematoxylin, ripariochromene, clausenin, calonilide (A), and nopy-
hyllum (B).[8,9] Chromanone heterocycles have also drawn much attention
because of their important pharmacological properties.[8] Many natural
products containing chromanone, chromane, and chromene moiety have
been isolated, of particular interest is eucomine, the first member of
arylidene chromanone found in nature.[10] As a part of our ongoing research
program in the area of cycloaddition reactions[11] and with a view to synthesiz-
ing a rare class of spiroheterocyclic derivatives,[12–14] we herein report the
facile synthesis of N-methyl spiropyrrolidines through the cycloaddition
reaction of azomethine ylides generated by a decarboxylation route with
conformationally locked s-trans enone functionality present in the (E)-3-
arylidene-4-chromanones as dipolarophile.
RESULTS AND DISCUSSION
Azomethine ylides can be generated by a number of methods of which
the decarboxylation route is convenient for the synthesis of substituted
pyrrolidines.[15] In this method an aldehyde and a secondary amino acid
are condensed to generate the reactive intermediate, which is then
trapped by dipolarophiles. The required dipolarophile (E)-3-arylidene-4-
chromanones 1a–e were prepared by the acid-catalyzed reaction of
4-chromanone with various benzaldehydes, and the products were assigned
E-configuration on the basis of their NMR spectra, in accordance with the
literature.[16] The arylidene proton signal is observed around d 7.85 in all
cases, more deshielded than in the Z isomer, which is reported to resonate
around d 6.0.[17]
The 1,3-dipolar cycloaddition reaction of azomethine ylides generated by
decarboxylative condensation of sarcosine with paraformaldehyde in the
presence of (E)-3-arylidene-4-chromanmone 1a–e in toluene under reflux
afforded the novel 1-N-methyl-spiro[3.31]chroman-41-one-4-aryl-pyrrolidines
2a–e in good yield (Scheme 1). The structure of the cycloadducts 2a–e were
confirmed with the help of spectral and analytical data.
Scheme 1. R1 ¼ a) H, b) CI, c) Me, d) OMe, e) NO2.

Synthesis of N-Methyl Spiropyrrolidines
2191
The IR spectrum of 2a revealed the presence of carbonyl peak at
1681 cm21, an increase of 13 cm21 from the normal value observed for ben-
1
zylidene chromanone, which indicates the loss of conjugation. The H NMR
spectrum of 2a showed a singlet at d 2.44 because of the N-methyl group in the
pyrrolidine ring. One doublet of a doublet appeared at d 4.39 with the J values
of 7.8 and 5.9 as a result of benzylic protons. It also showed two well separated
doublets at d 3.60 and 4.13 with coupling constant value of 11.7 Hz because of
the OCH2 protons in the chromanone ring. Nine aromatic protons resonated as
multiplets in the region of d 6.82–7.95. The 13C NMR spectrum of 2a showed
a peak at 193.8 ppm because of chromanone carbonyl. It showed six sp3
carbons, including one spiro carbon at 55.0 ppm, and the rest of the peak
well account for the proposed structure of 2a. This compound gave satisfac-
tory microanalysis.
Identical results were obtained with other derivatives of benzylidene
chromanones 1(b–e). In conclusion, an efficient synthesis of a series of
novel spiropyrrolidine derivatives has been achieved via the [3 þ 2] cyclo-
addition reaction of azomethine ylides generated by decarboxylative
condensation of sarcosine and paraformaldehyde with (E)-3-arylidene-4-chro-
manones.
EXPERIMENTAL
General
All melting points are uncorrected. IR spectra were recorded on Shimadzu
FT-IR 8300 instrument. Mass spectra were recorded on JEOL DX 303 HF
1
spectrometer. H NMR and 13C NMR spectra were recorded in CDCl3 with
TMS as an internal standard on the JEOL instrument at 400 MHz and
100 MHz respectively. Elemental analyses were carried out on a Perkin-
Elmer 240 B instrument.
General procedure for the cycloaddition reaction of benzylideneflavanone
with azomethine ylide generated from decarboxylation route using sarcosine
and paraformaldehyde: A mixture of sarcosine (0.22 g, 2.5 mmol), paraformal-
dehyde (0.36 g, 6 mmol), and arylidenechromanone (1 mmol) was heated
under reflux in 10 ml of toluene. The water formed in the reaction was conti-
nuously removed with the aid of Dean–Stark apparatus. After completion of
the reaction (12–24 h) the solvent was evaporated in vacuo. The residue
was chromatographed over silica gel (100–200 mesh) using petroleu-
mether-ethylacetate (4 : 1) to give pyrrolidine derivatives.
1-N-Methyl-spiro[3.31]flavan-41-one-4-phenyl-pyrrolidine (2a): Yield
85%, colorless solid, mp 118–1198C; reaction time: 12 h; Found: C, 77.65;
H, 6.68; N, 4.85. C19H19NO2 requires C, 77.79; H, 6.53, N, 4.77. IR (KBr):
1
1681 cm21; H NMR: 2.44 (s, 3H), 2.59 (d, J ¼ 9.3, Hz, 1H), 3.01–3.11

2192
G. Subramaniyan, J. Jayashankaran, and R. Raghunathan
(m, 3H), 3.60 (d, J ¼ 11.7 Hz, 1H), 4.13 (d, J ¼ 11.7 Hz, 1H), 4.39 (dd,
J ¼ 7.8, 5.9 Hz, 1H), 6.82–7.43 (m, 8H, Ar-H), 7.95 (dd, J ¼ 7.8, 1.5 Hz,
1H); 13C NMR: 41.80, 45.67, 55.03, 61.84, 62.20, 72.38, 117.56, 120.12,
121.17, 126.91, 127.88, 128.29, 128.52, 135.74, 138.75, 160.98, 193.89;
CIMS m/z: 293 (Mþ).
1-N-Methyl-spiro[3.31]flavan-41-one-4-(4-chlorophenyl)-pyrrolidine (2b):
Yield 74%, semi solid; reaction time: 15 h; Found: C, 69.77; H, 5.39; N, 4.33.
1
C19H18ClNO2 requires C, 69.62; H, 5.53, N, 4.27. IR (KBr): 1679cm21; H
NMR: 2.33 (s, 3H), 2.52 (d, J ¼ 9.7, Hz, 1H), 2.91–3.03 (m, 3H), 3.53
(d, J ¼ 11.7Hz, 1H), 4.03 (d, J ¼ 11.7Hz, 1H), 4.22 (dd, J ¼ 7.8, 5.4 Hz,
1H), 6.76–7.37 (m, 7H, Ar-H), 7.86 (dd, J ¼ 7.8, 1.5 Hz, 1H); 13C NMR:
42.06, 45.61, 55.34, 62.00, 62.07, 72.37, 117.95, 120.30, 121.65, 128.19,
128.76, 130.20, 133.05, 136.28, 137.64, 161.29, 194.00; CIMS m/z: 327 (Mþ).
1-N-Methyl-spiro[3.31]flavan-41-one-4-(4-methylphenyl)-pyrrolidine (2c):
Yield 68%, semi solid; reaction time: 24 h; Found: C, 78.29; H, 7.05; N, 4.70.
1
C20H21NO2 requires C, 78.14; H, 6.88, N, 4.56. IR (KBr): 1681 cm21; H
NMR: 2.17 (s, 3H), 2.29 (s, 3H), 2.49 (d, J ¼ 9.7, Hz, 1H), 2.89–2.96
(m, 3H), 3.51 (d, J ¼ 11.7 Hz, 1H), 4.02 (d, J ¼ 11.7 Hz, 1H), 4.26 (dd,
J ¼ 7.9, 5.8 Hz, 1H), 6.71–7.28 (m, 7H, Ar-H), 7.82 (dd, J ¼ 7.8, 1.5 Hz,
1H); 13C NMR: 20.82, 41.72, 45.11, 54.81, 61.56, 62.02, 72.26, 117.43,
120.00, 121.03, 127.74, 128.24, 128.86, 135.24, 135.61, 136.33, 160.88,
193.74; CIMS m/z: 307 (Mþ).
1-N-Methyl-spiro[3.31]flavan-41-one-4-(4-methoxyphenyl)-pyrrolidine (2d):
Yield 60%, semi solid; reaction time: 18 h; Found: C, 74.12; H, 6.75; N, 4.45.
1
C20H21NO3 requires C, 74.28; H, 6.55, N, 4.33. IR (KBr): 1685 cm21; H
NMR: 2.31 (s, 3H), 2.52 (d, J ¼ 9.3, Hz, 1H), 2.92–2.97 (m, 3H), 3.53
(d, J ¼ 11.7 Hz, 1H), 3.64 (s, 3H), 4.04 (d, J ¼ 11.7 Hz, 1H), 4.25 (dd,
J ¼ 7.8, 5.4 Hz, 1H), 6.69–7.33 (m, 7H, Ar-H), 7.84 (dd, J ¼ 7.8, 1.5 Hz,
1H); 13C NMR: 41.84, 44.98, 54.99, 55.11, 61.94, 62.15, 72.41, 113.64,
117.55, 120.12, 121.15, 127.86,129.49, 130.54, 135.74, 158.46, 161.02,
194.05; CIMS m/z: 323 (Mþ).
1-N-Methyl-spiro[3.31]flavan-41-one-4-(4-nitrophenyl)-pyrrolidine (2e):
Yield 75%, semi solid; reaction time: 24 h; Found: C, 67.25; H, 5.44; N,
8.19. C19H18N2O4 requires C, 67.44; H, 5.36, N, 8.28. IR (KBr):
1
1685 cm21; H NMR: 2.33 (s, 3H), 2.54 (d, J ¼ 9.3, Hz, 1H), 3.00–3.12
(m, 3H), 3.55 (d, J ¼ 11.7 Hz, 1H), 4.12 (d, J ¼ 11.7 Hz, 1H), 4.33 (dd,
J ¼ 7.8, 5.4 Hz, 1H), 7.40–7.53 (m, 7H, Ar-H), 8.19 (d, J ¼ 8.7 Hz, 1H);
13C NMR: 41.84, 45.12, 54.98, 61.82, 62.24, 72.48, 117.52, 120.18, 121.25,
128.33, 130.42, 135.74, 138.24, 143.66, 147.42, 160.88, 194.04; CIMS
m/z: 338 (Mþ).

Synthesis of N-Methyl Spiropyrrolidines
ACKNOWLEDGMENT
2193
G.S. thanks the Council of Scientific and Industrial Research (CSIR), New
Delhi, India, for the award of Senior Research Fellowship. Financial
support from CSIR and University Grants Commission (UGC) is gratefully
acknowledged.
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