A facile synthesis of 1-arenesulfonylazetidines through reaction of 1-arenesulfonylaziridines with dimethylsulfoxonium methylide generated under microwave irradiation

Article abstract of DOI:10.1055/s-2007-1000838

A simple, efficient and general method has been developed for the synthesis of 1-arenesulfonylazetidines through a one-pot reaction of 1- arenesulfonylaziridines with dimethylsulfoxonium methylide, generated under microwave irradiation, using alumina as s

Full text of DOI:10.1055/s-2007-1000838

108
LETTER
A Facile Synthesis of 1-Arenesulfonylazetidines through Reaction of
1-Arenesulfonylaziridines with Dimethylsulfoxonium Methylide Generated
under Microwave Irradiation
1
-Arenesulfon
a
ylazetidine
r
s
unde
r
M
i
icrow
k
ave Irradiati
aon Malik,* Upender K. Nadir
Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110 016, India
Fax +91(11)26582037; E-mail: sarika.malik@mail2.iitd.ac.in
Received 28 July 2007
SO2R3
Abstract: A simple, efficient and general method has been devel-
O
O
oped for the synthesis of 1-arenesulfonylazetidines through a one-
pot reaction of 1-arenesulfonylaziridines with dimethylsulfoxoni-
um methylide, generated under microwave irradiation, using alumi-
na as solid support.
N
–
–
+
NSO2R3
Me2S
CH2 SMe2
+
+
R2
R1
R1
R2
Key words: azo compounds, ring expansion, sulfur, ylides, hetero-
cycles
SO2R3
N
Azetidines are an important group of nitrogen-containing
heterocycles, which have continued to attract attention on
account of their useful biological activities.1–8
R1
R2
Scheme 1 Synthesis of 1-arenesulfonylazetidines through reaction
of 1-arenesulfonylaziridines with dimethylsulfoxonium methylide
However, there is a paucity of good synthetic methods for
making these. Known ones, generally suffer from lack of
generality, multiple steps and involve starting materials,
which are difficult to obtain.9–14
obtaining 1-arenesulfonylazetidines through reaction of
1-arenesulfonylaziridines with dimethylsulfoxonium
methylide (generated from trimethylsulfoxonium iodide
and KOH) under microwave irradiation using alumina
support (Scheme 2).
Different approaches for syntheses of 1-arenesulfonylazet-
idines have been reported, such as regioselective addition
of 1,3-dicarbonyl dianions to N-sulfonyl aldimines,15 ho-
mologation of a-amino acids,16 cyclization of tert-butyl
acetate,17 photocyclization of 2-acyl-3-allylperhydro-1,3-
benzoxazines,18 a-alkylation of SAMP hydrazones with
benzyloxymethyl chloride19 and b-elimination of amino
alcohols.20,21
We have shown previously22–25 that methylene transfer
from dimethylsulfoxonium methylide to 1-arenesulfonyl-
aziridines leads in a fairly simple and general way to the
corresponding azetidine through nucleophilic attack of
the ylide on the aziridine followed by 4-exo-tet ring clo-
sure of intermediate 1 (Scheme 1).
X
X
O
O
S
O
S
N
O
–
MW, 160 W, 90 °C
Al2O3, 7 min
N
O
CH2 SMe2
+
+
R1
R2
R2
R1
3
2
68–79%
Scheme 2 Synthesis of 1-arenesulfonylazetidines under microwave
irradiation
In all these reactions, however, side products accompa-
nied azetidine formation and the yields were modest. Be-
sides they involved use of solvents like DMSO and DMF.
We performed ring expansion of 1-arenesulfonylaziri-
dines 2a–k by dimethylsulfoxonium methylide using mi-
crowave irradiation in solvent-free conditions (on
Al2O3).33 All reactions were carried out in sealed reaction
vials by the focused microwave reactor Pelco with mea-
surement and control of power and temperature by the
thermocouple for the time given in Table 1.34,35
In recent years, solvent-free syntheses utilizing micro-
wave irradiation and surface mediation have received
considerable attention because these are often environ-
mentally benign, require shorter reaction times, are effi-
cient, high-yielding and have easy workups.26–30
As part of our efforts to explore these types of reaction
conditions,31,32 we herein describe a facile procedure for
It may be noted that the reaction was successful only when
alumina was used as the solid support; it failed when silica
gel or montmorillonite K-10 or KSF were used as the solid
support.
SYNLETT 2008, No. 1, pp 0108–0110
x
x.
x
x.
2
0
0
7
Advanced online publication: 11.12.2007
DOI: 10.1055/s-2007-1000838; Art ID: G26007ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
1-Arenesulfonylazetidines under Microwave Irradiation
109
Table 1 Various 1-Arenesulfonylazetidines33 Synthesizeda
CH3
Entryb R1
R2
X
Time Temp. Power Yield
O
S
(min) (°C)
(W)
160
320
160
160
160
160
160
160
160
160
160
(%)c
78
79
68
68
70
79
75
72
71
73
75
O
H
N
3a
3b
3c
3d
3e
3f
Ph
Ph (cis)
Me
7
3
7
7
7
7
7
7
7
7
7
90
110
90
90
90
90
90
90
90
90
90
H
2
3
Ph
Ph (trans) Me
Ph
H
Me
H
3a
Ph
H
Figure 1
Ph
H
Cl
and 7–11 show that, only those azetidines were obtained,
which corresponded to dimethylsulfoxonium methylide
attack at less substituted carbon of aziridine ring. Entry 6
shows ylide attack at the carbon bearing phenyl rather
than a methyl group, indicating the predominance of elec-
tronic effect.
Me
Ph (cis)
Me
Me
Me
Me
Me
Me
3g
3h
3i
C6H13
4-ClC6H4
4-BrC6H4
4-MeC6H4
Me
H
H
H
H
H
3j
The improved yields of azetidines and the absence of side
products could be due to the fact that, in solution phase
conformational mobility adversely affects azetidine for-
3k
a Reaction conditions: 1-arenesulfonylaziridines (1 mmol), trimethyl- mation and results in side products.
sulfoxonium iodide (3 mmol), KOH (3 mmol).
In summary, we have described an experimentally simple
b All new products were characterized by NMR, IR, mass and elemen-
tal analysis.
and convenient process for the synthesis of 1-arenesulfo-
nylazetidines. This protocol is fairly general and applica-
ble to a wide variety of 1-arenesulfonylaziridines. The
reaction is stereospecific as well as regioselective. The
yields are good; reaction times are short, reaction condi-
tions are benign and the workup procedure is simple.
c Isolated, unoptimized yields.
The starting aziridines 2a–e and 2h–j were prepared from
the appropriate olefin through a known three-step proce-
dure used by us previously.36 Aziridines 2f and 2g could
be accessed by the Sharpless method37 and 2k by the
Stephens method.38 The mixture was irradiated with mi-
crowaves of appropriate power and for reaction times
specified in Table 1.
Acknowledgment
We thank the Council of Scientific and Industrial Research (CSIR)
New Delhi, for a fellowship to Sarika Malik, and the Sophisticated
Analytical Instrument Facility (SAIF), CDRI Lucknow for provi-
ding elemental and FAB mass analyses.
Only a single product (as shown by TLC) was obtained
and could be easily extracted with minimal use of sol-
vents. It is clear from Table 1 that the reaction times were
short and the yields were uniformly good.
References and Notes
The workup was simple and avoided the use of expensive
bases for ylide generation. Entries 1 and 2 show that the
reaction was stereospecific: cis-Aziridines yielded the
trans-azetidines and the trans-aziridines led to the cis-
azetidines. The geometry of these isomers was assigned
on the basis of NMR observations and NOE experiment:
coupling constant of vicinal trans protons (J = 7.5 Hz)
was less than that of the cis protons (J = 9 Hz). C-2 proton
cis to the phenyl ring in the trans isomer appeared ca. 0.4
ppm upfield from that in the cis isomer.39 The 2,3-cis ste-
reochemistry of vicinal hydrogens in 3a was determined
by NOE experiment. The peak for the C-2 hydrogen was
enhanced (ca. 4%) on irradiation of the C-3 hydrogen
(Figure 1).
(1) Obika, S.; Andoh, J.; Onoda, M.; Nakagawa, O.; Hiroto, A.;
Sugimoto, T.; Imanushi, T. Tetrahedron Lett. 2003, 44,
5267.
(2) Jin, D.; Takai, S.; Yamada, M.; Sakaguchi, M.; Miyazaki, M.
Life Sci. 2002, 71, 437.
(3) Kumar, A.; Sharma, P.; Sharma, R.; Mohan, P. Indian J.
Chem., Sect. B: Org. Chem. Incl. Med. Chem. 2003, 42, 416.
(4) Zieminska, E.; Stafiej, A.; Lazarewicz, J. W. Neurochem.
Int. 2003, 43, 481.
(5) Couty, F.; Prim, D. Tetrahedron: Asymmetry 2002, 13,
2619; and references cited therein.
(6) Uoto, K.; Takeda, Y.; Sakamoto, A.; Takayanagi, Y. Jpn.
Patent, WO2007049575, 2007.
(7) Holmqvist, S.; Johansson, A.; Svensson, A.; Astrazeneca, A.
B. Swed. Patent, WO2006137790, 2006.
(8) Brunette, S. R. Ger. Patent, WO2006107941, 2006.
(9) Cromwell, N. H.; Philips, B. Chem. Rev. 1979, 79, 331.
(10) Moore, J. A. Heterocyclic Compounds with Three- and
Four-Membered Rings, Part 2; Weissheeger, A., Ed.;
Interscience Publishers: New York, 1965, 885.
(11) Cromwell, N. H. Heterocycl. Chem. 1976, 13, 1.
(12) Couty, F.; Evano, G.; Prim, D. Mini Rev. Org. Chem. 2004,
16, 133.
These results indicate that methylene transfer to 1-arene-
sulfonylaziridines is stereospecific and leads to the inver-
sion of configuration at the attacked carbon, thus lending
support to the rational of this methodology. The regiose-
lectivity of the reaction is substituent-dependent and gov-
erned by both steric and electronic factors. Entries 3–5
Synlett 2008, No. 1, 108–110 © Thieme Stuttgart · New York

110
S. Malik, U. K. Nadir
LETTER
(13) Padwa, A.; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V.
Comprehensive Heterocyclic Chemistry II, Three- and
Four-Membered Rings, Azetidines, Azetines and Azetes:
Monocyclic, Vol. 1B; Pergamon, Elsevier: Oxford, 1996,
Chap. 1.18, 507.
(14) For four-membered heterocyclic ring system, see: Parrick, J.
Prog. Heterocycl. Chem. 1991, 3, 58.
(15) Ghorai, M. K.; Kumar, A.; Halder, S. Tetrahedron 2007, 63,
4779.
(16) Ghorai, M. K.; Das, K.; Kumar, A. Tetrahedron Lett. 2007,
48, 2471.
Found: C, 67.10; H, 6.40; N, 4.51. MS (FAB): m/z = 302
[MH+].
2-Hexyl-1-(4-toluenesulfonyl)azetidine (3g): viscous oil;
yield: 79%. IR: 1333, 1164 (SO2) cm–1. 1H NMR (300 MHz,
CDCl3): d = 7.65 (d, 2 H), 7.32 (d, 2 H), 3.42–3.77 (complex
m, 3 H), 2.38 (s, 3 H), 1.84 (complex m, 2 H), 1.18–1.32 (m,
10 H, aliphatic), 0.81 (t, J = 7 Hz, 3 H). 13C NMR (75 MHz,
CDCl3): d = 128.26–143.80 (ArC), 66.35 (d), 47.50 (t),
36.02 (t), 31.70 (t), 29.66 (t), 28.59 (t), 24.13 (t), 22.66 (t),
21.42 (q), 14.09 (q). Anal. Calcd for C16H25NSO2: C, 65.08;
H, 8.47; N, 4.74. Found: C, 64.88; H, 7.80; N, 4.30. MS
(FAB): m/z = 296 [MH+].
(17) Ghorai, M. K.; Das, K.; Kumar, A.; Das, A. Tetrahedron
Lett. 2006, 47, 5393.
(18) Pedrosa, R.; Andres, C.; Nieto, J.; Pozo, S. D. J. Org. Chem.
2005, 70, 1408.
2-(4-Chlorophenyl)-1-(4-toluenesulfonyl)azetidine (3h):
white crystalline solid; mp 108–109.5 °C; yield: 72%. IR:
1333, 1160 (SO2) cm–1. 1H NMR (300 MHz, CDCl3): d =
7.51 (m, 4 H), 7.31 (s, 4 H), 4.89 (t, J = 8 Hz, 1 H), 3.77 (dd,
(19) Enders, D.; Gries, J.; Kim, Z. S. Eur. J. Org. Chem. 2004,
4471.
J = 6, 8 Hz, 2 H), 2.40 (s, 3 H), 2.25 (m, J = 8 Hz, 2 H). 13
C
(20) Ohno, H.; Hamaguchi, H.; Tanaka, T. J. Org. Chem. 2001,
66, 1867.
NMR (75 MHz, CDCl3): d = 127.83–139.14 (ArC), 65.11
(d), 47.43 (t), 25.89 (t), 21.41 (q). Anal. Calcd for
(21) Ibuka, T.; Nakai, K.; Habashita, H.; Hotta, Y.; Otaka, A.;
Tamamura, H.; Fujii, N. J. Org. Chem. 1995, 60, 2044.
(22) Nadir, U. K.; Koul, V. K. J. Chem. Soc., Chem. Commun.
1981, 9, 417.
(23) Nadir, U. K.; Koul, V. K. Synthesis 1983, 554.
(24) Nadir, U. K.; Sharma, R. L.; Koul, V. K. J. Chem. Soc.,
Perkin Trans. 1 1991, 2015.
C16H16NSO2Cl: C, 59.72; H, 4.97; N, 4.35. Found: C, 59.72;
H, 5.08; N, 4.07. MS (FAB): m/z = 322 [M+].
2-(4-Bromophenyl)-1-(4-toluenesulfonyl)azetidine (3i):
white crystalline solid; mp 118–119 °C; yield: 71%. IR:
1330, 1164 (SO2) cm–1. 1H NMR (300 MHz, CDCl3): d =
7.51 (m, 4 H), 7.28 (s, 4 H), 4.78 (t, J = 8 Hz, 1 H), 3.78 (dd,
J = 6, 8 Hz, 2 H), 2.38 (s, 3 H), 2.25 (m, J = 8 Hz, 2 H). 13
C
(25) Nadir, U. K.; Sharma, R. L.; Koul, V. K. Tetrahedron 1989,
25, 2915.
(26) Tanaka, K. Solvent-Free Organic Synthesis; Wiley-VCH:
Weinheim, 2003.
NMR (75 MHz, CDCl3): d = 127.83–139.14 (ArC), 65.15
(d), 47.43 (t), 25.89 (t), 21.42 (q). Anal. Calcd for
C16H16NSO2Br: C, 52.45; H, 4.37; N, 3.82. Found: C, 52.22;
H, 4.44; N, 3.14. MS (FAB): m/z = 366 [M+].
(27) Review: Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J.
Tetrahedron 2001, 57, 9225.
2-(4-Methylphenyl)-1-(4-toluenesulfonyl)azetidine (3j):
white crystalline solid; mp 110–111 °C; yield: 71%. IR:
1334, 1163 (SO2) cm–1. 1H NMR (300 MHz, CDCl3): d =
7.42 (m, 4 H), 7.02 (m, 4 H), 4.87 (t, J = 8 Hz, 1 H), 3.77 (dd,
J = 6, 8 Hz, 2 H), 2.40 (s, 3 H), 2.33 (s, 3 H), 2.28 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 123.3–140.29 (ArC), 65.83
(d), 47.27 (t), 25.83 (t), 21.4 (q), 21.38 (q). Anal. Calcd for
C17H19NSO2: C, 67.77; H, 6.31; N, 4.65. Found: C, 67.11; H,
5.95; N, 3.96. MS (FAB): m/z = 302 [MH+].
(28) Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199.
(29) Caddick, S. Tetrahedron 1995, 51, 10403.
(30) Nagendrappa, G. Resonance 2002, 7, 64.
(31) Nadir, U. K.; Singh, A. Tetrahedron Lett. 2005, 46, 2083.
(32) Singh, A. PhD Thesis; Indian Institute of Technology Delhi:
India, 2005.
(33) General Method for the Synthesis of 1-Arenesulfonyl-
azetidines: The pertinent aziridine (1 mmol), trimethyl-
sulfoxonium iodide (3 mmol) and KOH (3 mmol) were
loaded on neutral alumina (0.5 mmol) solid support. This
mixture was irradiated with microwaves for the specified
time (Table 1). Only a single product (as shown by TLC)
was formed. The reaction was quenched by addition of cold
H2O. The product was extracted with EtOAc and purified by
simple crystallization or through column chromatography on
silica gel.
(34) The reaction vials were placed in the MW reactor supplied
with a safety valve for release of overpressure.
(35) After the set temperature of 90 °C is reached, the power
regulates itself to maintain the reaction temperature.
(36) I.C.I. Ltd., FR 1544970, 1968; Chem. Abstr. 1970, 72,
12545.
(37) Jeong, J. E.; Tao, B.; Sagasser, I.; Henniges, H.; Sharpless,
K. B. J. Am. Chem. Soc. 1998, 120, 6844.
(38) Stephens, W. D.; Moffet, L. R. Jr.; Vaughan, H. W. Jr.; Hill,
W. E.; Brown, S. P. J. Am. Chem. Eng. Data 1963, 8, 62.
(39) (a) Gaudemer, A. Determination of Configurations by
Spectrometric Methods; Kagan, H. B., Ed.; Georg Thieme
Verlag: Stuttgart, 1977, 84. (b) Gaudemer, A.
cis-2-Methyl-3-phenyl-1-(4-toluenesulfonyl)azetidine
(3f): white crystalline solid; mp 105–106 °C; yield: 79%. IR:
1333, 1164 (SO2) cm–1. 1H NMR (300 MHz, CDCl3): d =
7.65 (m, 5 H), 7.32 (s, 4 H), 4.26 (q, J = 7 Hz, 1 H), 3.93
(distorted d, J = 6 Hz, 2 H), 3.41 (m, 1 H), 2.39 (s, 3 H), 0.98
(d, J = 7 Hz, 3 H). 13C NMR (75 MHz, CDCl3): d = 127.2–
137.4 (ArC), 63.02 (d), 53.47 (t), 38.17 (d), 21.42 (q), 17.02
(q). Anal. Calcd for C17H19NSO2: C, 67.77; H, 6.31; N, 4.65.
Determination of Configurations by Spectrometric Methods;
Kagan, H. B., Ed.; Georg Thieme Verlag: Stuttgart, 1977,
87.
Synlett 2008, No. 1, 108–110 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.