[2 + 2] Annulation of aldimines with sulfonic acids: A novel one-pot cis-selective route to β-sultams

Article abstract of DOI:10.1002/ejoc.201100628

A novel DMF/dimethyl sulfate promoted [2 + 2] annulation of aldimines with sulfonic acids afforded β-sultams in good to excellent yields (35-93%) under mild conditions. The protocol offers a convenient alternative to highly corrosive and hygroscopic sulfo

Full text of DOI:10.1002/ejoc.201100628

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100628
[2 + 2] Annulation of Aldimines with Sulfonic Acids: A Novel One-Pot cis-
Selective Route to β-Sultams
Ankita Rai,[a] Vijai K. Rai,[b] Atul K. Singh,[a] and Lal Dhar S. Yadav*[a]
Keywords: Sulfonamides / Annulation / Asymmetric synthesis / Diastereoselectivity
A novel DMF/dimethyl sulfate promoted [2 + 2] annulation
of aldimines with sulfonic acids afforded β-sultams in good
to excellent yields (35–93%) under mild conditions. The pro-
tocol offers a convenient alternative to highly corrosive and
hygroscopic sulfonyl chlorides to provide β-sultams with
complete diastereoselectivity in favour of the cis isomers.
N-sulfonylamines.[12] The intramolecular cyclization strat-
egy involves use of amino acids followed by introduction of
the sulfur moiety,[13] β-amino sulfonic acids,[6] heterocyclic
sulfonates[14] or β-aminosulfonyl chlorides,[15] for diastereo-
and enantioselective synthesis of β-sultams.[6,8,16]
Introduction
β-Sultams, the highly reactive sulfonyl analogues of β-
lactams, are interesting from both chemical and pharmaco-
logical viewpoints.[1a] They have revealed a wide spectrum
of biological activities[1b–3] and are interesting building
blocks for new synthetic drugs corresponding to β-lac-
tams.[4] Bacterial resistance to β-lactam antibiotics by pro-
ducing β-lactamase and elastase is a serious concern in the
fight against bacterial infections by β-lactam antibiotics,
which has motivated intensive research to overcome this
problem. Recently, β-sultams have been reported to serve as
β-lactamase- and elastase inhibitors by irreversible sulf-
onylation of the active site serine.[5a,5b] The β-sultam ring is
more distorted than the β-lactam ring, which makes β-sul-
tams more suitable for the design of new inhibitors. Chanet-
Ray and Vessiere have published an excellent review cover-
ing the preparation and uses of β-sultams.[5c]
From a chemical viewpoint, β-sultams can act as pepti-
domimetics in sulfonyl transfer reactions and as potent sul-
fonating agents for a variety of nucleophiles[6–8] to afford a
wide range of important chemicals. Page et al. have exhaus-
tively studied the reactivity of β-sultams with nucleophiles
and found that it depends on the N-substituent.[9] Despite
these promising synthetic and pharmacological applica-
tions, β-sultams have received less attention from synthetic
chemists. Generally, construction of the β-sultam ring in-
volves [2 + 2] cycloaddition or intramolecular cyclization
reactions. The [2 + 2] cycloaddition reported for β-sultam
synthesis utilizes mainly sulfene intermediates with im-
ines,[10] mesyl chloride with chiral imines,[11] or alkenes with
Most of the methods available for the synthesis of β-sul-
tams utilize sulfonyl chlorides A as C–SO2 transfer reagent
(Figure 1). As they are highly corrosive and hygroscopic in
nature, their use is cumbersome. This prompted us to search
for a new and efficient alternative to classical sulfonyl chlo-
rides A for β-sultam synthesis, and we envisioned the use
of the DMF/Me2SO4 system for the purpose, which worked
well. In fact, our choice for the DMF/Me2SO4 system was
guided by its application in β-lactam synthesis through the
activation of the COOH group,[17a,17b] Beckmann re-
arrangement of cyclohexanone oxime to caprolactam,[17c]
formation of 1,3-dioxolanes,[17d] and synthesis of 3-acylated
indolizines,[17e] pyrimidines and pyridinones.[17f,17g] Herein,
we report the first application of the DMF/Me2SO4 adduct
as a convenient and efficient reagent for the diastereoselec-
tive synthesis of β-sultams, which is a novel entry into β-
sultam chemistry. This is in continuation of our efforts to
develop new routes to chemically and pharmacologically
relevant, strained ring compounds,[18,19] especially β-lac-
tams.[19] The protocol involves [2 + 2] annulation of ald-
imines with sulfonic acids to afford β-sultams in good to
excellent yields (35–93%) with complete diastereoselectivity
in favour of the cis isomer (Scheme 1).
[a] Green Synthesis Laboratory, Department of Chemistry, Univer-
sity of Allahabad,
Allahabad 211002, India
Fax: +91-5322460533
E-mail: ldsyadav@hotmail.com
[b] School of Biology & Chemistry, Shri Mata Vaishno Devi Uni-
versity,
Katra, Jammu & Kashmir 182320, India
Figure 1. C–SO2 transfer reagents in β-sultam synthesis.
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2011, 4302–4306

[2 + 2] Annulation of Aldimines with Sulfonic Acids
Table 1. Optimization of reaction conditions[a] for the formation of
3a.
Entry
Catalyst 4
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
4a
1,4-dioxane
CHCl3
CH2Cl2
THF
66
54
59
74
91
80
77
85
–
Scheme 1. Synthesis of β-sultams 3.
4a
4a
4a
4b
THF
Results and Discussion
4b
CHCl3
CH2Cl2
1,4-dioxane
THF
4b
To begin with, ethoxy- and methoxy-methylene-N,N-di-
methyliminium salts (4a and 4b) were prepared by reacting
N,N-dimethylformamide (DMF) with Et2SO4 and Me2SO4,
respectively (Scheme 2).[17] The general procedure was first
optimized with respect to reagent 4 and solvents. For this
purpose, aldimine 1a and sulfonic acid 2a were chosen as a
4b
DMF
Me2SO4
THF
–
[a] Reaction conditions: Aldimine 1a (1.0 mmol) and sulfonic acid
2a (1.5 mmol) were used in dry THF (4 mL) in the presence of
alkoxy-methylene-N,N-dimethyliminium salt
4 and dry Et3N
set of model substrates for the synthesis of a representative (5.0 mmol). [b] Yield of isolated and purified product.
β-sultam 3a (Table 1). First, we performed the reaction in
THF using reagent 4a, which afforded the target compound
3a in 74% yield (Table 1, Entry 4). We then examined an-
Table 2. Synthesis of β-sultams 3.
Entry
3
R1
R2
R3
Time [h][a] Yield [%][b,c,d]
other reagent 4b, which was found to be better than 4a
(Table 1, Entries 4 and 5). However, the reaction did not
occur when using DMF or Me2SO4 alone (Table 1, Entries
9 and 10). Next, optimization of the solvents for the synthe-
sis of 3a by employing 4b was undertaken, and it was found
that among THF, 1,4-dioxane, CHCl3 and CH2Cl2 (Table 1,
Entries 5–8), the best solvent in terms of yield was THF
(Table 1, Entry 5). Use of a base, for example Et3N, was
necessary to bring about the reaction. It was noted that on
performing the reaction at 0 °C, instead of at room tem-
perature, considerably lower yields was obtained in longer
reaction times. In order to investigate the substrate scope
for generality of the present investigation, a variety of sub-
stituted aldimines 1 and sulfonic acids 2 were used with
the optimized reaction conditions, and different β-sultams
3 were synthesized. In most of the cases, the yields were
consistently good (Table 2) and the highest yield was 93%
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
4-ClPh
4-MeOPh
4-ClPh
4-MeOPh OPh
Ph
CCl3
CCl3
CCl3
CCl3
CCl3
H
H
OPh
4
4.5
5
5
5
4.5
4.5
5
4.5
4
4.5
4.5
5
91
85
87
84
85
88
86
82
89
93
84
82
81
85
84
83
35
42
OPh
Et
nPr
(CH2)2Cl
CH2Ph
Me
Ph
Me
Et
Ph
9
10
11
12
13
14
15
16
17
18
c-C6H11 Ph
c-C6H11 Ph
c-C6H11 Ph
c-C6H11 tBu
c-C6H11 4-MeOPh Ph
nBu
Ts
5
4.5
4.5
5
Ph
nBu
PhCH2
Ph
H
H
CH3
5
[a] See Experimental Section for general procedure. [b] Time re-
(Table 2, Entry 10). However, in the case of imines derived quired for the one-pot procedure. [c] Yield of isolated and purified
products. [d] All compounds gave C, H and N analyses of Ϯ0.39%
from enolizable aldehydes (Table 2, Entries 17 and 18), the
yields were considerably lower probably because of their
and satisfactory spectral (IR, 1H NMR, 13NMR and EI-MS) data.
easy α-deprotonation that leads to several side reactions.
cycloaddition step involves Et3N-mediated attack of the α-
carbon atom of 5 at the azomethine carbon atom of 1, fol-
lowed by an intramolecular SN2 reaction (Scheme 3). The
formation of β-sultams 3 was entirely diastereoselective in
favour of the cis isomer, which conforms with earlier obser-
vations of similar reactions.[16b,21] The cis configuration of
Scheme 2. Preparation of DMF/R2SO4 adducts.
the substituted β-sultams was proved by nuclear overhauser
effect measurements of 3 (Figure 2) along with the J values
The formation of sultam 3 may be tentatively rational- between the protons at C-3 and C-4 (J = 8.5–8.8 Hz), which
ized by initial formation of intermediate sulfene 5, as de- favourably compare with those reported by Enders and
picted in Scheme 3. A formal [2 + 2] cycloaddition of sulf- Moll (8.4 Hz)[6] and Zajac and Peters (7.3–9.1 Hz).[16b]
ene 5 to imine 1 then affords the target β-sultams 3. The However, cis-configured β-lactams typically exhibit a lower
Eur. J. Org. Chem. 2011, 4302–4306
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A. Rai, V. K. Rai, A. K. Singh, L. D. S. Yadav
SHORT COMMUNICATION
Scheme 3. Tentative mechanism for the formation of β-sultams 3.
on a Bruker WM-40 C (400 MHz) FT spectrometer in CDCl3 by
using TMS as internal reference. 13C NMR spectra were recorded
on the same instrument at 100 MHz in CDCl3, and TMS was used
as internal reference. Mass spectra were recorded on a JEOL D-
300 mass spectrometer. Elemental analyses were carried out in a
Coleman automatic carbon, hydrogen and nitrogen analyzer. All
chemicals used were reagent grade and were used as received with-
out further purification. Silica gel-G was used for TLC.
value for the coupling constants (around 5 Hz). The β-sul-
tam ring is more distorted than the β-lactam ring,[11] which
presumably causes a decrease in its outer H–C–C bond
angles and results in the higher J value of the cis-configured
β-sultams than the that for the corresponding β-lactams.
General Procedure for the Synthesis of β-Sultams: A mixture of
N,N-dimethylformamide (1.6 mmol) and dimethyl sulfate
(1.5 mmol) was stirred at 60–80 °C for 2 h. After cooling to room
temperature, the resulting solution was added to a mixture of aldi-
mine 1 (1.0 mmol), sulfonic acid 2 (1.5 mmol) and dry Et3N
(5.0 mmol) in dry THF (4 mL), and the reaction mixture was
stirred for 2–3 h at room temperature. After completion of the reac-
tion, as indicated by TLC, HCl (2 mL of a 10% solution) was
added, and the mixture was stirred well. It was then extracted with
CH2Cl2 (3ϫ5 mL). The combined organic layers were washed with
saturated NaHCO3 (10 mL) followed by brine (10 mL). The or-
ganic phase was dried with anhydrous magnesium sulfate and con-
centrated under reduced pressure to yield the crude product, which
was purified by silica gel column chromatography (EtOAc/hexane)
to give the corresponding β-sultams 3. The structure of the prod-
ucts was confirmed by their elemental and spectral analyses. In case
of known compounds, the data compared favourably with those
reported in the literature.[6,16,20,22]
Figure 2. NOE experiment of 3e.
A strong NOE is observed between the proton at C-3
and that at C-4. The proton at C-3 does not show any NOE
with the protons of substituent at C-4, and the proton at
C-4 shows no NOE with that of the substituent at C-3. This
conclusively demonstrates the cis stereochemistry of the
synthesized β-sultams 3, which is also finally confirmed by
comparison with authentic samples obtained by literature
methods.[6,16,20,22]
A comparison of the results in the case of known com-
pounds (cis-3f–3p) reveals that the present method is gen-
erally superior to the literature methods[16b,20a] in terms of
yield and diastereoselectivity. Furthermore, it requires
shorter times, i.e. 4–5 h compared to 3 d,[20a] and is per-
formed at room temperature instead of at –80 °C.[16b]
Characterization Data of Unknown Compounds 3
3-(4-Chlorophenyl)-2-tosyl-1,2-thiazetidine 1,1-Dioxide (cis-3a):
White solid (0.34 g). Yield: 91%. M.p. 184–186 °C. IR (KBr) ν
˜
max
= 3034, 2934, 1491, 1459, 1442, 1370, 1359, 1350, 1207, 1190, 1179,
1163, 1081, 1020, 905, 820, 815, 794 cm–1. 1H NMR (400 MHz.
CDCl3): δ = 2.40 (s, 3 H, CH3-Ts), 3.97 (dd, J = 8.8 Hz, 2 H, CH2),
5.65 (t, J = 8.8 Hz, 1 H, CH-4-ClC6H4), 7.30 (d, J = 8.1 Hz, 2 H,
Ts), 7.65–7.70 (m, 2 H, 4-Cl-C6H4), 7.72 (d, J = 8.3 Hz, 2 H, Ts),
8.10–8.17 (m, 2 H, 4-Cl-C6H4) ppm. 13C NMR (100 MHz, CDCl3):
δ = 24.2, 50.4, 59.5, 127.8, 128.6, 129.9, 131.2, 133.7, 136.4, 139.8,
142.2 ppm. EIMS: m/z = 371 [M+]. C15H14ClNO4S2 (371.85):
calcd. C 48.45, H 3.79, N 3.77; found C 48.61, H 3.49, N 4.04.
Conclusions
In summary, we have developed a novel, efficient asym-
metric synthesis of cis-2,3,4-trisubstituted β-sultams from
aldimines and sulfonic acids by employing a readily access-
ible DMF/dimethylsulfate adduct under mild conditions in
a one-pot procedure. The protocol offers a convenient alter-
native to highly corrosive and hygroscopic sulfonyl chlo-
rides and would be a practical method for the synthesis of
β-sultams.
3-(4-Methoxyphenyl)-2-tosyl-1,2-thiazetidine 1,1-Dioxide (cis-3b):
White solid (0.31 g). Yield: 85%. M.p. 181–184 °C. IR (KBr) ν
˜
max
= 2950, 2935, 1507, 1374, 1369, 1230, 1191, 1165, 1053, 1030, 934,
814 cm–1. 1H NMR (400 MHz. CDCl3): δ = 2.44 (s, 3 H, CH3-Ts),
3.85 (s, 3 H, CH3O), 3.95 (dd, J = 8.5 Hz, 2 H, CH2), 5.63 (t, J =
8.5 Hz, 1 H, CH-4-CH3OC6H4), 7.31 (d, J = 8.1 Hz, 2 H, Ts), 7.67–
7.69 (m, 2 H, 4-CH3O-C6H4), 7.74 (d, J = 8.2 Hz, 2 H, Ts), 8.01–
8.03 (m, 2 H, 4-CH3O-C6H4) ppm. 13C NMR (100 MHz, CDCl3):
δ = 24.4, 46.5, 55.1, 59.6, 114.1, 127.7, 128.4, 129.9, 135.8, 137.2,
Experimental Section
Melting points were determined by open glass capillary method
and are uncorrected. IR spectra in KBr were recorded on a Perkin–
Elmer 993 IR spectrophotometer, H NMR spectra were recorded
1
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Eur. J. Org. Chem. 2011, 4302–4306

[2 + 2] Annulation of Aldimines with Sulfonic Acids
141.9, 158.2 ppm. EIMS: m/z = 367 [M+]. C16H17NO5S2 (367.43):
calcd. C 52.30, H 4.66, N 3.81; found C 52.07, H 4.82, N 4.06.
Compounds cis-3f–3p are known compounds; their melting points,
1
and IR, H NMR, 13C NMR, and EIMS data compare favourably
with those reported in the literature.[6,16,20,22]
3-(4-Chlorophenyl)-4-phenoxy-2-tosyl-1,2-thiazetidine 1,1-Dioxide
(cis-3c): White solid (0.40 g). Yield: 87%. M.p. 176–178 °C. IR
(KBr) νmax = 3031, 2936, 1494, 1459, 1441, 1378, 1366, 1341, 1209, Acknowledgments
˜
1195, 1171, 1152, 1082, 1021, 914, 816, 809, 798 cm–1. 1H NMR
(400 MHz. CDCl3): δ = 2.46 (s, 3 H, CH3-Ts), 4.93 (d, J = 8.9 Hz,
1 H, CH- C6H5O), 5.65 (d, J = 8.9 Hz, 1 H, CH-4-ClC6H4), 7.32
(d, J = 8.2 Hz, 2 H, Ts), 7.64–7.70 (m, 5 H, C6H5), 7.64–7.69 (m,
2 H, 4-Cl-C6H4), 7.74 (d, J = 8.3 Hz, 2 H, Ts), 8.12–8.16 (m, 2 H,
4-Cl-C6H4) ppm. 13C NMR (100 MHz, CDCl3): δ = 24.5, 51.9,
106.9, 114.8, 120.2, 127.6, 128.7, 129.9, 130.0, 130.8, 131.7, 133.4,
135.3, 141.7, 144.5, 157.8 ppm. EIMS: m/z
C21H18ClNO5S (431.89): calcd. C 54.36, H 3.91, N 3.02; found C
54.75, H 3.70, N 2.83.
We sincerely thank SAIF, Punjab University, Chandigarh, for pro-
viding microanalyses and spectra. A. R. is grateful to the Council
of Scientific and Industrial Research, New Delhi, for the award of
a Research Associateship [CSIR File No. 09/001/(0327)/2010/
EMR-I].
=
463 [M+].
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3-(4-Methoxyphenyl)-4-phenoxy-2-tosyl-1,2-thiazetidine 1,1-Dioxide
(cis-3d): White solid (0.39 g). Yield: 84%. M.p. 179–181 °C. IR
(KBr) νmax = 2954, 2931, 1508, 1374, 1367, 1235, 1199, 1164, 1051,
˜
1
1036, 936, 811 cm–1. H NMR (400 MHz. CDCl3): δ = 2.40 (s, 3
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H, CH3-Ts), 3.89 (s, 3 H, CH3O), 4.95 (d, J = 8.5 Hz, 1 H, CH-
C6H5O), 5.62 (d, J = 8.5 Hz, 1 H, CH-4-CH3OC6H4), 7.34 (d, J =
8.1 Hz, 2 H, Ts), 7.61–7.72 (m, 5 H, C6H5), 7.63–7.70 (m, 2 H, 4-
CH3OC6H4), 7.71 (d, J = 8.3 Hz, 2 H, Ts), 8.09–8.15 (m, 2 H, 4-
CH3OC6H4) ppm. 13C NMR (100 MHz, CDCl3): δ = 24.1, 51.5,
54.2, 106.3, 114.0, 114.9, 121.1, 126.4, 127.2, 128.8, 130.4, 134.9,
136.1, 141.8, 157.2, 158.7 ppm. EIMS: m/z
C22H21NO6S2 (459.53): calcd. C 57.50, H 4.61, N 3.05; found C
57.20, H 5.00, N 2.87.
=
459 [M+].
4-Phenoxy-3-phenyl-2-tosyl-1,2-thiazetidine 1,1-Dioxide (cis-3e):
White solid (0.36 g). Yield: 85%. M.p. 188–189 °C. IR (KBr) ν
˜
max
= 3035, 2935, 1492, 1460, 1371, 1369, 1347, 1208, 1194, 1176, 1154,
1084, 1025, 910, 821, 814, 792 cm–1. 1H NMR (400 MHz. CDCl3):
δ = 2.41 (s, 3 H, CH3-Ts), 4.91 (d, J = 8.7 Hz, 1 H, CH- C6H5O),
5.62 (d, J = 8.7 Hz, 1 H, CHC6H5), 7.33 (d, J = 8.2 Hz, 2 H, Ts),
7.63–7.72 (m, 10 H, C6H5), 7.74 (d, J = 8.2 Hz, 2 H, Ts) ppm. 13C
NMR (100 MHz, CDCl3): δ = 24.3, 51.7, 106.4, 114.1, 120.6, 126.4,
127.1, 128.0, 128.8, 129.7, 130.5, 135.7, 140.8, 143.7, 157.1 ppm.
EIMS: m/z = 429 [M+]. C21H19NO5S2 (429.50): calcd. C 58.72, H
4.46, N 3.26; found C 58.89, H 4.15, N 3.51.
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3-(n-Butyl)-2-tosyl-1,2-thiazetidine 1,1-Dioxide (cis-3q): White solid
(0.11 g). Yield: 35%. M.p. 172–174 °C IR (KBr) νmax = 3032, 2924,
˜
1497, 1461, 1445, 1369, 1357, 1351, 1210, 1190, 1174, 1163, 1085,
1024, 905, 820, 816, 792 cm–1. 1H NMR (400 MHz. CDCl3): δ =
0.91 (t, J = 7.2 Hz, 3 H), 1.37 (m, 2 H), 1.62 (m, 2 H), 2.40 (s, 3
H, CH3-Ts), 2.53 (m, 2 H), 3.97 (dd, J = 8.8 Hz, 2 H, CH2), 5.65
(dt, J = 8.8, 4.8 Hz, 1 H, CH-nBut), 7.30 (d, J = 8.1 Hz, 2 H, Ts),
7.72 (d, J = 8.3 Hz, 2 H, Ts) ppm. 13C NMR (100 MHz, CDCl3):
δ = 14.2, 22.6, 24.9, 26.5, 32.7, 42.1, 55.9, 127.5, 129.6, 136.4,
141.7 ppm. EIMS: m/z = 317 [M+]. C13H19NO4S2 (317.42): calcd.
C 49.19, H 6.03, N 4.41; found C 48.90, H 6.23, N 4.16.
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3-(Benzyl)-2-methyl-1,2-thiazetidine 1,1-Dioxide (cis-3r): White so-
lid (0.08 g). Yield: 42%. M.p. 169–171 °C. IR (KBr) ν
= 3039,
˜
max
2937, 1490, 1455, 1448, 1372, 1354, 1348, 1202, 1195, 1176, 1162,
1084, 1029, 902, 824, 815, 791 cm–1. 1H NMR (400 MHz. CDCl3):
δ = 2.61 (s, 3 H, CH), 2.81 (m, 2 H, CH2C6H5), 3.94 (dd, J =
8.6 Hz, 2 H, CH2), 5.52 (m, 1 H, CH-CH2C6H5), 7.59–7.71 (m, 5
H, C6H5) ppm. 13C NMR (100 MHz, CDCl3): δ = 35.9. 41.9, 54.2,
55.6, 126.4, 128.7, 129.8, 138.1 ppm. EIMS: m/z = 211 [M+).
C10H13NO2S (211.28): calcd. C 56.85, H 6.20, N 6.63; found C
56.54, H 6.44, N 6.83.
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Received: May 4, 2011
Published Online: June 7, 2011
4306
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4302–4306