A simple and one-pot synthesis of β-sultams by using the vilsmeier reagent

Article abstract of DOI:10.1002/jhet.1630

Mild and efficient one-pot synthesis of β-sultams with the Vilsmeier reagent proceeded in good to excellent yield. [2 + 2] Cycloaddition of imines with sulfenes (prepared in situ) afforded the corresponding cis-β-sultams. Optimization of solvents, molar ratio of reagents,and temperature was performed. Toxic and corrosive compounds have been avoided in this novel method.

Full text of DOI:10.1002/jhet.1630

March 2013
A Simple and One-Pot Synthesis of b-Sultams by Using the Vilsmeier
438
Reagent
a
b
*
Maaroof Zarei and Aliasghar Jarrahpour
aDepartment of Chemistry, College of Sciences, Hormozgan University, Bandar Abbas 71961, Iran
bDepartment of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran
*
E-mail: jarrah@susc.ac.ir
Received November 28, 2011
DOI 10.1002/jhet.1630
Published online 29 March 2013 in Wiley Online Library (wileyonlinelibrary.com).
H
Me
Me
Cl
Cl
H H
R2
N
R3
O
R1N=CHR2
R3CH2SO2OH
+
S
N
CH2Cl2, Et3N
0o C to rt
R1
O
Mild and efficient one-pot synthesis of b-sultams with the Vilsmeier reagent proceeded in good to excellent
yield. [2+ 2] Cycloaddition of imines with sulfenes (prepared in situ) afforded the corresponding cis-b-sultams.
Optimization of solvents, molar ratio of reagents,and temperature was performed. Toxic and corrosive
compounds have been avoided in this novel method.
J. Heterocyclic Chem., 50, 438 (2013).
INTRODUCTION
b-Sultams can act as irreversible active-site-directed
inhibitors of elastases such as the human neutrophil elastase
[8], b-lactamase [9], and D,D-peptidase inhibitors [10].
The anti-inflammatory roles of these compounds have also
been reported [11].
The b-sultam ring consists of three different kinds of
hetero single bonds, namely, C–N, C–S, and N–S bonds,
which could be utilized as various synthetic equivalents
as well as building blocks for the construction of other
heterocycles [12].
To synthesize b-sultams, a number of methods has
been developed [13], most notably (a) cyclization of
2-aminosulfonyl halides [14]; (b) cyclization of acti-
vated b-hydroxysulfonamides [15]; (c) cyclization of
a-(halomethylsulfonamido) ketones, esters, or nitriles [16];
(d) [2+ 2] cycloaddition reactions of sulfonylamines with
particularly electron-rich olefins [17]; (e) ring contraction
of five-membered rings of pentafluorophenyl sulfonates
[18]; and (f) [2+ 2] cycloaddition reactions of sulfenes with
imines [19]. Among these methods, a widely used method
is via the [2 + 2] cyclocondensation of nucleophilic imines
and sulfenes.
The sulfonamide moiety has long been established to
display biological activity and, as such, is widely found in
molecules of medicinal interest, particularly antibacterial
agents [1]. It is generally assumed that the antibacterial
activity of b-lactam antibiotics depends on the stability and
reactivity of the four-membered ring [2]. Replacement of
the carbonyl group in b-lactams 1 by the sulphonyl group
results in 1,2-thiazetidine-1,l-dioxides (b-sultams). b-Sultams
2 are regarded as sulfonyl analogs of b-lactam antibiotics as
well as cyclic derivatives of taurine 3 (2-aminoethanesulfonic
acid). Taurine, which is present in mammals, shows various
biological activities [3].
Their reactivity is usually higher compared with the
analogous b-lactam systems (approx. 103-fold) [4] and at
least 107-fold more reactive than acyclic sulfonamides [5].
b-Lactams are stabilized by the p-bond overlap between
the lone-pair electrons of the nitrogen atom and the carbonyl
group and are much more stable than b-sultams. The overlap
between the nitrogen lone-pair electrons and the sulfonyl
group in b-sultams is much less compared with the stabiliza-
tion of the b-lactam ring [6]. In addition, b-sultams are desta-
bilized by the increased distortion of the b-sultam ring
because of the C–S and N–S bonds, which are longer than
the corresponding C–C and C–N bonds of the b-lactam ring
[7]. Therefore, b-sultams are important subunits for chemical
and pharmaceutical applications.
Sulfenes 4 are molecules of the formula RR0C═SO2 and
may be regarded either as the sulfonyl analogs of ketenes
5, although sulfenes are far less stable than ketenes [20],
or as derivatives of sulfur trioxide formally obtained by
replacement of one oxygen atom by a CRR0 group [21].
Sulfenes are formed by elimination of HCI from primary
sulfonyl chlorides in the presence of a base [22], reaction
of diazoalkanes with sulfur dioxide [23], thermolysis and
photolysis of appropriate compounds [24], and elimination
of nitrogen from a-diazosulfones [25]. Generally, sulfonyl
chlorides are used as precursor of sulfenes in the synthesis
© 2013 HeteroCorporation

March 2013
A Simple and One-Pot Synthesis of b-Sultams by Using the Vilsmeier Reagent
439
Table 1
of b-sultams, but sulfonyl chlorides are highly corrosive
and hygroscopic.
Reaction condition in the synthesis of b-sultam 9a.
We utilized alkoxymethylene-N,N-dimethyliminium salts
as acid activators in the synthesis of 2-azetidinone ring by
the ketene-imine cycloaddition [26]. In a recent communica-
tion, Yadav and co-workers used this reagent in the synthesis
of b-sultams from imines with sulfonic acids [27].
Previously, we reported the synthesis of 2-azetidinone from
imines and carboxylic acids via the Vilsmeier reagent
((chloromethylene)dimethylammonium chloride) [28]. The
Vilsmeier reagent 6 was easily prepared from DMF and oxalyl
chloride or thionyl chloride in dry CH2Cl2 [28], although it is
commercially available [29]. The Vilsmeier reagent, unlike
alkoxymethylene-N,N-dimethyliminium salt, does not need
the toxic Me2SO4. Also, it was obtained as white solid and
can be kept for a long time by storage in a well-capped bottle.
According to the earlier reports, in this letter, we describe
the versatility and utility of the Vilsmeier reagent in the one-
pot synthesis of b-sultams from imines and sulfonic acids
under simple and mild conditions.
Temperature
(ꢁC)
Reagent
(equiv.)
Yield
(%)
Entry Solvent
1
2
THF
1,4-
RT
RT
1.5
1.5
73
56
Dioxane
CH2Cl2
DMF
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
3
4
5
6
7
8
RT
RT
RT
0
1.5
1.5
1.5
1.5
1.5
1.3
80
40
51
94
92
78
ꢀ15
0
dichloromethane at 0ꢁC (Scheme 1, Table 2). Then, the mix-
tures were stirred overnight at room temperature. The b-sul-
tams 9a–k were obtained with complete cis-selectivity by
mild and simple reactions, and by-products (DMF and salts)
were removed by a simple aqueous work-up. The purifica-
tion of b-sultams was performed by short-column chroma-
tography on silica gel (EtOAc/hexane 3:7), and all products
were characterized by their spectral data and elemental
analyses.
The data in Table 2 indicate that the yields are decreased
when ethanesulfonic acid was used as a source of sulfene
(Entries 2, 4, and 6). This may be due to lower stability of
alkyl sulfenes than those corresponding to the aryl sulfenes.
The mechanism of b-sultam formation is a [2 + 2] cyclo-
addition reaction in which the nucleophilic imine attacks
the electrophilic sulfene [13b,19]. The sulfene was prepared
in situ by reaction of sulfonic acid and the Vilsmeier reagent
6 in the presence of triethylamine (Scheme 2).
RESULTS AND DISCUSSION
Treatment of imine 7a with phenylmethanesulfonic acid
8a and the Vilsmeier reagent 6 in dry dichloromethane at
room temperature in the presence of triethylamine afforded
b-sultam 9a. After purification by short-column chroma-
tography, the pure cis-b-sultam was obtained in high yield.
Indication of stereochemistry of the b-sultam 9a was
deduced from the coupling constant of H-3 and H-4, which
were calculated to be J = 8.6 Hz for the cis-stereoisomer.
The b-sultam ring is more distorted than the b-lactam ring,
which presumably causes a decrease in its outer H–C–C
bond angles and results in the higher J value of the cis-
configured b-sultams than the corresponding b-lactams [27].
As part of the efforts to arrive at the optimal set of
reaction parameters and choice of appropriate conditions,
we considered the effect of solvents, temperature, and mole
ratio of the reagents (Table 1).
As shown in Table 1 among the solvents considered,
dichloromethane showed the best result. When the reaction
started at 0 or ꢀ15ꢁC and then stirred overnight at room
temperature, the yield of 9a increased perhaps because of
low stability of sulfenes (Entries 6 and 7). It was found that
1.5 equiv. of the Vilsmeier reagent 6 was needed for the
complete disappearing of imine 7.
In conclusion, the use of the Vilsmeier reagent for the
one-pot synthesis of b-sultams from imines and sulfonic
acids under mild conditions has been reported. The method
is simple and versatile. The solvents, molar ratio of
reagent, and temperature have been optimized.
Scheme 1
On the basis of these successful results, b-sultams 9a–k
were synthesized by treatment of 1.0 mmol of imines,
1.5 mmol of corresponding sulfonic acids, and 1.5 mmol
of reagent 6 in the presence of triethylamine in dry
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

440
M. Zarei and A. Jarrahpour
Vol 50
4.91 (H-3, d, 1H, J = 8.6 Hz), 6.71–8.12 (ArH, m, 13H); 13C
NMR (62.9 MHz, CDCl3) d 55.3 (OMe), 55.9 (C-3), 56.5
(C-4), 116.3, 117.8, 119.0, 123.9, 125.0, 128.5, 129.2, 129.9,
135.7, 141.4, 143.8, 154.6 (aromatic carbons). Anal. Calcd for
C21H18N2O5S: C, 61.45; H, 4.42; N, 6.83. Found: C, 61.53; H,
4.55; N, 6.88.
Table 2
Synthesis of b-sultams 9a–k by reagent 6.
Isolated yield
(%)
Entry
R1
R2
R3
Product
1
2
3
4
5
6
7
8
4-MeOC6H4 4-NO2C6H4
4-MeOC6H4 4-NO2C6H4
Ph
Me
Ph
Me
Ph
Me
Ph
Ph
Ph
Ph
Ph
9a
9b
9c
9d
9e
9f
9g
9h
9i
93
67
88
65
92
72
86
88
85
84
90
4-Methyl-2-(p-methoxyphenyl)-3-(p-nitrophenyl)-1,2-thiazetidine-
1,1-dioxide (9b). White solid; mp: 138–140ꢁC. IR (KBr) cmꢀ1
:
c-C6H11
c-C6H11
c-C6H11
c-C6H11
Me
4-MeC6H4
4-MeC6H4
4-ClC6H4
4-ClC6H4
4-NO2C6H4
Ph
4-MeOC6H4
4-NO2C6H4
Ph
1133, 1318 (SO2), 1332, 1528 (NO2). 1H NMR (250 MHz,
CDCl3) d 1.14 (Me, d, 3H, J = 7.1 Hz), 3.66 (OMe, s, 3H), 4.45
(H-4, dq, 1H, J = 7.1, 8.8 Hz), 4.84 (H-3, d, 1H, J = 8.8 Hz), 6.84–
3
8.07 (ArH, m, 8H); C NMR (62.9MHz, CDCl3) d 12.7 (Me),
Me
Me
Me
55.5 (OMe), 55.8 (C-4), 56.2 (C-3), 117.1, 118.5, 122.4, 123.9,
126.2, 128.5, 140.8, 152.4 (aromatic carbons). Anal. Calcd for
C16H16N2O5S: C, 55.16; H, 4.63; N, 8.04. Found: C, 55.26; H,
4.76; N, 7.97.
9
10
11
9j
9k
PhCH2
Acknowledgment. The authors thank the Shiraz University
Research Council for the financial support (Grant no. 90-GR-SC-23).
EXPERIMENTAL
All needed chemicals were purchased from Merck, Fluka, and
Acros chemical companies. IR spectra were run on a Shimadzu
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FT-IR 8300 spectrophotometer. H NMR and 13C NMR spectra
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DOI 10.1002/jhet

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