An unprecedented synthesis of γ-lactams via mercaptoacetylation of aziridines in water

Article abstract of DOI:10.1039/c0gc00899k

A highly green and expeditious route to α-mercapto-γ-lactams from masked mercapto acids viz. 2-phenyl-2-methyl-1,3-oxathiolan-5-ones, and tosyl aziridines in an excellent yield (82-93%) is reported. The synthetic protocol involves regioselective opening of the terminal aziridine ring and mercaptoacetylative cyclisation cascades in a one-pot procedure wherein water acts as both a catalyst as well as a solvent. These reactions were carried out in aqueous media as well as under solvent-free conditions, however, under solvent-free conditions, lower yields are obtained.

Full text of DOI:10.1039/c0gc00899k

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Green Chemistry
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PAPER
An unprecedented synthesis of c-lactams via mercaptoacetylation of
aziridines in water
Vijai K. Rai,*a Prashant Kumar Rai,b Swati Bajaja and Anil Kumara
Received 8th December 2010, Accepted 14th February 2011
DOI: 10.1039/c0gc00899k
A highly green and expeditious route to a-mercapto-g-lactams from masked mercapto acids viz.
2-phenyl-2-methyl-1,3-oxathiolan-5-ones, and tosyl aziridines in an excellent yield (82–93%) is
reported. The synthetic protocol involves regioselective opening of the terminal aziridine ring and
mercaptoacetylative cyclisation cascades in a one-pot procedure wherein water acts as both a
catalyst as well as a solvent. These reactions were carried out in aqueous media as well as under
solvent-free conditions, however, under solvent-free conditions, lower yields are obtained.
reaction of glycine equivalents,15 Heck–Matsuda arylation,16
Introduction
N-alkenyl-a-PhSe-b-ketoamides,2 a-aminonitriles,17 3-aryl-2-
Since the pioneering studies by Breslow,1 organic reactions in
water have gained tremendous importance because of their green
diethoxyphosphoryl-4-nitroalkanoates,18 vinyl sulfonium salts,19
Baylis–Hillman acetates20 and cyclisation of N-alkyl and N,N-
chemistry perspective. g-Lactam motifs are ubiquitous in the
natural product arena and in pharmaceuticals with interesting
biological activities.2 Many g-lactam-based pharmaceutical in-
gredients have been approved for potential treatment toward
many common diseases such as hepatitis, diabetes, and cancers.3
From a chemical viewpoint, they are important intermediates in
the synthesis of five-membered heterocycles viz. pyrazole4 and
are also excellent precursors for the synthesis of biologically
active pyrrolidine derivatives such as (+)-a-allokainic acid
and its analogue (-)-a-kainic acid.5 Especially, a-substituted-
g-lactams are used in the synthesis of (-)-nakadomarin A,6
a marine alkaloid. Furthermore, pyrrolidin-2-ones have been
widely used as monomers in the assembly of polymers with
semiconducting properties.7 The presence of a thiol function
in many enzymes, called –SH enzymes, is essential for their
enzyme activity. Likewise, incorporation of a thiol function in
heterocycles, nucleosides, or nucleotides has led to a number
of analogues possessing interesting biological and therapeutic
properties.8
dimethyl amides.21,22 However, these methods are in disagree-
ment with green chemistry and suffer from one or more
disadvantages, such as the use of hazardous solvents, a tedious
work-up, high cost, need for a large amount of catalyst or a
special treatment for its activation, they are not time efficient
and tend to be lengthy and cumbersome if the lactam contains
any sort of substitution. Although the literature records a few
reports on the synthesis of b-mercapto-g-lactams,23,24 no effort
has been made to synthesise a-mercapto-g-lactams, although
they appear to be attractive scaffolds for exploiting chemical
diversity and generating a drug-like library to screen for lead
candidates.
Due to ring strain, the chemistry of aziridines is mainly
dominated by nucleophilic ring-opening reactions and this
strategy has been well utilised for the stereoselective synthesis of
N-containing molecules.25 In this context, Bad´ıa and coworkers
have reported the synthesis of g-lactams via regioselective ring
opening of aziridines with enolates (Scheme 1).26 Keeping the
synthetic and pharmacological importance of the –SH group
and Scheme 1 in mind, we turned our attention to utilize such a
type of substituted enolisable substrates, which can introduce
–SH groups at the a position into g-lactams, which are the
target molecules in the present investigation. For this purpose
we utilised masked mercaptoacetic acid, as given in Fig. 1.
Numerous methods for the synthesis of differently substituted
g-lactams are reported, which include sequential allylation of
imines with 2-alkoxycarbonyl alkylboronates and cyclisation,9
ring expansion of b-lactams,10 cyclisation of enamides,11 nitro-
Mannich/lactamisation cascades of 3-nitropropanoate with
imines,12 reductive amination-lactamisation of piperidine and
g-amino esters,13 cyclisation of N-benzylidenamide,14 Michael
Results and discussion
At the outset, we tried mercaptoacetic acid for the mercap-
toacetylation of aziridines 2, but were not successful, probably
due to the presence of free –COOH and –SH groups. Instead,
we turned our attention to block the –COOH and –SH groups
aSchool of Biology & Chemistry, Shri Mata Vaishno Devi University,
Katra, J & K, 182 320, India. E-mail: vijaikrai@hotmail.com
bDepartment of Chemical Technology, University of Johannesburg,
Doornfontien, 2028, Johannesburg, South Africa
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Table 1 Microwave (MW) assisted synthesis of 3a
MW
Entry
Catalyst system
Time (min)a
Yield (%)b
1
2
3
4
5
6
K-10 clay
12
15
13
18
20
20
57
43
51
24
11
17
CeCl3·7H2O
CeCl3·7H2O/NaI
Silica gel
Neutral alumina
Acidic alumina
a Time for the completion of the reaction at 90 ◦C as indicated by TLC.
b Yield of isolated and purified product 3a.
Scheme 1 The synthesis of g-lactams via aziridine ring opening.
these in water for 3.5 h and we successfully isolated the
corresponding lactam 3a in 90% yield (Table 2, entry 1). For
comparison purposes, the model experiment was also carried
out at 90 ◦C in a microwave (Chemical Laboratory Microwave
Oven, Model; BP-310/50, 230 volt, 50 Hz power input), but
the reaction did not occur in the absence of a catalyst. With
the aim to establish its solvent-free version and to compare the
synthetic efficiency, we have examined various mineral catalysts
for the formation of 3a at 90 ◦C. Among the catalysts tested, K-
10 clay gave the best result (Table 1, entry 1). CeCl3·7H2O and
a CeCl3·7H2O/NaI-system afforded the product 3a in moderate
to good yields, while poor yields of product 3a were obtained
in the case of silica gel and neutral or acidic alumina (Table 1).
Moreover, the reaction did not take place using basic alumina.
Thus, It was observed that a significantly lower yield of 3a was
obtained in the solvent-free version rather than its catalyst-free
aqueous medium version. Therefore, we relied upon water, which
not only acts as the solvent but also catalyses the reaction, in the
present investigation.
The current optimised synthesis is accomplished by refluxing
an equimolar mixture of aziridines 2 and 2-methyl-2-phenyl-
1,3-oxathiolan-5-ones 1 in water for 3–4 h (Table 2). The
isolation and purification steps are very simple and performed by
filtration with a Buchner funnel, followed by washing with water
(2 ¥ 10 mL) and recrystallization from EtOH. After isolation
of the product, the aqueous layer was extracted with EtOAc
(3 ¥ 10 mL) and acetophenone was easily collected from the
organic phase. For the general validity of the reaction, several
structurally varied aromatic and aliphatic aziridines 2 were
used, employing the present optimized reaction conditions to
afford the corresponding g-lactams 3 in good to excellent yields
summarized in Table 2. Furthermore, attempts to employ the
more sterically hindered 2,4-dimethyl-2-phenyl-1,3-oxathiolan-
5-one in place of 1 failed to produce the desired g-lactone
3¢ under similar reaction conditions, rather we isolated the
corresponding intermediate 5 (Scheme 4). In this case perhaps,
water catalysed only the aziridine ring opening step and failed
to cyclize intermediate 5 into the corresponding g-lactone 3¢.
In case of aziridines, the regioselective ring opening followed
either electronic or kinetic control, giving different compounds.
There are several reports of aziridine ring opening where
nucleophilic attack took place on the benzylic carbon following
electronic control. But, when the steric factor predominates over
kinetic control, the nucleophile prefers to attack on the terminal
carbon rather than the benzylic carbon.25 Herein, presumably
Fig. 1 The substrate designed for introducing mercapto functional
groups into g-lactams.
of mercaptoacetic acid and thus activate its methylene group by
converting it into a 1,3-oxathiolan-5-one moiety. In this regard,
we examined various aldehydes and ketones, viz., acetaldehyde,
acetone and acetophenone using LiBr in neat conditions.
Amongst these, acetophenone afforded the desired product in
excellent yield,27 while the reaction did not take place using
acetone and acetaldehyde. Thus, we relied upon acetophenone
and converted mercaptoacetic acid to 2-methyl-2-phenyl-1,3-
oxathiolan-5-one 1 (Scheme 2).27 Compound 1 not only acts as
a mercaptoacetyl transfer agent for the synthesis of a-mercapto
acids, but also provides a completely new route to a-mercapto-
g-lactams and is the cornerstone of our approach, presenting
its novel utility in g-lactam chemistry (Scheme 3). Furthermore,
the envisaged synthetic protocol is in continuation of our efforts
for developing new synthetic routes,28 especially using green
chemistry protocols.29
Scheme 2 The formation of the mercaptoacetyl transfer agent, 2-
methyl-2-phenyl-1,3-oxathiolan-5-one 1.
Scheme 3 The disconnection approach for targeting a-mercapto-g-
lactams.
We estimated the reactivity of aziridine 2a (2 mmol) and
2-methyl-2-phenyl-1,3-oxathiolan-5-one (2 mmol) by refluxing
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Table 2 One-step synthesis of a-mercapto-g-lactam 3 in water
Entry
1
Masked acid 1
Aziridine 2
Reaction time (h)a
g-Lactam 3
Yield (%)b,c
90
1
3.5
2
1
4
91
3
4
5
6
7
1
1
1
1
1
3
89
93
82
88
92
3
3.5
3.5
4
8
1
1
1
3.5
92
86
91
9
3
10
3.5
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Table 2 (Contd.)
Entry
11
Masked acid 1
Aziridine 2
Reaction time (h)a
4
g-Lactam 3
Yield (%)b,c
93
1
12
1
3.5
88
a Refluxing time in water. b Yield of isolated and purified products. c All compounds gave C, H and N analyses within 0.37%, and satisfactory
spectral (IR, 1H NMR, 13C NMR and EIMS) data.
carbon (C-5) of the oxathiolan-5-one moiety to yield target
compounds 3 with the elimination of acetophenone (Scheme
5), which was easily recovered and reused for the preparation
of the mercaptoacetyl transfer agent, 2-methyl-2-phenyl-1,3-
oxathiolan-5-one 1, by treatment with LiBr and mercaptoacetic
acid as depicted in Scheme 2. This conclusion is based on the
observation that the representative intermediate compounds 4a
(R = Ph), 4e (R = 4-ClC6H4) and 4j (R = 3-ClC6H4) could be
isolated in 46–51% yield, these could then be converted into the
corresponding lactones 3a, 3e and 3j in quantitative yields, and
Scheme 4 The use of masked 2-mercaptopropionic acid.
acetophenone was formed during the reaction (Scheme 5). Since
no product was formed upon MW irradiation of compound 1
and aziridine 2 without using a catalyst, it may be speculated that
the role of water is a catalyst in the present synthetic protocol.
Thus, the role of water in the envisaged synthetic protocol is not
only as a solvent but it also catalyses the reaction. Presumably, H-
bonding of H2O with the aziridine nitrogen renders the aziridine
ring more susceptible to nucleophilic attack. Furthermore, H2O
also may help in the enolization of 1 by hydrogen bonding with
the OH of 1¢ and thus increasing the nucleophilic character
due to the bulky nature of the attacking nucleophile, the steric
factor predominates over the electronic effect.
Thus, formation of 3 can be rationalized by nucleophilic
attack of the active methylene carbon (C-4) of 1 on to the less-
substituted carbon of tosyl aziridine 2 regioselectively, followed
by protonation of the aziridine nitrogen leading to intermediate
4. The adduct 4 undergoes intramolecular nucleophilic attack
of the nitrogen atom of the NHTs group at the carbonyl
Scheme 5 A plausible mechanism for the formation of g-lactams 3.
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of the methylene carbon (C-4) of 1. Therefore, water activates
both the steps, i.e. the nucleophilic opening of aziridines and
the mercaptoacetylative cyclization, in the envisaged synthetic
strategy (Scheme 5).
cooled to room temperature, filtered with a Buchner funnel
and washed with water (3 ¥ 10 mL). The crude product 3 thus
obtained was recrystallized from EtOH to afford an analytically
pure sample of 3. The acetophenone was extracted from aqueous
solution.
The reactions were clean and all the synthesised products
were characterized by their 1H NMR, 13C NMR, IR and mass
spectroscopic data. It was gratifying to find that the formation
of lactams 3 was entirely diastereoselective in favour of the cis
isomer. The cis stereochemistry of lactams 3 was assigned on the
basis of the J value of the 5-H peak and the literature precedent,30
J5-H,4-H = 7.0–7.3 Hz, J5-H,4-H = 6.8–6.9 Hz. Furthermore, the
3a. Colourless solid (Found: C, 58.46; H, 5.11; N, 4.21%.
C17H17NO3S2 requires C, 58.77; H, 4.93; N, 4.03%); mp 85–
87 ◦C (from EtOH); nmax(KBr)/cm-1 3021, 2925, 2551, 1708,
1605, 1583, and 1455; dH(400 MHz; DMSO-d6/TMS) 1.59 (1
H, d, J 7.7 Hz), 2.28 (3 H, s), 2.83 (1 H, ddd, J 11.4, 7.1, 4.9
Hz), 2.92 (1 H, ddd, J 11.4, 9.2, 6.9 Hz), 3.65 (1 H, ddd, J 9.2,
a
b
relative stereochemistry of lactams 3 was also established by
NOE observations (Fig. 2). The strong NOE at 3-H/5-H upon
irradiation of Ha indicates that 4-Ha and 3-H/5-H are located
on the same face of the molecule, that is, lactams 3 have 3,5-cis
configurations (Fig. 2).
7.7, 4.9 Hz), 4.97 (1 H, dd, J 7.1, 6.9 Hz) and 7.11–7.45 (9 Harom
,
m); dC(100 MHz; DMSO-d6/TMS) 25.5, 35.3, 41.3, 50.2, 126.5,
127.8, 129.5, 130.2, 131.2, 132.0, 133.1, 133.9 and 178.2; (m/z)
347 (M+).
3b. Colourless solid (Found: C, 59.52; H, 5.03; N, 3.95%.
C18H19NO3S2 requires C, 59.81; H, 5.30; N, 3.87%); mp 128–
◦
130 C (from EtOH); nmax(KBr)/cm-1 3025, 2929, 2555, 1705,
1603, 1585, and 1457; dH(400 MHz; DMSO-d6/TMS) 1.62 (1 H,
d, J 7.5 Hz), 2.31 (3 H, s), 2.37 (3 H, s), 2.81 (1 H, ddd, J 11.2,
7.3, 5.1 Hz), 2.94 (1 H, ddd, J 11.2, 9.3, 6.8 Hz), 3.61 (1 H, ddd,
J 9.3, 7.5, 5.1 Hz), 4.98 (1 H, dd, J 7.3, 6.8 Hz) and 7.19–7.61 (8
Harom, m); dC(100 MHz; DMSO-d6/TMS) 25.8, 26.5, 35.8, 41.8,
50.7, 125.5, 126.7, 127.8, 128.3, 129.5, 130.8, 131.7, 133.0 and
177.9; (m/z) 361 (M+).
Fig. 2 NOE observations of g-lactams 3.
3c. Colourless solid (Found: C, 57.49; H, 4.88; N, 3.53%.
Conclusions
C18H19NO4S2 requires C, 57.27; H, 5.07; N, 3.71%); mp 146–
◦
In summary, our work offers a general, efficient and green
method for the preparation of synthetically and pharmaceu-
tically important a-mercapto-g-lactams, adopting the stringent
and growing environmental regulations of green chemistry. The
envisaged synthetic protocol opens up a new conceptual aspect
for pyrrolidine chemistry.
148 C (from EtOH); nmax(KBr)/cm-1 3021, 2928, 2556, 1702,
1607, 1581, and 1451; dH(400 MHz; DMSO-d6/TMS) 1.57 (1
H, d, J 7.6 Hz), 2.29 (3 H, s), 2.85 (1 H, ddd, J 11.2, 7.0, 5.0 Hz),
2.91 (1 H, ddd, J 11.1, 9.1, 6.8 Hz), 3.62 (1 H, ddd, J 9.1, 7.6,
5.0 Hz), 3.69 (3 H, s), 5.01 (1 H, dd, J 7.0, 6.8 Hz), 7.19–7.35
(6 Harom, m) and 7.51–7.73 (2 Harom, m); dC(100 MHz; DMSO-
d6/TMS) 25.2, 35.5, 53.5, 41.5, 50.6, 125.3, 125.9, 127.1, 127.7,
129.2, 129.9, 131.2, 132.3 and 178.5; (m/z) 377 (M+).
Experimental
General
3d. Colourless solid (Found: C, 52.31; H, 3.81; N, 6.77%.
C17H16N2O5S2 requires C, 52.03; H, 4.11; N, 7.14%); mp 105–
Melting points were determined by the open glass capillary
method and are uncorrected. IR spectra in KBr were recorded
on a Perkin–Elmer 993 IR spectrophotometer. 1H NMR
spectra were recorded on a Bruker WM-40 C (400 MHz)
FT spectrometer in DMSO-d6 using TMS as an internal
reference. 13C NMR spectra were recorded on the same in-
strument at 100 MHz in DMSO-d6 and TMS was used as
an internal reference. Mass (EI) spectra were recorded on
a JEOL D-300 mass spectrometer. Elemental analyses were
carried out in a Coleman automatic carbon, hydrogen and
nitrogen analyzer. A Chemical Laboratory Microwave Oven
(Model; BP-310/50, 230 volt, 50 Hz power input) was used.
All chemicals used were reagent grade and were used as
received without further purification. Silica gel-G was used for
TLC.
◦
107 C (from EtOH); nmax(KBr)/cm-1 3023, 2925, 2553, 1704,
1602, 1579, and 1453; dH(400 MHz; DMSO-d6/TMS) 1.56 (1
H, d, J 7.7 Hz), 2.28 (3 H, s), 2.81 (1 H, ddd, J 11.5, 7.1, 5.2
Hz), 2.91 (1 H, ddd, J 11.5, 9.2, 6.7 Hz), 3.61 (1 H, ddd, J 9.2,
7.7, 5.2 Hz), 5.07 (1 H, dd, J 7.1, 6.7 Hz), 7.22–7.59 (6 Harom
,
m) and 7.71–7.89 (2 Harom, m); dC(100 MHz; DMSO-d6/TMS)
25.1, 35.5, 41.2, 50.2, 126.1, 126.7, 127.3, 128.8, 129.6, 130.5,
131.2, 132.5 and 178.3; (m/z) 392 (M+).
3e. Colourless solid (Found: C, 53.68; H, 4.31; N, 3.51%.
C17H16ClNO3S2 requires C, 53.47; H, 4.22; N, 3.67%); mp 118–
◦
120 C (from EtOH); nmax(KBr)/cm-1 3019, 2923, 2549, 1702,
1599, 1581, and 1452; dH(400 MHz; DMSO-d6/TMS) 1.63 (1
H, d, J 7.9 Hz), 2.32 (3 H, s), 2.80 (1 H, ddd, J 11.3, 7.1, 5.3
Hz), 2.92 (1 H, ddd, J 11.3, 9.2, 6.8 Hz), 3.63 (1 H, ddd, J 9.2,
a-Mercapto-c-lactam (3). 2-Methyl-2-phenyl-1,3-oxathio-
lan-5-one 1 (2 mmol) and tosyl aziridine 2 (2 mmol) were mixed
in 20 mL water and refluxed for 3–4 h (Table 2). After completion
of the reaction (monitored by TLC), the reaction mixture was
7.9, 5.3 Hz), 5.05 (1 H, dd, J 7.1, 6.8 Hz), 7.29–7.51 (6 Harom,
m) and 7.69–7.85 (2 Harom, m); dC(100 MHz; DMSO-d6/TMS)
25.5, 36.6, 41.6, 50.9, 125.8, 126.7, 127.5, 128.3, 130.1, 130.7,
131.5, 132.3 and 177.5; (m/z) 381, 383 (M, M + 2).
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3f. Colourless solid (Found: C, 48.26; H, 3.49; N, 3.03%.
C17H16BrNO3S2 requires C, 47.89; H, 3.78; N, 3.29%); mp 89–
90 ◦C (from EtOH); nmax(KBr)/cm-1 3017, 2921, 2551, 1701,
1608, 1588, and 1455; dH(400 MHz; DMSO-d6/TMS) 1.58 (1
H, d, J 7.8 Hz), 2.30 (3 H, s), 2.78 (1 H, ddd, J 11.3, 7.0, 4.8
Hz), 2.90 (1 H, ddd, J 11.3, 9.1, 6.9 Hz), 3.62 (1 H, ddd, J 9.1,
4.7 Hz), 5.04 (1 H, dd, J 7.3, 6.9 Hz) and 7.29–7.69 (11 Harom,
m); dC(100 MHz; DMSO-d6/TMS) 25.3, 36.3, 40.8, 51.5, 124.7,
125.5, 126.1, 126.9, 127.6, 128.3, 129.0, 129.7, 130.8, 132.7 and
177.8; (m/z) 397 (M+).
3l. Colourless solid (Found: C, 50.67; H, 5.21; N, 5.26%.
C12H15NO3S2 requires C, 50.50; H, 5.30; N, 4.91%); mp 152–
7.8, 4.8 Hz), 4.99 (1 H, dd, J 7.0, 6.9 Hz), 7.25–7.56 (6 Harom
,
◦
154 C (from EtOH); nmax(KBr)/cm-1 3022, 2926, 2551, 1703,
m) and 7.73–7.83 (2 Harom, m); dC(100 MHz; DMSO-d6/TMS)
25.2, 35.9, 41.5, 51.3, 126.2, 127.1, 127.8, 128.6, 129.3, 129.9,
130.6, 131.8 and 177.6; (m/z) 427 (M+).
1608, 1586, and 1459; dH(400 MHz; DMSO-d6/TMS) 1.61 (1
H, d, J 7.7 Hz), 1.90 (3 H, d, J 5.6 Hz), 2.31 (3 H, s), 2.86 (1 H,
ddd, J 11.2, 7.2, 4.8 Hz), 2.94 (1 H, ddd, J 11.2, 9.2, 6.9 Hz), 3.62
(1 H, ddd, J 9.2, 7.7, 4.8 Hz), 5.04 (1 H, m), 7.37–7.51 and (4
Harom, m); dC(100 MHz; DMSO-d6/TMS) 25.5, 26.7, 36.1, 41.7,
50.7, 126.5, 127.9, 129.8, 130.5 and 178.1; (m/z) 285 (M+).
3g. Colourless solid (Found: C, 55.66; H, 4.69; N, 3.58%.
C17H16FNO3S2 requires C, 55.87; H, 4.41; N, 3.83%); mp 93–
94 ◦C (from EtOH); nmax(KBr)/cm-1 3019, 2920, 2555, 1707,
1605, 1580 and 1452; dH(400 MHz; DMSO-d6/TMS) 1.59 (1
H, d, J 7.5 Hz), 2.30 (3 H, s), 2.81 (1 H, ddd, J 11.2, 7.1, 4.9
Hz), 2.95 (1 H, ddd, J 11.2, 9.3, 6.8 Hz), 3.67 (1 H, ddd, J 9.3,
Isolation of 4a (R = Ph), 4e (R = 4-Cl) and 4j (R = 3-Cl) and
their cyclisation into c-lactams 3a, 3e and 3j. The procedure
followed was the same as described above for the synthesis of 3,
except that the refluxing time in this case was only 75 min instead
of the 3–4 h used for 3. The adducts 4 were recrystallised from
ethanol to give an analytical sample of 4a, 4e and 4j. Finally,
these intermediates were refluxed in water for 2–3 h to give the
corresponding cyclized products 3a, 3e and 3j, quantitatively.
7.5, 4.9 Hz), 4.96 (1 H, dd, J 7.1, 6.8 Hz), 7.21–7.58 (6 Harom
,
m) and 7.79–7.87 (2 Harom, m); dC(100 MHz; DMSO-d6/TMS)
25.1, 37.1, 41.7, 51.5, 125.5, 126.7, 127.5, 128.4, 129.1, 129.7,
130.5, 132.7 and 178.2; (m/z) 365 (M+).
3h. Colourless solid (Found: C, 58.32; H, 5.29; N, 3.45%.
C19H19NO4S2 requires C, 58.59; H, 4.92; N, 3.60%); mp 121–
4a. Colourless solid (Found: C, 64.49; H, 5.21; N, 3.31%.
C25H25NO4S2 requires C, 64.21; H, 5.39; N, 3.00%); mp 96–
98 ◦C (from EtOH); nmax(KBr)/cm-1 3289, 3018, 2928, 1761,
1602, 1585 and 1451; dH(400 MHz; DMSO-d6/TMS) 2.12 (3 H,
s), 2.38 (3 H, s), 2.72–2.78 (2 H, m), 3.41 (1 H, dd, J 8.7, 4.9
◦
123 C (from EtOH); nmax(KBr)/cm-1 3022, 2928, 2552, 1708,
1602, 1585 and 1458; dH(400 MHz; DMSO-d6/TMS) 1.56 (1
H, d, J 7.7 Hz), 2.28 (3 H, s), 2.41 (3 H, s), 2.80 (1 H, ddd, J
11.1, 7.2, 4.9 Hz), 2.93 (1 H, ddd, J 11.1, 9.4, 6.8 Hz), 3.67 (1 H,
ddd, J 9.4, 7.7, 4.9 Hz), 5.11 (1 H, dd, J 7.2, 6.8 Hz), 7.31–7.58
(6 Harom, m) and 7.79–7.83 (2 Harom, m); dC(100 MHz; DMSO-
d6/TMS) 24.7, 25.5, 36.5, 41.6, 51.0, 126.2, 126.8, 127.6, 128.5,
129.7, 130.5, 131.2, 132.9, 177.3 and 178.1; (m/z) 389.
Hz), 3.81 (1 H, m), 5.21 (1 H, br, s) and 7.21–7.81 (14 Harom
,
m); dC(100 MHz; DMSO-d6/TMS) 24.8, 25.3, 38.5, 48.3, 52.5,
78.1, 123.8, 124.5, 125.3, 125.9, 126.8, 127.5, 128.3, 129.0, 129.6,
130.5, 131.9, 133.4 and 185.2; (m/z) 467 (M+).
3i. Colourless solid (Found: C, 47.67; H, 3.93; N, 3.36%.
4e. Colourless solid (Found: C, 59.96; H, 5.21; N, 2.58%.
C17H16BrNO3S2 requires C, 47.89; H, 3.78; N, 3.29%); mp 102–
C25H24ClNO4S2 requires C, 59.81; H, 4.82; N, 2.79%); mp 142–
◦
104 C (from EtOH); nmax(KBr)/cm-1 3025, 2921, 2552, 1705,
◦
144 C (from EtOH); nmax(KBr)/cm-1 3286, 3017, 2925, 1765,
1605, 1581, and 1449; dH(400 MHz; DMSO-d6/TMS) 1.57 (1
H, d, J 7.6 Hz), 2.29 (3 H, s), 2.83 (1 H, ddd, J 11.4, 7.1, 5.1
Hz), 2.92 (1 H, ddd, J 11.4, 9.2, 6.9 Hz), 3.62 (1 H, ddd, J 9.2,
1605, 1579 and 1448; dH(400 MHz; DMSO-d6/TMS) 2.15 (3
H, s), 2.32 (3 H, s), 2.71–2.81 (2 H, m), 3.39 (1 H, dd, J 8.7,
4.5 Hz), 3.83 (1 H, m), 5.18 (1 H, br, s), 7.18–7.69 (11 Harom
,
7.6, 5.1 Hz), 5.03 (1 H, dd, J 7.1, 6.9 Hz), 7.42–7.69 (6 Harom
,
m) and 7.78–7.83 (2 Harom, m); dC(100 MHz; DMSO-d6/TMS)
25.2, 26.1, 38.3, 48.6, 52.3, 78.5, 124.8, 125.5, 126.1, 126.9, 127.7,
128.5, 129.2, 130.0, 130.7, 131.5, 132.8, 134.1 and 183.4; (m/z)
501, 503 (M, M + 2).
m) and 7.81–7.88 (2 Harom, m); dC(100 MHz; DMSO-d6/TMS)
25.5, 35.9, 41.2, 52.4, 125.3, 125.9, 126.6, 127.5, 128.2, 129.1,
129.8, 130.7, 131.4, 132.8 and 178.5; (m/z) 427 (M+).
3j. Colourless solid (Found: C, 53.75; H, 4.08; N, 3.82%.
4j. Colourless solid (Found: C, 59.63; H, 4.91; N, 3.16%.
C17H16ClNO3S2 requires C, 53.47; H, 4.22; N, 3.67%); mp 136–
C25H24ClNO4S2 requires C, 59.81; H, 4.82; N, 2.79%); mp 165–
◦
138 C (from EtOH); nmax(KBr)/cm-1 3018, 2925, 2556, 1706,
◦
167 C (from EtOH); nmax(KBr)/cm-1 3288, 3017, 2922, 1762,
1604, 1585, and 1451; dH(400 MHz; DMSO-d6/TMS) 1.58 (1
H, d, J 7.8 Hz), 2.28 (3 H, s), 2.82 (1 H, ddd, J 11.5, 7.3, 5.0
Hz), 2.91 (1 H, ddd, J 11.5, 9.1, 6.8 Hz), 3.63 (1 H, ddd, J 9.1,
7.8, 5.0 Hz), 5.05 (1 H, dd, J 7.3, 6.8 Hz), 7.37–7.71 (6 Harom, m)
and 7.86–7.91 (2 Harom, m); dC(100 MHz; DMSO-d6/TMS) 25.2,
36.8, 40.9, 50.8, 124.8, 125.7, 126.5, 127.3, 128.0, 128.7, 129.4,
130.7, 132.0, 133.2 and 178.2; (m/z) 381, 383 (M, M + 2).
1605, 1581 and 1455; dH(400 MHz; DMSO-d6/TMS) 2.14 (3
H, s), 2.39 (3 H, s), 2.70–2.76 (2 H, m), 3.37 (1 H, dd, J 8.5,
4.8 Hz), 3.78 (1 H, m), 5.27 (1 H, br, s), 7.17–7.65 (11 Harom
,
m) and 7.73–7.81 (2 Harom, m); dC(100 MHz; DMSO-d6/TMS)
24.9, 25.5, 38.5, 48.1, 52.5, 78.4, 123.9, 124.5, 125.2, 125.9, 126.5,
127.3, 128.1, 128.7, 129.3, 130.1, 130.7, 131.3, 131.9, 133.4 and
184.9; (m/z) 501, 503 (M, M + 2).
3k. Colourless solid (Found: C, 63.66; H, 5.01; N, 3.41%.
2,2-Dimethyl-2-phenyl-1,3-oxathiolan-5-one. A mixture of
acetophenone (20 mmol), 2-mercaptopropionic acid (20 mmol)
and a catalytic amount of lithium bromide (2 mmol) was stirred
for 3 h at 80 ◦C and kept overnight at room temperature. Water
(50 mL) was added to the reaction mixture and the product thus
obtained was recrystallized from water to give an analytically
C21H19NO3S2 requires C, 63.45; H, 4.82; N, 3.52%); mp 133–
◦
135 C (from EtOH); nmax(KBr)/cm-1 3027, 2929, 2548, 1707,
1605, 1578, and 1453; dH(400 MHz; DMSO-d6/TMS) 1.62 (1
H, d, J 7.6 Hz), 2.30 (3 H, s), 2.81 (1 H, ddd, J 11.2, 7.3, 4.7 Hz),
2.91 (1 H, ddd, J 11.2, 9.2, 6.9 Hz), 3.61 (1 H, ddd, J 9.2, 7.6,
1222 | Green Chem., 2011, 13, 1217–1223
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pure sample. The aqueous part containing LiBr was evaporated
to dryness and thus LiBr was recovered without any loss. (Found:
C, 63.21; H, 5.93%. C11H12O2S requires C, 63.43; H, 5.81%); nmax
(KBr)/cm-1 3011, 2963, 1777, 1601, 1515, 1441 and 1019; dH(400
MHz; DMSO-d6/TMS) 1.73 (3 H, d), 1.85 (3 H, s), 3.12 (1 H,
m) and 7.23–7.27 (5 Harom, m); dC(100 MHz; DMSO-d6/TMS)
19.1, 20.8, 39.5, 89.5, 126.8, 128.3, 129.2, 135.8 and 175.2; (m/z)
194 (M+).
5 A. F. Parsons, Tetrahedron, 1996, 52, 4149 and references cited
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oxathiolan-5-one (5). A mixture of 2,4-dimethyl-2-phenyl-1,3-
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20 mL water was refluxed for 4 h (Table 2). After the completion
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pure sample of 5. The acetophenone was extracted from aqueous
solution.
9 T. G. Elford, A. U.-Lesanko, G. D. Pascale, G. D. Wright and D. G.
Hall, J. Comb. Chem., 2009, 11, 155.
10 B. Alcaide, P. Almendros, G. Cabrero and M. P. Ruiz, Org. Lett.,
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5. Colourless solid (Found: C, 64.55; H, 5.47; N, 3.02%.
C26H27NO4S2 requires C, C, 64.84; H, 5.65; N, 2.91%); mp 117–
◦
119 C (from EtOH); nmax(KBr)/cm-1 3286, 3021, 2933, 1758,
1599, 1581 and 1457; dH(400 MHz; DMSO-d6/TMS) 1.89 (3H,
s), 2.16 (3 H, s), 2.29 (3 H, s), 2.68 (2 H, d), 3.88 (1 H, t), 5.19
(1 H, br, s) and 7.21–7.81 (14 Harom, m); dC(100 MHz; DMSO-
d6/TMS) 21.5, 24.7, 25.9, 38.1, 48.8, 52.1, 78.5, 124.2, 124.9,
125.7, 126.3, 126.9, 127.5, 128.2, 129.0, 129.8, 130.6, 132.1, 133.7
and 185.5; (m/z) 481 (M+).
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Acknowledgements
We sincerely thank IIIM Jammu and SAIF, Punjab
University, Chandigarh, for providing microanalyses and
spectra.
20 D. Basavaiah and J. S. Rao, Tetrahedron Lett., 2004, 45, 1621.
21 S. Les´niak and B. Pasternak, Tetrahedron Lett., 2005, 46, 3093.
22 S. Les´niak, R. B. Nazarski and B. Pasternak, Tetrahedron, 2009, 65,
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