Regioselectivity in the ring opening of epoxides: A metal-free cascade C-S/C-O bond formation approach to 1,3-oxathiolan-2-ylidenes through heteroannulation of α-enolic dithioesters at room temperature

Article abstract of DOI:10.1055/s-0033-1341086

An operationally simple and efficient approach to hitherto unreported and synthetically demanding 1,3-oxathiolan-2-ylidenes has been developed. The approach involves a cascade [2+3] heteroannulation of α-enolic dithioesters with epoxides promoted by non-nucleophilic moderate base Cs ₂CO₃ at room temperature. Typical features of this strategy include metal-free mild reaction conditions, atom-economy, high yields, and efficacy of forming two consecutive C-S and C-O bonds, and one ring in a single stroke. MeSH is the only by-product, and the stereochemistry of the exocyclic α-oxoketene moiety of 1,3-oxathiolane was assigned to have Z-configuration. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1341086

PAPER
▌1815
paper
Regioselectivity in the Ring Opening of Epoxides: A Metal-Free Cascade
C–S/C–O Bond Formation Approach to 1,3-Oxathiolan-2-ylidenes through
Heteroannulation of α-Enolic Dithioesters at Room Temperature
Regioselectivity in the Ring Opening of Epoxides
Gaurav Shukla,a Anugula Nagaraju,a Abhijeet Srivastava,a Girijesh Kumar Verma,a Keshav Raghuvanshi,b
Maya Shankar Singh*a
a
Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi 221005, India
Fax +91(542)2368127; E-mail: mssinghbhu@yahoo.co.in
b
Institute für Organische und Biomolekulare Chemie, Georg-August-Universität, Tammannstr. 2, 37077 Göttingen, Germany
Received: 23.01.2014; Accepted after revision: 10.03.2014
oselective synthesis of functionalized 1,3-oxathiolanes
Abstract: An operationally simple and efficient approach to hither-
and their structural analogues continues to be an active
to unreported and synthetically demanding 1,3-oxathiolan-2-yli-
area of research in fine chemistry. Among the limited
denes has been developed. The approach involves a cascade [2+3]
heteroannulation of α-enolic dithioesters with epoxides promoted
number of approaches used for the construction of 1,3-ox-
by non-nucleophilic moderate base Cs2CO3 at room temperature. athiolan-2-ylidenes,6,7 the major route typically involves
Typical features of this strategy include metal-free mild reaction
conditions, atom-economy, high yields, and efficacy of forming two
reaction of 2-mercaptoethanol with α-oxoketene dithio-
acetals in the presence of strong base.6 However, most of
consecutive C–S and C–O bonds, and one ring in a single stroke.
these transformations involve the use of harsh reaction
MeSH is the only by-product, and the stereochemistry of the exocy-
conditions such as high-boiling solvents, expensive start-
clic α-oxoketene moiety of 1,3-oxathiolane was assigned to have Z-
ing material, step-wise synthesis, and they can also suffer
from low functional group tolerance.7 Although the open-
ing of epoxides with carbon, nitrogen, and oxygen nucleo-
philes is well known,8a–e ring opening of epoxides with
sulfur nucleophiles is rare,8f,g despite the clear synthetic
utility. In this context, we report herein a new one-pot
method for the regioselective synthesis of 1,3-oxathiolan-
2-ylidenes by the coupling of α-enolic dithioesters with
epoxides at room temperature.
configuration.
Key words: epoxides, oxathiolanes, heteroannulation, metal-free
conditions, regioselective, cascade reaction
The design, development and implementation of domi-
no/cascade protocols that provide maximum structural di-
versity with economies of step, atom, labor, and cost for
the rapid generation of function-oriented molecules is a
key goal in modern organic synthesis.1 A pressing chal-
lenge for synthetic chemists is to develop new synthetic
strategies by improving resource efficiency, avoiding the
use of toxic reagents, and reducing the amount of waste
and hazardous by-products. The synthesis of heterocycles
has become essential in chemical synthesis because they
are a vital part of new drug discovery, a major component
of the bulk chemical industry, and are indispensable ma-
terials in many areas of society.2 In this context, 1,3-oxa-
thiolanes, an important class of heterocyclic compounds,
have a wide range of applications in many industrial fields
such as organic semiconductors, photosensitive materials,
and light-emitting devices.3 They have also been utilized
in the construction of analogues of biological products
such as apricitabine (I), lamivudine (II), and emtricitabine
(III), which act as reverse transcriptase inhibitors (RTI)
against the HIV virus4 (Figure 1).
OH
S
OH
O
O
S
O
O
N
N
N
N
H2N
H2N
apricitabine (I)
lamivudine (II)
S
OH
O
O
N
N
H2N
emtricitabine (III)
F
Figure 1 Selected examples of bioactive 1,3-oxathiolanes
Chemical species containing both electrophilic and nu-
cleophilic sites have great potential for the development
of novel protocols and diverse molecular entities. Impor-
tantly, the suitable selection of synthons is crucial for the
success of a protocol. Two such simple polyfunctional
chemical species are α-enolic dithioesters 1 and epoxides
2, both of which can be exploited synthetically (Figure 2).
1,3-Oxathiolanes and their derivatives are not only impor-
tant privileged structural motifs, they are also utilized as
synthetic building blocks for the construction of a diverse
range of biologically active compounds.5 For these rea-
sons, the development of new methodologies for the regi-
The continuing interest in the chemistry of these frame-
works is mainly due to their nucleophilic and electrophilic
centers coupled with their versatile reactivity, making
them very useful building blocks in modern organic syn-
SYNTHESIS 2014, 46, 1815–1822
Advanced online publication: 17.04.2014
DOI: 10.1055/s-0033-1341086; Art ID: SS-2014-Z0063-OP
© Georg Thieme Verlag Stuttgart · New York
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1
1
4
3
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1
0
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1816
G. Shukla et al.
PAPER
are listed in Table 1. Generally, the base plays a crucial
role in enabling the thiocarbonyl sulfur to act as a strong
nucleophile by abstracting the enolic proton of 1.13d A test
reaction was performed without any base in ethanol at
room temperature to establish the real effectiveness of the
base, and it was found that, under these conditions, only a
trace amount of the desired product was obtained after 24
hours stirring, with the starting materials remaining en-
tirely unconsumed (Table 1, entry 1). With this result, we
then performed the above model reaction in the presence
of NaHCO3 in ethanol. Work up of the reaction provided
the desired compound 3a in 30% yield (Table 1, entry 2).
To improve the reaction efficiency and yield of 3a, a
range of solvents (MeOH, H2O, MeCN, THF, and DMF)
were evaluated (Table 1, entries 3–7). The use of polar
protic solvent MeOH resulted in the formation of product
3a in 40% yield (Table 1, entry 3), whereas the use of wa-
ter as the solvent shut down the reaction because of the
low solubility of the substrates in this medium (Table 1,
entry 4). Further screening of solvents revealed that the re-
action proceeded better in polar aprotic solvents, and
DMF turned out to be the most suitable solvent for the
present cascade annulation (Table 1, entry 7). Other inor-
ganic bases such as Na2CO3, K2CO3 and Cs2CO3 (1 equiv)
were screened to check their competence in the reaction
(Table 1, entries 8–10) and it was found that all the bases
tested afforded the desired product 3a in good yield;
Cs2CO3 promoted this transformation more efficiently
than other bases, resulting the desired product 3a in 87%
yield within three hours (Table 1, entry 10). Reducing the
nucleophilic
centers
nucleophilic
oxygen atom
O
Cl
OH
S
R1
SR2
electrophilic
carbon atoms
1
electrophilic site
2
Figure 2 Reactive sites in α-enolic dithioester 1 and epoxide 2
thesis. Epoxides (oxiranes) constitute a well-known, ver-
satile three-atom synthon with high synthetic potential,9
and such compounds are highly prone to ring opening
and/or nucleophilic substitution reactions with various
nucleophiles.10 Moreover, unsymmetrical substitution of
the epoxide allows the introduction of chirality, making
these molecules valuable substrates in enantioselective
synthesis.
The utility of α-enolic dithioesters as versatile intermedi-
ates in organic synthesis has been well-recognized.11 In a
continuation of our ongoing research on the synthetic util-
ity of α-enolic dithioesters for the synthesis of heterocy-
clic systems,12,13 we report herein
a
simple,
straightforward, and efficient synthesis of 1,3-oxathiolan-
2-ylidenes through [2+3] heteroannulation of α-enolic di-
thioesters with epoxides. Thus, when α-enolic dithioesters
1 were treated with epoxides 2 in N,N-dimethylformamide
(DMF) in the presence of Cs2CO3 at room temperature,
the corresponding 1,3-oxathiolan-2-ylidenes 3 were ob-
tained in good to excellent yields (Scheme 1). As an inter-
esting alternative, this two-component cascade process
led to the concomitant creation of two new (C–S and C–
O) bonds and one ring. To our knowledge, this is the first
report on the use of α-enolic dithioesters and epoxides for
the synthesis of 1,3-oxathiolan-2-ylidenes.
Table 1 Optimization of Reaction Conditionsa
OH
S
O
S
Cl
Cl
O
+
Ph
SMe
O
Ph
1a
2a
3a
Entry
Base
none
Solvent
Time (h)
Yield (%)b
Cl
Cl
O
S
O
1
2
3
4
5
6
7
8
9
EtOH
EtOH
MeOH
H2O
24
24
24
24
12
12
10
8
trace
30
2a
R1
O
OH
S
3a–k (70–90%)
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
Na2CO3
K2CO3
Cs2CO3
R1
SMe
DMF, stir
r.t.
1a–k
O
S
O
40
Ph
Ph
2b
R1
O
c
–
3l–o (75–85%)
MeCN
THF
60
55
65
70
75
87
78
1a: R1 = Ph, 1b: R1 = 4-MeC6H4, 1c: R1 = 4-MeOC6H4,
1d: R1 = 4-BrC6H4, 1e: R1 = 4-ClC6H4, 1f: R1 = 2-ClC6H4,
1g: R1 = 2-naphthyl, 1h: R1 = 4-F3CC6H4,
1i: R1 = 3,4-OCH2OC6H3, 1j: R1 = 2-thienyl, 1k: R1 = 2-furyl
DMF
DMF
DMF
DMF
DMF
Scheme 1 Synthesis of 1,3-oxathiolan-2-ylidenes 3a–o
5
At the outset of our research, we envisioned that 1,3-oxa-
thiolan-2-ylidenes might be formed by the coupling of α- 10
Cs2CO3
3
enolic dithioesters with epoxides. Initially, to optimize the
reaction conditions for the synthesis of 1,3-oxathiolan-2-
d
11
Cs2CO3
7
ylidenes, methyl 3-hydroxy-3-phenylprop-2-enedithioate a Reaction conditions: 1a (1 mmol), 2a (1 mmol), base (1 equiv), sol-
vent (5 mL), r.t., stirring.
(1a) and epichlorohydrin (2a) were taken as model sub-
strates. Thus, equimolar amounts of test substrates 1a and
2a were examined under an array of conditions; the results
b Isolated pure yield.
c No reaction.
d Cs2CO3 (0.5 equiv).
Synthesis 2014, 46, 1815–1822
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Regioselectivity in the Ring Opening of Epoxides
1817
O
S
OH
S
R2
O
Cs2CO3 (1 equiv)
DMF, r.t.
O
R2
+
R1
O
R1
SMe
1a–k
Cl
2a,b
3a–o
Cl
Cl
S
Cl
O
S
O
S
O
O
O
MeO
3a (3 h, 87%)
3b (2.5 h, 90%)
3c (2.5 h, 92%)
Cl
Cl
O
S
O
S
O
S
O
O
O
Br
Cl
Cl
3d (3.5 h, 82%)
3e (3 h, 80%)
3f (3 h, 76%)
Cl
Cl
O
S
O
S
Cl
O
S
O
O
O
O
O
F3C
3g (2.5 h, 89%)
3h (3.5 h, 72%)
3i (3 h, 85%)
O
S
Cl
Cl
Ph
Ph
O
S
O
S
O
O
O
S
3j (2.5 h, 85%)
O
3k (3 h, 82%)
3l (2 h, 84%)
O
S
O
S
O
S
Ph
Ph
O
O
O
O
Cl
3m (1.5 h, 87%)
3n (2.5 h, 75%)
3o (1.5 h, 86%)
Scheme 2 Substrate scope for the synthesis of 3
amount of Cs2CO3 (0.5 equiv) increased the required reac- scribed one-pot conditions, annulated 1,3-oxathiolanes
tion time and decreased the yield to 78% (Table 1, entry 3p–s were obtained in 70–80% yield (Scheme 3).
11). Thus, the best reaction conditions for the synthesis of
3a was found to be equimolar amounts of 1a and 2a in the
presence of 1.0 equivalent Cs2CO3 in DMF (5 mL) at
room temperature (Table 1, entry 10).
O
O
S
OH
S
2c
R1
O
R1
SMe
Cs2CO3
The scope and generality of this process with respect to
substrate under the optimized conditions is summarized in
Scheme 2. A broad spectrum of α-enolic dithioesters 1,
bearing R1 as aryl (containing either electron-donating or
electron-withdrawing groups), hetaryl, and extended aro-
matics, and R2 as chloromethyl and phenyl groups, could
be employed to afford 1,3-oxathiolanes 3 in good to excel-
lent yields. All the reactions proceeded smoothly and re-
sulted in the formation of the corresponding products 3 in
high yields. The steric and electronic nature of the substit-
uents had no noticeable impact on either the yield or the
rate of the reaction. To further investigate the scope of the
current method, styrene oxide (2b) was employed instead
of epichlorohydrin (2a), which was tolerated well under
the optimized reaction conditions and furnished the de-
sired products in 75–87% yields (3l–o; Scheme 2).
3p (4 h, 70%), R1 = Ph
1a–c
DMF, stir
r.t.
3q (3 h, 75%), R1 = 4-MeC6H4
3r (3 h, 75%), R1 = 4-MeOC6H4
O
S
OH
S
2c
O
SMe
Cs2CO3
DMF, stir
r.t.
3s (5 h, 80%)
OMe
OMe
1l
Scheme 3 Synthesis of annulated 1,3-oxathiolanes 3p–s
We then extended our study by using cyclic α-enolic di-
thioester 1l derived from 5-methoxy-α-tetralone as one of
the reaction partners with a view to adding a further point
of diversity at the 2-position of the 1,3-oxathiolane ring.
Thus, when α-enolic dithioester 1l was treated with either
epoxide 2a or 2b, under the optimized conditions, the de-
sired oxathiolanes 3t and 3u were obtained in 90 and 85%
yield, respectively (Scheme 4).
To illustrate the broad synthetic utility and generality of
the developed methodology, we then undertook the for-
mal synthesis of annulated 1,3-oxathiolane. Thus, when
α-enolic dithioesters 1a–c and 1l were separately treated
with epoxycyclohexane (2c) under the previously de-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1815–1822

1818
G. Shukla et al.
PAPER
spectra alone. The ultimate proof of structure of com-
pound 3 was made by X-ray analysis of two representative
compounds 3e and 3r (Figure 3).14
O
S
O
OH
S
R2
R2
O
SMe
2
Cs2CO3
DMF, stir, r.t.
OMe
OMe
1l
2a R2 = CH2Cl
2b R2 = Ph
3t (2 h, 90%)
3u (2 h, 85%)
Scheme 4 Synthesis of 1,3-oxathiolanes 3t and 3u
The structures of 1,3-oxathiolan-2-ylidenes 3a–u were
deduced from their satisfactory spectral (IR, 1H, 13C NMR
and HRMS) analysis and unequivocally established by the
X-ray single crystal diffraction analysis of 3e and 3r as
two representative compounds (Figure 3).14 It is notewor-
thy that the stereochemistry of the exocyclic double bond
of the α-oxoketene moiety was assigned as having Z-con-
figuration. The mass spectra of these compounds dis-
played molecular ion peaks at the expected m/z values.
The introduction of a chloromethyl functional group at the
5-position of the newly formed 1,3-dithiolane is of partic-
ular interest because it can act as an effective chemical
handle for further functionalization and diversification
through metal-catalyzed cross-coupling reactions.
Scheme 5 Plausible mechanism for the synthesis of 1,3-oxathiolanes 3
In summary, we have developed an experimentally conve-
nient, straightforward, and regioselective protocol for the
synthesis of functionalized 1,3-oxathiolan-2-ylidenes
through [2+3] heteroannulation of α-enolic dithioesters
with epoxides in the presence of Cs2CO3 at room temper-
ature. This transformation avoids the use of metal catalyst
and constructs two new bonds (C–S and C–O) and one
ring with both reactants being utilized efficiently. Impor-
tantly, the presence of the α-oxoketene moiety and the
chloromethyl group at the 2- and 5-positions of the 1,3-
oxathiolane ring makes these compounds excellent pre-
cursors for further derivatization. We expect that this fac-
ile and efficient protocol should be of value for both
synthetic and medicinal chemists for academic research
and practical applications.
Figure 3 ORTEP diagrams of 3e and 3r
On the basis of the above experimental results together
with related reports, a plausible reaction scenario for a
domino [2+3] heteroannulation is outlined in Scheme 5.
We speculate that the reaction occurs as a tandem oxirane-
opening/1,3-oxathiolane-closure process. The first step in
the mechanism is believed to be the abstraction of an acid-
ic enolic proton of α-enolic dithioester 1 by base followed
by regioselective nucleophilic attack of the thiocarbonyl
sulfur to the less hindered side of epoxide 2 to generate the
open-chain adduct intermediate α-oxoketene dithioacetal
A. Intermediate A then undergoes intramolecular O-cycli-
zation with the extrusion of MeSH to give 1,3-oxathiolan-
2-ylidene 3. The intermediacy of α-oxoketene dithioacetal
A has been confirmed by its isolation and characterization
through spectroscopic (1H and 13C NMR) and X-ray crys-
tallographic analyses.14 We did not detect the alternative
regioisomer 4 even in trace amounts, making this protocol
highly regioselective. It was not possible to distinguish
between structures 3 or 4 on the basis of NMR and IR
Commercially available materials were purchased from Merck, Al-
drich, or Fluka and were used as received. THF was distilled over
sodium, and other solvents were dried over 4 Å molecular sieves
prior to use. α-Enolic dithioesters were prepared by a reported pro-
cedure.7c IR spectra were recorded with a Varian 3100 FT-IR spec-
trophotometer. 1H and 13C NMR spectra were recorded with a JEOL
AL 300 FT NMR spectrometer. Chemical shifts were recorded in
parts per million (ppm, δ) relative to tetramethylsilane. Coupling
constants (J) are given in hertz (Hz). 1H NMR splitting patterns are
designated as singlet (s), doublet (d), triplet (t), quartet (q), dd (dou-
blet of doublets), and m (multiplets). All first-order splitting pat-
terns were assigned on the basis of the appearance of the multiplet.
Splitting patterns that could not be easily interpreted are designated
as multiplet (m). High-resolution mass spectrometry (HRMS) was
performed with a Water-Q-Tof premier HAB 213 instrument using
the electrospray ionization (ESI) technique. X-ray crystallographic
analysis was performed with an X-calibur Oxford CCD diffractom-
eter. All the reactions were monitored by thin-layer chromatogra-
phy (TLC) using pre-coated sheets of silica gel G/UV-254 of 0.25
mm thickness (Merck 60 F254) using UV light for visualization.
Melting points were determined with a Büchi B-540 melting point
apparatus and are uncorrected.
Synthesis 2014, 46, 1815–1822
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Regioselectivity in the Ring Opening of Epoxides
1819
(Z)-2-[5-(Chloromethyl)-1,3-oxathiolan-2-ylidene]-1-phenyl-
ethanone (3a); Typical Procedure
HRMS (ESI): m/z [M + H]+ calcd for C12H11BrClO2S+: 332.9346;
found: 332.9359.
A dry 25 mL round-bottomed flask equipped with a magnetic stir
bar was charged with a solution of α-enolic dithioester 1a (0.210 g,
1 mmol) in DMF (5 mL), and Cs2CO3 (0.325 g, 1 mmol) was added.
The solution was stirred at r.t. for 10 min, then epichlorohydrin (2a;
0.079 mL, 1 mmol) was added slowly to the reaction mixture by us-
ing a syringe. The resulting mixture was then stirred at r.t. until the
reaction was complete (monitored by TLC; time indicated in
Scheme 2), then H2O (20 mL) was added and the mixture was ex-
tracted with CH2Cl2 (2 × 10 mL). The combined organic extract
was dried over anhydrous Na2SO4, filtered, and the solvent was
evaporated under reduced pressure. The crude residue thus obtained
was purified by column chromatography over silica gel (EtOAc–
n-hexane) to afford the pure product 3a.
2-[5-(Chloromethyl)-1,3-oxathiolan-2-ylidene]-1-(4-chlorophe-
nyl)ethanone (3e)
Yield: 0.230 g (80%); yellow solid; mp 148–150 °C.
IR (KBr): 2920, 1735, 1675, 1580, 792, 696 cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.27 (dd, J = 11.4, 6.9 Hz, 1 H),
3.38 (dd, J = 11.4, 6.6 Hz, 1 H), 3.76 (d, J = 5.7 Hz, 2 H), 4.97–
4.89 (m, 1 H), 6.78 (s, 1 H), 7.41 (d, J = 8.4 Hz, 2 H), 7.85 (d,
J = 8.4 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 32.8, 42.7, 83.0, 95.1, 125.5, 127.8,
177.3, 187.3.
HRMS (ESI): m/z [M + H]+ calcd for C12H11Cl2O2S+: 288.9851;
found: 288.9850.
2-[5-(Chloromethyl)-1,3-oxathiolan-2-ylidene]-1-phenyleth-
anone (3a)
2-[5-(Chloromethyl)-1,3-oxathiolan-2-ylidene]-1-(2-chlorophe-
nyl)ethanone (3f)
Yield: 0.218 g (76%); yellow solid; mp 140–142 °C.
Yield: 0.220 g (87%); yellow solid; mp 150–152 °C.
IR (KBr): 2924, 1623, 1575, 1519, 765, 680 cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.27 (dd, J = 11.1, 6.9 Hz, 1 H),
3.38 (dd, J = 11.4, 6.6 Hz, 1 H), 3.76 (d, J = 6.0 Hz, 2 H), 4.96–
4.88 (m, 1 H), 6.84 (s, 1 H), 7.53–7.41 (m, 3 H), 7.92 (d, J = 7.2 Hz,
2 H).
IR (KBr): 2922, 1732, 1632, 1570, 793, 695 cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.29 (dd, J = 11.1, 7.2 Hz, 1 H),
3.40 (dd, J = 11.4, 6.6 Hz, 1 H), 3.76 (d, J = 5.4 Hz, 2 H), 4.97–4.88
(m, 1 H), 6.57 (s, 1 H), 7.40–7.39 (m, 3 H), 7.52 (d, J = 7.2 Hz,
1 H).
13C NMR (75 MHz, CDCl3): δ = 32.7, 42.7, 82.9, 94.9, 128.7, 128.9,
136.5, 138.3, 176.5, 187.3.
HRMS (ESI): m/z [M + H]+ calcd for C12H12ClO2S+: 255.0241;
13C NMR (75 MHz, CDCl3): δ = 32.7, 42.7, 83.0, 99.2, 126.7, 129.4,
130.2, 131.1, 132.8, 139.5, 175.7, 189.7.
found: 255.0242.
2-[5-(Chloromethyl)-1,3-oxathiolan-2-ylidene]-1-(naphthalen-
2-yl)ethanone (3g)
2-[5-(Chloromethyl)-1,3-oxathiolan-2-ylidene]-1-(p-tolyl)eth-
anone (3b)
Yield: 0.241 g (90%); yellow solid; mp 142–144 °C.
IR (KBr): 3095, 1611, 1598, 1516, 762, 693 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.39 (s, 3 H), 3.25 (dd, J = 10.8,
6.6 Hz, 1 H), 3.36 (dd, J = 11.1, 6.6 Hz, 1 H), 3.75 (d, J = 5.7 Hz,
2 H), 4.94–4.86 (m, 1 H), 6.82 (s, 1 H), 7.82 (d, J = 8.1 Hz, 4 H).
Yield: 0.270 g (89%); yellow solid; mp 152–154 °C.
IR (KBr): 2926, 1625, 1525, 1434, 790, 697 cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.29 (dd, J = 11.1, 6.6 Hz, 1 H),
3.40 (dd, J = 11.1, 6.6 Hz, 1 H), 3.78 (d, J = 5.7 Hz, 2 H), 4.99–
4.90 (m, 1 H), 7.01 (s, 1 H), 7.59–7.50 (m, 2 H), 7.95–7.85 (m,
3 H), 8.03 (d, J = 8.7 Hz, 1 H), 8.42 (s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 21.4, 32.6, 42.8, 82.6, 95.0, 127.4,
129.0, 135.5, 142.6, 175.4, 188.3.
HRMS (ESI): m/z [M + H]+ calcd for C13H14ClO2S+: 269.0398;
13C NMR (75 MHz, CDCl3): δ = 32.8, 42.8, 82.8, 95.4, 123.9, 126.5,
127.7, 127.8, 128.2, 128.5, 129.1, 129.4, 130.5, 132.7, 135.1, 175.8,
188.6.
found: 269.0406.
2-[5-(Chloromethyl)-1,3-oxathiolan-2-ylidene]-1-[4-(trifluoro-
methyl)phenyl]ethanone (3h)
2-[5-(Chloromethyl)-1,3-oxathiolan-2-ylidene]-1-(4-methoxy-
phenyl)ethanone (3c)
Yield: 0.261 g (92%); yellow solid; mp 155–157 °C.
Yield: 0.231 g (72%); yellow solid; mp 160–162 °C.
IR (KBr): 2920, 1615, 1590, 1480, 790, 660 cm–1.
IR (KBr): 2995, 1620, 1590, 1520, 770, 680 cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.29 (dd, J = 11.1, 6.9 Hz, 1 H),
3.40 (dd, J = 11.1, 6.9 Hz, 1 H), 3.77 (d, J = 5.7 Hz, 2 H), 5.00–4.91
(m, 1 H), 7.70 (d, J = 8.1 Hz, 2 H), 8.00 (d, J = 7.8 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 32.7, 42.7, 82.9, 94.9, 128.7, 128.9,
129.2, 136.5, 138.3, 176.5, 187.3.
1H NMR (300 MHz, CDCl3): δ = 3.24 (dd, J = 11.4, 6.9 Hz, 1 H),
3.36 (dd, J = 11.1, 6.6 Hz, 1 H), 3.75 (d, J = 5.7 Hz, 2 H), 3.86 (s,
3 H), 4.94–4.85 (m, 1 H), 6.81 (s, 1 H), 6.93 (d, J = 8.7 Hz, 2 H),
7.91 (d, J = 8.7 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 32.7, 42.8, 55.4, 82.6, 95.0, 113.6,
114.0, 129.6, 130.8, 162.7, 175.0, 187.5.
HRMS (ESI): m/z [M + H]+ calcd for C13H11ClF3O2S+: 323.0115;
found: 323.0121.
HRMS (ESI): m/z [M + H]+ calcd for C13H14ClO3S+: 285.0347;
found: 285.0355.
1-(Benzo[d][1,3]dioxol-5-yl)-2-[5-(chloromethyl)-1,3-oxathio-
lan-2-ylidene]ethanone (3i)
Yield: 0.253 g (85%); yellow solid; mp 165–167 °C.
1-(4-Bromophenyl)-2-[5-(chloromethyl)-1,3-oxathiolan-2-yli-
dene]ethanone (3d)
Yield: 0.272 g (82%); yellow solid; mp 160–162 °C.
IR (KBr): 2925, 1624, 1540, 1456, 790, 694 cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.27 (dd, J = 11.4, 6.9 Hz, 1 H),
3.38 (dd, J = 11.4, 6.6 Hz, 1 H), 3.76 (d, J = 5.7 Hz, 2 H), 4.97–4.88
(m, 1 H), 6.77 (s, 1 H), 7.57 (d, J = 8.4 Hz, 2 H), 7.78 (d,
J = 8.4 Hz, 2 H).
IR (KBr): 2918, 1624, 1598, 1489, 791, 655 cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.24 (dd, J = 11.4, 6.9 Hz, 1 H),
3.36 (dd, J = 11.4, 6.6 Hz, 1 H), 3.75 (d, J = 6.0 Hz, 2 H), 4.94–4.85
(m, 1 H), 6.02 (s, 2 H), 6.75 (s, 1 H), 6.83 (d, J = 8.4 Hz, 1 H), 7.50–
7.43 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 32.7, 42.8, 82.6, 95.0, 101.6, 107.7,
107.8, 123.1, 148.0, 150.9, 162.1, 173.6, 182.1.
13C NMR (75 MHz, CDCl3): δ = 32.8, 42.8, 82.9, 94.9, 129.0, 131.7,
HRMS (ESI): m/z [M + H]+ calcd for C13H12Cl4O4S+: 299.0139;
137.0, 176.4, 189.1.
found: 299.0144.
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G. Shukla et al.
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2-[5-(Chloromethyl)-1,3-oxathiolan-2-ylidene]-1-(thiophen-2-
yl)ethanone (3j)
IR (KBr): 2923, 1680, 1523, 1516, 777, 698 cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.27 (dd, J = 11.1, 9.9 Hz, 1 H),
3.55 (dd, J = 11.4, 6.3 Hz, 1 H), 5.60 (dd, J = 9.3, 6.3 Hz, 1 H), 6.51
(s, 1 H), 6.77 (s, 1 H), 7.13 (d, J = 3.3 Hz, 1 H), 7.41 (s, 5 H), 7.52
(s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 37.4, 85.9, 94.7, 112.1, 114.6,
126.0, 128.8, 129.1, 136.7, 145.0, 153.7, 176.1, 178.0.
Yield: 0.220 g (85%); yellow solid; mp 155–157 °C.
IR (KBr): 2940, 1690, 1540, 1458, 792, 690 cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.26 (dd, J = 10.8, 6.9 Hz, 1 H),
3.35 (dd, J = 11.1, 6.6 Hz, 1 H), 3.75 (d, J = 6.0 Hz, 2 H), 4.95–
4.86 (m, 1 H), 6.67 (s, 1 H), 7.11–7.08 (m, 1 H), 7.55 (d, J = 4.8 Hz,
1 H), 7.63 (d, J = 3.3 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 32.9, 42.8, 82.9, 95.4, 127.9, 129.6,
132.1, 145.6, 175.2, 181.4.
HRMS (ESI): m/z [M + H]+ calcd for C15H13O3S+: 273.0580; found:
273.0588.
2-(Hexahydrobenzo[d][1,3]oxathiol-2-ylidene)-1-phenyleth-
anone (3p)
Yield: 0.182 g (70%); yellow solid; mp 180–182 °C.
+
HRMS (ESI): m/z [M + H]+ calcd for C10H10 ClO2S2 : 260.9805;
found: 260.9810.
2-[5-(Chloromethyl)-1,3-oxathiolan-2-ylidene]-1-(furan-2-
yl)ethanone (3k)
IR (KBr): 2920, 1625, 1519, 1230, 780, 620 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.66–1.37 (m, 4 H), 2.01–1.89 (m,
2 H), 2.40–2.27 (m, 2 H), 3.11 (dd, J = 11.7, 8.4 Hz, 1 H), 3.81 (dd,
J = 11.4, 8.1 Hz, 1 H), 6.81 (s, 1 H), 7.51–7.40 (m, 3 H), 7.91 (d,
J = 7.5 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 23.7, 25.1, 28.0, 29.6, 50.5, 88.9,
95.7, 127.4, 128.3, 128.9, 131.8, 138.7, 174.8, 191.0.
Yield: 0.200 g (82%); yellow liquid.
IR (KBr): 2924, 1623, 1575, 1469, 781, 680 cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.24 (dd, J = 10.8, 6.9 Hz, 1 H),
3.37 (dd, J = 11.1, 6.6 Hz, 1 H), 3.74 (d, J = 5.7 Hz, 2 H), 4.94–4.86
(m, 1 H), 6.50 (s, 1 H), 6.70 (s, 1 H), 7.12 (d, J = 3.0 Hz, 1 H), 7.52
(s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 32.8, 42.7, 82.6, 95.1, 112.2, 114.8,
145.1, 153.5, 175.1, 177.9.
HRMS (ESI): m/z [M + H]+ calcd for C15H17O2S+: 261.0944; found:
261.0944.
2-(Hexahydrobenzo[d][1,3]oxathiol-2-ylidene)-1-(p-tolyl)eth-
anone (3q)
Yield: 0.205 g (75%); yellow solid; mp 185–187 °C.
HRMS (ESI): m/z [M + H]+ calcd for C10H10 ClO3S+: 245.0034;
found: 245.0030.
1-Phenyl-2-(5-phenyl-1,3-oxathiolan-2-ylidene)ethanone (3l)
IR (KBr): 2921, 1620, 1518, 1236, 784, 623 cm–1.
Yield: 0.236 g (84%); yellow solid; mp 155–157 °C.
1H NMR (300 MHz, CDCl3): δ = 1.65–1.49 (m, 4 H), 1.95–1.87 (m,
2 H), 2.55–2.26 (m, 5 H), 3.07 (dd, J = 20.4, 11.7 Hz, 1 H), 3.77
(dd, J = 19.2, 11.1 Hz, 1 H), 6.79 (s, 1 H), 7.22 (d, J = 7.5 Hz, 2 H),
7.81 (d, J = 7.8 Hz, 2 H).
IR (KBr): 2925, 1687, 1577, 1516, 770, 698 cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.28 (dd, J = 11.1, 9.6 Hz, 1 H);
3.55 (dd, J = 11.1, 6.3 Hz, 1 H), 5.61 (dd, J = 9.6, 6.3 Hz, 1 H), 6.90
(s, 1 H), 7.50–7.42 (m, 8 H), 7.94 (d, J = 7.2 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 21.5, 23.7, 25.1, 28.0, 29.6, 50.4,
13C NMR (75 MHz, CDCl3): δ = 37.3, 85.9, 94.9, 123.6, 126.1,
127.5, 128.4, 128.9, 129.2, 131.9, 136.8, 138.4, 172.7, 188.8.
88.8, 95.6, 127.5, 129.0, 136.1, 142.3, 165.5, 176.0, 188.5.
HRMS (ESI): m/z [M + H]+ calcd for C16H19O2S+: 275.1100; found:
HRMS (ESI): m/z [M + H]+ calcd for C17H15O2S+: 283.0787; found:
275.1102.
283.0798.
2-(Hexahydrobenzo[d][1,3]oxathiol-2-ylidene)-1-(4-methoxy-
phenyl)ethanone (3r)
2-(5-Phenyl-1,3-oxathiolan-2-ylidene)-1-(p-tolyl)ethanone (3m)
Yield: 0.257 g (87%); yellow liquid.
IR (KBr): 2926, 1682, 1607, 1495, 758, 698 cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.27 (dd, J = 9.9, 9.6 Hz, 1 H),
3.54 (dd, J = 9.6, 6.6 Hz, 1 H), 5.59 (dd, J = 9.6, 7.2 Hz, 1 H), 6.89
(s, 1 H), 7.23 (s, 3 H), 7.40 (s, 4 H), 7.85 (d, J = 7.2 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 21.5, 37.3, 85.7, 94.9, 126.0, 127.6,
128.9, 129.1, 135.9, 136.9, 142.5, 176.3, 188.5.
Yield: 0.217 g (75%); yellow solid; mp 182–184 °C.
IR (KBr): 2922, 1628, 1515, 1485, 790, 620 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.54–1.25 (m, 4 H), 2.00–1.88 (m,
2 H), 2.55–2.26 (m, 2 H), 3.08 (dd, J = 11.7, 8.4 Hz, 1 H), 3.77 (dd,
J = 11.1, 3.6 Hz, 1 H), 3.85 (s, 3 H), 6.78 (s, 1 H), 6.92 (d,
J = 8.7 Hz, 2 H), 7.90 (d, J = 8.7 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 23.7, 25.1, 28.1, 29.6, 50.5, 55.4,
88.6, 95.5, 113.5, 129.5, 129.8, 131.7, 162.5, 175.6, 187.6.
HRMS (ESI): m/z [M + H]+ calcd for C18H17O2S+: 297.0944; found:
297.0941.
HRMS (ESI): m/z [M + H]+ calcd for C16H19O3S+: 291.1049; found:
291.1056.
1-(2-Chlorophenyl)-2-(5-phenyl-1,3-oxathiolan-2-ylidene)eth-
anone (3n)
2-(Hexahydrobenzo[d][1,3]oxathiol-2-ylidene)-5-methoxy-3,4-
dihydronaphthalen-1(2H)-one (3s)
Yield: 0.237 g (75%); yellow liquid.
Yield: 0.252 g (80%); yellow liquid.
IR (KBr): 2940, 1680, 1565, 1215, 787, 690 cm–1.
IR (KBr): 2912, 1656, 1540, 1490, 780, 635 cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.30 (dd, J = 15.9, 9.9 Hz, 1 H),
3.57 (dd, J = 11.1, 6.3 Hz, 1 H), 5.62 (dd, J = 9.9, 6.3 Hz, 1 H), 6.63
(s, 1 H), 7.34–7.29 (m, 2 H), 7.42 (s, 6 H), 7.55 (s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 37.3, 86.2, 99.0, 126.1, 126.7,
128.5, 128.9, 129.2, 129.6, 130.1, 130.3, 131.0, 136.6, 176.5, 191.1.
HRMS (ESI): m/z [M + H]+ calcd for C17H14ClO2S+: 317.0398;
found: 317.0392.
1H NMR (300 MHz, CDCl3): δ = 1.41–1.25 (m, 4 H), 2.00–1.87 (m,
2 H), 2.41–2.25 (m, 2 H), 2.93–2.78 (m, 4 H), 3.13–3.04 (m, 1 H),
3.85–3.74 (m, 4 H), 6.97 (d, J = 8.1 Hz, 1 H), 7.69 (d, J = 7.5 Hz,
1 H).
13C NMR (75 MHz, CDCl3): δ = 20.4; 23.2, 23.7, 25.1, 28.1, 29.7,
50.7, 55.6, 88.6, 106.9, 113.3, 119.0, 126.6, 131.2, 135.3, 155.9,
168.0, 186.1.
HRMS (ESI): m/z [M + H]+ calcd for C18H21O3S+: 317.1206; found:
317.1213.
1-(Furan-2-yl)-2-(5-phenyl-1,3-oxathiolan-2-ylidene)ethanone
(3o)
Yield: 0.233 g (86%); yellow solid; mp 138–140 °C.
Synthesis 2014, 46, 1815–1822
© Georg Thieme Verlag Stuttgart · New York

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Regioselectivity in the Ring Opening of Epoxides
1821
2-[5-(Chloromethyl)-1,3-oxathiolan-2-ylidene]-5-methoxy-3,4-
dihydronaphthalen-1(2H)-one (3t)
ed.; John Wiley & Sons: Chichester, 2011. (b) Li, J. J.
Heterocyclic Chemistry in Drug Discovery; John Wiley &
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Chemistry, 5th ed.; John Wiley & Sons: Chichester, 2010.
(d) For a special issue, see: Chem. Rev. 2004, 104, issue 5.
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Tetrahedron Lett. 1989, 30, 1249. (b) Bryce, M. R.; Finn, T.;
Batsanov, A. S.; Kataky, R.; Howard, J. A. K.; Lyubchik, S.
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M. A.; Moore, A. J.; Batsanov, A. S.; Howard, J. A. K.
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T.; Marco, J.; Witvrouw, M.; Pannecouque, C.; De Clercq,
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Yield: 0.279 g (90%); yellow liquid.
IR (KBr): 2944, 1674, 1575, 1474, 792, 697 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.87 (s, 4 H), 3.24 (dd, J = 11.4,
6.9 Hz, 1 H), 3.37 (dd, J = 11.4, 6.6 Hz, 1 H), 3.77 (dd, J = 5.4,
1.5 Hz, 2 H), 3.86 (s, 3 H), 4.94–4.85 (m, 1 H), 6.99 (d, J = 8.1 Hz,
1 H), 7.29 (d, J = 7.8 Hz, 1 H), 7.69 (d, J = 7.8 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 20.4, 23.2, 33.4, 43.0, 55.7, 82.6,
106.8, 113.6, 119.0, 126.8, 131.3, 134.9, 156.1, 167.3, 186.1.
HRMS (ESI): m/z [M + H]+ calcd for C15H16ClO3S+: 311.0503;
found: 311.0505.
5-Methoxy-2-(5-phenyl-1,3-oxathiolan-2-ylidene)-3,4-dihydro-
naphthalen-1(2H)-one (3u)
Yield: 0.287 g (85%); yellow liquid.
IR (KBr): 2930, 1686, 1573, 1469, 798, 698 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.89 (s, 4 H), 3.26 (dd, J = 11.1,
10.2 Hz, 1 H), 3.53 (dd, J = 11.4, 6.6 Hz, 1 H), 3.85 (s, 3 H), 5.58
(dd, J = 9.9, 6.0 Hz, 1 H), 6.98 (d, J = 8.1 Hz, 2 H), 7.41–7.27 (m,
4 H), 7.70 (d, J = 7.5 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 20.4, 23.3, 38.1, 55.6, 85.9, 106.4,
113.4, 126.1, 126.8, 128.8, 131.3, 135.1, 137.2, 156.0, 171.5, 190.8.
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Ila, H.; Junjappa, H. Synthesis 1993, 959. (c) Bhat, L.; Ila,
H.; Junjappa, H. J. Chem. Soc., Perkin Trans. 1 1994, 1749.
(d) Guidot, J. P.; Gall, T. L. J. Org. Chem. 1993, 58, 5271.
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T.; Averett, D. R. Antimicrob. Agents Chemother. 1996, 40,
520. (f) Bollinger, F. G. Eur. Pat. Appl EP, 11473, 1980;
Chem. Abstr. 1981, 94, 175100a.
HRMS (ESI): m/z [M + H]+ calcd for C20H19O3S+: 339.1049; found:
339.1059.
Intermediate A
Yellow solid; mp 110–112 °C.
1H NMR (300 MHz, CDCl3): δ = 2.57 (s, 3 H), 2.85 (s, 1 H, D2O
exchangeable), 3.32–3.25 (m, 2 H), 3.73–3.70 (m, 2 H), 4.18–4.06
(m, 1 H), 6.69 (s, 1 H), 7.11 (s, 1 H), 7.58 (d, J = 4.8 Hz, 1 H), 7.67
(s, 1 H).
(6) Zhang, S.-J.; Liu, Q.; Chen, Y.-Z. Indian J. Chem., Sect. B:
Org. Chem. Incl. Med. Chem. 2000, 39, 147.
13C NMR (75 MHz, CDCl3): δ = 17.4, 35.7, 48.1, 70.1, 112.1, 128.0,
130.2, 132.7, 145.7, 168.6, 178.6.
(7) (a) Purkayastha, M. L.; Chandrasekharan, M.;
Vishwakarma, J. N.; Illa, H.; Junjappa, H. Synthesis 1993,
245. (b) Liu, Q.; Xu, B. L.; Zhao, H. W. Chemical Research
in Chinese University 1994, 10, 369. (c) Samuel, R.;
Asokan, C. V.; Suma, S.; Chandran, P.; Retnamma, S.;
Anabha, E. R. Tetrahedron Lett. 2007, 48, 8376.
(8) (a) Alam, M.; Wise, C.; Baxter, C. A.; Cleator, E.;
Walkinshaw, A. Org. Process Res. Dev. 2012, 16, 435.
(b) Smith, J. G. Synthesis 1984, 629. (c) Pineschi, M. Eur. J.
Org. Chem. 2006, 4979. (d) Hanson, R. M. Chem. Rev.
1991, 91, 437. (e) Schneider, C.; Brauner, J. Eur. J. Org.
Chem. 2001, 4445. (f) Ozaki, S.; Matsui, E.; Yoshinaga, H.;
Kitagawa, S. Tetrahedron Lett. 2000, 41, 2621. (g) Li, Z.;
Zhou, Z.; Li, K.; Wang, L.; Zhou, Q.; Tang, C. Tetrahedron
Lett. 2002, 43, 7609.
(9) (a) Williams, D. R.; Plummer, S. V.; Patnaik, S.
Tetrahedron 2011, 67, 5083. (b) Singh, G. S.; Mollet, K.;
D’hooghe, M.; De Kimpe, N. Chem. Rev. 2013, 113, 1441.
(c) Huerou, Y. L.; Doyon, J.; Gree, R. L. J. Org. Chem.
1999, 64, 6782. (d) Gu, X.-P.; Ikeda, I.; Okahara, M. Bull.
Chem. Soc. Jpn. 1987, 60, 667. (e) Chen, Y.-L.; Lu, C.-M.;
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C. Bioorg. Med. Chem. 2005, 13, 5710. (f) Toda, T.;
Karikomi, M.; Ohshima, M.; Yoshida, M. Heterocycles
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Acknowledgment
We gratefully acknowledge the generous financial support from the
Science and Engineering Research Board (SB/S1/OC-30/2013),
and the Council of Scientific and Industrial Research
[02(0072)/12/EMR-II], New Delhi. K.R. is highly grateful to
DAAD and George-August-Universität-Göttingen for financial
support as a DAAD fellowship. Prolific academic discussions with
Prof. H. Ila, JNCASR, Bangalore are greatly appreciated.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
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(14) CCDC 981652 (3e), CCDC 981650 (3r) and CCDC 981651
(A). Crystallographic data for these compounds can be
obtained free of charge from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; Fax: +44(1223)336033; E-mail:
deposit@ccdc.cam.ac.uk.
(13) Recent papers: (a) Verma, R. K.; Verma, G. K.; Shukla, G.;
Nagaraju, A.; Singh, M. S. ACS Comb. Sci. 2012, 14, 224.
Synthesis 2014, 46, 1815–1822
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