X. Chen, J. Xu / Tetrahedron Letters xxx (2017) xxx–xxx
3
Table 2
amount of the catalyst resulted in the decrease of the yield and the
The scope of substrates.a
yield decreased sharply when the amount of the catalyst was
decreased to 0.5 equiv. It was suggested that the equivalent
amount of the catalyst was necessary in the reaction system due
to the strong coordination ability of the sulfur atom in thiiranes.
The sulfur atom may consume an equivalent amount of the cata-
lyst (Table 1, entries 12–14). Solvents were screened because dif-
ferent solvents have different absorption of microwave energy,
and finally 1,2-dichloroethane (DCE) was chosen as the best sol-
vent. We considered whether the crystallized water in the
CuSO4Á5H2O catalyst would affect the yield, anhydrous CuSO4
was tried and the results showed that only a trace amount of the
product was obtained (Table 1, entry 18). 10 Equiv. of water were
added into the reaction system when anhydrous CuSO4 was
applied as the catalyst, a yield of 39% was obtained, similar to that
with CuSO4Á5H2O as the catalyst (Table 1, entry 19). Thus, we spec-
ulated that the crystallized waters as ligands of the copper ion
affected the catalytic activity of the catalyst. To attempt further
optimization of the reaction, ethylene glycol which is relatively
similar to water was selected as a ligand under anhydrous
CuSO4-assisted conditions, the final yield was 22%. However, when
ethylene glycol dimethyl ether without active hydrogen or
ethylenediamine were tested as ligands, no product was obtained
(Table 1, entries 20–22). It can be concluded that the ligand water
in the copper catalyst has a crucial effect on the reaction. Unfortu-
nately, although the amount of water was varied or an appropriate
amount of water was added to the other catalyst systems, the yield
was still not improved. A number of experiments have been
attempted to improve the yield through addition of different metal
ligands, some acids, bases, or inorganic salts in the catalytic sys-
tem, but all the attempts failed. The optimum reaction conditions
were finally identified as follows: 1a/2a = 2:1 under the catalysis
of 2 equiv. of CuSO4Á5H2O as the catalyst in DCE as solvent at
100 °C for 20 min microwave irradiation (Table 1, entry 12).
With the optimized reaction conditions, the reaction scope was
then evaluated (Table 2). First, different diazo compounds 2 were
examined. Methyl 2-diazo-3-oxobutanoate (2b) gave the desired
product 3b in a moderate yield of 47%, slightly lower than the ethyl
ester. Ethyl 2-diazo-3-oxo-3-phenylpropanoate (2c) generated the
corresponding product 3c in a similar yield. When the diazo com-
pound was replaced by cyclic diazodiketones, 2-diazocyclohexane-
1,3-diones 2d and 2e, 56% of product 3d and 43% of product 3e
were obtained, respectively. However, linear diazodiketones,
3-diazo-2,4-pentanedione (2f) and 2-diazo-1,3-butanedione (2g)
only generated trace amounts of products and diethyl 2-diazoma-
lonate (2h) and ethyl 2-diazo-4,4,4-trifluoro-3-oxobutanoate (2i)
failed in the reaction with thiirane 1a. We further expanded differ-
ent thiiranes 1 from 1,2-disubstituted bicyclic 7-thiabicyclo[4.1.0]
heptane (1a) to monosubstituted thiiranes, n-butylthiirane (1b),
n-hexythiirane (1c), and 2-phenylethylthiirane (1d). n-Butylthi-
irane (1b) generated the corresponding products 3j-3n in low to
moderate yields when it reacted with three diazoketoesters 2a-c
and two cyclic diazodiketones 2d,e. Both n-hexylthiirane (1c) and
2-phenylethylthiirane (1d) can react with representative diazoke-
toesters 2a,b and cyclic diazodiketone 2d, yielding the correspond-
ing products 3o-3t in low to moderate yields. The results indicate
that the yields of monosubstituted thiiranes are generally lower
than those of disubstituted thiiranes, and the longer the alkyl
chain, the more the yield decreased. This is possibly mainly attrib-
uted to the large ring tension in thiirane 1a, which leads to a more
favorable ring-opening reaction. Furthermore, when five-mem-
bered ring analog of thiirane 1a, 6-thiabicyclo[3.1.0]hexane (1e),
was attempted to react with ethyl 2-diazo-3-oxobutanoate (2a),
the corresponding product 3u was not observed. For 1,1-disubsti-
O
O
O
R1
R2
S
2 equiv CuSO4•5H2O
S
R4
R3
R4
+
microwave
100 °C 20 min DCE
R2
R3
R1
N2
O
3
( )
1
2
O
S
O
O
O
S
S
S
O
O
O
O
Ph
O
O
O
(+)
(+)
(+)
(+)
3a 55%b
3c 51%
3b
3d 56%
47%
O
S
O
O
O
S
S
S
O
O
Ph
O
O
O
O
(+)
(+)
(+)
3h
0%
3f trace
3e
3g
43%
trace
O
O
O
O
S
S
S
S
O
O
O
O
O
O
(
(
)
3
O
Ph
(
(
)
)
(
(
)
O
CF3
0%
O
3
O
O
3
3l 33%
3j 50%
3k
3i
42%
O
O
S
O
S
S
S
)
3
O
O
(
(
)
3
)
O
O
5
5
3n 35%
3o
3p
42%
O
40%
O
3m 38%
O
S
O
S
S
S
Ph
O
Ph
Ph
O
O
)
O
3q
O
3s
O
5
O
3r
27%
3t
24%
26%
O
30%
O
S
S
Ph
O
O
O
3u
3v
0%
trace
a
Reaction conditions: Diazo compounds 2 (0.3 mmol) and thiiranes 1 (0.6 mmol)
were added in DCE (1.0 mL) in a 10 mL microwave tube, then CuSO4Á5H2O
(0.6 mmol) was added, and the reaction mixture was stirred at 100 °C for 20 mins
under microwave irradiation in a sealed vessel. All yields are isolated yields.
amount of product 3v was obtained possibly due to the steric hin-
drance of 1,1-disubstituted thiirane.
In the previous report,13 Capozzi and coworkers synthesized
cis-1-(3-methyl-4a,7,8,8a-tetrahydro-6H-pyrano[2,3-b][1,4]
oxathiine-2-yl)ethan-1-one by the hetero-Diels-Alder reaction of
2,4-dioxopentane-3-thione and dihydropyrane and determined
two hydrogen atoms at the positions 4a and 8a were in cis-config-
uration. Moreover, Lacour and his coworkers prepared bicyclic 1,4-
dioxene derivatives with the two hydrogens at their positions 4a
and 8a in cis-configuration.14 However, after carefully analyzing
the coupling constants (Jab > 10 Hz) between the positions 4a and
8a of products 3a-3e, we identified the two hydrogens at the posi-
tions 4a and 8a should be trans. In other words, products 3a-e are
2-substituted trans-3-acyl-4a,5,6,7,8,8a-hexahydrobenzo[b][1,4]
oxathiines. To further verify our stereochemical assignment, we
cultivated single crystals of solid product 3c and determined its
single crystal X-ray diffraction analysis (Fig. 2).17 The results are
consistent with the assigned stereostructure identified by 1H
NMR analysis. At this point, we can be pleased to say that it is
the first time that we synthesized ethyl trans-3-acyl-
4a,5,6,7,8,8a-hexahydrobenzo[b][1,4]oxathiines.
After obtaining the above information, we proposed the follow-
ing mechanism, the reaction of cyclic thiirane 1a and diazo com-
pound 2a is selected as an example to illustrate the mechanism
(Scheme 3). First, diazo compound 2a reacts with the metallic cop-
per catalyst to form a metal carbene intermediate A by loss of
tuted 1-methyl-1-(2-phenylethyl)thiirane (1f), only
a trace
nitrogen. Then thiirane 1a as
a nucleophile attacks the