Organic Letters
Letter
energy.22 Instead, two C−F bonds cleaved under metal-free and
additive-free conditions (Scheme 1d). To the best of our
knowledge, this is the first literature report detailing a
thiocarbonylation reaction of gem-difluoroalkenes to date.
Initially, our study started with the optimization of reaction
conditions using methyl 4-(2,2-difluorovinyl)benzoate 1a with
4-methylbenzenethiol 2a as model substrates. This initial study
design involved the use of Lewis acids to facilitate the formation
of thioesters.23 Thus, B(C6F5)3 was applied to catalyze reaction
in DCE and successfully afforded desired product 3a in 72%
yield (Table 1, entry 1). Other Lewis acids such as BF3·Et2O,
a
Scheme 2. Substrate Scope of gem-Difluoroalkenes 1
a
Table 1. Optimization of Reaction Conditions
b
entry
catalyst
T (°C)
solvent
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
MeCN
THF
1,4-dioxane
DMF
toluene
yield (%)
1
2
3
4
5
6
7
8
B(C6F5)3
BF3·Et2O
Cu(OTf)2
AgOTf
Fe(OTf)2
FeCl3
60
60
60
60
60
60
60
80
80
80
80
80
80
72
60
52
67
46
62
64
76
0
0
0
0
70
a
Reaction conditions: 1a (0.5 mmol) and 2a (0.6 mmol) in DCE (0.1
mL) at 80 °C for 6 h. Isolated yields for each product.
a
Scheme 3. Substrate Scope of Thiols 2
9
10
11
12
13
a
Reaction conditions: 1a (0.5 mmol, 1.0 equiv), 2a (0.6 mmol, 1.2
b
equiv), catalyst (2 mol %), solvent (0.1 mL). Isolated yield.
Cu(OTf)2, AgOTf, Fe(OTf)2, and FeCl3 gave inferior results
(Table 1, entries 2−6). To our surprise, 64% of 3a could also be
obtained in the absence of a catalyst, providing evidence that
this reaction may have proceeded through an unexpected
mechanistic pathway. Furthermore, increasing the reaction
temperature to 80 °C improve the yield of compound 3a to
76%. Other solvents, such as MeCN, THF, 1,4-dioxane, DMF,
and toluene, provided product 3a in lower yields (entries 7−
13). Finally, the optimal conditions were determined as follows:
1a and 2a (1.2 equiv), DCE, 80 °C, 6 h.
a
With the optimized reaction conditions in hand, the scope
and limitations of gem-difluoroalkenes 1 were examined
(Scheme 2). gem-Difluorostyrenes, with both electron-with-
drawing (CO2Me, CN, Cl, and Br) and electron-donating
groups (tBu and Ph) at the para-, ortho-, and meta-positions of
the benzene ring, were found to be well tolerated and reacted
smoothly with 4-methylbenzenethiol 2a to afford compounds
3a−3h in 70−82% yields. Furthermore, the use of a
trimethoxyl-substituted gem-difluoroalkene provided com-
pound 3i in 82% yield. The reaction of heteroaryl gem-
difluoroalkenes 1j, 1k, and 1l successfully afforded 3j, 3k, and 3l
in 79%, 71%, and 64% yield, respectively. Moreover, 2-(2,2-
difluorovinyl)naphthalene 1m was also found to be capable of
reacting with 2a, providing 3m in 80% yield. However, no
corresponding products 3n or 3o could be obtained in this
reaction.
Reaction conditions: 1a (0.5 mmol) and 2a (0.6 mmol) in DCE (0.1
mL) at 80 °C for 6 h. Isolated yields for each product.
moderate yields and proceeded smoothly for thiophenols
bearing either electron-withdrawing (F, Cl, Br, and CF3) or
electron-donating (Me and OMe) substituents on the aromatic
ring. Moreover, hydroxyl group-substituted thiophenol and 2-
naphthalenethiol were well tolerated, leading to the corre-
sponding products 3u and 3aa in yields of 76% and 70%,
respectively. When a variety of alkyl-substituted substrates were
examined, no desired products were obtained (3ab−3ad).
To demonstrate the potential application of this method, a
gram-scale reaction was performed. The reaction of 1a was
performed on 6 mmol scale, affording 3a in 68% yield (Scheme
4a). Furthermore, we evaluated the protocol in the late-stage
functionalization of natural products. Estrone and L-menthol
derivatives could be thiocarbonylated under the standard
reaction conditions, and the corresponding products (3ae and
The substrate scope with respect to various thiol species was
also investigated (Scheme 3). The corresponding reaction
sequences afford the desired products (3p−3t and 3v−3z) in
B
Org. Lett. XXXX, XXX, XXX−XXX