Organic Letters
Letter
copper-catalyzed protocol for synthesis of benzodithiole
derivatives 2 through the reaction of 2-bromo-benzothioa-
mides 1 with S8 under alkaline conditions. Furthermore, this
copper-mediated reaction provided benzothiaselenole deriva-
tives 6 when S8 was replaced with Se powder.
As shown in Table 1, the model reaction of 2-bromo-N-
phenylbenzothioamide (1a) and S8 was performed in refluxing
With the optimized reaction conditions in hand, we
examined the generality of the protocol (Scheme 1). Initially,
substrates with various substituents on the imine nitrogen
atom were investigated.
In addition to aliphatic groups, the reaction tolerated various
aromatic substituents bearing either electron-donating (methyl,
methoxy, iso-propyl) or electron-withdrawing substituents,
such as nitro and chloro, as well as heteroaryl motifs. All of
these substrates underwent the cascade coupling/cyclization
smoothly to afford products 2a−q in good to excellent yields
(62−90%, Scheme 1). The structure of product 2 was
supported through single-crystal X-ray diffraction analysis of
2l, as shown in Scheme 1.
a
Table 1. Optimization of the Reaction Conditions
With respect to the substituents on the benzene ring, we
were delighted to find that various groups, such as methyl,
methoxy, chloro, and fluoro, at either the five- or seven-
position could be employed, furnishing the corresponding
benzodithiole products 2r−ad in 75−91% yields (Scheme 1).
Additionally, a pyridine derivative was also an effective
coupling/cyclization partner, affording product 2ae in 91%
yield.
To evaluate possible further applications of the developed
protocol, several benzodithioles were transformed into their
corresponding BDT derivatives (3a−e) in high yields via acidic
hydrolysis (Scheme 1). The developed protocol undoubtedly
provides an efficient and practical method for the preparation
of these valuable and medicinally relevant compounds.
Furthermore, the synthetic conversion of 3a into the important
compounds 422 (Beaucage’s reagent) and 523 was attained in
good yield by reacting with m-CPBA and hydrogen peroxide,
respectively.
Next, we reasoned that the corresponding selenium analogue
of 2 would be accessible by replacing the sulfur source with an
appropriate selenium source. Intriguingly, conducting the
reaction under the optimized reaction conditions using Se
powder instead of S8 provided (Z)-N-aryl-3H-benzo[d][1,2]-
thiaselenol-3-imines 6 rather than (Z)-N-aryl-3H-benzo[c]-
[1,2]thiaselenol-3-imines. The structure of product 6u was
supported by X-ray diffraction analysis. (See Scheme 2.)
Gratifyingly, a variety of substituted aromatic motifs, such as
alkylphenyl (e.g., methyl, isopropyl, and tert-butyl), alkox-
yphenyl (e.g., methoxy and ethoxy), and mono- and
dihalogenated phenyl (e.g., F and Cl) reacted smoothly to
give the desired products under the optimized reaction
conditions. A total of 30 benzothiaselenoles were obtained in
moderate to high yields (56−78%, Scheme 2).
A proposed mechanism for the synthesis of 2 and 6 is
detailed in Scheme 3. According to the structure of the
products 2 and 6, benzothietane-2-imine B is envisioned as a
key intermediate. Initially, benzothioamide 1 is believed to be
converted to anion A in the presence of a base. Then,
benzothietane-2-imine B is produced via an intramolecular
copper-catalyzed Ullmann coupling reaction to form thietane
adduct B.24 Subsequent cleavage of the C−S bond occurs to
give the ring-opened thiophenolate D. In the following step,
intermediate D reacts with S8 or Se to form an S−S or S−Se
bond, which is similar to reacting Na2S with S8 to form Na2S2.
Finally, intermediate E undergoes an addition/elimination
process to give the target structure 2 or 6. An alternative
mechanism involves the initial formation of a copper thiolate
adduct (G), which undergoes oxidative addition into the C−Br
bond to form the five-membered cupracycle H. The
subsequent migration and insertion of sulfur or selenium
b
entry
catalyst
CuI
base
ligand
solvent
yield (%)
1
2
3
4
5
6
7
8
py
py
py
py
py
py
py
py
py
py
py
py
46
37
26
39
CuBr
CuCl
CuOAc
CuBr2
Cu(OAc)2
CuI
CuI
CuI
CuI
CuI
PPh3
62
58
68
76
72
73
69
85
37
86
76
79
82
69
L-proline
o-phen
o-phen
o-phen
o-phen
o-phen
o-phen
o-phen
o-phen
o-phen
o-phen
o-phen
o-phen
9
10
11
12
13
14
15
16
17
18
19
20
Cs2CO3
K2CO3
CuI
CuI
Na2CO3
NaHCO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
c
py
CuI
DMF
DMF
DMF
dioxane
DMSO
DMA
toluene
d
CuI
e
CuI
CuI
CuI
CuI
CuI
a
Reaction conditions: 1a (146 mg, 0.5 mmol), S8 (154 mg, 0.6
mmol), catalyst (0.05 mmol), ligand (0.1 mmol), base (0.5 mmol),
solvent (5.0 mL), 100 °C. Isolated yield. Reaction carried out with
1.0 mmol NaHCO3 (100 mg, 1.2 mmol). Reaction run with 5 mol %
b
c
d
e
CuI (0.025 mmol). Reaction run with 20 mol % CuI (0.1 mmol).
pyridine using 10 mol % CuI as a catalyst, affording 2a in 46%
yield (Table 1, entry 1). To improve the yield, several reaction
parameters were varied, including the copper source, base,
ligand, and solvent. Using alternative copper precursors, such
as CuBr, CuCl, and CuOAc, demonstrated that CuI was
superior (cf. Table 1, entry 1 and entries 2−4). Furthermore,
the use of copper(II) precursors, such as CuBr2 and
Cu(OAc)2, led to no desired product formation (Table 1,
entries 5 and 6). The addition of frequently used ligands, such
as Ph3P, o-phen, and L-proline, revealed that a substantial
increase in yield was possible when using o-phen, providing 2a
in 68% yield (Table 1, entry 9). A survey of inorganic bases
showed that Cs2CO3 furnished product 2a in 76% yield (Table
1, entry 10). Other carbonate bases, such as K2CO3, Na2CO3,
and NaHCO3, also promoted the reaction (Table 1, entries
11−13) but provided lower yields of 2a compared with
Cs2CO3. Finally, the reaction also proceeded in common
organic solvents, such as DMF, dioxane, DMSO, DMA, and
toluene (Table 1, entries 14−20). Here DMF was found to be
the best solvent for this reaction, leading to 2a in 85% yield
(Table 1, entry 14).19−21
B
Org. Lett. XXXX, XXX, XXX−XXX