Organic Letters
Letter
a
Rhodium-catalyzed asymmetric hydroarylation of electron-
deficient double bonds (CC, CO, or CN) with
organoboronic acids or their derivatives represents one of
the most reliable and straightforward approaches to
enantioenriched compounds.10 Chiral diene ligands have
played a central role in the control of the enantioselectivity,
and Rh(I)/diene was discovered as a useful catalytic system in
these transformations.11,12 Recently, the hydroarylation of C
N bonds in N-containing arenes has been developed as an
important route to chiral N-containing heterocycles.13 Taking
advantage of the fact that benzo[b]thiophene 1,1-dioxides can
be regarded as containing a special type of electron-deficient
CC double bonds, we envisioned that chiral 2,3-
dihydrobenzo[b]thiophene 1,1-dioxides could be constructed
through the rhodium-catalyzed asymmetric hydroarylation/
hydroalkenylation of benzo[b]thiophene 1,1-dioxides with
organoboranes.14,15 Herein we describe that the Rh/diene
catalytic system is competent in the asymmetric hydro-
arylation/hydroalkenylation of benzo[b]thiophene 1,1-diox-
ides, and the merging with downstream diastereodivergent
alkylations enables the introduction of two continuous
quaternary stereocenters (Scheme 1b).
Our investigation started with the reaction between
benzo[b]thiophene 1,1-dioxides 1a and phenylboronic acid
2a using rhodium(I) precatalysts and chiral ligands (Table 1).
The chiral diphosphine ligands (R)-binap and (R)-segphos
were initially tested with 1,4-dioxane/H2O as the solvent at
120 °C, affording the desired product 3a in 66% yield with
36% ee and in 72% yield with 61% ee, respectively (entries 1
and 2). Although the reaction was sluggish with the simple C2-
symmetric chiral diene ligand (R,R)-Ph-bod, the enantiose-
lectivity was elevated to 83% (entry 3). Encouraged by this
result, a series of reported chiral diene ligands L1−L7, were
evaluated in this transformation (entries 4−10).16,17 As for the
enantioselectivity of the reaction, it was found that the amide
diene ligands were superior to the ester ligands (entries 4 and 5
vs entries 9 and 10). The bulkier diene ligands generally
expressed better enantioselectivity (entry 4 vs entry 5; entries
6−9 vs entry 10), providing the hydroarylation product in 68%
yield with 88% ee when using L7 as the ligand (entry 10).
Inspired by this observation, the sterically bulkier chiral diene
ligands L8−L10 were designed and synthesized according to a
similar procedure.17g Whereas L8 failed to improve the
enantioselectivity of this transformation (entry 10 vs entry
11), both L9 and L10 showed an improved ee value (entry 10
vs entries 12 and 13). In this stage, the desired product can be
obtained in 75% yield with 92% ee (entry 12). Further
optimization of the reaction temperature (entry 14), the ratio
of the solvent mixture (entries 15−17), and the concentration
(entries 18, 19) were conducted, and it was found that slightly
decreasing the reaction concentration was beneficial to the
efficiency, providing the product in 81% yield with 93% ee
(entry 18). The absolute configuration of 3a was determined
by referring to its optical rotation of the literature.6
Table 1. Optimization of the Reaction Conditions
1,4-dioxane (mL)/H2O
b
c
entry
ligand
(mL)
yield (%) ee (%)
1
2
3
4
5
6
7
8
(R)-binap
(R)-segphos
(R,R)-Ph-bod
0.5/0.5
0.5/0.5
0.5/0.5
0.5/0.5
0.5/0.5
0.5/0.5
0.5/0.5
0.5/0.5
0.5/0.5
0.5/0.5
0.5/0.5
0.5/0.5
0.5/0.5
0.5/0.5
0.66/0.33
0.8/0.2
0.3/0.3
0.75/0.75
1.0/1.0
66
72
34
70
80
68
58
66
62
68
77
75
65
51
73
50
63
81
77
36
61
83
65
76
84
82
83
84
88
51
92
90
93
93
93
92
93
93
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
L9
L9
L9
L9
L9
L9
9
10
11
12
13
d
14
15
16
17
18
19
a
Reaction conditions: 1a (0.10 mmol), 2a (0.15 mmol), Rh-
(C2H4)2acac (4 mol %), ligand (5 mol %) in 1,4-dioxane/H2O at
120 °C for 12 h. Isolated yield. ee value was determined by HPLC
using a chiral stationary phase column. Reaction was run at 100 °C.
b
c
d
Ad = 1-adamantyl.
products (3b−3g) in yields of 64−76% with high enantiose-
lectivities (entries 2−7). Remarkably, the strained cyclo-
propane ring remained intact during the reaction (entry 8).
The catalytic system was competent for alkenyl substrates 1i
and 1j, affording the desired products in satisfactory yields with
satisfactory enantioselectivities (entries 9 and 10). Benzo[b]-
thiophene 1,1-dioxides bearing methyl (1k), methoxyl (1l),
and sulfonamide (1m) at the six-position exhibited similar
reactivities, yielding the corresponding products 3k−3m in
63−74% yield with 88−93% ee (entries 11−13). In addition, a
substrate bearing a seven-substituent was also tolerated under
the optimized reaction conditions (entry 14).
Applying an identical catalytic system, a series of arylboronic
acids were investigated in this reaction with benzo[b]-
thiophene 1,1-dioxide 1a (Table 3). As depicted in entries
1−8, a range of arylboronic acids with different para-
substituted functional groups, including alkyl (2b, 2c),
methoxyl (2d), halogen (2e, 2f), trifluoromethyl (2g), ester
With the optimized conditions, the scope of this trans-
formation was then investigated. A wide variety of benzo[b]-
thiophene 1,1-dioxides were readily arylated with high yields
and enantioselectivities, as depicted in Table 2. First, numerous
five-substituted benzo[b]thiophene 1,1-dioxides were tested.
Electron-donating or -withdrawing substrates with different
functional groups, including methyl (1b), methoxyl (1c), free
hydroxy (1d), halogen (1e, 1f), and phenyl (1g), were
tolerated in the reaction, which provided the hydroarylation
897
Org. Lett. 2021, 23, 896−901
Hu, Fangdong
