Journal of the American Chemical Society
Communication
(to 1) of KOH, which is one of the standard conditions for
asymmetric hydroarylation of α,β-unsaturated ketones,1,2 the
product (R)-4a of 40% ee was formed in a slightly higher yield
(14%) (entry 7), and with 3.0 equiv of KOH the % ee of (R)-4a
was increased to 66% ee (entry 8). The higher % ee (40% and
66% ee vs 10% ee in entry 5) indicates that a part of 4a is
produced by the asymmetric arylation of 2 under these
conditions, but the isomerization of 1 into 2 is not fast enough
to supply 2 for the catalytic arylation to produce a high yield of
4a. The recovery of unreacted sulfolene as 3-sulfolene (1) is
consistent with this slow isomerization. The addition of
5.0 equiv of KOH greatly improved the result (entry 9). The
reaction gave (R)-4a of 94% ee in 87% yield. Finally, with
10 equiv of KOH, (R)-4a of 98% ee was produced in 91% yield
(entry 10). The amount of boronic acid 3a was decreased from
3.0 to 1.5 equiv (to 1) without loss of yield or selectivity
(entry 11). The high enantiomeric purity (98% ee) of 4a
produced with 10 equiv of KOH for the reaction starting with
3-sulfolene (1) (entries 10 and 11) is almost the same as 99%
ee observed for the reaction starting with 2-sulfolene (2)
(entry 6). Interestingly, the yield of 4a is higher in the reaction
of 3-sulfolene (1) under the basic conditions than that in the
reaction of 2-sulfolene (2) (entries 6 and 12) where the
formation of side product 519 is accompanied. It should be
noted that the yield and % ee of 4a are low with other ligands,
for example, Ph-bod22 and binap (entries 13 and 14). It is likely
that the Rh-catalyzed arylation of 2-sulfolene (2) is not fast
enough with other chiral ligands to produce a high yield of 4a.
Under the optimized conditions found for the reaction of
3-sulfolene (1) with 4-MeOC6H4B(OH)2 (3a) (entry 11 in
Table 1), the Rh/(R,R)-Fc-tfb catalyst was examined for its
scope in the asymmetric hydroarylation of 1 with several other
arylboronic acids 3. The results summarized in Table 2 show
that the reaction in the presence of 10 equiv of KOH is appli-
cable to a variety of arylboronic acids. Thus, the phenylboronic
acids substituted with methyl and alkoxy groups at para, meta,
and ortho positions all gave the corresponding products with
high % ee ranging between 98% and 99% ee except for
2-MeC6H4 (entries 3−8). The enantioselectivity was higher
(>99% ee) in the arylation with boronic acids bearing electron-
withdrawing groups, halides and trifluoromethyl, on the para
position (entries 9−12). The asymmetric introduction of
3-cyclopentyloxy-4-methoxyphenyl group provided us with
one step synthesis of enantiomerically enriched (S)-4o which
is of pharmaceutical interest23 (entry 15).
Table 1. Rhodium-Catalyzed Asymmetric Arylation of 3-
Sulfolene (1) and 2-Sulfolene (2)
a
additive
ratio of
c
yield
d
% ee
4a
b
entry 1 or 2 ligand on Rh
(equiv)
1:2:4a
(%) 4a
e
1
1
2
1
2
1
2
1
1
1
1
1
2
1
1
(S)-binap
(S)-binap
92:0:8
8
37 (S)
91 (R)
e
2
0:60:40
94:0: 6
0:0: 100
89:0:11
0:0:100
85:1:14
77:8:15
4:4:92
38
90
10
f
3
cod
f
4
cod
g
g
i
5
(R,R)-Fc-tfb
(R,R)-Fc-tfb
(R,R)-Fc-tfb
(R,R)-Fc-tfb
(R,R)-Fc-tfb
(R,R)-Fc-tfb
(R,R)-Fc-tfb
(R,R)-Fc-tfb
10 (R)
99 (R)
40 (R)
66 (R)
94 (R)
98 (R)
98 (R)
99 (R)
23 (R)
67 (R)
h
6
66
7
KOH (1.0)
KOH (3.0)
KOH (5.0)
14
13
87
91
90
i
8
i
9
i
10
11
12
13
14
KOH (10.0) 0:0:100
KOH (10.0) 0:0:100
j
j
j
j
i
i
h
KOH (10.0) 0:0:100
79
k
l
(S,S)-Ph-bod KOH (10.0)
39
30
m
l
(S)-binap
KOH (10.0)
a
Reaction conditions: 3- or 2-sulfolene (0.15 mmol), ArB(OH)2
(0.45 mmol unless otherwise noted), Rh catalyst (5 mol % of Rh),
b
c
dioxane/H2O (1.0/0.1 mL). Equivalents to sulfolene. Determined
d
e
by 1H NMR of the reaction mixture. Isolated yield. [Rh(OH)-
(coe)2]2/(S)-binap. [Rh(OH)(cod)]2. [Rh(OH)((R,R)-Fc-tfb)]2.
As a side product, the formation of 3,3′-(4-methoxy-1,2-phenylene)-
bis(tetrahydrothiophene 1,1-dioxide) (5) was observed. [RhCl((R,R)-
Fc-tfb)]2. ArB(OH)2 (0.23 mmol). [RhCl(coe)2]2/(S,S)-Ph-bod.
Not determined. [RhCl(coe)2]2/(S)-binap.
f
g
h
i
j
k
l
m
Scheme 2. Rhodium-Catalyzed Asymmetric Arylation of 3-
and 2-Sulfolenes
The absolute configuration of the product 4k (Ar = 4-Br-
C6H4) was determined to be (R) by its X-ray crystallographic
analysis.24 The R configuration obtained with (R,R)-Fc-tfb
is rationalized by the coordination of 2-sulfolene to an
aryl−rhodium intermediate with its si face. The coordination
with the other face is much less favorable due to the steric
repulsions between the cyclic alkyl chain of 2-sulfolene
and one of the ferrocenyl groups on the diene ligand25
(Scheme 3). All the products under the present conditions
with (R,R)-Fc-tfb ligand are predicted to have the same
absolute configuration (R).
For six-membered ring sulfone, the Rh-catalyzed asymmetric
arylation under the isomerization condition is more difficult
and challenging, because equilibration of the isomerization
between allyl sulfone 6 and alkenyl sulfone 7 is heavily on the
allyl sulfone side.26 In our experiments with DBU as a base in
THF at 25 °C, the equilibrated ratio was 97/3 for 6/7.27 Under
the standard conditions (1.5 equiv ArB(OH)2, 10 equiv KOH,
compatible with the rhodium-catalyzed asymmetric arylation of
2, we have a chance to obtain a high yield of the arylation
product 4a with high enantioselectivity.
Several basic conditions were examined by changing the
amount of KOH (entries 7−10 in Table 1). With 1.0 equiv
3202
J. Am. Chem. Soc. 2015, 137, 3201−3204