1552
Table 2. Scope of carboxylic acids 1 and ketene silyl acetals 2a
Table 3. Reductive cyanation of carboxylic acids 1a
OSiMe3
R2
HSiEt3
cat. InI3
Me3SiCN
HO
R1
H
HO
R1
H
TMDS
O
6
OR4
O
+
HO
R1
H
HO
R1
H
CN
H
R1
OH
rt, 3 min
rt, 1-2 h
HSiEt3
cat. InI3
H3SiPh
O
R3
OR4
H
2
+
1
7
4
R1
OH
R3
R2
rt, 3 min
rt, 1-2 h
1
3
4
HO
H
HO
8
H
2a; R2 = R3 = R4 = Me
2c; R2 = R3 = R4 = Et
2b; R2 = R3 = -(C5H10)-, R4 = Me 2d; R2 = H, R3 = Ph, R4 = Me
Ph
CN
CN
7a 88% (3%)
7l 90% (5%)
O
O
O
HO
4
H
HO
H
HO H
Cl
OMe
OMe
3ca 71% (0%)
OMe
HO
H
4
HO
H
HO
H
CN
3ba 89% (trace)
3da 86% (n.d.)
Ph
O
CN
7nb 77% (0%)
CN
O
O
O
HO
5
H
HO
3
H
HO
3
H
7mb 79% (6%)
7h 85% (12%)
Br
OMe
OMe
OMe
aReaction conditions: 1st step: 1 (1 equiv), HSiEt3 (1 equiv),
InI3 (0.05 equiv), CH2Cl2 (1 M), rt, 3 min. 2nd step: 6 (2 equiv),
TMDS (1 equiv), rt, 1 h. Yields were determined by H NMR
3ea 76% (15%)
3fa 70% (11%)
3gab 60% (n.d.)
O
O
O
HO
H
HO
H
HO
H
1
OMe
OMe
OMe
analysis using an internal standard for crude products. Yields
Ph
b
in parenthesis indicate side products 4. In the 2nd step, the
3ha 89% (1%)
3ja 82%c (8%)
3iab 21% (0%)
reaction was carried out for 2 h.
O
HO
H
O
HO
H
O
HO
H
OMe
Ph
OEt
Ph
OMe
3ac, and 3ad in moderate-to-high yields. Unfortunately, non-
substituted ketene silyl acetals were not applicable to this
reaction system because they are unstable under these con-
ditions.
Ph
3kbb 71% (trace)
3ac 95% (3%)
3ad 64%d (10%)
aReaction conditions: 1st step: 1 (1 equiv), HSiEt3 (1 equiv),
InI3 (0.05 equiv), CH2Cl2 (1 M), rt, 3 min. 2nd step: 2 (1.5
equiv), H3SiPh (1 equiv), rt, 1 h. Yields were determined by
1H NMR analysis using an internal standard for crude
products. Yields in parenthesis indicate side products 4. bIn
the 2nd step, 2 (2 equiv), H3SiPh (2 equiv), rt, 2 h. cthreo/
Silyl cyanide 6 was also found to be applicable to this
reaction instead of ketene silyl acetal 2 (Table 3). In this case,
the employment of TMDS in the second step successfully gave
reductive cyanation product 7a in 88% yield with a small
amount of alcohol 4a, and with no further reduction of the cyano
moiety.17 Alkenyl and benzyloxy groups were tolerated under
the reaction conditions to afford the corresponding cyanohydrins
7l and 7m, respectively. Cyclohexanecarboxylic acid (1h) also
provided cyanohydrin 7h along with 12% of side-product 4.
The transformation of pivalic acid (1n) to the corresponding
cyanohydrin 7n progressed despite the large steric hindrance.
Figure 1 shows a plausible reaction mechanism. The InI3
catalyst apparently affects the dehydrogenation of carboxylic
acid 1 with HSiEt3 to provide silyl ester 8, because no reaction
takes place without the catalyst.12b In the second step, the InI3-
catalyzed hydrosilylation of 8 with HSi2 such as H3SiPh and
TMDS produces acetal intermediate 9. The employment of
reactive HSi2 was essential because in situ generated silyl ester 8
has a bulky alkoxy moiety (OSiEt3) as compared to the ester.13a
Elimination of the siloxy moiety from 9 gives either the
oxocarbenium ion 10 or aldehyde 11. Then, the nucleophilic
addition of NuSiMe3 2 (or 6) affords silyl ether 12 and
regenerates InI3. When a mixture of 1a, 1 equiv of HSiEt3, and
ketene silyl acetal 2a was treated, a cross-Claisen condensation
proceeded sluggishly, furnishing 5aa in only 13% yield.18 This
result strongly suggested that the hydrosilylation of silyl ester 8
by a powerful HSi2 such as H3SiPh and TMDS is essential in the
second step. In contrast, mild hydrosilanes such as HSiEt3 and
HSiMe2Ph are appropriate in the first step.
d
erythro = 84:16. dr = 62:38.
yield of 3aa was increased to 87% along with a negligible
amount of side product 4a (Entry 8). It is noteworthy that no
formation of cross-Claisen condensation product 5aa was
observed. In contrast, the formation of 5aa was observed when
using PMHS, TMDS, H3SiPh, and HSi(OMe)3 as HSi1 because
of the presence of the coordinating group on the siloxy moiety of
the silyl ester intermediate (Entries 9-13).12b The combinations
of HSiMe2Ph/TMDS, HSiMe2Ph/H3SiPh, and HSiEt3/TMDS
also gave good yields of the desired product 3aa (Entries 6, 7,
and 14). The effect of InI3 was characteristic, and other indium
compounds such as InBr3, InCl3, and In(OTf)3 hardly promoted
the reaction despite the higher Lewis acidity (Entries 8 and
15-17).15
With the optimized conditions in hand (Table 1, Entry 8),
the scope of carboxylic acids 1 and ketene silyl acetals 2 was
investigated (Table 2). Simple aliphatic carboxylic acids 1b and
1c gave high yields of the desired products 3ba and 3ca,
respectively. Furthermore, several functional groups, chloro,
bromo, alkenyl, and alkynyl, were compatible with the reaction
conditions (3da, 3ea, 3fa, and 3ga). Cyclohexanecarboxylic acid
(1h) also gave the corresponding alcohol 3ha in an 89% yield.
However, the reaction of benzoic acid (1i) resulted in a low yield
of 3ia because of further reduction of the benzylic hydroxy
moiety.16 Carboxylic acid 1j possessed a chiral center at the
α-position and afforded the product 3ja with a reasonable
stereoselectivity. Disubstituted and monosubstituted ketene silyl
acetals (2b, 2c, and 2d) also provided the desired products 3kb,
In summary, we have demonstrated the indium triiodide-
catalyzed transformation of carboxylic acids to β-hydroxy esters
and cyanohydrins. The separate addition of two kinds of
hydrosilanes was an essential procedure, in which the generation
of silyl ester intermediates between the carboxylic acid and a
mild hydrosilane was followed by the addition of a powerful
Chem. Lett. 2013, 42, 1551-1553
© 2013 The Chemical Society of Japan
Inamoto, Yoshihiro
