Organic Letters
Letter
where α-hydroxycarboxylic acid was synthesized via Brook
rearrangement and successive CO2 insertion.15
In this Letter, we investigated steps B and C and further
applied this system to the iterative one-pot multistep reductive
coupling of aldehyde and carbon dioxide.
First, the conditions for the carboxylation step B were
examined (Scheme 2). The silyloxybenzyl complex 1a was
butyldimethylsilyl (TBS) analogue of 1a had failed possibly
because the steric hindrance of the TBS group retarded the
insertion of p-tolualdehyde into the silylcopper complex. On
the contrary, triethylsilyl analogue 1b was successfully
synthesized in 45% yield by the reaction of the silylcopper
complex with p-tolualdehyde (step A in Scheme 1b; see
was treated with atmospheric pressure of CO2 in C6D6 and
then quenched with 1 M hydrochloric acid to give α-
hydroxycarboxylic acid 4 in 40% yield (estimated by 1H
NMR analysis of the crude product) (Scheme 2b). Although
the intermediate complex 2b could not be isolated due to its
instability, the insertion of CO2 was suggested by the
formation of the corresponding α-hydroxycarboxylic acid 4.
As a result of solvent optimization, DMF gave the highest yield
of α-hydroxycarboxylic acid 4 (96%, Scheme 2b; see Figure S3,
results, triethylsilyl analogue 1b and DMF were used for the
following studies.
Scheme 2. (a) Attempt for Carboxylation of α-
Silyloxybenzyl Complex 1a, (b) Carboxylation of α-
Silyloxybenzyl Complex 1b, and (c) Regeneration of
a
Silylcopper Complex 5
To complete the catalytic cycle shown in Scheme 1b, the
regeneration of silylcopper complex I (step C) is necessary.
Thus we investigated the transmetalation step C in Scheme 1b.
The regeneration of silylcopper 5 was confirmed, as shown in
Scheme 2c. The reaction of complex 2b, generated in situ from
1b in DMF, with silylborane Et3SiBpin in the absence of any
base gave silylcopper complex 5 in 16% yield. Whereas
addition of NaOtBu, Zn(OMe)2, or CsF provided no
significant improvement of the yield of 5, Cs2CO3 or CsOH
was found to be effective in the regeneration of the silyl
complex 5. (See Table S2 for details.) In particular, CsOH
gave the highest yield of the silyl complex 5 (40% yield based
on 1b). Moreover, both with or without CsOH, α-
hydroxycarboxylic acid 4 was obtained in 72 or 71% yield
based on the starting complex 1b, respectively, after acid
quenching of the reaction mixture. Thus we concluded that
CsOH was the most effective base for this reaction.
As a last step, we assembled the elementary reactions A, B,
and C. An admixture of (IPr)CuOtBu, Et3SiBpin, p-
tolualdehyde, and CsOH in one pot did not afford the desired
α-hydroxycarboxylic acid 4 (Table 1, entries 1 and 2). The
corresponding benzyl alcohol 8 was obtained instead. Benzyl
alcohol 8 was probably produced via the protonation of 1b by
pinB−OH, which is generated from Et3SiBpin and CsOH,
followed by hydrolysis of the Si−O bond during the workup.
a
NMR yields in panels b and c are based on 1b and calculated using
1,3,5-trimethoxybenzene as an internal standard.
generated from p-tolualdehyde and (IPr)CuSiMe2Ph according
to the literature method.14 When 1a was placed under a CO2
atmosphere in C6D6, benzoate complex 3, instead of
carboxylate complex 2a, was obtained as a major product in
37% yield (Scheme 2a). Complex 3 was probably formed by
the intramolecular migration of the Ph group on the silicon
atom to the copper center followed by the insertion of CO2
into the Cu−Ph bond. To prevent this undesired phenyl
migration, we next replaced the PhMe2Si− group with
trialkylsilyl groups. The attempt to synthesize the t-
Table 1. Attempts for the Catalytic Formation of α-Hydroxycarboxylic Acid 4
a
yield (%)
entry
CO2 (MPa)
base
solvent
conv. of 6 (%)
4
7
8
b
1
0.1
0.1
0.1
2
CsOH
CsOH
NaOtBu
NaOtBu
NaOtBu
DMF
neat
neat
neat
DMF
7.73
70.1
92.1
83.4
1.5
0.0
0.0
10.5
11.1
0.0
0.0
0.0
21.1
20.0
0.0
4.96
31.3
0.0
0.0
0.0
b
2
b
3
c
4
b
5
0.1
a
b
NMR yield. Reaction conditions: 6 (0.5 mmol), Et3SiBpin (0.5 mmol), base (0.5 mmol), and CO2 (0.1 MPa) in DMF (3 mL) or under neat
c
conditions at 80 °C for 20 h. Reaction conditions: 6 (1 mmol), Et3SiBpin (1 mmol), NaOtBu (1 mmol), and CO2 (2 MPa) under neat conditions
at 80 °C for 20 h.
B
Org. Lett. XXXX, XXX, XXX−XXX