Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
b
entry
Pd/Cu
Pd(dba)2/CuBr2
Pd(OAc)2/CuBr2
Pd(TFA)2/CuBr2
Pd(PPh3)4/CuBr2
Pd(dba)2/CuCl2
Pd(dba)2/CuBr
solvent
X, Y
yield (%)
b
1
2
3
4
5
6
7
8
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
NMP
MeCN
toluene
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
3, 4
3, 4
3, 4
3, 4
3, 4
3, 4
3, 4
3, 4
3, 4
3, 4
3, 4
3, 4
3, 4
1, 1
3, 1
3, 2
3, 4
3, 4
3, 4
88 (75)
71
77
nd
70
nd
12
Pd(dba)2/CuI
Pd(dba)2/CuBr2
Pd(dba)2/CuBr2
Pd(dba)2/CuBr2
Pd(dba)2/CuBr2
Pd(dba)2/CuBr2
Pd(dba)2/CuBr2
Pd(dba)2/CuBr2
Pd(dba)2/CuBr2
Pd(dba)2/CuBr2
CuBr2 (no Pd)
44
17
9
10
11
nd
nd
nd
nd
29
18
59
nd
nd
68
c
12
d
13
14
15
16
17
18
Pd(dba)2 (no Cu)
Pd(dba)2/CuBr2 (no 1,4-BQ)
e
19
a
Reaction conditions: 1a (1−3 mmol), 2a (1 mmol), 3a (1−4
mmol), Pd catalyst (0.05 mmol, 5 mol %), Cu salt (0.1 mmol, 10 mol
%), and 1,4-BQ (0.4 mmol, 40 mol %) were stirred at 70 °C (oil bath
temperature) for 16 h under O2 (balloon). Yield was determined by
GC based on the amount of 2a (n-decane was used as an internal
Figure 1. (A) Oxidative coupling reactions and their advantages in
organic chemistry. (B) Previous reports for alkoxylations of olefin
through the intramolecular and intermolecular oxidative coupling
mechanism. (C) Three-component silylalkoxylation with 1,3-diene,
alcohol, and disilane via oxidative coupling
b
c
standard). Number in parentheses is the isolated yield. Under air.
d
e
Reaction performed with 1,4-BQ (1.2 equiv) under Ar. Reaction
performed in the absence of 1,4-BQ. Pd(TFA)2 = palladium bis(2,2,2-
trifluoroacetate); 1,4-BQ = 1,4-benzoquinone; DMF = N,N-
dimethylformamide; DMA = N,N-dimethylacetamide; NMP; N-
methyl-2-pyrrolidone. nd = not detected.
used as the solvent (entries 10 and 11). Interestingly, the
reaction under air or Ar did not afford 4a (entries 12 and 13),
thus indicating that molecular oxygen was necessary for the
reaction. Next, the substrate ratio was optimized. The
experimental data suggested that the stoichiometric ratio of
1a and 3a to 2a significantly impacted the reaction yield
(entries1 and 14−16) and that the highest yield was obtained
with (1a/2a/3a 3:1:4). Finally, control experiments were
carried out in the absence of Pd, copper salt, or 1,4-BQ. The
desired product 4a was not obtained without Pd or copper
(entries 17 and 18). The results in entries 13 and 18 indicated
that 1,4-BQ did not serve as the reoxidant of the catalytic
species. Notably, when the reaction was performed in the
absence of 1,4-BQ, 4a was produced in good yield (entry 19).
Second, we investigated the substrate scope of the
silylalkoxylation reaction (Scheme 1). The reaction with o-,
m-, and p-methyl benzyl alcohol afforded the corresponding
products in 74−76% yield (4b−4d), and the yields were in a
similar range. The use of p-tert-butyl benzyl alcohol afforded
the desired product (4e) in 75% yield, and p-methoxy benzyl
alcohol gave the desired product (4f) in 80% yield. The
silylalkoxylation with p-Cl benzyl alcohol also proceeded
smoothly to produce 4g, and the reaction with p-CF3 benzyl
alcohol afforded 4h in 56% yield. Secondary alcohols were also
suitable for this reaction (4i). With E-cinnamyl alcohol, the
corresponding product (4j) was obtained in 62% yield.
Interestingly, the cinnamyl alcohol-derived CC moiety
retained its conformation. A sterically hindered alcohol (1-
naphtalene methanol) was also applicable (affording 4k).
Heterocyclic alcohols were also tested with this catalytic
system. Oxygen-containing heterocyclic alcohols (e.g., piper-
onyl alcohol and furfuryl alcohol) successfully afforded the
corresponding products in good yield (4l and 4m,
respectively). Surprisingly, 2-thiophene methanol, which is
often poisonous for Pd species, was tolerated by this
silylalkoxylation (4n). However, no desired product was
detected in the presence of 2-pirydine methanol because the
high basicity of the pyridyl group rendered the catalytic species
inert. Further investigations concerning the scope of aliphatic
alcohol and 1,3-diene reagents were performed. With simple
aliphatic alcohols, such as 1-hexanol, the reaction achieved
56% yield (4o), and the longer-chain 1-octadecanol delivered
its corresponding product (4p) in 80% yield.
Importantly, a cyclopropyl ring, which has been integrated in
preclinical or clinical drugs, could be introduced (4q).10 In
addition, a bioactive compound, such as cholesterol, was
compatible with the silylalkoxylation and furnished the desired
product (4r). Moreover, configurational defined secondary
alcohols were used for the reaction to give the stereochemical
information on the chiral carbon center. (−)-Menthol
provided the product (4s) in 64% yield, whereas (+)-neo-
4899
Org. Lett. 2021, 23, 4898−4902