Organic Letters
Letter
a
excellent yields under mild conditions and tolerates a wide
range of functional groups as well as complicated drug
molecules.
Scheme 2. Pd-Catalyzed Hydroxylation of Aryl Chlorides
To start the discovery, the reaction between methyl 4-
chlorobenzoate (1a) and boric acid was examined under
various conditions. With Pd(OAc)2 as the catalyst, Xphos as
the ligand, and K3PO4 as the base in THF at 80 °C for 24 h,
the reaction mixture provided the desired product, methyl
paraben (2a), in 9% yield (Table 1, entry 1). Various ligands
a
Table 1. Optimization of the Reaction Conditions
b
entry
ligand
XPhos
BrettPhos
XantPhos
t-BuXPhos
t-BuBrettPhos
t-BuBrettPhos
t-BuBrettPhos
t-BuBrettPhos
t-BuBrettPhos
t-BuBrettPhos
t-BuBrettPhos
t-BuBrettPhos
t-BuBrettPhos
t-BuBrettPhos
base
solvent
THF
THF
THF
THF
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
NaOt-Bu
NaOEt
NaOAc
K2CO3
Cs2CO3
9
17
0
28
50
0
37
39
87
25
10
4
THF
toluene
MeCN
1,4-dioxane
NMP
NMP
NMP
NMP
NMP
NMP
a
Reaction conditions: 1 (1 mmol), B(OH)3 (1.5 mmol), Pd(OAc)2
(5 mol %), t-BuBrettPhos (12.5 mol %), Cs2CO3 (2 equiv), NMP (2
b
mL), 80 °C, Ar, 24 h. 100 °C, 14 h.
zaldehyde (2f) in 93% yield. p-Chlorobenzamide afforded 4-
hydroxybenzamide (2g) in 93% yield. 4-Nitro- and 4-
(methylsulfonyl)chlorobenzene gave the corresponding phe-
nols 2h and 2i in 95% and 84% yield, respectively. p-
Chlorostyrene provided the desired 4-vinylphenol (2j) in 67%
yield. Besides these electron-withdrawing groups, electron-rich
chlorobenzenes were also compatible with these conditions.
For example, p-chlorotoluene gave p-cresol (2k) in 82% yield
under these conditions. 4-Chloroanisole afforded the desired
mequinol (2l) in 76% yield, and 4-(methylmercapto)-
chlorobenzene provided 4-(methylmercapto)phenol (2m) in
94% yield. Moreover, heteroaryl chlorides successfully coupled
with boric acid under these conditions, and the desired
products were achieved in good yields. For example, 6-
chloroquinoline and 3-chloroquinoline delivered the corre-
sponding 6- and 3-hydroxyquinilines 2n and 2o in 83% and
77% yield, respectively. The coupling of 2-chlorobenzothiazole
with boric acid provided the tautomerized hydroxylation
product 2p in 69% yield.
These conditions are also applicable for the coupling
reaction between aryl bromides and boric acid, and the
desired phenols were obtained in good to excellent yields
(Scheme 3). Base-sensitive substituents on the bromobenzene
were well-tolerated. For example, aryl bromides bearing an
ester substituent at the para or meta position provided the
desired phenols 2a and 2b in 94% and 86% yield, respectively.
Cyano substituents on the bromoarene afforded the desired
cyano-substituted phenols 2c and 2d in 97% and 94% yield,
respectively, and 4-cyano-α-bromonaphthene gave the desired
α-naphthol 4a in 82% yield. Bromobenzenes bearing an acetal
substituent at the para or meta position afforded the desired
products 2e and 3-acetylphenol (4b) in 98% and 72% yield,
respectively. 4-Bromobenzaldehyde gave a 99% yield of 2f.
Besides, these conditions were also compatible strong electron-
withdrawing groups. For example, 4-nitro- and 4-
>99
>99
a
Reaction conditions: 1a (0.2 mmol), B(OH)3 (0.3 mmol),
Pd(OAc)2 (5 mol %), ligand (12.5 mol %), base (2 equiv), solvent
b
(1 mL), Ar atmosphere, 80 °C, 24 h. Yields were determined by 1H
NMR analysis of the crude reaction mixtures using 1,3,5-
trimethoxybenzene as the internal standard.
were screened, and Brettphos gave 2a in 17% yield (entry 2).
Bidentate XantPhos was inactive for the reaction (entry 3).
While sterically hindered monodentate phosphine ligands were
found to be effective for the transformation, t-BuXPhos
afforded 2a in 28% yield, and t-BuBrettPhos gave 2a in 50%
yield (entries 4 and 5). With t-BuBrettPhos as the ligand, the
solvent for the reaction was screened. Toluene was inert for the
transformation. CH3CN and 1,4-dioxane gave 2a in 37% and
39% yield, respectively. NMP was found to be the superior
solvent for the reaction, giving 2a in 87% yield (entries 6−9).12
The effect of the base was determined with t-BuBrettPhos and
NMP. NaOtBu afforded 2a in 25% yield, and NaOEt and
NaOAc provided 2a in very low yield (entries 10−12). Finally,
both K2CO3 and Cs2CO3 were found to be excellent bases for
the transformation, giving paraben 2a in >99% yield (entries
13 and 14).
The feasibility of using boric acid as a hydroxide reagent to
prepare phenols was surveyed with various (hetero)aryl
chlorides (Scheme 2). A variety of base-sensitive substituents
on (hetero)aryl chlorides were well-tolerated under these
conditions. For example, chlorobenzenes bearing an ester
group at the para or meta position provided the corresponding
phenols 2a and 2b in 98% and 75% yield, respectively.
Chlorobenzenes with cyano substituents at the para or meta
position afforded the desired phenols 2c and 2d in 95% and
97% yield, respectively. 4-Acetylchlorobenzene provided piceol
(2e) in 98% yield. 4-Chlorobenzaldehyde gave 4-hydroxyben-
B
Org. Lett. XXXX, XXX, XXX−XXX