780
Chemistry Letters 2002
Nucleophilic Borylation of Benzyl Halides with Bis(pinacolato)diboron
Catalyzed by Palladium(0) Complexes
Tatsuo Ishiyama,ꢀ Zengo Oohashi, Taka-aki Ahiko, and Norio Miyauraꢀ
Division of Molecular Chemistry, Graduate School of Engineering, Hokkaido University, Sapporo 060-8628
(Received April 30, 2002; CL-020374)
Nucleophilic borylation of benzyl halides with bis(pinaco-
of polar solvents such as DMSO resulted in the formation of
benzyl acetate (ca. 40%) by the direct reaction of benzyl chloride
with KOAc (Entry 10).
lato)diboron in the presence of KOAc in toluene was effectively
catalyzed by a palladium complex generated insitu from Pd(dba)2
and (4-MeOC6H4)3P, giving the corresponding pinacol benzyl-
boronates in high yields.
Table 1. Reaction conditions for nucleophilic borylation of
benzyl chloride with pin2B2 1 by using a Pd(dba)2 precatalysta
Entry
Ligand
none
(4-MeOC6H4)3P KOAc
Base
Solvent Yield/%b
Benzylboron compounds are useful synthetic intermediates,1
potential chiral Lewis acids,2 and potential 10B carriers for boron
neutron capture therapy,3 which have been prepared by catalytic
hydroboration of styrenes,4 transmetalation of benzylmetals to
BX3,5 homologation of arylboranes,6 or cross-coupling of
haloarenes with borylmethylzinc reagents.7 Nucleophilic boryla-
tion of benzyl electrophiles would also provide an efficient and
convenient route to benzylboron compounds; however, the lack
of suitable boron nucleophiles has limited this protocol. Recently,
we found that (alkoxo)diborons can undergo transmetalation with
organo(oxo)palladium(II) complexes, thus allowing the cross-
coupling reactions of (alkoxo)diborons with aryl,8 vinyl,9 and
allyl10 electrophiles in the presence of a palladium catalyst and a
base.11 We report herein the palladium-catalyzed nucleophilic
borylation of benzyl halides (2) with bis(pinacolato)diboron12
(pin2B2, pin ¼ Me4C2O2) (1) to provide pinacol benzylboronates
(3) in high yields (eq 1).13
1
2
3
4
5
6
7
8
9
KOAc
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
0
85
41
2
59
23
0
Ph3P
KOAc
KOAc
KOAc
KOAc
KOAc
(4-ClC6H4)3P
dppfc
Ph3As
(c-C6H11)3P
(4-MeOC6H4)3P K3PO4
(4-MeOC6H4)3P KO2CCF3 toluene
6H4)3P KOAc DMSO
21
6
10(4-MeOC
50
aA mixture of pin2B2 1 (1.1 mmol), benzyl chloride
(1.0mmol), Pd(dba) 2 (0.03 mmol), a ligand (0.06 mmol), a
base (1.5 mmol), and a solvent (6 ml) was stirred at 50 ꢁC for
24 h. bGLC yields based on benzyl chloride. c1,10-Bis(diphe-
nylphosphino)ferrocene (0.03 mmol) was used.
The synthesis of pinacol benzylboronates 3 by the reaction
between pin2B2 1 and representative benzyl halides 2 in the
presence of a Pd(dba)2-2(4-MeOC6H4)3P catalyst and a KOAc
base in toluene is summarized in Table 2.14 The protocol is
applicable not only to chlorides but also to bromides, providing
variously functionalized 3 in high yields. The reaction smoothly
proceeded at 50 ꢁC for 2 having an electron-withdrawing
substituent at the para position (Entries 1-4), whereas those
having a donating group required heating to 80 ꢁC (Entries 6 and
7). Either an electron-withdrawing or -donating substituent at the
ortho positiondecelerated thereaction because ofsteric hindrance
(Entries 8 and 9), while 1-(chloromethyl)naphthalene was
smoothly borylated at 50 ꢁC (Entry 10). The reaction is feasible
with various functional groups such as CN and CO2Me which
should be protected in the synthesis from benzyllithium or
-magnesium reagents (Entries 1 and 3).5 All attempts at the
borylation of 1-chloro-1-phenylpropane were unsuccessful
probably due to its slow oxidative addition to the palladium(0)
complex.
The borylation of benzyl chloride (1.0mmol) with pin 2B2 1
(1.1 mmol) was carried out at 50 ꢁC for 24 h by using Pd(dba)2
(0.03 mmol) as a catalyst precursor to examine the effects of
ligands (0.06 mmol), bases (1.5 mmol), and solvents (6 ml)
(Table 1). Although Pd(dba)2 itself did not catalyze the reaction
in the presence of KOAc in toluene (Entry 1), addition of a (4-
MeOC6H4)3P ligand successfully promoted the borylation to
afford the expected pinacol benzylboronate in 85% yield (Entry
2). The catalyst efficiency highly depends on the electron-
donating ability of phosphine ligands. Use of electron-neutral or -
poor triarylphosphines such as Ph3P and (4-ClC6H4)3P resulted in
significantly lower yields (Entries 3 and 4). Although dppf and
Ph3As have been used successfully for the analogous borylation
of aryl8a,b or allyl10 electrophiles, these ligands were not effective
for that of benzyl halides (Entries 5 and 6). The superiority of the
electron-rich phosphine, (4-MeOC6H4)3P, prompted us to
examine trialkylphosphines; however, (c-C6H11)3P complexes8c
failed to catalyze the reaction probably due totheir decomposition
yielding phosphonium salts of benzyl chloride (Entry 7). KOAc
was recognized to be the best base. Changing the base to an
inorganic or weaker base such as K3PO4 and KO2CCF3
remarkably slowed down the reaction (Entries 8 and 9). As for
solvents, non-polar ones such as toluene gave the best results. Use
A one-pot synthesis of bis(borylmethyl)benzene via the
sequential double borylation is shown in eq 2. The reaction of
pin2B2 1 (2.2 equiv) with 1,4-bis(chloromethyl)benzene (1.0
equiv) at 80 ꢁC in the presence of the palladium catalyst (6 mol%)
and KOAc (3.0equiv) in toluene (6 ml) gave the corresponding
diborylated product in 61% yield.
Copyright Ó 2002 The Chemical Society of Japan
Ishiyama, Tatsuo
