Synthesis of benzylic boronates via palladium-catalyzed cross-coupling reaction of bis(pinacolato)diboron with benzylic halides

Article abstract of DOI:10.1016/S0040-4039(02)02566-2

The palladium cross-coupling reaction of benzyl halides with diboron 1 yielded structurally diverse pinacol benzylic boronates. Under these reaction conditions, sensitive functionalities such as esters and nitriles are tolerated and the benzylic boronates

Full text of DOI:10.1016/S0040-4039(02)02566-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 233–235
Synthesis of benzylic boronates via palladium-catalyzed
cross-coupling reaction of bis(pinacolato)diboron with
benzylic halides
Andr e´ Giroux*
Department of Medicinal Chemistry, Merck-Frosst Centre for Therapeutic Research, PO Box 1005, Pointe-Claire-Dorval,
Qu e´ bec, Canada H9R 4P8
Received 18 October 2002; revised 8 November 2002; accepted 13 November 2002
Abstract—The palladium cross-coupling reaction of benzyl halides with diboron 1 yielded structurally diverse pinacol benzylic
boronates. Under these reaction conditions, sensitive functionalities such as esters and nitriles are tolerated and the benzylic
boronates are obtained in good to high yields. © 2002 Published by Elsevier Science Ltd.
The widespread use of organoboronates in various
metal catalyzed CꢀC bond forming reactions has cre-
ated a substantial demand for these versatile synthetic
(entry 1). Therefore, the cross-coupling reaction of ben-
zyl bromide 2 with the diboron 1 with different bases
was investigated. Using K CO as the base gave a 3:1
mixture of the desired product 3 with the presence of a
small amount of benzyl alcohol 4 and dimer 5 as side
products (entry 2).
2
3
1
intermediates. The Suzuki coupling offers several
advantages, such as mild reaction conditions, compara-
2
tive stability and low toxicity. However, their utility is
sometimes restricted because the most common meth-
3
ods for boronate preparation are based on anionic or
Other bases tried, K PO and Cs CO gave lower con-
4
3
4
2
3
hydroboration processes which are not always compat-
versions to the desired benzyl boronate 3 (entries 3, 4).
ible with sensitive, functionalized molecules. For exam-
ple, the most popular method for the synthesis of
benzylic boronates relies on the reaction of trialkyl
Similarly, changing the catalyst to Pd(PPh ) (entry 5)
3
4
also provided after 18 hours the same crude mixture as
entry 2. Many other conditions were surveyed using
different bases, solvents and catalysts in order to opti-
mize the conditions for the coupling while eliminating
the side products. Gratifyingly, an excellent conversion
of the benzyl bromide 2 to the desired coupled product
3 was obtained when dioxane was used as the solvent.
Running the reaction in dioxane eliminated the forma-
tion of the benzyl alcohol 4, and furthermore reduced
the reaction time, formation of the dimer 5, and cata-
lyst loading to 5 mol% (entry 6).
5
borate with the corresponding Grignard reagent. Other
6
methods include homologation, displacement of alpha-
7
haloboronates and cross-coupling of alphametallo-
8
9
boronates or alphahaloboronates. More recently CꢀH
borylation of alkylbenzenes has been reported using
1
0
compound 1 and pinacolborane. Herein, we report
the versatile and facile synthesis of pinacol benzyl-
boronates under Suzuki palladium catalyzed conditions
11
using diboron 1 (Scheme 1).
Our initial efforts were directed toward finding the
optimal condition using 4-methylbenzyl bromide (2) as
the model substrate under different reaction conditions
(
Table 1). The best conditions found for the cross-cou-
12
pling reaction of the diboron 1 with aryl halides,
using PdCl (dppf) and KOAc as the base in DMF,
2
provided exclusively the corresponding benzyl acetate
*
Tel.: (514) 428-3451; fax: (514) 428-4900; e-mail: andre giroux@
–
merck.com
Scheme 1.
0
040-4039/03/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)02566-2

2
34
A. Giroux / Tetrahedron Letters 44 (2003) 233–235
Table 1. Optimal reaction conditions
Entry
Conditions
Ratioa
Catalyst
Base
Solvent
Time (h)
2
3
4
5
1
2
3
4
5
6
PdCl (dppf)
KOAc
K CO
DMF
DMF
DMF
DMF
DMF
Dioxane
18
18
18
18
18
6
0
0
0
90
0
0
100b
15
43
0
15
0
0
10
0
0
10
4
2
PdCl (dppf)
75
57
10
75
96
2
2
3
PdCl (dppf)
K PO
2
3
4
PdCl (dppf)
Cs CO
2
2
3
Pd(PPh3)4
Pd(PPh3)4
K CO
2
3
c
K CO
0
2
3
a
b
c
Ratios were determined by 1H NMR.
The corresponding benzyl acetate was obtained.
% catalyst was used for the reaction.
5
With these results in hand, we next carried out the
Suzuki cross-coupling reaction on a variety of benzyl
bromides and the results are summarized in Table 2.
Under our optimal conditions p-methylbenzyl bromide
The cross-coupling reaction of benzyl chlorides with the
pinacol diboron 1 was also evaluated (Table 3). High
yields of the cross-coupling products were obtained for
para-substituted benzyl chlorides (entries 1, 2). How-
ever, a moderate yield of 68% was obtained for the
benzamide 22 (entry 3). In this case, a small amount of
the corresponding N-benzyl-4-methylbenzamide was
detected. Under these reaction conditions, the cross-
coupling occurs exclusively at the benzylic site, while an
2
gave an isolated yield of 83% for the corresponding
pinacol boronate 3. Similarly, benzyl bromide (6) and
p-fluorobenzyl bromide (8) also undergo the coupling
reaction in excellent yields providing the benzylic
boronates 7 in 79% yield and the benzylic boronate 9 in
14
aryl chloride is not affected.
82% yield (entries 2, 3). meta- and ortho-substituted
benzyl bromides were also evaluated under these reac-
tion conditions. The cross-coupling of m-methoxyben-
zyl bromide (10) cleanly provided the benzyl boronate
For example, m-chlorobenzyl chloride (23) was con-
verted to the desired m-chlorobenzyl boronate (24) in a
high yield of 91% (entry 4). Similarly, the cross-coupling
reaction of ortho-substituted benzyl chloride 25 and
1
1 in 91% yield (entry 4). Similarly, the coupling reac-
tion of methyl 3-(bromomethyl)benzoate (12) and 3-
bromomethyl)benzonitrile (14) under these mild
conditions afforded products 13 and 15 in good yields of
1
-(chloromethyl)naphthalene (27) afforded the coupled
products 26 and 28 in high yields of 70% (entry 5) and
0% (entry 6), respectively.
(
8
1
3
7
5% (entry 5) and 65% (entry 6), respectively. Substi-
tution at the ortho position required a longer reaction
time in order to achieve complete conversion, as seen for
the o-methylbenzyl bromide (16) which required 18 h to
go to completion, yet the boronate 17 was efficiently
obtained in 74% yield (entry 7).
In summary, we have developed a versatile high yielding
method for preparing benzyl boronates. This procedure
is advantageous when sensitive groups such as esters
and nitriles are present. Furthermore, this methodology
is applicable to benzylic bromides and chlorides.
a
Table 2. Cross-coupling of benzyl bromides with bis(pinacolato)diboron
Entry
Substrate
Time (h)
Productb
p-MeC H CH Bpin (3)
Yieldc
d
1
2
3
4
5
6
7
p-MeC H CH Br (2)
6
6
6
6
6
83
79
82
91
75
65
74
6
4
2
6
4
2
C H CH Br (6)
C H CH Bpin (7)
6
4
2
6 4 2
p-FC H CH Br (8)
p-BrC H CH Bpin (9)
6 4 2
6
4
2
m-MeOC H CH Br (10)
p-ClC H CH Bpin (11)
6
4
2
6 4 2
m-MeO CC H CH Br (12)
m-MeO CC H CH Bpin (13)
2 6 4 2
2
6
4
2
m-CNC H CH Br (14)
6
18
m-CNC H CH Bpin (15)
6
4
2
6 4 2
o-MeC H CH Br (16)
o-MeC H CH Bpin (17)
6 4 2
6
4
2
a
Reactions were carried out in dioxane using 5 mol% of Pd(PPh ) , benzyl bromide (1.0 equiv.), diboron 1 (1.2 equiv.) and K CO (3.0 equiv.)
as the base at 80 C for 6 h.
All new compounds were fully characterized and all analytical and spectral (IR, NMR, MS) data are fully consistent with the assigned structures.
3
4
2
3
o
b
All known compounds were characterized by NMR.
Isolated yield.
The pinB abbreviates 4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl group.
c
d

A. Giroux / Tetrahedron Letters 44 (2003) 233–235
235
a
Table 3. Cross-coupling of benzyl chlorides with bis(pinacolato)diboron
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