An efficient synthesis of sterically hindered arylboronic acids

Article abstract of DOI:10.1016/j.tetlet.2005.01.064

Boronic acids are important intermediates and molecular recognition moieties in a wide variety of applications. In our research, we have found that the synthesis of ortho-substituted arylboronic acids is problematic with the commonly used bis(pinacolato)diboron in palladium-mediated borylation reactions. As a substitute, we have found that bis(neopentyl glycolato)diboron is a much more efficient borylation agent for the synthesis of sterically hindered ortho-substituted arylboronic acids.

Full text of DOI:10.1016/j.tetlet.2005.01.064

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1671–1674
An efficient synthesis of sterically hindered arylboronic acids
Hao Fang,a,b Gurpreet Kaur,b Jun Yanb and Binghe Wangb,*
aSchool of Pharmacy, Shandong University, No. 44 Wenhuaxi Road, Jinan 250012, China
bDepartment of Chemistry and Center for Biotechnology and Drug Design, Georgia State University,
33 Gilmer St. S.E., Atlanta, GA 30303, USA
Received 10 December 2004; revised 11 January 2005; accepted 13 January 2005
Available online 29 January 2005
Abstract—Boronic acids are important intermediates and molecular recognition moieties in a wide variety of applications. In our
research, we have found that the synthesis of ortho-substituted arylboronic acids is problematic with the commonly used bis(pina-
colato)diboron in palladium-mediated borylation reactions. As a substitute, we have found that bis(neopentyl glycolato)diboron is a
much more efficient borylation agent for the synthesis of sterically hindered ortho-substituted arylboronic acids.
Ó 2005 Elsevier Ltd. All rights reserved.
Boronic acids are important intermediates in organic
synthesis and are useful for the development of biologi-
cally active agents.1 For example, boronic acids have
been widely used in Suzuki cross-coupling reactions,2
protection of diols,3 Diels–Alder reaction,4 selective
reduction of aldehydes,5 asymmetric synthesis of amino
acids,6 and as amidation catalysts.7,8 In addition, boro-
nic acids have been used in biological applications1 as
sensors for carbohydrates,9,10 artificial lectins (borono-
lectins) targeting cell surface carbohydrates,11,12 selec-
tive transporters of nucleosides, saccharides and
nucleotides,13,14 enzyme inhibitors,1,15 and therapeutic
agents in boron neutron capture therapy (BNCT) of cer-
tain brain tumors.16
colato)diboron is the most widely used agent in
palladium mediated borylation reactions due to its com-
mercial availability and good stability in the presence of
water and during chromatography.24
In our on-going research in the design and synthesis of
new fluorescent boronic acids,11,25,26 we were in need
of ortho-substituted arylboronic acids. In the synthesis
of such boronic acids, we encountered many problems
when bis(pinacolato)diboron was used as the borylation
agent. For example, complicated reaction mixtures were
obtained in the preparation of ortho-methoxy-substi-
tuted phenylboronic acid, which led to low yields (about
20%).26 Similar results have also been reported in the lit-
erature,18 although a few exceptions were reported when
aryltriflates were used instead of arylhalides.19 Baudoin
et al. utilized pinacolborane (Me4C2O2)BH to synthesize
phenylpinacol boronic esters from ortho-substituted aryl
bromides and found the best catalyst being Pd(OAc)2 in
the presence of 2-(dicyclohexyl phosphino)biphenyl
which is a sterically hindered phosphine ligand,23
although the yields were still poor when functional
groups such as nitro (20%), acetyl (0%), and Boc pro-
tected amino group (40%) were present. Later MiyauraÕs
group reported that Pd(dba)2/PCy3 could be used to
carry out borylation of some ortho-substituted
chloroarenes (nitro and methoxy) by using bis(pinaco-
lato)diboron (70% yield based on GC after 48 h of reac-
tion).27 Most recently, a new N-heterocyclic carbene–
palladium catalyst was used to borylate ortho-methoxy
substituted aryldiazonium with good yields using
bis(pinacolato)diboron.22
Generally, two methods are used to synthesize arylbo-
ronic acid or ester compounds. One is the transmetala-
tion between an arylmetal and a boron halide or
alkoxide;17 the other is the recently developed
PdCl2(dppf)-catalyzed borylation of aryl halides,18 tri-
flates,19,20 and diazonium21,22 with a tetra(alkoxy)dibo-
ron18,19,21 or dialkoxyborane reagent.20,23 The
palladium-catalyzed method can be used for the boryla-
tion of substrates that contain functional groups such as
cyano, nitro, amino, hydroxyl, ester, and carbonyl
groups, which may not be compatible with organome-
tallic agents such as n-butyllithium. Currently, bis(pina-
Keywords: Palladium-catalyzed borylation; Bis(neopentyl glyco-
lato)diboron; ortho-Arylboronic acids.
*
Corresponding author. Tel.: +1 404 651 0289; fax: +1 404 654
5827; e-mail: wang@gsu.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.064

1672
H. Fang et al. / Tetrahedron Letters 46 (2005) 1671–1674
Table 1. Reaction of representative 1 with 2
So far, research in this area has been focused on exam-
ining the effect of different leaving groups or designing
or experimenting new palladium catalysts. We envi-
sioned that some of the problems might be overcome
by manipulating the steric bulkiness of the borylation
agent. In our very first example, we examined the boryl-
ation of 2-methoxy-5-nitrophenylbromide using the
new commercially available bis(neopentyl glyco-
lato)diboron 2 in the presence of PdCl2 (dppf) and
observed much improved yield compared with the
reaction using bis(pinacolato)diboron as the borylation
agent (72% vs 20%) under similar conditions (Scheme
1). Such results suggested that the steric bulkiness of
the tetra(alkoxy)diboron agent may play an important
role in the borylation of other ortho-substituent arylha-
lide (bromide in this case) and a less hindered
bis(neopentyl glycolato)diboron might be used to over-
come the side reaction problems associated with the
use of sterically bulky bis(pinacolato)diboron.
Entry
1
Product 3
Time
(h)
3
(%)a
OCH3
Br
OCH3
O
B
1
2
2
72
69
O
O2N
O2N
1a
3a
NH2
NH2
O
O
2
B
Br
1b
1c
3b
3b
NH2
NHBoc
Br
O
O
3
4
5
465
B
NO2
NO2
Br
O
O
3
68
B
In order to understand the scope of the effect of the ste-
ric bulkiness of the borylation agent, we were interested
in examining the borylation of a series ortho-substituted
arylhalides. As a first step, we optimized the reaction
conditions with respect to the solvent and base used.
As expected and has been observed with reactions using
the bis(pinacolato)diboron borylation agent, DMSO
was the best solvent and KOAc was the best base. Tol-
uene and dioxane exhibited low reaction rate with more
debromo product. The reaction did not work when
using triethylamine as base.
1d
1e
3d
3e
F
F
O
4(90)
B
Br
O
CO2CH3
CO2CH3
Br
O
B
O
6
7
480
1f
3f
CN
O
CN
Br
6
73
70
B
The borylation of 12 additional arylhalides were stud-
ied using this method (entries 2–13, Table 1). In most
cases, the reaction was completed within 4h. Good
(65%) to excellent (90%) yields were obtained in most
cases except with 8-quinoline analog (entry 9, 35%),
2-bromophenol (entry 11, 5%), and 2-bromobenzalde-
hyde (entry 13, 7%). Unexpectedly, borylation of Boc
protected 2-bromoaniline (entry 3) gave the deprotec-
ted aniline neopentyl glycolato boronate. The mecha-
nism through which the Boc group was cleaved is
unclear. Comparing with literature and our own re-
search results, the yields were much better than the
reactions using bis(pinacolato)diboron or pinacolbo-
rane as the borylating agent. For example, ortho-
bromonitrobenzene (entry 4) and 2-bromomethylphe-
nylketone (entry 8) gave yields in the range of 0–20%
when pinacolborane was used as the borylating
agent.23 Even when the corresponding iodoarene was
used for the nitrobenzene analog, the yield was still
low (44%).23 In contrast, the corresponding reactions
using bis(neopentyl glycolato)diboron as the borylation
O
1g
3g
O
O
8
9
3
O
O
B
Br
1h
3h
NHBoc
NHBoc
12
35
N
N
N
B(OH)2
Br
1i
3i
N
Boc
N
Boc
10
11
12
12
85
5
N
B(OH)2
Br
1j
3j
OH
OH
OH
Br
O
O
B
1k
3k
OH
I
O
O
12
13
8
70
7
B
O
O
O
B B
1l
3k
R
O
R
CHO
CHO
Br
2
O
O
12
B
O
B
Br
PdCl2(dppf), KOAc
DMSO, 80 °C
O
1m
3m
1
3
a Isolated yield after flash chromatography. Yields in parentheses are
GC yields.
Scheme 1.

H. Fang et al. / Tetrahedron Letters 46 (2005) 1671–1674
1673
Table 2. Different palladium catalysts in the borylation of 2-bromo-
phenol and 2-bromobenzaldehyde
agent gave over 68% isolated yields for both nitro
(entry 4) and acetyl substituent (entry 8).
O
O
B
B
X
On a somewhat different note, where steric hindrance
may not necessarily be a factor, the borylation of quin-
oline bromide also benefited from using bis(neopentyl
glycolato)diboron instead of bis(pinacolato)diboron as
the borylation agent. For example, in the borylation of
8-bromoquinoline derivatives (entries 9 and 10), Suzuki
coupling product was the major product when bis(pina-
colato)diboron was used as a borylation agent in the
presence of KOAc.28 However, when bis(neopentyl gly-
colato)diboron was used, Suzuki coupling product was
not formed in the reaction mixture and the correspond-
ing 8-quinoline boronic acid was easily obtained.
O
O
X
X
2
O
B
Br
H
O
Catalyst, KOAc
k
X = -OH
X = -CHO
1
4 k X = -OH
3 k X = -OH
X = -CHO
m
m
X = -CHO
m
Entry Catalyst
(mol%)
Solvent
Heating
method
(temp °C,
time)
Product ratio
1k:3k:4ka
1
2
3
Pd(PPh3)4 (6) DMSO
PdCl2(dppf) (6) DMSO
100, 12 h
100, 12 h
80, 12 h
100:0:0
93:7:0
78:22:0
POPd (3)
DMSO
4POPd (3)
DMSO
120, 12 h0:0 60:4
It does need to be noted that entry 13 (with a formyl
substituent) gave less than 10% yield of the desired prod-
uct with the formation of 20% Suzuki coupling product
and the recovery of 50% of the starting material. In
addition, entry 11 (hydroxyl group) gave only 5% yield
of the desired product with over 85% of the starting
material recovered, while the corresponding iodide (en-
try 12) gave a good yield (70%). It is not clear why the
hydroxyl group (entry 11) and the formyl group (entry
13) presented special problems. In an effort to improve
the yields for entries 11 and 13, we also examined
whether different catalysts would be able to facilitate
these two reactions. Previous work by Baudoin and
co-workers23 and Miyaura and co-workers27 indicates
that a more reactive palladium catalyst may be able to
improve yield of entry 11. Several air stable and more
active palladium catalysts, such as [(t-Bu)2P(OH)]2-
5
6
7
POPd (3)
POPd (3)
POPd (3)
DMF
80, 12 h
Toluene 80, 12 h
Dioxane 80, 12 h
74:27:0
0:27:73b
0:10:80b
a Determined by GC–MS.
b Determined by 1H NMR.
reagent, bis(pinacolato)diboron, gives low yields and
side reactions for ortho-substituted bromoarenes, possi-
bly due to the steric hindrance of the ortho substituent.
This problem can be overcome by using a less hindered
borylation agent, bis(neopentyl glycolato)diboron, in
most of the cases. With the two cases (ortho substituent
being a hydroxyl or a formyl group) that give low yields
of the borylation product, the problem can be addressed
by using a new and more active palladium catalyst, such
as POPd.
PdCl2(POPd),
{[(t-Bu)2P(OH)][(t-Bu)2P(OÀ)]PdCl}2
(POPd1), and [(t-Bu)2P(OH)PdCl2]2 (POPd2), have been
employed for cross-coupling reactions of aryl chlo-
ride,29–32 and also for borylation of 5-bromofluorescein
diacetate.33 Therefore, the new active palladium cata-
lyst, POPd, was examined in the borylation of 2-bromo-
phenol and 2-bromobenzaldehyde.
Acknowledgements
Financial support from the National Institutes of Health
(NO1-CO-27184and CA88334), the Georgia Cancer
Coalition through a Distinguished Cancer Scientist
Award, and the Georgia Research Alliance through an
Eminent Scholar endowment are gratefully acknowl-
edged. We also thank Dr. George Y. Li of CombiPhos
Catalysts, Inc., for supplying the new air-stable palla-
dium catalysts to us.
Different palladium catalysts and solvents were exam-
ined in order to search for a condition that would give
a reasonable borylation yield from 2-bromophenol
(Table 2). The results showed that the POPd facilitates
the borylation reaction and works better than Pd(PPh3)4
and PdCl2 (dppf) in DMSO (entries 1–3). When the tem-
perature was raised to 120 °C, 40% of the desired boryl-
ation product was obtained, with the remaining portion
being the unreacted starting material (entry 4). When
the solvent was changed to toluene and dioxane, the
debromo product (4) was the main product (entries 6
and 7). Therefore, it seems that for the borylation of
2-bromophenol using POPd in DMSO at 120 °C gives
the best yield. When applying the same conditions to
the borylation of 2-bromobenzaldehyde, the starting
material completely disappeared with the formation of
35% (isolated yield) of the desired borylation product
and the remaining being the Suzuki coupling product.
Supplementary data
The supplementary data, including general experimental
procedures and NMR data, is available online with the
paper in ScienceDirect. Supplementary data associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2005.01.064.
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