A practical and scalable process for the preparation of 4-aminophenylboronic acid pinacol ester

Article abstract of DOI:10.3987/COM-14-13098

A practical process has been developed for scalable preparation of 4-aminophenylboronic acid pinacol ester through facile two-step procedure. After boron trifluoride etherate efficiently activated the reaction of 4-bromoaniline with diphenyl ketone, metalation reaction of protected 4-bromoaniline with lithium trialkylmagnesiate readily proceeded under mild conditions (-20 °C), which was subsequently subjected to esterification and deprotection reaction to give the 4-aminophenylboronic acid pinacol ester. The improved synthetic route has been successfully scaled up to kilogram quantities in good yield and high quality.

Full text of DOI:10.3987/COM-14-13098

HETEROCYCLES, Vol. 89, No. 12, 2014
2739
HETEROCYCLES, Vol. 89, No. 12, 2014, pp. 2739 - 2744. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 5th October, 2014, Accepted, 6th November, 2014, Published online, 17th November, 2014
DOI: 10.3987/COM-14-13098
A PRACTICAL AND SCALABLE PROCESS FOR THE PREPARATION
OF 4-AMINOPHENYLBORONIC ACID PINACOL ESTER
a
a
a
a
Feng Xue, * Chang-Gong Li, Yong Zhu, Tian-Jun Lou, and Guang-Jie
He*b
a. Key Laboratory of Functional Organic Molecules of Xinxiang City Henan
Province, College of Chemistry and Chemical Engineering, Henan Institute of
Science and Technology, Xinxiang Henan, 453002, P. R. China. E-mail:
fxuehist@sina.com
b. Department of Forensic Medicine, Xinxiang Medical University, Xinxiang
Henan, 453003, P. R. China. E-mail: guangjiehe@163.com
Abstract – A practical process has been developed for scalable preparation of
4
-aminophenylboronic acid pinacol ester through facile two-step procedure. After
boron trifluoride etherate efficiently activated the reaction of 4-bromoaniline with
diphenyl ketone, metalation reaction of protected 4-bromoaniline with lithium
trialkylmagnesiate readily proceeded under mild conditions (−20 °C), which was
subsequently subjected to esterification and deprotection reaction to give the
4
-aminophenylboronic acid pinacol ester. The improved synthetic route has been
successfully scaled up to kilogram quantities in good yield and high quality.
Arylboronic acids and arylboronates have shown great importance due to their widespread applications in
organic synthesis and other fields.1,2 In particular, functionalized arylboronic acids and arylboronates are
highly valuable because consecutive cross-coupling is possible from these compounds, which can rapidly
3
construct the complex structure of target molecules. Of these compounds, 4-aminophenylboronic acid
pinacol ester is one of important arylboronates for its versatile applications in a wide variety of
4
biologically active compounds, for example piperazine-substituted s-triazine derivatives exhibiting
various types of biological properties, such as antiHIV, antituberculosis, anticancer, antimycobacterial,
5
etc. In addition, the compound has also been successfully applied in synthesis of fluorescent sensors for
6
heavy and soft metal ions such as mercury. Up to now, some successes have been made in the
7
preparation of 4-aminophenylboronic acid pinacol ester, typical examples included Raj’s Pd-catalyzed

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HETEROCYCLES, Vol. 89, No. 12, 2014
8
9
cross-coupling reaction, Marder’s Cu-catalyzed borylation reaction, Maligre’s Ir-catalyzed C−H bond
activation reaction,10 Hsu’s aryl Grignard reagents or aryllithium species with trialkyl boronates,11
1
2
Wang’s transition-metal-free transformation from aromatic amines. Although these procedures have
shown some practical applications in synthesis, their application on a preparative scale has still been
limited and deficient in view of laborious synthetic process, harsh reaction conditions, heavy metal
contamination, with the result that it is difficult to meet the demands for large-scale preparation. To
overcome these problems, we herein wish to describe an improved and efficient process for the scalable
preparation of 4-aminophenylboronic acid pinacol ester. With smooth and simple reaction procedures
from readily available starting materials, this method of synthesis provides easy access to the target
compound (Scheme 1).
Scheme 1. Synthesis of 4-aminophenylboronic acid pinacol ester
Reagents and Conditions: (i) benzophenone, BF
3
.Et
2
O, toluene; (ii) i-Bu(n-Bu)
2
MgLi, B(OMe) , pinacol,
3
HCl, THF, −20 °C.
Over these years, the reaction of aryl Grignard reagents or aryllithium species with trialkyl boronates
remained the most general synthetic method to prepare aromatic boronic compounds in contrast to those
catalyzed by heavy metal complex. It was desirable to use readily available aryl bromides as substrates,
so we chose 4-bromoaniline as starting material in our synthetic route, 4-bromoaniline was firstly reacted
with benzophenone activated by boron trifluoride diethyl etherate (BF
3
.Et
O), which was more practical
2
in contrast to other activating reagents such as TsOH and 4Å molecular sieve through careful exploration
of reaction conditions, to afford 4-bromo-N-(diphenylmethylidene)aniline 2 on large scale and in high
4
yield (Table 1). Meanwhile, compared to the previous route in which n-BuLi and trimethylsilyl chloride
(TMSCl) was used, the present procedure both smoothed previously-reported harsh reaction conditions and
improved the yield of product. Moreover, the diphenyl methylidene group imparted excellent crystallinity
to the products, and the free primary amine could be readily liberated by hydrogenolysis under weakly
acidic conditions. When the reaction was completed, the recrystallization in methanol conveniently
afforded the pure intermediate 2 in 86% yield and high purity (Table 1, entry 3), thus bypassing

HETEROCYCLES, Vol. 89, No. 12, 2014
2741
time-consuming and laborious procedures through column chromatography. It was worthwhile to note
that since it was difficult to completely remove residual BF O through vacuum evaporation, which
.Et
could have a negative influence in crystallization course, tertiary amine such as Et N or i-Pr NEt with the
same equivalent as BF .
Et O was required to add in methanol to ensure the crystallization repeatable.
3
2
3
2
3
2
Table 1. Screening of activating reagents in the protection reaction of Compound 1a
b
entry
activating reagent
TsOH
product
yield (%)
1
2
2
2
2
70
65
86
4Å molecular sieve
3
BF .
3
Et O
2
a
The reaction was carried out with benzophenone (1.1 eq), activating reagent (0.08 eq) in refluxed toluene
b
for 12 h . Isolated yield based on compound 1.
Next, our attention was shifted to metalation of the intermediate 2 needed for the subsequent borylation
reaction. Although metalation of the intermediate 2 could be performed with n-BuLi under cryogenic
conditions (−78 °C), the instability of the resulting organolithium species precluded its use on large
quantity, which was apparently inappropriate for industrial large-scale production. We therefore explored
an improved route involving metalation for large-scale production to avoid cryogenic conditions (−78 °C).
Subsequently, we explored lithium trialkylmagnesiate (R
3
MgLi) in place of n-BuLi in view of the fact
that lithium trialkylmagnesiate are generally more stable than the corresponding organolithium species,
1
3
and reactions can be performed under noncryogenic conditions in halogen-magnesium exchange. To our
delight, we found that i-Bu(n-Bu) MgLi generated in situ readily allowed for metalation under
2
noncryogenic conditions (−20 °C) (Table 2). In our optimized procedure, i-BuMgBr and n-BuLi in a 1:2
ratio were added sequentially to a solution of 2 in THF at −20 °C. This operationally simple process has
proved easy to perform on 20 kg scale and obviated the need for a separate vessel to prepare
1
4
i-Bu(n-Bu) MgLi as reported previously. Thus, the prepared 4-bromo-N-(diphenylmethylidene)aniline 2
2
was conveniently converted into the corresponding arylboronate through transmetalation, esterification
and submitted to acid deprotection to generate 4-aminophneylboronic acid pinacol ester 3 in 70% yield
using i-Bu(n-Bu) MgLi, trimethyl borate and pinacol in dry tetrahydrofuran solvent (Table 2, entry 5),
2
thus making the reaction facile, safe, and easy to scale-up. The large-scale applicability of this improved
method has been tested by conducting the reactions on kilogram scale to produce the desired product in
high yield and quality.

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HETEROCYCLES, Vol. 89, No. 12, 2014
Table 2. Bromine-Magnesium exchange of Compound 2a
b
entry
R
3
MgLi
(n-Bu) MgLi
(n-Bu)Me MgLi
i-Bu(n-Bu) MgLi
i-Pr(n-Bu) MgLi
i-Bu(n-Bu) MgLi
i-Bu(n-Bu) MgLi
temperature
−40 °C
−40 °C
−40 °C
−40 °C
−20 °C
0 °C
product
yield (%)
1
2
3
4
5
3
3
3
3
3
3
3
59
62
70
67
70
65
2
2
2
2
6
2
a
b
The reaction was carried out with B(OMe) (1.5 eq), pinacol (1.5 eq) . Isolated yield based on
3
compound 2.
In conclusion, we have reported a practical two-step process for the scalable preparation of
-aminophenylboronic acid pinacol ester from 4-bromoaniline. It has been demonstrated that a lithium ate
complex, lithium trialkylmagnesiate (i-Bu(n-Bu) MgLi) instead of n-BuLi, induced the facile
4
2
halogen-magnesium exchange of 4-bromo-N-(diphenylmethylidene)aniline under noncryogenic
conditions. Thus, the reaction proceeded smoothly at - 20 °C, which was capable of delivering a kilogram
of the target compound. Compared with the reported procedures, the overall process was more
environmentally friendly as well as cost-effective, which enabled the successful delivery of
kilogram-scale batches of 4-aminophenylboronic acid pinacol ester for further development studies.
EXPERIMENTAL
Solvents and reagents were purchased and used without further purification. Melting points were
determined on a Mettler FP5 melting point apparatus and are uncorrected. NMR spectra were recorded on
Bruker DRX 400 MHz spectrometer using CDCl
standard. High resolution mass spectra were recorded on Applied Biosystems Mariner System 5303.
-Bromo-N-(diphenylmethylidene)aniline (2). A 1-L flask equipped with mechanical stirring,
thermometer and Dean-Stark trap was charged with 4-bromoaniline 1 (68.0 g, 0.50 mol), benzophenone
109.4 g, 0.60 mol, 1.2 equiv) and BF .
Et O (5.6 g, 0.04 mol) in toluene (400 mL). After the reaction
mixture was refluxed for 12 h, the solvent was removed via vacuum evaporation. The thick yellow
residue was added by 5 mL Et N and then recrystallized with MeOH to afford 4-bromo-N-(diphenyl-
methylidene)aniline 2 (145.3 g, 86 % yield) as a yellow solid. mp 83-84 C (lit. : 82-83 °C).
3
as solvent, and tetramethylsilane (TMS) as internal
4
(
3
2
3
o
15

HETEROCYCLES, Vol. 89, No. 12, 2014
2743
4
-Aminophenylboronic acid pinacol ester (3). To a solution of isobutylmagnesium bromide (prepared
with 3.9 g Mg, 20.4 g isobutylbromide in 60 mL THF) was added n-butyllithium (80.4 g, 2.5 M in
hexanes) at 0 °C, and the mixture was stirred for 10 min. The resulting yellow solution was cooled to
−20 °C, and a solution of 4-bromo-N-(diphenylmethylidene)aniline 2 (100.8 g, 0.3 mol) in dry THF (600
mL) was introduced dropwise under nitrogen atmosphere. After 1 h of stirring at same temperature,
trimethyl borate (47.1 g, 0.45 mol) was added into the reaction mass. The reaction mass was stirred for
1
3
h at same temperature. The mixture was then warmed to 25 °C over 1 h. After an additional stirring for
0 min at same temperature, the reaction was quenched with cool saturated aqueous NH Cl solution, then
4
rinsed with EtOAc (3 x 150 mL). The organic solvent was collected, a solution of pinacol (54 g, 0.45
mmol) in EtOAc (60 mL) was added and stirred for 1 h, 156 mL of 10% hydrochloric acid was then
added dropwise, and continued to stir for 1 h to ensure complete deprotection, then saturated aqueous
NaHCO solution was added until the pH reached 7-8. After 45 min of stirring at room temperature, the
3
mixture was diluted with EtOAc, and transferred into a 1-L separatory funnel, then rinsed with EtOAc (3
x 120 mL). The combined organic phases were dried, filtered and concentrated under reduced pressure.
The residue was recrystallized in ethanol to afford 4-aminophenylboronic acid pinacol ester 3 (45.8 g,
4
1
7
7
0 % yield) as a light yellow solid, mp 164–166 °C (lit. : 162–165 °C). H NMR (400 MHz, CDCl
3
): δ
). C NMR (100
), 150.4 (1C, C–B, broad), 141.9, 123.3 (4C, Ar–C), 83.1 (2C, O–C
1
3
.63 (d, J = 8.0 Hz, 2H), 6.65 (d, J = 8.0 Hz, 2H), 3.83 (b, 2H, NH
): δ 156.9 (1C, C-NH
), 23.9 (4C, CH ).
2
), 1.32 (s, 12H, CH
3
MHz, CDCl
3
2
(CH
3
)
2
3
ACKNOWLEDGEMENTS
This work was supported by the National Natural Science Foundation of China (21072046 and
1371148).
2
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