Easily accessible 2-(2-bromophenyl)-4,4,5,5-tetramethyl-[1,3,2] dioxaborolane for Suzuki-Miyaura reactions

Article abstract of DOI:10.1002/jccs.200700118

A simple and direct method has been developed for the preparation of the title compound from 1,2-dibromobenzene. Suzuki-Miyaura reactions of this compound with substituted bromoaryls proceeded smoothly to give 2-bromobiphenyl derivatives in moderate to excellent yields. Instead of converting each of the bromoaryl compounds to the corresponding arylmetals followed by reacting with 2-iodobromobenzene, the advantage of this protocol is that the substituted bromoaryls were used directly to couple with the title compound.

Full text of DOI:10.1002/jccs.200700118

Journal of the Chinese Chemical Society, 2007, 54, 811-816
811
Note
Easily Accessible
2-(2-Bromophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane for
Suzuki-Miyaura Reactions
Tein-Fu Wanga* (
Chih-Neng Chena (
), Ching-Lung Linb (
),
) and Tan-Ching Wanga (
)
aInstitute of Chemistry, Academia Sinica, Taipei, Taiwan, R.O.C.
bDepartment of Chemistry, National Central University, Chung-Li, Taiwan, R.O.C.
A simple and direct method has been developed for the preparation of the title compound from 1,2-
dibromobenzene. Suzuki-Miyaura reactions of this compound with substituted bromoaryls proceeded
smoothly to give 2-bromobiphenyl derivatives in moderate to excellent yields. Instead of converting each
of the bromoaryl compounds to the corresponding arylmetals followed by reacting with 2-iodobromoben-
zene, the advantage of this protocol is that the substituted bromoaryls were used directly to couple with the
title compound.
Keywords: Suzuki; Biphenyl; Coupling; Spirobifluorene.
Substituted 2-bromobiphenyls are important as inter-
(Scheme I). This approach works well for most cases; how-
ever, the reactions fail if the substituents (R) are sensitive
to the alkyllithium reagent.
mediates for pharmaceuticals1 and bulky phosphine lig-
ands2 and as building blocks of spirobifluorenes.3 The
preparation of 2-bromobiphenyls are usually carried out by
metal-halogen exchange of the corresponding arylhalides
with alkyllithium reagent, followed by reacting with 2-io-
dobromobenzene via various coupling methodologies,4
such as Stille,5 Negishi6 and Suzuki-Miyaura couplings7
We have examined the reaction in a reverse way. That
is, by the reaction of substituted arylhalides with 2-bromo-
phenylboronic ester C (Scheme II). By using this reverse
approach, the coupling products 2-bromobiphenyls were
isolated in moderate to excellent yields. The advantage of
Scheme I
Scheme II
* Corresponding author. Tel: +886-2-27898546; Fax: +886-2-27831237; E-mail: tfwang@chem.sinica.edu.tw

812 J. Chin. Chem. Soc., Vol. 54, No. 3, 2007
Wang et al.
Table 1. Suzuki-Miyaura coupling of A with various substrates
Yield,
c
%
Entry
Substrate
oC /hr
Producta
Mp,b o
C
70/2
81—82
96
96
76
1
70/2
80/5
88—89
2
3
oil b
90/5
87—88
70
4
90/5
oil
5
52
90/5
70/2
70/3
oil
oil
40
90
85
6
7
8d
219
a All products gave satisfactory elemental analyses and/or high resolution mass measurement.
b The m.p. means the melting point of the compound and oil means the compound is oil.
c Yields are reported after purification.
d Entry 8 requires 2.1 equivalents (10.5 mmol) of C.

Formation of 2-Bromobiphenyls
J. Chin. Chem. Soc., Vol. 54, No. 3, 2007 813
this approach is two fold. First, we don’t have to prepare
each of the arylmetal intermediates from the corresponding
bromoaryls separately. Second, the alkyllithium labile sub-
stituents such as NO2 and CN remain intact under the reac-
tion conditions (see Table 1).
coupling products were not observed. It is generally ac-
cepted that both boronic acid and the corresponding boro-
nic ester work equally well with bromoarenes in the Suzuki-
Miyaura coupling reactions. Attempts to purify the boronic
acid D were found to be troublesome. Therefore, the crude
boronic acid D was converted to the corresponding dioxa-
borolane C.
Electron-withdrawing substituted arylbromides re-
acted smoothly with boronic ester C at 70 °C in 2~3 hours
to give the corresponding 2-bromobiphenyls in excellent
yields (entries 1, 2, 7 and 8). The electron-releasing substi-
tuted arylbromides (entries 3, 4, 5 and 6) reacted much
slower with C, required higher temperature (90 °C) and
longer reaction time (5 hrs) to provide moderate to good
yields of the corresponding 2-bromobiphenyls. Small
amounts of further coupling product of the resultant 2-bro-
mobiphenyl with C were also isolated for entry 3.
In conclusion, we have developed an easy method to
prepare 2-bromophenylboronic ester C from the easily ac-
cessible 1,2-dibromobenzene. Compound C could be seen
as a complement of 2-iodobromobenzene in the prepara-
tion of 2-bromobiphenyl derivatives. Suzuki-Miyaura cou-
pling reactions of C with substituted bromoaryl compounds
proceeded smoothly to give 2-bromobiphenyls in good
yields. Instead of converting each of the bromobiphenyl
compounds to the corresponding arylmetals and reacting
with 2-iodobromobenzene, the advantage of this protocol
is that the substituted bromoaryls could be used directly to
couple with 2-bromophenylboronic ester C.
The costly, commercially available 2-bromophenyl-
boronic acid (D) has been getting more and more use in the
preparation of 2-bromobiphenyl derivatives.8 However, an
inexpensive and simple method for the preparation of C is
needed. Lithium-halogen exchange of the bromoaryl com-
pounds with n-butyllithium9 followed by reacting with
trialkylborate is a common procedure for the preparation of
the corresponding arylboronic acid. It is conceivable that
lithium-halogen exchange of 1,2-dibromobenzene with
n-butyllithium would give only mono-lithiated anion, be-
cause double lithiation is unlikely at low temperature. In-
deed, when we treated a mixture of 1,2-dibromobenzene
and triisopropyl borate with n-butyllithium at -78 °C, using
the “in situ quench” protocol,10 followed by conversion of
the boronic acid to the boronic ester, the desired compound
C was obtained in good yield. This was probably because
the lithium-halogen exchange on 1,2-dibromobenzene is
much faster than that of the reaction between n-butyllith-
ium and triisopropyl borate. Upon warming, the residual
n-butyllithium reacts faster than the resultant bromophenyl
anion with triisopropyl borate. Thereby, clean and mono-
lithiation product C was obtained (Scheme III). As we sub-
jected C to the Suzuki-Miyaura reaction condition (80 °C,
2 hr), C was recovered in greater than 95% purity. Self-
EXPERIMENTAL
All chemicals and reagents were used as received from
commercial sources without further purification. Tetrahy-
drofuran (THF) was dried by distillation over sodium/ben-
zophenone. Toluene was distilled over calcium hydride.
Melting points were determined using a Yanaco Model MP
micro melting point apparatus and were uncorrected. The
1H and 13C NMR spectra were recorded on Bruker AC400
or AC500 spectrometers. Mass spectra (FAB) were re-
corded on a Hewlett-Packard GC/MS 5995 spectrometer.
Elementary analyses were performed on a Perkin-Elmer
2400 CHN analyzer.
2-(2-Bromophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxabo-
rolane (C)11
A 1 L flask equipped with a magnetic stir bar was
charged with 1,2-dibromobenzene (30.7 g, 130 mmol), tri-
Scheme III

814 J. Chin. Chem. Soc., Vol. 54, No. 3, 2007
Wang et al.
isopropyl borate (36.3 mL, 156 mmol), toluene (200 mL)
and THF (50 mL) under an argon atmosphere. The solution
was cooled in a dry ice/acetone bath to below -70 °C. A
hexane solution of n-BuLi (1.6 M, 90 mL) was added
slowly over a period of 1 hr. After stirring for an additional
5 min, the cool bath was removed and the mixture was al-
lowed to stir at room temperature for an hour. 2 N HCl solu-
tion (250 mL) was added and the mixture was stirred vigor-
ously for 30 min. The mixture was combined with ether
(500 mL) and transferred to a 1 L separatory funnel. The or-
ganic layer was washed once with water and concentrated
under reduced pressure. To the residual solids was added
pinacol (21.3 g, 180 mmol) followed by toluene (300 mL).
The mixture was heated under reflux for 2 hr, using a
Dean-Stark apparatus for continuously removal of water.
After evaporation of toluene under reduced pressure, the
residue was subjected to vacuum distillation. Desired prod-
uct C was collected at 92-98 °C (0.3 torr) as colorless liquid
in 85% yield (31.38 g).1H NMR (500 MHz, CDCl3): d 7.60
(1H, dd, J = 7.2, 2.0 Hz), 7.51 (1H, dd, J = 7.8, 1.3 Hz),
7.25 (1H, td, J = 7.3, 1.4 Hz), 7.21 (1H, td, J = 7.5, 2.0 Hz),
1.36 (12H, s). 13C{1H} NMR (125 MHz, CDCl3): d 136.3
(CH), 132.6 (CH), 131.7 (CH), 128.0 (C), 126.2 (CH), 84.2
(C ´ 2), 24.7 (CH3 ´ 4), C-B not observed. Elemental anal-
ysis, calcd for C12H16BBrO2: C, 50.93; H, 5.70. Found: C,
50.75; H, 5.95. HRMS (FAB, M++1, B11Br79): Calcd for
C12H17BBrO2: 283.0505, Observed: 283.0512.
Hz), 7.28 (1H, t, J = 7.5 Hz). 13C NMR (125 MHz, CDCl3):
d 147.4 (C), 147.2 (C), 140.3 (C), 133.4 (CH), 130.8 (CH),
130.4 (CH ´ 2), 129.9 (CH), 127.7 (CH), 123.2 (CH ´ 2),
122.0 (C). Anal. Calcd for C12H8BrNO2: C, 51.83; H, 2.90;
N, 5.04. Found: C, 51.99; H, 2.73; N, 5.02. HRMS (FAB,
M+, Br79): Calcd for C12H8BrNO2: 276.9736. Observed:
276.9741.
2¢-Bromo-biphenyl-4-carbonitrile (2B)
1H NMR (500 MHz, CDCl3): d 7.72 (2H, d, J = 8.2
Hz, AA’BB’), 7.69 (1H, d, J = 7.5 Hz), 7.53 (2H, d, J = 8.2
Hz, AA’BB’), 7.39 (1H, t, J = 7.5 Hz), 7.30 (1H, d, J = 7.5
Hz), 7.27 (1H, t, J = 7.5 Hz). 13C{1H} NMR (125 MHz,
CDCl3): d 145.5 (C), 140.6 (C), 133.4 (CH), 131.8 (CH ´
2), 130.8 (CH), 130.2 (CH ´ 2), 129.7 (CH), 127.6 (CH),
122.0 (C), 118.7 (C), 111.5 (C). Anal. Calcd for C13H8BrN:
C, 60.49; H, 3.12; N, 5.43. Found: C, 60.50; H, 2.98; N,
5.38. HRMS (FAB, M+, Br79): Calcd for C13H8BrN:
256.9838. Observed: 256.9832.
2-Bromo-4¢-tert-butyl-biphenyl (3B)
1H NMR (400 MHz, CDCl3): d 7.66 (1H, dd, J = 7.6
1.6 Hz), 7.44 (2H, d, J = 8.5 Hz, AA’BB’), 7.37-7.33 (4H,
m), 7.20-7.16 (1H, m), 1.37 (9H, s). 13C{1H} NMR (100
MHz, CDCl3): d 150.4 (C), 142.4 (C), 138.1 (C), 133.1
(CH), 131.4 (CH), 129.0 (CH ´ 2), 128.4 (CH), 127.3 (CH),
124.8 (CH ´ 2), 122.6 (C), 34.6 (C), 31.4 (CH3 ´ 3). HRMS
(FAB, M+, Br79): Calcd for C16H17Br: 288.0509. Observed:
288.0518.
General Suzuki-Miyaura coupling reactions
Under an argon atmosphere, the corresponding sub-
stituted arylbromides (5 mmol), o-bromophenylboronic
ester C (5.25 mmol), aliquate 336 (0.2 g), Na2CO3 (2.12 g,
20 mmol) and tetrakis(triphenylphosphine)palladium(0)
(116 mg, 0.1 mmol) were placed successively to a flask.
Degased toluene (20 mL) and distilled water (10 mL) were
then added. The mixture was heated in an oil bath at the
specified temperature (see Table 1). After stirring for a pe-
riod of time (indicated in Table 1), the mixture was cooled
to room temperature, and the toluene layer was washed
twice with water. The residue after concentration was chro-
matographed on silica gel to give the desired compounds.
1-(2-Bromo-phenyl)-naphthalene (4B)
1H NMR (500 MHz, CDCl3): d 7.96-7.93 (2H, m),
7.77 (1H, d, J = 8.0 Hz), 7.57 (1H, t, J = 7.5 Hz), 7.54-7.50
(2H, m), 7.46-7.43 (2H, m), 7.41-7.38 (2H, m), 7.32 (1H, t,
J = 7.5 Hz). 13C{1H} NMR (125 MHz, CDCl3): d 141.3
(C), 139.1 (C), 133.5 (C), 132.7 (CH), 132.0 (CH), 131.6
(C), 129.2 (CH), 128.3 (CH), 128.2 (CH), 127.1 (CH),
127.0 (CH), 126.2 (CH), 125.9 (CH), 125.8 (CH), 125.1
(CH), 124.4 (C). Anal. Calcd for C16H11Br: C, 67.87; H,
3.92. Found: C, 68.02; H, 3.87. HRMS (FAB, M+, Br79):
Calcd for C16H11Br: 282.0041. Observed: 282.0038.
2-Bromo-4¢-nitro-biphenyl (1B)
(2¢-Bromo-biphenyl-4-yl)-diphenyl-amine (5B)
1H NMR (500 MHz, CDCl3): d 8.29 (2H, d, J = 8.5
Hz, AA’BB’), 7.70 (1H, d, J = 7.5 Hz), 7.58 (2H, d, J = 8.5
Hz, AA’BB’), 7.40 (1H, t, J = 7.5 Hz), 7.32 (1H, d, J = 7.5
1H NMR (500 MHz, CDCl3): d 7.68 (1H, d, J = 7.4
Hz), 7.38-7.36 (2H, m), 7.33-7.28 (6H, m), 7.20-7.17 (5H,
m), 7.14 (2H, d, J = 8.5 Hz, AA’BB’), 7.06 (2H, t, J = 7.4

Formation of 2-Bromobiphenyls
J. Chin. Chem. Soc., Vol. 54, No. 3, 2007 815
Hz). 13C{1H} NMR (125 MHz, CDCl3): d 147.6 (C × 2),
147.2 (C), 142.2 (C), 134.8 (C), 133.2 (CH), 131.3 (CH),
130.2 (CH × 2), 129.3 (CH × 4), 128.3 (CH), 127.3 (CH),
124.7 (CH × 4), 123.1 (CH × 2), 122.7 (C), 122.4 (CH × 2).
HRMS (FAB, M+, Br79): Calcd for C24H18BrN: 399.0618.
Observed: 399.0616.
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We are grateful to the National Science Council of
Taiwan for financial support.
Received October 19, 2006.

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