An efficient high yielding approach for the homocoupling of aryl boronic acids

Article abstract of DOI:10.1055/s-2002-34855

A concise, mild, and high yielding method yielding C₂-symmetric biaryls is described. The addition of Cu(II) nitrate enhances the rate and the yield of the desired biaryl products. The conditions employed have yielded a number of substituted symmetric biaryls including 1,1′ and 2,2′ BINAP and are useful for the producing symmetric biaryls from their corresponding aryl boronic acids.

Full text of DOI:10.1055/s-2002-34855

PAPER
2183
An Efficient High Yielding Approach for the Homocoupling of Aryl Boronic
Acids
Homocoupling of
a
A
ryl
B
oron
r
ic
A
cidsrell J. Koza,* Eric Carita
Center for Antimicrobial Resistance, Eastern Connecticut State University, 83 Windham St., Willimantic, Connecticut 06226, USA
Fax +1(860)4654662; E-mail: kozad@easternct.edu
Received 24 May 2002; revised 24 July 2002
Our interests in a number of naturally occurring biaryl
Abstract: A concise, mild, and high yielding method yielding C2-
moieties in natural products led to the investigation of a
number of convenient and high yielding approaches for
the synthesis of biaryl compounds. The palladium cata-
symmetric biaryls is described. The addition of Cu(II) nitrate en-
hances the rate and the yield of the desired biaryl products. The con-
ditions employed have yielded a number of substituted symmetric
biaryls including 1,1 and 2,2 BINAP and are useful for the produc- lyzed cross coupling between a formal electrophile C X
ing symmetric biaryls from their corresponding aryl boronic acids.
and organometallic species C B is a versatile synthetic
method for contemporary carbon carbon bond forma-
tion.16 Furthermore, Suzuki coupling has become increas-
ingly popular due to its compatibility with a variety of
functional groups, the stability of the organoboron precur-
sors, and the ease of working up the reaction mixture. As
such, a wide variety of aryl boronic acids are available
commercially. The development of a homocoupling reac-
tion of aryl boronic acids would be convenient in allowing
the synthesis of a wide variety of C2-symmetric biaryls.
Key Words: arenes, biaryls, coupling, palladium catalyzed reac-
tions
Biaryls exhibit a wide variety of physical and chemical
properties1 with versatile applications in pharmaceuticals,
polymers, nonlinear optics,2 liquid crystals,3 and optically
active ligands.4 The diverse applications of these mole-
cules has recently led to a number of transition metal cat-
alyzed approaches to yield the biaryl moiety. Recently,
the preparation of biaryls by the Pd(0) catalyzed cross
coupling of aryl halides with aryl stannanes,5 arylboronic
acids,6 and arylzinc derivatives7 have been used. The ho-
mocoupling of aryl halides in the presence of nickel(II)8
complexes, activated copper,9 indium metal,10 and palla-
dium(II) acetate11 have been shown to yield biaryls in
good yield. Additionally, the synthesis of biaryls from the
homocoupling of organostannanes,12 organotellurides,13
and organosilicon14 compounds have been reported in the
literature. Notably absent in the literature is a concise
method for the homocoupling of aryl boronic acids yield-
ing symmetric biphenyls.
One troublesome feature of the Suzuki coupling reaction
is that no generally applicable set of reaction conditions
has been found to effect this reaction. A variety of sol-
vents, bases, and catalysts must be evaluated with respect
to each unique substrate. We began our investigation op-
timizing the solvent and catalyst for the homocoupling of
phenyl boronic acid (Table 1) under the conditions em-
ployed in the current literature. After 48 hours only entries
13 and 14 showed significant formation of the desired
product. Although aqueous carbonate bases are frequently
employed,17 we observed no product formation in the
presence of sodium carbonate or cesium carbonate. The
base is thought to form a boronate anion that is capable of
effecting boron to palladium transmetallation.18 The rela-
tively poor nucleophilicity of the acetate anion and the
weakness of the palladium-oxygen bond suggest that ac-
etate could act as a valuable base in the transmetallation
process. In addition, mechanistic studies have shown15
that atmospheric oxygen or oxygen enriched conditions
accelerates the desired homocoupling reaction. Thus, the
homocoupling of boronic acids should be considered as an
oxidative coupling process in contrast with reductive cou-
plings of aryl halides, which typically require stoichio-
metric amounts of reducing agents. The oxidative
mechanism for the reaction should then be accelerated by
the addition of an oxidizing agent since a reductive elimi-
nation is required to form the final biaryls.
Moreno-Manas et al. have reported a mechanistic study
on the self-coupling of aryl boronic acids15 with accept-
able yields for a small number of aryl boronic acids. Al-
though the initial findings for this method appear
promising, the versatility of the reaction with respect to
various functional groups and steric hindrance has not
been fully investigated. Moreover, the self-coupling
method described requires the isolation of the organobo-
ronic acid precursor. Although these compounds are gen-
erally stable, their high solubility in aqueous solvents
often complicates their isolation and purification. In-
trigued by this initial report we set out to examine the
scope of this interesting reaction in the hopes of develop-
ing a facile reaction for producing symmetric biaryl com-
pounds from their organoboron precursors.
We next set out to examine whether or not the addition of
an oxidant (Table 2) to the reaction would enhance the
proposed oxidative coupling. Selecting the two solvent
systems (EtOH and DMF H2O, 3:1) that provided the
highest yields, we tested a number of oxidizing agents.
Synthesis 2002, No. 15, Print: 29 10 2002.
Art Id.1437-210X,E;2002,0,15,2183,2186,ftx,en;M01902SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

2184
D. J. Koza, E. Carita
PAPER
Table 1 Solvent and Catalyst Optimizationa
Table 2 Oxidant Evaluationa
Pd catalyst
Pd(PPh3)4
ethanol
B(OH)2
B(OH)2
solvent
Entry
1
Solvent
DMF
Catalyst
% Yield
Entry
Oxidant
% Yield
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
0
0
1
2
3
4
5
6
7
8
9
AgNO3
0
0
2
H2O
HgSO4
3
CH3CN
THF
0
NiSO4
0
4
0
Zn(NO3)2
Fe(NO3)3
Bi(NO3)2
Co(NO3)2
Cu(NO3)2
Cu(NO3)2
trace
0
5
Toluene
DMF H2O, 3:1
EtOH
0
6
trace
trace
trace
0
0
7
23
88
8
DMF
9
H2O
0 (in absence of catalyst)
10
11
12
13
14
CH3CN
THF
0
a Conditions: Phenyl boronic acid (1.0 equiv), Pd(PPh3)4 (0.1 equiv),
NaOAc (5 equiv), specified oxidant (3 equiv) in EtOH at r.t after 8 h.
0
Toluene
DMF H2O, 3:1
EtOH
0
the mild reaction conditions, easily isolable products, and
characteristic high yields associated with the homocoup-
ling. Efforts in our laboratory are focused on the further
exploration concerning the scope, limitations, and mecha-
nistic aspects of this reaction.
23
17
a Conditions: Phenyl boronic acid (1.0 equiv), palladium catalyst (0.1
equiv), and NaOAc (5.0 equiv) in the specified solvent at r.t. Yields
were determined by GC analysis of the crude reaction mixtures com-
pared to an internal standard after 48 h.
Reagents were used as obtained from commercial sources or puri-
fied according to standard procedures. IR spectra were run at r.t. as
cast films or nujol mulls on a Perkin Elmer 1450 IR spectrophotom-
eter between 4000 and 600 cm–1. Mass spectral data was obtained
by flow injection in electrospray mode (70 eV) on an Applied Bio-
The majority of the oxidants employed did not enhance
the formation of the desired biphenyl. In fact, compared
with the results in Table 1 the majority of the oxidants in-
hibited the formation of biphenyl. Cobalt(II) nitrate gave
a slightly enhanced yield while copper(II) nitrate afforded
the greatest yield of the product after 8 hours.
systems Mariner API-TOF mass spectrometer. H and 13C NMR
1
spectra were obtained on a Jeol GSX400 at ambient temperature op-
erating at 400 MHz and 100 MHz respectively and are referenced to
residual proteo solvent or internal TMS. In some cases peaks denot-
ed q, CH, CH2, or CH3 were determined using DEPT experiments.
Analytical TLC was carried out on Whatman silica G/UV plates and
developed with hexane. Visualization was carried out using short
(265 nm) and long (360 nm) wave UV light as well as by staining
with iodine. Column chromatography was carried out using Merck
silica 60 eluted with hexane. Melting points were measured using a
Mel-Temp apparatus and are uncorrected. All literature melting
points were obtained from the Aldrich catalogue.
Encouraged by the enhancement of the yield of biphenyl
by copper(II) nitrate we set out to investigate the general
utility of the reaction conditions with a variety of aryl bor-
onic acid precursors. The effect of electron donating and
electron withdrawing substituents were examined. In gen-
eral, electron withdrawing or electron donating substitu-
ents did not significantly decrease the yield of the
substituted biphenyl when they were present in the 2- or
4- position of the aryl boronic acid. No significant steric
effect was exhibited (4-methyl, 71% vs. 2-methyl substit-
uent, 68%) for the aryl boronic acids tested. Furthermore,
the conditions employed were tolerant of aryl groups with
significant steric effects as exhibited by the high yields of
1,1 and 2,2 binapthyl (Table 3, compounds 8 and 9).
Biphenyl (1); Typical Procedure
Phenylboronic acid (150 mg, 1.23 mmol), Pd(PPh3)4 (75 mg, 0.065
mmol), and NaOAc (501 mg, 6.11 mmol) were dissolved in 95%
EtOH (20 mL) with stirring. After 2 hours at r.t., copper(II) nitrate
(231 mg, 0.90 mmol) was added to the soln and the reaction stirred
for 8 h at r.t. The solvent was removed in vacuo and the solid residue
was chromatographed on silica using hexane to yield 76.0 mg
(80%) of the title compound as white crystals.
Mp 69–70 °C (Lit. 69–71 °C).
IR: 3046, 1669, 1481, 1377, 1092, 730, 700 cm–1.
1H NMR (400 MHz, CDCl3): = 7.57 (d, J = 7.79 Hz, 2 H), 7.41 (t,
J = 7.79 Hz, 2 H), 7.32 (t, J = 7.45 Hz, 1 H).
In summary, the general conditions reported herein for the
homocoupling of aryl boronic acids are applicable to a
number of substituted and sterically demanding boronic
acids. This method has a number of advantages including
Synthesis 2002, No. 15, 2183–2186 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Homocoupling of Aryl Boronic Acids
2185
Table 3 Substituted Biaryl Synthesisa
IR: 3071, 3048, 1681, 1581, 1498, 1276, 1080, 1045, 1006, 1000,
723, 507 cm–1.
1H NMR (400 MHz, CDCl3): = 7.48 (d, J = 7.88 Hz, 1 H), 7.33 (t,
Ar B(OH)2
Ar Ar
J = 7.47 Hz, 1 H), 7.31 (t, J = 7.46 Hz, 1 H), 7.26 (d, J = 7.84 Hz, 1
H).
Com- Ar
pound
Product
Yield
%
b
13C NMR: = 137.9, 133.1 (2 q), 130.7, 129.0, 128.8, 126.1 (4
CH).
1
2
3
Phenyl
80
66
61
4,4 -Dichlorobiphenyl (4)
Yield: 77.0 mg (72%); white crystals.
4-Fluorophenyl
2-Fluorophenyl
F
F
Mp 142–144 °C (Lit. 142–145 °C).
IR: 3038, 1612, 1583, 1503, 1172, 1006, 726, 509 cm–1.
F
1H NMR (400 MHz, CDCl3): = 7.45 (d, J = 8.23 Hz, 2 H), 7.38 (d,
J = 8.22 Hz, 2 H).
13C NMR: = 138.2, 133.6 (2 q), 128.7, 127.9 (2 CH).
F
4
4-Chlorophenyl
72
4,4 -Dimethylbiphenyl (5)
Cl
Cl
Yield: 71.0 mg (71%); white crystals.
5
6
4-Methylphenyl
2-Methylphenyl
71
68
Mp 117–119 °C (Lit. 118–120 °C).
IR: 3024, 2943, 1610, 1502, 1179, 1003, 725, 503 cm–1.
1H NMR (400 MHz, CDCl3): = 7.47 (d, J = 7.22 Hz, 2 H), 7.22 (d,
J = 7.47 Hz, 2 H), 2.37 (s, 3 H).
CH3
CH3
CH3
13C NMR: = 138.4, 136.7 (2 q), 129.5, 126.8 (2 CH), 21.1 (CH3).
CH3
2,2 -Dimethylbiphenyl (6)
Yield: 67.0 mg (68%); off white crystals.
7
8
4-Methoxyphenyl
2-Napthyl
16c
81
H3CO
OCH3
Mp 17–18 °C (Lit. 18 °C).
IR: 3030, 2945, 1607, 1511, 1168, 1004, 723, 506 cm–1.
1H NMR (400 MHz, CDCl3): = 7.41 (d, J = 7.33 Hz, 1 H), 7.32 (t,
J = 7.32 Hz, 1 H), 7.27 (t, J = 7.40 Hz, 1 H), 7.24 (d, J = 7.38 Hz, 1
H).
9
1-Napthyl
78
13C NMR: = 136.5, 135.6 (2 q), 129.4, 128.9, 126.3, 126.1 (4
CH).
4,4 -Dimethoxybiphenyl (7)
Yield: 16.0 mg (16%); light yellow crystals.
a Conditions: Aryl boronic acid (1.0 equiv), Pd(PPh3)4 (0.1 equiv),
NaOAc (5.0 equiv) and Cu(NO3)2 (3.0 equiv) were added to 95%
EtOH and the soln allowed to stir at ambient temperature for 8 h. The
solvent was removed in vacuo, the reaction mixture was chromato-
graphed on silica with hexane, and the product fractions were com-
bined.
Mp 155–157 °C (Lit. 179–180 °C).
IR: 2925, 2890, 1595, 1490, 1250, 1050, 810, 790 cm–1.
1H NMR (400 MHz, CDCl3): = 7.49 (d, J = 8.76 Hz, 2 H), 6.97 (d,
J = 8.80 Hz, 2 H), 3.86 (s, 3 H).
13C NMR: = 158.9, 133.7 (2 q), 127.9, 114.4 (2 CH), 55.5
(OCH3).
b Isolated yield.
c The reaction also afforded 4-methoxybiphenyl (19%).
1,1 -Binaphthyl (8)
Yield: 90.0 mg (81%); white crystals.
13C NMR: = 140.8 (q), 128.4, 126.9, 126.8 (3 CH).
Mp 158–160 °C (Lit. 158–160 °C)
4,4 -Difluorobiphenyl (2)
IR: 3073, 3058, 1590, 1505, 1402, 1385, 1216, 1200, 1137, 793,
739, 682, 620 cm–1.
1H NMR (400MHz, CDCl3): = 7.95 (m, 2 H), 7.59 (t, J = 7.83 Hz,
1 H), 7.47 (m, 2 H), 7.39 (d, J = 7.68 Hz, 1 H), 7.28 (t, J = 7.66 Hz,
1 H).
13C NMR: = 138.4, 133.5, 132.8 (3 q), 128.0, 127.8, 126.5, 125.9,
125.7, 125.3 (6 CH).
Yield: 67.0 mg (66%); white crystals.
Mp 90–93 °C (Lit. 92–95 °C).
IR: 3050, 1900, 1612, 1497, 1238, 806, 501 cm–1.
1H NMR (400 MHz, CDCl3): = 7.47 (d, J = 7.43 Hz, 2 H), 7.10 (d,
J = 7.42 Hz, 2 H).
13C NMR: = 162.5, 136.5 (2 q), 128.6, 115.7 (2 CH ).
2,2 -Difluorobiphenyl (3)
2,2 -Binaphthyl (9)
Yield: 62.0 mg (61%); white crystals.
Yield: 87.0 mg (78%); white crystals.
Mp 115–117 °C (Lit. 116–117 °C).
Mp 183–185 °C (Lit. 187–188 °C).
Synthesis 2002, No. 15, 2183–2186 ISSN 0039-7881 © Thieme Stuttgart · New York

2186
D. J. Koza, E. Carita
PAPER
IR: 3073, 1966, 1594, 1499, 1392, 1201, 1011, 883, 816, 627, 469
cm–1.
(4) Rosini, C.; Franzini, L.; Raffael, A.; Dalvadori, P. Synthesis
1992, 503.
(5) Farina, V. Pure Appl. Chem. 1996, 68, 73.
(6) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(7) Neguishi, E. Acc. Chem. Res. 1982, 15, 340.
(8) Iyoda, M.; Otsuka, H.; Sato, K.; Nisato, N.; Oda, M. Bull.
Chem. Soc. Jpn. 1990, 63, 80.
(9) Ginah, F. O.; Donovan, T. A.; Suchan, S. D.; Pfennig, D. R.;
Ebert, G. W. J. Org. Chem. 1990, 55, 584.
(10) Ranu, B.; Dutta, P.; Sarkar, A. Tetrahedron Lett. 1998, 39,
9557.
1H NMR (400 MHz, CDCl3): = 8.17 (s, 1 H), 7.96 (d, J = 7.12 Hz,
1 H), 7.94 (d, J = 7.39 Hz, 1 H), 7.89 (d, J = 7.51 Hz, 2 H), 7.53 (t,
J = 7.38 Hz, 1 H), 7.50 (t, J = 7.12 Hz, 1 H).
13C NMR: = 138.7, 134.0, 133.0 (3 q), 128.6, 128.4, 127.8, 126.4,
126.2, 126.1, 125.8 (7 CH).
Acknowledgements
(11) Penalva, V.; Hassan, J.; Lavenot, L.; Gozzi, C.; Lemaire, M.
Tetrahedron Lett. 1998, 39, 2559.
(12) Kang, S.; Baik, T.; Jiao, X.; Lee, Y. Tetrahedron Lett. 1999,
40, 2383.
(13) Nishibayashi, Y.; Cho, C.; Ohe, K.; Uemura, S. J.
Organomet. Chem. 1996, 526, 335.
(14) Kang, S.; Kim, T.; Pyun, S. J. Chem. Soc., Perkin Trans. 1
1997, 797.
We gratefully acknowledge Eastern Connecticut State University
and the Connecticut State University Research Award Grant
(KOZR11) for financial support of this work. We also thank Gary
Allred of Frontier Scientific, Inc. for a generous donation of starting
materials and Dr. William Howald of the Medicinal Mass Spectro-
metry Center at the University of Washington for providing mass
spectral data of the synthetic compounds.
(15) Moreno-Manas, M.; Perez, M.; Pleixats, R. J. Org. Chem.
1996, 61, 2346.
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Synthesis 2002, No. 15, 2183–2186 ISSN 0039-7881 © Thieme Stuttgart · New York