Palladium-catalyzed homocoupling of arylboronic acids and esters using fluoride in aqueous solvents

Article abstract of DOI:10.1055/s-2004-832845

Homocoupling of both arylboronic acids and esters has been found to proceed using catalytic amounts of Pd¹¹ and stoichiometric amounts of TBAF under air atmosphere at room temperature, offering a mild and efficient protocol for the synthesis of symmetrical biaryls via C(sp²)-C(sp ²) bond formation. Aryl boronic acids bearing bromide substitution form polyphenylenes.

Full text of DOI:10.1055/s-2004-832845

LETTER
2351
Palladium-Catalyzed Homocoupling of Arylboronic Acids and Esters Using
Fluoride in Aqueous Solvents
Arylboronic
C
r
oupling
e
w
ith Pd/Flu
e
oride/Wate
n
r
ivas Punna, David D. Díaz, M. G. Finn*
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd.,
La Jolla, CA 92037, USA
Fax +1(858)7848850; E-mail: mgfinn@scripps.edu
Received 14 April 2004
salts have only been used thus far in the cross-coupling of
Abstract: Homocoupling of both arylboronic acids and esters has
arylboronic acids and aryl halides.13
been found to proceed using catalytic amounts of PdII and stoichio-
metric amounts of TBAF under air atmosphere at room tempera-
ture, offering a mild and efficient protocol for the synthesis of
symmetrical biaryls via C(sp2)–C(sp2) bond formation. Aryl boron-
ic acids bearing bromide substitution form polyphenylenes.
Omission of either Pd or TBAF prevents any conversion
of starting material, and a stoichiometric amount of TBAF
was found to be essential for complete conversion. Very
little conversion (a few percent yield) was observed after
several days when the reaction was performed in dry THF
or under a nitrogen atmosphere, in the presence of either
catalytic or stoichiometric amounts of Pd(PPh3)2Cl2, but
introduction of a stoichiometric amount of CuII as an oxi-
dant under inert atmosphere restored full catalytic activi-
ty. An extensive survey established the optimal pH of the
aqueous component of the solvent mixture to be 7.0–9.5,
with the reaction being completely suppressed at pH <5.0.
Other tetrabutylammonium halides (chloride, bromide,
and iodide) were ineffective, and only CsF was found to
work as well as TBAF from a collection of fluoride salts
(ammonium, barium, calcium, lead, magnesium, sodium
and thulium). As source of palladium, Pd(PPh3)2Cl2
showed the best results. Table 1 outlines the results ob-
tained with a variety of both arylboronic acids and aryl-
boronic esters under a standard set of conditions.
Alkylboronic derivatives were found to be unreactive,
showing decomposition rather than coupling after extend-
ed periods.
Key words: boronic acids, palladium, fluoride, biaryls, water
Palladium-catalyzed carbon–carbon bond forming reac-
tions such as the Suzuki–Miyaura cross-coupling of or-
ganic halides with organoboron compounds1 have been
widely used in the synthesis of building blocks for active
pharmaceutical components and natural products,2 poly-
mers and electronic materials,3 liquid crystals4 and cata-
lysts.5 Several other methods used for the homocoupling
of organoboron compounds predate the palladium pro-
cesses, including nickel-mediated reactions.6 The applica-
tion of Pd catalysis to the production of symmetrical
products from aryl or vinylboronic compounds has recent-
ly been advanced by reports of: (a) new phosphorus
ligands to promote homocoupling;7 (b) dimerization of
arylboronic acids using catalytic PdII under an oxygen at-
mosphere with water as solvent;8 (c) similar dimerization
initiated by transmetallation of palladium enolates;9 (d)
the unexpected dimerization of an aryl bromide during
Pd-catalyzed borylation under base-free conditions, pre-
sumably via Suzuki coupling of the desired boronic ester
with the bromide;10 (e) base-free oxidative homocoupling
of arylboronic esters with catalytic amounts of Pd-dppp
[dppp = 1,3-bis(diphenylphophino)propane] complexes
under O2 in DMSO at 80 °C;11 and (f) radical coupling
mediated by manganese(III) acetate.12
Pd(PPh3)2Cl2 (10 mol%)
Bu4NF·H2O (1.0 equiv)
Ar Ar
Ar [B]
THF/H2O (4:1), air, r.t.
[B] = boronic acid, boronic ester
Scheme 1
Most of these transformations require long reaction times
(>20 h), polar solvents (DMSO, DMF, NMP), base
(Na2CO3, K2CO3, NaOH), or elevated temperatures. Here
we report the discovery of mild and convenient conditions
for the homocoupling of arylboronic acids or esters with
simple Pd(II) catalysts, featuring the use of (n-Bu)4NF
(TBAF) in 4:1 THF–H2O as solvent at room temperature
in air (Scheme 1). To the best of our knowledge, fluoride
As shown in Table 1, both arylboronic acids and aryl-
boronic esters gave the corresponding biaryls in good
yields, along with small amounts (5–10%) of the corre-
sponding phenols. The base-free nature of the process
allowed the sensitive methyl ester to be used without dif-
ficulty (entry 9). Bromoarylboronic acids formed oligo- or
polyphenylenes (entries 10–12),14 which could offer a
very easy route to interesting polymeric materials.
Equimolar mixtures of phenylboronic acid and n-butyl-
acrylate or allylbenzene provided both biphenyl and cin-
namate compounds (plus small amounts of unidentified
by-products), reflecting the presence of a competing
Heck-type coupling pathway (Scheme 2).15 Similarly,
SYNLETT 2004, No. 13, pp 2351–2354
Advanced online publication: 24.09.2004
DOI: 10.1055/s-2004-832845; Art ID: S03504ST
© Georg Thieme Verlag Stuttgart · New York
0
3
.1
1
.2
0
0
4

2352
S. Punna et al.
LETTER
CO2nBu
a
a
Suzuki-type reactivity was observed from mixtures of
arylboronic acids and aryl iodides, providing nearly
equimolar amounts of homocoupled and cross-coupled
products (Scheme 2). The use of arylboronic acids bear-
ing silyl, carboxylic acid, aldehyde or hydroxyl substitu-
ents gave mixtures of products that were troublesome to
isolate and identify. In the case of hydroxyl groups, the
formation of some polymeric material was also observed.
+
CO2nBu
Ph
PhB(OH)2
Ph Ph
26%
+
11%
Ph Ph + Ar Ph
37% 51%
PhB(OH)2
+
Ar
I
Scheme 2 (a) Pd(PPh3)2Cl2 (10 mol%), Bu4NF·H2O (1.0 equiv),
THF–H2O (4:1) air, r.t., 8 h. Ar = (p-OMe)C6H4.
Table 1 Results of the Palladium-Catalyzed Homocoupling of Arylboronic Acids and Esters
Entry
Boronic acid/ester
PhB(OH)2
Time (h)
Product a
Ph-Ph
Yield (%)b
1
2
9
9
77
74
Ph-Ph
O
B
O
3
10
72
H3C
CH3
OH
B
OH
CH3
4
5
6
9
9
81
85
59
OH
H3C
CH3
CH3
H3C
B
OH
O
O
H3C
O2N
H3C
O2N
B
12
NO2
OH
OH
B
7
8
10
12
76
73
OH
B
B
OH
O
O
9
8
67
–
OH
OH
MeO2C
CO2Me
MeO2C
Br
B
10c
12
OH
HO
B
HO
B
Br
Br
OH
n
11c
12d
12
12
–
–
O
O
HO
B
HO
Br
Br
B
n
Br
OCH3
OH
OMe
B
HO
OH
B
HO
OMe
n
MeO
a In most cases, a small amount (ca. 8%) of the corresponding phenol was also obtained.
b Isolated yields of pure compounds after column chromatography.
c The polymer obtained was insoluble in all solvents tested, making unambiguous characterization difficult. Approximately 70 mg polymer was
isolated from 200 mg of starting material.
d The oligomer obtained was soluble in THF. MALDI analysis showed the maximum value of n as 12.
Synlett 2004, No. 13, 2351–2354 © Thieme Stuttgart · New York

LETTER
Arylboronic Coupling with Pd/Fluoride/Water
2353
It is unusual for Pd-catalyzed coupling reactions to occur oxide was detected by a standard Amplex Red-horserad-
without the oxidative addition of an organic electrophile. ish peroxidase assay (Molecular Probes. Inc.) at roughly
A simple mechanism is proposed (Scheme 3), requiring the same concentration as that of Pd catalyst at the
two aryl-for-halide ligand exchange steps followed by re- completion of boronic acid coupling reactions in air, and
ductive elimination and regeneration of PdII by oxygen. that the use of CuII as oxidant under a nitrogen atmosphere
Both fluoride and water16 are necessary for reactivity to completely suppressed the formation of oxygenated by-
occur under the mild conditions described here, and the products. Olefinic or halide components can become
optimal pH range for the reaction spans the pKa values of incorporated through well-established mechanisms at the
arylboronic acids and esters.17 We therefore suspect that Pd0 stage, suggesting that such alternative pathways can
both fluoride and hydroxide18 boronate complexes are ac- be suppressed if oxidation of Pd0 to PdII is made more
tive nucleophiles in charging the PdII center; their order of rapid.
addition, if it is ordered, is not known. The observation of
In conclusion, the efficient homocoupling of arylboronic
mixed coupling products from a sequential reaction of
acids and arylboronic esters to give biaryls occurs with
arylboronic esters with stoichiometric amounts of Pd pre-
PdII catalysis under mild conditions, using fluoride ion in
cursor (Scheme 4) shows that charging of the metal center
the presence of water and air, and is crucially dependent
with the first aryl fragment is either incomplete or revers-
on each of these factors. Further refinement of this process
ible under these conditions (otherwise, the mixed biaryl
and its application to the synthesis of polymers are under-
product would have been formed selectively). The use of
way in our laboratory.
ArBF2 or ArBF3 K+ under the above conditions gave no
–
reaction,19 suggesting that boron does not play a Lewis
acidic role and that the ate complex intermediates must
Typical Procedure:
possess a minimum level of nucleophilicity.
Phenylboronic acid (122 mg, 1.0 mmol, 1.0 equiv) was dissolved in
THF–H2O (4:1, 3 mL) in a scintillation vial, and Pd(PPh3)2Cl2 (70
mg, 0.1 mmol, 0.1 equiv) and tetrabutylammonium fluoride hydrate
OR
M-F or HO
(261 mg, 1.0 mmol, 1.0 equiv) were added sequentially. TBAF in
THF solution can be also used. The reaction mixture was vigorously
stirred for 10 h at r.t., and was then diluted with EtOAc (5 mL), ex-
tracted with EtOAc (3 × 5 mL), and washed with H2O (5 mL). The
combined organic layers were dried with MgSO4, concentrated
under vacuum, and subjected to flash chromatography (hexanes) to
afford biphenyl (102 mg, 77%).
Ar
B
(X = F, OH)
ArB(OR)2
OR
X
M = Bu4N , Cs
OR
PdL2Cl2
Ar
B
O2 or
Cu(II)
OR
cross-coupling
X
R-X or
2 Cl
Cl
Ar
R
L2Pd0
Ar Ar
L2Pd
O2
H2O
ArB(OR)2
L2Pd
Acknowledgment
OH
OR
Ar
B
Ar
L2Pd
Ar
OOH
OR
We thank The Skaggs Institute for Chemical Biology for support of
this work. S.P. is a Skaggs Postdoctoral Fellow. D.D. thanks the
Spanish MECD (Ministerio de Educación, Cultura y Deportes de
España; Secretaría de Estado de Educación y Universidades) for a
postdoctoral fellowship co-financed by Fondo Social Europeo.
X
ArOH
Scheme 3
O
Bu4NF·H2O
(0.95 equiv)
Pd(PPh3)2Cl2
(0.95 equiv)
B
O
References
B
THF/H2O (4:1)
air, 15 min
Bu4NF·H2O (0.95 equiv)
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34%
Scheme 4
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Synlett 2004, No. 13, 2351–2354 © Thieme Stuttgart · New York

2354
S. Punna et al.
LETTER
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Synlett 2004, No. 13, 2351–2354 © Thieme Stuttgart · New York