facilitating transmetalation from boron, possibly through
direct coordination to trivalent boron. The requirement of a
full equivalent of Cu(I) in the process is dictated by the need
to scavenge thiolate as the reaction proceeds. Any readily
available or easily prepared copper(I) carboxylate should
suffice in this chemistry; the use of CuTC and CuMeSal was
guided by a combination of low cost (of the corresponding
acid) and relative air-stability of the copper carboxylate
product.
Scheme 2. Cross-Coupling Mechanism
In conclusion, the scope and limitations of the copper
carboxylate-mediated, palladium-catalyzed cross-coupling of
thioalkynes and boronic acids have been studied. The
methodology allows the synthesis of unsymmetrical and
symmetrical alkynes in good yields under nonbasic condi-
tions.12
Acknowledgment. The National Cancer Institute, DHHS,
supported this investigation through Grant CA40157. We are
most grateful to Dr. Paul Reider of Merck Pharmaceutical
Co. for his interest in and generous support of this work
and to Dr. Gary Allred of Frontier Scientific, Inc. of Logan,
UT, for facilitating this study with a generous supply of
boronic acids.
was prepared in 63% yield by mixing phenylethynyl p-tolyl
sulfide 2 with Pd(PPh3)4 in benzene at room temperature.11
Compound 19 was treated with PhB(OH)2 under various
conditions. PhCtCPh was produced in the presence of PhB-
(OH)2 and CuMeSal, but not with PhB(OH)2 alone or with
PhB(OH)2 in the presence of NaOAc. These results highlight
the critical role played by the copper(I) carboxylate cofactor
in facilitating transmetalation from boron to palladium, which
does not occur directly from boron to the alkynylpalladium
thiolate. A logical intermediate is the Cu(I) carboxylate-
alkynylpalladium thiolate complex 20 (Scheme 3). Trans-
Supporting Information Available: A complete descrip-
tion of experimental details and product characterization. This
material is available free of charge via the Internet at
OL006807D
(10) Other references to C-S oxidative addition are found within
Kuniyasu, H.; Ohtaka, A.; Nakazono, T.; Kinomoto, M.; Kurosawa, H. J.
Am. Chem. Soc. 2000, 122, 2375-2376.
Scheme 3. Transmetalation and the Copper Cofactor
(11) Phenylethynyl p-tolyl sulfide 2 (101 mg, 0.45 mmol, 1.0 equiv)
was mixed with Pd(PPh3)4 (502 mg, 0.43 mmol, 1.0 equiv) in dry and
degassed benzene (11 mL), at room temperature, in the dark, under argon.
After 10 h, pentane (60 mL), was added and an orange solid precipitated.
After filtration of the solid, the palladium complex 19 (230 mg, 0.27 mmol,
63%) was obtained as a lightly orange solid.
(12) Typical experimental procedure: The boronic acid (1.0-1.5
equiv), Pd catalyst (3-10%), copper salt (CuTC or CuMeSal, 1.0-1.5
equiv), and thioalkyne (1.0 equiv) were placed in a 25 mL Schlenk tube.
After a vacuum and argon cycle, dry and degassed solvent was added. The
reaction mixture was stirred for 3-18 h at 45-50 °C. Following the typical
procedure, dry and degassed THF (2.5 mL) was added to the steroidal
derivative 7 (50 mg, 0.11 mmol, 1.0 equiv), CuMeSal (26 mg, 0.12 mmol,
1.1 equiv), p-methoxyphenylboronic acid (20 mg, 0.13 mmol, 1.1 equiv),
and Pd(PPh3)4 (7 mg, 0.01 mmol, 5%). The reaction was stirred for 14 h at
45 °C; after chromatography on an SiO2 preparative plate (CH2Cl2 as eluent),
18 (37 mg, 0.09 mmol, 81%) was obtained as white crystals. Full details
are contained in the Supporting Information.
metalation to palladium would then proceed directly from
the alkynylpalladium thiolate-Cu(I) carboxylate complex or
be preceded by prior boron to copper transmetalation.
The stoichiometric pairing of the Cu(I) cation and car-
boxylate anion are crucial to the success of the process. The
ineffectiveness of the copper(I) halides indicates that the
carboxylate counterion of the copper is clearly important in
Org. Lett., Vol. 3, No. 1, 2001
93