Mild and efficient formation of symmetric biaryls via Pd(II) catalysts and Cu(II) oxidants

Article abstract of DOI:10.1016/S0040-4039(01)01691-4

Described herein is a mild and efficient palladium-catalyzed synthesis of symmetric biaryls from organostannanes. This methodology offers products rapidly in very high yields.

Full text of DOI:10.1016/S0040-4039(01)01691-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7729–7731
Mild and efficient formation of symmetric biaryls via Pd(II)
catalysts and Cu(II) oxidants
Jay P. Parrish, Vincent L. Flanders, Ryan J. Floyd and Kyung Woon Jung*
Department of Chemistry, University of South Florida, 4202 E. Fowler Avenue, Tampa, FL 33620-5250, USA
Received 22 June 2001; revised 4 September 2001; accepted 10 September 2001
Abstract—Described herein is a mild and efficient palladium-catalyzed synthesis of symmetric biaryls from organostannanes. This
methodology offers products rapidly in very high yields. © 2001 Elsevier Science Ltd. All rights reserved.
Carbonꢀcarbon bond formation is an essential process
in organic chemistry. Of particular importance to natu-
ral product synthesis are reactions that form new sp
and sp2 bonds. Examples of these include Stille, Heck,
Suzuki, and Sonogashira couplings.1 Interestingly,
many of these palladium-catalyzed carbonꢀcarbon
bond-forming reactions have been known to give an
oxidative dimerization side product.2 This ‘homocou-
pling’ reaction has been developed into a useful tool for
the preparation of a number of symmetric materials
such as biaryls, 1,3-dienes and 1,3-diynes.3,4
First, we undertook reaction optimization using com-
mercially available tributylphenyltin 1 as the homocou-
pling partner. It was found that Pd(OAc)2 and Pd2dba3
were the most effective catalysts for this transforma-
tion, providing biphenyl 2 in 94% yield or greater in
less than 15 minutes. Pd(OAc)2 was the catalyst of
choice due to its lower cost and greater air and water
stability when compared to Pd2dba3. Catalyst amounts
as low as 1 mol% could be used with little drop off in
yield and reaction time. Additionally, it was found that
THF was the optimal solvent for the reaction. Other
solvents like EtOH, DMF, and benzene did not work
well.
Recently, we described a modification of the Heck
reaction that employs aryl stannanes as surrogates for
Of the catalyst reoxidants screened, CuCl2 was the most
effective. FeCl3 gave lower yields, and MnO2 was com-
pletely inactive. As shown in Table 1, the reaction of 1
aryl halides.5 This methodology offers
a milder
approach to CꢀC bond formation, delivering di- and
trisubstituted olefins at room temperature in short reac-
tion times. During the development of the reaction
parameters, aryl–aryl dimerization products were
noticed. These products formed via a standard homo-
coupling reaction and often competed directly with
desired olefin formation. More importantly, it was
found that when the reaction was run without adding
any olefin source, homocoupling was the exclusive
product.
Table 1. Effect of reoxidant amount on reaction yield
Pd(OAc)2, CuCl2
PhSnBu3
Ph Ph
THF, 23 °C
1
2
time
yield
entry
amount of CuCl2
0 equiv.
0.5 equiv.
1.0 equiv.
2.0 equiv.
3.0 equiv.
1
2
3
4
5
24 h
24 h
20%
45%
94%
97%
96%
Reported herein is the development of the palladium-
catalyzed homocoupling reaction into a useful CꢀC
bond-forming tool, which prepares symmetric biaryls,
dienes and diynes in high yields and very short reaction
times. Likewise, our methodology allows for the synthe-
sis of certain sterically hindered biphenyl systems.
2 h
15 min
15 min
CuCl2, THF
23 °C, 24 h
1
2
Keywords: biaryls; catalysis; dienes; diynes; homocoupling.
* Corresponding author. Tel.: 1-813-974-7306; fax: 1-813-974-1733;
e-mail: kjung@chuma.cas.usf.edu
(No reaction)
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01691-4

7730
J. P. Parrish et al. / Tetrahedron Letters 42 (2001) 7729–7731
with varying amounts of CuCl2 gave us insight into the
course of the reaction. With submolar amounts of the
reoxidant, yields of biphenyl were retarded and the
reaction did not go to completion (entry 2). Addition-
ally, 1 equivalent of CuCl2 provided 2 in high yield at a
reasonable rate (entry 3). From these results, 2 equiva-
lents of the reoxidant appears to be optimal in terms of
reaction time and yield (entry 4). Adding more CuCl2
does not provide any increase in product formation
(entry 5).
atmospheric moisture to give both acid and alcohol side
products resulting from the Cannizzaro reaction.
These results demonstrate that our methodology offers
one of the mildest conditions for symmetric biphenyl
formation to date. With the exception of a few exam-
ples, reaction conditions are not moisture sensitive and
an inert atmosphere was not required. Furthermore,
stannanes with varying degrees of electron density and
steric hindrance worked well with our conditions.
With these results in hand, several control experiments
were performed to glean additional insight. The
Pd(OAc)2 catalyst delivers the product in low yield
when run in the absence of reoxidant (entry 1). Further-
more, many examples of Cu(I) and Cu(II) initiated
oxidative dimerizations of organostannanes have been
reported providing homocoupling products.4 In order
to determine the role of CuCl2 in our methodology, 1
was treated with only the reoxidant and no sign of
biphenyl was detected after 24 hours.
Having obtained excellent results with biaryl formation,
we next focused our attention on coupling of other
stannane classes as shown in Table 3. First, we screened
heterocyclic stannanes, and 2,2%-bipyridine was synthe-
sized from its corresponding stannane in 89% yield
after 1 h (entry 1). Next, 2-(tributylstannyl)thiophene
was screened and found to give high yields of the biaryl
in 25 min (entry 2). Additionally, 2-(tributylstan-
nyl)furan delivered 2,2%-bifuran in 91% after only 15
min (entry 3). We found this material was air-sensitive
as reported by Larock.8
Next, as shown in Table 2, synthesis of various
biphenyls proceeded at room temperature in good
yields and in short reaction times. Sterically encum-
bered (2-methoxyphenyl)-tributylstannane gave the cor-
responding biaryl in 95% after 7 min, showing little
steric effects from the ortho methoxy group (entry 1).6
Additionally, electron rich (3,4-dimethoxyphenyl)-
tributylstannane was an efficient substrate, providing
the coupled compound in 93% yield (entry 2).7
We then turned our attention to the synthesis of 1,3-
dienes and 1,3-diynes. First, (E)-2-(tributylstan-
nyl)styrene was subjected to our conditions, and after
2.5 h gave 93% of (1E,3E)-1,4-diphenyl-1,3-butadiene
1
(entry 4). Based on H NMR analysis, only this isomer
was detected. Next, 1,4-diphenylbutadiyne was pre-
pared from its corresponding stannane in 94% after 25
min (entry 5). Our synthesis of dienes and diynes is
both mild and efficient, and offers access to Diels–Alder
precursors and other important materials.9
Next, stannanes with electron withdrawing groups were
screened.
(4-Trifluoromethylphenyl)tributylstannane
offered the coupled biphenyl in 94% after 20 min (entry
3). Also, air- and moisture-sensitive (4-tributylstan-
nyl)benzaldehyde was found to give 77% of desired
biphenyl after 3 h (entry 4). Despite careful handling,
the aldehyde moiety on the phenyl ring reacted with
Based on our observations, the proposed catalytic cycle
is shown in Scheme 1. The initial step involves
transmetallation of the stannane by a Pd(II) catalyst.
The intermediate RPdX then undergoes a second
Table 3. Formation of biaryls, dienes, and diynes from
stannanes
Table 2. Formation of biphenyls from aryl stannanes
Pd(OAc)2, CuCl2
Pd(OAc)2, CuCl2
ArSnBu3
Ar Ar
RSnBu3
R R
THF, 23 °C
THF, 23 °C
3
4
5
6
stannane
OMe
time
yield
95%
entry
1
stannane
time
1 h
yield
89%
entry
1
N
SnBu3
7 min
SnBu3
S
SnBu3
SnBu3
MeO
2
3
25 min
15 min
99%
91%
93%
94%
30 min
93%
2
MeO
SnBu3
SnBu3
O
3
4
20 min
3 h
94%
77%
F3C
SnBu3
SnBu3
4
5
2.5 h
Ph
Ph
OHC
SnBu3
25 min

Cu(I)
PdX2
R
S
n
B
u3
J. P. Parrish et al. / Tetrahedron Letters 42 (2001) 7729–7731
7731
2. For examples of homocoupling as a side reaction, see: (a)
Hirabayashi, K.; Ando, J.-I.; Kawashima, J.; Nishihara,
Y.; Mori, A.; Hiyama, T. Bull. Chem. Soc. Jpn. 2000, 73,
1409; (b) Matoba, K.; Motofusa, S.-I.; Cho, C. S.; Ohe,
K.; Uemura, S. J. Organomet. Chem. 1999, 547, 3; (c)
Farina, V.; Krishnan, B.; Marshall, D. R.; Roth, G. P. J.
Org. Chem. 1993, 58, 5434; (d) Farina, V.; Roth, G. P.
Tetrahedron Lett. 1991, 32, 4243.
3. For examples of palladium-catalyzed homocouplings, see:
(a) Kang, S.-K.; Namkoong, E.-Y.; Yamaguchi, T. Synth.
Commun. 1997, 27, 641; (b) Wright, M. E.; Porsch, M. J.;
Buckley, C.; Cochran, B. B. J. Am. Chem. Soc. 1997, 119,
8393; (c) Tamao, K.; Ohno, S.; Yamaguchi, S. J. Chem.
Soc., Chem. Commun. 1996, 1873; (d) Boons, G.-J.;
Entwistle, D. A.; Ley, S. V.; Woods, M. Tetrahedron Lett.
1993, 34, 5649; (e) Liebeskind, L. S.; Riesinger, S. W.
Tetrahedron Lett. 1991, 32, 5681; (f) Tolstikov, G. A.;
Miftakhov, M. S.; Danilova, N. A.; Vel’der, Y. L.;
Spirikhin, L. V. Synthesis 1989, 633.
4. For Cu(I)- and Cu(II)-based homocoupling reactions, see:
(a) Kang, S.-K.; Baik, T.-G.; Jiao, X. H.; Lee, Y.-T.
Tetrahedron Lett. 1999, 40, 2383; (b) Piers, E.; McEachern,
E. J.; Romero, M. A. Tetrahedron Lett. 1996, 37, 1173; (c)
Piers, E.; Romero, M. A. J. Am. Chem. Soc. 1996, 118,
1215; (d) Beddoes, R. L.; Cheeseright, T.; Wang, J.;
Quayle, P. Tetrahedron Lett. 1995, 36, 283; (e) Ghosal, S.;
Luke, G. L.; Kyler, K. S. J. Org. Chem. 1987, 52, 4296; (f)
Hay, A. S. J. Org. Chem. 1962, 27, 3320.
5. Mild and efficient coupling between olefins and aryl stan-
nanes in the presence of Pd(II) catalyst and Cu(II) oxi-
dants: Parrish, J. P.; Shin, S.-I.; Jung, K. W. Synlett.,
submitted for publication.
Cu(II)
XSnBu3
Pd(0)
RPdX
RSnBu3
R R
RPdR
XSnBu3
Scheme 1. Proposed catalytic cycle for homocoupling.
transmetallation with a second mole of stannane to
provide RPdR. This then undergoes a reductive elimi-
nation to provide the homocoupled product and Pd(0).
The Cu(II) additive then oxidizes the palladium species
back to Pd(II), which reenters the cycle and continues
the process. Our methodology has proven to be milder
and more rapid than others and does not require
additional additives to facilitate the coupling. We
attribute this factor to the relative ease of transmetalla-
tion with the Pd(II) catalyst and the rapid reoxidation
that the Cu(II) provides.
6. Tributylphenyltin, tributyl(phenylethynyl)tin, 2-(tributyl-
stannyl)thiophene, and 2-(tributylstannyl)furan were pur-
chased from the Aldrich Chemical Company. For the
preparation of (E)-2-(tributylstannyl)styrene, see: Mitchell,
T. N.; Amamria, A. J. Organomet. Chem. 1983, 252, 47.
(4-Tributylstannyl)benzaldehyde was prepared by treating
4-iodobenzaldehyde with Bu6Sn2 and Pd(PPh3)4 in benzene
at 80°C. The remaining aryl stannanes were prepared by
treatment of the corresponding aryl iodide with n-BuLi at
−78°C in THF, followed by quenching with Bu3SnCl
and warming to room temperature.
In summary, we have developed a mild and efficient
method for the oxidative dimerization of organostan-
nanes. Our methodology offers rapid access to symmet-
ric biaryls along with dienes and diynes in high yields
and short reaction times.
Acknowledgements
7. Representative experimental procedure: Tributylphenyltin
(0.16 mL, 0.5 mmol, 1 equiv.) was dissolved in tetra-
hydrofuran (2.5 mL, 0.2 M solution) and rapid stirring
was begun. Into the clear solution was added CuCl2 (134
mg, 1.0 mmol, 2 equiv.) and Pd(OAc)2 (11 mg, 0.05 mmol,
0.1 equiv.). The suspension was stirred at room tempera-
ture for 5 min, after which the mixture was diluted with
diethyl ether (10 mL), filtered through a plug of neutral
alumina, and washed with diethyl ether (3×10 mL). The
filtrate was then concentrated in vacuo, and followed by
flash chromatography (30 g SiO2, eluted with petroleum
ether (100 mL), then 9:1 hexanes/EtOAc) to afford
biphenyl (35 mg, 97%).
We acknowledge generous financial support from the
National Institutes of Health (RO1 GM 62767).
References
1. For reviews of Stille couplings, see: (a) Stille, J. K. Angew.
Chem., Int. Ed. Engl. 1986, 25, 508. For Heck couplings,
see: (b) de Meijere, A.; Meyer, F. E. Angew. Chem., Int.
Ed. Engl. 1994, 33, 2379. For Suzuki couplings, see: (c)
Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. For
Sonogashira couplings, see: (d) Sonogashira, K. In Metal-
catalyzed Cross-coupling Reactions; Diederich, F.; Stang,
P. J., Eds.; Wiley: New York, 1998; pp. 203–229.
8. Larock, R. C.; Bernhardt, J. C. J. Org. Chem. 1977, 42,
1680.
9. For related work on the synthesis of dienes and diynes, see
Refs. 3a, 4c, and 4f.