C O M M U N I C A T I O N S
Scheme 1. SNAr Mechanism of Oxidative Addition
Table 1. Stille Coupling of Aryl Fluoridesa
#
R
R
R
catalyst/ligand
isolated yield
1
2
In summary, when activated by strong electron-withdrawing
group(s), aryl fluorides are capable of undergoing Pd(0)-catalyzed
amination, Stille coupling, and Suzuki coupling. The mechanism
of these reactions is not known with certainty; notwithstanding,
the experimental data appeared to converge on the oxidative
addition/reductive elimination pathway. Oxidative addition does not
have to proceed via a concerted mechanism. In the cases of electron-
deficient aryl fluorides, the Pd(0) species may act as a nucleophile
and displace the fluoride in an SNAr manner to form the carbon-
palladium bond, as suggested by Amatore and others,2,7a,b (Scheme
1). The fact that a second electron-withdrawing group is only
required for Stille and Suzuki reactions (but not amination) implied
that oxidative addition is perhaps not even rate determining for
these processes (electron-withdrawing groups do accelerate reduc-
tive elimination3e,f). The details of the mechanism and the full scope
of these reactions, as well as other palladium-catalyzed coupling
reactions, are under investigation in our laboratories, and the results
will be reported in due course.
1
2
3
4
5
6
methyl
butyl
butyl
butyl
butyl
butyl
phenyl
phenyl
phenyl
vinyl
phenyl
vinyl
H
CN
CN
CN
CHO
CHO
Pd(PPh3)4, 10%
Pd(PPh3)4, 10%
PPh3, 40%
Pd(PPh3)4, 10%
Pd(PPh3)4, 10%
Pd(PPh3)4, 10%
-
56
-
28
65
45
a The reactions were carried out using 2.7 mmol of the tin compound,
4.0 mmol (1.5 equiv) of aryl fluoride, and 10 mol % Pd(PPh3)4 in 25 mL
of DMF. The reaction mixtures were degassed three times by alternately
connecting to the house vacuum and nitrogen prior to heating.
Table 2. Suzuki Coupling of Aryl Fluoridesa
temp
(°C)
isolated
yield
#
R
R
ligand
catalyst
1
2
1
H
CN
CHO
CHO
Pd(PPh3)4, 10%
Pd(PPh3)4, 10%
80
80
80
80
80
65
65
65
65
65
64
86
-
-
-
49
33
-
-
-
2
3
4
5
6
7
8
9
H
H
H
H
Acknowledgment. The authors are indebted to Drs. Kim F.
Albizati, Bennett C. Borer, and Jayaram K. Srirangam for their
guidance and support throughout this project. We would like to
thank Profs. E. J. Corey and Larry Overman for bringing the SN-
Ar-based mechanism of oxidative addition to our attention. We are
grateful to Dr. Rene Wilhelm for kindly providing us a copy of his
Ph.D. thesis. Y.M.K. (UCSD) thanks Drs. Melissa Rewolinski,
Qingping Tian, as well as the Pfizer summer internship program
for financial support. We also thank Drs. Dave Kucera and Mark
Guzman for suggestions and proofreading the manuscript.
CHO PPh3, 40%
CHO
Pd2(dba)3, 5%
Pd(PPh3)4, 10%
Pd(PPh3)4, 10%
OMe CN
OMe CHO
OMe CHO
OMe CHO PPh3, 40%
10 OMe CHO
Pd2(dba)3, 5%
a The reactions were carried out using 2.7 mmol of boronic acid, 4.0
mmol (1.5 equiv) of aryl fluoride, 3.7 mmol of Cs2CO3 in 25 mL of DMF;
the amounts of the catalyst, ligand, and temperature are indicated in the
table. The reaction mixtures were degassed three times by alternately
connecting to the house vacuum and nitrogen prior to heating.
Supporting Information Available: Experimental procedures and
spectral data for all of the new compounds (PDF). This material is
remarkable. In these reactions, the palladium was introduced as
Pd(0). Because it has been well documented in the literature that
in Stille couplings organotin compounds reduce Pd(II) to Pd(0),4
the presence of Pd(II) in these reactions is unlikely. Consequently,
the Stille couplings listed in Table 1 are probably Pd(0) catalyzed.
The third reaction investigated was the Suzuki coupling. When
the highly activated 4-methoxyphenylboronic acid and 2-fluoro-
nitrobenzene were subjected to the conditions of the amination
reaction [Pd(PPh3)4, Cs2CO3, DMF, 65 °C], the expected Suzuki
coupling product was detected by LC/MS, although the conversion
was no more than 20%.5 Reasoning that electron-withdrawing
groups would favor the desired process,3e,f aryl fluorides that bear
strong electron-withdrawing groups at both the ortho- and the para-
positions (see Table 1) were subjected to Suzuki4 coupling reactions
with phenyl boronic acid and 4-methoxy-phenylboronic acid. The
results are summarized in Table 2. In the presence of Pd(PPh3)4,
all four reactions (entries 1, 2, 6, 7 in Table 2) afforded the Suzuki
coupling product, in 33-86% yield. In the control reactions (entries
3-5, 8-10), no Suzuki product was detected by HPLC. Because
boronic acids are also capable of reducing Pd(II) to Pd(0), the
presence of Pd(II) in these reactions is not likely. These results
further suggest Pd(0) catalysis.
References
(1) (a) Hegedus, L. S. In Organometallics in Synthesis: A Manual, 2nd ed.;
Schlosser, M., Ed.; Wiley: New York, 2002; pp 1123-1217. (b) Grushin,
V. V. Chem.-Eur. J. 2002, 8, 1006-1014.
(2) (a) Widdowson, D. A.; Wilhelm, R. Chem. Commun. 1999, 21, 2211-
2212. (b) Wilhelm, R.; Widdowson, D. A. J. Chem. Soc., Perkin Trans.
1 2000, 22, 3808-3814. (c) Jakt, M.; Johannissen, L.; Rzepa, H. S.;
Widdowson, D. A.; Wilhelm, R. J. Chem. Soc., Perkin Trans. 2 2002,
576-581. (d) Wilhelm, R. Arenetricarbonylchromium(0) Complexes in
Synthesis; Ph.D. Thesis; University of London, London, 2001. In Rene
Wilhelm’s thesis (Widdowson advisor), a single example of Suzuki
coupling of phenyl boronic acid and 2,4-dinitrofluorobenzene was
described.
(3) (a) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L. J.
Org. Chem. 2000, 65, 1158-1174. (b) Littke, A. F.; Dai, C.; Fu, G. C. J.
Am. Chem. Soc. 2000, 122, 4020-4028 and references therein. (c)
Hartwig, J. F. In Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E.-i., de Meijere, A., Eds.; Wiley: New York, 2002;
pp 1051-1096. (d) Singh, U. K.; Strieter, E. R.; Blackmond, D. G.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 14104-14114. (e)
Widenhoefer, R. A.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 6504-
6511. (f) Roy, A. H.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 1232-
1233.
(4) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. ReV.
2002, 102, 1359-1469.
(5) Raising the reaction temperature did not make any difference.
(6) Sanger’s reagent was not employed for safety considerations.
(7) (a) Amatore, C.; Pfluger, F. Organometallics 1990, 9, 2276-2282. (b)
Jutand, A.; Mosleh, A. Organometallics 1995, 14, 1810-1817.
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