2
P d (OH) /C (P ea r lm a n ’s Ca ta lyst): A High ly
Active Ca ta lyst for F u k u ya m a ,
Son oga sh ir a , a n d Su zu k i Cou p lin g
Rea ction s
Yoshikazu Mori and Masahiko Seki*
CMC Research Laboratory, Tanabe Seiyaku Co., Ltd.,
-16-89, Kashima, Yodogawa-ku, Osaka 532-8505, J apan
3
F IGURE 1. Comparison of the activity of Pd catalysts,
Pd(OH) /C and Pd/C, in the coupling reaction between 1b and
. The reaction was conducted in the presence of 0.15 mol %
Received October 5, 2002
2
2
of the Pd catalyst. Conversion of the reaction was determined
by HPLC (see, Experimental Section).
Abstr a ct: Treatment of thiol esters 1 with zinc reagent 2
in the presence of a small amount (<ca. 1 mol %) of
nonpyrophoric Pd(OH)2/C (Pearlman’s catalyst) provided
functionalized asymmetrical ketones 3 in high yields. The
use of Pd(OH)2/C was further applied to Sonogashira and
Suzuki coupling reactions to afford the desired products in
high yields.
conversion were observed in the reaction with Pd(OH)
2
/C
than that with Pd/C. The isolated yields of ketone 3b in
2
50 h with Pd(OH) /C and Pd/C were 84% and 30%,
respectively.
The method was then applied to the reaction of various
functionalized thiol esters 1c-i with zinc reagent 2
The palladium-catalyzed coupling reactions have found
wide application in the preparation of valuable com-
pounds such as drugs and natural products. One of the
most attractive features of the method lies in the fact
that it can be applied to the substrates carrying var-
ious functional groups. It eliminates the protection-
deprotection sequence as well as the functional group
2
(Table 1). In all cases, Pd(OH) /C is superior to Pd/C,
1
providing the desired coupling products 3c-i in much
higher yields. The reaction between 2 and primary or
secondary alkane thiol esters 1c-f with or without an
ester or a keto group afforded the corresponding ketones
3
c-f in good yields (Table 1, entries 2-5). Noteworthy
is the reaction with aromatic thiol esters 1h ,i: while a
transformation. From a practical point of view, reducing
the amount of expensive Pd catalyst, its ready recovery,2
chloro or a sulfide group in the thiol ester was detrimen-
tal when Pd/C was employed as the catalyst, Pd(OH)
exerted higher activity as well for the reaction of 1h and
i with 2 to provide ketones 3h and 3i in 73% and 61%
2
/C
and safe handling are crucial issues to be considered. We
have recently reported a facile synthesis of an intermedi-
1
ate 3a for (+)-biotin through the nonpyrophoric Pd(OH)
2
/C
yield, respectively (Table 1, entries 7 and 8).
(
Pearlman’s catalyst)-promoted coupling reaction of thio-
In a previously reported workup,3 the reaction mix-
ture was directly filtered through Celite to recover the
Pd catalyst. However, viscous zinc salts in the reaction
mixture sometimes caused a prolonged period for filtra-
tion. As an improvement, prior to filtration, aqueous
hydrochloric acid was added to the reaction mixture. It
dissolved the zinc salts and permitted a facile filtration
to leave the Pd catalyst as a filter cake. Any amount of
,4
3
lactone 1a with 4-ethoxycarbonylbutylzinc iodide 2. The
synthesis is advantageous over the previously reported
4
method using Pd/C in terms of quite low catalyst loading
(
ca. 1/8 amount of the catalyst compared to the method
with Pd/C) and safe handling of the catalyst. We report
/C-promoted Fukuyama,5 Sonogashira,
herein Pd(OH)
and Suzuki coupling reactions to demonstrate efficiency
and versatility of the synthetic method with Pd(OH) /C.
2
2
(2) Recoverable heterogeneous Pd/C-catalyzed coupling reactions,
see: (a) De La Rosa, M. A.; Velarde, E.; Guzman, A. Synth. Commun.
1
7
1
990, 20, 2059. (b) Augustine, R. L.; O’Leary, S. T. J . Mol. Catal. 1992,
2, 229. (c) Marck, G.; Villiger, A.; Buchecker, R. Tetrahedron Lett.
994, 35, 3277. (d) Roth, G. P.; Farina, V.; Liebeskind, L. S.; Pena-
Cabrera, E. Tetrahedron Lett. 1995, 36, 2191. (e) Rossi, R.; Bellina,
F.; Carpita, A.; Gori, R. Synlett 1995, 344. (f) Bleicher, L.; Cosford, N.
D. P. Synlett 1995, 1115. (g) Zhang, T. Y.; Allen, M. J . Tetrahedron
Lett. 1999, 40, 5813. (h) Liebeskind, L. S.; Pena-Cabrera, E. Org. Synth.
1
999, 77, 135. (i) Ennis, D. S.; McManus, J .; Wood-Kaczmar, W.;
Richardson, J .; Smith, G. E.; Carstairs, A. Org. Proc. Res. Dev. 1999,
, 248. (j) LeBlond, C. R.; Andrews, A. T.; Sun, Y.; Sowa, J . R., J r.
Reaction rate of the coupling reaction in the presence
of Pd(OH) /C or Pd/C was initially tested with thiol ester
b used as a typical substrate. Into zinc reagent 2 in THF
prepared according to Knochel procedure were added 1b
in toluene, 0.15 mol % of the Pd catalyst, and DMF, and
2
3
1
Org. Lett. 2001, 3, 1555. (k) Sakurai, H.; Tsukuda, T.; Hirao, T. J . Org.
Chem. 2002, 67, 2721. (l) Heidenreich, R. G.; K o¨ hler, K.; Krauter, J .
G. E.; Pietsch, J . Synlett 2002, 1118. (m) K o¨ hler, K.; Heidenreich, R.
G.; Krauter, J . G. E.; Pietsch, J . Chem. Eur. J . 2002, 8, 622.
(3) Mori, Y.; Seki, M. Heterocycles 2002, 58, 125.
6
the mixture was stirred at 25 °C under N
2
atmosphere.
(
4) Shimizu, T.; Seki, M. Tetrahedron Lett. 2001, 42, 429.
5) Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Fukuyama, T.
As shown in Figure 1, both higher reaction rate and
(
Tetrahedron Lett. 1998, 39, 3189.
*
(
To whom correspondence should be addressed.
1) Tsuji, J . In Palladium Reagents and Catalyts; J ohn Wiley and
Sons: New York, 1995.
(6) (a) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J . J . Org.
Chem. 1988, 53, 2390. (b) Lipshutz, B. H.; Wood, M. R.; Tirado, R. J .
Am. Chem. Soc. 1995, 117, 6126.
1
0.1021/jo0265277 CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/11/2003
J . Org. Chem. 2003, 68, 1571-1574
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