7990
J . Org. Chem. 1998, 63, 7990-7992
Th e F or m a tion of a Novel P d /C-Eth ylen ed ia m in e Com p lex
Ca ta lyst: Ch em oselective Hyd r ogen a tion w ith ou t Dep r otection of
th e O-Ben zyl a n d N-Cbz Gr ou p s
Hironao Sajiki, Kazuyuki Hattori, and Kosaku Hirota*
Laboratory of Medicinal Chemistry, Gifu Pharmaceutical University, Mitahora-higashi,
Gifu 502-8585, J apan
Received J uly 27, 1998
A Pd/C catalyst formed an isolable complex with ethylenediamine employed as the catalytic poison
via one-to-one interaction between Pd metal and ethylenediamine, and this complex catalyst [Pd/
C(en)] chemoselectively hydrogenated a variety of reducible functionalities such as olefin, acetylene,
nitro, benzyl ester, and azido in the presence of an O-benzyl or N-Cbz protective group. These
findings reinforce the versatility potential of O-benzyl and N-Cbz as protective groups in organic
synthesis, and the Pd/C(en) catalyst has been identified as a novel and chemoselective catalyst for
the hydrogenation.
The development of modified Pd catalysts for chemose-
Resu lt a n d Discu ssion
lective hydrogenation has been a long-standing goal in
synthetic chemistry.1 Many applications of catalyst poi-
sons have been studied, but those methods are usually
lacking in generality except for only a few examples such
as the Lindlar catalyst.2 Recently, we documented that
addition of ammonia, pyridine, or ammonium acetate to
a Pd/C-catalyzed reduction system selectively inhibited
the hydrogenolysis of an aliphatic benzyl ether with
smooth hydrogenation of other reducible functionalities
such as olefin, Cbz, benzyl ester, and azido.3 However,
the benzyl group of a phenolic ether is easily deprotected
under the same conditions.3,4 During our efforts to
overcome this problem, we found that a Pd/C catalyst
formed an isolable complex with ethylenediamine em-
ployed as the catalytic poison and it selectively catalyzed
hydrogenation of various functional groups without the
hydrogenolysis of the O-benzyl protective group (even in
phenolic benzyl ethers) or the N-Cbz protective group of
aliphatic amines. This paper describes the creation and
application of a novel Pd/C-ethylenediamine complex
catalyst [Pd/C(en)].
Upon addition of ethylenediamine instead of ammonia3
to the 5% Pd/C-catalyzed system, the hydrogenolysis of
the phenolic benzyl ether, for example, N-Boc-O-benzyl-
tyrosine (1), was not suppressed similar to the case of
addition of ammonia to give the debenzylated product (2)
in 81% yield (Figure 1 and Table 1, entry 9). However,
we noticed that the catalyst activity was gradually
suppressed depending on the time taken for the prelimi-
nary processing with ethylenediamine. The hydrogenoly-
sis activity of 5% Pd/C toward the benzyl protective group
of 1 was analyzed in relation to the time elapsed in
pretreatment with ethylenediamine as indicated in Fig-
ure 1. After processing with ethylenediamine for 30 h,
the 5% Pd/C was no longer active catalytically in the
hydrogenolysis of even the phenolic benzyl ether (see
Figure 1).5 From these results, isolation of the pretreated
5% Pd/C catalyst with ethylenediamine was attempted.
Thus, a suspension of 10 g of commercial Pd/C6 and
large excess (ca. 70 equiv vs Pd metal of Pd/C) of
ethylenediamine in methanol was stirred for 48 h7 at
ambient temperature under an argon atmosphere to
prevent ignition (Pd/C is highly pyrophoric), and then the
solid phase was filtered, washed vigorously with metha-
nol and ether, and finally dried under a vacuum pump
for 48 h at ambient temperature. The nitrogen analysis
of the isolated catalysts indicated that ethylenediamine
and Pd metal are approximately in the molar ratio 1:1.8
The isolated catalysts [Pd/C(en)] also completely lost the
catalytic activity toward the hydrogenolysis of 1. Since
the treatment of ethylenediamine with Pd black or 5%
Pd on alumina powder instead of Pd/C did not form such
* Corresponding author. Tel: +81-58-237-3931 (ext. 224). Fax:
+81-58-237-5979. e-mail: hirota@gifu-pu.ac.jp.
(1) (a) Freifelder, M. In Practical Catalytic Hydrogenation Tech-
niques and Applications; Wiley-Interscience: New York, 1971; p 398.
(b) Rylander, P. N. In Catalytic Hydrogenation in Organic Synthesis;
Academic Press: New York, 1979; p 271. (c) Idem. In Hydrogenation
Methods; Academic Press: New York, 1985; p 157. (d) Siegel, S. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: New York, 1991; Vol. 8, p 417. (e) Hudlicky, M. In
Reductions in Organic Chemistry; American Chemical Society: Wash-
ington, DC, 1996.
(2) An ingenious Pd-based catalyst using catalyst poisons for the
improvement of the desired selectivity is represented by the Lindlar
catalyst: (a) Lindlar, H. Helv. Chim. Acta 1953, 35, 446. (b) Ulan, J .
G.; Kuo, E.; Maier, F.; Rai, R. S.; Thomas, G. J . Org. Chem. 1987, 52,
3126. (c) Ulan, J . G.; Maier, W. F.; Smith, D. A. J . Org. Chem. 1987
152, 3132 and references therein.
(5) Control experiment was run with no ethylenediamine in the
presence of the commercial 5% Pd/C for the hydrogenation of 1 in
MeOH. The hydrogenation does not tolerate the O-benzyl protective
group of 1 even after 30 h prestirring.
(3) (a) Sajiki, H. Tetrahedron Lett. 1995, 36, 3465. (b) Czech and
Bartsh have reported a single example of the inhibition of the benzyl
ether hydrogenolysis of 11-(benzyloxy)-1-undecene with n-BuNH2 to
form benzyl undecyl ether: Czech, B. P.; Bartsh, R. A. J . Org. Chem.
1984, 49, 4077.
(6) The catalysts used were 5% Pd/C (Aldrich, Nakarai or Kishida),
and no difference in the quality among 5% Pd/C(en) catalysts was
detected depending upon their supplier.
(7) The mixture was stirred for appropriate time (48 h) just to make
sure.
(4) Sajiki, H.; Kuno, H.; Hirota, K. Tetrahedron Lett. 1997, 38, 399.
(8) 5% Pd/C(en) catalyst contains 1.35-1.75% nitrogen.
10.1021/jo9814694 CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/16/1998