More efficient palladium catalyst for hydrogenolysis of benzyl groups

Full text of DOI:10.1080/00397910500466199

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More Efficient Palladium Catalyst for
Hydrogenolysis of Benzyl Groups
Yong Li a , Govindaswamy Manickam b , Atanu Ghoshal, b & Prasad
Subramaniam b
a Kosan Biosciences Inc., Hayward, California, USA
b Syngene International Pvt. Ltd., Bangalore, India
Published online: 16 Aug 2006.
To cite this article: Yong Li , Govindaswamy Manickam , Atanu Ghoshal, & Prasad Subramaniam (2006): More
Efficient Palladium Catalyst for Hydrogenolysis of Benzyl Groups, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 36:7, 925-928
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Synthetic Communicationsw, 36: 925–928, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500466199
More Efficient Palladium Catalyst for
Hydrogenolysis of Benzyl Groups
Yong Li
Kosan Biosciences Inc., Hayward, California, USA
Govindaswamy Manickam, Atanu Ghoshal, and Prasad Subramaniam
Syngene International Pvt. Ltd., Bangalore, India
The most widely used O- and N-debenzylation method in organic synthesis is
hydrogenolysis catalyzed by palladium on carbon (Pd/C) or palladium
hydroxide on carbon (Pd(OH)2/C).[1] Here we report our finding that a com-
bination of Pd/C and Pd(OH)2/C serves as a better catalyst than either catalyst
alone.
While working on a project where debenzylation of ether I[2] was
required to make alcohol II (Scheme 1), we were surprised to find that
neither Pd/C (5%, 10%, and Pd black) nor Pd(OH)2/C (20%) succeeded
under various conditions (up to 15 kg hydrogen pressure and 708C in temp-
erature and variety of solvents). Only starting material was recovered. We
subsequently discovered that the combination of these two catalysts would
carry out the transformation smoothly (Table 1, entry 1). The same
phenomena was observed when para-methoxybenzyl (PMB) was the protect-
ing group (Table 1, entry 2). We decreased the catalyst amount to 10% each,
and the same results were observed. However, when a combination of 5%
Pd/C and 10% Pd(OH)2/C was used, the reaction stopped after 50% conver-
sion. With 1% Pd/C and 10% Pd(OH)2/C, little reaction was observed. We
then looked into the effects of different lots and different brands of catalysts
Received in the USA September 15, 2005
Address correspondence to Govindaswamy Manickam, Syngene International Pvt.
Ltd., 20th KM Hosur Road, Electronics City, Bangalore 560 100, India. Tel.: þ91-80-
2852-3434; Fax: þ91-80-2852-3423; E-mail: manickam.govindaswamy@biocon.com
925

926
Y. Li et al.
Scheme 1.
(Fluka, Aldrich, Johnson Matthey, Arrora Mattew). Although the rate of
hydrogenolysis may vary, the trend remains the same: combination of Pd/
C and Pd(OH)2/C in a 1 : 1 ratio afforded the product whereas a single
catalyst alone gave little or no product. Although a mechanistic basis for
this observation is currently lacking, we feel that this combination catalyst
may, in general, be a more efficient catalyst for debenzylation. We
compared the effectiveness of these three catalysts on a set of benzyl
ethers (Table 2) and a set of benzyl amines (Table 3). In all cases tested,
Pd/C and Pd(OH)2/C gave similar results, and the combination catalyst
shortened reaction time by half. It does not matter whether the starting
ether/amine is aliphatic or aromatic nor whether the starting amine is
secondary or tertiary.
In conclusion, we demonstrate that the combination of Pd/C and
Pd(OH)2/C provides a more efficient catalyst than either Pd/C or Pd(OH)2/
C alone for O- and N-debenzylation.
Table 1. Hydrogenolysis of the chiral ethers
15% Pd/C þ 15%
Pd(OH)2/Ca
catalyst
30% Pd/C
catalyst
30% Pd(OH)2/C
catalyst
Reaction Yieldb Reaction Yieldc Reaction Yieldc
time (h) (%) time (h) (%) time (h) (%)
Substrate
8
85
85
48
48
0
0
48
48
0
0
48
aPercent of the catalyst is relative to the substrate by weight. Pd/C (10% on carbon)
was purchased from Lancaster, and Pd(OH)2/C (20% on carbon, 50% water wet) was
purchased from Alfa Aesar.
bYields are isolated yields.
cStarting material was recovered.

Efficient Palladium Catalyst
927
Table 2. Hydrogenolysis of aryl and alkyl ethers
15% Pd/C þ 15%
30% Pd(OH)2/C
catalyst
Pd(OH)2/Ca catalyst 30% Pd/C catalyst
Reaction
time (h)
Yieldb
(%)
Reaction
time (h)
Yield
(%)
Reaction
time (h)
Yield
(%)
Substrate
6
6
6
95
85
85
12
12
12
95
85
85
12
12
12
95
85
85
6
90
70
12
30
90
70
12
30
90
70
12
aPercent of the catalyst is relative to the substrate by weight. Pd/C (10% on carbon)
was purchased from Lancaster, and Pd(OH)2/C (20% on carbon, 50% water wet was
purchased from Alfa Aesar.
bYields are isolated yields.
GENERAL PROCEDURE
For the results shown in Table 1, the substrate in a mixed solvent (THF–2-
propanol/3 : 1) was hydrogenated under, hydrogen balloon (ꢀ2 kg of pressure).
The reaction was monitored by TLC. After completion of the reaction, the
mixture was filtered over a celite bed, washed with THF, and concentrated in
vacuo. The crude product was further purified by column chromatograph on
silica gel (60–120 mesh) using 10% ethyl acetate in petroleum ether. The
reactions were run on scales from 1 g to 500g, and the purity was determined
by HPLC to be greater then 97%. Analytic data for compound II: LC/MS: m/z
1
455.0 [M þ Na]þ; H NMR (CDCl3, 300 MHz) d 4.70 (s, 1H), 3.83 (m, 3H),
3.80 (m, 1H), 3.40 (d, J ¼ 6.9 Hz, 1H), 3.36 (m, 1H), 2.6 (brs, 1H), 1.71
(m, 1H), 1.03–1.23 (m, 25H), 0.93 (s, 9H), 0.12 (d, J ¼ 6.6 Hz, 6H); 13C NMR
(CDCl3, 75 MHz) d 218.6, 102.9, 77.5, 70.5, 69.7, 64.6, 53.6, 46.4, 39.2, 26.8,
26.1, 25.8, 23.2, 22.5, 21.9, 21.6, 20.8, 18.2, 16.0, 15.5, 23.8, 23.9.
For the results shown in Table 2, the same general procedure was
followed. The reactions were run on scale of 0.5 to 5.0 g. All compounds

928
Y. Li et al.
Table 3. Hydrogenolysis of aryl and alkyl amines
15% Pd/C þ 15%
30% Pd/C
catalyst
30% Pd(OH)2/C
catalyst
Pd(OH)2/Ca catalyst
Reaction
time (h)
Yieldb Reaction Yield Reaction Yield
Substrate
(%)
time (h)
(%)
time (h)
(%)
6
90
12
90
12
90
18
70
24
70
24
70
18
6
80
90
24
12
80
90
24
12
80
90
6
90
12
90
12
90
aPercent of the catalyst is relative to the substrate by weight. Pd/C (10% on carbon)
was purchased from Lancaster, and Pd(OH)2/C (20% on carbon, 50% water wet was
purchased from Alfa Aesar.
bYields are isolated yields.
are known, and NMR was used to compare the reported value and to determine
purity to be greater than 95%.
For the results shown in Table 3, the same general procedure was
followed. The reactions were run on scale of 0.5 to 5.0 g. All compounds
are known, and NMR was used to compare the reported value and to
determine purity to be greater than 95%.
REFERENCES
1. Greene, T. W.; Wuts, P. G. W. Protective Groups in Organic Synthesis, 3rd Ed.;
Wiley-Interscience: New York, 1999; p. 79, 416, 532, 579.
2. Rivkin, A.; Yoshimura, F.; Gabarda, A. E.; Chou, T.-C.; Dong, H.; Tong, W. P.;
Danishefsky, S. J. J. Am. Chem. Soc. 2003, 125, 2899.