Markedly chemoselective hydrogenation with retention of benzyl ester and N-Cbz functions using a heterogeneous Pd-fibroin catalyst

Article abstract of DOI:10.1016/j.tetlet.2003.09.137

The chemoselective catalytic hydrogenation of acetylene, olefin and azido derivatives bearing benzyl ester and N-Cbz functionalities using a Pd-fibroin (Pd/Fib) catalyst was investigated. Perfect selectivity was accomplished, and the benzyl ester and N-Cbz functionalities are tolerated under the reaction conditions.

Full text of DOI:10.1016/j.tetlet.2003.09.137

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8437–8439
Markedly chemoselective hydrogenation with retention of benzyl
ester and N-Cbz functions using a heterogeneous
Pd-fibroin catalyst
Hironao Sajiki,* Takashi Ikawa and Kosaku Hirota*
Laboratory of Medicinal Chemistry, Gifu Pharmaceutical University, Mitahora-higashi, Gifu 502-8585, Japan
Received 30 July 2003; revised 4 September 2003; accepted 12 September 2003
Abstract—The chemoselective catalytic hydrogenation of acetylene, olefin and azido derivatives bearing benzyl ester and N-Cbz
functionalities using a Pd-fibroin (Pd/Fib) catalyst was investigated. Perfect selectivity was accomplished, and the benzyl ester and
N-Cbz functionalities are tolerated under the reaction conditions.
© 2003 Elsevier Ltd. All rights reserved.
Despite numerous literature precedents, chemoselective
reduction of reducible functionalities such as alkynes
alkenes and azides remains a challenge in organic syn-
thesis.1 Especially, while benzyl ester or N-Cbz protec-
tive groups are widely used in organic synthesis, they
are labile under hydrogenation conditions, and it is
extremely difficult to keep such groups intact during a
synthetic process involving hydrogenation steps.2 In
order to solve this problem, Misiti et al. have reported
3% Pd/C-catalyzed selective hydrogenation of a di-sub-
stituted olefin of g-amino-a,b-unsaturated (conjugate)
esters in the presence of a benzyl ester or N-Cbz
protective group.3 However, the method has limitation
with regard to generality, and the stability of the benzyl
esters and N-Cbz groups under the conditions was
time-dependent.3,4 Recently, we reported the Pd/C-
ethylenediamine [Pd/C(en)] catalyzed chemoselective
hydrogenation with retention of the N-Cbz protective
group of aliphatic amines although the chemoselective
hydrogenation with retention of the aromatic N-Cbz
groups or benzyl esters could not be accomplished.5,6
We have also recently established that Pd(OAc)2
formed an isolable Pd(0) complex with silk fibroin as a
stationary phase using methanol as a solvent and a
reductant, and the resulting fibroin-supported catalyst
(Pd/Fib) selectively catalyzed the hydrogenation of
olefins and azides without hydrogenolysis of the aro-
matic carbonyl, aromatic halogen and benzyl ether
functionalities.7,8
During our efforts to extend the applicability of the
Pd/Fib catalyst, we found that Pd/Fib indicates almost
no catalytic activity towards the hydrogenolysis of benz-
yl ether, benzyl ester and N-Cbz functionalities, com-
pared with Pd/C and Pd/C(en).5 The hydrogenolysis of
4-benzyloxyphenylacetic acid benzyl ester (1) catalyzed
by 2.5% Pd/Fib resulted in no reaction even after 24 h
at ordinary hydrogen pressure (Scheme 1).
On the other hand, the use of 5% Pd/C (Aldrich) as a
catalyst resulted in the hydrogenolysis of both the
benzyl ether and the benzyl ester of 1 to give the
corresponding 4-hydroxyphenylacetic acid (2) in 99%
isolated yield. 5% Pd/C(en) catalyzed chemoselective
hydrogenation of only the benzyl ester of 1 with reten-
tion of the benzyl ether to give the corresponding
4-benzyloxyphenylacetic acid (3) in 94% isolated yield.5a
Judging from these results so far obtained, we are now
in a position to disclose that the Pd/Fib catalyst is very
efficient for chemoselective hydrogenation with reten-
tion of the benzyl ester within a molecule.
Scheme 1. Influence of catalysts on the hydrogenolysis of 1.
* Corresponding author. Tel.: +81-58-237-3931; fax: +81-58-237-5979;
e-mail: sajiki@gifu-pu.ac.jp
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.137

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H. Sajiki et al. / Tetrahedron Letters 44 (2003) 8437–8439
Table 1. Chemoselective hydrogenation of the olefin or azido functionality with retention of the benzyl ester or aromatic
N-Cbz protective group using 2.5% Pd/Fib catalysta
To explore the scope of the 2.5% Pd/Fib catalyst, the
hydrogenation of a number of substrates containing a
benzyl ester was investigated (Table 1, entries 1–8). The
results shown in entries 1–7 demonstrated that the
chemoselective hydrogenation could be accomplished
by employing benzyl ester derivatives including a,b-
unsaturated benzyl esters with terminal and internal
olefin and azido functionalities. On occasions when the

H. Sajiki et al. / Tetrahedron Letters 44 (2003) 8437–8439
8439
partial hydrogenolysis of the benzyl ester of the substrate
occurred in MeOH, the use of THF as a solvent gave
satisfactory results (entries 1, 2, 5 and 8).5,9,10 A similar
tolerance was observed in the 2.5% Pd/Fib-catalyzed
hydrogenolysis of an aliphatic N-Cbz protected phenyl-
alanine (entry 8). There is no report in the literature
where an N-Cbz protective group2 of aromatic amines
was not hydrogenolyzed under the palladium-catalyzed
hydrogenation conditions although we have recently
reported the N-Cbz group of aliphatic amines is inert
toward the Pd/C(en)-catalyzed hydrogenolysis.5 Accord-
ingly, this background encouraged us to examine the
chemoselective hydrogenation of various aromatic N-
Cbz compounds possessing other reducible functionali-
ties within a molecule. The chemoselective hydro-
genation of olefin (entries 9–12) and acetylene (entry 13)
functionalities was completely achieved and the desired
products were obtained in excellent isolated yields. It is
noteworthy that the hydrogenolysis of the benzyl ester
and aromatic N-Cbz functionalities is also entirely
depressed under 3-10 atm pressure of hydrogen condi-
tions (entries 3, 11 and 13).
N-Cbz protective group using Raney Ni, which must be
added into the reaction mixture in small portions with
careful monitoring to avoid cleavage of the N-Cbz group:
Kuzuhara, H.; Mori, O.; Emoto, S. Tetrahedron Lett. 1976,
379–382.
5. (a) Sajiki, H.; Hattori, K.; Hirota, K. J. Org. Chem. 1998,
63, 7990–7992; (b) Hattori, K.; Sajiki, H.; Hirota, K.
Tetrahedron 2000, 56, 8433–8441.
6. Quit a few methods to maintain the benzyl ester intact
during a synthetic process involving conjugate reduction
(non-hydrogenation) steps have been reported. (a)
Mathoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am.
Chem. Soc. 1988, 110, 291–293; (b) Evans, D. A.; Fu, G.
C. J. Org. Chem. 1990, 55, 5678–5680; (c) Kelly, T. R.; Xu,
W.; Ma, Z.; Li, Q.; Bhushan, V. J. Am. Chem. Soc. 1993,
115, 5843–5844.
7. Sajiki, H.; Ikawa, T.; Yamada, H.; Tsubouchi, K.; Hirota,
K. Tetrahedron Lett. 2003, 44, 171–174.
8. Akabori and Izumi et al. reported the pioneering prepara-
tion of the silk-supported palladium catalyst in a fundamen-
tally different way although their catalyst indicates totally
different catalyst activity from our Pd/Fib catalyst. (a)
Akabori, S.; Sakurai, S.; Izumi, Y.; Fujii, Y. Nature 1956,
178, 323–324; (b) Izumi, Y. Bull. Chem. Soc. Jpn. 1959, 32,
932–936, 936–942 and 942–945; (c) Akamatsu, A.; Izumi,
Y.; Akabori, S. Bull. Chem. Soc. Jpn. 1961, 34, 1067–1072;
(d) Akamatsu, A.; Izumi Y.; Akabori, S. Bull. Chem. Soc.
Jpn. 1961, 35, 1706–1711.
The chemoselectivity of the hydrogenation could be
attributable to the catalyst poison effect of the coordi-
nated silk fibroin support toward the zero valent palla-
dium metal. In the Pd/Fib catalyst, the original affinity
of palladium for benzyl esters and N-Cbz protective
groups1b,d was drastically reduced by fibroin.11
9. Sajiki, H.; Hattori, K.; Hirota, K. Chem. Eur. J. 2000, 6,
2200–2204.
In summary, we have developed a mild and chemoselec-
tive hydrogenation method using 2.5% Pd/Fib as a
catalyst, which is widely applicable to the selective
hydrogenation of a variety of olefin, azido and acetylene
functionalities leaving intact the benzyl esters and aro-
matic N-Cbz protective groups. The hydrogenolysis of
the extremely reducible benzyl ester and aromatic N-Cbz
protective groups could be completely suppressed. We
believe that the present method should find broad
application in organic synthesis.
10. We have quite recently reported the frequent and unex-
pected cleavage of tert-butyldimethylsilyl (TBDMS) ethers
to form the parent alcohols under mild hydrogenation
conditions using 10% Pd/C in MeOH although TBDMS
ethers have been believed to be stable under hydrogenation
conditions. Furthermore, we have reported a remarkable
solvent effect toward the Pd/C-catalyzed cleavage of
TBDMS and triethylsilyl (TES) ethers and it was applied
to the development of a chemoselective hydrogenation
method for olefin, benzyl ether and acetylene functionalities
distinguishing from the TBDMS and TES protective groups
of a hydroxy group by the employment of EtOAc or MeCN
as a solvent. See: Sajiki, H.; Ikawa, T.; Hattori, K.; Hirota,
K. Chem. Commun. 2003, 654–655 and references cited
therein.
Acknowledgements
This work was partially supported by the Research
Foundation for the Electrotechnology of Chubu.
11. The catalyst activity of commercial 5% Pd/C (Aldrich)
toward reducible functionalities is much higher than the
catalyst activity of 2.5% Pd/Fib. The olefins of 4 and 7 were
completely hydrogenated within 1 h (Scheme 2) while the
complete hydrogenation of the olefins required much longer
time (24 h and 5 h, respectively; Table 1, entries 5 and 9).
References
1. For selected reviews on reductions, see: (a) Larock, R. C.
Comprehensive Organic Transformations; 2nd ed.; Wiley-
VCH: New York, 1999; (b) Nishimura, S. Handbook of
Heterogeneous Catalytic Hydrogenation for Organic Syn-
thesis; Wiley-Interscience: New York, 2001; (c) Hudlicky,
M. Reductions in Organic Chemistry; 2nd ed.; ACS: Wash-
ington, DC, 1996; (d) Rylander, P. N. Hydrogenation
Methods; Academic Press: New York, 1985.
2. Green, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed; John Wiley & Sons: New York, 1999.
3. Misiti, D.; Zappia, G.; Monach, G. D. Synthesis 1999,
873–877.
4. Kuzuhara et al. have reported the chemoselective hydro-
genation of an azido group in the presence of an aliphatic
Scheme 2. Hydrogenation of 4 and 7 using commercial 5%
Pd/C catalyst in THF.