Pd-C-Induced Catalytic Transfer Hydrogenation
reduced without harm. In this communication, we present several
examples of TES/Pd-C-mediated CTH of a wide variety of
substrates.
with Triethylsilane
Table 1 illustrates the utility of the reaction. Compounds 1-6
show that reduction of simple alkene, alkyne, and conjugate
double and triple bonds occurs rapidly and in high yield. Mirza-
Aghayan et al. demonstrated that treatment of 1-alkenes with 1
equiv of TES with Pd-C catalysis resulted in partial reduction
Pijus K. Mandal and John S. McMurray*
Department of Experimental Therapeutics, The UniVersity of
Texas M. D. Anderson Cancer Center, 1515 Holcombe BlVd.,
Houston, Texas 77030
9
and double bond migration. However, with 2 equiv of the
silane, only the alkane was observed. In keeping with this work,
our results show that excess TES leads to complete reduction
of unsaturated bonds.
ReceiVed March 29, 2007
The Fmoc group is stable to these conditions (compounds 5,
9
, 15, and 21). This protecting group, highly used in peptide
10
synthesis, is subject to hydrogenolysis using H2 and Pd-C.
Interestingly, substrates 7a and 8a, containing both benzylic
alcohol functionality and multiple carbon-carbon bonds, were
reduced completely to alkyl arenes. Benzyl esters and N-
benzyloxycarbonyl (Z) groups are removed in 5-10 min (entries
9 and 10). Previous studies using TES and PdCl or Pd(OAc )
In situ generation of molecular hydrogen by addition of
triethylsilane to palladium-charcoal catalyst results in rapid
and efficient reduction of multiple bonds, azides, imines, and
nitro groups, as well as benzyl group and allyl group
deprotection under mild, neutral conditions.
2
2
required extended reaction times at elevated temperatures to
1
1
cleave benzyl-based protecting groups in peptide applications.
12
Transprotection to a Boc-amino acid was achieved by the TES/
Pd-C-mediated hydrogenolysis of the Z group in 11a in the
presence of di-tert-butyl dicarbonate (11b). Cleavage of benzyl
ethers requires longer reaction times than benzyl esters or the
Z group (12 and 13). Aromatic benzyl ethers are removed more
rapidly than aliphatic ones (compare 14 versus 12 and 13).
Azetidine-2-ones bearing 4-aryl substituents are susceptible to
1,4-ring cleavage reactions by hydrogenolysis. As shown in
14, the â-lactam ring is stable to TES/Pd-C, whereas the benzyl
ether was cleaved.
The reduction of alkenes, alkynes, nitrates, etc. is often carried
out by hydrogenation reactions using metal catalysts. Catalytic
transfer of hydrogen (CTH) is a widely accepted alternative
method that does not require the use of potentially dangerous
1
3
1
hydrogen gas. For this simple operation H2 is replaced by a
2
3
hydrogen donor such as 1,4-cyclohexadiene, hydrazine, formic
4
5
6
acid, ammonium formate, phosphinic acid, or sodium hypo-
phosphite with Pd-C as the catalyst. Though these methods
Allylic protecting groups such as the allyl ester (All) for
protection of carboxylic acids and the allyloxycarbonyl (Alloc)
group for amine protection are widely used in synthetic organic
chemistry and in peptide synthesis. These groups can be
removed with catalytic palladium (Pd(PPh3)4 or Pd(OAc)2)
π-allyl methodology using hydride donors such as HCO2H, Bu3-
7
are elegant, some transfer agents require high temperature, and
some are not applicable to acid-sensitive or base-sensitive
8
substrates. Following the lead of Fukuyama et al., we found
that TES/Pd-C is a widely applicable, very convenient CTH
reagent. The reactions are carried out at room temperature and
are rapid, often complete in 10 min or less using excess TES
and 10-20% Pd-C (by weight) in MeOH. The conditions are
neutral, and thus acid- or base-sensitive substrates can be
14
SnH, NaBH4, PhSiH3, and TES. We were able to deprotect
both All and Alloc groups using simple TES/Pd-C (15 and
1
7). For substrate 16a simple reduction of the triple bond to
the alkane was observed. We did not detect formation of allyl
esters or cleavage of the presumed allyl ester intermediate.
Alloc-to-Boc transprotection was also achieved by treating
allyloxycarbamates with TES/Pd-C in the presence of di-tert-
butyl dicarbonate (18).
(
1) Johnstone, R. A. W.; Wilby, A. H.; Entwistle, I. D. Chem. ReV. 1985,
5, 129-170.
2) Felix, A. M.; Heimer, E. P.; Lambros, T. J.; Tzougraki, C.;
Meienhofer, J. J. Org. Chem. 1978, 43, 4194-4196.
3) (a) Anwer, M. K.; Khan, S. A.; Sivanandaiah, K. M. Synthesis 1978,
51. (b) Furst, A.; Berlo, R. C.; Hooton, S. Chem. ReV. 1965, 65, 51-68.
4) (a) Gray, B. D.; Jeffs, P. W. J. Chem. Soc., Chem. Commun. 1987,
329. (b) Elamin, B.; Anantharamaiah, G. M.; Royer, G. P.; Means, G. E.
8
(
(
7
1
(
(9) Mirza-Aghayan, M.; Boukherroub, R.; Bolourtchian, M. Appl.
Organomet. Chem. 2006, 20, 214-219.
J. Org. Chem. 1979, 44, 3442-3444.
5) (a) Anwer M. K.; Spatola, A. F. Synthesis 1980, 929-931 (b) Adger,
B. M.; O’Farrell, C.; Lewis, N. J.; Mitchell, M. B. Synthesis 1987, 53-54.
(10) Martinez, J.; Tolle, J. C.; Bodanszky, M. J. Org. Chem. 1979, 44,
3596-3598.
(
(11) (a) Watanabe, Y.; Maki, Y.; Kikuchi, K.; Sugiyama, H. Chem. Ind.-
London 1984, 7, 272. (b) Birkofer, L.; Bierwirth, E.; Ritter, A. Chem. Ber.
1961, 94, 821-824.
(
c) Carpino, L.; Tunga, A. J. Org. Chem. 1986, 51, 1930-1932. (d) Ram,
S.; Ehrenkaufer, R. E. Synthesis 1986, 133-135. (e) For a recent review,
see: Ranu, B. C.; Sarkar, A.; Guchhait, S. K.; Ghosh, K. J. Ind. Chem.
Soc. 1998, 75, 690-694.
(12) Bajwa, J. S. Tetrahedron Lett. 1992, 3, 2955-2956.
(13) (a) Ojima, I. Acc. Chem. Res. 1995, 28, 383-389 and references
therein. (b) Banik, B. K.; Barakat, K. J.; Wagle, D. R.; Manhas, M. S.;
Bose, A. K. J. Org. Chem. 1999, 64, 5746-5753. (c) Bertha, F.; Fetter, J.;
Kajt a´ -Peredy, M.; Lempert, K. Tetrahedron 1999, 55, 5567-5580. (d)
Srirajan, V.; Desmukh, A. R. A. S.; Puranik, V. G.; Bhawal, B. M.
Tetrahedron: Asymmetry 1996, 7, 2733-2738.
(6) Entwistle, I. D.; Gilkerson, T.; Johnstone, R. A. W.; Telford, R. P.
Tetrahedron 1978, 34, 213-215.
(
7) Sala, R.; Doria, G.; Passarotti, C. Tetrahedron. Lett. 1984, 25, 4565-
4
7
568.
(
8) Fukuyama, T., Lin S. C.; Li, L. J. Am. Chem. Soc. 1990, 112, 7050-
051.
(14) Guibe, F. Tetrahedron 1998, 54, 2967-3042.
1
0.1021/jo0706123 CCC: $37.00 © 2007 American Chemical Society
Published on Web 07/14/2007
J. Org. Chem. 2007, 72, 6599-6601
6599