Chemoselective deprotection of teriary benzylamines and reduction of carbon-carbon double bonds in the presence of benzyl and benzyloxymethyl ethers

Article abstract of DOI:10.1016/S0040-4039(00)01013-3

Catalytic transfer hydrogenation using 10% Pd-C in the presence of 1,4-cyclohexadiene as the hydrogen donor selectively debenzylates amines and reduces carbon-carbon double bonds while leaving benzyl and benzyloxymethyl ethers intact. (C) 2000 Elsevier Sc

Full text of DOI:10.1016/S0040-4039(00)01013-3

Tetrahedron Letters 41 (2000) 6025±6028
Chemoselective deprotection of tertiary benzylamines and
reduction of carbon±carbon double bonds in the presence of
benzyl and benzyloxymethyl ethers
Joginder S. Bajwa,* Joel Slade and Oljan Repic
Process R&D, Chemical and Analytical Development, Novartis Institute for Biomedical Research, 59 Route 10,
East Hanover, NJ 07936, USA
Received 27 April 2000; revised 5 June 2000; accepted 6 June 2000
Abstract
Catalytic transfer hydrogenation using 10% Pd±C in the presence of 1,4-cyclohexadiene as the hydrogen
donor selectively debenzylates amines and reduces carbon±carbon double bonds while leaving benzyl and
benzyloxymethyl ethers intact. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: chemoselective; deprotection; benzylamines; reduction; ole®ns.
The use of catalytic transfer hydrogenation (CTH) has increased considerably in recent years,1
and a large number of functional groups have been successfully reduced using a variety of
hydrogen donors such as cyclohexene,2,3 1,4-cyclohexadiene,4 formic acid,5 7 ammonium
formate,8 10 hydrazine,10,11 and sodium hydrogen hypophosphite.10,12 However, despite the
Scheme 1.
* Corresponding author. E-mail: joginder.bajwa@pharma.novartis.com
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01013-3

6026
dramatic increase in the use of CTH, selective deprotection of N-benzylamines in the presence of
benzyl ethers has not been reported to the best of our knowledge.13 We would like to describe
herein that CTH using 10% Pd±C in the presence of 1,4-cyclohexadiene as the hydrogen donor,
selectively debenzylates amines and reduces carbon±carbon double bonds while leaving benzyl
and benzyloxymethyl ethers intact (Scheme 1).
As illustrated in Table 1, N-debenzylation of tertiary amines proceeds selectively compared to
O-debenzylation of benzyl ethers. It was found that the reactions were cleaner when carried out in
Table 1
Selective deprotection of benzylamines in the presence of benzyl ethersa

6027
the presence of acetic acid. It is worth noting that even prolonged reaction times failed to cleave
any signi®cant amount of the benzyl ether (entry 8). This selectivity is particularly surprising since
it is generally assumed that O-debenzylation takes place with greater ease than does removal of
an N-benzyl group.14,15 Since hydrogenolysis of benzyl ethers is promoted by acids16 and retarded
by alkali bases,17 selective N-debenzylations in the presence of benzyl ethers has been rationalized13a
as being due to the basicity of the amine functionality present in the molecule. However, under
our protocol, the reaction is run under acidic conditions, and we believe that the selectivity
observed in the N-debenzylation in preference to the O-debenzylation is inherent in the unique
source of hydrogen donor, 1,4-cyclohexadiene.
We next examined the synthetically attractive possibility of reducing carbon±carbon double
bonds in the presence of benzyl and benzyloxymethyl ethers.18 As shown in Scheme 2, isolated
mono- and trisubstituted double bonds and conjugated double bonds were reduced to give
products in good yields without a€ecting the benzyl or benzyloxymethyl ethers. These reactions
were carried out without acetic acid.
Scheme 2.
In summary, CTH using 1,4-cyclohexadiene as the hydrogen donor is a mild and ecient
method for selective N-debenzylation of amines and reduction of carbon±carbon double bonds in
the presence of benzyl and benzyloxymethyl ethers.
General procedure: To a stirred solution of benzylamine (1 mmol) in absolute ethanol (10 mL)
and acetic acid (3 mmol) was added, under a nitrogen atmosphere, 10% Pd±C19 (1:1 catalyst:
substrate by weight) followed by 1,4-cyclohexadiene (0.43 mL, 5 mmol). After stirring the
reaction mixture overnight (ꢀ16 h) the catalyst was removed by ®ltration through Celite, and the
®ltrate was evaporated to dryness under vacuum. The crude product was then puri®ed by ¯ash
chromatography over silica gel using CH2Cl2:MeOH:NH4OH (50:10:1) as the eluent.
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6028
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