Conventional and microwave assisted hydrogenolysis using zinc and ammonium formate

Article abstract of DOI:10.1081/SCC-120034165

The selective deprotection of several N-Bzl amino derivatives to the corresponding amines and the removal of S-Bzl and O-Bzl groups from the protected amino acids with ammonium formate and commercial zinc dust are reported. Many other reducible or hydrogenolysable substituents such as halogens, methoxy, phenol, ester, acid, ethene, and Boc groups are unaffected.

Full text of DOI:10.1081/SCC-120034165

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Conventional and Microwave Assisted Hydrogenolysis
Using Zinc and Ammonium Formate
a
a
a
a
G. R. Srinivasa , S. N. Narendra Babu , C. Lakshmi & D. Channe Gowda
a
Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore,
Karnataka, 570 006, India
Version of record first published: 20 Aug 2006.
To cite this article: G. R. Srinivasa, S. N. Narendra Babu, C. Lakshmi & D. Channe Gowda (2004): Conventional and
Microwave Assisted Hydrogenolysis Using Zinc and Ammonium Formate, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 34:10, 1831-1837
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w
SYNTHETIC COMMUNICATIONS
Vol. 34, No. 10, pp. 1831–1837, 2004
Conventional and Microwave Assisted
Hydrogenolysis Using Zinc and
Ammonium Formate
G. R. Srinivasa, S. N. Narendra Babu, C. Lakshmi,
*
and D. Channe Gowda
Department of Studies in Chemistry, University of Mysore,
Manasagangotri, Mysore, Karnataka, India
ABSTRACT
The selective deprotection of several N-Bzl amino derivatives to the cor-
responding amines and the removal of S-Bzl and O-Bzl groups from the
protected amino acids with ammonium formate and commercial zinc dust
are reported. Many other reducible or hydrogenolysable substituents such
as halogens, methoxy, phenol, ester, acid, ethene, and Boc groups are
unaffected.
Key Words: Catalytic transfer hydrogenation; Ammonium formate;
Zinc dust; Protected derivatives; Deprotection; Microwave irradiation.
*
Correspondence: D. Channe Gowda, Department of Studies in Chemistry, University
of Mysore, Manasagangotri, Mysore, Karnataka 570 006, India; Fax: 091-0821-
2
421263 or 2518835; E-mail: dcgowda@yahoo.com.
1
831
DOI: 10.1081/SCC-120034165
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Srinivasa et al.
INTRODUCTION
The Bzl protecting groups are very popular for amines, alcohols, and
[
1,2]
thiols.
The facile removal of protecting groups from labile or reactive
organic functionalities is an important objective. Although, a number of
methods have been reported for debenzylation, catalytic transfer hydrogeno-
[
3–6]
lysis,
monly used method. The application of Pd/C with ammonium formate for
which involves a catalyst and hydrogen donor is the most com-
[3,7]
the rapid debenzylation of N-Bzl amino derivatives
has been reported.
Although, catalytic transfer hydrogenation is a more effective deprotection
procedure than catalytic hydrogenation, it has not been largely used as it
must be carried out for relatively long times at reflux temperature with poten-
[8]
tial damage of particularly other hydrogenolysable functional groups. The
major disadvantage of this method being the use of palladium as catalyst,
which is highly expensive and its pyrophoric nature makes it difficult to
handle.
[
9]
[10]
[11]
The use of low-cost metals such as magnesium, zinc,
and lead
as
catalysts for the transfer reduction reactions was reported from our lab. The
utility of magnesium as low-cost metal for the selective hydrogenolysis of
some commonly used protecting groups in peptide synthesis was also
[
12]
reported.
There are no reports on the use of other low-cost metal as
catalyst for the transfer hydrogenolysis of N-Bzl derivatives. In this context,
we wish to report the conventional hydrogenolysis of N-Bzl, S-Bzl, and
O-Bzl derivatives by using zinc dust and ammonium formate in methanol
(
Sch. 1).
The deprotection proceeds in a selective and smooth manner but requires
longer reaction time with moderate to good yields. Based on the reports on the
microwave-induced organic reaction enhancement (MORE) chemistry tech-
[
13]
niques
leading to reaction rapidity and quantitative yield has provoked
us to test the feasibility of debenzylation under microwave irradiation in ethyl-
ene glycol. This method gives the corresponding products in good to excellent
yields (85–95%). The deprotection can be accompanied within 2–3 min. This
deprotection procedure has been employed successfully for a wide range of
protected derivatives and the results are summarised in Table 1.
Scheme 1.

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Hydrogenolysis Using Zinc and Ammonium Formate
1833
a

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Srinivasa et al.
a
a
b
a
b

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Hydrogenolysis Using Zinc and Ammonium Formate
1835
All the products were characterised by comparison of their TLC, melting
1
points, IR spectra, H-NMR spectra, and specific rotation wherever necessary
with authentic samples. Studies were also carried out to determine the opti-
mum conditions for deprotection. An excess of 2–4 equiv. of ammonium for-
mate (per protecting group) was found to be ideal. We observed the optimal
ratio of zinc catalyst to substrate to be 1 : 5 by weight for each protecting
group to be removed. Methanol was most preferred solvent of choice for con-
ventional method while ethylene glycol in microwave-assisted deprotection.
In summary, we are reporting a new transfer hydrogenolysis method for
the deprotection of N-Bzl, O-Bzl, and S-Bzl derivatives using zinc dust with
ammonium formate. During this process many other reducible or hydrogeno-
lysable substituents such as halogens, methoxy, phenol, ester, acid, ethene,
and Boc groups are remain unaffected.
EXPERIMENTAL
Materials
All protected amino acid derivatives were purchased from Advanced
Chem. Tech., (Louisville, KY). Some of the N-Bzl amino derivatives were
[15]
prepared in our laboratory according to standard procedure.
Ammonium
formate and zinc dust (particle size ,45 mm) was purchased from E-Merck
Mumbai (India) Ltd. All the solvents used were analytical grade or were
purified according to standard procedures. Thin layer chromatography was
carried out on silica gel plates prepared by following the standard procedure
and detected by UV light. The melting points were determined by a Selaco
Can.No103 Melting point apparatus and are uncorrected. The optical rotation
were determined on a Perkin–Elmer 241 MC Polarimeter, IR spectra were
1
recorded on a Shimadzu FTIR-8300 spectrometer. The H-NMR spectra
were recorded on an AMX-400 MHz spectrometer using CDCl as solvent
and TMS as internal standard. A commercial, domestic microwave oven
3
(LG little chef model 194A) operating at 2450 MHz frequency was used in
all experiments.
Typical Procedure
Conventional Deprotection
A suspension of substrate (10 mmol), ammonium formate (20 mmol), and
zinc dust (2 mmol) in methanol (15 mL) was stirred at room temperature,

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Srinivasa et al.
under nitrogen until the completion of the reaction. After the completion of the
reaction (monitored by TLC), the reaction mixture was filtered through celite
pad, washed with solvent and then the combined filtrate and washings were
evaporated under vacuum. The residue was taken into chloroform or ether,
washed twice with saturated brine solution and finally with water. The organic
layer was dried over anhydrous sodium sulphate, filtered and evaporation of
the organic layer followed by purification either by preparative TLC or by
column chromatography.
Microwave-Assisted Deprotection
A suspension of substrate (10 mmol), ammonium formate (20 mmol), and
zinc dust (2 mmol) in ethylene glycol (15 mL) in an Erlenmeyer flask was
allowed for microwave irradiation 160 power. A filter funnel was placed
over the Erlenmeyer flask to prevent any accidental spillage. A “heat sink”
was maintained to control the microwave energy input into the small-scale
reaction mixture. After the reaction, the reaction mixture was cooled and
then filtered. The filtrate was diluted with water and extracted with ether or
ethyl acetate, and the organic layer was washed twice with saturated brine sol-
ution and finally with water. The organic layer was dried over anhydrous
sodium sulphate, filtered and evaporation of the organic layer followed by
purification either by preparative TLC or by column chromatography.
ACKNOWLEDGMENT
The authors wish to thank University Grants Commission, New Delhi,
India for financial assistance.
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Received in India January 1, 2004

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