A facile synthesis of N-benzylallylglycine

Article abstract of DOI:10.1016/S0040-4039(00)01371-X

N-Benzylallylglycine can be prepared in good yield through a one-pot reaction of N-benzylhomoallylamine with glyoxylic acid monohydrate in methanol. The reaction method described requires only mild conditions and avoids the need for purification of the amino acid product. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01371-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7961–7964
A facile synthesis of N-benzylallylglycine
D. Jonathan Bennett* and Niall M. Hamilton
Medicinal Chemistry Department, Research and Development, Organon Laboratories Ltd., Newhouse,
Lanarkshire ML1 5SH, UK
Received 24 July 2000; accepted 10 August 2000
Abstract
N-Benzylallylglycine can be prepared in good yield through a one-pot reaction of N-benzylhomoallyl-
amine with glyoxylic acid monohydrate in methanol. The reaction method described requires only mild
conditions and avoids the need for purification of the amino acid product. © 2000 Elsevier Science Ltd.
All rights reserved.
Keywords: amines; amino acids and derivatives; aza-Cope rearrangement; iminium ion solvolysis; tandem reactions.
Allylglycine is a non-DNA encoded a-amino acid which possesses interesting biological
1
activity. In addition, allylglycine and its derivatives represent interesting synthons for the
2
preparation of other amino acids and natural products. A number of synthetic strategies have
3
been utilised to synthesise allylglycine derivatives, including allylation of glycine equivalents,
4
5,6
[2,3]-aza-Wittig and cationic aza-Cope rearrangements.
For the synthesis of acyclic amino acids via cationic aza-Cope methodology the rearrange-
ment requires a subsequent reaction to drive the equilibrium toward the desired product. To
5
date this has been effected either via an iminium ion reduction as reported by Esch et al. or an
6
iminium ion hydrolysis step as reported by Agami et al. (Scheme 1).
In this letter we wish to report a facile synthesis of the previously unreported N-benzylallyl-
glycine based on an aza-Cope/tandem iminium ion solvolysis. In addition to the simplicity of the
procedure, the method can afford the amino acid derivative in good yield and excellent purity
without recourse to laborious purification techniques, e.g. liquid/liquid extraction or
chromatography.
*
Corresponding author.
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01371-X

7962
Scheme 1. Agami aza-Cope/iminium ion hydrolysis tandem reaction
7
N-Benzylallylglycine 2 was prepared by condensation of N-benzylbut-3-enylamine 1 and
8
glyoxylic acid monohydrate at room temperature in methanol (Scheme 2). During the course of
the reaction the product precipitated from solution as a white solid. The bulk of the methanol
was then removed in vacuo and diethyl ether added. The insoluble N-benzylallylglycine 2 was
then isolated via filtration and dried in vacuo. This facile procedure afforded the product 2 in
an overall yield of 60% and 98% purity (measured by spectroscopic, HPLC and elemental
analytical techniques).
Scheme 2. Synthesis of N-benzylallylglycine 2
Analysis of the liquors from the reaction showed that the major by-product was the lactone
3
, which is derived from a competing ring closure mechanism. This is consistent with a reported
synthesis of the lactone in which homoallylamine 1 is condensed with glyoxylic acid mono-
hydrate in acetonitrile/water as solvent (Scheme 3).
9

7963
9
Scheme 3. Synthesis of lactone 3 in aqueous medium
To begin evaluating the general scope and utility of the procedure, homoallylamines 4, 5 and
(Fig. 1) were synthesised and these amines reacted as outlined in Scheme 2. In each case the
1
0
6
product should be N-benzylallylglycine 2 since the carbon atom to which the alkyl substituent
is attached will be cleaved during the aza-Cope/tandem iminium ion hydrolysis.
Figure 1.
In all cases the expected product 2 precipitated from the reaction solutions. Precipitation of
N-benzylallylglycine 2 was considerably faster for reactions involving amines 4 and 6 than it was
for amine 1 (approximately 5 min compared with 1 h). For amine 5 no precipitate was evident
after stirring overnight at room temperature but precipitation did occur after heating the
reaction mixture at reflux for 30 min. In addition to the apparent rate enhancing effect, the
reaction of 6 afforded N-benzylallylglycine 2 in 88% yield as compared with 60% for the
reaction of simple homoallylamine 1. This result demonstrates that under these conditions the
aza-Cope/tandem iminium ion solvolysis is more rapid than the competing cyclisation/lactonisa-
tion reaction.
In summary, an efficient one-pot synthesis of N-benzylallylglycine 2 has been developed
through the condensation of N-benzylhomoallylamines with glyoxylic acid monohydrate in
methanol. The scope of this method is currently being extended to other functionalised and
chiral homoallylamines, and we intend to report the results of these studies in the near future.
Acknowledgements
We are grateful to the Analytical Chemistry Department, Research and Development,
Organon Laboratories Ltd., Newhouse, Lanarkshire ML1 5SH, UK for all analytical data.

7964
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1
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2
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