Ruthenium-catalyzed selective N,N-diallylation- and N,N,O-triallylation of free amino acids

Article abstract of DOI:10.1039/b911097f

Selective N,N-diallylation and N,N,O-triallylation of free amino acids in the presence of catalytic amounts of RuCp*(MeCN)₃PF₆ is reported. The crucial influence of the solvent makes these allylation reactions selectively possible.

Full text of DOI:10.1039/b911097f

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Ruthenium-catalyzed selective N,N-diallylation- and N,N,O-triallylation
of free amino acids†
Basker Sundararaju,a Mathieu Achard,a Gangavaram V. M. Sharmab and Christian Bruneau*a
Received 5th June 2009, Accepted 21st July 2009
First published as an Advance Article on the web 31st July 2009
DOI: 10.1039/b911097f
Selective N,N-diallylation and N,N,O-triallylation of free
amino acids in the presence of catalytic amounts of
RuCp*(MeCN)3PF6 is reported. The crucial influence of the
solvent makes these allylation reactions selectively possible.
with concomitant protection of the amino group as an ammonium
salt, and water removal using the Dean Stark technique.12,13 Recent
works have revealed that Cp*Ru-containing catalyst precursors
are very efficient for allylic activation and nucleophilic substitution
by a variety of C, N, and O-nucleophiles.14 However, very few
examples of substitution by multifunctional nucleophiles have
been reported.
We report here a ruthenium-catalyzed allylic substitution reac-
tion, which makes possible selective N,N-diallylation and N,N,O-
triallylation directly from free amino acids and allyl chloride or
cinnamyl chloride at room temperature without previous N- and
O-protection (Scheme 1).
Amino acids belong to a very attractive and useful class of
widely available natural products. They have been involved in a
variety of chemical transformations, especially for the synthesis of
artificial amino acids and short peptides with specific biological
activities, and polypeptides in life science. In most cases, these
bifunctional substrates have to be protected, either at the amino
or at the carboxylic end to ensure selective transformations. Even
though N-mono- and N,N-diallylated amino acids themselves
have revealed photosynthesis accelerator properties and have been
used as hydrogen bond surrogates for stabilization of helical
conformations,1 they have been mostly involved in chemical
modifications from their ester derivatives. From N,N-diallyl-a-
amino esters, the most common transformation consists in the ring
closing metathesis reaction, which leads to functional pyrrolines
and pyrroles.2 N,N-Diallyl-a-amino acid derivatives have also
potential in transformations where only one N-allyl group is
involved such as the Lewis acid-mediated sigmatropic migration
of an allyl group to the a-carbon of amino amides,3 and the
cyclization of nitrilimines into bicyclic heterocycles.4
Scheme 1 Di- and tri-allylation of a-amino acids.
In a previous report, we highlighted the crucial role of N,O-
carboxylate ligands such as quinaldic acid in the allylation of phe-
nol with 1,3-diene dicarbonates,15 whereas RuCp*(MeCN)3PF6 I
alone was found to be inactive with these substrates. We have also
observed that in the same reaction the presence of a catalytic
amount of L-alanine allowed the diastereo- and regioselective
formation of the expected allylated compound suggesting that the
amino acid could act as ligand (Scheme 2). Based on this result, we
investigated the fate of the amino acids and their possible direct
allylation.
The O-protection of the carboxylic group as an allylic ester
offers an easily removable protecting group and for this reason
has been used in peptide and glycopeptide syntheses.5
Most syntheses of N-allylated amino acid derivatives start from
O-alkyl esters. They usually involve allylic bromides and take place
in the presence of a base such as a carbonate,6 a hydroxide7 or a
tertiary amine.8 The strategy based on the reaction of allylamine
with bromoacetate has been exemplified in the case of glycine
derivatives.9 Some scarce examples of the palladium-catalyzed
nucleophilic substitution of allylic substrates by the amino group
of amino esters have also been reported.10
For allylation of the carboxylic end, a method based on the
use of allyl bromide under basic conditions has been used but it
requires the prior protection of the amino group to avoid simulta-
neous N-allylation.11 The most common procedure consists in the
direct esterification in refluxing benzene under acidic conditions,
Scheme 2 Influence of catalytic amount of amino acid in allylation.
From L-phenylglycine 1a as starting material, allylation studies
were attempted in the presence of allyl chloride 2a and catalytic
amounts of RuCp*(MeCN)3PF6,14c,14d,16 I at room temperature
(Scheme 3). We found that the treatment of L-phenylglycine 1a
with two equivalents of allyl chloride 2a in the presence of one
equivalent of potassium carbonate avoiding the formation of
zwitterionic ammonium-carboxylate species, led to the complete
conversion within 16 hours reaction time using methanol as
solvent. Filtration and acidic workup followed by 1H-NMR
analysis revealed the chemoselective formation of N,N-diallyl
aUMR6226 CNRS–Universite´ de Rennes, Sciences chimiques de Rennes,
Catalyse et Organome´talliques, Campus de Beaulieu, 35042, Rennes Cedex,
France. E-mail: christian.bruneau@univ-rennes1.fr; Fax: +33 223236939;
Tel: +33 223236283
bOrganic Chemistry Division III, D 211, Discovery Laboratory, Indian
Institute of Chemical Technology, Hyderabad, 500 007, India
† Electronic supplementary information (ESI) available: Experimental
procedures and characterization data for compounds 3a-h and 4a-i. See
DOI: 10.1039/b911097f
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Table 1 N,N-Diallylation of a-amino acids 1a
phenylglycine 3a in 75% isolated yield (Scheme 3). A blank
experiment carried out in the absence of ruthenium precatalyst I
led to the formation of a mixture of N-mono- and N,N-diallylated
products with only 10% conversion. With I as catalyst, other
polar solvents such as acetonitrile, water and acetone also led
to the formation of a mixture of compounds with less than 60%
conversion of the starting amino acid 1a. It is noteworthy that the
use of three equivalents of allyl chloride using methanol as solvent
afford exclusively N,N-diallylated compound 3a. Interestingly,
during the solvent screening we observed that the use of less
polar solvent such as dichloromethane or THF in the presence
of potassium carbonate allowed the conversion of the starting
material into the N,N,O-triallylated compound 4a in 50% yield.
Further reaction optimization revealed that three equivalents of
caesium carbonate were suitable for a complete conversion of 1a
affording 4a in 63% yield after purification (Table 2). Chiral HPLC
analysis of compounds 3a, 3b, 4a and 4b demonstrated that no
racemization occurred at the stereogenic center.17
entry
1
R1
Ph
R2
H
product
yieldc
3a
3b
75%
2
3
4
Bn
H
H
H
88%
i-Pr
i-Bu
3c
3d
40%
60%
5
H
H
3e
3f
92%
81%
6b
Ph
Ph
7b
8b
i-Pr
Ph
Ph
3g
3h
67%
79%
i-Bu
Scheme 3 Di- and tri-allylation of a-amino acids.
With these protocols in hands, the substrate scope for the
chemoselective formation of N,N-diallylated 3 and triallylated
compounds 4 was investigated. First the generality of the N,N-
diallylation was studied; the results are reported in Table 1.‡
Reaction of amino acids 1a-e with 2.2 equivalents of allyl chloride
2a led to complete conversion of the amino acid and formation of
the N,N-diallylated amino acids derivatives 3a-e in moderate to
excellent yields (entries 1-5). Whereas, good yields were obtained
with glycine 1e (entry 5), and amino acids 1a and 1b featuring
an aromatic side chain (entries 1-2), lower isolated yields were
obtained with amino acids 1c-d containing an aliphatic side chain
suggesting that a partial solubilization in water of compounds 3c-
d occurred during the acidic workup (entries 3-5). The scope was
further tested in the reaction with unsymmetrical allylic substrates.
Longer reaction times were required for the transformation of the
amino acids 1a, 1c and 1d and, and only the linear (E,E)-N,N-
diallylated compounds 3f-h were obtained in high yields due to
their lower solubility in the acidic water phase (entries 6-8). Under
our optimized conditions for the formation of N,N,O-triallylated
compound 4a, we evaluated the scope of the reaction with the
amino acids 1a-i. The results are reported in Table 2.‡ Reactions
were conducted at room temperature in dichloromethane in the
presence of allylic substrate 2a and 3 equivalents of caesium
carbonate. In all cases, triallylated amino acids products 4a-i were
a All reactions were carried out in 4 ml MeOH at rt for 16 h under an
inert atmosphere with 2/1/[Ru]/K2CO3 in a 2.2/1/0.05/1.2 molar ratio.
b Reaction time 48 h. c Isolated yield.
obtained in moderate to good yield after purification over silica gel
(entries 1-5). Under similar conditions but using four equivalents
of allyl chloride 2a, the reaction of tyrosine containing a third
nucleophilic centre afforded the tetraallylated product 4h in 66%
yield (entry 7). In contrast, amino acids such as tryptophan 1g
and serine 1i containing a less reactive third nucleophilic centre
gave only triallylated compounds 4g and 4i in 76 and 70% yield,
respectively (entries 6 and 8). We checked that when the triallylated
compound 4b was treated at room temperature in the presence of
5 mol% of catalyst I and 1.2 equivalent of K2CO3 in MeOH, the
selective deprotection of the ester group took place and the acid
3b was recovered. This is in line with previous results obtained by
Kitamura et al concerning the deprotection of allylic carbamates
into amines18 and allylic ethers into alcohols19a with ruthenium
catalysts.
Regarding the mechanism of the reaction, a plausible expla-
nation for the ruthenium-catalyzed double and triple allylation
of amino acid 1 is depicted in Scheme 4. It might be suggested
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Table 2 N,N,O-Triallylation of a-amino acids 1 with allyl chloride 2aa
ruthenium centre affording (N,O)-aminocarboxylate ruthenium
intermediate as active catalytic species.
Acknowledgements
The authors wish to thank CEFIPRA/IFCPAR (IFC/A/3805-
2/2008/1720) for a grant to BS.
entry
1
R1
Ph
product
yieldb
63%
4a
4b
Notes and references
‡ Typical procedure for the preparation of diallylated compounds 3: Complex
RuCp*(CH3CN)3PF6 I (5.0 ¥ 10-3 mmol, 5 mol%) was added to a
mixture of L-amino acid 1 (0.1 mmol) in MeOH (4 mL) under inert
atmosphere and the resulting solution was stirred at room temperature for
two minutes. Then, potassium carbonate (0.12 mmol) and allyl chloride
2a (0.22 mmol) were successively added and the resulting mixture was
stirred at room temperature for 16 hours. The crude mixture obtained
after filtration and concentration in vacuo was acidified with 1 N HCl
to pH 2 and then extracted with EtOAc (5 ¥ 3mL) to afford compound
3 after drying over Na2SO4 and evaporation. Typical procedure for the
preparation of triallylated compounds 4: Complex RuCp*(CH3CN)3PF6 I
(5.0 ¥ 10-3 mmol, 5 mol%) was added to a mixture of L-amino acid 1
(0.1 mmol) in CH2Cl2 (6 mL) under inert atmosphere and the resulting
solution was stirred at room temperature for two minutes. Then caesium
carbonate (0.3 mmol) and allyl chloride 2a (0.33 mmol) were successively
added and the resulting mixture was stirred at room temperature for
16 hours. The crude mixture obtained after filtration on a short pad of
silica using dichloromethane as eluent and concentration in vacuo was
purified by flash chromatography (silica gel) to afford 4.
2
3
4
Bn
78%
64%
77%
i-Pr
i-Bu
4c
4d
5
6
Me
4f
58%
76%
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