A simple synthesis of γ-aminoacids

Article abstract of DOI:10.1016/j.tetlet.2007.03.037

The addition of dianions of carboxylic acids to bromoacetonitrile, leads, in good yields, to the corresponding γ-cyanoacids that give γ-aminoacids on hydrogenation. This two-step methodology improves the results previously described.

Full text of DOI:10.1016/j.tetlet.2007.03.037

Tetrahedron Letters 48 (2007) 3451–3453
A simple synthesis of c-aminoacids
*
Salvador Gil, Margarita Parra and Pablo Rodr ´ı guez
Department de Organic Chemistry, Universitat de Val e` ncia, C/Dr. Moliner 50, 46100 Burjassot, Spain
Received 22 December 2006; revised 6 March 2007; accepted 7 March 2007
Available online 12 March 2007
Dedicated to Professor Julio Gonzalez Urones on the occasion of his 65th birthday
Abstract—The addition of dianions of carboxylic acids to bromoacetonitrile, leads, in good yields, to the corresponding c-cyano-
acids that give c-aminoacids on hydrogenation. This two-step methodology improves the results previously described.
ꢀ
2007 Elsevier Ltd. All rights reserved.
c-Aminoacids is a family of compounds exhibiting
important biological functions, for example, c-aminobu-
tyric acid (GABA) is the main inhibitory neurotransmit-
ium enediolates8,9 due to their strength and low nucleo-
philicity combined with their solubility in non-polar
9
,10
solvents.
It is well established that lithium enolates
1
–4
ter in the mammalian central nervous system.
exist as complex ion pair aggregates in these solvents,
whose metal centre may be coordinated to solvent mole-
cules or to other chelating ligands, such as the amines
resulting from a deprotonation of the acid by the lithium
amide. The data available so far confirm the complexity
present in these aggregated reactive species, whose reac-
tivity and selectivity can be influenced by many different
Those facts have created an important demand for the
5
synthesis of c-aminoacids. In particular, those ana-
logues bearing a phenyl group in the a, b or c positions
6
have received much attention.
8
,10,11
Some authors have developed a stereoselective synthesis
of these compounds with a deracemization strategy from
a chiral ester. This ester is obtained from a racemic acid
via protection as a methyl ester, alkylation of the corre-
sponding enolate, hydrolysis (described combined yields
factors
and an optimization study for each new
electrophile is required.
We wish to describe a simple method to obtain c-amino
acids in two steps: addition of enediolates of carboxylic
acids to bromoacetonitrile followed by catalytic hydro-
genation of the nitrile group (Scheme 1).
6
0–70%) and a new esterification with a chiral auxiliary.
One of the chiral auxiliaries with best results is (R)-
7
pantolactone.
Our group has a long experience in the addition of
1
2
13
In this Letter, we wish to report a new approach to the
synthesis of racemic c-amino acids by applying the car-
boxylic acid dianion methodology. This allows a two-
step reduction of the synthetic strategies described
above. Carboxylic acids are synthetically useful building
blocks because, after double deprotonation, they afford
enediolates that react with several electrophiles under
carboxylic acids to alkyl halides and nitriles. The
former is a fast reaction which can be completed at
low temperature, whereas the latter is a reversible pro-
cess that requires a final exergonic step for the reaction
to progress to completion. Despite having both a nitrile
and a halide in the same electrophile, we discovered
that optimizing the reaction time and the amount of
amine enabled the reaction to generate the alkylated
product.
8
the appropriate conditions. Lithium dialkylamides are
the most common bases for the generation of their lith-
The dianion is generated by treating the corresponding
acid with lithium dialkylamine. After addition of the
bromoacetonitrile, 24 h at room temperature has proven
to be the best reaction conditions. The corresponding
yields are provided in Table 1.
Keywords: GABA; c-Aminoacids; Bromoacetonitrile; Enediolate;
Regioselectivity.
1
4
*
Corresponding author. Fax: +34
margarita.parra@uv.es
9
639083152;
e-mail:
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.037

3452
S. Gil et al. / Tetrahedron Letters 48 (2007) 3451–3453
R'
R
R'
CO2H
CN
R
1
) Et2NLi
2
CO H
R
2
H /Pd/C
CO2H
2
) BrCH2CN
R'
+
NH2
3
3) H3O
4
5
a R = CH2CH2CH3; R' = H
b R = R' = CH3
c R = Ph; R' = H
d R = CH2Ph; R' = H
R2
R2
R2
R1
1
) Et2NLi
CO2H
CO H
CO H
2
2
+
NC
2
) BrCH2CN
R1
+
R1
3) H3O
CN
6
7
8
a R1 = H; R2 = H
b R = CH3; R2 = H
1
c R = H; R2 = CH3
1
Scheme 1. Reaction of bromoacetonitrile with saturated and unsaturated carboxylic acids.
Table 1. Addition of dianions of carboxylic acids to bromoacetonitrile
O
Et2NLi
Et2NH
R'
2
n-BuH
Entry Acid Eq. Amine
Yield (%)
Regioselectivity
OH
Li
R
a (%)
c (%)
1
2
3
4
5
6
7
8
9
0
1
3a
3a
3b
3c
3d
3d
6a
6b
6b
6c
6c
2
0
71
42
78
67
97
73
77
84
69
80
O
0.5
0.5
0.5
2
0.5
0.5
2
0.5
2
0.5
R'
O
2
n-BuLi
O
Li
R
Li
51
40
60
100
100
49
60
40
0
O
R'
R'
R
O
- LiBr
O
Li
Li
R
1
1
C N
C
N
0
Br
Scheme 2. Catalytic cycle for dianion generation and the alkylation
mechanism.
Previous studies led us to develop a substoichiometric
lithium amide procedure for the generation of dianions
of carboxylic acids which, in some cases, improved the
yield and selectivity of the reaction. We optimized a
complete generation of dianions of carboxylic acids by
using an equimolecular amount of n-BuLi combined
with a sub-stoichiometric amount of amine. A small
amount of amine is necessary to promote the deprotona-
tion without nucleophilic addition of the n-BuLi to the
carboxylic group (the lower limit is around 10%). A cat-
alytic cycle (Scheme 2) is possible as a carboxylate and
the corresponding dianion can be held together without
self-condensation.1 This is the advantage that enedio-
lates offer over simple enolates, especially those derived
from esters.
to the aggregation nature of these complex systems, as
mentioned above.
Products are isolated in high purity after a work-up sep-
aration of neutral and acid fractions. Small variable
amounts of starting acid are found in some cases in
the acid fraction.
Usually, products 4 are efficiently reduced to c-amino
acids 5 by catalytic hydrogenation in quantitative
yields, and their spectroscopical data agree with those
described in the literature.
longer reaction time are required for 4a. This methodol-
ogy improves the results described to date, which re-
quires at least two additional steps: protection and
deprotection of the carboxyl group.
5
c
5
7
,16
A higher pressure and a
We tried with several amines, namely, diethylamine,
diisopropylamine, cyclohexyl isopropylamine and
1
,3,3-trimethyl-6-azabicycle[3.2.1.]octane, but diethyl-
amine proved to be the most efficient for this reaction.
Table 1 displays that, in some cases, yields are better
when an equimolecular amount of amine is used.
Although no explanation has been found, it is well
known that some dianions of carboxylic acids undergo
an easy reprotonation by the amine while others do
not. We think that this is the crucial factor to determine
whether yields are higher with sub-stoichiometric or
equimolecular amounts of amine. However, it is not
easy to predict the behaviour of a particular acid due
We have extended this methodology to a,b-unsaturated
carboxylic acids, whose double deprotonation led to
dienediolates that behave as ambident nucleophiles
8
through their a or c carbon atoms. Although the a at-
tack predominates for irreversible reactions, strong devi-
1
2
ations are observed in alkylation reactions. Results
with bromoacetonitrile are summarized in Table 1. Only
a-adducts (Products 7) are observed with the addition of
dimethylacrylic acid 6c. The regioselectivity has not
been controlled for the remaining acids and mixtures

S. Gil et al. / Tetrahedron Letters 48 (2007) 3451–3453
3453
CN
Field, M. J.; Vartanian, M. G.; Kinsora, J. J.; Lotarski, S.
M.; El-Kattan, A.; Walters, K.; Cherukury, M.; Taylor, C.
P.; Wustrow, D. J.; Schwarz, J. B. Bioorg. Med. Chem.
Lett. 2006, 16, 2333; (b) Denis, J.-N.; Tchertchian, S.;
Tomassini, A.; Vall e´ e, Y. Tetrahedron Lett. 1997, 38, 5503;
57%
S
COOH
S
COOH
COOH
9
1) Et2NLi
1
0
(
c) Azam, S.; D’Souza, A. A.; Wyatt, P. B. J. Chem. Soc.,
COOH
2) BrCH2CN
Perkin Trans. 1 1996, 621.
6
7
. See for example: (a) Martin, C. J.; Rawson, D. J.;
Williams, J. M. J. Tetrahedron: Asymmetry 1998, 9,
3723; (b) Dryonska, V.; Pasnkuleva, I. Org. Prep. Proced.
Int. 1999, 31, 232.
. (a) Calm e` s, M.; Escale, F.; Martinez, J. Tetrahedron:
Asymmetry 2002, 13, 293; (b) Camps, P.; Mu n˜ oz-Torrero,
D.; S a´ nchez, L. Tetrahedron: Asymmetry 2004, 15, 311.
7
0%
O
CN
O
12
11
Scheme 3. Reaction of bromoacetonitrile with o-methyl aromatic
acids.
of a, and c adducts were observed. It is worth noting
that the regioselectivity is modified according to the pro-
gress of the reaction. This phenomenon is explained by
8. (a) Thomson, C. M. Dianion Chemistry in Organic
Synthesis; CRC Press: Boca Raton (FL), 1994; pp 88–
1
29; (b) Gil, S.; Parra, M. Curr. Org. Chem. 2002, 6, 283;
(
c) Gil, S.; Parra, M. Recent Res. Dev. Org. Chem. 2002, 6,
the presence of LiBr; generated as the reaction pro-
gresses (Scheme 2).17
449.
9
. Clayden, I. Organolithiums: Selectivity for Synthesis;
Pergamon Press: Oxford, 2002; pp 73.
The method can be extended to o-methyl aromatic acids,
as seen in Scheme 3. Acids 10 and 12 are obtained in
1
0. Juaristi, E.; Beck, A. K.; Hansen, J.; Matt, T.; Muk-
hopedhyay, T.; Simon, M.; Seebach, D. Synthesis 1993,
1271.
5
7% and 70% yields, respectively. Unfortunately, reac-
tions with o-toluic and 2-methylnicotinic acids, under
different conditions, mainly led to the starting acid.
11. (a) Streitwieser, A.; Husemann, M.; Kim, Y.-J. J. Org.
Chem. 2003, 68, 7937; (b) Eames, J.; Suggate, M. J. Angew.
Chem., Int. Ed. 2005, 44, 186; (c) Scott, R.; Granader, J.;
Hilmersson, G. Chem. Eur. J. 2002, 8, 2081; (d) Sotoca, E.;
Bouillon, J. P.; Gil, S.; Parra, M.; Portella, C. Tetrahedron
In conclusion, we describe a general procedure for the
addition of dianions of carboxylic acids to bromoaceto-
nitrile. This methodology is a new approach from satu-
rated carboxylic acids to the synthesis of c-aminoacids
that are obtained in higher yields (around 75%) than
2
005, 61, 4395.
1
2. (a) Aurell, M. J.; Gil, S.; Mestres, R.; Parra, M.; Parra, L.
Tetrahedron 1998, 54, 4357; (b) Brun, E. M.; Gil, S.;
Mestres, R.; Parra, M. Tetrahedron 1998, 54, 15305; (c)
Brun, E. M.; Gil, S.; Mestres, R.; Parra, M. Synthesis
2000, 1160; (d) Brun, E. M.; Gil, S.; Mestres, R.; Parra, M.
Synlett 2001, 156.
7
those described. The method can be extended to unsat-
urated carboxylic acids.
1
3. (a) Brun, E. M.; Gil, S.; Mestres, R.; Parra, M. Synlett
Acknowledgements
1
999, 1088; (b) Brun, E. M.; Gil, S.; Mestres, R.; Parra, M.
Synthesis 2000, 273; (c) Brun, E. M.; Gil, S.; Parra, M.
Arkivoc 2002, 80.
The present research has been financed by DGCYT
(
CTQ2005-07562-C04-01/BQU) and by the Agencia
14. General procedure: n-BuLi (1.6 M in hexane, 5 mmol) was
introduced with stirring into a reaction flask that has been
purged. Hexane was evaporated under vacuum, the flask
cooled at À78 ꢁC and then THF (2 mL) was added to
redissolve the BuLi. Diethylamine (1 mmol) was added at
À78 ꢁC. The mixture was stirred for 15 min at 0 ꢁC. The
acid (2.25 mmol) in THF (2 mL) was added slowly at
À78 ꢁC. After 30 min at 0 ꢁC usually a clear solution of the
dianion was formed. Bromoacetonitrile (2.25 mmol) in
THF (2 mL) was added slowly at À78 ꢁC. The solution
was stirred at room temperature for 24 h and quenched
Valenciana de Ciencia y Tecnolog ´ı a (GV06/050).
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1
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3
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anhyd MgSO . After evaporation of the solvent, the
4
cyanoacids are obtained pure enough for the following
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