An Efficient Synthesis of γ-Aminoacids and Attempts to Drive Its Enantioselectivity
ABSTRACT Addition of carboxylic acid dianions to bromoacetonitrile lead, in good yields, to the corresponding γ-cyanoacids, which on hydrogenation yielded γ-aminoacids. This two step methodology improves upon previously described results. Poor e.e's resulted from our attempts to drive the enantioselectivity of this transformation by chiral amide induction.
- SourceAvailable from: Margarita Parra[Show abstract] [Hide abstract]
ABSTRACT: The reactivity of dianions of carboxylic acids towards aziridines has been studied. Although, a similar reactivity to that of enolates from ketones, esters or amides has been observed, the method directly yields γ-aminoacids in one step. The method is complementary of previous results of enenediolate reactivity with other electrophiles. A comparative study with the reactivity of this enediolates with epoxides is included.Molecules 01/2010; 15(12):9135-44. · 2.43 Impact Factor
Molecules 2008, 13, 716-728
© 2008 by MDPI
An Efficient Synthesis of γ γ-Aminoacids and Attempts to Drive
Salvador Gil, Margarita Parra* and Pablo Rodríguez
Department de Organic Chemistry, Universitat de València, Dr. Moliner 50, 46100 Burjassot, Spain.
Fax +34(9)63543831; E-mails: Salvador.email@example.com; firstname.lastname@example.org
* Author to whom correspondence should be addressed; E-mail: Margarita.Parra@uv.es
Received: 10 March 2008; in revised form: 26 March 2008 / Accepted: 26 March 2008 / Published: 27
Abstract: Addition of carboxylic acid dianions to bromoacetonitrile lead, in good yields,
to the corresponding γ-cyanoacids, which on hydrogenation yielded γ-aminoacids. This
two step methodology improves upon previously described results. Poor e.e’s resulted
from our attempts to drive the enantioselectivity of this transformation by chiral amide
Keywords: GABA, γ-aminoacids, bromoacetonitrile, enediolate, regioselectivity.
4-Aminobutanoic acid (GABA, 1, R=H) is the main inhibitory neurotransmitter in the mammalian
central nervous system and in the retina . GABA acts at inhibitory synapses in the brain and by
binding to specific transmembrane receptors in the plasma membrane of both pre- and postsynaptic
neurons. This binding causes the opening of ion channels to allow either the flow of negative ions into
the cell or positively-charged ions out of the cell. There is growing evidence that GABA participates in
another slower and more diffuse form of signaling often referred to as ionic inhibition .
Molecules 2008, 13
On the other hand, the racemic 2-methyl (1, R=CH3) and 2-phenyl (1, R=Ph) derivatives were
shown to inhibit binding of the clinically effective anticonvulsant gabapentin 2 to synaptic plasma
membranes of the rat cerebral cortex . These facts have prompted a high demand for the synthesis
of γ-amino acids  and, in particular of analogs bearing a phenyl group (1, R=Ph) in the α, β, or γ-
Some authors have developed stereoselective syntheses of these compounds from a chiral ester
using a deracemization strategy. The ester is obtained from a racemic acid via protection, alkylation of
the corresponding enolate and hydrolysis (reported combined yields 60-70%), followed by
esterification with a chiral auxiliary, deracemization and a new hydrolysis under essentially non-
racemizing conditions. One of the chiral auxiliaries giving best results is (R)-pantolactone .
Our experience in the direct alkylation of enediolates of carboxylic acids , led us to consider the
feasibility of a direct synthesis of racemic γ-aminoacids by reaction with bromoacetonitrile. Upon
catalytic hydrogenation, the obtained γ-cyanoacids allow a rapid and easy access to γ-aminoacids, thus
avoiding the commonly used protection-deprotection sequences (Scheme 1) .
Scheme 1: Reaction of bromoacetonitrile with saturated and unsaturated carboxylic acids.
a R = CH2CH2CH3; R' = H
bR = R' = CH3
c R = Ph; R' = H
d R = CH2Ph; R' = H
a R1= H; R2= H
b R1= CH3; R2= H
c R1= H; R2= CH3
On the other hand, our studies on enantioselectivity induction of this alkylation, by using chiral
amides both as bases and chiral auxiliaries , led us to think that chiral γ-aminoacids might be
obtained in two steps. We report here this approach to the synthesis of γ-aminoacids.
Results and Discussion
Carboxylic acids are synthetically useful building blocks because, after double deprotonation, they
afford enendiolates (or dienediolates when starting from α,β-unsaturated carboxylic acids) that can
react with various electrophiles under appropriate conditions . Lithium dialkylamides are
commonly used as bases to generate the lithium dianions [10,11], due to their strength and low
nucleophilicity, specially when derived from sterically hindered amines, combined with their solubility
in non-polar solvents [11,12]. It is well established that, in these solvents, lithium enolates exist as
Molecules 2008, 13
complex ion pair aggregates, whose metal center may be coordinated to solvent molecules or other
chelating ligands, such as the amines resulting from deprotonation of the acid by the lithium amide.
The available data confirm the complexity present in those aggregated reactive species, whose
reactivity and selectivity products can be influenced by many factors [9-13]. Thus, an optimization
study for each new electrophile is typically required.
We began describing the optimization of the alkylation reaction of enediolates and dienediolates of
carboxylic acids with bromoacetonitrile (Scheme 1). From our experience on the addition of
carboxylic acids to alkyl halides  and nitriles , we knew that the first is a fast reaction, which
may be completed at low temperature, whereas the latter is a reversible process that requires a final
exoergonic step for the reaction to progress. Here, having both a nitrile and a halide in the same
electrophile, an optimization of reaction was required in order to drive the reaction towards the
alkylated product. We have focused the optimization study in three variables: reaction time, type of
amine used to generate the lithium amide and the amount of this amine. Valeric, isobutyric,
phenylacetic and hydrocinnamic acids 3a-3d were used in this study.
On the other hand, we have extended this methodology to α,β-unsaturated carboxylic acids, whose
double deprotonation lead to dienediolates that behave as ambident nucleophiles through their α or γ
carbon atoms . Although α attack predominates for irreversible reactions, strong deviations are
observed in alkylation reactions , that should be avoided in this case because only α−products
would lead to the corresponding γ-aminoacid. From the results shown in Table 1 we have found that
the optimized standard conditions are 24 h at room temperature using 10 mol % of diethylamine. Use
of other amines was not advantageous.
Previous studies lead us to develop sub-stoichiometric amide conditions for the generation of
dianions of carboxylic acids which, in some cases improve the yield and selectivity of the reaction. We
have 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 deprotonation without nucleophilic addition of the n-BuLi to the carboxylic
group (the lower limit is around 10%). A catalytic cycle is possible because a carboxylate and the
corresponding dianion can be held together without self-condensation , this is an advantage of
enediolates over simple enolates, especially those derived from esters. These conditions are especially
adequate when the electrophile is attacked quicker by the lithium amide than by the dianion.
Among the various amines tested, namely disopropylamine (entry 2), cyclohexylisopropylamine
(entries 5 and 9), 1,3,3-trimethyl-6-azabicyclo[3.2.1]octane (entry 3), diethylamine proved to be the
most efficient for this reaction. As shown in Table 1, 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 deprotonation by the amide while others do not.
We think that this factor is crucial to determine whether yields are higher with sub-stoichiometric or
with equimolecular amounts of amine. However, it is not easy to predict the behaviour of a particular
acid due to the aggregation nature of these complex systems. In this case, good yields with
equimolecular amounts of amine will be convenient for the chiral induction in the enantioselective
studies described below.
Molecules 2008, 13
Table 1. Addition of dianions of carboxylic acids to bromoacetonitrile.
Entry Acid Amine Eq. Amine Time (h) Yield (%)
α α (%)
γ γ (%)
* AZA: 1,3,3-trimethyl-6-azabiclyclo[3.2.1]octane; i-PrCyNH: cyclohexylisopropylamine.
** Double bond in product 7a is in the 2,3-position
All products described in Table 1 were isolated in high purity after a simple work-up consisting in
the separation of neutral and acidic fractions. Sometimes, small amounts of starting acid are found in
the acidic fraction.
Products 4 are efficiently reduced to γ-aminoacids 5 in quantitative yield by catalytic hydrogenation
and their spectroscopic data agreed with those described in the literature [6, 16]. Higher pressure and
longer reaction timer were required for 4a.
This methodology improves the results described to date that require at least two additional steps:
protection and deprotection of the carboxyl group.
α,β-Unsaturated carboxylic acids (entries 11-18, Table 1) behave in a similar way as that observed
in other alkylation reactions . Only α-adducts (products 7) are observed in the addition of
dimethylacrylic acid (6c). Although the dianion of dimethylacrylic acid typically gives good α-
regioselectivity due to stereoelectronic effects ; in this case this is quantitative, probably due to the
fact that alkylation with bromoacetonitrile is slower. Despite this, regioselectivity cannot be controlled
for the rest of acids 6 and mixtures of α and γ adducts result. The fluctuation in regioselectivity can be
attributed to the presence of LiBr in the aggregates states of the dianion system; that is generated as the
reaction progress [9, 17]. Koga and we have observed the influence of the LiBr in the stereoselectivity
whose change to the reaction evolution. This phenomenon is explained by the parallel presence of
LiBr whose concentration is low at the early stage of the reaction, but increases as the reaction
Molecules 2008, 13
progress. It seems that the effect of the LiBr slowly released in situ cannot be reproduced by its
external addition .
We would like to emphasize that the α−adduct from crotonic acid (6a) undergoes migration of the
double bond. Such an isomerization to the thermodynamically more stable products has already been
observed in allyl alkylation products , but a thermal activation (to at least 170ºC) was required as,
under kinetic conditions, dianions reprotonate in the α−position, leading to the deconjugation of the
double bond . An isomerization at room temperature under basic conditions has been observed
only in gamma-adducts from the addition to perfluoroketene dithioacetals [2c]. Here, the introduction
of nitrile may lead to an increment of acidic positions, this is specially so for crotonic acid, and this
could produce different equilibria allowing the most stable product, the conjugated one, to accumulate.
The method can be extended to o-methyl aromatic acids as can be seen in Scheme 2. Acids 10 and
12 are obtained in 57 and 70 % yield respectively. Unfortunately reaction with o-toluic and 2-
methylnicotinic acids under different conditions led mainly to starting acid.
Scheme 2: Reaction of bromoacetonitrile with o-methyl aromatic acids.
We have reported some promising results on the effect of several lithium amide bases on the
stereoselectivity of the alkylation of dienediolates of unsaturated carboxylic acids . Application of
these bases as chiral inductors in an enantioselective synthesis of γ-aminoacids could be an important
extension of the methodology described above.
The use of chiral bases as both strong bases and chiral auxiliaries has attracted considerable
attention in asymmetric synthesis through enolates . For example; Koga et al.  studied the
alkylation of phenylacetic acid with some halides, under several conditions, using a diamine as chiral
auxiliary attaining from 1 to 68% e.e. We have described similar results for π-extended enolates of
unsaturated carboxylic acids using both enantiomers of N-benzyl-2-hydroxypropanamide . Main
advantages of this method are: simple setup and work-up of the reactions, chiral compounds can be
obtained in a single step and chiral bases are easily recovered during work-up in a re-usable form.
To undertake the studies of the enantioselectivity of this reaction we have chosen the alkylation of
phenylacetic acid (3c) with bromoacetonitrile because both cyanoacids 5c are described in the
literature [6b]. The chiral bases that have been used are depicted in Figure 2; namely, (R)-(-)-
pyrrolidine methanol (13), (+) and (-)-ephedrine (14) and (R)-(-) and (S)-(+)-1-(benzylamino)propan-
2-ol (15), previously synthetized by us .
Molecules 2008, 13
It was necessary to re-optimize the reaction conditions because an equimolecular amount of amine
was required. Results are shown in Table 2. Enantiomeric excesses were determined by HPLC using a
semipreparative CHIRAL PACK AD-H column.
Table 2. Addition of phenylacetic acid dianion to bromoacetonitrile using chiral lithium
amides as bases.
Entry Amine Aditive
h / ºC
24 / 0
24 / 0
24 / -20
24 / -78
3 / -78
3 / -78
24 / -20
24 / -78
24 / -78
3 / -78
3 / -78
3 / -78
* Around 20% of starting acid is recovered.
No reaction was observed with (-)-13 as base and additive when following the standard conditions
described above for dianion generation. A similar behaviour occurred with both enantiomers of 14 and
15. After studying the time and temperature dependence of the enantioselectivity we concluded that
similar results are observed at different temperatures but shorter reaction time improve the recovered
starting acid. In all cases, the chiral induction was very poor. Some authors  explain that the
presence of LiBr, whose concentration is low at the early stages of the reaction but increases as the
reaction progresses is determinant in the stereoselectivity of reaction of enolates. Accordingly we tried
to mimic this effect by addition as an external additive of two equivalents of lithium halides, but no
effect was observed (entries 10-12). It seems that the effect of LiBr, slowly released in situ cannot be
reproduced by external addition. Although similar behaviour are expected for LiCl or LiF this is not
Molecules 2008, 13
always the case as it is known that sometimes LiCl and LiBr lead to different results and no
explanation have been found . Both enantiomers of the amines 14 and 15 give the antipodal
enantiomer of 5, as expected.
In summary, a general procedure for the addition of dianions of carboxylic acids to
bromoacetonitrile is described. This methodology, with saturated carboxylic acids, is a new approach
to the synthesis of γ-aminoacids that are obtained with higher yields than those described.
Unfortunately, too poor e.e’s resulted in our attempts to drive the enantioselectivity by chiral amide
induction. Despite this fact, application of deracemization process to these susbtrates would be a better
choice than that described up to now in the literature.
Melting points were determined with a Cambridge Instruments Hot Plate Microscope and are
uncorrected. IR spectral data were obtained for liquid film or KBr discs, the measurements were
carried out by the SCSIE (Servei Central de Suport a la Investigació Experimental de la Universitat de
Valencia) on a Matteson Satellite FTIR 3000 model Spectrophotometer. NMR spectra were recorded
at 25ºC for solutions in the stated solvent on Bruker Avance 300, 400 or 500 spectrometers. High
resolution mass spectra were determined with a Fison VG Autospec spectrometer. Flash Column Silica
Gel (230-400 mesh, Scharlau) was used for flash column chromatography, with hexane/ethyl acetate
mixtures for elution. All reactions were carried out under argon atmospheres, in oven dried glassware,
using standard conditions for exclusion of moisture. THF was freshly distilled from blue
benzophenone ketyl and amines were distilled from CaH2 and stored over molecular sieves and kept
under Ar. The BuLi used was a 1.6 M hexane solution. This solution’s concentration was periodically
checked before use. The -78 oC reaction temperature was achieved by cooling with a CO2/acetone bath
and 0 oC achieved by an ice/water bath. Organic extracts were dried over anhydrous MgSO4, and
solutions were evaporated under reduced pressure with a rotatory evaporator and a bath set at 40 oC.
General procedure for the synthesis of β-cyanoacids
n-BuLi (1.6 M in hexane) was introduced into a previously purged reaction flask. The hexane was
evaporated under vacuum and THF (2 mL), followed by diethylamine (5 or 1.25 mmol) were added
at -78 ºC. The mixture was stirred for 15 min at 0 ºC. The acid (2.25 mmol) in THF (2 mL) was added
slowly at -78 ºC. After 30 min at 0 ºC, bromoacetonitrile (0.16 mL, 2.25 mmol) in THF (2 mL) was
added slowly at -78 ºC. The solution was stirred at room temperature for 24 h and quenched with H2O
(15 mL). The reaction mixture was extracted with Et2O (3 x 15 mL). The aqueous phase was acidified
to pH 1 with conc. HCl and then extracted with EtOAc (3 x 15 mL) and the combined extracts were
Molecules 2008, 13
dried over anh. MgSO4. After evaporation of the solvent, the cyanoacids obtained were pure enough
for the following hydrogenation step.
2-(Cyanomethyl)pentanoic acid (4a). From valeric acid (3a, 230 mg); yield: 247 mg (71%); amber
solid (m.p. 138-140 ºC); IR (KBr): υ= 3500-2400, 2386, 1712, 1666, 1591, 1410, 1243, 1106, 845,
765 cm-1; 1H-NMR (300 MHz, CD3CN): δ = 0.92 (t, J = 7.4 Hz, 3H, CH3-), 1.33 (m, 2H, CH3CH2),
1.67 (m, 2H, -CHCH2-), 1.94 (m, 1H, -CHCH2-), 2.59 (m, 1H, CHHCN), 2.94 (m, 1H, CHHCN) ppm;
13C-NMR (75 MHz, CD3CN): δ = 14.1 (CH3-), 20.1 (CH3CH2-), 20.9 (-CH2CN), 33.4
(-CH2CH2COOH), 41.4 (CH), 118.0 (CN), 178.7 (COOH) ppm; MS: m/z (%) = 141 (M+, 2), 118
(C7H4NO+, 26), 114 (M+-HCN, 27.6), 100 (C7H7N+, 100), 73 (C3H5O2+, 77), 59 (C2H5NO+, 93);
HRMS: m/z calcd. for C7H11NO2 [M+]: 141.0789; found: 141.0769.
3-Cyano-2,2-dimethylpropanoic acid (4b). From 2-methylpropanoic acid (3b, 198 mg); yield: 120 mg
(42%); oil; IR (KBr): υ= 3500-2400, 2385, 1710, 1650, 1410, 1375, 1106, 845, 765 cm-1; 1H-NMR
(300 MHz, CD3CN): δ = 1.32 (s, 6H, 2CH3), 2.64 (s, 2H, CH2).
3-Cyano-2-phenylpropanoic acid (4c). From phenylacetic acid (3c, 306 mg); yield: 379 mg (97%); oil
; IR (KBr): υ= 3600-2700, 2257, 1713, 1602, 1497, 1415, 1231, 1176, 839, 724 cm-1; 1H-NMR
(400 MHz, CD3CN): δ = 2.89 (dd, J1 = 17.0 Hz, J2 = 8.1 Hz, 1H, -CHHCN), 3.01 (dd, J1 = 17.0 Hz, J2
= 6.9 Hz, 1H, -CHHCN), 4.00 (m, 1H, PhCH-), 7.3 (m, 5H, CHAr) ppm; 13C-NMR (100 MHz,
CD3CN): δ = 21.0 (CH2CN), 47.4 (PhCH), 118.2 (CN), 128.1 (CHAr), 130.2 (CHAr), 133.4 (CHAr),
138.6 (CAr), 175.0 (COOH) ppm; MS: m/z (%) = 175 (M+, 12), 136 (M+-C2NH, 46), 130 (M+-COOH,
16), 104 (M+-COOH-CN, 30), 103 (M+-COOH-CN-H, 30), 92 (C7H8+, 22), 91 (C7H7+, 100), 77
(C6H5+, 100); HRMS: m/z calcd. for C10H9NO2 [M+]: 175.0633; found: 175.0630.
2-Benzyl-3-cyanopropanoic acid (4d). From hydrocinnamic acid (3d, 338 mg); yield: 324 mg (78%);
amber solid (m.p. 99-101ºC); IR (KBr): υ= 3500-2500, 3050, 2920, 2351, 1796, 1730, 1550, 1410,
1220, 693 cm-1; 1H-NMR (300 MHz, CD3CN): δ = 2.53 (dd, J1 = 2.6 Hz, J2 = 3.2 Hz, 2H, CH2CN),
2.90 (m, 1H, PhCHH-), 3.05 (m, 2H, PhCHH-, CHCOOH), 7.20-7.25 (m, 5H, CHAr) ppm; 13C-NMR
(75 MHz, CD3CN): δ = 19.3 (CH2CN), 37.4 (PhCH2), 43.5 (CHCOOH), 119.2 (CN), 127.9 (CHAr),
129.6 (CHAr), 130.0 (CHAr), 138.6 (CAr), 174.2 (COOH) ppm; MS: m/z (%) = 190 (M++H, 4), 189
(M+, 4), 149 (M+-CH2CN, 64.7), 131 (M+-CH2CN-H2O, 64.8), 91 (C7H7+, 100); HRMS: m/z calcd. for
C10H9NO2 [M+]: 189.079; found: 189.0754.
Reaction with crotonic acid (6a). Yield: 206 mg (73 %) as a mixture of 7a and 8a (51:49).
2-(Cyanomethyl)but-2-enoic acid (7a): yellow solid (m.p. 131-133 ºC); IR (KBr): υ= 3400-2700,
2928, 2253, 1775, 1682, 1409, 1293, 1220, 1149, 927 cm-1; 1H-NMR (300 MHz, CDCl3): δ = 2.00 (d,
J = 7.2 Hz, 3H, CH3), 3.40 (s, 2H, CH2CN), 7.32 (q, J = 7.2 Hz, CH=) ppm; 13C-NMR (75 MHz,
CDCl3): δ = 14.9 (CH2), 15.6 (CH3), 117.1 (CN), 123.0 (CH=C). 146.3 (CH=C), 171.0 (COOH) ppm;
MS: m/z (%) = 125 (M+, 7), 107 (M+-H2O, 3), 99 (M+-HCN, 19), 85 (C4H5O2+, 42), 55 (C4H7+, 49);
HRMS: m/z calcd for C7H9NO2 [M+]: 125.0477; found: 125.0459.
Molecules 2008, 13
5-Cyanopent-2-enoic acid (8a): powder (m.p. 46-51 ºC); IR (KBr): υ= 3500-2400, 2252, 1705, 1651,
1530, 1394, 1287, 1212, 969, 667 cm-1; 1H-NMR (300 MHz, MeOD): δ = 3.19-3.31 (m, 4H,
CH2CH2CN), 6.60 (d, J = 12.0 Hz, CHCOOH), 7.64 (dt, J1 = 12.1 Hz, J2 = 7.2 Hz, 1H,
CH=CHCOOH) ppm; 13C-NMR (75 MHz, MeOD): δ = 16.8 (CH2CN), 29.1 (CH2CH2CN), 120.6
(CN), 125.3 (CHCOOH), 146.5 (CH=CHCOOH), 169.7 (COOH) ppm; MS: m/z (%) = 126 (M+-H, 5),
125 (M+, 2), 107 (M+-H2O, 63), 85 (C4H5O2+, 23), 80 (C5H6N+, 100); HRMS: m/z calcd for C7H9NO2
[M+]: 125.0477; found: 125.0486.
Reaction with tiglic acid (6b): Yield: 262 mg (84%) as a mixture of 7b and 8b (60:40).
2-(Cyanomethyl)-2-methylbut-3-enoic acid (7b): oil; IR (KBr): υ= 3500-2700, 2251, 1861, 1779,
1693, 1416, 1281, 1136, 1000, 927 cm-1; 1H-NMR (500 MHz, MeOD): δ = 1.47 (s, 3H, CH3-), 2.80 (d,
J = 16.7 Hz, 1H, -CHHCN), 2.87 (d, J = 16.7 Hz, 1H, -CHHCN), 5.27 (d, J = 10.8 Hz, 1H, CHH=),
5.29 (d, J = 17.5 Hz, 1H, CHH=), 6.04 (dd, J1 = 17.5 Hz, J2 = 10.7 Hz, -CH=) ppm; 13C-NMR (125
MHz, MeOD): δ = 21.0 (CH3-), 25.5 (-CH2CN), 47.5 (C-COOH), 114.6 (CN), 117.7 (CH2=), 139
(CH=) 175.0 (COOH) ppm; MS: m/z (%) = 139 (M+, 4), 121 (M+-H2O, 49), 112 (M+-HCN, 37), 100
(C5H9O2+, 64), 99 (C5H8O2+, 93), 82 (C5H6O+, 46), 81 (C5H5O+, 33), 71 (C4H7O+, 83), 68 (C5H8+, 98),
67 (C5H7+, 100); HRMS: m/z calcd for C7H9NO2 [M+]: 139.0633; found: 139.0674.
5-Cyano-2-methylpent-2-enoic acid (8b): oil; IR (KBr): υ= 3500-2700, 2251, 1861, 1779, 1693, 1416,
1281, 1136, 1000, 927 cm-1; 1H-NMR (500 MHz, MeOD): δ = 1.84 (s, 3H, CH3-), 2.35 (m, 2H, -
CH2CH2CN), 2.61 (m, 2H, -CH2CH2CN), 6.78 (m, 1H, -CH=) ppm. 13C-NMR (125 MHz, MeOD): δ =
11.2 (CH3-), 24.2 (-CH2CN), 27.2 (-CH2-C=), 118.2 (CN), 128.5 (C-COOH), 140.0 (CH=) 170.1
(COOH) ppm; MS: m/z (%) = 139 (M+, 4), 121 (M+-H2O, 49), 112 (M+-HCN, 37), 100 (C5H9O2+, 64),
99 (C5H8O2+, 93), 82 (C5H6O+, 46), 81 (C5H5O+, 33), 71 (C4H7O+, 83), 68 (C5H8+, 98), 67 (C5H7+,
100); HRMS: m/z calcd for C7H9NO2 [M+]: 139.0633; found: 139.0674.
2-(Cyanomethyl)-3-methylbut-3-enoic acid (7c). From dimethylacrylic acid (6c, 225 mg); yield: 250
mg (80%); oil; IR (KBr): υ= 3500-2750, 2349, 1767, 1695, 1403, 1243, 978, 914, 870, 751, 720 cm-1;
1H-NMR (400 MHz, CDCl3): δ = 1.85 (s, 3H, CH3), 2.69 (dd, J1 = 16.9 Hz, J2 = 8.2 Hz,
1H, -CHHCN), 2.86 (dd, J1 = 16.9 Hz, J2 = 7.0 Hz, 1H, -CHHCN), 3.48 (t, J = 7.1 Hz, 1H,
CHCOOH), 5.09 (s, 1H, CHH=), 5.16 (s, 1H, CHH=) ppm; 13C-NMR (100 MHz, CDCl3): δ = 18.7
(CH2CN), 20.2 (CH3), 48.0 (CHCOOH), 117.1 (CH2=), 117.4 (CN), 138.7 (CH3-C), 175.7 (COOH)
ppm; MS: m/z (%) = 139 (M+, 12), 121 (M+-H2O, 10), 112 (M+-HCN, 8), 107 (M+-O2, 19), 94 (M+-
CH2CN, 30), 93 (M+-H2O-CO, 19), 82 (C5H6O+, 17), 73 (C3H7NO+, 100), 68 (C5H8+, 38), 67 (C5H7+,
66); HRMS: m/z calcd for C7H9NO2 [M+]: 139.0633; found: 139.0622.
3-(2-cyanoethyl)thiophene-2-carboxylic acid (10). From 3-methylthiophene-2-carboxylic acid (9, 320
mg); yield: 378 mg (57%); amber oil; IR (KBr): υ= 3400-2400, 2242, 1680, 1599, 1433, 1376, 1265,
1091, 825, 692 cm-1; 1H-NMR (400 MHz, CD3CN): δ = 2.74 (t, J = 7.1 Hz, 2H, CH2CN), 3.30 (t, J =
7.0 Hz, CH2CH2CN), 7.12 (d, J = 5.1 Hz, 1H, CHCH-S), 7.62 (d, J = 5.0 Hz, 1H, CH-S) ppm; 13C-
NMR (100 MHz, CD3CN): δ = 17.4 (CH2CN), 25.9 (CH2CH2CN), 117.3 (CN), 129.0 (CHCH-S),
Molecules 2008, 13
130.8 (CH-S), 131.1 (C-COOH), 146.5 (C-CH2), 163.0 (COOH) ppm; MS: m/z (%) = 181 (M+, 65),
154 (M+-HCN, 63), 141 (M+-CH2CN, 100); HRMS: m/z calcd. for C8H7NO2S [M+]: 181.0198; found:
2-(2-Cyanomethyl)-5-methylfuran-3-carboxylic acid (12). From 2,5-dimethylfuran-3-carboxylic acid
(11, 315 mg); yield: 278 mg (70%); powder (m.p. 105-107ºC); IR (KBr): υ= 3500-2500, 2283, 1789,
1591, 1424, 1379, 1227, 1076, 851, 747 cm-1; 1H-NMR (300 MHz, CDCl3): δ = 2.29 (s, 3H, CH3),
2.74 (t, J = 7.5 Hz, 2H, CH2CN), 3.34 (t, J = 7.4 Hz, 2H, CH2CH2CN), 6.30 (s, 1H, CHAr) ppm; 13C-
NMR (75 MHz, CDCl3): δ = 13.4 (CH3), 16.1 (CH2CN), 24.1 (CH2CH2CN), 106.8 (CHAr), 115.0 (C-
COOH), 152.2 (C-CH3), 157.6 (C-CH2-), 168.8 (COOH) ppm; MS: m/z (%) = 179 (M+, 13), 152 (M+-
HCN, 17), 139 (C7H7O3+, 84), 118 (C8H8N+, 29), 78 (C5H2O+, 100); HRMS: m/z calcd. for C9H9NO3
[M+]: 179.0582; found: 179.0572.
4-Amino-2-phenylbutanoic acid (5c). The cyanoacid 4c (3.79 mg, 2.16 mmol) in AcOH (15 mL) was
hydrogenated at room temperature under 40 psi hydrogen atmosphere for 3 days and filtrated through
Celite®. After evaporation of the filtrate the crude product 5c (380 mg, >99%) was obtained. No
further purification was needed. IR (KBr): υ= 3500-2100, 3013, 1655, 1508, 1477, 1350, 1293, 1039,
721, 637 cm -1; 1H-NMR (300 MHz, MeOD): δ = 2.02 (bs, 1H, CH-CHH), 2.27 (bs, 1H, CH-CHH),
2.80 (bs, 1H, CHH-NH2), 2.91 (bs, 1H, CHH-NH2), 3.55 (bs, 1H, CH-COOH), 7.31 (m, 5H, Ph-H)
ppm; 13C-NMR (75 MHz, MeOD): δ = 32.8 (CH-CH2), 39.2 (CH2-NH2), 53.2 (CH-COOH), 127.9
(CHAr), 129.6 (CHAr), 129.7 (CHAr), 142.0 (CAr), 178.1 (COOH) ppm; MS: m/z (%) = 179 (M+, 2), 161
(M+-H2O, 53), 117 (C9H9+, 100), 91 (C7H7+, 63); HRMS: m/z calcd. for C10H13NO2 [M+]: 179.0946;
The present research has been financed by DGCYT (CTQ2005-07562-C04-01/BQU) and by the
Agencia Valenciana de Ciencia y Tecnología (GV06/050, GVACOMP2007-080, REVIV:QUIMICA
References and Notes
1. (a) McGeer, P. L.; McGeer, E. G. In Basic Neurochemistry, 4th ed.; Seigel, G.; Agranoff, B.;
Albers, R. W.; Molinof, P., Eds.; Raven: New York, 1989; (b) Hansen, J. J.; Krogsgaardlarsen, P.
Structural, Conformational and Sterochemical requirements of Central Excitatory Amino-Acid
Receptors. Med. Res. Rev. 1990, 10, 55-94.
2. (a) Lindquist, C. E. L.; Birnir, B. Graded response to GABA by native extrasynaptic GABA(A)
receptors. J. Neurochem. 2006, 97, 1349-1356; (b) Sinclair, J.; Granfeldt, D.; Pihl, J.; Millingen,
M.; Lincoln, P.; Farre, C.; Peterson, L.; Orwar, O. A biohybrid dynamic random access memory.
J. Am. Chem. Soc. 2006, 128, 5109-5113.
Molecules 2008, 13
3. Suman-Chauhman, N.; Webdale, L.; Hill, D. R.; Woodruff, G. N. Characterization of
[3H]Gabapentin Binding to a Novel Site in Rat-Brain – Homogenate Binding-Studies. Eur. J.
Pharmacol. Mol. Pharmacol. Sect. 1993, 244, 293-301.
4. See for example: (a) Burgos-Lepley, C. E.; Thompson, L. R.; Kneen, C. O.; Osborne, S. A.;
Bryans, J. S.; Capiris, T.; Suman-Chauhan, N.; Dooley, D. J.; Donovan, C. M.; 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. Carboylate bioisosteres of Gabapentin. Bioorg. Med.
Chem. Lett. 2006, 16, 2333-2336; (b) Denis, J-N.; Tchertchian, S.; Tomassini, A.; Vallée, Y. The
reaction of propiolate acetylides with nitrones. Synthesis of γ-amino-α,β-ethyleninc acid
derivatives. Tetrahedron Lett. 1997, 38, 5503-5506; (c) Azam, S.; D’Souza, A. A.; Wyatt, P. B. J.
Enantioselective synthesis of 2-substituted-4-aminobutanoic acid (GABA) analogues via
cyanomethyl methylation of chiral enolates. J. Chem. Soc. Perkin Trans. I 1996, 621-627. (d)
Deng, J.; Duan, Z.C.; Huang, J.D.; Hu, X.P.; Wang, D.Y.; Yu, S.B.; Xu, X.F.; Zheng, Z. Rh-
catalyzed asymmetric hydrogenation of gamma-phthalimido-substituted alpha,beta-unsaturated
carboxylic acid esters: An efficient enantioselective synthesis of beta-aryl-gamma-amino acids.
Org. Lett. 2007, 9, 4825-4828. (e) Winkler, M.; Knall, A.C.; Kulterer, M.R.; Klempier, N.
Nitrilases catalyze key step to conformationally constrained GABA analogous gamma-amino
acids in high optical purity. J. Org Chem. 2007, 72, 7423-7426. (f) Ordonez, M.; Cativiela, C.
Stereoselective synthesis of gamma-amino acids. Tetrahedron: Asymmetry 2007, 18, 3-99.
5. See for example: (a) Martin, C. J.; Rawson, D. J.; Williams, J. M. J. The preparation of
enenatiomerically enriched γ-aminoacids (GABAs) using palladium catalyzed allylic substitution.
Tetrahedron: Asymmetry 1998, 9, 3723-3730; (b) Dryanska, V.; Pashkuleva, I. A simple and
efficient synthesis of gamma-aminobutyric acid (GABA). Org. Prep. Proced. Int. 1999, 31, 232-
236; (c) Dryanska, V.; Pashkuleva, I.; Angelov, V. A convenient synthesis of threo-4-amino-3, 4-
diphenylbutanoic acid and its derivatives. J. Chem. Res.-S 2003, 89-90. (d) Kohler, F.; Gais, H.J.;
Raabe, G. Asymmetric synthesis of highly substituted gamma-amino acids from allyltitanium
sulfoximines. Org. Lett. 2007, 9, 1231-1234.
6. (a) Calmès, M.; Escale, F.; Martinez, J. Synthesis of N-Boc-(R)-α-phenyl-γ-aminobutyric acid
using and in situ diastereoselective protonation strategy. Tetrahedron: Asymmetry 2002, 13, 293-
296; (b) Camps, P.; Muñoz-Torrero, D.; Sánchez, L. Stereoselective synthesis of both enantiomers
of N-Boc- α-phenyl-γ-aminobutyric acids. Tetrahedron: Asymmetry 2004, 15, 311-321. (c)
Bergner, I.; Opatz, T. alpha-Aminonitriles and alpha-(alkylideneamino)nitriles can serve as
readily available alpha-aminocarbanion equivalents. Their conjugate addition to alpha,beta-
unsaturated esters followed by reduction furnishes polysubstituted gamma-amino acid esters in
moderate to high yield. Synthesis 2007, 918-928. (d) Amruta Reddy, P.; Hsiang, B.C.H.; Latifi,
T.N.; Hill, M.W.; Woodward, K.E.; Rothman, S.M.; Ferrendelli, J.A.; Covey, D.F. 3,3-Dialkyl-
and 3-alkyl-3-benzyl-substituted 2-pyrrolidinones: a new class of anticonvulsant agents. J. Med.
Chem. 1996, 39, 1898-1906.
7. (a) Brun, E.M.; Gil, S.; Mestres, R.; Parra, M. Lithium enediolates and dienediolates of carboxylic
acids in synthesis: Alkylation with secondary halides. Tetrahedron. 1998, 54, 15305-15320; (b)
Aurell, M. J.; Gil, S.; Mestres, R.; Parra, M.; Parra, L. Alkylation of lithium dienediolates of
Molecules 2008, 13
butenoic acids. Regioselectivity effects of structure and leaving group of the alkylating agent.
Tetrahedron 1998, 54, 4357-4366.
8. Gil, S; Parra, M; Rodriguez, P. A simple synthesis of γ-aminoacids. Tetrahedron Lett. 2007, 48,
9. Brun, E.M.; Gil, S.; Parra, M. Enantioselective alpha-alkylation of unsaturated carboxylic acids
using a chiral lithium amide. Tetrahedron: Asymmetry 2001, 12, 915-921.
10. (a) Thomson, C. M. In Dianion Chemistry in Organic Synthesis; CRC Press: Boca Raton, FL,
1994; pp. 88-129; (b) Gil, S.; Parra, M. Dienediolates of carboxylic acids in synthesis. Recent
advances. Curr. Org. Chem. 2002, 6, 283-302; (c) Gil, S.; Parra, M. Reactivity control of dianions
of carboxylic acids. Synthetic applications. Recent Res. Devel. Org. Chem. 2002, 6, 449-481.
11. Clayden, I. In Organolithiums: selectivity for synthesis; Pergamon Press: Oxford, 2002; p. 73.
12. Juaristi, E.; Beck, A. K.; Hansen, J.; Matt, T.; Mukhopadhyay, T.; Simson, M.; Seebach, D.
Enantioselective Aldol and Michael Additions of Achiral Enolates in the presence of chiral
lithium amides and amines. Synthesis 1993, 1271-1290.
13. (a) Streitwieser, A.; Husemann, M.; Kim, Y-J. Aggregation and reactivity of the dilithium and
dicesium N-diolates of 1-naphthyl acetic acid. J. Org. Chem. 2003, 68, 7937-7942; (b) Eames, J.;
Suggate, M. J. Recent developments in the transfer of chirality within enolate alkylation reactions.
Angew. Chem. Int. Ed. 2005, 44, 186-189; (c) Sott, R.; Granader, J.; Hilmersson, G. Solvent-
dependent mixed complex formation –NMR studies and asymmetric addition reactions of
lithiumacetonitrile to benzaldehyde mediated by chiral lithium amides. Chem. Eur. J. 2002, 8,
2081-2087; (d) Sotoca, E.; Bouillon, J. P.; Gil, S.; Parra, M.; Portella, C. Reaction of lithium
enediolates with perfluoroketene dithioacetals. Synthesis of α-trifluoromethyl γ-dicarboxylic acid
derivatives. Tetrahedron 2005, 61, 4395-4402.
14. (a) Brun, E. M.; Gil, S.; Mestres, R.; Parra, M. Dienediolates of α,β-unsaturated carboxylic acids
in synthesis: A new synthetic method to 2-pyridones. Synlett. 1999, 1088-1090; (b) Brun, E. M.;
Gil, S.; Mestres, R.; Parra, M. A new synthetic method to 2-pyridones. Synthesis 2000, 273-280;
(c) Brun, E. M.; Gil, S.; Parra, M. New approach to condensed pyrid-2-ones. Arkivoc 2002, X, 80-
15. (a) Brun, E. M.; Casades, I.; Gil, S.; Mestres, R.; Parra, M. New conditions for the generation of
dianions of carboxylic acids. Tetrahedron Lett. 1998, 39, 5443-5446; (b) Gil, S.; Torres, M.;
Ortúzar, N.; Wincewicz, R.; Parra, M. Eficient addition of acid enediolates to epoxides. Eur. J.
Org. Chem. 2004, 2160-2165.
16. Enders, D; Gröbner, R.; Raaba, G. Enantioselective synthesis of 2-substituted 5-, 6- and 7-
membered lactams via α-alkylation of their chiral N-dialkylamino derivatives. Synthesis 1996,
17. Murakata, M.; Yasukata, T.; Aoki, T.; Nakajima, M.; Koga, K. Stereoselective reactions. 30.
Enantioselective alkylation of the lithium enolates of 6-membered cyclic ketones using
tetradentated chiral amines in the presence of lithium bromide. Tetrahedron 1998, 54, 2449-2458.
18. Domingo, L.R.; Gil, S.; Parra, M.; Saez, J.A.; Torres, M. Experimental and theoretical
investigations for the tandem alkvlation-isomerization reactions between unsaturated carboxylic
acids and allyl halides. Tetrahedron 2003, 59, 6223-6239.
Molecules 2008, 13
19. (a) O’Brien, P. Recent advances in asymmetric synthesis using chiral lithium amide bases. J.
Chem. Soc. Perkin Trans I 1998, 1439-1457; (b) Duguet, N.; Harrison-Marchand, A.; Maddamno,
J’y; Tomioka, K. Enantioselective conjugate addition of a lithium ester enolate catalyzed by chiral
lithium amides. Org. Lett. 2006, 8, 5745-5748; (c) Matsubara, H.; Maeda, L.; Sugiyama, H.; Ryn,
I. Chiral and achiral lithium amides having a fluorous ponytail: Preparation and evaluation as a
recycling reagent for lithium enolate generation. Synthesis 2007, 2901-2912.
20. Matsuo, J.-i; Koga, K. Enantioselective alpha-alkylation of phenylacetic acid using a chiral
bidentate lithium amide as a chiral auxiliary. Chem. Pharm. Bull. 1997, 45, 2122-2124.
21. (a) Parra, M.; Sotoca, E.; Gil, S. A convenient generation of acetic acid dianion. Eur. J. Org.
Chem. 2003, 1386-1388; (b) Newton, R.; Marsden, S. P. Efficient synthesis of quaternary alpha-
hydroxy acids by alkylation of alpha-ketoamide-derived dienediolates. Synthesis 2005, 3263-
Sample Availability: Samples of the compounds 4c, 4d, 7c, 7b and 12 are available from the authors.
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