Synthesis of new β-trifluoromethyl containing GABA and β-fluoromethyl containing N-benzylpyrrolidinones

Article abstract of DOI:10.1016/j.jfluchem.2009.11.014

A whole series of 3-(mono-, di-, trifluoro)methyl-substituted N-benzylpyrrolidinones 5a-c was synthesized by deoxyfluorination of corresponding 3-functionalized N-benzylpyrrolidinones. New β-trifluoromethyl containing GABA 4a was obtained in two alternative ways: by successive hydrolysis and hydrogenolysis of 3-trifluoromethyl N-benzylpyrrolidinone 5a and from trifluoroacetone as starting compound.

Full text of DOI:10.1016/j.jfluchem.2009.11.014

Journal of Fluorine Chemistry 131 (2010) 224–228
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis of new
b
-trifluoromethyl containing GABA and b-fluoromethyl
containing N-benzylpyrrolidinones
*
Igor I. Gerus , Roman V. Mironets, Elena N. Shaitanova, Valery P. Kukhar
Department of Fine Organic Synthesis, Institute of Bioorganic Chemistry and Petrochemistry NUAS, Murmanskaya Str. 1, Kiev 02094, Ukraine
A R T I C L E I N F O
A B S T R A C T
Article history:
A
whole series of 3-(mono-, di-, trifluoro)methyl-substituted N-benzylpyrrolidinones 5a–c was
Received 17 September 2009
Received in revised form 17 November 2009
Accepted 18 November 2009
Available online 24 November 2009
synthesized by deoxyfluorination of corresponding 3-functionalized N-benzylpyrrolidinones. New
b
-
trifluoromethyl containing GABA 4a was obtained in two alternative ways: by successive hydrolysis and
hydrogenolysis of 3-trifluoromethyl N-benzylpyrrolidinone 5a and from trifluoroacetone as starting
compound.
ß 2009 Elsevier B.V. All rights reserved.
Keywords:
Trifluoromethyl ketones
Deoxyfluorination reactions
Fluoro-containing GABA
Fluoro-containing pyrrolidinones
DAST
Ishikawa reagent
Sulfur tetrafluoride
Dedicated to fluorine
chemistry in Ukraine.
1. Introduction
example: vigabatrin [5], baclofen (Lioresal1 and Baclon1) [6],
gabapentin (GBP, Neurontin1) [7], pregabalin (Lyrica1) [8] (Fig. 1);
Fluorinated analogs of natural substances play an important
role in the design of new biologically active compounds [1].
Although a large number of various fluorine-containing amino
acids have been synthesized during the past 50 years, they still are
of particular interest due to their widespread bioorganic applica-
tions, e.g. as biological tracers, mechanistic probes and enzyme
inhibitors. Every described pathway to a new fluorinated amino
acid is paid considerable attention [2].
and it is easy to see that the introduction of bulky lipophilic
substituents in -position of GABA’s core is an essential condition
b
to get new effective CNS regulators. It has been confirmed [9] that
the steric parameters of the trifluoromethyl group are between i-Pr
and t-Bu substituents (e.g. Taft steric values Es for i-Pr < i-
Bu < CF3 < t-Bu are À1.76, À2.17, À2.40 and À2.78, respectively).
On the other hand, it is noteworthy that only few examples of
GABAs bearing fluoro-substituents at
b-position have been
GABA (4-aminobutanoic acid,
g
-aminobutyric acid) is the key
synthesized, including some of 3-(fluoroaryl)- [10] and 3-fluoro-
GABAs [11].
central nervous system (CNS) inhibitory neurotransmitter [3].
Activators or inhibitors of GABA-metabolic enzymes (such as
GABA-aminotransferase, GABA-AT or glutamate decarboxylase,
GAD) as well as agonists/antagonists of GABA-receptors are active
in therapy of Alzheimer’s disease, Parkinson disorder, Huntington’s
chorea and epilepsy [4].
Recently we published the synthesis of
difluoro)methyl GABAs 2a,b based on addition reaction of
trimethylsililcyanide to readily available -ethoxyvinyl (tri-,
difluoro)methyl ketones 1a,b (Scheme 1) [12]. Also
omethyl carnitine 3 was synthesized from -hydroxy-
b-hydroxy-b-(tri-,
b
b
-trifluor-
b
b-trifluor-
One of the most effective methodologies to develop new
regulators of active concentration of GABA in the neuronal tissues
omethyl GABA 2a and some biological tests of the amino acids 2a,b
and 3 in vitro and in vivo were performed [13].
is a structural modification of
derivatives and analogs are widely known as medicines, for
g
-aminobutyric acid. Various GABA
Continuing our research on synthesis of polyfluoroalkyl
containing GABAs, we report here about effective synthesis of
3-(mono-, di-, trifluoro)methyl containing N-benzylpyrrolidi-
nones 5a–c (as intermediates towards b-fluoromethyl-GABAs) by
deoxyfluorination reactions from corresponding readily available
* Corresponding author.
E-mail address: igerus@hotmail.com (I.I. Gerus).
3-functionalized N-benzylpyrrolidinones bearing carboxylic,
0022-1139/$ – see front matter ß 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2009.11.014

I.I. Gerus et al. / Journal of Fluorine Chemistry 131 (2010) 224–228
225
Scheme 1. Reported synthetic way to
b-polyfluoromethyl containing GABAs 2 and carnitine 3.
pyrrolidinones 5a,c were conveniently purified by vacuum
distillation. The aldehyde 9 was involved in the reaction with
DAST immediately after regeneration from bisulfite adduct owing
to its instability. Therefore, the yield of difluoromethyl pyrrolidi-
none 5b did not exceed 30% after column chromatography. The
pyrrolidinones 5a–c are colorless oils and they are fully
characterized by 1H, 13C and 19F NMR spectra.
In order to transform the pyrrolidinones 5a–c into the
fluorinated GABAs 4a–c a two-step procedure can be used:
hydrogenolysis and hydrolysis in any sequence. However, our
attempts to perform catalytic debenzylation of pyrrolidinones 5a–
c failed. Reduction of pyrrolidinone 5c in the presence of 20%
Pd(OH)2/C, 100 8C and 100 bar H2 led to the fully saturated product
10 (Scheme 4).
Fig. 1. GABA and its derivatives and analogues.
On the other hand, hydrolysis of various pyrrolidinones is a
common method to obtain GABAs (for example the synthesis of N-
Me-GABA from the N-Me-pyrrolidinone by refluxing in concen-
trated hydrochloric acid [17]). We found hydrolysis of pyrrolidi-
nones 5a–c not a trivial task. Thus, under the usual hydrolytic
conditions the pyrrolidinone ring of 5a–c was totally stable.
Moreover, we observed elimination of hydrogen fluoride as a result
of degradation of the fluoromethyl groups of pyrrolidinones 5b,c
under harder hydrolytic conditions. Only GABA 11 was obtained
after heating of pyrrolidinone 5a with conc. HCl in a sealed tube at
135 8C for 2 days in 22% yield and 74% conversion. Debenzylation of
aldehyde and carbinol groups with sulfur tetrafluoride, DAST and
Ishikawa’s reagent, respectively. It is worth to mention that a lot of
pyrrolidinone derivatives are of interest as CNS regulators, for
example Piracetam and Levetiracetam [14]. Also racemic
b-
trifluoromethyl- -aminobutyric acid 4a was synthesized both
g
from N-benzyl-3-trifluoromethylpyrrolidinone 5a by successive
hydrolysis and hydrogenolysis and from trifluoroacetone 6 via 3-
trifluoromethylcrotonic acid derivatives (Scheme 2).
2. Results and discussion
Some N-substituted or unsubstituted pyrrolidinones bearing
mono- and trifluoromethyl groups at the position 3 were published
previously [15]. 3-Trifluoromethyl containing pyrrolidinone was
obtained from methyl 3-trifluoromethylacrylate as starting
compound and 3-monofluoromethyl-analog of piracetam was
synthesized by nucleophilic substitution of a mesyl group by
fluorine using CsF.
The synthesis of a series of desired fluoro-containing pyrroli-
dinones 5a–c by deoxyfluorination reactions demands the
availability of corresponding heterocycles with carboxylic, alde-
hyde and carbinol functional groups (Scheme 3). The starting 1-
benzyl-5-oxopyrrolidine-3-carboxylic acid 7 has been prepared
readily from itaconic acid and benzylamine in 86% yield [16]. The
acid 7 was transformed to the corresponding alcohol 8 and
aldehyde 9 by common reactions. The alcohol 8 was synthesized in
93.5% overall yield by successive esterification and borohydride
reduction. The aldehyde 9 was obtained in 37% yield by Swern
oxidation of alcohol 8.
Scheme 3. Reagents and conditions: (a) MeOH, SOCl2, 0–15 8C; (b) NaBH4, i-PrOH;
(c) Swern’s oxidation; (d) SF4, HF, 80 8C; (e) Ishikawa’s reagent, NaF, CH2Cl2, RT; (f)
DAST, CH2Cl2, RT.
Deoxyfluorination of acid 7 with SF4 by heating in a stainless
autoclave afforded pyrrolidinone 5a in 64% yield. Monofluoro-
methyl pyrrolidinone 5c was obtained in 80% yield. Both
Scheme 4. Reagents and conditions: (a) 20–130 8C, H2 40–150 bar, 5–20% Pd/C; (b)
aq. HOAc–H2SO4, 100 8C, H2 100 bar, 20% Pd(OH)2/C.
Scheme 2. Synthetic ways to
b-polyfluoromethyl containing GABAs 4.

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I.I. Gerus et al. / Journal of Fluorine Chemistry 131 (2010) 224–228
Scheme 5. Reagents and conditions: (a) conc. HCl, 135 8C, sealed tube; (b) H2O, H2 100 bar, 20% Pd(OH)2/C.
4.2. 1-Benzyl-4-(hydroxymethyl)pyrrolidin-2-one (8)
(a) In a 250 ml three-necked flask fitted with thermometer, a
reflux condenser connected to a calcium chloride tube and a
dropping funnel, was placed a solution of acid 7 (17.52 g,
80 mmol) in dry methanol (170 ml). The mixture was cooled to
0 8C and SOCl2 (6.2 ml, 10.12 g, 85 mmol) was added at a rate
that did not cause the temperature to rise above 15 8C. Then the
bath was removed and the mixture was allowed to stay at rt for
12 h. The methanol was distilled off under reduced pressure,
and the viscous liquid obtained was dissolved in chloroform
(200 ml). After washing with water (3 Â 40 ml), drying over
anhydrous MgSO4 and filtering, chloroform was removed
under reduced pressure to give a light yellow oil which
Scheme 6. Reagents and conditions: (a) Ph3P = CHCOOEt, CH2Cl2, 0 8C; (b) NBS, CCl4,
80 8C, (C6H5COO)2; (c) PhthNK, DMF, 80 8C; (d) H2, 10% Pd/C, EtOH, HCOOH; (e) HCl,
CH3COOH, 110 8C.
solidifies on standing. The yield of methyl 1-benzyl-5-
oxopyrrolidine-3-carboxylate was 18.59 g (99.7%). The crude
product was used in the next step without purification. 1H NMR
(500 MHz, CDCl3):
d 2.70–2.83 (2H, m, CH2C55O), 2.23 (1H, m,
CH), 3.46–3.52 (2H, m, CH2N), 3.73 (3H, s, COOCH3), 4.45 (1H, d,
Ha of CH2Ph, J = 14.7 Hz), 4.52 (1H, d, Hb of CH2Ph, J = 14.7 Hz),
7.24–7.38 (5H, m, Ph).
GABA 11 to the target compound 4a was performed in water in the
presence of 20% Pd(OH)2/C, 20 8C and 100 bar H2 (Scheme 5).
We have also developed an alternative synthetic route to 3-CF3-
GABA 4a based on trifluoroacetone 6 via the crotonate 12 as shown
on Scheme 6. The crotonates 12 and 13 were readily obtained using
procedures published previously: the Wittig reaction of trifluor-
oacetone afforded crotonate 12 in 70% yield [18], and the following
bromination with N-bromosuccinimide gave 13 in 80% [19] yield.
We found optimal reaction conditions (freshly prepared potassium
phthalimide in dry DMF at 80 8C) to obtain pure phthalimide
derivative 14. Enhancement of reaction temperature or using a
mixture of K2CO3 and phthalimide gave a large quantity of
admixtures. Catalytic reduction of 14 in the presence of 10% Pd/C
afforded 15 in 85% yield. Further acidic hydrolysis led to
deprotection of both amine and carboxylic acid groups resulting
in the 3-CF3-GABA 4a in good overall yield.
(b) To a cooled, vigorously stirred solution of methyl 1-benzyl-5-
oxopyrrolidine-3-carboxylate (10.9 g, 47 mmol) of in dry i-
propanol (100 ml) NaBH4 (5.4 g, 143 mmol) was poured
portionwise over 30 min, keeping the temperature between
0 and 5 8C. After 2 h the cooling bath was removed and the
reaction mixture was stirred overnight. Then saturated NH4Cl
solution (20 ml) was added carefully (foaming occurs),
followed by acetone (10 ml). The mixture was left over 1 h
at rt. The solvent was removed completely on a rotary
evaporator, the residue was treated with CH2Cl2 (200 ml)
and filtered. Filter cake was washed with additional portions of
CH2Cl2 (2 Â 50 ml). Combined organic phase was washed with
brine (50 ml), dried over MgSO4, filtered and evaporated to give
9 g (93.8%) of pure carbinol 8 as a colorless viscous liquid; 1H
NMR (500 MHz, CDCl3):
d 2.25–2.34 (2H, m, CH2C55O), 2.50–
3. Conclusions
2.62 (2H, m, CH + OH), 3.13 (1H, dd, Ha of CH2N, J = 10.0, 4.7 Hz),
3.38 (1H, dd, Hb of CH2N, J = 10.0, 8.2 Hz), 3.54–3.64 (2H, m,
CH2OH), 4.43 (1H, d, Ha of CH2Ph, J = 14.7 Hz), 4.48 (1H, d, Hb of
CH2Ph, J = 14.7 Hz), 7.22–7.37 (5H, m, Ph); 13C NMR (125 MHz,
In summary, we have developed a new synthetic route to 3-
polyfluoromethyl containing N-benzylpyrrolidinones 5a–c based
on deoxyfluorination reactions. Owing to high stability of N-
benzylpyrrolidinone ring to acid hydrolysis and catalytic hydro-
genolysis, we succeeded only in the synthesis of 3-CF3-GABA 4a.
Another effective synthetic route was also proposed to synthesis of
the amino acid 4a. The latter is a new isosteric analog (see Section
1) of the widespread drug pregabalin (Pfizer).
CDCl3)
d: 33.41, 34.60, 49.82, 50.27, 64.68, 127.62, 128.14,
128.71, 136.86, 135.49, 173.89; Anal. Calcd for C12H15NO2: C,
70.22; H, 7.37; N, 6.82. Found: C, 70.17; H, 7.52; N, 6.75.
4.3. 1-Benzyl-5-oxopyrrolidine-3-carbaldehyde (9)
4. Experimental
To stirred solution of dimethylsulfoxide (2.85 ml, 2.59 g,
33.2 mmol) in dry dichloromethane (20 ml) the solution of
trifluoroacetic anhydride (4.50 ml, 6.71 g, 31.9 mmol) in dichlor-
omethane (10 ml) was slowly added at À70 8C. After the 15 min the
solution of hydroxymethyl compound 8 (4.35 g, 21.2 mmol) in
dichloromethane (25 ml) was added dropwise. Stirring was
continued for 1.5 h at À65 8C, and triethylamine (8.40 ml, 6.10 g,
50.4 mmol) was added in such a rate to maintain the temperature
near À55 8C. The mixture was allowed to stand at À60 8C for
30 min and water (35 ml) was added. The phases were separated
and the water was extracted with dichloromethane (2 Â 30 ml).
4.1. General
The 1H, 13C and 19F NMR spectra were recorded on a Bruker
DRX-500 instrument at 500, 125 and 470 MHz respectively.
Chemical shifts (d
) are given in ppm relative to TMS (1H, 13C)
and CFCl3 (19F). Compounds 7, 13 and 14 were prepared according
literature procedures [14,17,18]. Palladium catalysts were com-
mercially available from ‘‘Aldrich Chemical Company, Inc.’’.
Column chromatography was performed on silica gel 60 (Merck).

I.I. Gerus et al. / Journal of Fluorine Chemistry 131 (2010) 224–228
227
Combined organic phase was washed with water (15 ml), dried
4.6. 1-Benzyl-4-(fluoromethyl)pyrrolidin-2-one (5c)
over the MgSO4, filtered and evaporated to give oily crude
aldehyde 9. The letter was dissolved in methanol (40 ml) and
mixed with a solution of NaHSO3 (2.8 g, 26.9 mmol) in water (5 ml)
and heated at 60 8C for 5 min. After the cooling the precipitated
solid was filtered, washed with ether twice, dried under reduced
pressure and 2.4 g (36.8%) of bisufite adduct of 9 was obtained. 1H
To the mixture of carbinol 8 (3.6 g, 17.6 mmol) and dry NaF
(1.0 g, 23.8 mmol) in dichloromethane (50 ml) Ishikawa reagent
was added (4.7 g, 21.1 mmol) under stirring at 0–5 8C. The reaction
mixture was slowly warmed to rt and stirred for 3 days (reaction
was controlled by TLC, eluent CH2Cl2/MeOH, 40/1, Rf = 0.72). After
completing the reaction the mixture was poured into ice-cold
saturated aqueous sodium bicarbonate (50 ml), organic phase was
separated and aqueous layer was extracted with dichloromethane
(2 Â 30 ml). Combined organic phase was washed sequentially
with 10% aqueous sodium bisulfate and dried over anhydrous
MgSO4. Then dichloromethane and main part of tetrafluoropro-
pionyl diethylamide (hydrolysate of Ishikawa reagent) was
removed under reduced pressure. The rest was distilled and
2.9 g (79.8%) of product 5c was obtained as a colorless oil; bp 142–
NMR (500 MHz, DMSO-d6):
d 2.36 (2H, m, CH2C55O), 2.74 (1H, m,
CH2CHCH2), 3.17 (1H, dd, Ha of CH2N, J = 9.8, 8.8 Hz), 3.89 (1H, dd,
Hb of CH2N, J = 9.8, 5.0 Hz), 4.31 (1H, d, Ha of CH2Ph, J = 15.4 Hz),
4.39 (1H, d, Hb of CH2Ph, J = 15.4 Hz), 5.67 (1H, d, J = 5.3 Hz,
CH(OH)SO2ONa), 7.18–7.37 (5H, m, Ph); Anal. Calcd for
C12H14NNaO5S: S, 10.43. Found: S, 10.06.
4.4. 1-Benzyl-4-(trifluoromethyl)pyrrolidin-2-one (5a)
A mixture of acid 7 (6.5 g, 30 mmol) and 15 ml of anhydrous HF
was placed in a 50 ml high-pressure stainless still autoclave.
Gaseous SF4 (11.0 g, 0.1 mol) was placed in the autoclave under
cooling with a liquid nitrogen. The reaction mixture was stirred at
85 8C for 4 h, then cooled to the rt and gaseous products were
vented off. The residue was poured carefully into 100 g of ice and
the bomb was rinsed three times with water. Combined water
phase was extracted with ethyl acetate (3 Â 100 ml). The organic
phase was washed with 5% sodium carbonate solution, saturated
NaCl solution, and dried over anhydrous MgSO4. After the filtration
and evaporation of EtOAc the dark brown oily residue was distilled
under reduced pressure. The yield of the desired lactame was 4.6 g
(63.8%) as colorless liquid, bp 81 8C/1 mmHg; 1H NMR (500 MHz,
144 8C/0.1 mmHg; 1H NMR (500 MHz, CDCl3)
d: 2.29 (1H, dd, Ha of
CH2C55O, J = 16.2, 6.0 Hz), 2.60 (1H, dd, Hb of CH2C55O, J = 16.2,
9.3 Hz), 2.97 (1H, m, CH), 3.17 (1H, m, Ha of CH2N), 3.34 (1H, m, Hb
of CH2N), 4.23–4.49 (4H, m, CH2F and CH2Ph), 7.27–7.39 (5H, m,
Ph); 13C NMR (125 MHz, CDCl3)
d: 31.52 (d, J = 20.3 Hz), 32.80 (d,
J = 7.0 Hz), 46.61, 48.30 (d, J = 6.1 Hz), 84.30 (d, J = 170.0 Hz),
127.74, 128.16, 128.80, 136.16, 173.12; 19F NMR (470 MHz, CDCl3)
d
: À211.99 (m, CH2F); Anal. Calcd for C12H14FNO: C, 69.55; H, 6.81;
N, 6.76. Found: C, 69.47; H, 6.97; N, 6.45.
4.7. 1-(Cyclohexylmethyl)-4-(fluoromethyl)pyrrolidin-2-one (10)
A mixture of pyrrolidinone 5c (190 mg, 0.92 mmol), water
(0.2 ml), HOAc (0.2 ml), conc. H2SO4 (180 mg) and 20% Pd(OH)2/C
(100 mg) was hydrogenated at 100 8C under the 100 bar pressure
overnight. Then water (1.5 ml) was added, the mixture was filtered
through silica gel which was washed with water (2 ml). The
filtered catalyst on silica gel was washed with dichloromethane
(30 ml), after drying over MgSO4 dichloromethane was evaporated
and 186 mg (95.1%) of the product 10 was obtained as colorless oil;
CDCl3) d: 2.65 (1H, dd, Ha CH2C55O, J = 17.5; 6.9 Hz), 2.74 (1H, dd,
Hb CH2C55O, J = 17.5, 9.8 Hz), 3.06 (1H, m, CHCF3), 3.37 (1H, dd, Ha
of CH2N, J = 10.0, 5.6 Hz), 3.46 (1H, dd, Hb of CH2N, J = 10.0,
10.4 Hz), 4.46 (1H, d, Ha of CH2Ph, J = 15.0 Hz), 4.52 (1H, d, Ha of
CH2Ph, J = 15.0 Hz), 7.27–7.39 (5H, m, Ph); 13C NMR (125 MHz,
CDCl3)
J = 277.2 Hz), 127.97, 128.13, 128.90, 135.49, 171.24; 19F NMR
(470 MHz, CDCl3)
: À73.62 (d, CF3, J = 9.0 Hz); Anal. Calcd for
12H12F3NO: C, 59.26; H, 4.97; N, 5.76. Found: C, 59.17; H, 5.22; N,
5.55.
d: 30.86, 35.18 (q, J = 29.0 Hz), 45.47, 46.62, 126.59 (q,
d
1H NMR (500 MHz, CDCl3)
d: 0.87–1.75 (11H, m, C6H11), 2.20 (1H,
C
dd, Ha CH2C55O, J = 17.0, 6.1 Hz), 2.53 (1H, dd, Hb CH2C55O, J = 17.0,
9.3 Hz), 2.72 (1H, m, CHCH2F), 3.08 (2H, m, CH2C6H11), 3.24 (1H, dd,
Ha CH2N, J = 10.0, 5.1 Hz), 3.48 (1H, dd, Hb CH2N, J = 10.0, 8.3 Hz),
4.26–4.45 (2H, m, CH2F); Anal. Calcd for C12H20FNO: C, 67.57; H,
9.45; N, 6.57. Found: C, 67.38; H, 5.66; N, 6.35.
4.5. 1-Benzyl-4-(difluoromethyl)pyrrolidin-2-one (5b)
To the solution of aldehyde 9 (0.390 g, 1.9 mmol) (freshly
regenerated from its bisulfite adduct, Section 4.3) in dry
dichloromethane (5 ml) the cooled solution of morpholinosulfur
trifluoride (0.4 g, 2.5 mmol) in the CH2Cl2 (5 ml) was slowly added
at 0 8C and stirring. The mixture was slowly warmed to rt and after
the 5 h the reaction mixture was poured in dichloromethane
(30 ml), concentrated aqueous sodium bicarbonate (5 ml) was
added and the mixture was carefully shaken. Dichloromethane
phase was separated, dried over anhydrous MgSO4 and concen-
trated on a rotary evaporator. The product 5b was purified by
column chromatography on silica gel, Rf = 0.55, eluent EtOAc/
Hexane (3/2). The yield of difluoromethyl compound 5b was
4.8. 3-((Benzylamino)methyl)-4,4,4-trifluorobutanoic acid (11)
hydrochloride
A mixture of pirrolidinone 5c (1.79 g, 7.37 mmol) and 20 ml of
conc. hydrochloricacidwasheatedinasealedtubeat130 8Cfor48 h.
The excess of hydrochloric acid was evaporated under reduced
pressure to dryness and the residue was triturated with ether
(15 ml). The white crystals formed was filtered and washed with
ether (2 Â 2 ml) giving 480 mg (21.9%) of the product. Evaporation
of mother liquors gave 1.26 g of starting pyrrolidinone 11
(conversion 74.0%); 1H NMR (500 MHz, D2O)
d: 2.57 (1H, dd, Ha
128 mg (29.6%) as colorless oil; 1H NMR (500 MHz, CDCl3)
d
: 2.52
CH2C55O, J = 17.5, 8.4 Hz), 2.53 (1H, dd, Hb CH2C55O, J = 17.6, 4.4 Hz),
3.16(1H, m, CHCF3), 3.22(1H, dd, Ha CH2N, J = 13.6, 5.3 Hz), 3.39(1H,
dd, Hb CH2N, J = 13.6, 6.4 Hz), 4.22 (1H, d, Ha CH2Ph, J = 13.3 Hz), 4.25
(1H, d, Hb CH2Ph, J = 13.3 Hz), 7.41 (5H, s, Ph); 19F NMR (470 MHz,
(1H, dd, Ha CH2C55O, J = 17.2; 6.3 Hz), 2.65 (dd, 1H, Hb CH2C55O,
J = 17.2; 9.9 Hz), 3.06 (m, 1H, CHCHF2), 3.37 (dd, 1H, Ha of CH2N,
J = 10.3; 5.3 Hz), 3.46 (dd, 1H, Hb of CH2N, J = 10.3; 9.3 Hz), 4.46 (d,
1H, Ha of CH2Ph, J = 14.9 Hz), 4.49 (d, 1H, Hb of CH2Ph, J = 14.9 Hz),
5.76 (td, 1H, CHF2, J = 56.4, 4.3 Hz), 7.27–7.39 (m, 5H); 13C NMR
D2O)
d
: À71.48 (d, J = 9.9 Hz); Anal. Calcd for C12H16F3NO2ÁHCl: C,
48.09; H, 5.72; N, 4.67. Found: C, 47.91; H, 5.94; N, 4.55.
(125 MHz, CDCl3)
52.83, 115.70 (t, J = 243.2 Hz), 127.21, 127.57, 128.25, 135.22,
171.46; 19F NMR (470 MHz, CDCl3)
J = 284.1, 56.1, 12.8 Hz), À124.27 (ddd, Fb of CHF2, J = 284.1, 56.1,
15.3 Hz); Anal. Calcd for C12H13F2NO: C, 63.99; H, 5.82; N, 6.22.
Found: C, 64.17; H, 5.92; N, 6.25.
d: 30.18, 34.20 (t, J = 22 Hz), 45.96 (t, J = 66.5 Hz),
4.9. 3-(Aminomethyl)-4,4,4-trifluorobutanoic acid (4a)
hydrochloride
d
: À122.89 (ddd, Fa of CHF2,
A mixture of N-benzylaminoacid hydrochloride 11 (240 mg,
0.81 mmol) and 20% Pd(OH)2/C (100 mg) in distilled water (2 ml)

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I.I. Gerus et al. / Journal of Fluorine Chemistry 131 (2010) 224–228
was hydrogenated at room temperature and a pressure of 100 bar
for 24 h. The solution was then filtered through silica gel and
washed with water (10 ml). Evaporation of the filtrate under
reduced pressure yielded desired amino acid hydrochloride 4a as a
thick white powder (130 mg, yield 77.6%); 1H NMR (500 MHz, D2O)
HCl (2 ml) was stirred at 110 8C for 2 days. After completing the
reaction the solvents were evaporated in vacuum, the rest was
treated by water (20 ml), the solution was extracted by EtOAc
(2 Â 15 ml) and amino acid 4a was isolated from water phase by
ion exchange resin Amberlite IR-120 with following aq. NH3
elution and evaporation. The yield of GABA 4a was 0.31 g (74.5%);
d
: 2.53 (1H, dd, Ha CH2C55O, J = 17.2, 8.0 Hz), 2.74 (1H, dd, Hb
CH2C55O, J = 17.2, 3.3 Hz), 3.01 (1H, m, CHCF3), 3.18 (1H, dd, Ha
CH2N, J = 13.4, 4.0 Hz), 3.30 (1H, dd, Hb CH2N, J = 13.4, 7.1 Hz); 13
NMR (125 MHz, D2O) : 32.02, 37.82, 38.41 (q, J = 27.4 Hz), 126.46
(q, J = 279.9 Hz), 174.94; 19F NMR (470 MHz, D2O)
1H NMR (500 MHz, D2O)
d: 2.33 (1H, dd, Ha of CH2C55O, J = 16.2,
C
8.0 Hz), 2.56 (1H, dd, 1H, Hb of CH2C55O, J = 16.2, 5.2 Hz), 2.98 (1H,
m, CH), 3.11 (1H, dd, Ha of CH2N, J = 13.6, 5.6 Hz), 3.26 (1H, dd, Hb of
d
d
: À69.52 (d,
CH2N, J = 13.6, 6.7 Hz); 19F NMR (470 MHz, D2O)
d
: À71.63 (d,
J = 9.1 Hz); Anal. Calcd for C15H10F3NO2ÁHCl: C, 28.65; H, 5.29; N,
J = 6.4 Hz); 13C NMR (125 MHz, D2O)
d: 34.75, 38.31, 39.32 (q,
6.68. Found: C, 28.83; H, 5.42; N, 6.27.
J = 26.7 Hz), 124.69 (q, J = 280.0 Hz), 177.72. Anal. Calcd for
C5H8F3NO2: C, 35.29; H, 4.90; N, 7.81. Found: C, 35.10; H, 4.71;
N, 8.19.
4.10. (E)-Ethyl 3-((1,3-dioxoisoindolin-2-yl)methyl)-4,4,4-
trifluorobut-2-enoate (14)
Acknowledgement
A mixture of crotonate 13 (3.0 g, 11.5 mmol) and potassium
phthalimide (2.13 g, 11.5 mmol) in 15 ml of dry DMF was heated at
80–90 8C and stirring for 3–4 h (reaction was controlled by TLC).
After completing the reaction the mixture was cooled and
concentrated in vacuum. The rest was treated with EtOAc
(30 ml), washed with water (2 Â 25 ml) and organic phase was
dried over the MgSO4. After evaporation of the solvent in vacuum
the product 14 was purified by column chromatography, the yield
was 3.1 g (82.4%) as white crystals, Rf = 0.56, eluent EtOAc/Hexane
We thank Enamine Ltd. (Kiev) for technical and financial
support and for NMR experiments.
References
´
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d: 1.37 (3H, t, J = 7.1 Hz,
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N, 4.10. Found: C, 54.73; H, 4.29; N, 4.25.
4.12. 3-(Aminomethyl)-4,4,4-trifluorobutanoic acid (4a)
A mixture of ethyl 3-((1,3-dioxoisoindolin-2-yl)methyl)-4,4,4-
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