A convenient one-pot synthesis of (R)-2-amino-3,3,3-trifluoro-2-methyl-N- phenylpropanamide derivatives

Article abstract of DOI:10.1016/j.tetlet.2012.10.086

A convenient one-pot synthesis of enantiopure (R)-2-amino-3,3,3-trifluoro- 2-methyl-N-phenylpropanamide derivatives has been developed. The key step in this synthetic methodology turned out to be the amide formation in which (R)-2-amino-3,3,3-trifluoro-2-

Full text of DOI:10.1016/j.tetlet.2012.10.086

Tetrahedron Letters 54 (2013) 134–137
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Tetrahedron Letters
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A convenient one-pot synthesis of (R)-2-amino-3,3,3-trifluoro-2-methyl-
N-phenylpropanamide derivatives
Tian-Wen Li a, Pei-Hua Shang b, Chang-Mei Cheng a, , Yu-Fen Zhao a
⇑
a Key Laboratory of Bioorganic Phosphorus and Chemical Biology, The Ministry of Education, Department of Chemistry, Tsinghua University, Beijing 100084, PR China
b 92117, Unit of PLA, Beijing 100072, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient one-pot synthesis of enantiopure (R)-2-amino-3,3,3-trifluoro-2-methyl-N-phenylpropana-
mide derivatives has been developed. The key step in this synthetic methodology turned out to be the
amide formation in which (R)-2-amino-3,3,3-trifluoro-2-methylpropanoic acid hydrochloride was simul-
taneously protected and activated by Vilsmeier reagent.
Received 16 August 2012
Revised 12 October 2012
Accepted 18 October 2012
Available online 26 October 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
a-Trifluoromethyl-a-amino acids
Amide formation
One-pot
Vilsmeier reagent
Introduction
and is orally bioavailable.9 Hence, we envisioned that the
structurally similar (R)-2-amino-3,3,3-trifluoro-2-methyl-N-phe-
Comparing to natural amino acids,
a-trifluoromethyl-a-amino
nylpropanamide (Fig. 1) derivatives that contain a
a-trifluoro-
acids exhibit number of unique properties such as high
a
methyl- -amino acid fragment might have some special
a
electronegativity, high lipophilicity, high electron density, and high
steric hindrance that are imparted by the trifluoromethyl group,
which endows them significant potentials with practical applica-
properties, particularly the anti-cancer activities. To the best of
our knowledge, (R)-2-amino-3,3,3-trifluoro-2-methyl-N-phenyl-
propanamide derivatives have not yet been explored. Herein we
report the one-pot synthesis of (R)-2-amino-3,3,3-trifluoro-2-
methyl-N-phenylpropanamide derivatives from (R)-2-amino-
3,3,3-trifluoro-2-methylpropanoic acid via the intermediate of a
N,N-dimethylformamidine protected acid chloride.
tions.1 Therefore,
a-trifluoromethyl-a-amino acids are of great
attraction in the design of biologically active molecules, particularly
peptides.2 (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-N-phenylpro-
panamide (Fig. 1) derivatives were originally reported as potent
antiandrogen agents.3,4 It was also found that some derivatives pos-
sessed undesirable hypotensive activity, which is most likely due to
the activation of ATP-sensitive K+ channels (KATP channels).5–7
Moreover, these compounds can also act as inhibitors of Pyruvate
Dehydrogenase Kinase (PDK), which is much more potent than the
anti-cancer agent dichloroacetate8 in primary enzymatic assay
Results and discussion
(R)-2-Amino-3,3,3-trifluoro-2-methylpropanoic acid hydrochlo-
ride was prepared according to the literature procedures.10,11 In
short, a solution of 1,1,1-trifluoropropan-2-one and (R)-phenylgly-
cinol in toluene was refluxed in the presence of pyridinium 4-tolu-
enesulfonate, furnishing oxazolidine 2 as the product. Afterward
the oxazolidine 2 reacted with trimethylsilyl cyanide (TMSCN) to af-
ford the amino nitriles 3 and 4, which were further conveniently
converted into 2-amino-3,3,3-trifluoro-2-methylpropanoic acids
hydrochloride 5 and 6 by treating withconcentrated HCl (Scheme 1).
For synthesizing (R)-2-amino-3,3,3-trifluoro-2-methyl-N-phe-
nylpropanamide derivatives, we initially envisaged that the target
molecule could be achieved by protecting the NH2 group of (R)-5
with amino protecting reagents and subsequently coupling with
anilines or transforming into acyl chloride followed by aniline
treatment (Table 1). However, our preliminary experiments
OH
NH2
NH
NH
F3C
H3C
F3C
H3C
O
O
(
R
)-1a
( )-1b
R
Figure 1. Structure of (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-N-phenylpropana-
mide (1a) and (R)-2-amino-3,3,3-trifluoro-2-methyl-N-phenylpropanamide (1b).
⇑
Corresponding author. Tel./fax: +86 10 62784642.
E-mail address: chengcm@mail.tsinghua.edu.cn (C.-M. Cheng).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.086

T.-W. Li et al. / Tetrahedron Letters 54 (2013) 134–137
135
O
O
O
Coupling reagents/
Chloride reagents
O
O
NH
COOH
TMSCN
H3C
CF3
N
BF3 Et2O
HN
CF3
OH
O
PPTS/toluene
reflux
F3C
)-10
H2N
O
F3C
(
)-13, 72%
R
(
R
(R)-2, 98%
Scheme 2. (R)-N-Cbz-2-amino-3,3,3-trifluoro-2-methylpropanoic acid undergoes
an intramolecular dehydration in the presence of coupling reagents or chloride
reagents.
Ph
NH2 HCl
OH
HN
F3C
conc HCl
COOH
F3C
CN
reflux
(
)-5, 55%, 98% ee
R
results were also observed with different chloride reagents
(Table 1). We isolated the product from the above reactions and
it was assigned as (R)-2-(benzyloxy)-4-methyl-4-(trifluoro-
methyl)oxazol-5(4H)-one (13). The result is consistent with Bur-
[α]20D = +10.7 (c 0.90, H2O)
(R, R)-3, 59%
[α]20D (lit)11= +10.9 (c 0.90, H2O)
Ph
NH2 HCl
ger’s report that (R)-N-Cbz-a-trifluoromethylalanine would
OH
conc HCl
reflux
HN
transform into compound 13 under the mediation of coupling
reagents such as DCC or chloride reagents such as SOCl2
(Scheme 2).13 Aliphatic amides of (R)-5 could be prepared from
13 and aliphatic amines. However, the formation of aromatic
amides from 13 and anilines was problematic, which may due to
the much lower reactivity of anilines than aliphatic amines. Other
types of amino protecting reagents such as TsCl, CH3COCl, and
PhCHO had also been employed (Table 1). The reaction of (R)-5
with TsCl or PhCHO only gives a very low yield of amino protected
COOH
CF3
CN
CF3
(S)-6, 53%
(
)-4, 34%
R, S
PPTS=Pyridinium 4-Toluenesulfonate
Scheme 1. Synthesis of (R)-2-amino-3,3,3-trifluoro-2-methylpropanoic acid hydro-
chloride using (R)-phenylglycinol as
a chiral auxiliary. PPTS = pyridinium 4-
toluenesulfonate
product (R)-10, while CH3COCl gives a good yield of (R)-N-Ac-a-tri-
fluoromethylalanine. However they all failed to give our desired
products (R)-12 after subsequent treatment with aniline.
Considering the poor basicity of the amino group of (R)-5, we
next turned our attention to a new working scenario, in which ani-
lines reacted with ester of (R)-5 to give our desired products
(Scheme 3). However, our experiments with (R)-methyl-2-amino-
3,3,3-trifluoro-2-methylpropanoate (8) and aniline completely
failed, probably owing to the poor reactivity of the aromatic amine
moiety of anilines.
showed that the reaction of (R)-5 with Boc2O failed to give any de-
sired product, which may because of the poor basicity of the amino
group in (R)-5 (Table 1).12
Then we turned to a more active reagent CbzCl for protecting
the NH2 group, which led to the formation of (R)-N-Cbz-a-trifluo-
romethylalanine. To our surprise, the subsequent treatment with
aniline in the presence of various coupling reagents resulted in
no formation of the desired product but something else; similar
Table 1
Amide formation using various amino protecting reagents to protect the amino groups of (R)-5
NH2 HCl
NHR
COOH
(R)-10
Protecting reagents
F3C
COOH
(R)-5
F3C
ArNH2
Coupling reagents
O
RHN
F3C
NHAr
(R)-12
Chloride
reagents
NHR
COCl
(R)-11
ArNH2
Et3N
F3C
a
Protecting reagents
R
Coupling reagents
Chloride reagents
10, % yield
12, % yield
Boc2O
CbzCl
CbzCl
CbzCl
CbzCl
CbzCl
CbzCl
TsCl
Boc
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Ts
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
DCC
EDCÁHCl
—
—
—
—
DCC
—
DCC
—
DCC
—
60
60
60
60
60
60
11
11
66
66
8
(COCl)2
SOCl2
PCl3
POCl3
—
SOCl2
—
SOCl2
—
TsCl
Ts
CH3COCl
CH3COCl
PhCHO
PhCHO
CH3CO
CH3CO
PhCH@N
PhCH@N
SOCl2
8
a
Yield of pure, isolated yield.

136
T.-W. Li et al. / Tetrahedron Letters 54 (2013) 134–137
in (R)-5 and aniline. Actually, we did notice that the basicity of
Ph
HCl
Ph
the amino group in (R)-5 is significantly reduced, while the acidity
of (R)-5 is increased, comparing to the corresponding non-
fluorinated counterparts.12 A similar situation also exists in amino-
benzoic acids comparing to the aliphatic amino acids. Recently,
Zhichkin et al developed a successful one-pot amidation of amino-
benzoic acid which was simultaneously protected and activated
with Vilsmeier reagent.14 Therefore, we wondered that Vilsmeier
reagent could be applied in our case for the synthesis of the desired
compounds.
OH
OH
MeOH
HN
F3C
HN
CN
F3C
COOMe
(R, R)-3
(R, R)-7, 72%
NH2
NH2
COOMe
ArNH2
NHAr
H2-Pd(OH)2
F3C
F3C
O
(R)-9
(
R
)-8, 99%
Thus,
(R)-2-amino-3,3,3-trifluoro-2-methylpropanoic
acid
hydrochloride was added to a suspension of 2 equivalents of the
in situ prepared Vilsmeier reagent from DMF and oxalyl chloride
in CH2Cl2 at room temperature, directly furnishing the unstable
acid chloride 14. Then a further treatment with anilines and N,N-
diisopropylethylamine (DIPEA) afforded the protected amide 15.
Afterward 15 underwent a deprotection in the presence of ethy-
lenediamine in ethanol under reflux to give the desired products.15
By utilizing this methodology, a variety of (R)-2-amino-3,3,3-tri-
fluoro-2-methyl-N-phenylpropanamide derivatives were synthe-
sized in moderate yields (Table 2).
Scheme 3. Amide formation using aniline and ester of (R)-2-amino-3,3,3-trifluoro-
2-methylpropanoic acid.
The unsuccessful amidation of (R)-2-amino-3,3,3-trifluoro-2-
methylpropanoic acid with aniline under standard or modified
peptide synthesis conditions prompted us to seek an alternative
synthetic route for (R)-2-amino-3,3,3-trifluoro-2-methyl-N-phe-
nylpropanamide derivatives. The low reactivity of the starting
materials was attributed to the poor basicity of the amino groups
Table 2
Synthesis of (R)-2-amino-3,3,3-trifluoro-2-methyl-N-phenylpropanamide derivatives using Vilsmeier reagent for simultaneous protection and activation of (R)-2-amino-3,3,3-
trifluoro-2-methylpropanoic acid hydrochloride
N
N
O
NH2 HCl
O
DMF
N
ArNH2
DIPEA
ethylenediamine
EtOH
(COCl)2
H2N
F3C
N
F3C
NHAr
F3C
NHAr
CO2H
CH3
F3C
COCl
CH3
CH2Cl2
CH3
CH3
(R)-4
(R)-15
(R)-14
(R)-9
O
O
O
O
O
H2N
F3C
H2N
F3C
H2N
F3C
H2N
F3C
H2N
F3C
N
H
N
H
N
N
H
N
H
H
F
9a, 53% a, >96%b ee
9d, 57%, >96% ee
9b, 51%, >96% ee
9c, 49%, >96% ee
9e, 37%, >96% ee
Cl
O
O
O
O
O
H2N
F3C
H2N
F3C
H2N
F3C
H2N
F3C
H2N
F3C
N
N
H
N
H
F
N
H
Cl
N
H
H
Br
Cl
9f, 38%, >96% ee
9j, 43%, >96% ee
9h, 40%, >96% ee
9g, 39%, >96% ee
9i, 32%, >96% ee
Br
O
O
O
O
O
H2N
F3C
H2N
F3C
H2N
F3C
H2N
F3C
H2N
F3C
N
H
Br
N
N
H
N
H
I
N
H
H
I
OMe
9k, 41%, >96% ee
9l, 38%, -c ee
9m, 50%, >96% ee
9n, 47%, >96% ee
9o, 66%, >96% ee
CN
OMe
O
O
O
O
O
H2N
F3C
H2N
F3C
H2N
F3C
H2N
F3C
H2N
F3C
N
H
OMe
N
H
CN
N
N
H
N
H
H
CN
9p, 62%, >96% ee
9s, 33%, >96% ee
9t, 35%, >96% ee
9q, 68%, >96% ee
9r, 38%, >96% ee
CF3
O
O
O
O
O
H2N
F3C
H2N
F3C
H2N
F3C
H2N
F3C
H2N
F3C
N
N
H
OCF3
N
H
CF3
N
H
N
H
H
OCF3
CF3
9v, 35%, -% ee
9x, 38%, -% ee
9y, 38%, -% ee
9w, 41%, -% ee
9u, 38%, -% ee
O
O
O
H2N
F3C
H2N
F3C
H2N
F3C
N
H
N
H
N
H
SMe
SMe
9ab, 46%, 96% ee
9aa, 56%, -% ee
9z, 68%, >96% ee
a Yield of pure, isolated yield.
b Determined by HPLC equipped with a chiral Crownpak Cr(+) column (operated isocratically at 1 mL/min with 100% perchloric acid (pH = 1.0)).
c Means enantiopurity could not be determined owing to the poor solubility in water.

T.-W. Li et al. / Tetrahedron Letters 54 (2013) 134–137
137
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In conclusion, a convenient one-pot method for the simulta-
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neous protection and activation of (R)-2-amino-3,3,3-trifluoro-2-
methylpropanoic acid for amide formation has been developed.
The transformation was effected by the reaction of (R)-2-amino-
3,3,3-trifluoro-2-methylpropanoic acid with Vilsmeier reagent,
affording N,N-dimethylformamidine protected acid chlorides.
These acid chlorides were used in situ for direct coupling reactions
with weakly nucleophilic anilines to form the corresponding ani-
lides. The pharmacological evaluations of these (R)-2-amino-
3,3,3-trifluoro-2-methyl-N-phenylpropanamide derivatives, such
as PDK inhibitory and anti-cancer activities, are in progress.
8. Bonnet, S.; Archer, S. L.; Allalunis-Turner, J.; Haromy, A.; Beaulieu, C.;
Thompson, R.; Lee, C. T.; Lopaschuk, G. D.; Puttagunta, L.; Bonnet, S.; Harry,
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Acknowledgment
We would like to thank the National Natural Science Founda-
tion of China for financial support (No. 20872078).
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Supplementary data
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Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
10.086.
15. Typical procedure: The Vilsmeier reagent was prepared by adding oxalyl
chloride (2.52 g, 19.8 mmol) dropwise to a solution of anhyd. DMF (1.50 g,
20.5 mmol) in CH2Cl2 (20 mL) at 0–5 °C (CAUTION: Foaming!) and stirring at rt
for 30 min. Compound 5 (1.57 g, 10.0 mmol) was added at 0 °C to Vilsmeier
reagent (20.0 mmol) in CH2Cl2 (20 mL) prepared as described above, and the
mixture was stirred at rt for 1 h. At 0 °C, a solution of substituted aniline
(0.93 g, 10.0 mmol) in CH2Cl2 (10 mL) was added, followed by DIPEA (5.16 g,
31.0 mmol), and the mixture was stirred for 1 h at rt. It was then concentrated
to dryness, and the residue was heated at reflux in ethanol (25 mL) with
ethylenediamine (2.70 g, 45.0 mmol) for 3 h. The resulting mixture was
evaporated to dryness, stirred with water (50 mL), and partitioned between
CH2Cl2 and water. The organic layer was dried (Na2SO4) and concentrated. The
residue was purified by column chromatography (petroleum ether/ethyl
acetate) to afford compound 9a (53%, 1.23 g). (R)-2-amino-3,3,3-trifluoro-2-
methyl-N-phenylpropanamide (9a):Brown oil, 1H NMR (300 MHz, CDCl3) d 9.39
(s, 1H), 7.57 (d, J = 8.2 Hz, 2H), 7.32 (t, J = 7.8 Hz, 2H), 7.12 (t, J = 7.0 Hz, 1H),
1.96 (s, 2H), 1.58 (s, 3H). 13C NMR (75 MHz, CDCl3) d 167.3, 137.2, 129.4, 125.8
(q, J = 284.7 Hz), 124.9, 119.8, 118.6, 115.3, 61.4 (q, J = 27.5 Hz), 21.3. ESI-
MS:m/z = 233.1 [M+H]+, 255.0 [M+Na]+.
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