Methyl α-iminotrifluoropropionate: A novel convenient building block for the preparation of functionalized derivatives bearing a trifluoroalanine residue

Article abstract of DOI:10.1055/s-0030-1260249

A convenient synthesis of methyl α-iminotrifluoropropionate (methyl 3,3,3-trifluoro-2-iminopropanoate, 3), based on the aza-Wittig reaction of methyl trifluoropyruvate with triphenylphosphine imide, was developed. The synthetic potential of N-H imine 3, e

Full text of DOI:10.1055/s-0030-1260249

3426
PRACTICAL SYNTHETIC PROCEDURES
Methyl a-Iminotrifluoropropionate: A Novel Convenient Building Block for
the Preparation of Functionalized Derivatives Bearing a Trifluoroalanine
Residue
Yuliya V. Rassukana*
Institute of Organic Chemistry, National Academy of Sciences, 5 Murmans’ka St, Kiev 02660, Ukraine
Fax +380(44)5732643; E-mail: juravi@rambler.ru
Received 21 July 2011
PSP
No208
Abstract: A convenient synthesis of methyl a-iminotrifluoropropionate (methyl 3,3,3-trifluoro-2-iminopropanoate, 3), based on the aza-
Wittig reaction of methyl trifluoropyruvate with triphenylphosphine imide, was developed. The synthetic potential of N–H imine 3, existing
as equilibrium mixture (10:1) of E/Z isomers, in the preparation of functionalized acyclic and heterocyclic derivatives possessing a phar-
macophoric trifluoroalanine fragment, is disclosed.
Key words: N–H imines, trifluoropyruvate, trifluoroalanine, iminocarboxylates, cyclization, nucleophilic addition
OH
O
C
O
C
F3C
N
PPh3
+
Ph3P NH
F3C
OMe
O
1
MeO
2
+
O–
PPh3
F3C
MeOOC
Δ
F3C
N H
N
H
– Ph3PO
O
MeO
3
A
Scheme 1
Activated imines are valuable building blocks in the syn- cially available methyl trifluoropyruvate (1) with triphen-
thesis of functionalized nitrogen-containing compounds.1 ylphosphine imide has been developed (Scheme 1). It is
Specifically, compounds bearing an alkoxycarbonyl noteworthy that at room temperature the reaction of 1 and
group at the imine carbon atom are convenient precursors triphenylphosphine imide leads initially to a mixture
of a-amino acids. Trifluoropyruvate imines are especially (~1:10) of imine 3 and phosphine imide 2. The latter re-
promising as their functionalization leads to biorelevant sults from nucleophilic addition of the imino N–H func-
a-amino acids possessing the trifluoromethyl group. The tion of triphenylphosphine imide across highly electro-
latter brings in its unique properties such as high elec- philic C=O bond of 1. Imide 2 is stable at room tempera-
tronegativity, high lipophilicity, and steric demand.2 For ture in ethereal or benzene solutions, but upon heating or
this reason, trifluoropyruvate imines with various substit- thermal distillation it cleanly converts into imine 3. The
uents at nitrogen atom are widely used in the design of bi- transformation of 2 into 3 is believed to involve 1,3-pro-
ologically active amino acids derivatives.3 Surprisingly, ton transfer followed by elimination of triphenylphos-
the parent a-iminotrifluoropropionate with a free imine phine oxide in the classical aza-Wittig reaction
N–H group is apparently unknown so far. At the same intermediate A (Scheme 1).
time, the presence of the =N–H function in this compound
offers additional opportunities connected with the possi-
bility of their functionalization by both nucleophilic (at
the imine carbon atom) and electrophilic agents (at the ni-
Imine 3 is quite stable in a dry inert atmosphere and can
be easily purified by distillation. In solution (CDCl3, ben-
zene-d6) iminocarboxylate 3 exists as an equilibrium mix-
ture of E/Z isomers (E/Z ~10:1 at 25 °C). Identification of
trogen atom).
E,Z-isomers is based on the comparison of H and 19F
A convenient synthetic approach to methyl a-iminotri- NMR characteristics with the respective iminophospho-
fluoropropionate (methyl 3,3,3-trifluoro-2-iminopropa- nates analogues.4
1
noate, 3), based on the aza-Wittig reaction of commer-
Imine 3 contains a polarized azomethine group and it is a
promising building block in the synthesis of amino acid
derivatives containing a trifluoromethyl group. Its syn-
thetic potential is demonstrated in Scheme 2. Specifically,
SYNTHESIS 2011, No. 21, pp 3426–3428
Advanced online publication: 05.10.2011
DOI: 10.1055/s-0030-1260249; Art ID: N71811SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
1
reaction with indole leads directly to methyl a-amino-a-

PRACTICAL SYNTHETIC PROCEDURES
Methyl a-Iminotrifluoropropionate
3427
standard methods. All reactions were carried out under an argon at-
mosphere in oven-dried glassware.
(1H-indol-2-yl)trifluoroalanine [methyl 2-amino-3,3,3-
trifluoro-2-(1H-indol-3-yl)propanoate, 4] in 90% yield.
Cyclocondensations with mercaptoacetic, 3-mercaptopro-
pionic, or thiosalicylic acid allow the preparation of bio-
logically promising thiazolidinone 5, thiazinanone 6, or
benzothiazine derivatives 7 bearing a trifluoroalanine
fragment as part of the five- or six-membered heterocycle.
[3+2]-Dipolar cycloaddition with nitrile oxide leads to
functionalized dihydro-1,2,4-oxadiazole 8. Reaction with
salicylaldehyde opens the way to 2H-1,3-benzoxazines of
type 9. This interesting approach involves most probably
addition of the O–H function across the C=N bond of
imine 3 followed by the creation of a novel C=N bond by
means of intramolecular condensation of the amino and
carbonyl groups. The possibility for functionalization at
the nitrogen atom of N–H imine 3 is exemplified by reac-
tion with methyl trifluoropyruvate leading to the stable,
highly functionalized imine 10. Note that the two latter re-
actions are possible only for imines with a free N–H func-
tion.
Methyl 3,3,3-Trifluoro-2-iminopropanoate (3)
Methyl trifluoropyruvate (1, 7 g, 45 mmol) was added to a stirred
soln of Ph3P=NH (12.4 g, 45 mmol) in anhyd Et2O (30 mL) at 0 °C
and was allowed to warm to r.t. The solvent was evaporated under
reduced pressure to give a mixture (~1:10) of imine 3 and phosphine
imide 2.
19F NMR (benzene-d6): d = –80.4.
31P NMR (benzene-d6): d = 4.2.
Distillation of imine 3 and phosphine imide 2 gives imine 3 as a yel-
low liquid; yield: 5.6 g (80%); bp 108–109 °C.
IR (film): 1720, 1750 (C=N, C=O), 3250, 3270 cm–1 (NH).
(E)-3
1H NMR (300 MHz, CDCl3): d = 3.97 (s, 3 H, CH3O), 12.24 (1 H,
NH).
13C NMR (125.76 MHz, CDCl3): d = 53.75 (s, CH3O), 118.66 (q,
2
1JCF = 278 Hz, CF3), 156.65 (s, C=O), 156.84 (q, JCF = 36.5 Hz,
C=N).
19F NMR (188 MHz, CDCl3): d = –71.1.
NH2
F3C
(Z)-3
OH
F3C
1H NMR (300 MHz, CDCl3): d = 3.99 (s, 3 H, CH3O), 11.80 (1 H,
MeOOC
N
COOMe
NH
4
NH).
MeOOC
CF3
COOMe
F3C
19F NMR (188 MHz, CDCl3): d = –72.9.
10
i
H
N
S
vii
Anal. Calcd for C4H4F3NO2: C, 30.98; H, 2.60; N, 9.03. Found: C,
31.02; H, 2.62; N, 8.99.
ii
MeOOC
F3C
F3C
O
O
vi
5
NH
Methyl 2-Amino-3,3,3-trifluoro-2-(1H-indol-3-yl)propanoate
(4)
The mixture of indole (0.08 g, 0.65 mmol) and imine 3 (0.1 g, 0.65
mmol) in Et2O (2 mL) was left at r.t. for 10 h. The solvent was evap-
orated under vacuum and the residue was triturated (hexane); yield:
0.16 g (90%).
MeOOC
N
iii
O
3
v
H
9
N
COOMe
iv
F3C
O
S
CF3
N
F3C
MeOOC
MeOOC
S
N
6
C6H4Cl-p
Physicochemical constants of compound 4 are in agreement with
H
N
the literature data.5
8
H
O
7
Methyl 4-Oxo-2-(trifluoromethyl)thiazolidine-2-carboxylate
(5) and Methyl 4-Oxo-2-(trifluoromethyl)-1,3-thiazinane-2-car-
boxylate (6); General Procedure
Mercaptoacetic acid or 3-mercaptopropionic acid (1 mmol) was
added to a stirred soln of the imine 3 (1 mmol) in Et2O (2 mL). After
reacting at r.t. for 8 h the solvent was evaporated under vacuum and
the residue was triturated (hexane) to give compounds 5 or 6.
Scheme 2 Reagents and conditions: (i) indole, Et2O, r.t., 90%; (ii)
HSCH2CO2H, Et2O, r.t., 92%; (iii) HS(CH2)2CO2H, Et2O, r.t., 92%;
(iv) thiosalicylic acid, THF, r.t., 95%; (v) 4-ClC6H4C(Cl)=NOH,
Et3N, Et2O, –30 °C to r.t., 90%; (vi) salicylaldehyde, p-TsOH, ben-
zene, 80 °C, 60%; (vii) CF3C(O)CO2Me, r.t, 100%.
In summary, a simple and efficient synthesis of methyl a-
iminotrifluoropropionate has been developed and its syn-
thetic potential for the preparation of functionalized
Thiazolidine-2-carboxylate 5
White solid; yield: 0.21 g (92%); mp 133–134 °C.
IR (KBr): 1730, 1775 (C=O), 3200 cm–1 (NH).
acyclic and heterocyclic derivatives possessing
a
1H NMR (300 MHz, CDCl3): d = 3.56 (d, JHAHB = 15.3 Hz, 1 H),
2
pharmacophoric trifluoroalanine fragment has been
demonstrated.
2
3.80 (d, JHBHA = 15.3 Hz, 1 H) (SCHAHB), 3.93 (s, 3 H, CH3O),
7.32 (br s, 1 H, NH).
19F NMR (188 MHz, CDCl3): d = –77.9.
IR spectra were obtained with an UR-20 instrument. NMR spectra
were recorded on Varian VXR-300 spectrometer (operating fre-
quency 299.95 MHz), 19F and 31P NMR spectra on a Gemini 200
Varian instrument operating at 188.14 and 80.95 MHz, respective-
ly. 13C NMR spectra were obtained on Bruker Avance DRX 500
spectrometer operating at 125.76 MHz. Chemical shifts are reported
relative to internal TMS (1H, 13C) or CFCl3 (19F) standards. Melting
points are uncorrected. Solvents were dried before use according to
Anal. Calcd for C6H6F3NO3S: C, 31.45; H, 2.64; S, 13.99. Found:
C, 31.38; H, 2.62; S, 13.94.
Methyl 4-Oxo-2-(trifluoromethyl)-1,3-thiazinane-2-carboxy-
late (6)
White solid; yield: 0.22 g (92%); mp 83–84 °C.
IR (KBr): 1680, 1760 (C=O), 3200 cm–1 (NH).
Synthesis 2011, No. 21, 3426–3428 © Thieme Stuttgart · New York

3428
Y. V. Rassukana
PRACTICAL SYNTHETIC PROCEDURES
IR (KBr): 1650 (C=N), 1770 cm–1 (C=O).
1H NMR (300 MHz, CDCl3): d = 3.85 (s, 3 H, CH3O), 6.99 (d,
3JHH = 8.4 Hz, 1 H, Ar), 7.05 (t, 3JHH = 8.4 Hz, 1 H, Ar), 7.26 (d,
3JHH = 8.4 Hz, 1 H, Ar), 7.45 (t, 3JHH = 8.4 Hz, 1 H, Ar), 8.35 (s, 1
H, CH=N).
1H NMR (300 MHz, CDCl3): d = 2.67–2.88 (m, 3 H), 3.21–3.30 (m,
1 H) (SCH2CH2), 3.93 (s, 3 H, CH3O), 7.34 (br s, 1 H, NH).
19F NMR (188 MHz, CDCl3): d = –76.0.
Anal. Calcd for C7H8F3NO3S: C, 34.57; H, 3.32; S, 13.18. Found:
C, 34.62; H, 3.28; S, 13.21.
19F NMR (188 MHz, CDCl3): d = –79.5.
Methyl 4-Oxo-2-(trifluoromethyl)-3,4-dihydro-2H-1,3-benzo-
thiazine-2-carboxylate (7)
Thiosalicylic acid (0.23 g, 1.5 mmol) was added to a stirred soln of
the imine 3 (0.23 g, 1.5 mmol) in THF (2 mL) and was allowed to
react overnight. The solvent was evaporated under vacuum and the
residue was crystallized (Et2O, 3 mL) to give a white solid; yield:
0.41 g (95%); mp 138–139 °C.
Anal. Calcd for C11H8F3NO3: C, 50.98; H, 3.11; N, 5.40. Found: C,
51.09; H, 3.12; N, 5.32.
Methyl 3,3,3-Trifluoro-2-hydroxy-2-[(1,1,1-trifluoro-3-meth-
oxy-3-oxopropan-2-ylidene)amino]propanoate (10)
The mixture of imine 3 (0.27 g, 1.75 mmol) and methyl trifluoropy-
ruvate (1, 0.27 g, 1.75 mmol) was left at r.t. for 12 h to produce oily
adduct 10; yield: 0.54 g (100%).
IR (KBr): 1695, 1780 (C=O), 3200 cm–1 (NH).
1H NMR (300 MHz, CDCl3): d = 4.02 (s, 3 H, CH3O), 7.00 (br s, 1
H, NH), 7.29 (d, 3JHH = 8.4 Hz, 1 H, Ar), 7.34 (t, 3JHH = 8.4 Hz, 1 H,
Ar), 7.48 (t, 3JHH = 8.4 Hz, 1 H, Ar), 8.17 (d, 3JHH = 8.4 Hz, 1 H, Ar).
19F NMR (188 MHz, CDCl3): d = –77.0.
IR (film): 1730, 1760, 1780 (C=N, C=O), 3350 cm–1 (OH).
1H NMR (300 MHz, CDCl3): d = 3.95 (s, 3 H, CH3O), 3.98 (s, 3 H,
CH3O), 4.60 (br s, 1 H, OH).
19F NMR (188 MHz, CDCl3): d = –72.1 (CF3C=N), –79.6
(CF3COH).
Anal. Calcd for C11H8F3NO3S: C, 45.36; H, 2.77; S, 11.01. Found:
C, 45.42; H, 2.81; S, 10.98.
Anal. Calcd for C8H7F6NO5: C, 30.88; H, 2.27; N, 4.50. Found: C,
30.74; H, 2.31; N, 4.48.
Methyl 3-(4-Chlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-
1,2,4-oxadiazole-5-carboxylate (8)
4-Chloro-N-hydroxybenzenecarboximidoyl chloride (0.3 g, 1.7
mmol) was added to a stirred soln of imine 3 (0.22 g, 1.4 mmol) and
Et3N (1.17 g, 0.24 mL, 1.7 mmol) in Et2O (5 mL) at –30 °C and was
allowed to warm to r.t. After reacting at r.t. for 3 h the precipitated
solid was filtered off. The solvent was evaporated under vacuum
and the residue was crystallized (heptane) to give white crystals;
yield: 0.39 g (90%); mp 97–98 °C.
References
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Pirozhenko, V. V.; Onys’ko, P. P. Synthesis 2007, 2627.
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IR (KBr): 1610 (C=N), 1760 (C=O), 3160 cm–1 (NH).
1H NMR (300 MHz, CDCl3): d = 3.95 (s, 3 H, MeO), 6.18 (br s, 1
H, NH), 7.43 (d, 3JHH = 8.4 Hz, 2 H, Ar), 7.67 (d, 3JHH = 8.4 Hz, 2
H, Ar).
19F NMR (188 MHz, CDCl3): d = –82.4.
Anal. Calcd for C11H8ClF3N2O3: C, 42.81; H, 2.61; Cl, 11.49; N,
9.08. Found: C, 42.79; H, 2.64; Cl, 11.54; N, 9.02.
Methyl 2-(Trifluoromethyl)-2H-1,3-benzoxazine-2-carboxylate
(9)
A mixture of imine 3 (0.2 g, 1.3 mmol) and salicylaldehyde (0.16 g,
1.3 mmol) was left at r.t. for 10 h, and then p-TsOH·H2O (10 mg,
0.05 mmol) was added; the mixture was heated in benzene (5 mL)
under reflux for 2 h. The solvent was evaporated under vacuum and
the residue was triturated (hexane) to give a yellow oil; yield: 0.2 g
(60%).
Synthesis 2011, No. 21, 3426–3428 © Thieme Stuttgart · New York