Synthesis of derivatives of 4-amino-2-trifluoromethylnicotinic acid

Article abstract of DOI:10.1007/s11172-005-0120-z

The method for the synthesis of ethyl 4-R-amino-2- trifluoromethylnicotinates from a diphenylboron complex of ethyl 2-acetyl-3-amino-4,4,4-trifluorobut-2-enoate was developed.

Full text of DOI:10.1007/s11172-005-0120-z

Russian Chemical Bulletin, International Edition, Vol. 53, No. 10, pp. 2319—2321, October, 2004
2319
Synthesis of derivatives of 4ꢀaminoꢀ2ꢀtrifluoromethylnicotinic acid
L. S. Vasil´ev, F. E. Surzhikov, and V. A. Dorokhovꢀ
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5328. Eꢀmail: vador@ioc.ac.ru
The method for the synthesis of ethyl 4ꢀRꢀaminoꢀ2ꢀtrifluoromethylnicotinates from a
diphenylboron complex of ethyl 2ꢀacetylꢀ3ꢀaminoꢀ4,4,4ꢀtrifluorobutꢀ2ꢀenoate was developed.
Key words: diphenylboron chelates, ethyl 4ꢀRꢀaminoꢀ2ꢀtrifluoromethylnicotinates, 3ꢀbenꢀ
zylꢀ5ꢀtrifluoromethylpyrido[4,3ꢀd]pyrimidinꢀ4(3H )ꢀone, dimethylformamide dimethyl acetal.
Derivatives of 2ꢀ and 4ꢀaminonicotinic acids attract
attention not only as potential biologically active subꢀ
stances and medicines,1—5 but also as convenient starting
reagents for construction of nitrogenꢀcontaining bicyclic
systems.6—9 However, the number of papers devoted to
2ꢀaminonicotinic acid and its esters is significantly
higher than that concerned with their less accessible
4ꢀamino isomers (ethyl 4ꢀaminonicotinate is usually synꢀ
thesized in five steps from 3ꢀmethylꢀ4ꢀnitropyridine
1ꢀoxide8—9).
Recently,10 we proposed a comparatively simple route
to ethyl 4ꢀaminoꢀ2,6ꢀdiarylnicotinates starting from nickel
chelates and aroylacetonitriles. The goal of the present
work was to obtain 4ꢀaminonicotinic acid derivatives conꢀ
taining a trifluoromethyl substituent in the pyridine ring,
because such reagents are of interest for use in the syntheꢀ
sis of fused heterocycles with a potential biological acꢀ
tivity.
Earlier, we found11 that diphenylboron chelate 2 easꢀ
ily prepared from ethyl 2ꢀacetylꢀ3ꢀaminoꢀ4,4,4ꢀtrifluoroꢀ
butꢀ2ꢀenoate (1) reacts under mild conditions with
dimethylformamide dimethyl acetal (DMF DMA) to give
condensation product 3, which can be converted through
alcoholysis into ethyl 4ꢀhydroxyꢀ2ꢀtrifluoromethylnicoꢀ
tinate (4). It was also noted that heating of chelate 2 with
benzylamine yields βꢀdiiminate complex 5a (Scheme 1).
In continuation of those studies, chelates 5b,c were
obtained by reactions of compound 2 with nꢀbutylamine
and 2ꢀfurfurylamine in boiling benzene (a slight excess of
the primary amine was used). An analogous reaction with
a solution of ammonia in toluene in a sealed tube at
120 °C afforded complex 5d in 84% yield.
Scheme 1
R = Bn (a), Bu (b),
(c), H (d)
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 2221—2223, October, 2004.
1066ꢀ5285/04/5310ꢀ2319 © 2004 Springer Science+Business Media, Inc.

2320
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 10, October, 2004
Vasil´ev et al.
Scheme 2
Diphenylboron chelates 5a—d reacted with DMF
DMA in boiling toluene to give the corresponding comꢀ
plexes 6a—d. Without isolation, they were heated with
ethanol in a sealed tube at 120 °C to form, via the opening
of the boronꢀcontaining ring, ethyl 4ꢀRꢀaminoꢀ2ꢀtrifluoroꢀ
methylpyridineꢀ3ꢀcarboxylates 7a—d in 37—60% yields.
The esters obtained are crystalline compounds, which are
well soluble in chloroform, benzene, and ether and poorly
soluble in hexane. Their mass spectra contain molecular
ion peaks and their 1H NMR spectra in CDCl3 show douꢀ
blet signals at δ 6.65—6.78 for the H(5) proton and at
δ 8.26—8.32 for the H(6) proton of the pyridine ring. The
IR spectrum of pyridine derivative 7d contains absorption
bands at 3500, 3390 (NH2), and 1710 cm–1 (C=O).
Ester 7d was used to construct a bicyclic system. When
heated with benzylamine, it yielded amide 8 which,
through refluxing with DMF DMA, afforded 3ꢀbenzylꢀ5ꢀ
trifluoromethylpyrido[4,3ꢀd]pyrimidinꢀ4(3H )ꢀone (9).
The mass spectrum of compound 9 contains a moꢀ
lecular ion peak with [305]+. Its IR spectrum shows an
absorption band at 1688 cm–1 (C=O). Structure 9 was
also confirmed by 1H NMR data.
Table 1. Yields, physicochemical properties, and 1H NMR data for compounds 5, 7, 8, and 9
Comꢀ
pound
Yield
(%)
M.p.
/°C
Found
Calculated
Molecular
formula
1H NMR (CDCl3)
(%)
N
δ, J/Hz
C
H
5b
5c
86
79
69—70 65.14 6.50 6.20
64.86 6.30 6.30
C24H28BF3N2O2
0.57 (t, 3 Н, Ме); 0.80—1.10 (m, 4 Н, 2 СН2);
1.26 (t, 3 Н, Ме, J = 6.9); 2.53 (s, 3 Н, Ме);
3.32 (t, 2 Н, CH2N, J = 6.5); 4.15 (q, 2 Н,
СН2О, J = 6.9); 6.48 (br.s, 1 Н, NH); 7.20—7.40
(m, 10 Н, 2 Ph)
1.27 (t, 3 Н, Ме, J = 6.9); 2.68 (s, 3 Н, Ме);
4.15 (q, 2 Н, СН2О, J = 6.9); 4.60 (s, 2 Н, CH2N);
5.27 (d, 1 Н, Н(3), J = 3.5); 6.10 (dd, 1 Н, Н(4),
J = 1.6, J = 3.5); 6.62 (br.s, 1 Н, NH); 7.15—7.10
(m, 11 Н, 2 Ph+Н(5))
91—92 64.11 5.16 6.06
64.10 5.13 5.98
C25H24BF3N2O3
5d
7a
83.5 170—171 61.62 5.09 7.27
61.85 5.19 7.21
C20H20BF3N2O2
C16H15F3N2O2
1.30 (t, 3 Н, Ме, J = 6.9); 2.51 (s, 3 Н, Ме);
4.18 (q, 2 Н, СН2О, J = 6.9); 6.80 (br.s, 1 Н, NH);
6.86 (br.s, 1 Н, NH); 7.21—7.53 (m, 10 Н, 2 Ph)
1.39 (t, 3 Н, Ме, J = 6.8); 4.39 (q, 2 Н, СН2О,
J = 6.8); 4.40 (d, 2 Н, CH2N, J = 5.5); 6.63 (d, 1 Н,
H(5), J = 6.1); 7.00 (br.s, 1 Н, NH); 7.25—7.50
(m, 5 Н, Ph); 8.26 (d, 1 Н, H(6), J = 6.1)
0.98 (t, 3 Н, Ме, J = 6.9); 1.30—1.50 (m, 4 Н,
2 СН2); 1.65 (t, 3 Н, Ме, J = 6.9); 3.20 (t, 2 Н,
CH2N, J = 6.5); 4.38 (q, 2 Н, СН2О, J = 6.9);
6.50 (br.s, 1 Н, NH); 6.65 (d, 1 Н, Н(5), J = 6.1);
8.28 (d, 1 Н, H(6), J = 6.1)
1.39 (t, 3 Н, Ме, J = 6.8); 4.37 (q, 2 Н, СН2О,
J = 6.8); 4.42 (d, 2 Н, CH2N, J = 6.0); 6.28 (d, 1 Н,
H(3´), J = 3.5); 6.35 (dd, 1 Н, H(4´), J = 1.6,
J = 3.5); 6.78 (d, 1 Н, H(5), J = 6.1); 6.90 (br.s, 1 Н,
NH); 7.40 (d, 1 Н, H(5´), J = 1.6); 8.32 (d, 1 Н,
H(6), J = 6.1)
40
76—77 59.32 5.15 8.46
59.26 4.83 8.69
7b
7c
40
19—20 54.01 6.03 9.33
53.79 5.86 9.65
C13H17F3N2O2
37
70—71 53.61 4.39 8.97
53.50 4.14 8.92
C14H13F3N2O3
(to be continued)

Synthesis of new nicotinic acid derivatives
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 10, October, 2004
2321
Table 1 (continued)
Comꢀ
pound
Yield
(%)
M.p.
/°C
Found
Calculated
Molecular
formula
1H NMR (CDCl3)
(%)
N
δ, J/Hz
C
H
7d
8
60
68
60
82—83 46.16 4.04 11.90 C9H9F3N2O2
46.15 3.84 11.96
1.38 (t, 3 Н, Ме, J = 6.9); 4.38 (q, 2 Н, СН2О,
J = 6.9); 5.58 (br.s, 2 Н, NH2); 6.69 (d, 1 Н, Н(5),
J = 6.0); 8.21 (d, 1 Н, Н(6), J = 6.0)
4.45 (d, 2 Н, CH2N, J = 6.0); 6.20 (br.s, 2 Н, NH2);
6.80 (d, 1 Н, Н(5), J = 5.9); 7.18—7.50 (m, 5 Н, Ph);
8.10 (d, 1 Н, Н(6), J = 5.9); 8.95 (t, 1 Н, NH, J = 5.0)
5.23 (s, 2 Н, CH2); 7.35—7.45 (m, 5 Н, Ph);
7.75 (d, 1 Н, Н(7), J = 5.5); 8.29 (s, 1 H, H(2);
8.88 (t, 1 Н, H(8), J = 5.5)
180—181 56.88 4.26 14.22 C14H12F3N3O
56.94 4.06 14.23
9
131—132 58.90 3.26 13.47 C15H10F3N3O
59.01 3.27 13.77
DMA (0.1 mL, 0.8 mmol) in 5 mL of xylene was refluxed for 5 h
and concentrated in vacuo. The residue was eluted with benzene
through a thin layer of SiO2 to give compound 9 (0.075 g).
Experimental
1
H NMR spectra were recorded on a Bruker WMꢀ250 specꢀ
trometer (250.13 MHz). IR spectra were recorded on a Perkinꢀ
Elmer 577 instrument. Mass spectra were recorded on a Varian
MATꢀ311A instrument.
References
Diphenylboron complexes 2 and 5a were prepared as deꢀ
scribed by us earlier.11
The yields and physicochemical and spectral characteristics
of all the compounds obtained are given in Table 1.
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Diphenylboron complexes of ethyl 2ꢀ(1ꢀalkyliminoethyl)ꢀ3ꢀ
aminoꢀ4,4,4ꢀtrifluorobutꢀ2ꢀenoates 5b,c. A mixture of chelate 2
(1.0 g, 2.5 mmol) and an amine (3.5 mmol) in 15 mL of benzene
was refluxed for 3 h and concentrated in vacuo. Crystallization
of the residue from hexane gave chelates 5b,c.
Diphenylboron complex of ethyl 3ꢀaminoꢀ4,4,4ꢀtrifluoroꢀ2ꢀ
(1ꢀiminoethyl)butꢀ2ꢀenoate (5d). A mixture of chelate 2 (3.0 g,
7.7 mmol) and 0.2 M NH3 (62 mL, 12 mmol) in toluene was
heated in a sealed tube at 120 to 140 °C for 15 h. The reaction
mixture was concentrated in vacuo. Recrystallization of the resiꢀ
due from hexane gave chelate 5d (2.5 g).
Ethyl 4ꢀRꢀaminoꢀ2ꢀtrifluoromethylnicotinates 7a—d (general
procedure). A mixture of complex 5a—d (2.6 mmol) and DMF
DMA (0.4 mL, 3.1 mmol) in 15 mL of toluene was refluxed for
10 h (monitoring by TLC) and concentrated in vacuo. Ethanol
(20 mL) and xylene (10 mL) were added. The resulting mixture
was heated in a sealed tube at 115 to 120 °C for 5 h and then
concentrated in vacuo. The residue was chromatographed on
SiO2 with benzene as an eluent to give nicotinates 7a—d.
NꢀBenzylꢀ4ꢀaminoꢀ2ꢀtrifluoromethylpyridineꢀ3ꢀcarboxamide
(8). Compound 7d (0.2 g, 0.85 mmol) was refluxed in 2 mL of
benzylamine for 5 h, cooled to 20 °C, and diluted with hexane
(3 mL). The oil that formed was separated and benzene (3 mL)
was added. The crystals that formed were filtered off and
washed with benzene (10 mL) and hexane (10 mL) to give
amide 8 (0.17 g).
3ꢀBenzylꢀ5ꢀtrifluoromethylpyrido[4,3ꢀd]pyrimidinꢀ4(3H )ꢀ
one (9). A mixture of amide 8 (0.12 g, 0.4 mmol) and DMF
Received June 1, 2004;
in revised form July 9, 2004