Trifluoromethyl-substituted 1,6-naphthyridines and pyrido[4,3-d]pyrimidines

Article abstract of DOI:10.1007/s11172-013-0173-3

A convenient method for the synthesis of 1-alkyl-5-trifluoromethyl-1,6- naphthyridin-4(1H)-ones was elaborated based on the reaction of 4-alkylamino-3-trifluoroacetimidoyl-3-penten-2-one diphenylboron chelates with dimethylformamide dimethyl acetal. 3-Acetyl-4-amino-2-trifluoromethylpyridine was used to obtain 5-trifluoromethyl-1,6-naphthyridin-4(1H)-one and its 2-methoxycarbonyl derivative, as well as 4-methyl-5-trifluoromethylpyrido-[4,3- d]pyrimidine.

Full text of DOI:10.1007/s11172-013-0173-3

Russian Chemical Bulletin, International Edition, Vol. 62, No. 5, pp. 1255—1261, May, 2013
1255
Trifluoromethylꢀsubstituted 1,6ꢀnaphthyridines and pyrido[4,3ꢀd]pyrimidines
L. S. Vasil´ev, F. E. Surzhikov, S. V. Baranin, and V. A. Dorokhov†
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: svbar@ioc.ac.ru
A convenient method for the synthesis of 1ꢀalkylꢀ5ꢀtrifluoromethylꢀ1,6ꢀnaphthyridinꢀ
4(1H)ꢀones was elaborated based on the reaction of 4ꢀalkylaminoꢀ3ꢀtrifluoroacetimidoylꢀ3ꢀ
pentenꢀ2ꢀone diphenylboron chelates with dimethylformamide dimethyl acetal. 3ꢀAcetylꢀ4ꢀ
aminoꢀ2ꢀtrifluoromethylpyridine was used to obtain 5ꢀtrifluoromethylꢀ1,6ꢀnaphthyridinꢀ4(1H)ꢀ
one and its 2ꢀmethoxycarbonyl derivative, as well as 4ꢀmethylꢀ5ꢀtrifluoromethylpyridoꢀ
[4,3ꢀd]pyrimidine.
Key words: 1ꢀalkylꢀ5ꢀtrifluoromethylꢀ1,6ꢀnaphthyridinꢀ4(1H)ꢀone, 5ꢀtrifluoromethylꢀ1,6ꢀ
naphthyridinꢀ4(1H)ꢀone, dimethylformamide dimethyl acetal, ethyl orthoformate, dimethyl
oxalate, 2ꢀmethoxycarbonylꢀ5ꢀtrifluoromethylꢀ1,6ꢀnaphthyridinꢀ4(1H)ꢀone, 4ꢀmethylꢀ5ꢀtriꢀ
fluoromethylpyrido[4,3ꢀd]pyrimidine.
In the last years, 1,6ꢀnaphthyridine and pyrido[4,3ꢀd]ꢀ
pyrimidine derivatives attract much attention of researchꢀ
es, because these compounds were found to possess a wide
range of biological activity (see Refs 1 and 2 and referencꢀ
es cited therein). At the same time, the interest to organoꢀ
fluorine compound have sharply grown, especially, beꢀ
cause of their use in medicine and agrochemistry. Thus, if
in 1970 only 2% of new produced drugs contained fluorine
atoms, in 2002 this index increased to 18% worldwide,
and to 29% in the USA (see Ref. 3). In this connection,
the interest to 1,6ꢀnaphthyridines and pyrido[4,3ꢀd]ꢀ
pyrimidines is explainable, in particular, to those containꢀ
ing a CF3 group directly bonded to the heterocycle, which
were not described in the literature before our works.
In the present work, we suggest a method for the synꢀ
thesis of these compounds with the use of available boron
diiminates.
Recently, we have found4 that the reaction of 3ꢀacetylꢀ
4ꢀaminoꢀ5,5,5ꢀtrifluoroꢀ3ꢀpentenꢀ2ꢀone diphenylboron
chelate (1) with ammonia or primary amines led to
4ꢀaminoꢀ or 4ꢀalkylaminoꢀ3ꢀtrifluoroacetimidoylꢀ3ꢀpentꢀ
enꢀ2ꢀones (2), which under the reaction conditions were
converted to boron diiminates (3) (Scheme 1, Table 1). This
process is slow at room temperature and considerably accelꢀ
erates upon reflux in benzene. For the reaction of 1 with
ammonia, MeNH2, and EtNH2 to proceed, solutions of
the corresponding amine in THF should be used and the
reaction of mixture should be kept at ~20 C for ~24 h.
The complexation activated (with respect to amines)
not only the carbonyl group of the chelate ring, but also
the free acetyl group, which resulted in the formation of
compound 4 as the side product. The reaction of complex
1 with PrNH2 was studied in detail as a model example. It
was shown that when the ratio 1 : PrNH2 = 1 : 1.5,* the
Scheme 1
R = H (a), Me (b), Et (c), Pr (d), All (e), MeO(CH2)3 (f), 4ꢀFC6H4CH2 (g),
(h),
(i)
†
Deceased.
* When the ratio was 1 : 1, the starting compound 1 was not completely usedꢀup and was difficult to separate from the reaction
products.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 1255—1261, May, 2013.
1066ꢀ5285/13/6205ꢀ1255 © 2013 Springer Science+Business Media, Inc.

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Vasil´ev et al.
Table 1. Yields, melting points, elemental analysis and 1H NMR spectroscopic data for compounds 3a—i, 4, and 10
Comꢀ Yield M.p./C
pound (%)
Found
Calculated
Molecular
formula
1H NMR (CDCl3, , J/Hz)
(%)
С
Н
N
3а
3b
3c
65
81
74
184—185 64.01
63.68
113—114 64.35
64.54
142—143 65.24
65.30
5.34 7.91 С19Н18BF3N2O
5.06 7.81
5.57 7.38 С20Н20BF3N2O
5.42 7.52
5.46 7.31 С21Н22BF3N2O
5.74 7.25
2.28 (s, 3 H, MeCO); 2.36 (s, 3 H, MeCN);
6.51, 6.88 (2 H, 2 NH); 7.22—7.42 (m, 10 H, 2 Ph)
2.25 (s, 3 H, MeCO); 2.30 (s, 3 H, MeCN); 2.97 (s, 3 H,
MeN); 6.07 (s, 1 H, NH); 7.29—7.38 (m, 10 H, 2 Ph)
0.78 (t, 3 H, MeCH2, J = 7.0); 2.18 (s, 3 H, MeCO);
2.38 (s, 3 H, MeCN); 3.42 (q, 2 H, СН2N, J = 7.0);
6.20 (s, 1 H, NH); 7.08—7.62 (m, 10 H, 2 Ph)
0.50 (t, 3 H, MeCH2, J = 7.0); 1.05—1.20 (m, 2 Н,
MeCH2); 2.20 (s, 3 H, MeCO); 2.36 (s, 3 H, MeCN);
3.25 (t, 2 H, СН2N, J = 6.5); 6.20 (s, 1 H, NH);
7.18—7.48 (m, 10 H, 2 Ph)
3d
3е
3f
70
63
76
144—145 66.12
66.01
6.28 6.98 С22Н24BF3N2O
6.04 7.00
137—138 66.33
66.33
5.74 7.20 С22Н22BF3N2O
5.52 7.03
2.20 (s, 3 H, MeCO); 2.34 (s, 3 H, MeCN); 4.06 (d, 2 H,
СН2N, J = 6.0); 4.87 (d, 1 Н, СН2=СН, J = 17.0);
5.01 (d, 1 Н, СН2=СН, J = 10.0); 5.25 (m, 1 Н, СН2=СН);
6.27 (s, 1 H, NH); 7.27—7.35 (m, 10 H, 2 Ph)
85—86
64.01
64.20
6.12 6.63 С23Н26BF3N2O2 1.28 (m, 2 H, CH2); 2.21 (s, 3 H, MeCO); 2.38 (s, 3 H,
6.09 6.51
MeCN); 2.92 (t, 2 Н, СН2О, J = 6.0); 3.12 (s, 3 Н,
МеОСН2); 3.45 (t, 3 H, СН2N, J = 6.0); 6.21 (s, 1 H,
NH); 7.20—7.40 (m, 10 H, 2 Ph)
3g
3h
80
82
128—129 68.17
68.44
5.12 6.08 С26Н23BF4N2O
5.08 6.14
2.18 (s, 3 H, MeCO); 2.22 (s, 3 H, MeCN); 4.70 (s, 2 H,
СН2N); 6.41 (s, 1 H, NH); 6.70 (m, 2 Н, С6Н4);
6.85 (t, 2 Н, С6Н4, J = 7.5)
135—137 65.69
65.77
5.30 6.38 С24Н22BF3N2O2 2.17 (s, 3 H, MeCO); 2.52 (s, 3 H, MeCN); 4.55 (s, 2 H,
5.06 6.39
СН2N); 5.36 (d, 1 Н, Н(3´), J = 6.0); 6.14 (t, 1 Н, Н(4´),
J = 6.0, J = 2.0); 6.36 (s, 1 H, NH); 7.21—7.27 (m, 11 H,
2 Ph + Н(5´))
3i
4
86
119—121 63.62
63.46
4.92 6.12 С24Н22BF3N2OS 2.16 (s, 3 H, MeCO); 2.38 (s, 3 H, MeCN); 4.83 (s, 2 H,
4.88 6.17
СН2N); 6.40 (d, 1 Н, Н(3´), J = 3.0); 6.44 (s, 1 H, NH);
6.79 (t, 1 Н, Н(4´); J = 6.0, J = 3.0); 7.10 (d, 1 Н, Н(5´),
J = 6.0); 7.24—7.28 (m, 10 H, 2 Ph)
112—113 68.06
68.03
7.37 9.53 С25Н31BF3N3
7.08 9.52
0.48, 1.02 (both t, 2 Н, 2 МеСН2, J = 7.0, Еꢀisomer)*;
0.52, 1.06 (both t, 2 Н, 2 МеСН2, J = 7.0, Zꢀisomer);
1.05—1.80 (m, 4 Н, 2 СН2, E+Zꢀisomers); 1.88, 2.20
(both s, 2 Н, 2 Ме, Еꢀisomer); 2.14, 2.24 (both s, 4 Н, 2 Ме,
Zꢀisomer); 2.85—3.34 (m, 4 Н, 2 СН2N, E+Zꢀisomers);
5.75 (br.s, 0.33 Н, NH, Еꢀisomer); 5.85 (br.s, 0.67 Н,
NH, Zꢀisomer); 7.24—7.42 (m, 10 H, 2 Ph)
10
43
214—215 65.07
65.24
5.28 9.87 С23Н21BF3N3O
5.00 9.92
3.27 (br.s, 6 Н, Me2N)**; 6.03 (d, 1 Н, С(4)Н, J = 9.5);
7.12—7.28 (m, 10 Н, 2 Ph); 7.50 (d, 1 H, C(5)H, J = 9.5);
7.80 (s, 1 H, C(3)=NH); 8.20 (s, 1 H, Me2NCH=);
9.46 (s, 1 H, C(10)NH)
* The spectrum was recorded on a Bruker Avance 600 spectrometer.
** The spectrum was recorded in DMSOꢀd6.
yield of 3 and chelate 4 (R = Pr) was 72% and 18%,
respectively. For the ratio complex 1 : PrNH2 = 1 : 5.3,
the yield of diiminate 3d decreased to 34%, whereas the
yield of 4 increased to 61%. In other cases, the side prodꢀ
ucts similar to compound 4 were also isolated, however,
they were not studied.
Boron diiminates 3a—i and 4 are yellow crystalline
compounds, well soluble in acetone, ethanol, CHCl3, and
DMSO, have limited solubility in benzene, and poorly
soluble in light petroleum. In the mass spectra,
strong peaks of the [M – Ph]+ ions are observed. The
structure of compounds 3a—i and 4 was also confirmed
by elemental analysis and NMR spectroscopy. In the
1H NMR spectrum of compound 4, a double set of sigꢀ
nals is observed, that indicates the presence of Eꢀ and
Zꢀisomers.
Besides, a possibility of the formation of an alternative
structure 5 was not excluded either (a similar structure

1,6ꢀNaphtyridines and pyrido[4,3ꢀd]pyrimidines
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 5, May, 2013
1257
nol to the side of the formation of ligand 8, that finally
leads to naphthyridinones 6.
The structure of naphthyridinones 6c—i was confirmed
by elemental analysis and spectroscopic data, which are
given in Table 2.
Quite unexpected pattern was observed in the reaction
of compound 3a with two equivalents of DMF DMA.
Instead of expected naphthyridine 6a, a resinꢀlike subꢀ
stance was obtained, which after multiple column chroꢀ
matography on SiO2 yielded boron chelate 10. Such
a different behavior of complex 3a and chelates 3c—i can
be probably explained by the smaller steric hindrance and,
hence, the higher stability of the intermediately formed
chelate 7 to methanolysis, which causes the cyclization
with elimination of Me2NH to follow an alternative
scheme (Scheme 3).
The 1H NMR spectrum of compound 10 in DMSOꢀd6
exhibited signals for the protons of the Me2N group
( 3.27), two doublets for the protons of the CH= fragꢀ
ment ( 6.03 and 7.50), two signals for the protons of the
NH groups ( 7.80 and 9.46), a singlet for the proton of
the N—CH= fragment ( 8.20), as well as signals for the
protons of two Ph groups. The structure of compound 10
was established using 2D COSY and ROESY spectra. The
ROESY spectrum exhibited the following correlation
peaks: MeN/H(11), MeN/H(5), and H(4)/NH(7), that
unambiguously confirmed the formation of structure 10,
rather than 11. The mass spectrum of compound 10 exꢀ
hibited a peak of the ion [M – Ph]+ (364) characteristic of
diphenylboron chelates. A signal at  –2.1 observed in the
11B NMR spectrum of this compound indicates the presꢀ
ence of a fourꢀcoordinated boron atom.
was initially obtained when 3ꢀacetylꢀ4ꢀaminoꢀ5,5,5ꢀ
trichloroꢀ3ꢀpentenꢀ2ꢀone was treated with Ph2BOBu5).
In this case, the 2D 1H/15N HMBC NMR spectrum
should exhibit a correlation of the signal for the NH proton
with the lowꢀfield signal for the nitrogen atom. However,
a correlation of the signal for the proton of the NH group
with the signal for the highꢀfield nitrogen atom is actually
observed in the spectra of both isomers, that confirms the
formation of the structure 4. The 19F NMR spectrum of
compound 4 also exhibits two signals (the signal of Zꢀ
isomer is observed more upfield), with the ratio Zꢀ and Eꢀisoꢀ
mers in CDCl3 being 2 : 1, whereas in DMSOꢀd6 it is 4 : 1.
Diiminates 3c—i in refluxing toluene or xylene react
with two equivalents of dimethylformamide dimethyl aceꢀ
tal (DMF DMA) with the formation of 5ꢀtrifluoromethꢀ
ylꢀ1,6ꢀnaphthyridineꢀ4(1H)ꢀones (6) in 40—87% yields
(see preliminary communication6). The following scheme
can be suggested for the process: initially DMF DMA
undergoes condensation at the two methyl groups with the
formation of chelate 7 (Scheme 2), which reacts with
methanol liberated in the process (apparently, this reacꢀ
tion is reversible) with the formation of ligand 8, isomerizꢀ
ing to 9. The latter cyclizes to 1,6ꢀnaphthyridinone 6, thus
shifting the equilibrium reaction of chelate 7 with methaꢀ
This approach failed to yield compound 6a, therefore,
we used an alternative method for its synthesis. Earlier,7
based on chelate 3a we obtained 3ꢀacetylꢀ4ꢀaminoꢀ2ꢀtriꢀ
fluoromethylpyridine (12), which was treated with DMF
DMA to afford amidine 13. The latter reacted with
MeONa to be converted to 6a according to the procedure
described earlier.8,9 (Scheme 4).
Scheme 2

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Russ.Chem.Bull., Int.Ed., Vol. 62, No. 5, May, 2013
Vasil´ev et al.
Scheme 3
Scheme 5
solution of NH3 to obtain 5ꢀmethylꢀ4ꢀtrifluoromethylpyridoꢀ
[4,3ꢀd]pyrimidine. We expected that this approach would
be a convenient method for the synthesis of 4ꢀmethylꢀ5ꢀ
trifluoromethylpyrido[4,3ꢀd]pyrimidine (16) from amidine
13. However, it appeared that the yield of compound 16 was
only 21% after heating of 13 with the methanolic solution
of NH3 in a sealed tube. This reaction gave naphthyridiꢀ
none 6a as the major product. It is obvious, that in this
case ammonia played the role of a base, too (Scheme 6).
Scheme 4
Scheme 6
An alternative approach to the synthesis of pyridoꢀ
pyrimidine 16 has proved more successful. The reaction of
pyridine 12 with ethyl orthoformate gave imine 17, which
reacted with NH3 in methanol at room temperature to be
converted to 16 in 96% yield (Scheme 7).
The reaction of pyridine 12 with an excess of dimethyl
oxalate in the presence of MeONa in methanol (following
the method suggested in Refs. 10 and 11) led to 2ꢀmethoxyꢀ
carbonylnaphthyridinone 14. Apparently, this reaction folꢀ
lows two alternative directions, since, besides product 14,
amide 15 was also isolated. The latter under the reaction
conditions undergoes hydrolysis back to pyridine 12, which
in the large excess of dimethyl oxalate is gradually conꢀ
verted to naphthyridinone 14. And in fact, the isolated
amide 15 reacts with MeONa in methanol to give pyridine 12,
whereas in the presence of dimethyl oxalate and MeONa,
it is converted to naphthyridinone 14 (Scheme 5).
Scheme 7
The isomer of compound 16, viz., 5ꢀmethylꢀ4ꢀtrifluoꢀ
romethylpyrido[4,3ꢀd]pyrimidine, synthesized by us earꢀ
lier can add alcohols, water, and amines12,13 to give
the corresponding 1,4ꢀdihydropyrido[4,3ꢀd]pyrimidines.
However, this property is not characteristic of pyridopyriꢀ
Recently,12 we reacted 5ꢀacetylꢀ4ꢀdimethylaminoꢀ
vinylꢀ6ꢀtrifluoromethylpyrimidine with the methanolic

1,6ꢀNaphtyridines and pyrido[4,3ꢀd]pyrimidines
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 5, May, 2013
1259
Table 2. Yields, melting points, elemental analysis and 1H NMR spectroscopic data for compounds 6a,c—i and 13—18
Comꢀ Yield M.p./C
pound (%)
Found
Calculated
Molecular
formula
1H NMR (CDCl3, , J/Hz)
H(2) H(3) H(7) H(8) Other signals
(%)
N
(d, 1 Н)
С
Н
J = 8 J = 6
6a
6c
6d
72
67
76
>350
50.45
50.47
54.81
54.55
56.13
56.25
2.66 12.91 С9Н5F3N2O
2.35 13.08
3.72 11.15 С11Н9F3N2O
3.74 11.36
4.56 11.01 С12Н11F3N2O
4.32 10.93
7.98 6.20 8.61 7.71
7.51 6.39 8.70 7.48
7.50 6.36 8.68 7.74
12.0 (s, 1 Н, NH)
203—204
182—183
1.51 (t, 3 H, Me, J = 7);
4.18 (q, 2 H, CH2N, J = 7)
1.03 (t, 3 H, Me, J = 7);
1.88 (m, 2 H, CH2);
4.06 (t, 2 H, CH2N, J = 7)
4.52 (d, 2 H, CH2N, J = 7);
5.15 (d, 1 H, CH2=CH,
J = 17); 5.40 (d, 1 H, CH2=CH,
J = 10); 5.98 (m, 1 H, CH=)
2.05 (m, 2 H, CH2); 3.35 (m, 5 H,
СН2О + MeO); 4.23 (t, 2 H,
CH2N, J = 7)
6e
6f
63
69
186—187
154—155
56.60
56.69
3.59 10.81 С12Н9F3N2O
3.54 11.02
7.50 6.39 8.65 7.39
54.37
54.55
4.62 9.65 С13Н13F3N2O2 7.52 6.34 8.67 7.48
4.58 9.78
6g
6h
78
76
187—188
164—165
59.49
59.63
57.08
57.15
3.08 8.75 С16Н10F4N2O
3.13 8.69
3.11 9.47 С14Н9F3N2O2
3.08 9.52
7.58 6.40 8.58 7.32
7.59 8.66 7.62
5.27 (s, 2 H, CH2N); 7.06—7.15
(m, 4 H, C6H4F)
5.21 (s, 2 H, CH2N); 6.33—6.46
(m, 3 H, H(3), H(3´), H(4´));
7.41 (d, 1 H, H(5´), J = 2)
5.75 (s, 2 H, CH2N); 7.01
(t, 1 H, H(4´), J4´,5´ = 5,
6i
72
95
182—183
112—113
54.05
54.19
2.87 8.97 С14Н9F3N2OS 8.27 6.34 8.72 8.08
2.92 9.03
J
3´,4´ = 3); 7.22 (d, 1 H, H(3´),
J = 3); 7.50 (d, 1 H, H(5´), J = 3)
2.55 (s, 3 H, Me); 3.00, 3.08
(both s, 6 H, NMe2); 6.90 (d, 1 H,
C(5)H, J = 6); 8.39 (d, 1 H, C(6)H,
J = 6); 8.42 (s, 1 H, CH=N)
3.98 (s, 3 H, Me); 12.45 (br.s,
1 H, NH)
2.62 (s, 3 H, MeCO); 4.00 (s, 3 H,
MeO), 8.50 (d, 1 H, H(5), J = 6);
8.75 (d, 1 H, H(6), J = 6);
9.90 (s, 1 H, NH)
13
50.80
50.96
4.78 16.68 С11Н12F3N3O
4.66 16.47
—
—
—
—
14
15
90
46
>300
48.38
48.58
45.40
45.52
2.71 10.15 С11Н7F3N2O3
2.60 10.29
3.20 9.52 С11Н9F3N2O4
3.13 9.66
—
—
6.75 8.68 8.08
(s)
136—138
—
—
—
16
17
96
93
102—103
71—72
50.65
50.62
2.84 19.79 С9Н6F3N3
2.95 19.64
9.32
(s)
—
—
8.92 8.08
(J = (J =
5.5) 5.5)
3.16 (q, 3 Н, Mе, JMe,CF3 = 6)
50.67
50.77
4.31 10.72 С11Н11F3N2O2
4.26 10.77
—
—
—
1.37 (t, 3 H, MeCH2, J = 7);
2.25 (s, 3 H, Me); 4.31 (q, 2 H,
CH2O, J = 7); 6.99 (d, 1 H, C(5)H,
J = 6); 7.73 (s, 1 H, EtOCH=);
8.58 (d, 1 H, C(6)H, J = 6)
18
97
130—131
53.67
53.54
4.13 20.97 С12Н11F3N4
4.25 20.89
8.67
(s)
—
8.65 7.64
3.03, 3.26 (both br.s, 6 H, NMe2);
5.87 (d, 1 Н, CH=, J = 12);
8.42 (d, 1 Н, Me2NCH=, J = 12)
Scheme 8
midine 16, that indicates that the reactivity of substituted
pyrido[4,3ꢀd]pyrimidines is considerably affected by the
location of CF3 group.
Pyridopyrimidine 16 readily reacted with DMF DMA
in refluxing benzene to be converted to dimethylaminoꢀ
vinyl compound 18 (Scheme 8), which can be used for the
synthesis of new nitrogenꢀcontaining heterocycles.

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Vasil´ev et al.
4ꢀEthylaminoꢀ3ꢀtrifluoroacetimidoylꢀ3ꢀpentenꢀ2ꢀone dipheꢀ
nylboron complex (3c) was obtained similarly to complex 3b.
4ꢀnꢀPropylaminoꢀ3ꢀtrifluoroacetimidoylꢀ3ꢀpentenꢀ2ꢀone (3d)
and 4ꢀnꢀpropylaminoꢀ2ꢀnꢀpropyliminoꢀ3ꢀtrifluoroacetimidoylpentꢀ
3ꢀene diphenylboron complexes (4). A mixture of chelate 1 (1.0 g,
2.6 mmol) and PrNH2 (0.34 mL, 4.1 mmol) in benzene (5 mL)
was refluxed for 3 h. Benzene and excess of amine were evaporated,
the residue was subjected to column chromatography on SiO2
(eluent: first a mixture of benzene—light petroleum (2 : 1), then benzꢀ
ene, and finally a mixture of benzene—acetone (4 : 1)). The isoꢀ
lation gave product 3d (0.85 g) and compound 4 (0.22 g). 15N NMR
of chelate 4 (CDCl3), , Zꢀisomer/Eꢀisomer): –261.8/–263.5
(NH, correlation with proton NH); –204/–206 (NB, correlation
with protons MeCNB); –42.5/–39.7 (C=N, correlation with
protons MeC=N). 19F NMR (CDCl3), : –68.6 (Zꢀisomer), –66.8
(Eꢀisomer) (the ratio Z : E = 2 : 1). 19F NMR (DMSOꢀd6),
: –66.2 (Zꢀisomer), –64.6 (Eꢀisomer) (the ratio Z : E = 4 : 1).
The following compounds were obtained similarly to 3d:
4ꢀallylaminoꢀ3ꢀtrifluoroacetimidoylꢀ3ꢀpentenꢀ2ꢀone diphenylꢀ
boron complex (3e), 4ꢀ(3ꢀmethoxypropylamino)ꢀ3ꢀtrifluoroacetꢀ
imidoylꢀ3ꢀpentenꢀ2ꢀone diphenylboron complex (3f), 4ꢀ(4ꢀfluꢀ
orobenzylamino)ꢀ3ꢀtrifluoroacetimidoylꢀ3ꢀpentenꢀ2ꢀone dipheꢀ
nylboron complex (3g), 4ꢀ(2ꢀfurfurylamino)ꢀ3ꢀtrifluoroacetꢀ
imidoylꢀ3ꢀpentenꢀ2ꢀone diphenylboron complex (3h), 4ꢀ(2ꢀthiꢀ
enylmethylamino)ꢀ3ꢀtrifluoroacetimidoylꢀ3ꢀpentenꢀ2ꢀone diꢀ
phenylboron complex (3i).
2ꢀ(1´ꢀAminoꢀ2´,2´,2´ꢀtrifluoroethylidene)ꢀ6ꢀdimethylaminoꢀ
methyleneꢀ3ꢀiminocyclohexꢀ4ꢀenꢀ1ꢀone diphenylboron complex
(10). A mixture of chelate 3a (1.6 g, 4.47 mmol) and DMF
DMA (2.6 g, 22.35 mmol) in toluene (15 mL) was refluxed for
9 h. The solvent was evaporated, the residue was subjected to
column chromatography on SiO2 (eluent: a mixture of benzene—
acetone, first 10 : 1, then 4 : 1) to sequentially isolate 4ꢀaminoꢀ
6ꢀdimethylaminoꢀ3ꢀtrifluoroacetimidoylhexaꢀ3,5ꢀdienꢀ2ꢀone
diphenylboron complex (0.35 g, 19%), whose m.p. and spectroꢀ
scopic data completely agreed with those of this compound
obtained earlier,6 and compound 10 (0.82 g). MS, m/z: 346
[M – Ph]+. IR (KBr), /cm–1: 3395 (NH), 1640 (C=O). 13C NMR
(DMSOꢀd6), : 41.2, 48.1 (Me2N); 105.8 (C(4)); 115.3 (C(6));
118.4 (C(2)); 120.2 (CF3); 125.5 (pꢀCPh); 126.8 (mꢀCPh); 128.5
(CPhꢀB); 132.5 (oꢀCPh); 136.7 (C(5)); 152.1 (C(3)); 152.8
(C(10)); 178.0 (C=O). 11B NMR (CDCl3), : –2.1.
Experimental
1
H NMR spectra were recorded on a Bruker WMꢀ250
spectrometer (250.13 MHz), 13C NMR spectra were recorded
on a Bruker AMꢀ300 spectrometer (75.47 MHz). Chemical shifts
in the 1H NMR spectra were calculated using residual signals of
deuterated solvents as references ( 7.27 for CDCl3 and  2.50
for DMSOꢀd6), in 13C NMR spectra the reference was the mulꢀ
tiplet signals of the deuterated solvents ( 39.50 for DMSOꢀd6
1
1
and  77.00 for CDCl3). 2D H/13C and H/15N HMBC NMR
spectra were recorded on a Bruker Avance 600 spectrometer
(600 MHz, 150 MHz, and 60.8 MHz for 1H, 13C, and 15N,
respectively). The signals in the 1H and 13C NMR spectra of
were assigned based on the 2D 1H/13C HMBC NMR spectra.
Chemical shifts for 15N were measured relative to MeNO2 as an
external standard (the upfield chemical shifts are given as negaꢀ
tive values) based on the analysis of 2D 1H/15N HMBC NMR
spectra. The 1H NMR spectrum of compound 10 was interpretꢀ
ed using a 2D procedure COSY and ROESY, the signals of the
protonated carbon atoms were assigned based on the analysis of
the 2D H/13C HSQC heteronuclear spectrum. IR spectra were
1
recorded on a SpecordꢀM82 spectrometer, mass spectra were
obtained on a Kratos MSꢀ30 instrument (EI, 70 eV, temperature
of the ionizing chamber 250 C, direct injection of the comꢀ
pounds). High resolution mass spectra (HRMS) were recorded
on a Bruker micrOTOF II instrument using electrospray ionizaꢀ
tion (ESI). The measurements were performed for the positive
ions (capillary voltage 4500 V). The scanning range of masses
m/z 50—3000 Da, an external and an internal calibration (Elecꢀ
trospray Calibrant Solution, Fluka). Solutions of samples in
CH3CN were injected with a syringe, the flow rate 3 L min–1
.
Sprayer gas nitrogen (4 L min–1), the interface temperature
180 C. 3ꢀAcetylꢀ4ꢀaminoꢀ5,5,5ꢀtrifluoroꢀ3ꢀpentenꢀ2ꢀone diꢀ
phenylboron complex5 and 3ꢀacetylꢀ4ꢀaminoꢀ2ꢀtrifluoromethylꢀ
pyridine6 were synthesized according to the procedures described
earlier. Amines and dimethylformamide dimethyl acetal were
purchased from Acros. Merkꢀ60 silica gel (0.063—0.200 nm)
was used for column chromatography. The yields, melting points,
elemental analysis data, and 1H NMR spectra of compounds
3a—i, 4, and 10 are given in Table 1, those for naphthyridinones
6a,c—i, as well as for compounds 13—18 — in Table 2.
4ꢀAminoꢀ3ꢀtrifluoroacetimidoylꢀ3ꢀpentenꢀ2ꢀone diphenylꢀ
boron complex (3a). Compound 1 (5.44 g, 15 mmol) was disꢀ
solved in 0.6 M solution of NH3 in THF NMR (60 mL) and kept
for 24 h at ~20 °C. The solvent was evaporated, the residue
recrystallized from a mixture of benzene (20 mL) and light peꢀ
troleum (15 mL) to obtain compound 3a (2.21 g). The filtrate
was concentrated, the residue was subjected to column chromaꢀ
tography on SiO2 (eluent: first benzene, then benzene—chloroꢀ
form) to additionally obtain compound 3a (1.31 g). The total
1ꢀnꢀPropylꢀ5ꢀtrifluoromethylꢀ1,6ꢀnaphthyridinꢀ4(1H)ꢀone (6d).
A mixture of complex 3d (1.47 g, 3.7 mmol) and DMF DMA
(1.5 mL, 11 mmol) in oꢀxylene (25 mL) was refluxed for 4 h. The
solvent was evaporated, the residue was subjected to column
chromatography on SiO2 (eluent: first benzene, then a mixture
of benzene—acetone (first 10 : 1, then 4 : 1) to obtain naphthyriꢀ
dinone 6d (0.72 g). MS, m/z: 256 [M]+. IR (KBr), /cm–1: 1635
(C=O). 13C NMR (CDCl3), : 10.9 (Me); 21.8 (CH2); 54.9 (CH2N);
113.3 (C(8)); 115.0 (C(3)); 120.2 (C(4a)); 121.3 (CF3); 143.3
(C(2)); 146.9 (C(8a)); 147.7 (C(7)); 148.1 (C(5)); 175.3 (C=O).
The following compounds were obtained similarly to 6d:
1ꢀethylꢀ5ꢀtrifluoromethylꢀ1,6ꢀnaphthyridinꢀ4(1H)ꢀone (6c),
1ꢀallylꢀ5ꢀtrifluoromethylꢀ1,6ꢀnaphthyridinꢀ4(1H)ꢀone (6e),
1ꢀ(3ꢀmethoxypropyl)ꢀ5ꢀtrifluoromethylꢀ1,6ꢀnaphthyridinꢀ4(1H)ꢀ
one (6f), 1ꢀ(4ꢀfluorobenzyl)ꢀ5ꢀtrifluoromethylꢀ1,6ꢀnaphthyrꢀ
idinꢀ4(1H)ꢀone (6g), 1ꢀ(2ꢀfurfuryl)ꢀ5ꢀtrifluoromethylꢀ1,6ꢀnaphꢀ
thyridinꢀ4(1H)ꢀone (6h), 1ꢀ(2ꢀthienylmethyl)ꢀ5ꢀtrifluoromethꢀ
ylꢀ1,6ꢀnaphthyridinꢀ4(1H)ꢀone (6i).
yield was 3.52 g. MS, m/z: 281 [M – Ph]+. IR (KBr), /cm–1
:
3385 (NH), 1675 (C=O). 19F NMR (CDCl3), : –67.0. 13C NMR
(CDCl3), : 24.7 (q, MeCN, J = 129 Hz); 32.5 (q, MeCO,
J = 129 Hz); 106.0 (s, C—COMe); 120.0 (q, CF3, 1JC,F = 280 Hz);
126.8, 127.6, 132.2, 149.00 (2 Ph); 151.0 (q, CF3—C, 2JC,F = 34 Hz);
167.6 (s, NC—Me); 197.9 (q, C=O, J = 6 Hz).
4ꢀMethylaminoꢀ3ꢀtrifluoroacetimidoylꢀ3ꢀpentenꢀ2ꢀone diꢀ
phenylboron complex (3b) was obtained similarly to 3a, but the
reaction mixture was subjected to column chromatography on
SiO2 (eluent: first a mixture of benzene—light petroleum, then
benzene) immediately after evaporation of the solvent.
3ꢀAcetylꢀ4ꢀ(dimethylaminomethyleneamino)ꢀ2ꢀtrifluoromethꢀ
ylpyridine (13). A mixture of pyridine 12 (0.37 g, 1.8 mmol) and

1,6ꢀNaphtyridines and pyrido[4,3ꢀd]pyrimidines
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 5, May, 2013
1261
DMF DMA (0.5 mL) in benzene (15 mL) was refluxed for 2 h.
Benzene was evaporated, the residue was triturated with light
petroleum (10 mL). A precipitate formed was washed with light
petroleum to obtain amidine 13 (0.45 g). MS, m/z: 259 [M]+. IR
(KBr), /cm–1: 1700 (C=O); 1635, 1570 (the region of multiple
bonds); 1260—1140 (C—F).
5ꢀTrifluoromethylꢀ1,6ꢀnaphthyridinꢀ4(1H)ꢀone (6a). A. A soꢀ
lution of amidine 13 (0.05 g, 0.19 mmol) and 1 N methanolic
solution of MeONa (0.19 mL) in methanol (5 mL) was refluxed
for 3 h, followed by the addition of a threefold excess of acetic
acid. The solvents were evaporated, the residue was washed with
water, and dried to obtain compound 6a (0.03 g). MS, m/z: 214
[M]+. IR (KBr), /cm–1: 3258 (NH), 1645 (C=O). 13C NMR
(DMSOꢀd6), : 113.9 (C(8)); 117.0 (C(3)); 118.5 (C(4a)); 121.6
(CF3); 140.0 (C(2)); 145.7 (C(5)); 147.0 (C(7)); 147.4 (C(8a));
174.6 (C=O). 19F NMR (CDCl3), : –61.8.
B. A solution of amidine 13 (0.12 g, 0.46 mmol) in 4.5 N
methanolic solution of NH3 (10 mL) was heated in a sealed tube
for 10 h at 80—90 C. The solvent was evaporated, the residue
was subjected to column chromatography on SiO2 (eluent:
a mixture of benzene—acetone, first 20 : 1, then 5 : 1, further 1 : 1,
and finally 1 : 3) to sequentially isolate pyrido[4,3ꢀd]pyrimidine
16 (0.021 g, 21%) and naphthyridine 6a (0.059 g, 60%).
procedure was repeated three more times. The residue was exꢀ
tracted with warm light petroleum (4×10 mL), then light petroꢀ
leum was evaporated to obtain crude compound 17 (0.25 g, 93%).
Pure product 17 (0.173 g, 65%) was obtained after crystallization
from light petroleum (7 mL). HRMS: found, m/z: 261.052
[M + H]+. C11H11F3N2O2. Calculated: 261.0845 [M + H]+.
4ꢀMethylꢀ5ꢀtrifluoromethylpyrido[4,3ꢀd]pyrimidine (16). A mixꢀ
ture of compound 17 (0.69 g, 2.6 mmol) and a 1.7 M solution of NH3
in methanol (25 mL) was stirred for 1.5 h, the solvent was evapꢀ
orated, the residue was sublimed in vacuo (1—2 Torr) at 65—90 C
using a water bath to obtain compound 16 as a white powder
(0.542 g). 19F NMR (CDCl3), : –60.3. HRMS: found, m/z:
214.0592 [M + H]+. C9H6F3N3. Calculated: 214.0587 [M + H]+.
4ꢀDimethylaminovinylꢀ5ꢀtrifluoromethylpyrido[4,3ꢀd]pyrꢀ
imidine (18). A mixture of pyridopyrimidine 16 (0.1 g, 0.47 mmol)
(0.1 g, 0.47 mmol) and DMF DMA (0.2 mL) in benzene (2 mL)
was refluxed for 5 h. The solvent was evaporated, the residue was
subjected to column chromatography on SiO2 (eluent: first benzꢀ
ene, then a mixture of benzene—acetone (5 : 1)) to obtain comꢀ
pound 18 (0.122 g).
The authors are grateful to A. S. Shashkov for his help
in registration and interpretation of 2D NMR spectra.
3ꢀAcetylꢀ4ꢀ(methyloxalylamino)ꢀ2ꢀtrifluoromethylpyridine
(15). Dimethyl oxalate (0.95 g) and a 1.17 M solution of MeONa
in methanol (7 mL) were sequentially added to a solution of
pyridine 12 (0.4 g, 1.96 mmol) in methanol (10 mL). After 3 h,
acetic acid (0.6 mL) was added. The solvents were evaporated,
the residue was diluted with water (30 mL). A precipitate formed
was filtered off, washed with water (3×15 mL), dried, and subꢀ
jected to column chromatography on SiO2 (eluent: a mixture of
benzene—acetone, first 20 : 1, then 2 : 1) to sequentially isolate
amide 15 (0.264 g) and naphthyridine 14 (0.08 g).
2ꢀMethoxycarbonylꢀ5ꢀtrifluoromethylꢀ1,6ꢀnaphthyridinꢀ
4(1H)ꢀone (14). A. Dimethyl oxalate (0.1 g, 0.85 mmol) was
added to a solution of compound 15 (0.08 g, 0.28 mmol) in
methanol, then after 20 min a 1.1 M solution of MeONa in
methanol (0.8 mL) was also added, and the mixture was allowed
to stand for 18 h at ~20 C. Then, dimethyl oxalate (0.075 g) and
a 1.1 M solution of MeONa in methanol (0.6 mL) were added to
the reaction mixture once more and it was allowed to stand for
another 18 h. The latter procedure was repeated one more time,
then a solution of acetic acid (0.25 mL) in water (75 mL) was
added. A precipitate formed was filtered off, washed with water
(2×15 mL), dried, and finally washed with benzene (25 mL) to
obtain naphthyridine 14 (0.068 g).
References
1. V. P. Litvinov, Khimiya naftiridinov [Chemistry of Naphtꢀ
hyridines], Ekonomika, 2008, pp. 88—120 (in Russian)).
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3. C. Jsanbor, D. O´Hagan. J. Fluorine Chem., 2008, 127, 303.
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Bogdanov, V. A. Dorokhov, Russ. Chem. Bull. (Engl. Transl.),
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Supunitsky, J. Heterocycl. Chem., 2007, 44, 843.
B. A 1.17 M solution of MeONa in methanol (2.3 mL) was
added to a solution of compound 12 (0.18 g, 0.88 mmol) and
dimethyl oxalate (0.312 g) in methanol (10 mL), and the mixture
was allowed to stand for 5 h at ~20 C. Then another portion of
dimethyl oxalate (0.21 g) was added, and after standing for 18 h,
a 1.17 M solution of MeONa in methanol (1.55 mL) was added.
After 24 h, a solution of acetic acid (0.5 mL) in water (15 mL)
was added to the mixture. A precipitate formed was filtered off,
washed with water (2×15 mL), and dried to obtain naphthyridꢀ
ine 14 (0.182 g). 19F NMR (DMSOꢀd6), : –63.6. HRMS: found,
m/z: 273.0483 [M + H]+, 295.097 [M + Na]+. C11H7F3N2O3.
Calculated: 273.0482 [M + H]+, 295.0301 [M + Na]+.
10. S. C. W. Coltman, S. C. Eyley, R. A. Raphael, Synthesis, 1984, 150.
11. A. V. Komkov, V. A. Dorokhov, Russ. Chem. Bull. (Int. Ed.),
2002, 51, 1875 [Izv. Akad. Nauk, Ser. Khim., 2002, 1726].
12. L. S. Vasil´ev, S. V. Baranin, A. V. Ignatenko, Yu. V. Nelyuꢀ
bina, V. A. Dorokhov, Russ. Chem. Bull. (Int. Ed.), 2010, 59,
1403 [Izv. Akad. Nauk, Ser. Khim., 2010, 1373].
13. L. S. Vasil´ev, S. V. Baranin, V. A. Dorokhov, Tez. dokl. III
Mezhdunar. konf. "Khimiya geterotsiklicheskikh soedinenii",
posvyashchennaya 95ꢀletiyu so dnya rozhdeniya professora
Alekseya Nikolaevicha Kosta [Abstr. III Internat. Conf. "Chemꢀ
istry of Heterocyclic Compounds" dedicated to 95 birthday anꢀ
niversary of Professor Aleksei Nikolaevich Kost (Moscow, Ocꢀ
tober 18—21, 2010), Moscow, 2010, C40.
3ꢀAcetylꢀ2ꢀtrifluoromethylꢀ4ꢀethoxymethyleneaminopyridine
(17). A mixture of pyridine 12 (0.21 g, 0.1 mmol) and ethyl
orthoformate (3 mL) (3 mL) was refluxed for 2 h, then ethanol
and an excess of ethyl orthoformate were slowly evaporated. The
Received December 28, 2012;
in revised form March 26, 2013