Synthesis of 3-(trifluoromethyl)benzo[c][1,6]naphthyridines from substituted 4H-pyran-4-ones via 4-amino-5-aryl-2-(trifluoromethyl)pyridines

Article abstract of DOI:10.1016/S0040-4020(00)00637-2

The cyclization of acylated 4-amino-5-aryl-2-(trifluoromethyl)pyridines under the action of P₂O₅/POCl₃ smoothly afforded 3-(trifluoromethyl)benzo[c][1,6]naphthyridines in good yields. Intermediate aminopyridines were synthesized in a two-step sequence from the corresponding 4H-pyran-4-ones, which were prepared by reaction of 2-acetyl-2-aryloxiranes and 4-dimethylamino-3-(4-methoxyphenyl)-3-buten-2-one with ethyl trifluoroacetate under basic conditions. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00637-2

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 7313–7318
Synthesis of 3-(Trifluoromethyl)benzo[c][1,6]naphthyridines
from Substituted 4H-Pyran-4-ones via
4-Amino-5-Aryl-2-(trifluoromethyl)pyridines
a
a
b
Vladimir I. Tyvorskii,a, Denis N. Bobrov, Oleg G. Kulinkovich, Wim Aelterman and
*
Norbert De Kimpeb
aDepartment of Organic Chemistry, Belarussian State University, Fr. Scorina Av., 4, 220050 Minsk, Belarus
bDepartment of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, Ghent University, Coupure Links 653,
B-9000 Ghent, Belgium
Received 22 March 2000; revised 26 June 2000; accepted 13 July 2000
Abstract—The cyclization of acylated 4-amino-5-aryl-2-(trifluoromethyl)pyridines under the action of P2O5/POCl3 smoothly afforded
3-(trifluoromethyl)benzo[c][1,6]naphthyridines in good yields. Intermediate aminopyridines were synthesized in a two-step sequence
from the corresponding 4H-pyran-4-ones, which were prepared by reaction of 2-acetyl-2-aryloxiranes and 4-dimethylamino-3-(4-methoxy-
phenyl)-3-buten-2-one with ethyl trifluoroacetate under basic conditions. ᭧ 2000 Elsevier Science Ltd. All rights reserved.
Introduction
DMAP analogues have been synthesized via a palladium-
catalyzed coupling reaction of 3-bromo-4-aminopyridines
with arylboronic acids.8
Benzannelated [1,6]naphthyridines are currently of interest
as structural units of naturally occurring compounds, e.g.
the marine alkaloids aaptamines.1 The bronchodilator drug
benafentrine has been developed based on the derivatives of
partially hydrogenated benzo[c][1,6]naphthyridines, which
are phosphodiesterase III/IV inhibitors.2 A number of
compounds related to benafentrine have a potential applica-
tion for the treatment of bronchial disorders, dermatoses3
and thrombosis.4 Screening of some benzo fused
[1,6]naphthyridines also showed potent and often specific
antimicrobial properties against the different bacterial
strains tested.5
Since perfluoroalkylated heterocyclic compounds have
received considerable interest mainly because of specific
biological activities, in this paper a convenient synthesis
of new 4-amino-5-aryl-2-(trifluoromethyl)pyridines 9 and
their transformation into 3-(trifluoromethyl)benzo[c][1,6]-
naphthyridines 11 is disclosed.
Results and Discussion
As shown previously, the dehydration of hydroxydihydro-
pyranone 3a by the action of thionyl chloride in pyridine is a
convenient method for the preparation of 5-phenyl-2-
(trifluoromethyl)-4H-pyran-4-one (7a),9 which can be used
for the synthesis of 4-aminopyridine 9a. Compound 3a is
formed from the condensation of 2-acetyl-2-phenyloxirane
(1a) with ethyl trifluoroacetate through cyclization of the
intermediate 2a, occurring via highly regioselective three-
membered ring cleavage at the terminal carbon atom.10 In
this reaction, side product 4a was isolated by column
chromatography in very low yield.
The parent benzo[c][1,6]naphthyridine was obtained in low
yield by photocyclization of 4-(benzylideneamino)pyri-
dine,6 as well as through the more successful reaction of
the corresponding o-chlorobenzylidene derivative with
potassium amide.5 Toward this end, photocyclization
of 4-(1-cyclohexenylcarboxamido)pyridine was also
employed as a key-step.7 Suitable precursors of substituted
benzo[c][1,6]naphthyridines can be 4-amino-3-arylpyri-
dines, which still remain rather difficult to access, in contrast
with the piperidine congeners.4 Recently, in order to
develop novel chiral catalysts, 3-arylated atropo-isomeric
The same condensation of 4-(methoxyphenyl)-substituted
oxirane 1b, aimed at the preparation of pyranone 7b, led
to the furanone 4b as the main reaction product in 44%
yield, the desired hydroxydihydropyranone 3b being
obtained only in 11% yield. The predominant formation of
Keywords: 2-(trifluoromethyl)-4H-pyran-4-ones; 3(2H)-furanones; 4-
aminopyridines; benzo[c][1,6]naphthyridines; Pictet–Hubert cyclization.
* Corresponding author. Tel.: ϩ375-0172265609; fax: ϩ375-
0172264998; e-mail: tyvorskii@chem.bsu.unibel.by
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00637-2

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V. I. Tyvorskii et al. / Tetrahedron 56 (2000) 7313–7318
Scheme 1.
furanone 4b can be attributed to the electron-donating effect
of the 4-methoxyphenyl group, which promotes nucleo-
philic attack at the adjacent carbon atom of the oxirane
provides an efficient and practical route to symmetrical
4-amino-2,6-disubstituted pyridines.14 However, our
attempts to prepare 2-(trifluoromethyl)-4-aminopyridines
9a,b from pyranones 7a,b using the above sequence failed
completely. Due to the strong electron-withdrawing charac-
ter of the trifluoromethyl group, impeding reactions of pyra-
nones 7a,b with electrophiles (such as TsNCO), the reported
procedure14 for the preparation of compounds 9a,b was
modified. The sequence applied is given in Scheme 3.
Thus, 4-pyridinols 8a,b were prepared in almost quanti-
tative yield upon heating pyranones 7a,b with aqueous
ammonia in i-PrOH solution at reflux. Treatment of
compounds 8a,b with tosyl isocyanate in boiling toluene
solution and successive hydrolysis of these reaction
products with hot 90% H2SO4 led to the formation of the
desired 4-aminopyridines 9a,b in 82% overall yield.
ring through
a
borderline SN2-like transition state
(Scheme 1).11
1
As compared with pyranone 3b, the H NMR spectrum of
furanone 4b showed a specific coupling between the proton
of the hydroxy group and the diastereotopic methylene
protons, appearing as a set of two doublets of doublets at
4.03 (Jˆ4.5, 12.0 Hz) and 4.18 (Jˆ7.0, 12.0 Hz). In the
presence of CF3CO2H, the signal for the CH2 group of 4b
collapsed to a pair of doublets with the same geminal
coupling constant of 12.0 Hz. In the IR spectrum of fura-
none 4b, absorption of the conjugated carbonyl group is
observed at 1725 cmϪ1 (cf. 1695 cmϪ1 for pyranone 3b),
which is typical for related 3(2H)-furanones.12
1
The H NMR spectra of 4-pyridinols 8a,b and 4-amino-
Since difficulties were encountered in the preparation of
dihydropyranone 3b, the alternative way to 5-(4-methoxy-
phenyl)substituted pyranone 7b based on the readily avail-
able b-dimethylaminoenone 5 was employed (Scheme 2).13
pyridines 9a,b showed the expected 0.18–0.68 ppm
deshielding for protons 2-H and 5-H in comparison with
the starting pyranones 7a,b. In addition, the 13C NMR spec-
trum of compound 8b contains the signal due to a quaternary
carbon at 162.09, which is consistent with a C-4 atom of
4-pyridinol 8b rather than the tautomeric 4(1H)-pyridi-
none.15 The almost complete absence of the carbonyl
stretching band in the IR spectra of compounds 8a,b
suggests the predominance of the hydroxy tautomer.
Reaction of compound 5 with ethyl trifluoroacetate
proceeded in the presence of potassium tert-butoxide to
give enamino diketone 6 in 92% yield. The latter enaminone
was subjected to a workup with aqueous 6 M HCl in i-PrOH
solution, giving rise to cyclization to the target pyranone 7b
in 89% yield. Although this method for the preparation of
compound 7b is quite simple, the approach starting from
acyloxiranes is more versatile and also allows the prepara-
tion of the corresponding alkyl substituted pyranones.9 The
structure of pyranone 7b was confirmed by its spectral data
that resemble those of the 5-phenyl analogue 7a.9
With amines 9a,b in hand, their acylated derivatives 10a–e
were prepared easily and subjected to a Pictet–Hubert
cyclization. To our knowledge, such transformation of
3-aryl-4-(N-acylamino)pyridines (like 10) has not been
reported previously. After several initial failures to use
POCl3 as standard condensing agent, compounds 10a–d
were found to cyclize smoothly under the action of P2O5
in boiling POCl3, affording the desired benzo[c][1,6]-
naphthyridines 11a–d in 56–82% yield (Scheme 3).
Unfortunately, all attempts to convert the formyl derivative
10e (R2ˆH) in this reaction were unsuccessful.
It is known that the three-step reaction involving amination
of 4H-pyran-4-ones with tosyl isocyanate followed by the
addition of ammonia and subsequent hydrolysis of the
intermediate p-toluenesulfonamide with sulfuric acid
Scheme 2.

V. I. Tyvorskii et al. / Tetrahedron 56 (2000) 7313–7318
7315
Scheme 3.
The structural proof of benzonaphthyridines 11a–d was
supported by the spectral data and microanalytical results.
Compounds 11a–d all exhibit an intensive molecular ion
signal (base peak usually) in the GS–MS analysis and have
no appreciable nCvO absorption in the IR spectra in
the 1695–1715 cmϪ1 region, which is typical for amides
10a–d. The distinctive characteristic of the 1H NMR
spectra of 11a–d is the extreme lowfield position of the
signal for H-1, appearing as a sharp singlet at 9.87–10.08
in good agreement with the reported data for related
systems.5
ammonium iodide16 according to the procedure described
previously for the preparation of 1a.17 1b: (51%), pale
1
yellow oil; IR (CCl4) 1720 cmϪ1; H NMR 2.19 (s, 3H),
3.05 and 3.27 (2×d, Jˆ5.5 Hz, 2H), 3.81 (s, 3H), 6.90 and
7.39 (2×d, Jˆ8.5 Hz, 4H). Anal. Calcd for C11H12O3: C,
68.74; H, 6.29. Found: C, 68.97; H, 6.48.
Condensation of acetyloxiranes 1a,b with ethyl
trifluoroacetate
To a vigorously stirred suspension of sodium isopropoxide
(1.3 g, 15.6 mmol) in dry ether (30 mL) was added dropwise
a mixture of acetyloxirane 1a or 1b (7.8 mmol) and ethyl
trifluoroacetate (1.9 mL, 15.6 mmol) at Ϫ15ЊC over a
period of 30 min. The stirred reaction mixture was gradually
warmed to ambient temperature over 5 h, then cooled to 0ЊC
and quenched by careful addition of glacial acetic acid
(0.9 mL, 15.6 mmol). The aqueous layer was separated
and extracted with Et2O (5 mL×5). The combined organic
phases were washed with saturated aqueous NaHCO3 solu-
tion and dried over Na2SO4. After removal of the solvent
under reduced pressure, the residue was chromatographed
on silica gel using hexane–ether (1:11:2), providing subse-
quently pyranones 3a,b and furanones 4a,b.
In conclusion, a convenient approach to 3-(trifluoromethyl)-
benzo[c][1,6]naphthyridines via 4-amino-5-aryl-2-(trifluoro-
methyl)pyridines was developed, starting from the easily
available 2-acetyl-2-(4-methoxyphenyl)oxirane and (E)-4-
dimethylamino-3-(4-methoxyphenyl)-3-buten-2-one. Both
the latter compounds were reacted with ethyl trifluoro-
acetate in order to prepare the corresponding 4H-pyran-4-
ones as suitable precursors of the target aminopyridines.
Experimental
IR spectra were measured on a Specord 75 IR (CCl4 or
CHCl3 solution) or a UR 20 (KBr) spectrophotometer. H
1
2,3-Dihydro-3-hydroxy-3-phenyl-6-(trifluoromethyl)-4H-
pyran-4-one (3a). (65%). This compound was identical in
all aspects with a sample obtained formerly.9
NMR and 13C NMR spectra were recorded on a Bruker
AC-200 spectrometer at 200 and 50.3 MHz, respectively,
with Me4Si as the internal standard. Unless otherwise
noted, NMR samples were dissolved in CDCl3. Mass
spectra were recorded on a Shimadzu QP-5000 GC/MS
spectrometer. Melting points were determined in open
capillaries and are uncorrected. Preparative column chroma-
tography was carried out on silica gel L Chemapol (40–100
Mesh). All chemicals were reagent grade; solvents were
dried and distilled prior to use. (E)-4-Dimethylamino-3-(4-
methoxyphenyl)-3-butene-2-one (5) was synthesized by a
known procedure.13 5-Phenyl-2-(trifluoromethyl)-4H-
pyran-4-one (7a) was prepared by dehydration of 2,3-di-
hydro-3-hydroxy-3-phenyl-6-(trifluoromethyl)-4H-pyran-
4-one (3a) as previously reported.9
2-(Hydroxymethyl)-2-phenyl-5-(trifluoromethyl)-3(2H)-
furanone (4a). (7%), colourless oil; 1H NMR 3.92 and 4.29
(2×d, Jˆ12.5 Hz, 2H), 5.17 (br s, 1H), 5.95 (s, 1H), 7.12–
7.56 (m, 5H). Anal. Calcd for C12H9F3O3: C, 55.82; H, 3.51.
Found: C, 55.99; H, 3.68.
2,3-Dihydro-3-hydroxy-3-(4-methoxyphenyl)-6-(trifluoro-
methyl)-4H-pyran-4-one (3b). (11%), colourless oil; IR
(CCl4) 3505, 1695, 1640 cmϪ1 1H NMR 3.76 (s, 3H),
;
4.47 and 4.91 (2×d, Jˆ12.0 Hz, 2H), 4.57 (br s, 1H), 5.92
(s, 1H), 6.87 and 7.34 (2×d, Jˆ8.5 Hz, 4H). 13C NMR 55.25
(OCH3), 72.35 (COH), 75.64 (CH2O), (102.78 (s,
CHvCCF3)), 114.36 and 127.20 (HCortho and HCmeta or
vice versa), 118.44 (q, Jˆ275 Hz, CF3), 129.33 (Cquat),
159.16 (q, Jˆ38 Hz, CCF3), 160.28 (COCH3), 193.77
2-Acetyl-2-(4-methoxyphenyl)oxirane (1b). It was synthe-
sized from 2-(4-methoxyphenyl)-3-oxobutyl(trimethyl)-

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V. I. Tyvorskii et al. / Tetrahedron 56 (2000) 7313–7318
(CvO). EIMS (70 eV) m/z (rel. int.) 288 (Mϩ, 2), 151
(10), 150 ([4-CH3OC6H4COCH3]ϩ, 100), 135 (73), 108
(10), 92 (8), 78 (10), 77 (33), 69 (13), 43 (10). Anal.
Calcd for C13H11F3O4: C, 54.17; H, 3.85. Found: C, 54.32;
H, 4.03.
Preparation of pyridinols 8a,b
To a solution of pyranone 7a or 7b (10 mmol) in i-PrOH
(20 mL) was added 25% aqueous ammonia (1.1 mL,
15 mmol). The resulting solution was heated under reflux
for 24 h. Then the reaction mixture was poured into 40 mL
of water, and the precipitate was filtered off. Pyridinols 8a,b
were obtained as a white powder after recryctallization.
2-(Hydroxymethyl)-2-(4-methoxyphenyl)-5-(trifluoro-
methyl)-3(2H)-furanone (4b). (44%), mp 88–89ЊC (CCl4);
1
IR (CCl4) 3625, 1725, 1640 cmϪ1; H NMR 2.08 (m, 1H),
3.81 (s, 3H), 4.03 (d×d, Jˆ12.0, 4.5 Hz, 1H), 4.18 (d×d,
Jˆ12.0, 7.0 Hz, 1H), 6.07 (s, 1H), 6.92 and 7.46 (2×d,
Jˆ9.0 Hz, 4H). 13C NMR 55.34 (OCH3), 67.07 (CH2OH),
95.40 (CCH2O), (106.16 (s, CHvCCF3)), 114.34 and
126.11 (HCortho and HCmeta or vice versa), 118.03 (q,
Jˆ274 Hz, CF3), 124.27 (Cquat), 160.25 (COCH3), 173.62
(q, Jˆ41 Hz, CCF3), 201.84 (CvO). EIMS (70 eV) m/z (rel.
int.) 288 (Mϩ, 2), 259 (13), 258 ([MϪCH2O]ϩ, 100), 257
(30), 243 (28), 215 (12), 135 (41), 121 (12), 107 (7), 92 (12),
79 (6), 77 (35), 69 (14), 63 (11), 53 (10), 51 (11), 39 (10).
Anal. Calcd for C13H11F3O4: C, 54.17; H, 3.85. Found: C,
54.25; H, 3.98.
5-Phenyl-2-(trifluoromethyl)-4-pyridinol (8a). (95%), mp
238–239ЊC (toluene–i-PrOH, 3:1); IR (KBr) 3445 (br),
1
1650 (weak), 1615 (weak), 1540 cmϪ1; H NMR (DMSO-
d6) 7.37 (s, 1H), 7.41–7.67 (m, 5H), 8.54 (s, 1H), 11.71 (br s,
1H). EIMS (70 eV) m/z (rel. int.) 240 (Mϩϩ1, 17), 239 (Mϩ,
100), 238 (69), 218 (45), 168 (7), 115 (17), 110 (6), 89 (10),
77 (8), 69 (4), 63 (9), 51 (10), 50 (6), 39 (10). Anal. Calcd
for C12H8F3NO: C, 60.26; H, 3.37. Found: C, 60.32; H, 3.53.
5-(4-Methoxyphenyl)-2-(trifluoromethyl)-4-pyridinol (8b).
(93%), mp 252–253ЊC (i-PrOH); IR (KBr) 3450 (br), 1650
(weak), 1615 (weak), 1525 cmϪ1; 1H NMR (DMSO-d6) 3.81
(s, 3H), 7.05 and 7.59 (2×d, Jˆ8.0 Hz, 4H), 7.33 (s, 1H),
8.51 (s, 1H), 11.65 (br s, 1H). 13C NMR (DMSO-d6) 55.17
(OCH3), (108.52 (s, CHvCCF3)), 113.92 and 130.50
(HCortho and HCmeta or vice versa), 121.82 (q, Jˆ274 Hz,
CF3), 126.05 and 126.79 (2×Cquat), 146.26 (q, Jˆ33 Hz,
CCF3), 150.89 (CHvCAr), 159.29 (COCH3), 162.09
(C–OH). EIMS (70 eV) m/z (rel. int.) 270 (Mϩϩ1, 15),
269 (Mϩ, 100), 254 (20), 206 (30), 178 (9), 158 (5), 128
(8), 77 (6), 69 (3), 63 (6), 51 (7). Anal. Calcd for
C13H10F3NO2: C, 58.00; H, 3.74. Found: C, 58.12; H, 3.97.
(E)-6-Dimethylamino-1,1,1-trifluoro-5-hydroxy-5-(4-
methoxyphenyl)-5-hexene-2,4-dione (6). To a vigorously
stirred suspension of potassium tert-butoxide (4.2 g,
37 mmol) in dry Et2O (70 mL) was added dropwise a solu-
tion of enaminoketone 5 (4.1 g, 19 mmol) and ethyl
trifluoroacetate (3.9 mL, 33 mmol) in 10 mL of dry Et2O
at 0ЊC over a period of 15 min. The reaction mixture was
refluxed for 9 h, then cooled to 0ЊC and quenched by careful
addition of glacial acetic acid (2.1 mL, 37 mmol) followed
by water (10 mL). The aqueous layer was separated and
extracted with Et2O (10 mL×5). The combined organic
phases were washed with saturated aqueous NaHCO3 solu-
tion and dried over Na2SO4. The solvent was evaporated in
vacuo and the residue was recrystallized to afford 6 as
yellow-green needles (5.4 g, 92%), mp 118–119ЊC (hex-
General procedure for the preparation of 4-amino-
pyridines 9a,b
To a suspension of 4-pyridinol 8a or 8b (10 mmol) in 30 mL
of dry toluene was added tosyl isocyanate (3.5 mL,
23 mmol) in one portion and the reaction mixture was
heated at reflux for 60 h. Then 90% sulphuric acid
(4.0 mL) was added to the stirred solution, cooled to 0ЊC.
The two-phase mixture was warmed at 60ЊC with stirring for
12 h. After cooling to 0ЊC, crushed ice (5 g) was added
followed by 46% aqueous sodium hydroxide (9.5 mL).
The precipitated sodium sulphate was then filtered off and
washed thoroughly with CH2Cl2. The filtrate was extracted
with CH2Cl2 (10 mL×5), the combined organic phases
being washed with brine and dried over Na2SO4. After
evaporation of the solvent, the resulting solid was recrystal-
lized to obtain 4-aminopyridines 9a,b.
ane–EtOAc, 5:1); IR (CCl4) 2530 (br), 1580 cmϪ1 1H
;
NMR 2.36–3.34 (m, 6H), 3.84 (s, 3H), 5.27 (s, 1H), 6.90
and 7.09 (2×d, Jˆ8.5 Hz, 4H), 7.87 (s, 1H), 16.28 (br s, 1H).
Anal. Calcd for C15H16F3NO3: C, 57.14; H, 5.11. Found: C,
57.25; H, 5.28.
5-(4-Methoxyphenyl)-2-(trifluoromethyl)-4H-pyran-4-
one (7b). To a stirred suspension of diketone 6 (5.4 g,
17 mmol) in isopropyl alcohol (30 mL) was added 17 mL
of 6 M HCl. After 3 h of stirring at room temperature
the mixture was deluted with brine (250 mL) and, then,
the solid was filtered off, washed with water and air-dried.
Recrystallization afforded pyranone 7b as colourless
needles (4.1 g, 89%), mp 118–119ЊC (hexane–toluene,
4-Amino-5-phenyl-2-(trifluoromethyl)pyridine (9a). (82%),
mp 93–94ЊC (cyclohexane–toluene, 1:1); IR (CCl4) 3495,
1
2:1); IR (CCl4) 1670, 1650 cmϪ1; H NMR 3.84 (s, 3H),
1
3395, 1610 cmϪ1; H NMR 4.59 (br s, 2H), 6.99 (s, 1H),
6.65 (s, 1H), 6.97 and 7.45 (2×d, Jˆ8.5 Hz, 4H), 7.93 (s,
1H). 13C NMR 55.33 (OCH3), 114.19 and 129.90 (HCortho
and HCmeta or vice versa), (115.43 (q, Jˆ2.5 Hz,
CHvCCF3), 118.35 (q, Jˆ274 Hz, CF3), 121.94 and
130.52 (2×Cquat), 151.74 (CHvCAr)), 152.13 (q,
Jˆ40 Hz, CCF3), 160.36 (COCH3), 176.19 (CvO). EIMS
(70 eV) m/z (rel. int.) 271 (Mϩϩ1, 14), 270 (Mϩ, 100), 269
(26), 255 (10), 133 (9), 132 (74), 117 (32), 102 (7), 89 (50),
75 (12), 69 (17), 63 (26), 62 (10), 51 (16), 50 (11), 39 (14).
Anal. Calcd for C13H9F3O3: C, 57.79; H, 3.36. Found: C,
57.95; H, 3.48.
7.33–7.58 (m, 5H), 8.26 (s, 1H). EIMS (70 eV) m/z (rel.
int.) 239 (Mϩϩ1, 13), 238 (Mϩ, 100), 237 (52), 217 (50),
167 (7), 140 (9), 115 (11), 109 (11), 89 (8), 77 (8), 75 (6), 71
(8), 69 (6), 63 (9), 51 (11), 49 (7), 39 (12). Anal. Calcd for
C12H9F3N2: C, 60.51; H, 3.81. Found: C, 60.62; H, 3.95.
4-Amino-5-(4-methoxyphenyl)-2-(trifluoromethyl)pyri-
dine (9b). (82%), mp 101–102ЊC (cyclohexane–toluene,
1
1:1); IR (CCl4) 3505, 3395, 1610 cmϪ1; H NMR 3.86 (s,
3H), 4.67 (br s, 2H), 6.98 (s, 1H), 7.03 and 7.34 (2×d,

V. I. Tyvorskii et al. / Tetrahedron 56 (2000) 7313–7318
7317
Jˆ8.5 Hz, 4H), 8.20 (s, 1H). 13C NMR 55.35 (OCH3),
106.06 (q, Jˆ2.5 Hz, CHvCCF3), 114.84 and 130.05
(HCortho and HCmeta or vice versa), 122.40 (q, Jˆ274 Hz,
CF3), 124.16 and 126.50 (2×Cquat), 147.34 (q, Jˆ33.5 Hz,
CCF3), 150.13 (CHvCAr), 151.96 (C–NH2), 160.32
(COCH3). EIMS (70 eV) m/z (rel. int.) 269 (Mϩϩ1, 15),
268 (Mϩ, 100), 253 (33), 249 (6), 205 (36), 178 (6), 155
(7), 128 (5), 102 (4), 89 (4), 77 (6), 69 (4), 63 (7), 51 (8), 39
(8). Anal. Calcd for C13H11F3N2O: C, 58.21; H, 4.13. Found:
C, 58.43; H, 4.32.
(br s, 1H), 8.44 (s, 1H), 8.50 (s, 1H), 8.86 (s, 1H). Anal.
Calcd for C14H11F3N2O2: C, 56.76; H, 3.74. Found: C,
56.94; H, 3.97.
General procedure for the cyclization of
acylaminopyridines 10a–d
To a solution of amide 10a–d (3 mmol) in 12 mL of POCl3
was added P2O5 (3 g, 21 mmol). After heating for 15–20 h
at reflux the excess of POCl3 was distilled off at reduced
pressure and the resulting mixture was cooled to 0ЊC and
carefully quenched by the addition of crushed ice (5 g). The
pH was adjusted to 10–11 with aqueous ammonia and
the mixture was then extracted with CH2Cl2 (10 mL×5).
The combined organic phases were washed with brine,
and dried over Na2SO4. After evaporation of the solvent,
the resulting solid was crystallized to obtain benzo-
naphthyridines 11a–d. Compounds 11a,b were sublimated
in vacuo (10 mmHg) prior to crystallization.
Preparation of acetamides 10a,b
Compounds 10a,b were obtained by treatment of
aminopyridines 9a,b (5 mmol) with acetic anhydride
(3.3 mL, 35 mmol) at reflux for 1 h. Excess of anhydride
was evaporated, and the residue was recrystallized to give
colourless crystalline amides 10a,b.
4-Acetamido-5-phenyl-2-(trifluoromethyl)pyridine (10a).
(83%), mp 131.5–132.5ЊC (i-PrOH–cyclohexane, 2:1); IR
6-Methyl-3-(trifluoromethyl)benzo[c][1,6]naphthyridine
(11a). (68%), mp 165.0–165.5ЊC (heptane–i-PrOH, 5:1); IR
1
(CCl4) 3415, 1715 cmϪ1; H NMR 2.10 (s, 3H), 7.34–7.69
1
(CCl4) 1615, 1585 cmϪ1; H NMR 3.11 (s, 3H), 7.82–7.90
(m, 6H), 8.49 (s, 1H), 8.88 (s, 1H). Anal. Calcd for
C14H11F3N2O: C, 60.00; H, 3.96. Found: C, 60.17; H, 4.09.
(m, 1H), 7.96–8.04 (m, 1H), 8.30 (s, 1H), 8.32 (d,
Jˆ8.0 Hz, 1H), 8.76 (d, Jˆ8.0 Hz, 1H), 9.95 (s, 1H).
EIMS (70 eV) m/z (rel. int.) 263 (Mϩϩ1, 15), 262 (Mϩ,
100), 247 (5), 243 (4), 241 (6), 227 (4), 200 (4), 193 (7),
178 (1), 166 (3), 164 (3), 152 (3), 140 (3), 131 (5), 106 (4),
101 (3), 96 (2), 87 (2), 82 (2), 77 (3), 75 (6), 69 (8), 63 (5),
51 (5), 50 (4), 39 (5). Anal. Calcd for C14H9F3N2: C, 64.12;
H, 3.46. Found: C, 64.34; H, 3.61.
4-Acetamido-5-(4-methoxyphenyl)-2-(trifluoromethyl)-
pyridine (10b). (78%), mp 170.5–171.5ЊC (i-PrOH); IR
1
(CHCl3) 3410, 1710 cmϪ1; H NMR 2.11 (s, 3H), 3.89 (s,
3H), 7.09 and 7.31 (2×d, Jˆ8.5 Hz, 4H), 7.58 (br s, 1H),
8.46 (s, 1H), 8.84 (s, 1H). Anal. Calcd for C15H13F3N2O2: C,
58.07; H, 4.22. Found: C, 58.21; H, 4.35.
Preparation of benzamides 10c,d
8-Methoxy-6-methyl-3-(trifluoromethyl)benzo[c][1,6]-
naphthyridine (11b). (71%), mp 205–206ЊC (EtOH–
1
Benzoyl chloride (0.6 mL, 5.3 mmol) was added to a solu-
tion of amines 9a,b (5 mmol) in 3 mL of pyridine, and the
mixture was kept for 24 h at rt. After workup with 10 mL of
water, recrystallization of the precipitated crude product
afforded amides 10c,d.
toluene, 2:1); IR (CHCl3) 1630, 1585 cmϪ1; H NMR 3.07
(s, 3H), 4.04 (s, 3H), 7.56–7.66 (m, 2H), 8.27 (s, 1H), 8.66
(d, Jˆ9.5 Hz, 1H), 9.87 (s, 1H). EIMS (70 eV) m/z (rel. int.)
293 (Mϩϩ1, 18), 292 (Mϩ, 100), 277 (8), 262 (7), 250 (9),
249 (62), 179 (10), 146 (9), 126 (2), 121 (3), 113 (2), 99 (2),
86 (3), 75 (4), 68 (4), 63 (5), 51 (3). Anal. Calcd for
C15H11F3N2O: C, 61.65; H, 3.79. Found: C, 61.83; H, 3.91.
4-Benzamido-5-phenyl-2-(trifluoromethyl)pyridine (10c).
(86%), mp 123.5–124.5ЊC (i-PrOH–toluene, 2:1); IR
1
(CCl4) 3425, 1700 cmϪ1; H NMR 7.39–7.71 (m, 10H),
6-Phenyl-3-(trifluoromethyl)benzo[c][1,6]naphthyridine
(11c). (56%), mp 238.0–238.5ЊC (toluene); IR (CHCl3)
8.38 (br s, 1H), 8.58 (s, 1H), 9.10 (s, 1H). Anal. Calcd for
C19H13F3N2O: C, 66.67; H, 3.83. Found: C, 66.79; H, 3.68.
1610, 1575, 1560 cmϪ1 1H NMR 7.29–7.68 (m, 6H),
;
8.00–8.08 (m, 1H), 8.26 (d, Jˆ8.0 Hz, 1H), 8.47 (s, 1H),
8.87 (d, Jˆ8.0 Hz, 1H), 10.08 (s, 1H). EIMS (70 eV) m/z
(rel. int.) 325 (Mϩϩ1, 8), 324 (Mϩ, 45), 323 (100), 283 (4),
254 (5), 253 (19), 226 (7), 202 (4), 200 (3), 152 (21), 138
(2), 126 (21), 113 (23), 101 (5), 100 (19), 94 (3), 88 (4), 87
(5), 77 (4), 75 (5), 74 (3), 69 (4), 51 (7). Anal. Calcd for
C19H11F3N2: C, 70.37; H, 3.42. Found: C, 70.55; H, 3.60.
4-Benzamido-5-(4-methoxyphenyl)-2-(trifluoromethyl)-
pyridine (10d). (85%), mp 138.5–139.0ЊC (i-PrOH); IR
1
(CHCl3) 3410, 1695 cmϪ1; H NMR 3.92 (s, 3H), 7.14 (d,
Jˆ8.5 Hz, 2H), 7.34–7.71 (m, 7H), 8.40 (br s, 1H), 8.54 (s,
1H), 9.06 (s, 1H). Anal. Calcd for C20H15F3N2O2: C, 64.52;
H, 4.06. Found: C, 64.75; H, 4.23.
4-Formamido-5-(4-methoxyphenyl)-2-(trifluoromethyl)-
pyridine (10e). Compound 10e was obtained from amino-
pyridine 9b (1.3 g, 5 mmol) in dry THF (4 mL) under the
action of a formylating mixture prepared from formic acid
(0.9 mL, 23 mmol) and acetic anhydride (2.1 mL,
23 mmol). After standing for 48 h at rt the mixture was
evaporated to dryness at reduced pressure. The residue
was recrystallyzed to afford formamide 10e (1.3 g, 90%),
mp 161–162ЊC (i-PrOH); IR (CHCl3) 3400, 1730 cmϪ1; 1H
NMR 3.89 (s, 3H), 7.09 and 7.31 (2×d, Jˆ8.5 Hz, 4H), 7.64
8-Methoxy-6-phenyl-3-(trifluoromethyl)benzo[c][1,6]-
naphthyridine (11d). (82%), mp 217–218ЊC (toluene); IR
1
(CCl4) 1625, 1570 cmϪ1; H NMR 3.88 (s, 3H), 7.55–7.82
(m, 7H), 8.43 (s, 1H), 8.76 (d, Jˆ9.0 Hz, 1H), 9.98 (s, 1H).
EIMS (70 eV) m/z (rel. int.) 355 (Mϩϩ1, 21), 354 (Mϩ,
100), 353 (99), 340 (10), 339 (48), 338 (27), 335 (7), 324
(20), 311 (16), 310 (38), 290 (8), 269 (7), 253 (10), 241 (10),
214 (13), 188 (5), 176 (7), 170 (15), 167 (6), 160 (28), 155
(13), 145 (21), 135 (6), 130 (13), 127 (7), 120 (18), 113 (14),
107 (20), 100 (10), 93 (10), 87 (6), 69 (5), 63 (7), 51 (8).

7318
V. I. Tyvorskii et al. / Tetrahedron 56 (2000) 7313–7318
7. Ninomiya, I.; Kiguchi, T.; Yamauchi, S.; Naito, T. J. Chem.
Soc., Perkin Trans. 1 1976, 1861–1865.
Anal. Calcd for C20H13F3N2O: C, 67.80; H, 3.70. Found: C,
67.98; H, 3.93.
8. Spivey, A. C.; Fekner, T.; Spey, S. E.; Adams, H. J. Org. Chem.
1999, 64, 9430–9443.
9. Tyvorskii, V. I.; Bobrov, D. N.; Kulinkovich, O. G.; De Kimpe,
N.; Abbaspour Tehrani, K. Tetrahedron 1998, 54, 2819–2826.
10. Tyvorskii, V. I.; Stanishevskii, L. S.; Tischenko, I. G. Khim.
Geterotsikl. Soedin. 1978, 897–900.
Acknowledgements
We are indebted to INTAS (project 97-0217) for financial
support of this work.
11. The regioselectivity in the cleavage of oxiranes is discussed in
a number of reviews and papers, for example: (a) Semenova, S. N.;
El Sadani, S. K.; Karavan, V. S.; Temnikova, T. I. Zh. Org. Khim.
1981, 17, 983–986. (b) Kirk, D. N. Chem. Ind. 1973, 109–116.
(c) Parker, R. E.; Isaaks, N. S. Chem. Rev. 1959, 59, 737–799.
12. Sosnovskikh, V. Ya.; Mel’nikov, M. Yu.; Kutsenko, V. A. Izv.
Akad. Nauk, Ser. Khim. 1997, 1553–1554.
13. Clark, B. P.; Ross, W. J.; Todd, A. Ger. Offen. DE 3,012,597,
1980; Chem. Abstr. 1981, 94, 83945b.
14. Watkins, W. J.; Robinson, G. E.; Hogan, P. J.; Smith, D. Synth.
Commun. 1994, 24, 1709–1713.
15. Vgeli, U.; Philipsborn, W. Org. Magn. Reson. 1973, 5, 551–
559.
16. Juday, R. E. J. Am. Chem. Soc. 1953, 75, 4071–4074.
17. Tyvorskii, V. I.; Kukharev, A. S. Zh. Org. Khim. 1993, 29,
1019–1023.
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