Polyfluorobenzoyl chlorides and isothiocyanates in reactions with CH-reactive benzimidazoles

Article abstract of DOI:10.1007/s11172-005-0312-6

Reactions of 2-benzoylmethylbenzimidazole with tetra- and pentafluorobenzoyl chlorides afford fluorine-containing 6-benzoyl-7H- benzimidazo[3,2-a]quinolones. 2-Cyanomethyl- or 2-benzoylmethylbenzimidazole reacts with tetra(penta) fluorobenzoyl isothiocyanates to give fluorine containing 1,3-benzothiazinones, which differently behave in reactions with cycloalkylimines.

Full text of DOI:10.1007/s11172-005-0312-6

Russian Chemical Bulletin, International Edition, Vol. 54, No. 3, pp. 733—737, March, 2005
733
Polyfluorobenzoyl chlorides and isothiocyanates in reactions
with CHꢀreactive benzimidazoles
E. V. Nosova,a G. N. Lipunova,a A. A. Laeva,a and V. N. Charushinb
ꢀ
aUral State Technical University,
19 ul. Mira, 620002 Ekaterinburg, Russian Federation.
Fax: +7 (343) 374 0458. Eꢀmail: charushin@prm.uran.ru
bI. Ya. Postovskii Institute of Organic Synthesis,
Ural Division of the Russian Academy of Sciences,
22 ul. S. Kovalevskoi, 620219 Ekaterinburg, Russian Federation.
Fax: +7 (343) 374 1189. Eꢀmail: charushin@ios.uran.ru
Reactions of 2ꢀbenzoylmethylbenzimidazole with tetraꢀ and pentafluorobenzoyl chlorides
afford fluorineꢀcontaining 6ꢀbenzoylꢀ7Hꢀbenzimidazo[3,2ꢀa]quinolones. 2ꢀCyanomethylꢀ or
2ꢀbenzoylmethylbenzimidazole reacts with tetra(penta)fluorobenzoyl isothiocyanates to give
fluorineꢀcontaining 1,3ꢀbenzothiazinones, which differently behave in reactions with
cycloalkylimines.
Key words: 2ꢀcyanomethylbenzimidazole, 2ꢀbenzoylmethylbenzimidazole, polyfluoroꢀ
benzoyl chlorides, polyfluorobenzoyl isothiocyanates, fluorobenzimidazo[a]quinolones, fluoꢀ
rineꢀcontaining 1,3ꢀbenzothiazinones.
A considerable number of [a]ꢀannelated derivatives of
fluoroquinolonecarboxylic acids have found to exhibit a
high bactericidal activity.1—9 For construction of such
systems, heterocyclic derivatives of acetonitriles and keꢀ
tones are widely used as CHꢀreactive reagents.10—13 For
instance, reactions of 2ꢀcyanomethylbenzimidazole with
polyfluorobenzoyl chlorides yielded new fluorineꢀcontainꢀ
ing benzimidazo[1,2ꢀa]quinolones.14 Benzoyl chlorides
are key intermediate products for the synthesis of benzoyl
isothiocyanates, which are promising precursors of a variꢀ
ety of azaheterocycles.15 The presence of a halogen atom
in the orthoꢀposition of the latter allows not only an attack
on the carbonyl group of the intermediate but also a comꢀ
petitive pathway involving intramolecular replacement of
the halogen atom to give 2ꢀsubstituted 1,3ꢀbenzothiazinꢀ
ones.16 Recently, polyfluorobenzoyl isothiocyanates were
used to construct new fluorineꢀcontaining 1,3ꢀbenzoꢀ
thiazinones.17 Recent studies18,19 of the cyclocondensaꢀ
tion of isocyanates with cyanomethylbenzothiazole and
other C,Nꢀdinucleophiles showed that this approach is
promising for the synthesis of annelated azaheterocycles.
In continuation of our studies into structural modifiꢀ
cation of fluoroquinolones,14,20—23 we synthesized fluoꢀ
rineꢀcontaining 6ꢀbenzoylbenzimidazo[3,2ꢀa]quinolones
3a—d. Roomꢀtemperature reactions of polyfluorobenzoyl
chlorides 1a,b with 2ꢀbenzoylmethylbenzimidazole 2a in
methylene dichloride in the presence of triethylamine afꢀ
forded tetracyclic imidazoquinolines 3a,d in 73 and 81%
yields, respectively (Scheme 1). Intermediates A, which
are analogous to 2ꢀ(1,3ꢀdihydrobenzimidazolꢀ2ꢀylidene)ꢀ
3ꢀoxoꢀ3ꢀ(polyfluorophenyl)propionitriles,14 were isolated
neither under the above conditions nor upon the reaction
of reagents 1a,b and 2a in boiling toluene.
1
The H NMR spectra of compounds 3a,d contain a
broadened singlet for the NH group, unsymmetrical mulꢀ
tiplets for the H(8)—H(11) protons of the benzimidazole
fragment, and signal for the benzoyl protons. The
1H NMR spectrum of quinolone 3a shows a characteristic
3
4
5
signal for H(4) (ddd, J = 9.0 Hz, J = 7.8 Hz, J =
2.2 Hz). The 19F NMR spectrum of compound 3a conꢀ
tains signals for three fluorine atoms, which indicates the
replacement of one F atom in the formation of the cyclic
system. The mass spectra of benzimidazoquinolones 3a,d
contain highly intense molecular ion peaks [M]+ and
[M – 1]+, which, as with 6ꢀcyano derivatives,14 suggest a
high stability of the aromatic tetracyclic system.
2ꢀCycloalkylimino derivatives 3b,c were synthesized
without isolation of the corresponding 2ꢀfluoroquinoꢀ
1
lone 3a. According to H NMR data, heating of comꢀ
pounds 1a and 2a in toluene for 1 h gave a mixture of
1,3ꢀdihydrobenzimidazolꢀ2ꢀylidene intermediate A and
compound 3a in the 7 : 3 ratio. After the toluene was
removed, the residue was refluxed with pyrrolidine or
morpholine in DMF for 5 h to give 2ꢀamino derivaꢀ
tives 3b,c. The replacement of the F(2) atom was conꢀ
cluded from a signal for the H(4) proton (dd, 3J = 8.5 Hz,
1
5J = 1.5 Hz) in the H NMR spectra of quinolones 3b,c.
In addition, these spectra contain signals for NH
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 720—724, March, 2005.
1066ꢀ5285/05/5403ꢀ0733 © 2005 Springer Science+Business Media, Inc.

734
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 3, March, 2005
Nosova et al.
Scheme 1
Benzothiazinones 5b—d were synthesized without isoꢀ
lation of intermediate product B. The starting reagents
2a,b and 4a,b were kept in acetonitrile at room temperaꢀ
ture. The solvent was removed and the residue was reꢀ
fluxed with triethylamine in toluene for 3 h. The strucꢀ
tures of benzothiazinone derivatives 5a—d were confirmed
1
by H NMR and mass spectra (for compound 5a, addiꢀ
1
tionally by 19F NMR data). The H NMR spectra of
compounds 5a—d contain the multiplets at δ 7.25—7.36
and 7.47—7.65 for the benzimidazole fragment and the
broadened signal at δ 13.3—13.4 for NH. The spectra of
trifluoro derivatives 5a,c show the characteristic signal at
3
δ 7.99—8.03 for the H(5) proton (ddd, J = 9.8—10 Hz,
5
4J = 7.5—7.6 Hz, J = 1.8—2.0 Hz). The ylidene strucꢀ
tures of compounds 5a—d agree well with the absence of a
singlet for the methine proton from their 1H NMR specꢀ
tra and with the symmetric signals for the benzimidazole
fragment, a signal for two NH groups being broadened. In
the mass spectra of compounds 5a—d, the intensities of
the peaks of the molecular ions [M]+ are comparatively
low (I < 50%), especially for derivative 5d (I = 3%). At
the same time, the mass spectra of compounds 5a—d
show the characteristic peak of the [ZCN]+ ion (Z is the
substituent in position 2); its intensity for benzothiazinꢀ
ones 5a—c equals 100%. Detachment of ZCN as the maꢀ
jor pathway of fragmentation was observed earlier in the
mass spectra of 2ꢀaryl, 2ꢀheteryl, and 2ꢀpolymethylene
imino derivatives of fluorineꢀcontaining benzothiazinꢀ
ones.17 The spectra of compounds 5c,d containing the
benzoyl fragment show the peaks with m/z 77 and 105,
which corresponds to detachment of C6H5 and C6H5CO.
The 19F NMR spectrum of benzothiazinone 5a contains
multiplets for three fluorine atoms.
1: X = H (a), F (b);
3: X= H, R1 = F (а),
(b),
(c), X = R1 = F (d)
Aminodefluorination reactions of benzothiazinones
5a—d were also studied. As expected, compounds 5a,b
(R = CN) reacted with morpholine to give compounds
7b,c through replacement of F(7) for 5a or F(5) and F(7)
for 5b by the morpholine residue. The 1H NMR spectrum
of product 7b shows the characteristic signal at δ 7.76
for the H(5) proton (dd, J = 12.2 Hz, J = 1.6 Hz)
in addition to the signals for the benzimidazole and
morpholine residues. The mass spectrum of compound 7b
contains the molecular ion peak with m/z 439 (I = 59%);
the peak of ZCN (m/z 182) is most intense, as with the
starting reagent 5a. The structure of compound 7c was
confirmed by 1H and 19F NMR data.
The reaction of benzothiazinone 5c (R = COPh) with
morpholine followed a different pathway: the amine resiꢀ
due replaced not only F(7) but also the group in posiꢀ
tion 2 to give 2,7ꢀbis(morpholinꢀ4ꢀyl)benzothiazinꢀ
one (6a). The 1H NMR spectrum of product 6a shows no
signals for the protons of the benzimidazole and benzoyl
fragments, but it contains signals for the protons of
two morpholine residues. The mass spectrum of comꢀ
pound 6a contains an intense molecular ion peak and the
(δ 12.5—12.6), the amine residue, and the protons of the
benzimidazole and benzoyl fragments. In the mass specꢀ
trum of compound 3c, the peak [M – H]+ is most intense.
The proposed method for the synthesis of compounds
3b,c is more convenient than aminodefluorination of comꢀ
pound 3a (compounds 3b,c were obtained in higher
yields).
Polyfluorobenzoyl isothiocyanates 4a,b prepared from
the corresponding polyfluorobenzoyl chlorides 1a,b were
studied in reactions with 2ꢀcyanomethylꢀ and 2ꢀbenzoylꢀ
methylbenzimidazoles 2a,b. In the roomꢀtemperature reꢀ
action between compounds 4a and 2a in acetonitrile
for 1 h, the methylene fragment of compound 2a added to
the N=C bond of isothiocyanate 4a and subsequent cyꢀ
clization gave benzothiazinone 5a (Scheme 2). However,
under the above conditions, product 5a was obtained only
as a mixture with compound B (B : 5a = 9 : 10, 19F NMR
data). Heating of the mixture with triethylamine in toluꢀ
ene for 3 h afforded individual benzothiazinone 5a in 72%
yield.
3
5

Reactions of CHꢀreactive benzimidazoles
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 3, March, 2005
735
Scheme 2
2: R1 = COPh (a), CN (b); 5: R1 = CN, X = H (a), F (b); R1 = COPh, X = H (c), F (d);
6: R2 = morpholinꢀ4ꢀyl (a), 4ꢀethoxycarbonylpiperazinꢀ1ꢀyl (b);
7: R1 = COPh, R3 = morpholinꢀ4ꢀyl (a); R1 = CN, R3 = H (b), morpholinꢀ4ꢀyl (c)
100%ꢀintensity peak [M – (morpholinꢀ4ꢀyl)CN]+ charꢀ
acteristic of benzothiazinone fragmentation. Similarly,
benzothiazinone 5c reacted with 1ꢀethoxycarbonylpiperꢀ
azine to give compound 6b. In the case of 5,6,7,8ꢀtetraꢀ
fluorobenzothiazinone 5d, the morpholine residue reꢀ
placed only the F(5) and F(7) atoms, as with comꢀ
pound 5b, while the group in position 2 was retained
(product 7a). Obviously, introduction of the electronꢀ
donating amine residues lowers the electrophilicity of the
C(2) atom, thus impeding nucleophilic substitution for
the group in position 2. Structure 7a was confirmed by 1H
and 19F NMR data.
benzimidazole 2b was synthesized by condensation of ethyl
cyanoacetate with oꢀphenylenediamine according to a known
procedure.24
6ꢀBenzoylꢀ1,2,3ꢀtrifluoroꢀ7Hꢀbenzimidazo[1,2ꢀa]quinolinꢀ5ꢀ
one (3a). A solution of tetrafluorobenzoyl chloride 1a (0.53 g,
2.5 mmol) in toluene (2 mL) and triethylamine (0.7 mL, 0.51 g,
5 mmol) were added to a suspension of 2ꢀbenzoylmethylꢀ
benzimidazole 2a (0.6 g, 2.5 mmol) in dry methylene dichloride
(10 mL). The reaction mixture was kept at room temperature for
a day and concentrated. The residue was washed with water and
recrystallized from DMSO. The yield of compound 3a was 0.72 g
1
(73%), m.p. > 250 °C. H NMR (DMSOꢀd6), δ: 7.41 (m, 3 H,
Ph); 7.54 (m, 2 H, Ph); 7.62 (m, 1 H, benzimid.); 7.67 (m,
3
4
2 H, benzimid.); 8.19 (ddd, H(4), J = 9.0 Hz, J = 7.8 Hz,
5J = 2.2 Hz); 8.61 (m, 1 H, benzimid.); 12.6 (br.s, 1 H,
Thus, we obtained new derivatives of benzimidꢀ
azo[1,2ꢀa]quinolones and fluorinated 1,3ꢀbenzothiazinꢀ
ones, which are of interest for biological tests.
NH). 19F NMR (DMSOꢀd6), δ : 8.40, 21.87, 31.48 (all m,
F
1 F each). MS, m/z: 392 [M+] (100), 391 (99), 315 (24), 287
(24), 259 (14), 105 (52), 77 (53), 51 (12). Found (%): C, 67.40;
H, 2.87; N, 7.08. C22H11F3N2O2. Calculated (%): C, 67.35;
H, 2.83; N, 7.14.
Experimental
1
H NMR spectra were recorded on Bruker WMꢀ250 and
6ꢀBenzoylꢀ1,2,3,4ꢀtetrafluoroꢀ7Hꢀbenzimidazo[1,2ꢀa]quinoꢀ
linꢀ5ꢀone (3d) was obtained analogously in 81% yield,
m.p. > 250 °C. 1H NMR (DMSOꢀd6), δ: 7.33 (m, 3 H, Ph); 7.34
(m, 2 H, Ph); 7.36 (m, 1 H, benzimid.); 7.37 (m, 2 H, benzimid.);
8.59 (m, 1 H, benzimid.); 12.5 (br.s, 1 H, NH). MS, m/z: 410
[M+] (100), 409 (87), 391 (13), 390 (18), 333 (25), 305 (19), 277
(17), 105 (59), 102 (16), 77 (64), 76 (11), 51 (14). Found (%):
C, 64.35; H, 2.42; N, 6.87. C22H10F4N2O2. Calculated (%):
C, 64.40; H, 2.46; N, 6.83.
Bruker DRXꢀ400 spectrometers (250.14 and 400.13 MHz, reꢀ
spectively). 19F NMR spectra were recorded on a Bruker
DRXꢀ400 spectrometer (376.45 MHz). Tetramethylsilane
(1H NMR) and hexafluorobenzene (19F NMR) were used as the
internal standards. Mass spectra were recorded on a Varian
MAT 311A spectrometer (accelerating voltage 3 kV, cathode
emission current 300 µA, energy of ionizing electrons 70 eV,
direct inlet probe).
2ꢀBenzoylmethylbenzimidazole 2a was prepared from
2ꢀmethylbenzimidazole as described earlier;13 2ꢀcyanomethylꢀ
6ꢀBenzoylꢀ1,3ꢀdifluoroꢀ2ꢀpyrrolidinoꢀ7Hꢀbenzimidꢀ
azo[1,2ꢀa]quinolinꢀ5ꢀone (3b). A solution of tetrafluorobenzoyl

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Nosova et al.
chloride 1a (0.74 g, 3.5 mmol) in toluene (3 mL) was added to
a suspension of 2ꢀbenzoylmethylbenzimidazole 2a (0.6 g,
2.5 mmol) in dry toluene (15 mL). The reaction mixture was
refluxed for 1 h and filtered hot and the filtrate was concenꢀ
trated. Dimethylformamide (5 mL) and pyrrolidine (0.5 mL,
0.43 g, 6 mmol) were added and the mixture was refluxed for 4 h
and then cooled. Water (15 mL) was added and the precipitate of
compound 3b was filtered off, washed with ethanol, and recrysꢀ
tallized from DMSO. The yield of compound 3b was 0.69 g
zo[e][1,3]thiazinꢀ2ꢀyl)acetonitrile (5a) was filtered off, washed
with water, and recrystallized from DMSO. The yield of comꢀ
pound 5a was 1.2 g (72%), m.p. > 310 °C. 1H NMR (DMSOꢀd6),
δ: 7.29, 7.65 (both m, 2 H each, benzimid.); 8.03 (ddd, H(5),
4
5
3J = 9.8 Hz, J = 7.5 Hz, J = 2.0 Hz); 13.4 (br.s, 2 H, NH).
19F NMR (DMSOꢀd6), δ : 7.80, 23.65, 26.67 (all m, 1 F each).
F
MS, m/z: 372 [M+] (31), 183 (12), 182 (100), 177(13).
Found (%): C, 54.90; H, 1.98; N, 14.97. C17H7F3N4OS. Calcuꢀ
lated (%): C, 54.84; H, 1.90; N, 15.05.
1
(62%), m.p. > 250 °C. H NMR (DMSOꢀd6), δ: 1.97 (m, 4 H,
Compounds 5b—d were obtained analogously.
(CH2)2); 3.75 (m, 4 H, N(CH2)2); 7.13, 7.25—7.35 (both m,
(1,3ꢀDihydrobenzimidazolꢀ2ꢀylidene)(5,6,7,8ꢀtetrafluoroꢀ4ꢀ
oxoꢀ4Hꢀbenzo[e][1,3]thiazinꢀ2ꢀyl)acetonitrile (5b). The yield was
76%, m.p. > 310 °C. 1H NMR (DMSOꢀd6), δ: 7.30, 7.62
(both m, 2 H each, benzimid.); 13.3 (br.s, 2 H, NH). MS, m/z:
390 [M+] (16), 182 (100), 103 (20), 63 (11). Found (%): C, 52.26;
N, 14.44. C17H6F4N4OS. Calculated (%): C, 52.31; H, 1.54;
N, 14.39.
5
2 H each); 7.42 (dd, 1 H, H(4), 3J = 8.5 Hz, J = 1.5 Hz);
7.40—7.50 (m, 5 H); 12.5 (br.s, 1 H, NH). MS, m/z: 442
[M – H]+ (100), 372 (23), 354 (26), 257 (23), 193 (24), 190 (26),
78 (32), 63 (36), 55 (21). Found (%): C, 70.49; H, 4.38; N, 9.43.
C26H19F2N3O2. Calculated (%): C, 70.42; H, 4.32; N, 9.48.
An analogous reaction with morpholine gave 6ꢀbenzoylꢀ1,3ꢀ
difluoroꢀ2ꢀmorpholinoꢀ7Hꢀbenzimidazo[1,2ꢀa]quinolinꢀ5ꢀone
2ꢀ[Benzoyl(1,3ꢀdihydrobenzimidazolꢀ2ꢀylidene)methyl]ꢀ
6,7,8ꢀtrifluoroꢀ4Hꢀbenzo[e][1,3]thiazinꢀ4ꢀone (5c). The yield
1
(3c) in 58% yield, m.p. 275—277 °C. H NMR (DMSOꢀd6), δ:
1
3.11 (m, 4 H, N(CH2)2); 3.40, 3.80 (both m, 2 H each, OCH2);
7.20—7.45 (m, 5 H, Ph); 7.47 (m, 2 H, benzimid.); 7.60 (m,
1 H, benzimid.); 7.78 (dd, 1 H, H(4), 3J = 8.5 Hz, 5J = 1.5 Hz);
7.86 (m, 1 H, benzimid.); 12.6 (br.s, 1 H, NH). Found (%):
C, 67.91; H, 4.10; N, 9.21. C26H19F2N3O3. Calculated (%):
C, 67.97; H, 4.17; N, 9.15.
was 81%, m.p. 307—309 °C. H NMR (DMSOꢀd6), δ: 7.19 (m,
2 H, Ph); 7.36 (m, 2 H, benzimid.); 7.49 (m, 3 H, Ph); 7.63 (m,
3
4
2 H, benzimid.); 7.99 (ddd, H(5), J = 10.0 Hz, J = 7.6 Hz,
5J = 1.8 Hz); 13.3 (br.s, 2 H, NH). MS, m/z: 451 [M+] (46), 423
(13), 422 (43), 260 (100), 206 (23), 184 (14), 105 (36), 77 (57).
Found (%): C, 61.27; H, 2.74; N, 9.25. C23H12F3N3O2S. Calꢀ
culated (%): C, 61.20; H, 2.68; N, 9.31.
A mixture of (1,3ꢀdihydrobenzimidazolꢀ2ꢀylidene)(6,7,8ꢀ
trifluoroꢀ4ꢀoxoꢀ4Hꢀbenzo[e][1,3]thiazinꢀ2ꢀyl)acetonitrile (5a)
and Nꢀ(2,3,4,5ꢀtetrafluorobenzoyl)cyano(1,3ꢀdihydrobenzimidꢀ
azolꢀ2ꢀylidene)thioacetamide (B). A solution of NH4SCN (0.35 g,
4.5 mmol) in dry acetone (5 mL) was added to a solution of
tetrafluorobenzoyl chloride 1a (0.46 g, 4.5 mmol) in toluene
(1.7 mL). The reaction mixture was kept at 40 °C for 5 min and
NH4Cl was filtered off. A suspension of 2ꢀcyanomethylbenzꢀ
imidazole 2b (0.7 g, 4.5 mmol) in dry acetone (5 mL) was added
to the resulting solution of compound 4a. The reaction mixture
was kept at room temperature for 1 h and the precipitate of a
mixture of products 5a and B was filtered off. 1H NMR
(DMSOꢀd6), δ: 7.29 (m, 2 H, benzimid., 5a); 7.39 (m, 1 H,
H(6´), B); 7.43, 7.63 (both m, 1 H each, benzimid., B); 7.65 (m,
2 H, benzimid., 5a); 7.95 (m, 2 H, benzimid., B); 8.03 (ddd,
H(5), 3J = 9.8 Hz, 4J = 7.5 Hz, 5J = 2.0 Hz, 5a); 13.4 (br.s, 2 H,
NH, 5a); 13.6 (br.s, 2 H, NH, B); 15.3 (br.s, 1 H, NH, B).
2ꢀ[Benzoyl(1,3ꢀdihydrobenzimidazolꢀ2ꢀylidene)methyl]ꢀ
5,6,7,8ꢀtetrafluoroꢀ4Hꢀbenzo[e][1,3]thiazinꢀ4ꢀone (5d). The
yield was 79%, m.p. 268—270 °C. 1H NMR (DMSOꢀd6), δ: 7.25
(m, 2 H, benzimid.); 7.34 (m, 2 H, Ph); 7.47 (m, 2 H, benzimid.);
7.55 (m, 3 H, Ph); 13.3 (br.s, 2 H, NH). MS, m/z: 469 [M+] (3),
261 (54), 260 (80), 206 (11), 156 (12), 105 (54), 77 (100), 51
(11). Found (%): C, 58.92; H, 2.41; N, 8.89. C23H11F4N3O2S.
Calculated (%): C, 58.85; H, 2.36; N, 8.95.
6,8ꢀDifluoroꢀ2,7ꢀdimorpholinobenzo[e][1,3]thiazinꢀ4ꢀone
(6a). Morpholine (0.35 mL, 0.35 g, 4 mmol) was added to a
solution of benzothiazinone 5c (0.4 g, 0.89 mmol) in DMF
(5 mL). The reaction mixture was refluxed for 5 h, cooled, and
diluted with water. The precipitate of compound 6a was filtered
off and recrystallized from DMSO. The yield of compound 6a
was 0.25 g (77%), m.p. > 250 °C. 1H NMR (DMSOꢀd6), δ: 3.27
(m, 4 H, N(CH2)2); 3.72 (m, 8 H, N(CH2)2, O(CH2)2); 3.83
(m, 4 H, O(CH2)2); 7.70 (dd, H(5), 3J = 12.5 Hz, 5J = 1.8 Hz).
MS, m/z: 369 [M+] (55), 327 (10), 257 (100), 215 (10), 199 (55).
Found (%): C, 51.94; H, 4.58; N, 11.44. C16H17F2N3O3S. Calꢀ
culated (%): C, 52.03; H, 4.64; N, 11.38.
19F NMR (DMSOꢀd6), δ : 7.80 (m, 1 F, 5a); 9.47, 12.28
F
(both m, 1 F each, B); 23.65 (m, 1 F, 5a); 25.53 (m, 1 F, B);
26.67 (m, 1 F, 5a); 27.19 (m, 1 F, B). The ratio of compounds
5a and B was 10 : 9.
(1,3ꢀDihydrobenzimidazolꢀ2ꢀylidene)(5ꢀXꢀ6,7,8ꢀtrifluoroꢀ
4ꢀoxoꢀ4Hꢀbenzo[e][1,3]thiazinꢀ2ꢀyl)acetonitriles (5a,b) and
5ꢀXꢀ2ꢀ[benzoyl(1,3ꢀdihydrobenzimidazolꢀ2ꢀylidene)methyl]ꢀ
6,7,8ꢀtrifluoroꢀ4Hꢀbenzo[e][1,3]thiazinꢀ4ꢀones (5c,d). A soluꢀ
tion of NH4SCN (0.35 g, 4.5 mmol) in dry acetone (5 mL) was
added to a solution of tetrafluorobenzoyl chloride 1a (0.46 g,
4.5 mmol) in toluene (1.7 mL). The reaction mixture was kept at
40 °C for 5 min and NH4Cl was filtered off. A suspension of
2ꢀcyanomethylbenzimidazole 2b (0.7 g, 4.5 mmol) in dry acꢀ
etone (5 mL) was added to the resulting solution of isothioꢀ
cyanate 4a. The reaction mixture was kept at ~20 °C for 1 h and
the precipitate that formed was filtered off. The precipitate was
refluxed with triethylamine (1.35 mL, 9 mmol) in toluene
(15 mL) for 3 h. On cooling, the precipitate of (1,3ꢀdiꢀ
hydrobenzimidazolꢀ2ꢀylidene)(6,7,8ꢀtrifluoroꢀ4ꢀoxoꢀ4Hꢀbenꢀ
2,7ꢀBis(4ꢀethoxycarbonylpiperazinꢀ1ꢀyl)ꢀ6,8ꢀdifluorobenꢀ
zo[e][1,3]thiazinꢀ4ꢀone (6b) was obtained analogously from
compound 5c and 1ꢀethoxycarbonylpiperazine. The yield
of compound 6b was 67%, m.p. 245—247 °C. 1H NMR
(DMSOꢀd6), δ: 1.23, 1.25 (both t, 3 H each, Me); 3.28, 3.53,
3.58, 3.87 (all m, 4 H each, N(CH2)2); 4.07, 4.11 (both q,
2 H each, OCH2); 7.72 (dd, H(5), J = 12.5 Hz, J = 1.8 Hz).
MS, m/z: 511 [M+] (35), 398 (14), 397 (24), 396 (43), 384 (15),
383 (71), 328 (21), 313 (14), 308 (17), 226 (18), 214 (21), 213
(17), 199 (22), 141 (17), 128 (16), 115 (15), 84 (12), 70 (14), 57
(11), 56 (100). Found (%): C, 51.72; H, 5.37; N, 13.61.
C22H27F2N5O5S. Calculated (%): C, 51.66; H, 5.32; N, 13.69.
2ꢀ[Benzoyl(1,3ꢀdihydrobenzimidazolꢀ2ꢀylidene)methyl]ꢀ6,8ꢀ
difluoroꢀ5,7ꢀdimorpholinꢀ4ꢀylꢀ4Hꢀbenzo[e][1,3]thiazinꢀ4ꢀone
(7a). Morpholine (0.42 mL, 0.42 g, 4.8 mmol) was added to a
3
5

Reactions of CHꢀreactive benzimidazoles
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 3, March, 2005
737
solution of compound 5d (0.56 g, 1.19 mmol) in DMF (5 mL).
The reaction mixture was refluxed for 5 h, cooled, and diluted
with water. The precipitate of compound 7a was filtered off and
recrystallized from ethanol. The yield of compound 7a was 0.47 g
(65%), m.p. > 250 °C. 1H NMR (DMSOꢀd6), δ: 3.19, 3.39
(both m, 4 H each, N(CH2)2); 3.48, 3.71 (both m, 4 H each,
O(CH2)2); 7.15 (m, 2 H, benzimid.); 7.45 (m, 3 H, Ph); 7.54
(m, 2 H, Ph); 7.78 (m, 2 H, benzimid.); 12.9 (br.s, 2 H, NH).
4. M. Taguchi, H. Kondo, Y. Inoue, Y. Kawahata, Y. Jinbo,
F. Sakamoto, and G. Tsukamoto, J. Med. Chem.,
1992, 35, 94.
5. Y. Inoue, H. Kondo, M. Taguchi, J. Jinbo, F. Sakamoto,
and G. Tsukamoto, J. Med. Chem., 1994, 37, 586.
6. Y. Jinbo, H. Kondo, M. Taguchi, F. Sakamoto, and
G. Tsukamoto, J. Org. Chem., 1994, 59, 6057.
7. H. Kondo, M. Taguchi, Y. Inoue, F. Sakamoto, and
Y. Tsukamoto, J. Med. Chem., 1990, 33, 2012.
19F NMR (DMSOꢀd6), δ : 32.28, 33.35 (both m, 1 F each).
F
Found (%): C, 61.75; H, 4.54; N, 11.53. C31H27F2N5O4S. Calꢀ
culated (%): C, 61.69; H, 4.48; N, 11.61.
8. J. Segawa, K. Kazuno, M. Matsuoka, I. Shirahase, M. Ozaki,
M. Matsuda, Y. Tomii, M. Kitano, and M. Kise, Chem.
Pharm. Bull., 1995, 43, 63.
9. D. Barret, H. Sasaki, T. Kinoshita, A. Fujikawa, and
K. Sakane, Tetrahedron, 1996, 52, 8471.
10. Yu. M. Volovenko, A. G. Nemazanyi, I. G. Ryabokon´, and
F. S. Babichev, Ukr. Khim. Zh., 1988, 54, 295.
11. F. S. Babichev, Yu. M. Volovenko, A. G. Nemazanyi, and
S. I. Tyukhtenko, Ukr. Khim. Zh., 1986, 52, 506.
12. F. S. Babichev, V. K. Patratii, Yu. M. Volovenko, N. G.
Prodanchuk, V. G. Sinchenko, A. G. Nemazanyi, and T. A.
Silaeva, Khim.ꢀFarm. Zh., 1989, 23, 834 [Pharm. Chem. J.,
1989, 23 (Engl. Transl.)].
13. I. B. Dzvinchuk, M. O. Lozinskii, and A. V. Vypirailenko,
Zh. Org. Khim., 1994, 30, 909 [Russ. J. Org. Chem., 1994, 30
(Engl. Transl.)].
14. G. N. Lipunova, E. V. Nosova, P. V. Vasil´eva, and V. N.
Charushin, Izv. Akad. Nauk, Ser. Khim., 2003, 436 [Russ.
Chem. Bull., Int. Ed., 2003, 52, 457].
15. El. H. E. Gabal and Abd El. M. Fatma, Heterocycles, 1986,
24, 349.
16. D. Koscik, P. Kristian, and J. Gonda, Collect. Czech. Chem.
Commun., 1983, 48, 3320.
17. E. V. Nosova, G. N. Lipunova, A. A. Laeva, N. N.
Mochul´skaya, and V. N. Charushin, Karbonil´nye
soedineniya v sinteze geterotsiklov [Carbonyl Compounds in the
Syntheses of Heterocycles], Saratov, 2004, 209 (in Russian).
18. M. V. Vovk, P. S. Lebed´, A. I. Cherpega, V. V. Pirozhenko,
V. I. Boiko, and I. F. Tsimbal, Khim. Geterotsikl. Soedin.,
2004, 52 [Chem. Heterocycl. Compd., 2004 (Engl. Transl.)].
19. M. V. Vovk, P. S. Lebed´, V. A. Sukach, and M. Yu. Kornilov,
Zh. Org. Khim., 2003, 39, 1852 [Russ. J. Org. Chem., 2003, 39
(Engl. Transl.)].
20. G. N. Lipunova, G. A. Mokrushina, E. V. Nosova, L. I.
Rusinova, and V. N. Charushin, Mendeleev Commun.,
1997, 109.
21. V. N. Charushin, G. N. Lipunova, E. V. Nosova, L. P.
Sidorova, and O. M. Chasovskikh, Mendeleev Commun.,
1998, 131.
(1,3ꢀDihydrobenzimidazolꢀ2ꢀylidene)(6,8ꢀdifluoroꢀ7ꢀ
morpholinꢀ4ꢀylꢀ4ꢀoxoꢀ4Hꢀbenzo[e][1,3]thiazinꢀ2ꢀyl]acetonitrile
(7b). Morpholine (0.47 mL, 0.47 g, 5.4 mmol) was added to a
solution of compound 5a (0.5 g, 1.34 mmol) in DMF (5 mL).
The reaction mixture was refluxed for 5 h, cooled, and diluted
with water. The precipitate of compound 7b was filtered off and
recrystallized from DMSO. The yield of compound 7b was 0.4 g
1
(68%), m.p. > 250 °C. H NMR (DMSOꢀd6), δ: 3.41 (m, 4 H,
N(CH2)2); 3.56 (m, 4 H, O(CH2)2); 7.34, 7.63 (both m,
2 H each, benzimid.); 7.76 (dd, H(5), 3J = 12.2 Hz, 5J = 1.6 Hz);
13.2 (br.s, 2 H, NH). MS, m/z: 439 [M+] (59), 338 (52), 337
(20), 324 (15), 322 (27), 258 (63), 257 (82), 215 (23), 199 (70),
182 (100), 103 (23), 91 (24), 84 (25), 77 (24). Found (%):
C, 57.29; H, 3.38; N, 16.01. C21H15F2N5O2S. Calculated (%):
C, 57.35; H, 3.41; N, 15.93.
(1,3ꢀDihydrobenzimidazolꢀ2ꢀylidene)(6,8ꢀdifluoroꢀ5,7ꢀdiꢀ
morpholinꢀ4ꢀylꢀ4ꢀoxoꢀ4Hꢀbenzo[e][1,3]thiazinꢀ2ꢀyl)acetonitrile
(7c). Morpholine (0.42 mL, 0.42 g, 4.8 mmol) was added to a
solution of compound 5b (0.45 g, 1.15 mmol) in DMF (5 mL).
The reaction mixture was refluxed for 5 h, cooled, and diluted
with water. The precipitate of compound 7c was filtered off and
recrystallized from DMSO. The yield of compound 7c was 0.37 g
(62%), m.p. > 250 °C. 1H NMR (DMSOꢀd6), δ: 3.14, 3.28
(both m, 4 H each, N(CH2)2); 3.70 (m, 8 H, 2×O(CH2)2); 7.29,
7.62 (both m, 2 H each, benzimid.); 13.2 (br.s, 2 H, NH).
19F NMR (DMSOꢀd6), δ : 33.41, 33.51 (both m, 1 F each).
F
Found (%): C, 57.29; H, 4.27; N, 15.95. C25H22F2N6O3S. Calꢀ
culated (%): C, 57.25; H, 4.20; N, 16.03.
This work was financially supported by the Russian
Foundation for Basic Research (Project Nos. 03ꢀ03ꢀ32254
and 04ꢀ03ꢀ96107ꢀUral), the Ministry of Education of the
Russian Federation, and the Civilian Research and Deꢀ
velopment Foundation of the United States (CRDF
Grants Annex BF4M05 and EKꢀ005ꢀX2(RECꢀ005))
within the scope of the Program "Basic Research and
Higher Education" (BRHE 2004 PostꢀDoctoral Fellowꢀ
ship Award, Grant Y2ꢀCꢀ05ꢀ01).
22. G. N. Lipunova, E. V. Nosova, N. N. Mochul´skaya, A. A.
Andreiko, O. M. Chasovskikh, and V. N. Charushin, Izv.
Akad. Nauk, Ser. Khim., 2002, 613 [Russ. Chem. Bull., Int.
Ed., 2002, 51, 663].
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Received January 14, 2005