Fluoro-containing heterocycles: XIII. Fluoro-containing derivatives of thiazolo[3,2-a]-, benzothiazolo[3,2-a]-, and benzimidazo [3,2-a]quinazolinones

Article abstract of DOI:10.1007/s11178-006-0017-9

Reactions of 2-aminothiazole, derivatives of 2-aminobenzothiazole and 2-aminobenzoimidazole with polyfluorobenzoyl chlorides gave rise to acylation products that at heating in the diphenyl ether formed fluoro-containing derivatives of thiazolo[3,2-a]-, be

Full text of DOI:10.1007/s11178-006-0017-9

Russian Journal of Organic Chemistry, Vol. 41, No. 11, 2005, pp. 1671-1677. Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 11, 2005,
pp. 1705-1711.
Original Russian Text Copyright Ó 2005 by Nosova, Lipunova, Laeva, Charushin.
.
Fluoro-containing Heterocycles: XIII. Fluoro-containing
Derivatives of Thiazolo[3,2-a]-, Benzothiazolo[3,2-a]-,
and Benzimidazo[3,2-a]quinazolinones
E.V. Nosova, G.N. Lipunova,A.A. Laeva, and V.N. Charushin
Ural State Technical University, Yekaterinburg, 620002 Russia
Received November 20, 2004
Abstract—Reactions of 2-aminothiazole, derivatives of 2-aminobenzothiazole and 2-aminobenzoimidazole with
polyfluorobenzoyl chlorides gave rise to acylation products that at heating in the diphenyl ether formed fluoro-
containing derivatives of thiazolo[3,2-a]-, benzothiazolo[3,2-a]-, and benzimidazo[3,2-a]quinazolinone.
In the last two decades the chemistry of fluoroquino-
lones and other fluoro-containing heterocycles has
vigorously developed [2–6]. In the series of thiazolo-
[3,2-a]-annelated fluoroquinolones and 1,8-naphthiridin-
4-ones compounds were found possessing high anti-
bacterial [7, 8], and also antitumor and antiviral activity
[9]. [a]-Annelated quinazolinones which may be regarded
as azaanalogs of [a]-annelated quinolones also
demonstrated a wide range of biological activity [10, 11].
In the series of benzimidazo-annelated quinazolinones
highly active immunosuppressors are also known [12].
in the spectra of amides IIIa, IIIc, and IIIe. We failed
to perform the cyclization of compounds IIIa–IIIf into
tetracyclic derivatives IVa–IVf by heating in toluene with
triethylamine, in dimethylformamide in the presence of
cycloalkyl imines, or in acetonitrile using a strong base
like 1,8-diazabicyclo[5.4.0]undec-1-ene, i.e., under
conditions we had previously used in the synthesis of
polycyclic fluoroquinolones and quinazolinones [1, 18, 19].
For instance, the heating of amide IIIe in DMF in the
presence of cycloalkyl imines resulted only in the
replacement of the F4' atom to yield compounds VIa and
VIb whose stucture was confirmed by 1H NMR and mass
spectra (see EXPERIMENTAL).
The reaction of 2-halobenzoyl chlorides with
N,N-dinucleo-philes is a convenient method of building
up [a]- and [b]-annelated quinazolinones [13]. In
publications [14–17] was described the application of this
method to the synthesis of benzimidazo[3,2-a]-, benzo-
thiazolo-[3,2-a]-, benzoxazolo[3,2-a]quinazolin-4-ones,
and also of thiazolo[3',2':1,2]pyrimido[4,5-b]quinazolin-4-
ones, azaanalogs of thiazoloquinazolinones. We described
the fluorinated imidazo[1,2-a]quinazoline-1,2-dicarbo-
nitriles in [1]. However up till now no fluoro-containing
derivatives of thiazolo-, benzothiazolo-, and benzimidazo-
[a]-annelated quinazolinones were synthesized.
However the heating of compounds IIIa–IIIf in the
diphenyl ether proved to be an efficient procedure for
the preparation of tetracyclic quinazolinones IVa–IVf. The
structure of fluoro-containing benzothiazolo[3,2-a]quin-
azolin-4-ones IVa–IVf was confirmed by 1H, 19F NMR,
and mass spectra. Thus in the 1H NMR spectra are retain-
ed proton signals from the benzothiazole fragment, and
a signal from the NH group is lacking; in the spectra of
derivatives IVa, IVc, and IVe (Y = H) the multiplicity of
the signal from H5 is reduced to two doublets of doublets
in the region of d 8.0 ppm, and the 19F NMR spectrum of
compound IVa contains characteristic d.d.d from three
fluorine atoms. The mass spectra of tetracyclic aromatic
compounds IVa–IVf contain strong peaks of the molecular
ions.
We demonstrated that acylation of 2-aminobenzo-
thiazole derivatives IIa–IIc with polyfluorobenzoyl
chlorides Ia and Ib in boiling toluene afforded polyfluoro-
N-(benzothiazol-2-yl)benzamides IIIa–IIIf (Scheme 1).
1H NMR spectra of compounds IIIa–IIIf confirm the
presence of protons belonging to the benzothiazole frag-
ment, NH group (broadened signal at d 13.0–13.5 ppm),
and also possess the characteristic multiplet of the singtle
proton from the tetrafluorobenzene fragment (7.9 ppm)
The boiling of compound IVd with pyrrolidine in DMF
for 5 h resulted in formation of amino derivative V whose
mass spectrum contained the molecular ion (100%), and
in the 1H NMR spectrum the signals from two pyrrolidine
1070-4280/05/4111-1671Ó2005 Pleiades Publishing, Inc.

NOSOVAet al.
1672
Scheme 1.
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,,,jꢁꢁꢁ,,,I
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20H
,9jꢁꢁꢁ,9I
9,jꢂꢁ9,E
9
I,Y= H (a), F (b); II, R1 = R2 = H (a), R1 = H, R2 = OCH3 (b), R1 = R2 = F (c); III, IV, R1 = R2 = H,Y= H (a), F (b); R1 = H, R2 = OCH3,
Y= H (c), F (d); R1 = R2 = F, Y = H (e), F (f); VI, R3 = pyrrolidin-1-yl (a), morpholin-4-yl (b).
Scheme 2.
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;jꢁꢁꢁ;F
VIII, IX, Y = H (a), F (b); X, R3 = pyrrolidin-1-yl (a), morpholin-4-yl (b), 4-ethoxycarbonylpiperazin-1-yl (c).
B
,;jꢀꢁ,;E
moieties were observed. The substitution of F5 and F7
atoms in the tetrafluoro-substituted tetracyclic hetero-
cycles we already mentioned in [20].
to acylation with polyfluorobenzoyl chlorides Ia and Ib in
boiling toluene yielding polyfluoro-N-(thiazol-2-yl)benz-
amides VIIIa and VIIIb (Scheme 2). The H NMR
1
To annelate a thiazole ring to the [a]-edge of the
quinazoline skeleton 2-aminothiazol (VII) was subjected
spectra of amides VIIIa and VIIIb contain characteristic
doublet signals from the protons of the thiazole fragment,
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 11 2005

FLUORO-CONTAINING HETEROCYCLES: XIII.
1673
Scheme 2.
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1
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,jꢀꢁ,Eꢀꢂ
1
+
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;,,
;,,,jꢀꢁ;,,,E
Y = H (a), F (b).
;,9jꢀꢁ;,9E
1
ative XIIIa (Scheme 3). The H NMR spectrum of
compound XIIIa contains a broadened singlet from two
NH groups and two symmetric multiplets from the protons
of the benzimidazole fragment in the region d 7.15 and
7.41 ppm; basing on these data we ascribed an ylidene
structure to compound XIIIa.
and a broadened one-proton singlet from the NH group;
in the spectrum of amide VIIIa a characteristic multiplet
from H6 is present.
Heating of amides VIIIa and VIIIb in the diphenyl
ether for 2 h same as in the case of benzothiazolyl deriv-
atives of polyfluorinated benzamides IIIa–IIIf resulted
in a thermal intramolecular cyclization to afford thiazolo-
[3,2-a]quinazolin-4-ones IXa and IXb. In the 1H NMR
spectrum of compound IXa appeared a characteristic
signal from H5 as two doublets of doublets at d 7.99
ppm, and in the spectra of compounds IXa and IXb were
present the doublets belonging to the thiazole fragments
and were absent the signals of NH groups. The intensity
of molecular ions in their mass spectra reached 100%.
The heating of N-(1,3-dihydrobenzimidazol-2-ylidene)-
2,3,4,5-tetrafluorobenzamide (XIIIa) in diphenyl ether for
3 h as previously had occurred with thiazolyl derivatives
of polyfluorobenzamides IIIa–IIIf and VIIIa, VIIIb
resulted in the thermal intramolecular cyclization affording
benzimidazo[3,2-a]quinazolin-4-one XIVa. The reaction
of pentafluorobenzoyl chloride (Ib) with aminobenz-
imidazole XII in dichloromethane in the presence of
triethylamine at room temperature for 24 h resulted
directly in tetracyclic derivative XIVb. Apparently
intermediate XIIIb is very prone to cyclization. The higher
reactivity in intramolecular cyclization of pentafluoro
derivatives of benzoic acids compared to tetrafluoro
derivatives was reported in [21, 22].
1H NMR spectrum of compound XIVa contained
a characteristic signal from H5 as a doublet of doublets
at d 8.02 ppm. In the spectra of tetracylic derivatives
XIVa and XIVb are observed the signals from a single
NH group in the region 12.9–13.0 ppm; the signals from
aromatic protons of the benzimidazole fragment are
asymmetric, and in the spectrum of XIVa these signals
are displaced downfield as compared to the corresponding
peaks in the spectrum of the intermediate XIIIa.
Molecular ion peaks are the most abundant in the mass
spectra of compounds XIVa and XIVb (m/z 289 and 307
for compounds XIVa and XIVb respectively). No strong
peaks of fragment ions are observed testifying to the
stability of the tetracyclic aromatic system.
It was established that the boiling of (thiazol-2-yl)-
benzamide VIIIa in DMF in the presence of pyrrolidine
led not only to replacement of the F4 atom by the amine
moiety but also to an intramolecular cyclization.As a result
a mixture of compounds Xa and XI was obtained in a
ratio 5:4 (as shown by the 1H NMR spectrum).Apparent-
ly due to the lower melting point of amide VIIIa compared
to those of benzothiazolyl derivatives IIIa–IIIf the thermal
cyclization of the former becomes possible in a lower
boiling solvent than the diphenyl ether. Individual pyrro-
lidinyl drivative Xa was obtained at boiling thiazoloquin-
azolinone IXa with pyrrolidine in DMF. The other
cycloalkylamines also are readily involved into the amino-
defluorination reaction. The structures of the derivatives
1
Xa–Xc obtained are confirmed by their H NMR and
mass spectra; the substitution of the F7 atom is confirmed
by appearance of the H5 signal as a doublet of doublets
3
5
with the coupling constants J 11.6–13.8 and J 1.5–
1.8 Hz.
We applied one more N,N-dinucleophile: 2-aminobenzi-
midazole. The reaction of tetrafluorobenzoyl chloride (Ia)
with 2-aminobenzimidazole (XII) in boiling toluene for
2 h or in dichloromethane in the presence of triethylamine
at room temperature for 24 h afforded acyl deriv-
Hence this study led to preparation of new fluoro-
containing thiazolo-, benzothiazolo-, and benzimidazo[a]-
annelated quinazolinones.
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 11 2005

NOSOVAet al.
1674
EXPERIMENTAL
3J 10.8, 4J 7.1 Hz), 8.21 d.d (1H, H7 or H4, 3J 10.1,
4J 8.2 Hz), 7.92 m (1H, H6'), 13.3 br.s (1H, NH). Mass
spectrum, m/z (Irel, %): 362 (22) [M]+, 177 (100), 149
(25.2). Found, %: C 46.47; Hꢀ. N 7.65. C14H4F6N2OS.
Calculated, %: C 46.42; H 1.11; N 7.73.
1H NMR spectra were registered on spectrometers
Bruker WM-250 and Bruker DRX-400 with operting
frequencies 250.14 and 400.13 MHz respectively, 19F
NMR spectra were recorded on spectrometer Bruker
DRX-500 at operating frequency 376.45 MHz. As
internal references served TMS (1H) and hexafluoro-
benzene (19F), as solvent was used DMSO-d6. Mass
spectra were measured on Varian MAT 311A instrument
at accelerating voltage 3kV, cathode emission current
300 mA, ionizing electrons energy 70 eV, direct sample
admission into the ion source.
Pentafluoro(5,6-difluorobenzothiazol-2-yl)-
benzamide (IIIf). Yield 84%, mp 220–222°C. 1H NMR
spectrum, d, ppm: 8.06 d.d (1H, H4 or H7, 3J 10.3,
4J 7.9 Hz), 8.25 d.d (1H, H7 or H4, 3J 10.1, 4J 8.0 Hz),
13.2 br.s (1H, NH). Found, %: C 44.29; H... N 7.31.
C14H3F7N2OS. Calculated, %: C 44.22; H 0.79; N 7.37.
6,7,8-Trifluorobenzothiazolo[3,2-a]quinazolin-4-
one (IVa). To 1.0 g (3.1 mmol) of amide IIIa was added
3 g of diphenyl ether, and the reaction mixture was boiled
for 2 h. On cooling the precipitate of thiazoloquinazolinone
IVa was filtered off, washed with 2-propanol, and
recrystallized from DMSO. Yield 0.67 g (71%), mp 202–
204°C. 1H NMR spectrum, d, ppm: 7.50 m (1H, benzo-
thiazole), 7.59 m (1H, benzothiazole), 7.87 m (1H, benzo-
thiazole), 8.04 m (2H, H5,benzothiazole). Mass spectrum,
m/z (Irel, %): 306 (100) [M]+, 305 (63), 278 (40), 220
(16), 139 (13). 19F NMR spectrum, d, ppm: 11.48 d.d.d
2,3,4,5-Tetrafluoro(benzothiazol-2-yl)benzamide
(IIIa). To a dispersion of 0.7 g (4.7 mmol) of 2-amino-
benzothiazole IIa in 10 ml of dry toluene was added
1.49 g (7 mmol) of 2,3,4,5-tetrafluorobenzoyl chloride (Ia).
The reaction mixture was heated at reflux for 2 h, and
on cooling the precipitate of compound IIIa was filtered
off and recrystallized from ethanol. Yield 1.2 g (82%),
mp 170–172°C. 1H NMR spectrum, d, ppm: 7.37 m (1H,
benzothiazole), 7.79 m (1H, benzothiazole), 7.92 m (1H,
C6HF4), 7.99 m (1H, benzothiazole), 8.04 m (1H,
benzothiazole), 13.2 br.s (1H, NH). Found, %: C 51.45;
H 1.92; N 8.63. C14H6F4N2OS. Calculated, %: C 51.54;
H 1.85; N 8.58.
3
3
4
(1F, F7, JFF 22.9, JFF 20.2, JFH 8.0 Hz), 27.64 d.d.d
3
3
4
(1F, F6, JFF 22.9, JFH 9.7, JFF 6.5 Hz), 35.69 m (1F,
F8). Found, %: C 54.83; H 1.72; N 9.06. C14H5F3N2OS.
Calculated, %: C 54.91; H 1.65; N 9.15.
Compounds IIIb–IIIf were obtained similarly.
Compounds IVb–IVf were obtained similarly.
Pentafluoro(benzothiazol-2-yl)benzamide (IIIb).
5,6,7,8-Tetrafluorobenzothiazolo[3,2-a]quinazo-
lin-4-one (IVb). Yield 72%, mp 218–220°C. 1H NMR
spectrum, d, ppm: 7.49 m (1H, benzothiazole), 7.57 m
(1H, benzothiazole), 7.78 m (1H, benzothiazole), 8.03 m
(1H, benzothiazole). Mass spectrum, m/z (Irel, %): 324
(100) [M]+, 325 (19), 323 (45), 305 (19), 296 (37), 238
(20). 19F NMR spectrum, d, ppm: 4.05 m (1F), 14.46 m
(1F), 21.02 m (1F), 29.18 m (1F). Found, %: C 51.79;
H...N 8.71. C14H4F4N2OS. Calculated, %: C 51.86;
H 1.24; N 8.64.
1
Yield 86%, mp > 230°C. H NMR spectrum, d, ppm:
7.39 m (1H, benzothiazole), 7.51 m (1H, benzothiazole),
7.81 m (1H, benzothiazole), 8.07 m (1H, benzothiazole),
13.5 br.s (1H, NH). Found, %: C 48.94; Hꢀ N 8.06.
C14H5F5N2OS. Calculated, %: C 48.85; H 1.46; N 8.14.
2,3,4,5-Tetrafluoro(6-methoxybenzothiazol-2-yl)-
benzamide (IIIc). Yield 77%, mp 170–172°C. H NMR
1
spectrum, d, ppm: 3.87 s (3H, OCH3), 7.08 d.d (1H, H5,
3J5,4 8.8, 4J5,7 2.6 Hz), 7.63 d (1H, H7, 4J7,5 2.6 Hz), 7.69
d (1H, H4, 3J4,5 8.8 Hz), 7.91 m (1H, H6'), 13.0 br.s (1H,
NH). Found, %: C 50.49; H 2.22; N 7.93. C15H8F4N2O2S.
Calculated, %: C 50.57; H 2.26; N 7.86.
6,7,8-Trifluoro-62 -methoxybenzothiazolo[3,2-a]-
quinazolin-4-one (IVc). Yield 76%, mp 230–232°C.
1H NMR spectrum, d, ppm: 3.82 s (3H, OCH3), 7.15 d.d
(1H, H52 , 3J52 ,42 9.3, 4J52 ,72 2.7 Hz), 7.69 d (1H, H72 ,
4J72 ,52 2.7 Hz), 7.80 d.d (1H, H42 , 3J42 ,52 9.3, 5J42 ,72
2.1 Hz), 8.03 d.d.d (H5, 3J 9.8, 4J 7.8, 5J 2.0 Hz). Mass
spectrum, m/z (Irel, %): 336 (100) [M]+, 337 (19), 335
(25), 321 (11), 293 (15), 278 (15), 207 (12). Found, %:
C 53.51; H 2.04; N 8.38. C15H7F3N2O2S. Calculated, %:
C 53.57; H 2.10; N 8.33.
Pentafluoro(6-methoxybenzothiazol-2-yl)benz-
amide (IIId). Yield 81%, mp 147–149°C. H NMR
1
spectrum, d, ppm: 3.83 s (3H, OCH3), 7.10 d.d (1H, H5,
3J5,4 8.9, 4J5,7 2.6 Hz), 7.65 d (1H, H7, 4J7,5 2.6 Hz), 7.72
d (1H, H4, 3J4,5 8.9 Hz), 13.4 br.s (1H, NH). Found, %:
C 48.21; H 1.95; N 7.39. C15H7F5N2O2S. Calculated, %:
C 48.14; H 1.89; N 7.48.
2,3,4,5-Tetrafluoro(5,6-difluorobenzothiazol-2-
yl)-benzamide (IIIe). Yield 78%, mp 180–182°C.
1H NMR spectrum, d, ppm: 7.91 d.d (1H, H4 or H7,
5,6,7,8-Tetrafluoro-62 -methoxybenzothiazolo-
[3,2-a]-quinazolin-4-one (IVd). Yield 69%, mp 216–
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 11 2005

FLUORO-CONTAINING HETEROCYCLES: XIII.
1675
1
218°C. 1H NMR spectrum, d, ppm: 3.85 s (3H, OCH3),
7.14 m (1H), 7.72 m (2H). Mass spectrum, m/z (Irel, %):
354 (100) [M]+, 353 (21), 339 (13), 311 (23), 148 (15).
Found, %: C 50.92; H 1.76; N 7.85. C15H6F4N2O2S.
Calculated, %: C 50.85; H 1.71; N 7.91.
the same way. Yield 79%, mp 257–259°C. H NMR
spectrum, d, ppm: 3.29 m [4H, N(CH2)2], 3.73 m [4H,
O(CH2)2], 7.44 d.d.d (1H, H6', 3J 12.5, 4J 6.3, 5J 2.5 Hz),
7.67 d.d (1H, H4 or H7, 3J 11.3, 4J 7.5 Hz), 7.97 d.d (1H,
H7 or H4, 3J 10.0, 4J 8.0 Hz), 12.7 br.s (1H, NH). Found,
%: C 55.19; H 3.02; N 10.80. C18H12F3N3O2S.
Calculated, %: C 55.24; H 3.09; N 10.74.
6,7,8,52,62-Pentafluorobenzothiazolo[3,2-a]-
quinazolin-4-one (IVe). Yield 67%, mp 226–228°C.
3
1H NMR spectrum, d, ppm: 8.04 d.d.d (H5, J 9.8,
2,3,4,5-Tetrafluoro(thiazol-2-yl)benzamide
(VIIIa). To 0.5 g (5 mmol) of 2-aminothiazole VII in
10 ml of dry toluene was added 1.7 g (8 mmol) of
tetrafluorobenzoyl chloride (Ia), the reaction mixture was
heated at reflux for 2 h and filtered while hot. The
precipitate of amide VIIIa separated on cooling was
filtered off and recrystallized from ethanol. Yield 1.0 g
(73%), mp 128–130°C. 1H NMR spectrum, d, ppm: 7.35 d
4J 7.6, 5J 1.9 Hz), 8.17 d.d (1H, H42 , 3J42 ,52 10.5, 4J42 ,62
6.9, 3J42 ,1 1.5 Hz), 8.24 d.d (1H, H72 , 3J72 ,62 9.8, 4J72 ,52
8.0 Hz). Found, %: C 49.08; H...N 8.24. C14H3F5N2OS.
Calculated, %: C 49.13; H 0.88; N 8.18.
5,6,7,8,52 ,62-Hexafluorobenzothiazolo[3,2-a]-
quinazolin-4-one (IVf). Yield 65%, mp 165–167°C.
1H NMR spectrum, d, ppm: 8.12 m (1H, H42 ), 8.23 d.d
(1H, H5, J 3.7 Hz), 7.58 d (1H, H4, J 3.7 Hz),
7.85 m (1H, H6'), 12.9 br.s (1H, NH). Found, %: C 43.55;
H 1.52; N 10.08. C10H4F4N2OS. Calculated, %: C 43.49;
H 1.46; N 10.14.
3
3
3
4
(1H, H72 , J72 ,62 10.0, J72 ,52 8.0 Hz). Found, %:
C 46.64; H...N 7.83. C14H2F6N2OS. Calculated, %:
C 46.68; H 0.66; N 7.78.
2,4-Bis(pyrrolidin-1-yl)-1,3-difluoro-62-methoxy-
thiazol[3,2-a]quinazolin-4-one (V). To 0.45 g
(1.3 mmol) of compound IVa in 5 ml of DMF was added
0.36 g (5.2 mmol) of pyrrolidine. The reaction mixture
was boiled for 5 h, on cooling the solution was diluted
with 15 ml of water, the precipitate of compound V was
filtered off and recrystallized from acetonitrile. Yield
Pentafluoro(thiazol-2-yl)benzamide (VIIIb) was
similarly obtained. Yield 75%, mp 186–188°C. 1H NMR
spectrum, d, ppm: 7.40 d (1H, H5, 3J 3.7 Hz), 7.59 d (1H,
H4, 3J 3.7 Hz), 13.3 br.s (1H, NH). Found, %: C 40.78;
H...N 9.57. C10H3F5N2OS. Calculated, %: C 40.83;
H 1.03; N 9.52.
1
0.43 g (73%), mp 212–214°C. H NMR spectrum, d,
6,7,8-Trifluorothiazolo[3,2-a]quinazolin-4-one
(IXa). To 1.0 g (3.6 mmol) of amide VIIIa was added
2.5 g of diphenyl ether, and the mixture was boiled for
2 h. On cooling the precipitate of thiazoloquinazolinone
IXa was filtered off, washed with 2-propanol, and
ppm: 1.88 m [4H, (CH2)2], 1.95 m [4H, (CH2)2], 3.32 m
[4H, N(CH2)2], 3.66 m [4H, N(CH2)2], 3.83 s (3H,
OCH3), 7.08 d.d (1H, H52 , 3J52 ,42 9.2, 4J52 ,72 2.7 Hz),
7.59 d (1H, H72 , 4J72 ,52 2.7 Hz), 8.73 d (1H, H42 , 3J42 ,52
9.2 Hz). Mass spectrum, m/z (Irel
,
%): 456 (100) [M]+,
recrystallized from DMSO. Yield 0.64 g (69%), mp 246–
428 (44), 413 (16), 387 (34), 386 (46), 228 (40), 70 (17). 248°C. H NMR spectrum, d, ppm: 7.42 d (H52,
1
3
4
5
Found, %: C 60.62; H 4.93; N 12.19. C23H22F2N4O2S.
Calculated, %: C 60.51; H 4.86; N 12.27.
3J 4.8 Hz), 7.99 d.d.d. (H5, J 10.1, J 8.1, J 2.3 Hz),
8.20 d (H42 , 3J 4.8 Hz). Mass spectrum, m/z (Irel
, %): 256
(100) [M]+, 228 (67), 170 (10), 157 (11), 130 (18), 58
(11). Found, %: C 46.95; H...N 10.87. C10H3F3N2OS.
Calculated, %: C 46.88; H 1.18; N 10.93.
N-(5,6-Difluorobenzothiazol-2-yl)-2,3,5-trifluoro-
4-(pyrrolidin-1-yl)benzamide (VIa). To 0.8 g
(2.2 mmol) of amide IIIe in 5 ml of DMF was added
0.62 ml (8.8 mmol) of pyrrolidine. The reaction mixture
was boiled for 5 h and then cooled. The separated
precipitate of compound VIa was filtered off and
recrystallized from DMSO. Yield 0.67 g (81%), mp 265–
267°C. 1H NMR spectrum, d, ppm: 1.93 m [4H, (CH2)2],
5,6,7,8-Tetrafluorothiazolo[3,2-a]quinazolin-4-
one (IXb) was analogously prepared. Yield 64%,
1
mp 248–250°C. H NMR spectrum, d, ppm: 7.45 d
(H52 , 3J 4.8 Hz), 8.21 d (H42, 3J 4.8 Hz). Mass spectrum,
m/z (Irel, %): 274 (100) [M]+, 246 (80), 175 (10), 148
(28), 58 (13). Found, %: C 43.85; HꢀN 10.17.
C10H2F4N2OS. Calculated, %: C 43.80; H 0.74; N 10.22.
3
3.68 m [4H, N(CH2)2], 7.39 d.d.d (1H, H6', J 14.8,
5
3
4J 6.8, J 2.3 Hz), 7.65 d. d (1H, H4 or H7, J 11.5,
4J 7.5 Hz), 7.95 d.d (1H, H7 or H4, 3J 11.5, 4J 7.5 Hz),
12.4 br.s (1H, NH). Found, %: C 57.67; H 3.27; N 11.12.
C18H12F3N3OS. Calculated, %: C 57.59; H 3.22; N 11.19.
6,8-Difluoro-7-(morpholin-4-yl)thiazol[3,2-a]-
quinazolin-4-one (Xb). To 0.6 g (2.3 mmol) of compound
IXa in 5.5 ml of DMF was added 0.76 ml (7.7 mmol) of
morpholine. The reaction mixture was boiled for 5 h and
then evaporated to a half of its volume. The separated
N-(5,6-Difluorobenzothiazol-2-yl)-2,3,5-trifluoro-
4-(morpholin-4-yl)benzamide (VIb) was obtained in
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 11 2005

NOSOVAet al.
1676
precipitate of derivative Xb was filtered off, washed with
of anhydrous toluene was added a solution of 0.81 g
(4 mmol) of tetrafluorobenzoyl chloride (Ia) in 2 ml of
toluene. The reaction mixture was heated at reflux for
2 h; on cooling the separated precipitate of the acylation
product XIIIa was filtered off and recrystallized from
ethanol, and recrystallized from DMSO. Yield 0.6 g
1
(81%), mp 280–282°C. H NMR spectrum, d, ppm:
3.33 m [4H, N(CH2)2], 3.74 m [4H, O(CH2)2], 7.36 d
(H52 , 3J 4.9 Hz), 7.68 m (H5), 8.20 d (H42 , 3J 4.9 Hz).
Mass spectrum, m/z (Irel, %): 323 (100) [M]+, 265 (66),
237 (45), 118 (22). Found, %: C 51.93; H 3.38; N 13.07.
C14H11F2N3O2S. Calculated, %: C 52.01; H 3.43;
N 13.00.
1
ethanol. Yield 1.0 g (85%), mp > 250°C. H NMR
spectrum
H7), 7.75 m (1H, H6'), 12.4 br.s (2H, NH). Mass
spectrum, m/z (Irel
%): 309 (43%) [M]+, 290 (29), 289
,
d, ppm: 7.15 m (2H, H5, H6), 7.41 m (2H, H4,
,
Compounds Xa and Xc were obtained in the similar
way.
(28), 281 (19), 262 (17), 177 (100), 160 (20), 149 (35),
132 (15), 105 (24), 99 (13), 90 (10). Found, %: C 54.43;
H 2.34; N 13.52. C14H7F4N3O. Calculated, %: C 54.38;
H 2.28; N 13.59.
6,8-Difluoro-7-(pyrrolidin-1-yl)thiazol[3,2-a]-
quinazolin-4-one (Xa). Yield 73%, mp 254–256°C.
1H NMR spectrum, d, ppm: 1.90 m [4H, (CH2)2], 3.67 m
[4H, N(CH2)2], 7.32 d (H52 , 3J 4.9 Hz), 7.56 d.d (H5,
b. To a dispersion of 0.5 g (3.8 mmol) of 2-amino-
benzimidazola (XII) in 12 ml of anhydrous dichloro-
methane was added a solution of 0.81 g (4 mmol) of
tetrafluorobenzoyl chloride (Ia) in 2 ml of toluene and
1.2 ml (8 mmol) of triethylamine. The reaction mixture
was left standing at room temperature for 24 h. The
separated precipitate of the acylation product XIIIa was
filtered off, washed with water, and recrystallized from
DMSO. Yield 0.94 g (80%).
5
3
3J 13.8, J 1.8 Hz), 8.14 d (H42 , J 4.9 Hz). Mass
spectrum, m/z (Irel, %): 307 (100) [M]+, 306 (81),
265 (13), 223 (16), 221 (11). Found, %: C 54.77; H 3.72;
N 13.61. C14H11F2N3OS. Calculated, %: C 54.72; H 3.67;
N 13.67.
6,8-Difluoro-7-(4-ethoxycarbonylpiperazin-1-
yl)thiazolo[3,2-a]quinazolin-4-one (Xc). Yield 78%,
mp 230–232°C. 1H NMR spectrum, d, ppm: 1.22 t (3H,
CH3), 3.30 m [4H, N(CH2)2], 3.52 m [4H, N(CH2)2],
4.08 q (2H, OCH2), 7.36 d (H52 ,3J 5.0 Hz), 7.69 d.d (H5,
1'H-6,7,8-Trifluorobenzimidazo[3,2-a]quinazolin-
4-one (XIVa). To 0.25 g (0.81 mmol) of compound XIIIa
was added 1.5 ml of diphenyl ether, and the mixture was
boiled for 2 h. On cooling the separated precipitate of
compound XIVa was filtered off, washed with 2-propanol,
and recrystallized from DMSO. Yield 0.17 g (72%),
5
3
3J 11.6, J 1.5 Hz), 8.19 d (H42 , J 5.0 Hz). Mass
spectrum, m/z (Irel, %): 394 (100) [M]+, 379 (20), 293
(13), 292 (48), 266 (31), 265 (20), 252 (12), 238 (18), 56
(67). Found, %: C 51.82; H 4.13; N 14.17.
C17H16F2N4O3S. Calculated, %: C 51.77; H 4.09;
N 14.21.
1
mp > 250°C. H NMR spectrum, d, ppm: 7.23–7.37 m
(2H, H52 , H62 ), 7.55 m (1H, H72 ), 7.97 m (1H, H42),
8.02 d.d.d (1H, H5, 3J 10.1, 4J 8.3, 5J 2.4), 12.9 br.s (1H,
NH). Mass spectrum, m/z (Irel, %): 289 (100%) [M]+,
288 (12), 261 (26), 123 (12). Found, %: C 58.19; H 2.14;
N 14.48. C14H6F3N3O. Calculated, %: C 58.14; H 2.09;
N 14.53.
Mixture of 6,8-difluoro-7-(pyrrolidin-1-yl)-
thiazolo[3,2-a]quinazolin-4-one (Xa) and N-(thiazol-
2-yl)-2,3,5-trifluoro-4-(pyrrolidin-1-yl)benzamide
(XI). To 0.5 g (1.6 mmol) of amide VIIIa in 5 ml of
DMF was added 0.5 ml (6.4 mmol) of pyrrolidine. The
reaction mixture was boiled for 5 h, on cooling the
precipitate was filtered off and recrystallized from
1'H-5,6,7,8-Tetrafluorobenzimidazo[3,2-a]-
quinazolin-4-one (XIVb). To a dispersion of 0.5 g
(3.8 mmol) of 2-aminobenzimidazole XII in 12 ml of
anhydrous dichloromethane was added a solution of
0.88 g (4 mmol) of pentafluorobenzoyl chloride (Ib) in
2 ml of toluene and 1.2 ml (8 mmol) of triethylamine.
The reaction mixture was left standing at room tempera-
ture for 24 h. The separated precipitate of compound
XIVb was filtered off, washed with water, and recrystal-
lized from DMSO. Yield 0.91 g (78%), mp > 250°C.
1H NMR spectrum, d, ppm: 7.31 m (1H, benzimidazole),
7.40 m (2H, benzimidazole), 8.38 m (1H, benzimidazole),
13.0 br.s (1H, NH). Mass spectrum, m/z (Irel, %):
DMSO. 1
H NMR spectrum, d, ppm: 1.87 m [4H, (CH2)2
(XI)], 1.91 m [4H, (CH2)2 (Xa)], 3.62 m [4H, N(CH2)2
(XI)], 3.67 m [4H, N(CH2)2 (Xa)], 7.27 d [1H, H5, 3J 3.6
3
Hz (XI)], 7.31 d [1H, H2, J 5.0 Hz (Xa)], 7.42 d.d.d
[1H, H6', 3J 14.6, 4J 6.7, 5J 2.2 Hz (XI)], 7.53 d [1H, H4,
3
5
3J 3.6 Hz (XI)], 7.55 d.d [1H, H6, J 13.5, J 3.6 Hz
(Xa)], 8.14 d [1H, H1, 3J 5.0 Hz (Xa)], 12.9 br.s [1H, NH
(XI)]. The ratio of compounds Xa and XI was 5:4.
N-(1,3-Dihydrobenzimidazol-2-ylidene)-2,3,4,5-
tetrafluorobenzamide (XIIIa). a. To a dispersion of
0.5 g (3.8 mmol) of 2-aminobenzimidazol (XII) in 12 ml
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 11 2005

FLUORO-CONTAINING HETEROCYCLES: XIII.
1677
307 (100) [M]+, 279 (14), 260 (11). Found, %: C 54.77;
H 1.69; N 13.62. C14H5F4N3O. Calculated, %: C 54.72;
H 1.63; N 13.68.
Chem., 1986, vol. 29, p. 1531.
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shin, V.N., Izv. Akad. Nauk, Ser. Khim., 2003, p. 436.
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The study was carried out under financial support of
the Russian Foundation for Basic Research (grants nos.
03-03-32254, 04-03-96107-Ural, and 04-03-96011-Ural),
grants of the Ministry of Education of the Russian
Federation (PD 02-1.3-81) and CRDF, Annex BF4M05,
EK-005-X2[REC-005], “BRHE 2004 post-doctoral
fellowship award” Y2-C-05-01.
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