Heteroannulation of 6-polyfluoroalkyl-2-thiouracils

Article abstract of DOI:10.1007/s11172-013-0142-x

A multi-component double Mannich cyclocondensation of 6-polyfluoroalkyl-2- thiouracils with formalin and heterocyclic amines (2-aminopyridine, 2-aminopyrimidine, 4-aminoantipyrine) proceeded regiospecifically at the C=S and NH centers giving rise to 3-hetaryl-8-polyfluoroalkylpyrimido[2,1-b][1,3,5] thiadiazines. The regioisomeric structure of the products was established by X-ray crystallography, IR and NMR spectroscopy, GLC-MS spectrometry. 6-Trifluoromethyl-2-thiouracil and 8-polyfluoroalkylpyrimido[2,1-b]thiadiazines exhibited weak tuberculostatic activity.

Full text of DOI:10.1007/s11172-013-0142-x

Russian Chemical Bulletin, International Edition, Vol. 62, No. 4, pp. 1060—1065, April, 2013
1060
Heteroannulation of 6ꢀpolyfluoroalkylꢀ2ꢀthiouracils*
O. G. Khudina,a A. E. Ivanova,a Ya. V. Burgart,a P. A. Slepukhin,a V. I. Saloutin,a
O. N. Chupakhin,a and M. A. Kravchenkob
aI. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
22 ul. S. Kovalevskoi, 620041 Ekaterinburg, Russian Federation.
Fax: +7 (343) 374 5954. Eꢀmail: saloutin@ios.uran.ru
бUral Research Institute of Phthisiopulmonology, Ministry of Healthcare and Social Development of the Russian Federation,
50 ul. XXII parts´ezda, 620039 Ekaterinburg, Russian Federation.
Fax: +7 (343) 333 4463. Eꢀmail: kravchenko@nexcom.ru
A multiꢀcomponent double Mannich cyclocondensation of 6ꢀpolyfluoroalkylꢀ2ꢀthiouracils
with formalin and heterocyclic amines (2ꢀaminopyridine, 2ꢀaminopyrimidine, 4ꢀaminoantiꢀ
pyrine) proceeded regiospecifically at the C=S and NH centers giving rise to 3ꢀhetarylꢀ8ꢀ
polyfluoroalkylpyrimido[2,1ꢀb][1,3,5]thiadiazines. The regioisomeric structure of the products
was established by Xꢀray crystallography, IR and NMR spectroscopy, GLCꢀMS spectrometry.
6ꢀTrifluoromethylꢀ2ꢀthiouracil and 8ꢀpolyfluoroalkylpyrimido[2,1ꢀb]thiadiazines exhibited
weak tuberculostatic activity.
Key words: 6ꢀpolyfluoroalkylꢀ2ꢀthiouracil, Mannich reaction, formalin, heterocyclic
amines, pyrimido[2,1ꢀb][1,3,5]thiadiazines, tuberculostatic activity.
Pyrimidine derivatives are structural elements of nuꢀ
cleic acids, that explains a wide spectrum of their biologiꢀ
cal activity. Methyluracil and pentoxyl (5ꢀhydroxymethꢀ
ylꢀ4ꢀmethyluracil) are used as anabolic and anticatabolic
medicines, which accelerate processes of cell regeneraꢀ
tion, promote wound healing, stimulate immune cell and
humoral factors. 5ꢀFluorouracil is widely used in clinical
practice as antitumor agent. Thiouracil derivatives possess
pronounced thyreostatic effect, suppressing functional acꢀ
tivity of the thyreoid gland, whereas propicyl (6ꢀpropylꢀ
thiouracil) is used as antithyreoid agent.1 Heptafluoroproꢀ
pylꢀcontaining 2ꢀthiouracil was reported to exceed a nonꢀ
fluorinated analog in this activity.2
2ꢀThiouracil is a valuable object for chemical modifiꢀ
cation of pyrimidine framework because of the presence of
four nucleophilic centers (N(1) and N(3) nitrogen atoms,
exocyclic sulfur atom, and the carbon atom at position 5
of the pyrimidine system). Many derivatives obtained based
on 2ꢀthiouracil are of interest as pharmacologically active
compounds. Thus, Sꢀalkyl derivatives of 6ꢀbenzylꢀ2ꢀthioꢀ
uracils are a family of nonnucleoside inhibitors of the reꢀ
verse transcryptase of the type 1 human immune deficienꢀ
cy virus.3 SꢀAlkylꢀsubstituted 6ꢀnꢀpropylꢀ2ꢀthiouracils
possess antimicrobial, cytotoxic, and antimalarial activity.4
Glycosides of Sꢀsubstituted 5,6ꢀdibenzylꢀ2ꢀthiouracil disꢀ
play activity against hepatitis B virus.5 The wide range of
biological activity demonstrates the prospects of the search
for new pharmaceutical drugs among 2ꢀthiouracil derivaꢀ
tives, including fluorinated ones.
In the present work, we suggested a method for the
structural modification of 6ꢀpolyfluoroalkylꢀ2ꢀthiouracils
using the Mannich reaction, which allowed us to introꢀ
duce an aminomethylene fragment into the structure of
the synthesized molecule. For this purpose, we used forꢀ
malin and heterocyclic amines: 2ꢀaminopyridine, 2ꢀaminoꢀ
pyrimidine, and 4ꢀaminoantipyrine.
Earlier, the condensation of ethyl 4,4,4ꢀtrifluoroꢀ3ꢀ
oxobutanoate (1a) with thiourea in the presence of NaOEt
as the condensing agent was used to obtain 6ꢀtrifluoroꢀ
methylꢀ2ꢀthiouracil (2a) in rather low yield (40%).6 The
use of 57—63% suspension of NaH in mineral oil instead
of NaOEt allowed us to increase the yield of 6ꢀtrifluoroꢀ
methylꢀ2ꢀthiouracil 2a from 40 to 60%. Similarly, 3ꢀoxo
ethers 1b,c were used to obtain new 6ꢀpolyfluoroalkylꢀ2ꢀ
thiouracil 2b,c in 62—65% yields (Scheme 1). The strucꢀ
ture of heterocycles 2a—c was confirmed by IR and NMR
spectroscopy and Xꢀray crystallography.
6ꢀPolyfluoroalkylꢀ2ꢀthiouracils 2a—c were found to
react with formalin and heterocyclic amines 3a—c in EtOH
(MeCN) forming 8ꢀpolyfluoroalkylpyrimido[2,1ꢀb]thiaꢀ
diazines 4a—g (Scheme 2) as a result of the regiospecific
"double" Mannich reaction at the C=S and NH centers.
Acetonitrile has proved the most appropriate solvent for
the reactions of thiouracils 2a,b with 2ꢀaminopyridine (3a),
since it provided the full conversion of the reagents at
* Dedicated to academician of the Russian Academy of Sciences
I. P. Beletskaya on the occasion of her anniversary.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 1059—1064, April, 2013.
1066ꢀ5285/13/6204ꢀ1060 © 2013 Springer Science+Business Media, Inc.

Heteroannulation of polyfluoroalkylthiouracils
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 4, April, 2013
1061
Scheme 1
It is known that nonfluorinated 2ꢀthiouracil and
6ꢀmethylꢀ2ꢀthiouracil (2d) in the Mannich reaction form
5ꢀaminomethylated thiouracil at the CH center.7—9 The
difference in the behavior of 6ꢀpolyfluoroalkylꢀ2ꢀthioꢀ
uracils 2a—c in the Mannich reaction found by us can be
explained by the fact that their CHꢀreaction center is
deactivated for the electrophilic attack because of the elecꢀ
tronꢀwithdrawing influence of the polyfluoroalkyl group.
A comparison of the geometric characteristics of
6ꢀtrifluoromethylꢀ2ꢀthiouracil (2a) (Fig. 1) and 6ꢀmethylꢀ
2ꢀthiouracil (2d)10,11 obtained by Xꢀray crystallography of
their single crystals showed that the replacement of the
Me group with the electronꢀwithdrawing CF3 group proꢀ
duced neither considerable changes in the bond distances
and bond angles of the compounds, nor arising of tautomꢀ
erism. In both cases, uracils 2a,d in the crystal exist in the
thioxoꢀform with localization of the protons on the nitroꢀ
gen atoms of the pyrimidine ring. The O(1) oxygen atom
of the carbonyl group in heterocycle 2a is involved into the
formation of full intermolecular hydrogen bond (IMHB)
with proton H(1) of the amino group, while the thione
group forms a shortened contact C=S..H—N with the
distance S(1)..N(2) of 3.356 Å.
1, 2: RF = CF3 (a), HCF2CF2 (b), C4F9 (c)
room temperature, and the yields of products 4a,b were
higher than in EtOH.
Scheme 2
The active reaction centers in 6ꢀpolyfluoroalkylꢀ2ꢀ
thiouracils 2a—c are the NH and C=S groups, which are
involved into the "double" Mannich cyclocondensation
with two formaldehyde molecules and the NH2 group of
heterocyclic amine 3a—c. In this case, probably, the
aminomethylation reaction initially occurs at the more
reactive C=S group of thiouracil 2. Then occurs the conꢀ
densation of the second formalin molecule at the lactam
NH group and the NH group of the heterocyclic residue,
which leads to the annulation of the pyrimidine frameꢀ
work with the [1,3,5] thiadiazine ring and the formation of
pyrimido[2,1ꢀb]thiadiazines 4a—g (see Scheme 2).
The formation of such a regioisomeric form of pyrꢀ
imido[2,1ꢀb]thiadiazines 4a—g was confirmed by the Xꢀray
O(1)
H(3)
Starting compounds
Product
RF
4
C(4)
3
R
2
F(2)
3a
2a
CF3
4a
C(3)
H(1)
2b
2c
HCF2CF2
C4F9
4b
4c
C(2)
C(1)
N(1)
3b
3c
2a
2c
CF3
4d
4e
C(5)
F(1)
C4F9
N(2)
F(3)
H(4)
S(1)
2a
2c
CF3
4f
C4F9
4g
Fig. 1. Molecular structure of 6ꢀtrifluoromethylꢀ2ꢀthiouracil 2a.

1062
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 4, April, 2013
Khudina et al.
diffraction studies of the single crystal of heterocycle 4e
(Fig. 2). According to the Xꢀray crystallographic data,
compound 4e crystallizes in the centrosymmetric space
group of the P–1 symmetry. The general view of the moleꢀ
cule is shown in Fig. 2. The bond distances and bond
angles in the molecule are close to the standard values.
The pyrimidine ring of the heterocyclic system is planar,
the tetrahydrothiadiazine ring has the "sofa" conformaꢀ
tion, with N(5) nitrogen atom deviating from the plane.
The pyrimidine substituent at N(5) atom occupies the axial
position, forcing the molecule to adopt a rigth angleꢀtype
conformation. The molecular packing in the crystal is
characterized by the alternating zones of perfluoroalkyl
substituents and heterocyclic fragments. No specific inꢀ
termolecular contacts are present in the packing.
The regiospecific formation of the heterocyclic sysꢀ
tem 4 at the lactam N(1)H(1) group, rather than at the
competing N(2)H(4) group of the pyrimidine ring, can be
explained by the deactivating influence of the electronꢀ
withdrawing polyfluoroalkyl substituent toward the neighꢀ
boring amino group (see Fig. 1).
A comparative analysis of the IR spectral data and the
1H and 19F NMR spectral characteristics of heterocycles
4a—g (see Experimental) indicates their similar regioisoꢀ
meric structure.
3.1 g mL–1. Pyrimidothiadiazines 4e,g containing pyriꢀ
midine and antipyrine fragments showed 4 times weaker
tuberculostatic activity as compared to the pyrimidine 2a,
exhibiting MIC at 12.5 g mL–1
.
In conclusion, we improved the synthesis of 6ꢀpolyfluꢀ
oroalkylꢀ2ꢀthiouracils 2a—c and suggested the method for
their heteroannulation to 3ꢀhetarylꢀ8ꢀpolyfluoroalkylꢀ
pyrimido[2,1ꢀb][1,3,5]thiadiazinꢀ6ꢀones 4a—g through
the regiospecific double Mannich reaction.
Experimental
NMR spectra were recorded in deuterochloroform on Brukꢀ
er DRXꢀ400 (1H: 400 MHz, relative to SiMe4, 19F: 75 MHz,
relative to C6F6) and Avance 500 spectrometers (13C: 126 MHz,
relative to SiMe4). IR spectra were recorded on a Perkin—Elmer
Spectrum One IR Fourierꢀspectrometer in the range of
4000—400 cm–1 using a diffusion reflection appliance (DRA) or
frustrated total internal reflection (FTIR). Melting points were
measured in unsealed capillary tubes on a Stuart SMP30 apparaꢀ
tus for determination of melting point. Column chromatography
was carried out on Merck silica gel 60 (0.063—0.02 mm). Mass
spectra were recorded on an Agilent GC 7890A MSD 5975C
inert XL EI/CI gas chromatograph—mass spectrometer with
a HP5ꢀMS quartz capillary column (dimethylpolysiloxane with
5% of phenyl groups, 30 m×0.25 mm, 0.25 m thick film) and
quadrupole massꢀspectrometric detector in the electron ionizaꢀ
tion mode (70 eV). Helium was the carrier gas, CHCl3 was the
solvent. Elemental analysis (C, H, N) was performed on a Perꢀ
kin—Elmer PE 2400 series II analyzer.
The antimicrobial properties of thiadiazinoꢀannulated
thiouracils12 and thiadiazines13 prompted us to study tuberꢀ
culostatic activity of fluoroalkylꢀcontaining thiouracil 2a
and pyrimidothiadiazines 4e,g in the in vitro experiments
toward the H37Rv laboratory strain of tuberculosis micoꢀ
bacteria (TMB). Isoniazide was used as the comparison
agent, the minimum inhibiting concentration (MIC) of
which, necessary for the decrease in the rate of the TMB
growth, is 0.15 g mL–1. Thiouracil 2a turned out to posꢀ
sess moderate tuberculostatic activity with MIC equal to
Synthesis of 6ꢀpolyfluoroalkylꢀ2ꢀthiouracils 2a—c (general
procedure). A suspension of 57—63% sodium hydride in mineral
oil (20 mmol) was added to anhydrous acetonitrile (15 mL) and
stirred for 5 min. 3ꢀOxo ether 1a—c (20 mmol) and thiourea
(20 mmol, 76 mg) were added to the suspension obtained, the
reaction mixture was refluxed for 16—20 h. The solvent was
evaporated in vacuo. A precipitate formed was dissolved in disꢀ
F(9)
F(5)
F(8)
F(4)
C(12)
F(2)
S(1)
C(14)
C(13)
C(2)
N(2)
F(7)
N(3)
C(11)
F(6)
C(1)
N(1)
C(8)
C(7)
N(4)
C(6)
C(5)
F(3)
F(1)
C(3)
N(5)
C(9)
C(4)
C(10)
O(1)
Fig. 2. Molecular structure of 8ꢀnonafluorobutylꢀ3ꢀ(pyrimidinꢀ2ꢀyl)ꢀ3,4ꢀdihydroꢀ2H,6Hꢀpyrimido[2,1ꢀb][1,3,5]thiadiazinꢀ6ꢀone (4e)
in thermal ellipsoids of 50% probability.

Heteroannulation of polyfluoroalkylthiouracils
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 4, April, 2013
1063
tilled water (15 mL), acidified with concentrated hydrochloric
acid to pH 2—3, and was allowed to stand for 12 h. A precipitate
formed was filtered off and recrystallized from 80% EtOH.
2ꢀThioxoꢀ6ꢀtrifluoromethylꢀ2,3ꢀdihydropyrimidinꢀ4(1H)ꢀone
(2a). The yield was 60%, m.p. 248—250 C. (Ref. 6: m.p.
247—249 C).
(s, 2 H, SCH2N); 5.74 (s, 2 H, NCH2N); 6.47 (s, 1 H, H(7));
6.85 (d, 1 H, H(3´), 3J = 8.5 Hz); 6.88 (dd, 1 H, H(5´), 3J = 7.3 Hz,
3
3
3J = 4.9 Hz); 7.57 (ddd, 1 H, H(4´), J = 8.5 Hz, J = 7.3 Hz,
4J = 1.9 Hz); 8.26—8.27 (m, 1 H, H(6´)). 19F NMR, :
35.87—35.94 (m, 2 F, CF2); 39.16—39.22 (m, 2 F, CF2); 44.51
(t, 2 F, CF2, J = 13.2 Hz); 80.82 (tt, 3 F, CF3, 3J = 9.6 Hz,
4J = 2.4 Hz). MS, m/z (Irel (%)): 42 [C2H4N]+ (11.4), 51 [C4H3]+
(25.9), 52 [C4H4]+ (22.6), 69 [CF3]+ (12.7), 72 (24.2), 75
[C2H5NS]+ (14.2), 78 [NC5H4]+ (70), 79 [NC5H5]+ (99.9), 94
[NC5H4 – NH2]+ (21.3), 105 [NC5H4 – N=CH]+ (24.3), 107
[NC5H4 – NHCH2]+ (81.8), 118 (14.7), 119 [C2F5]+ (62.3),
137 [NC5H4 – N=CHS]+ (48.4), 161 (21.1), 431 [M – SH]+
(14.4), 464 [M]+ (29.1). Found (%): C, 38.99; H, 2.04; F, 36.87;
N, 11.93; S, 6.89. C15H9F9N4OS. Calculated (%): C, 38.8;
H, 1.95; F, 36.83; N, 12.07; S, 6.90.
6ꢀ(1,1,2,2ꢀTetrafluoroethyl)ꢀ2ꢀthioxoꢀ2,3ꢀdihydropyrimidinꢀ
4(1H)ꢀone (2b). The yield was 62%, m.p. 198—200 C. IR
(FTIR), /cm–1: 2954, 3116 (N—H); 1674 (C=O); 1110—1174
(C—F). 1H NMR (DMSOꢀd6), : 6.25 (d, 1 H, H(7), J = 1.6 Hz);
3
6.75 (tt, 1 H, H(CF2)2, 2JH,F = 51.6 Hz, JH,F = 5.2 Hz); 12.87
(s, 1 H, NH); 13.11 (br.s, 1 H, NH). 19F NMR (DMSOꢀd6),
: 25.09 (dt, 2 F, HCF2, 2JF,H = 51.6 Hz, 3JF,F = 7.9 Hz); 41.94
(dd, 2 F, CF2, J = 13.3 Hz, J = 7.8 Hz). Found (%): C, 31.75;
H, 1.75; F, 33.46; N, 12.35; S, 14.13. C6H4F4N2OS. Calculatꢀ
ed (%): C, 31.59; H, 1.77; F, 33.31; N, 12.28; S, 14.05.
3ꢀ(Pyrimidinꢀ2ꢀyl)ꢀ8ꢀtrifluoromethylꢀ3,4ꢀdihydroꢀ2H,6Hꢀ
pyrimido[2,1ꢀb][1,3,5]thiadiazinꢀ6ꢀone (4d). The yield was 59%,
m.p. 165—167 C. IR (FTIR), /cm–1: 1688 (C=O); 1261—1283
(C—F). 1H NMR, : 5.58 (s, 2 H, SCH2N); 5.99 (s, 2 H,
NCH2N); 6.53 (s, 1 H, H(7)); 6.90 (t, 1 H, H(5´), 3J = 4.8 Hz);
8.51 (d, 2 H, H(4´), H(6´), 3J = 4.8 Hz). 19F NMR, : 89.99
(s, CF3). Found (%): C, 41.65; H, 2.48; F, 17.97; N, 21.93;
S, 10.28. C11H8F3N5OS. Calculated (%): C, 41.91; H, 2.56;
F, 18.08; N, 22.21; S, 10.17.
6ꢀNonafluorobutylꢀ2ꢀthioxoꢀ2,3ꢀdihydropyrimidinꢀ4(1H)ꢀone
(2c). The yield was 65%, m.p. 218—220 C. IR (DRA), /cm–1
:
2891, 3071 (N—H); 1684 (C=O); 1134—1232 (C—F). 1H NMR,
: 6.26 (s, 1 H, H(7)); 9.25 (br.s, 1 H, NH). Found (%): C, 27.54;
H, 0.75; F, 49.54; N, 8.12; S, 9.34. C8H3F9N2OS. Calculatꢀ
ed (%): C, 27.76; H, 0.87; F, 49.39; N, 8.09; S, 9.26.
Synthesis of pyrimido[2,1ꢀb][1,3,5]thiadiazinꢀ6ꢀones 4a—g
(general procedure). Amine 3a—c (10 mmol) and 37% aqueous
formalin (3.24 g) were added to a solution of (6ꢀpolyfluoroalkylꢀ
2ꢀthiouracil 2a—c (10 mmol) in EtOH (for 4c,e,g) or MeCN
(for 4a,b,d,f) (20 mL) with stirring. The reaction mixture was
kept at room temperature (for compounds 4a,b,f) or refluxed
(for heterocycles 4c—e,g) for 8—10 h. The solvent was evaporatꢀ
ed in vacuo. The residue diluted with distilled water and left to
stand for 12 h to remove excessive formaldehyde. A precipitate
formed was filtered off. Heterocycles 4b,c,f were purified by
column chromatography (eluent hexane—ethyl acetate, 2 : 1),
compound 4d was recrystallized from 50% aq. EtOH, product 4g
reprecipitated with hexane from the solution in chloroform.
Heterocycles 4 were obtained as white powders.
3ꢀ(Pyridinꢀ2ꢀyl)ꢀ8ꢀtrifluoromethylꢀ3,4ꢀdihydroꢀ2H,6Hꢀpyrꢀ
imido[2,1ꢀb][1,3,5]thiadiazinꢀ6ꢀone (4a). The yield was 68%,
m.p. 110—112 C. IR (FTIR), /cm–1: 1684 (C=O); 1498, 1575,
1594 (C=C, C=N); 1127—1215 (C—F). 1H NMR, : 5.57 (s, 2 H,
SCH2N); 5.8 (s, 2 H, NCH2N); 6.52 (s, 1 H, H(7)); 6.91—6.96
(m, 2 H, H(3´), H(5´)); 7.64 (ddd, 1 H, H(4´), 3J = 8.6 Hz,
3J = 7.4 Hz, 4J = 1.9 Hz); 8.32—8.34 (m, 1 H, H(6´)). 19F
NMR, : 89.98 (s, CF3). Found (%): C, 45.81; H, 2.84; F, 18.08;
N, 17.76; S, 10.26. C12H9F3N4OS. Calculated (%): C, 45.86;
H, 2.89; F, 18.13; N, 17.83; S, 10.20.
3ꢀ(Pyridinꢀ2ꢀyl)ꢀ8ꢀ(1,1,2,2ꢀtetrafluoroethyl)ꢀ3,4ꢀdihydroꢀ
2H,6Hꢀpyrimido[2,1ꢀb][1,3,5]thiadiazinꢀ6ꢀone (4b). The yield
was 54%, m.p. 100—102 C. IR (FTIR), /cm–1: 1684 (C=O);
1475, 1496, 1575, 1594 (C=C, C=N); 1115—1247 (C—F).
1H NMR, : 5.56 (s, 2 H, SCH2N); 5.79 (s, 2 H, NCH2N); 6.14
(tt, 1 H, H(CF2)2, 2JH,F = 53 Hz, 3JH,F = 5.4 Hz); 6.55 (s, 1 H,
H(7)); 6.91—6.96 (m, 2 H, H(3´), H(5´)); 7.62—7.66 (m, 1 H,
H(4´)); 8.34 (d, 1 H, H(6´)). 19F NMR, : 22.75 (dt, 2 F, HCF2,
2JF,H = 53 Hz, 3JF,F = 8.2 Hz); 38—38.06 (m, 2 F, CF2). Found (%):
C, 44.79; H, 3.06; F, 21.49; N, 16.03; S, 9.19. C13H10F4N4OS.
Calculated (%): C, 45.09; H, 2.91; F, 21.94; N, 16.18; S, 9.26.
8ꢀNonafluorobutylꢀ3ꢀ(pyridinꢀ2ꢀyl)ꢀ3,4ꢀdihydroꢀ2H,6Hꢀpyrꢀ
imido[2,1ꢀb][1,3,5]thiadiazinꢀ6ꢀone (4c). The yield was 50%,
m.p. 84—85 C. IR (FTIR), /cm–1: 1684 (C=O); 1476, 1496,
1575, 1594 (C=C, C=N); 1135—1235 (C—F). 1H NMR, : 5.49
8ꢀNonafluorobutylꢀ3ꢀ(pyrimidinꢀ2ꢀyl)ꢀ3,4ꢀdihydroꢀ2H,6Hꢀ
pyrimido[2,1ꢀb][1,3,5]thiadiazinꢀ6ꢀone (4e). The yield was 62%,
m.p. 122—124 C. IR (FTIR), /cm–1: 1683 (C=O); 1237—1254
(C—F). 1H NMR, : 5.58 (s, 2 H, SCH2N); 6.00 (s, 2 H,
NCH2N); 6.56 (s, 1 H, H(7)); 6.90 (t, 1 H, H(5´), 3J = 4.8 Hz);
8.51 (d, 2 H, H(4´), H(6´), 3J = 4.8 Hz). 13C NMR, : 47.8
(SCH2N), 56.6 (NCH2N), 107.8—114.9 (m, ,ꢀCF2CF2),
1
110.25 (t, C(7), 3JC,F = 5.1 Hz); 112.1 (tt, ꢀCF2, JC,F = 259.5 Hz,
2JC,F = 31.7 Hz); 114.7 (Cp); 117.4 (qt, CF3, 1JC,F = 288.3 Hz,
2JC,F = 33.2 Hz); 151.2 (t, C(8), 2JC,F = 26.4 Hz); 158.6 (C(4´),
C(6´)); 159.1 (C(5´)); 160.2 (C=O); 161.0 (C(10)). 19F NMR,
: 35.89—35.97 (m, 2 F, CF2); 39.20—39.22 (m, 2 F, CF2); 44.54
(t, 2 F, CF2, 3J = 13.2 Hz); 80.82 (t, 3 F, CF3, 3J = 9.8 Hz).
Found (%): C, 36.25; H, 1.86; F, 36.85; N, 15.31; S, 7.02.
C14H8F9N5OS. Calculated (%): C, 36.14; H, 1.73; F, 36.75;
N, 15.05; S, 6.89.
3ꢀ(1,5ꢀDimethylꢀ3ꢀoxoꢀ2ꢀphenylꢀ2,3ꢀdihydroꢀ1Hꢀpyrazolꢀ
4ꢀyl)ꢀ8ꢀtrifluoromethylꢀ3,4ꢀdihydroꢀ2H,6Hꢀpyrimido[2,1ꢀb]ꢀ
[1,3,5]thiadiazinꢀ6ꢀone (4f). The yield was 51%, m.p. 85—87 C.
IR (DRA), /cm–1: 1677 (C=O); 1493, 1593 (C=C, C=N);
1122—1194 (C—F). 1H NMR, : 2.21 (s, 3 H, Me); 3.04 (s, 3 H,
NMe); 4.86 (s, 2 H, SCH2N); 5.29 (s, 2 H, NCH2N); 6.5 (s, 1 H,
H(7)); 7.27—7.33 (m, 3 H, H(2´), H(4´), H(6´)); 7.42 (t, 2 H,
H(3´), H(5´), 3J = 7.8 Hz). 19F NMR, : 90.32 (s, CF3). Found (%):
C, 50.85; H, 3.87; F, 13.17; N, 16.8; S, 7.31. C18H16F3N5O2S.
Calculated (%): C, 51.06; H, 3.81; F, 13.46; N, 16.54; S, 7.57.
3ꢀ(1,5ꢀDimethylꢀ3ꢀoxoꢀ2ꢀphenylꢀ2,3ꢀdihydroꢀ1Hꢀpyrazolꢀ
4ꢀyl)ꢀ8ꢀnonafluorobutylꢀ3,4ꢀdihydroꢀ2H,6Hꢀpyrimido[2,1ꢀb]ꢀ
[1,3,5]thiadiazinꢀ6ꢀone (4g). The yield was 55%, m.p. 131—132 C.
IR (DRA), /cm–1: 1667 (C=O); 1494, 1593, 1614 (C=C, C=N);
1132—1244 (C—F). 1H NMR (DMSOꢀd6), : 2.25 (s, 3 H, Me);
3.04 (s, 3 H, NMe); 4.97 (s, 2 H, SCH2N); 5.22 (s, 2 H, NCH2N);
6.6 (s, 1 H, H(7)); 7.26—7.32 (m, 3 H, H(2´), H(4´), H(6´));
7.45 (t, 2 H, H(3´), H(5´), 3J = 7.8 Hz). 19F NMR (DMSOꢀd6),
: 37.13—37.27 (m, 2 F, CF2); 40.14—40.26 (m, 2 F, CF2); 46.48
(t, 2 F, CF2, 3J = 11.6 Hz); 82.19 (t, 3 F, CF3, 3J = 9.4 Hz).
Found (%): C, 44.28; H, 2.79; F, 29.77; N, 11.95; S, 5.82.

1064
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 4, April, 2013
Khudina et al.
Table 1. Principal crystallographic data and Xꢀray diffraction parameters of compounds 2a and 4e
Parameter
2a
4e
Molecular formula
Molecular weight
C5H3F3N2OS
196.15
C14H8F9N5OS
465.31
Crystal system
Space group
Triclinic
Triclinic
–
–
P1
P1
a/Å
b/Å
c/Å
/deg
6.2986(8)
6.7703(12)
9.5946(12)
82.349(12)
85.016(10)
63.797(15)
363.65(9)
2
5.0372(4)
9.3276(17)
18.286(2)
101.920(13)
93.685(9)
95.622(12)
833.4(2)
2
/deg
/deg
V/Å3
Z
dcalc/g cm–3
1.791
0.450
1.854
0.310
/mm–1
Angle of scanning, /deg
Total number of reflections
Number of independent reflections
Number of reflections with I > 2(I)
Number of refined parameters
R1/wR2 (I > 2(I))
R1/wR2 (on all the reflections)
3.37—28.28
3525
2.73—28.28
5068
1740
1079
121
4069
1664
275
0.0494/0.1245
0.0737/0.1291
0.0336/0.0413
0.0953/0.0430
C
21H16F9N5O2S. Calculated (%): C, 43.99; H, 2.81; F, 29.82;
lions of the microbial bodies in 1 mL. The suspension obtained
in amount of 0.2 mL was seeded in the test tubes with the culturꢀ
ing medium and with 5.0 mL of the compound under study in the
corresponding dilution. Sequential dilution was used to prepare
the following concentrations of the agents: 100, 50, 12.5, 6.25,
3.5, 1.5, 0.7, 0.3, 0.15 g mL–1. The testꢀtubes were incubated
for 7—10 days in a thermostat at 37 C15. The studies of the
effect of compounds on TMB were carried out simultaneously in
three testꢀtubes with each concentration.
N, 12.21; S, 5.59.
Xꢀray diffraction studies. Single crystals of 2ꢀthiouracil 2a
were obtained by crystallization from EtOH, whereas those of
pyrimido[2,1ꢀb][1,3,5]thiadiazine 4e were grown in CHCl3.
Xꢀray diffraction experiments were performed on a Xcalibur S CCD
diffractometer ((MoꢀК) = 0.71073 Å, graphite monochromaꢀ
tor, ꢀscan technique, temperature of 295(2) К. No allowance
was made for the absorption. Crystal structures were solved by
direct method and refined by the fullꢀmatrix least squares method
on F2 using the SHELXTL software.14 Refinement for nonꢀ
hydrogen atoms was performed in anisotropic approximation,
the hydrogen atoms, except those on the NH group, were placed
in the geometrically calculated positions and included into reꢀ
finement in the riding model in isotropic approximation with
thermal parameters dependent on the parent atoms. The hydroꢀ
gen atoms of the NH group were refined independently in isoꢀ
tropic approximation. The principal crystallographic data for
compounds 2a and 4e and some experimental characteristics are
given in Table 1.*
This work was financially supported by the Ural Branch
of the Russian Academy of Sciences (Project Nos 12ꢀPꢀ3ꢀ
1030 and 12 Pꢀ1035), the Council on Grants at the Presiꢀ
dent of the Russian Federation (Program of State Support
for Leading Scientific Schools of the Russian Federation
and Young Scientists, Grant MKꢀ837.2012.3).
References
Studies of tuberculostatic activity. Determination of tuberꢀ
culostatic activity of compounds 2a, 4e,g was carried out using
a Novaya solid culturing medium by the vertical diffusion
method. Laboratory strain H37Rv was prepared for the seeding.
The culture of the laboratory strain was weighed on a torsional
balance and a portion of 10 mg was placed in a porcelain mortar
and thoroughly triturated. A suspension of the culture was preꢀ
pared according to the bacterial standard of turbidity: 100 milꢀ
1. M. D. Mashkovskii, Lekarstvennye sredstva [Medicines],
Novaya Volna, Moscow, 2010, 2 (in Russian).
2. M. E. Abdullah, H. Y. AboulꢀEnein, M. M. A. Hassan, S. A.
Taha, Proc. Int. Symp. Appl. Technol. Ioniz. Radiat., 1983,
1, 531.
3. M. B. Nawrozkij, D. Rotili, D. Tarantino, G. Botta, A. S.
Eremiychuk, I. Musmuca, R. Ragno, A. Samuele, S. Zanoli,
M. ArmandꢀUgon, I. ClotetꢀCodina, I. A. Novakov, B. S.
Orlinson, G. Maga, J. A. Este, M. Artico, A. Mai, J. Med.
Chem., 2008, 51, 4641.
* The full set of crystallographic data for compounds 2a and 4e
was deposited with the Cambridge Structural Database (CCDC
914700 and CCDC 914699) and is available at www.ccdc.cam.
ac.uk/conts/retrieving.html (CCDC, 12 Union Road, Camꢀ
bridge CB2 1EZ, UK; eꢀmail: deposit@ccdc.cam.ac.uk).
4. S. Prachayasittikul, N. Sornsongkhram, R. Pingaew, S. Techꢀ
atanachai, S. Ruchirawat, V. Prachayasittikul, Eur. J. Sci.
Res., 2009, 36, 236.
5. T. A. A. Mohammed, Arch. Pharm. Res., 2010, 33, 797.

Heteroannulation of polyfluoroalkylthiouracils
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 4, April, 2013
1065
6. W. H. Miller, A. M. Dessert, G. W. Anderson, J. Am. Chem.
Soc., 1948, 70, 500.
13. M. S. Chande, R. N. Dravid, N. P. Shetgiri, Proc. Indian
Acad. Sci., Chem. Sci., 1988, 100, 53.
7. L. Monti, G. Franchi, Gazz. Chim. Ital., 1955, 85, 516.
8. T. Pospieszny, I. Maіecka, Z. Paryzek, Tetrahedron Lett.,
2010, 51, 4166.
9. W. J. Serfontein, H. H. E. Schroeder, J. S. African Chem.
Inst., 1966, 19, 38 (Chem. Abstr., 1966, 65, 13700).
10. G. S. Parry, F. Strachan, Acta Crystallogr., 1958, 11, 303.
11. C. Delange, A. H´Naifi, M. Goursolle, A. Carpy, C. R. Acad.
Sci., Ser. 2, 1986, 302, 219.
14. G. M. Sheldrick, Acta Crystallogr., 2008, A64, 112.
15. V. N. Vasilev, Mikobakteriozy i mikozy legkikh [Lung Micoꢀ
bacteriosis and Micosis], Meditsina i Fizkul´tura, Sofia, 1971,
p. 377 (in Russian).
12. H. A. H. ElꢀSherief, A. H. Zeinab, A. F. M. ElꢀMahdy,
A. A. O. Sarhan, J. Heterocycl. Chem., 2010, 47, 1294.
Received December 21, 2012;
in revised form February 19, 2013