6-Polyfluoroalkylated 2-thiouracils in the synthesis of pyrimido[2,1-b][1,3,5]thiadiazines by the double Mannich reaction

Article abstract of DOI:10.1016/j.jfluchem.2013.01.018

6-Polyfluoroalkyl-2-thiouracils react with formaldehyde and primary amines in EtOH (MeCN) at 2-mercapto and 3-amino groups to yield pyrimido[2,1-b][1,3,5] thiadiazines via the multicomponent double Mannich reaction. The structure of 3-benzyl-8-nonafluorobutyl-3,4-dihydro-2H,6H-pyrimido[2,1-b][1,3,5] thiadiazin-6-one was studied by the X-ray diffraction analysis. The use of ethylenediamine in these reactions yields 3,3′-ethane-1,2-diyl- bis(pyrimido[2,1-b]thiadiazinone) as a result of the bis-double Mannich cyclocondensation. 8-Polyfluoroalkyl-pyrimido[2,1-b]thiadiazines exhibit weak tuberculostatic activity.

Full text of DOI:10.1016/j.jfluchem.2013.01.018

Journal of Fluorine Chemistry 147 (2013) 31–35
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
6-Polyfluoroalkylated 2-thiouracils in the synthesis of pyrimido
[2,1-b][1,3,5]thiadiazines by the double Mannich reaction
a
a
a
b
Ol’ga G. Khudina a, , Anna E. Ivanova , Yanina V. Burgart , Victor I. Saloutin , Marionella A. Kravchenko
*
a Postovsky Institute of Organic Synthesis, Russian Academy of Sciences (Ural Branch), 22/20, S. Kovalevskoy/Akademicheskaya Street, 620990 Ekaterinburg, Russia
b Phthisiopulmonology Research Institute, Ministry of Public Health of the Russian Federation, 50, 22 Parts’ezda Street, 620039 Ekaterinburg, Russia
A R T I C L E I N F O
A B S T R A C T
Article history:
6-Polyfluoroalkyl-2-thiouracils react with formaldehyde and primary amines in EtOH (MeCN) at 2-
mercapto and 3-amino groups to yield pyrimido[2,1-b][1,3,5]thiadiazines via the multicomponent
double Mannich reaction. The structure of 3-benzyl-8-nonafluorobutyl-3,4-dihydro-2H,6H-pyri-
mido[2,1-b][1,3,5]thiadiazin-6-one was studied by the X-ray diffraction analysis. The use of
ethylenediamine in these reactions yields 3,30-ethane-1,2-diyl-bis(pyrimido[2,1-b]thiadiazinone) as a
result of the bis-double Mannich cyclocondensation. 8-Polyfluoroalkyl-pyrimido[2,1-b]thiadiazines
exhibit weak tuberculostatic activity.
Received 25 September 2012
Received in revised form 17 January 2013
Accepted 18 January 2013
Available online 29 January 2013
Keywords:
The double Mannich reaction
6-Polyfluoroalkyl-2-thiouracil
Formaldehyde
ß 2013 Elsevier B.V. All rights reserved.
Aliphatic and aromatic amines
Ethylenediamine
Pyrimido[2,1-b][1,3,5]thiadiazines
Tuberculostatic activity
1. Introduction
regioselective and take place at the CH-center rather than at the
alternative NH- and SH-centers.
The Mannich reaction has attracted much attention as a
convenient method for the introduction of the aminomethylene
fragment in compounds bearing an acidic proton [1]. Basically, the
In this paper we investigated 6-polyfluoroalkyl-2-thiouracils in
the Mannich reaction with formaldehyde and primary amines. An
electron-withdrawing polyfluoroalkyl substituent at the 6-posi-
tion of 2-thiouracil can change its reactivity. The use of primary
amines in the Mannich reaction provides opportunities for further
transformations including the construction of various heterocyclic
systems [6,7].
Mannich reaction is
a three-component condensation of a
substrate with formaldehyde and secondary amine. A large class
of organic compounds, including heterocycles with an acidic
proton positioned next to an activating functional group, can serve
as substrates in the Mannich reaction. They may have the CH-, OH-,
NH-, SH- or PH-activated centers.
2. Results and discussion
2-Thiouracils have proved to be suitable substrates for the
aminomethylation. The hydroxy group in the pyrimidine fragment
activates the CH-center at the 5-position for electrophile attack of
an iminium ion which is formed from amine and formaldehyde [2].
(6-Methyl)-2-thiouracil reacts with formaldehyde and primary
(aniline, 4-carboxyphenylamine) [3] or secondary amines (mor-
pholine, piperidine, bis(2-chloroethyl)amine) [4,5] in a similar
manner yielding 5-aminomethylated thiouracils as a result of the
Mannich reaction. The reactions of 2-thiouracils are highly
2.1. Synthesis of 8-polyfluoroalkyl-3,4-dihydro-2H,6H-pyrimido[2,1-
b][1,3,5]thiadiazin-6-ones
It has been found that 6-polyfluoroalkyl-2-thiouracils 1a-c in
the Mannich reaction with primary amines 2a-f, such as
methylamine sulfate, benzylamine, hexylamine, aniline, 4-fluor-
oanilin and p-anisidine, and an excess of formaldehyde form
products 3a-i in 65–81% yields (Scheme 1). EtOH and MeCN were
the solvents of choice in this synthesis. The reactions were carried
out at room temperature for 10–60 min. The yields of products 3a-i
depended on the length of polyfluoroalkyl substituent. Compounds
3c,e,f,h,i having the nonafluorobutyl and tridecafluorohexyl
substituents were obtained in the higher yields.
* Corresponding author. Tel.: +7 3433623491.
E-mail addresses: kog@ios.uran.ru, hudinaolga@mail.ru (O.G. Khudina),
saloutin@ios.uran.ru (V.I. Saloutin).
0022-1139/$ – see front matter ß 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2013.01.018

32
O.G. Khudina et al. / Journal of Fluorine Chemistry 147 (2013) 31–35
3
RF
O
N
RF
O
1: RF = CF3 (a), C4F9 (b), C6F13 (c);
2: R = Me (a), CH2Ph (b), (CH2)5Me (c),
Ph (d), C6H4-F-4 (e), C6H4-OMe-4 (f);
N
N
N
NH
S
R
F
3: R = Me, R = CF3 (a),
1a-c
SH
+
3a-i, 65-81%
F
R = CH2Ph, R = CF3 (b), C4F9 (c),
EtOH
RF
O
H
F
R = (CH2)5Me, R = CF3 (d), C6F13 (e),
(MeCN)
20 oC
2
O
F
NH2R
2a-f
R = Ph, R = C6F13 (f),
X
H
N
N
F
R = C6H4-F-4, R = CF3 (g), C6F13 (h),
F
R = C6H4-OMe-4, R = C4F9 (i)
N
S
A
R
Scheme 1.
The 1H NMR spectra of heterocycles 3 in the region of 4.61–
2.2. Synthesis of 3,30-ethane-1,2-diyl-bis(8-tetrafluoroethyl-3,4-
dihydro-2H,6H-pyrimido[2,1-b][1,3,5]thiadiazin-6-one)
5.65 ppm had two singlet signals of methylene protons located
between the heteroatoms, which is typical for [1,3,5]thiadiazine
system. Moreover, the signals of methylene carbons of the
thiadiazine cycle in the 13E NMR spectrum of product 3a were
observed at 58.09 and 65.33 ppm. In the IR spectra of products 3a-i,
the absorption band of carbonyl group remained and the bands of
stretching vibrations of NH groups disappeared compared with the
IR spectra of the starting thiouracils 1a-c.
The multicomponent double Mannich cyclocondensation can
occur at the lactam nitrogen atom (N-3) or the competitive
nitrogen atom (N-1) of the pyrimidine cycle to form the
regioisomeric pyrimidothiadiazin-6-ones 3a-i or pyrimidothiadia-
zin-8-ones A (Scheme 1). To determine the direction of the double
Mannich cyclocondensation and the structure of heterocyclic
products, the single-crystal X-ray diffraction analysis of product 3c
was performed (Fig. 1). According to the X-ray diffraction, 8-
polyfluoroalkylpyrimido[2,1-b][1,3,5]thiadiazinones 3a-i were
formed as a result of the highly regioselective multicomponent
cyclocondensation at the lactam nitrogen atom (N-3). The
thiadiazine cycle N3C9S1C8N2C10 is nonplanar and exists in the
envelope conformation. The C9, S1, C8, N2, C10 atoms form a plane
(the root–mean–square deviations of the atoms from this plane do
The use of ethylenediamine in the double Mannich reaction
of thiouracil
1 can result in 3-(2-aminoetyl)pyrimido[2,1-
b]thiadiazine B and/or the product of the bis-double Mannich
cyclocondensation which involves two amino groups of
ethylenediamine (Scheme 2). It has been found that 6-
tetrafluoroethyl-2-thiouracil 1d and formaldehyde react with
ethylenediamine at two amino groups to form 3,30-ethane-1,2-
diyl-bis(pyrimido[2,1-b]thiadiazinone) 4 in 32% yield. The 1H
NMR spectrum of product 4 corresponds precisely to this
structure, because the ratio of the methylene protons signal
intensities of thiadiazine cycle and ethylenediamine fragment
is 2:1. In the 19F NMR spectrum, two HEF2CF2 groups appear as
one set of signals because of their equivalence. It is possible
only for a symmetrical structure of product 4. The low yield of
compound 4 in the bis-double Mannich reaction with ethyle-
nediamine is due to instability of its thiadiazine cycle.
bis(Pyrimido[2,1-b]thiadiazinone)
4 was subjected to the
retro-Mannich reaction to give the starting 2-thiouracil 1d
which was isolated from the reaction mixture. It is likely to be
due to the steric hindrances in the molecule because of its
short ethylenediamine chain.
˚
not exceed 0.040(1) A) which gives an angle of 53.88 with the plane
formed by the C9, C10 and N3 atoms.
Highly regioselective course of the double Mannich reaction at
the nitrogen in the 3-position of pyrimidine ring was expected. The
nitrogen at the 1-position is less reactive than the lactam nitrogen
atom (N-3) due to the electron-withdrawing effect of the
neighboring polyfluoroalkyl group.
2.3. Discussion on the 6-polyfluoroalkyl-2-thiouracils reactivity in the
Mannich reaction
We have found the different reactivity of 6-methyl-2-thiouracil
[3,4] and 6-polyfluoroalkyl-containing analogs in the Mannich
Fig. 1. X-Ray structure of 3-benzyl-8-nonafluorobutyl-3,4-dihydro-2H,6H-pyrimido[2,1-b][1,3,5]thiadiazin-6-one 3F.

O.G. Khudina et al. / Journal of Fluorine Chemistry 147 (2013) 31–35
33
H(CF2)2
O
N
(CF2)2H
O
N
N
N
N
N
H(CF2)2
O
2
S
S
HN
NH
1d
4, 37%
S
MeCN
H(CF2)2
O
N
H
+
20 oC
4
NH2
H2N
N
N
H
O
X
B
NH2
S
Scheme 2.
F
F
F
F
F
+
H
O
O
Me
O
O
F
Me
N
NH
N
NH
SH
N
NH
N
N
SH
SH
SH
1a'
1a
Scheme 3.
reaction. Undoubtedly, it is due to the effect of an electron-
withdrawing polyfluoroalkyl substituent.
polyfluoroalkyl substituent in the 6-position of pyrimidine ring
deactivates the 5-position in the Mannich reaction and leads to
changes in the reactivity of 2-thiouracil.
All polyfluoroalkyl groups have electron-withdrawing char-
acter regardless of the type of bond (
s-bond or p-bond) to the
reaction center. However, when the CF3 group is attached to a
p
-
2.4. Tuberculostatic activity of 8-polyfluoroalkylpyrimido[2,1-
b][1,3,5]thiadiazinones
electron system such as vinyl or phenyl groups, the electron-
withdrawing resonance effect of the CF3 group is possible
(Scheme 3).
The concept of negative hyperconjugation was used to explain
the reactivity of polyfluoroalkylated 2-thiouracils in the Mannich
Antibacterial biological effects of thiadiazines [11] and thia-
diazine-annelated thiouracils [9] encouraged us to investigate the
tuberculostatic activity of new pyrimidothiadiazine 3 derivatives
containing an electron-withdrawing polyfluoroalkyl substituent.
We studied in vitro activity of products 3a,b,i against a
laboratory strain of Micobacterium tuberculosis H37Rv. Isoniazid
was used as a reference drug, its minimum concentration required
reaction. The interaction of the C–F bond with the
a-C55C bond is
typical for negative hyperconjugation [8]. The structure 1a0 with
the so-called double bond/no bond resonance was suggested as a
contributing resonance structure (Scheme 3).
Additionally, to confirm increasing
d
+ at the C-5 center of 6-
for the inhibition of M. tuberculosis growth is 0.15 m .
g mLꢀ1
trifluoroalkyl-2-thiouracil 1a compared with non-fluorinated
analog we registered their 13C NMR spectra. The resonance of C-
5 carbon in 2-thiouracil (103.7 ppm) was shifted upfield as
compared to C-5 carbon in heterocycle 1a (105.2 ppm, see Section
4). Therefore, the CH-center in the 5-position of 6-polyfluoroalkyl-
2-thiouracils 1a-d is deactivated for the electrophilic substitution
reactions and cannot be involved in the Mannich reaction.
For this reason, the SH-, OH- or NH-centers are preferable for
the attack of electrophilic iminium ion in the case of polyfluor-
oalkylated 2-thiouracils 1a-d. However, the non-fluorinated
pyrimidines containing these groups were alkylated to form
primarily the alkylmercapto derivatives [2].
Isoniazid (Laniazid, Nydrazid) also known as isonicotinoyl hydra-
zide is the first-line medication in prevention and treatment
of tuberculosis. The mechanism of isoniazid action is associated
with inhibition of mycolic acid synthesis in the cell wall of
M. tuberculosis.
As a result of our research it has been shown that pyrimido[2,1-
b][1,3,5]thiadiazines 3a,b,i possess weak tuberculostatic activity.
Moreover, the starting 6-trifluoromethyl-2-thiouracil 1a was more
active (the minimum inhibition concentration (MIC) 3.1
compared to the thiadiazine-annelated thiouracils which MIC was
m )
g mLꢀ1
2–4 times lower (MIC was 6.25 and 12.5
m
g mLꢀ1 for compound 3a
and 3b,i, respectively).
The use of primary amines in the Mannich reaction leads to the
double cyclocondensation [6]. The nitrogen at 3-position in
pyrimidines 1a-d is the second nucleophilic reaction center for
such a cyclization. It is significantly distant from the polyfluor-
oalkyl group and activated by the adjacent OH group with electron-
donating mesomeric effect.
It should be noted that the non-fluorinated 2-thiouracils with
the cyano group at the 5-position form similar products (8-aryl-7-
cyano-pyrimido[2,1-b]thiadiazin-6-ones) via the double Mannich
reaction [9,10]. These reagents cannot react at the position C-5
because of the CN-substituent. However, in 6-polyfluoroalkyl-2-
thiouracils the position C-5 is free for an electophilic attack.
Therefore, the introduction of an electron-withdrawing
3. Conclusion
Thus, we have found that the presence of electron-withdraw-
ing polyfluoroalkyl substituents in the 6-position of 2-thiour-
aciles changes their reactivity in the Mannich reaction by
deactivating C-5 center for electophilic attack of the iminium
ion. 6-Polyfluoroalkyl-2-thiouracils react with formaldehyde and
primary amines in EtOH (MeCN) at the 2-mercapto and 3-amino
groups to produce pyrimido[2,1-b][1,3,5]thiadiazines via the
multicomponent double Mannich reaction. The use of ethylene-
diamine in these reactions results in the product of the bis-double
Mannich cyclocondensation.

34
O.G. Khudina et al. / Journal of Fluorine Chemistry 147 (2013) 31–35
4. Experimental
4.1.2. 3-Benzyl-8-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[2,1-
b][1,3,5]thiadiazin-6-one (3b)
Yield after washing with hexane, 69%; mp 118–119 8C. 1H
The melting points were measured in the unsealed capillaries
on a Stuart SMP 30 apparatus. The IR spectra in the region of 4000–
400 cmꢀ1 were recorded on a Perkin Elmer Spectrum One Fourier-
transformed IR spectrometer equipped with a diffuse reflectance
attachment (DRA) or a frustrated total internal reflection (FTIR)
technique or in a layer. The NMR spectra were measured in CDCl3
on Bruker DRX-400 (1H: 400 MHz, relative to SiMe4; 19F: 376 MHz,
relative to E6F6) and Avance 500 (13C: 126 MHz, relative to the
signal from CDCl3 77 ppm). The chemical shifts were converted
from C6F6 to CCl3F. The microanalyses were carried out on a Perkin
Elmer PE 2400 series II elemental analyzer. The column
chromatography was performed on Merck silica gel 60 (0.063–
0.2 mm).
NMR:
NCH2N), 6.53 (1H, s, H-7), 7.34–7.38 (5H, m, Ph). 19F NMR:
(s, CF3). IR (DRA): 1678 (C55O), 1648, 1503 (C55N, C55C), 1115–
d
3.91 (2H, s, CH2Ph), 4.61 (2H, s, SCH2N), 5.14 (2H, s,
d
ꢀ72.8
n
1194 (C-F) cmꢀ1. Anal. Calcd for C14H12F3N3OS: C, 51.37; H, 3.70; F,
17.41; N, 12.84; S, 9.79. Found: C, 51.37; H, 3.72; F, 17.68; N, 12.69;
S, 9.86.
4.1.3. 3-Benzyl-8-nonafluorobutyl-3,4-dihydro-2H,6H-pyrimido[2,1-
b][1,3,5]thiadiazin-6-one (3c)
Yield after washing with hexane, 81%; mp 107–108 8C. 1H
NMR:
d 3.91 (2H, s, CH2Ph), 4.61 (2H, s, SCH2N), 5.15 (2H, s,
NCH2N), 6.55 (1H, s, H-7), 7.34–7.38 (5H, m, Ph). 19F NMR:
d
The tuberculostatic activity of compounds 1a, 3a,b,i was
determined by the vertical diffusion using the Novaya solid
growing medium. A weighed amount (10 mg) of the H37Rv
laboratory strain was placed into a porcelain mortar and
thoroughly ground; the culture suspension was prepared
ꢀ127.3 (2F, m, CF2), ꢀ123.9 (2F, m, CF2), ꢀ126.9 (4F, m, CF2CF2),
ꢀ123.7 (2F, m, CF2), ꢀ118.3 (2F, t, CF2, J = 13 Hz), ꢀ82 (3F, tt, CF3,
3J = 9.8, 4J = 2.4 Hz). IR (DRA):
n 1676 (C55O), 1644, 1500 (C55N,
C55C), 1113–1252 (C-F) cmꢀ1. Anal. Calcd for C17H12F9N3OS: C,
42.78; H, 2.53; F, 35.82; N, 8.80; S, 6.72. Found: C, 42.66; H, 2.50; F,
35.81; N, 8.77; S, 6.58.
using
a bacterial turbidity standard of 100 million of
microbial bodies in 1 mL. The resulting suspension (0.2 mL)
was seeded into the test tubes with the culture medium and
the compound under study in the corresponding dilution
(5 mL). The compounds of the following concentrations were
Main crystallographic data for 3c: C17H12F9N3OS, M = 477.36,
space group P2(1)/n, monoclinic, a = 17.300(3), b = 5.4611(8),
3
˚
˚
c = 22.231(3) A,
T = 295(2) K, Z = 4, Dcalc = 1.638 g/cm3,
7494 reflections measured, 3518 unique reflections which were
used in all calculations, 1084 reflections with I > 2 (I). The final R is
a
= 908,
b
= 112.796(15)8,
g
m
= 908, V = 1936.2(5) A ,
(Mo-K ) = 0.266 mmꢀ1
,
a
prepared by
a successive dilution: 12.5, 6.25, 3.1, 1.5,
0.75
m
g mL–1. A test tube was incubated for 7–10 days in a
s
thermostat at 37 8C [12].
0.0494. CCDC 899963 contains the supplementary crystallographic
data for this compound1.
The X-ray diffraction study was performed on an Xcalibur 3 CCD
diffractometer with
v-scanning and graphite monochromatic Mo-
K
radiation. The crystal structures were solved by direct methods
4.1.4. 3-Hexyl-8-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[2,1-
a
followed by Fourier synthesis with SHELXS-97 and refined by full-
matrix least-squares methods for all non-hydrogen atoms with
SHELXL-97 software packages [13].
6-Polyfluoroalkyl-2-thiouracils 1a-d and 2-thiouracil were
obtained by the condensation of 3-oxo esters with thiourea [14].
b][1,3,5]thiadiazin-6-one (3d)
Yield after washing with hexane, 70%; mp 86–87 8C. 1H NMR:
d
1.19–2.73 (13H, m, (CH2)5CH3), 4.83 (2H, s, SCH2N), 5.19 (2H, s,
NCH2N), 6.49 (1H, s, H-7). 19F NMR:
1684 (C55O), 1494 (C55N, C55C), 1120–1190 (C-F) cmꢀ1. Anal. Calcd
for C13H18F3N3OS: C, 48.59; H, 5.65; F, 17.74; N, 13.08; S, 9.98.
Found: C, 48.88; H, 5.71; F, 17.65; N, 12.85; S, 10.04.
d
ꢀ72.8 (s, CF3). IR (in lay):
n
6-Trifluoromethyl-2-thiouracil 1a – 13C NMR (DMSO-d6):
d
3
1
105.2 (q, C-5, JC-F = 3.9 Hz), 118.9 (q, CF3, JC-F = 275.1 Hz), 140.6
2
(q, C-6, JC-F = 36.8 Hz), 159.9 (s, C55O), 176.8 (s, C-2).
2-Thiouracil – 13C NMR (DMSO-d6):
d 18.1 (s, Me), 103.7 (s, C-5),
4.1.5. 3-Hexyl-8-tridecafluorohexyl-3,4-dihydro-2H,6H-
pyrimido[2,1-b][1,3,5]thiadiazin-6-one (3e)
153.2 (s, C-6), 161.0 (s, C55O), 175.9 (s, C-2).
Yield after recrystallisation from hexane, 77%; mp 123–125 8C.
1H NMR:
d
1.19–2.74 (13H, m, (CH2)5CH3), 4.82 (2H, s, SCH2N), 5.19
(2H, s, NCH2N), 6.51 (1H, s, H-7). 19F NMR:
ꢀ127.3 (2F, m, CF2),
ꢀ123.9 (2F, m, CF2), ꢀ122.8 (4F, m, CF2CF2), ꢀ118.2 (2F, t, CF2,
J = 12.3 Hz), ꢀ81.9 (3F, t, CF3, J = 10 Hz). IR (DRA): 1688 (C55O),
1504 (C55N, C55C), 1138–1242 (C-F) cmꢀ1
Anal. Calcd for
18H18F13N3OS: C, 37.84; H, 3.18; F, 43.22; N, 7.35; S, 5.61. Found:
C, 38.02; H, 3.04; F, 43.29; N, 7.38; S, 5.58.
4.1. Synthesis of 8-polyfluoroalkyl-3,4-dihydro-2H,6H-pyrimido[2,1-
b][1,3,5]thiadiazin-6-ones
d
Primary amine (10 mmol) and 37% aqueous formaldehyde
n
(1.62 g) were added to
a solution of 6-polyfluoroalkyl-2-
.
thiouracil 1a-c (10 mmol) in EtOH (20 mL) or MeCN (20 mL,
for 3b) under stirring. The reaction mixture was kept at room
temperature for 10 min (for 3a-e) or 3–5 h (for 3f-i). The
solvent was removed under reduced pressure. The residue was
treated with distilled water and left overnight. The resulting
precipitate was filtered and dried to give compounds 3a-i as
white powders.
C
4.1.6. 3-Phenyl-8-tridecafluorohexyl-3,4-dihydro-2H,6H-
pyrimido[2,1-b][1,3,5]thiadiazin-6-one (3f)
Yield after recrystallisation from hexane, 76%; mp 124–
126 8C. 1H NMR:
d
5.24 (2H, s, SCH2N), 5.65 (2H, s, NCH2N), 6.54
(1H, s, H-7), 7.04–7.09 (3H, m, H-o,p), 7.34 (2H, dd, H-m, J = 8.5,
7.6 Hz). 19F NMR:
ꢀ127.3 (2F, m, CF2), ꢀ124 (2F, m, CF2),
ꢀ122.8 (4F, m, CF2CF2), ꢀ118.2 (2F, m, CF2), ꢀ82 (3F, t, J = 10 Hz,
CF3). IR (DRA): 1685 (C55O), 1514, 1505 (C55N, C55C), 1142–
4.1.1. 3-Methyl-8-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[2,1-
b][1,3,5]thiadiazin-6-one (3a)
d
Yield after recrystallization from hexane, 65%; mp 95–96 8C. 1H
n
1231 (C-F) cmꢀ1. Anal. Calcd for C18H10F13N3OS: C, 38.38 H,
1.79; F, 43.84; N, 7.46; S, 5.69. Found: C, 38.59; H, 1.91; F, 43.92;
N, 7.52; S, 5.88.
NMR:
d 2.63 (1H, s, NMe), 4.7 (2H, s, SCH2N), 5.03 (2H, s, NCH2N),
6.51 (1H, s, H-7). 13C NMR:
d
38.6 (NMe), 58.1 (SCH2N), 65.3
(NCH2N), 107.8 (q, C-7, 3JC-F = 3.2 Hz), 120.1 (q, CF3, 1JC-F = 275 Hz),
151.2 (q, C-8, 2JC-F = 35.8 Hz), 161.2 (C55O), 161.9 (C-10). 19F NMR:
d
ꢀ72.9 (s, CF3). IR (DRA):
n 1678 (C55O), 1485 (C55N, C55C), 1116–
1205 (C-F) cmꢀ1. Anal. Calcd for C8H8F3N3OS: C, 38.25; H, 3.21; F,
22.69; N, 16.73; S, 12.76. Found: C, 38.02; H, 3.36; F, 22.44; N,
16.91; S, 13.00.
1
These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/
retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK;
fax: +44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk).

O.G. Khudina et al. / Journal of Fluorine Chemistry 147 (2013) 31–35
35
4.1.7. 3-(4-Fluorophenyl)-8-trifluoromethyl-3,4-dihydro-2H,6H-
was evaporated under reduced pressure. The column chromatog-
raphy (with AcOEt as an eluent) gave product 4 (0.9 g, 32%) as a
pyrimido[2,1-b][1,3,5]-thiadiazin-6-one (3g)
Yield, 75%; mp 58–60 8C. 1H NMR:
d
5.2 (2H, s, SCH2N), 5.59 (2H,
s, NCH2N), 6.52 (1H, s, H-7), 7.02, 7.04 (4H, 2 br.s, 4-FC6H4). 19F
NMR:
white powder, mp 179–181 8C. 1H NMR:
d
2.98 (2H, s, CH2), 4.73
(2H, s, SCH2N), 5.11 (2H, s, NCH2N), 6.21 (1H, tt, H(CF2)2, 2JH-F = 53,
d
ꢀ120.4 (1F, m, 4-FC6H4), ꢀ72.9 (3H, s, CF3). IR (FTIR):
n
3JH-F = 5.3 Hz), 6.56 (1H, s, H-7). 19F NMR:
d
ꢀ140 (2F, dt, H(CF2)2,
1684 (C55O), 1513, 1496 (C55N, C55C), 1124–1194 (C-F) cmꢀ1. Anal.
Calcd for C13H9F4N3OS: C, 47.13; H, 2.74; F, 22.94; N, 12.68; S, 9.68.
Found: C, 47.34; H, 2.76; F, 23.15; N, 12.60, S, 9.56.
2JF-H = 53, 3JF-F = 8 Hz), ꢀ124.7 (2F, td, H(CF2)2, 3JF-F = 8,
3JF-H = 5.3 Hz). IR (DRA):
n 1667 (C55O), 1487, 1466 (C55N, C55C),
1149–1247 (C-F) cmꢀ1. Anal. Calcd for C18H16F8N6O2S2: C, 38.30;
H, 2.86; F, 26.93; N, 14.89; S, 11.36. Found: C, 38.19; H, 2.82; F,
26.85; N, 14.81; S, 11.50.
4.1.8. 3-(4-Fluorophenyl)-8-tridecafluorohexyl-3,4-dihydro-2H,6H-
pyrimido[2,1-b][1,3,5]thiadiazin-6-one (3h)
Yield after recrystallization from EtOH, 77%; mp 121–122 8C. 1H
Acknowledgements
NMR:
7.02, 7.04 (4H, 2 br.s, 4-FC6H4). 19F NMR:
ꢀ123.9 (2F, m, CF2), ꢀ122.8 (4F, m, CF2CF2), ꢀ120.3 (1F, m, 4-
FC6H4), ꢀ118.2 (2F, m, CF2), ꢀ82.0 (3F, t, CF3, J = 10 Hz). IR (DRA):
1686 (C55O), 1592, 1514, 1503 (C55N, C55C), 1119–1259 (C-F) cmꢀ1
d
5.19 (2H, s, SCH2N), 5.6 (2H, s, NCH2N), 6.54 (1H, s, H-7),
d
-127.3 (2F, m, CF2),
This work was supported by the Ural Branch of the Russian
Academy of Sciences (Grant No. 12-M-34-2064, 12-P-3-1035), the
Russian Foundation for Basic Research (Grant No. 13-03-00617)
and the Council on Grants of the President of the Russian
Federation (Grant No. MK-837.2012.3).
n
.
Anal. Calcd for C18H9F14N3OS: C, 37.19; H, 1.56; F, 45.75; N, 7.23; S,
5.51. Found: C, 37.39; H, 1.70; F, 45.69; N, 7.32, S, 5.62.
References
4.1.9. 3-(4-Methoxyphenyl)-8-nonafluorobutyl-3,4-dihydro-2H,6H-
[1] J.J. Li, Name Reactions, a Collection of Detailed Reaction Mechanisms, Springer–
Verlag, Berlin, 2003.
[2] R.C. Elderfield (Ed.), Heterocyclic Compounds, Vol. 6, John Wiley & sons, New
York, 1957.
[3] L. Monti, G. Franchi, Gazz. Chim. Ital. 85 (1955) 516–520.
[4] T. Pospieszny, I. Małecka, Z. Paryzek, Tetrahedron Lett. 51 (2010) 4166–4169.
[5] W.J. Serfontein, H.H.E. Schroeder, J.S. African, Chem. Inst. 19 (1966) 38–44 (Chem.
Abst. 65 (1966) 13700).
[6] Y.S. Shabarov, Kurs Organicheskoi Khimii[nt]Course of Organic Chemistry, Chem-
istry, Moscow, 1998.
pyrimido[2,1-b][1,3,5]-thiadiazin-6-one (3i)
Yield, 80%; mp 127–128 8C. 1H NMR:
d
3.77 (3H, s, OMe), 5.18
(2H, s, SCH2N), 5.57 (2H, s, NCH2N), 6.53 (1H, s, H-7), 6.86 (2H, d, H-
m, J = 9.1), 7.0 (2H, d, H-o, J = 9.1). 19F NMR:
ꢀ127.0 (2F, m, CF2),
ꢀ123.8 (2F, m, CF2), ꢀ118.4 (2F, t, CF2, J = 12.8 Hz), ꢀ82.1 (3F, tt,
CF3, 3J = 9.5, 4J = 2.2 Hz). IR (DRA):
1684 (C55O), 1609, 1514, 1490
(C55N, C55C), 1124–1262 (C-F) cmꢀ1
Anal. Calcd for
17H12F9N3O2S: C, 41.39; H, 2.45; F, 34.66; N, 8.52; S, 6.50. Found:
C, 41.53; H, 2.46; F, 34.93; N, 8.46, S, 6.24.
d
n
.
C
[7] J. Clayden, S. Warren, N. Greeves, P. Wothers, Organic Chemistry, Oxford Univer-
sity Press, New York, 2001, pp. 1420–421.
[8] K. Uneyama, Organofluorine Chemistry, Blackwell Publishing Ltd., Oxford, 2006,
p. 52.
[9] H.A.H. El-Sherief, A.H. Zeinab, A.F.M. El-Mahdy, A.A.O. Sarhan, J. Heterocycl. Chem.
47 (2010) 1294–1302.
[10] V.V. Dotsenko, S.G. Krivokolysko, E.B. Rusanov, V.P. Litvinov, Russ. Chem. Bull. Int.
Ed. 56 (2007) 1437–1440.
4.2. Synthesis of 3,30-ethane-1,2-diyl-bis(8-(1,1,2,2-
tetrafluoroethyl)-3,4-dihydro-2H,6H-pyrimido[2,1-
b][1,3,5]thiadiazin-6-one) (4)
[11] M.S. Chande, R.N. Dravid, N.P. Shetgiri, Proc. Indian Acad. Sci., Chem. Sci 100
(1988) 53–58.
[12] V.N. Vasilev, Mikobakteriozy i Mikozy Legkikx[nt]Mycobacterioses and Mycoses
of Lungs, Meditsina i Fizkul’tura, Sofia, 1971, p. 377.
[13] G.M. Scheldrik, SHELXS 97 and SHELXL 97, University of Gottingen, Germany,
1997.
Ethylenediamine (0.3 g, 5 mmol) and 37% aqueous formalde-
hyde (3.25 g) were added to a solution of 2-thiouracil 1d (2.28 g,
10 mmol) in MeCN (20 mL) under stirring. The reaction mixture
was kept at room temperature for 1 h and was concentrated to
dryness. The residue was treated with CHCl3. The CHCl3 solution
[14] E.D. Bergmann, S. Cohen, I. Shahak, J. Chem. Soc. (1959) 3278–3285.