Synthesis and mechanism of formation of 5-benzylidene-2-thioxo-2,3-dihydro- (1H,5H)-pyrimidine-4,6-diones difluoromethoxy derivatives

Article abstract of DOI:10.1134/S1070363211020228

Reactions of 5-benzylidene-2-thioxo-2,3-dihydro-(1H,5H)-pyrimidine-4,6- diones with a singlet difluorocarbene afford difluoromethoxy derivatives in 20-34% yield. The quantum-chemical analysis of the reaction mechanism showed that N,N-dimethylformamide is

Full text of DOI:10.1134/S1070363211020228

ISSN 1070-3632, Russian Journal of General Chemistry, 2011, Vol. 81, No. 2, pp. 415–419. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © A.I. Rakhimov, I.Yu. Kameneva, S.A. Avdeev, R.G. Fedunov, 2011, published in Zhurnal Obshchei Khimii, 2011, Vol. 81, No. 2,
pp. 317–321.
Synthesis and Mechanism of Formation
of 5-Benzylidene-2-thioxo-2,3-dihydro-(1Н,5Н)-pyrimidine-
4,6-diones Difluoromethoxy Derivatives
A. I. Rakhimova, I. Yu. Kamenevaa, S. A. Avdeevb, and R. G. Fedunovb
a Volgograd State Technical University, pr. Lenina 28, Volgograd, 400131 Russia
e-mail: rakhimov@sprint-v.com.ru
b Institute of Chemical Problems in Ecology, Russian Academy of Natural Sciences, Volgograd, Russia
Received March 4, 2010
Abstract—Reactions of 5-benzylidene-2-thioxo-2,3-dihydro-(1Н,5Н)-pyrimidine-4,6-diones with a singlet
difluorocarbene afford difluoromethoxy derivatives in 20–34% yield. The quantum-chemical analysis of the
reaction mechanism showed that N,N-dimethylformamide is involved into the formation of difluoromethoxy
derivatives.
DOI: 10.1134/S1070363211020228
Difluoromethoxy group is known [1] to favor the
occurrence of the pharmacological activity. Also the
physiological activity of the thiobarbituric acid and its
derivatives has been widely studied [2]. Therefore
difluoromethylation of thiobarbituric acid arylidene
derivatives, synthesized previously [3], is an actual
task.
In this work we studied difluoromethylation of 5-
benzylidene- (I), 5-(4-methylbenzylidene)- (II), 5-(4-
methoxybenzylidene)- (III) and 5-(4-fluorobenzyl-
idene)-2-thioxo-2,3-dihydro-(1Н,5Н)-pyrimidine-4,6-
diones (IV) with singlet difluorocarbene generated in
situ by the reaction of difluoro(chloro)methane (Freon-
22, V) with tert-BuOK or KOH in anhydrous DMF.
F
O
O
F
CHF2Cl, KOH
DMF
HN
N
S
N
O
S
N
H
O
R
R
H
I−IV
VI−IX
The yield of difluoromethylation products is 20–
34% relative to the consumed compounds I–IV.
followed by its adding to difluorocarbene. As the
valence of difluorocarbene carbon with attached hyd-
rogen must be saturated, this particle tries to form a
bond with either the free N3 atom, or with the oxygen
atom attached to the carbon C4 of pyrimidine ring, or
with the sulfur atom attached to the carbon C2 of
pyrimidine. Other tautomeric forms are also capable to
react with difluorocarbene to afford different products
of difluoromethylation of the 5-benzylidene-2-thioxo-
2,3-dihydro-(1Н,5Н)-pyrimidine-4,6-dione. The nature
The quantum-chemical analysis of the proposed
mechanisms of the formation of difluoromethyl
derivatives of different structure shows that the reac-
tion can proceed by the paths (1)–(4).
The attack of difluorocarbene on the N3–H bond of
the starting reagent [path (1)] can result in eliminating
the hydrogen atoms from N3 atom of pyrimidine ring
415

416
RAKHIMOV et al.
F
C
F
O
O
H
(1)
H
C
F
N3
C2
N3
C2
C
F
O
N
H
O
N
H
S
S
F
F
F
C
O
O
F
H
(2)
H
C4
C4
N3
N3
O
N
H
O
N
SH
C
SH
F
O
O
H
F
C4
F
C4
C
(3)
(4)
N3
N3
F
O
O
N
H
S
O
N
H
S
F
F
H
O
O
C
H
F
C4
C4
C
N3
N3
F
N
SH
O
N
SH
of these reactions was studied using quantum-chemical
simulation of the reaction mechanism shown on the
schemes (1)–(4).
simulate this stage one reaction coordinate C–H was
chosen. The reaction path was created as the sequential
decrease in the length RC–H. Geometric and electronic
structure of the molecular system was calculated
by optimizing all parameters save the reaction coor-
dinate, which remains a constant during the optimiza-
tion. Step of change in the reaction coordinate was
0.01 Å.
All calculations were performed in an approach of
isolated molecules in the gas phase by the quantum-
chemical semi-empirical method AM1 [4]. The latter
was parameterized for the best representation of
hydrogen bonds. This method is preferable to other
semi-empirical quantum-chemical methods (MNDO,
CNDO, PM3) for calculating the structure of
complexes with associative interactions. Since the
search for an optimal mechanism, where the reactions
are characterized by the lowest energy barrier, requires
large calculations, the use of the non-empirical method
is not advantageous even with the modern high
performance computers.
When difluorocarbene is brought closer to the
hydrogen atom [path (1)], the charge on the atoms of
the reagents is redistributed. The positive charge on the
carbene carbon atom increases, while simultaneously
increases the positive charge on the hydrogen atom.
The negative charge on the nitrogen atom is
significantly reduced, i.e., the largest restructuring of
electronic shells of atoms occurs on the carbon atom of
difluorocarbene and N3 atom of the pyrimidine ring.
The transformation of electronic shells at the atom N3
initiates the localization of more negative charge on
The studied reaction directions can be characterized
in the context of one common mechanism, namely the
difluorocarbene attack on the hydrogen atom. To
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SYNTHESIS AND MECHANISM OF FORMATION OF 5-BENZYLIDENE-2-THIOXO-...
417
the sulfur and oxygen atoms. A significant lengthening
of the bonds C–N, C=S, or C=O was not observed.
Since the sulfur is characterized by a larger electronic
orbitals, in the initial step of reagents rapprochement
the difluorocarbene changes its orientation from the
oxygen direction to the sulfur. The increase in the
positive charge on the carbon atom of difluorocarbene
and the more negative charge on the sulfur atom
contribute to the Coulomb attraction between them.
Further rapprochement of the difluorocarbene and the
hydrogen atom leads to the covalent bonding of
difluorocarbene carbon with sulfur atom at the carbon
C2 in the pyrimidine ring. At the same time, pyri-
midine ring undergoes restructuring to form a single
C–S bond and a double C=N bond. Finally, the
hydrogen atom is detached from pyrimidine ring and
attached to difluorocarbene.
carbene at the O–H bond leads to difluoromethylation
of N3 atom of pyrimidine ring. The geometric and
electronic structure of the transition state for each of
these reactions is characterized by the formation of
five-membered ring by the atoms directly involved
into the reaction.
As can be seen from Fig. 1, the addition of singlet
difluorocarbene to various tautomeric forms of deriva-
tive I occurs with overcoming the energy barrier. The
minimum barrier is 4 kcal mol–1 and corresponds to the
S-difluoromethylation of the derivative I. The remain-
ing tautomeric forms of I participating in reac-
tions (2)–(4) are significantly disadvantageous in compare-
son with those involved in to the path (1). This is
consistent with the results of S-difluoromethylation,
described in [5]. In the case of a reaction in DMF the
S-difluoromethylation does not occur that can be
ascribed to the participation of DMF in complexation
with difluorocarbene and derivative I.
Similarly, the singlet difluorocarbene reacts with
thiol form [path (2)]. In this case the difluoro-
methylation occurs at the oxygen atom bound to the
carbon C4 of pyrimidine ring, since sulfur is blocked.
The interaction of singlet difluorocarbene with enol
form [path (3)], as well as with the structure containing
simultaneously SH and OH groups [path (4)], proceeds
by the same mechanism, i.e., the attack of difluoro-
The quantum-chemical analysis of the reaction of
singlet difluorocarbene with derivative I in DMF
solution shows that two mechanisms can exist, with
different orientation of the polar hydrogen atom of
DMF: toward sulfur [Eq. (5)] or oxygen atoms [Eq. (6)].
F
F
F
F
C
C
O1
C1
O1
C1
O
O
H
H
CH3
(5)
CH3
N3
C2
N3
C2
H1
N
C6H5
C6H5
N
H1
H3C
O
N
H
S
O
N
H
H3C
CH3
S
H3C
N
H3C
CH3
N
C1
O1
C
O
H1
C1
(6)
N3
C2
O1
O
H1
F
C6H5
H
F
N3
C2
C6H5
O
N
H
S
F
C
H
F
O
N
S
H
The participation of DMF molecule [Eqs. (5), (6)]
does not promote the S-difluoromethylation reaction.
Since the path (5) includes blocking the S-reaction
center with polar hydrogen atom H1 to form a stable
ion structure (Fig. 2, curve 1), the total negative charge
at the atoms N3 and S is close to –1. The largest
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418
RAKHIMOV et al.
–112335
–112340
–112345
–112350
–112355
–112360
–89050
–89060
–89070
–89080
–89090
2
4
3
1
2
–89100
1
–89110
–89120
2.2
2.0
1.8
1.6
1.4
1.2
1.0
RCH
3.0
2.5
2.0
1.5
1.0
Fig. 2. Changes in the total energy of the reaction between
a singlet difluorocarbene with I in the presence of DMF
oriented by the polar hydrogen atom toward (1) sulfur or
(2) oxygen.
RCH
Fig. 1. Changes in the total reaction energy [paths (1)–(4)].
positive charge focuses on the atoms H1, C1, and the
difluorocarbene carbon atom. In the case of path (6) a
stable ionic structure is also formed (Fig. 2, curve 2).
diluted with water to pH 7. The precipitate formed was
filtered off and recrystallized from an ethanol–hexane
mixture (2:1). Yield 0.36 g (20%). Orange crystals, mp
128–130°С. IR spectrum (vaseline oil, KBr), ν, cm–1:
1072 (C–F), 1240 (C=S), 1570 (C=C), 1624 (C=O),
2848 (NH). ¹Н NMR spectrum, δ, ppm: 5.96 s (1Н,
СН), 6.97–7.56 m (5Н, С6Н5), 7.94 t (1Н, CHF2, J 57
Hz), 11.57 s (1Н, NH). Found, %: N 10.10.
C11H10FN2O2S. Calculated, %: N 9.90.
From a comparison of the reaction barrier
(Fig. 2) follows that the path (5) dominates. The ion
formed can transform into the reaction product with
CF2 group at the oxygen atom (there is an obvious
opportunity of the attack by the carbon atom of the CF2
group on the oxygen). The observed by us direction of
O-difluoromethylation of derivatives I–IV and data [5]
are due to this opportunity.
5-(4-Methylbenzylidene)-6-difluoromethoxy-2-
thioxo-2,3-dihydro-(5H)-pyrimidin-4-one (VII) was
prepared similarly from 0.74 g (3 mmol) of II and
0.88 g (15 mmol) of KOH. Yield 0.30 g (34%). Orange
crystals, mp 145–147°С. IR spectrum, ν, cm–1: 1172
(C–F), 1204 (C=S), 1582 (C=C), 1630 (C=O), 2854
(NH). ¹Н NMR spectrum, δ, ppm: 2.18 s (3Н, CH3),
5.93 s (1Н, СН), 7.2–7.6 m (4Н, С6Н4), 8.06 t (1Н,
CHF2, J 55 Hz), 12.3 s (1Н, NH). Found, %: N 10.0.
C12H9F2N2O2S. Calculated, %: N 9.45.
EXPERIMENTAL
The H1 NMR spectra were registered on a Varian
Mercury 300BB instrument with internal HMDS, in
DMSO-d6. Melting points were measured on a
MelTemp 3.0 instrument, heating at 10 deg min–1.
5-Benzylidene-6-difluoromethoxy-2-thioxo-2,3-
dihydro-(5Н)-pyrimidin-4-one (VI). To a solution of
1.5 g (6.4 mmol) of I in anhydrous DMF (15 ml) was
added 1.8 g (32 mmol) of finely powdered KOH and
5-fold excess of difluorocarbene source at room
temperature under vigorous stirring. The reaction
temperature rises to 34°С. The stirring was continued at
this temperature for 15 min, then the temperature was
increased up to 50–60°С, and the reaction mixture was
stirred at this temperature for 60 min. The mixture was
cooled to room temperature, filtered, concentrated, and
5-(4-Methoxybenzylidene)-6-difluoromethoxy-2-
thioxo-2,3-dihydro-(5H)-pyrimidin-4-one (VIII) was
prepared similarly from 1.5 g (5.7 mmol) of III and
1.6 g (28.6 mmol) of KOH. Yield 0.45 g (25%). Pale
orange crystals, mp 120–122°С. IR spectrum, ν, cm–1:
1066 (C–F), 1258 (C=S), 1564 (C=C), 1630 (C=O),
2920 (NH). ¹Н NMR spectrum, δ, ppm: 2.48 s (3Н,
CH3), 5.88 s (1Н, СН), 6.82–7.6 m (4Н, С6Н4), 7.31 t
(1Н, CHF2, J 59 Hz), 11.54 s (1Н, NH). Found, %: N
9.28. C12H12FN2O3S. Calculated, %: N 8.97.
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SYNTHESIS AND MECHANISM OF FORMATION OF 5-BENZYLIDENE-2-THIOXO-...
419
5-(4-Fluorobenzylidene)-6-difluoromethoxy-2-
thioxo-2,3-dihydro-(5H)-pyrimidin-4-one (IX) was
prepared similarly from 1.2 g (4.2 mmol) of IV and
1.17 g (20 mmol) of KOH. Yield 0.56 g (31%). Yellow
crystals, mp 150–152°С. IR spectrum, ν, cm–1: 1078
(C–F), 1222 (C=S), 1546 (C=C), 1624 (C=O), 2920
(NH). ¹Н NMR spectrum, δ, ppm: 5.03 s (1Н, СН),
7.94 t (1Н, CHF2, J 55 Hz), 6.94–7.73 m (4Н, С6Н4),
12.3 s (1Н, NH). Found, %: N 10.20. C11H10F2N2OS.
Calculated, %: N 9.33.
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