Reaction of singlet difluorocarbene with 6-methylpyrimidin-4(3H)-one derivatives

Article abstract of DOI:10.1134/S107036320805023X

Regularities of regioselective O-difluoromethylation of 6-methylpyrimidin-4(3H)-one derivatives with difluorocarbene generated in situ were studied.

Full text of DOI:10.1134/S107036320805023X

ISSN 1070-3632, Russian Journal of General Chemistry, 2008, Vol. 78, No. 5, pp. 971–972. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © A.I. Rakhimov, I.Yu. Kameneva, M.B. Navrotskii, E.S. Titova, S.V. Kudashev, 2008, published in Zhurnal Obshchei Khimii, 2008,
Vol. 78, No. 5, pp. 828–829.
Reaction of Singlet Difluorocarbene
with 6-Methylpyrimidin-4(3Н)-one Derivatives
A. I. Rakhimov, I. Yu. Kameneva, M. B. Navrotskii,
E. S. Titova, and S.V. Kudashev
Volgograd State Technical University,
pr. Lenina 28, Volgograd, 400131 Russia
e-mail: organic@vstu.ru
Received December 13, 2007
Abstract—Regularities of regioselective O-difluoromethylation of 6-methylpyrimidin-4(3Н)-one derivatives
with difluorocarbene generated in situ were studied.
DOI: 10.1134/S107036320805023X
Proceeding with our previously initiated research
on difluoromethylation of 6-mehyl-2-thioxo-2,3-
dihydropyrimidin-4(1Н)-one with singlet difluorocar-
bene [1], we extended this reaction on various
derivatives of 6-methylpyrimidin-4(3Н)-one, contain-
ing alkylsulfanyl and aralkylsulfanyl groups in the 2 posi-
tion of the pyrimidine heteroring.
Our data suggest that the possibility of the reaction
and its direction are controlled by a steric factor.
Hence in derivatives II–V the least shielded and most
susceptible to the attack of difluorocarbene is the
oxygen atom, whereas in derivative VI the 5-Me group
creates additional steric hindrances to difluorocarbene
attack and prevents О-difluoromethylation.
Difluorocarbene was generated in situ via the
reaction of chlorodifluoromethane (Freon 22) (I) with
t-BuOK or KOH in anhydrous DMF.
Hypothetically, the reaction involves incorporation
of difluorocarbene and intermediate formation of a 2,2-
difluoro-7-methyl-1-oxa-4,6-diazaspiro[2.5]octa-5,7-
diene derivative that further rearranges to form the
target product.
It was found that 2-(methylsulfanyl)- (II), 2-
(ethylsulfanyl)- (III), 2-(benzylsulfanyl)- (IV), and 2-
[(3-phenoxybenzyl)sulfanyl]-6-methylpyrimidin-4-(3Н)-
ones (V) are difluoromethylated regioselectively by the
exocyclic oxygen atom.
The low yields of the target products are explained
by incomplete conversion of starting compounds II–V.
This phenomenon is associated with a high reactivity
of difluorocarbene, as well as its tendency for dimeri-
zation (to form tetrafluoroethylene) and reaction with
the solvent.
F
O
O
N
F
2,2-Difluro-3-(dimethylamino)oxirane formed by
this reaction is in itself an unstable compound and
undergoes immediate oligo- and polymerization.
[CF2]
DMF
NH
N
H3C
N
S
H3C
S
The reaction yield is also strongly dependent on
the strength of the base: With t-BuOK instead of KOH,
the yield of diflurocarbene is higher, which affects the
yield of the target product. Furthermore, with t-BuOK,
the side reaction product is t-BuOH and with KOH,
water. tert-Butanol is much less mobile, contains a
stronger shielded proton, and is more inert in the
reaction with diflurocarbene, yielding t-BuOCHF2. By
R
R
II_V
VII_X
Attempted reaction of 5,6-dimethyl-2-(methylsul-
fanylpyrimidin-)-4(3Н)-one (VI) under the same condi-
tions failed.
971

972
RAKHIMOV et al.
F
F
O
N
O
N
F
O
F
[CF3]
HN
HN
N
H3C
H3C
H3C
S
CH3
S
N
CH3
S
CH3
F
F
CH3
CH3
O
[CF3]
CH3
O
N
N
CH3
contrast, water formed in the case of KOH can actively
react with difluorocarbene to form F2CHOH and
(F2CH)2O.
4-(Difluoromethoxy)-6-methyl-2-(methylsulfa-
nyl)pyrimidine was prepared in a similar way. Yield
0.4 g (11%), mp 42–45°С. 1Н NMR spectrum, δ, ppm:
2.34 s (3Н, CH3), 6.72 s (1Н, СН), 7.74 t (1Н, CHF2, J
72 Hz). Found, %: N 13.83. C7H8F2N2OS. Calculated,
%: N 13.59.
In summary it should be noted that the yields of the
target products can be improved by performing the
reaction in the presence of a base able to irreversibly
deprotonate the starting chlorodifluromethane (for
example, NaH). Furthermore, a positive effect can be
reached by using a large excess of the base and
compound I.
2-(Benzylsulfanyl)-4-(difluoromethoxy)-6-me-
thylpyrimidine. Chlorodifluoromethane was intro-
duced into a stirred solution of 2.8 g of t-BuOK in 15 ml
of anhydrous DMF until the reagent was no longer
absorbed; therewith, the reaction mixture was
maintained at a temperature of no higher than 22°С.
Compound III, 1.16 ml, was added, and the mixture
was stirred for 30 min at 40–50°С, filtered, evaporated
in a vacuum, and the residue was crystallized from
aqueous EtOH. Yield 0.28 g (20%), mp 193–195°С.
1Н NMR spectrum, δ , ppm: 1.82 s (3Н, CH3), 4.36 s
(2Н, SCH2), 6.74 s (1Н, СН), 7.10–7.35 m (5Н, Нarom),
7.76 t (1Н, CHF2, J 72 Hz). Found, %: N 10.12.
C13H12F2N2OS. Calculated, %: N 9.93.
EXPERIMENTAL
1
The H NMR spectra were registered on a Varian
Mercury 300BB instrument in CDCl3, internal
reference HMDS. The melting points were determined
on a MelTemp 3.0 device, heating rate 10 deg min–1.
2-(Ethylsulfanyl)-4-(difluromethoxy)-6-methyl-
pyrimidine. Chlorodifluoromethane was introduced
into a stirred solution of 5.6 g of KOH in 15 ml of
anhydrous DMF until the reagent was no longer
absorbed; therewith, the reaction mixture was
maintained at a temperature of no higher than 22°С.
Compound III, 3.4 g, was then added, and the mixture
was stirred for 30 min at 40–50°С, filtered, and
evaporated in a vacuum. Ethyl ether was added to the
residue, and the mixture was filtered, evaporated, and
the residue was distilled at reduced pressure. Yield
4-(Difluoromethoxy)-6-methyl-2-[(3-phenoxy-
benzyl)sulfanyl]pyrimidine was prepared in a similar
1
way. Yield 0.3 g (24%), mp 145–147°С. Н NMR
spectrum, δ, ppm: 2.03 s (3Н, CH3), 4.28 s (2Н, SCH2),
5.91 s (1Н, СН), 6.84–7.34 m (10Н, Нarom). Found, %:
N 8.64. C19H16F2N2OS. Calculated, %: N 7.49.
1
1.25 g (28%), bp 78–80°С (3.5 mm Hg). Н NMR
REFERENCES
spectrum, δ, ppm: 1.27 t (3Н, SCH2CH3, J 7.5 Hz),
2.15 s (3Н, CH3), 3.02–3.09 q (2Н, SCH2), 6.68 s (1Н,
СН), 7.71 t (1Н, CHF2, J 72 Hz). Found, %: N 12.73.
C8H10F2N2OS. Calculated, %: N 13.80.
1. Rakhimov, A.I. and Kameneva, I.Yu., Izv. Volgograd.
Gos. Tekh. Univ., Ser. Khim. Khim. Tekhnol., 2006, no. 3,
p. 43.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 5 2008