Synthesis of 5-[3-(diphenylphosphinoyl)propyl]-2-thiobarbituric acid

Full text of DOI:10.1007/s11176-008-2025-7

ISSN 1070-3632, Russian Journal of General Chemistry, 2008, Vol. 78, No. 2, pp. 320 322.
Pleiades Publishing, Ltd., 2008.
Original Russian Text
A.N. Reznikov, N.K. Skvortsov, 2008, published in Zhurnal Obshchei Khimii, 2008, Vol. 78, No. 2, pp. 335 337.
LETTERS
TO THE EDITOR
Synthesis
of 5-[3-(Diphenylphosphinoyl)propyl]-2-thiobarbituric Acid
A. N. Reznikov and N. K. Skvortsov
St. Petersburg State Technological Institute,
Moskovskii pr. 26, St. Petersburg, 190013 Russia
e-mail: orgphos@yandex.ru
Received October 9, 2007
DOI: 10.1134/S1070363208020254
2-Thiobarbituric acids are widely used for the
synthesis of diverse pyrimidine derivatives [1 3]
possessing antiphlogistic, anesthetic, anticonvulsive,
bactericidal, cytostatic, antitumor, and antiviral ac-
tivities. 5-Phosphinoylalkyl-2-thiobarbituric acids that
combine in their molecules two active fragments, a
phosphorus-containing group and a pharmacogenic
malonate (II) under conditions of radical initiation by
UV illumination or by adding 2,2 -azobisisobutiro-
nitrile (AIBN) to an equimolar mixture of the reagents.
1
Reaction selectivity was monitored by H and 31P
NMR spectroscopy. It was found that this reaction
proceeds with high conversion (over 95%) and
regioselectivity (90.1%) to form dimethyl 2-[3-(di-
easily
modified
2-thioxodihydropyrimidine-4,6-
phenylphosphinoyl)propyl]malonate
31.3 ppm). The yield of isomeric product IV (
30.7 ppm) is 9.9%.
(III)
(
P
P
(1H,5H)-dione groups are interesting as valuable
intermediates in the synthesis of biologically active
compounds. The main method of synthesis of 5-sub-
stituted 2-thiobarbituric acids is condensation of
2-substituted diethyl malonates with thiourea in the
presence of base [4]. However, malonic acid deriv-
atives with phosphoruscontaining substituents form a
poorly studied class of compounds. The syntheses
of diethyl 2-[2-(diphenylphosphinoyl)ethyl]malonate
and diethyl 2,2-bis[2-(diphenylphosphinoyl)ethyl]-
malonate by adding diethyl malonate to diphenyl(vi-
nyl)phosphine oxide [5] and of diethyl 2-[3-(diethoxy-
phosphinoyl)propyl]malonate from diethyl phosphite,
1,3-dibromopropane, and diethyl malonate [6] have
been described. We suggest that phosphorylation of
unsaturated derivatives of malonic esters provides a
more promising synthetic approach to such com-
pounds.
O
O
Ph2P(O)H +
O
O
I
II
O
O
O
O
O
P
Ph
Ph
Ph
P
+
Ph
O
O
O
O
O
III
IV
Malonate III reacts with thiourea (V) in the pres-
ence of sodium methylate to give 5-[3-(diphenylpho-
sphinoyl)propyl]-2-thiobarbituric acid (VI).
Earlier we reported the catalytic hydrophosphoryla-
tion of dialkyl 2-allylmalonates with diakyl phos-
phites, leading to phosphorylated malonates [7, 8].
By contrast, the reaction of diphenylphosphine oxide
with dialkyl 2-allylmalonates results in dealkoxycar-
bonylation [8].
Compound VI forms sodium and ammonium salts
1
readily soluble in water. The H NMR spectrum of
compound VI contains multiplets of methylene groups
in the phosphinoylalkyl substituent and a broad
singlet of the NH group in the region characteristic of
2-thiobarbituric acids [9]. The phosphorus chemical
shift of compound VI is specific of phosphine oxides.
The presence in the 13C NMR spectrum of this com-
Continuing these investigations, we reacted di-
phenylphosphine oxide (I) with dimethyl 2-allyl-
320

SYNTHESIS OF 5-[3-(DIPHENYLPHOSPHINOYL)PROPYL]-2-THIOBARBITURIC ACID
321
0.443 g of thiourea was added to the resulting yellow
solution. The reaction mixture was refluxed for 4 h,
methanol was then removed in a vacuum. The non-
volatile residue was dissolved in 15 ml of water, and
the solution was filtered and acidified with conc. HCl
to ®H 2. The precipitate that formed was dissolved in
1.02 g of 25% aqueous ammonia and 10 ml of water,
the solution was filtered, and the filtrate was acidified
with a solution of 1.66 g of conc. H2SO4 in 3 ml of
water. The precipitate that formed was filtered off,
dried, and recrystallized from ethanol. Yield 1.22
O
O
O
P
Ph
Ph
+ (NH2)2CS
O
O
III
V
Ph
Ph
P
O
(1) MeONa; MeOH
(2) HCl; H2O
NH
O
S
1
O
N
(55.2%), mp 248 C. H NMR spectrum (DMSO-d6),
H
, ppm: 1.57 m (2H, CH2), 2.35 m (4H, 2CH2), 7.52
m (6H, Ph), 7.75 m (4H, Ph), 11.98 br.s (2H, 2NH).
13C NMR spectrum, C, ppm: 20.15 s (CH2), 21.83 d
VI
pound of a singlet at 92.82 ppm, characteristic of the
carbon atom at a double bond, as well as a signal of
the carbon atom bound to hydroxyl (170.62 ppm)
points to partial enolization of compound VI dis-
solved in DMSO.
3
2
(CH2, JCP 7.30 Hz), 26.27 d (CH2, JCP 69.7 Hz),
92.82 s (C= tautomeric form), 128.72 d (Ph, m-C,
3JCP 12.1 Hz), 130.40 d (Ph, o-C, JCP 9.4 Hz),
2
131.96 s (Ph, p-C), 132.87 s (Ph, Ci), 160.83 s (C=O),
170.62 s (C OH tautomeric form), 173.10 s (C=S).
31P NMR spectrum (DMSO-d6), P, ppm: 33.1. IR
The IR spectrum of compound VI has much in
common with the spectrum of 2-thiobarbituric acid
[10, 11]. Besides, strong bending bands of aromatic
1
spectrum, cm : 425 m, 472 m, 511 s, 544 s, 586 m,
632 w, 672 s, 696 s, 716 s, 722 s, 732 s, 748 s, 785 m,
817 m, 865 m, 884 m, 924 m, 937 m, 997 m, 1022 m,
1057 m, 1071 m, 1078 s, 1089 s, 1123 s, 1144 s,
1175 s, 1184 s, 1210 s, 1247 s, 1290 s, 1328 s, 1354 s,
1391 m, 1436 s, 1482 m, 1548 s, 1562 s, 1605 s,
1651 s, 1721 m, 1978 w, 2180 m, 2243 m, 2620 m,
2858 s, 2896 s, 2925 s, 3013 s, 3057 s, 3421 m.
1
C H bonds [ (C H) 696, 715, 722, 731, 748 cm ]
are observed.
Dimethyl 2-[3-(diphenylphosphinoyl)propyl]-
malonate (III). Dimethyl 2-allylmalonate (0.852 g)
and diphenylphosphine oxide (0.950 g) were illum-
inated under an inert atmosphere with unfiltered light
of a DRT-400 lamp for 4 h. The reaction product was
isolated by column chromatography. Yield 1.72 g
(98.0%).
1
The H, 13C and 31P NMR spectra were registered
on Brucker NW 400 and AC 200 instruments in
CDCl3 and (CD3)2SO at 400.14 (1H), 50.33 (13C), and
81.01 (31P) MHz. All data are represented in ppm
relatively to TMS (1H) and 85% H3PO4 (31P). No
additional reference compounds were used, the
frequencies were tied to the signal of the deuterated
solvent.
Dimethyl 2-allylmalonate (0.999 g), diphenylphos-
phine oxide (1.166 g), and AIBN (22 mg) were heated
under argon for 3 h, and then 6 mg of AIBN was
added additionally. The reaction product was isolated
by column chromatography. Rf 0.55 (methanol ethyl
acetate, 1:10). Yield 1.94 g (90.0%). H NMR spec-
trum (CDCl3), , ppm: 1.66 m (2H, CH2), 2.00 m (2H,
1
The IR spectra were registered on a Shimadzu
1
FTIR-8400S instrument (4000 500 cm ) from KBr
3
pellets.
CH2), 2.27 m (2H, CH2P), 3.34 t (1H, CH, JHH
7.5 Hz), 3.67 s (6H, CH3), 7. 46 m (6H, Ph), 7.70 m
Chromatography was performed on silica gel 60 of
chromatographic grade, methanol from Merck, AIBN
of pure grade, sodium of analytical grade, and
thiourea, HCl and ethyl acetate of chemical grade.
Dimethyl 2-allylmalonate was prepared by the
procedure in [12] and diphenylphosphine oxide, by
the procedure in [13].
(4H, Ph). 13C NMR spectrum (CDCl3), C, ppm:
2
19.58 s (CH2), 29.15 d (CH2, JCP 52.7 Hz), 30.03 s
(CH2), 51.14 s [CH(COOMe)2], 52.46 s (CH3O),
3
128.64 d (Ph, m-C, JCP 13.2 Hz), 130.70 d (Ph, o-C,
2JCP 8.6 Hz), 131.75 s (Ph, p-C), 133.72 s (Ph, Ci),
169.37 s [C(O)O]. 31P NMR spectrum (CDCl3):
P
31.3 ppm.
ACKNOWLEDGMENTS
5-[3-(Diphenylphosphinoyl)propyl]-2-thiobar-
bituric acid (VI). To a solution of sodium methylate
prepared from 0.263 g of sodium and 3 ml of me-
thanol, 2.14 g of dimethyl 2-[3-(diphenylphosphinoyl)-
propyl]malonate in 10 ml of methanol was added, and
The work was financially supported by the Russian
Foundation for Basic Research (project no. 07-03-
00823a) and Administration of St. Petersburg (grant
PD06-1.3-61).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 2 2008

322
REZNIKOV, SKVORTSOV
7. Reznikov, A.N., Sokolova, M.V., and Skvortsov, N.K.,
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