An efficient acylation/base-catalyzed cyclization of thioureas affords N,N′-disubstituted thiobarbituric acids

Article abstract of DOI:10.1016/S0040-4039(01)00011-9

Acylation of 1,3-disubstituted thioureas with methyl malonyl chloride followed by base-catalyzed cyclization leads to the preparation of 1,3-disubstituted-2-thiobarbituric acids in high yield.

Full text of DOI:10.1016/S0040-4039(01)00011-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1607–1610
An efficient acylation/base-catalyzed cyclization of thioureas
affords N,N%-disubstituted thiobarbituric acids
Perry C. Heath,a,* Charles Q. Huang,b Richard F. Lowe,b James R. McCarthy,b Leland O. Weigela
and Jeffery P. Whittenb
aLilly Research Laboratories, A Division of Eli Lilly and Company, Chemical Process Research and Development Division,
Indianapolis, IN 46285-4813, USA
bNeurocrine Biosciences, Inc., San Diego, CA 92121, USA
Received 27 December 2000; accepted 2 January 2001
Abstract—Acylation of 1,3-disubstituted thioureas with methyl malonyl chloride followed by base-catalyzed cyclization leads to
the preparation of 1,3-disubstituted-2-thiobarbituric acids in high yield. © 2001 Published by Elsevier Science Ltd.
Certain substituted 2-thiobarbituric acids have long been
used as intravenous anesthetics1 and as intermediates in
the preparation of dyes.10a More recently there has been
interest in 2-thiobarbituric acids as anticonvulsants,2
immunotropic and anti-inflammatory compounds,3 anti-
neoplastic agents,4 and as platforms in the synthesis of
other biologically active compounds.5 While deceptively
simple in structure, 1,3-disubstituted-2-thiobarbituric
acids have been prepared in only three ways.6 Simple
1,3-dialkyl substituted-2-thiobarbituric acids are pre-
pared in high yield by the base-catalyzed condensation
of dialkyl malonate esters with alkyl substituted
thioureas.7 However, this protocol has not been reported
for the preparation of 1,3-diaryl and 1,3-diarylalkyl
substituted thiobarbituric acids.8 Rather, they are pre-
pared by the condensation of substituted thioureas with
malonyl dichloride,2,3,9 or with malonic acid and acetyl
chloride.2b,10 The former protocol, while reported to
generate 1,3-diaryl-2-thiobarbituric acids in 50% yield,
has not been reported for the preparation of 1,3-diaryl-
alkyl-2-thiobarbituric acids. The latter protocol has been
used to prepare 1,3-diarylalkyl-2-thiobarbituric acids in
yields of <10%.10b We report herein our work on the
development of an efficient synthesis of 1,3-diarylalkyl
substituted 2-thiobarbituric acids by the acylation and
base-catalyzed cyclization of substituted thioureas and
the extension of this methodology to the preparation of
1,3-diaryl substituted 2-thiobarbituric acids (Scheme 1).
Substituted arylalkyl amines (1) were reacted with 1,1%-
thiocarbonyldiimidazole to afford substituted thioureas
(2) in 95% yield. These thioureas were reacted with
malonyl dichloride, however the excessive reactivity of
this reagent led to poor yields of the 2-thiobarbituric
acids (4). The less reactive methyl malonyl chloride11 was
substituted for malonyl dichloride and when combined
with 2 in refluxing 1,2-dichloroethane afforded 4 in
16–60% yields. The HCl formed from the condensation
of methyl malonyl chloride and 2 was thought to catalyze
the cyclization to 4.
Scheme 1. (a) 1,1%-Thiocarbonyldiimidazole/ACN 0°C; (b) methyl malonyl chloride/1,2-dichloroethane/reflux 15 min; (c) 1N
NaOH/EtOAc/rt. R=Ar(CH2)n−; n=1,2.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)00011-9

1608
P. C. Heath et al. / Tetrahedron Letters 42 (2001) 1607–1610
The reaction between 2 and methyl malonyl chloride
proved to be problematic. The yields were low and
often not reproducible. The reaction times were exces-
sive, in one case requiring 72 hours at reflux for com-
pletion. Moreover, the impurities formed during the
cyclization made isolation and purification of the prod-
ucts difficult. Therefore, to better understand the mech-
anism, the conversion was monitored by HPLC and
NMR spectroscopy. Both techniques showed the for-
mation of an intermediate, that on the basis of NMR
spectroscopy, was identified as an N-acylthiourea (3).
This intermediate was formed nearly quantitatively
within 15 minutes at 83°C. The only byproduct
observed was the diacylthiourea, which was present in
52%. Prolonged heating of the reaction mixture at
83°C in the presence of HCl led to the formation of 4
and impurities as well as a small amount of 2. How-
ever, we found that 3 was stable enough to be isolated
and slowly cyclized to 4 over the course of several days
when stored at ambient temperature.
We next turned our attention to the cyclization of 3
under basic conditions. The base-catalyzed condensa-
tion of thiourea and diethylmalonate is well known in
the literature7a,b and leads to quantitative yields of
2-thiobarbituric acid. We felt that the cyclization of 3
under basic conditions would likewise lead to high
yields of 4. Thus, treatment of 3 with a slight excess of
aqueous NaOH at 23°C led quantitatively to 4. The
yields after recrystallization were 87–90% (Table 1).12
The protocol was effective for the preparation of both
benzyl and 2-phenethyl substituted thioureas. We found
the yield of the reaction was unaffected by the presence
of either electron withdrawing or electron donating
substituents on the aromatic groups. The protocol can
be conveniently run on 100 g scale without any loss in
yield.
We then examined the preparation of 1,3-diaryl-2-thio-
barbituric acids with the newly developed protocol.
Table 1. Preparation of 1,3-disubstituted-2-thiobarbituric acids 4 from N,N%-disubstituted thioureas 2
Entry
Conditiona
Yield (%)
R
F
1
87
A
CH2CH2-
CH3O
CH3O
2
3
CH2-
A
A
87
88
CH2CH2-
CH2-
S
Cl
4
5
A
B
90
85
CH3
6
7
84
90
B
B
CH3O
CH3
43
8
B
a A: methyl malonyl chloride, 1,2-dichloroethane, reflux, then NaOH, EtOAc; B: 2 equiv of
methyl malonyl chloride, CH2Cl2, rt, then conc. under vacuum, rt

P. C. Heath et al. / Tetrahedron Letters 42 (2001) 1607–1610
1609
Scheme 2.
References
Treatment of thiocarbanilide (5) with methyl malonyl
chloride in refluxing 1,2-dichloroethane led primarily to
the formation of phenylisothiocyanate (8) and the
mixed ester amide (9) (Scheme 2). The identity of 8 and
9 were established by GC/MS. The identity of 9 was
also confirmed by comparison to an authentic sample
of the mixed amide ester prepared by the reaction of
aniline with methyl malonyl chloride. Compounds 8
and 9 were thought to be formed through thermal
rearrangement of the intermediate N-acylthiourea (6).
We overcame the thermal instability of 6 by performing
the reaction at 23–25°C with 2 equiv. of methyl mal-
onyl chloride in methylene chloride. A slow stream of
nitrogen was passed over the reaction mixture to
remove HCl formed during the reaction. This modified
protocol provided high yields of 6. However, treatment
of 6 with aqueous NaOH at 23–25°C again led primar-
ily to the formation of 8 and 9. Noting earlier that 3
cyclized spontaneously to 4 when isolated as an oil, 6
was similarly concentrated to an oil. After concentra-
tion to an oil, 6 cyclized to 7 over the course of several
days at 23–25°C. The crude product (7) was purified by
reslurrying in hot methyl t-butyl ether. The modified
protocol afforded excellent yields of 1,3-diaryl substi-
tuted-2-thiobarbituric acids (Table 1, entries 5–7).13
However, the sterically congested 1,3-di-o-tolyl
thiourea produced only a moderate yield of product
(entry 8).
1. Doran, W. J. In Barbituric Acid Hypnotics; Blicke, F. F.;
Cox, R. H., Eds. Medicinal chemistry. John Wiley and
Sons: New York, 1959; Vol. 4, p. 5.
2. (a) Vasey, C. H. Br. Patent 741 097, 1955; (b) Dhasmana,
A.; Barthwal, J. P.; Pandey, B. R.; Ali, B.; Bhargava, K.
P.; Parmer, S. S. J. Heterocyclic Chem. 1981, 18, 635.
3. Zawisza, T.; Matczak, H.; Kowalczyk-Bronisz, S. H.;
Jakobiec, T. Pol. Arch. Immunol. Ther. Exp. 1981, 29,
235.
4. Singh, S.; Behl, C. K. Indian J. Chem., Sect. B 1980, 19B,
625.
5. (a) Bogue, J. Y.; Carrington, H. C. Br. J. Pharmacol.
1953, 230; (b) Ahluwalia, V. K.; Sharma, H. R.; Tyagi,
R. Tetrahedron 1986, 42, 4045; (c) Whitten, J. P.;
McCarthy, J. R.; Behan, D. P.; Xie, Y. F.; Liu, Z.;
Huang, C. Q.; Erickson, P. E.; Lowe, R. PCT Int. Appl.
WO 9 745 421 A1 971204.
6. There is a report of a Pd(0)-catalyzed allylation of 2-thio-
barbituric acid, however it lacks regioselectivity. See:
Moreno-Manas, M.; Pleixats, R.; Villarroya, M. Tetra-
hedron 1993, 49, 1457.
7. (a) Michael, A. J. Prakt. Chem. 1887, 35, 456; (b)
Michael, A. J. Prakt. Chem. 1894, 49, 38; (c) Brooker, L.
G. S.; Keyes, G. H.; Sprague, R. H.; VanDyke, R. H.;
VanLare, E.; VanZandt, G.; White, F. L. J. Am. Chem.
Soc. 1951, 73, 5326; (d) Salvesen, Medd. Nor. Farm.
Selsk. 1963, 25, 1; Chem. Abstr. 59, 3923.
8. The authors examined the condensation of 1,3-bis-(2-
thiophen-2-yl-ethyl)-thiourea and diethyl malonate in
refluxing ethanol containing sodium ethoxide using the
procedure mentioned in reference 7c. A 39% yield of the
corresponding 2-thiobarbituric acid was obtained, which
compares with an 88% yield (Table 1, entry 3) when the
protocol disclosed in this paper was utilized.
9. (a) Whiteley, M.; Mountain, H. Proc. Chem. Soc. 1909,
25, 121; Chem. Abstr. 1910, 4, 304; (b) Whiteley, M. J.
Chem. Soc. 1907, 91, 1330; (c) Nightingale, A. J. Am.
Chem. Soc. 1936, 58, 794.
In summary, an efficient and high-yielding synthesis of
1,3-diarylalkyl and 1,3-diaryl substituted 2-thiobarbi-
turic acids from 1,3-disubstituted thioureas and methyl
malonyl chloride has been realized.
Acknowledgements
We would like thank Jerry Misner, Marvin Hansen,
Michael Martinelli, Tony Zhang, Eric Moher and
Andrew Fray for helpful discussions during the course
of this work.
10. (a) Dass, J. N.; Dutt, S. Indian Acad. Sci. 1938, 8A 145;
Chem. Abstr. 1939, 33, 620; (b) Berg, U.; Patterson, I. J.
Org. Chem. 1987, 52, 5177.

1610
P. C. Heath et al. / Tetrahedron Letters 42 (2001) 1607–1610
11. Methyl malonyl chloride (methyl 3-chloro-3-oxopropi-
onate) is available from Aldrich.
diaryl-2-thiobarbituric acids: Methyl malonyl chloride
(2.06 mL, 19.2 mmol) was added dropwise to a suspen-
sion of N,N%-di-(4-methoxyphenyl) thiourea (2.52 g, 8.76
mmol) and methylene chloride (100 mL). The solids
dissolved within 15 minutes. A slow nitrogen stream was
passed over the reaction, while stirring at 20–23°C. After
stirring for 24 h most of the solvent had evaporated.
HPLC of the residue indicated complete conversion of
starting material to the N-acylthiourea intermediate. The
remaining solvent was evaporated and the residue was
placed under vacuum. The progress of the cyclization was
monitored by HPLC and after 48 h, the conversion to
thiobarbituric acid was complete. The resulting yellow
solid was broken up with a spatula and purified by
refluxing in 25 mL of methyl t-butyl ether to give 2.8 g
(90%) of 1,3-di-(4-methoxyphenyl)-2-thiobarbituric acid.
12. Representative procedure for the preparation of 1,3-
diarylalkyl-2-thiobarbitutric acids: Methyl malonyl chlo-
ride (25.6 mL, 0.24 mol) was added dropwise to a
suspension of N,N%-di-(3-chlorobenzyl) thiourea (65 g,
0.19 mol) in dry 1,2-dichloroethane (100 mL). The reac-
tion mixture was heated at reflux for 15 minutes and then
cooled to 25°C. The solvent was evaporated and replaced
with ethyl acetate (650 mL). 1N NaOH (250 mL) was
added and the two-phase mixture was stirred for 2 h at
23°C. The solvent was then evaporated from the organic
layer and the residue was purified by recrystallization
from ethanol (400 mL) to give 73.1 g (90%) of 1,3-di-(3-
chlorobenzyl)-2-thiobarbituric acid as a yellow solid.
13. Representative procedure for the preparation of 1,3-
.
.