Synthesis of Polysubstituted Pyrimidines from Ketene Dithioacetals Using KF/Al2O3 Catalyst

Article abstract of DOI:10.1081/SCC-120026325

KF/Al₂O₃ was first used to catalyze the synthesis of 2-alkylthio-4-amino-5-cyano-6-methylthiopyrimidines 3a-f via the reaction of the ketene dithioacetals 1 (prepared from malononitrile) with isothiuronium salts 2a-f. Six pyrimidine compounds were prepared and all of their structures were confirmed by elemental analysis, ¹H NMR, and IR. The reaction conditions (solvents, catalyst amounts, and temperature) were investigated for the first time. The separation yield reached 89%.

Full text of DOI:10.1081/SCC-120026325

This article was downloaded by: [Ondokuz Mayis Universitesine]
On: 13 November 2014, At: 02:27
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Synthesis of Polysubstituted Pyrimidines from Ketene
Dithioacetals Using KF/Al O Catalyst
2
3
a
a
Shen-Yi Yu & Ya-Xian Cai
a
The Key Laboratory of Science and Technology of Controllable Chemical Reactions ,
Ministry of Education , Beijing University of Chemical Technology , Beijing, P.R. China
Published online: 19 Aug 2006.
To cite this article: Shen-Yi Yu & Ya-Xian Cai (2003) Synthesis of Polysubstituted Pyrimidines from Ketene Dithioacetals
Using KF/Al O Catalyst, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
2
3
Chemistry, 33:22, 3989-3995, DOI: 10.1081/SCC-120026325
To link to this article: http://dx.doi.org/10.1081/SCC-120026325
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 22, pp. 3989–3995, 2003
Synthesis of Polysubstituted Pyrimidines from
Ketene Dithioacetals Using KF/Al O Catalyst
2
3
Shen-Yi Yu* and Ya-Xian Cai
The Key Laboratory of Science and Technology of
Controllable Chemical Reactions,
Ministry of Education, Beijing University of
Chemical Technology, Beijing, P.R. China
ABSTRACT
2 3
KF/Al O was first used to catalyze the synthesis of 2-alkylthio-4-
amino-5-cyano-6-methylthiopyrimidines 3a–f via the reaction
of the ketene dithioacetals 1 (prepared from malononitrile) with
isothiuronium salts 2a–f. Six pyrimidine compounds were prepared
and all of their structures were confirmed by elemental analysis,
1
H NMR, and IR. The reaction conditions (solvents, catalyst
amounts, and temperature) were investigated for the first time. The
separation yield reached 89%.
*
Correspondence: Shen-Yi Yu, The Key Laboratory of Science and Technology
of Controllable Chemical Reactions, Ministry of Education, Beijing University of
Chemical Technology, Beijing, 100029, P.R. China.
3
989
DOI: 10.1081/SCC-120026325
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
3
990
Yu and Cai
Since Yamawaki and Ando reported in 1979 that KF supported on
Al O was able to produce much stronger activities than KF itself which
was used either in DMF, in DMSO, on molecular sieve, on silica gel, or on
2
3
[
1]
other solid supports, KF/Al O reagent has been widely used as an
3
2
effective mixed solid catalyst to catalyze many important organic synthesis
[
2]
[3]
reactions, such as Michael addition, Wittig, and Knoevenagel
[4]
[5]
reactions. The highly desirable applicability of the reagent to various
synthesis reactions is due to its following advantages. First, the
KF/Al O reagent is inexpensive and easy to be prepared and recovered.
2
3
Second, the workup of the reactions is simple. Third, the reaction
conditions are mild and safe. To our knowledge, however, KF/Al O
2
3
has been only used in the alkylation of C, N, O, S, and some condensation
reactions of straight chain carbon compounds. The synthesis of
heterocyclic compounds using KF/Al O as a catalyst has not been
2
3
reported yet.
It is well known that the pyrimidine derivatives are very important
heterocyclic compounds, especially in life science, medical chemistry, and
pesticide chemistry. This importance is seen from a large amount of
publications, including several reviews and books, dealing with the
[
6,7]
synthesis methods of pyrimidines.
Consequently, it is of significant to
synthesize new polysubstituted pyrimidine compounds, especially those
having good biological activities, and to find better synthesis methods.
[
8]
Middleton and Engelhardt employed sodium methoxide as a base
to obtain 6-amino-5-cyano-2,4- dimethylthiopyrimidine 3a in a 60% yield
via the reaction of 3,3-dimethylthio-2-cyanoacrylonitrile 1 with 2-methyl-
2-thiopseudourea sulfrate 2a. Later, Tominaga et al. reported that the
yield of the same reaction using potassium carbonate or triethylamine as
[7]
the bases was only 38%.
In this article, we report an application of KF/Al O as a solid base
2
3
catalyst for the synthesis of pyrimidine derivatives 3a–f via the reaction of
ketene dithioacetal 1 with the isothiuronium salts 2a–f. Our study show
that, as KF/Al O takes the place of above mentioned bases, the
2
3
reactions occur under the heterogeneous conditions. As a result, the
workup of the reactions become very easy and the yields are increased.
We first optimized the reaction conditions. The reaction between 1
and 2c was carried out under various experimental conditions, including
solvents, amounts of KF/Al O , and temperatures. We found that the
2
3
highest yields could reach 83% when the reaction was carried out under
the reflux condition in acetonitrile and the optimum amount of the
catalyst was 1.5 g of KF/Al O for each of 5 mmol of 1 (Table 1).
2
3
After the isothiuronium salts 2a–f were prepared via the reactions of
sulfourea with the corresponding halohydrocarbon or other materials

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
KF/Al O Catalyst
2
3991
3
a
Table 1. The data of 1 reacting with 2c.
Catalyst amounts
(g/5 mmol 1)
Reaction
time (h)
Entry
Solvent
CH Cl
Yield (%)
1
2
3
4
5
6
7
8
9
1.5
1.5
1.5
1.5
1.5
1.5
0.75
1.0
2.0
1.5
5.0
3.5
70
83
76
82
70
2
2
CH
CH
3
CN
CH
3
2
OH
2.0
1.5
1,4-dixoane
Toluene
DMF
2.5
0.75
10.0
7.0
50
b
CH CN
3
CH
CH
3
3
CN
CN
74
85
2.0
10.0
c
1
0
CH CN
3
75
a
All reactions were proceeded at refluxing temperature except 10.
b
1 had not reacted completely based on TLC after refluxing 10 h.
This reaction was proceeded at room temperature.
c
[
9–13]
following Lits.,
were novel were synthesized (Table 2) via the reactions of 1 with 2a–f
six pyrimidine compounds in which five 3b–f
in the presence of KF/Al O , according to the optimum conditions
3
2
obtained in Table 1. All of the structures of 3a–f were confirmed by
1
elemental analysis, H NMR, and IR.
EXPERIMENTAL
All reagents were purchased from commercial sources. Melting points
were measured using a Yanaco Mp-500 and was not corrected.
1
The H NMR spectra were recorded at room temperature using
a DMX300 spectrometer with TMS as internal reference. The IR
spectra were recorded as KBr disks on a BRUKER Vector22 spectrom-
eter. The elemental analyses data were obtained on a CARLO ERBA 1106.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
3
992
Yu and Cai
Table 2. The data of 2-alkylthio-4-amino-5-cyano-6-methylthio pyrimidines 3a–f.
Entry
R
X
Reaction time (h)
Yield (%)
3a
3b
3c
3d
3e
3f
Me
Et
1/2H
2
SO
4
1
89
74
83
84
63
73
Br
Br
Cl
Cl
Cl
2
n-Bu
t-Bu
3.5
6
n-C12H
25
PhCH2
6
4
Preparation of KF/Al O
2
3
KF 2H O (97.2 g) was dissolved in water (250 mL) and mixed with
2
Al O (90 g). The slurry was evaporated using a rotary evaporator under
2
3
ꢀ
reduce pressure in 80–100 C. The white solid obtained was dried in an
ꢀ
oven at 110 C for 6 h.
3,3-Dimethylthio-2-cyanoacrylonitrile
To a mixture of malononitrile (9.9 g, 0.15 mol), CS (13 g, 0.17 mol),
2
and ethanol (100 mL), a solution of sodium ethoxide (150 mL, 0.37 mol)
was added drop by drop. The mixture was stirred for 1 h at room
temperature, then dimethyl sulfate (43 mL, 0.45 mol) was added. The
reaction mixture was stirred overnight, then was poured to water. The
precipitate was collected by filtration and recrystallized from ethanol–
ꢀ
[14]
water to give 21.7 g pale yellow needles in 85% yield, m.p. 80–81 C.
1
H NMR (CDCl ): ꢀ 2.79 (s, 6H, 2SCH ).
3
3

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
KF/Al O Catalyst
2
3993
3
General Procedure for the Reaction of 3,3-Dimethylthio-2-
cyanoacrylonitrile with Isothiuronium Salts
To a mixture of isothiuronium salts (5.5 mmol) in acetonitrile
10 mL) was added KF-Al O (1.5 g) and the mixture was stirred and
(
2
3
heated to reflux. Then, a solution of 3,3-dimethylthio-2-cyanoacrylo-
nitrile (5 mmol) in acetonitrile (20 mL) was added from a dropping
funnel for 15 min and the reaction mixture was allowed to stand at reflux-
ing temperature until the TLC indicated that no 3,3-dimethylthio-2-cya-
noacrylonitrile was present. The solid catalyst was filtered from the
reaction mixture. The hot DMF (5 mL ꢁ 2) was used to wash the solid.
The organic solution was poured into water (100 mL). The precipitate
was collected and recrystallized from ethanol–water.
4
-amino-5-cyno-2,6-dimethylthio-pyrimidine 3a. This compound was
ꢀ
prepared from 2a in 89% yield. M.p.: 231 C. IR (KBr): ꢁ max 3356, 3166,
ꢂ1
926, 2216, 1656, 1529, 1452 cm . H NMR (aceton-d ): ꢀ 2.51 (s, 3H,
6
1
2
SCH ), ꢀ 2.59 (s, 3H, SCH ), ꢀ 7.02 (bs, 2H, NH ). Anal. Calcd. for
3
3
2
C H N S : C, 39.60; H, 3.80; N, 26.39. Found: C, 39.36; H, 3.92;
7
8
4 2
N, 26.50.
4-amino-5-cyno-2-ethylthio-6-methylthiopyrimidine 3b. This com-
pound was prepared from 2b in 74% yield. M.p.: 211–214 C. IR (KBr):
ꢀ
ꢂ1
1
max 3371, 3159, 2212, 1650, 1527, 1446 cm . H NMR (DMSO-d ): ꢀ
ꢁ
6
1
.30 (t, 3H, J ¼ 4.9 Hz, CH ), ꢀ 2.54 (s, 3H, SCH ), ꢀ 3.03–3.09 (q, 2H,
3
3
CH ) ꢀ 7.77 (bs, 2H, NH ). Anal. Calcd. for C H N S : C, 42.46; H, 4.45;
8
2
2
10
4 2
N, 24.76. Found: C, 42.66; H, 4.35; N, 24.52.
4
-amino-2-butylthio-5-cyno-6-methylthiopyrimidine 3c. This com-
ꢀ
pound was prepared from 2c in 83% yield. M.p.: 169–171 C. IR
ꢂ1
KBr): ꢁ max 3354, 3158, 2217, 1657, 1526 cm . H NMR (CDCl ): ꢀ
3
1
(
0
2
2
.94 (t, 3H, J ¼ 7.5 Hz, CH ), ꢀ 1.39–1.51 (m, 2H, CH ), ꢀ 1.65–1.75 (m,
3
2
H, CH ), ꢀ 2.57 (s, 3H, SCH ), ꢀ 3.10 (t, 3H, J ¼ 7.4, SCH ), ꢀ 6.64 (bs,
2 3 2
H, NH ). Anal. Calcd. for C H N S : C, 47.22; H, 5.55; N, 22.03.
2
10 14
4 2
Found: C, 47.50; H, 5.32; N, 22.32.
4-amino-2-tert-butylthio-5-cyno-6-methylthiopyrimidine 3d. This com-
pound was prepared from 2d in 84% yield. M.p.: 84–85 C. IR (KBr):
ꢀ
ꢂ1
1
max 3289, 3132, 2966, 2926, 2207, 1635, 1530, 1427 cm . H NMR
ꢁ
(
NH ). Anal. Calcd. for C H N S : C, 47.22; H, 5.55; N, 22.03. Found:
DMSO-d ): ꢀ 1.56 (s, 9H, 3CH ), ꢀ 2.53 (s, 3H, SCH ), ꢀ 7.77 (bs, 2H,
6
3
3
2
10 14
4 2
C, 47.25; H, 5.52; N, 21.15.
4-amino-5-cyno-2-dodecylthio-6-methylthiopyrimidine 3e. This com-
pound was prepared from 2e in 63% yield. M.p.: 136–137 C. IR
ꢀ
ꢂ1
1
(
(
KBr): ꢁ max 3371, 3164, 2926, 2849, 2213, 1647, 1528 cm . H NMR
CDCl ): ꢀ 0.88 (t, 3H, CH ), ꢀ 1.26–1.42 (m, 18H, (CH ) ), ꢀ 1.66–1.74
3
3
2 9

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
3
994
Yu and Cai
(
Calcd. for C H N S : C, 58.97; H, 8.25; N, 15.28. Found: C, 58.75;
m, 2H, CH ), ꢀ 2.59 (s, 3H, SCH ), ꢀ 3.10 (t, 2H, J ¼ 7.4, SCH ). Anal.
2
3
2
1
8
30
4 2
H, 8.53; N, 15,62.
4-amino-2-benzylthio-5-cyno-6-methylthiopyrimidine 3f. This com-
pound was prepared from 2f in 73% yield. M.p.: 177 C. IR (KBr):
ꢀ
ꢂ1
1
ꢁ
ꢀ
ꢀ
max 3356, 3152, 2220, 1662, 1550, 1528 cm . H NMR (CDCl3):
2.55 (s, 3H, SCH ), ꢀ 4.40 (s, 2H, CH ), ꢀ 5.49 (bs, 2H, NH ),
7.28–7.39 (m, 5H, C H ). Anal. Calcd. for C H N S : C, 54.14;
3
2
2
6
5
13 12
4 2
H, 4.19; N, 19.43. Found: C, 54.25; H, 4.05; N, 19.63.
REFERENCES
1
2
3
. Ando, T.; Yamawaki, J. Potassium fluoride on celite. A versatile
reagent for C-, N-, O- and S-alkylations. Chem. Lett. 1979, 85 (1),
45–46.
. Yu, S.Y.; Chen, F.H. Development in the application of KFAl O
2
3
reagent to organic synthesis reactions. Youji Huaxue 1999, 19 (2),
27–134.
1
. Clark, J.H.; Cork, D.G.; Robertson, M.S. Fluoride ion catalyzed
michael reactions. Chem. Lett. 1983, 8, 1145–1148; Ando, T.;
Clark, J.H.; Cork, D.G.; Hanafusa, T.; Ichihara, J.; Kimura, T.
Fluorid-alumina reagents: the active basic species. Tetrahedron
Lett. 1987, 28 (13), 1421–1424; Bergbreiter, D.E.; Lalonde, J.J.
Michael additions of nitroalkanes to a,b-unsaturated carbonyl
compounds using KF/basic alumina. J. Org. Chem. 1987, 52 (8),
1601–1603.
4
5
. Texier-Boullet, F.; Villemin, D.; Ricard, M.; Moison, H.; Foucaud, A.
Reactions de wittig, wittig-horner et knoevenagel par activation anio-
nique avec l’alumine ou le fluorure de potassium depose sur l’alumine
sans solvant. Tetrahedron 1985, 41 (7), 1259–1266.
. Yamawaki, J.; Kawate, T.; Ando, T.; Hanafusa, T. Potassium fluoride
on alumina. An efficient solid base for elimination, addition, and
condensation. Bull. Chem. Soc. Jpn. 1983, 56 (6), 1885–1886;
Villemin, D.; Alloum, A.B. Dry reaction under microwave: conden-
sation of sulfones with aldehydes on KFAlumina. Syn. Comm. 1991,
21 (1), 63–68; Villemin, D. Anionic reactions by chromatography on
alumina-potassium fluoride. Chem. Indus. 1985, 4, 166.
6. Brown, D.J. The principal synthetic method. In The Pyrimidines
Supplement I; Weissberger, A., Taylor, E.C., Eds.; New York,
1970; 20–52.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
KF/Al O Catalyst
2
3995
3
7
8
9
. Tominaga, Y.; Kohra, S.; Harumasa; Hosomi, A. Synthesis of
pyrimidine derivatives and their related compounds using ketene
dithioacetals. Heterocycles 1989, 7, 1409–1429.
. Middleton, W.J.; Engelhardt, V.A. Cyanocarbon chemistry. IX.
Heterocyclic compounds from dicynoketene acetals. J. Am. Chem.
Soc. 1958, 80, 2829.
. Taylor, J. J. Chem. Soc. 1917, 111, 655.
1
0. Riemschneider, R.; Pehlmann, H. Influence of nonphysiological
compounds on metabolic proceses. III. F-containing pyrimidine
derivatives and dicarboxylic acid derivatives. Z. Naturforsch 1965,
20b (6), 540–543.
1
1
1
1. Kresze, G.; Uhlich, U. Structure of organosulfur compounds. II.
Properties of thionitrites. Chem. Ber. 1959, 92, 1048–1055.
2. Spraue, J.M.; Johnson, T.B. Prepation of alkylsulfonyl chlorides
from isothioureas. II. J. Am. Chem. Soc. 1937, 59, 1837–1840.
3. Donleavy, J. Utilization of S-benzylthiuronium chloride for the
isolation and identification of organic acids. J. Am. Chem. Soc.
1936, 58, 1004–1005.
14. Soderback, E. Condensation of carbon disulfide with reactive
methylene groups. Acta. Chem. Scand. 1963, 17, 362–376.
Received in Japan May 12, 2003

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.