One-pot synthesis of 6-substituted amino-2,4-diaminopyrimidine derivatives using ketene dithioacetals with amines and guanidine carbonate

Article abstract of DOI:10.3987/COM-08-11587

6-Substituted amino-2,4-diaminopyrimidine derivatives were prepared by one-pot synthesis using ketene dithioacetals, amine compounds, and guanidine carbonate in pyridine. These pyrimidine products displayed blue fluorescence in the solid state.

Full text of DOI:10.3987/COM-08-11587

HETEROCYCLES, Vol. 78, No. 4, 2009
899
HETEROCYCLES, Vol. 78, No. 4, 2009, pp. 899 - 903. © The Japan Institute of Heterocyclic Chemistry
Received, 28th October, 2008, Accepted, 8th December, 2008, Published online, 10th December, 2008
DOI: 10.3987/COM-08-11587
ONE-POT SYNTHESIS OF 6-SUBSTITUTED
AMINO-2,4-DIAMINOPYRIMIDINE DERIVATIVES USING KETENE
DITHIOACETALS WITH AMINES AND GUANIDINE CARBONATE
Miki Hirose,a Masayori Hagimori,b Yasuhiro Shigemitsu,c Naoko
Mizuyama,d Bo-Cheng Wang,e and Yoshinori Tominagaa*
aFaculty of Environmental Studies, Nagasaki University, 1-14, Bunkyo-machi,
Nagasaki 852-8521; bFaculty of Pharmaceutical Sciences, Nagasaki International
c
University, 2825-7, Huis Ten Bosch Sasebo 859-3298; Technology Center of
Nagasaki 2-1308-8, Ikeda, Omura Nagasaki 856-0026, Japan. dDepartment of
Pharmacy, Saga University Hospital, 5-1-1, Nabeshima, Saga 849-8521;
eDepartment of Chemistry, Tamkang University, Tamsui 251, Taiwan. E-mail:
ytomi@nagasaki-u.ac.jp
Abstract – 6-Substituted amino-2,4-diaminopyrimidine derivatives were
prepared by one-pot synthesis using ketene dithioacetals, amine compounds, and
guanidine carbonate in pyridine. These pyrimidine products displayed blue
fluorescence in the solid state.
Appropriately functionalized ketene dithioacetals are versatile reagents that have been extensively utilized
in heterocyclic synthesis. Ketene dithioacetals are readily prepared by condensation of active methylene
compounds with carbon disulfide in an appropriate solvent in the presence of a base followed by
methylation with dimethyl sulfate.1
Pyrimidine derivatives constitute a partial structure of purine bases and many biologically active
compounds in living organisms. They have attracted much attention from the viewpoint of medicinal
chemistry.2 The soporific and hypnotic barbiturates, as well as several antibacterial and antimalarial drugs,
contain pyrimidine rings.3 It has been reported that the synthesis of pyrimidine derivatives is attained by
the condensation reaction of ketene dithioacetals with amidine derivatives in the presence of an
appropriate base.4 Pyrimidines obtained by this method leave one more methylsulfanyl group, but these
pyrimidine derivatives are not used as an important potential precursor for directing various heterocycles
owing to low activity. Displacing a methylsulfanyl group on the pyrimidine ring with nucleophilic

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HETEROCYCLES, Vol. 78, No. 4, 2009
reagents is difficult. To circumvent this problem, the first reaction should be by the reaction of ketene
dithioacetals with amines, then with guanidine, and finally cyclization should be between a guanidinyl
group and a cyano group.
Ketene dithioacetal (1a)5, benzylamine (2a) (as amine) and guanidine carbonate (4) were selected in a
preliminary experiment. Ketene dithioacetal (1a) was allowed to react with benzylamine (2a) at room
temperature without a solvent and a catalyst to give caramel oil (3a) in quantitative yield. On the other
hand, the reaction of ketene dithioacetal (1a) with guanidine carbonate (4) under reflux conditions in
pyridine gave 2,4-diamino-6-methylsulfanyl-5-carbonitrile (5) in 87% yield (Scheme 1).4,6 Hence, we
attempted to synthesize 6-substituted amino-2,4-diaminopyrimidine derivatives by one-pot reaction of
ketene dithioacetals with amines and guanidine.
CN
CN
MeS
NH
CN
CN
MeS
MeS
H2N
+
1a
3a
2a
NH2
N
NC
NH2
NH2
CN
CN
MeS
MeS
reflux
HN
+
in pyridine
N
NH2
MeS
H2CO3
1a
4
5
Scheme 1
A mixture of ketene dithioacetal (1a; 10.0 mmol), benzylamine (2a; 11.0 mmol) and guanidine carbonate
(4; 15.0 mmol) in 10 mL of pyridine was refluxed for 3 h, and then 200 mL of water was added to yield
the desired compound; pyrimidine derivative (6a). The crystallized precipitate from DMF was collected
by filtration to give colorless needles, mp 187–188°C, in 93% yield. Other 6-subsituted
amino-2,4-diaminopyrimidine-5-carbonitriles (6b–d) were readily obtained by a similar method (Table
1).
Next, 6-arylamino-2,4-diaminopyrimidine-5-carbonitriles (6e–i) were synthesized using ketene
dithioacetal (1a), substituted aniline (2e-i) and guanidine carbonate (4). Preparation of the intermediate
3-methylsulfanyl-3-arylamino-2-cyanoacrylonitriles (3e–i), which could be prepared by refluxing for 1–2
h in ethanol or by direct heating at 150–200°C, was the key part of the reaction. After the reaction of 1a

HETEROCYCLES, Vol. 78, No. 4, 2009
901
Table 1. Synthesis of 6-substituted amino-2,4-Diamino-6-alkylaminopyrmidine-5-carbonitrilesa
NH2
NC
CN
CN
NH2
NH2
MeS
MeS
N
reflux
+
H-NR2
+
HN
N
NH2
R2N
in pyridine
H2CO3
2a-d
1a
4
6a-d
Yield %b
NR2
Mp°C
Appearance (solvent)
colorless needles (MeOH)
colorless needles (EtOH)
6a
187-188
157-158
93
94
NH-CH2-C6H5
b
c
NH-CH(Me)-C6H5
O
N
N
70
85
colorless prisms (MeOH)
colorless leaflets (MeOH)
228-229
259-260
d
a1a (1.0 equiv); 2 (1.1 equiv); 4 (3.0 equiv). b Isolated yield.
with arylamines (2e-i) under reflux conditions in pyridine for 1 h, guanidine carbonate (4) was added to
reaction mixture. This mixture was refluxed continuously for 3 h and then poured into 200 mL of water.
Product (6e) was recrystallized from DMF to give colorless prisms, mp 263–264°C, in 73% yield.
Compounds (6f–i) were synthesized in a manner similar to that described for the preparation of 6e and
yields are shown in Table 2.
Table 2. Synthesis of 6-arylamino-2,4-diamino-6-arylaminopyrmidine-5-carbonitrilesa
NH2
HN
NH2
NH2
N
NH2
H2CO3
NC
CN
CN
MeS
NH
R
CN
CN
MeS
MeS
4
2e-i
reflux
N
NH2
N
R
R
H
in pyridine
3e-i
1a
6e-i
Yield %b
6
Appearance (solvent)
R
Mp°C
e
f
H
73
90
263-264
268-269
190-191
colorless prisms (DMF)
colorless needles (MeOH)
2-OMe
3-OMe
g
h
i
68
66
63
colorless needles (MeOH)
pale yellow prisms (DMF)
colorless prisms (DMF)
4-OMe
4-Cl
309-310
261-262
a1a (1.0 equiv); 2 (1.1 equiv); 4 (3.0 equiv). b Isolated yield.

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HETEROCYCLES, Vol. 78, No. 4, 2009
Various pyrimidine derivatives (7–9) could be readily obtained from other ketene dithioacetals (except
1a) by this one-pot reaction (Scheme 2). Ketene dithioacetal 1b7 was allowed to react with benzylamine
(2a) and guanidine carbonate (4) under reflux conditions in pyridine and then poured into 200 mL of
water to give 2-amino-6-benzylamino-4-hydroxypyrimidine-5-carbonitrile (7)8 in 62% yield. In a similar
manner, 2,4-diamino-6-benzylamino-5-phenylsulfonylpyrimidine (8) was synthesized from sulfonyl
ketene dithioacetal (1c)9, 2a and 4 in 75% yield. 2-Amino-4-benzylaminoindeno[2,1-d]pyrimidin-5-one
(9) was also synthesized from α-oxoketene dithioacetal (1d)10, benzylamine (2a) and 4 in 92% yield.
OH
NC
CN
MeS
MeS
N
reflux
+
+
+
+
2a
2a
4
N
NH2
N
H
in pyridine
CO2Me
7
1b
O2
S
NH2
N
Ph
CN
MeS
MeS
reflux
4
N
NH2
N
H
in pyridine
SO2-Ph
8
1c
HN
O
O
SMe
SMe
N
reflux
+
+
2e
4
N
NH2
in pyridine
O
9
1d
Scheme 2
FLUORESCENCE OF PYRIMIDINES
The 6-substituted amino-2,4-diaminopyrimidine derivatives obtained were fluorescent materials; they
emitted blue light in the solid state. Organic electron luminescent materials which show fluorescence in
the solid state have been considerably interest because of their attractive characteristics and potential
applications as next-generation display devices. Studies of 2-pyrone derivatives clarified that
6-aryl-2-pyrone derivatives having a phenylsulfonyl group showed stronger fluorescence than
corresponding 2-pyrone-bearing cyano or ester groups at position 3.11 The fluorescence of 6-substituted
amino-2,4-diaminopyrimidine derivatives in the solid state was of considerable interest to our research
group. Alq3 [tris(8-hydroxyquinolinato)aluminum]12 was used as a standard sample for fluorescence
spectra. In general, the synthesized pyrimidine derivatives did not show strong fluorescence. However, in
these derivatives, the strongest fluorescent compound was 2,4-diamino-6-(2-methoxyphenyl)-pyrimidine-

HETEROCYCLES, Vol. 78, No. 4, 2009
903
5-carbonitrile (6f), which emitted light 0.67-times that of Alq3 at 442 nm in the solid state. Evaluating of
the structure–activity relationship with fluorescence intensity on the amino group at the 6 position in
these pyrimidines is currently being conducted.
In conclusion, a new one-pot procedure for the synthesis of 6-substituted amino-2,4-diaminpyrimidines
and fused pyrimidines (e.g., 9) using ketene dithioacetals, alkyl or aromatic amines, and guanidine
carbonate in pyridine has been described. The notable advantages offered by this method are an
environmentally friendly reaction that is easy to carry out, high yields of products, and cost effectiveness.
REFERENCES AND NOTES
1.
(a) Y. Tominaga and Y. Matsuda, J. Heterocycl. Chem., 1985, 22, 937; (b) Y. Tominaga and Y.
Matsuda, Yuki Gousei Kyoukaishi (J. Synth. Org. Chem. Japan), 1985, 43, 669; (c) Y. Tominaga,
Yuki Gousei Kyoukaishi (J. Synth. Org. Chem. Japan), 1989, 47, 413; (d) Y. Tominaga, Trends in
Heterocyclic Chemistry, 1991, 2, 43; (e) Y. Tominaga, Y. Shigemitsu, and K. Sasaki, J. Heterocycl.
Chem., 2002, 39, 571.
2.
3.
(a) R. L. Shriner and F. W. Newmann, Chem. Rev., 1944, 35, 351; (b) D. J. Brown, ‘Pyrimidines
and Their Benzo Derivatives in Comprehensive Heterocyclic Chemistry,’ in Vol. 3, ed. by A. R.
Katrizky and C. W. Rees, Pergamon Press, Oxford, 1984, p. 57, p. 443; (c) H. Yamanaka and T.
Sakamoto, Yuki Gousei Kagaku Kyoukaishi (J. Synth. Org, Chem. Japan), 1985, 43, 951.
(a) F. A. El-Essay, N. R. El-Brollosy, and E. B. Pedwesen, J. Heterocycl. Chem., 2003, 40, 213; (b)
G. Wollein and R. Troschutz, J. Heterocycl. Chem., 2002, 39, 1195.
4.
5.
6.
7.
8.
9.
Y. Tominaga, S. Kohra, H. Honkawa, and A. Hosomi, Heterocycles, 1989, 29, 1409.
1a: Y. Tominaga, J. K. Luo, L. W. Castle, and R. N. Castle, J. Heterocycl. Chem., 1993, 30, 267.
Compound 6a was not obtained by the reaction of 5 with benzylamine.
1b: R. Gompper and W. Toepfl, Chem. Ber., 1962, 95, 2861.
A. Kumar, V. Aggarwal, H. Ila, and H. Junjappa, Synthesis, 1980, 748.
1c: M. Augustin, R. Schmidt, and W. D. Rudorf, Z. Chem., 1977, 17, 289.
10. 1d: M. Augustin, Ch. Groth, H. Kristen, K. Peseke, and Ch. Wiehmann, J. Prakt. Chem., 1979, 320,
205.
11. N. Mizuyama, Y. Murakami, S. Kohra, K. Ueda, K. Hiraoka, J. Nagaoka, K. Takahashi, Y.
Shigemitsu, and Y. Tominaga, J. Heterocycl. Chem., 2007, 44, 115.
12. H. Odaka, Y. Okimoto, T. Yamada, H. Okamoto M. Kawasaki, and Y. Tokuda, Appl. Phys Lett.,
2006, 88, 123501.