One-pot two-step solvent-free rapid and clean synthesis of 2-(substituted amino)pyrimidines by microwave irradiation

Article abstract of DOI:10.1246/bcsj.82.1175

abs A series of diversely 2-(substituted amino)pyrimidines (along with ring substitution) has been synthesized under solvent- and catalyst-free microwave conditions from substituted guanidines and β-diketones. The substituted guanidines are synthesized from (S)-methylisothiourea sulfate and different amines (various alkyl, aryl, or heterocyclic and also chiral amines) under microwave irradiation. These two-step reactions are performed in one-pot without isolating any intermediate. This protocol has been successfully applied for the synthesis of bisaminopyrimidines and 2-substituted aminopyrimidines containing chiral moiety where chirality remains undisturbed.

Full text of DOI:10.1246/bcsj.82.1175

© 2009 The Chemical Society of Japan
Bull. Chem. Soc. Jpn. Vol. 82, No. 9, 1175–1181 (2009) 1175
One-Pot Two-Step Solvent-Free Rapid and Clean Synthesis of
2-(Substituted Amino)pyrimidines by Microwave Irradiation
³
Shyamaprosad Goswami,* Anita Hazra, and Subrata Jana
Department of Chemistry, Bengal Engineering and Science University, Shibpur, Howrah 711103, India
Received January 29, 2009; E-mail: spgoswamical@yahoo.com
A series of diversely 2-(substituted amino)pyrimidines (along with ring substitution) has been synthesized under
solvent- and catalyst-free microwave conditions from substituted guanidines and ¢-diketones. The substituted guanidines
are synthesized from (S)-methylisothiourea sulfate and different amines (various alkyl, aryl, or heterocyclic and also
chiral amines) under microwave irradiation. These two-step reactions are performed in one-pot without isolating any
intermediate. This protocol has been successfully applied for the synthesis of bisaminopyrimidines and 2-substituted
aminopyrimidines containing chiral moiety where chirality remains undisturbed.
2-(Substituted amino)pyrimidines are of great interest due to
their pharmacological importance.1-4 Specifically 2-anilino-
pyrimidines are fungicides and bipyrimidines have antiamoebic
activity.5 Substituted pyrimidines are also important synthons
for the synthesis of pterin and purine related compounds.6,7
These different substituted aminopyrimidines are used as hosts
for recognition as well as supramolecular studies with neutral
molecules and metal ions.8
These types of compounds are synthesized either by direct
condensation of substituted guanidines9 with ¢-dicarbonyls,
ethyl acetoacetate, and ethyl cyanoacetate or by nucleophilic
aromatic substitution reactions of amines with halogenated
pyrimidines.10 The amino group of 2-aminopyrimidine is
substituted by aryl- or alkylamines under acidic conditions
for the synthesis of this type of compounds.11 The other
important type of synthesis is the condensation reaction
between alkyl(aryl)amines with 2-methylthiopyrimidine under
drastic conditions.12 However all these reactions are carried out
under drastic conditions following multi-step procedures. Here
we have developed this new efficient, quick, and clean method
for the synthesis of such pyrimidines.
Different organic synthesis has been exploited under micro-
wave irradiation due to its immense environmental impact and
short reaction time.13 Currently this technique has been widely
used for different organic transformations including the syn-
thesis of a wide range of heterocyclic compounds.14,15 Our
continuing efforts for the successful implementation of micro-
wave technique in solid-phase organic synthesis,16 led us to
attempt the one-pot synthesis of 2-(substituted amino)pyrimi-
dines.
secondary amino substitution in the pyrimidine ring is an
important criteria for different pharmacological activities,1-4 we
report here a new one-pot synthesis of substituted amino-
pyrimidines where substituents in both ring and amine moiety
may be varied simultaneously.
In conventional methods, substituted guanidines are pre-
pared by the reaction of isothiourea (=aminoiminomethane-
thiol) salts10d and alkyl(aryl)amine in the presence of a strong
base in ethanol for several hours under refluxing conditions.
These substituted guanidines are condensed with ¢-diketones
to produce 2-(substituted amino)pyrimidine under refluxing
condition.9 So both the steps require several hours along with
drastic reaction conditions. But in our method, both the steps
are performed in a single reaction vessel under microwave
irradiation without using any solvent or catalyst.
Monosubstituted guanidines are obtained initially by the
microwave reaction of (S)-methylisothiourea salt and corre-
sponding amines in solid phase. In one representative case,
benzyl-substituted guanidine is obtained from benzylamine
(2b) (4 mmol), isothiourea salt (2 mmol), and potassium
carbonate (2.5 mmol) by irradiation at 450 W for 18 min
(Scheme 1). The unreacted benzylamine in the reaction mixture
is removed by washing with chloroform and the solid residue
is then dried well. This solid residue is again irradiated
with acetylacetone (7a) at 300 W for 5 min to afford the
2-benzylamino-4,6-dimethylpyrimidine (8d) in an overall 78%
yield. The required temperatures are 90-100 and 55-65 °C
for the first step and second step of the reaction respectively,
which have been measured by introducing a thermometer in
the reaction mixture just at the end of the reactions.18 We
also followed the same reaction conditions in a conventional
method in a preheated oil bath where the yields were very low.
The synthesis of substituted guanidines from isothiourea salt
and different amines is summarized in Table 1 whereas their
condensation with ¢-diketones, ethyl acetoacetate, and ethyl
cyanoacetate are shown in Table 2. Both the steps are carried
out in solvent-free conditions and the final substituted amino-
pyrimidines are isolated by a simple workup.
Results and Discussion
We have recently reported the synthesis of substituted
2-aminopyrimidines under microwave irradiation where sub-
stituents are varied only in the heterocyclic ring.17 But as the
³ Present address: Department of Chemistry, University of
Victoria, Victoria, Canada
Published on the web September 9, 2009; doi:10.1246/bcsj.82.1175

1176 Bull. Chem. Soc. Jpn. Vol. 82, No. 9 (2009)
Synthesis of 2-(Substituted Amino)pyrimidines
NH
R1 NH2
R1
2
H2N
N
H
NH
4
MW, K2CO3
12-40 min
.
H2SO4
H3CS
NH2
NH
2
NH
NH2
1
X
H2N
N
N
NH2
H2N
X
H
H
5
3
Scheme 1. Synthesis of substituted guanidines (for R1 and X see Table 1) from (S)-methylisothiourea salt 1.
O
CH3
O
Table 1. Microwave-Assisted Synthesis of Substituted
Guanidines from (S)-Methylisothiourea Salt 1 and Various
Amines 2 and 3
H
NH
NH2
4b
Ac2O
Ph
N
N
60-700C, 2h
Ph
N
MW conditions Substituted
N
H
H
Entry Mono/diamine (2/3)
guanidine
(4/5)
P/W t/min
CH3
a
b
c
d
e
f
g
h
i
R1 = -C4H9
R1 = -CH2C6H5
R1 = -C6H5
R1 = 4-MeO-C6H4-
R1 = 1-Phenylethyl
R1 = 2-Furfuryl
R1 = 6-CH3-C5H3N-
X = -(CH2)6-
450
450
450
450
450
450
450
450
12
18
30
27
12
20
40
18
25
40
45
4a
4b
4c
4d
4e
4f
4g
5h
6
Scheme 2. Synthesis of the acetyl derivative of benzyl-
guanidine.
benzyl-substituted guanidine moiety are converted to their
acetyl derivatives. The molecular ion peak of compound 6 is
observed at 234.4 (MH+, 20%).
X = 1,3-CH2(-C6H4-)CH2- 450
R1 = 3-NO2-C6H4-
R1 = Diphenyl
5i
These substituted guanidines are used for the condensation
in the next step. Upon condensation with ¢-diketones, ethyl
acetoacetate, and ethyl cyanoacetate, diversely substituted
2-aminopyrimidines are synthesized. The subsequent con-
densation of these substituted guanidines with ¢-diketones
(Scheme 3) affords the fully aromatized 2-(substituted amino)-
pyrimidines (8a-8p and 9q-9r, Table 2). The interesting
observation in this study is that the substituted amino groups
are always attached to “C2” of the substituted pyrimidine
rings. So the ring formation always takes places through
two unsubstituted amine and imine groups of the substituted
guanidines with ¢-diketones. During the condensation reac-
tions, no dihydropyrimidines were isolated which indicates that
the substituted amine moiety of guanidines are not involved in
the cyclization process.
The overall yields at Table 2 are directly influenced by the
nucleophilicity order of the alkyl, aryl, and heterocyclic
amines. The yields of the 2-(substituted amino)pyrimidine
containing alkyl group (8a, 8e, 8g, 8i, and 9q) are higher
as alkyl groups enhance nucleophilicity of the guanidinium
moiety. But the isolated yield of pyrimidines containing
heteroaryl moiety (8p) is lower than the pyrimidines contain-
ing aryl moiety (8c and 8f) as both aryls and heteroaryls
reduce the nucleophilic reactivity of the guanidine moiety.
In the case of 2-(substituted amino)pyrimidines containing
benzylic substituents (8b, 8d, 8h, 8m, 8n, 8o, and 9r),
the yields are in the intermediate range of both alkyl and
aryl/heteroaryl 2-(substituted amino)pyrimidines. The other
significant observation is that the chirality of the amine 2e
j
k
450
450
no reaction
no reaction
So the substituted guanidines are easily synthesized by
nucleophilic replacement of a thiomethyl group by various
amines including alkyl, aromatic, heteroaromatic, and chiral
moieties (Scheme 1) under microwave irradiation. The impor-
tant observation during the synthesis of substituted guanidines
is that no substituted products of (S)-methylisothiourea salt
with secondary amine like di-n-butylamine, diisopropylamine,
or diphenylamine are formed. Similar results are also observed
in the case of nitro-substituted aryl amines, which are very
much less reactive toward nucleophilic displacement. So the
substituted guanidines containing these groups are not obtained
under microwave irradiation.
The formation of substituted guanidine in the first step
(Scheme 1) under microwave irradiation is proven by the
formation of the acetyl derivative of benzyl-substituted
guanidine 4b. The acetate derivative 6 is obtained by
acetylation (Ac2O, 60-70 °C, 2 h) of compound 4b (Scheme 2).
The 1H NMR spectrum of this benzylguanidine diacetate
(6) shows the appearance of a secondary benzylamine proton at
a very downfield position (¤ 13.18) due to intramolecular
hydrogen bonding with one of the amide carbonyl groups. The
other amide proton appears at ¤ 9.33. The appearance of a
doublet of two benzylic protons at ¤ 4.65 (J = 5.7 Hz) implies
that benzyl-substituted N-H is not acetylated with acetic
anhydride. So only the imino and primary amino groups of the

S. Goswami et al.
Bull. Chem. Soc. Jpn. Vol. 82, No. 9 (2009) 1177
R2
NH
N
R1
H2N
NH
N
R1
O
O
H
R3
N
N
N
4
H
MW
8
R3
R2
R2
N
R2
N
4-25 min
7
NH
N
X
H2N
N
H
N
NH2
H
X
N
R3
5
R3
N
H
H
9
Scheme 3. Synthesis of 2-(substituted amino)pyrimidine from monosubstituted guanidines or diguanidino compound and
¢-diketones (for R1, R2, R3, and X, see Table 2).
Table 2. Microwave-Supported Synthesis of 2-(Substituted Amino)pyrimidines from Monosubstituted Guanidines and
Diguanidino Compounds with ¢-Diketones
Mono/bis
Entry substituted
MW conditions
Mp19a,19b
(lit)/°C
¢-Diketone 7
Product 8/9
Yielda)/%
P/W
t/min
guanidine 4/5
Me
N
a
4a
7a: R2 = R3 = Me
300
4
80
Dense liquid
112-114
H9C4
N
H
N
Me
8a
Ph
N
b
4b
4c
7b: R2 = Ph
R3 = Me
300
300
5
9
74
65
N
H
N
Me
Ph
8b
Me
N
N
c
7a: R2 = R3 = Me
7a: R2 = R3 = Me
84-86 (96-97)
Ph
N
H
N
Me
Me
8c
Me
d
e
4b
4a
300
300
300
300
5
8
8
5
78
68
67
75
110-112 (111-112)
68-70 (91)
N
H
N
Ph
8d
O
7c: R2 = OEt
R3 = Me
HN
H9C4
N
H
Me
N
8e
Me
MeO
N
f
4d
4a
7a: R2 = R3 = Me
80-82 (88-89)
55-56
N
N
Me
H
8f
Ph
N
g
7b: R2 = Ph
R3 = Me
H9C4
N
H
N
Me
8g
Continued on next page:

1178 Bull. Chem. Soc. Jpn. Vol. 82, No. 9 (2009)
Synthesis of 2-(Substituted Amino)pyrimidines
Continued:
Mono/bis
Entry substituted
guanidine 4/5
MW conditions
Mp19a,19b
Yielda)/%
¢-Diketone 7
Product 8/9
(lit)/°C
P/W
t/min
O
HN
h
4b
7c: R2 = OEt
R3 = Me
300
7
65
72
62-63
65-66
Ph
N
H
N
Me
Ph
8h
Ph
N
i
4a
4b
7d: R2 = R3 = Ph
300
300
6
H9C4
N
H
N
8i
O
CO2Et
HN
j
7e:
20
56
116-118
Ph
N
H
N
NH2
CN
8j
O
CO2Et
HN
k
4a
4a
7e:
300
300
300
300
18
25
6
58
25
75
69
146-148
76-78
H9C4
N
N
NH2
CN
H
8k
8l
OH
l
7f: R2 = OEt
R3 = OEt
N
H9C4
N
H
N
OH
Me
H
N
Me
Ph
m
4e
7a: R2 = R3 = Me
Dense liquid
74-76
N
H
N
Me
8m
Ph
H
N
Me
Ph
n
o
4e
7d: R2 = R3 = Ph
7
N
N
Ph
H
8n
Ph
N
4f
7b: R2 = Ph
R3 = Me
300
6
70
120-122
N
N
Me
H
O
8o
8p
Me
N
p
q
4g
5h
7a: R2 = R3 = Me
7a: R2 = R3 = Me
300
300
9
7
55
64
88-90
Me
N
N
N
N
Me
H
Me
Me
N
122-124 (135)
Me
N
N
N
H
N
Me
6
H
9q
Me
N
NH
Me
HN
N
r
5i
7a: R2 = R3 = Me
300
8
60
162-164
N
N
9r Me
Me
a) Isolated yields are of chromatographically obtained pure material.

S. Goswami et al.
Bull. Chem. Soc. Jpn. Vol. 82, No. 9 (2009) 1179
O
O
CH3
R1 NH2
CH3
H3C
CH3
NH
NH2
2
7a
N
N
.
H2SO4
MW, K2CO3
H3CS
MW, 450W
10 -50 min
R1
MeS
N
CH3
N
N
CH3
300W, 12 min
2
H
1
10
8
Scheme 4. Synthesis of substituted 2-methylthiopyrimidine.
remains undisturbed during the whole course of the reac-
tions leading to the synthesis of chiral 2-(substituted amino)-
pyrimidines 8m and 8n in good yields. The yield of sub-
stituted pyrimidinamines also depends on ¢-diketones or
related compounds. In the case of acetyl acetone, the yield
is higher whereas the reactivity gradually decreases when
ethyl acetoacetate (7c), ethyl cyanoacetate (7e), and diethyl
malonate (7f) are used for the condensation with substituted
guanidines. The yield is low (25%) in the case of diethyl
malonate.
To establish the effectiveness of the reaction, we attempt
to study the reaction in a different pathway. Initially, the
condensation of ¢-diketones with (S)-methylisothiourea salt is
carried out under microwave irradiation to produce 2-methyl-
thiopyrimidines. Then 2-methylthiopyrimidines are used for
the synthesis of 2-(substituted amino)pyrimidines by the
substitution of methylthio group of 2-methylthiopyrimidines
with various amines under microwave irradiation. But the
substitution of 2-methylthio by amine failed to produce the
desired product under these conditions, though through
conventional means,10a substitution of methylthio group was
performed by primary amine with poor yield under refluxing
conditions for several hours.
So from this alternate attempt for the synthesis of 2-
(substituted amino)pyrimidines it is found that substitution
of methylthio group in the pyrimidine ring by substituted
amines is unfavorable under the present microwave conditions
(Scheme 4). Though this reaction pathway should be advanta-
geous regarding the synthesis of a series of 2-(substituted
amino)pyrimidines from a single intermediate in one step but
unfortunately this has not happened in our case. Therefore our
reaction schemes (Schemes 1 and 3) are an effective alternate
for the synthesis of 2-(substituted amino)pyrimidines under
solvent-free microwave conditions.
Experimental
General Procedure for the Synthesis of Substituted Guani-
dine and 2-(Substituted Amino)pyrimidines. A mixture of (S)-
methylisothiourea sulfate (1) (pseudourea) (556 mg, 2.0 mmol) and
potassium carbonate (345 mg, 2.5 mmol) was thoroughly ground
together. Then benzylamine (2b) (428 mg, 4.0 mmol) was added
and mixed thoroughly, placed in an open mouth conical flask and
then irradiated at 450 W (or at 90-100 °C) for 18 min (the time
period varied from 12 to 40 min depending on amines) (Scheme 1
and Table 1) in a microwave oven. The reaction was carried out in
a well-ventilated hood. The solid mass was washed with CHCl3 to
remove the unreacted amine and then dried. The solid mass
(benzylguanidine) was mixed with acetylacetone (7a) (400 mg,
4.0 mmol) and again irradiated at 300 W (or at 55-65 °C) for 5 min
(in the case of various ¢-diketones the time period varied from 4 to
25 min) (Scheme 3 and Table 2). The residue was dissolved in
water and then extracted with CHCl3. The organic layer was
evaporated under reduced pressure. The crude product was then
purified by column chromatography (silica gel, 100-200 mesh)
to afford pure 2-benzylamino-4,6-dimethylpyrimidine (8d) using
ethyl acetate-petroleum ether (1:10) as eluent. Representative
spectral data for 2-(substituted amino)pyrimidines are as follows.
2-Butylamino-4,6-dimethylpyrimidine (8a):
Dense liquid; Rf (15% ethyl acetate/petroleum ether) = 0.42; IR:
3282, 2961, 2927, 1570, 1552, 1357, 1338, 1213, 1142 cm
1H NMR (CDCl3, 500 MHz): ¤ 6.28 (s, 1H), 4.89 (br s, 1H), 3.41
(q, 2H, J = 12.5 Hz), 2.27 (s, 6H), 1.57 (m, 2H), 1.41 (m, 2H),
0.94 (t, 3H, J = 7.3 Hz); 13C NMR (CDCl3, 75 MHz): ¤c 167.3,
162.4, 109.3, 40.9, 31.8, 23.8, 20.0, 13.8; HRMS (ES+) Calcd for
C10H18N3 (M + H+): 180.1500. Found: 180.1482.
2-Benzylamino-4-methyl-6-phenylpyrimidine (8b): Yield:
74%; White solid; Rf (12% ethyl acetate/petroleum ether) = 0.42;
Mp 112-114 °C; IR: 3272, 3065, 2920, 1594, 1553, 1346, 1135,
1030, 825 cm¹1; 1H NMR (CDCl3, 400 MHz): ¤ 8.01 (m, 2H), 7.43
(m, 3H), 7.39 (d, 2H, J = 7.4 Hz), 7.32 (t, 2H, J = 7.4 Hz), 7.27
(t, 1H, J = 7.2 Hz), 6.89 (s, 1H), 5.44 (br s, 1H), 4.75 (d, 2H,
J = 5.9 Hz), 2.39 (s, 3H); 13C NMR (CDCl3, 125 MHz): ¤c 168.4,
164.6, 162.6, 139.7, 137.7, 130.2, 128.6, 128.5, 127.6, 127.0,
106.4, 45.5, 24.3; HRMS (ES+): Calcd for C18H18N3 (M + H+):
276.1484. Found: 276.1493.
2-Anilino-4,6-dimethylpyrimidine (8c): Yield: 65%; Rf (15%
ethyl acetate/petroleum ether) = 0.40; Mp 84-86 °C (lit.19 96-
97 °C); IR: 3269, 3060, 1600, 1563, 1531, 1496, 1439, 1340, 1247,
824 cm¹1; 1H NMR (CDCl3, 500 MHz): ¤ 7.67 (d, 2H, J = 8.6 Hz),
7.31 (t, 2H, J = 8.0 Hz), 7.04 (br s, 1H), 7.01 (m, 1H), 6.49 (s, 1H),
2.37 (s, 6H); 13C NMR (CDCl3, 125 MHz): ¤c 167.9, 160.2, 140.4,
129.2, 122.4, 119.2, 112.1, 24.3; HRMS (ES+): Calcd for
C12H14N3 (M + H+): 200.1187. Found: 200.1181.
Yield: 80%;
¹1
;
Conclusion
We have thus developed a clean, rapid, and convenient
solvent-free synthesis of various 2-(substituted amino)pyrimi-
dines (alkyl, aryl, heteroaryl, and chiral amino moieties along
with the alkyl or aryl substituents in the pyrimidine ring). All
the reactions afford moderate to high yield of the desired
products under microwave conditions. The significant advan-
tage of this reaction is the flexibility of the substituents of
the pyrimidine ring including amino moiety, which may be
selected according to the requirement for the synthesis of
various analogs for pharmacological study. Besides these,
bis[2-(substituted amino)pyrimidine]s have also been synthe-
sized by this procedure which may be used for both supra-
molecular and metal coordination chemistry.
2-Benzylamino-4,6-dimethylpyrimidine (8d): Yield: 78%;
White crystalline solid; Rf (15% ethyl acetate/petroleum ether) =
0.45; Mp 110-112 °C (lit.19 111-112 °C); IR: 3276, 3045, 2926,

1180 Bull. Chem. Soc. Jpn. Vol. 82, No. 9 (2009)
Synthesis of 2-(Substituted Amino)pyrimidines
1542, 1484, 1362, 1024, 832 cm¹1; 1H NMR (CDCl3, 500 MHz): ¤
7.34 (d, 2H, J = 6.9 Hz), 7.31 (t, 2H, J = 7.4 Hz), 7.25 (m, 1H),
6.33 (s, 1H), 5.25 (br s, 1H), 4.65 (d, 2H, J = 5.9 Hz), 2.28 (s, 6H);
13C NMR (CDCl3, 125 MHz): ¤c 167.9, 162.7, 140.1, 128.9, 127.9,
127.4, 110.3, 45.8, 24.3; HRMS (ES+): Calcd for C13H16N3
(M + H+): 214.1344. Found: 214.1339.
2H), 0.86 (t, 3H, J = 7.28 Hz); 13C NMR (CDCl3, 125 MHz): ¤c
165.9, 154.9, 124.6, 78.4, 40.7, 31.8, 20.4, 14.1; HRMS (ES+):
Calcd for C8H15N4O (M + H+) 183.1242. Found: 183.1418.
2-Butylaminopyrimidine-4,6-diol (8l): Yield: 25%; Rf (4%
MeOH/CHCl3) = 0.43; Mp 76-78 °C; IR: 3420, 3181, 2929,
1709, 1626, 1526, 1250, 837 cm¹1; 1H NMR (CDCl3, 400 MHz): ¤
5.19 (s, 1H), 5.10 (s, 1H), 4.97 (s, 1H), 3.48 (s, 1H), 3.28 (m, 2H),
1.50 (m, 2H), 1.34 (m, 2H), 1.26 (t, 3H, J = 7.28 Hz); 13C NMR
(CDCl3, 75 MHz): ¤c 169.2, 167.7, 166.0, 40.4, 29.6, 19.9, 13.7;
MS (FIA): m/z (%): 182.0 [(M ¹ H)+, 5], 208.0 [(M + 2H +
Na)+, 50]; HRMS (ES+): Found: 182.1368 (M ¹ H)+.
2-Butylamino-6-methyl-3H-pyrimidin-4-one (8e):
Yield:
68%; Off-white solid; Rf (25% ethyl acetate/petroleum ether) =
0.40; Mp 68-70 °C (lit.19 91 °C); IR: 3255, 2958, 2872, 1656,
1
1608, 1518, 1451, 1331, 1220, 967 cm¹1; H NMR (CDCl3, 400
MHz): ¤ 11.70 (br s, 1H), 5.89 (br s, 1H), 5.57 (s, 1H), 3.37 (m,
2H), 2.16 (s, 3H), 1.57 (m, 2H), 1.37 (m, 2H), 0.94 (t, 3H, J = 7.4
Hz); 13C NMR (CDCl3, 125 MHz): ¤c 164.2, 163.1, 154.7, 108.2,
102.7, 41.7, 31.8, 20.4, 14.1; HRMS (ES+): Calcd for C9H16N3O
(M + H+): 182.1250. Found: 182.1283.
4,6-Dimethyl-2-(1-phenylethylamino)pyrimidine
(8m):
Yield: 75%; Rf (10% ethyl acetate/petroleum ether) = 0.43;
25
Liquid; ½¡ꢀD +95.4 (c 0.074, CHCl3); IR: 3425, 2975, 2930,
1644, 1567, 1367, 1224 cm¹1, 1H NMR (CDCl3, 500 MHz): ¤ 7.49
(d, 2H, J = 7.0 Hz), 7.40 (t, 2H, J = 7.6 Hz), 7.31 (t, 1H, J = 7.3
Hz), 6.37 (s, 1H), 5.35 (br s, 1H), 5.32 (m, 1H), 2.34 (s, 6H), 1.63
(d, 3H, J = 6.6 Hz); 13C NMR (CDCl3, 125 MHz): ¤c 167.8, 161.9,
145.3, 128.8, 127.2, 126.6, 110.2, 50.6, 24.3, 23.3; HRMS (ES+):
Calcd for C14H18N3 (M + H+): 228.1500. Found: 228.1489.
2-(4-Methoxyanilino)-4,6-dimethylpyrimidine (8f): Yield:
67%; Rf (15% ethyl acetate/petroleum ether) = 0.45; Mp 80-82 °C
(lit.19 88-89 °C); IR: 3260, 2933, 1588, 1562, 1508, 1458, 1339,
1
1034, 826 cm¹1; H NMR (CDCl3, 500 MHz): ¤ 7.55 (d, 2H, J =
6.8 Hz), 6.93 (br s, 1H), 6.87 (d, 2H, J = 9.0 Hz), 6.44 (s, 1H), 3.79
(s, 3H), 2.34 (s, 6H); 13C NMR (CDCl3, 75 MHz): ¤c 167.4, 159.9,
154.9, 133.1, 120.9, 113.9, 110.9, 55.4, 23.7; HRMS (ES+): Calcd
for C13H16N3O (M + H+): 230.1293. Found: 230.1302.
4,6-Diphenyl-2-(1-phenylethylamino)pyrimidine
(8n):
Yield: 69%; Rf (8% ethyl acetate/petroleum ether) = 0.43; Mp
25
74-76 °C; ½¡ꢀD +46.58 (c 0.068, CHCl3); IR: 3066, 2919, 2849,
2-Butylamino-4-methyl-6-phenylpyrimidine (8g):
Yield:
1568, 1543, 1491, 1214, 1028; 1H NMR (CDCl3, 500 MHz): ¤
8.02 (m, 5H), 7.49 (m, 7H), 7.39 (s, 1H), 7.34 (t, 2H, J = 6.8 Hz),
7.23 (m, 1H), 5.58 (d, 1H, J = 7.1 Hz), 5.37 (m, 1H), 1.67 (d, 3H,
J = 6.9 Hz); 13C NMR (CDCl3, 125 MHz): ¤c 166.1, 162.5, 145.6,
138.4, 130.7, 129.1, 128.9, 127.5, 127.3, 126.6, 103.5, 51.5, 23.4;
HRMS (ESI-TOF): Calcd for C24H22N3 (M + H+): 352.1808.
Found: 352.1813.
75%; Rf (15% ethyl acetate/petroleum ether) = 0.45; Mp 55-
56 °C; IR: 3278, 2926, 2856, 1557, 1462, 1376, 1230, 1028,
1
822 cm¹1; H NMR (CDCl3, 500 MHz): ¤ 8.02 (m, 2H), 7.45 (m,
3H), 6.85 (s, 1H), 5.06 (br s, 1H), 3.52 (q, 2H, J = 12.9 Hz), 2.39
(s, 3H), 1.63 (m, 2H), 1.45 (m, 2H), 0.97 (t, 3H, J = 7.4 Hz);
13C NMR (CDCl3, 75 MHz): ¤c 168.2, 164.5, 162.7, 137.8, 130.1,
128.5, 126.9, 105.8, 41.1, 31.9, 24.2, 20.1, 13.8; HRMS (ES+):
Calcd for C15H20N3 (M + H+): 242.1641. Found: 242.1653.
2-Benzylamino-6-methyl-3H-pyrimidin-4-one (8h): Yield:
2-Furfurylamino-4-methyl-6-phenylpyrimidine (8o): Yield:
70%; Rf (6% ethyl acetate/petroleum ether) = 0.39; Mp 120-
¹1
122 °C; IR: 3247, 3066, 2926, 1600, 1555, 1439, 1069 cm
;
65%; Rf (25% ethyl acetate/petroleum ether) = 0.43; Mp 62-
1H NMR (CDCl3, 400 MHz): ¤ 8.02 (s, 2H), 7.44 (m, 3H), 7.35 (s,
1H), 6.90 (s, 1H), 6.30 (s, 1H), 6.26 (s, 1H), 5.38 (br s, 1H), 4.73
(d, 2H, J = 5.7 Hz), 2.39 (s, 3H); 13C NMR (CDCl3, 125 MHz):
¤c 168.9, 164.8, 162.6, 151.3, 142.9, 130.7, 129.0, 128.6, 127.4,
110.8, 107.8, 107.1, 40.6, 24.7; HRMS (ES+): Calcd for
C16H16N3O (M + H+) 266.1287. Found: 266.1255 (M + H+).
4,6-Dimethyl-2-(6-methyl-2-pyridylamino)pyrimidine (8p):
Yield: 55%; Rf (20% ethyl acetate/petroleum ether) = 0.42; Mp
¹1
63 °C; IR: 3279, 3030, 2925, 1656, 1602, 1515, 1326, 967 cm
;
1H NMR (CDCl3, 400 MHz): ¤ 11.52 (br s, 1H), 7.33 (m, 5H), 6.62
(s, 1H), 5.31 (s, 1H), 4.56 (s, 2H), 2.11 (s, 3H); 13C NMR (CDCl3,
75 MHz): ¤c 164.3, 153.9, 138.1, 129.3, 128.5, 127.3, 126.5,
100.5, 44.8, 23.5; HRMS (ES+): Calcd for C12H14N3O (M + H+):
216.1094. Found: 216.1134.
2-Butylamino-4,6-diphenylpyrimidine (8i): Yield: 72%; Rf
(12% ethyl acetate/petroleum ether) = 0.45; Mp 65-66 °C; IR:
88-90 °C; IR: 3245, 2927, 2885, 2410, 1623, 1595, 1250, 827
1
¹1
3248, 2968, 2846, 1558, 1548, 1480, 1208, 856 cm¹1; H NMR
cm ;
1H NMR (CDCl3, 500 MHz): ¤ 8.28 (d, 1H, J = 8.3 Hz),
(CDCl3, 500 MHz): ¤ 8.09 (d, 4H, J = 5.1 Hz), 7.49 (m, 6H),
7.39 (s, 1H), 5.26 (t, 1H, J = 5.3 Hz), 3.59 (q, 2H, J = 13.3 Hz),
1.67 (m, 2H), 1.48 (m, 2H), 0.98 (t, 3H, J = 7.1 Hz); 13C NMR
(CDCl3, 125 MHz): ¤c 166.1, 163.6, 138.6, 130.7, 129.1, 127.5,
103.1, 41.8, 32.4, 20.7, 14.4; HRMS (ES+): Calcd for C20H22N3
(M + H+): 304.1813. Found: 304.1807.
7.80 (br s, 1H), 7.55 (t, 1H, J = 7.9 Hz), 6.76 (d, 1H, J = 7.4 Hz),
6.53 (s, 1H), 2.44 (s, 3H), 2.38 (s, 6H); 13C NMR (CDCl3,
125 MHz): ¤c 167.4, 158.9, 156.6, 152.4, 137.9, 116.6, 112.2,
109.2, 24.1, 23.9; HRMS (ES+): Calcd for C12H15N4 (M + H+):
215.1328. Found: 215.1293.
N-(2,6-Dimethylpyrimidin-4-yl)-N¤-(4,6-dimethylpyrimidin-
6-Amino-2-benzylamino-3H-pyrimidin-4-one (8j):
Yield:
2-yl)-1,6-hexanediamine (9q):
Yield: 64%; Rf (10% ethyl
56%; Rf (3% MeOH/CHCl3) = 0.44; Mp 116-118 °C; IR: 3330,
acetate/petroleum ether) = 0.42; Mp 122-124 °C (lit19 135 °C);
1
¹1
2926, 1614, 1467, 1275, 1104, 792 cm¹1; H NMR (CDCl3, 400
IR: 3270, 2925, 2854, 1599, 1574, 1468, 1357, 1142 cm ;
MHz): ¤ 12.70 (br s, 1H), 7.24 (m, 5H), 6.66 (br s, 1H), 4.59 (s,
1H), 4.52 (s, 2H), 4.49 (d, 2H, J = 5.3 Hz); 13C NMR (CDCl3,
125 MHz): ¤c 165.8, 154.8, 138.9, 128.9, 127.9, 127.6, 124.0,
78.6, 44.7; HRMS (ESI-TOF): Calcd for C11H13N4O (M + H+),
217.1084. Found: 217.1160.
1H NMR (CDCl3, 500 MHz): ¤ 6.28 (s, 2H), 4.94 (br s, 2H),
3.39 (q, 4H, J = 13.4 Hz), 2.27 (s, 12H), 1.58 (m, 4H), 1.43 (m,
4H); 13C NMR (CDCl3, 75 MHz): ¤c 167.2, 162.3, 109.3, 41.2,
29.6, 26.5, 23.7; HRMS (ES+): Calcd for C18H29N6 (M + H+):
329.2422. Found: 329.2441.
6-Amino-2-butylamino-3H-pyrimidin-4-one (8k):
Yield:
Compound 9r: Yield: 60%; Rf (8% ethyl acetate/petroleum
58%; Rf (3% MeOH/CHCl3) = 0.43; Mp 146-148 °C; IR: 3340,
ether) = 0.44; Mp 162-164 °C; IR: 3264, 2928, 2824, 1636, 1565,
¹1
¹1
2931, 1615, 1478, 1428, 1281 cm
;
1H NMR (DMSO-d6 in
1468, 1332, 832 cm ;
1H NMR (CDCl3, 500 MHz): ¤ 7.34 (s,
CDCl3, 400 MHz): ¤ 10.03 (br s, 1H), 5.66 (br s, 1H), 4.76 (s, 1H),
4.49 (br s, 2H), 3.22 (q, 2H, J = 12.3 Hz), 1.46 (m, 2H), 1.31 (m,
1H), 7.25 (s, 1H), 7.24 (s, 2H), 6.32 (s, 2H), 5.26 (br s, 2H), 4.63
(d, 4H, J = 5.9 Hz), 2.28 (s, 12H); 13C NMR (CDCl3, 125 MHz):

S. Goswami et al.
Bull. Chem. Soc. Jpn. Vol. 82, No. 9 (2009) 1181
¤c 167.8, 162.6, 140.3, 128.8, 127.1, 126.7, 110.3, 45.7, 24.2;
HRMS (ESI-TOF): Calcd for C20H25N6 (M + H+): 349.2135.
Found: 349.2147.
5
a) A. B. Sen, S. K. Gupta, J. Indian Chem. Soc. 1962, 39,
129. b) M. Botta, F. D. Angelis, G. Finizia, A. Gambacorta, R.
Nicoletti, Synth. Commun. 1985, 15, 27.
1,2-Diacetyl-3-benzylguanidine (6): Acetate derivative 6 of
the benzylguanidine 4b is obtained by acylation (Ac2O at 60-
70 °C, 2 h), which was initially synthesized from benzylamine and
isothiourea salt under microwave irradiation (450 W, 18 min). Rf
(3% MeOH/CHCl3) = 0.47; Mp 126-27 °C; IR (KBr): 3432,
2469, 2118, 1686, 1637, 1586, 1445, 1235 cm¹1; 1H NMR (CDCl3,
500 MHz): ¤ 13.18 (br s, 1H), 9.33 (br s, 1H), 7.34 (m, 5H), 4.65
(d, 2H, J = 5.7 Hz), 2.18 (s, 3H), 2.15 (s, 3H); 13C NMR (CDCl3,
125 MHz): ¤c 186.2, 172.5, 155.4, 137.2, 128.6, 127.7, 127.6,
44.6, 28.6, 24.9; MS (FIA-MS): m/z (%): 234.4 [(M + H)+, 20],
192.3 (100), 150.3; HRMS (ES+): m/z (%): 192.1100 [(M + 2H ¹
CH3CO)+, 27], 150.0999 [(M + 3H ¹ CH3CO)+, 100].
6
a) D. J. Brown, Fused Pyrimidines: Pteridines in The
Chemistry of Heterocyclic Compounds, John Wiley & Sons, New
York, 1988, Vol. 24, p. 3. b) D. J. Brown, The Pyrimidines in The
Chemistry of Heterocyclic Compounds, Wiley, New York, 1962,
Vol. 16; D. J. Brown, The Pyrimidines in The Chemistry of Hetero-
cyclic Compounds, Wiley, New York, 1970, Vol. 16, Suppl. 1;
D. J. Brown, The Pyrimidines in The Chemistry of Heterocyclic
Compounds, Wiley, New York, 1985, Vol. 16, Suppl. 2.
7
C. J. Suckling, J. K. Huggan, C. L. Gibson, in Bicyclic 6-6
System: Pteridines in Comprehensive Heterocyclic Chemistry III,
ed. by A. R. Katritzky, C. A. Ramsden, E. F. V. Scriven, R. J. K.
Taylor, Elsevier, Oxford, 2008, Vol. 10, p. 915.
4,6-Dimethyl-2-methylthiopyrimidine (10):
Acetylacetone
8
a) M. C. Etter, Acc. Chem. Res. 1990, 23, 120. b) S.
(200 mg, 2.0 mmol) was added to a mixture of (S)-methylisothio-
urea sulfate (278 mg, 1.0 mmol) and potassium carbonate (172 mg,
1.5 mmol), and irradiated at 300 W (or at 55 °C) for 12 min
(Scheme 4). The residue was dissolved in water and extracted with
CHCl3. The organic layer was evaporated under reduced pressure.
The crude product was then purified by column chromatography
(silica gel, 100-200 mesh) to afford pure 4,6-dimethyl-2-methyl-
thiopyrimidine (10) using ethyl acetate-petroleum ether (1:20)
as eluent. Yield: 70%; Liquid; Rf (5% ethyl acetate/petroleum
ether) = 0.49; IR: 3252, 2924, 1624, 1042 cm¹1; 1H NMR (CDCl3,
500 MHz): ¤ 6.67 (s, 1H), 2.54 (s, 3H), 2.39 (s, 6H); MS (FIA-
MS): m/z (%): 155.1 [(M + H)+, 50], 149.1 (40).
Goswami, S. Jana, N. K. Das, H.-K. Fun, S. Chantraproma, J. Mol.
Struct. 2008, 876, 313. c) S. Goswami, S. Jana, A. Hazra, H.-K.
Fun, S. Chantrapromma, Supramol. Chem. 2008, 20, 495, and
references cited therein. d) Y.-H. Wang, K.-L. Chu, H.-C. Chen,
C.-W. Yeh, Z.-K. Chan, M.-C. Suen, J.-D. Chen, J.-C. Wang,
CrystEngComm 2006, 8, 84. e) Y.-N. Chi, K.-L. Huang, F.-Y. Cui,
Y.-Q. Xu, C.-W. Hu, Inorg. Chem. 2006, 45, 10605.
9
a) E. Brand, F. C. Brand, Org. Synth., Coll. Vol. 1955, 3,
440.
10 a) F. H. S. Curd, F. L. Rose, J. Chem. Soc. 1946, 343. b) Y.
Ma, L. Margarida, J. Brookes, G. M. Makara, S. C. Berk, J. Comb.
Chem. 2004, 6, 426. c) G. Luo, L. Chen, G. S. Poindexter,
Tetrahedron Lett. 2002, 43, 5739. d) P. R. Shildneck, W. Windus,
Org. Synth., Coll. Vol. 1976, 2, 411.
11 a) D. J. Brown, B. T. England, J. M. Lyall, J. Chem. Soc. C
1966, 226. b) C. W. Whitehead, J. J. Traverso, J. Am. Chem. Soc.
1960, 82, 3971.
We thank the DST [SR/S1/OC-13/2005] and CSIR
[01(1913)/04/EMR-II], Government of India for financial
support. A.H. thanks the CSIR, Government of India for a
research fellowship.
12 H. Eck, G. Fisher, F. Mueller, S. Wihrheim, E. Swen,
Chem. Abstr. 1974, 81, 63670m; H. Eck, G. Fisher, F. Mueller, S.
Wihrheim, E. Swen, Ger. Off. 2,256,289, June, 1974.
13 For recent book and reviews on microwave-assisted organic
reactions: a) B. L. Hayes, Mircowave Synthesis: Chemistry at the
Speed of Light, CEM Publishing, Mattaws, NC 28105, 2002. b) B.
Wathey, J. Tierney, P. Lidström, J. Westman, Drug Discov. Today
2002, 7, 373. c) C. O. Kappe, Angew. Chem., Int. Ed. 2004, 43,
6250. d) B. A. Roberts, C. R. Strauss, Acc. Chem. Res. 2005, 38,
653.
14 a) D. Dallinger, C. O. Kappe, Chem. Rev. 2007, 107, 2563.
b) For a recent review on the synthesis of heterocyclic compounds
under microwave irradiation; see: Y. Xu, Q.-X. Guo, Heterocycles
2004, 63, 903.
15 H. Sandin, M.-L. Swanstein, E. Wellner, J. Org. Chem.
2004, 69, 1571.
Supporting Information
Supporting Information for general procedure and spectral data
are available free of charge on the web at http://www.csj.jp/
journals/bcsj/.
References
1
a) F. H. S. Curd, M. I. Davis, F. L. Rose, J. Chem. Soc.
1946, 351. b) R. Hull, B. J. Lovell, H. T. Openshaw, L. C. Payman,
A. R. Todd, J. Chem. Soc. 1946, 357. c) F. H. S. Curd, F. L. Rose,
J. Chem. Soc. 1946, 362. d) F. H. S. Curd, C. G. Raison, F. L.
Rose, J. Chem. Soc. 1946, 366. e) F. H. S. Curd, M. I. D. Vis,
E. C. Owen, F. L. Rose, G. A. P. Tuey, J. Chem. Soc. 1946, 370.
f) F. H. S. Curd, D. N. Richardson, F. L. Rose, J. Chem. Soc. 1946,
378.
2
F. X. Tavares, J. A. Boucheron, S. H. Dickerson, R. J.
16 a) S. Goswami, A. K. Adak, Tetrahedron Lett. 2002, 43,
8371. b) S. Goswami, A. K. Adak, Synth. Commun. 2003, 33, 475.
c) S. Goswami, S. Dey, S. Jana, A. K. Adak, Chem. Lett. 2004, 33,
916. d) S. Goswami, S. Jana, A. Hazra, A. K. Adak, J. Heterocycl.
Chem. 2007, 44, 1191.
17 S. Goswami, S. Jana, S. Dey, A. K. Adak, Aust. J. Chem.
2007, 60, 120, and references therein.
18 a) M. Raghavendra, H. S. Bhojya Naik, B. S. Sherigara,
Can. J. Chem. 2007, 85, 1041. b) C.-S. Jia, Z. Zhang, S.-J. Tu,
G.-W. Wang, Org. Biomol. Chem. 2006, 4, 104.
Griffin, F. Preugschat, S. A. Thomson, T. Y. Wang, H.-Q. Zhou,
J. Med. Chem. 2004, 47, 4716.
3
R. J. Chorvat, R. Bakthavatchalam, J. P. Beck, P. J.
Gilligan, R. G. Wilde, A. J. Cocuzza, F. W. Hobbs, R. S.
Cheeseman, M. Curry, J. P. Rescinito, P. Krenitsky, D. Chidester,
J. A. Yarem, J. D. Klaczkiewicz, C. N. Hodge, P. E. Aldrich, Z. R.
Wasserman, C. H. Fernandez, R. Zaczek, L. W. Fitzgerald, S.-M.
Huang, H. L. Shen, Y. N. Wong, B. M. Chien, C. Y. Quon, A.
Arvanitis, J. Med. Chem. 1999, 42, 833.
4
D. Lednicer, L. A. Mitscher, The Organic Chemistry of
19 a) G. Menichi, M. Hubert-Habart, J. Heterocycl. Chem.
1984, 21, 209. b) A. R. Katrizky, J. Chem. Soc., Parkin Trans. 1
1982, 153.
Drug Synthesis, John Wiley & Sons, New York, 1977, Vols. 1, 2,
3, and 4.