Synthesis of novel imidazo[1,2-a]pyrimidin-5(1H)-one derivatives by intramolecular cycloisomerization of 2-amino-3-alkynylpyrimidin-4(3H)-one in the presence of aqueous base

Article abstract of DOI:10.1246/cl.130454

An efficient strategy has been developed for the synthesis of novel imidazo[1,2-a]pyrimidin-5(1H)-one derivatives 4 from 2-amino-3-alkynylpyrimidin- 4(3H)-one 2 and alkyl halides in single step by intramolecular cycloisomerization followed by N-alkylation in the presence of aqueous base.

Full text of DOI:10.1246/cl.130454

doi:10.1246/cl.130454
1018
Published on the web September 5, 2013
Synthesis of Novel Imidazo[1,2-a]pyrimidin-5(1H)-one Derivatives by Intramolecular
Cycloisomerization of 2-Amino-3-alkynylpyrimidin-4(3H)-one in the Presence of Aqueous Base
P. Nagender, G. Malla Reddy, P. Sambasiva Rao, C. Kurumurthy, P. Shanthan Rao, and B. Narsaiah*
Fluoroorganic Division, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India
(Received May 16, 2013; CL-130454; E-mail: narsaiah@iict.res.in)
An efficient strategy has been developed for the synthesis of
novel imidazo[1,2-a]pyrimidin-5(1H)-one derivatives 4 from
2-amino-3-alkynylpyrimidin-4(3H)-one 2 and alkyl halides in a
single step by intramolecular cycloisomerization followed by
N-alkylation in the presence of aqueous base.
CF3
CF3
CF3
Br
K2CO3, rt
DMF, 4h
N
N
N
+
+
O
N
H
NH2
O
N
NH2
O
N
NH2
1
2
3
The imidazo[1,2-a]pyrimidine nuclei are present in many
biologically active compounds, and their derivatives are found
to possess anxiolytic,1 cardiovascular,2 analgesic,3 antihyperten-
sive,4 and neuroleptic5,6 activities. The structure of the imida-
zo[1,2-a]pyrimidine is related to the purine ring system and
possesses anti-inflammatory,7 as well as insecticidal, acaricidal,
and nematocidal activities.8 Because of a wide range of
activities, several methods are available for the preparation of
imidazo[1,2-a]pyrimidine derivatives by fusion of a pyrimidine
ring over imidazole and vice versa. Thus, pyrimidine9-15 earlier
accomplished by the reaction of 1,3-bifunctional compounds
with 2-aminoimidazoles as well as imidazoles16 was prepared by
the reaction of 1,2-bifunctional compounds with 2-aminopyr-
imidine. Further, intramolecular addition of amine to alkynes is
a challenging and highly desirable transformation which can
be mediated and catalysed by Ru,17-19 Ag,20 and Au21 metal
complexes. Recently, imidazo[1,2-a]pyrimidine derivatives22
are also prepared by Pd/C-catalyzed heterocyclization starting
from 2-aminopyrimidine. Compounds having fluorine23 or a
trifluoromethyl24,25 group at a specified position were found to
influence dramatically change in reactivity and the properties of
molecule in terms of lipid solubility, oxidative thermal stability,
and oral bioavailability. Therefore, the trend is driving more
toward fluorinated molecules. In view of the importance of
imidazo[1,2-a]pyrimidine nuclei and trifluoromethyl group, we
have designed and accomplished a series of novel imidazo-
[1,2-a]pyrimidin-5(1H)-one derivatives in a single step by
intramolecular cycloisomerization in the presence of aqueous
base. The method is simple, operated under mild conditions and
provides high yield.
CF3
CF3
N
Catalyst
rt or
N
+
CH3CH2-I
O
N
NH2
O
N
N
4a
2
CF3
N
K2CO3,
Acetonitrile
K2CO3,
Acetone
O
N
NH
80°C
CH3CH2I
5
Scheme 1. Reaction of 2-amino-6-trifluoromethyl-3(H)-pyri-
midin-4-one (1) with propargyl bromide and reaction of 2-
amino-3-(2-propynyl)-6-trifluoromethyl-3H-pyrimidin-4-one (2)
with ethyl iodide.
CF3
CF3
CF3
N
Base
N
N
+ [BH]+
NH-
O
N
NH2
O
N
O
N
NH
H
2
CF3
N
CF3
N
CH3CH2I
Base
N
O
O
N
N
NH
The 2-amino-6-trifluoromethyl-3(H)-pyrimidin-4-one26 (1)
was reacted with 2-propynyl(propargyl) bromide in the presence
of base resulting in the formation of two regioisomers i.e., N-
propargylated compound 227 (polar) in 80% and O-propargy-
lated product 327 (nonpolar) in 10%. Both the regioisomers were
separated based on their difference in polarity. Compound 2 was
further reacted with ethyl iodide in the presence of different
bases in various solvents at different temperatures, and imidazo-
[1,2-a]pyrimidin-5(1H)-one 4a was obtained. In order to confirm
the reaction sequence, compound 2 was initially cyclized in the
presence of K2CO3 as a base and acetonitrile as solvent to form
imidazo[1,2-a]pyrimidine 5. Compound 5 was further alkylated
using alkyl halide to obtain compound 4a. Out of all the
conditions used, reaction temperature 50 °C, reaction time five
4a
Scheme 2. Mechanistic pathway for the conversion of 2 to 4a.
hours, and aqueous sodium hydroxide was considered the best
medium to give 96% yield. The mechanistic path of the reaction
was presumed to be an abstraction of proton from amine by base,
and intramolecular cycloisomerization of amine onto alkyne
followed by N-alkylation to obtain product 4a. The detailed
reactions outlined in Scheme 1, mechanism in Scheme 2, and
products formed in each case are tabulated in Table 1.
The optimized reaction protocol was extended to the
reaction of compound 2 with diverse alkyl halides using 10%
Chem. Lett. 2013, 42, 1018-1019
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1019
Table 1. Preparation of compound 4a in different solvents and
bases
pyrimidine derivatives in a single step and is applicable to the
synthesis of diverse substituted imidazo[1,2-a]pyrimidine de-
rivatives.28
Temp
/°C
Time
/h
Yield
/%
Entry
Solvent
Catalyst
Authors are thankful to the Director, IICT for her constant
encouragement and authors (P. Nagender, G. Malla Reddy, P.
Sambasiva Rao, C. Kurumurthy) are also thankful to the CSIR-
India for providing financial assistance in the form of a Research
Fellowship and contingency grant.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
H2O
H2O
H2O
H2O
K2CO3
NaOH
NaOH
Et3N
Piperidine
NaOH
K2CO3
K2CO3
Et3N
K2CO3
Et3N
K2CO3
K2CO3
Et3N
60
RT
50
60
60
80
80
70
70
RT
RT
90
80
80
70
24
24
5
6
5
®
70
96
93
91
86
90
®
®
30
®
89
®
®
®
H2O
DMF
DMF
THF
6
7
References and Notes
1
2
3
4
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24
24
24
24
6
24
24
24
THF
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Scheme 3. Preparation of substituted imidazo[1,2-a]pyrimi-
din-5(1H)-one derivatives.
Table 2. Preparation of compounds 4a-4oa
Yieldb
/%
Mp
/°C
S.No Product
R
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
CH3CH2-
96
89
92
85
89
87
94
84
88
96
91
85
92
89
95
90-92
65-67
72-74
77-79
130-132
76-78
CH3(CH2)2CH3-
CH3(CH2)6CH3-
CH3(CH2)8CH3-
n-C10H4F17-
CH2=CH-CH2-
C3H3-
CH3C(O)CH2-
C6H5C(O)CH2-
4-ClC6H4C(O)CH2-
4-FC6H4C(O)CH2-
4-CF3C6H4C(O)CH2-
C6H5CH2-
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4-FC6H4CH2-
4-ClC6H4CH2-
85-87
100-102
aAll the reactions were carried out using 10% NaOH, 1 equiv
b
of 2 and 1.1 equiv of alkyl halide at 50 °C. Isolated yields.
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NaOH as catalyst at 50 °C and provided respective products 4 in
high yield. The general reaction is drawn in Scheme 3 and
products are tabulated in Table 2.
In conclusion, a straightforward reaction has been devel-
oped for the synthesis of a series of novel imidazo[1,2-a]-
Chem. Lett. 2013, 42, 1018-1019
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/