Hypervalent Iodine in Synthesis 93. A Facile Synthesis of 2-Substituted Imidazo[1,2-a]pyrimidines by Cyclocondensation of Alkynyl(phenyl)iodonium Salts and 2-Aminopyrimidine

Article abstract of DOI:10.1002/jhet.5570400526

Simple stirring of a mixture of the alkynyl(phenyl)iodonium salts 1 with 2-aminopyrimidine 2 in chloroform under reflux for two hours in the presence of K₂CO₃ gave, after workup, the 2-substituted imidazo[1,2-a]pyrimidines 3 in moderate to good yields. A possible mechanism for the formation of 3 involves the intramolecular cyclization of the intermediate alkylidenecarbene 6.

Full text of DOI:10.1002/jhet.5570400526

Sep-Oct 2003
909
Hypervalent Iodine in Synthesis 93. A Facile Synthesis of
2-Substituted Imidazo[1,2-a]pyrimidines by Cyclocondensation of
Alkynyl(phenyl)iodonium Salts and 2-Aminopyrimidine
Zhi liu [a,b], Zhen-Chu Chen* [a,b] and Qin-Guo Zheng [c]
[a] Ningbo Institute of Technology, Zhejiang University,
Ningbo, 315104, P. R. China
[b] Department of Chemistry, Zhejiang University (XiXi
Campus), Hangzhou, 310028, P. R. China
E-mail: zhenchuc@mail.hz.zj.cn
[c] Pharmaceutical Sciences Research Institute, Aston
University, Aston Triangle, Birmingham B4 7ET, UK
Received January 8, 2003
Simple stirring of a mixture of the alkynyl(phenyl)iodonium salts 1 with 2- aminopyrimidine 2 in chloro-
form under reflux for two hours in the presence of K CO gave, after workup, the 2-substituted imi-
2
3
dazo[1,2-a]pyrimidines 3 in moderate to good yields. A possible mechanism for the formation of 3 involves
the intramolecular cyclization of the intermediate alkylidenecarbene 6.
J. Heterocyclic Chem., 40, 909 (2003).
Introduction.
Results and Discussion.
Imidazo[1,2-a]pyrimidines show much importance in
pharmaceutical and biochemical fields and some of their de-
rivatives, particularly the 2-substituted derivatives, possess
effective antifungal and antibacterial activities [1-3].
Therefore, their synthesis has become increasingly impor-
tant. To date, various methods for the synthesis of 2-substi-
tuted imidazo[1,2-a]pyrimidines have been reported [4-18].
Among these procedures, the most conveniently and fre-
quently used was one carried out by cyclocondensation of
2-aminopyrimidine with the appropriate α-halogenoketone
(Tschitschibabin method). A variety of starting compounds
are available, either commercially or synthetically, for this
procedure and it does not require severe reaction conditions.
However, this method has the major disadvantage of using
lachrymatory and toxic α-halogenoketones.
We found that the cyclocondensation of alkynyl-
(phenyl)iodonium salts with 2-aminopyrimidine occurred
easily in CHCl in the presence of K CO . In fact, simple
3
2
3
stirring of a mixture of the alkynyl(phenyl)iodonium salts
1 with 2-aminopyrimidine 2 in chloroform under gentle
reflux for two hours in the presence of K CO gave, after
2
3
workup, the corresponding 2-substituted imidazo[1,2-
a]pyrimidines 3 in moderate to good yields (Scheme 1).
The results are summarized in Table 1.
Scheme 1
Alkynyl(phenyl)iodonium salts have found broad appli-
cation in synthetic organic chemistry [19-23]. Our recent
investigations dealing with hypervalent iodine mediated
synthesis have shown that the alkynyl(phenyl)iodonium
salt is an extremely important equivalent reagent of
α-haloketones, providing novel and useful synthesis of var-
ious heterocyclic compounds such as 2-mercaptothiazoles
[24], selenazoles [25], imidazoles [26] and 2-substituted-
imidazo[1,2-a]pyridines [27]. As part of our program
directed towards the use of hypervalent iodine reagents in
organic synthesis, we were interested in the development
of a new synthetic method using alkynyl(phenyl)iodonium
salts to replace α-haloketones for the synthesis of five-
membered heterocyclic compounds. We tried to examine
the reaction of alkynyl(phenyl)iodonium salts with
2-aminopyrimidine for providing a new route to 2-substi-
tuted imidazo[1,2-a]pyrimidines. Herein, we would like to
report our results, a new facile synthesis of 2-substituted
imidazo[1,2-a]pyrimidines by cyclocondensation of
alkynyl(phenyl)iodonium salts with 2-aminopyrimidine.
Table 1
Preparation of 2-Substituted-imidazo[1,2-a]pyrimidines 3a-g
3
R
Yield (%)
[a]
a
b
c
d
e
f
C H
69
78
80
75
57
61
66
6
5
4-F-C H
6
4
4-Cl-C H
6
4
4
4-Br-C H
6
MeOCH
2
EtOCH
2
g
4-MeO-C H
6 4
[a] Isolated yield based on alkynyl(phenyl)- iodonium salt 1.
The reaction was found to be general and applicable to
alkylethynyl(phenyl)iodonium salts and arylethynyl(phenyl)-
iodonium salts. Several arylethynyl(phenyl)iodonium salts
containing various substituents, such as fluoro, chloro, bromo
and methoxy groups were successfully reacted.

910
Z. liu, Z.-C. Chen and Q.-G. Zheng
Vol. 40
internal standard. IR spectra were recorded on a Perkin-Elmer
683 spectrometer at room temperature.
In order to examine the regiochemistry of the reaction,
we then performed the reaction by cyclocondensation of
α-bromo-p-fluoroacetophenone with 2- aminopyrimidine
according to standard procedure [5]. The product obtained
by this method is known to be 2-(p-fluorophenyl)imi-
dazo[1,2-a]pyrimidine, which is identical in respects
with the product prepared by our present method.
Therefore, 3 is proved to be 2-substituted imidazo[1,2-a]-
pyrimidines, not the 3-substituted isomers. All products
were also characterized by mp, IR spectral data and
microanalyses. They are identical to the data reported by
the literature. The spectral data are summarized in the
experimental section.
General Procedure for the Preparation of 2-Substituted
imdazo[1,2-a]pyrimidines 3a-g.
To a solution of 2-aminopyrimidine (1.2 mmol) in CHCl (15
3
mL) was added K CO (0.6 mmol). While stirring, the corre-
2
3
sponding alkynyl(phenyl)iodonium salt (1 mmol) was added to
the mixture. The resulting mixture was refluxed for 2 hours and
water (20 mL) was added. The chloroform phase was dried
(Na SO ), concentrated and chromatographed on a silical gel
2
4
plate using petroleum ether (b.p. 60-90°)/Et O (4:1) as eluent to
2
afford the 2-substituted imdazo[1,2-a]pyrimidine.
2-Phenylimidazo[1,2-a]pyrimidine (3a) [5].
A possible mechanism for the formation of 2-substituted
imidazo[1,2-a]pyrimidines 3 may involve the electrophilic
attack of the β-carbon of alkynyl(phenyl)iodonium salts 1
on the exocyclic nitrogen to form the primary addition
products 4, followed by 1,1-elimination of iodobenzene to
generate the carbene 6, and cycloaromatization of 6 to give
2-substituted imidazo[1,2-a]pyrimidines 3 (Scheme 2).
This compound was obtained as a white powder, mp 196-197°;
lit. mp 202°; ir (potassium bromide): 3080, 1680, 830 cm ; H
-1
1
nmr (DMSO-d ): δ 7.06 (dd, 1H, J = 6.7 Hz, J = 4.1 Hz), 7.36
6
1
2
(t, 1H, J = 7.4 Hz), 7.47 (t, 2H, J = 7.4 Hz), 8.00 (d, 2H, J = 7.1
Hz), 8.38 (s, 1H), 8.53 (dd, 1H, J = 4.1 Hz, J = 2.0 Hz), 8.96
2
3
(dd, 1H, J = 6.7 Hz, J = 2.0 Hz ).
1
3
2-(p-Fluorophenyl)imidazo[1,2-a]pyrimidine (3b) (This
Procedure).
This compound was obtained as a white powder, mp 237°; lit.
mp 238°; ir (potassium bromide): 3085, 1685, 1220 (C-F), 830
Scheme 2
-1
1
cm ; H nmr (CDCl ): δ 6.88 (dd, 1H, J = 6.8 Hz, J = 4.0 Hz),
3
1
2
7.15 (t, 2H, J = 8.8 Hz), 7.79 (s, 1H), 8.02 (dd, 2H, J = 8.8 Hz, J
1
2
= 5.6 Hz), 8.44 (dd, 1H, J = 6.8 Hz, J = 2.0 Hz), 8.55 (dd, 1H,
1
3
J = 4.0 Hz, J = 2.0 Hz ).
2
3
2-(p-Fluorophenyl)imidazo[1,2-a]pyrimidine (Standard
Procedure) [5].
This compound was obtained as a white powder, mp 236-237°;
1
lit. mp 238°; H nmr (CDCl ): δ 6.88 (dd, 1H, J = 6.8 Hz, J =
3
1
2
4.0 Hz), 7.15 (t, 2H, J = 8.4 Hz), 7.79 (s, 1H), 8.02 (dd, 2H, J =
1
8.4 Hz, J = 5.6 Hz), 8.44 (dd, 1H, J = 6.8 Hz, J = 2.0 Hz), 8.55
2
1
3
(dd, 1H, J = 4.0 Hz, J = 2.0 Hz).
2
3
2-(p-Chlorophenyl)imidazo[1,2-a]pyrimidine (3c) [5].
This compound was obtained as a white powder, mp 271°; lit.
mp 274°; ir (potassium bromide): 3083, 1685, 825 cm ; H nmr
Conclusion
-1
1
(DMSO-d ): δ 7.05 (dd, 1H, J = 4.0 Hz, J = 6.8 Hz), 7.52 (d, 2H,
The present study provides a new facile method of syn-
thesis of 2-substituted imidazo[1,2-a]pyrimidines by
cyclocondensation of alkynyl(phenyl)iodonium salts with
2-aminopyrimidine, which has some advantages over
existing methods such as avoiding the use of lachrymatory
and toxic α-halogenoketones, mild reaction conditions,
ready availability of starting materials and short reaction
time. Furthermore, the range of useful applications of
alkynyl(phenyl)iodonium salts in organic chemistry has
been extended.
6
1
2
J = 8.8 Hz), 8.01 (d, 2H, J = 8.8 Hz), 8.40 (s, 1H), 8.53 (dd, 1H, J
1
= 4.0 Hz, J = 1.6 Hz), 8.96 (dd, 1H, J = 6.8 Hz, J = 1.6 Hz ).
3
2
3
2-(p-Bromophenyl)imidazo[1,2-a]pyrimidine (3d) [17,18].
This compound was obtained as a white powder, mp 224°; lit.
-1
1
mp 226°; ir (potassium bromide): 3080, 1680, 825 cm ; H nmr
(DMSO-d ): δ 7.05 (dd, 1H, J = 4.0 Hz, J = 6.8 Hz), 7.65 (d, 2H,
6
1
2
J = 8.4 Hz), 7.94 (d, 2H, J = 8.4 Hz), 8.40 (s, 1H), 8.52 (dd, 1H, J
= 4.0 Hz, J = 1.6 Hz), 8.95 (dd, 1H, J = 6.8 Hz, J = 1.6 Hz ).
1
3
2
3
2-Methoxymethylimidazo[1,2-a]pyrimidine (3e).
This compound was obtained as a white powder, mp 63-65°; ir
-1
1
EXPERIMENTAL
(potassium bromide): 3060, 1672, 825 cm ; H nmr (CDCl ): δ
3
3.50 (s, 3H), 4.72 (s, 2H), 6.86 (dd, 1H, J = 4.4 Hz, J = 6.8 Hz),
1
2
7.54 (s, 1H), 8.42 (dd, 1H, J = 4.4 Hz, J = 2.0 Hz), 8.54 (dd, 1H,
Melting points were determined on a X - Data microscopic
1
3
4
J = 6.8 Hz, J = 2.0 Hz).
melting point apparatus and were uncorrected. Microanalyses
were obtained using Carlo-Erba 1106. H NMR spectra were
2
3
1
Anal. Calcd. for C H N O: C, 58.89; H, 5.56; N, 25.75.
8
9 3
Found: C, 58.86; H, 5.53; N, 25.73.
obtained at 400 MHz in CDCl or DMSO-d using TMS as an
3
6

Sep-Oct 2003
Hypervalent Iodine in Synthesis 93
911
[9] L. Almirante, A. Mugnaini, L. P. Fritz and E. Provinciali,
Boll. Chim. Farm., 105, 32 (1966).
[10] L. Petit and P. Touratier, Bull. Soc. Chim. Fr., 8, 2529
(1966).
[11] P. Luciano and P. Vasco, Gazz. Chim. Ital., 100, 110 (1970).
[12] G. Patrick, J. Robert and M. Georges, Bull. Soc. Chim. Fr.,
191, 3503 (1972).
[13] J. A. Mazur, Farm. Zh., 6, 37 (1977).
[14] R. J. Sundberg, D. J. Dahlhausen, G. Manikumar, B.
Mavunkel, A. Biswas, V. Srinivasan, F. J. King and P. Waid, J.
Heterocyclic Chem., 25, 129 (1988).
2-Ethoxymethylimidazo[1,2-a]pyrimidine (3f).
This compound was obtained as a white powder, mp 68-69°; ir
-1
1
(potassium bromide): 3055, 1670, 825 cm ; H nmr (CDCl ):
3
δ1.24 (t, 3H, J = 4.4 Hz), 3.68 (q , 2H, J = 4.4 Hz), 4.76 (s, 2H),
6.86 (dd, 1H, J = 4.0 Hz, J = 6.4 Hz), 7.54 (s, 1H), 8.40 (dd, 1H,
1
2
J = 6.4 Hz, J = 1.6 Hz), 8.53 (dd, 1H, J = 4.0 Hz, J = 1.6 Hz).
2
3
1
3
Anal. Calcd. for C H N O: C, 61.00; H, 6.26; N, 23.71.
9
11 3
Found: C, 60.96; H, 6.26; N, 23.66.
2-(p-Methoxyphenyl)imidazo[1,2-a]pyrimidine (3g) [16].
This compound was obtained as a white powder, mp 188°; lit.
[15] E. Abignente, F. Arena, P. Caprariis and L. II. Parente,
Farmaco. Ed. Sci., 32, 735 (1977).
[16] N. P. Buu-Hoi and N. D. Xuong, C. R. Acad. Sci., 243,
2090 (1956).
-1
1
mp 190°; ir (potassium bromide): 3075, 1660, 820 cm ; H nmr
(DMSO-d ): δ 3.81 (s, 3H), 7.05 (m, 3H), 7.94 (d, 2H, J = 8.8
6
Hz), 8.28 (s, 1H), 8.50 (dd, 1H, J = 6.4 Hz, J = 1.2 Hz), 8.93 (d,
2
3
[17] N. Saldabols and O. E. Lando, Khim. Geterotsikl. Soedin.,
2, 258 (1978).
1H, J = 3.6 Hz, J = 1.2 Hz).
1
3
[18] T. Matsukawa and S. Ban, Yakugaku Zasshi, 72, 610
(1952).
REFERENCES AND NOTES
[19] P. J. Stang, Angew. Chem., Int. Ed. Engl., 31, 274 (1992).
[20] P. J. Stang and V. V. Zhdankin, Chem. Rev., 96, 1123
(1996).
[1] Y. Rival, G. Grassy, A. Taudou and R. Ecalle, Eur. J. Med.
Chem., 26, 13 (1991).
[21] V. V. Zhdankin and P. J. Stang, Tetrahedron, 54, 10927
(1998).
[2] Y. Rival, G. Grassy and G. Michel, Chem. Pharm. Bull.,
40, 1170 (1992).
[22] V. V. Zhdankin and P. J. Stang, Chem. Rev., 102, 2523
(2002).
[3] M. Patra, S. K. Mahapatra and B. Dash, J. Indian Chem.
Soc., 51, 1031 (1974).
[23] A. Varvoglis, Hypervalent Iodine in Organic Synthesis,
Academic Press, London, 1997.
[4] T. Matsukawa and S. Ban, J. Pharm. Soc. Jpn., 71, 760
(1951).
[24] P.-F. Zhang and Z.-C. Chen, Synthesis, 358 (2001).
[25] P.-F. Zhang and Z.-C. Chen, J. Heterocyclic Chem., 38, 503
(2001).
[5] N. P. Buu-Hoi and N. D. Xuong, Compt. rend., 243, 2090
(1956).
[6] N. P. Buu-Hoi and N. D. Xuong, Bull. Soc. Chim. Fr., 1344
[26] P.-F. Zhang and Z.-C. Chen, Synthesis, 2075 (2001).
[27] Z. Liu, Z.-C. Chen and Q.-G. Zheng, Hypervalent Iodine in
Synthesis 94: A Facile Synthesis of 2-Substituted-imidazo[1,2-a]-
pyridines by Cyclocondensation of Alkynyl(phenyl)iodonium Salts
and 2-Aminopyridine, Synth. Commun., to be published.
(1961).
[7] N. P. Buu-Hoi and N. D. Xuong, Bull. Soc. Chim. Fr., 1000
(1963).
[8] I. Iwai and T. Hiraoka, Chem. Pharm. Bull., 12, 813
(1964).