Synthesis of polysubstituted 3H-pyrimidin-4-ones from cyanoacetamides under Vilsmeier conditions

Article abstract of DOI:10.1016/j.tet.2011.07.006

A facile and efficient approach to a variety of 6-chloro-3,5-disubstituted 3H-pyrimidin-4-ones 2/6 from the readily available cyanoacetamides 1/5 under Vilsmeier conditions was developed, in which the Vilsmeier reagent plays multiple roles and the possible mechanism is discussed.

Full text of DOI:10.1016/j.tet.2011.07.006

Tetrahedron 67 (2011) 7081e7084
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Synthesis of polysubstituted 3H-pyrimidin-4-ones from cyanoacetamides under
Vilsmeier conditions
,
b
Zhiguo Zhang a, Can Xue b, Xiao Liu b, Qian Zhang b , Qun Liu
*
a School of Chemistry and Environmental Science, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Henan Normal University,
Xinxiang 453007, PR China
b Department of Chemistry, Northeast Normal University, Changchun 130024, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 May 2011
Received in revised form 17 June 2011
Accepted 1 July 2011
Available online 7 July 2011
A facile and efficient approach to a variety of 6-chloro-3,5-disubstituted 3H-pyrimidin-4-ones 2/6 from
the readily available cyanoacetamides 1/5 under Vilsmeier conditions was developed, in which the
Vilsmeier reagent plays multiple roles and the possible mechanism is discussed.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Polysubstituted 3H-pyrimidin-4-ones
Vilsmeier reagent
Cyclopropanes
Ring expansion
1. Introduction
Functionalized 3H-pyrimidin-4-ones and their benzo- and het-
erofused analogues are pharmacophores present in many bi-
ologically active compounds.1 Examples include angiotensin II
receptor antagonists,1a PPAR agonists,1b the atypical antipsychotic
drug risperidone,1c compounds with anticancer activity1d and ty-
rosine kinase inhibitors.1e In the synthesis of 3H-pyrimidin-4-ones,
most approaches have focused on the 3-substituted 3H-pyrimidin-
4-ones by means of dehydration of an enediamide (Scheme 1, route
A),2 the Pinner condensation of
b-keto esters with non-N-
substituted amidines (Scheme 1, route B)3 and condensation of N-
substituted amidines with malonyl dichlorides (Scheme 1, route
C).4 However, the methods mentioned above suffer from more or
less time-consuming procedures, low yields, long reaction time,
competing reactions, large excess of reactants or limited scope of
substrates.1e4 Herein, we describe a new efficient approach to
a broad range of 6-chloro-3,5-disubstituted 3H-pyrimidin-4-ones
through the reaction of the readily available cyanoacetamides un-
der Vilsmeier conditions in which Vilsmeier reagent (POCl3/DMF)
plays multiple roles in the tandem process (Scheme 1, route D).
Scheme 1. Synthetic methods for pyrimidinones.
During the course of our studies on transformations from easily
accessible acetoacetanilide derivatives5,6 to relatively complex
products, very recently, several new routes have been developed
for the synthesis of furo/pyrano quinolines5a,b and quinoline
derivatives.5c,d Also with acetoacetanilide derivatives as substrates,
we achieved the synthesis of halogenated pyridine-2(1H)-one un-
der Vilsmeier reaction conditions.5e As part of our continuing in-
terest in the synthetic potential of substituted (functionalized)
acetanilides under Vilsmeier conditions,5e,6b,7 the reactions of
a variety of cyanoacetamides 1 and 5 were examined and the sig-
nificantly different results from the previous investigations5e,6b,7
were obtained and presented in this article.
* Corresponding author. Fax: þ86 431 8509 8213; e-mail addresses: zhangzhi-
guo3030@yahoo.com.cn (Z. Zhang), zhangq651@nenu.edu.cn (Q. Zhang).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.07.006

7082
Z. Zhang et al. / Tetrahedron 67 (2011) 7081e7084
Based on the ring expansion of activated cyclopropanes,5cee the
Table 1
Synthesis of 3H-pyrimidin-4-ones 2aefa
substrate, 1-cyano-N-p-tolylcyclopropanecarboxamide 1a was
synthesized from easily available 2-cyano-N-p-tolylacetamide and
1,2-dibromoethane in high yield (94%) according to the known
procedure5a,8 and taken as a model substrate to optimize the re-
action conditions, including reaction temperature and the feed
ratio of 1a and Vilsmeier reagent. It was found that, upon treatment
of 1a (2.0 mmol) with POCl3 (1.1 equiv) in DMF (1 mL) at 100 ꢀC for
20 h, 4-chloro-2-cyano-N-p-tolylbutanamide 3a was obtained in
95% yield (Scheme 2). Compound 3a could be further converted
into 6-chloro-5-(2-chloroethyl)-3-p-tolylpyrimidin-4(3H)-one 2a
in 40% yield when 4 equiv of POCl3 were used at 100 ꢀC for 0.5 h.
After repeated experiments, the optimal conditions for the forma-
tion of 3H-pyrimidin-4-one 2a were obtained. Therefore, treatment
of 1a with 4 equiv of POCl3 in DMF at 100 ꢀC for 0.5 h led to 2a in
66% of yield together with 25% yield of N,N-dimethyl-N0-p-tol-
ylformimidamide 4a (Scheme 2). The structure of 2a was further
confirmed by the X-ray single crystal analysis9 (Fig. 1).
Entry
Substrate
Time (h)
Product
Yieldb (%)
1
R
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
4-MeC6H4
C6H5
4-ClC6H4
4-COOEtC6H4
3-MeC6H4
CH2C6H5
0.5
3.0
1.0
1.7
0.5
1.2
2a
2b
2c
2d
2e
2f
66
53
57
54
50
50
a
Reagents and conditions: 1 (2.0 mmol), POCl3(8.0 mmol)/DMF, 100 ꢀC.
Isolated yields.
b
generate intermediate A.10 Subsequent VilsmeiereHaack reactions
at the amide moietyof Ayields the iminium intermediate B. Then the
nucleophilic nitrogen of nitrile grouping attacks on the iminium
intermediate B7d,11 and followed cyano carbon captures the chlorine
ion to give the ring closing intermediate C. Finally, pyrimidin-4(3H)-
ones 2 is produced by the elimination of a dimethylamine.5e,6b,7d,e
On the other hand, the cleavage of the CeN bond of the amide
moiety of iminium intermediate B lead to byproducts 4 (Scheme 3
and 2).10,12
Scheme 2. The reactions of 1a under different conditions.
Scheme 3. The proposed mechanism for the formation of 2.
According to the proposed mechanism (Scheme 3), it is clear
that the Vilsmeier reagent plays multiple roles in the reaction
process and thus helps the introduction of two chloro substituents
on the 6-position of the pyrimidine ring and the side chain, re-
spectively. Encouraged by these results and the transformation 3a
to 2a (Scheme 2), the versatility of this facile approach to 3H-pyr-
imidin-4-ones was further evaluated by performing the reactions of
Fig. 1. ORTEP drawing of 2a.
Having established the optimal conditionsforthe synthesis of 3H-
pyrimidin-4-one 2a, the scope with respect to the amide motif was
then examined. Under the optimized conditions (Scheme 2), it was
observed that the selected precursors, 1-cyano-N-substituent-
cyclopropanecarboxamides 1bee, bearing either electron-donating
or electron-withdrawing group(s) on the aryl ring, efficiently gave
the corresponding dichloro products 2bee in good yields (Table 1,
entries 2e5). In addition, the above cyclization reaction was proven
effective for N-Bz substituted substrates. Under the optimized con-
ditions, product 2f was produced in 61% yield from the reaction of 1-
cyano-N-alkylcyclopropanecarboxamide 1f with POCl3/DMF (Table
1, entry 6). However, a complicated mixture was afforded by the re-
action of N-unsubstituted 1-cyanocyclopropanecarboxamide under
the identical conditions.
cyanoacetamides with a variety of substitutes at a-position instead
of a cyclopropane subunit under Vilsmeier conditions. All the
typical reactions, for example, 5aed,8 proceeded smoothly to give
the corresponding substituted 3H-pyrimidin-4-ones 6aed in good
yields (Table 2, entries 1e4) under the optimized conditions. The
reactive allyl functional group (Table 2, entries 3 and 4) was found
intact under the reaction conditions. Much to our delight, cyanoa-
cetamides 5eeh (unsubstituted at the a-position) could efficiently
produce the annulation products 6eeh, with a CHO group at the 5-
position of 3H-pyrimidin-4-one ring (Table 2, entries 5e8).13 It
should be noted that, the above method of making 3H-pyrimidin-4-
ones is complementary to other methods (A, B and C in Scheme 1)
and produces 3H-pyrimidin-4-ones with substituents (X or CHO)
that might permit further elaboration of the structure.
On the basis of the above results and our previously reports,5e,6b,7
plausible mechanism for the formation of 6-chloro-5-(2-
chloroethyl)-3-substituted pyrimidin-4(3H)-ones 2aef is pre-
sented and depicted in Scheme 3. The transformation commences
from the ring opening of 1 mediated by Vilsmeier reagent, to
a

Z. Zhang et al. / Tetrahedron 67 (2011) 7081e7084
7083
Table 2
Synthesis of 3H-pyrimidin-4-ones 6aeha
Entry
Substrate
Time (h)
Product
Yieldb (%)
1
R1
R2
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
Me
Bz
Allyl
Allyl
H
H
H
H
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-ClC6H4
4-OMeC6H4
4-MeC6H4
4-ClC6H4
4.0
1.2
3.0
1.2
0.5
1.7
1.0
0.5
6a
6b
6c
6d
6e
6f
74
58
53
64
70
71
56
48
5g
5h
6g
6h
3-MeC6H4
a
Reagents and conditions: 5 (2.0 mmol), POCl3/DMF (8.0 mmol), 100 ꢀC.
Isolated yields.
b
2. Conclusions
Supplementary data
In summary, a facile and efficient route to polysubstituted
(functionalized) 3H-pyrimidin-4-ones 2 and 6 has been developed
by the reactions of readily available cyanoacetamides 1 and 5 under
Vilsmeier conditions. The reaction has many advantages, such as
simple operation, good yields, short reaction time and a broad
range of substrates and the potential of the products. Further re-
search is in progress.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.07.006.
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Acknowledgements
Financial supports of this research by NCET-08-0756, NSFC
(21002051), JLSDP (20080547), PCSIRT (IRT1061) and the Funda-
mental Research Funds for the Central Universities (09ZDQD07)
and the doctoral scientific research Foundation of Henan Normal
University.

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