A facile method for the synthesis of nicotinonitriles from ketones via a one-pot chloromethyleneiminium salt mediated three-component reaction

Article abstract of DOI:10.1016/j.tetlet.2007.06.032

Simple enolizable ketones such as acetophenones and benzalacetones were treated with malononitrile under Vilsmeier-Haack reaction conditions to afford 2-chloronicotinonitriles. The reaction proceeds via a one-pot chloromethyleneiminium salt mediated three

Full text of DOI:10.1016/j.tetlet.2007.06.032

Tetrahedron Letters 48 (2007) 5641–5643
A facile method for the synthesis of nicotinonitriles from ketones
via a one-pot chloromethyleneiminium salt mediated
three-component reaction
*
C. V. Asokan, E. R. Anabha, Ajith Dain Thomas, Ann Maria Jose, K. C. Lethesh,
M. Prasanth and K. U. Krishanraj
School of Chemical Sciences, Mahatma Gandhi University, Kottayam, Kerala 686 650, India
Received 9 April 2007; revised 26 May 2007; accepted 7 June 2007
Available online 9 June 2007
We dedicate this Letter to our beloved teacher and research guide Dr. C. V. Asokan who passed away on February 3, 2007 due to leukaemia
Abstract—Simple enolizable ketones such as acetophenones and benzalacetones were treated with malononitrile under Vilsmeier–
Haack reaction conditions to afford 2-chloronicotinonitriles. The reaction proceeds via a one-pot chloromethyleneiminium salt med-
iated three-component reaction followed by sequential cyclization and aromatization under Vilsmeier–Haack reaction conditions.
ꢀ
2007 Elsevier Ltd. All rights reserved.
The Vilsmeier–Haack reaction has emerged as a popular
tool for the formylation and acylation of a large number
reaction as a three-component reaction for the synthesis
of nicotinonitriles from acetophenones and benzal ace-
tones. This approach is novel in heterocyclic synthesis
and should have wide applications in chloromethylenei-
minium salt mediated annulation reactions.
1
–4
of aromatic and heteroaromatic compounds. Appro-
priately substituted alkenes, alcohols, acetals, ketals,
dithioketals and ketene dithioacetals undergo a variety
of transformations on treatment with the Vilsmeier–
5
–12
Haack reagent.
Typically the reactions of active
On treatment with the Vilsmeier–Haack reagent, enoliz-
able carbonyl compounds undergo iminoalkylation to
afford chloro-substituted vinamidinium salts. The syn-
methylene compounds with reagents of the Vilsmeier
type afford b-chloromethyleneiminium salts or b-chloro-
1
3
vinyl aldehydes, which have been recognized as useful
thetic potential of these iminium salts has been exploited
1
21–23
intermediates in heterocyclic synthesis. We have made
for the synthesis of substituted pyrroles
and pyri-
2
4
attempts to explore the synthetic utility of these func-
tionalized chloromethyleneiminium salt intermediates
for the synthesis of heterocyclic compounds, in particu-
dines employing multistep reaction strategies. During
the course of our attempts to synthesize functionalized
chloropyridines from a-oxoketenedithioacetals,
1
8
we
1
4–18
19,20
lar substituted pyridines
and pyrroles.
Recently,
observed that functionalized methyleneiminium salts
undergo in situ addition reactions with malononitrile to
afford simple Knoevenagel type adducts, which are cyc-
lized and aromatized under the same conditions to give
substituted 2-chloropyridines. In an attempt to prepare
6-aryl-2-chloropyridines, which are usually synthesized
we have shown that the Vilsmeier–Haack reagent can
act as a Knoevenagel base/buffer for the synthesis of
5
-aroyl-2-chloro-6-(methylsulfanyl)nicotinonitriles from
1
8
a-oxoketene dithioacetals. We envisioned that this
new strategy would be applicable to simple enolizable
ketones for the synthesis of a variety of pyridine deriva-
tives. Our results, which are communicated in this Let-
ter, demonstrate an example of the Vilsmeier–Haack
2
5
via a three-step reaction from acetophenones, simple
O
R2
R1
1
. POCl , DMF, rt, 12 h
CN
Cl
3
R2
R1
o
2
. NCCH CN, 90 C, 2 h
2
Keywords: Vilsmeier–Haack reaction; Three-component synthesis;
N
Nicotinonitrile; Knoevenagel reaction.
1
3. Aq. K CO
2 3
2
*
Corresponding author. Fax: +91 481 2731009; e-mail: anabhaer@
rediffmail.com
Scheme 1.
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.032

5642
C. V. Asokan et al. / Tetrahedron Letters 48 (2007) 5641–5643
Table 1. Synthesis of 4,5-disubstituted 2-chloronicotinonitriles 2
enolizable ketones such as acetophenones were treated
with malononitrile under the Vilsmeier–Haack reaction
conditions. According to the reported procedure, the
Vilsmeier–Haack reagent was prepared and ketone 1a
was added. The reaction mixture was stirred at room
temperature for 12 h, followed by addition of 1.5 equiv
of malononitrile and heating at 90 ꢁC for 2 h. Work-
up using aqueous saturated potassium carbonate solu-
tion and purification of the crude product by column
chromatography using hexane/ethyl acetate gave 6-
1
2
1
, 2
R
R
Yield (%)
52
a
H
H
b
c
64
44
H C
3
2
6
H
aryl-2-chloronicotinonitrile 2a in good yield. It is
interesting to note that functionalized ketones such as
benzalacetones 1b–l also react under these conditions
to give the corresponding chloropyridines 2b–l (Scheme
H CO
3
d
e
H
H
37
52
1
, Table 1).
Br
Cl
A literature survey showed that 2-chloro-6-phenylnicoti-
nonitrile is an important substrate for the synthesis of
2
5
natural products such as vitamins. In 1998, Cyranski
et al. reported crystallographic studies on this substance
2
7
and showed that the molecule was not planar. The
angle between the phenyl group and the pyridinyl group
is 3ꢁ and hence the symmetry of the molecule is lost.
f
H
49
OCH3
1
3
This was also evident from the C NMR data herein
2
5
reported.
g
h
i
CH
3
79
5
The mechanism for the formation of pyridines 2a–l can
S
be explained by the well known Vilsmeier–Haack reac-
H
1
tion of acetophenones for the formation of functional-
ized chloromethyleneiminium salt intermediates
3
followed by addition of malononitrile to the intermedi-
ates, which results in the formation of adducts 4. The
adducts, on intramolecular cyclization with elimination
of dimethylamine and 1,3-shift of the chlorine atom fol-
lowed by aromatization affords 2-chloropyridines 2
87
j
H
H
H
24
58
2
(
Scheme 2).
k
l
In conclusion, simple enolizable ketones undergo one-
pot iminoalkylation followed by sequential condensa-
tion with malononitrile, cyclization and aromatization
under Vilsmeier–Haack reaction conditions to afford
Cl
H CO
3
2
-chloronicotinonitriles. This methodology opens a
N
C
CN
CH3
O
Cl
Cl
R2
CN
NC
POCl3
CH3
R1
R1
R1
N
N
DMF
R2 CH3
R2 CH3
1
3
4
N(CH3)2
Cl
Cl
CN
CN
H
CN
H
N
N
N
heat
1,3-shift
Cl
R1
1
R1
R
R2
R2
R2
2
5
6
Scheme 2.

C. V. Asokan et al. / Tetrahedron Letters 48 (2007) 5641–5643
5643
new route to a one-pot multicomponent reaction under
Vilsmeier–Haack reaction conditions.
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1
2
2
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1
Acknowledgements
4
We thank CDRI, Lucknow and SIF, IISc, Bangalore,
for spectral and elemental analyses. E.R.A. thanks
CSIR, New Delhi, for financial support.
22. Gupton, J. T.; Krolikowski, D. A.; Yu, R. H.; Riesinger,
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992, 57, 5480.
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Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2007.
0
6.032.
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6. Representative experimental procedure: The Vilsmeier–
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