Selective one-pot multicomponent synthesis and anti-tubercular evaluation of 5-(aryl/cyclohexylsulfanyl)-2-alkoxy-4,6-diarylnicotinonitriles

Article abstract of DOI:10.1016/j.bmcl.2010.04.025

A new set of highly substituted pyridine derivatives has been synthesized by a product selective four component reaction of aryl aldehyde, malononitrile and 2-aryl/cyclohexylsulfanyl-1-aryl-1-ethanones in presence of sodium hydroxide in methyl/ethyl alcoh

Full text of DOI:10.1016/j.bmcl.2010.04.025

Bioorganic & Medicinal Chemistry Letters 20 (2010) 3352–3355
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Bioorganic & Medicinal Chemistry Letters
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Selective one-pot multicomponent synthesis and anti-tubercular evaluation
of 5-(aryl/cyclohexylsulfanyl)-2-alkoxy-4,6-diarylnicotinonitriles
b
b
Ramaiyan Manikannan a, Shanmugam Muthusubramanian a, , Perumal Yogeeswari , Dharmarajan Sriram
*
a Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, India
b Tuberculosis Drug Discovery Laboratory, Pharmacy Group, Birla Institute of Technology & Science—Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500 078, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new set of highly substituted pyridine derivatives has been synthesized by a product selective four
component reaction of aryl aldehyde, malononitrile and 2-aryl/cyclohexylsulfanyl-1-aryl-1-ethanones
in presence of sodium hydroxide in methyl/ethyl alcohol. Among the compounds, 4,6-bis(4-chloro-
phenyl)-5-[(4-chlorophenyl)sulfanyl]-2-methoxynicotinonitrile (4n) inhibited Mycobacterium tuberculo-
Received 29 October 2009
Revised 11 March 2010
Accepted 9 April 2010
Available online 13 April 2010
sis (MTB) with minimum inhibitory concentration (MIC) of 3.1 lM and was more potent than
ethambutol and pyrazinamide.
Keywords:
Ó 2010 Elsevier Ltd. All rights reserved.
Pyridine derivatives
Malononitrile
Arylaldehyde
Multicomponent reaction
Antimycobacterial activity
Mycobacterium tuberculosis
Tuberculosis (TB) is an ancient infectious disease of global influ-
ence, re-emerged with multi-drug resistant strains (MDR-TB) and
acquired immune deficiency syndrome (AIDS). According to World
Health Organization (WHO), one third of the world’s populations
are infected with Mycobacterium tuberculosis (MTB) and it is pre-
dicted that more new TB cases will occur worldwide.1,2 Further-
more, it has been more than 40 years since a new drug for TB
was discovered. Therefore, it is an imperative need to develop no-
vel anti-tubercular drugs that can be equally effective against MTB
and MDR-TB, and shorten the duration of therapy. The anti-tuber-
cular activity of pyridine containing compounds is being investi-
gated from early days. In our earlier works, we have reported
various 4-pyridinecarboxylic acid hydrazides, some of which were
found to be most potent with a minimum inhibitory concentration
heterocycle or a nitrogen heterocycle or even a carbocyclic system.
It has been shown that the reaction of RCOCH2R0 in presence of
Vilsmeier’s reagent followed by malononitrile treatment gives a
3-cyanopyridine derivative.5 A 1,3-diketone reacts with arylalde-
hyde and malononitrile in the presence of quaternary ammonium
salt giving a tetrahydrobenzopyran derivative.6 Similar reaction
with a b-ketoester has been shown to yield two products, a pyran
derivative and a piperidone derivative.7 A microwave initiated
reaction of the above type in presence of ionic liquid has found
to yield only pyran system selectively with excellent yield.8
6-Methoxytetralone undergoes condensation with malononitrile
and aromatic aldehyde in presence of sodium methoxide to give
a pyridine derivative. It is to be noted that the methoxy group
has been incorporated as a substituent in the pyridyl ring.9,10 How-
ever, when piperidine or sodium hydroxide is used in DMF, instead
of sodium methoxide in methanol, the pyran ring is generated. It is
interesting to note that this multicomponent reaction leads to car-
bocyclic rings also. Thus when the reaction was carried out in the
presence of triethylamine and alumina, a benzene ring with cyano
and amino substituents is created.11 Formation of pyran12,13 as
well as pyridine ring system12,14 from this approach seems to be
facile - the solvent, base used and the other conditions determining
the outcome of the reaction.
(MIC) of 0.49 l
M against MTB and isoniazide-resistant MTB.3 We
have also reported various pyridylthiourea compounds endowed
with high activity toward MDR-TB.4 In continuation of work on
pyridine derivatives, herewith we are reporting the synthesis of
novel poly substituted pyridines by product selective one-pot mul-
ticomponent synthesis and their anti-tubercular activities.
The reaction of malononitrile and arylaldehyde with ketone
having active methylene group is interesting as the course of this
multicomponent reaction is normally decided by different factors,
mainly the solvent polarity. The product may be either an oxygen
Having realized that the multicomponent reaction of malononit-
rile, arylaldehyde and appropriate ketone leads to a variety of prod-
ucts, it has been planned to carry out one such reaction with a ketone
* Corresponding author. Tel./fax: +91 452 2459845.
E-mail address: muthumanian2001@yahoo.com (S. Muthusubramanian).
with arylthio group in the a-position of the ketone. The identified
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.04.025

R. Manikannan et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3352–3355
3353
substrates, 2-aryl/cyclcohexylsulfanyl-1-aryl-1-ethanones 1, have
been prepared from substituted phenacyl bromides and aryl/cyclo-
hexylthiols. All the compounds of the series 1, except 1-(4-chloro-
phenyl)-2-[(4-methoxyphenyl)sulfanyl]-1-ethanone, have been
reported in the literature.15–22
An equimolar mixture of ketone 1, malononitrile 2, arylalde-
hyde 3 and sodium hydroxide, was stirred at room temperature
in the presence of in ethanol/methanol. The reaction proceeds
smoothly taking 10–60 min for completion as revealed by TLC
studies. Only one product was obtained quantitatively in all the
cases. The product after column purification, has been character-
ized as a highly substituted pyridine derivative, 5-[aryl/cyclo-
hexylsulfanyl]-2-alkoxy-4,6-diarylnicotinonitrile 4/523 vide infra
(Scheme 1). The compounds 4a–p have arylthio group in the 5-po-
sition, while compounds 5a–n have cyclohexylthio group in that
position.
COSY spectrum helps to identify the coupling pairs in the three aryl
systems. The signals at 6.55 and 6.97 ppm are due to the p-N,N-
dimethylaminophenyl ring hydrogens. The doublets at 6.67 and
7.19 and 7.33 and 7.54 ppm are the other partners. The HMBC
spectrum helps to identify the ipso carbons to N,N-dimethylamino
and methoxy groups, 150.9 and 163.8 ppm, respectively. The car-
bon at 150.9 ppm gives
a contour with the hydrogens at
6.97 ppm confirming the latter hydrogens to be that of the N,N-
dimethylaminophenyl ring. The C,H-COSY spectrum is useful to
identify the carbon at 111.1 ppm to be that ortho to N,N-dimethyl-
amino group. The spectral features hence support the proposed
structure for 4/5.
The mechanism for the formation of 4/5 in the above reaction is
given in Scheme 2. It can be seen that only one product in good
yield is obtained, even though there are other possible product for-
mations. The reason for the preferential formation of pyridine
derivative rather than pyran derivative can be accounted by the
fact that the initial enolisation of A, which is essential to attack cy-
ano group internally to give pyran derivative, seems to be slow.
The alkoxide/alcohol present in the reaction medium is nucleo-
philic enough to attack the cyano group, paved the way for a pyr-
idine nucleus.
The 1H NMR spectrum of 4m has three pairs of doublets in the
aromatic region, each accounting for two hydrogens, indicating the
presence of three para substituted aryl rings. Singlets at 3.00 and
4.10 ppm, the former accounting for six hydrogens of the N,N-
dimethylamino group and the latter probably for a methoxy group
as it accounts for three hydrogens, are the other signals present.
The 13C NMR spectrum also has signals for N,N-dimethylamino
group and methoxy group. Apart from the carbons identified to
be those due to the three aryl rings, the presence of six other qua-
ternary carbons (DEPT 135) are noticed in the spectrum. The H,H-
The antimycobacterial activity of the synthesized pyridines
(4/5) have been screened for their in vitro activity against M. tuber-
culosis H37Rv (MTB) by agar dilution method for the determination
of MIC in triplicates. The minimum inhibitory concentration (MIC)
O
Ar
N
OR'
CN
NaOH/R'OH
rt, 10-60 min.
S
CN
CN
2
Ar
R
Ar'-CHO
+
+
S
R
Ar'
1
3
4/5
Ar = C6H5/
R = C6H5/
Ar' = C6H5/
R' = CH3/C2H5
p-OCH
p-Cl-C6H4/
3
-C6H4/
p-OCH3-C6H4/
p-Cl-C6H4/
p-N(CH3)2-C6H4/
p-Cl-C6H4
p-CH3-C6H4/
Cyclohexyl
p-OCH3-C6H4/
p-CH3-C6H4/
o-Cl-C6H4
p-Br-C6H4/
p-NO2-C6H4/
p-CH3-C6H4/
Scheme 1. Synthesis of poly substituted pyridines 4/5.
OR1
O
Ar
O
N
C
CN
+
S
Ar'-CHO
+
Ar
R
S
CN
CN
R
Ar'
1
2
3
A
HN
OH
O
Ar
Ar
N
OR1
CN
Ar
air Oxidation
N
OR1
CN
OR1
CN
Ar
N
OR1
CN
-H2O
S
S
S
S
R
Ar'
R
Ar'
R
Ar'
R
Ar'
D
C
B
4
Scheme 2. The mechanism for the formation of 4/5.

3354
R. Manikannan et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3352–3355
Table 1
Physical constants and anti-TB activities of poly substituted pyridines
Compd
Ar
R
Ar0
R1
Yield (%)
Mp (°C)
MIC (lM)
a
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
p-Cl–C6H4
p-Cl–C6H4
p-Cl–C6H4
p-Cl–C6H4
p-Cl–C6H4
p-Cl–C6H4
p-OCH3–C6H4
p-Cl–C6H4
p-Cl–C6H4
p-Br–C6H4
C6H5
p-Cl–C6H4
p-CH3–C6H4
p-CH3–C6H4
C6H5
p-CH3–C6H4
C6H5
p-Cl–C6H4
p-CH3–C6H4
p-OCH3–C6H4
p-Cl–C6H4
p-Cl–C6H4
p-Cl–C6H4
p-Cl–C6H4
p-Cl–C6H4
p-Cl–C6H4
p-Cl–C6H4
C6H11
C6H11
C6H11
C6H11
C6H11
C6H11
C6H11
C6H11
C6H11
C6H5
C6H5
Et
Et
Et
Et
Et
Et
Et
Et
92
93
90
87
92
90
88
85
87
82
90
90
91
92
92
89
94
92
95
98
99
94
90
88
96
99
99
99
99
99
—
13.1
54.8
>50.0
>51.4
25.5
26.2
24.2
51.3
48.5
5.6
26.5
27.0
12.4
3.1
25.4
27.1
25.0
27.8
6.8
248–249
238–239
241–242
158–159
143–144
136–137
98–99
p-N(CH3)2C6H4
p-N(CH3)2C6H4
p-Cl–C6H4
p-Cl–C6H4
p-N(CH3)2C6H4
p-OCH3–C6H4
p-N(CH3)2C6H4
p-N(CH3)2C6H4
p-N(CH3)2C6H4
p-Cl–C6H4
p-N(CH3)2C6H4
p-Cl–C6H4
p-OCH3–C6H4
C6H5
Et
Et
80–81
110–111
114–115
124–125
103–104
225–226
144–145
93–94
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
Et
Et
Et
Me
Me
Me
Me
Me
Me
C6H5
p-Cl–C6H4
p-Cl–C6H4
p-Cl–C6H4
p-Cl–C6H4
C6H5
a
C6H5
C6H5
C6H5
—
p-Cl–C6H4
p-NO2–C6H4
p-NO2–C6H4
p-Cl–C6H4
p-Cl–C6H4
p-CH3–C6H4
p-Cl–C6H4
p-Cl–C6H4
p-Cl–C6H4
p-Cl–C6H4
p-Cl–C6H4
p-Cl–C6H4
p-Cl–C6H4
152–153
84–85
p-N(CH3)2C6H4
p-N(CH3)2C6H4
p-Cl–C6H4
p-N(CH3)2C6H4
p-CH3–C6H4
p-Cl–C6H4
p-N(CH3)2C6H4
p-OCH3–C6H4
p-CH3–C6H4
C6H5
171–172
151–152
161–162
149–150
155–156
144–145
172–173
140–141
142–143
143–144
255–256
12.5
25.4
6.5
26.5
27.0
13.3
13.1
26.9
28.0
57.6
13.3
0.4
C6H11
C6H11
C6H11
C6H11
C6H11
o-Cl–C6H4
Isoniazid
Ethambutol
Pyrazinamide
7.6
50.8
a
Viscous liquid.
is defined as the minimum concentration of compound required to
completely inhibit the bacterial growth. The MIC values of 4/5
along with the standard drugs for comparison are furnished in
Table 1. Twenty nine compounds have been screened and the com-
pounds showed in vitro activity against MTB with MIC ranging
support from Madurai Kamaraj University, Madurai for one of the
authors (R.M.) is gratefully acknowledged.
Supplementary data
from 3.1 to 57.6
MTB with MIC of less than 10
first line anti-TB drug ethambutol (MIC 7.6
l
M. Four compounds (4j, 4n, 5c, and 5f) inhibited
M. When compared to one of the
M), four compounds,
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.04.025.
l
l
4j, 4n, 5c, and 5f were found to be more potent and compound
4n was found to be 2.4 times more active than ethambutol. When
compared to pyrazinamide (MIC 50.8 lM), all the compounds,
except 4b–d, 4h, and 5m, were found to be more potent, though
all the compounds were less potent than another anti-Tb drug iso-
niazid. Compound 4,6-bis(4-chlorophenyl)-5-[(4-chlorophenyl)
sulfanyl]-2-methoxynicotinonitrile (4n) inhibited MTB with MIC
References and notes
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M.; Krishanraj, K. U. Tetrahedron Lett. 2007, 48, 5641.
of 3.1 lM and was 2.4 times and 16.1 times more potent than eth-
ambutol and pyrazinamide, respectively.
6. Jin, T.-S.; Wang, A.-Q.; Shi, F.; Han, L.-S.; Liu, L.-B.; Li, T.-S. ARKIVOC 2006, xiv, 78.
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A. E.-F. G. Bioorg. Med. Chem. 2006, 14, 5481.
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13. Armesto, D.; Horspool, W. M.; Martin, N.; Ramos, A.; Seoane, C. J. Org. Chem.
1989, 54, 3069.
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Chem. Res., Synop. 1985, 184.
Between 5i and 5n, where the groups at R, Ar, and R0 are all con-
stant and the structural change is effected only in Ar0, the activity is
found to increase with electron releasing ability of the para-substi-
tuent. Among 5-phenyl sulfanyl derivatives (4a–p), introduction of
chlorine atom in the para position of the phenylsulfanyl ring
increases potency compared to the unsubstituted, but the introduc-
tion of a methyl or methoxy substituent has no statistically signifi-
cant effect. In between methoxy and ethoxy groups at 2-position,
in general, the ethoxy derivatives showed better activity in many in-
stances (5b vs 5m, 5e vs 5j, 4a vs 4p).
Acknowledgments
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The authors thank Department of Science and Technology, New
Delhi for assistance for the NMR spectrometer facility. Financial

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3355
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the solidified compound was filtered and the crude mixture was purified by
column chromatography using petroleum ether–ethyl acetate mixture as eluent.
The product 4/5 was recrystallised from dichloromethane. Spectroscopic data
for representative compound is given below.
21. Yimin, L.; Wei, Z. QSAR Comb. Sci. 2006, 25, 728.
22. Manikannan, R.; Muthusubramanian, S. Synth. Commun., Submitted for
publication.
23. General procedure for the synthesis of the 6-aryl-5-[aryl/cyclohexylsulfanyl]-2-
alkoxy-4-arylnicotinonitriles (4/5): A mixture of malononitrile 2 (0.002 mol),
sodium hydroxide (0.002 mol), p-substituted benzaldehyde 3 (0.002 mol), and
6-(4-Chlorophenyl)-5-[(4-chlorophenyl)sulfanyl]-4-[4-(dimethylamino)phenyl]-2-
methoxynicotinonitrile (4m): (Table 1, entry 13) yellow solid (dichloromethane);
yield 98%; mp 103–104 °C; time 15 min; 1H NMR (300 MHz, CDCl3): d 3.00 (s,
6H), 4.10 (s, 3H), 6.55 (d, J = 8.1 Hz, 2H), 6.67 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.1 Hz,
2H), 7.19 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.1 Hz, 2H); 13C
NMR (75 MHz, CDCl3): d 40.1, 54.8, 96.9, 111.1, 114.9, 120.9, 122.6, 127.9, 128.6,
129.5, 130.2, 130.8, 131.8, 135.2, 135.6, 137.8, 150.9, 162.5, 163.6, 163.8. Anal.
Calcd for C27H21Cl2N3OS: C, 64.03; H, 4.18; N, 8.30. Found: C, 64.15; H, 4.27; N,
8.44.
2-(aryl/cyclohexylsulfanyl)-1-aryl-1-ethanone
1
(0.002 mol) in ethanol/
methanol, added in that order, was stirred for 15–60 min at room
temperature. The progress of the reaction was monitored by TLC. After
completion of the reaction, the reaction mixture was poured into crushed ice,