Synthesis of highly substituted pyridines via a one-pot, three-component cascade reaction of malononitrile with aldehydes and S-alkylisothiouronium salts in water

Article abstract of DOI:10.1055/s-0029-1217529

A novel methodology for the synthesis of 2-amino-4-aryl(alkyl)-6-sulfanyl pyridine-3,5-dicarbonitriles via a one-pot, three-component reaction of structurally diversified aldehydes with various S-alkylisothiouronium salts and malononitrile in water has be

Full text of DOI:10.1055/s-0029-1217529

2020
LETTER
Synthesis of Highly Substituted Pyridines via a One-Pot,
Three-Component Cascade Reaction of Malononitrile with Aldehydes
and S-Alkylisothiouronium Salts in Water
Synthesis of
H
ig
h
hly Substitu
o
ted Pyridine
n
s
g-qing Wang, Ze-mei Ge,* Tie-ming Cheng, Run-tao Li*
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University,
Beijing 100191, P. R. of China
Fax +86(10)82716956; E-mail: lirt@mail.bjmu.edu.cn
Received 6 March 2009
2a, R = HOCH2CH2
Ar
Y
Abstract: A novel methodology for the synthesis of 2-amino-4-ar-
yl(alkyl)-6-sulfanyl pyridine-3,5-dicarbonitriles via a one-pot,
three-component reaction of structurally diversified aldehydes with
various S-alkylisothiouronium salts and malononitrile in water has
been developed. Utilization of S-alkylisothiouronium salts as thiol
equivalents greatly broadens the application of the current method,
and also makes the reaction more environmentally friendly.
NC
CN
SR
NC
X
CN
Z
2b, R = 4-ClC6H4
N
2c, R =
H2N
N
N
CH2
N
H
1
2
Figure 1 3,5-Dicyanopyridines heterocyclic scaffolds
Key words: Multicomponent reactions, 2-amino-4-aryl(alkyl)-6-
sulfanyl pyridine-3,5-dicarbonitrile, S-alkylisothiouronium salts,
thiols, green chemistry
considerable amount of side product, enaminonitrile, us-
ing bases such as DABCO and Et3N in ethanol under re-
flux, therefore resulting in low yields of 20–48%.
Kornienko’s group further improved this procedure by
adding strong oxidizing agent TCQ or DDQ in the reac-
tion system and improved the yields to 50%.3j Meanwhile,
Ranu and co-workers revealed that a basic ionic liquid,
[bmIm]OH could efficiently promote this one-pot, three-
component condensation and greatly improve the yields
to 62–92%.3k Nevertheless, all the reported procedures
used organic solvents and highly volatile thiols with nasty
smell, which led to serious environmental and safety
problems. Moreover, only a few examples involved the
condensation of aliphatic aldehydes and aliphatic thiols in
this type of reactions in low yields. Therefore, it is still
critically needed to develop a more environmental friend-
ly and efficient procedure for the synthesis of this class of
compounds.
During the past decades, multicomponent reactions
(MCR) have attracted much attention in synthetic organic
chemistry, not only due to their convergent nature, supe-
rior atom economy, and straightforward experimental
procedures but also because of their broad application in
the pharmaceutical industry for the construction of low-
molecular-weight-compound libraries through combina-
torial strategies and parallel synthesis.1
The 3,5-dicyanopyridines represent an important class of
heterocyclic scaffold (1, Figure 1), through which a great
number of diverse libraries were produced through the
substitution at X-, Y-, and Z-positions of the pyridine ring,
and various biological activities were discovered.2a The
representative examples include 2-amino-4-aryl-6-sulfa-
nylpyridine-3,5-dicarbonitriles (2, Figure 1) which exhib-
it important biological activities. For examples,
compound 2a is an important lead in developing stage for
the treatment of Creutzfeldt–Jacob disease.2b–d and com-
pounds 2b2e and 2c2f are selective modulators of human
adenosine receptors with potential therapeutic application
in Parkinson’s disease, hypoxia/ischemia, asthma, kidney
disease, epilepsy, and cancer.
Previously, we successfully utilized S-alkylisothiouroni-
um salts as a class of inexpensive, readily available, and
odorless equivalents of thiols in the thia-Michael addition
in water.4a As an extension of our work, herein we report
an efficient one-pot, three-component synthesis of 2-ami-
no-4-aryl-6-sulfanylpyridine-3,5-dicarbonitriles from al-
dehydes, malononitrile, and S-alkylisothiouronium salts
as thiol equivalents in water.
Due to the various therapeutic utility of 2-amino-4-aryl-6-
sulfanylpyridine-3,5-dicarbonitriles, a number of synthet-
ic procedures for this type of derivatives were developed
using different protocols.3 Kornienko’s group reported a
convenient, three-component condensation of aldehyde,
malononitrile, and thiol for the construction of the highly
substituted pyridines.3i However, this method produced
We initially investigated the reaction of benzaldehyde,
malononitrile, and S-methylisothiouronium sulfate in the
presence of NaOH at room temperature under solvent-free
conditions based on our previous work.4b The desired
product
2-amino-4-phenyl-6-(methlsulfanyl)pyridine-
3,5-dicarbonitrile (3a) was obtained in 53% yield
(Scheme 1). This result indicated that it was feasible to
use S-alkylisothiouronium salts as thiol equivalents in this
reaction though the product yield was still not satisfacto-
ry. The low yield was likely attributed to the incompletion
of the reaction in the absence of solvent.
SYNLETT 2009, No. 12, pp 2020–2022
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x
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x
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Advanced online publication: 01.07.2009
DOI: 10.1055/s-0029-1217529; Art ID: W03209ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Highly Substituted Pyridines
2021
Ph
Table 1 Synthesis of Pyridine-3,5-dicarbonitrile6
CN
+ MeS
CN
NC
CN
NH
⋅1/2H2SO4
NH2
2.0 equiv NaOH
Entry R1
R2
Producta Yield (%)b
PhCHO + 2
H2N
N
3a
SMe
1
2
Ph
Me
Et
3a
3b
3c
89
82
76
71
83
87
85
51
75
79
82
87
91
84
92
80
Ph
Scheme 1 Synthesis of 3a under solvent-free conditions
3
Ph
n-Bu
Considering the broad applications of phase-transfer cata-
lyst in organic synthesis,5 we wondered whether this ap-
proach could be used to overcome the drawback of low
yield we just found in the first trial. Thus, we used the
model reaction of benzaldehyde, malononitrile, and S-methyl-
isothiouronium sulfate in water in the presence of NaOH
at room temperature to search for the suitable phase-trans-
fer catalysts. Various catalysts, such as TBAB, TEAB,
PEG-400, and sodium dodecyl sulfate (SDS), were exam-
ined. As expected, the yields increased significantly under
phase-transfer catalytic conditions. Among the tested cat-
alysts, SDS demonstrated the highest yield of 85%
through a simple and easy procedure.
4
Ph
–CH2CH2– 3d
5
Ph
c-C5H9
Bn
3e
3f
6
Ph
7
Ph
allyl
Me
3g
3h
3i
8
H
9
CH3
Me
10
11
12
13
14
15
16
4-O2NC6H4
3-HO-4-MeOC6H3
2,4-(MeO)2C6H3
2-MeOC6H4
3,4-CH2O2C6H3
2-thienyl
4-HOC6H4
Me
3j
Me
3k
3l
Me
To further optimize the reaction conditions, we tried to re-
place NaOH with different weak bases including both or-
ganic and inorganic bases, such as Na2CO3, NaHCO3,
K3PO4, DABCO, and Et3N. Unfortunately, NaOH was
still the most suitable base. We speculated that weak bases
are unfavorable to completely release the thiol from S-alkyl-
isothiouronium salts. Meanwhile, the effect of the amount
of NaOH in a range of 1 to 4 equivalents on the reaction
was also explored, and the best result was obtained when
3.0 equivalents of NaOH was used (Scheme 2). The reac-
tion mechanism should be same as that of the Kornienko’s
method.3i
Me
3m
3n
3o
3p
Me
Me
Me
a All new compounds were characterized by 1H NMR, 13C NMR, MS,
IR, and elemental analysis.
b Isolated yields based on aldehydes.
compatible. Usually, aliphatic thiols were seldom used in
previously reported procedures due to the very strong foul
smell and difficult operation. However, the utilization of
S-alkylisothiouronium salts as thiol equivalents has over-
come the limitations. The current method makes the sub-
stitute of methylthiol with S-methylisothiouronium
sulfate possible (entries 1, 8–16). During the reaction and
workup processes, only a very faint odor of thiol was no-
ticed. Furthermore, utilizing water as solvent makes this
method more environmental friendly. More gratifyingly,
this procedure is suitable not only for aromatic aldehydes,
but also for aliphatic aldehydes, such as formaldehyde
with 51% yield (entry 8) and acetaldehyde with 75% yield
(entry 9).
R1
NC
CN
CN
NH
⋅HX
NH2
3.0 equiv NaOH, H2O
0.1 equiv SDS, r.t.
R1CHO + 2
R2S
+
CN
H2N
N
3a–p
SR2
Scheme 2 Synthesis of pyridine-3,5-dicarbonitriles
After reaction conditions were optimized, we then inves-
tigated the generality of this method. A wide range of sub-
stituted aromatic, heteroaromatic, and aliphatic aldehydes
were studied for their one-pot, three-component conden-
sation with different S-alkylisothiouronium salts and ma-
lononitrile under the optimized reaction conditions. The
results are summarized in Table 1.
In conclusion, we have developed a novel method for the
synthesis of 2-amino-4-aryl(alkyl)-6-sulfanylpyridine-
3,5-dicarbonitriles via a one-pot, three-component reac-
tion of structurally diversified aldehydes with various
S-alkylisothiouronium salts and malononitrile in water.
More importantly, using S-alkylisothiouronium salts as
thiol equivalents provides a broad application and makes
the reaction more environmentally friendly.
All the reactions were performed smoothly within 60 min-
utes to afford the desired products in good yields, except
for entry 8 (51% yield). After the completion of the reac-
tions, the pure product was conveniently obtained by sim-
ple filtration and then recrystallization from acetonitrile or
ethanol. Owing to the short reaction time and mild reac-
tion conditions, several functionalities such as NO2, OH,
NH2, CN, methylenedioxy, and OMe were found to be
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2009, No. 12, 2020–2022 © Thieme Stuttgart · New York

2022
Z.-q. Wang et al.
LETTER
2003, 59, 1749. (i) Evdokimov, N. M.; Magedov, I. V.;
Kireev, A. S.; Kornienko, A. Org. Lett. 2006, 8, 899.
(j) Evdokimov, N. M.; Kireev, A. S.; Yakovenko, A. A.;
Antipin, M. Y.; Magedov, I. V.; Kornienko, A. J. Org.
Chem. 2007, 72, 3443. (k) Ranu, B. C.; Jana, R.; Sowmiah,
S. J. Org. Chem. 2007, 72, 3152.
Acknowledgment
This work is supported by the Natural Science Foundation of China
(NSFC 20672009) and National Key Technology R&D Program
(No: 2007BAI34B00)
(4) (a) Zhao, Y.; Ge, Z. M.; Cheng, T. M.; Li, R. T. Synlett 2007,
10, 1529. (b) Lei, M.; Shi, L. X.; Li, G.; Chen, S.; Fang, W.
H.; Ge, Z. M.; Cheng, T. M.; Li, R. T. Tetrahedron 2007, 63,
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(6) Representative Procedure for the Synthesis of
Compound 3a
A mixture of benzaldehyde (106 mg, 1 mmol), malononitrile
(132 mg, 2 mmol), NaOH (120 mg, 3 mmol), and SDS (29
mg, 0.1 mmol) in H2O (10 mL) was stirred for 10 min at r.t.
The S-methylisothiouronium sulfate (139 mg, 1 mmol) was
added. The reaction mixture was further stirred for 50 min
until the completion of the reaction (monitored by TLC).
The reaction mixture was then filtered and washed with H2O
to give the crude solid, which was recrystallized from MeCN
to furnish the crystals of 2-amino-4-phenyl-6-methyl-
sulfanylpyridine-3,5-dicarbonitrile (238 mg, 89%); mp 295–
296 °C. 1H NMR (300 MHz, CDCl3): d = 2.59 (s, 3 H,
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C
NMR (75 MHz, DMSO-d6): d = 12.79, 85.55, 93.49, 115.31,
115.46, 128.42, 128.71, 130.33, 133.98, 158.17, 159.72,
167.53. Anal. Calcd for C14H10N4S2: C, 63.14; H, 3.78; N,
21.04. Found: C, 63.13; H, 3.96; N, 21.24.
This procedure was followed for all the reactions listed in
Table 1. The unknown compounds were properly
characterized by their spectroscopic (1H NMR, 13C NMR)
and elemental analysis. The known compounds were
confirmed by 1H NMR and mp which were consistent with
the reported data (see Supporting Information).
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