Multi-component synthesis of 2-amino-6-(alkylthio)pyridine-3,5- dicarbonitriles using Zn(II) and Cd(II) metal-organic frameworks (MOFs) under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2012.06.139

Multi-component synthesis of 2-amino-3,5-dicarbonitrile-6-thio-pyridines has been developed by using the reaction of aldehydes, malononitrile, and thiophenols in the presence of a Zn(II) or a Cd(II) metal-organic framework (MOF) as the heterogeneous catalyst. This protocol tolerates different functional groups on the substrates and does not require the use of any organic solvent. Moreover, the Zn(II) and Cd(II) MOF catalysts can be recovered and reused for a number of runs without loss of activity.

Full text of DOI:10.1016/j.tetlet.2012.06.139

Tetrahedron Letters 53 (2012) 4870–4872
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Multi-component synthesis of 2-amino-6-(alkylthio)pyridine-3,5-dicarbonitr-
iles using Zn(II) and Cd(II) metal–organic frameworks (MOFs) under solvent-
free conditions
⇑
⇑
Muralidhara Thimmaiah , Peng Li , Sridhar Regati , Banglin Chen , John Cong-Gui Zhao
Department of Chemistry, University of Texas at San Antonio, One UTSA Circle, San Antonio, Texas 78249-0698, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Multi-component synthesis of 2-amino-3,5-dicarbonitrile-6-thio-pyridines has been developed by using
the reaction of aldehydes, malononitrile, and thiophenols in the presence of a Zn(II) or a Cd(II) metal–
organic framework (MOF) as the heterogeneous catalyst. This protocol tolerates different functional
groups on the substrates and does not require the use of any organic solvent. Moreover, the Zn(II) and
Cd(II) MOF catalysts can be recovered and reused for a number of runs without loss of activity.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 23 June 2012
Revised 26 June 2012
Accepted 28 June 2012
Available online 5 July 2012
Keywords:
Metal–organic frameworks
Multi-component reaction
Heterogeneous catalysis
Benzaldehyde
Pyridine
Among the nitrogen-containing heterocycles, densely substi-
tuted pyridine derivatives are one of the most important classes
of compounds as they widely occur as key structural subunits in
numerous natural products that exhibit many interesting biologi-
cal activities.1 In addition, these heterocyclic compounds have
found a variety of applications in medicinal and pharmaceutical
sciences.2 Among these pyridine derivatives, 2-amino-6-(aryl-
thio)pyridine-3,5-dicarbonitrile is a privileged scaffold for develop-
ing pharmaceutical agents because various compounds with this
structural motif display significant and diverse biological activities.
For example, adenosine receptors are associated with Parkinson’s
disease, hypoxia, asthma, epilepsy, cancer, and cardiovascular dis-
eases.3 These pyridine compounds have been shown to be active
inhibitors of the adenosine receptors and, therefore, can be used
for treating these diseases.3 They are also inhibitors of cholinester-
ases and may be used for treating neurodegenerative diseases.4
These compounds have also been studied as potential anti-HBV,5
anti-bacterial, antibiofilm, and anti-infective agents,6 and as potas-
sium channel openers with applications in treating urinary incon-
tinence.7 Moreover, some of these derivatives also inhibit prion
replication and may be used for treating Creutzfeldt–Jacob dis-
ease.8 A few examples of recently reported biologically significant
2-amino-6-(alkylthio)pyridine-3,5-dicarbonitrile derivatives are
collected in Figure 1. Compound 1 is an agonist for adenosine A1
receptor,3c while compound 2 is a highly potent agonist for human
adenosine A2B receptor.3b Compounds 38b and 48a have been pro-
posed as potential therapeutics for prion disease due to their abil-
ity in inhibiting prion replication.8
OH
O
O
NC
S
CN
NC
S
CN
N
HO
N
NH2
N
NH2
NH
1
2
O
S
NC
S
CN
NC
S
CN
N
NH2
NH2
N
NH2
⇑
Corresponding authors.
E-mail addresses: banglin.chen@utsa.edu (B. Chen), cong.zhao@utsa.edu
(J.C.-G. Zhao).
3
4
Figure 1. Examples of biologically active 2-amino-6-(arylthio)pyridine-3,5-
These authors contributed equally to this work.
dicarbonitriles
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.139

M. Thimmaiah et al. / Tetrahedron Letters 53 (2012) 4870–4872
4871
Table 2
Owing to the broad spectrum of biological activities exhibited
by these 2-amino-6-thiopyridine-3,5-dicarbonitrile derivatives,
many synthetic methods have been developed for the construction
of these compounds.9 Among these reported methods, the Lewis/
Brønsted base-catalyzed three-component reaction of aldehydes,
malononitrile, and thiophenols is the most common approach.9
The reported Lewis/Brønsted base catalysts include DBU,9f
Et3N,9b,9d piperidine,9e,9h KF/alumina,9j,9k K2CO3/KMnO4,9p etc. Be-
sides bases, Lewis acid, Brønsted acid, nanoparticles, and ionic liq-
uids, such as ZnCl2,9g boric acid,9l silica nanoparticles,9i nano
MgO,9m [bmim]OH,9c and [bmim]Br,9o are also occasionally used.
Good to high yields of the desired 2-amino-3,5-dicarbonitrile-6-
thio-pyridines may be obtained using these methods. Neverthe-
less, most of these methods require the use of hazardous organic
solvents, and some of them need exotic reaction conditions such
as the use of microwave irradiation or an ionic liquid. Because of
our continuing interest in developing green methods for the syn-
thesis of biologically significant molecules,10 the development of
an environmentally benign and practical synthetic route for
accessing these important pyridine derivatives became our goal.
Metal–organic frameworks (MOFs),11,12 have been shown to be
a class of emerging catalysts with many promising characters.
These new heterogeneous catalysts usually are very stable and
may be easily recycled and reused after the application. Recently
we have reported the synthesis of two new iso-structural Zn-
and Cd-based MOFs M(4,40-Bpe)2(H2O)4ꢀ(m-BDS) (M = Zn2+ and
Cd2+; 4,40-Bpe = 1,2-bis(4-pyridyl)ethylene; m-BDS = 1,3-benzen-
edisulfonic acid) and their application as robust and green catalysts
for the Biginelli reaction.13 In continuation of our interest in MOF-
catalyzed reactions, we recently explored the synthesis of 2-ami-
no-6-(arylthio)pyridine-3,5-dicarbonitriles using a multi-compo-
nent reaction of aldehyde, malononitrile, and thiophenol
catalyzed by these Zn(II) and Cd(II) MOFs. Once again we demon-
strated the remarkable catalytic activity of these robust MOF cata-
lysts. Herein we wish to report our findings.
Multi-component synthesis of 2-amino-6-thiopyridine-3,5-dicarbonitriles catalyzed
by Zn-MOF and Cd-MOFa
R1
NC
NC
CN
catalyst
neat, 100oC
2
R1 CHO
+
+
R SH
NC
R2S
N
4
NH2
1
2
3
Entry
MOF
R1
R2
Time (min)
Yield (%)b
1
2
3
4
5
6
7
8
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Cd
Cd
Cd
Cd
Cd
Cd
Cd
Cd
Cd
Cd
Cd
Ph
4-FC6H4
4-ClC6H4
4-NO2C6H4
4-MeC6H4
4-MeOC6H4
2-Thiophenyl
n-C5H11
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
30
30
30
30
45
45
40
60
40
30
30
30
30
30
30
45
45
40
60
40
30
30
86
80
86
87
79
73
83
61
87
80
81
87
82
87
88
81
73
85
61
87
81
84
9
4-ClC6H4
4-MeC6H4
4-MeOC6H4
Ph
Ph
Ph
Ph
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
Ph
Ph
Ph
4-FC6H4
4-ClC6H4
4-NO2C6H4
4-MeC6H4
4-MeOC6H4
2-Thiophenyl
n-C5H11
Ph
Ph
Ph
Ph
4-ClC6H4
4-MeC6H4
4-MeOC6H4
Ph
Ph
a
Unless otherwise specified, all reactions were carried out with 1 (0.2 mmol), 2
(0.3 mmol), and 3 (0.1 mmol) and the MOF catalyst (0.002 mmol, 2.0 mol %) under
neat conditions.
b
Yield of the isolated product after column chromatography.
MOFs, after 10 h, the desired product was obtained in high yields of
82 and 84%, respectively (Table 1, entries 2 and 3). When the reac-
tions were performed under solvent-free conditions, the reaction
times were decreased to 30 minutes with the same catalyst loading
(Table 1, entries 4 and 5).14 This is a great advantage of this new
catalytic system in terms of green chemistry since no toxic organic
solvent is required for realizing the desired transformation.
In order to demonstrate the scope of this reaction, a series of
substituted aldehydes and thiophenols were then studied and
the results are summarized in Table 2. As is evident from the re-
sults shown in Table 2, this method is highly compatible with
many substituted benzaldehydes. Benzaldehydes with both an
electron-donating and an electron-withdrawing group, such as,
4-fluoro, 4-chloro, 4-nitro, 4-methyl, and 4-methoxy groups, all
give the desired products in excellent yields (Table 2, entries 2–6
and 13–17). In addition, good to high yields were also obtained
for a heteroaromatic aldehyde (thiophene-2-carbaldehyde, entries
7 and 18) and an aliphatic aldehyde (n-hexanal, entries 8 and 19)
when they were applied in this reaction. Similarly, the substituents
on thiophenol show almost no effects on the reaction: 4-Chloro, 4-
methyl, and 4-methoxy substituted thiols afforded the correspond-
ing pyridine derivatives in good to excellent yields with both cata-
lysts (Table 2, entries 9–11 and 20–22).
Benzaldehyde (1a), malononitrile (2), and thiophenol (3a) were
adopted as the model substrates for investigating the multi-com-
ponent synthesis of 2-amino-6-(arylthio)pyridine-3,5-dicarbonitr-
iles. The Zn(II) and Cd(II) MOFs developed in our lab were used
as the catalysts.13 The results of the optimizations are summarized
in Table 1.
Initial screenings were performed using toluene as a solvent. In
the absence of catalyst, the product was obtained in only 30% yield
after refluxing for 16 h (Table 1, entry 1), In contrast, in the pres-
ence of only a catalytic amount (2.0 mol %) of the Zn(II) and Cd(II)
Table 1
Reaction condition optimizationsa
O
SH
NC
NC
catalyst
T, time
+
+
H
NC
Ph
CN
S
N
4a
NH2
1a
2
3a
Entry
MOF
T (°C)
Solvent
Time (h)
Yield (%)b
The other advantage of these heterogeneous MOF catalysts lies
in the fact that they may easily be recovered by simple filtrations
and can be reused for many cycles without significant loss of the
catalytic activities. As our results in Table 3 show, when the reac-
tion of benzaldehyde (1a), malononitrile (2), and thiophenol (3a)
was used as a model reaction, both the Zn(II) and the Cd(II) MOF’s
can be recovered in high yields and reused for five cycles with al-
most no loss of the catalytic activity for the first three cycles (Table
3, entries 1–10).
1c
2
3
4
5
–
reflux
reflux
reflux
100
Toluene
Toluene
Toluene
Neat
16
10
10
0.5
0.5
30
82
84
86
87
Zn
Cd
Zn
Cd
100
Neat
a
Unless otherwise specified, all reactions were carried out with 1a (0.20 mmol),
2 (0.30 mmol), and 3a (0.10 mmol) and the MOF catalyst (0.0020 mmol, 2.0 mol %).
b
Yield of the isolated product after column chromatography.
Without any catalyst.
c

4872
M. Thimmaiah et al. / Tetrahedron Letters 53 (2012) 4870–4872
L. C. W.; Von Frijtag Drabbe Künzel, J. K.; Mulder-Krieger, T.; Spanjersberg, R. F.;
Table 3
Catalyst recycling and stability studya
Brussee, J.; Ijzerman, A. P. J. Med. Chem. 2004, 47, 3707; (c) Chang, L. C. W.; Von
Frijtag Drabbe Künzel, J. K.; Mulder-Krieger, T.; Spanjersberg, R. F.; Roerink, S.
F.; van den Hout, G.; Beukers, M. W.; Brussee, J.; Ijzerman, A. P. J. Med. Chem.
2005, 48, 2045; (d) Vakalopoulos, A.; Meibom, D.; Nell, P.; Suessmeier, F.;
Albrecht-Kuepper, B.; Zimmermann, K.; Keldenich, J.; Schneider, D.; Krenz, U.
PCT Int. Appl. WO 2012, 2012000945, A1; (e) Rosentreter, U.; Kraemer, T.;
Vaupel, A.; Huebsch, W.; Diedrichs, N.; Krahn, T.; Dembowsky, K.; Stasch, J.-P.
PCT Int. Appl. WO 2002, 2002070520, A1.
Zn(II) or Cd(II) MOFs
1a + 2 + 3a
4a
neat, 100°C
Entry MOF
T
Cycle Catalyst recovery
(%)
Time
(min)
Yield
(%)b
(°C)
4. (a) Samadi, A.; Chioua, M.; Alvarez Perez, M.; Soriano Santamaria, E.; Valderas
Cortina, C.; Marco Contelles, J. L.; De Los Rios, S. C.; Romero Martinez, A.;
Villarroya Sanchez, M.; Garcia Lopez, M.; Garcia Garcia, A., Span. Patent ES 2011,
2365233 A1; (b) Samadi, A.; Marco-Contelles, J.; Soriano, E.; Alvarez-Perez, M.;
Chioua, M.; Romero, A.; Gonzalez-Lafuente, L.; Gandia, L.; Roda, J. M.; Lopez, M.
G.; Villarroya, M.; Garcia, A. G. De Los Rios C. Bioorg. Med. Chem. 2010, 18, 5861.
5. (a) Chen, H.; Zhang, W.; Tam, R.; Raney, A. K. PCT Int. Appl. WO 2005,
2005058315, A1; Fredholm, B. B.; Ijzerman, A. P.; Jacobson, K. A.; Klotz, K.-N.;
Linden, J. Pharmacol. Rev. 2001, 53, 527.
6. Levy, S. B.; Alekshun, M. N.; Podlogar, B. L.; Ohemeng, K.; Verma, A. K.; Warchol,
T.; Bhatia, B.; Bowser, T.; Grier, M. US Pat. Appl. Publ. US 2005, 2005124678, A1.
7. Harada, H.; Watanuki, S.; Takuwa, T.; Kawaguchi, K.; Okazaki, T.; Hirano, Y.;
Saitoh, C. PCT Int. Appl. WO 2002, 2002006237 Al.
1
2
3
4
5
6
7
8
9
Znc
Znd
Zne
Znf
Zng
Cdc
Cdd
Cde
Cdf
Cdg
100
100
100
100
100
100
100
100
100
100
I
II
III
IV
V
I
99
97
94
93
90
>99
98
96
94
91
30
30
40
50
60
30
30
30
40
50
86
85
83
81
79
87
85
84
81
80
II
III
IV
V
10
a
Unless otherwise specified, all reactions were carried out with 1a (0.20 mmol),
8. (a) Perrier, V.; Wallace, A. C.; Kaneko, K.; Safar, J.; Prusiner, S. B.; Cohen, F. E.
Proc. Nat. Acad. Sci. U.S.A. 2000, 97, 6073; (b) Reddy, T. R. K.; Mutter, R.; Heal,
W.; Guo, K.; Gillet, V. J.; Pratt, S.; Chen, B. J. Med. Chem. 2006, 49, 607; (c) Guo,
K.; Mutter, R.; Heal, W.; Reddy, T. R. K.; Cope, H.; Pratt, S.; Thompson, M. J.;
Chen, B. Eur. J. Med. Chem. 2008, 43, 93.
2a (0.30 mmol), and 3a (0.10 mmol) and the MOF catalyst (0.0020 mmol, 2.0 mol %)
under neat conditions.
b
Yield of the isolated product after column chromatography.
The scale of this reaction was 8.0 mmol.
The scale of this reaction was 7.0 mmol.
The scale of this reaction was 6.0 mmol.
The scale of this reaction was 5.0 mmol.
The scale of this reaction was 4.0 mmol.
c
d
9. (a) Kambe, S.; Saito, K.; Sakurai, A.; Midorikawa, H. Synthesis 1981, 531; (b)
Evdokimov. N. M.; Magedov, I. V.; Kireev, A. S.; Kornienko, A. Org. Lett. 2006, 8,
899.; (c) Ranu, B. C.; Jana, R.; Sowmiah, S. J. Org. Chem. 2007, 72, 3152; (d)
Evdokimov, N. M.; Kireev, A. S.; Yakovenko, A. A.; Antipin, M. Y.; Magedov, I. V.;
Kornienko, A. J. Org. Chem. 2007, 72, 3443; (e) Guo, K.; Thompson, M. J.; Reddy,
T. R. K.; Mutter, R.; Chen, B. Tetrahedron 2007, 63, 5300; (f) Mamgain, R.; Singh,
R.; Rawat, D. S. J. Heterocycl. Chem. 2009, 46, 69; (g) Sridhar, M.; Ramanaiah, B.
C.; Narsaiah, C.; Mahesh, B.; Kumaraswamy, M.; Mallu, K. K. R.; Ankathi, V. M.;
Rao, P. S. Tetrahedron Lett. 2009, 50, 3897; (h) Guo, K.; Thompson, M. J.; Chen, B.
J. Org. Chem. 2009, 74, 6999; (i) Banerjee, S.; Sereda, G. Tetrahedron Lett. 2009,
50, 6959; (j) Das, B.; Ravikanth, B.; Kumar, A. S.; Kanth, B. S. J. Heterocycl. Chem.
2009, 46, 1208; (k) Singh, K. N.; Singh, S. K. ARKIVOC 2009, 13, 153; (l) Shinde, P.
V.; Sonar, S. S.; Shingate, B. B.; Shingare, M. S. Tetrahedron Lett. 2010, 51, 1309;
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Poor Heravi, M. R.; Fakhr, F. Tetrahedron Lett. 2011, 52, 6779; (o) Davoodnia, A.;
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Asian. J. Chem. 2011, 23, 1273; (p) Mishra, S.; Ghosh, R. Synth. Commun. 2012,
42, 2229.
e
f
g
In summary, we have demonstrated that the Zn(II) and Cd(II)
MOFs are efficient, robust, and recyclable catalysts for the multi-
component reaction of aldehydes, malononitrile, and thiophenols.
This reaction offers a new convenient and green method for the
synthesis of the biologically significant 6-(alkylthio)-2-amino-pyr-
idine-3,5-dicarbonitrile derivatives. These MOF-mediated green
reactions are mild and easy to operate with the advantage of the
solvent-free reaction conditions.
10. (a) Bhanushali, M.; Zhao, C.-G. Synthesis 2011, 1815; (b) Ding, D.; Zhao, C.-G.
Eur. J. Org. Chem. 2010, 3802; (c) Gogoi, S.; Zhao, C.-G. Tetrahedron Lett. 2009,
50, 2252.
Acknowledgments
11. For reviews, see (a) Leadbeater, N. E.; Marco, M. Chem. Rev. 2002, 102, 3217; (b)
Song, C. E.; Lee, S.-G. Chem. Rev. 2002, 102, 3495; (c) Van Heerbeek, R.; Kamer,
P. C. J.; Van Leeuwen, P. W. N. M.; Reek, J. N. H. Chem. Rev. 2002, 102, 3717.
12. For reviews, see (a) Ma, L.; Abney, C.; Lin, W. Chem. Soc. Rev. 2009, 38, 1248; (b)
Lee, J. Y.; Farha, O. K.; Roberts, J.; Scheidt, K. A.; Nguyen, S. B. T.; Hupp, J. T.
Chem. Soc. Rev. 2009, 38, 1450; (c) Ma, L.; Lin, W. Top. Curr. Chem. 2010, 293,
175; (d) Jiang, H.-L.; Xu, Q. Chem. Commun. 2011, 47, 3351; (e) Shi, L.-X.; Wu,
C.-D. Chem. Commun. 2011, 47, 2928; (f) Corma, A.; Garcia, H. Llabres i Xamena
F. X. Chem. Rev. 2010, 110, 4606; (g) Zou, C.; Wu, C.-D. Dalton Trans. 2012, 41,
3879; (h) Yoon, M.; Srirambalaji, R.; Kim, K. Chem. Rev. 2012, 112, 1196; (i) Zhu,
C.; Yuan, G.; Chen, X.; Yang, Z.; Cui, Y. J. Am. Chem. Soc. 2012, 134, 8058.
13. Li, P.; Regati, S.; Butcher, R. J.; Arman, H. D.; Chen, Z.; Xiang, S.; Chen, B.; Zhao,
C.-G. Tetrahedron Lett. 2011, 52, 6220.
14. General Experimental Procedures: To a mixture of benzaldehyde (1a, 21.2 mg,
0.20 mmol), malononitrile (2, 19.8 mg, 0.30 mmol), and thiophenol (3a,
11.0 mg, 0.10 mmol) was added the Zn(II) MOF (1.5 mg, 0.0020 mmol,
2.0 mol %) or the Cd(II) MOF (1.6 mg, 0.0020 mmol, 2.0 mol %). The mixture
was then kept at 100 °C for 30 min until the full conversion of the starting
materials was achieved (monitored by TLC). The reaction mixture was then
filtered and washed with hot ethanol to recover the catalyst. The filtrate was
stripped off the solvent and then purified using column chromatography to
give the desired product 4a (28.1 mg, 86% for Zn(II) MOF and 28.5 mg, 87% for
Cd(II) catalyst, respectively).
BC thanks the financial support of this research from the Welch
Foundation (Grant No. AX-1730). JCZ thanks the generous financial
support of this research from the National Institutes of Health-Na-
tional Institute of General Medical Sciences (Grant no.
SC1GM082718) and the Welch Foundation (Grant No. AX-1593).
Supplementary data
Supplementary data associated with this article can be found, in
theonlineversion, at http://dx.doi.org/10.1016/j.tetlet.2012.06.139.
References and notes
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