One-pot synthesis of 2-amino-3-cyanopyridine derivatives catalyzed by ytterbium perfluorooctanoate [Yb(PFO)3]

Article abstract of DOI:10.1016/j.tetlet.2010.11.102

A family of 2-amino-3-cyanopyridine derivatives are synthesized from aldehydes, ketones, malononitrile, and ammonium acetate via one-pot reaction catalyzed by ytterbium perfluorooctanoate [Yb(PFO)₃]. This procedure tolerates most of substrates

Full text of DOI:10.1016/j.tetlet.2010.11.102

Tetrahedron Letters 52 (2011) 509–511
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot synthesis of 2-amino-3-cyanopyridine derivatives catalyzed by
ytterbium perfluorooctanoate [Yb(PFO)3]
Jun Tang a, Limin Wang a,b, , Yinfang Yao a, Liang Zhang a, Wenbo Wang a
⇑
a Laboratory for Advanced Materials & Institute of Fine Chemicals, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, PR China
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A family of 2-amino-3-cyanopyridine derivatives are synthesized from aldehydes, ketones, malononitrile,
and ammonium acetate via one-pot reaction catalyzed by ytterbium perfluorooctanoate [Yb(PFO)3]. This
procedure tolerates most of substrates and has the advantages of short routine, high yields, and environ-
mentally friendly. Furthermore, the possible mechanism is also proposed.
Received 20 October 2010
Revised 8 November 2010
Accepted 19 November 2010
Available online 24 November 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
2-Amino-3-cyanopyridine derivatives
Ytterbium perfluorooctanoate
One-pot reaction
Lewis acid
1. Introduction
of 2-amino-3-cyanopyridine derivatives catalyzed by Yb(PFO)3
in good to excellent yields.
The pyridine ring system is an important structural motif in
naturally occurring products as well as in many synthetic com-
pounds of pharmaceutical interest. Among them, 2-amino-3-cya-
nopyridine derivatives have raised considerable attentions1 since
this class of compounds allowed an access to many demonstrated
bio-active agents.2 For example, recently 2-aminopyridine deriva-
tives (Fig. 1) have been identified as novel IKK-b inhibitors,3 A2A
adenosine receptor antagonists,4 potent inhibitor of HIV-1 integr-
ase,5 and so on. Despite the existence of extensive literature for
the synthesis of 2-amino-3-cyanopyridines have been reported,
most common procedures need multiple steps,6 long reaction time,
toxic benzene as solvent,7 high temperature or microwave assis-
tance,8 resulting in unsatisfactorily low yields. However, a straight-
forward and efficient one-pot reaction by catalysis in mild
conditions is still limited.
2. Results and discussion
According to previous work,1a,3 ethanol was found to be the pre-
ferred solvent for this one-pot transformation. The one-pot reac-
tion of synthesis of 2-amino-4,6-diphenylnicotinonitrile (1a) was
selected as model reaction. A mixture of benzaldehyde (1 mmol),
acetophenone (1 mmol), malononitrile (1 mmol), ammonium ace-
tate (1.5 mmol), and 5 mol % of Yb(PFO)3 were stirred in ethanol
(2 mL) at refluxing temperature for 12 h. To our delight, almost full
conversion of substrates into a new product (which was character-
ized later to be the desired product 1a) was found according to TLC.
The mixture was allowed to cool to room temperature and stand
The rare earth catalysts are well known as mild and efficient
Lewis acid catalysts for various organic transformations.9 In our
previous work, we have developed rare earth perfluorooctanoates
[RE(PFO)3] for the first time,10 which are easily prepared, air sta-
ble, water-tolerated, and recyclable. Several multicomponent con-
densation reactions (MCRs) were efficiently promoted by
RE(PFO)3.11 In order to continue our work on the development
of simple and efficient rare earth Lewis acid catalysts, herein
we report a straightforward and efficient method for synthesis
H
N
O
N
Br
O
R1
CN
CN
NC
CN
S
Br
R2
N
NH2
N
NH2
H2N
R
O
O
OH
a
b
c
⇑
Corresponding author. Tel./fax: +86 21 64253881.
E-mail address: wanglimin@ecust.edu.cn (L. Wang).
Figure 1. (a) novel IKK-b inhibitors; (b) as A2A adenosine receptor antagonists; (c) a
potent inhibitor of HIV-1 integrase.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.102

510
J. Tang et al. / Tetrahedron Letters 52 (2011) 509–511
Table 2
for half an hour. The resultant precipitate was isolated by filtration,
washed with cold ethanol carefully, and recrystallized from tetra-
hydrofuran affording the crude product in 92% yield.
Scope of one-pot synthesis of 2-amino-3-cyanopyridines catalyzed by Yb(PFO)3
R1
O
NH4OAc / Yb(PFO)3
ethanol
R3
R2
CN
CN
NC
The product 1a was afforded in 40% yield after 12 h reaction
without catalyst. A variety of Lewis acid catalysts were also exam-
ined for this one-pot reaction. As can be seen from Table 1, all the
traditional Lewis acid catalysts with 20 mol % loadings provided
poorer yields (entries 2–4), probably due to the water in reaction
system making the catalysts be decomposed or deactivated. Ytter-
bium chloride and lanthanide triflates both with 5 mol % loadings
provided moderate yields (entries 5–7). Overall, Yb(PFO)3 provided
the best result. Even when the catalyst loading decreased to
1 mol %, 84% yield of 1a was still afforded. Further optimization
of the reaction conditions revealed that, ethanol was the best sol-
vent which provided the highest yield, comparing with some usual
organic solvents (e.g., benzene, toluene, dichloromethane and tet-
rahydrofuran). Trace product was afforded when the solvent was
water, which may ascribe to the insolubility of the reactants. The
best catalyst loading was 2.5 mol %, with that the reaction can be
achieved in 4 h affording 90% yield of the product. As expected,
the catalyst could be reused for at least three times by recycling
the filtrate directly without any significant loss of activity (entry
11).
Scope of the synthesis of 2-amino-3-cyanopyridine derivatives
was investigated that can be seen in Table 2. Aromatic ketones
with substituents or not, as well as aliphatic and cyclic ketones,
are all suitable substrates for the reaction. Electron-deficient aro-
matic aldehydes could react very readily at room temperature with
just 1 mol % of catalyst. Interestingly, no corresponding product
was afforded at ethanol refluxing temperature, instead of black
complex mixtures. Aliphatic aldehydes gave just moderate yields
(entry 12). Surprisingly, while para-substituted and meta-substi-
tuted aromatic aldehydes tolerated very well for the transforma-
tion, ortho-substituted aromatic aldehydes gave trace products
(entries 16 and 17). There was also no report for the product
coming from ortho-substituted aromatic aldehydes. Obviously,
the reactivity of aldehyde is the key factor for this one-pot
transformation.
R1CHO
+
+
R2
CH2R3
H2N
N
1 mmol
1 mmol
1 mmol
Entry
R1
R2
R3
Cond.a
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Ph
Ph
Ph
Ph
CH3
H
CH3
H
CH3
H
H
H
H
H
H
A
A
A
A
A
A
A
B
B
B
B
A
B
A
B
B
B
90
86
93
81
77
79
80
87
i-C4H9
CH3
i-C4H9
4-OCH3C6H4
Ph
4-OCH3C6H4
4-OCH3C6H4
4-OCH3C6H4
4-CH3C6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
C2H5
4-NO2C6H4
Ph
3-NO2C6H4
2-NO2C6H4
2-ClC6H4
Ph
CH3
90
85
4-OHC6H4
4-OCH3C6H4
CH3
H
H
CH3
92
60c
95
Ph
–(CH2)4–
Ph
92
88
H
H
H
Ph
Ph
Trace
Trace
a
Conditions A: the reactions were carried out with NH4OAc (1.5 mmol) and
Yb(PFO)3 (2.5 mol %) in ethanol (2 mL) at refluxing temperature for 4 h; conditions
B: the reactions were carried out with NH4OAc (1.5 mmol) and Yb(PFO)3 (1 mol %)
in ethanol (2 mL) at room temperature for 1.5 h.
b
Isolated yield.
10 mol % of Yb(PFO)3 was used.
c
Yb
NH
O
HN
R2
Yb3+
NH4OAc
-H2O
R3
R3
R3
R2
R2
3
R1
CN
Yb
O
-H2O
R1
+
NC
CN
NC
NH4OAc
malononitrile
According to the above results, our proposed mechanism is de-
picted in Scheme 1. The reaction may proceed via enamine 3,
2
H
H
Yb
N
R2
R3
N
NH
CN
R2
R3
N
NH2
CN
NH
R2
R3
Table 1
CN
Synthesis of 2-amino-4,6-diphenyl-nicotinonitrile catalyzed by various catalystsa
R1
R1
H
H
R1
PFO
4
5
6
O
O
NH4OAc / ethanol
catalyst
R2
R3
N
NH2
CN
NC
+
+
NC
H
CN
O2(air)
-H2
H2N
N
R1
1a
Scheme 1. Possible mechanism of the one-pot reaction.
Entry
Cat.
Amount (mol %)
Time (h)
Yield of 1ab (%)
1
2
3
4
5
6
7
8
9
None
ZnCl2
SnCl2
AlCl3
/
12
12
12
12
12
12
12
12
12
4
40
38
35
20
60
77
70
92
which formed from ketone and ammonium acetate, and then acti-
vated by Yb3+ cation, reacts with alkylidenemalononitrile 2 (from
condensation of aldehyde with malononitrile) to give intermediate
4, followed by cycloaddition, isomerization, and aromatization to
afford the final product. Electron-deficient aromatic aldehydes
can react with malononitrile to generate arylidenemalonitriles 2
more readily than electron-rich aromatic aldehydes, which need
more catalyst loadings and harsher reaction conditions. When R1
is an aromatic substitution, the intermediate 6 is very easy to oxi-
dize to the final product because a larger conjugated system can be
formed. However, when R1 is an aliphatic substitution, it’s hard to
form the conjugated pyridine ring, which might be the possible
reason why aliphatic aldehydes give such poor yields. There is no
20
20
20
5
5
5
5
1
2.5
YbCl3
Yb(OTf)3
La(OTf)3
Yb(PFO)3
Yb(PFO)3
Yb(PFO)3
84
11
90(88,87,85)c
a
General procedure:
a mixture of benzaldehyde (1 mmol), acetophenone
(1 mmol), malononitrile (1 mmol), ammonium acetate (1.5 mmol) and catalyst
were stirred in one-pot in ethanol (2 mL) at refluxing temperature.
b
Isolated yield.
The catalyst was reused for three times.
c

J. Tang et al. / Tetrahedron Letters 52 (2011) 509–511
511
50, 828; (b) Drabu, S.; Archna; Singh, S.; Munirajam, S.; Kumar, N. Indian J.
Heterocycl. Chem. 2007, 16, 411; (c) Victory, P.; Cirujeda, J.; Anton Vidal-Ferran,
A. Tetrahedron 1995, 51, 10253.
product coming from ortho-substituted aromatic aldehydes, prob-
ably ascribe to the steric hindrance effect of the bi-aromatic ring of
intermediate 6.
In summary, we have developed a straightforward and efficient
method for the preparation of 2-amino-3-cyanopyridine deriva-
tives via one-pot reaction of aldehydes, ketones, malononitrile,
and ammonium acetate promoted by Yb(PFO)3. This method toler-
ates most of the substrates, and the catalyst can be recycled and re-
used at least three times without significant loss of activity.
2. (a) May, B. C. H.; Zorn, J. A.; Witkop, J.; Sherrill, J.; Wallace, A. C.; Legname, G.;
Prusiner, S. B.; Cohen, F. E. J. Med. Chem. 2007, 50, 65; (b) Guo, K.; Mutter, R.;
Heal, W.; Reddy, T. K. R.; Cope, H.; Pratt, S.; Thompson, M. J.; Chen, B. Eur. J. Med.
Chem. 2008, 43, 93; (c) Cocco, M. T.; Congiu, C.; Lilliu, V.; Onnis, V. Bioorg. Med.
Chem. 2007, 15, 1859.
3. Murata, T.; Shimada, M.; Sakakibara, S.; Yoshino, T.; Kadono, H.; Masuda, T.;
Shimazaki, M.; Shintani, T.; Fuchikami, K.; Sakai, K.; Inbe, H.; Takeshita, K.; Niki,
T.; Umeda, M.; Bacon, K. B.; Ziegelbauer, K. B.; Lowinger, T. B. Bioorg. Med. Chem.
Lett. 2003, 13, 913.
4. Mantri, M.; De Graaf, O.; Van Veldhoven, J.; Göblyös, A.; Von Frijtag Drabbe
Künzel, J. K.; Mulder-Krieger, T.; Link, R.; De Vries, H.; Beukers, M. W.; Brussee,
J.; Ijzerman, A. P. J. Med. Chem. 2008, 51, 4449.
Acknowledgments
5. Deng, J.; Sanchez, T.; Al-Mawsawi, L. Q.; Dayam, R.; Yunes, R. A.; Garofalo, A.;
Bolger, M. B.; Neamati, N. Bioorg. Med. Chem. 2007, 15, 4985.
6. Girgis, A. S.; Kalmouch, A.; Hosni, H. M. Amino Acids 2004, 26, 139.
7. Kambe, S.; Saito, K. Synthesis 1980, 366.
This research was financially supported by the National Nature
Science Foundation of China (20672035) and Key Laboratory of
Organofluorine Chemistry, Shanghai Institute of Organic Chemis-
try, Chinese Academy of Sciences.
8. Shi, F.; Tu, S. J.; Fang, F.; Li, T. J. Arkivoc 2005, 137.
9. (a) Aspinall, H. C. Chem. Rev. 2002, 102, 1807; (b) Mihara, H.; Xu, Y. J.; Shepherd,
N. E.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 8384; (c)
Schoffers, E.; Kohler, L. Tetrahedron: Asymmetry 2009, 20, 1897; (d) Harada, S.;
Toudou, N.; Hiraoka, S.; Nishida, A. Tetrahedron Lett. 2009, 50, 5652; (e)
Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W.-L. Chem. Rev. 2002, 102,
2227.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.11.102.
10. Wang, L. M.; Han, J. W.; Sheng, J.; Tian, H.; Fan, Z. Y. Catal. Commun. 2005, 6,
201.
11. (a) Wang, L. M.; Hu, L.; Chen, H. J.; Sui, Y. Y.; Shen, W. J. Fluorine Chem. 2009,
130, 406; (b) Wang, L. M.; Shao, J. H.; Tian, H.; Wang, Y. H.; Liu, B. J. Fluorine
Chem. 2006, 127, 97; (c) Wang, L. M.; Han, J. W.; Tian, H.; Sheng, J.; Fan, Z. Y.;
Tang, X. P. Synlett 2005, 2, 337; (d) Shen, L.; Cao, S.; Liu, N. J.; Wu, J. J.; Zhu, L. J.;
Qian, X. H. Synlett 2008, 9, 1341.
References and notes
1. (a) Chang, L. C. W.; Von Frijtag Drabbe Künzel, J. K.; Mulder-Krieger, T.;
Westerhout, J.; Spangenberg, T.; Brussee, J.; Ijzerman, A. P. J. Med. Chem. 2007,