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

Tetrahedron Letters 52 (2011) 509–511

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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 b

Laboratory for Advanced Materials & Institute of Fine Chemicals, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, PR China 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

Article history: Received 20 October 2010 Revised 8 November 2010 Accepted 19 November 2010 Available online 24 November 2010

a b s t r a c t 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 environmentally friendly. Furthermore, the possible mechanism is also proposed. Ó 2010 Elsevier Ltd. All rights reserved.

Keywords: 2-Amino-3-cyanopyridine derivatives Ytterbium perfluorooctanoate One-pot reaction Lewis acid

1. Introduction The pyridine ring system is an important structural motif in naturally occurring products as well as in many synthetic compounds of pharmaceutical interest. Among them, 2-amino-3-cyanopyridine 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 derivatives (Fig. 1) have been identified as novel IKK-b inhibitors,3 A2A adenosine receptor antagonists,4 potent inhibitor of HIV-1 integrase,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 assistance,8 resulting in unsatisfactorily low yields. However, a straightforward and efficient one-pot reaction by catalysis in mild conditions is still limited. 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 stable, water-tolerated, and recyclable. Several multicomponent condensation 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

of 2-amino-3-cyanopyridine derivatives catalyzed by Yb(PFO)3 in good to excellent yields. 2. Results and discussion According to previous work,1a,3 ethanol was found to be the preferred solvent for this one-pot transformation. The one-pot reaction 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 acetate (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 characterized later to be the desired product 1a) was found according to TLC. The mixture was allowed to cool to room temperature and stand

H N

Br R1 CN N

R

E-mail address: [email protected] (L. Wang). 0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2010.11.102

NH2

CN 2

R

N

NC

NH2 H N 2

CN N

Br O

S O

OH a

⇑ Corresponding author. Tel./fax: +86 21 64253881.

O

b

O

c

Figure 1. (a) novel IKK-b inhibitors; (b) as A2A adenosine receptor antagonists; (c) a potent inhibitor of HIV-1 integrase.

510

J. Tang et al. / Tetrahedron Letters 52 (2011) 509–511

for half an hour. The resultant precipitate was isolated by filtration, washed with cold ethanol carefully, and recrystallized from tetrahydrofuran affording the crude product in 92% yield. The product 1a was afforded in 40% yield after 12 h reaction without catalyst. A variety of Lewis acid catalysts were also examined 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. Ytterbium 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 solvent which provided the highest yield, comparing with some usual organic solvents (e.g., benzene, toluene, dichloromethane and tetrahydrofuran). 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 aromatic 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-substituted aromatic aldehydes tolerated very well for the transformation, 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. According to the above results, our proposed mechanism is depicted in Scheme 1. The reaction may proceed via enamine 3,

Table 2 Scope of one-pot synthesis of 2-amino-3-cyanopyridines catalyzed by Yb(PFO)3

R1 O 1

+

R CHO

CH2R3

NH4OAc / Yb(PFO) 3

CN

ethanol

1 mmol

1 mmol

N

R2

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 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 i-C4H9 CH3 i-C4H9 4-OCH3C6H4 Ph Ph CH3 4-OHC6H4 4-OCH3C6H4 CH3 Ph –(CH2)4– Ph Ph Ph

H CH3 H CH3 H H H H H H H H CH3

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 90 85 92 60c 95 92 88 Trace Trace

H H H

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. c 10 mol % of Yb(PFO)3 was used.

O R2

NH

NH4OAc

R3

R3

2

R

-H2O

Yb

HN

Yb3+

R3

R2 3

Yb O

R1

R1 -H2O

+

NC

CN

malononitrile

R

NH

R3 H PFO

R1

Yb N

R2

NH4OAc

NC

CN 2

H N

R3

CN

R1

4 O

R3

NC H2N

2

Table 1 Synthesis of 2-amino-4,6-diphenyl-nicotinonitrile catalyzed by various catalystsa

R2

CN

+

5

NH

R2

CN

R3

H N

NH2 CN R1

H 6

O H +

+ NC

NH4OAc / ethanol CN

NC

O2(air)

catalyst H2N

N

-H2

R2

N

R3

NH2 CN

R1 1a Entry

Cat.

Amount (mol %)

Time (h)

Yield of 1ab (%)

1 2 3 4 5 6 7 8 9 11

None ZnCl2 SnCl2 AlCl3 YbCl3 Yb(OTf)3 La(OTf)3 Yb(PFO)3 Yb(PFO)3 Yb(PFO)3

/ 20 20 20 5 5 5 5 1 2.5

12 12 12 12 12 12 12 12 12 4

40 38 35 20 60 77 70 92 84 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. c The catalyst was reused for three times.

Scheme 1. Possible mechanism of the one-pot reaction.

which formed from ketone and ammonium acetate, and then activated 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 oxidize 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

J. Tang et al. / Tetrahedron Letters 52 (2011) 509–511

product coming from ortho-substituted aromatic aldehydes, probably 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 derivatives via one-pot reaction of aldehydes, ketones, malononitrile, and ammonium acetate promoted by Yb(PFO)3. This method tolerates most of the substrates, and the catalyst can be recycled and reused at least three times without significant loss of activity.

2.

3.

4.

Acknowledgments 5.

This research was financially supported by the National Nature Science Foundation of China (20672035) and Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences.

6. 7. 8. 9.

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. 11.

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,

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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. (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. 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. 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. 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. Girgis, A. S.; Kalmouch, A.; Hosni, H. M. Amino Acids 2004, 26, 139. Kambe, S.; Saito, K. Synthesis 1980, 366. Shi, F.; Tu, S. J.; Fang, F.; Li, T. J. Arkivoc 2005, 137. (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. Wang, L. M.; Han, J. W.; Sheng, J.; Tian, H.; Fan, Z. Y. Catal. Commun. 2005, 6, 201. (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.