Glycerol/Hypophosphorous Acid

Tetrahedron Letters 54 (2013) 3215–3218

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Tetrahedron Letters

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Glycerol/hypophosphorous acid: an efﬁcient system solvent-reducing agent for the synthesis of 2-organylselanyl pyridines ⇑ ⇑ Samuel Thurow, Rodrigo Webber, Gelson Perin, Eder J. Lenardão , Diego Alves

Laboratório de Síntese Orgânica Limpa - LASOL, CCQFA, Universidade Federal de Pelotas - UFPel, PO Box 354, 96010-900 Pelotas, RS, Brazil article info abstract

Article history: We describe herein an efficient and simple method to synthesize 2-organylselanyl pyridines by reactions Received 25 February 2013 of 2-chloropyridines with organylselenols, generated in situ by reaction of diorganyl diselenides, using Revised 10 April 2013 glycerol as solvent and hypophosphorous acid (H3PO2) as reducing agent. Using this methodology, a Accepted 15 April 2013 range of selenium substituted pyridines was obtained in high yields. The system solvent-reducing agent Available online 20 April 2013 glycerol/H3PO2 can be easily recovered and reused for five times without loss of efficiency. Ó 2013 Elsevier Ltd. All rights reserved. Keywords: Organoselenium compounds Selenol Pyridines Glycerol Green solvent

Pyridines are among the most found heterocyclic units in phar- 2 maceutically active compounds.1 Pyridine derivatives2 including 1) glycerol R nicotinamide (niacin), nicotine, nicotinamide adenine dinucleotide N2,90ºC r.t. RSe SeR + H3PO2 1 diphosphate (NADP), and pyridoxine (vitamin B6), for example, oc- R2 R N SeR 3 1a-k cupy biological key positions. In addition, pyridine derivatives are 3a-n 4 2) used as agrochemicals (e.g., picloram) and recently in complexes R1 N Cl 5 with magnetic properties. Due to their recognized biological activ- 2a-d ities, there is a continued interest in the synthesis of functionalized pyridines and their derivates. Direct nucleophilic aromatic Scheme 1. General scheme of the reaction. substitution of halopyridines provides an efficient approach for 6 the synthesis of functionalized pyridines. For example, 2-sulfanyl- protocols suffer from long reaction times, the necessity for high pyridines were efficiently synthesized by reaction of 2-halopyri- temperatures and are suitable for a relatively narrow scope of sub- dines (Br and Cl) with arylthiols using water as solvent. This strates. Furthermore, there is still an attention in the developing of protocol was considered inexpensive and environmentally benign simple, selective, and greener methodologies to produce selanyl- 6f and the products were easily isolated. pyridines in high yields. However, in the case of selenium analogues, there are few re- In this context, the development of methodologies employing 7 ports on the preparation of 2-selanyl-substituted pyridines, and recyclable and environmentally friendly solvents has gained much no protocols involving arylselenols (ArSeH) were described. interest recently, because of the extensive use of solvents in almost Organoselenium compounds are attractive molecules due their all of the chemical and pharmaceutical industries, and of the pre- 8 selective reactions and the interest in the synthesis of these com- dicted disappearance of fossil oil.10 Biodegradability, high avail- pounds has increased in the last years because of their biological ability, no flammability, being obtained from renewable sources 9 activities. General methods for the synthesis of 2-selanyl-substi- are among the desirable characteristics of a green solvent.11 With tuted pyridines require the use of selenolate anions or transition- the increase in biodiesel production world-wide, the market satu- metal cross-coupling reactions using diselenides as a coupling ration of glycerol, a side product of biodiesel production, is inevita- 7 partner, specially in copper-catalyzed protocols. Sometimes, these ble.12 The use of glycerol13 and its eutetics14 as a sustainable solvent was recently related and a great number of organic reactions were performed using this solvent. More recently, glycerol ⇑ Corresponding authors. Tel./fax: +55 5332757533. proved to be an efficient and recyclable solvent for the synthesis E-mail addresses: [email protected] (E.J. Lenardão), diego.alves@ufpel. 15 edu.br (D. Alves). of a range of organochalcogenium compounds.

Table 1 Optimization of reaction conditions H3PO2 1) glycerol glycerol

90 °C, 30 min., N2 PhSeSePh +HPO 3 2 N2,90ºC r.t. 1a N SePh PhSeSePh 2) 3a 1a N SePh N Cl 3a 2a N Cl 2a a b Entry H3PO2 (mL) Time (h) Yield (%) 1 1.0 1.5 99 2 0.1 1.5 99 3 0.05 24 75 4 0.01 24 4 5c 0.1 2.0 99 6 — 24 —

a This time include preliminary 30 min of diphenyl diselenide cleavage to in situ formation of benzeneselenol. b Determined by CG–MS analysis. c After generating the benzeneselenol the temperature was allowed to decrease to rt. Then, 2-chloropyridine was added and the stirring remained at rt for additional 1.5 h.

Figure 1. Reuse of system solvent-reducing agent glycerol/H3PO2. In view of the explained above, here we describe the simple synthesis of 2-organylselanyl pyridines by reaction of organyl with a mixture of hexane/ethyl acetate 95:5 (3 Â 5 mL). The upper diselenides with 2-chloropyridines using glycerol as solvent and phase was dried and the solvent evaporated. The inferior, glycerol hypophosphorous acid (H3PO2) as reducing agent (Scheme 1). phase, was dried under vacuum and directly reused in a new reac- Initially, we chose diphenyl diselenide 1a (0.5 mmol) and 2- tion with diphenyl diselenide 1a at 90 °C without the addition of chloropyridine 2a (1.0 mmol) as model substrates to establish more H3PO2. To our satisfaction, after 30 min at this temperature, the best conditions for the reaction using glycerol as solvent and benzeneselenol was formed in situ and reacted with 2-chloropyri- some experiments were preformed to synthesize compound 3a dine 2a at rt, furnishing the corresponding product 3a in 96% yield in satisfactory yield (Table 1). According the literature, diorganyl after 2 h. After this successful experiment, we speculate the possi- diselenides are reduced to the corresponding organyl selenols by ble reuse of the system solvent/reducing agent for additional cycles treatment with H3PO2 and this fact encouraged us to use this (Fig. 1). It was observed that a good level of efﬁciency was main- reducing agent to obtain in situ the nucleophilic selenium species tained even after four reactions. These results showed that the 2- of our reaction.16 phenylselanyl pyridine 3a was obtained in 99%, 96%, 95%, 90%,

Thus, a mixture of diphenyl diselenide 1a and 1.0 mL of H3PO2 and 80% yields after successive cycles. After 5 runs, the efﬁciency (50 wt.% in H2O) in glycerol (0.5 mL) was stirred at 90 °C for of our solvent-reducing agent system decreased and the yield of 30 min under N2 atmosphere to afford in situ the benzeneselenol. compound 3a was only 60% (Fig. 1). After this time, 2-chloropyridine 2a (1.0 mmol) was added in the After that, the versatility of our methodology was evaluated, by reaction vessel and the reaction remained at 90 °C for additional reacting other diaryl diselenides 1b–i with 2-chloropyridine 2a 1 h. Under these reaction conditions, the product 3a was obtained (Table 2). The obtained results reveal that the reaction worked well quantitatively (Table 1, entry 1). This excellent result prompted us with a range of diaryl diselenides tested, affording excellent yields to perform this reaction decreasing the quantity of H3PO2 in the of the products 3b–i (Table 2, entries 2–9). According to the results, reaction. To our satisfaction, the use of 0.1 mL of H3PO2 furnished the reactions are not sensitive to electronic effects in the aromatic the desired product in the same yield after 1.5 h (Table 1, entry ring on diaryl diselenide. Diaryl diselenides containing both elec-

2). When we used 0.05 and 0.01 mL of H3PO2 a great decrease in tron-donating (OMe, Me) or electron-withdrawing groups (Cl, Br, the yield of product 3a was observed. Gratefully, when the reaction F, CF3) gave excellent yields of desired arylselanyl pyridines (Table was performed using 0.1 mL of H3PO2 at room temperature, the 2, entries 2–9). Extending the scope of this methodology, when the corresponding product 3a was obtained in excellent yield after reaction was performed with dibenzyl diselenide 1j or dibutyl 2.0 h (Table 1, entry 5). When the reaction was carried out without diselenide 1k, the respective 2-organylselanyl pyridines 3j and

H3PO2 no product 3a was formed demonstrating the involvement 3k were obtained in high yields. However, for these reactions the of H3PO2 in the reaction (Table 1, entry 6). Analysis of the results temperature of the second step was 90 and 60 °C, respectively (Ta- shown in Table 1 indicated that the best conditions17 were the pre- ble 2, entries 10 and 11). vious reaction of diphenyl diselenide 1a (0.5 mmol) with H3PO2 In addition, under the optimized reaction conditions, the possi- (0.1 mL) in glycerol (0.5 mL) at 90 °C for 30 min under N2 to bility of performing the reaction with other substituted 2-chloro- in situ formation of benzeneselenol. Following, the reaction mix- pyridines 2b–d was also investigated. Thus, reactions of diphenyl ture was cooled to room temperature and 2-chloropyridine diselenide 1a with 3-amino-2-chloropyridine 2b and 2,3-dichloro- (1.0 mmol) was added drop wise and the stirring continued until pyridine 2c gave good yields of desired products (Table 2, entries complete consumption of the starting material. We believe that 12–13). However, when 2,6-dichloropyridine 2d (1.0 mmol) and the benzeneselenol acts as a nucleophilic species in the direct diphenyl diselenide 1a (0.5 mmol) were reacted at 90 °C, both nucleophilic aromatic substitution (SNAr), and the glycerol, a polar products 2,6-bis(phenylselanyl)pyridine 3n and 2-chloro-6-(phe- protic solvent, possibly exhibits an activation of this reaction. A nylselanyl)pyridine were formed in a 68:32 ratio. When the similar situation was described by Sreedhar using thiophenols.6f amount of diphenyl diselenide 2a was increased to 1 mmol and After reaction optimization, a study regarding the recovering the temperature was maintained at 90 °C for all the reaction times and reusing of glycerol was performed. Subsequent to the forma- (steps 1 and 2), only the formation of bis(phenylselanyl)pyridine tion of product 3a, the reaction mixture was diluted and extracted 3n was observed, however in moderate yield (Table 2, entry 14). S. Thurow et al. / Tetrahedron Letters 54 (2013) 3215–3218 3217

Table 2 Scope and variability of reaction

1) glycerol R2 N2,90ºC r.t. RSeSeR + H3PO2 2 1 1a-k R R N SeR 2) 3a-n R1 N Cl 2a-d

Entry Diorganyl diselenide 1 Pyridine 2 Timea (h) Product 3 Yieldb (%)

Se)2

c 1 N Cl 2.0 N Se 96 (87) 1a 2a 3a

Se)2

2 2a 2.5 N Se 90 1b 3b

Se)2

3 2a 2.5 N Se 93 1c 3c

Se)2 4 2a 2.0 N Se 95 3d 1d

Se)2 O

5 O 2a 2.0 N Se 97 1e 3e

Se)2 Cl

6 Cl 2a 2.0 N Se 92 1f 3f

Se)2 Br

7 2a 2.0 96 Br N Se 1g 3g

Se)2 F

8 F 2a 1.5 N Se 96 1h 3h

Se)2

N Se CF3 9 2a 2.0 93 CF 3 3i 1i

Se)2

10 2a 1.5 N Se 93d 1j 3j

Se)2

e 11 1k 2a 4.5 N Se 70 3k

NH2 NH2

12 1a 3.0 87 N Cl N Se 2b 3l Cl Cl

d 13 1a N Cl 2.5 N Se 87 2c 3m

(continued on next page) 3218 S. Thurow et al. / Tetrahedron Letters 54 (2013) 3215–3218

Table 2 (continued)

Entry Diorganyl diselenide 1 Pyridine 2 Timea (h) Product 3 Yieldb (%)

e,f 14 1a Cl N Cl 5.5 Se N Se 44 2d 3n

a For the two-steps (generation of ArSeH followed by reaction with chloropyridines. b Yields are given for isolated products. c Yield in parentheses correspond to reaction performed in 10 mmol scale. d After the cleavage of diorganyl diselenide at 90 °C, the reaction was carried out at 60 °C. e The reaction remained at 90 °C after addition of 2d. f 1 mmol of diphenyl diselenide 1a was used.

In summary, a simple and direct protocol to synthesize 2-orga- J.; Chabaud, B.; Labaudiniere, R.; Christol, H. Organomettalics 1985, 4, 657; (h) nylselanyl pyridines was described by reactions of organic disele- Bhasin, K. K.; Doomra, S.; Kaur, G.; Arora, E.; Singh, N.; Nagpal, Y.; Kumar, R.; Rishu, ; Klapoetke, T. M.; Mehta, S. K. Phosphorus, Sulfur Silicon Relat. Elem. 2008, nides with 2-chloropyridine using glycerol as solvent and H3PO2 183, 992; (i) Freitas, C. S.; Barcellos, A. M.; Ricordi, V. G.; Pena, J. M.; Perin, G.; as reducing agent. Using this methodology, a range of selenium Jacob, R. G.; Lenardão, E. J.; Alves, D. Green Chem. 2011, 13, 2931. substituted pyridines was selectively obtained in high yields. The 8. (a) Alberto, E. E.; Braga, A. L. In Selenium and Tellurium Chemistry—From Small Molecules to Biomolecules and Materials; Derek, W. J., Risto, L., Eds.; Springer: system solvent/reducing agent glycerol/H3PO2 can be recovered Berlin Heidelberg, 2011; (b) Wirth, T. Organoselenium Chemistry: Synthesis and and utilized for further reactions without any pre-treatment. Reactions; Wiley-VCH: Weinheim, 2011; (c) Menezes, P. H.; Zeni, G. Vinyl Selenides. In Patai’s Chemistry of Functional Groups; John Wiley & Sons: Oxford, 2011; (d) Perin, G.; Lenardão, E. J.; Jacob, R. G.; Panatieri, R. B. Chem. Rev. 2009, Acknowledgments 109, 1277; (e) Freudendahl, D. M.; Santoro, S.; Shahzad, S. A.; Santi, C.; Wirth, T. Angew. Chem., Int. Ed. 2009, 48, 8409; (f) Santi, C.; Santoro, S.; Battistelli, B. Curr. We are grateful to CAPES, CNPq (473165/2012-0, 305272/2010- Org. Chem. 2010, 14, 2442; (g) Freudendahl, D. M.; Shahzad, S. A.; Wirth, T. Eur. J. Org. Chem. 2009, 1649. 1), FINEP and FAPERGS (PRONEM 11/2024-9, PqG 11/1045-8) for 9. (a) Parnham, M. J.; Graf, E. Prog. Drug Res. 1991, 36,9; (b) Mugesh, G.; du Mont, the ﬁnancial support. W. W.; Sies, H. Chem. Rev. 2001, 101, 2125; (c) Nogueira, C. W.; Zeni, G.; Rocha, J. B. T. Chem. Rev. 2004, 104, 6255; (d) Alberto, E. E.; Nascimento, V.; Braga, A. L. J. Braz. Chem. Soc. 2010, 21, 2032; (e) Nogueira, C. W.; Rocha, J. B. T. J. Braz. Supplementary data Chem. Soc. 2010, 21, 2055; (f) Nogueira, C. W.; Rocha, J. B. T. Arch. Toxicol. 2011, 85, 1313. Supplementary data associated with this article can be found, 10. (a) Handy, S. T. Chem. Eur. J. 2003, 9, 2938; (b) Leitner, W. Green Chem. 2007, 9, 923; (c) Horváth, I. T. Green Chem. 2008, 1024,10; (d) Giovanni, I.; Silke, H.; in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013. Dieter, L.; Burkhard, K. Green Chem. 2006, 1051,8; (e) Clark, J. H. Green Chem. 04.057. 1999, 1,1. 11. Nelson, W. M. Green Solvents for Chemistry: Perspectives and Practice; Oxford University Press: Oxford, 2003. References and notes 12. Johnson, D. T.; Taconi, K. A. Environ. Prog. 2007, 26, 338. 13. (a) Gu, Y.; Jèrôme, F. Green Chem. 2010, 12, 1127; (b) Bakhrou, N.; Lamaty, F.; 1. For examples, see: (a) Thurkauf, A.; Yuan, J.; Chen, X.; He, X. S.; Wasley, J. W. S.; Martinez, J.; Colacino, E. Tetrahedron Lett. 2010, 51, 3935; (c) Li, M.; Chen, C.; Hutchison, A.; Woodruff, K. H.; Meade, R.; Hoffman, D. C.; Donovan, H.; Jones- He, F.; Gu, Y. Adv. Synth. Catal. 2010, 352, 519; (d) Francos, J.; Cadierno, V. Green Hertzog, D. K. J. Med. Chem. 1997, 40,1; (b) Carey, J. S.; Laffan, D.; Thomson, C.; Chem. 2010, 12, 1552; (e) Silveira, C. C.; Mendes, S. R.; Líbero, F. M.; Lenardão, E. Williams, M. T. Org. Biomol. Chem. 2006, 4, 2337; (c) Holladay, M. W.; Wasicak, J.; Perin, G. Tetrahedron Lett. 2009, 50, 6060; (f) Radatz, C. S.; Silva, R. B.; Perin, J. T.; Lin, N.-H.; He, Y.; Ryther, K. B.; Bannon, A. W.; Buckley, M. J.; Kim, D. J. B.; G.; Lenardão, E. J.; Jacob, R. G.; Alves, D. Tetrahedron Lett. 2011, 52, 4132; (g) Decker, M. W.; Anderson, D. J.; Campbell, J. E.; Kuntzweiler, T. A.; Donnelly- Wolfson, A.; Dlugy, C. Chem. Pap. 2007, 61, 228; (h) Wolfson, A.; Litvak, G.; Roberts, D. L.; Piattoni-Kaplan, M.; Briggs, C. A.; Williams, M.; Arneric, S. P. J. Shotland, C.; Dlugy, Y.; Tavor, D. Ind. Crops Prod. 2009, 30,78; (i) Wolfson, A.; Med. Chem. 1998, 41, 407. Dlugy, C.; Shotland, Y. Environ. Chem. Lett. 2007, 5,67. 2. (a) Pestka, S. In Antibiotics; Corcoran, J. W., Hahn, F. E., Eds.; Springer: New York, 14. Abbott, A. P.; Harris, R. C.; Ryder, K. S.; D’Agostino, C.; Gladden, L. F.; Mantle, M. 1975; vol. 3, p 480; (b) Lewis, A. M.; Ough, M.; Hinkhouse, M. M.; Tsao, M.-S.; D. Green Chem. 2011, 13,82. Oberley, L. W.; Cullen, J. J. Mol. Carcinog. 2005, 43, 215; (c) Ken, W. R.; Soti, R.; 15. (a) Alves, D.; Sachini, M.; Jacob, R. G.; Lenardão, E. J.; Contreira, M. E.; Rittschof, D. Biomol. Eng. 2003, 20, 355; (d) Friesen, R. W.; Brideau, C.; Chan, C. Savegnago, L.; Perin, G. Tetrahedron Lett. 2011, 52, 133; (b) Lenardão, E. J.; Silva, C.; Charleson, S.; Deschênes, D.; Dubé, D.; Ethier, D.; Fortin, R.; Gauthier, J. Y.; M. S.; Sachini, M.; Lara, R. G.; Jacob, R. G.; Perin, G. ARKIVOC 2009, xi, 221; (c) Girard, Y.; Gordon, R.; Greig, G. M.; Riendeau, D.; Savoie, C.; Wang, Z.; Wong, E.; Ricordi, V. G.; Freitas, C. S.; Perin, G.; Lenardão, E. J.; Jacob, R. G.; Savegnago, L.; Visco, D.; Xu, L. J.; Young, R. N. Bioorg. Med. Chem. Lett. 1998, 8, 2777; (e) Quirk, Alves, D. Green Chem. 2012, 1030,14; (d) Perin, G.; Mello, L. G.; Radatz, C. S.; J.; Thornton, M.; Kirkpatrick, P. Nature 2003, 2, 769; (f) Capdeville, R.; Savegnago, L.; Alves, D.; Jacob, R. G.; Lenardão, E. J. Tetrahedron Lett. 2010, 51, Buchdunger, E.; Zimmermann, J.; Matter, A. Nature 2002, 1, 493; (g) Chung, J. 4354; (e) Cabrera, D. M. L.; Líbero, F. M.; Alves, D.; Perin, G.; Lenardão, E. J.; Y. L.; Cvetovich, R. J.; McLaughlin, M.; Amato, J.; Tsay, F.-R.; Jensen, M.; Jacob, R. G. Green Chem. Lett. Rev. 2012, 5, 329; (f) Gonçalves, L. C.; Fiss, G. F.; Weissman, S.; Zewge, D. J. Org. Chem. 2006, 71, 8602. Perin, G.; Alves, D.; Jacob, R. G.; Lenardão, E. J. Tetrahedron Lett. 2010, 51, 6772. 3. Schlosser, M.; Mongin, F. Chem. Soc. Rev. 2007, 36, 1161. 16. (a) Günther, W. H. H. J. Org. Chem. 1966, 31, 1202; (b) Salmond, W. G.; Barta, M. 4. Henry, G. D. Tetrahedron 2004, 60, 6043. A.; Cain, A. M.; Sobala, M. C. Tetrahedron Lett. 1977, 20, 1683; (c) Comasseto, J. 5. An, G.; Yuan, B.; Tao, J.; Cui, A.; Kou, H. Inorg. Chim. Acta 2012, 387, 401. V.; Petragnani, N. J. Organomet. Chem. 1978, 152, 295. 6. (a) Katritzky, A. R.; Pozharskii, A. F. Handbook of Heterocyclic Chemistry, 2nd ed.; 17. General procedure for the synthesis of 2-organylselanyl pyridines 3a–n: To a 5 mL Pergamon: Oxford, 2000; (b) Eicher, T.; Hauptmann, S. The Chemistry of round-bottomed ﬂask containing a solution of appropriate diorganyl

Heterocycles, 2nd ed.; Wiley, 2003; (c) Cheng, Y. Tetrahedron 2002, 58, 4931; (d) diselenide 1a–k (0.5 mmol) in glycerol (0.5 mL) under N2 atmosphere, was McDonald, J. W.; Le Bleu, R. E.; Quin, L. D.; Bradsher, C. K. J. Org. Chem. 1961, 26, added H3PO2 50 wt % in H2O (0.1 mL). The resulting solution was stirred for 4944; (e) Tundo, P.; Anastas, P.; Black, D. S.; Breen, J.; Collins, T.; Memoli, S.; 30 min at 90 °C, when its color changes from yellow to colorless. After this Miyamoto, J.; Polyakoff, M.; Tumas, W. Pure Appl. Chem. 2000, 72, 1207; (f) time, the reaction was cooled to room temperature and the corresponding 2- Sreedhar, B.; Reddy, P. S.; Reddy, M. A. Synthesis 2009, 1732. chloropyridine 2a–d (1.0 mmol) was added and the mixture was stirred for the 7. (a) Varala, R.; Ramu, E.; Adapa, S. R. Bull. Chem. Soc. Jpn. 2006, 79, 140; (b) time indicated in Table 2. After that, the reaction mixture was received in

Dandapat, A.; Korupalli, C.; Prasad, D. J. C.; Singh, R.; Sekar, G. Synthesis 2011, water (20 mL), extracted with ethyl acetate (3 Â 5 mL), dried over MgSO4, and 2297; (c) Li, Y.; Wang, H.; Li, X.; Chen, T.; Zhao, D. Tetrahedron 2010, 66, 8583; concentrated under vacuum. The residue was puriﬁed by column (d) Taniguchi, N.; Onami, T. J. Org. Chem. 2004, 69, 915; (e) Zhang, Y.; Guo, H. chromatography on silica gel using ethyl acetate/hexanes as the eluent. Heteroatom Chem. 2001, 12, 539; (f) Tiecco, M.; Testaferri, L.; Tingoli, M.; Chianelli, D.; Bartoli, D.; Balducci, R. Tetrahedron 1988, 44, 4883; (g) Cristau, H.