Isocyanide Purification: C-2 Silica Cleans Up a Dirty Little Secret

Abstract

EtSiCl₃-treated silica gel, ‘C-2 silica,’ proved exceptionally effective for purifying isocyanides that are otherwise irreversibly adsorbed during silica gel chromatography. Purification of a prototypical isocyanide on several chromatographic matrices provided valuable insight into the requirements for purifying silica-sensitive isocyanides. EtSiCl₃-modified silica proved optimal as the solid phase, providing up to 90% recovery of pure isocyanides that otherwise fail to elute during silica gel purification.

Key words

isocyanide - isonitrile - purification - silica - sensitive

• References

• 1 Chakrabarty S, Choudhary S, Doshi A, Liu FQ, Mohan R, Ravindra MP, Shah D, Yang X, Fleming FF. Adv. Synth. Catal. 2014; 356: 2135
• 2 Walborsky HM. Periasamy MP. Recent Advances in Isocyanide Chemistry in The Chemistry of Functional Groups, Supplement C. Patai S. Rappoport Z. John Wiley and Sons; 835-883 , Chap. 20, 1983
• 3 Isocyanide Chemistry: Applications in Synthesis and Material Science. Nenajdenko VG. Wiley-VCH; Weinheim: 2012
• 4a Zarganes-Tazitzikas T, Dömling A. Org. Chem. Front. 2014; 1: 834
• 4b Rostamnia S. RSC Adv. 2015; 5: 97044
• 5 Determined by searching SciFinder the terms isocyanide and isocyanide for years 2010 onwards.
• 6 Ugi I. Isocyanide Chemistry . Academic Press; New York: 1971
• 7a Nenajdenko VG, Gulevich AV, Sokolova NV, Mironov AV, Balenkova ES. Eur. J. Org. Chem. 2010; 1445
• 7b McClure KF, Abramov YA, Laird ER, Barberia JT, Cai W, Carty TJ, Cortina SR, Danley DE, Dipesa AJ, Donahue KM, Dombroski MA, Elliott NC, Gabel CA, Han S, Hynes TR, LeMotte PK, Mansour MN, Marr ES, Letavic MA, Pandit J, Ripin DB, Sweeney FJ, Tan D, Tao Y. J. Med. Chem. 2005; 48: 5728
• 7c Kotha S, Sreenivasachary N. Bioorg. Med. Chem. Lett. 1998; 8: 257
• 7d Saikachi H, Sasaki H, Kitagawa T. Chem. Pharm. Bull. 1983; 31: 723
• 7e Sasaki T, Eguchi S, Kadata T. J. Org. Chem. 1974; 39: 1239
• 8a Spallarossa M, Wang Q, Riva R, Zhu J. Org. Lett. 2016; 18: 1622
• 8b Szczepaniak G, Urbaniak K, Wierzbicka C, Kosinski K, Skowerski K, Grela K. ChemSusChem 2015; 8: 4139
• 8c Kapeller DC, Hammerschmidt F. Chem. Eur. J. 2009; 15: 5729
• 8d Kobayashi K, Irisawa S, Akamatsu H, Takahashi M, Kitamura T, Tanmatsu M, Morikawa O, Konishi H. Bull. Chem. Soc. Jpn. 1999; 72: 2307
• 8e Kotha S, Brahmachary E, Sreenivasachary N. Tetrahedron Lett. 1998; 39: 4095
• 9 Rikimaru K, Yanagisawa A, Kan T, Fukuyama T. Heterocycles 2007; 73: 403
• 10a El Kaim L, Grimaud L, Schiltz A. Tetrahedron Lett. 2009; 50: 5235
• 10b El Kaim L, Grimaud L, Schiltz A. Org. Biomol. Chem. 2009; 7: 3024
• 10c El Kaim L, Grimaud L, Schiltz A. Synlett 2009; 1401
• 11 Chao A, Montelongo JA, Fleming FF. Org. Lett. 2016; 18: 3062
• 12 No isocyanide is eluted even upon increasing the solvent polarity to 100% EtOAc.
• 13 A 15 mL/min flow rate was used.
• 14 Particle distribution size 2–20 μm. https://www.sorbtech. com/chromatography/adsorbents/polyamide-6/. Accessed 10/18/2018.
• 15 Budarin V, Clark JH, Deswarte FE. I, Hardy JJ. E, Hunt AJ, Kerton FM. Chem. Commun. 2005; 2903
• 16 https://www.silicycle.com/products/functionalized-silica-gels/chromatographic-phases/normal-phases/r35030b (accessed Oct 18, 2018).
• 17 https://www.silicycle.com/products/functionalized-silica-gels/ chromatographic-phases/r38030b (accessed Oct 18, 2018).
• 18 Jost W, Hauck HE, Fischer W. Chromatographia 1986; 21: 375
• 19 Jansma MJ, Hoye TR. Org. Lett. 2012; 14: 4738
• 20a Wang M, Svatunek D, Rohlfing K, Liu Y, Wang H, Giglio B, Yuan H, Wu Z, Li Z, Fox JM. Theranostics 2016; 6: 887
• 20b Zhang H, Dicker K, Xu X, Jia X, Fox JM. ACS Macro Lett. 2014; 3: 727
• 20c Xie X, Li Y, Fox JM. Org. Lett. 2013; 15: 1500
• 20d Boruta DT, Dmitrenko O, Yap GP. A, Fox JM. Chem. Sci. 2012; 3: 1589
• 20e Ma Z, Lu J, Wang X, Chen C. Chem. Commun. 2011; 47: 427
• 20f Blackman ML, Royzen M, Fox JM. J. Am. Chem. Soc. 2008; 130: 13518
• 20g Panne P, Fox JM. J. Am. Chem. Soc. 2007; 129: 22
• 21 Purification on the less polar matrices (Table 1, entries 7–14) were performed with a longer column length, 10 inch compared to 6 inch, than with silica gel, Florisil, or alumina (Table 1, entries 1–2, and 4–5).
• 22 Douglas K. Synth. Commun. 1985; 15: 267
• 23 Preparation following the same procedure with purification on silica gel afforded a 57% yield of 7 and a 47% yield of 8 (cf. 80% and 88%, respectively, for purification on C-2 silica; Table 2, entries 6 and 7): Qiu G, Sornay C, Savary D, Zheng S.-C, Wang Q, Zhu J. Tetrahedron 2018; 74: 6966
• 24 Alwedi E, Lujan-Montelongo JA, Pitta BR, Chao A, Cortés-Mejía R, del Campo JM, Fleming FF. Org. Lett. 2018; 20: 5910
• 25 Alwedi, E.; Fleming, F. F. Unpublished results.