Chlorination of Conjugated Nitroalkenes with PhICl₂ and SO₂Cl₂ for the Synthesis of α-Chloronitroalkenes

Abstract

Chlorination of conjugated nitroalkenes with iodobenzene dichloride or sulfuryl chloride to give target α-chloronitroalkenes in good yields is described. Details of the procedure depend on the donating ability of the nitroalkene substituents. The activity of the described chlorinating agents increases in order ‘PhICl₂/Py’ < ‘SO₂Cl₂’ < ‘SO₂Cl₂/HCl’ with the former producing the best yields for highly donating substrates and the latter for non-activated groups. An autocatalytic role of hydrogen chloride and the chemoselectivity of chlorination were also demonstrated.

Key words

nitroalkenes - halogenation - chlorination - nitro compounds - chemoselectivity

• References

• 1a Ono N. The Nitro Group in Organic Synthesis. Wiley; New York: 2001
• 1b Sukhorukov AY, Sukhanova AA, Zlotin SG. Tetrahedron 2016; 72: 6191
• 1c Ballini R, Marcantoni E, Petrini M. Nitroalkenes as Amination Tools. In Amino Group Chemistry: From Synthesis to the Life Sciences. Ricci A. Wiley; Weinheim: 2008: 93
• 1d Ballini R, Araujo N, Gil MV, Roman E, Serrano J. Chem. Rev. 2013; 113: 3493
• 1e Nair DK, Kumar T, Namboothiri IN. N. Synlett 2016; 27: 2425
• 2a Soengas RG, Acurcio RC, Silva AM. S. Eur. J. Org. Chem. 2014; 6339
• 2b Motornov VA, Ioffe SL, Tabolin AA. In Targets in Heterocyclic Systems, Vol. 23. Attanasi OA, Merino P, Spinelli D. Italian Chemical Society; Rome: 2019: 237-260
• 2c Politanskaya LV, Selivanova GA, Panteleeva EV, Tretyakov EV, Platonov VE, Nikul’shin PV, Vinogradov AS, Zonov YV, Karpov VM, Mezhenkova TV, Vasilyev AV, Koldobskii AB, Shilova OS, Morozova SM, Burgart YV, Shchegolkov EV, Saloutin VI, Sokolov VB, Aksinenko AY, Nenajdenko VG, Moskalik MY, Astakhova VV, Shainyan BA, Tabolin AA, Ioffe SL, Muzalevskiy VM, Balenkova ES, Shastin AV, Tyutyunov AA, Boiko VE, Igumnov SM, Dilman AD, Adonin NY, Bardin VV, Masoud SM, Vorobyeva DV, Osipov SN, Nosova EV, Lipunova GN, Charushin VN, Prima DO, Makarov AG, Zibarev AV, Trofimov BA, Sobenina LN, Belyaeva KV, Sosnovskikh VY, Obydennov DL, Usachev SA. Russ. Chem. Rev. 2019; 88: 425 ; Usp. Khim. 2019, 88, 425
• 3a Motornov VA, Tabolin AA, Novikov RA, Nelyubina YV, Ioffe SL, Smolyar IS, Nenajdenko VG. Eur. J. Org. Chem. 2017; 6851
• 3b Jana S, Adhikari S, Cox MR, Roy S. Chem. Commun. 2020; 56: 1871
• 4a Motornov VA, Tabolin AA, Nelyubina YV, Nenajdenko VG, Ioffe SL. Org. Biomol. Chem. 2019; 17: 1442
• 4b Motornov VA, Tabolin AA, Nelyubina YV, Nenajdenko VG, Ioffe SL. Org. Biomol. Chem. 2020; 18: 1436
• 5a Aldoshin AS, Tabolin AA, Ioffe SL, Nenajdenko VG. Eur. J. Org. Chem. 2019; 4384
• 5b Vara BA, Johnston JN. J. Am. Chem. Soc. 2016; 138: 13794
• 6a Bauvois B, Puiffe M.-L, Bongui J.-B, Paillat S, Monneret C, Dauzonne D. J. Med. Chem. 2003; 46: 3900
• 6b Pechalrieu D, Dauzonne D, Arimondo PB, Lopez M. Eur. J. Med. Chem. 2020; 186: 111829
• 7 Deng X, Liang JT, Mani NS. Eur. J. Org. Chem. 2014; 410
• 8 Jasinski R, Mikulska M, Koifman O, Baranski A. Chem. Heterocycl. Compd. 2013; 49: 1188 ; In Russian: Khim. Geterotsikl. Soedin. 2013, 1275
• 9a Raut VS, Marion J, Vanthuyne N, Roussel C, Constantieux T, Bressy X, Bonne D, Rodriguez J. J. Am. Chem. Soc. 2017; 139: 2140
• 9b Bao X, Rodriguez J, Bonne D. Chem. Sci. 2020; 11: 403
• 9c Becerra D, Raimondi W, Dauzonne D, Constantieux T, Bonne D, Rodriguez J. Synthesis 2017; 49: 195
• 9d Raimondi W, Dauzonne D, Constantieux T, Bonne D, Rodriguez J. Eur. J. Org. Chem. 2012; 6119
• 9e Dauzonne D, Royer R. Synthesis 1988; 339
• 10a Huang K, Ma Q, Shen X, Gong L, Meggers E. Asian J. Org. Chem. 2016; 5: 1198
• 10b Dauzonne D, Josien H, Demerseman P. Synthesis 1992; 309
• 11a Ganesh M, Namboothiri IN. N. Tetrahedron 2007; 63: 11973
• 11b Yu S.-W, Zhao S.-H, Chen H, Xu X.-Y, Yuan W.-C, Zhang X.-M. ChemistrySelect 2018; 3: 4827
• 11c Romashov LV, Khomutova YA, Danilenko VM, Ioffe SL, Lesiv AV. Synthesis 2010; 407

For the synthesis of α-fluoronitroalkenes, see:
• 12a Motornov VA, Muzalevskiy VM, Tabolin AA, Novikov RA, Nelyubina YV, Nenajdenko VG, Ioffe SL. J. Org. Chem. 2017; 83: 5274
• 12b Opekar S, Pohl R, Beran P, Rulisek L, Beier P. Chem. Eur. J. 2014; 20: 1453

For selected rare examples of α-iodonitroalkenes, see:
• 12c Bresser T, Knochel P. Angew. Chem. Int. Ed. 2011; 50: 1914 ; Angew. Chem. 2011, 123, 1954
• 12d Tokumitsu T, Hayashi T. J. Org. Chem. 1985; 50: 1547
• 13 Carroll FI, Kepler JA. Can. J. Chem. 1966; 44: 2909
• 14 Kim JN, Son JS, Lee HJ, Jung KS. Synth. Commun. 1997; 27: 1885
• 15 Liu L, Zhang-Negrerie D, Du Y, Zhao K. Org. Lett. 2014; 16: 436
• 16a Dauzonne D, Demerseman P. Synthesis 1990; 66
• 16b Dauzonne D, Royer R. Synthesis 1987; 1020
• 17a Fang W.-Y, Ravindar L, Rakesh KP, Manukumar HM, Shantharam CS, Alharbi NS, Qin H.-L. Eur. J. Med. Chem. 2019; 173: 117
• 17b Smith BR, Eastman CM, Njardarson JT. J. Med. Chem. 2014; 57: 9764
• 18a Steinhilber D, Schubert-Zsilavecz M. Pharm. Unserer Zeit 2007; 36: 108
• 18b Wilson T, Brown PJ, Sternbach DD, Henke BR. J. Med. Chem. 2000; 43: 527
• 18c Liu Z.-M, Hu M, Chan P, Tomlinson B. Expert Opin. Invest. Drugs 2015; 24: 611
• 18d Giembycz MA. Expert Opin. Invest. Drugs 2001; 10: 1361
• 18e Card GL, England BP, Suzuki Y, Fong D, Powell B, Lee B, Luu C, Tabrizizad M, Gillette S, Ibrahim PN, Artis DR, Bollag G, Milburn MV, Kim SH, Schlessinger J, Zhang KY. J. Structure 2004; 12: 2233

For chloronium cations, see:
• 19a Olah GA, Westerman PW, Melby EG, Mo YK. J. Am. Chem. Soc. 1974; 96: 3565
• 19b Ohta BK, Hough RE, Schubert JW. Org. Lett. 2007; 9: 2317

For Ph₃PO-promoted dichlorination of alkenes with SO₂Cl₂, see:
• 19c Zeng X, Gong C, Zhang J, Xie J. RSC Adv. 2016; 6: 85182
• 20 We can also note that hydrolysis of SO₂Cl₂ (e.g., by traces of water or alcohols, that are often used for the crystallization of aromatic nitroalkenes) should result in release of HCl, thus activating the reaction.

For activation of halogenating agents, see for example:
• 21a Galabov B, Nalbantova D, Schleyer PV. R, Schaefer HF. III. Acc. Chem. Res. 2016; 49: 1191
• 21b Cresswell AJ, Eey ST.-C, Denmark SE. Angew. Chem. Int. Ed. 2015; 54: 15642 ; Angew. Chem. 2015, 127, 15866
• 22a Treatment of substrate 1t with PhICl₂ (1.2 equiv) according to Method A resulted in a mixture of 1t and 2k in ca. 1:1 ratio (¹H NMR and GC-MS). Method B (1.2 equiv of SO₂Cl₂) gave monochloro- and dichloro-product (2k) in 2:1 ratio.
• 22b Treatment of substrate 1u with PhICl₂ (1.2 equiv) according to Method A resulted in predominant monochlorination of the aromatic ring. 2.4 equiv (overnight reaction) gave products 4 and 5 in ca. 1:1 ratio.
• 23 Zhao X.-F, Zhang C. Synthesis 2007; 551
• 24 Dauzonne D, Folleas B, Martinez L, Chabot GG. Eur. J. Med. Chem. 1997; 32: 71