Discovering the Site-Selective Umpolung of Ketones Triggered by Hypervalent Fluoro-Iodanes – Why Investigating Side Reactions Matters!

Abstract

In this account, we describe our journey leading to the discovery of a generally applicable umpolung method for the α-functionalization of ketones. Central to this reaction is the cyclic hypervalent fluoro-iodane, which is mostly known for various alkene functionalizations enabling, for example, the synthesis of fluoro-benzoxazepines, indoles, and ketones. During this work, we encountered α-functionalized ketones as minor side products. This observation prompted us to further investigate this reactivity, thus revealing a directed umpolung of pyridyl ketones by the fluoro-iodane. The key to the success was the unexpected non-covalent interaction between the nucleophile, substrate, and iodane.

1 Introduction

2 Cyclizations Triggered by the Fluorination of Styrenes

3 Umpolung Reactions Facilitated by Hypervalent Iodanes

4 Discovering and Evolving a Fluoro-Iodane-Triggered Regioselective α-Functionalization of Carbonyl Compounds

5 First Investigations on the Nitrogen-Directed Umpolung

6 Conclusion

Key words

hypervalent iodane - fluorination - umpolung of ketones - non-covalent interactions - α-functionalization - halogen bonding

• References

• 1 Dumas J, Péligot E. Ann. Pharm. 1835; 15: 59
• 2 Berger R, Resnati G, Metrangolo P, Weber E, Hulliger J. Chem. Soc. Rev. 2011; 40: 3496
• 3a Jeschke P. ChemBioChem 2004; 5: 570
• 3b Jeschke P. Pest Manage. Sci. 2010; 66: 10
• 3c Jeschke P, Kaiho T. Agrochemicals and Anthelmintics . In Iodine Chemistry and Applications . Kaiho T. John Wiley & Sons; Hoboken: 2015: 439
• 3d Jeschke P. Eur. J. Org. Chem. 2022; 12: e202101513
• 4a Yerien DE, Bonesi S, Postigo A. Org. Biomol. Chem. 2016; 14: 8398
• 4b Ilardi EA, Vitaku E, Njardarson JT. J. Med. Chem. 2014; 57: 2832
• 4c Gillis EP, Eastman KJ, Hill MD, Donnelly DJ, Meanwell NA. J. Med. Chem. 2015; 58: 8315
• 4d Mueller K, Faeh C, Diederich F. Science 2007; 317: 1881
• 4e Wang J, Sanchez-Rosello M, Acena JL, del Pozo C, Sorochinsky AE, Fustero S, Soloshonok VA, Liu H. Chem. Rev. 2014; 114: 2432
• 4f Purser S, Moore PR, Swallow S, Gouverneur V. Chem. Soc. Rev. 2008; 37: 320
• 5 Geary GC, Hope EG, Stuart AM. Angew. Chem. Int. Ed. 2015; 54: 14911
• 6 Banks RE, Mohialdin-Khaffaf SN, Lal GS, Sharif I, Syvret RG. J. Chem. Soc., Chem. Commun. 1992; 595
• 7 Champagne PA, Desroches J, Hamel J.-D, Vandamme M, Paquin J.-F. Chem. Rev. 2015; 115: 9073
• 8a Legault CY, Prevost J. Acta Crystallogr., Sect. E 2012; 68: o1238
• 8b Geary GC, Hope EG, Singh K, Stuart AM. Chem. Commun. 2013; 49: 9263
• 8c Matousek V, Pietrasiak E, Schwenk R, Togni A. J. Org. Chem. 2013; 78: 6763
• 9 Gregorcic A, Zupan M. Bull. Chem. Soc. Jpn. 1977; 50: 517
• 10a Arnold AM, Ulmer A, Gulder T. Chem. Eur. J. 2016; 22: 8728
• 10b Kohlhepp SV, Gulder T. Chem. Soc. Rev. 2016; 45: 6270
• 10c Zhdankin VV, Stang PJ. Chem. Rev. 2008; 108: 5299
• 10d Yoshimura A, Zhdankin VV. Chem. Rev. 2016; 116: 3328
• 10e Li Y, Hari DP, Vita MV, Waser J. Angew. Chem. Int. Ed. 2016; 55: 4436
• 10f Romero RM, Woeste TH, Muniz K. Chem. Asian J. 2014; 9: 972
• 10g Brand JP, Gonzalez DF, Nicolai S, Waser J. Chem. Commun. 2011; 47: 102
• 11 Ilchenko NO, Tasch BO, Szabo KJ. Angew. Chem. Int. Ed. 2014; 53: 12897
• 12 Ilchenko NO, Hedberg M, Szabo KJ. Chem. Sci. 2017; 8: 1056
• 13 Yang S, Shi S, Chen Y, Ding Z. J. Org. Chem. 2021; 86: 14004
• 14 Yuan W, Szabo KJ. Angew. Chem. Int. Ed. 2015; 54: 8533
• 15 Xu K, Yang R, Yang S, Jiang C, Ding Z. Org. Biomol. Chem. 2019; 17: 8977
• 16 Xing B, Ni C, Hu J. Angew. Chem. Int. Ed. 2018; 57: 9896

For selected examples using the cyclic fluoro-iodane 1 as a F-reagent, see:
• 17a Geary GC, Hope EG, Singh K, Stuart AM. RSC Adv. 2015; 5: 16501
• 17b Yuan W, Eriksson L, Szabo KJ. Angew. Chem. Int. Ed. 2016; 55: 8410
• 17c Ilchenko NO, Cortes MA, Szabo KJ. ACS Catal. 2016; 6: 447
• 17d Yang B, Chansaenpak K, Wu H, Zhu L, Wang M, Li Z, Lu H. Chem. Commun. 2017; 53: 3497
• 17e Riley W, Jones AC, Singh K, Browne DL, Stuart AM. Chem. Commun. 2021; 57: 7406
• 18 Ulmer A, Brunner C, Arnold AM, Poethig A, Gulder T. Chem. Eur. J. 2016; 22: 3660

For selected examples on 1,2-aryl shifts in hypervalent iodane chemistry please see:
• 19a Boye AC, Meyer D, Ingison CK, French AN, Wirth T. Org. Lett. 2003; 5: 2157
• 19b Guerard KC, Guerinot A, Bouchard-Aubin C, Menard MA, Lepage M, Beaulieu MA, Canesi S. J. Org. Chem. 2012; 77: 2121
• 19c Prakash O, Pahuja S, Goyal S, Sawhney SN, Moriarty RM. Synlett 1990; 337
• 20 Yan T, Zhou B, Xue X.-S, Cheng J.-P. J. Org. Chem. 2016; 81: 9006
• 21 Zhang J, Szabó KJ, Himo F. ACS Catal. 2017; 7: 1093
• 22 Andries-Ulmer A, Brunner C, Rehbein J, Gulder T. J. Am. Chem. Soc. 2018; 140: 13034
• 23 Cabrele C, Reiser O. J. Org. Chem. 2016; 81: 10109
• 24 Brunner C, Andries-Ulmer A, Kiefl GM, Gulder T. Eur. J. Org. Chem. 2018; 2615
• 25a Ortgies S, Breder A. Org. Lett. 2015; 17: 2748
• 25b Sharma HA, Hovey MT, Scheidt KA. Chem. Commun. 2016; 52: 9283
• 25c Frischmuth A, Knochel P. Angew. Chem. Int. Ed. 2013; 52: 10084
• 26a Liang S, Xu K, Zeng C.-C, Tian H.-Y, Sun B.-G. Adv. Synth. Catal. 2018; 360: 4266
• 26b Liu Y, Dong W. Chin. J. Chem. 2017; 35: 1491
• 26c Guillena G. Alpha-Heteroatom Functionalization of Carbonyl Compounds. In Comprehensive Enantioselective Organocatalysis. Dalko PI. Wiley-VCH; Weinheim: 2013: 757
• 26d Lee H.-E, Kim D, You A, Park MH, Kim M, Kim C. Catalysts 2020; 10: 861
• 27a Seebach D, Corey EJ. J. Org. Chem. 1975; 40: 231
• 27b Seebach D. Angew. Chem. Int. Ed. 1979; 18: 239
• 28 Erian AW, Sherif SM, Gaber HM. Molecules 2003; 8: 793
• 29a Wu Y.-K, Dunbar CR, McDonald R, Ferguson MJ, West FG. J. Am. Chem. Soc. 2014; 136: 14903
• 29b Miyoshi T, Miyakawa T, Ueda M, Miyata O. Angew. Chem. Int. Ed. 2011; 50: 928
• 30 Xu Z, Chen H, Wang Z, Ying A, Zhang L. J. Am. Chem. Soc. 2016; 138: 5515
• 31 Mizukami F, Ando M, Tanaka T, Imamura J. Bull. Chem. Soc. Jpn. 1978; 51: 335
• 32 Arava S, Kumar JN, Maksymenko S, Iron MA, Parida KN, Fristrup P, Szpilman AM. Angew. Chem. Int. Ed. 2017; 56: 2599

For selected examples, see:
• 33a Kieltsch I, Eisenberger P, Togni A. Angew. Chem. Int. Ed. 2007; 46: 754
• 33b Lodaya JS, Koser GF. J. Org. Chem. 1988; 53: 210
• 33c Koser GF, Lodaya JS, Ray DG. III, Kokil PB. J. Am. Chem. Soc. 1988; 110: 2987
• 33d Koser GF, Relenyi AG, Kalos AN, Rebrovic L, Wettach RH. J. Org. Chem. 1982; 47: 2487
• 33e Moriarty RM, Hu H, Gupta SC. Tetrahedron Lett. 1981; 22: 1283
• 33f Lee JC, Kim S, Shin WC. Synth. Commun. 2000; 30: 4271
• 33g Ochiai M, Takeuchi Y, Katayama T, Sueda T, Miyamoto K. J. Am. Chem. Soc. 2005; 127: 12244
• 33h Sanz-Marco A, Martinez-Erro S, Pauze M, Gomez-Bengoa E, Martin-Matute B. Nat. Commun. 2019; 10: 5244
• 33i Mizar P, Wirth T. Angew. Chem. Int. Ed. 2014; 53: 5993
• 33j Shen H, Li J, Liu Q, Pan J, Huang R, Xiong Y. J. Org. Chem. 2015; 80: 7212
• 33k Vita MV, Waser J. Org. Lett. 2013; 15: 3246
• 33l More AA, Pathe GK, Parida KN, Maksymenko S, Lipisa YB, Szpilman AM. J. Org. Chem. 2018; 83: 2442
• 33m Li J, Bauer A, Di Mauro G, Maulide N. Angew. Chem. Int. Ed. 2019; 58: 9816
• 33n Maksymenko S, Parida KN, Pathe GK, More AA, Lipisa YB, Szpilman AM. Org. Lett. 2017; 19: 6312
• 33o Bauer A, Di Mauro G, Li J, Maulide N. Angew. Chem. Int. Ed. 2020; 59: 18208
• 34 Kiefl GM, Gulder T. J. Am. Chem. Soc. 2020; 142: 20577
• 35 Cavallo G, Metrangolo P, Milani R, Pilati T, Priimagi A, Resnati G, Terraneo G. Chem. Rev. 2016; 116: 2478
• 36a Pinto de Magalhaes H, Togni A, Luthi HP. J. Org. Chem. 2017; 82: 11799
• 36b Matousek V, Vaclavik J, Hajek P, Charpentier J, Blastik ZE, Pietrasiak E, Budinska A, Togni A, Beier P. Chem. Eur. J. 2016; 22: 417
• 37 Corbo R, Dutton JL. Coord. Chem. Rev. 2018; 375: 69