A Practical, Large-Scale Synthesis of p-(Difluoroiodo)toluene (p-TolIF₂)

Abstract

p-(Difluoroiodo)toluene (p-TolIF₂) is a versatile fluorinating agent that acts as both a surrogate for elemental fluorine, and as a source of ‘electrophilic’ fluorine. Described here is a detailed three-step synthesis of p-TolIF₂, carried out on a 50 mmol scale, that consistently provides high-quality product that is suitable for long-term storage. The reactions employ inexpensive, readily available starting materials and reagents, and uses the commodity chemical 48% aqueous HF as the source of fluorine atoms.

Key words

hypervalent iodine - p-(difluoroiodo)toluene - fluorination - synthetic methodology - oxidation

• References

• 1a Zhdankin V. Hypervalent Iodine Chemistry: Preparation, Structure, and Synthetic Applications of Polyvalent Iodine Compounds. John Wiley & Sons; Weinheim: 2013
• 1b Yoshimura A, Zhdankin VV. Chem. Rev. 2016; 116: 3328
• 1c Wirth T. Hypervalent Iodine Chemistry 2016
• 2 Weinland RF, Stille W. Justus Liebigs Ann. Chem. 1903; 328: 132
• 3a Lemal DM. Difluoroiodotoluene. In e-EROS. Wiley; New York: 2003
• 3b Murphy GK, Gulder T. Fluorination. In Synthetic Organofluorine Chemistry, Vol. 1. Hu J, Umemoto T. Springer; Berlin: 2018: 1-32
• 4a Hara S, Sekiguchi M, Ohmori A, Fukuhara T, Yoneda N. Chem. Commun. 1996; 1899
• 4b Yoshida M, Fujikawa K, Sato S, Hara S. ARKIVOC 2003; (vi): 36
• 4c Arrica MA, Wirth T. Eur. J. Org. Chem. 2005; 395
• 5 Motherwell WB, Wilkinson JA. Synlett 1991; 191
• 6a Carpenter W. J. Org. Chem. 1966; 31: 2688
• 6b Zhao Z, Racicot L, Murphy GK. Angew. Chem. Int. Ed. 2017; 56: 11620
• 6c Hara S, Nakahigashi J, Ishi-i K, Sawaguchi M, Sakai H, Fukuhara T, Yoneda N. Synlett 1998; 495
• 6d Hara S, Nakahigashi J, Ishi-i K, Fukuhara T, Yoneda N. Tetrahedron Lett. 1998; 39: 2589
• 7 Tao J, Tran R, Murphy GK. J. Am. Chem. Soc. 2013; 135: 16312
• 8 Emer E, Twilton J, Tredwell M, Calderwood S, Collier TL, Liegault B, Taillefer M, Gouverneur V. Org. Lett. 2014; 16: 6004
• 9 Zhou Y, Zhang Y, Wang J. Org. Biomol. Chem. 2016; 14: 10444
• 10a Sinclair GS, Tran R, Tao J, Hopkins WS, Murphy GK. Eur. J. Org. Chem. 2016; 4603
• 10b Zhao Z, Kulkarni KG, Murphy GK. Adv. Synth. Catal. 2017; 359: 2222
• 11a Naumann D, Ruther G. J. Fluorine Chem. 1980; 15: 213
• 11b Ruppert I. J. Fluorine Chem. 1980; 15: 173
• 12 Zupan M, Pollak A. J. Chem. Soc., Chem. Commun. 1975; 715
• 13 Lyalin VV, Orda VV, Alekseev LA, Yagupols LM. Zh. Org. Khim. 1970; 6: 329
• 14 Ye CF, Twamley B, Shreeve JM. Org. Lett. 2005; 7: 3961
• 15 Sarie JC, Thiehoff C, Mudd RJ, Daniliuc CG, Kehr G, Gilmour R. J. Org. Chem. 2017; 82: 11792
• 16a Yoshida M, Yoshikawa S, Fukuhara T, Yoneda N, Hara S. Tetrahedron 2001; 57: 7143
• 16b Hara S, Hatakeyama T, Chen SQ, Ishi-i K, Yoshida M, Sawaguchi M, Fukuhara T, Yoneda N. J. Fluorine Chem. 1998; 87: 189
• 17 Sawaguchi M, Hara S, Nakamura Y, Ayuba S, Fukuhara T, Yoneda N. Tetrahedron 2001; 57: 3315
• 18 Sawaguchi M, Ayuba S, Hara S. Synthesis 2002; 1802
• 19 Zhao XF, Zhang C. Synthesis 2007; 551
• 20 Lucas HJ, Kennedy ER. Org. Synth. 1942; 22: 69
• 21 Lucas HJ, Kennedy ER, Formo MW. Org. Synth. 1942; 22: 70
• 22 We maintained the angled filtration setup while adding solvents for washing, and then slowly rotated it more upright such that the filtrate could be drained through the unclogged portion of the filter funnel.
• 23 This aqueous layer contains extremely toxic hydrofluoric acid. Appropriate protective equipment and handling procedures for safe HF use should be adhered to. This aqueous hydrofluoric acid was quenched using a dilute solution of calcium or magnesium hydroxide.