Practical Synthesis of Precursors of Cyclohexyne and 1,2-Cyclohexadiene

Abstract

This study investigated a practical method for regiocontrolled synthesis of precursors of strained cyclohexynes and 1,2-cyclohexadienes, which is a one-pot procedure consisting of a rearrangement of silyl enol ether and subsequent formation of the enol triflates. Triethylsilyl enol ether, derived from cyclohexanone, was treated with a combination of LDA and t-BuOK in n-hexane/THF to encourage the migration of the silyl group to generate an α-silyl enolate. Subsequently, the α-silyl enolate was reacted with Comins’ reagent to yield the corresponding enol triflate. Finally, the α-silylated trisubstituted lithium enolate for the synthesis of 1,2-cyclohexadiene precursor was isomerized in the presence of a stoichiometric amount of water for one hour at room temperature to exclusively provide tetrasubstituted lithium enolate for the synthesis of cyclohexyne precursor in one pot.

Key words

strained molecules - allenes - alkynes - enolate - isomerization - lithiation - rearrangement - solvent effects

• References

• 1a Hoffmann RW. Dehydrobenzene and Cycloalkynes . Academic Press; New York: 1967
• 1b Wittig G. Angew. Chem., Int. Ed. Engl. 1962; 1: 415
• 1c Buchwald SL, Nielsen RB. Chem. Rev. 1988; 88: 1047
• 1d Johnson RP. Chem. Rev. 1989; 89: 1111
• 1e Wenk HH, Winkler M, Sander W. Angew. Chem. Int. Ed. 2003; 42: 502
• 1f Pellissier H, Santelli M. Tetrahedron 2003; 59: 701
• 1g Suzuki N. Synth. Org. Chem., Jpn 2007; 65: 347
• 1h Sletten EM, Bertozzi CR. Angew. Chem. Int. Ed. 2009; 48: 6974
• 1i Gampe CM, Carreira EM. Angew. Chem. Int. Ed. 2012; 51: 3766
• 1j Yoshida S, Hosoya T. Chem. Lett. 2015; 44: 1450
• 2a Yoshida H, Tanino K, Ohshita J, Kunai A. Angew. Chem. Int. Ed. 2004; 43: 5052
• 2b Gampe CM, Boulos S, Carreira EM. Angew. Chem. Int. Ed. 2010; 49: 4092
• 2c Gampe CM, Carreira EM. Angew. Chem. Int. Ed. 2011; 50: 2962
• 2d Devlin AS, Du Bois J. Chem. Sci. 2013; 4: 1059
• 2e Medina JM, McMahon TC, Jiménez-Osés G, Houk KN, Garg NK. J. Am. Chem. Soc. 2014; 136: 14706
• 2f Tlais SF, Danheiser RL. J. Am. Chem. Soc. 2014; 136: 15489
• 2g McMahon TC, Medina JM, Yang Y.-F, Simmons BJ, Houk KN, Garg NK. J. Am. Chem. Soc. 2015; 137: 4082
• 2h Shah TK, Medina JM, Garg NK. J. Am. Chem. Soc. 2016; 138: 4948
• 2i Picazo E, Anthony SM, Giroud M, Simon A, Miller MA, Houk KN, Garg NK. J. Am. Chem. Soc. 2018; 140: 7605
• 3a Moore WR, Moser WR. J. Am. Chem. Soc. 1970; 92: 5469
• 3b Christl M, Schreck M. Angew. Chem., Int. Ed. Engl. 1987; 26: 449
• 3c Barber JS, Styduhar ED, Pham HV, McMahon TC, Houk KN, Garg NK. J. Am. Chem. Soc. 2016; 138: 2512
• 3d Lofstrand VA, West FG. Chem. Eur. J. 2016; 22: 10763
• 3e Barber JS, Yamano MM, Ramirez M, Darzi ER, Knapp RR, Liu F, Houk KN, Garg NK. Nat. Chem. 2018; 10: 953
• 4a Blomquist AT, Liu LH. J. Am. Chem. Soc. 1953; 75: 2153
• 4b Wittig G, Krebs A. Chem. Ber. 1961; 94: 3260
• 4c Wittig G, Pohlke R. Chem. Ber. 1961; 94: 3276
• 4d Franzen V, Joschek H.-I. Liebigs Ann. Chem. 1967; 703: 90
• 4e Wittig G, Hutchison JJ. Liebigs Ann. Chem. 1970; 741: 79
• 4f Agard NJ, Prescher JA, Bertozzi CR. J. Am. Chem. Soc. 2004; 126: 15046
• 4g Codelli JA, Baskin JM, Agard NJ, Bertozzi CR. J. Am. Chem. Soc. 2008; 130: 11486
• 4h Sletten EM, Bertozzi CR. Acc. Chem. Res. 2011; 44: 666
• 5a Orita A, Hasegawa D, Nakano T, Otera J. Chem. Eur. J. 2002; 8: 2000
• 5b Debets MF, van Berkel SS, Schoffelen S, Rutjes F, van Hest JC. M, van Delft FL. Chem. Commun. 2010; 46: 97
• 5c Gordon CG, MacKey JL, Jewett JC, Sletten EM, Houk KN, Bertozzi CR. J. Am. Chem. Soc. 2012; 134: 9199
• 6a Ni R, Mitsuda N, Kashiwagi T, Igawa K, Tomooka K. Angew. Chem. Int. Ed. 2015; 54: 1190
• 6b Igawa K, Aoyama S, Kawasaki Y, Kashiwagi T, Seto Y, Ni R, Mitsuda N, Tomooka K. Synlett 2017; 28: 2110
• 7a Moore WR, Moser WR. J. Org. Chem. 1970; 35: 908
• 7b Harada T, Iwazaki K, Otani T, Oku A. J. Org. Chem. 1998; 63: 9007
• 7c Fujita M, Sakanishi Y, Kim WH, Okuyama T. Chem. Lett. 2002; 31: 908
• 7d Al-Omari M, Banert K, Hagedorn M. Angew. Chem. Int. Ed. 2006; 45: 309
• 7e Yoshida S, Karaki F, Uchida K, Hosoya T. Chem. Commun. 2015; 51: 8745
• 7f Hioki Y, Okano K, Mori A. Chem. Commun. 2017; 53: 2614
• 7g Hioki Y, Yukioka T, Okano K, Mori A. Asian J. Org. Chem. 2018; 7: 1298
• 8 Scardiglia F, Roberts JD. Tetrahedron 1957; 1: 343
• 9 Wittig G, Fritze P. Angew. Chem., Int. Ed. Engl. 1966; 5: 846
• 10a Atanes N, Escudero S, Pérez D, Guitián E, Castedo L. Tetrahedron Lett. 1998; 39: 3039
• 10b Peña D, Iglesias B, Quintana I, Pérez D, Guitián E, Castedo L. Pure Appl. Chem. 2006; 78: 451
• 10c Quintana I, Peña D, Pérez D, Guitián E. Eur. J. Org. Chem. 2009; 5519

Generation of benzyne from 2-trimethylsilylbenzene triflate by fluoride ion:
• 10d Himeshima Y, Sonoda T, Kobayashi H. Chem. Lett. 1983; 12: 1211
• 11a Corey EJ, Rücker C. Tetrahedron Lett. 1984; 25: 4345
• 11b Kuwajima I, Takeda R. Tetrahedron Lett. 1981; 22: 2381
• 12 Inoue K, Nakura R, Okano K, Mori A. Eur. J. Org. Chem. 2018; 3343
• 13 The commercially available LDA solution consists of 20–27% (w/w) LDA, in heptane/THF/ethylbenzene.
• 14a Hoepker AC, Gupta L, Ma Y, Faggin MF, Collum DB. J. Am. Chem. Soc. 2011; 133: 7135
• 14b Reich HJ. Chem. Rev. 2013; 113: 7130
• 15a Comins DL, Dehghani A. Tetrahedron Lett. 1992; 33: 6299
• 15b Comins DL, Dehghani A, Foti CJ, Joseph SP. Org. Synth. 1997; 74: 77
• 16 Prinsell MR, Everson DA, Weix DJ. Chem. Commun. 2010; 46: 5743