CC BY 4.0 · SynOpen 2018; 02(03): 0234-0239
DOI: 10.1055/s-0037-1610361
letter
Copyright with the author

(Sila)Difluoromethylation of Fluorenyllithium with CF3H and CF3TMS

Kenichi Maruyama
,
Daichi Saito
,
Koichi Mikami*
Financial support was provided by JST ACT-C Grant Number JPMJCR12Z7 and JSPS KAKENHI Grant Number 26620078. We thank TOSOH F-TECH, INC. for the gift of CF3H and CF3TMS. We are grateful to Dr. Kohsuke Aikawa for his useful discussions and suggestions.
Further Information

Publication History

Received: 11 April 2018

Accepted: 25 May 2018

Publication Date:
19 July 2018 (online)


Dedicated to Professor V. Snieckus on the occasion of his 80th birthday.

Abstract

Difluoromethylation of the C9-H site of the fluorene ring using lithium base and fluoroform (CF3H), which is one of the most cost-effective difluoromethylating reagents, is attained to give difluoromethylated fluorenes with an all-carbon quaternary center. The Ruppert–Prakash reagent (CF3TMS) can also be applied to the present reaction system, providing siladifluoromethylated fluorenes that can be utilized for sequential carbon–carbon bond-forming reactions through activation of the silyl group.

Supporting Information

 
  • References and Notes

    • 1a Müller K. Faeh C. Diederich F. Science 2007; 317: 1881
    • 1b Hagmann WK. J. Med. Chem. 2008; 51: 4359
    • 1c Ojima I. Fluorine in Medicinal Chemistry and Chemical Biology . Wiley-Blackwell; Chichester U. K.: 2009
    • 1d Xing L. Blakemore DC. Narayanan A. Unwalla R. Lovering F. Denny RA. Zhou H. Bunnage ME. ChemMedChem 2015; 10: 715
    • 1e O’Hagan D. Deng H. Chem. Rev. 2015; 115: 634
    • 1f Tirotta I. Dichiarante V. Pigliacelli C. Cavallo G. Terraneo G. Bombelli FB. Metrangolo P. Resnati G. Chem. Rev. 2015; 115: 1106

      For reviews, see:
    • 2a Charpentier J. Fruh N. Togni A. Chem. Rev. 2015; 115: 650
    • 2b Yang X. Wu T. Phipps RJ. Toste FD. Chem. Rev. 2015; 115: 826
    • 2c Sugiishi T. Amii H. Aikawa K. Mikami K. Beilstein J. Org. Chem. 2015; 11: 2661
    • 2d Liang T. Neumann CN. Ritter T. Angew. Chem. Int. Ed. 2013; 52: 8214
    • 2e Tomashenko OA. Grushin VV. Chem. Rev. 2011; 111: 4475
    • 2f Nie J. Guo H.-C. Cahard D. Ma J.-A. Chem. Rev. 2011; 111: 455
    • 3a Zafrani Y. Yeffet D. Sod-Moriah G. Berliner A. Amir D. Marciano D. Gershonov E. Saphier S. J. Med. Chem. 2017; 60: 797
    • 3b Sessler CD. Rahm M. Becker S. Goldberg JM. Wang F. Lippard SJ. J. Am. Chem. Soc. 2017; 139: 9325

      For reviews, see:
    • 4a Hu J. Wang F. Chem. Commun. 2009; 7465
    • 4b Hu J. J. Fluorine Chem. 2009; 130: 1130
    • 4c Liu Y.-L. Yu J.-S. Zhou J. Asian J. Org. Chem. 2013; 2: 194
    • 4d Ni C. Hu J. Synthesis 2014; 46: 842
    • 4e Chen B. Vicic D. Top. Organomet. Chem. 2014; 52: 113
    • 4f Ni C. Hu M. Hu J. Chem. Rev. 2015; 115: 765
    • 4g Belhomme M.-C. Besset T. Poisson T. Pannecoucke X. Chem. Eur. J. 2015; 21: 12836
    • 4h Rong J. Ni C. Hu J. Asian J. Org. Chem. 2017; 6: 139
    • 5a Singh RP. Shreeve JM. Synthesis 2002; 2561
    • 5b Kirk KL. Org. Process Res. Dev. 2008; 12: 305
    • 5c Umemoto T. Singh RP. Xu Y. Saito N. J. Am. Chem. Soc. 2010; 132: 18199
    • 5d Fujimoto T. Becker F. Ritter T. Org. Process Res. Dev. 2014; 18: 1041

      Selected reports for metal-mediated or -catalyzed difluoromethylations of aryl halides, see:
    • 6a Fujikawa K. Fujioka Y. Kobayashi A. Amii H. Org. Lett. 2011; 13: 5560
    • 6b Fier PS. Hartwig JF. J. Am. Chem. Soc. 2012; 134: 5524
    • 6c Prakash GK. S. Ganesh SK. Jones J.-P. Kulkarni A. Masood K. Swabeck JK. Olah GA. Angew. Chem. Int. Ed. 2012; 51: 12090
    • 6d Gu Y. Leng X.-B. Shen Q. Nat. Commun. 2014; 5: 5405
    • 6e Xu L. Vicic DA. J. Am. Chem. Soc. 2016; 138: 2536
    • 6f Serizawa H. Ishii K. Aikawa K. Mikami K. Org. Lett. 2016; 18: 3686
    • 6g Aikawa A. Serizawa H. Ishii K. Mikami K. Org. Lett. 2016; 18: 3690
    • 6h Bour JR. Kariofillis SK. Sanford MS. Organometallics 2017; 36: 1220
    • 6i Lu C. Gu Y. Wu J. Gu Y. Shen Q. Chem. Sci. 2017; 8: 4848

      For reviews, see:
    • 7a Han W. Haodong YL. Tang H. Liu H. J. Fluorine Chem. 2012; 140: 7
    • 7b Zhang C. ARKIVOC 2017; 67
    • 8a Shono T. Ishifune M. Okada T. Kashimura S. J. Org. Chem. 1991; 56: 2
    • 8b Barhdadi R. Troupel M. Périchon J. Chem. Commun. 1998; 1251
    • 8c Folléas B. Marek I. Normant J.-F. Saint-Jalmes L. Tetrahedron Lett. 1998; 39: 2973
    • 8d Russell J. Roques N. Tetrahedron 1998; 54: 13771
    • 8e Folléas B. Marek I. Normant J.-F. Saint-Jalmes L. Tetrahedron 2000; 56: 275
    • 8f Large S. Roques N. Langlois BR. J. Org. Chem. 2000; 65: 8848
    • 8g Billard T. Bruns S. Langlois BR. Org. Lett. 2000; 2: 2101
    • 8h Langlois BR. Billard T. Synthesis 2003; 185
    • 8i Langlois BR. Billard T. ACS Symp. Ser. 2005; 911: 57
    • 8j Popov I. Lindeman S. Daugulis O. J. Am. Chem. Soc. 2011; 133: 9286
    • 8k Zanardi A. Novikov MA. Martin E. Benet-Buchholz J. Grushin VV. J. Am. Chem. Soc. 2011; 133: 20901
    • 8l Prakash GK. S. Jog PV. Batamack PT. D. Olah GA. Science 2012; 338: 1324
    • 8m Novák P. Lishchynskyi A. Grushin VV. Angew. Chem. Int. Ed. 2012; 51: 7767
    • 8n Kawai H. Yuan Z. Tokunaga E. Shibata N. Org. Biomol. Chem. 2013; 11: 1446
    • 8o Takemoto S. Grushin VV. J. Am. Chem. Soc. 2013; 135: 16837
    • 8p Zhang Y. Fujiu M. Serizawa H. Mikami K. J. Fluorine Chem. 2013; 156: 367
    • 8q van der Born D. Herscheid JD. M. Orru RV. A. Vugts DJ. Chem. Commun. 2013; 4018
    • 8r Lishchynskyi A. Novikov MA. Martin E. Escudero-Adán EC. Novák P. Grushin VV. J. Org. Chem. 2013; 78: 11126
    • 8s Miloserdov FM. Grushin VV. J. Fluorine Chem. 2014; 167: 105
    • 8t Mazloomi Z. Bansode A. Benavente P. Lishchynskyi A. Urakawa A. Grushin VV. Org. Process Res. Dev. 2014; 18: 1020
    • 8u Konovalov AI. Lishchynskyi A. Grushin VV. J. Am. Chem. Soc. 2014; 136: 13410
    • 8v Lishchynskyi A. Berthon G. Grushin VV. Chem. Commun. 2014; 10237
    • 8w van der Born D. Sewing C. Herscheid JD. M. Windhorst AD. Orru RV. A. Vugts DJ. Angew. Chem. Int. Ed. 2014; 53: 11046
    • 8x Okusu S. Hirano K. Tokunaga E. Shibata N. ChemistryOpen 2015; 4: 581
    • 8y He L. Tsui GC. Org. Lett. 2016; 18: 2800
    • 8z Yang X. He L. Tsui GC. Org. Lett. 2017; 19: 2446
    • 8aa He L. Yang X. Tsui GC. J. Org. Chem. 2017; 82: 6192
    • 9a Iida T. Hashimoto R. Aikawa K. Ito S. Mikami K. Angew. Chem. Int. Ed. 2012; 51: 9535
    • 9b Honda K. Harris TV. Hatanaka M. Morokuma K. Mikami K. Chem. Eur. J. 2016; 22: 8796
    • 9c Aikawa K. Maruyama K. Honda K. Mikami K. Org. Lett. 2015; 17: 4882
    • 9d Mikami K. Tomita Y. Itoh Y. Angew. Chem. Int. Ed. 2010; 49: 3819
    • 9e Aikawa K. Maruyama K. Nitta J. Hashimoto R. Mikami K. Org. Lett. 2016; 18: 3354

      Difluoromethylations with fluoroform reported by other groups:
    • 10a Riofski MV. Hart AD. Colby DA. Org. Lett. 2013; 15: 208
    • 10b Thomoson CS. Dolbier Jr WR. J. Org. Chem. 2013; 78: 8904
    • 10c Thomoson CS. Wang L. Dolbier WR. J. Fluorine Chem. 2014; 168: 34
    • 10d Okusu S. Tokunaga E. Shibata N. Org. Lett. 2015; 17: 3802
  • 11 Hashimoto R. Iida T. Aikawa K. Ito S. Mikami K. Chem. Eur. J. 2014; 20: 2750
    • 12a Prakash GK. S. Yudin AK. Chem. Rev. 1997; 97: 757
    • 12b Prakash GK. S. Mandal M. J. Fluorine Chem. 2001; 112: 123
    • 12c Liu X. Xu C. Wang M. Liu Q. Chem. Rev. 2015; 115: 683
  • 13 Typical Procedure for Difluoromethylation with CF3HTo a solution of 9-phenyl-9H-fluorene 1a (0.10 mmol, 24.2 mg) in THF (1.0 mL) was added n-butyllithium solution (1.6 M in hexane, 0.11 mmol, 69 μL) at –78 °C. After stirring for 5 minutes at the same temperature, fluoroform (0.20 mmol, 4.5 mL) was bubbled slowly into the mixture via a gas-tight syringe. After stirring for 1 h at –78 °C, the reaction was quenched with water. The organic layer was extracted with diethyl ether, washed with brine, and dried over anhydrous MgSO4. After filtration, the solvent was removed under reduced pressure. The NMR yield was determined by using benzotrifluoride (BTF) as an internal standard. The residue was purified by silica-gel column chromatography (hexane/ethyl acetate, 50:1 as eluent) to afford 2a (44% NMR yield, 37% isolated yield) as a colorless liquid.Compound 2a: 1H NMR (300 MHz, CDCl3): δ = 7.81(d, J = 7.6 Hz, 2 H), 7.50–7.44 (m, 4 H), 7.35–7.26 (m, 7 H), 6.12 (t, J H–F = 55.5 Hz, 1 H); 13C NMR (75 MHz, CDCl3): δ = 145.2 (t, J C–F = 3.2 Hz), 141.3 (s), 138.5 (s), 128.8 (s), 128.6 (s), 127.9 (s), 127.6 (s), 127.4 (s), 126.6 (s), 120.2 (s), 117.7 (t, J C–F = 248.7 Hz), 62.5 (t, J C–F = 19.6 Hz); 19F NMR (282 MHz, CDCl3): δ = –119.3 (d, J H–F = 55.2 Hz, 2 F); FTIR (neat): 3062, 3037, 2961, 2928, 1497, 1450, 1376, 1128, 1064, 734 cm–1; HRMS (APCI-TOF): m/z [M+H]+ calcd for C20H15F2: 293.1142; found: 293.1143.
  • 14 Typical Procedure for Siladifluoromethylation with CF3TMSTo a solution of 9-phenyl-9H-fluorene 1a (0.10 mmol, 24.2 mg) in THF (1.0 mL) was added n-butyllithium solution (1.6 M in hexane, 0.11 mmol, 69 μL) at –78 °C. After stirring for 5 minutes at the same temperature, CF3TMS (0.20 mmol, 30 μL) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction was quenched with water, the organic layer was extracted with diethyl ether, washed with brine, and dried over anhydrous MgSO4. After filtration, the solvent was removed under reduced pressure. The NMR yield was determined by using benzotrifluoride (BTF) as an internal standard. The residue was purified by silica-gel column chromatography (hexane/ethyl acetate, 50:1 as eluent) to afford 4a as a colorless liquid.Compound 4a: 1H NMR (300 MHz, CDCl3): δ = 7.82 (d, J = 7.6 Hz, 2 H), 7.60 (d, J = 7.6 Hz, 2 H), 7.52–7.44 (m, 4 H), 7.34–7.20 (m, 5 H), –0.50 (s, 9 H); 13C NMR (75 MHz, CDCl3): δ = 146.8 (t, J C–F = 4.4 Hz), 141.5 (s), 140.1 (s), 131.5 (t, J C–F = 272.0 Hz), 128.8 (t, J C–F = 2.7 Hz), 128.7 (s), 128.3 (s), 128.1 (s), 127.9 (s), 126.7 (s), 120.0 (s), 65.2 (t, J C–F = 19.5 Hz), –3.8 (t, J C–F = 2.3 Hz); 19F NMR (282 MHz, CDCl3): δ = –107.7 (s, 2 F); FTIR (neat): 3060, 2958, 2899, 1495, 1449, 1253, 1075, 985, 847, 745 cm–1; HRMS (APCI-TOF): m/z [M+H+CH3CN]+ calcd for C25H26F2NSi: 406.1803; found: 406.1818.
    • 15a McCluskey GE. Watkins SE. Holmes AB. Ober CK. Lee J.-K. Wong WW. H. Polym. Chem. 2013; 4: 5291
    • 15b Honmou Y. Hirata S. Komiyama H. Hiyoshi J. Kawauchi S. Iyoda T. Vacha M. Nat. Commun. 2014; 5: 4666 ; and references cited therein
    • 16a Snieckus V. Chem. Rev. 1990; 90: 879
    • 16b Schlosser M. Angew. Chem. Int. Ed. 2005; 44: 376
    • 16c Hashimoto R. Iida T. Aikawa K. Ito S. Mikami K. Chem. Eur. J. 2014; 20: 2750
    • 16d Nitta J. Bachelor Thesis; Tokyo Institute of Technology, 2015
    • 17a Matthews WS. Bares JE. Bartmess JE. Bordwell FG. Cornforth FJ. Drucker GE. Margolin Z. McCallum RJ. Vanier NR. J. Am. Chem. Soc. 1975; 97: 7006
    • 17b Symons EA. Clermont M. J. J. Am. Chem. Soc. 1981; 103: 3127