Abstract
The presence of fluorine on a carbanion center will dramatically influence the nucleophilic alkylation reactions. Based on our own experience, we noticed that the fluorine substitution on the carbanionic carbon poses a negative effect in many nucleophilic fluoroalkylation reactions [we propose this effect as “negative fluorine effect (NFE)”]. Two factors were believed to contribute to the NFE: (1) thermal instability of fluorinated carbanions caused by α-elimination (self-decomposition) and (2) the intrinsic nucleophilicity of fluorinated carbanion influenced by the fluorine atoms (such as hard/soft nature of the fluorinated carbanions). By tackling the NFE, our research group has attempted to design nucleophilic fluoroalkylation reactions with fluorinated sulfones and related reagents. These results were summarized as four methods to modulate the fluoroalkylation reactions: (1) changing the number of fluorine atoms, (2) slightly changing the neighboring groups, (3) changing the metal counterion, including using carbon-metal covalent bond to tune the reactivity, and (4) enhancing the generation of carbene species.
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Abbreviations
- Bn:
-
Benzyl
- DFT:
-
Density functional theory
- dr :
-
Diastereomeric ratio
- ee :
-
Enantiomeric excess
- i-Pr:
-
iso-Propyl
- KHMDS:
-
Potassium bis(trimethylsilyl)amide
- LiHMDS:
-
Lithium bis(trimethylsilyl)amide
- NaHMDS:
-
Sodium bis(trimethylsilyl)amide
- Ph:
-
Phenyl
- Py:
-
Pyridine
- TBAT:
-
Tetrabutylammonium triphenyldifluorosilicate
- t-Bu:
-
tert-Butyl
- TMS:
-
Trimethylsilyl
- Ts:
-
Tosyl (p-toluenesulfonyl)
References
Müller K, Faeh C, Diederich F (2007) Fluorine in pharmaceuticals: looking beyond intuition. Science 317:1881
Bégué J-P, Bonnet-Delpon D (2008) Bioorganic and medicinal chemistry of fluorine. Wiley, Hoboke
Hagmann WK (2008) The many roles for fluorine in medicinal chemistry. J Med Chem 51:4359
Prakash GKS, Chacko S (2008) Novel nucleophilic and electrophilic fluoroalkylation methods. Curr Opin Drug Discov Dev 11:793
Kirsch P (2004) Modern fluoroorganic chemistry: synthesis, reactivity, applications. Wiley-VCH, Weinheim
Banks RE, Smart BE, Tatlow JC (1994) Organofluorine chemistry: principles and commercial applications. Plenum, New York
O’Hagan D, Schaffrath C, Cobb SL, Hamilton JTG, Murphy CD (2002) Biochemistry: biosynthesis of an organofluorine molecule. Nature 416:279
Uneyama K (2006) Organofluorine chemistry. Blackwell, Oxford
Chambers RD (2004) Fluorine in organic chemistry. Blackwell, Oxford
Prakash GKS, Hu J (2007) Selective fluoroalkylations with fluorinated sulfones, sulfoxides, and sulfides. Acc Chem Res 40:921
Farnham WB (1996) Fluorinated carbanions. Chem Rev 96:1633
Prakash GKS, Yudin AK (1997) Perfluoroalkylation with organosilicon reagents. Chem Rev 97:757
Prakash GKS, Krishnamurti R, Olah GA (1989) Synthetic methods and reactions. 141. Fluoride-induced trifluoromethylation of carbonyl compounds with trifluoromethyltrimethylsilane (TMS-CF3). A trifluoromethide equivalent. J Am Chem Soc 111:393
Hagiwara T, Fuchikami T (1995) Difluoroalkylation of carbonyl compounds with (1,1-difluoroalkyl)silane derivatives. Synlett 7:717
Hu J, Zhang W, Wang F (2009) Selective difluoromethylation and monofluoromethylation reactions. Chem Commun 7465
Ni C, Hu J (2011) Selective nucleophilic fluoroalkylations facilitated by removable activation groups. Synlett 6:770
Bickelhaupt FM, Hermann HL, Boche G (2006) α-Stabilization of carbanions: fluorine is more effective than the heavier halogens. Angew Chem Int Ed 45:823
Faustov VI, D’yachenko AI, Nefedov OM (1979) Unstable organolithium halide compounds. Communication 7. Thermodynamic calculations of the mechanism of decomposition of organolithium halide compounds. Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya 2183
Boche G, Lohrenz JCW (2001) The electrophilic nature of carbenoids, nitrenoids, and oxenoids. Chem Rev 101:697
Capriati V, Florio S (2010) Anatomy of long-lasting love affairs with lithium carbenoids: past and present status and future prospects. Chem Eur J 16:4152
Stahly GP (1989) Nucleophilic addition of difluoromethyl phenyl sulfone to aldehydes and various transformations of the resulting alcohols. J Fluor Chem 43:53
Hine J, Porter JJ (1960) Formation of difluoromethylene from difluoromethyl phenyl sulfone and sodium methoxide. J Am Chem Soc 82:6178
Hu J (2009) Nucleophilic, radical, and electrophilic (phenylsulfonyl) difluoromethylations. J Fluor Chem 130:1130
Ni C, Li Y, Hu J (2006) Nucleophilic fluoroalkylation of epoxides with fluorinated sulfones. J Org Chem 71:6829
Ni C, Liu J, Zhang L, Hu J (2007) A remarkably efficient fluoroalkylation of cyclic sulfates and sulfamidates with PhSO2CF2H: facile entry into β-difluoromethylated or β-difluoromethylenated alcohols and amines. Angew Chem Int Ed 46:786
Fleming I (1976) Frontier orbitals and organic chemical reactions. Wiley, New York
Ho T-L (1977) Hard and soft acids and bases principle in organic chemistry. Academic, New York
Ni C, Zhang L, Hu J (2008) Nucleophilic fluoroalkylation of α, β-enones, arynes, and activated alkynes with fluorinated sulfones: probing the hard/soft nature of fluorinated carbanions. J Org Chem 73:5699
Prakash GKS, Hu J, Olah GA (2003) Preparation of tri- and difluoromethylsilanes via an unusual magnesium metal-mediated reductive tri- and difluoromethylation of chlorosilanes using tri- and difluoromethyl sulfides, sulfoxides, and sulfones. J Org Chem 68:4457
Prakash GKS, Hu J, Wang Y, Olah GA (2004) Nucleophilic difluoromethylation of primary alkyl halides using difluoromethyl phenyl sulfone as a difluoromethyl anion equivalent. Org Lett 6:4315
Prakash GKS, Hu J, Wang Y, Olah GA (2004) Difluoromethyl phenyl sulfone, a difluoromethylidene equivalent: use in the synthesis of 1,1-difluoro-1-alkenes. Angew Chem Int Ed 43:5203
Prakash GKS, Hu J, Mathew T, Olah GA (2003) Difluoromethyl phenyl sulfone as a selective difluoromethylene dianion equivalent: one-pot stereoselective synthesis of anti-2,2-difluoropropane-1,3-diols. Angew Chem Int Ed 42:5216
Prakash GKS, Hu J, Wang Y, Olah GA (2005) Convenient synthesis of difluoromethyl alcohols from both enolizable and non-enolizable carbonyl compounds with difluoromethyl phenyl sulfone. Eur J Org Chem 2218
Ye J-D, Liao X, Piccirilli JA (2005) Synthesis of 2′-C-difluoromethylribonucleosides and their enzymatic incorporation into oligonucleotides. J Org Chem 70:7902
Liu J, Ni C, Wang F, Hu J (2008) Stereoselective synthesis of α-difluoromethyl-β-amino alcohols via nucleophilic difluoromethylation with Me3SiCF2SO2Ph. Tetrahedron Lett 49:1605
Li Y, Hu J (2005) Facile synthesis of chiral α-difluoromethyl amines from N-(tert-butylsulfinyl)aldimines. Angew Chem Int Ed 44:5882
Liu J, Li Y, Hu J (2007) Stereoselective synthesis of di- and monofluoromethylated vicinal ethylenediamines with di- and monofluoromethyl sulfones. J Org Chem 72:3119
Li Y, Ni C, Liu J, Zhang L, Zheng J, Zhu L, Hu J (2006) Stereoselective nucleophilic monofluoromethylation of N-(tert-butanesulfinyl)imines with fluoromethyl phenyl sulfone. Org Lett 8:1693
Liu J, Zhang L, Hu J (2008) Stereoselective monofluoromethylation of N-tert-butylsulfinyl ketimines using pregenerated fluoro(phenylsulfonyl)methyl anion. Org Lett 10:5377
Reggelin M, Zur C (2000) Sulfoximines. Structures, properties, and synthetic applications. Synthesis 1:1
Boys ML, Collington EW, Finch H, Swanson S, Whitehead JF (1988) α-Fluoromethyl-n-methyl-phenylsulfoximine: a new fluoromethylenation reagent. Tetrahedron Lett 29:3365
Zhang W, Wang F, Hu J (2009) N-Tosyl-S-difluoromethyl-S-phenylsulfoximine: A new difluoromethylation reagent for S-, N-, and C-nucleophiles. Org Lett 11:2109
Noritake S, Shibata N, Makamura S, Toru T, Shiro M (2008) Fluorinated Johnson reagent for transfer-trifluoromethylation to carbon nucleophiles. Eur J Org Chem 3465
Nomura Y, Tokunaga E, Shibata N (2011) Inherent oxygen preference in enolate monofluoromethylation and a synthetic entry to monofluoromethyl ethers. Angew Chem Int Ed 50:1885
Zhang W, Huang W, Hu J (2009) Highly stereoselective synthesis of monofluoroalkenes from α-fluorosulfoximines and nitrones. Angew Chem Int Ed 48:9858
Zhang W, Hu J (2010) Efficient synthesis and ring-opening reactions of monofluorinated epoxides derived from α-fluorosulfoximines. Adv Synth Catal 352:2799
Zhao Y, Huang W, Zhu L, Hu J (2010) Difluoromethyl 2-pyridyl sulfone: a new gem-difluoroolefination reagent for aldehydes and ketones. Org Lett 12:1444
Prakash GKS, Ni C, Wang F, Hu J, Olah GA (2011) From difluoromethyl 2-pyridyl sulfone to difluorinated sulfonates: a protocol for nucleophilic difluoro(sulfonato)methylation. Angew Chem Int Ed 50:2559
Liu J, Hu J (2010) Highly diastereoselective synthesis of α-difluoromethyl amines from N-tert-butylsulfinyl ketimines and difluoromethyl phenyl sulfone. Chem Eur J 16:11443
Shen X, Zhang L, Zhao Y, Zhu L, Li G, Hu J (2011) Nucleophilic fluoromethylation of aldehydes with fluorobis(phenylsulfonyl)methane: the importance of strong Li-O coordination and fluorine substitution for C-C bond formation. Angew Chem Int Ed 50:2588
Zhu J, Zhang W, Zhang L, Liu J, Zheng J, Hu J (2010) Copper-mediated fluoroalkylation reactions with iododifluoroacetamides: controlling the selectivity among cross-coupling, intramolecular cyclization, and homocoupling reactions. J Org Chem 75:5505
Zhu J, Wang F, Huang W, Zhao Y, Ye W, Hu J (2011) Copper-mediated fluoroalkylation reactions with [(phenylsulfonyl)-difluoromethyl] trimethylsilane: synthesis of PhSO2CF2-containing allenes and alkynes. Synlett 7:899
Zhang L, Zheng J, Hu J (2006) 2-Chloro-2,2-difluoroacetophenone: a non-ODS-based difluorocarbene precursor and its use in the difluoromethylation of phenol derivatives. J Org Chem 71:9845
Zheng J, Li Y, Zhang L, Hu J, Meuzelaar GJ, Federsel H-J (2007) Chlorodifluoromethyl phenyl sulfone: a novel non-ozone-depleting substance-based difluorocarbene reagent for O- and N-difluoromethylations. Chem Commun 48:5149
Wang F, Zhang W, Zhu J, Li H, Huang K-W, Hu J (2011) Chloride ion-catalyzed generation of difluorocarbene for efficient preparation of gem-difluorinated cyclopropenes and cyclopropanes. Chem Commun 47:2411
Wang F, Luo T, Hu J, Wang Y, Krishnan HS, Jog PV, Ganesh SK, Prakash GKS, Olah GA (2011) Synthesis of gem-difluorinated cyclopropanes and cyclopropenes using TMSCF3 as a difluorocarbene source. Angew Chem Int Ed. 50:7153
Brahms LS, Dailey WP (1996) Fluorinated carbenes. Chem Rev 96:1585
Hudlicky M, Pavlath AE (1995) Chemistry of organic fluorine compounds II. American Chemical Society, Washington DC
Acknowledgments
We are grateful to the following agencies for financial support: the National Natural Science Foundation of China (20825209, 20772144, 20832008) and the Chinese Academy of Sciences.
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Zhang, W., Ni, C., Hu, J. (2011). Selective Fluoroalkylation of Organic Compounds by Tackling the “Negative Fluorine Effect”. In: Horváth, I. (eds) Fluorous Chemistry. Topics in Current Chemistry, vol 308. Springer, Berlin, Heidelberg. https://doi.org/10.1007/128_2011_246
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DOI: https://doi.org/10.1007/128_2011_246
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