Synthesis of gem-Difluoroalkenes via a Sequence of Hydroboration and 1,2-Elimination of α,β-Unsaturated Carbonyls

Shiyun An; Jinlong Zhang; Gaoxi Jiang

doi:10.1055/s-0040-1707311

Synlett, Table of Contents

Synlett 2021; 32(01): 91-94
DOI: 10.1055/s-0040-1707311

letter

Synthesis of gem-Difluoroalkenes via a Sequence of Hydroboration and 1,2-Elimination of α,β-Unsaturated Carbonyls

Shiyun An

^aState Key Laboratory for Oxo Synthesis and Selective Oxidation, Center for Excellence in Molecular Synthesis, Suzhou Research Institute of LICP, Lanzhou Institute of Chemical Physics (LICP), Chinese Academy of Sciences, Lanzhou 730000, P. R. of China Email: gxjiang@licp.cas.cn

^bUniversity of Chinese Academy of Sciences, Beijing 100049, P. R. of China

,

Jinlong Zhang

^aState Key Laboratory for Oxo Synthesis and Selective Oxidation, Center for Excellence in Molecular Synthesis, Suzhou Research Institute of LICP, Lanzhou Institute of Chemical Physics (LICP), Chinese Academy of Sciences, Lanzhou 730000, P. R. of China Email: gxjiang@licp.cas.cn

,

Gaoxi Jiang∗

^aState Key Laboratory for Oxo Synthesis and Selective Oxidation, Center for Excellence in Molecular Synthesis, Suzhou Research Institute of LICP, Lanzhou Institute of Chemical Physics (LICP), Chinese Academy of Sciences, Lanzhou 730000, P. R. of China Email: gxjiang@licp.cas.cn

› Author Affiliations

Abstract

All articles of this category

Abstract

We reported a simple protocol for the synthesis of gem-difluoroalkenes via a reaction sequence of hydroboration and 1,2-elimination of α,β-unsaturated carbonyl substrates under mild conditions. Two steps of this method could be executed in one pot. The β-CF₂H- and β-CFH₂-α,β-unsaturated carbonyls can be obtained smoothly from the α,β-unsaturated gem-difluoroamide with NaH as the base and via a boration–1,2-elimination sequence.

Key words

gem-difluoroalkene - boration - 1,2-elimination - α,β-unsaturated carbonyls - fluoroalkene

Full Text

References

References and Notes
1 Motherwell WB, Tozer MJ, Ross BC. J. Chem. Soc., Chem. Commun. 1989; 1437

2a Rogawski MA. Epilepsy Res. 2006; 69: 273
2b Altenburger J.-M, Lassalle GY, Matrougui M, Galtier D, Jetha J.-C, Bocskei Z, Berry CN, Lunven C, Lorrain J, Herault J.-P, Schaeffer P, O’Connor SE, Herbert J.-M. Bioorg. Med. Chem. 2004; 12: 1713
2c Pan Y, Qiu J, Silverman RB. J. Med. Chem. 2003; 46: 5292
2d Weintraub PM, Holland AK, Gates CA, Moore WR, Resvick RJ, Bey P, Peet NP. Bioorg. Med. Chem. 2003; 11: 427
2e Moore WR, Schatzman GL, Jarvi ET, Gross RS, McCarthy JR. J. Am. Chem. Soc. 1992; 114: 360
2f McDonald IA, Lacoste JM, Bey P, Palfreyman MG, Zreika M. J. Med. Chem. 1985; 28: 186

For reviews on the synthesis of gem-difluoroalkenes and their applications in organic synthesis, see:

3a Zhang X.-X, Cao S. Tetrahedron Lett. 2017; 58: 375
3b Chelucci G. Chem. Rev. 2012; 112: 1344
3c Ichikawa J. J. Fluorine Chem. 2000; 105: 257

For recent examples of the gem-difluoroolefination of carbonyl compounds, see:

4a Krishnamoorthy S, Kothandaraman J, Saldana J, Prakash GK. S. Eur. J. Org. 2016; 4965
4b Gao B, Zhao Y.-C, Hu J.-Y, Hu J.-B. Org. Chem. Front. 2015; 2: 163
4c Aikawa K, Toya W, Nakamura Y, Mikami K. Org. Lett. 2015; 17: 4996
4d Wang X.-P, Lin J.-H, Xiao J.-C, Zheng X. Eur. J. Org. Chem. 2014; 928
4e Gao B, Zhao Y.-C, Hu M.-Y, Ni C.-F, Hu J.-B. Chem. Eur. J. 2014; 20: 7803
4f Li Q, Lin J.-H, Deng Z.-Y, Zheng J, Cai J, Xiao J.-C. J. Fluorine Chem. 2014; 163: 38
4g Thomoson CS, Martinez H, Dolbier WR. Jr. J. Fluorine Chem. 2013; 150: 53
4h Zheng J, Cai J, Lin J.-H, Guo Y, Xiao J.-C. Chem. Commun. 2013; 49: 7513
4i Zheng J, Lin J.-H, Cai J, Xiao J.-C. Chem. Eur. J. 2013; 19: 15261
4j Zhao Y.-C, Huang W.-Z, Zhu L.-G, Hu J.-B. Org. Lett. 2010; 12: 1444
4k Nowak I, Robins MJ. Org. Lett. 2005; 7: 721

For selected examples of the gem-difluoroolefination of diazo compounds, see:

5a Zhang Z.-K, Yu W.-Z, Wu C.-G, Wang C.-P, Zhang Y, Wang J.-B. Angew. Chem. Int. Ed. 2016; 55: 273
5b Hu M.-Y, Ni C.-F, Li L.-C, Han Y.-X, Hu J.-B. J. Am. Chem. Soc. 2015; 137: 14496
5c Zheng J, Lin J.-H, Yu L.-Y, Wei Y, Zheng X, Xiao J.-C. Org. Lett. 2015; 17: 6150
5d Hu M.-Y, He Z.-B, Gao B, Li L.-C, Ni C.-F, Hu J.-B. J. Am. Chem. Soc. 2013; 135: 17302

For selected examples of the synthesis of gem-difluoroalkenes via organometallic- or strong-base-mediated nucleophilic addition to trifluoromethyl alkenes involving β-F-elimination, see:

6a Wang M.-Y, Pu X.-H, Zhao Y.-F, Wang P.-P, Li Z.-X, Zhu C.-D, Shi Z.-Z. J. Am. Chem. Soc. 2018; 140: 9061
6b Wu X.-T, Xie F, Gridnev ID, Zhang W.-B. Org. Lett. 2018; 20: 1638
6c Dai W.-P, Lin Y.-Y, Wan Y, Cao S. Org. Chem. Front. 2018; 5: 55
6d Yang J.-R, Zhou X.-F, Zeng Y, Huang C.-Q, Xiao Y.-J, Zhang J.-L. Org. Biomol. Chem. 2017; 15: 2253
6e Huang Y.-H, Hayashi T. J. Am. Chem. Soc. 2016; 138: 12340
6f Fuchibe K, Takahashi M, Ichikawa J. Angew. Chem. Int. Ed. 2012; 51: 12059
6g Ichikawa J, Iwai Y, Nadano R, Mori T, Ikeda M. Chem. Asian J. 2008; 3: 393
6h Tomoya M, Yoshiteru I, Masahiro M. Chem. Lett. 2008; 37: 1006
6i Junji I, Takashi M, Yu I. Chem. Lett. 2004; 33: 1354
6j Ichikawa J, Ishibashi Y, Fukui H. Tetrahedron Lett. 2003; 44: 707
6k Ichikawa J, Fukui H, Ishibashi Y. J. Org. Chem. 2003; 68: 7800
6l Bégué J.-P, Bonnet-Delpon D, Rock MH. J. Chem. Soc., Perkin Trans.1 1996; 1: 1409
6m Bégué J.-P, Bonnet-Delpon D, Rock MH. Tetrahedron Lett. 1995; 36: 5003
6n Fuchikami T, Shibata Y, Suzuki Y. Tetrahedron Lett. 1986; 27: 3173
6o Hiyama T, Obayashi M, Sawahata M. Tetrahedron Lett. 1983; 24: 4113

For selected examples, see:

7a Kim JH. Jeong Y. R, Jeon SL, Jeong IH. J. Fluorine Chem. 2014; 167: 166
7b Wilson PG, Percy JM, Redmond JM, McCarter AW. J. Org. Chem. 2012; 77: 6384
7c Pschierer J, Peschek N, Plenio H. Green Chem. 2010; 12: 636
7d Han SY, Jeong IH. Org. Lett. 2010; 12: 5518
7e Gøgsig TM, Søbjerg LS, Lindhardt AT, Jensen KL, Skrydstrup T. J. Org. Chem. 2008; 73: 3404
7f Raghavanpillai A, Burton DJ. J. Org. Chem. 2006; 71: 194
7g Nguyen BV, Burton DJ. J. Org. Chem. 1998; 63: 1714
7h Ichikawa J, Ikeura C, Minami T. Synlett 1992; 739

8a Lang SB, Wiles RJ, Kelly CB, Molander GA. Angew. Chem. Int. Ed. 2017; 56: 15073
8b Xiao T.-B, Li L.-Y, Zhou L. J. Org. Chem. 2016; 81: 7908

9 Ichitsuka T, Fujita T, Ichikawa J. ACS Catal. 2015; 5: 5947

10a Neeve EC, Geier SJ, Mkhalid IA. I, Westcott SA, Marder TB. Chem. Rev. 2016; 116: 9091
10b Lawson YG, Lesley MJ. G, Norman NC, Rice CR, Marder TB. Chem. Commun. 1997; 2051

11 Typical Procedure for the Synthesis of 4,4,4-Trifluoro-N-phenyl-3-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)butanamide (3a) The reaction mixture of α,β-unsaturated carbonyl substrate 1a (0.2 mmol), B₂pin₂ (2, 0.3 mmol, 1.5 equiv), CuCl (10 mol%), t-BuOLi (15 mol%), and i-PrOH (0.4 mol, 2.0 equiv) was stirred in THF (2.0 mL) at room temperature for 12 h. After the reaction was accomplished, the solvent was evaporated, and the crude mixture purified by flash chromatography on silica gel to afford the desired compound 3a in 92% yield. ¹H NMR (300 MHz, CDCl₃): δ = 8.15 (br, 1 H), 7.53–7.40 (m, 2 H), 7.33–7.18 (m, 2 H), 7.15–7.03 (m, 1 H), 2.80 (qd, J = 16.4, 7.9 Hz, 2 H), 2.23 (dd, J = 17.3, 10.1 Hz, 1 H), 1.26 (d, J = 7.6 Hz, 12 H). ¹³C NMR (75 MHz, MeOD): δ = 176.83, 137.86, 130.42 (d, J = 273.8 Hz), 130.25, 127.21, 121.97, 83.04, 33.17, 33.12, 25.41, 25.15. ¹⁹F NMR (282 MHz, CDCl₃): δ = –63.10. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₂₂BF₃NO₃: 344.1642; found: 344.1647.

Supplementary Material

Supporting Information