Synthesis 2019; 51(24): 4549-4567
DOI: 10.1055/s-0039-1690027
short review
© Georg Thieme Verlag Stuttgart · New York

Recent Progress on the Synthesis of CF2H-Containing Derivatives

Noam Levi
,
Dafna Amir
,
,
Yossi Zafrani
Further Information

Publication History

Received: 20 June 2019

Accepted after revision: 26 August 2019

Publication Date:
30 September 2019 (online)

Abstract

Recent years have witnessed a growing interest in the development of novel synthetic methods and new reagents for the synthesis of difluoromethylated compounds. Dozens of studies have been published on this topic each year over the past few years. These studies are focused on direct and indirect difluoromethylation of various organic functionalities via nucleophilic-, electrophilic-, radical-, carbene- or metal-mediated mechanisms. The present short review covers the very recent studies, published between mid-2017 and early 2019, on the synthesis of compounds containing a CF2H group. A brief summary of the physicochemical properties and medicinal applications of difluoromethylated compounds is also included.

1 Introduction

2 Nucleophilic Difluoromethylation

2.1 Metal-Mediated Nucleophilic Difluoromethylation

2.2 Non-Metal Difluoromethyl Nucleophiles

3 Radical Difluoromethylation

3.1 Metal-Induced Radical Difluoromethylation

3.2 Non-Metal-Induced Radical Difluoromethylation

3.3 Electrochemically Induced Radical Difluoromethylation

4 Carbene-Based Difluoromethylation

4.1 Metal-Induced Carbene Difluoromethylation

4.2 Non-Metal-Induced Difluoromethyl Carbenes

5 Cross-Coupling Difluoromethylation

5.1 Palladium-Catalyzed Difluoromethylation

5.2 Nickel-Catalyzed Difluoromethylation

5.3 Copper-Mediated Difluoromethylation

5.4 Iron-Catalyzed Difluoromethylation

5.5 Gold-Mediated Difluoromethylation

6 Electrophilic Difluoromethylation

7 Other Examples

7.1 A Difluoromethyl-Borane Complex

7.2 A Tellurium Difluoromethyl Derivative

8 Summary

 
  • References

  • 1 Bohm H.-J, Banner D, Bendels S, Kansy M, Kuhn B, Müller K, Obst-Sander U, Stahl M. ChemBioChem 2004; 5: 637
  • 2 Müller K, Faeh C, Diederich F. Science 2007; 317: 1881
  • 3 Liang T, Neumann CN, Ritter T. Angew. Chem. Int. Ed. 2013; 52: 8214
  • 4 Wang J, Sánchez-Roselló M, Aceña JL, del Pozo C, Sorochinsky AE, Fustero S, Soloshonok VA, Liu H. Chem. Rev. 2014; 114: 2432
  • 5 Gillis EP, Eastman KJ, Hill MD, Donnelly DJ, Meanwell NA. J. Med. Chem. 2015; 58: 8315
  • 6 Swallow S. Fluorine in Medicinal Chemistry . In Progress in Medicinal Chemistry, Vol. 54. Lawton G, Witty DR. Elsevier; Amsterdam: 2015: 65
  • 7 Zhou Y, Wang J, Gu Z, Wang S, Zhu W, Acenã JL, Soloshonok VA, Izawa K, Liu H. Chem. Rev. 2016; 116: 422
  • 8 Hu J, Zhang W, Wang F. Chem. Commun. 2009; 7465
  • 9 Ni C, Hu J. Synthesis 2014; 46: 842
  • 10 Rong J, Ni C, Hu J. Asian J. Org. Chem. 2017; 6: 139
  • 11 Yerien DE, Barata-Vallejo S, Postigo A. Chem. Eur. J. 2017; 23: 14676
  • 12 Krishnamoorthy S, Prakash GK. S. Synthesis 2017; 49: 3394
  • 13 Feng Z, Xiao YL, Zhang X. Acc. Chem. Res. 2018; 51: 2264
  • 14 Feng G, Evangelisti L, Cacelli I, Carbonaro L, Prampolini G, Caminati W. Chem. Commun. 2014; 50: 171
  • 15 Jones CR, Baruah PK, Thompson AL, Scheiner S, Smith MD. J. Am. Chem. Soc. 2012; 134: 12064
  • 16 Caminati W, Melandri S, Moreschini P, Favero PG. Angew. Chem. Int. Ed. 1999; 38: 2924
  • 17 Erickson JA, McLoughlin JI. J. Org. Chem. 1995; 60: 1626
  • 18 Hartz RA, Ahuja VT, Rafalski M, Schmitz WD, Brenner AB, Denhart DJ, Ditta JL, Deskus JA, Yue EW, Arvanitis AG, Lelas S, Li YW, Molski TF, Wong H, Grace JE, Lentz KA, Li J, Lodge NJ, Zaczek R, Combs AP, Olson RE, Mattson RJ, Bronson JJ, Macor JE. J. Med. Chem. 2009; 52: 4161
  • 19 Camerino E, Wong DM, Tong F, Körber F, Gross AD, Islam R, Viayna E, Mutunga JM, Li J, Totrov MM, Bloomquist JR, Carlier PR. Bioorg. Med. Chem. Lett. 2015; 25: 4405
  • 20 Thompson S, McMahon SA, Naismith JH, O’Hagan D. Bioorg. Chem. 2016; 64: 37
  • 21 Zheng B, D’Andrea SV, Sun LQ, Wang AX, Chen Y, Hrnciar P, Friborg J, Falk P, Hernandez D, Yu F, Sheaffer AK, Knipe JO, Mosure K, Rajamani R, Good AC, Kish K, Tredup J, Klei HE, Paruchuri M, Ng A, Gao Q, Rampulla RA, Mathur A, Meanwell NA, McPhee F, Scola PM. ACS Med. Chem. Lett. 2018; 9: 143
  • 22 Zafrani Y, Yeffet D, Sod-Moriah G, Berliner A, Amir D, Marciano D, Gershonov E, Saphier S. J. Med. Chem. 2017; 60: 797
  • 23 Zafrani Y, Sod-Moriah G, Yeffet D, Berliner A, Amir D, Marciano D, Elias S, Katalan S, Ashkenazi N, Madmon M, Gershonov E, Saphier S. J. Med. Chem. 2019; 62: 5628
  • 24 Sessler CD, Rahm M, Becker S, Goldberg JM, Wang F, Lippard SJ. J. Am. Chem. Soc. 2017; 139: 9325
  • 25 O’Reilly D, Stein RS, Patrascu MB, Jana SK, Kurian J, Moitessier N, Damha MJ. Chem. Eur. J. 2018; 24: 16432
  • 26 Giuffredi GT, Gouverneur V, Bernet B. Angew. Chem. Int. Ed. 2013; 52: 10524
  • 27 Dalvit C, Invernizzi C, Vulpetti A. Chem. Eur. J. 2014; 20: 11058
  • 28 Dalvit C, Vulpetti A. Chem. Eur. J. 2016; 22: 7592
  • 29 Huchet QA, Kuhn B, Wagner B, Kratochwil NA, Fischer H, Kansy M, Zimmerli D, Carreira EM, Müller K. J. Med. Chem. 2015; 58: 9041
  • 30 Vorberg R, Trapp N, Zimmerli D, Wagner B, Fischer H, Kratochwil NA, Kansy M, Carreira EM, Müller K. ChemMedChem 2016; 11: 2216
  • 31 Huchet QA, Trapp N, Kuhn B, Wagner B, Fischer H, Kratochwil NA, Carreira EM, Müller K. J. Fluorine Chem. 2017; 198: 34
  • 32 Linclau B, Wang Z, Compain G, Paumelle V, Fontenelle CQ, Wells N, Weymouth-Wilson A. Angew. Chem. Int. Ed. 2016; 55: 674
  • 33 Kubyshkin V, Budisa N. Beilstein J. Org. Chem. 2017; 13: 2442
  • 34 The Merck Index Online; Royal Society of Chemistry; https://www.rsc.org/Merck-Index (accessed Sept. 10, 2019).
  • 35 Theodoridis G. Fluorine-Containing Agrochemicals: An Overview of Recent Developments. In Fluorine and the Environment: Agrochemicals, Archaeology, Green Chemistry & Water. Tressaud A. Elsevier; Amsterdam: 2006: 121
  • 36 Pesticides; United States Environmental Protection Agency (EPA); https://www.epa.gov/pesticides (accessed Sept. 10, 2019).
  • 37 Fujiwara T, O’Hagan D. J. Fluorine Chem. 2014; 167: 16
  • 38 Jeanmart S, Edmunds AJ. F, Lamberth C, Pouliot M. Bioorg. Med. Chem. 2016; 24: 317
  • 39 Meanwell NA. J. Med. Chem. 2018; 61: 5822
  • 40 Canadian Centre for Occupational Health and Safety (CCOHS); http://ccinfoweb.ccohs.ca/cheminfo/search.html (accessed Sept. 10, 2019).
  • 41 DRUGBANK; https://www.drugbank.ca (accessed Sept. 10, 2019)
  • 42 TOXNET (Toxicology Data Network); U.S. National Library of Medicine; https://toxnet.nlm.nih.gov (accessed Sept. 10, 2019).
  • 43 Zhu S, Xu X, Qing F. Chem. Commun. 2017; 53: 11484
  • 44 Trifonov AL, Levin VV, Struchkova MI, Dilman AD. Org. Lett. 2017; 19: 5304
  • 45 Krishnamoorthy S, Kar S, Kothandaraman J, Prakash GK. S. J. Fluorine Chem. 2018; 208: 10
  • 46 Keereewan S, Soorukram D, Kuhakarn C, Reutrakul V, Pohmakotr M. Eur. J. Org. Chem. 2018; 295
  • 47 Chen J, Lin JH, Xiao JC. Tetrahedron 2018; 74: 4295
  • 48 Dong T, Nie J, Zhang CP. Tetrahedron 2018; 74: 5642
  • 49 Phetcharawetch J, Betterley NM, Soorukram D, Pohmakotr M, Reutrakul V, Kuhakarn C. Eur. J. Org. Chem. 2017; 6840
  • 50 Tian P, Xiao H, Wang L, Yu Y, Huang Y. Tetrahedron Lett. 2019; 60: 1015
  • 51 Ran Y, Lin QY, Xu XH, Qing FL. J. Org. Chem. 2017; 82: 7373
  • 52 Hu WQ, Xu XH, Qing FL. J. Fluorine Chem. 2018; 208: 73
  • 53 Zhang Z, Martinez H, Dolbier WR. J. Org. Chem. 2017; 82: 2589
  • 54 Zou G, Wang X. Org. Biomol. Chem. 2017; 15: 8748
  • 55 Zhu M, Fun W, Guo W, Tian Y, Wang Z, Xu C, Ji B. Eur. J. Org. Chem. 2019; 1614
  • 56 Zhu M, Fu W, Wang Z, Xu C, Ji B. Org. Biomol. Chem. 2017; 15: 9057
  • 57 Yin G, Zhu M, Fu W. Heterocycl. Commun. 2017; 23: 275
  • 58 Kim YJ, Kim DY. J. Fluorine Chem. 2018; 211: 119
  • 59 Yu J, Wu Z, Zhu C. Angew. Chem. Int. Ed. 2018; 57: 17156
  • 60 Lin JS, Wang FL, Dong XY, He WW, Yuan Y, Chen S, Liu XY. Nat. Commun. 2017; 8: 1
  • 61 Tung TT, Christensen SB, Nielsen J. Chem. Eur. J. 2017; 23: 18125
  • 62 Ma J.-J, Liu Q.-r, Lu G.-P, Yi W.-b. J. Fluorine Chem. 2017; 193: 113
  • 63 Heine NB, Studer A. Org. Lett. 2017; 19: 4150
  • 64 Xu X, Liu F. Org. Chem. Front. 2017; 4: 2306
  • 65 Sakamoto R, Kashiwagi H, Maruoka K. Org. Lett. 2017; 19: 5126
  • 66 Lytkina MA, Eliseenkov EV, Boyarskii VP, Petrov AA. Russ. J. Org. Chem. 2017; 53: 539
  • 67 Dai P, Yu X, Teng P, Zhang WH, Deng C. Org. Lett. 2018; 20: 6901
  • 68 Fang J, Shen WG, Ao GZ, Liu F. Org. Chem. Front. 2017; 4: 2049
  • 69 Wu QY, Ao GZ, Liu F. Org. Chem. Front. 2018; 5: 2061
  • 70 Noto N, Koike T, Akita M. Chem. Sci. 2017; 8: 6375
  • 71 Noto N, Tanaka Y, Koike T, Akita M. ACS Catal. 2018; 8: 9408
  • 72 Supranovich VI, Levin VV, Struchkova MI, Korlyukov AA, Dilman AD. Org. Lett. 2017; 19: 3215
  • 73 Zhang S, Li L, Zhang J, Zhang J, Xue M, Xu K. Chem. Sci. 2019; 10: 3181
  • 74 Xu H, Song J, Xu H. ChemSusChem 2019; 12: 1
  • 75 Xiong P, Xu HH, Song J, Xu HC. J. Am. Chem. Soc. 2018; 140: 2460
  • 76 Yang J, Jiang M, Jin Y, Yang H, Fu H. Org. Lett. 2017; 19: 2758
  • 77 Ding T, Jiang L, Yi W. Org. Lett. 2018; 20: 170
  • 78 Zafrani Y, Amir D, Yehezkel L, Madmon M, Saphier S, Karton-lifshin N, Gershonov E. J. Org. Chem. 2016; 81: 9180
  • 79 Mao T, Zhao L, Huang Y, Lou YG, Yao Q, Li XF, He CY. Tetrahedron Lett. 2018; 59: 2752
  • 80 Petko KI. J. Fluorine Chem. 2018; 205: 5
  • 81 Landelle G, Schmitt E, Panossian A, Vors JP, Pazenok S, Jeschke P, Gutbrod O, Leroux FR. J. Fluorine Chem. 2017; 203: 155
  • 82 Yu J, Lin JH, Xiao JC. Angew. Chem. Int. Ed. 2017; 56: 16669
  • 83 Li Z, Dong J, Yuan Z, Yang DY, Weng Z. Org. Lett. 2018; 20: 6407
  • 84 Deng J, Gao Y, Zhu Z, Xu L, Li Z, Tang R. Org. Lett. 2019; 21: 545
  • 85 Zhu J, Zheng H, Xue X.-S, Xiao Y, Liu Y, Shen Q. Chin. J. Chem. 2018; 36: 1069
  • 86 Zhu J, Liu Y, Shen Q. Angew. Chem. Int. Ed. 2016; 55: 9050
  • 87 Wang J, Tokunaga E, Shibata N. Chem. Commun. 2018; 54: 8881
  • 88 Xie Q, Zhu Z, Li L, Ni C, Hu J. Angew. Chem. Int. Ed. 2019; 58: 6405
  • 89 Xie Q, Ni C, Zhang R, Li L, Rong J, Hu J. Angew. Chem. Int. Ed. 2017; 56: 3206
  • 90 Huang Y, Wang AJ, Kong J, Lou YG, Li XF, He CY. Synth. Commun. 2018; 48: 91
  • 91 Zafrani Y, Sod-Moriah G, Segall Y. Tetrahedron 2009; 65: 5278
  • 92 Geng Y, Zhu M, Liang A, Niu C, Li J, Zou D, Wu Y, Wu Y. Org. Biomol. Chem. 2018; 16: 1807
  • 93 Polley A, Bairy G, Das P, Jana R. Adv. Synth. Catal. 2018; 360: 4161
  • 94 Feng Z, Min QQ, Fu XP, An L, Zhang X. Nat. Chem. 2017; 9: 918
  • 95 Hori K, Motohashi H, Saito D, Mikami K. ACS Catal. 2019; 9: 417
  • 96 Lu C, Gu Y, Wu J, Gu Y, Shen Q. Chem. Sci. 2017; 8: 4848
  • 97 Lu C, Lu H, Wu J, Shen HC, Hu T, Gu Y, Shen Q. J. Org. Chem. 2018; 83: 1077
  • 98 Ferguson DM, Malapit CA, Bour JR, Sanford MS. J. Org. Chem. 2019; 84: 3735
  • 99 Pan F, Boursalian GB, Ritter T. Angew. Chem. 2018; 130: 17113
  • 100 Fu XP, Xiao YL, Zhang X. Chin. J. Chem. 2018; 36: 143
  • 101 Sheng J, Ni HQ, Bian KJ, Li Y, Wang YN, Wang XS. Org. Chem. Front. 2018; 5: 606
  • 102 Xu C, Guo WH, He X, Guo YL, Zhang XY, Zhang X. Nat. Commun. 2018; 9: 1
  • 103 Gao X, He X, Zhang X. Chin. J. Org. Chem. 2019; 39: 215
  • 104 Bacauanu V, Cardinal S, Yamauchi M, Kondo M, Fernández DF, Remy R, MacMillan DW. C. Angew. Chem. Int. Ed. 2018; 57: 12543
  • 105 Motohashi H, Mikami K. Org. Lett. 2018; 20: 5340
  • 106 Merchant RR, Edwards JT, Qin T, Kruszyk MM, Bi C, Che G, Bao D, Qiao W, Sun L, Collins MR, Fadeyi OO, Gallego GM, Mousseau JJ, Nuhant P, Baran PS. Science 2018; 80: 75
  • 107 Aikawa K, Ishii K, Endo Y, Mikami K. J. Fluorine Chem. 2017; 203: 122
  • 108 Zeng X, Yan W, Zacate SB, Chao T.-H, Sun X, Cao Z, Bradford KG. E, Paeth M, Tyndall SB, Yang K, Kuo T.-C, Cheng M.-J, Liu W. J. Am. Chem. Soc. 2019; 141: 11398
  • 109 Gu Y, Lu C, Gu Y, Shen Q. Chin. J. Chem. 2018; 36: 55
  • 110 Bour JR, Kariofillis SK, Sanford MS. Organometallics 2017; 36: 1220
  • 111 Zhu SQ, Liu YL, Li H, Xu XH, Qing FL. J. Am. Chem. Soc. 2018; 140: 11613
  • 112 Yan SY, Zhang ZZ, Liu YH, Liao G, Li PX, Shi BF. Asian J. Org. Chem. 2018; 7: 1319
  • 113 An L, Xiao YL, Zhang S, Zhang X. Angew. Chem. Int. Ed. 2018; 57: 6921
  • 114 An L, Tong F, Zhang X. Acta Chim. Sinica 2018; 76: 977
  • 115 Miao W, Zhao Y, Ni C, Gao B, Zhang W, Hu J. J. Am. Chem. Soc. 2018; 140: 880
  • 116 Liu S, Kang K, Liu S, Wang D, Wei P, Lan Y, Shen Q. Organometallics 2018; 37: 3901
  • 117 Lu SLe, Li X, Qin WB, Liu JJ, Huang YY, Wong HN. C, Liu GK. Org. Lett. 2018; 20: 6925
  • 118 Ito S, Kato N, Mikami K. Chem. Commun. 2017; 53: 5546
  • 119 Pietrasiak E, Togni A. Organometallics 2017; 36: 3750