Synthesis of Fluoropyrrolidines and (Fluoroalkyl)pyrrolidines

To Professor Kenji Uneyama and Professor Donald J. Burton for their great contribution to fluoroorganic chemistry

Abstract

Pyrrolidines and their derivatives are of great interest in medicinal chemistry and organic synthesis. Fluoropyrrolidines and (fluoroalkyl)pyrrolidines have been utilized in the preparation of medicinal drugs and also as organocatalysts. The synthesis of such compounds is achieved through the fluorination of pyrrolidine derivatives or by multistep synthesis from already containing fluoroalkyl precursors.

1 Introduction

1.1 General Interest of Fluorine-Containing Pyrrolidines

1.2 Fluoroalkylpyrrolidines and the Gauche Effect

2 Fluoropyrrolidines

2.1 3-Fluoropyrrolidines

2.2 3,3- and 3,4-Difluoropyrrolidines

2.3 3,3,4-Trifluoropyrrolidines

2.4 3,3,4,4-Tetrafluoropyrrolidines

3 (Difluoromethyl)- and (Trifluoromethyl)pyrrolidines

3.1 2-(Trifluoromethyl)pyrrolidines

3.2 3- and 4-(Trifluoromethyl)pyrrolidines

3.3 2-(Difluoromethyl)pyrrolidines

3.4 3- and 4-(Difluoromethyl)pyrrolidines

4 (Monofluoroalkyl)pyrrolidines

4.1 2-(Monofluoromethyl)pyrrolidines

4.2 2-(Monofluoroalkyl)pyrrolidines

4.3 2-(Monofluoroalkenyl)pyrrolidines

5 Conclusion

Key words

pyrrolidine - proline - monofluoroalkenes - fluoropyrrolidine - trifluoromethyl - difluoromethyl

• References

• 1a Morgenthaler M. Schweizer E. Hoffmann-Röder A. Benini F. Martin RE. Jaeschke G. Wagner B. Fischer H. Bendels S. Zimmerli D. Schneider J. Diederich F. Kansy M. Müller K. ChemMedChem 2007; 2: 1100
• 1b Böhm H.-J. Banner D. Bendels S. Kansy M. Kuhn B. Müller K. Obst-Sander U. Stahl M. ChemBioChem 2004; 5: 637
• 2a Koo KD. Kim MJ. Kim S. Kim K.-H. Hong SY. Hur GC. Yim HJ. Kim GT. Han HO. Kwon O. Kwon TS. Koh JS. Lee C.-S. Bioorg. Med. Chem. Lett. 2007; 17: 4167
• 2b Kim BC. Kim K.-Y. Lee HB. Shin H. Org. Process Res. Dev. 2008; 12: 626
• 3 Kubyshkin V. Afonin S. Kara S. Budisa N. Mykhailiuk PK. Ulrich AS. Org. Biomol. Chem. 2015; 13: 3171
• 4a Bocheva A. Nocheva H. Jlalia I. Lensen N. Chaume G. Brigaud T. Med. Chem. (Los Angeles, CA, U. S.) 2013; 3: 2 ; https://www.omicsonline.org/medicinal-chemistry.php
• 4b Simon J. Pytkowicz J. Lensen N. Chaume G. Brigaud T. J. Org. Chem. 2016; 81: 5381
• 4c Asante V. Mortier J. Schlüter H. Koksch B. Bioorg. Med. Chem. 2013; 21: 3542
• 5 Buissonneaud DY. van Mourik T. O’Hagan D. Tetrahedron 2010; 66: 2196
• 6 Batsanov AS. Howard JA. K. Acta Crystallogr., Sect. C 2000; 56: e467
• 7 Jakobsche CE. Choudhary A. Miller SJ. Raines RT. J. Am. Chem. Soc. 2010; 132: 6651
• 8 Sparr C. Schweizer WB. Senn HM. Gilmour R. Angew. Chem. Int. Ed. 2009; 48: 3065
• 9 Tanzer E.-M. Zimmer LE. Schweizer WB. Gilmour R. Chem. Eur. J. 2012; 18: 11334
• 10a Ulbrich D. Daniliuc CG. Haufe G. J. Fluorine Chem. 2016; 188: 65
• 10b Wu X. Meng C. Yuan X. Jia X. Qian X. Ye J. Chem. Commun. 2015; 51: 11864
• 11 Yarmolchuk VS. Mykhailiuk IV. Tetrahedron Lett. 2011; 52: 1300
• 12 Mason JM. Murkin AS. Li L. Schramm VL. Gainsford GJ. Skelton BW. J. Med. Chem. 2008; 51: 5880
• 13 Umemoto T. Singh RP. Xu Y. Saito N. J. Am. Chem. Soc. 2010; 132: 18199
• 14a Beaulieu F. Beauregard L.-P. Courchesne G. Couturier M. LaFlamme F. L’Heureux A. Org. Lett. 2009; 11: 5050
• 14b L’Heureux A. Beaulieu F. Bennett C. Bill DR. Clayton S. LaFlamme F. Mirmehrabi M. Tadayon S. Tovell D. Couturier M. J. Org. Chem. 2010; 75: 3401
• 14c Giardina G. Dondio G. Grugni M. Synlett 1995; 55
• 15 Doi M. Nishi Y. Kiritoshi N. Iwata T. Nago M. Nakano H. Uchiyama S. Nakazawa T. Wakamiya T. Kobayashi Y. Tetrahedron 2002; 58: 8453
• 16 Caldwell CG. Chen P. He J. Parmee ER. Leiting B. Marsilio F. Patel RA. Wu JK. Eiermann GJ. Petrov A. He H. Lyons KA. Thornberry NA. Weber AE. Bioorg. Med. Chem. Lett. 2004; 14: 1265
• 17 Hulin B. Cabral S. Lopaze MG. Van Volkenburg MA. Andrews KM. Parker JC. Bioorg. Med. Chem. Lett. 2005; 15: 4770
• 18 McAlpine I. Tran-Dubé M. Wang F. Scales S. Matthews J. Collins MR. Nair SK. Nguyen M. Bian J. Alsina LM. Sun J. Zhong J. Warmus JS. O’Neill B. J. Org. Chem. 2015; 80: 7266
• 19 Li Y. Hu J. Angew. Chem. Int. Ed. 2007; 46: 2489
• 20 Fedorov OV. Struchkova MI. Dilman AD. J. Org. Chem. 2017; 82: 3270
• 21 Sekiguchi T. Sato K. Ishihara T. Konno T. Yamanaka H. Chem. Lett. 2004; 33: 666
• 22 Yamada S. Higashi M. Konno T. Ishihara T. Eur. J. Org. Chem. 2016; 4561
• 23 Roberts RD. Spencer TA. Tetrahedron Lett. 1978; 29: 2557
• 24 Siegel C. Bastos CM. Harris DJ. Dios A. Lee E. Silva R. Cuff LM. Levine M. Celatka CA. Jozafiak TH. Vinick F. Xiang Y. Kane J. Liao J. US Patent 8309593, 2012
• 25 Shevchenko NE. Balenkova ES. Röschenthaler G.-V. Nenajdenko VG. Synthesis 2010; 120
• 26 Bezdudny AV. Alekseenko AN. Mykhailiuk PK. Manoilenko OV. Shishkin OV. Pustovit YM. Eur. J. Org. Chem. 2011; 1782
• 27 Rey YP. Gilmour R. Beilstein J. Org. Chem. 2013; 9: 2812
• 28 Caupène C. Chaume G. Ricard L. Brigaud T. Org. Lett. 2009; 11: 209
• 29 Zhi Y. Zhao K. Liu Q. Wang A. Enders D. Chem. Commun. 2016; 52: 14011
• 30 Dong Z. Zhu Y. Li B. Wang C. Yan W. Wang K. Wang R. J. Org. Chem. 2017; 82: 3482
• 31 Aparici I. Guerola M. Dialer C. Simon-Fuentes A. Sanchez-Rosello M. del Pozo C. Fustero S. Org. Lett. 2015; 17: 5412
• 32 Tran G. Meier R. Harris L. Browne DL. Ley SV. J. Org. Chem. 2012; 77: 11071
• 33 Ponce A. Alonso I. Adrio J. Carretero JC. Chem. Eur. J. 2016; 22: 4952
• 34 Bonnet-Delpon D. Bégué J.-P. Lequeux T. Ourévitch M. Tetrahedron 1996; 52: 59
• 35 Leroy J. Wakselman C. Can. J. Chem. 1976; 54: 218
• 36 Yarmolchuk VS. Shishkin OV. Starova VS. Zaporozhets OA. Kravchuk O. Zozulya S. Kamarov IV. Mykhailiuk PK. Eur. J. Org. Chem. 2013; 3086
• 37 Bégué J.-P. Bonnet-Delpon D. Lequeux T. Tetrahedron Lett. 1993; 34: 3279
• 38 Fukui H. Shobata T. Naito T. Nakano J. Maejima T. Senda H. Iwatani W. Tatsumi Y. Suda M. Arika T. Bioorg. Med. Chem. Lett. 1998; 8: 2833
• 39 Li Q.-H. Xue Z.-Y. Tao H.-Y. Wang C.-J. Tetrahedron Lett. 2012; 53: 3650
• 40 Qiu X.-L. Qing F.-L. J. Org. Chem. 2002; 67: 7162
• 41 Zhu J. Price BA. Walker J. Zhao SX. Tetrahedron Lett. 2005; 46: 2795
• 42 Hugenberg V. Fröhlich R. Haufe G. Org. Biomol. Chem. 2010; 8: 5682
• 43 Qiu X.-L. Qing F.-L. J. Org. Chem. 2005; 70: 3826
• 44 Nadano R. Iwai Y. Mori T. Ichikawa J. J. Org. Chem. 2006; 71: 8748
• 45 Michurin OM. Radchenko DS. Komarov IV. Tetrahedron 2016; 72: 1351
• 46 Shaitanova EN. Gerus II. Kukhar VP. Haufe G. J. Fluorine Chem. 2014; 160: 8
• 47 Bigotti S. Malpezzi L. Molteni M. Mele A. Panzeri W. Zanda M. Tetrahedron Lett. 2009; 50: 2540
• 48 Li Q. Ding C.-H. Li X.-H. Weissensteiner W. Hou X.-L. Synthesis 2012; 44: 265
• 49 Krause-Heuer AM. Howell NR. Matesic L. Dhand G. Young EL. Burgess L. Jiang CD. Lengkeek NA. Fookes CJ. R. Pham TQ. Sobrio F. Greguric I. Fraser BH. Med. Chem. Commun. 2013; 4: 347
• 50 Rosen T. Chu DT. W. Lico IM. Fernandes PB. Marsh K. Shen L. Cepa VG. Pernet AG. J. Med. Chem. 1988; 31: 1598
• 51 Evans G. Furneaux RH. Gainsford GJ. Schramm VL. Tyler PC. Tetrahedron 2000; 56: 3053
• 52 Déchamps I. Gomez Pardo D. Cossy J. Eur. J. Org. Chem. 2007; 4224
• 53 Orlia A. Routier J. Burgat Chavillon F. Sauer WH. B. Bombrin A. Kulkarni SS. Gomez Pardo D. Cossy J. Chem. Eur. J. 2014; 20: 3813
• 54 Wu T. Cheng J. Chen P. Liu G. Chem. Commun. 2013; 49: 8707
• 55 Li Y. Ni C. Liu J. Zhang L. Zheng J. Zhu L. Hu J. Org. Lett. 2006; 8: 1693
• 56 O'Hagan D. Royer F. Tavasli M. Tetrahedron: Asymmetry 2000; 11: 2033
• 57 Van der Veken P. Senten K. Kertesz I. Haemers A. Augustyns K. Tetrahedron Lett. 2003; 44: 969
• 58 Molnar IG. Holland MC. Houk KN. Gilmour R. Synlett 2016; 27: 1051
• 59 Kohlhepp SV. Gulder T. Chem. Soc. Rev. 2016; 45: 6270
• 60 Takeuchi Y. Yama A. Suzuki T. Koizumi T. Tetrahedron 1996; 52: 225
• 61 Jakobsche CE. Peris G. Miller SJ. Angew. Chem. Int. Ed. 2008; 47: 6707
• 62 Cui H. Chai Z. Zhao G. Zhu S. Chin. J. Chem. 2009; 27: 189
• 63 Yang M.-H. Matikonda SS. Altman RA. Org. Lett. 2013; 15: 3894
• 64 Le Guen C. Tran Do M.-L. Chardon A. Lebargy C. Lohier J.-F. Pfund E. Lequeux T. J. Org. Chem. 2016; 81: 6714