Synthesis of Cyclopropyl- and Cyclobutylpiperidines: Advanced Building Blocks for Drug Discovery

Dedicated to the 25th anniversary of Enamine Ltd.

Abstract

A library of cyclopropyl- and cyclobutylpiperidine derivatives were synthesized from commonly available starting materials through Wittig reactions.

Key words

amines - azetidines - piperidines - phosphonium salts - Wittig reaction

• References

• 1 Rubiralta M, Giralt E, Diez A. Piperidine: Structure, Preparation, Reactivity and Synthetic Applications of Piperidine and its Derivatives. Elsevier; Amsterdam: 1991
• 2 Watson PS, Jiang B, Scott B. Org. Lett. 2000; 2: 3679
• 3a Weintraub PM, Sabol JS, Kane JM, Borcherding DR. Tetrahedron 2003; 59: 2953
• 3b Laschat S, Dickner T. Synthesis 2000; 1781
• 3c Merino P, Tejero T, Greco G, Marca E, Delso I, Gómez-SanJuan A, Matute R. Heterocycles 2011; 84: 75
• 3d Felpin F.-X, Lebreton J. Eur. J. Org. Chem. 2003; 3693
• 3e Buffat MG. P. Tetrahedron 2004; 60: 1701
• 4a Källström S, Leino R. Bioorg. Med. Chem. 2008; 16: 601
• 4b Berardi F, Abate C, Ferorelli S, Colabufo NA, Perrone R. Centr. Nerv. Syst. Agents Med. Chem. 2009; 9: 205
• 5 Röhricht F, Gadhia S, Alam R, Willis M. Sci. World J. 2012; 512047 ; doi: 10.1100/2012/512047
• 6a Makovec F, Revel L, Letari O, Mennuni L, Impicciatore M. Eur. J. Pharmacol. 1999; 369: 81
• 6b Scarpignato C, Pelosini I, Di Mario F. Dig. Dis. Sci. 2006; 24: 11
• 6c Graul A, Mealy N, Bayés M. Drugs Future 2003; 28: 797
• 7a Lovell PJ, Bromidge SM, Dabbs S, Duckworth DM, Forbes IT, Jennings AJ, King FD, Middlemiss DN, Rahman SK, Saunders DV, Collin LL, Hagan JJ, Riley GJ, Thomas DR. J. Med. Chem. 2000; 43: 342
• 7b Mahé C, Loetscher E, Feuerbach D, Müller W, Seiler MP, Schoeffter P. Eur. J. Pharmacol. 2004; 495: 97
• 8a Aslanian RG, Berlin MY, Huang Y, McCormick KD, Mutahi MW, Shin N.-Y, Ting P, Tom WC, Zheng J. US 20070010513, 2007
• 8b Fernandez MC, Gonzalez-Garcia MR, Liu B, Pfeifer LA. WO 2013112323, 2013
• 8c Glatthar R, Orain D, Spanka C. WO 2007071358, 2007
• 9a Matsuda T, Tsuboi T, Murakami M. J. Am. Chem. Soc. 2007; 129: 12596
• 9b Wang B, Shen Y.-M, Shi Y. J. Org. Chem. 2006; 71: 9519
• 9c Jiang M, Liu L.-P, Shi M, Li Y. Org. Lett. 2010; 12: 116
• 9d de Meijere A, Becker H, Stolle A, Kozhushkov SI, Bes MT, Salaün J, Noltemeyer M. Chem. Eur. J. 2005; 11: 2471
• 9e Utimoto K, Tamura M, Sisido K. Tetrahedron 1973; 29: 1169
• 9f Zhou H, Huang X, Chen W. Synlett 2003; 2080
• 9g Li S, Luo Y, Wu J. Org. Lett. 2011; 13: 3190
• 9h Lechevallier A, Huet F, Conia JM. Tetrahedron 1983; 39: 3307
• 9i Bernard AM, Piras PP. Synth. Commun. 1997; 27: 709
• 9j Rousseau G, le Perchec P, Conia JM. Tetrahedron 1976; 32: 2533
• 10a de Meijere A, Wenck H, Zöllner S, Merstetter P, Arnold A, Gerson F, Schreiner PR, Boese R, Bläser D, Gleiter R, Kozhushkov SI. Chem. Eur. J. 2001; 7: 5382
• 10b Bräse S, Wertal H, Frank D, Vidović D, de Meijere A. Eur. J. Org. Chem. 2005; 4167
• 10c Widjaja T, Fitjer L, Pal A, Schmidt H.-G, Noltemeyer M, Diedrich C, Grimme S. J. Org. Chem. 2007; 72: 9264
• 10d Meyer-Wilmes I, Gerke R, Fitjer L. Tetrahedron 2009; 65: 1689
• 10e Fitjer L, Majewski M, Monzó-Oltra H. Tetrahedron 1995; 51: 8835
• 11a Qiu Y.-L, Wang C, Cao H, Peng X, Tang D, Or YS. US 2011300104, 2011
• 11b Lechevallier A, Huet F, Conia JM. Tetrahedron 1983; 39: 3317
• 11c Taber DF, Tian W. J. Org. Chem. 2008; 73: 7560
• 11d von Seebach M, Kozhushkov SI, Schill H, Frank D, Boese R, Benet-Buchholz J, Yufit DS, de Meijere A. Chem. Eur. J. 2007; 13: 167
• 12a Löhr S, Jacobi C, Johann A, Gottschalk G, de Meijere A. Eur. J. Org. Chem. 2000; 2979
• 12b Lillo VJ, Gomez C, Yus M. ARKIVOC 2010; (iii): 29
• 12c Loehr S, de Meijere A. Synlett 2001; 489
• 12d Miyazawa K, Löhr S, de Meijere A. Mol. Cryst. Liq. Cryst. Sci. Technol., Sect. A 2002; 373: 83
• 13a Behrens C, Christensen IT, Lau J, Ling A, Luntd BF, Madsen P, Plewe MB, Sams C, Sidelmann UG, Thogersen H, Truesdale LK, Vagner J. EP 1183229, 2005
• 13b Jorgenson MJ. J. Am. Chem. Soc. 1969; 91: 6432
• 13c O’Dowd H, Lewis JG, Trias J, Asano R, Blais J, Lopez SL, Park CK, Wu C, Wang W, Gordeev MF. Bioorg. Med. Chem. Lett. 2008; 18: 2645
• 14 The Wittig reaction of N-(tert-butoxycarbonyl)pyrrolidin-2-one failed with 3a,b due to the high activity of the NCH₂C(O) group, which enolizes easily in the presence of a base.
• 15a Maercker A, Daub VE. E. Tetrahedron 1994; 50: 2439
• 15b van den Heuvel CJ. M, Hofland A, van Velzen JC, Steinberg H, de Boer TJ. Recl. Trav. Chim. Pays-Bas 1984; 103: 233
• 15c de Meijere A, von Seebach M, Kozhushkov SI, Boese R, Blaeser D, Cicchi S, Dimoulas T, Brandi A. Eur. J. Org. Chem. 2001; 3789
• 16a Fitjer L, Quabeck U. Synthesis 1987; 299
• 16b Krapcho AP, Jahngen EG. E. J. Org. Chem. 1974; 39: 1650

For our ongoing interest in unique secondary amines, see:
• 17a Kubyshkin V, Kheylik Y, Mykhailiuk PK. J. Fluorine Chem. 2015; 175: 73
• 17b Druzhenko T, Denisenko O, Kheylik Y, Zozulya S, Shishkina SS, Tolmachev A, Mykhailiuk PK. Org. Lett. 2015; 17: 1922
• 17c Artamonov OS, Slobodyanyuk EY, Volochnyuk DM, Komarov IV, Tolmachev AA, Mykhailiuk PK. Eur. J. Org. Chem. 2014; 3592
• 17d Yarmolchuk VS, Shishkin OV, Starova VS, Zaporozhets OA, Kravchuk O, Zozulya S, Komarov IV, Mykhailiuk PK. Eur. J. Org. Chem. 2013; 3086
• 17e Artamonov OS, Slobodyanyuk EY, Shishkin OV, Komarov IV, Mykhailiuk PK. Synthesis 2013; 45: 225
• 17f Shcherbatiuk AV, Shyshlyk OS, Yarmoliuk DV, Shishkin OV, Shishkina SV, Starova VS, Zaporozhets OA, Zozulya S, Moriev R, Kravchuk O, Manoilenko O, Tolmachev AA, Mykhailiuk PK. Tetrahedron 2013; 69: 3796
• 18a Hercouet A, Le Corre M. Tetrahedron 1981; 37: 2861
• 18b Schmidbaur H, Schier A, Neugebauer D. Chem. Ber. 1983; 116: 2173
• 18c Corey EJ, Desai MC. Tetrahedron Lett. 1985; 26: 5747