Synthesis 2017; 49(12): 2589-2604
DOI: 10.1055/s-0036-1589491
review
© Georg Thieme Verlag Stuttgart · New York

Recent Advances in Piperazine Synthesis

Kristen E. Gettys
Department of Chemistry and Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA   Email: mjdai@purdue.edu
,
Zhishi Ye
Department of Chemistry and Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA   Email: mjdai@purdue.edu
,
Department of Chemistry and Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA   Email: mjdai@purdue.edu
› Author Affiliations
Further Information

Publication History

Received: 13 January 2017

Accepted after revision: 20 February 2017

Publication Date:
25 April 2017 (online)


Abstract

Piperazine ranks as the third most common N-heterocycle appearing in small-molecule pharmaceuticals. This review highlights recent advances in methods development for the construction of the piperazine­ ring system with particular emphasis on preparing carbon-substituted piperazines.

1 Introduction

2 Reduction of (Di)ketopiperazine

3 N-Alkylation

4 Transition-Metal-Catalyzed/Mediated Piperazine Synthesis

4.1 The SnAP and SLAP Methods

4.2 Palladium-Catalyzed Cyclization

4.3 Gold-Catalyzed Cyclization

4.4 Other Metal-Catalyzed/Mediated Cyclization

4.5 Borrowing Hydrogen Strategy

4.6 Imine Reductive Cyclization

5 Reduction of Pyrazines

6 Miscellaneous

7 Conclusion

 
  • References

    • 1a Taylor RD. MacCoss M. Lawson AD. G. J. Med. Chem. 2014; 57: 5845
    • 1b Zhang TY. Adv. Heterocycl. Chem. 2017; 121: 1
  • 2 Vitaku E. Smith DT. Njardarson JT. J. Med. Chem. 2014; 57: 10257
  • 3 Walker MA. Expert Opin. Drug Discov. 2014; 9: 1421
  • 4 For a review, see: Vo C.-VT. Bode JW. J. Org. Chem. 2014; 79: 2809
  • 5 Ye Z. Gettys KE. Dai M. Beilstein J. Org. Chem. 2016; 12: 702
    • 6a For an excellent review, see: Dinsmore CJ. Beshore DC. Org. Prep. Proced. Int. 2002; 34: 367 For examples
    • 6b Schanen V. Riche C. Chiaroni A. Quirion J.-C. Husson H.-P. Tetrahedron Lett. 1994; 35: 2533
    • 6c König B. Maity P. Org. Lett. 2008; 10: 1473
    • 6d Mickelson JW. Belonga KL. Jacobsen EJ. J. Org. Chem. 1995; 60: 4177
    • 6e Jung ME. Rohloff JC. J. Org. Chem. 1985; 50: 4909
    • 6f Viso A. de la Pradilla RF. López-Rodríguez ML. García A. Tortosa M. Synlett 2002; 755
    • 6g Yokoshima S. Watanabe K. Uehara F. Usui Y. Tanaka H. Bioorg. Med. Chem. Lett. 2014; 24: 5749
    • 6h Opatz T. Eur. J. Org. Chem. 2004; 4113
    • 6i Ashton KS. Denti M. Norman MH. St Jean DJ. Jr. Tetrahedron Lett. 2014; 55: 4501
    • 6j Jida M. Laconde G. Soueidan O.-M. Lebegue N. Revelant G. Pelinski L. Agbossou-Niedercorn F. Deprez B. Deprez-Poulain R. Tetrahedron Lett. 2012; 53: 5215
    • 7a Sanchez-Rosello M. Delgado O. Mateu N. Trabanco AA. Van Gool M. Fustero S. J. Org. Chem. 2014; 79: 5887
    • 7b Napolitano C. Borriello M. Cardullo F. Donati D. Paio A. Manfredini F. Synth. Commun. 2011; 41: 2031
    • 7c Bourbeau MP. Siegmund A. Allen JG. Shu H. Fotsch C. Bartberger MD. Kim K.-W. Komorowski R. Graham M. Busby J. Wang M. Meyer J. Xu Y. Salyers K. Fielden M. Véniant MM. Gu W. J. Med. Chem. 2013; 56: 10132
    • 7d Katz J. Knowles SL. Jewell JP. Sloman DL. Stanton MG. Noucti N. Patent WO2010017046 A1, 2010
    • 8a Ruppert I. Schlich K. Volbach W. Tetrahedron Lett. 1984; 25: 2195
    • 8b Prakash GK. S. Krishnamurti R. Olah GA. J. Am. Chem. Soc. 1989; 111: 393
  • 9 Robak MT. Herbage MA. Ellman JA. Chem. Rev. 2010; 110: 3600
  • 10 Liu Y. Han S.-J. Liu W.-B. Stoltz BM. Acc. Chem. Res. 2015; 48: 740
  • 11 Korch KM. Eidamshaus C. Behenna DC. Nam S. Horne D. Stoltz BM. Angew. Chem. Int. Ed. 2015; 54: 179
    • 12a Castagnoli NJr. J. Org. Chem. 1969; 34: 3187
    • 12b Cushman M. Castagnoli NJr. J. Org. Chem. 1972; 37: 1268
  • 13 Dar’in D. Bakulina O. Chizhoba M. Krasavin M. Org. Lett. 2015; 17: 3930

    • For examples:
    • 14a Liu KG. Robichaud AJ. Tetrahedron Lett. 2005; 46: 7921
    • 14b Mishani E. Dence CS. McCarthy TJ. Welch MJ. Tetrahedron Lett. 1996; 37: 319
    • 14c Van Brabandt W. Vanwalleghem M. D’hooghe M. De Kimpe N. J. Org. Chem. 2006; 71: 7083
    • 14d Balsells J. DiMichele L. Liu J. Kubryk M. Hansen K. Armstrong III JD. Org. Lett. 2005; 7: 1039
    • 14e Gao R. Canney DJ. J. Org. Chem. 2010; 75: 7451
    • 14f Crestey F. Witt M. Jaroszewski JW. Franzyk H. J. Org. Chem. 2009; 74: 5652
    • 14g Huang J. Xu W. Xie H. Li S. J. Org. Chem. 2012; 77: 7506
    • 15a Halland N. Braunton A. Bachmann S. Marigo M. Jørgensen KA. J. Am. Chem. Soc. 2004; 126: 4790
    • 15b Marigo M. Bachmann S. Halland N. Braunton A. Jørgensen KA. Angew. Chem. Int. Ed. 2004; 43: 5507
    • 16a O’Reilly MC. Lindsley CW. Org. Lett. 2012; 14: 2910
    • 16b O’Reilly MC. Lindsley CW. Tetrahedron Lett. 2012; 53: 1539
  • 17 Yar M. McGarrigle EM. Aggarwal VK. Angew. Chem. Int. Ed. 2008; 47: 3784
  • 18 Yar M. McGarrigle EM. Aggarwal VK. Org. Lett. 2009; 11: 257
  • 19 Kwon SH. Lee SM. Byun SM. Chin J. Kim BM. Org. Lett. 2012; 14: 3664
  • 20 Matlock JV. Svejstrup TD. Songara P. Overington S. McGarrigle EM. Aggarwal VK. Org. Lett. 2015; 17: 5044
  • 21 Bagnoli L. Scarponi C. Rossi MG. Testaferri L. Tiecco M. Chem. Eur. J. 2011; 17: 993
  • 22 Couty F. Durrat F. Prim D. Tetrahedron Lett. 2004; 45: 3725
    • 23a Leuscher MU. Geoghegan K. Nichols PL. Bode JW. Aldrichimica Acta 2015; 48: 43
    • 23b Vo C.-VT. Leuscher MU. Bode JW. Nat. Chem. 2014; 6: 310
    • 23c Vo C.-VT. Mikutis G. Bode JW. Angew. Chem. Int. Ed. 2013; 52: 1705
    • 24a Luescher MU. Vo C.-VT. Bode JW. Org. Lett. 2014; 16: 1236
    • 24b Geoghegan K. Bode JW. Org. Lett. 2015; 17: 1934
  • 25 Leuscher MU. Bode JW. Angew. Chem. Int. Ed. 2015; 54: 10884
  • 26 Siau W-Y. Bode JW. J. Am. Chem. Soc. 2014; 136: 17726
  • 27 Hsieh S-Y. Bode JW. Org. Lett. 2016; 18: 2098
    • 28a Nakhla JS. Wolfe JP. Org. Lett. 2007; 9: 3279
    • 28b Nakhla JS. Schultz DM. Wolfe JP. Tetrahedron 2009; 65: 6549
  • 29 Cochran BM. Michael FE. Org. Lett. 2008; 10: 329
  • 30 Lu Z. Stahl SS. Org. Lett. 2012; 14: 1234
    • 31a Chen MS. White MC. J. Am. Chem. Soc. 2004; 126: 1346
    • 31b Chen MS. Prabagaran N. Labenz NA. White MC. J. Am. Chem. Soc. 2005; 127: 6970
    • 31c Fraunhoffer KJ. White MC. J. Am. Chem. Soc. 2007; 129: 7274
  • 32 Montgomery TD. Rawal VH. Org. Lett. 2016; 18: 740
  • 33 James T. Simpson I. Grant JA. Sridharan V. Nelson A. Org. Lett. 2013; 15: 6094
  • 34 Yao L.-F. Wang Y. Huang K.-W. Org. Chem. Front. 2015; 2: 721
  • 35 Haack K.-J. Hashiguchi S. Fujii A. Ikariya T. Noyori R. Angew. Chem. Int. Ed. 1997; 36: 285
  • 36 Zhai H. Borzenko A. Lau YY. Ahn SH. Schafer LL. Angew. Chem. Int. Ed. 2012; 51: 12219
  • 37 Leitch DC. Schafer LL. Organometallics 2010; 29: 5162
  • 38 Kour H. Paul S. Singh PP. Gupta M. Gupta R. Tetrahedron Lett. 2013; 54: 761
    • 39a Watanabe Y. Tsuji Y. Ohsugi Y. Tetrahedron Lett. 1981; 22: 2667
    • 39b Grigg R. Mitchell TR. B. Sutthivaiyakit S. Tongpenyai N. J. Chem. Soc., Chem. Commun. 1981; 611
    • 39c Khai B.-T. Concilio C. Porzi G. J. Org. Chem. 1981; 46: 1759

      For reviews:
    • 40a Dobereiner GE. Crabtree RH. Chem. Rev. 2010; 110: 681
    • 40b Guillena G. Ramón DJ. Yus M. Chem. Rev. 2010; 110: 1611
    • 40c Gunanathan C. Milstein D. Science 2013; 341: 249
  • 41 Leonard J. Blacker AJ. Marsden SP. Jones MF. Mulholland KR. Newton R. Org. Process Res. Dev. 2015; 19: 1400
  • 42 Tsuji Y. Huh K-T. Ohsugi Y. Watanabe Y. J. Org. Chem. 1985; 50: 1365
    • 43a Nordstrøm LU. Madsen R. Chem. Commun. 2007; 5034
    • 43b Lorentz-Petersen LL. R. Nordstrøm LU. Madsen R. Eur. J. Org. Chem. 2012; 6752
  • 44 Mercer GJ. Sigman MS. Org. Lett. 2003; 5: 1591
  • 45 Vairaprakash P. Periasamy M. J. Org. Chem. 2006; 71: 3636
  • 46 Chen Z.-P. Zhou Y.-G. Synthesis 2016; 48: 1769
  • 47 Rossen K. Weissman SA. Sager J. Reamer RA. Askin D. Volante RP. Reider PJ. Tetrahedron Lett. 1995; 36: 6419
  • 48 Pye PJ. Rossen K. Reamer RA. Tsou NN. Volante RP. Reider PJ. J. Am. Chem. Soc. 1997; 119: 6207
  • 49 Kuwano R. Ito Y. J. Org. Chem. 1999; 64: 1232
    • 50a Fuchs R. EP 0803502, 1997
    • 50b Fuchs R. US 5945534, 1999
    • 51a Huang W.-X. Liu L.-J. Feng G.-S. Wang B. Zhou Y.-G. Org. Lett. 2016; 18: 3082
    • 51b Huang W.-X. Yu C.-B. Shi L. Zhou Y.-G. Org. Lett. 2014; 16: 3324
  • 52 Leclerc J.-P. Fagnou K. Angew. Chem. Int. Ed. 2006; 45: 7781
  • 53 Lyle RE. Thomas JJ. J. Org. Chem. 1965; 30: 1907
  • 54 Miyake FY. Yakushijin K. Horne DA. Org. Lett. 2000; 2: 3185
  • 55 Andersson H. Banchelin TS.-L. Das S. Gustafsson M. Olsson R. Almqvist F. Org. Lett. 2010; 12: 284
  • 56 Raw SA. Wilfred CD. Taylor RJ. K. Chem. Commun. 2003; 2286
  • 57 Vidal-Albalat A. Rodríguez S. González FV. Org. Lett. 2014; 16: 1752
  • 58 Trinchera P. Musio B. Degennaro L. Moliterni A. Falcicchio A. Luisi R. Org. Biomol. Chem. 2012; 10: 1962
    • 59a Suárez-Pantiga S. Colas K. Johansson MJ. Mendoza A. Angew. Chem. Int. Ed. 2015; 54: 14094
    • 59b Chen Z. Wu J. Chen Y. Li L. Xia Y. Li Y. Liu W. Lei T. Yang L. Gao D. Li W. Organometallics 2012; 31: 6005
    • 59c Cariou R. Gibson VC. Tomov AK. White AJ. P. J. Organomet. Chem. 2009; 694: 703
    • 59d Trepanier SJ. Wang S. Can. J. Chem. 1996; 74: 2032
  • 60 Lu C. Lu X. Org. Lett. 2002; 4: 4677
    • 61a For a review: Dömling A. Huang Y. Synthesis 2010; 2859
    • 61b Zhu D. Xia L. Pan L. Chen R. Mou Y. Chen X. J. Org. Chem. 2012; 77: 1386
  • 62 Rossen K. Sager J. DiMichele LM. Tetrahedron Lett. 1997; 38: 3183
  • 63 Yavari I. Bayat MJ. Ghazanfarpour-Darjani M. Tetrahedron Lett. 2014; 55: 5595
  • 64 Dong H.-R. Chen Z.-B. Li R.-S. Dong H.-S. Xie Z.-X. RSC Adv. 2015; 5: 10768
  • 65 Ruider SA. Müller S. Carreira EM. Angew. Chem. Int. Ed. 2013; 52: 11908