Synthesis 2012; 44(23): 3551-3578
DOI: 10.1055/s-0032-1316797
review
© Georg Thieme Verlag Stuttgart · New York

Advances in the Synthesis of Morpholin-3-ones and Morpholin-2-ones

Uroš Trstenjak
Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia   Fax: +386(1)4258031   Email: danijel.kikelj@ffa.uni-lj.si
,
Janez Ilaš
Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia   Fax: +386(1)4258031   Email: danijel.kikelj@ffa.uni-lj.si
,
Danijel Kikelj*
Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia   Fax: +386(1)4258031   Email: danijel.kikelj@ffa.uni-lj.si
› Author Affiliations
Further Information

Publication History

Received: 24 July 2012

Accepted after revision: 17 September 2012

Publication Date:
05 November 2012 (online)


Abstract

This review covers advances in the synthesis of morpholin-3-ones and morpholin-2-ones. Besides the classical approaches for the preparation of both heterocycles that utilize intermolecular cyclizations of reactants or oxidation of morpholine and its derivatives, strategies employing various ring-expansion reactions using smaller heterocyclic substrates or multicomponent reactions are described.

1 Introduction

2 Synthesis of Morpholin-3-ones

2.1 By Formation of Two Bonds

2.2 By Formation of One Bond

2.3 By Introduction of Substituents

3 Synthesis of Morpholin-2-ones

3.1 By Formation of Two Bonds

3.2 By Formation of One Bond

3.3 By Introduction of Substituents

4 Conclusion

 
  • References

  • 1 Axe FU, Bembenek SD, Butler CR, Edwards JP, Fourie AM, Grice CA, Savall BM, Tays KL, Wei J. PCT Int. Appl WO 2005012296, 2005 ; Chem. Abstr. 2005, 142, 219285.
  • 2 Roehrig S, Straub A, Pohlmann J, Lampe T, Pernerstorfer J, Schlemmer KH, Reinemer P, Perzborn E. J. Med. Chem. 2005; 48: 5900
  • 3 Beswick PJ, Gleave RJ. PCT Int. Appl WO 2010091721, 2010 ; Chem. Abstr. 2010, 153, 333896.
  • 4 Liang P.-H, Hsin L.-W, Cheng C.-Y. Bioorg. Med. Chem. 2002; 10: 3267
  • 5 Nisihida H, Saitoh F, Hirabayashi T, Chackalamannil S, Chan TY, Chelliah M, Clasby M, Dwyer MP, Greenlee WJ, Xia Y. PCT Int. Appl WO 2010065717, 2010 ; Chem. Abstr. 2010, 153, 62269.
  • 6 Mannino C, Nievo M, Machetti F, Papakyriakou A, Calderone V, Fragai M, Guarna A. Bioorg. Med. Chem. 2006; 14: 7392
  • 7 TenBrink RE. J. Org. Chem. 1987; 52: 418
  • 8 Pigza JA, Quach T, Molinski TF. J. Org. Chem. 2009; 74: 5510
  • 9 Monasson O, Ginisty M, Mravljak J, Bertho G, Gravier-Pelletier C, Le Merrer Y. Tetrahedron: Asymmetry 2009; 20: 2320
  • 10 Wang B, Wong OA, Zhao MX, Shi Y. J. Org. Chem. 2008; 73: 9539
  • 11 Tayama E, Otoyama S, Tanaka H. Tetrahedron: Asymmetry 2009; 20: 2600
  • 12 Hong C, Shiling L, Yong L, Haifeng R, Manping T. CN 1017978, 2010
  • 13 Song Y, Zhu BY, Bhakta C, Scarborough R. PCT Int. Appl WO 20060063293, 2006 ; Chem. Abstr. 2006, 145, 63144.
  • 14 Seredenin SB, Mozhaeva TJ. J, Viglinskaja AO, Jarkova MA. N, Kolyvanov GB, Zherdev VP, Litvin AA. RU 2373202, 2009 ; Chem. Abstr. 2009, 151, 550578.
  • 15 Artus Surroca JJ, Fernandez BD, Iacoangeli T, Lluis TJ. PCT Int. Appl WO 2007057681, 2007 ; Chem. Abstr. 2007, 147, 9926.
  • 16 Mederski WK. R, Wendel PL, Woissyk M. Heterocycles 2007; 74: 437
  • 17 Wei C, Kejie W, Jianjun Y. CN 1131764, 2009
  • 18 Fish P, Mackenny MC, Stobie A, Wakenhut F, Whitlock GA. US Patent Appl. 250775, 2005 ; Chem. Abstr. 2005, 143, 460166.
  • 19 Allen AJ, Hemrick-Luecke S, Sumner CR, Wallace OB. PCT Int. Appl WO 2005060949, 2005 ; Chem. Abstr. 2005, 143, 115550.
  • 20 Schwarz M, Gaillard P, Page P, Gotteland JP, Thomas RJ. PCT Int. Appl WO 2005026159, 2005 ; Chem. Abstr. 2005, 142, 336386.
  • 21 Gore J, Kasum B, Scharfbillig IM, Ward AD. Aust. J. Chem. 1996; 49: 1235
  • 22 Chen B, Burns JF, Doller D. PCT Int. Appl WO 2010108052, 2010 ; Chem. Abstr. 2010, 153, 456483.
  • 23 Heaton DW, Thomas AP. PCT Int. Appl WO 2004101564, 2004 ; Chem. Abstr. 2004, 142, 6552.
  • 24 Kashima C, Harada K. J. Chem. Soc., Perkin Trans. 1 1988; 1521
  • 25 Nelson TD, Rosen JD, Brands KM. J, Craig B, Huffman MA, McNamara JM. Tetrahedron Lett. 2004; 45: 8917
  • 26 Zhang QY, Xu JM, Chen WQ, Wu Q, Lin XF. Synlett 2008; 679
  • 27 Fan MJ, Li GQ, Liang YM. Tetrahedron 2006; 62: 6782
  • 28 Mckennon MJ, Meyers AI. J. Org. Chem. 1993; 58: 3568
  • 29 Barvian K, Basarab GS, Gowravaram MR, Hauck SI, Zhou F. PCT Int. Appl WO 2010043893, 2010 ; Chem. Abstr. 2010, 152, 501391.
  • 30 Norman BH, Kroin JS. J. Org. Chem. 1996; 61: 4990
  • 31 Fairfax DJ, Yang Z. PCT Int. Appl WO 2008019372, 2008 ; Chem. Abstr. 2008, 148, 262574.
  • 32 Brown GR, Foubister AJ, Stribling D. J. Chem. Soc., Perkin Trans. 1 1987; 547
  • 33 Axten JM, Blackledge CW, Brady GP, Feng YG, Grant SW, Medina JR, Miller WH, Romeril SP. PCT Int. Appl WO 2010059658, 2010 ; Chem. Abstr. 2010, 153, 11671.
  • 34 Alexander R, Balasundaram A, Batchelor M, Bookings D, Crepy K, Crabbe T, Deltent MF, Driessens F, Gill A, Harris S, Hutchinson G, Kulisa C, Merriman M, Mistry P, Parton T, Turner J, Whitcombe I, Wright S. Bioorg. Med. Chem. Lett. 2008; 18: 4316
  • 35 Alexander RP, Aujla PS, Crepy KV. L, Foley AM, Franklin RJ, Haughan AF, Horsley HT, Jones WM, Lallemand BI. L, Mack SR, Morgan T, Pasau PM. G, Phillips DJ, Sabin VM, Buckley GM, Jenkins K, Perry BG. PCT Int. Appl WO 2008001076, 2008 ; Chem. Abstr. 2008, 148, 121697.
  • 36 Kimura T, Kawano K, Doi E, Kitazawa N, Takaishi M, Ito K, Kaneko T, Sasaki T, Sato N, Miyagawa T, Hagiwara H. US Patent Appl. 117798, 2007 ; Chem. Abstr. 2007, 147, 9927.
  • 37 Celanire S, Denonne FValade A. PCT Int. Appl WO 2008128919, 2008 ; Chem. Abstr. 2008, 149, 513838.
  • 38 Qin D, Norton B, Liao X, Knox AN, Fang Y, Lee J, Dreabit JC, Christensen SB, Benowitz AB, Aubart KM. PCT Int. Appl WO 2009061879, 2009 ; Chem. Abstr. 2009, 150, 539727.
  • 39 Tang PC, Feng J, Feng F, Zhang L, Ye J, Wang L, Song Z, Zhang Q, Dang Y, Lu Y, Zong L, Jing C, Zang J, Zhou Y. PCT Int. Appl WO 2009012647, 2009 ; Chem. Abstr. 2009, 150, 168388.
  • 40 Morie T, Kato S, Harada H, Matsumoto J. Heterocycles 1994; 38: 1033
  • 41 Collins I, Reader JC, Cheung KM, Matthews TP, Proisy N, Klair SS. PCT Int. Appl WO 2008075007, 2008 ; Chem. Abstr. 2008, 149, 104737.
  • 42 Kangasmetsa J, Liley M. PCT Int. Appl WO 2008006715, 2007 ; Chem. Abstr. 2007, 148, 128332.
  • 43 Jobson NK, Crawford AR, Dewar D, Pimlott SL, Sutherland A. Bioorg. Med. Chem. Lett. 2009; 19: 4996
  • 44 Metro TX, Pardo DG, Cossy J. J. Org. Chem. 2008; 73: 707
  • 45 Jobson NK, Crawford AR, Dewar D, Pimlott SL, Sutherland A. Bioorg. Med. Chem. Lett. 2008; 18: 4940
  • 46 Tan W, Zhao BX, Shi M, Sha L, Miao JY, Shin DS. Chin. J. Chem. 2006; 24: 396
  • 47 He Q, Zhu X, Shi M, Zhao B, Zhao J, Zhang S, Miao J. Bioorg. Med. Chem. 2007; 15: 3889
  • 48 Greenwood DT, Mallion KB, Todd AH, Turne RW. J. Med. Chem. 1975; 18: 573
  • 49 Zindell R, Riether D, Bosanac T, Berry A, Gemkow MJ, Ebneth A, Löbbe S, Raymond EL, Thome D, Shih DT, Thomson D. Bioorg. Med. Chem. Lett. 2009; 19: 1604
  • 50 Perrone R, Berardi F, Leopoldo M, Tortorella V, Lograno MD, Daniele E, Govoni S. J. Med. Chem. 1992; 35: 3045
  • 51 Ackley MA. PCT Int. Appl WO 2008087512, 2008 ; Chem. Abstr. 2008, 149, 200935.
  • 52 Sakai D, Watanabe K. PCT Int. Appl WO 2009035159, 2009 ; Chem. Abstr. 2009, 150, 329813.
  • 53 Okuyama M, Uehara F, Iwamura H, Watanabe K. PCT Int. Appl WO 2007011065, 2007 ; Chem. Abstr. 2007, 146, 184478.
  • 54 Barta NS, Glase SA, Gray DL, Reichard GA, Simons LJ, Xu W. US Patent Appl. 245519, 2005 ; Chem. Abstr. 2005, 143, 440426.
  • 55 Melloni P, Della Torre A, Lazzari E, Mazzini G, Meroni M. Tetrahedron 1985; 41: 1393
  • 56 Santosh Reddy R, Choithaiwale PV, Suryavanshi G, Chavan VB, Sundalai A. Chem. Commun. 2010; 46: 5012
  • 57 Alcazar L, Bailey A, Bull RJ, Johnson T, Kindon ND, Lister AS, Robbins AJ, Stocks MJ, Tobald BJ. PCT Int. Appl WO 2009098448, 2009 ; Chem. Abstr. 2009, 151, 267048.
  • 58 Balsamo A, Calderone V, Rapposelli S. PCT Int. Appl WO 2008007210, 2008 ; Chem. Abstr. 2008, 148, 144783.
  • 59 Pfeil E, Harder U. Angew. Chem. Int. Ed. Engl. 1967; 6: 178
  • 60 Zeng Z, Shreeve JM. J. Fluorine Chem. 2009; 130: 727
  • 61 Brown DS, Elliott MC, Moody CJ, Mowlem TJ, Marino JP. Jr, Padwa A. J. Org. Chem. 1994; 59: 2447
  • 62 Aparicio DM, Terán JL, Roa LF, Gnecco D, Juárez JR, Orea ML, Mendoza A, Flores-Alamo M, Micouin L. Synthesis 2011; 2310
  • 63 Baldwin JE. J. Chem. Soc., Chem. Commun. 1976; 734
  • 64 Yoshioka D, Inoue K, Yonezawa Y, Shin C. Heterocycles 2003; 60: 1377
  • 65 Alcaide B, Almendros P, Martinez del Campo T. Chem.–Eur. J. 2008; 14: 7756
  • 66 Danklmaier J, Hönig H. Liebigs Ann. Chem. 1988; 1149
  • 67 Lucas HJ, Baumgarten W. J. Am. Chem. Soc. 1941; 63: 1653
  • 68 Dahlgren A, Johansson PO, Kvarnström I, Musil D, Nilsson I, Samuelsson B. Bioorg. Med. Chem. 2002; 10: 1829
  • 69 Nilsson JW, Kvarnström I, Musil D, Nilsson I, Samuelsson B. J. Med. Chem. 2003; 46: 3985
  • 70 Levy OE, Semple JE, Lim ML, Reiner J, Rote WE, Dempsey E, Richard BM, Zhang E, Tulinsky A, Ripka WC, Nutt RF. J. Med. Chem. 1996; 39: 4527
  • 71 Liu H, He X, Phillips D, Zhu X, Yang K, Lau T, Wu B, Xie Y, Nguyen TN, Wang X. PCT Int. Appl WO 2008076754, 2008 ; Chem. Abstr. 2008, 149, 128815.
  • 72 Kimura T, Kawano K, Doi E, Kitazawa N, Takaishi M, Ito K, Kaneko T, Sasaki T, Sato N, Miyagawa T, Hagiwara H. US Patent Appl. 207900, 2008 ; Chem. Abstr. 2008, 149, 308005.
  • 73 Mederski WK. R, Cezanne B, van Amsterdam C, Bühring KU, Dorsch D, Gleitz J, März J, Tsaklakidis C. Bioorg. Med. Chem. Lett. 2004; 14: 5817
  • 74 Wagner H, Langkopf E, Stricher R, Eckhardt M, Schuler-Metz A, Pautsch A, Schoelch C. PCT Int. Appl WO 2008099000, 2008 ; Chem. Abstr. 2008, 149, 288938.
  • 75 Astle MJ, Welks JD. J. Org. Chem. 1961; 26: 4325
  • 76 Dorsch D, Cezanne B, Mederski WK. R, Tsaklakidis C, Wurziger H. PCT Int. Appl WO 2005016899, 2005 ; Chem. Abstr. 2005, 142, 261542.
  • 77 Mingfeng S. PCT Int. Appl WO 2010133180, 2010 ; Chem. Abstr. 2010, 153, 643501.
  • 78 Kubota H, Nakamura Y, Higashijima T, Yamamoto Y, Oka K, Shigeki I. PCT Int. Appl WO 2005095395, 2005 ; Chem. Abstr. 2005, 143, 387010.
  • 79 Ishii Y, Nakano T. JP 11106377, 1999 ; Chem. Abstr. 1999, 130, 281986.
  • 80 Perrone R, Bettoni G, Tortorella V. Synthesis 1976; 598
  • 81 Sheehan JC, Tulis RW. J. Org. Chem. 1974; 39: 2264
  • 82 Huisgen R, Szeimies G, Moebius L. Chem. Ber. 1966; 99: 475
  • 83 Rossi L, Trimarco P. Synthesis 1978; 743
  • 84 Markgraf JH, Sangani PK, Finkelstein M. Synth. Commun. 1997; 27: 1285
  • 85 Markgraf JH, Stickney CA. J. Heterocycl. Chem. 2000; 37: 109
  • 86 Elliott ML, Howard HR. Jr. PCT Int. Appl WO 2005061491, 2005 ; Chem. Abstr. 2005, 143, 115570.
  • 87 Nazare M, Wehner V, Laux V, Urmann M, Bauer A, Matter H. EP 1479675, 2004 ; Chem. Abstr. 2004, 142, 6526.
  • 88 Wenkert E, Angell EC. Synth. Commun. 1988; 18: 1331
  • 89 Möhrle H, Engelsing R. Arch. Pharm. Ber. Dtsch. Pharm. Ges. 1970; 303: 1
  • 90 Möhrle H, Schillings P. Arch. Pharm. 1987; 320: 258
  • 91 Nechev LV, Dobrev A, Ivanov C. Bulg. Chem. Commun. 1992; 25: 509
  • 92 Yamanaka T, Ohki H, Ishida J, Toda A, Harayama Y, Makino T, Kunikawa S, Mizuno H, Ohtake H. PCT Int. Appl WO 2008139986, 2008 ; Chem. Abstr. 2008, 149, 576837.
  • 93 Owen DR, Bull DJ, Bunnage ME, Glossop MS, Maguire RJ, Strang RS. Bioorg. Med. Chem. Lett. 2010; 20: 92
  • 94 Dobrev A, Nechev L, Ivanov C, Bon M. J. Chem. Res., Synop. 1999; 3: 188
  • 95 Roehrig S, Jeske M, Akbaba M, Rosentreter U, Boyer S, Fischer K, Pohlmann J, Tuch A, Perzborn E, Gerdes C, Schlemmer KH, Burkhardt N, Allerheiligen S, Nell P, Arndt S, Lobell M. PCT Int. Appl WO 2006061116, 2006 ; Chem. Abstr. 2006, 145, 62922.
  • 96 Vasylyev M, Alper H. Org. Lett. 2008; 10: 1357
  • 97 Kashima C, Harada K. J. Org. Chem. 1989; 54: 789
  • 98 Allerton CM. N, Cook AS, Hepworth D, Miller DC. PCT Int. Appl WO 2005115985, 2005 ; Chem. Abstr. 2005, 144, 36256.
  • 99 Chong HS. PCT Int. Appl WO 2010011367, 2010 ; Chem. Abstr. 2010, 152, 215488.
  • 100 Chong HS, Ma X, Lee H, Bui P, Song HA, Birch N. J. Med. Chem. 2008; 51: 2208
  • 101 Nakata H, Imai T, Yokoshima S, Fukuyama T. Heterocycles 2008; 76: 747
  • 102 Looper RE, Williams RM. Tetrahedron Lett. 2001; 42: 769
  • 103 Chen X, Chen J, Zhu J. Synthesis 2006; 4081
  • 104 Dellaria JF. Jr, Santarsiero BD. J. Org. Chem. 1989; 54: 3916
  • 105 Baker WR, Condon SL, Spanton S. Tetrahedron Lett. 1992; 33: 1573
  • 106 Dastlik KA, Giles RG. F, Roos GH. P. Tetrahedron: Asymmetry 1996; 7: 2525
  • 107 Stanković S, D’hooghe M, De Kimpe N. Org. Biomol. Chem. 2010; 8: 4266
  • 108 Sosa-Rivadeneyra MS, Quintero L, Parrodi CA, Bernes S, Castellanos E, Juaristi E. ARKIVOC 2003; (xi): 61
  • 109 Guesne S, Comesse S, Kadouri-Puchot C. Lett. Org. Chem. 2006; 3: 315
  • 110 Agami C, Comesse S, Kadouri-Puchot C. J. Org. Chem. 2002; 67: 2424
  • 111 Yamauchi T, Higashiyama K, Kubo H, Ohmiya S. Tetrahedron: Asymmetry 2000; 11: 3003
  • 112 Park YS, Lee YM, Kang KH, Min HM, Lim HJ, Park EH. ARKIVOC 2010; (ii): 1
  • 113 Rulev AY, Maddaluno J. J. Phys. Org. Chem. 2002; 15: 590
  • 114 Churches QI, Johnson JK, Fifer NL, Hutton CA. Aust. J. Chem. 2011; 64: 62
  • 115 Petasis NA, Akritopoulou I. Tetrahedron Lett. 1993; 34: 583
  • 116 Murakami M, Hayashi M, Ito Y. J. Org. Chem. 1994; 59: 7910
  • 117 Mullen GB, St Georgiev V, Acker CG. Heterocycles 1986; 24: 1285
  • 118 Kim YB, Choi EH, Keum G, Kang SB, Lee DH, Koh HY, Kim Y. Org. Lett. 2001; 3: 4149
  • 119 Ashwood MS, Cotrell IF, Davies AJ. Tetrahedron: Asymmetry 1997; 8: 957
  • 120 McNamara JM, Zhao MM. PCT Int. Appl WO 2005096319, 2005 ; Chem. Abstr. 2005, 143, 397437.
  • 121 Mitsudome T, Noujima A, Mizugaki T, Jitsukawa K, Kaneda K. Green Chem. 2009; 11: 793
  • 122 Su WY. US Patent Appl. 5136035, 1992 ; Chem. Abstr. 1993, 118, 38931.
  • 123 Anelli PL, Bafi S, Montanari F, Quici S. J. Org. Chem. 1989; 54: 2970
  • 124 Devine PN, Foster BS, Grabowski EJ. J, Reider PJ. Heterocycles 2002; 58: 119
  • 125 Ding K, Ma D. Tetrahedron 2001; 57: 6361
  • 126 Chakraborty TK, Reddy GV, Hussain KA. Tetrahedron Lett. 1991; 32: 7597
  • 127 Song HA, Dadwal M, Yeseul L, Mick E, Chong HS. Angew. Chem. Int. Ed. 2009; 48: 1328
  • 128 Moyer MP, Feldman PL, Rapoport H. J. Org. Chem. 1985; 50: 5223
  • 129 Pansare SV, Jain RP, Bhattacharyya A. Tetrahedron Lett. 1999; 40: 5255
  • 130 West FG, Glaeske KW, Naidu BN. Synthesis 1993; 977
  • 131 West FG, Naidu BN. J. Org. Chem. 1994; 59: 6051
  • 132 Yamazaki S, Iwata Y, Fukushima Y. Org. Biomol. Chem. 2009; 7: 655
  • 133 Agami C, Couty F, Hamon L, Prince B, Puchot C. Tetrahedron 1990; 46: 7003
  • 134 Agami C, Couty F, Prince B, Puchot C. Tetrahedron 1991; 47: 4343
  • 135 Tabushi I, Kodera M. J. Am. Chem. Soc. 1986; 108: 1103
  • 136 Williams RM, Sinclair PJ, Zhani D, Chen D. J. Am. Chem. Soc. 1988; 110: 1547
  • 137 Reno DS, Lotz BT, Miller MJ. Tetrahedron Lett. 1990; 31: 827
  • 138 Dong Z. Tetrahedron Lett. 1992; 50: 7725
  • 139 Aoyagi Y, Williams RM. Tetrahedron 1998; 54: 10419
  • 140 Shen K, Keng YF, Wu L, Guo XL, Lawrence DS, Zhang ZY. J. Biol. Chem. 2001; 276: 47311
  • 141 Williams RM, Colson PJ, Zhai W. Tetrahedron Lett. 1994; 50: 9371