Development of Heterocyclic Multicomponent Reactions through Guided Exploration: Direct, Reasonable and Unpredictable Processes

This Account is dedicated to Prof. Mercedes Alvarez (University of Barcelona) on the occasion of her retirement, for her mentorship and support

Abstract

This Account summarizes the research of the group on the multicomponent reactions arena with fundamental heterocycles as substrates, using mechanistic considerations to hypothesize new processes and to rationalize results. Biomedical applications of the ensuing adducts were also envisaged, which brought about interesting discoveries.

1 Introduction and Context

2 The Beginnings: Unexplored Heterocyclic Substrates

3 Interrupted Processes

4 Multiple Multicomponent Reactions: Problem of Selectivity

5 Extended Multicomponent Reactions

6 Conclusions and Wishes

Key words

azines - azoles - heterocycles - multicomponent reactions - reaction discovery - reaction mechanism

Publication History

Received: 23 December 2021

Accepted after revision: 25 January 2022

Accepted Manuscript online:
25 January 2022

Article published online:
14 February 2022

• References


For reflections on the ideal synthesis, see:
• 1a Trost BM. Science 1991; 254: 1471
• 1b Kolb HC, Finn MG, Sharpless KB. Angew. Chem. Int. Ed. 2001; 40: 2004
• 1c Burke MD, Schreiber SL. Angew. Chem. Int. Ed. 2003; 43: 46
• 1d Wender PA, Verma VA, Paxton TJ, Pillow TH. Acc. Chem. Res. 2008; 41: 40
• 1e Newhouse T, Baran PS, Hoffmann RW. Chem. Soc. Rev. 2009; 38: 3010
• 1f Gaich T, Baran PS. J. Org. Chem. 2010; 75: 4657
• 1g Hayashi Y. J. Org. Chem. 2021; 86: 1
• 2a Dömling A, Ugi I. Angew. Chem. Int. Ed. 2000; 39: 3168

For overviews in the field, see:
• 2b Multicomponent Reactions. Zhu J, Bienaymé H. Wiley-VCH; Weinheim: 2005
• 2c Multicomponent Reactions in Organic Synthesis. Zhu J, Wang Q, Wang M.-X. Wiley-VCH; Weinheim: 2015
• 2d Multicomponent Reactions towards Heterocycles . Van der Eycken E, Sharma UK. Wiley-VCH; Weinheim: 2021
• 3 Tietze LF, Brasche G, Gericke KM. Domino Reactions in Organic Synthesis. Wiley-VCH; Weinheim: 2006
• 4a Horton DA, Bourne GT, Smythe ML. Chem. Rev. 2003; 103: 893

For an overview of the field, see:
• 4b Wess G, Urmann M, Sickenberger B. Angew. Chem. Int. Ed. 2001; 40: 3341
• 4c Blakemore DC, Castro L, Churcher I, Rees DC, Thomas AW, Wilson DM, Wood A. Nat. Chem. 2018; 10: 383

For representative examples, see:
• 5a Sunderhaus JD, Martin SF. Chem. Eur. J. 2009; 15: 1300
• 5b Jiang B, Rajale T, Wever W, Tu S.-J, Li G. Chem. Asian J. 2010; 5: 2318
• 5c Rotstein BH, Zaretsky S, Rai V, Yudin AK. Chem. Rev. 2014; 114: 8323

For representative contributions of our group, see:
• 6a Isambert N, Lavilla R. Chem. Eur. J. 2008; 14: 8444
• 6b Vicente-García E, Kielland N, Lavilla R. In Multicomponent Reactions in Organic Synthesis . Zhu J, Wang Q, Wang M.-X. Wiley-VCH; Weinheim: 2015: 159
• 6c Ghashghaei O, Pedrola M, Escolano C, Lavilla R. In Multicomponent Reactions towards Heterocycles . Van der Eycken E, Sharma UK. Wiley-VCH; Weinheim: 2021: 1

See also:
• 6d Ibarra IA, Islas-Jácome A, González-Zamora E. Org. Biomol. Chem. 2018; 16: 1402
• 7a Lavilla R, Kumar R, Coll O, Masdeu C, Spada A, Bosch J, Espinosa E, Molins E. Chem. Eur. J. 2000; 6: 1763
• 7b Lavilla R, Spada A, Bosch J. Org. Lett. 2000; 2: 1533
• 7c Lavilla R, Bernabeu MC, Brillas E, Carranco I, Díaz JL, Llorente N, Rayo M, Spada A. Chem. Commun. 2002; 850
• 7d Lavilla R, Spada A, Carranco I, Bosch J. J. Org. Chem. 2001; 66: 1487
• 8 Tejedor D, García-Tellado F. Chem. Soc. Rev. 2007; 36: 484
• 9a Kouznetsov VV. Tetrahedron 2009; 65: 2721
• 9b Ghashghaei O, Masdeu C, Alonso C, Palacios F, Lavilla R. Drug Discovery Today: Technol. 2018; 29: 71 ; and references cited therein
• 10 Lavilla R. Curr. Org. Chem. 2004; 8: 715
• 11 Lavilla R, Coll O, Kumar R, Bosch J. J. Org. Chem. 1998; 63: 2728
• 12a Lavilla R, Bernabeu MC, Carranco I, Díaz JL. Org. Lett. 2003; 5: 717
• 12b Carranco I, Díaz JL, Jiménez O, Vendrell M, Albericio F, Royo M, Lavilla R. J. Comb. Chem. 2005; 7: 33
• 13a Smith CD, Gavrilyuk JI, Lough AJ, Batey RA. J. Org. Chem. 2010; 75: 702
• 13b Xu HJ, Zuend SG, Woll M, Tao YN, Jacobsen E. Science 2010; 327: 986
• 13c Domingo LR, Aurell MJ, Sáez JA, Mekelleche SM. RSC Adv. 2014; 4: 25268
• 14 Vicente-García E, Catti F, Ramón R, Lavilla R. Org. Lett. 2010; 12: 860
• 15 Vicente-García E, Ramón R, Lavilla R. Synthesis 2011; 2237
• 16a Liu H, Dagousset G, Masson G, Retailleau P, Zhu J. J. Am. Chem. Soc. 2009; 131: 4598

For an overview, see:
• 16b Fochi M, Caruana L, Bernardi L. Synthesis 2014; 46: 135
• 17 Vicente-García E, Ramón R, Preciado S, Lavilla R. Beilstein J. Org. Chem. 2011; 7: 980
• 18 Oku A, Kinugasa M, Kamada T. Chem. Lett. 1993; 22: 165
• 19 di Pietro O, Vicente-García E, Taylor MC, Berenguer D, Viayna E, Lanzoni A, Sola I, Sayago H, Riera C, Fisa R, Clos MV, Pérez B, Kelly JM, Lavilla R, Muñoz-Torrero D. Eur. J. Med. Chem. 2015; 105: 120
• 20a Camps P, Formosa X, Galdeano C, Muñoz-Torrero D, Ramírez L, Gómez E, Isambert N, Lavilla R, Badia A, Clos MV, Bartolini M, Mancini F, Andrisano V, Arce MP, Rodríguez-Franco MI, Huertas O, Dafni T, Luque FJ. J. Med. Chem. 2009; 52: 5365
• 20b di Pietro O, Viayna E, Vicente-García E, Bartolini M, Ramón R, Juárez-Jiménez J, Clos MV, Pérez B, Andrisano V, Luque FJ, Lavilla R, Muñoz-Torrero D. Eur. J. Med. Chem. 2014; 73: 141
• 20c di Pietro O, Pérez-Areales FJ, Juárez-Jiménez J, Espargaró A, Clos MV, Pérez B, Lavilla R, Sabaté R, Luque FJ, Muñoz-Torrero D. Eur. J. Med. Chem. 2014; 84: 107
• 21 Dömling A. Chem. Rev. 2006; 106: 17
• 22 Masdeu C, Díaz JL, Miguel M, Jiménez O, Lavilla R. Tetrahedron Lett. 2004; 45: 7907
• 23 Masdeu C, Gómez E, Williams NA, Lavilla R. QSAR Comb. Sci. 2006; 25: 465
• 24 Díaz JL, Miguel M, Lavilla R. J. Org. Chem. 2004; 69: 3550
• 25 Kielland N, Lavilla R. In Synthesis of Heterocycles via Multicomponent Reactions II . Orru RV. A, Ruitjer E. Springer; Heidelberg: 2010: 127
• 26 de Moliner F, Kielland N, Lavilla R, Vendrell M. Angew. Chem. Int. Ed. 2017; 56: 3758
• 27 Loudet A, Burgess K. Chem. Rev. 2007; 107: 4891
• 28 Vázquez-Romero A, Kielland N, Arévalo MJ, Preciado S, Mellanby RJ, Feng Y, Lavilla R, Vendrell M. J. Am. Chem. Soc. 2013; 135: 16018
• 29 For an excellent review on interrupted reactions, see: Trudel V, Tien CH, Trofimova A, Yudin AK. Nat. Rev. Chem. 2021; 5: 604
• 30 Carranco I, Díaz JL, Jiménez O, Lavilla R. Tetrahedron Lett. 2003; 44: 8449
• 31 Jiménez O, de la Rosa G, Lavilla R. Angew. Chem. Int. Ed. 2005; 44: 6521
• 32 Isambert N, Cruz M, Arévalo MJ, Gómez E, Lavilla R. Org. Lett. 2007; 9: 4199
• 33 Pérez-Perarnau A, Preciado S, Palmeri CM, Moncunill-Massaguer C, Iglesias-Serret D, González-Gironés D, Miguel M, Karasawa S, Sakamoto S, Cosialls AM, Rubio-Patiño C, Saura-Esteller J, Ramón R, Caja L, Fabregat I, Pons G, Handa H, Albericio F, Gil J, Lavilla R. Angew. Chem. Int. Ed. 2014; 53: 10150
• 34 Preciado S, Vicente-García E, Llabrés S, Luque FJ, Lavilla R. Angew. Chem. Int. Ed. 2012; 51: 6874
• 35 Llabrés S, Vicente-García E, Preciado S, Guiu C, Pouplana R, Lavilla R, Luque FJ. Chem. Eur. J. 2013; 19: 13355
• 36 Ugi I, Böttner E. Liebigs Ann. Chem. 1963; 670: 74
• 37 Williams NA. O, Masdeu C, Díaz JL, Lavilla R. Org. Lett. 2006; 8: 5789
• 38 Masdeu C, Gómez E, Williams NA. O, Lavilla R. Angew. Chem. Int. Ed. 2007; 46: 3043
• 39 Tarragó T, Masdeu C, Gómez E, Isambert N, Lavilla R, Giralt E. ChemMedChem 2008; 3: 1558
• 40 Arévalo MJ, Kielland N, Masdeu C, Miguel M, Isambert N, Lavilla R. Eur. J. Org. Chem. 2009; 617
• 41 Pérez-Rentero S, Kielland N, Terrazas M, Lavilla R, Eritja R. Bioconjugate Chem. 2010; 21: 1622
• 42 Kielland N, Vendrell M, Lavilla R, Chang Y.-T. Chem. Commun. 2012; 48: 7401
• 43 Sintes M, De Moliner F, Caballero-Lima D, Denning DW, Read ND, Kielland N, Vendrell M, Lavilla R. Bioconjugate Chem. 2016; 27: 1430
• 44 Wessjohann LA, Neves Filho RA. W, Rivera DG. In Isocyanide Chemistry: Applications in Synthesis and Materials Science . Nenajdenko VG. Wiley-VCH; Weinheim: 2012: 233
• 45 For a detailed analysis, see: Ghashghaei O, Seghetti F, Lavilla R. Beilstein J. Org. Chem. 2019; 15: 521
• 46 Ghashghaei O, Caputo S, Sintes M, Revés M, Kielland N, Estarellas C, Luque FJ, Aviñó A, Eritja R, Serna-Gallego A, Marrugal-Lorenzo JA, Pachón J, Sánchez-Céspedes J, Treadwell R, de Moliner F, Vendrell M, Lavilla R. Chem. Eur. J. 2018; 24: 14513
• 47 Pedrola M, Jorba M, Jardas E, Jardi F, Ghashghaei O, Viñas M, Lavilla R. Front. Chem. 2019; 7: 475
• 48 Jorba M, Pedrola M, Ghashghaei O, Herráez R, Campos-Vicens L, Luque FJ, Lavilla R, Viñas M. Antibiotics 2021; 10: 709
• 49 For a representative review, see: Sharma UK, Sharma N, Vachhani DD, Van der Eycken E. Chem. Soc. Rev. 2015; 44: 1836
• 50 Zarganes-Tzitzikas T, Chandgude AL, Dömling A. Chem. Rec. 2015; 15: 981
• 51 Kishore KG, Ghashghaei O, Estarellas C, Mestre MM, Monturiol C, Kielland N, Kelly JM, Francisco AF, Jayawardhana S, Muñoz-Torrero D, Pérez B, Luque FJ, Gámez-Montaño R, Lavilla R. Angew. Chem. Int. Ed. 2016; 55: 8994
• 52 Ghashghaei O, Pedrola M, Seghetti F, Martin VV, Zavarce R, Babiak M, Novacek J, Hartung F, Rolfes K, Haarmann-Stemmann T, Lavilla R. Angew. Chem. Int. Ed. 2021; 60: 2603
• 53 Granda JM, Donina L, Dragone V, Long D.-L, Cronin L. Nature 2018; 559: 377