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Synthetic Synthetic Strategies, Strategies, Reactivity Reactivity and and Applications Applications of of 1,5-Naphthyridines 1,5-Naphthyridines

, Carme MasdeuEndika , Endika Martin-Encinas, Asier Selas, Gloria Rubiales, Maria Maria Fuertes Fuertes, Carme Masdeu, Martin-Encinas, Asier Selas, Gloria Rubiales, Francisco Palacios * and Concepcion Alonso * Francisco Palacios * and Concepcion Alonso * Departamento Departamento de de Química Química Orgánica Orgánica I,I, Facultad Facultad de de Farmacia, Farmacia. Universidad Universidaddel delPaís PaísVasco/Euskal Vasco/EuskalHerriko Herriko Unibertsitatea (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; Unibertsitatea (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; [email protected] [email protected] (M.F.); [email protected] (C.M.); [email protected] (E.M.-E.); (M.F.); [email protected] (C.M.); [email protected] (E.M.-E.); [email protected] (A.S.); [email protected] (A.S.); [email protected] (G.R.) [email protected] (G.R.) ** Correspondence: [email protected] (F.P.); (F.P.);[email protected] [email protected](C.A.) (C.A.) Correspondence: [email protected] Academic Babaev Academic Editors: Editors: Philippe PhilippeBelmont, Belmont,Richard RichardA. A.Bunce, Bunce,Wim WimDehaen Dehaenand andEugene Eugene Babaev Received: 29 June 2020; Accepted: 15 July 2020; Published: 16 July 2020 Received: 29 June 2020; Accepted: 15 July 2020; Published: date







Abstract: This review covers the synthesis and reactivity of 1,5-naphthyridine derivatives published Abstract: This review covers the synthesis and reactivity of 1,5-naphthyridine derivatives published in the last 18 years. These heterocycles present a significant importance in the field of medicinal in the last 18 years. These heterocycles present a significant importance in the field of medicinal chemistry because many of them exhibit a great variety of biological activities. First, the published chemistry because many of them exhibit a great variety of biological activities. First, the published strategies related to the synthesis of 1,5-naphthyridines are presented followed by the reactivity of strategies related to the synthesis of 1,5-naphthyridines are presented followed by the reactivity of these compounds with electrophilic or nucleophilic reagents, in oxidations, reductions, cross-coupling these compounds with electrophilic or nucleophilic reagents, in oxidations, reductions, crossreactions, modification of side chains or formation of metal complexes. Finally, some properties and coupling reactions, modification of side chains or formation of metal complexes. Finally, some applications of these heterocycles studied during this period are examined. properties and applications of these heterocycles studied during this period are examined. Keywords: 1,5-naphthyridines; heterocycle synthesis; metal complexes; biological activity Keywords: 1,5-naphthyridines; heterocycle synthesis; metal complexes; biological activity

1. Introduction 1. Introduction The focus of this review is on the collection of recent advances in the synthesis, reactivity and The focus of this review is on the collection of recent advances in the synthesis, reactivity and applications of the 1,5-naphthyridines that have been published in the last 18 years, excluding fused applications of the 1,5-naphthyridines that have been published in the last 18 years, excluding fused 1,5-naphthyridine analogues. Several reviews have appeared in the naphthyridine area [1–4], so the 1,5-naphthyridine analogues. Several reviews have appeared in the naphthyridine area [1–4], so the coverage of this review is not designed to overlap with these contributions, and therefore, references coverage of this review is not designed to overlap with these contributions, and therefore, references are, in general, presented from 2003 to the present. are, in general, presented from 2003 to the present. The first derivative of the cyclic naphthyridine system (a 1,8-naphthyridine) was obtained The first derivative of the cyclic naphthyridine system (a 1,8-naphthyridine) was obtained in in 1893 by Reissert [5], who proposed this name for the new class of heterocyclic derivatives, 1893 by Reissert [5], who proposed this name for the new class of heterocyclic derivatives, since since naphthyridine was considered to be the naphthalene analog, containing two fused pyridine naphthyridine was considered to be the naphthalene analog, containing two fused pyridine rings rings with different mutual arrangements of nitrogen atoms. As indicated in Figure 1, six isomeric with different mutual arrangements of nitrogen atoms. As indicated in Figure 1, six isomeric naphthyridines are possible: naphthyridines are possible: 5

6

N

7 8

4 3

1

1,5-naphthyridine

N

N

N

N

2

N

N

N

1,6-naphthyridine

1,7-naphthyridine

N

N

1,8-naphthyridine

N

N 2,6-naphthyridine

2,7-naphthyridine

Figure Structures of Figure 1. 1. Structures of isomeric isomeric naphthyridines. naphth