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Review
. 2020 Jul 31;25(15):3508.
doi: 10.3390/molecules25153508.

Fused 1,5-Naphthyridines: Synthetic Tools and Applications

Carme Masdeu  1 , Maria Fuertes  1 , Endika Martin-Encinas  1 , Asier Selas  1 , Gloria Rubiales  1 , Francisco Palacios  1 , Concepcion Alonso  1
Affiliations
Review

Fused 1,5-Naphthyridines: Synthetic Tools and Applications

Carme Masdeu et al. Molecules. .

Abstract

Heterocyclic nitrogen compounds, including fused 1,5-naphthyridines, have versatile applications in the fields of synthetic organic chemistry and play an important role in the field of medicinal chemistry, as many of them have a wide range of biological activities. In this review, a wide range of synthetic protocols for the construction of this scaffold are presented. For example, Friedländer, Skraup, Semmlere-Wolff, and hetero-Diels-Alder, among others, are well known classical synthetic protocols used for the construction of the main 1,5-naphthyridine scaffold. These syntheses are classified according to the nature of the cycle fused to the 1,5-naphthyridine ring: carbocycles, nitrogen heterocycles, oxygen heterocycles, and sulphur heterocycles. In addition, taking into account the aforementioned versatility of these heterocycles, their reactivity is presented as well as their use as a ligand for metal complexes formation. Finally, those fused 1,5-naphthyridines that present biological activity and optical applications, among others, are indicated.

Keywords: biological activity; fused 1,5-naphthyridines; heterocycle synthesis; metal complexes.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Fused naphthyridines with biological applications.
Figure 2
Figure 2
Examples of fused 1,5-naphthyridines with carbocycles.
Scheme 1
Scheme 1
Preparation of benzo[b][1,5]naphthyridines by Friedländer reaction.
Scheme 2
Scheme 2
A modified Friedländer reaction for the preparation of pbn ligand.
Scheme 3
Scheme 3
Friedländer reaction for the synthesis of benzo[b][1,5]naphthyridine derivatives 9 and 10.
Scheme 4
Scheme 4
Formation of a cyano benzo[b][1,5]naphthyridine derivative in two steps.
Scheme 5
Scheme 5
Modified Skraup synthesis of 5,10-dihydrobenzo[b][1,5]naphthyridin-10-one.
Scheme 6
Scheme 6
Skraup synthesis of 9-chloroacridine derivative.
Scheme 7
Scheme 7
Michael addition of 4-aminoisoquinoline to methyl vinyl ketone for the formation of 24.
Scheme 8
Scheme 8
Formation of 3,4-dihydrobenzo[c][1,5]naphthyridin-2(1H)-ones by a Semmlere–Wolff transposition of oximes.
Scheme 9
Scheme 9
Synthesis of benzo[c][1,5]naphthyridines through a [4+2] cycloaddition reaction.
Scheme 10
Scheme 10
Microbial biosynthesis of benzo[c][1,5]naphthyridine alkaloids.
Scheme 11
Scheme 11
Rhodamine 6G synthesis of 5-phenyldibenzo[b,h][1,5]naphthyridine derivative.
Scheme 12
Scheme 12
Synthesis of benzo[b][1,5]naphthyridines by reduction of biaryl bromonitriles.
Scheme 13
Scheme 13
Skraup synthesis of a naphtho[2,1-b][1,5]naphthyridine.
Scheme 14
Scheme 14
Formation of naphtho[1,8-bc][1,5]naphthyridines using nitropyridylnaphthalene.
Scheme 15
Scheme 15
Povarov reaction for the preparation of substituted 7H-indeno[2,1-c][1,5]naphthyridines.
Figure 3
Figure 3
Examples of fused 1,5-naphthyridines with five-membered nitrogen heterocycles.
Scheme 16
Scheme 16
Enantioselective total synthesis of the potent antibiotic GSK966587.
Scheme 17
Scheme 17
Modified Friedländer reactions for the synthesis of imidazo[1,2-a][1,5]naphthyridines.
Scheme 18
Scheme 18
Preparation of tricyclic imidazo[4,5-c][1,5]naphthyridine derivatives.
Figure 4
Figure 4
Examples of indolo and indazolo[1,5]naphthyridine derivatives.
Scheme 19
Scheme 19
Preparation of indol 1,5-naphthyridines by a Semmier–Wolf transposition of oximes.
Scheme 20
Scheme 20
Syntheses of canthin-6-ones through a Suzuki-Miyaura coupling.
Scheme 21
Scheme 21
Copper-catalyzed Buchwald cyclization to ethyl canthin-6-one-1-carboxylates.
Scheme 22
Scheme 22
Formation of hexahydrobenzo[h]indolo[3,2,1-de][1,5]naphthyridine hydrochloride.
Scheme 23
Scheme 23
Synthesis of fused isoxazole and pyrrol[1,5]naphthyridine derivatives.
Scheme 24
Scheme 24
Condensation reaction of chloro benzo[b][1,5]naphthyridinone with hydrazines.
Scheme 25
Scheme 25
Synthesis of fused 1,5-naphthyridine porphyrin dimers.
Figure 5
Figure 5
Examples of fused 1,5-naphthyridines with six-membered nitrogen heterocycles.
Scheme 26
Scheme 26
Preparation of pyrido[4,3 or 3,4 or 2,3-c][1,5]naphthyridinones.
Scheme 27
Scheme 27
Intramolecular Povarov synthesis of quinolino[4,3-b][1,5]naphthyridine derivatives.
Figure 6
Figure 6
Examples of fused 1,5-naphthyridines with oxygen-containing heterocycles.
Scheme 28
Scheme 28
Preparation of [1,3]oxazino[3,2-a][1,5]naphthyridine.
Scheme 29
Scheme 29
A three-component synthesis of chromeno[4,3-b][1,5]naphthyridine derivatives.
Scheme 30
Scheme 30
A domino reaction for the synthesis of chromeno[4,3-b][1,5]naphthyridine derivatives.
Scheme 31
Scheme 31
Intramolecular aza-Diels-Alder reaction to obtain hybrid, fused naphthyridines.
Scheme 32
Scheme 32
Palladium-catalyzed synthesis of thieno[1,5]naphthyridines.
Scheme 33
Scheme 33
Preparation of dithieno[3,2-c:3,2-h][1,5]naphthyridine NT, a precursor of PTNT.
Scheme 34
Scheme 34
N-alkylation of fused 1,5-naphthyridines.
Scheme 35
Scheme 35
N-alkylation of dithieno[3,2-c:3,2-h][1,5]naphthyridine NT.
Scheme 36
Scheme 36
Nitration and bromination of benzo[b][1,5]naphthyridines.
Scheme 37
Scheme 37
Cyanation of benzo[c][1,5]naphthyridine by means of N-oxide derivative.
Scheme 38
Scheme 38
SNAr at position 4 of benzo[b][1,5]naphthyridine ring.
Scheme 39
Scheme 39
SNAr at position 10 of benzo[b][1,5]naphthyridine ring.
Scheme 40
Scheme 40
Double SNAr using diamines for the synthesis of dimeric benzo[b][1,5]naphthyridines.
Scheme 41
Scheme 41
Methanethiolation of benzo[b][1,5]naphthyridine.
Scheme 42
Scheme 42
Preparation of pyrido[c][1,5]naphthyridines from pyrido[c][1,5]naphthyridin-6-ones.
Scheme 43
Scheme 43
Hydride reduction of benzo[c]indolo[3,2,1-ij][1,5]naphthyridin-9(2H)-one.
Scheme 44
Scheme 44
Oxidation reactions of 1,2,3,4-tetrahydrobenzo[c][1,5]naphthyridin-2(1H)-ones.
Scheme 45
Scheme 45
Dehydrogenation of 1,2,3,4-tetrahydroindeno[c][1,5]naphthyridines.
Scheme 46
Scheme 46
Oxidation of tetrahydro-2H-indolo[3,2-c][1,5]naphthyridinones.
Scheme 47
Scheme 47
Dehydrogenation of tetrahydro-6H-chromeno[4,3-b][1,5]naphthyridines.
Scheme 48
Scheme 48
Oxidation of 6-methylbenzo[b][1,5]naphthyridine.
Scheme 49
Scheme 49
Transformation of nitrile group of benzo[c][1,5]naphthyridine-6-carbonitrile.
Scheme 50
Scheme 50
Preparation of pyronaridine tetraphosphate 21.
Scheme 51
Scheme 51
Transformation of the nitro group into imine in a benzo[b][1,5]naphthyridine derivative.
Scheme 52
Scheme 52
Preparation of tridentate ligand bnqp.
Scheme 53
Scheme 53
Preparation of the 10-indenylbenzo[b][1,5]naphthyridine ligand.
Scheme 54
Scheme 54
Oxidation and reduction reactions over indeno[1,5]naphthyridines.
Scheme 55
Scheme 55
Enantioselective synthesis of the antibiotic GSK966587.
Scheme 56
Scheme 56
Synthesis of the antibiotic GSK966587 from a racemic diol.
Scheme 57
Scheme 57
N-methylation reaction of 1,3-dihydro-2H-imidazo[4,5-c][1,5]naphthyridin-2-ones.
Scheme 58
Scheme 58
Tosyl deprotection of 5-tosylhexahydroquinolino[4,3-b][1,5]naphthyridines.
Scheme 59
Scheme 59
Polymerization of dithieno[3,2-c:3,2-h][1,5]naphthyridine.
Scheme 60
Scheme 60
Formation of rhodium complexes.
Scheme 61
Scheme 61
Formation of a rhodium complex from pbn.
Scheme 62
Scheme 62
Preparation of heteroleptic pbn–ruthenium complex.
Scheme 63
Scheme 63
Syntheses of pbn–ruthenium complexes.
Scheme 64
Scheme 64
Reversible 4H+/4e− redox reactions of the pbn–ruthenium complexes.
Scheme 65
Scheme 65
Preparation of a four-electron-reduced ruthenium(II) NADH-type complex.
Scheme 66
Scheme 66
Preparation and subsequent transformations of pbn–ruthenium complexes.
Scheme 67
Scheme 67
Formation of bnqp- and bbnp-palladium complexes.
Figure 7
Figure 7
Inhibitory activity of compounds 71bd and 71be on BET bromodomain family.
Figure 8
Figure 8
Cytotoxic activity of 162b on K562 and HepG-2 cell lines.
Figure 9
Figure 9
Cytotoxic activity of 51g and 51d on A549 cell line.
Figure 10
Figure 10
Cytotoxic activity of 127a on A549 and SKOV3 cell lines.
Figure 11
Figure 11
Cytotoxic activity of 110a, 115a, and 179 on A549 and SKOV3 cell lines.
Figure 12
Figure 12
Inhibition of 52 on hERG.
Figure 13
Figure 13
Cytotoxic activity of 94d on PC-3 prostate cancer cells.
Figure 14
Figure 14
PI3K/mTOR dual kinase inhibition of PF-04979064.
Figure 15
Figure 15
Cytotoxic activity of 65 and 66 on HT-1080, HT-29, M-21, and MCF-7 cell lines.
Figure 16
Figure 16
Dimeric benzo[b][1,5]naphthyridines 164 as bis-acridine analogs.
Figure 17
Figure 17
β-Hematin inhibition of 21.
Figure 18
Figure 18
Antileishmanial activity of 50e, 50h, and 51b.
Figure 19
Figure 19
Activity of 187n against Nippostrongylus brazilliensis.
Figure 20
Figure 20
Fused 1,5-naphthyridines with hypotensive and pain-relieving activities.
Scheme 68
Scheme 68
Formation of the NADH-like species from bpn–ruthenium(II) complex.
Figure 21
Figure 21
Ruthenium complexes containing fused 1,5-naphthyridines.
Scheme 69
Scheme 69
Photo- and electrochemical reduction of CO2 with bpn–ruthenium complexes.
Scheme 70
Scheme 70
Electrochemical reduction of CO2 using bpn–ruthenium–NAD-type complexes.
Figure 22
Figure 22
Fused 1,5-naphthyridine with OLED properties.
Figure 23
Figure 23
Fused 1,5-naphthyridine as optical DNA biosensor.
Scheme 71
Scheme 71
Redox system of 1,5-naphthyridine-fused porphyrin dimers.
Figure 24
Figure 24
Fused 1,5-naphthyridine as colorimetric sensor for detection of Cu2+ ions.
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