Indolo naphthyridine

Cycloadditions between 2-vinylindoles as heterodienes and acceptor substituted enamines can be induced by formation of 2-vinylindole radical cations either via anodic oxidation or photoelectron transfer. In this way pyridoindoles and indolo-naphthyridines are formed in one step under complete regio- and stereochemical control [Eq. (24b)] [248b]. 

Synthetic studies in this area have thus concentrated mainly on routes to indolonaphthyridines. A widely applicable route, leading to various indolo[2,3- ]naphthyridines, for example, 5-7, and aza-analogues such as 8, involves the reaction of an o-alkynylaryl isocyanate, for example, 4, with a pyridyliminophosphorane, followed by thermolysis of the resulting carbodiimide (Scheme 1) <2000JOC7977, 2002JOC5412>. 

A different type of synthesis, which leads to a benzannulated indolo[2,3-3][l,6]naphthyridine 15, is illustrated in Scheme 3 <1999TL3797>, and the use of an azaindolone as starting material may introduce an additional heteroatom into the indole moiety of the product, as in 16 (Equation 2) <1994TL1995>. The dipyrrolo[2,3-3 2, 3 -g][l,8]naphthyridine 18 is produced by reaction of the naphthyridine 17 with ethyl glycinate in the presence of a phase-transfer catalyst (Scheme 4) <2000PS(163)29>. 

Tetracyclic /3-carboline alkaloids, known as canthines, have a peri-fused indolo[3,2,Tnaphthyridine structure. Over 40 members of this class of compound have been isolated, and they are of interest on account of their broad range of pharmacological effects (antimicrobial, cytotoxic, antibacterial, anticancer). 

Many other synthetic benzo a]quinolizidine derivatives, structurally more or less related to the alkaloids of types 72-75, have been available a number of indole alkaloids carrying the indolo[2, 3 3,4]pyrido[l,2-b][2,7]-naphthyridine ring system, structurally analogous to the A. lamarckii alkaloids 56-64, have been isolated from other plants and/or synthesized. However, this section is not intended to cover them because of the limited space. 

Tryptamine, tryptophan and their derivatives are widely used in the synthesis of indolo[3,2,l-naphthyridine derivatives. Thus, refluxing tryptamine 35 with 2-formylbenzoic acid 36 in alcohol followed by the addition of concentrated hydrochloric acid afforded hexahydrobenzo[/z]indolo[3,2,l-[Pg.194]

Methyl (+ )-3-ethyl-2,3,3n,4-tetrahydro-1 i/-indolo[3,2,1 -de][ 1,5]naphthyridine-6-carboxylate 293 possessing psychostimulating activity was prepared by the alkylation of ester 294 with iodoethane in DMSO or by dehydration of hydroxyl derivative 295 (1988FRP2590990). 

JHC64l>. Some of their benzenoid derivatives have been prepared, and examples are indolo-[2,5-b]-, indolo[3,2-ft] and indolo[3,2-c]naphthyridines <76JHC97, 77JOC1725, 80TL4485), benzofuro-[2,3-ft]naphthyridines <93JHC909> and benzothieno[2,3-c]naphthyridines <87JHC1009>. 

No systematic studies of UV and IR spectra of the parent tricyclic rings have appeared in literature. UV Spectra data of some l/f-pyrrolo[3,2-c][l,8]naphthyridine (38), ll/f-indolo[3,2-c] [l,8]naphthyridine (39) and 10/f-indolo[2,3- >]naphthyridine (40) derivatives is listed in Table 4. 

Methylation of indolonaphthyridines has been reported to take place on the nitrogen of the terminal pyridine <80TL4485> for example, 6//-indolo[3,2-Z)][l,7]naphthyridine (49) reacted with excess methyl iodide to afford quaternary salt (50) (Equation (1)) <89JHC105>. 

A one-step synthesis of 10/f-indolo[2,3-Z/][l,8]naphthyridines (40) has been achieved efficiently by photolyzing tetrazolonaphthyridines in TFA and products were obtained in very good yield (84-97%) (Scheme 6) <77JOC1725, 86FES577>. 

The only known example based on this synthetic strategy is the preparation of 4-oxo-l,2,3,4-tetrahydro-7/f-indolo[2,3-c][l,7]naphthyridine from the reduction and cyclization of 4-cyano-methyl- S-carboline as shown below (Equation (25)) <89JMC1799>. 

Most of the compounds are named on the basis of indolizine and quinolizine nuclei with the exception of pyrrolo[l,2]naphthyridines, i.e. indolizine fused to a pyridine ring. In practice, two systems are used for numbering indolo[2,3-a]quinolizine examples shown below are indolo[2,3-ajquinolizine which is numbered according to the lUPAC recommendations also used in Chemical Abstracts, and tetrahydroindolo[2,3-a]benzo[9]quinolizine numbered following the generally accepted biogenetic numbering system. 

N-Heterocychc scaffolds such as indolo[2,l-ii]isoquinohnes, pyrrolo[2,l-a] isoquinolines, and indolo/pyrrolo[2,l [l,6]naphthyridines are abundant in natural products and biologically active scaffolds, semiconductors, and luminescent materials. Verma and coworkers have described a rapid high yield synthesis of medicinally important indolo-, pyrrolo[2,l [l,6]naph-thyridines, and isoquinolines 89 via a copper-catalyzed tandem approach (2014TL(55)4724). This microwave-assisted protocol uses hydroxymethyl... 

Scheme 24 Synthesis of indolo-, pyrrolo[2,1-/][1,6]naphthyridines, and isoquinolines 89.

Aryl azides undergo indolization upon photolysis, and several examples are known (Scheme 8) [67-70]. Thus, p-phenyl-substituted (Me, OMe, Cl) azidopyrimi-dines 11 were converted to the corresponding 9H-pyrimido[4,5- ]indole (equation 1) [67, 68]. The azide precursor is in equilibrium with the ring-opened 8-phenyltetrazolo[l,5-c]pyrimidine (10) (in trifluoroacetic acid). Similarly, Da Settimo and colleagues synthesized the new ring system 67/-indolo[2,3- ][l,8]naphthyridine 12 by photolysis in trifluoroacetic acid of the equilibrium mixture of 4-phenyltetrazolo[l,5-fl][l,8]naphthyridines... 

The Friedlander quinoline synthesis was applied in a one-step synthesis of 67/-indolo[3,2-fe]naphthyridines (azaellipticines) by Queguiner s team by condensing A -acetylindoxyl with aminofomyl pyridines (Scheme 15,... 

Hydroxy-6,7-dimethoxy-lH-indolo[3,2, /-de][7,5] naphthyridin-l-one, 9CI. 10-Hydroxy-1,11-dimethoxycanthin-6-one [165967-62-4]... 

Me ether [116353-93-6]. 2-Methoxy-6 -indolo[3,2J-dQ][L5] naphthyridin-6-one, 9CI. 2-Methoxycanthin-6-one CisHjoNjOj M 250.256 Alkaloid from stem wood of Quassia amara (Simaroubaceae). Pale yellow powder (MeOH/CHCl3). Mp 262-264°. 

Me ether [86293-40-5]. 10-Methoxy-6W-indolo[3,2,l-dQ l,5 naphthyridin-6-one, 9CI. lO-Methoxycanthin-6-one. Methylaervin... 

H-benzo[d,f] [l,3]diazepines dibenzo[b,g]-l,8-naphthyridines imidazoles (glyoxalines) imidazo [1,2-a] pyridines indolopyridines 12H-indolo[2,3-a]pyridocoli-nium rings... 

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