Thieno -2,5-naphthyridine

Pyridine-containing tricyclic compounds have been produced via a sequence consisting of a Suzuki reaction and a subsequent annulation. Gronowitz et al. coupled 2-formylthienyl-3-boronic acid with 3-amino-4-iodopyridine. The resulting adduct spontaneously condensed to yield thieno[2,3-c]-l,7-naphthyridine 59 [47]. They also synthesized thieno[3,4-c]-l,5-naphthyridine-9-oxide (60) in a similar fashion [48]. Neither the amino nor the N-oxide functional group was detrimental to the Suzuki reactions. 

Japanese workers recently designed a synthesis of 5-amino-2,3-dihydrothiepino[2,3- >]pyridine-4-carbonitrile 2 based on Thorpe-Ziegler cyclisation of 2-(3-cyanopropylthio)pyridine-3-carbonitrile 1. Treatment of 1 with potassium t-butoxide however, did not, give 2, but produced the thieno[2,3-/i][l,6]naphthyridine 3 in 82% yield. 

It was also demonstrated (1997HC183) that the reactions can be performed under analogous conditions not only with pyridine 130 but also with 2-chloro-formylpyri-dine Ar-oxide or 2-bromo-3-(l,3-dioxolan-2-yl)pyridine TV-oxide. The latter reactions produce the corresponding thieno[Z>][2,5]naphthyridine IV-oxides, which can also be prepared by oxidation of the parent systems with m-chloroperoxybenzoic acid. 

Isomeric thienonaphthyridines were synthesized using the Suzuki reaction. For example, 2-formyl-3-thiopheneboronic acid (200) with aminopyridines 201 and 202 produced thieno[2,3-c][l,7]naphthyridine (203) and thieno[2,3-c][l,8]naphthyridine (204) (1994JHC11). This method was also used to synthesize (1993H245) isomeric A-oxides 205 and 206 from pyridine A-oxides 207 and 208, respectively. 

The tricyclic skeleton of thieno[3,2-c][l,5]naphthyridine 9-7V-oxidc (263) was constructed (1993H245) in two ways by condensation of aldehyde 256 with pyridine /V-oxide 207 or (in lower yield) by the modified Suzuki reaction of the latter with 3-formylthiophene-2-boronic acid (264). 

The one-pot Stille cross-coupling reaction of compound 256 produced all four isomeric thieno[3,2-c]naphthyridines (1994JHC11). The stepwise formation of the C(7)-C(7a) and C(4)-N(5) bonds of the thieno[3,2-c]pyridine system can be considered as a modification of the above-described approaches. For example, aldehyde 256 reacts with arene 265 to give 266 reduction of its nitro group is accompanied by cyclization to form thieno[3,2-c]isoquinoline A-oxide (267) (1990JHC1127). 

Cyclocondensations involving thioxo or alkylthio substituents are represented by the conversion of 6-methyl-4-(thien-2-yl)-2-thioxo-l,2,5,6,7,8-hexahydro-l,6-naphthyridine-3-catbonitrile into 4-hydroxy-9-methyl-4-(thien-2-yl)-7,8,9,10-tetrahydropyrido 2, 3 4,5 thieno 2.3-ft [ l,6Jnaphthyridin-2(17/)-one (3) (ClCH2C0CH2C02Et, EtOH, EtONa, reflux, 10 min 88%) 1429 also of 2-acetonylithio-8-benzylidene-6-isopropyl-4-phenyl-5,6,7,8-tetrahydro-l,6-naphthyridine-3-carbonitrile into 2-acetyl-8-benzylidene-6-isopropyl-4-phe-nyl-5,6,7,8-tetrahydrothieno 12,37 1,6]naphthyridin-3-amine (4) (EtONa, EtOH, 20°C 15 min 75%).946... 

The carbanion generated from the dinitrile 24 causes a Smiles-type nucleophilic rearrangement to produce new anions 25 and 26. The tandem intramolecular cyclization of the latter affords dihydrothiophene 27. Thieno[2,3-3][l,6]naphthyridine 28 is derived from 27 in four steps (Scheme 6) <1995H(41)1307>. 

Treatment with sodium ethoxide of thioethers 316, prepared by the reaction of l,2,5,6,7,8-hexahydro-l,6-naphthyridine-2thiones 317 with halo ketones, esters, amides or nitriles, resulted in the synthesis of thieno[2,3-Z>]-l,6-naphthyridines 318 (1993BCJ3716). 

The synthesis and biological activity of 2-(alkoxycarbonyl)thieno[2,3-c]-2,7-nap-hthyridine and isothiazolo[4,5-Z>]-2,7-naphthyridine derivatives have been described (2002MI3, 2002MI4). 

Procedures for the synthesis of compounds containing a five-membered heterocycle with a linearly fused 1,8-naphthyridine fragment (thiazolo[5,4-Z>]- (1979CPB410), imidazolo[4,5-Z>]-, triazolo[4,5-Z>]- (1980CPB235), oxazolo[5,4-/ ]-, thiadiazolo[5,4-b]-, isothiazolo[5,4-Z>]-, pyrazolo[3,4-Z>]-, thieno[2,3-Z>]-, furo[2,3-/ ]-l,8-naphthyridines (1980CPB761, 1984CPB4914)) were described and the antibacterial activity of these compounds was studied. 

Thieno[3,2-c][l,5]naphthyridine 5A-oxide (54) and 9A-oxide (53) underwent non-selective bromination with DBI and the corresponding mono- and dibrominated compounds were formed in... 

By analogy with pyridine oxide, thieno[2,3-c]naphthyridine lA(-oxide (51) was transformed into the corresponding pyridinone (44) in 54% yield by the action of tosyl chloride (Equation (11)) <95ACS744>. 

Reductive cyclization of 2-(o-formylthienyl)-3-nitropyridine (119) and (120), which were obtained by the Pd(0)-catalysed coupling reaction of 2-bromo-3-nitropyridine and o-formylthienyl boronic acids, by the action of ferrous sulfate in aqueous ammonia, gave thienonaphthyridine TV-oxides (52) and (56) in 30 and 86% yields (Equations (35) and (36), respectively). Surprisingly, the other isomer, thieno[3,2-c][l,5]naphthyridine SWoxide (54) cannot be obtained using the same method <93H(35)245>. 

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