2.7- Naphthyridines from pyridines

Syntheses of 1,5- and naphthyridine from pyridine side-chain... 

In 1994, a procedure for the synthesis of benzo[c]-2,7-naphthyridines from pyridine methylstannanes and ort/jo-bromoacetanilides was reported based on a palladium catalyst. " By using CuO as a promoter, good yields of the products were formed (Scheme 3.26a). In 2004, Banwell s group reported the synthesis of quinolines, 2-quinolones, phenanthridines, and 6(5H)-phe-nanthridinones via palladium-mediated Ullmann cross-coupling of... 

Several syntheses of 1,8-naphthyridines (82) from pyridines (81) already bearing substituents in the 2- and 3-positions have been reported.47,48 These preparations are, however, limited in that the starting pyridine derivatives require multistep syntheses. 

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. 

Other general methods for the synthesis of naphthyridines 1-4 start from pyridine derivatives containing an amino (or protected amino) group and a carbonyl group or its synthetic equivalent in vicinal positions. Cyclization of ethyl aminopyridineacry-lates 33 in ethanol with sodium ethoxide has served as a rout to V(l),lV(z)-nap-hthyridin-2(l//)-ones 34 (1985CPB4764). 

Naphthyridine (XI-113) has been synthesized from pyridine side-chain acids via two different routes. Treatment of the dinitiile XI-108 with anhydrous hydrogen bromide yielded the naphthyridine (XI-107), Boiling XI-109 with hydrazine gave the dihydrazino naphthyridine Xl-110. The hydrazino groups... 

One representative of the oxazolo[4,5-/][ 1,6]naphthyridine system, viz. the ester 62, is produced in four steps by annulation of 2-(dicthy lam ino)oxazolo[4,5- pyridine (Scheme 20). Whether the final product exists mainly as the hydroxy tautomer or as the 9//-6-one cannot be deduced from the spectral data presented alkylation occurs either at the oxygen or at N-9, and gives either 63 or 64 <1993SC2931>. 

Whilst many alkaloids contain the pyridine ring system, the combination of two pyridine rings as exemplified in the naphthyridines is rather uncommon in nature. The alkaloid jasminine (436), a 2,7-naphthyridine derivative, has been isolated from Jasminium species (68AJC1321) whilst 4-methyl-2,6-naphthyridine (437) occurs in the aerial parts of Antirrhinum majus and aronticus (71P2849). 

N-Substituted amides derived from 2-chloro- or4-chloronicotinic acid react with CH-acidic nitriles in the presence of base to yield amino derivatives of [l,6]naphthytid-5(6//)-ones and [2,7]naphthyrid-l(2//)-ones <1997JHC397>. 3-(l-Alkylamino)pyridines react with electron-deficient alkynes (acetylene dicatboxylates) in the presence of acid to give l,2-dihydro[2,7]naphthyridine-3,4-dicarboxylates in up to 72% yield compounds unsubstituted at C-1 were readily oxidized with potassium permanganate to naphthyridine-l-ones <2005TL3953>. 

The amino carbinol pyridines 264, prepared from 263 by DoM reaction and aliphatic or aromatic carboxaldehyde quench, are useful intermediates for condensed naphthyridines 266-268. The thermolytic reaction proceeds via intramolecular Diels-Alder reactions of the aza-orf/io-quinodimethane species 265 (Scheme 79) (84CC1304). 

In a sequence analogous to the Suzuki reaction and annulation described in section 4.2.4, pyridine-containing tricyclic compounds have also been prepared via the Stille reaction and a subsequent annulation [80, 81]. For instance, benzo[c]-2,7-naphthyridine 94 was assembled from the adduct of 3-formyl-4-(trimethylstannyl)pyridine (93) and 2-bromo-4-methoxyacetanilide. The reaction was facilitated by addition of CuO as the co-catalyst. 

Krohnke126 synthesized compound 106 by an unequivocal route starting with a 3,4-disubstituted pyridine and showed that the product was identical with the fluorescent compound described by Huff. Ikekawa10 converted compound 101 (R = CH3) into 107 with POCl3, and then into 102 (R = CH3), which was shown to be different from 7-methyl-l,6-naphthyridine which he had previously prepared. In the meantime, Birkofer and Kaiser127 retracted their earlier structure assignment of material 104 because oxidation of Huff s fluorescent compound with nitric acid gave pyridine-3,4-dicarboxylic acid (108). 

Recently, Eisch s142 bromination method (Br2-CCl4-pyridine) has been applied to all the 1, -naphthyridines (x = 5, 6, 7, 8).90 1,5-Naphthyridine afforded 3-bromo- (27%) and 3,7-dibromo-l,5-naphthyridine (10%). The 3-bromo-, 8-bromo-, and 3,8-dibromo-1,6-naphthyridines were obtained from 1,6-naphthyridine.96 1,7-... 

The primary synthesis of 1,5-naphthyridines may be accomplished by double cyclization of appropriate aliphatic substrates by cyclization of appropriately substituted pyridines by cyclocondensation of pyridine substrates with one or more aliphatic synthons or from other heterocyclic substrates by degradation, rearrangement, or the like. Partially or fully reduced 1,5-naphthyridines are often made by somewhat similar procedures such cases are usually illustrated toward the end of each subsection. Some reviews of naphthyridine chemistry contain material on the primary synthesis of 1,5-naphthyridines49 52 61 231 265 670 1260 1273 1430 1432... 

The primary synthesis of 1,6-naphthyridines has been accomplished by condensation of two or more aliphatic substrates by cycbzation of a single pyridine substrate by condensation of a pyridine substrate with an aliphatic synthon that provides one, two, three, or even four ring atoms by condensation of a pyridine substrate with two or more synthons or from other heterocyclic substrates by degradation, rearrangement, or other elaborative processes. 

Like the primary syntheses of other naphthyridines, the primary synthesis of 1,8-naphthyridines may be done by cyclization of appropriate aliphatic substrates, with or without auxiliary synthons, by cyclization of appropriately substituted pyridines with or without synthons, or from other heterocyclic substrates by several processes. 

Primary syntheses of 2,6-naphthyridines have been achieved by cyclization of appropriately substituted pyridine substrates, by cyclocondensation of pyridine substrates with synthons that provide one or more ring atoms, and from other... 

Ethoxycarbonyl-2-(phosphoranylideneamino)vinyl]pyridine (12) with phenyl isocyanate gave a mixture of two isomers from which ethyl l-amino-2,6-naphthyridine-3-carboxylate (13) was isolated (PhMe, 20°C then 180°C, sealed 22%) analogs likewise.442... 

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