Preparation of 1-substituted and 1,4-disubstituted derivatives of 2,6-naphthyridine

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We have extended these reactions to the synthesis of 2,6-naphthyridines.We were motivated by the paucity of synthetic methodology reported for these potentially biologically important heterocyclics, since the other naphthyridine ring systems have been investigated extensively. 4or example, 2,6-naphthyridines were the last of the six isomeric naphthyridines to be synthesized since none of the usual method of synthesis for these heterocycles 5 lead to the 2,6isomer.The first synthesis involved a 4-step synthesis of the parent 2,6-naphthyridine from 4carbethoxynicotinic acid. 6However, the overall yield was quite low, and the reaction could not be easily extended to substituted 2,6-naphthyridines.Subsequently, a base-mediated cyclization of 3-cyanomethylpyridine-4-carbonitrile and some alkoxides was reported 7 in which 2,6naphthyridines were obtained directly, however mixtures of 1-amino-3-alkoxy and 3-amino-1alkoxy derivatives were obtained, and product yields were not reported.The first substituted 3-yields ranging from 50 to 100%.In the case of G = phenyl, the isomerized product (7d) was the sole naphthyridine product; it was obtained in 38% yield.In addition, smaller amounts of the isomerized products (7a-c) were also obtained in 6-30% yields.The use of the sterically hindered 2-methoxyphenyllithium resulting in very low yield (12%) of the 1-(2-methoxyphenyl) derivative (6h).
With compounds (6) on hand, Hegedus coupling reactions were then carried out under catalytic conditions using PdCl 2 (MeCN) 2 (20 mol%), benzoquinone (1 equiv) and 10 equiv of LiCl in refluxing THF.As shown in Scheme 1 substrates with unsubstituted allyl side-chains (5a-c) cyclized to pyrroles (6a-c) in 62-71% yield via attack at the secondary carbon of the olefin.However substrates with allyl groups possessing one methyl (6j-m) or two methyl groups (6e-i) gave no cyclized product, but rather complex mixtures.A modest increase in yield of only one pyrrole product (11b) was obtained when stoichiometric conditions (i.e.PdCl 2 (MeCN) 2 / Et-3 N/rt) were used.The failure of the substituted allyl naphthyrdines to undergo Hedegus cyclization may reflect the decreased stability of the corresponding alkene-palladium 11 as compared to the unsubstituted allyl derivatives.Hence these complexes would be expected to be less firmly bound to palladium.Consequently, undesirable side reactions such as displacement of alkene by triethylamine yielding unreactive bisaminopalladium complexes (stoichiometric), prevail over the desired displacement of the aniline required for the cyclization process.The relative stabilities of the olefin-palladium(II) complexes required for the cyclization process are presumably less than those of the unsubstituted allyl group. 12Consequently, the alkyl substituted olefins would be less firmly bound to palladium than the unsubstituted olefins.In these cases, displacement of the substituted olefin by palladium by the base, triethylamine occurs exclusively yielding unreactive bisaminopalladium complexes.
In summary, the chemistry presented here offers an attractive method for the synthesis of a wide variety of 2,6-naphthyridines.The palladium-assisted intramolecular cyclization proceeds well with 4-allyl-2,6-naphthyridines yielding pyrrolo [2,3-c][2,6]naphthyridines regiospecifically.The cyclization however fails with methyl substituted allyl analogs.This cyclization should find application in the synthesis of natural products containing structural features intolerant of the conditions required for other indole syntheses which are very important in pharmaceutical industry.

Experimental Section
General Procedures.Melting points were taken on a Mel-Temp capillary apparatus and are uncorrected with respect to stem correction.IR spectra were recorded on a Nicolet Magna-IR TM 550 FTIR spectrometer and the 1 H and 13 C NMR spectra were recorded on a 400 MHz Bruker AVANCE DRX-400 Multi-nuclear NMR spectrometer; chemical shifts were referenced to TMS as internal standard.The MS were run on a HP G1800C, GCD SeriesII.The amines were distilled before use.The alkyllithiums and phenyllithium were purchased from Aldrich Chemical Company and used as received.The glassware was heated at 125 o C in an oven overnight prior to use.The reactions carried out in glassware, which had been heated at 125 o C overnight prior to use, under an atmosphere of dry O 2 -free N 2 via balloon.

General procedure for the preparation of 3-(1-cyano-3-alkenyl)pyridine-4-carbonitriles (5a-c)
To the solution of 1 (20 mmol) in THF (50 ml) was added n-BuLi (20 mmol, 1.6 M in hexane) at -70 °C.After stirring for 10 min, a solution of the appropriate 2-propenylbromide (30 mmol) in THF (25 ml) was added slowly at -70 °C.A vigorous reaction ensued and the reaction mixture turned dark.The reaction mixture was allowed to warm to rt where it was stirred for 4h, then quenched with water.The resulting mixture was diluted with ethyl acetate, washed twice with water, followed by brine, dried over Na 2 SO 4 , and concentrated.The crude product was purified by silica gel chromatography using hexane-ethyl acetate as the eluent.IR, 1 H NMR spectral data of isolated compounds 5a-c are given below.

General procedure for the preparation of 1-substituted derivatives of 3-amino-2,6naphthyrdines (3a-g) and 1-substituted 4-alkenyl-3-amino-2,6-naphthyrdines (9a-c,e-m)
In a flame-dried flask flushed with argon, the lithium amides was prepared by adding 6.4 ml of n-BuLi (10 mmol, 1.6 M in hexane) to a solution of an appropriate amine (10 mmol) in THF (30 ml) at -70 °C.The alkyllithiums and phenyllithium (10 mmol) were added directly to THF (30 ml).The 4-methyl-and 4-methoxyphenyllithium were prepared by adding 6.4 ml of n-BuLi (10 mmol, 1.6 M in hexane) to a solution of an appropriate bromobenzene (10 mmol) in THF (30 ml) at -70 °C.After stirring for 10 min, the dinitrile (1) or alkenyldinitriles (1 mmol) in THF (10 ml) was added dropwise over 5 min.The stirring was continued for 30 min at -70 °C, then the reaction mixture was allowed to warm to -30 °C to -20 °C, where it was stirred for an additional 2 h.The reaction mixture was then quenched with water, and the THF evaporated under reduced pressure to give a residue which was extracted with dichloromethane (2 x 20 ml).
The combined extracts were washed with brine, dried over Na 2 SO 4 , and concentrated by a rotary evaporator.The remaining mixture was subjected to flash column chromatography (silica gel) using hexane/ethyl acetate as an eluent to give a liquid or solid product.) and 20 ml of THF, the resulting mixture was stirred at rt for 5 min.The substrates (6) (1 equiv.) in 5 ml of THF was then added to the flask, and the resulting solution was refluxed for 15 h.The mixture was then filtered through Celite ® and concentrated on a rotary evaporator.Products were isolated by silica gel column chromatography using hexane-ethyl acetate as the eluent.b) Under stoichiometric conditions.Into a flame-dried flask flushed with argon were placed PdCl 2 (MeCN) 2 (1 equiv.)and 10 ml THF and allowed to stir for 5 min.The substrate (6) (1 equiv) in 5 ml of THF was then added to slurry of the palladium complex.After the mixture was stirred for 1.5 h at rt, triethylamine (1 equiv.) was added and the resulting mixture stirred for 3 h.A second equiv. of triethylamine was added.Finally a third equiv of triethylamine was added after an additional 1 h of stirring.The mixture was then allowed to stir for a further 2 h, and was then worked up in a similar procedure described above.The physical and spectral properties of products (8)