Simple and efficient synthesis of 2,7-difunctionalized-1,8-naphthyridines.

The syntheses in good yields of some new difunctionalized 1,8-naphthyridines 4, 6, 8 and 9 and a novel triethylene glycol ether-linked dinaphthyridine, 10a, along with the mononaphthyridine-linked ether alcohol 10b are described. An improved and milder method for the synthesis of 2,7-diamino-1,8-naphthyridine (14) is also reported.

Introduction

Naphthyridine or naphthyridone systems are of great importance due to their broad spectrum of biological activities. Substituted 1,8-naphthyridine compounds are used as antihypertensives, antiarrhythmics, herbicide safeners and also as immunostimulants [1,2,3]. We are interested in 2,7-difunctionalized-1,8-naphthyridines because of their aforesaid potential medicinal activity as well as for their use as important binding units in the molecular design of synthetic receptors [4]. This communication describes the first synthesis of four 2,7-difunctionalized-1,8-naphthyridines; viz. 2-amino-7-hydroxymethyl-1,8-naphthyridine (5), 2-amino-1,8-naphthyridine-7-carboxaldehyde (6), 2,7-dimethyl-4-methoxy-1,8-naphthyridine (8) and 4-methoxy-1,8-naphthyridine-2,7-dicarboxaldehyde (9) and a novel triethylene glycol ether-linked dinaphthyridine compound, 1,2-bis-[2-(2,7-dimethyl-1,8-naphthyridin-4-yloxy)ethoxy]ethane (10a) along with the mononaphthyridine-linked ether alcohol (10b). A new synthesis of 2,7-diamino-1,8-naphthyridine 14 by a more efficient reaction under milder conditions is also reported here.

Results and Discussion

Naphthyridines 2-6 were synthesized starting from 2-amino-7-methylnaphthyridine (1), which is obtained by the condensation of commercially available 2,6-diaminopyridine and 3-oxo-butyraldehyde dimethyl acetal following a reported procedure [5]. The 7-methyl group of 2-acetylamino-7-methyl-1,8-naphthyridine (2) is oxidized with selenium dioxide in dioxane to the corresponding aldehyde 3, followed by deprotection of the N-acetyl group by hydrolysis with 1N hydrochloric acid, which afforded the desired 2-amino-1,8-naphthyridine-7-carboxaldehyde (6) in 85% yield (Scheme 1).

Scheme 1

 

Reagents, conditions and yields: (i) acetic anhydride, 80°C, 12h., 87%. (ii) SeO2, dioxane, 50-55°C, 4h., 75%. (iii) 1N HCl, reflux, 0.5h., 85%. (iv) NaBH4, dry THF, 3-4h, 85%. (v) 1N NaOH, r.t.,12h., 80%.

The conversion of aldehyde 3 into 2-amino-7-hydroxymethyl-1,8-naphthyridine (5) was achieved by sodium borohydride reduction of the former to give 2-acetylamino-7-hydroxymethyl-1,8-naphthyridine (4), followed by mild alkaline hydrolysis (1N NaOH).

Compound 8 is made in excellent yield (95%) starting from 4-chloro-2,7-dimethyl-1,8-naphthyridine (7) [6] by stirring at room temperature with methanolic potassium hydroxide. Compound 8 is then oxidized with SeO2 in dioxane at room temperature to produce 4-methoxy-1,8-naphthyridine-2,7-dicarboxaldehyde (9) in 90% yield. The synthesis of the novel di- and mono-naphthyridines 10a-b with triglycol spacers is achieved by substitution of the chlorine atom by both two as well as only one of the hydroxyl functions of triethylene glycol, respectively (Scheme 2).

Scheme 2

 

Reagents, conditions and yields: (i) Triethylene glycol, KOH, THF, 60°C, 80%. (ii) MeOH, KOH, 4h., 90%. (iii) SeO2, dioxane, r.t., 90%.

The synthesis of 2,7-diamino-1,8-naphthyridine 14 is described in Scheme 3. The advanced starting compound 11 was prepared according to the literature method [7, 8]. Compound 11 was then converted into the chloroamino intermediate 12 by direct reaction with POCl3 without conventional protection of the amino group. The substitution of chloro by azide was smoothly achieved by the treatment of 12 with sodium azide in DMF at 60 °C to produce 13 in 90% yield, while the reaction of 12 with benzylamine lead to 15 in 50% yield. The target compound 14 was then synthesized, albeit in poor yield (25%), by refluxing compound 12 with NaNH2 in xylene. However, excellent yields (98%) of 14 can be achieved via the reduction of the azide derivative 13 with Zn/AcOH.

Scheme 3

 

Reagents, conditions and yields. (i) POCl3, reflux, 4h., 60%. (ii) PhCH2NH2, 120°C, 6h., 50%. (iii) NaN3, DMF, 60°C, 4h., 90%. (iv) Zn, AcOH, reflux, 3h., 98%. (v) NaNH2, xylene, reflux, 25%. (vi) ammonolysis.

Compound 14 is also obtained by direct ammonolysis of compound 12 at high temperature in a sealed tube. But care must be taken during this procedure as it was found to be dangerous and the yield is also poor compared to that of azide reduction with Zn/AcOH .

Conclusions

We have synthesized a series of functionalized naphthyridines and novel triethylene glycol-linked mono- and di-naphthyridines in good yields by simple and efficient procedures. All the naphthyridines and the intermediates were well characterized by spectroscopic means. A new, efficient and practical method under mild conditions for the synthesis of 2,7-diamino-1,8-naphthyridine (14) has also been developed, which also improves the yield for the synthesis of this compound.