Cobalt-Catalyzed One-Step Synthesis of Annulated Pyridines

The present invention relates to new methods and products wherein the pyridine nucleus is incorporated into a more complex structure and these compounds are known as annulated pyridines. The synthesis of annulated pyridines in the past has relief on condensations, cyclo additions and special methods. Fusion of rings in this heterocycle has generally been achieved by the use of intramolecular Friedel-Crafts cyclizations.

This invention relates to a novel approach based upon cobalt-catalyzed co-oligomerization of .delta., .omega.-diynes with nitriles. The cobalt catalyst of choice is cyclopentadienyl cobalt dicarbonyl.

The prior art relative to the present invention shows utilization of monoacetylenes but not utilizing the present diacetylenes.

Cairns et al, Journal of American Chemical Society, 74:3989-3992 (1952).

Wakatsuki, Synthesis, January 1976, pages 26-28.

Wakatsuki et al, Tetrahedron Letters, 36:3383-84 (1973).

Naiman and Vollhardt, Angewante Chemie (Int. Ed. (Engl) 16:708-709, No. 10 (1977).

The preparation of substituted pyridines from monoacetylenes and nitriles using cobalt catalysts or reagents is old. However, yields were unimpressive and the product and selectivity was low and the product mixtures were synthetically useless. In the present approach based on the synthesis of 2-substituted annulated pyridines by a cobalt-catalyzed co-oligomerization of diacetylenes with nitriles allows in one step the formation of oligoheterocyclic systems with pronounced chemo- and regio-selectivity which is quite tolerant of functional groups on the nitrile and permits the reaction to form medium-sized (seven membered) rings. A preferred catalyst is cyclopentadienyl cobalt dicarbonyl, a group VIII carbonyl catalyst.

In the following experiments the reaction of diyne with about an equal equivalent of nitrile was observed to produce an annulated substituted pyridine structure (cf. Table 1, post). ##STR1## Cyclization of (1) where n=3 or 4, utilizing excess cyanoacetic ester, results in a novel 7,8-annulated 2-amino-4-oxo-4H-quinolizine-1-carboxylate. In this case the extra measure of cyanoacetic ethyl ester converts the intermediate 3-(tetrahydroisoquinoline)acetate by condensation with a second equivalent of nitrile to form a 3-ring heterocycle. New compounds are produced by this method which are 7,8-annulated 2-amino-4-oxo-4H-quinolizine-1-carboxylates (6,7 above).

Additional compounds synthesized by the process of this invention are expressed by the following equation: ##STR2##

In this specification and claims, the term "lower alkyl" is defined as C.sub.1 -C.sub.6 and may be either straight or branched chain.

The results in Table 1 above illustrate that strongly electron-withdrawing groups bound directly to the cyano carbon appear to be disadvantageous and also that large excess of any one reactant (in particular nitrile) is unnecessary and does not lead to improved yields.

The R group at the 2 position of the annulated pyridine produced thus may be -lower alkyl, -substituted lower alkyl, -lower alkyl ethers, -carboxy alkyl, -lower alkyl ester, -lower alkyl nitrile, -pentafluoromonoaryl, or -monoaryl.

Pronounced regioselectivity is observed in the reaction of 1,7-decadiyne (8, below) with valeronitrile (2a) resulting in the preferred formation of product (4m), at the expense of (4n) (17:1 ratio). ##STR3##

In the laboratory procedures, syringe pump techniques were utilized. Furthermore, work up of the reaction mixture involved extraction with diluent acid and simple column chromatography on silica or alumina. Side products consisted of oligomers derived from the starting diyne. Analytically pure samples were obtained by distillation, sublimation, recrystallization, or preparative gas chromatography (10'.times.3/8" glass, 20% SE 30 on 60/80 Chrom W-AW, 240.degree. C.). The structures of products 2-7 were in accord with spectral data (m/e, NMR, IR). Yields are subject to some variation in yield with solvent, temperature (for example the yield of 2c formed at 80.degree. is 30%), reaction time, and mode of addition (e.g., variations in concentrations of the various reactants in syringe and flask). A set of preferred reaction conditions consists of a solution of diyne in n-octane being added to a refluxing solution of nitrile in n-octane under N.sub.2 over a multi-day period. Monosubstituted diyne 1a was obtained from the disodium salt of 1,7-octadiyne and one equivalent ethyl iodide in liquid NH.sub.3 followed by p.g.l.c. (column temperature 170.degree. C.) in ca. 50% yield.

Ethyl 3-(5,6,7,8-tetrahydroisoquinoline)acetate (4f).

A solution of 1,7-octadiyne (1), n=4, (650 .mu.l, 5.00 mmol), cyanoacetic ester (2f) (531 .mu.l, 5.00 mmol) and (C.sub.5 H.sub.5)Co(CO).sub.2 (63 .mu.l, 0.50 mmol) in xylene (15 ml) was added over 117 h (by syringe pump) to o-xylene (15 ml) warmed to reflux under N.sub.2 (all reagents deoxygenated).

After removal of solvent under reduced pressure, the reaction mixture was chromatographed on silica gel (60 g; ether elution). The crude product was microdistilled (85.degree.-105.degree. C./0.02 torr) to give a clear oil, analytically pure (510 mg=47.1%).