Pyridine synthesis from 1,5-diketones

The synthesis of the pyridine ring from ethyl acetoacetate, aldehydes, and ammonia proceeds extraordinarily readily. The mechanism is as follows. In the first phase the aldehydes react with the acetoacetic ester to form alkylidene bis-acetoacetic esters. The 1 5-diketone derivatives so formed undergo ring closure by introduction of a molecule of ammonia and elimination of two molecules of water ... 

Shiga, T., Ohba, M., and Okawa, H. (2004) A series of trinuclear Cu Ln Cu complexes derived from 2,6-di(acetoacetyl)pyridine synthesis, structure, and magnetism. Inorganic Chemistry, 43, 4435 446. Albrecht, M., Schmid, S., Dehn, S., et al. (2007) Diastereoselective formation of luminescent dinuclear lan-thanide(III) helicates with enantiomerically pure tartaric acid derived bis(P-diketonate) ligands. New Journal of Chemistry, 31, 1755-1762. 

Such order of bases activity corresponds almost precisely to that observed in the synthesis of pyrroles from ketoximes and acetylene and, obviously, is caused by the same reasons. It is assumed [109,152] that the inability of trimethylbenzylam-monium hydroxide to catalyze vinylation reaction is due to the lack of coordination ability of this base. This fact as well as inhibition of the reaction with water, pyridine, phenanthroline, and diketones evidences [109,152] that the reaction proceeds via two mechanisms, that is, complex and ionic ones (in the latter case, participation of a complex ion as intermediate is not excluded). 

The reaction of appropriate 1,3-diketones (302) with hydroxylamine hydrochloride in pyridine (79MI41601) has been reported to result in a regiospecific synthesis of 3-alkyl-5-arylisoxazoles, as has the reaction of an a -bromoenone (307) with hydroxylamine hydrochloride in ethanol in the presence of potassium carbonate (81H(16)145). Regiospecific syntheses of 5-alkyl-3-phenylisoxazoles also result from the reaction of an a-bromoenone (307) with hydroxylamine in the presence of sodium ethoxide (81H(16)145). 3-Aryl-5-methylisoxazoles were prepared from phosphonium salts (304) and hydroxylamine (80CB2852). 

Our own group is also involved in the development of domino multicomponent reactions for the synthesis of heterocycles of both pharmacologic and synthetic interest [156]. In particular, we recently reported a totally regioselective and metal-free Michael addition-initiated three-component substrate directed route to polysubstituted pyridines from 1,3-dicarbonyls. Thus, the direct condensation of 1,3-diketones, (3-ketoesters, or p-ketoamides with a,p-unsaturated aldehydes or ketones with a synthetic equivalent of ammonia, under heterogeneous catalysis by 4 A molecular sieves, provided the desired heterocycles after in situ oxidation (Scheme 56) [157]. A mechanistic study demonstrated that the first step of the sequence was a molecular sieves-promoted Michael addition between the 1,3-dicarbonyl and the cx,p-unsaturated carbonyl compound. The corresponding 1,5-dicarbonyl adduct then reacts with the ammonia source leading to a DHP derivative, which is spontaneously converted to the aromatized product. 

The second major class of enamines contains the enamino ketones, made from ammonia or an amine and a 1,3-diketone. By this route the same 1,3-diketone can provide both halves of the resulting pyridine such an example is provided by the synthesis of 5-benzoyl-2-phenylpyridine (444) (54YZ259). As in the case of the crotonates, the first examples of the condensation of an enamino ketone with an a,/ -unsaturated ketone were provided by Knoevenagel and Ruschhaupt (1898CB1025), who prepared the range of 3-acetyldihy-dropyridines (445) to (447). Similarly, Mumm and Bohme obtained the 3-acetyl- and 3-benzoyl-2,6-dimethylpyridines (448) and (449) from ethyl acetylpyruvate (21CB726). 

Among the methods available for the synthesis of the pyridine system, Hantzsch synthesis is probably the most important and widely used synthetic route. However, the pyridine ring can be synthesized from the reaction between pentan-2,4-dione and ammonium acetate. Cyclization of 1,5-diketones is also considered as a convenient method for the synthesis of corresponding pyridine derivatives. Commercially, pyridine is obtained from distillation of coal tar. 

Figure 2.30 Representation of the asymmetric unit of [Nd(L )4(H20)][(TTF—CH=CH—Py+)] 2-The radical cation donors are drawn as balls and sticks the paramagnetic anionic coordination complexes of Nd(III) are drawn as capped sticks [23d], (Reprinted with permission from F. Pointillart, O. Maury, Y. Fe Gal, S. Golhen, O. Cador and F. Ouahab, 4-(2-Tetrathiafulvalenyl-ethenyl)pyridine (TTF—CH=CH—py) radical cation salts containing poly(P-diketonate) rare earth complexes synthesis, crystal structure, photoluminescent and magnetic properties, Inorganic Chemistry, 48, 7421-7429, 2009. 2009 American Chemical Society.)...

For the synthesis of (69), the enol ether (71) from the indanone (70) was carboxylated with COa-n-butyl-Iithium in THF at —70 C to yield (72). The methyl ester (73) was converted into (75) via the maleic anhydride adduct (74), essentially as described in earlier work. Lithium aluminium hydride reduction followed by oxidation with dicyclohexylcarbodi-imide afforded the aldehyde (76). This was condensed with excess (77) to yield a mixture of the diastereomers (78). Oxidation with chromium trioxide-pyridine in methylene dichloride gave (79), which could be converted into the diketone (80) by treatment with excess benzenesulphonylazide. The diketo-lactam (81) was prepared from (80) as described for the synthesis of the analogous intermediate used in the synthesis of napelline. Reduction of (81) with lithium tri-t butoxyaluminohydride gave the desired dihydroxy-lactam (82). Methylation of (82) with methyl iodide-sodium hydride gave (83). Reduction of this lactam to the amine (84) with lithium aluminium hydride, followed by oxidation with potassium permanganate in acetic acid, gave (69). 

The synthesis of arsonium ylides 384 from diazocyclopentadienes 383 and tri-phenylarsine has been reexamined with respect to the efficiency of various copper-containing catalysts Whereas copper bronze gave only ca. 55 % of ylide, yields over 80% were provided by the use of Ou(II) complexes of p-diketonates derived from acetylacetone, 3-methylacetylacetone, benzoylacetone or dibenzoylmethane, as well as by bis[4-(phenylimino)-2-pentanonato-N,0-]copper(II) and Cu(II) acetate, all used in boiling benzene. The sterically more demanding complex bis(dipivaloyl-methanato)copper(II) as well as dichlorodipyridinecopper(II) proved less efficient. CopperfTI) tartrate, the dibenzo-14-crown 6/copper complex and furthermore the acetylacetonate complexes of Co, Ni, Pt and Zn were totally ineffective. When 383a was decomposed by Cu(acac)2 in the presence of pyridine or thioanisole. 

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