Hantzsch-type pyridine synthesis

As might be expected, there are relatively few reactions for the preparation of heterocyclic systems which are useful on a laboratory scale and which involve the formation of four ring bonds. The Hantzsch pyridine synthesis (equation 148) (and a number of variations of the original procedure) is perhaps the classic example of this type of reaction, which is... 

Highly substituted pyridinium salts of type 1 are easily accessible by Hantzsch-type synthesis. They are valuable products in that they can often be transformed easily into otherwise difficultly accessible, highly substituted benzenes or pyridines by base-catalysed rearrangement. For example, treatment of the salt 2 with ethanolic sodium hydroxide at room temperature for one hour gives 2,4-diacetyl-lV,5-dimethylaniline 3 in 85% yield, while 3-acetyl-5-cyano-6-methyl-2-methylamino-4-phenylpyridine 5 is obtained in 88% yield from the salt 4 under the same conditions. 

In support of an hypothesis that clivacetine (188) might be a possible biosynthetic precursor of the unusual alkaloid clivimine (192), a biogenetic-type, partial synthesis of 192 from 188 has been completed, exploiting a classic Hantzsch pyridine synthesis (136). Thus, treatment of 188 with 35% formalin and 25% ammonium hydroxide gave dihydroclivimine, which underwent facile oxidation to clivimine (192) on dehydrogenation with sodium nitrite and acetic acid. 

In a synthesis of pateamine A, it was found that the optimum yield could only be obtained from a Hantzsch-type thiazole formation by isolation and purification of the nonaromatic intermediate. This was followed by dehydrogenation by treatment with TFAA, pyridine, and Hiinig s base, giving a 62% yield over the two steps (Scheme 25) <2004JA10582>. 

The reaction mixture was irradiated in a domestic MW oven for 5 min on a surface of bentonite clay. Not only traditional j8-keto esters, but also, for example, cyclic 1,3-diketones can participate in this MCR, thus enabling a four-component Hantzsch-type synthesis of unsymmetrically substituted 1,4-pyridines 20 (Scheme 17.15) [29, 37]. 

The Hantzsch-type of pyridine synthesis was also used in the total synthesis and stereochemical assignment of the thiopeptide antibiotic micrococcin Pl. ... 

The action part of NADH constitutes a simple dihy-dropyridine of the type readily accessible in the first step of the Hantzsch pyridine synthesis (Section 25-5). Therefore chemists have prohed whether such compounds can he used as metal-free alternatives to hydride reagents, such as... 

Our own approach to the combination of crown ether and dihydropyridine chemistry has involved constructing the dihydropyridine as an integral portion of the macrocyclic crown ether ring (see 24b, for example). The first synthetic approach involved ring-closure of an alicyclic precursor by means of the Hantzsch 1,4-dihydropyridine synthesis as illustrated for the preparation of (50, eq. 24). Such Hantzsch esters (general type 46) are attractive in that the acid functionalities at the 3,5-positions can be used as handles for attaching the (dihydro)pyridine... 

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