Pyridin-2-ones, 3,4,5-trisubstituted, from

Cobalt metal catalyses the co-trimerization of one molecule of acetonitrile with two of 1 -pentyne or 1 -hexyne to yield mixtures of the pyridines 610 and 611 (R = Pr or Bu). The regioselctivity of the reaction of nitriles with terminal acetylenes has been investigated. It was found that, in general, mixtures of 2,4,6- and 2,3,6-trisubstituted pyridines are produced. The selectivity depends on the size of the substituents attached to the triple bond and the cyanide group. If either of these is large, only 2,4,6-substituted pyridines are obtained. Ethyl propiolate and aliphatic or aromatic nitriles (RCN) yield, in addition to the usual type of product, i.e. 612 and 613, the 2,3,5-isomer 614. Pyridines 617 result from the action of alkynes RC=CH (R = Ac, PrCO or C02Me) on the electron-rich... 

The Hantzsch pyridine synthesis involves the condensation of two equivalents of a 3-dicarbonyl compound, one equivalent of an aldehyde and one equivalent of ammonia. The immediate result from this three-component coupling, 1,4-dihydropyridine 1, is easily oxidized to fully substituted pyridine 2. Saponification and decarboxylation of the 3,5-ester substituents leads to 2,4,6-trisubstituted pyridine 3. 

The Bohlmann-Rahtz synthesis of trisubstituted pyridines from /3-aminocrotonates and an ethynyl ketone has found application in the preparation of a variety of heterocycles based on the substituted pyridine motif. Bagley and coworkers have developed a microwave-assisted modification of this one-pot heteroannulation method that is best conducted in dimethyl sulfoxide at 170 °C for 20 min, providing the desired pyridines in 24—94% yield (Scheme 6.227) [406, 407]. Typically, 2 equivalents of the /3-aminocrotonates were employed. 

Trisubstituted ureas have been obtained, under mild conditions (333 K, 0.1 MPa, 6h), in the presence of pyridine, from primary amines, C02 and hexaalkylphos-phorous triamides, P(NR2)3 [124]. The latter compounds are able to react with C02 by converting into phosphocarbamate species, P(02CNR2)3 (NR2) (x = 1, 2). The yields of ureas R2NC(C))NHR" were almost quantitative, if based on one amino group of P(NR2)3, but could not be further improved by the addition of an excess of primary amine. This indicates that, in general, only one of the three P-N bonds of P(NR2)3 takes part in the reaction. 

In the laboratory of P. Kocovsky, novel pyridine-type P,A/-ligands were prepared from various monoterpenes. The key step was the Krohnke pyridine synthesis, and the chirality was introduced by the a,(3-unsaturated ketone component, which was derived from enantiopure monoterpenes. One of these ligands was synthesized from (+)-pinocarvone which was condensed with the acylmethylpyridinium salt under standard conditions to give good yield of the trisubstituted pyridine product. The benzylic position of this compound was deprotonated with butyllithium, and upon addition of methyl iodide the stereoselective methylation was achieved. The subsequent nucleophilic aromatic substitution (Sw/ r) gave rise to the desired ligand. 

The Bohlmann-Rahtz reaction is a classic pyridine synthesis that has been studied and modified in many ways. Bagley et al. has elaborated on his previous work and reported an iodine-mediated catalytic Bohlmann-Rahtz reaction of aminodienone intermediates <05SL649>. This modified process is reported to be rapid at ambient temperatures resulting in good yields. Moreover, Bagley and co-workers presented a one-pot, three-component Bohhnann-Rahtz reaction to synthesize 2,3,6-trisubstituted and 2,3,4,6-tetrasubstituted pyridines 8 and 9 from P-ketoesters 10 and alkynes 11 as shown in Seheme 3 <05JOC1389>. 

Pyridine can become involved in nucleophilic substitution when very reactive triflates are being synthesized. One approach to minimize this disadvantage is to replace it with ster-ically hindered bases, such as 2,6-di-r-butyl-4-methylpyridine, 2,4,6-trisubstituted pyrimidines, or nonnucleophilic aliphatic amines (usually N,(V-diisobutyl-2,4-dimethyl-3-pentylamine). No salt formation appears to take place under these conditions. The triflic anhydride seems to be the direct triflating agent and the base only neutralizes the triflic acid formed. Numerous alkyl triflates have been prepared in the literature by the above method. Some recent examples of triflates prepared from alcohols are illustrated in eqs 2 and 3. As an exception, 2,6-dinitrobenzyl alcohol does not react with Tf20 although similar sulfonyl esters could be prepared. ... 

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