2-Pyrones, from enamines

The synthesis of a large number of y-pyrones and y-pyranols from enamines has been brought about through the use of a wide variety of bifunctional molecules. These molecules include phenolic aldehydes (126,127), phenolic Mannich bases (128), ketal esters (129), and diketene (120-132). All of these molecules have an electrophilic carbonyl group and a nucleophilic oxygen center in relative 1,4 positions. This is illustrated by the reaction between salicylaldehyde (101) and the morpholine enamine of cyclohexanone to give pyranol 102 in a quantitative yield (127). 

Macrocyclic 2-pyrones (113) and (114) are prepared from enamine (115) and ketene (75HCA2409). Reduction of cyano ketone (116) with LAH affords an amino ketone which spontaneously cyclizes to generate a tetrahydropyridine (117) dehydrogenation by palladium on charcoal produces the aromatized phane (118) (71TL671). 

The reaction of ketene with the enamine (113) is reported (88) to give l-morpholino-2-acetyl-l-cyclohexene i.e., the enamino ketone expected from acylation of (113). The pyrrolidine enamine (28), however, has been shown to react (73) with excess ketene to give the a-pyrone (124). On the... 

The reactions of vinylogous amides and vinylogous urethanes with excess ketene were found to give a-pyrones (421), which could also be obtained from further reactions of acylated enamines with ketene (383,421). 

On the other hand y-pyrones or 1,3-diketones could be obtained from the reactions of ketone derived enamines with diketene 423-426). The addition of dimethyl ketene dimer to aldehyde or ketone derived enamines produced cyclohexanediones 425,426). 

From the reactions of sulfur and carbon disulfide with cyclic ketone-derived enamines (570-573) 3H-l,2-dithiole-3-thiones were obtained, whereas the addition of carbon disulfide to other enamines gave a-dithio-pyrones (574), through initial dimerization of the enamine. 

Enamine (235) obtained from cyclic ketones and the acetal of /V-methyl-2-pyrrolidone gave a fused 2-pyrone [83IJC(B)1083]. 2//-Chromenes were obtained from of 3,5-dichlorosalicylaldehyde and enamines (94RRC183) (Scheme 42). The pyran ring is formed by a reaction of aminals of conjugated w-dimethylaminoaldehydes with cyclic /1-dicarbonyl compounds (94IZV285) (Scheme 43). 

Another ketene reaction, the enamine ketene reaction, can also be used for ring enlargement. An application of this reaction is shown in Scheme IV/15, in which the enamine of morpholine and cyclotridecanone IV/95 has been transformed to ( )-muscone (IV/99) [53] [54] [55]. Two moles of ketene -generated in situ from acetylchloride and triethylamine or introduced as gaseous ketene - were condensed step-wise with the enamine IV/95 to form the a-pyrone, IV/97. The yield is low (10-28 %). Base catalyzed hydrolysis of IV/97 gave a mixture of the four isomers, IV/98a to IV/98d, yielding, after catalytic hydrogenation, ( )-muscone (IV/99) [53]. 

When one of the carbonyl carbons is at the oxidation level of acid (as in a 2-pyrone), then the product, reflecting this oxidation level, is a 2-pyridone. Similarly, 4-pyrones react with ammonia or primary amines to give 4-pyridones and the bis-enamines which can be obtained directly from ketones by condensation on both sides of the carbonyl group with DMFDMA, produce 4-pyridones on reaction with primary amines. When one of the carbonyl units is actually a nitrile, then an amino-pyridine results. ... 

The a-pyrone analogues (101) have been synthesized by a [24]cycloaddition reaction between cyclic a-keto-enamines (100) and di(thioethyl)ketene/ 5-Enamino- 8-keto-esters, derived from the corresponding acetylenic keto-esters, undergo smooth alkylation to give /35-diketo-esters, which can be cyclized to 4-hydroxy-a-pyrones with hot polyphosphoric acid/ ... 

Acetylacetone and malonyl chloride give 5-acetyl-4-hydroxyd-methyl-2-pyrone (XII-253), a positional isomer of dehydroacetic acid, which reacts with aqueous ammonia or aqueous methylamine to form XII-254 (R = H, CHs), which can also be prepared from the enamine of acetylacetone and carbon suboxide (see Section I.3.E., p. 635). The //-methylpyridone XII-2S4 (R = CH3) is deacetylated to 4-hydroxy-l,6-dimethyl-2-pyridone with sulfuric acid however, W-254 (R = H) was not deacetylated under these conditions. Acetylacetone and carbon suboxide give 8-acetyl-4-hydroxy-7-methylpyrano-[4,3-6] pyiane-2,5-dione (XI-255) with catalytic amounts of sulfuric acid. This is also formed from acetylacetone and malonyl chloride or from carbon suboxide and the intermediate 5-acetyl-4-hydroxy-6-methyl-2-pyrone (XU-253). 3,5-Diacetyl-4-hydroxy-6-methyl-2-pyrone (XI-256) can be formed by acetylation of XII-253 with acetic acid and phosphorus oxychloride or by degradation of XII-255. 3,5-Diacetyl-4-hydroxy-6-methyl-2-pyridone can... 

A pyrone 32 can be obtained from the reaction of two molecules of ketene and one of enamine 31 and loss of amine (Scheme 13) (1965JOC2642). 

The overall result of this process is the formation of two new CT-bonds in addition to the generation of a new stereocaiter adjacent to the heteroatom, thereby constituting a tandem anionic—pericyclic ring-closure sequence. It can be considered formally an equivalent of a [3+3] cycloaddition in which the three carbons of aldehyde 2 have been added to the two carbons and one oxygen atom of pyrone 1 [3a,b,4,13,14]. The term [3+3] cycloaddition was adapted by us from Seebach s work describing a Stork-type carbo-[3+3] cycloaddition reaction between nitroalkenes and enamines [14]. 

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