Methyl dihydropyridone

Seeds of Areca catechu (betel nut) (Palmae) contain the simple jV-methyltetrahydropyridine 3-carboxylic acid (jV-methyl-A -tetrahydronicotinic acid) arecaidine and arecoline (arecai-dine methyl ester) (Section 1, Appendix) that are mACh-R agonists and accordingly parasympathetic stimulants. Betel nut also yields guvacine (A -tetrahydronicotinic acid) that is an anti-epileptic GABA transport inhibitor. Conversely the jV-methyl dihydropyridone derivative ricinine from seeds of Ricinus communis (castor seed) (Euphorbiaceae) is a stimulatory agonist acting at the benzodiazepine site of the GABA(A) receptor. 

A far more successful sequence (62) which produced a fully substituted pyridone (66) involved ethoxide promoted condensation of (65) with cyanoacetamide. Similarly, (65) could be combined with (67) to give, after methylation, dihydropyridone (68) which on dehydrogenation yielded the fully substituted pyridone (69). 

Methyl acrylate reacts with the enediamine 230 to yield the spiro-tetrahydroimidazo-pyridone 232 via the transient intermediate 231120. The reaction with methyl propiolate gives an analogous intermediate 233, which, however, is stable. It is transformed into the bicyclic dihydropyridone 234 by the action of methanol121 (equation 98). 

Methyl-2,3-dihydropyridone was isolated by hydrolysizing the Step 3 product with trifluoroacetic acid as described in Step 4. 

The first systematic investigation toward Lewis acid catalyzed vinylogous Mukaiya ma Mannich reactions was reported by the group of Ojima in 1987 who showed that acyclic vinylketene silyl 0,0 acetals 10 reacted with imines activated by stoichio metric amounts of TiCU to furnish either 5 amino 2 alkenoates 11 or 5,6 dihydro pyridones 12 selectively in excellent yields depending upon the substitution of the silyl dienolate employed (Scheme 5.4) [5]. Although 2 methyl substituted vinylketene acetal 10a gave rise to acyclic 5 amino 2 alkenoates 11 exclusively, 3 methyl substi tuted vinylketene acetal 10b furnished 5,6 dihydropyridones 12 as the sole products. 

Crooksidine (4), the alkaloid of Haplophyton crooksii, has been synthesized by two groups of workers. The first of these (272) consists of a very straightforward route in which condensation of 2-ethyltryptamine with methyl 4-formylhexanoate gave the dihydropyridone derivative 425. Reduction followed by oxidation then gave crooksidine (4) (Scheme 3S). 

Asymmetric synthesis of dihydropyridones. 8-Phcnylmcnthol has been used frequently as a chiral auxiliary, but this derivative (1) is more effective as the chiral auxiliary for cnantioselcctivc reactions of N-acylpyridinium salts with organomctallic reagents. Thus 2, prepared by reaction of 4-methoxy-3-(triisopropylsilyl)pyridine with the chloroformate of 1 reacts with the Grignard reagent 3 to give an adduct that on acidic deprotection provides the dihydropyridone 4 in 94% dc. Conversion of the alcohol to a chloride [P(CftH5)j and NCS] followed by treatment with sodium methoxide in methanol cleaves the chiral auxiliary as the methyl carbonate (94% yield) and at the same time effects cyclization to form the chiral bicyclic dihydropyridone 5 in 84% yield. 

Methyl acrylate (37) was used as a reagent for annulation with the phenyl imine derivative of acetophenone. For example, phenyl imine 78 was converted to 79 by treatment with 37 in the presence of AICI3 (eq. 20).34 The enamine formed from acetophenone (80) and NH4OAC was converted to 82 by combination with 81 (eq. 21).17 In the case of 81, the aryl substituent provided a steric and electronic hindrance to the aza-annulation reaction, but the reactivity of the reagent was enhanced by the combined effects of the C02Et and CN functionality. Due to the nature of the substituents on the intermediate dihydropyridone, dehydrogenation occurred to form pyridone 82. 

The same explanation of the microwave effect can be advanced for the solvent-free synthesis of 4-aryl substituted 5-alkoxycarbonyl-6-methyl-3,4-dihydropyridones [131] by condensation of Meldrum s acid, methyl acetoacetate, and benzaldehyde derivatives (Eq. 44) ... 

Loupy et al. have reported a specific non-thermal microwave effect in the synthesis of 4-atyl substituted 5-alkoxycarbonyl-6-methyl-3,4-dihydropyridones (81-91% under the action of microwaves compared with 17-28% with conventional heating) [188]. 

The reaction mixture created from the addition of the ct-amino carban-ions 267 to cyclobutenediones 266 was initially treated with 2.5 equivalent of MeOTf at 78 °C. The subsequent quenching of this reaction mixture with aqueous NaHCOs afforded the methylated products 268 in pure form after column chromatography in satisfactory yields. After N-Boc deprotection of 268, upon thermolysis, an intramolecular nucleophiHc addition of ketene 269 occurred to give dihydropyridones 270 (Scheme 85) (1999JOC4042). 

L. Zhang, S. R. Sheng, M. H. Wei, X. L. Liu, Synth. Common. 2008, 38, 1249-1258. Rapid microwave-assisted hquid-phase synthesis of 4-substituted-5-methoxycarbonyl-6-methyl-3,4-dihydropyridones on poly(ethylene glycol) support. 

By incorporating a chiral auxiliary, ( + )-fra/w-2-(a-cumyl)cyclohexyl (TCC), into pyridinium salt 688, Comins and co-workers were assured of excellent asymmetric induction in a divergent synthesis of three 5,8-disubstituted amphibian indolizidine alkaloids (Scheme 93) (467,499). Addition of but-3-enylmagnesium bromide to 688 yielded the dihydropyridone 689 as a single diastereomer in 91% yield after recrystallization. After a series of functional group manipulations, the C-8 methyl group was introduced stereoselectively by enolate alkylation (690 -> 691),... 

The reaction between ethyl Hthiopropiolate and the N-acylpyridinium salt formed by reaction of 4-methoxy-3-methyl-5-(triisopropylsilyl)pyridine 2363 with (+)-frafis-2-(a-cumyl)-cyclohexyl chloroformate (TCC chloro-formate) was the starting point in the synthesis of (-l-)-aUopumihotoxin 267A (1718) by Comins et al. (Scheme 301). The dihydropyridone product (—)- 2364 was obtained diastereoselectively (>96%) before hydrogenation to the saturated ester (+)-2365. However, some epimerization of the methyl substituent was apparent after cleavage of the TCC carbamate with lithium methoxide and cyclization to the indolizidinone (—)-2366 (dr 8 1). Acetoxylation at C-8 with lead tetraacetate was stereoselective, and introduced the acetate from the axial direction, possibly by stereoelec-tronicaUy-controUed intramolecular transfer of acetate from a lead—enol intermediate. The acetoxy product (—)-2367 was protodesilylated with formic acid, after which a one-pot tandem reduction with K-Selectride followed by hthium aluminum hydride gave diol (- -)-2368 with complete... 

Photoreaction of 2-pyridone with aliphatic and aromatic amines leads to addition of the amines at C4 and C6 to give mixtures of dihydropyridone products (Scheme 15). All of these reactions appear to derive from a single electron transfer process. Tertiary aliphatic amines such as triethylamine 150 yield pyridones 151 and 152 (2 1) plus the reductively coupled pyridone dimer 153. Pyrrole 154 leads to a similar mixture of 4- and 6-substituted dihydropyridones 155 and 156 (1 1). Dimethylpyrrole 157 and indole 158 lead to analogous products of 4- and 6-substition of the pyridone (at C3 of the pyrrole 157). N-Methyl pyrrole 159, however, does not yield photoproducts. When the N-methyl pyrrole is alkyl substituted at C2 (160), addition to the pyridone yields 161 and 162 (1 1). ... 

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