2-Pyridone ring synthesis

Scheme 9. Pyridone ring reduction (a) and synthesis of (-)-strychnine (1) (b).

In pyrrolopyridine synthesis reactions, nitropyridines are less reactive than the corresponding nitropyridone derivatives due to the decreased aromaticity of the pyridone ring. The pyridone is more attractive for nucleophilic attack in the reaction <2002H(58)301> (see Section 10.06.5.3). 

An analogue in which a carboxylic acid attached to the 3 position takes the place of the polar pyridone ring in the previous examples also exhibits antiandrogenic activity. The synthesis starts by reaction of the intermediate (44-1) common to the preceding antiandrogens with phosphorus tribromide. This reagent converts the... 

The role of the pyridone ring as a pharmacophore in cardiotonic agents such as amrinone (25-6) has been noted earlier very analogous activity is obtained with compounds in which the heterocylic ring is replaced by a pyridazinone. The synthesis of the first of these agents, pimobendan (35-6), starts with the acylation of the amino group in nitro-aniline (35-2) with anisoyl chloride (35-1) to give amide (35-3). 

A 2-pyridone ring can be a building block for the synthesis of isoquinoline derivatives by acting as a dienophile in a Diels-Alder reaction. An electron-withdrawing group at C-4 is necessary for reaction with various substituted 1,3-butadienes (Equation 109) <2000CPB1814>. 

Campiani, G. Kozikowski, A. R Wang, S. Ming, L. Nacci, V. Saxena, A. Doctor, B. P. Synthesis and anticholinesterase activity of huperzine A analogues containing phenol and catechol replacements for the pyridone ring. Bioorg. Med. Chem. Lett., 1998, 8(11) 1413-1418. 

A convergent total synthesis of tenellin (81) has been reported. A key step in the synthesis was a cyclocondensation reaction between two preformed segments to form the pyridone ring [223],... 

Shamma s synthesis (Scheme 29) leaves the formation of the quinoline ring to a late stage, building up a tricyclic pyridone-ketone (121) which is then subjected to a Friedlander quinoline ring synthesis. 

A similar approach has been used for the synthesis of 3-lH-pyrazolo[3,4-fc]pyridyl-indole ° and 2-aminochromene libraries, the latter being performed solvent free using a clay as a support and base. In addition, a library of over 100 derivatized substituted 2-pyridones (21 x 5 members) has been prepared by the reaction of 1,3-cyclohexane-diones, dimethylformamide dimethylacetal, and various cyanoacetamides (Scheme 4.10). The outcome of the reaction could be controlled to furnish different products by changing the basicity of the medium to involve either the amide or nitrile functionality of the cyanoacetamide substrate during the 2-pyridone ring-formation step. 

Danishefsky etal. [61] reported an improved route to (20/ .J)-camptothe-cin in connection with their original total synthesis [60, 62-64], Reaction of tricyclic compound (14) with sodium hexamethyldisilazide and benzalde-hyde afforded a 90% yield of the benzylidene acid (15). A mechanism similar to a Stobbe condensation with participation of the methoxycarbonyl function on the pyridone ring is suggested for this reaction step. Ozonolysis of this compound (15) Scheme 2.2) afforded a 96% yield of the acid (16) which, upon esterification, provided (17) in 81% yield. Compound (17) is readily converted to (20/ S)-camptothecin. 

Pemberton N, Chorell E, Almqvist F (2006) Microwave-Assisted Synthesis and Functionalization of 2-Pyridones, 2-Quinolones and Other Ring-Fused 2-Pyridones. T. 1-30... 

Microwave-Assisted Synthesis of Ring-Fused /V-Substituted 2-Pyridones... 

This method has been extended to include imines other than A -thia-zolines, hence enabling the synthesis of multi ring-fused 2-pyridones (28,30, and 33, Scheme 8). Thus, by reacting dihydroisoquinoUnes 27 or /1-carboUnes 29 with acyl Meldrum s acid derivatives 24, a set of new ring-fused heterocycles was prepared in moderate to excellent yields (a and b. Scheme 8). These systems were prepared by using trifluoro acetic acid (TFA) as a proton source instead of solutions saturated with HCl (g). The switch of acid proved to be advantageous since it reduced the formation of by-products and increased the isolated yields. From a practical point of view, TFA is also su-... 

Scheme 9 Synthesis of ring-fused 2-pyridones via aminopropenoates using both solution-phase and solid-phase conditions...

The cycloadducts formed from the Diels-Alder reaction of 3-amino-5-chloro-2(17/)-pyrazinones with methyl acrylate in toluene are subject to two alternative modes of ring transformation yielding either methyl 6-cyano-l,2-dihydro-2-oxo-4-pyridinecarboxylates or the corresponding 3-amino-6-cyano-l,2,5,6-tetrahydro-2-oxo-4-pyridinecarboxylates. From the latter compounds, 3-amino-2-pyridones can be generated through subsequent loss of HCN <96 JOC(61)304>. Synthesis of 3-spirocyclopropane-4-pyridone and furo[2,3-c]pyridine derivatives can be achieved by the thermal rearrangement of nitrone and nitrile oxide cycloadducts of bicyclopropylidene <96JCX (61)1665>. 

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