Diels-Alder reaction, with pyridones

Kuzuya M., Noguchi A. The Nature of Substituent Effects on Tautomeric Equilibria of 2-Pyridones and Their Reactions Trends Org. Chem. 1991 2 73-92 Keywords chemo- and regiochemistry of Diels-Alder reactions with benzyne,... 

Trimethylsilylketene and acyl isocyanates generate 4-trimethylsiloxy-l,3-oxazin-6-ones 12 in situ, which smoothly react with the enamines of cycloalkanones to give bicyclic 2-pyridones 13 <96TL(37)4977>. The heterocycles 12 also undergo the Diels-Alder reaction with dimethyl acetylenedicarboxylate or methyl propiolate to furnish substituted 2-pyridones <96TL(37)4973>. 

The montmorillonite KlO-catalyzed aza-Diels-Alder reaction of Danishefsky s diene with aldimines, generated in situ from aliphatic aldehydes and p-anisidine, proceeded smoothly in H20 or in aqueous CH3CN to afford 2-substituted 2,3-dihydro-4-pyridones in excellent yields (Eq. 12.47).115 Also, complex [(PPh3)Ag(CBiiH6Br6)] was shown to be an effective and selective catalyst (0.1 mol% loading) for a hetero-Diels-Alder reaction with Danishefsky s diene and the reaction showed a striking dependence on the presence of trace amounts of... 

Pyridones can act as diene components in [4+2] cycloadditions. The Diels-Alder reaction with activated alkenes or alkynes lead to derivatives of 2-azabicyclo[2.2.2]octa-5,7-dien-3-one 12 by the addition of acetylenedicarboxylate to l,4,6-trimethyl-2-pyridone 11, as shown below [84] ... 

The Diels-Alder reaction of 2-azadienes also benefits from the presence of an electron-donating substituent, to enhance the reactivity with electron-deficient dienophiles. Cycloaddition with alkynyl dienophiles and aromatization leads to substituted pyridines (3.54). Silyloxy-substituted 2-azadienes such as 68 are effective dienes and have been used to prepare substituted 2-pyridones and piperidones after methanolysis (3.55). Asymmetric hetero Diels-Alder reactions with the chiral Lewis acid catalyst 66 provide access to the piperidone products with very high enantioselectivity. ... 

JCycloadditions. Posner et al. have reviewed Diels-Alder reactions with 2-pyrones and 2-pyridones in detail, with special attention to the selectivity (213 references). 

Cycloaddition of trimethylsilylketene 108 with benzoylisocya-nate 282 was suggested to give 4-trimethylsilyloxy-l,3-oxazin-6-one 283. Interestingly, this six-membered heterocycle can be subjected to the Diels—Alder reaction with electron-deficient alkynes to afford 2-pyridone... 

Trimethylsilylketene reacts similarly with carbonyl isocyanates to give [4+2] cycloadducts, which undergo a Diels-Alder reaction with acetylenes or enamines to give 2-pyridones. A theoretical study of the reaction of silylketenes with carbonyl isocyanates and subsequent Diels-Alder reaction with ynamines was conducted recently. ... 

The Boekelheide reaction has found utility in other synthetic methodology. An approach to 2,3-pyridynes made use of this chemistry in the preparation of the key intermediate 30. Treatment of 28 with acetic anhydride produced the desired pyridone 29. Lithiation was followed by trapping with trimethylsilyl chloride and exposure to triflic anhydride gave the pyridyne precursor 30. Fluoride initiated the cascade of reactions that resulted in the formation of 2,3-pyridyne 31 that could be trapped with appropriate dienes in Diels-Alder reactions. 

High-pressure Diels-Alder reaction of 1-methyl-2-(1H)-pyridones having a phenyl group with N-phenylmaleimide [94]... 

Another approach towards monocyclic N-unsubstituted 2-pyridones is based on a solid-phase supported Diels-Alder reaction where a resin-bound 2(lH)-pyrazinone 9 is reacted with acetylenic dienophiles (Fig. 4) [43]. The initially formed cycloadduct then undergoes a retro Diels-Alder reaction and depending on the substitution pattern of the starting pyrazinone the reaction... 

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>. 

Hoomaert has studied Diels-Alder reactions of pyridine oquinodimethane analogs generated from functionalized o-bis(chloromethyl)pyridines <96T(52)11889>. The photochemical cycloaddition of 2-alkoxy-3-cyano-4,6-dimethylpyridine with methacrylonitrile gives a bicyclic azetine, 6-alkoxy-3,5-dicyano-2,5,8-trimethyl-7-azabicyclo[4.2.0]octa-2,7-diene, in moderate yield <96CC1349>. Regiospecific hydroxylation of 3-(methylaminomethyl)pyridine to 5-(methylaminomethyl)-2-(17/)-pyridone by Arthrobacter ureafaciens has been reported <96MI173>. 

As in the case of Diels-Alder reactions, aqueous aza-Diels-Alder reactions are also catalyzed by various Lewis acids such as lanthanide triflates.113 Lanthanide triflate-catalyzed imino Diels-Alder reactions of imines with dienes or alkenes were developed. Three-component aza-Diels-Alder reactions, starting from aldehyde, aniline, and Danishefsky s diene, took place smoothly under the influence of HBL4 in aqueous media to afford dihydro-4-pyridone derivatives in high yields (Eq. 12.46).114... 

Similar aza-Diels-Alder reactions of Danishefsky s diene with imines or aldehydes and amines in water took place smoothly under neutral conditions in the presence of a catalytic amount of an alkaline salt such as sodium triflate or sodium tetraphenylborate to afford dihydro-4-pyridones in high yields (Eq. 12.49).117 Antibodies have also been found to catalyze hetero-Diels-Alder reactions.118... 

The aza-Diels-Alder reaction of Danishefsky s diene with imines provides a convenient method for the synthesis of 2-substituted 2,3-dihydro-4-pyridones, a compound class that has important synthetic applications. Kobayashi and co-workers have studied the reaction in detail using ytterbium (III) triflate as the Lewis acid30. Although the reaction is often run at low temperature (—78°C to 0°C) for a number of hours, we have found that the reaction also worked well at elevated temperatures (150°C) in the microwave for a few minutes (J. Westman and A. Hurynowics, unpublished results) (see Scheme 5.15). The imines could either be preformed prior to the addition of the Danishefsky s diene or the reaction could be performed as a multi-component protocol, where all components were added at once. 

Recently, it has been shown that 2-pyridones with the nitrogen atom substituted by alkyl,262 aryl, or methoxyl265 do undergo Diels-Alder reactions. Heating l-methyl-2-pyridone with DMAD to 195°, the first successful example studied,262 gave 51, which was thought to be formed via 49 as shown. Under milder conditions,265 Diels-Alder adducts (cf. 49) can be isolated and, on further heating, yield phthalic esters and isocyanates. 

Vankar and co-workers709 have shown that Nafion-H can catalyze the hetero Diels-Alder reaction between the Danisefsky diene 164 and aromatic imines to form 2,3-dihydro-y-pyridones (Scheme 5.69). The reaction with aromatic aldehydes, however, yields only the Mukaiyama aldol condensation products. 

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>. 

In the field of [4 + 2]-cycloadditions, silver catalysts have been used mainly for aza-Diels-Alder reactions of Danishefsky s diene 447 with various imines. Kobayashi and co-workers364 have recently shown that this transformation can be carried out with catalytic amounts of silver(i) triflate in water (Scheme 133). Various aryl- or alkenyl-substituted pyridone derivatives 448 were obtained in high yields. A survey of other silver catalysts revealed that... 

Enantioselective silver-catalyzed aza-Diels-Alder reactions have also been described. Whereas the use of BINAP as the chiral ligand gave only unsatisfactory enantioselectivities,367,367a Hoveyda etal 6 used the peptidic phosphine 373 which has already been used for silver-catalyzed asymmetric Mannich reactions (see Scheme 108) in the efficient Ag(i)-catalyzed cycloaddition of arylimines 449 with Danishefsky s diene (Scheme 135). After acidic work-up, the chiral pyridones 450 were obtained with excellent yields and enantioselectivities. The presence of isopropanol as a proton source is essential for obtaining high conversions and stereoselectivities. Similar to the Mannich reactions, the cycloaddition is not affected by the presence of air or the use of undistilled THF. 

Snider et al. have synthesised the antiinsectan ( )-leporin [496] 7-26 using the domino-Knoevenagel-hetero Diels-Alder sequence. The intermediate 1-oxa-1,3-butadiene 7-25 was formed in situ by condensation of the pyridone 7-23 and the dienal 7-24. Subsequently, a hetero Diels-Alder reaction occurred accompanied by minor side reactions. Thus, the desired cycloadduct 7-27 was formed only in moderate yield as 5 1 mixture with its trans-fused diastereomer (Fig. 7-6). Functionalisation of the nitrogen atom yielded the natural product. A similar reaction sequence occurred in the synthesis of the structurally related free radical scavenger ( )-pyridoxatin, however, in this approach the hetero Diels-Alder reaction represented only a side reaction competing with the desired intramolecular ene reaction [497]. 

Narsaiah and Krishnaiah (2002) reported that the hetero-Diels-Alder reaction of A(-acetyl perflnoroalkyl substituted 2(1//) pyridones with DMAD on neutral alumina under solvent-free microwave irradiation conditions extended to undergo an inverse electron demand hetero-Diels-Alder reaction, resulting exclusively in E, Z isomers (3 1) of Michael-type A-adducts. 

Krishnaiah, A. and Narsaiah, B. 2002. Studies on inverse electron demand hetero Diels-Alder reaction of perfluoroalkyl 2(1H) pyridones with different dienophiles under microwave irradiation. Journal of Fluorine Chemistry, 113 133-37. 

The acetoxy group was hydrolyzed using hydrazine to give (46). Nucleophilic substitution of the fluorine atom produced the tricyclic /3 lactam (47). A diastereoselective aza-Diels-Alder reaction was used in a synthesis of (-)-lasubine (I). Tin tetrachloride mediated reaction of complex (48) with Danishefsky s diene afford 2,3-dihydro-4-pyridone (49) as a single diastereomer (Scheme 86). Chiral benzaldehyde imines can be aUylated with high diastereoselectivity to give optically active homoaUyhc amines (Scheme 87). 

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