Pyridones regioselectivity

Bach, T., Bergmann, H., Brummerhop, H., Lewis, W., and Harms, K., The [2-t2]-photocycloaddition of aromatic aldehydes and ketones to 3,4-dihydro-2-pyridones regioselectivity, diastereoselectivity and reductive ring opening of the product oxetanes, Chem.-Eur. /., 7,4512, 2001. 

More general processes rely on variations of the Guareschi-Thorpe reaction [14] where condensations between 1,3-dicarbonyls and cyanoacetamide yield functionalized monocyclic 2(lff)-pyridones (a and b. Scheme 2) [15, 16]. Unless the carbonyls are sufficiently different in reactivity, the reaction suffers from poor regioselectivity. The use of 3-alkoxy or 3-amino enones instead of 1,3-dicarbonyls has proven to be a versatile and reliable synthetic methodology where the 1,4-addition controls the regioselective outcome (c and d. Scheme 2) [17-19]. 

The direct bromination of 2-hydroxypyridine is regioselective at C-3 whereas chlorination is not. Qu6guiner has developed a halide exchange reaction. Heating 3-bromo-2-hydroxypyridine in pyridine hydrochloride at reflux gives 3-chloro-2-hydroxypyridine in good yield <96TL(37)6695>. The directed aminomethylation of 3-hydroxy-2(lH)-pyridones and 3-hydroxy-4(lfl)-pyridones has been studied <96T(52)1835>. 

Regiospecific N- or C-benzylations of 2-pyridone were observed under solvent-free conditions in the absence of base. The regioselectivity was controlled by the activation method (MW or A) or, when using microwaves, by the emitted power level or the leaving group of the benzyl halides [58] (Eq. 59). 

FMO calculations using PM3-C1 were used to investigate the regioselectivities obtained by the photochemical reactions between 2-pyridone and pcnta-2,4-dienoate.46 The hard and soft acid-base principle has been successfully used to predict product formation in Patemo-Buchi reactions.47 The 2 + 2-photo-cycloaddition of homobenz-valene with methyl phenylglyoxylate, benzyl, benzophenone, and 1,4-benzoquinone produced the corresponding Patemo-Buchi products.48 The photo-cycloaddition of acrylonitrile to 5-substituted adamantan-2-ones produces anti- and svn-oxetanes in similar ratios irrespective of the nature of the 5-substituent49... 

An alternative stereoselective synthesis of chiral heterocycles based on carbohydrate-induced stereodifferentiation includes nucleophilic addition reactions on heterocyclic systems already bound to the carbohydrate auxiliary. An example of this strategy has been shown by stereoselective addition of Grignard reagents to carbohydrate-linked 4-pyridones [61]. For this purpose, trimethylsiloxypyridine was glycosylated regioselectively using pivaloyl-protected glycosyl fluorides. 

A Ni°-based system related to those already described in connection with syntheses of both cyclobut-enediones and several five-membered heterocycles (Sections 9.4.2.1, 9.4.3.3 and 9.4.3.5) is also capable of catalyzing pyridone synthesis from isocyanates and alkynes. However, the structures found for the isolable metallacyclic intennediates in this system imply a completely different insertion sequence isocyanate first, followed by the two alkynes (Scheme 35). As a consequence, the regiochemistry found in the products of reaction of unsymmetrical alkynes is the reverse of that typical of Co larger substituents end up at positions 4 and 6. Thus, starting wiA the carbonyl carbon of the isocyanate, each carbon-caib-on bond forming event is strongly regioselective for the less-hindered alkyne caibon (equation 46). The... 

Regioselectivity in a ring closure by internal nucleophilic attack is often puzzling. While the substituent appears to make the difference in equation (57) a similar reaction of a diethynylketone with aryl amines leads to both 5- and 6-rings, i.e. oxo-A -pyrrolines and pyridones - -. The question that arises most frequently here is illustrated by the choice given in equation (58). 

A nucleophile-induced ring transformation reaction of 2-pyranones was reported (Scheme 6) to result in a regioselective synthesis of 2-aminopyridines 21 or 2-pyridones 22 <05SL623>. Urea was used to generate ammonia as a nucleophile source. The reaetion of 23 (R=CN) was initially examined under elevated temperatures and solvent-free conditions. This system yielded a mixture of both 21 and the pyridone equivalent of 23, in equal amounts. The reaction conditions were modified to yield 2-aminopyridine 21 selectively as shown in Scheme 6. However, the only reaction found to be selective for 2-pyridone 22 formation is where the cyano group was replaced with an ester, shown in Scheme 6. Compound 24 was converted to pyridone 22 in good yield. 

This product was used by Comins in his synthesis of mappicine. The antiviral alkaloid is the alcohol formed by borohydride reduction of mappicine ketone 124. Strategic disconnections 124 split the molecule into a quinoline 125 and a pyridone 126 and correspond to a simple SN2 and a Heck reaction. If the Heck reaction is performed last it will be intramolecular and hence regioselective. 

Substitutions usually proceed via attack on the neutral pyridone, but in very strong acid, where there is almost complete 0-protonation, 4-pyridone undergoes a slower nitration, via attack on the salt, but with the same regioselectivity. ... 

The nucleophilic reactivity of 17 can be increased by N-deprotonation and the best results were obtained with the in situ generated lithium salts. The latter react with acrylates by Michael addition and ring closure to give a single product. The problem of regioselectivity arises because the enamine anion 47 is delocalized and can react both at the nitrogen anion and/or at the enamine carbon. Both cases are known in the literature with similar substrates (ref. 49). These two pathways should lead to the isomeric dihydro a- or y-pyridones (Scheme 53). 

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