Alkoxycarbonylation ketones

Some trimethylsilyl enol ethers, not able to undergo /3-H elimination, have been stoichiometrically converted into a-alkoxycarbonyl ketones via the intermediate formation of oxa-7r-allyl complexes (Scheme 23) [123,124]. 

Also known as Morita-Baylis-Hillman reaction, and occasionally known as Rauhut-Currier reaction. It is a carbon—carbon bond-forming transformation of an electron-poor alkene with a carbon electrophile. Electron-poor alkenes include acrylic esters, acrylonitriles, vinyl ketones, vinyl sulfones, and acroleins. On the other hand, carbon electrophiles may be aldehydes, a-alkoxycarbonyl ketones, aldimines, and Michael acceptors. 

The Dieckmann, Thorpe and Thorpe-Ziegler reactions all involve intramolecular cyclization of a stabilized anion to form a cyclic ketone. The Dieckmann reaction is the intramolecular equivalent of the Claisen condensation and yields cyclic 2-alkoxycarbonyl ketones as primary products, whereas the primary products of the Thorpe reaction are 2-cyanoenamines (Scheme 13). Sub quent hydrolysis affords cyclic ketones but the primary products, particularly those from the Dieckmann reaction, have a useful synthetic role (see Section 3.6.3.S.1). 

The reversibility of the process means that cyclic 2-alkoxycarbonyl ketones can be cleaved by alkoxide in the retro-Dieckmann reaction, a process of synthetic significance (see Section 3.6.9.1). More recently, nonequilibrium conditions have been employed in the reaction and this may lead to a change in regioselectivity (see Section 3.6.3.3.3). 

In 1959 Carboni and Lindsay first reported the cycloaddition reaction between 1,2,4,5-tetrazines and alkynes or alkenes (59JA4342) and this reaction type has become a useful synthetic approach to pyridazines. In general, the reaction proceeds between 1,2,4,5-tetrazines with strongly electrophilic substituents at positions 3 and 6 (alkoxycarbonyl, carboxamido, trifluoromethyl, aryl, heteroaryl, etc.) and a variety of alkenes and alkynes, enol ethers, ketene acetals, enol esters, enamines (78HC(33)1073) or even with aldehydes and ketones (79JOC629). With alkenes 1,4-dihydropyridazines (172) are first formed, which in most cases are not isolated but are oxidized further to pyridazines (173). These are obtained directly from alkynes which are, however, less reactive in these cycloaddition reactions. In general, the overall reaction which is presented in Scheme 96 is strongly... 

Alkyltriphenylphosphonium halides are only weakly acidic, and a strong base must be used for deprotonation. Possibilities include organolithium reagents, the anion of dimethyl sulfoxide, and amide ion or substituted amide anions, such as LDA or NaHMDS. The ylides are not normally isolated, so the reaction is carried out either with the carbonyl compound present or with it added immediately after ylide formation. Ylides with nonpolar substituents, e.g., R = H, alkyl, aryl, are quite reactive toward both ketones and aldehydes. Ylides having an a-EWG substituent, such as alkoxycarbonyl or acyl, are less reactive and are called stabilized ylides. 

Other functional groups which have a heteroatom rather than a hydroxyl group capable of directing the hydrogenation include alkoxyl, alkoxycarbonyl, carboxylate, amide, carbamate, and sulfoxide. The alkoxy unit efficiently coordinates to cationic iridium or rhodium complexes, and high diastereoselectivity is induced in the reactions of cyclic substrates (Table 21.3, entries 11-13) [25, 28]. An acetal affords much lower selectivity than the corresponding unsaturated ketone (Table 21.3, entries 14 and 15) [25]. 

Pd-catalyzed carbonylation of heteroaryl halides provides a quick entry to heteroaryl carbonyl compounds such as heteroaryl aldehydes, carboxylic acids, ketones, esters, amides, a-keto esters and a-keto amides. In addition, Pd-catalyzed alkoxycarbonylation and aminocarbonylation are compatible with many functional groups, and therefore, are more advantageous than conventional methods for preparing esters and amides [78],... 

Ketones can be oxidatively carbonylated at the a-carbon via enol intermediates using PdCl2 as the catalyst and Q1CI2 as oxidant [122], The initially formed carbonylation products correspond to a-chlorination and a-alkoxycarbonylation. Under the reaction conditions, these compounds undergo further transformations involving C - C cleavage eventually leading to a mixture of esters and an alkyl chloride or (in the case of cyclic ketones) to a diester and a chloroester (Schemes 20-21). 

Active methylene or methine compounds, to which two EWGs such as carbonyl, alkoxycarbonyl. formyl, cyano. nitro, and sulfonyl groups are attached, react with butadiene smoothly and their acidic hydrogens are displaced with the 2,7-octadienyl group to give mono- and disubstituted compounds[59], 3-Substituted 1,7-octadienes are obtained as minor products. The reaction is carried out with a /3-keto ester, /3-diketone, malonate, a-formyl ketones, a-cyano and a-nitro esters, cyanoacetamide, and phenylsulfonylacetate. Di(octadienyl)malonate (61) obtained by this reaction is converted into an... 

When a -amino ketones with an additional acyl or alkoxycarbonyl substituent are used, the cyclization can follow one of two alternative courses (Scheme 6) (71JOC853). The first represents the normal Knorr cyclization. The product of the competing deacylation pathway is also a pyrrole and the utilization of the reaction gives a pyrrole synthesis, as is described in Section 3.06.3.5. The reaction does, however, constitute a limitation on the Knorr synthesis itself. 

As is to be expected, an alkynic ketone undergoes a Michael addition with a carbanion, leading eventually to a pyranone (50JA1022). Using malonic esters, a 3-alkoxycarbonyl derivative results, which is hydrolyzed to the 2-oxopyran-3-carboxylic acid under alkaline conditions, but to the pyranone by sulfuric acid. Rapid ester exchange is observed with the initial products, the alcohol used as solvent determining the nature of the alkyl group in the 3-carboxylic esters (Scheme 90). 

Support-bound alkylating agents have been used to N-alkylate pyridines and dihydropyridines (Entries 7 and 8, Table 15.21). Similarly, resin-bound pyridines can be N-alkylated by treatment with a-halo ketones (DMF, 45 °C, 1 h [267]) or other alkylating agents [246]. Polystyrene-bound l-[(alkoxycarbonyl)methyl]pyridinium salts can be prepared by N-alkylating pyridine with immobilized haloacetates (Entry 8, Table 15.21). These pyridinium salts react with acceptor-substituted alkenes to yield cyclopropanes (Section 5.1.3.6). Pyridinium salts have also been prepared by reaction of resin-bound primary amines with /V-(2,4-dinitrophenyl)pyridinium salts [268,269]. 

As shown in Eqs. (17) and (18), the isolated formyls 19 and 24 are capable of reducing aldehydes and ketones (37, 38, 42. 47, 66). Thus there is no doubt that hydride transfer is an intrinsic chemical property of anionic formyl complexes. One reaction of a neutral formyl complex with an aldehyde has been reported addition of benzaldehyde to (i7-C5H5)Re(NO)(CO)(CHO) (38) yields the alkoxycarbonyl complex (i7-C5H5)Re(NO)(CO)(C02CH2C6Hs) (62). This transformation, which appears to require catalysis by adventitious acid, can be viewed as occurring via attack of initially formed benzyl alcohol upon the intermediate carbonyl cation [(i -C5H5)Re(NO)(CO)2]+. 

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