Carboxylic a,/?-unsaturated

Formation of carboxylic acids ami their derivatives. Aryl and alkenyl halides undergo Pd-catalyzed carbonylation under mild conditions, offering useful synthetic methods for carbonyl compounds. The facile CO insertion into aryl- or alkenylpalladium complexes, followed by the nucleophilic attack of alcohol or water affords esters or carboxylic acids. Aromatic and a,/ -unsaturated carboxylic acids or esters are prepared by the carbonylation of aryl and alkenyl halides in water or alcohols[30l-305]. 

These compounds can be converted by hydrolysis into the corresponding carboxylic acids RCH2CO2H, or they can undergo a Wittig reaction, albeit only in moderate yield, to produce a,/ -unsaturated carboxylic acids. 

Pyrazolones have been prepared by palladium promoted cyclization of a,/ -unsaturated carboxylic acid hydrazides but yields are only moderate (Scheme 91)15 6 and no attempt has been made to effect a catalytic conversion. 

It has already been mentioned that utilization of the permethylated ligand (L19)2 in place of (L23)2 drastically alters the ease of substitution reactions of the [M2(L19)(C1)]+ complexes (Section III.D). Further studies revealed a remarkable influence of the hydrophobic pocket on the rate and course of several substrate transformations, as for instance the fixation of carbon dioxide (239) (Scheme 8), the cis-bromination of a,/)-unsaturated carboxylate ligands (256), and some Diels-Alder reactions (215). Of these the latter two reactions will now be discussed. 

The observation that a,/ -unsaturated carboxylate ligands can be readily accommodated in the binding pocket led us to study an orienting reaction between the dinickel complex 101 and 2,3-dimethylbutadiene (Scheme 10). However, the reaction did not proceed, even when the reaction mixture was heated at 210°C for 24 h. The inhibition of the Diels-Alder reaction can be traced to the limited space in the binding pocket of 101. 

The bisfunctionalization of alkynes by both C02 and another electrophile can also be achieved, as shown in Scheme 9.17,17a The titanium-carbon bond in the titanacycle complex 31, which was formed by reaction of C02 with the titanacyclopropene 30, can be substituted with various electrophiles. For example, its reaction with NBS or I2 afforded the synthetically useful vinyl bromide or iodide 32, respectively, while the reaction with D20 yielded the /3-deuterated a,/ -unsaturated carboxylic acid. When an aldehyde such as PhCHO was used as an electrophile, butenolide 33 was produced after acidic workup. 

With ferrocenes, an alternative approach has been to attach the phosphorus moieties only to side chains. The WalPhos family (36) forms an eight-mem-bered chelate with the metal. Members of this family provide good selectivity and reactivity for the reductions of dehydroamino and itaconic acid derivatives as well as a,/ -unsaturated carboxylic acids [145, 156],... 

Enantioselective Hydrogenation of Unsaturated Acids and Esters 26.3.5.1 a,/ -Unsaturated Carboxylic Acids... 

Limited progress has been achieved in the enantioselective hydrogenation of a,/ -unsaturated carboxylic acid esters, amides, lactones, and ketones (Scheme 26.10). The Ru-BINAP system is efficient for the hydrogenation of 2-methy-lene-y-butyrolactone, and 2-methylene-cyclopentanone [98]. With a dicationic (S)-di-t-Bu-MeOBIPHEP-Ru complex under a high hydrogen pressure, 3-ethoxy pyr-rolidinone could be hydrogenated in isopropanol to give (R)-4-ethoxy-y-lactam in 98% ee [39]. 

A cobalt complex containing this type of ligand is effective in the sodium borohydride-mediated enantioselective reduction of a variety of a,/ -unsaturated carboxylates. As can be seen from Scheme 6-8, in the presence of a catalytic amount of a complex formed in situ from C0CI2 and chiral ligand 11, reduction proceeds smoothly, giving product with up to 96% ee. The chiral ligand can easily be recovered by treating the reaction mixture with acetic acid. 

J.-L Xiao, S. C. A Nefkens, P. G. Jessop, T. Ikariya, R. Noyori, Asymmetric Hydrogenation of a, -Unsaturated Carboxylic Adds in Supercritical Carbon Dioxide , Tetrahedron Lett. 1996,37,2813-2816. 

R = t-Bu, 81%) and r-butylbenzene (5%) (Scheme 119) [447]. Similarly, the Pd(II) complex catalyzes the electrosynthesis of aromatic carboxylic acids under CO2 atmosphere [448]. The electrocar-boxylation of vinyl triflates is performed with CO2 and a catalytic amount of PdCl2(PPh3)2 to give a,/ -unsaturated carboxylic acids [449]. 

Ll-Rh complex was employed for the enantioselective synthesis of (S)-2-(4-fluorophe-nyl)-3-mefhylbutanoic acid (98% ee) [107], while the Pr-DuPhos-Rh complex was utilized for the enantioselective hydrogenation of a,/ -unsaturated carboxylic acids, as exemplified by tiglic acid [29]. 

The same group expanded their study to see how well nitrenes derived from N-(alkoxycarbonyl) 0-(arenesulfonyl)hydroxyfamines 3i-o perform in a-amination of a,fi-unsaturated carljonyl compounds by aziridination. Good results are obtained when a,-unsaturated carboxylates and y-lactones are reacted with the amination reagents 3k, 31 and 3n in the presence of CaO. 

The Michael acceptor can be an a, -unsaturated carboxylic ester. This possibility is illustrated with the conjugate addition of phenylmagnesium bromide to ethyl arecaidinate, which leads to 4-phenylnipecotic acid (equation 33). 

Dihydroquinoline-3-carbonitriles can also be prepared by the tandem reaction between 2-(mediylamino)-benzophenone and a,/3-unsaturated carbonitriles in the presence of magnesium amide under the same conditions as for the reaction with a,-unsaturated carboxylates (equation 39). 

In similar work, CF3CC12C02CH3 yields methyl a-trifluoromethyl-o<, )-un-saturated carboxylates when reacted with a zinc-copper couple, aldehydes, and acetic anhydride [67] (equation 55). This methodology gives (Z)-a-fluoro-a- -unsaturated carboxylates from the reaction of carbonyl compounds with CFCI2CO2CH3 and zinc and acetic anhydride [68],... 

Reactions. Malonie acid is a useful tool lor synthesizing a-unsaturaled carboxylic acids because of its ability lo undergo decarboxylation and condensation with aldehydes or ketones at the methylene group. Cinnamic... 

Analogous to the use of chiral enoates (see previous section), a, -unsaturated carboxylic amides, prepared from chiral amines, may be utilized in asymmetric 1,4-additions. When Grignard reagents are added to unsaturated amides (21), derived from (-)-ephedrine (20),25 highly optically active fi-sub-stituted alkanoic acids (22 R and R = alkyl or phenyl) are obtained in a variety of cases, after hydrolysis of the initially formed adducts (Scheme 7). This method was used for the synthesis of the antibiotic (-) malyngolide and its stereoisomers.26 Recrystallization of the intermediate (saturated) amide was necess-... 

Keywords phenol, 1,3-dihydroxybenzene, a,/ -unsaturated carboxylic compound, ethyl acetoacetate, microwave irradiation, coumarin... 

A mixture of phenol 1 (10 mmol) and a,/ -unsaturated carboxylic derivative 2, 4 or ethyl acetoacetate 6 (15-20 mmol) supported on 1 g of solid acid support (by dissolving the mixture in 5 mL of diethyl ether followed by evaporation of the solvent) was exposed to microwave irradiation in a focused microwave reactor (Prolabo MX350). For isolation of the compounds, the solid support was removed by extraction with ethanol (for reactants 2 and 6) or acetonitrile (reactions of 4). After solvent evaporation, the products were purified by column chromatography on silica gel (hexane-ethyl acetate, 3 1). 

Two examples of Pd(II)-catalyzed carbomethoxylations of vinyl(phenyl)iodonium salts have been reported (equations 251 and 252)125,126. The mild reaction conditions and stereospecificity of carbonylation recommend further applications of vinyliodonium compounds for the synthesis of a,/ -unsaturated carboxylate esters. By way of comparison, similar carbobutoxylations of vinyl halides (Br, I) typically require higher temperatures (60-100 °C) and longer reaction times, and they sometimes proceed with low stereospecificity151. 

Lactam-fused compounds 127 are obtained by the reaction of secondary 1,1-enediamines with a,/ -unsaturated carboxylic acid derivatives such as methyl acrylate,... 

Activated a,-unsaturated carboxylic acids 466 undergo a domino condensation/aza-Michael reaction to form hydantoins 467." ... 

By Reaction with a. -Unsaturated Carboxylic Acid Derivatives.117... 

The decarboxylation of the sodium salts of perfluorinated a. -unsaturated carboxylic acids gives perfluoroacetylenes and allcnes (3-10 %) when the thermal reaction is carried out without solvent, e.g. formation of 9 and 10. When the reaction is carried out in ethylene glycol, the alkene is formed in the presence of iodine, the corresponding iodoalkene can be obtained. ... 

Enzymes catalyze the reversible enantioselective addition of ammonia to a./ -unsaturated carboxylic acids to give L-a-amino acids. Immobilized enzymes and whole-cell bioreactor technology competes well with chemical methods31,32. For practical purposes, immobilized whole cells are preferred over immobilized enzyme because of the added cost of enzyme isolation. 

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