Methylcinnamate

Pd/P(t-Bu)., in the presence of Cy2NMe, is an unusually mild and versatile catalyst for Heck reactions of aryl chlorides (Tables 1 and 2) (as well as for room-temperature reactions of aryl bromides).21 22 23 Example A, the coupling of chlorobenzene with butyl methacrylate, illustrates the application of this method to the stereoselective synthesis of a trisubstituted olefin a-methylcinnamic acid derivatives are an important family of compounds that possess biological activity (e.g., hypolipidemic24 and antibiotic25) and serve as intermediates in the synthesis of pharmaceuticals (e.g., Sulindac, a non-steroidal anti-inflammatory drug26). Example B, the coupling of 4-chlorobenzonitrile with styrene, demonstrates that Pd/P(t-Bu). can catalyze the Heck reaction of activated aryl chlorides at room temperature. 

Brick et al. have studied this bromination in more detail and showed that the extent of the bromination can be controlled by changing the ratio of the reagents. The first substitution was found to be in the para position but subsequent intramolecular rearrangements allowed the formation of 2-5-dibrominated species. Brick et al. also reported the functionalization of such species using Pd-catalyzed reactions such as Heck and Suzuki couplings to give fully substituted p-stilbenes, p-biphenyls, diarylamines, and methylcinnamates. Hydrogenation of... 

Neither tritium or deuterium gas, with zero dipole moments, can be expected to interact positively with microwave radiation. Their low solubilities are seen as a further disadvantage. Our thoughts therefore turned towards an alternative procedure, of using solid tritium donors and the one that has found most favor with us is formate, usually as the potassium, sodium or ammonium salt. Catalytic hydrogen transfer of this kind is remarkably efficient as the results for a-methylcinnamic acid show [50]. The thermal reaction, when performed at a temperature of 50 °C, takes over 2 h to come to equilibrium whereas the microwave-enhanced reaction is complete within 5 min. A further advantage is that more sterically hindered al-kenes such as a-phenylcinnamic acid which are reduced with extreme difficulty when using H2 gas and Wilkinson s catalyst are easily reduced under microwave-enhanced conditions. 

The degree of enantioselective bias was improved shortly after this time. In 1971, Morrison et al. reported that the rhodium(I) complex [RhCl(NMDPP)3] (NMDPP= neomethyldiphenylphosphine) reduces ( )-/ -methylcinnamic and ( )-a-methylcinnamic acids with 61 and 52% ee, respectively (Scheme 1.9) [41]. NMDPP is a monodentate phosphine derived from (-)-menthol, and its asymmetry lies at carbon atoms. 

The 1-t-butylphospholane sulfide intermediate to TangPhos was also used to prepare the P,N ligands 48 by reacting the lithium complex with C02 and then oxazoline formation with a range of chiral amino alcohols [69b, 74]. The Ir complexes of these ligands have been successfully used in the reduction of / -methylcinnamic esters (80-99% ee) and methylstilbene derivatives (75-95% ee), a particularly challenging class of unfunctionalized olefins [4 c]. 

The e.e.-values were moderate, an improved result of 79% e.e. being obtained with nmdpp (2f) which is not chiral on phosphorus. The use of the other, non P-chiral, ligand mdpp (2e) gave low enantioselectivity. Ligand 2f was also successfully used in the hydrogenation of 2-methylcinnamic and (l )-3-methylcinnamic acid [24]. 

Methylcinnamic acid, hydrogenation of, 25 89 2-Methyl-cis-byciclo [3.3.0] octane, 20 269 Methyl cyanide, catalytic hydrogenation, 35 145... 

Recently developed ligand SIPHOX 16a-d proved to be a valuable tool in the asymmetric reduction of a,(3-unsaturated acids [66]. In a complete break with what is typically observed with iridium-based N,P ligands, SiPHOX catalysts were observed to reduce the strongly coordinating carboxylic acid triethylamine salt of a methylcinnamic acid in excellent enantioselectivity and yield (Table 5). Equally surprising is the use of methanol as a solvent, which normally inhibits reductions mediated by iridium N,P catalysts. 

More recent patents describe the following preparation from a-methylcinnam-aldehyde. a-Methylcinnamaldehyde (from benzaldehyde and propionaldehyde) is hydrogenated to a-methyldihydrocinnamic alcohol. The alcohol is alkylated with tert-butyl chloride or isobutene to 4-tert-butyl-o -methyldihydrocinnamic alcohol, which is subsequently dehydrogenated to the desired aldehyde [152, 153]. 

Bromolactonization of /3,y-unsaturated acids has proven to be a much more satisfactory method of synthesis of /3-lactones, giving good yields of stable crystalline -y-bromo-/3-lactones, except when the substitution at the -y-carbon atom can favor development of carbonium character there. Thus 1,4-dihydrobenzoic acid and 2-methyl-l,4-dihydrobenzoic acid form /3-lactones (equation 95), while 3-methyl-l,4-dihydrobenzoic acid forms the -y-lactone (75JOC2843). The reaction of the sodium salt of a-methylcinnamic acid with bromine in water or methanol also gives /3-lactone, but the yield is low (78JOC3131). 

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