Methylcinnamic acid

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. 

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 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. 

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). 

Methyl n-amyl carbinol. 247, 254 Methyl n-amyl ketone, 482 Methylaniline (mono), pure, from commercial methylaniline, 562, 570 P-Methylanthraquinone, 728, 740 Methyl benzoate, 780, 781 p-Methyl benzyl alcohol, 811,812 Methyl benzyl ketone, 727, 735 Methyl y-bromocrotonate, 926, 927 2-Methyl-2-butene, 239 Methyl n-butyl carbinol, 247,255 Methyl n-butyl ether, 314 Methyl n-butyl ketone, 475, 481 4-Methylcarbostyril, 855 p-Methylcinnamic acid, 719 4-Methylcoumarin, 853, 854 Methyl crotonate, 926, 927 Methylethylacetic acid, 354, 358 Methylethylethynyl carbinol, 468 Methyl ethyl ketone, 335, 336 purification of, 172 Methyl n-hexyl ether, 314 Methyl n-hexyl ketone, 335, 336 Methyl n-hexyl ketoxime, 348 Methyl hydrogen adipate, 938 Methyl hydrogen sebacate, 938,939 4-Methyl-7-hydroxycoumarin, 834 Methyl iodide, 287 Methyl isopropyl carbinol, 247,255 Methyl 4-keto-octanoate, 936... 

Methyl cinnamate, AR55 -Methylcinnamic acid, AR56... 

SYNTHESIS To a solution of 25 g 2,5-dimethoxy-4-methylbenzaldehyde (see the recipe for 2C-D for the preparation) and 29.2 g malonic acid in 50 mL anhydrous pyridine, there was added 2 mL piperidine and this was heated on the steam bath for several h. The mixture was added to a solution of 125 mL concentrated HC1 in 500 mL HjO at 0 °C, and the solid product that was formed was removed by filtration, and washed with H20. Recrystallization from aqueous EtOH yielded 31 g 2,5-dimethoxy-4-methylcinnamic acid with a mp of 163-166 °C. Anal. (C 2H1404) C,H. 

In a cooled high-pressure reaction vessel there was placed a suspension of 30 g 2,5-dimethoxy-4-methylcinnamic acid in 150 mL liquid isobutene. This was treated dropwise with 0.6 mL concentrated I1 S04, then sealed and brought to room temperature. After 48 h shaking, the vessel was cooled again to -10 °C, opened, and poured into 200 mL of 10% Na2C03. This was extracted with hexane, the pooled extracts washed with H,0, and the solvent removed to yield 17.0 g of (t)-butyl 2,5-dimethoxy-4-methylcinnamate as an amber oil. Anal. (C16H2204) C,H. 

Only limited successful examples of asymmetric hydrogenation of acrylic acids derivatives have included the use of chiral Rh complexes (Scheme 1.17). The diamino phosphine (28) utilizes selective ligation of the amino unit to a Rh center and also exerts electrostatic interaction with a substrate. Its Rh complex catalyzes enantioselective hydrogenation of 2-methylcinnamic acid in 92% optical yield [116], Certain cationic Rh complexes can attain highly enantioselective hydrogenation of trisubstituted acrylic acids [ 1171. 2-(6 -Methoxynaphth-2 -yl)acrylic acid is hydrogenated by an (.S ..S )-BIPNOR- Rh complex in methanol at 4 atm to give (.S)-naproxen with 98% ee but only in 30% yield [26]. 

Cognate preparations. p-Methylcinnamic acid. From p-tolualdehyde heat for 6 hours. Recrystallise from glacial acetic acid m.p. 198 °C. Yield 87 per cent. 

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