Cinnamates epoxidation

Selective oxidation of either the aromatic ring or the side chain can also be accompHshed. For example, epoxidation of the double bond of cinnamic acid is effected in excellent yield by treatment with potassium hydrogen persulfate (10). 

Physical and Chemical Properties. The (F)- and (Z)-isomers of cinnamaldehyde are both known. (F)-Cinnamaldehyde [14371-10-9] is generally produced commercially and its properties are given in Table 2. Cinnamaldehyde undergoes reactions that are typical of an a,P-unsaturated aromatic aldehyde. Slow oxidation to cinnamic acid is observed upon exposure to air. This process can be accelerated in the presence of transition-metal catalysts such as cobalt acetate (28). Under more vigorous conditions with either nitric or chromic acid, cleavage at the double bond occurs to afford benzoic acid. Epoxidation of cinnamaldehyde via a conjugate addition mechanism is observed upon treatment with a salt of /-butyl hydroperoxide (29). 

When heated in the presence of a carboxyHc acid, cinnamyl alcohol is converted to the corresponding ester. Oxidation to cinnamaldehyde is readily accompHshed under Oppenauer conditions with furfural as a hydrogen acceptor in the presence of aluminum isopropoxide (44). Cinnamic acid is produced directly with strong oxidants such as chromic acid and nickel peroxide. The use of t-butyl hydroperoxide with vanadium pentoxide catalysis offers a selective method for epoxidation of the olefinic double bond of cinnamyl alcohol (45). 

Due to the high reactivity of sulfonium ylide 2 for a,P-unsaturated ketone substrates, it normally undergoes methylene transfer to the carbonyl to give the corresponding epoxides. However, cyclopropanation did take place when 1,1-diphenylethylene and ethyl cinnamate were treated with 2 to furnish cyclopropanes 53 and 54, respectively. 

The asymmetric epoxidation of electron-poor cinnamate ester derivatives was highlighted by Jacobsen in the synthesis of the Taxol side-chain. Asymmetric epoxidation of ethyl cinnamate provided the desired epoxide in 96% ee and in 56% yield. Epoxide ring opening with ammonia followed by saponification and protection provided the Taxol side-chain 46 (Scheme 1.4.12). 

To a solution of m-ethyl cinnamate (44, 352 mg, 85% pure, 1.70 mmol) and 4-phenylpyridine-A-oxide (85.5 mg, 29 mol%) in 1,2-dichloromethane (4.0 mL) was added catalyst 12 (38.0 mg, 3.5 mol%). The resulting brown solution was cooled to 4°C and then combined with 4.0 mL (8.9 mmol) of pre-cooled bleach solution. The two-phase mixture was stirred for 12 h at 4°C. The reaction mixture was diluted with methyl-t-butyl ether (40 mL) and the organic phase separated, washed with water (2 x 40 mL), brine (40 mL), and then dried over Na2S04. The drying agent was removed by filtration the mother liquors concentrated under reduce pressure. The resulting residue was purified by flash chromatography (silica gel, pet ether/ether = 87 13 v/v) to afford a fraction enriched in cis-epoxide (45, cis/trans . 96 4, 215 mg) and a fraction enriched in trans-epoxide cis/trans 13 87, 54 mg). The combined yield of pure epoxides was 83%. ee of the cis-epoxide was determined to be 92% and the trans-epoxide to be 65%. 

While asymmetric approaches are certainly important, other synthetically significant epoxidation protocols have also been reported. For example, buffered two-phase MCPBA systems are useful for epoxidations in which the alkenes and/or resultant epoxides are acid-sensitive. Bicarbonate works quite well for cinnamate derivatives (e.g., 55) <96SC2235> however, 2,6-di-t-butyl-pyridine was shown to give superior results in the case of certain allyl acetals (e.g., 57) <96SC2875>. 

Isomerization has been observed with many a,j3-unsaturated carboxylic acids such as w-cinnamic 10), angelic, maleic, and itaconic acids (94). The possibility of catalyzing the interconversion of, for example, 2-ethyl-butadiene and 3-methylpenta-l,3-diene has not apparently been explored. The cobalt cyanide hydride will also catalyze the isomerization of epoxides to ketones (even terminal epoxides give ketones, not aldehydes) as well as their reduction to alcohols. Since the yield of ketone increases with pH, it was suggested that reduction involved reaction with the hydride [Co" (CN)jH] and isomerization reaction with [Co (CN)j] 103). A related reaction is the decomposition of 2-bromoethanol to acetaldehyde... 

Deng and Jacobsen38 used Mn-salen complex for the asymmetric epox-idation of ethyl cinnamate. Over 95% ee was obtained for the epoxide compound (Scheme 7-81). 

After 5 minutes the cooling bath was removed and the two-phase reaction mixture was stirred at room temperature. The reaction was monitored by TLC (eluent petroleum ether-diethyl ether, 9 1). (Z)-Ethyl cinnamate was UV active, Rf 0.42. The epoxide visualized withp-anisaldehyde dip stained yellow, Rt 0.28. 

The asymmetric hydrogenation of cinnamic acid derivatives has been developed by Knowles at Monsanto [4], The synthesis of L-dopa (Figure 4.3), a drug for the treatment of Parkinson s disease, has been developed and is applied on an industrial scale. Knowles received the Nobel Prize for Chemistry in 2001 together with Noyori (see below, BINAP ) and Sharpless (asymmetric epoxidation). 

Ketone 8 epoxidizes a wide range of olefins in good yields. The steric hindrance and electronegativity of the substitnents (X) at positions 3 and 3 greatly affect the epoxidation reactivity and enantioselectivity. In general, pnra-snbstituted trans-stilbenes are very effective snbstrates for the epoxidation using ketone 8 (Table 1, entries 1-8, 16-18). The enantioselectivity for the epoxidation increases as the size of the substituents increases. However, the size of the mefn-substituents had little effect on enantioselectivity. Later, Seki and coworkers extended the epoxidation scope to cinnamates using ketone 8 (Table 1, entry 26) [35, 36]. 

In the present work, the Jacobsen s catalyst was immobilized inside highly dealuminated zeolites X and Y, containing mesopores completely surrounded by micropores, and in Al-MCM-41 via ion exchange. Moreover, the complex was immobilized on modified silica MCM-41 via the metal center and through the salen ligand, respectively. cis-Ethyl cinnamate, (-)-a-pinene, styrene, and 1,2-dihydronaphtalene were used as test molecules for asymmetric epoxidation with NaOCl, m-CPBA (m-chloroperoxybenzoic acid), and dimethyldioxirane (DMD) generated in situ as the oxygen sources. 

Epoxidation of cis-ethyl cinnamate, styrene, and 1,2-dihydronaphtalene over MCMIHC, MCM2HC, and MCM3HC materials was carried out using different oxygen sources (e.g., NaOCl, m-CPBA, and DMD generated in situ). The catalyst stability was checked by recording the infrared spectra of the catalyst before and after the reaction. When NaOCl and m-CPBA were employed as oxygen sources. 

The relative rates of epoxidation of ethyl 4-substituted-(E)-cinnamates by 200 gave a Hammett p value of —1.53, indicating an electrophilic oxygen-atom transfer316 the reaction rate is increased by protic solvents317. 

The 6-dcoxy-/J-D-c -c//hHohexofuranoside-5-ulose, a constituent of the sugar-cinnamate unit 234 of the antibiotic hygromycin, and several related analogues, have been synthesized from 6-deoxy-/J-D-glucofuranosides via a 2,3-epoxide and selective oxidation at C-5 with the Jones reagent.445... 

Yang s chiral ketones 75 have also been used as catalysts in the kinetic resolution of acyclic secondary allyl silyl ethers <2001JOC4619>. Dioxiranes generated in situ from dehydrocholic acid derivatives 122 and Oxone have been used in the asymmetric epoxidations of cinnamic acid derivatives with product ee s up to 95% <2001TA1113, 2002JOC5802> and unfunctionalized olefins (up to 98% ee) <2006T4482>. 

Asymmetric Epoxidation of Electron-deficient trans-Olefins. (f )-l can also catalyze epoxidation of electron-deficient trans -olefins, especially ( )-cinnamate derivatives (eq 4). With 5 mol % of (f )-l, epoxidation of acrylate (5) is completed in 27 h with 74% yield and 85% ee. The crude product can be purified using a continuous dissolution and crystallization process to afford enantiomerically pure product and recover the ketone catalyst simultaneously. A similar practical method has been employed for large-scale synthesis of a key intermediate for diltiazem hydrochloride (a potent calcium antagonist for treatment of cardiovascular disease). 

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