Ethyl cinnamate, addition

The addition of diazomethane to unsaturated esters (1), as ethyl acrylate, methyl crotonate and ethyl cinnamate, was investigated by Auwers who showed that the primary addition product is a A -pyrazoline (2) which rearranges spontaneously to the conjugated A -pyrazoline (3). 

In Corey and Chaykovsky s initial investigation, a cyclic ylide 79 was observed from the reaction of ethyl cinnamate with ylide 1 in addition to 32% of cyclopropane 53. In a similar fashion, an intermolecular cycloaddition between 2-acyl-3,3-bis(methylthio)acrylnitrile 80 and 1 furnished 1-methylthiabenzene 1-oxide 81. Similar cases are found in transformations of ynone 82 to 1-arylthiabenzene 1-oxide 83 and N-cyanoimidate 84 to adduct ylide 85, which was subsequently transformed to 1-methyl-lX -4-thiazin-l-oxide 86. ... 

Waters, H. D. C., A. R. Caverhill and P. W. Robertson The Kinetics of Halogen Addition to Unsaturated Compounds, Part XII. Iodine Catalysis of Chlorine and Bromine Addition to Ethyl Cinnamate. J. chem. Soc. (London) 1947, 1168. 

Much more conveniently, even a,)S-unsaturated esters can he transformed into a,)S-unsaturated alcohols by very careful treatment with lithium aluminum hydride [1073], sodium bis(2-methoxyethoxy)aluminum hydride [544] or diiso-butylalane [1151] (Procedure 18, p. 208). An excess of the reducing agent must be avoided. Therefore the inverse technique (addition of the hydride to the ester) is used and the reaction is usually carried out at low temperature. In hydrocarbons as solvents the reduction does not proceed further even at elevated temperatures. Methyl cinnamate was converted to cinnamyl alcohol in 73% yield when an equimolar amount of the ester was added to a suspension of lithium aluminum hydride in benzene and the mixture was heated at 59-60° for 14.5 hours [1073]. Ethyl cinnamate gave 75.5% yield of cinnamyl alcohol on inverse treatment with 1.1 mol of sodium bis(2-methoxy-ethoxy)aluminum hydride at 15-20° for 45 minutes [544]. 

In its original form, the Michael addition consisted on the addition of diethyl malonate across the double bond of ethyl cinnamate in the presence of sodium ethoxide to afford a substituted pentanedioic acid ester. Currently, all reactions that involve a 1,4-addition of stabilized carbon nucleophiles to activated 7i-systems are known as Michael additions. Among the various reactants, enolates derived from p-dicarbonyl compounds are substrates of choice due to their easy deprotonation under mild conditions. Recently, Michael addition-based MCRs emerged as highly potential methodologies for the synthesis of polysubstituted heterocycles in the five- to seven-membered series. 

The overall reaction is illustrated here by the specific example of the addition of diethyl propanedioate (diethyl malonate) to ethyl 3-phenylpro-penoate (ethyl cinnamate) ... 

The addition of stabilized nucleophiles to activated ir-systems is one of the oldest and most useful constructive methods in organic synthesis, dating back more than a hundred years. In 1887 Michael, after whom the most well-known example of this reaction was named, published the first of a series of papers on this reaction describing the addition of the sodium salt of both diethyl malonate (1) and ethyl ace-toacetate (2) to ethyl cinnamate (3) to give the products (4) and (5), respectively (equation 1).1 This Mi-... 

Grignard solution is added dropwise over a period of 40-50 min, so that the temperature of the reaction mixture remains below -60°C. The addition funnel is removed from the setup, with the septum/nitrogen inlet connected directly to the flask. After the cold mixture is stirred for 15 min more, ethyl cinnamate (10.32 g, 0.0586 mol) (Note 7) is added via syringe over a 2-3 min period. Stirring is continued as the flask is allowed to warm slowly to room temperature (Note 8). The off-white to beige reaction mixture is cooled to <5°C (ice-water bath) and quenched by the portion-wise addition of chilled 1 M hydrochloric acid (200 mL), so that the internal temperature remains below 20°C (Note 9). The layers are separated, and the aqueous phase is extracted twice with ethyl ether (100 mL each). The combined organic layers are washed with saturated sodium bicarbonate solution (Note 10), dried over sodium sulfate, and the solvents are removed at a rotary evaporator (25°C/60 mm). The residual oil is transferred to a 100-mL, round-bottomed flask and distilled bulb-to-bulb (Note 11). The product (9.69-9.85 g. 76.5-78%) (Note 12) is collected at an air bath temperature of 110-112°C, 0.20 mm. 

Scheme 2 shows Rapoport s synthesis [15]. The cinnamic acid derivative 3 prepared from m-methoxy benzaldehyde [20] was ethylated by diethyl sulfate to give ethyl cinnamate derivative 4, followed by Michael addition with ethyl cyanoacetate to afford compound 5. Compound 5 was converted to lactam 6 by the reduction of the cyano group and subsequent cyclization. Selective reduction of the lactam moiety of 6 was achieved by treatment with trimethy-loxonium fluorob orate followed by sodium borohydride reduction. Amine 8 was obtained by the reductive methylation of amine 7. Amine 8 was converted to compound 9 by methylene lactam rearrangement [21], followed by selenium dioxide oxidation to provide compound 10. Allylic rearrangement of compound 10 and subsequent hydrolysis gave compound 12. The construction of the decahydroisoquinoline structure began with compound 12,... 

The benzylic free radical produced by the addition of the carbamoyl radical to the ethyl cinnamate molecule is more stable than the alternative radical alpha to the ester group. With such an orientation of addition to the a,p-unsaturated ester, this reaction should lead to derivatives of malonic acid. However, it has been found that the intermediate radical, being a stable benzylic free radical, fails to perform the subsequent abstraction of a hydrogen atom from formamide, and thus no chain-transfer step takes place. Instead of performing this step it favours the combination with a semi-pinacol radical, which is present in solution, to yield the hydroxy ester which subsequently lactonizes to give the major product of the reaction (67). 

When a solution of tellurium dioxide in concentrated hydrochloric or hydrobromic acid was added to a solution of allyl cinnamate in diethyl ether cooled to — 30°, only the allyl-double bond reacted3. The allyl group rearranged during the addition of X3Te—X forming l-halomethyl-2-trihalotelluro-l-ethyl cinnamates. 

Cognate preparations. Phenylpropynoic acid. Place a solution of 88 g (84 ml, 0.5 mol) of ethyl cinnamate (Expt 6.137) in 50 ml of carbon tetrachloride in a 500-ml round-bottomed flask. Immerse the flask in ice and add 80 g (25.5 ml, 0.5 mol) of bromine from a separatory funnel slowly with frequent shaking. The halogen will disappear rapidly at first, but more slowly towards the end of the reaction no hydrogen bromide is evolved and the time of the addition is about 20-25 minutes. Allow the mixture to stand for 1 hour, pour the solution into a large evaporating dish and permit the excess of bromine and the carbon tetrachloride to evaporate spontaneously in the fume cupboard. The crude ethyl 2,3-dibromo-3-phenylpropanoate will remain as a solid cake this... 

Cinnamoyl- 6-CD (6-CiO-/3-CD) was sparingly soluble in water, although most 6-substituted 6-CDs are soluble. However, 6-CiO-/3-CD was solubilized in water on the addition of adamantane carboxylic acid or p-iodoaniline which could be included in a 6-CD cavity. These results suggest that 6-CiO-/l-CD formed supramolecular polymers in the solid state, as shown in the proposed structure in Fig. 17. The X-ray powder pattern of 6-CiO-/l-CD was similar to that of the complex between p-CD and ethyl cinnamate, in which /3-CDs formed a layer structure. The crystal structure of 6-aminocinnamoyl-/3-CD (6-aminoCiO-/l-CD) is shown in Fig. 12 and we discussed the relationship between crystal packing and the substituent group in Sect. 2.8. 

The Sn2 mechanism is ruled out for reaction between the tertiary halide, r-BuBr, and radical anions derived from the more easialy reduced compounds cinnamonitrile (9) ethyl cinnamate (12a), methyl styryl ketone (23a), and phenyl styryl ketone (20a). Reduction of the activated alkenes in the presence of an excess of r-BuBr leads to mixtures of products where a r-Bu group has been introduced in a- or j0-position or in the phenyl ring. For 9 and 12a small amounts of butylated hydrodimers were obtained in addition, and for the enone 23a formation of the unsaturated alcohol with introduction of the /-Bu group at C-1 was a major product [192]. In this case the mechanism is unambiguously reduction of the activated alkene followed by electron transfer to r-BuBr concerted with halide cleavage, in... 

The mechanism is illustrated with the addition of a malonate anion across the double bond of ethyl cinnamate. The reaction is reversible in protic solvents and the thermodynamically most stable product usually predominates. When organometallic reagents are used as Michael donors (e.g., copper-catalyzed organomagnesium additions) SET-type mechanisms may be operational. 

DehydrohalogenaUon. Newman and Merrill developed a procedure for de-hydrohalogenation of ethyl cinnamate dibromide by adding sodium hydride to a solution of the ester in benzene and heating under reflux with occasional addition... 

Marvel and McCain 49> have shown that ethyl cinnamate can be homopolymerized by use of typical radical-type thermal initiators, such as benzoyl peroxide or 2,2 -azobis(isobutyronitrile). Ethyl cinnamate and poly(vinyl cinnamate) can, therefore, take part in radical addition reactions. 

The sodium dianions obtained from acids, treated by NaNH2 in liquid ammonia are easily alkylated (refs. 28-30). These dianions have also been used for Michael addition with benzalacetophenone or ethyl cinnamate. A similar Michael addition (ref. 31) is also observed with the enolate of ethyl phenylacetate (Fig. 4). Nitriles can also be deprotonated with NaNH2 in liquid ammonia. The resulting anion was able to give aldol reaction followed by dehydration (ref. 32) or an alkylation reaction (ref. 33). 

A rate acceleration in the reaction of iodobenzene (39a) and ethyl acrylate (40) has been observed qualitatively [13] while at room temperature under atmospheric pressure no reaction occurs, ethyl cinnamate (41) is obtained in high yield if a pressure of 10 kbar is applied (Scheme 7.10). Surprisingly, diarylated acrylate 42, which arises by a second Heck reaction onto 41, is not formed at normal pressure, while at 10 kbar 42 can be obtained as the sole product. Interestingly, if bromo-benzene (39b) is used instead of iodobenzene (39a), the adduct 43 was also formed, which is explained by the addition of 45 to a second molecule of ethyl acrylate and subsequent reductive elimination and double bond isomerization. In this case, high pressure seems to slow down the reductive elimination leading to 41 suf-... 

Additions similar to those in water and methanol can be effected with other alcohols and with organic acids as solvent and yield the corresponding alkoxy and acyloxy derivatives as, for example, Spengler and Weber197 have shown for styrene and ethyl cinnamate. 

The intermolecular Michael addition of ethyl 2-cyano-3-phenyl-2-butenoate and ethyl cinnamate in benzene containing sodium hydride and a little dry ethanol followed by aromatisation of the intermediate by refluxing for 1 hour gave after acidification ethyl 3-cyano-4,6-diphenyl-2-hydroxybenzoate in 52% yield (ref.40). 

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