Lithium cinnamate

Ester enolates which contain the chiral information in the acid moiety have been widely used in alkylations (see Section D.1.1.1,3.) as well as in additions to carbon-nitrogen double bonds (sec Section D.1.4.2.). Below are examples of the reaction of this type of enolate with aldehydes720. The (Z)-enolate generated from benzyl cinnamate (benzyl 3-phenylpropcnoate) and lithium (dimethylphenylsilyl)cuprate affords the /h/-carboxylic acid on addition to acetaldehyde and subsequent hydrogenolysis, The diastereoselectivity is 90 10. 

The conjugate addition of lithium cuprates to cinnamates 1 bearing a chiral oxazolidine or imidazolidine ring at the ortho position produced 2 in good to excellent yield upon hydrolysis14. 

To a stirred slurry of copper(i) cyanide (110 mmol) in THF (100 ml), cooled to 0 °C, was added a solution of dimethylphenylsilyl lithium (220 mmol, 1.3 m in THF), and the mixture was stirred at 0°C for a further 30min. After cooling to —78°C, a solution of methyl cinnamate (100mmol) in THF (50 ml) was added, and stirring was continued at —78°Cfor6h. At this time, iodomethane (300 mmol) (CAUTION—CANCER SUSPECT AGENT) was added, and the mixture allowed to warm to ambient temperature with... 

The trimethylsilyl ester of a-trimethylsilyacetic acid 1613 is converted by LDA and TCS 14 into the C,0,0-tris(trimethylsilyl)ketene acetal 1614 in 91% yield. Reaction of 1614 with benzaldehyde in the presence of ZnBr2 proceeds via 1615 to afford a high yield of trimethylsilyl cinnamate 1616 [18], which gives on work-up free ( )-cinnamic acid in nearly quantitative yield (Scheme 10.7). In contrast, reaction of the lithium salt of 1613 with benzaldehyde then acidic hydrolysis affords a 1 1 mixture of ( )- and (Z)-cinnamic acid in 86% yield [18]. 

Chrysene, 45, 95 Cinnamaldehyde, 45, 36 48, 79 reaction with hydrazine, 47, 99 Cinnamic acids and derivatives, conversion to phenylcyclopropanes with lithium aluminum hydride,... 

Although lithium aluminium hydride does not reduce alkenes or acetylene hydrocarbons, it reduces allylic alcohols and their acetylenic counterparts. Thus cinnamic acid is reduced to dihydrocinnamyl alcohol. 

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]. 

ArSCu(RMgX)n. These heterocuprates are more useful than lithium dialkyl-cuprates for conjugate addition to enones.5 They are also useful for conjugate addition to the less reactive cinnamates and crotonates.6 Yields are markedly improved by use of 2-methoxyphenylthio as the ligand in additions to the crotonates. 

EXTENSIONS AND COMMENTARY There are about twenty different synthetic routes in the literature for the preparation of MDA. Many start with piperonal, and employ it to make methylenedioxyphenylacetone or a mcthylcnedioxydihydro-cinnamic acid amide instead of the nitrostyrene. The phenylacetone can be reduced in several ways other than the cyanoborohydride method mentioned here, and the amide can be rearranged directly to MDA. And there are additional methods for the reduction of the nitrostyrene that use no lithium aluminum hydride. Also there are procedures that have safrole or isosafrole as starting points. There is even one in the underground literature that starts with sassafras root bark. In fact, it is because safrole is one of the ten essential oils that MDA can humorously be referred to as one of the Ten Essential Amphetamines. See the comments under TMA. 

A recently published full account of another synthesis [69] of the same alkaloid starting from the /rans-cinnamic ester 264 represented a different approach (ACD -> ACDB) to ( )-lycorine (Scheme 42). An intramolecular Diels-Alder reaction of 264 in o-dichlorobenzene furnished the two diastereomeric lactones 265 (86%) and 266 (5%) involving the endo and exo modes of addition respectively. The transposition of the carbonyl group of 265 to 267 was achieved by reduction with lithium aluminium hydride, followed by treatment of the resulting diol with Fetizon s reagent, which selectively oxidised the less substituted alcohol to give isomeric 5-lactone 267. On exposure to iodine in alkaline medium 267 underwent iodolactonisation to afford the iodo-hydroxy y-lactone 268. The derived tetrahydropyranyl ether... 

Compound 85 was dehydrogenated at 300° over palladium black under reduced pressure to a pyridine derivative 96 which was independently synthesized by the following route. Anisaldehyde (86) was treated with iodine monochloride in acetic acid to give the 3-iodo derivative 87. The Ullmann reaction of 87 in the presence of copper bronze afforded biphenyldialdehyde (88). The Knoevenagel condensation with malonic acid yielded the unsaturated diacid 91. The methyl ester (92) was also prepared alternatively by a condensation of 3-iodoanisaldehyde with malonic acid to give the iodo-cinnamic acid (89), followed by the Ullmann reaction of its methyl ester (90). The cinnamic diester was catalytically hydrogenated and reduced with lithium aluminium hydride to the diol 94. Reaction with phosphoryl chloride afforded an amorphous dichloro derivative (95) which was condensed with 2,6-lutidine in liquid ammonia in the presence of potassium amide to yield pyridine the derivative 96 in 27% yield (53). 

The N-metallated azomethine ylides having a wider synthetic potential are N-lithiated ylides 141, derived from the imines of a-amino esters, lithium bromide, and triethylamine, and 144 from the imines of a-aminonitriles and LDA (Section II,G). Ester-stabilized ylides 144 undergo regio- and endo-selective cycloadditions, at room temperature, to a wide variety of unsym-metrically substituted olefins bearing a carbonyl-activating substituent, such as methyl acrylate, crotonate, cinnamate, methacrylate, 3-buten-2-one, ( )-3-penten-2-one, ( )-4-phenyl-3-buten-2-one, and ( )-l-(p-tolyl)-3-phenyl-propenone, to give excellent yields of cycloadducts 142 (88JOC1384). 

Table XIX shows the results of reactions of silyl ketene acetals derived from propionates with crotonate, cinnamate, sorbate, and fumarate in the presence of aluminum ion-exchanged montmorillonite (Al-Mont) (62). The reactions proceeded at low temperatures. The Michael products could be isolated in the unstable form of a trimethylsilyl ketene acetal in good yield owing to an easy work-up procedure (removal of the solid catalyst). It is noteworthy that the montmorillonite-induced Michael addition to a polyenoate occurred regioselectively in a 1,4-fashion in the case of methyl sorbate (Table XIX, Entry 4), the preference for 1,4-addition (98%) over 1,6-addition (2%) is notable because the addition of a lithium enolate (a conventional...

Compared to the older procedures the use of acid iodides in acetonitrile or dichloromethane as solvent constituted a remarkable improvement. Aromatic and aliphatic acyl cyanides are accessible by this route. For example acyl cyanides of cinnamic acid and phenylacetic acid could be obtained in 33% and 49% yields. Copper(I) cyanide in diethyl ether in the presence of lithium iodide gave a-cyano ketones in 50-70%. The reaction can be carried out at room temperature in diethyl ether or slightly above or at 80 C in acetonitrile. It is not possible to obtain the acyl cyanide from acryloyl chloride, chloroformate or oxalyl chloride by this approach. 

Reduction of allylic andpropargylic alcohols. Although lithium aluminum hydride does not reduce ethylenie or acetylenic hydrocarbons, it reduces allylic alcohols and their acetylenic counterparts. The reaction was first encountered by Nystrom and W. G. Brown in the reduction of cinnamic acid to dihydrocinnamyl alcohol. Investigation showed that the anomaly is not in the reduction of the carboxyl group. 

The product of a lithium aluminum hydride reduction of a cinnamic acid or ester 1 is highly dependent on the solvent. The product of exclusive carbonyl reduction, cinnamyl alcohol 2, was obtained in hydrocarbon solvents (pentane, hexane or benzene) even under prolonged reflux. 3-Phenylpropanol 3, resulting from carbonyl and C-C double bond reduction was produced in diethyl ether. However, phenylcyclopropane 4 was obtained in tetrahy-drofuran or 1,2-dimethoxyethane, notably after prolonged reflux. 

The use of the mixed lithium phenylthio(alkyl)cuprates, PhSCuRLi, for conjugate addition to a,p-un-saturated carbonyl compounds is well known. - The reaction of phenylthiocuprates derived from Grignard reagents with cinnamates and crotonates has also been reported (Scheme 50). ... 

As shown in Scheme 3, (Z)-enolate (57), prepared by conjugate addition of lithium bis(phenyldi-methylsilyl)cuprate to methyl crotonate or methyl cinnamate, reacts with acetaldehyde or benzaldehyde to give a mixture of two diastereomeric aldols, (58) and (59), with excellent diastereomeric excess favoring (58) (ratios of 85 15 to 94 6). On the other hand, deprotonation of ester (60) by LDA provides the ( )-enolate (61), which reacts with the same two aldehydes to give the aldol (59) as the major product... 

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