Crotonates conjugate additions

Chiral fl-amino esters. The conjugate addition of primary amines to alkyl crotonates proceeds in satisfactory yield when carried out under high pressure. French chemists have recently examined this reaction using crotonates derived from chiral alcohols. Thus addition of diphenylmethylamine to 8-phenylmenthyl croton-ate proceeds in 85-90% chemical yield and in 60% de. Optical yields are increased... 

Based on our previous results on the nucleophilic alkenoylation of aldehydes via metallated a, 3-unsaturated aminonitriles [50], we now envisaged an enanti-oselective variant. Thus, the enantiopure a-aminonitriles 60 were metallated with LDA and by reaction with aldehydes the adducts 61 could be obtained. Subsequent cleavage of the aminonitrile function with silver nitrate led to the desired a -hydroxyenones 62 in overall yields of 29-80% and enantiomeric excesses ee of 50-69%. Alternatively, the conjugate addition of the lithiated aminonitrile 63 to t-butyl crotonate led to the y-keto ester 63 in 35% yield and an enantiomeric excess ee of >90% (Scheme 1.1.18). 

An initial stndy demonstrated that Josiphos and its inverted analogue 11 were very effective in promoting the Cu-catalyzed conjugate addition of EtMgBr to unsaturated crotonates (Scheme 5). It is noteworthy that the use of sterically hindered esters, which nsnally helps to avoid nndesired 1,2-additions, or alternatives for esters such as an oxa-zolidinone, are not reqnired. Indeed, the highest conversions and stereoselectivities are obtained with methyl crotonate. ... 

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. 

While sluggish under thermal conditions,274-275 the asymmetric conjugate addition of amines to alkyl crotonates is achieved at room temperature under high pressure (15 kbar).276 Thus, benzylamine can be added to the crotonate derived from 8-p-naphthyl menthol, with virtually complete diastereoselectivity. A related intramolecular 1,4-addition of an amine to a chiral enoate was used in a total synthesis of the alkaloid (-)-tylophorine.277 Additions of amines to chiral iron complexes of type (116) proceed with excellent selectivity and allow the preparation of homochiral p-lactams.l27128,l3() l32 In contrast, the addition of amine nucleophiles to chiral vinylic sulfoxides278-2811 and to chiral vinylsulfoximines281 proceeds with comparably low selectivities. 

The stereochemistry of conjugate additions requires similar considerations to those used to predict nucleophilic attack on a carbonyl. Acyclic substrates may yield up to three contiguous chiral centres (Scheme 18). The relative stereochemistry of carbons C(l) and C(2) will depend upon the approach of the two reagents. The stereochemistry of carbon C(3) will depend upon the lifetime of the intermediate 30 if it has even a short lifetime it will take up the most stable conformation. For example, the base-catalysed additions of ethanol-d and 2-methyl-2-propanethiol-d to ethyl crotonate give a (2R, 3R )/(2R, 3S ) diastereoisomeric ratio of the addition products of approximately 10 190. The authors90 suggest the reaction proceeds in two steps and the protonation of the enolate determines the stereoselectivity. 

Asymmetric Michael addition to enoatesThe known conjugate addition of RCu BF, (8, 324-325) to a,/(-unsaturated carbonyl compounds4 proceeds with high chiral induction to trans- )-8-phenylmenthyl crotonate (2). Addition to the isomeric ei.v-crotonate (5) is less selective, but results mainly in the enantiomeric acid (6). 

A synthesis of this compound was devised by Ohmizu, Iwasaki and co-workers and featured a three-component tandem conjugate addition/enolate trapping as key step (Scheme 12.24) [82]. In this synthesis, the acyl anion equivalent cyanohydrin 165 was first treated with LDA and allowed to react with methyl crotonate 166. The resulting enolate was trapped with 2,3,5-trimethoxy benzylbromide 168 to afford crude intermediate 169, which was immediately deprotected in situ to afford ketone product 170. Both the ester and the ketone functionalities were then reduced at low temperature to afford the corresponding diol 171. Upon treatment with trifluoroacetic acid, the desired Friedel-Craft cyclization adduct 172 was obtained. The latter tricyclic compound was then further elaborated to the final target 164 through a short sequence of standard transformations. 

Das and co-workers have described the generation of a-aminoalkyl radicals from cyclic secondary amines using anthraquinone-photocatalysis [95JCS(P1)1797]. The conjugate addition of the a-aminoalkyl radical to enoates has been examined. The cyclized compound is obtained directly from the reaction. The chemical yield of 149 is low and it is accompanied by 148, a product arising from nucleophilic addition of the amine to the crotonate. 

The value of malonate esters is illustrated in this synthesis of a substituted cyclic anhydride by conjugate addition to ethyl crotonate, hydrolysis, and decarboxylation, followed by dehydration with acetic anhydride. This route is very general and could be used to make a range of anhydrides with different substituents simply by ehoosing an appropriate unsaturated ester. 

Asymmetric conjugate addition of RiCuLij The chiral crotonyl ester 1, prepared from (+ )-camphor by addition of 1-naphthylmagnesium bromide followed by esterification with crotonic acid, undergoes conjugate addition with BuaCuLi at -25° to give the adduct 2 in 95% de. Reduction of 2 with LiAUtj gives (S)-3-... 

With a, p-un saturated esters, competition between cydopropa nation (l,4addition) and acylation (1,2-addition) becomes acute. With ethyl acrylate (63) and ethyl crotonate (64), the small R groups on the p-carbon atom permit facile conjugate addition leading to good yields (60-65%) of the corresponding cyclopropane derivatives (67) (Scheme 25). On the... 

This conjugate addition proceeds in excellent yields. High regio- and diastereo-selectivity is observed with lanthanide and other Lewis acids (entries 3, 4 and 6), but little selectivity is seen in the absence of a chelating Lewis acid (entries I and 2) and with substoichiometric amounts of Lewis acid (entry 5). It had previously been established that radical addition to crotonates and cinnamates could be accomplished with catalytic amounts of Lewis acid. However, the fumarate substrate is orders of magnitude more reactive, and hence radical addition to the uncom-plexed substrate presumably competes, leading to lower observed selectivity. 

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... 

Conjugate addition of the lithium dienolate derived from crotonic acid to diphenylpropenone produces mainly the 1,4-a-product 15 with R, R configuration. The reaction occurs via a regio- and diastereoselective tandem 1,2-addition/Cope rearrangement of the intermediate 13. If the reaction is carried out at — 90°C, the intermediate 1,2-y-adduct 14 can be isolated 1000. 

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