Chlorotrimethylsilane conjugate addition reactions

Addition of Lewis acids may not only accelerate the reaction rate of a conjugate addition but may also alter the stereochemical outcome of a cuprate addition. Interestingly when the 6-t-butyl-substituted cyclohexenone derivative 17 was exposed to dibutylcuprate, followed by silylation of the resulting enolate, the cis enol ether 18 was obtained (Scheme 6.3) [8]. If, however, the cuprate addition was performed in the presence of chlorotrimethylsilane, the stereochemical outcome of the conjugate addition reaction was reversed to give trans enol ether 19. 

This result fits with the notion that addition of chlorotrimethylsilane changes the rate and selectivity-determining step of the conjugate addition reaction [22, 42). 

Due to their high conformational flexibility, chiral acyclic Michael acceptors often display low diastereofacial selectivities in copper-mediated conjugate addition reactions.80 Nevertheless, acceptable levels of diastereoselection can be obtained, in particular with heteroatom-substituted Michael acceptors. For example, treatment of the y-benzyloxymethyl-substituted enoate 100 with lithium dimethylcuprate in the presence of chlorotrimethylsilane gives the anti-adduct 101 with excellent diastereoselectivity (Scheme 26). a Products of this type can be easily... 

Better stereosdectivities have been noted for conjugate addition reactions to the steroidal enone 95 (Scheme 6.20, Tab. 6.2). Irrespective of the enone geometry, addition of lithium dimethylcuprate provided the anti addition product 96 in hi yid-d and with good diastereoselectivity (Tab. 6.2, entries 1 and 2). Interestin y, addition of chlorotrimethylsilane to the reaction mixture had a dramatic effect. The E isomer of enone 95 still gave the anti addition product 96 with perfect stereoselectivity (entry 3). "With the 2 isomer of the enone, however, the syn addition product 97 was formed in good yield and with hi diastereoselect vity (entry 4)... 

The conjugate addition of bis(iodozincio)methane to -unsaturated carbonyl compound gives y-zincio substituted enolate. As shown in equation 31, bis(iodozincio)methane reacts with. v-cis a,/3-unsaturated ketone in the presence of chlorotrimethylsilane to afford the silyl enol ether carrying a C—Zn bond. These zinc-substituted silyl enolates can be used for further coupling reactions (equation 32)54. 

The combinations of chlorotrimethylsilane-hexamethylphosphoramide (HMPA) or chlorotrimethylsi-lane-4-(dimethylamino)pyridine (DMAP) are also powerful accelerants for copper(I)-catalyzed Grignard conjugate additions,33 and stoichiometric organocopper and homocuprate additions (Scheme 21 ).36 However, these reactions must be performed in tetrahydrofuran instead of ether.37 These procedures are noted for their high yields with stoichiometric quantities of Grignard reagents, excellent chemoselectivity and efficiency with a,3-unsaturated amides and esters and enals.58 Typically, additions to enals proceed via the S-trans conformers to afford stereo-defined silyl enol ethers for example, enals (122) and (124) give the ( )-silyl enol ether (123) and (Z)-silyl enol ether (125), respectively. 

Besides simple enones and enals, less reactive Michael acceptors like /3,/3-disubstituted enones, as well as a,/3-unsaturated esters, thioesters, and nitriles, can also be transformed into the 1,4-addition products by this procedure.44,44a,46,46a The conjugate addition of a-aminoalkylcuprates to allenic or acetylenic Michael acceptors has been utilized extensively in the synthesis of heterocyclic products.46-49 For instance, addition of the cuprate, formed from cyclic carbamate 53 by deprotonation and transmetallation, to alkyl-substituted allenic esters proceeded with high stereoselectivity to afford the adducts 54 with good yield (Scheme 12).46,46a 47 Treatment with phenol and chlorotrimethylsilane effected a smooth Boc deprotection and lactam formation. In contrast, the corresponding reaction with acetylenic esters46,46a or ketones48 invariably produced an E Z-mixture of addition products 56. This poor stereoselectivity could be circumvented by the use of (E)- or (Z)-3-iodo-2-enoates instead of acetylenic esters,49 but turned out to be irrelevant for the subsequent deprotection/cyclization to the pyrroles 57 since this step took place with concomitant E/Z-isomerization. 

The protection of an a, p-unsaturated ketone by a conjugate addition strategy is the subject of our last example but it does not involve the use of an 0,0-acetal. During a synthesis of the cockroach pheromone Periplanone B. Still needed to perform a copper(I)-mediated Sn2 reaction on the allylic acetate 37.1 [Scheme 2.37], In order to prevent competing addition to the a, p-unsaturated ketone, it was protected temporarily by conjugate addition of trimethylstannyl-lithium and trapping of the intermediate enolate with chlorotrimethylsilane. The desired Sn2 reaction was then performed on the adduct 37.2 and the a.p-un-saturated ketone recovered by oxidation of the C-Sn bond to a C-OH using m-chloroperbenzoic acid. Concomitant destruction of the labile enol ether and -elimination of water returned the a, p-unsaturated ketone 373. 

Annelatlott. The reagent does not react with saturated ketones, but does undergo conjugate addition to a,/3-unsaturated ketones and esters at —78° in THF to give, after quenching with chlorotrimethylsilane, cyclohexene derivatives. An example is the reaction of ethyl acrylate (equation I). This reaction is an alternative to Diels-Alder reactions with alkoxybutadienes, which require much higher temperatures. 

This cuprate also underwent the conjugate addition with acyclic enones, for example, 2-hexene-4-one, to give 5-methyl-3-tridecanone in 47% yield. We have not attempted further optimization. Reaction of this calcium cuprate with a sterically hindered enone, for example, isophorone, produced <3% of the desired compound in 24h. The isolated yield, however, increased to 84% when the additives BF3 etherate and chlorotrimethylsilane [12] were used. In the aryl case, / -tolylcalcium cuprate also underwent this transformation with 2-cyclohexenone to give 3-(p-methylphenyl)cyclohexanone in reasonable yield (Table 9.3). 

Reaction of the lithium enolate of (1) followed by reaction with chlorotrimethylsilane provides ketene acetal (3). This enol reacts with aldehydes in the presence of a Lewis acid to provide unsaturated esters (eq 7). With conjugated enones, (3) undergoes conjugate addition when Titanium(IV) Chloride is used as catalyst (cf. eq 5). ... 

Conjugate reduction.1 This stable copper(I) hydride cluster can effect conjugate hydride addition to a,p-unsaturated carbonyl compounds, with apparent utilization of all six hydride equivalents per cluster. No 1,2-reduction of carbonyl groups or reduction of isolated double bonds is observed. Undesirable side reactions such as aldol condensation can be suppressed by addition of water. Reactions in the presence of chlorotrimethylsilane result in silyl enol ethers. The reduction is stereoselective, resulting in hydride delivery to the less-hindered face of the substrate. 

The nucleophilic addition of a carbanion to an aldehyde or a ketone having a conjugated double bond and the subsequent dehydration sequence (Knoevenagei reaction) is a popular method for generating dienes and polyenes (equation 37). This reaction takes place efficiently and stereoselectively, when LDA is used as a base in the presence of chlorotrimethylsilane (equation 38). Knoevenagei condensation was a key reaction during many classical carotenoid syntheses. Recently, Seltzer and coworkers used the dimefiiyl acetal of acetylacetaldehyde for aldol condensation with a Cis-aldehyde, to generate the tetraenyl ketone acetal (equation 39). ... 

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