Conjugate addition lithium enolates

Because of the six-membered ring mechanism for the addition, lithium enolates don t usually do conjugate additions. For enol equivalents that do, see Chapter 29. 

Jones and colleagues have prepared 1,4-dicarbonyl compounds by conjugate additions of enolate and related anions to a,P-unsaturated sulfoxides [80,81]. For example, the lithium enolate of acetone dimethylhydrazone (83), in the presence of dimethyl sulfide-copper(I) bromide complex, underwent conjugate addition to 2-phenylsulfinyloct-l-ene (82). Quenching the reaction mixture with dimethyl disulfide gave the doubly protected 1,4-diketone derivative (84), which, on sequential hydrolysis with copper(II) acetate and trifluoroacetic acid gave the dodecane-2,5-dione (85) as the product in 54% yield from (82) (Scheme 5.27). Other examples of the addition of enolate-type species to a,p-unsaturated sulfoxides have also been reported [82.83]. 

The conjugate addition of enolate anions to activated 3-trimethylsilyl-3-buten-2-one helped solve another long-standing problem in organic synthesis by permitting the annulation reaction to be carried out in aprotic solvents under conditions where enolate equilibration is avoided. The annulation of thermodynamically unstable lithium enolates with MVK, where equilibration to the more stable enolate occurs prior to Michael addition, often yields a mixture of stractmal isomers. For exan le, Boeckman successfully employed 3-trimethylsilyl-3-buten-2-one in a Robinson annulation sequence (eq 2). Thus treatment of cyclohexenone with lithium dimethylcuprate in diethyl ether and then with 3-trimethylsilyl-3-buten-2-one gives the desired Michael adduct, which is converted into the functionalized octalone in 52% overall yield. ... 

A partial explanation of the above findings must lie in the known ease of addition of nucleophilic reagents to the conjugated double bond of pregn-16-en-20-ones. The amide ion that is a by-product of the reduction probably adds to a portion of the unreduced pregn-16-en-20-one giving the lithium enolate of amino ketone (74). This enolate may well be relatively stable at — 33° and would be protonated to the free 16-amino-20-one during work-up... 

Posner recently reported a very simple and fast way to activate epoxides towards nucleophilic opening by ketone lithium enolate anions by use of BF3 Et20 (1 equiv.) [73]. The application of this procedure to the nucleophilic opening of propene oxide with the lithium enolate of 2-cycloheptanone, obtained by the conjugate addition of trimethylstannyllithium to 2-cycloheptenone, afforded the stan-... 

Several examples of conjugate addition of carbanions carried out under aprotic conditions are given in Scheme 2.24. The reactions are typically quenched by addition of a proton source to neutralize the enolate. It is also possible to trap the adduct by silylation or, as we will see in Section 2.6.2, to carry out a tandem alkylation. Lithium enolates preformed by reaction with LDA in THF react with enones to give 1,4-diketones (Entries 1 and 2). Entries 3 and 4 involve addition of ester enolates to enones. The reaction in Entry 3 gives the 1,2-addition product at —78°C but isomerizes to the 1,4-product at 25° C. Esters of 1,5-dicarboxylic acids are obtained by addition of ester enolates to a,(3-unsaturated esters (Entry 5). Entries 6 to 8 show cases of... 

In spite of the apparent difference between conjugate addition and carbocupra-tion reactions (Sect. 10.3.2), the similarities between the key organometallic features of the two reactions are now evident. In both reactions, inner sphere electron-transfer converts the stable C-Cu bond into an unstable C-Cu bond, and the cluster-opening generates a nucleophilic, tetracoordinated alkyl group. The difference is that the product of conjugate addition (PD) remains as a lithium enolate complexed with RCu (Scheme 10.5), while the initial product of carbocupration... 

INT2, Scheme 10.7) undergoes further reaction (Li/Cu transmetalation) and generates a new organocuprate compound. (Note however that this difference could become more subtle since the product of conjugate addition (PD) might behave more like an a-cuprio(I) ketone complexed with a lithium cation [52] than a lithium enolate complexed with copper(I)). In neither reaction was any evidence of radical intermediates (i.e., SET) found by theoretical calculations [79]. 

Diastereoselectivity in the aldol and the conjugate additions of 2 -hydroxy-1,T-binaphthyl ester enolates with a variety of carbonyl electrophiles has also been explored the tendency of the ester enolates, generated by BuLi, to react with aldehydes to give threo products preferentially with high diastereoselectivity has been interpreted in terms of an acyclic transition state of chelated lithium enolate involving the aldehyde carbonyl and the 2 -hydroxy group. 

MeOC6H4, respectively. The titanium enolates were converted into silyl enol ethers 54 by treatment with chlorotrimethylsilane and lithium isopropoxide. Additionally, cyclic enones lb and Ic, and linear enones Id and le, are also good substrates for the asymmetric conjugate addition of phenyltitanium triisopropoxide, giving the corresponding arylation products with over 97% enantioselectivity. 

Three approaches to zinc enolates are commonly adopted the process associated to the classical Reformatsky reaction is based on the insertion of Zn(0) into the carbon—halogen bond of an a-haloester. Two additional routes involve (i) transmetallation of a lithium enolate with a Zn(II) salt (Section V.A) and (ii) the transition-metal-catalysed conjugate addition of diethylzinc to Michael acceptors (Section V.B). 

---