Lithium dialkylcuprates, addition

The preparation and some synthetic applications of lithium dialkylcuprates were described earlier (Section 14 11) The most prominent feature of these reagents is then-capacity to undergo conjugate addition to a p unsaturated aldehydes and ketones... 

Conjugate Addition. To a solution of 1.5 mmol of lithium dialkylcuprate at — 25 CC is added 1 mmol of methyl ( )-3-[(25,45,55)-3-benzyloxycarbonyl-4-methyl-5-phenyl-2-oxazolidinyl]-propenoate dissolved in 1 mL of dry diethyl ether. After 30 ntin at — 25 C, the mixture is treated with an aq NH3/NH4C1 pH 8 buffer solution and then stirred at r.t. for 15 min. After diethyl ether extraction, the organic layers are dried over Na,S()4 and filtered and the solvent is evaporated under reduced pressure. The crude products are checked by H- and l3C-NMR analyses in order to determine the diastereomer ratios (g 95 5) and then purified by flash chromatography (hexane/ethyl acetate 80 20) yield 70-72%. 

One diastereomer 5 was formed in large excess (98-76% de) on addition of the 2-(l-dimethyl-aminoethyl)phenyl group from the corresponding lithium dialkylcuprate and or lithium alkyl(2-thienyl)cuprate to prostereogenic enones64. 

The addition of alkyllithium, lithium dialkylcuprates and lithium trialkylzincates to either ( )-(2-nitroethenyl)benzene or E)- -nitropropene in the presence of the nonracemic chiral solvent, ( + )-(S,S)-2,3-dimethoxy-Af,AhA, iV -tetramethyl-l,4-butanediamine, gave adducts in low enantiomeric excess (15-28%) as determined by HNMR35. 

Addition to enals. s Conjugate addition of lithium dialkylcuprates is favored over 1,2-addition by use of low temperatures and a nonpolar solvent (pentane). However, 1,2-addition becomes more important if the double bond is trisubstituted. 

Review Taylor has reviewed the conjugate addition-enolate trapping reactions of organocopper reagents, in particular of lithium dialkylcuprates (131 references). 

The catalyzed addition of Grignard reagents to 1,1-doubly activated alkenes (105-108) is a highly efficient process 93 -0 notable are additions to /V-acyldehydroamino acid ester (119), which cannot be accomplished with lithium dialkylcuprates (Scheme 44).93d... 

In addition of organometallic reagents to some arynes, prior counterion complexation with the substituent can direct the incoming group to the ortho position (kinetic control). Addition of alkyllithiums to oxazolinyl (OXZ) aryne (51) to give the ortho product (52) is explained in this manner. In contrast, lithium dialkylcuprates add to the aryne (51) exclusively at the meta position. This is ascribed to thermodynamic control of the reaction, which results in the formation of the more ligated and stable adduct (S3).i2 Control of nucleophilic addition to arynes by complex-induced proximity effects has not been explored with substituents other than OXZ,83 but has considerable synthetic potential if it can be achieved, say through solvent manipulation. 

Secondary and tertiary dialkylcuprates, lithium dialkenyl-, and even diphenyl-cuprates, add in very good yields to the reactive propionaldehyde diethyl acetal. The syn addition products may be trapped with a variety of electrophiles such as alkyl, alkenyl, alkynyl and aryl halides. The method has been used for the synthesis of several natural products. Substituted alkynic acetals also react with lithium dialkylcuprates in ether to furnish stable dialkenylcuprates of type (128) which do not eliminate to the corresponding alkoxy allenes (129) if the temperature is maintained below -20 C.164-179... 

The mechanism of conjugate addition of lithium dialkylcuprates to enones has been explored by the determination of 13C kinetic isotope effects by an NMR method reductive elimination from Cu is implicated as the rate-determining step.109... 

Addition to x,( y,S-dienyI sulfones. Lithium dialkylcuprates react with these diunsaturated sulfones by 1,6-addition, and the new double bond formed has the (Z>-geometry. The adducts on treatment with base extrude S02(Ramberg-Backlund reaction) to give a mixture of polyenes.20... 

A second solution to the synthesis of 4-methyl-2-octanone by conjugate addition of a lithium dialkylcuprate reagent to an a,[3-unsaturated ketone is revealed by the disconnection shown ... 

The addition of a lithium dialkylcuprate (Gilman reagent) to an acyl chloride at low temperatures produces a ketone. This method produces a good yield of acetophenone. 

Addition of Lithium Dialkylcuprates to cr,/3-Unsaturated Phosphoryl Compounds... 

The addition of lithium dialkylcuprates to a,8-unsaturated compounds is one of the effective and simple methods for carbon -carbon bond formation (2). In recent years significant synthetic importance has been gained by the reaction sequence in which orga-nocopper adducts are utilized as nucleophiles (2, Z, ). This sequence enables geminal functionalization of activated olefins particularly useful for the synthesis of natural products. 

Mechanistic picture of the conjugate addition of lithium dialkylcuprates to enones is not clearly delineated, despite essential meaning of this reaction in organic synthesis. l3C KIE studies were used in order to determine the rate-limiting step for the reaction of Bu2CuLi with cyclohexanone (Equation (45)).80... 

Selenium-stabilized carbanions can be also generated by 1,4-addition of nucleophilic reagents to a-selanyl a,[3-unsaturated carbonyl compounds. The conjugate addition of trialkylsilyllithium compounds to 133, followed by reaction with allyl iodide, afforded the addition products 134 with good m-stereoselectivity (R = Me dr 86 14 R = Ph dr 94 6) (Scheme 34).214 The addition of lithium dialkylcuprates to 2-phenylselanylcycloalk-2-enones has also been used for the synthesis of natural products.215,216... 

A group at Miles Laboratories has been particularly active in this regard, having synthesized many 7- and 8-alkyl derivatives of 4,5-epoxymorphinans. They generated 229 a series of 8/3-alkyldihydrocodeinones (143) by the conjugate addition of lithium dialkylcuprates to codeinone (52) according to Scheme 2.19. Three products were isolated, the 8/3-alkyldihydrocodcinone, 143 (54%) ... 

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