Ketones with cuprates

The titaniated (25)-2,5-dihydro-2-isopropyl-3,6-dimethoxypyrazines derived from cyclo(L-Val, Gly) or cyclo(L-Val, Ala) (1, R1 = H, CH3) react with a,/I-unsaturatcd aldehydes exclusively by 1.2-addition (cf. nearly exclusive 1,4-addition of ,//-unsaturated ketones with cuprate complexes of 2,5-dialkoxy-3,6-dihydropyrazines, see Section D. 1.5.2.3.1.4.) in a highly diastereoselective mode to give virtually only the (l S,2R)-diastereoniers 2 ". In reactions with the corresponding lithiated pyrazines both regioselectivity and diastereofacial differentiation at C-2 are also remarkably high (dc 95 %), but the diastereomeric excess at C-l is substantially smaller (30 50%) ... 

Cheng, K.F., Nagakura, I., and Piers, E. 1982. Reaction of P-halo aP-unsaturated ketones with cuprate reagents. Efficient syntheses of PP-dialkyl ketones and P-alkyl P-unsaturated ketones. A synthesis of (Z)-jasmone. The Canadian Journal of Chemistry, 60(10) 125 6-63. 

Etiolates formed by organocopper conjugate addition may be acylated cleanly by acid chlorides to give 3-diketones. Although 0- and C-acylation are both possible, the latter is favored by the use of acid chlorides rather than anhydrides and by the use of diethyl ether as solvent, rather than DME. Good yields of 3-diketones have been obtained by acylation of the anions derived from both acyclic and cyclic unsaturated ketones with cuprates, or in copper-catalyzed Grignard reactions. Some synthetic applications are given in Scheme 54. 

The reaction of 1,2-allenyl ketones with organocuprates afforded /3,y-unsaturated enones. The reaction with mixed cuprates RR CuLi delivered, depending on the properties of R and R, two products 430 and 431 [192]. 

Heteroatoms were also tolerated in the cuprate, as demonstrated by the reaction of methyl vinyl ketone with (13 equation 10).36 A good yield of the conjugate addition product was reported (85%), without evidence of competing side reactions. 

Two highly unusual reactions were noted in this study which merit attention. First, the treatment of (59) with cuprate (60) gave rise to 1,2-addition of the alkyne as the only product (67% equation 57). Second, when trifluoromethyl ketone (59) was treated with either the higher or lower order methylcu-prates, the cyanohydrin (61) was isolated in addition to the normal 1,4-addition product (equation 58). 

Knochel cuprates likewise add to tt,/i-unsaturated ketones with 1,4 selectivity, but only in the presence of Me3SiCl or BF3-OEt2 (Figure 10.43, right). Under the same conditions, how-... 

Acceptor ability of a group can be enhanced by interaction with a suitable electrophile (proton, Lewis acid). This is very likely in the Ni(acac)2-catalysed reaction of cyclopropyl ketones with trimethylaluminium and in the synthetically more significant addition of several cuprates to alkyl cyclopropyl ketones. The BFs-activated organometallic reagent attacks the less substituted cyclopropane carbon regioselectively. Yet steric hindrance can be a problem in this reaction (equation 40) . 

An interesting transformation, carried out by Paquette, demonstrates the selectivity that can be achieved with these reagents. The reaction of the acid chloride (77) and cuprates (78) or (79) takes place selectively in the presence of the lactone. The cuprates must be added to a solution of the acid chloride to obtain hi yields. A later transformation demonstrated that a lactone can be converted easily to the ketone with phenyllithium (Scheme 30).No loss of stereochemistry occurs in either permutation. 

On treatment of an f/,/7-urisaturated ketone with the cuprate (11) in the pres-... 

Because of the reactivity of aldehydes with cuprates (sec. 8.7.A.v), 1,2-addition to a,p-unsaturated aldehydes can compete with 1,4-addition, although the former usually predominates. a,p-Unsaturated ketones normally give 1,4-addition. In Table 8.21, 12 Marshall showed how the copper reagent and proportion of RLi to Cu influenced the ratio of 1,2- to 1,4-addition with 439 and di(4-pentenyl)cuprate. Reaction with this... 

The procedure described here illustrates the preparation of mixed lithium arylhetero(alkyl)cuprate reagents and their reactions with carboxylic acid chlorides. These mixed cuprate reagents also react with a,a -dihromoketonea, primary alkyl halides, and a, 8-unsaturated ketones, with selective transfer of only the alkyl group. 

Ring-expansion Reactions. More work has been reported on the formation of seven-membered rings by rearrangement of divinylcyclopropanes. For example good yields of cyclohepta-1,4-dienes were obtained by treatment of P-iodo-aP-unsaturated ketones with the mixed cuprate LiCu(PhS)(2-vinylcyclopropyl), and thermolysis of the adduct mixture so obtained 3-iodocyclohex-2-enone was converted into bicyclo-[5,4,0]undeca-l(7),4-dien-8-one (75%) in this way. Vinylcyclopropyl-lithium... 

The metallacycles can also be used for carbon-carbon bond-forming reactions (Scheme 5.67). Transmet-allation with cuprates, or the use of catalysis by copper(I) salts allows reaction with a variety of electrophiles. With an acid chloride, reaction occurs at one of the carbon-zirconium bonds of the metallacycle 5.234. This leaves the second carbon-zirconium bond of the acylated product 5.235 available for further chemistry by, for instance, halogenation, or back attack onto the ketone. More elaborate multiple component couplings can also be achieved (Scheme 5.68). ... 

The carbonyl compound can also contain additional functionality. Thus, treatment of an a,fi- poxy ketone with excess lithium reagent (1) provides the allyl alcohol (2) (eq 2). The use of an a-phenyl selenoaldehyde as electrophile allows either an allyl selenide or a /3-silyl aldehyde to be obtained, depending upon the reaction conditions used with the hydroxysilane (eq 3). With a,/8-unsaturated ketones, the lithium reagent (1) adds in the 1,2-sense the Grignard analog can provide 1,4-addition. The cuprate derived from (1) undergoes the expected reactions for this class of compounds, such as 1,4-addition. ... 

Addition to Ketones and Aldehydes. o -(Trimethylsilyl)-vinyUithium 1 adds to ketones and aldehydes. The adducts do not undergo the expected Peterson elimination reaction when treated with sodium hydride or potassium hydride, but the corresponding aUene can stiU he obtained if the alcohol is converted to the chloride followed by fluoride-catalyzed -elimination (eq 1). Other uses have also been made of the aUyl chlorides made in this manner they react with cuprates, or they can be oxidized to the epoxides to serve as precursors to aUene oxides. ... 

There is also a correlation between the reduction potential of the carbonyl compound and the ease of reaction with cuprate reagents. The more easily reduced, the more reactive is the compound toward organocuprate reagents. Compounds such as a,/3-unsaturated esters and nitriles which are not as easily reduced as a,j3-unsaturated ketones do not react readily with simple alkyl cuprates even though they are good acceptors in conjugate addition reactions involving other types of nucleophiles (Michael reactions). 

All of the mixed organocopper reagents shown in Scheme 6.6 react with a,/3-unsaturated ketones. The efficiency of the reaction can be promoted by the addition of trialkylphosphines. a,/0-Unsaturated esters are borderline in terms of reactivity toward simple cuprates. Unsubstituted and monosubstituted acrylates generally are reactive but more extensively substituted acrylates are not. The R-Cu-BFs reagents are more reactive than simple cuprates toward a,j8-unsaturated esters and also react with a,/3-unsaturated nitriles. Boron trifluoride has been found to catalyze addition of dimethylcuprate to very hindered a,)0-unsaturated ketones.Conjugated acetylenic esters react readily with cuprate reagents, with syn addition being the kinetically preferred mode of addition. ... 

The product is a ketone with methyl groups at the a and p positions, which could have been installed by treating the following a,p-unsaturated ketone with lithium dimethyl cuprate, followed by methyl iodide ... 

---