Preparation of Gilman Reagents

There are two major reactions of organocuprates, and both give products reminiscent of a carbon nucleophile (1) reaction with alkyl halides and (2) conjugate addition with a,p-unsaturated ketones. Conjugate addition to a, 3-unsaturated ketones is promoted when ether is used as a solvent.381 The substitution reaction is promoted by the use of THF or ether-HMPA as a solvent. l As mentioned earlier, the mechanism of these reactions probably involves a one-electron transfer, although other mechanistic proposals are in the literature,but the synthetic result is that expected of a carbon nucleophile. 85 The general reactivity of organocuprates with electrophiles follows the order  

The R groups can be primary, secondary, tertiary alkyl, aryl, or heteroaryl and can bear remote functionality such as ethers, acetals or ketals, sulfides, or other labile groups.  

Chapter 8. Nucleophilic Species That Form Carbon-Carbon Bonds 

Organocuprates can react with compounds containing an allylic leaving group even when there is steric hindrance, but if the steric encumbrance becomes too great it can also proceed by a Sn2 like pathway (sec. 2.7.A.iii).39i The reaction of dimethylcuprate and 409 to give the methyl derivative (410) illustrates this 

Coupling reactions with alkyl halides often use large excess of cuprate, as mentioned above, which can be a severe limitation if the halide precursor to the organocuprate is difficult to prepare or unavailable from commercial sources. A solution to this problem is to prepare a cuprate with a ligand that is less reactive, allowing selective transfer of the substituent of choice. An example is the use of 417 in a reaction with 418 that 

The preparation of a Gilman reagent from an alkyl halide is a two-step process. First, hthium reacts with haloalkanes to give organolithium reagents (Section 9.8). For example, methyl bromide reacts with lithium to give methyl lithium. 

In Section 16.3, we saw that cychc ethers called crown ethers form complexes with cations. The crown ether called 12-crown-4 specificahy binds hthium. The name 12-crown-4 tells us three things first, the compound is a cychc ether second, the ether contains 12 atoms third, that there are four oxygen atoms in the ring that are hnked by ethylene bridges. In the presence 12-crown-4, dimethylcuprate exists as a linear complex. However, the hthium ion is important because the reaction does not occur if hthium is sequestered by the crown ether. 

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Transmetallation of allyltributyltin with organolithium species has been used for the generation of allyllithium solutions free of the coupling byproducts which often result from reduction of allylic halides with lithium metal. These solutions may then be used directly for the preparation of Gilman reagents and other reactive modifications of the parent allyllithium. 

A variation on the preparation of Gilman reagents is to use a Grignard reagent in the presence of a catalytic amount of Cu(I). Zoecon Corporation has developed a synthesis of 150 kg batches of the housefly sex attractant muscalure by treating (Z)-l-bromo-9-octadecene with pentylmagnesium bromide in the presence of catalytic amounts of Cu(I). The starting bromoalkene is easily prepared from the readily available (Z)-9-octadecenoic acid (oleic acid. Section 26.1). Yields of muscalure are nearly quantitative. 

An important use of organolithium reagents (Section 15.1) is in the preparation of diorganocopper reagents, often called Gilman reagents after Henry Gilman (1893-1986) of Iowa State University who was the first to develop their chemistry. 

Formation of Gilman Reagents (Section 15.2A) Lithium diorganocopper (Gilman) reagents are prepared by treating an organolithium compound with copper(I) iodide. 

In Problem 15.8, you used a series of lithium diorganocopper (Gilman) reagents. Show how to prepare each Gilman reagent from an appropriate alkyl or vinylic halide. 

Highly enantioselective 1,5-substitution reactions of enyne acetates are also possible under carefully controlled conditions (Eq. 4.31) [46]. For example, treatment of enantiomerically pure substrate 70 with the cyano-Gilman reagent tBu2CuLi-LiCN at —90 °C provided vinylallene 71 as a 1 3 mixture of E and 2 isomers with 20% and 74% ee, respectively. This mediocre selectivity might be attributable to race-mization of the allene by the cuprate or other reactive copper species formed in the reaction mixture. The use of phosphines as additives, however, can effectively prevent such racemizations (which probably occur by one-electron transfer steps) [47]. Indeed, vinylallene 71 was obtained with an ee of 92% for the E isomer and of 93% for the 2 isomer if the substitution was performed at —80 °C in the presence of 4 eq. of nBusP. Use of this method enabled various substituted vinylallenes (which are interesting substrates for subsequent Diels-Alder reactions Sect. 4.2.2) to be prepared with >90% ee. 

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