ReviewCopper-mediated 1,6-, 1,8-, 1,10- and 1,12-addition and 1,5-substitution reactions in organic synthesis
Introduction
Although the element copper has been known since ancient times and has been used for a long time in established reactions, such as the Sandmeyer reaction, the Ullmann coupling and coupling reactions of alkynes, the deliberate utilization of organocopper reagents in organic synthesis started only about 40 years ago. Based on the seminal work of Gilman who carried out the first investigations of organocopper compounds RCu [1] and lithium diorganocuprates R2CuLi [2], it was quickly established by House et al. and Corey et al. that the latter are the reagents of choice for carbon–carbon bond formation since they are highly reactive towards a wide variety of electrophiles (even today, cuprates of the type R2CuLi are referred to as Gilman reagents in honor of his pioneering work). Thus, organocuprates undergo substitution reactions on many saturated (haloalkanes, acid chlorides, oxiranes) and unsaturated electrophiles (allylic and propargylic derivatives), as well as 1,4-additions to α,β-unsaturated carbonyl compounds and carbocuprations of nonactivated alkynes [3].
Nowadays, reactivity is only one of the necessary qualities of a successful class of reagents, the others being efficiency and selectivity. The major advantage of organocopper compounds is that each of these features can be controlled by ‘tuning’ of the reagent, making them highly useful for the total synthesis of complex target molecules like natural products, pharmaceuticals and chiral auxiliaries [3]. For example, many different combinations of copper(I) salts and organometallic compounds can be employed for the preparation of organocopper reagents with different composition and reactivity; particularly commonly used are CuI, CuBr·Me2S and CuCN as copper source and organolithium, Grignard and organozinc reagents as transmetalating agents (the latter also allows for the introduction of functional groups into cuprates [4]). Diethyl ether, THF, and dimethyl sulfide are suitable solvents for the preparation and reactions of organocopper reagents RCu and cuprates R2CuLi. Since these solvents also serve as ligands [5], a change of the solvent strongly affects the reactivity [3]. By variation of the stoichiometry of copper salt and organometallic reagent, different cuprates can be obtained; for example, the reaction of 1 equiv. of CuCN with 1 equiv. of RLi leads to the so-called lower-order cyanocuprates RCu(CN)Li wherein the cyanide is bound to the copper center [6], [7] (see [7a–c] for solid-state structures of cyanocuprates); after addition of a second equiv. of RLi, cyano-Gilman reagents R2CuLi·LiCN are formed which do not contain a copper-bound cyanide ion in their thermodynamically most stable form [7]. The former are an example of mixed cuprates of the type RtRrCuLi, in which Rt is an easily transferred ligand and Rr is a tightly held, ‘residual’, nontransferable ‘dummy ligand’. These reagents are particularly useful with ‘valuable’ substituents Rt since generally only one of the two R groups in a cuprate of the stoichiometry R2CuLi can be introduced into a substrate. Besides cyanide, commonly used dummy ligands are cheap and easily accessible alkynyl, thienyl, alkoxy, thiolato, and amido groups [3].
Recent developments in organocopper chemistry focus on the discovery of new catalytic and/or enantioselective versions of copper-mediated transformations. Although copper-catalyzed 1,4-addition reactions of Grignard reagents to enones were reported by Kharasch and Tawney already in 1941 [8], the search for new copper-catalyzed reactions has continued ever since, because copper is a problematic element in environmental terms [9], [10]. A particularly promising approach makes use of the conversion of terminal alkynes into alkenylzirconocenes by hydrozirconation with the Schwartz reagent Cp2Zr(H)Cl; these can then be used in copper-catalyzed 1,4-additions to enones [10]. Enantioselective 1,4-additions have been carried out with limited success by using chirally modified mixed cuprates RCu(L*)Li wherein the chiral nontransferable ligand L* (usually an alcoholate or amide) controls the stereochemical course of the transfer of the group R to the substrate [11]. The well known dynamic behavior of organocopper species in solution has presented difficulties inasmuch as the only very modest enantioselectivities often observed with chiral cuprates RCu(L*)Li may well be due to equilibria with the achiral, but more reactive homocuprates R2CuLi which form racemic 1,4-adducts. Recently, these problems have been overcome by the discovery of a new class of chiral ligands wherein binaphthol and a chiral amine are bridged via a phosphorus center, allowing highly enantioselective copper-catalyzed 1,4-addition reactions of organozinc compounds to selected enones [12].
All recent investigations described above have led to the development of highly sophisticated organocopper reagents and new protocols for conducting their reactions. In terms of the substrates, however, little has changed until recently, i.e. the usual 1,4-Michael addition and 1,3-(SN2′)-substitution reactions of simple unsaturated substrates were carried out. Only in the last 10 years or so, reactions involving ambident substrates with extended multiple bond systems (in other words, with two or more reactive positions) were examined and found to take place with high regio- and stereoselectivities. Indeed, this is true not only for substitutions (1,5-substitutions), but also for additions (1,6- and 1,8-additions, etc.), in particular when the substrate contains at least one triple bond besides one or more conjugated double bonds. These unusual reaction types not only open up novel entries to interesting target molecules but also provide deeper insight into the mechanisms of copper-mediated bond formation [3], [13].
Section snippets
Acceptor-substituted dienes
Due to their ambident character, acceptor-substituted dienes can provide several isomeric products in copper-mediated Michael additions, making it particularly important to control the regio- and stereoselectivity of these transformations (Scheme 1). Besides direct nucleophilic attack at the acceptor group, an activated diene may undergo a 1,4- or 1,6-addition; in the latter case, capture of the ambident enolate with a soft electrophile can also take place at two different positions. Thus, the
Copper-mediated substitution reactions of extended substrates
Compared to addition reactions of extended Michael acceptors, only a few examples of copper-mediated substitutions of extended electrophiles have been reported to date. Goering and coworkers [41] studied substitution reactions of various dienylic carboxylates with organocuprates (and Grignard reagents in the presence of catalytic amounts of copper salts) and found that the ratio of the three possible regioisomers (i.e. α-, γ- and ε-alkylated product) depends strongly on the substrate and
Concluding remarks
Organocopper reagents have been utilized with great success in organic synthesis in the last 30 years. The more recent examples discussed in this review document the excellent performance of these organometallic compounds in regio- and stereoselective transformations of substrates with extended π-networks. Significant new developments include 1,6-, 1,8-, 1,10-, and 1,12-additions, as well as 1,5-substitution reactions. These new transformations not only proceed with high regio- and
Acknowledgements
The work on copper-mediated addition and substitution reactions was sponsored by the Deutsche Forschungsgemeinschaft, the Volkswagen-Stiftung, the Fonds der Chemischen Industrie, the European Community, and the Ministerium für Wissenschaft und Forschung des Landes Nordrhein-Westfalen. We also thank all coworkers whose names are listed in the references for their contributions.
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