Acceptor-substituted enynes

2 Copper-mediated Addition Reactions to Extended Michael Acceptors 151, Acc 

4 Copper-mediated Addition and Substitution Reactions of Extended Multiple Bond Systems 

As is implicit in the fact that the products of the (stoichiometric) 1,6-cuprate addition - the lithium allenyl enolate and the organocopper compound - are formed as independent species, it is also possible to conduct the reaction catalytically through in situ regeneration of the cuprate. The reaction can thus be run in a continuous mode, with only catalytic amounts of the preformed cuprate being necessary (with simultaneous addition of the substrate and the organolithium compound) enabling the desired allenes to be prepared even on larger scales (Eq. 4.17) [3oj. 

Several preparative applications of the 1,6-cuprate addition to acceptor-substituted enynes have been described in recent years. In addition to its use in the formation of 

The Diels-Alder reaction outlined above is a typical example of the way in which axially chiral allenes, accessible through 1,6-addition, can be utilized to generate new stereogenic centers in a selective fashion. This transfer of chirality is also possible by means of intermolecular Diels-Alder reactions of vinylallenes [30], aldol reactions of allenyl enolates [31], and Ireland-Claisen rearrangements of silyl allenylketene acetals [32]. 

---

Scheme 2.21 Regioselectivity in conjugate addition reactions to acceptor-substituted enynes 58.

Scheme 2.23 1,6-Cuprate addition to different acceptor-substituted enynes 66.

Remarkably, the regioselectivity of the cuprate addition to acceptor-substituted enynes is also insensitive to the steric properties of the substrate. Thus, enynes with tert-butyl substituents at the triple bond (e.g. 68) underwent 1,6-additions even when the cuprate was also sterically demanding (Scheme 2.24) [47]. The method is therefore highly suitable for the preparation of sterically encumbered allenes of type 69. 

Lower order cyanocuprates RCu(CN)Li displayed again a different behavior although they usually do not react with acceptor-substituted enynes, the cyanocuprate tBuCu(CN)Li nevertheless underwent anti-Michael additions to 2-en-4-ynoates (e.g. 70) and nitriles affording allenes of type 73 (Scheme 2.26) [51]. Unfortunately, an adequate interpretation of the abnormal behavior of this particular cuprate is still lacking. 

Scheme 2.28 Functionalized allenes obtained by 1,6-cuprate addition to acceptor-substituted enynes and regioselective enolate trapping with methyl triflate (77), aldehydes (78, 79), ketones (80) and silyl halides (81).

As was the case for allene synthesis by copper-promoted Sn2 substitution reactions, the corresponding 1,6-addition to acceptor-substituted enynes has found sev-... 

Scheme 2.34 Mechanistic model for the 1,6-addition of organo-cuprates to acceptor-substituted enynes.

The conjugate addition of an organocopper reagent to an acceptor-substituted enyne proceeds via 1,6-addition to give an allenic species (Scheme 3.81) [121]. 

Additional routes to a-allenic-a-amino acids were described more recently and utilize radical [136] or transition metal-catalyzed [137] allenylations, in addition to copper-promoted Michael additions [15b]. Thus, sterically demanding amino acid derivatives (e.g. 151) are accessible via a 1,6-addition reaction of lithium di-tert-butyl-cyanocuprate with acceptor-substituted enynes of type 150 (Scheme 18.48). 

As in the case of addition reactions of carbon nucleophiles to activated dienes (Section HA), organocopper compounds are the reagents of choice for regio- and stereoselective Michael additions to acceptor-substituted enynes. Substrates bearing an acceptor-substituted triple bond besides one or more conjugated double bonds react with organocuprates under 1,4-addition exclusively (equation 51)138-140 1,6-addition reactions which would provide allenes after electrophilic capture were not observed (cf. Section IV). 

So-called lower order cyanocuprates RCu(CN)Li do not generally react with acceptor-substituted enynes. An exception is the cuprate t-BuCu(CN)Li which undergoes anti-Michael additions with 2-cn-4-ynoates and nitriles (equation 61)151. The mechanistic aspects of this very unusual reaction are unknown radical intermediates and electron transfer steps have not been found. 

In a thorough investigation of thiolate additions to acceptor-substituted enynes, Shus-trova and coworkers180,181 were able to demonstrate that the ratio of 1,4- and 1,6-addition depends on the reaction conditions, in particular on the duration of the experiment (equation 75) whereas only 1,4-adduct was observed in the reaction of methyl 6,6-dimethyl-2-hepten-4-ynoate and ethyl thiolate after 1 h, the product distribution shifted towards the 1,6-addition product with increasing reaction time, the latter being the sole... 

As previously mentioned, allenes can only be obtained by 1,6-addition to acceptor-substituted enynes when the intermediate allenyl enolate reacts regioselectively with an electrophile at C-2 (or at the enolate oxygen atom to give an allenyl ketene acetal see Scheme 4.2). The regioselectivity of the simplest trapping reaction, the protonation, depends on the steric and electronic properties of the substrate, as well as the proton source. Whereas the allenyl enolates obtained from alkynyl enones 22 always provide conjugated dienones 23 by protonation at G-4 (possibly... 

In contrast to nucleophilic addition reactions to activated dienes (Sect. 4.2.1), the mechanism of 1,6-cuprate additions to acceptor-substituted enynes is quite well understood, largely thanks to kinetic and NMR spectroscopic investigations [3oj. 

---