Electrophilic 5-endo-trig cyclization

Electrophilic 5-endo-trig cyclizations continue to be the subject of considerable research efforts by several groups. Interest has been focused on the stereoselectivity of the ring closure reactions of homoallylic alcohols to substituted... 

Regiochemistry of the electrophilic cyclization of 166 has been studied. Interestingly, 6(S)-endo-Trig cyclization seems to be more favoured than the expected 5(S)-exo-Trig... 

It might, at first glance, come as a surprise that, despite the ban on 5-endo-trig cyclizations, 5-endo-dig cyclizations are allowed. A possible reason for this observation is that intramolecular nucleophilic or electrophilic attack at an alkyne can proceed with the substrate in a flat conformation, because two orthogonal jt (or jt) orbitals are available. Similarly, hydroxymethyl allenes cyclize on treatment with a base (Scheme 9.7), because the terminal Jt orbital of the allene and the hydroxymethyl group can readily achieve a synperiplanar orientation. Intramolecular... 

A combinatorial natural-product-like and diversity-orientated library of 10 000 benzopyran-based small molecules was constructed by Nicolaou and coworkers [74, 75]. They chose a solid-phase approach and an anchoring strategy that does not limit complexity building operations (Scheme 14.11). They used a polystyrene-based selenyl bromide resin (43) on which substrates can be immobilized by electrophilic cyclization reactions. Here, ortho-prenylated phenol 44 was reacted with the selenyl bromide (43) to form the benzopyran scaffold (45) via a 6-endo-trig cyclization. 

In contrast to the 5-endo-trig anionic cyclization reactions, rarely observed, there are several examples in which 5-endo-dig processes are involved. Hence 2,3-disubstituted benzofurans, benzothiophenes and indoles 374 have been synthesized starting from triflu-oroethyl ethers, thioethers and anilines 373, respectively, and alkyllithium compounds. A 5-endo-dig carbolithiation reaction on 375, generated by two successive eliminations, one substitution and one ortho-lithiation reactions, is proposed to account for the formation of the corresponding 2-lithiated heterocycles. Further reaction of these intermediates with electrophiles affords compounds 374 (Scheme 98)159. In the case of thioether 373 (X = S) a bromine substituent must be present at the ortho position. 

Mechanistically, formation of products of exo-trig and endo-tng cyclization can be explained by the attack of the nucleophiles to cyclopropyl gold(l) carbene intermediates XXVI at carbons a or ft to form products 86 or 87 (Scheme 47), similarly to that found for Pt(ll) ([235], an example of gold-catalyzed methoxycy-clization of an allenene [237]). In the first step, the alkene reacts with the alkyne-gold(I) complex in an electrophilic addition process. 

Hydrolysis of the acetal releases an aldehyde and Mannich-style condensation leads to the produ The cyclization step in which the enol attacks the iminium ion is endo in both components (6-eni.i . trig for both the electrophile and the nucleophile) and thus difficult to do. However, by folding > molecule in a chair (frame in margin) a reasonable overlap between the required p orbital i possible. 

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