Palladium-catalyzed selective activation of allyl alcohols as allyl cations, allyl anions, and zwitterionic trimethylenemethanes

Pure and Applied Chemistry, May, 2008 by Yoshinao Tamaru, Masanari Kimura

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Already almost one century ago, hexa-methylation of benzenetriol was examined under alkaline conditions [6]. Despite many trails, changing the concentration of KOH, the reaction temperatures, and the amounts of MeI, the expected product was never obtained in good yield (Scheme 6).

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In the light of today's chemical knowledge, this failure may be attributed to the retro-aldol of the hexa-methylation product under alkaline conditions which causes ring-opening and many side reactions. In this context, our success of hexa-allylation is remarkable, and the success may be attributed to the mild reaction conditions undertaken at room temperature and especially under neutral conditions [7].

Indole is an ambident nucleophile (at N and C3), however, it underwent allylation selectively at C3 position under our conditions using 1 equiv of allyl alcohol and Pd[(P[Ph.sub.3]).sub.4] and [Et.sub.3]B both in a catalytic amount (Scheme 7) [8]. Among many indole derivatives examined, 2-Me indole was exceptionally unreactive and required long heating. In sharp contrast, 3-Me indole was very reactive and the reaction was complete within 2 h. It should be noted that electron-deficient 5-nitroindole is more reactive than electron-rich 5-methoxy and 5-hydroxyindoles. At the moment, we cannot rationalize this contrasting reactivity.

The reaction of 3-methylindole creating a quaternary carbon center is extended successfully to asymmetric allylic alkylation by Trost, which shows up to 85 % ee [9].

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Trypthophan methyl ester shows interesting diastereoface selectivity and allylation takes place exclusively from the Si face at C3 position with concomitant amination at C2 position, providing a pyrroloindole skeleton in good yield (Scheme 8). Selective C-allylation, remaining both aliphatic and aromatic amines unchanged, should be noted.

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By exposing to an excess amount of allyl alcohol, further allylation at both aromatic and aliphatic nitrogen atoms took place and provided a C,N,N-tri-allylation product in remarkably good yield (Scheme 8) [10]. This reaction may be useful for the preparation of naturally occurring pyrroloindole alkaloids, such as flustramines A and B [11].

[alpha]-Allylation of ketones and esters can be performed easily in good yields, however, [alpha]-allylation of aldehydes is known to be rather difficult. For example, under Pd-catalysis, the [alpha]-allylation of aldehydes can be only performed successfully by pre-activation of both reaction partners: allyl alcohols as their carbonates and aldehydes as either their silyl enol ethers [12] or enamines [13].

We have succeeded in the [alpha]-allylation of aldehydes without pre-activation of these reaction partners by slight modification of the reaction conditions described so far, by using [Et.sub.3]N and LiCl as additives (Scheme 9) [14]. Here, [Et.sub.3]N may serve to generate an aldehyde enolate and LiCl may serve to retard the conversion of II to III by replacing a HO-B[Et.sub.3.sup.-] anion with a [Cl.sup.-] anion (Scheme 2).