Iridium-Catalyzed Enantioselective α-Allylic Alkylation of Amides Using Vinyl Azide as Amide Enolate Surrogate

Abstract

Among the unstabilized enolates used as nucleophiles in iridium-catalyzed asymmetric allylic alkylation reactions, amide enolates are the least explored. Vinyl azides are now employed as amide enolate surrogates in Ir-catalyzed asymmetric allylic alkylation with branched allylic alcohols as the allylic electrophile. Competing reaction pathways are suppressed through the systematic tuning of the steric and electronic properties of vinyl azide to effect the α-allylic alkylation of secondary acetamides with high atom economy, exclusive branched selectivity, and mostly excellent enantioselectivity.

Iridium‐Catalyzed Enantioselective and Chemodivergent Allenylic Alkylation of Vinyl Azides for the Synthesis of α‐Allenylic Amides and Ketones**

“…While these selectivity issues pose a potential hurdle to our strategy, taking a cue from our earlier study, [15a] we were confident in controlling the diastereoselectivity of iminodiazonium ion in favor of ( E )‐ E using sterically and electronically tuned vinyl azides, and thereby eliminating the possibility of formation of G′ . At the same time, we wondered about turning the chemoselectivity problem (Schmidt rearrangement vs. hydrolysis of E ) into our advantage with controlling the hydroxide (or water) concentration and thereby developing an enantioselective synthesis of α‐allenylic ketones [17] from the same set of starting materials by harnessing the reactivities of either ( E )‐ E or F .…”

“…The seminal studies by the Carreira group offer sufficient evidence that the regioselectivity in favor of the allene over 1,3‐diene could be achieved using the Ir I /(phosphoramidite,olefin) complex as the catalyst [11] . At the same time, hydroxide concentration can be kept at check with the help of a suitable desiccant [15a] to navigate the reaction pathways either towards α‐allenylic amides or ketones.…”

“…This shortcoming of amide α-reactivity has previously been supplemented using amide enolate surrogates. [15] Vinyl azide is one such surrogate, whose synthetic potential has been demonstrated by the pioneering studies of Chiba and coworkers. [16] We envisioned an enantioselective allenylic alkylation reaction of vinyl azide for the synthesis of α-allenylic amides (Scheme 1D).…”

“…Even though the use of vinyl azide as amide enolate surrogate in enantioselective reactions has recently been reported, [15a–b, 16a] its application as ketone enolate surrogate, [16i] to the best of our knowledge, is yet to be disclosed for an enantioselective transformation.…”

Iridium-Catalyzed Diastereo- and Enantioselective [4 + 3] Cycloaddition of 4-Indolyl Allylic Alcohols with Azomethine Ylides

“…On the other hand, pioneered by Takeuchi and Helmchen, iridium-catalyzed asymmetric allylic substitution has emerged as a reliable protocol to construct carbon–carbon and carbon–heteroatom bonds . In particular, since Carreira’s groundbreaking contribution, simple and unactivated allylic alcohols were documented as an ideal substrate in iridium-catalyzed asymmetric allylic substitution by the addition of an acid promoter . In this context, we envisioned that easily available 4-indolyl allylic alcohol could be identified as a potential four-carbon dipolarophile by the combination of indole C3 nucleophilicity, which could be trapped by azomethine ylides through the cascade allylation /Pictet–Spengler cyclization (Scheme ).…”