Synthesis of Homoallylic Alcohols with Acyclic Quaternary Centers through Co^III‐Catalyzed Three‐Component C−H Bond Addition to Internally Substituted Dienes and Carbonyls

Abstract

An efficient Co III -catalyzed three-component strategy to prepare homoallylic alcohols containing acyclic quaternary centers is disclosed. This transformation enables the introduction of two CÀC s bonds through CÀHb ond activation and sequential addition to internally substituted dienes and aw ide range of aldehydes and activated ketones. Isoprene and other internally monosubstituted dienes are effective inputs,w ith the reaction proceeding with high diastereoselectivity for those substrate combinations that result in more than one stereogenic center.M oreover,t he opposite relative stereochemistry can be achieved by employing 1,2-disubstituted dienes.Amechanism for the transformation is proposed based upon the relative stereochemistry of the products and studies with isotopically labeled starting materials.

Synthesis of Nitrile Bearing Acyclic Quaternary Centers through Co(III)‐Catalyzed Sequential C−H Bond Addition to Dienes and N‐Cyanosuccinimide

“…Based on the observed product connectivity, experiments with deuterated substrates, and literature precedents, [9b, 11a,c] we propose the following mechanism for the three‐component cyanation (Figure 1). First, reversible concerted metalation and deprotonation assisted by pivalate forms cobaltacycle A .…”

“…Recently, we [11] and others [12] have reported a multicomponent strategy for Rh(III) or Co(III)‐catalyzed C−H activation and sequential addition to π‐bonds and various electrophiles. Relevant to this work, our lab has reported the synthesis of homoallylic alcohols bearing quaternary centers by C−H activation and sequential additions to internally substituted dienes and carbonyls using Cp*Co(III) [11a] . We sought to capitalize on this approach to construct the synthetically challenging all‐carbon quaternary centers bearing a C(sp 3 )−CN bond through sequential diene addition and electrophilic cyanation.…”

“…We commenced our studies with an extensive exploration of reaction parameters with 1‐ m ‐tolyl‐1 H ‐pyrazole, isoprene, and N ‐cyanosuccinimide to form 4 a (see Table 1 and Optimization Tables S1–S7 in Supplementary Information). Having observed success with Cp*Co(III) catalysis for three‐component reactions using dienes, [11a,c] and literature precedents of Cp*Co(III) catalysis for directed C(sp 2 )‐H cyanation, [9] we initiated our optimization with Cp*Co(CO)I 2 and AgSbF 6 . We found that N ‐cyanosuccinimide, reported by Chang and co‐workers, [9b] was the optimal electrophilic cyanating reagent.…”

Cp*Co(III)-Catalyzed C–H Hydroarylation of Alkynes and Alkenes and Beyond: A Versatile Synthetic Tool

“…This time, they managed to use internally substituted dienes 112 , allowing the synthesis of a variety of homoallylic alcohols 113 possessing acyclic quaternary centers ( Scheme 44 ). 68 Furthermore, regarding the carbonyl coupling partners, in some cases, activated ketones could be used instead of aldehydes 73 . It was proven that, in this case, the C–H cobaltation step is not the rate-limiting one.…”

Cobalt‐Catalyzed Multi‐Component Reactions: Recent Advances and Perspectives in Organic Synthesis

“…A new synthetic protocol towards secondary and tertiary homoallylic alcohols carrying acyclic quarternary carbons was established by Ellman and co-workers in 2019. [30] Two CÀ C σ bonds were introduced by CÀ H bond activation. Sequentially, CÀ H bond addition to internally substituted dienes and various aldehydes and activated ketones takes place.…”