Abstract
The addition of alkyl fragments to aliphatic aldehydes is a highly desirable transformation for fragment couplings, yet existing methods come with operational challenges related to the basicity and instability of the nucleophilic reagents commonly employed. We report herein that nickel catalysis using a readily available bioxazoline (BiOx) ligand can catalyze the reductive coupling of redox-active esters with aliphatic aldehydes using zinc metal as the reducing agent to deliver silyl-protected secondary alcohols. This protocol is operationally simple, proceeds under mild conditions, and tolerates a variety of functional groups. Initial mechanistic studies suggest a radical chain pathway. Additionally, alkyl tosylates and epoxides are suitable alkyl precursors to this transformation providing a versatile suite of catalytic reactions for the functionalization of aliphatic aldehydes.
Highlights
Cross-coupling reactions have revolutionized the landscape of carbon–carbon bond construction, with extensive application in the synthesis of natural products, pharmaceuticals, agrochemicals, and functionalized polymers.[1]
Barbier-type reactions[3] and Nozaki-Hiyama-Kishi (NHK)[4] couplings are attractive as they avoid the handling of air- and moisture-sensitive organometallic reagents, and have been employed in many complex settings,[5] the reaction scope is often limited in cases where sp[3] alkyl fragments are added to aliphatic enolizable aldehydes
In order to address this gap in the field, our lab recently described a catalytic process involving the reductive coupling of aliphatic aldehydes with alkyl bromides in a pathway proposed to proceed through the intermediacy of a-silyloxyalkylnickel intermediates derived from aldehydes, silyl chlorides, and low-valent nickel (Figure 1B).[15]
Summary
Our initial investigation geared towards developing the catalytic reductive coupling of aldehydes 1a with the N-hydroxyphthalimide (NHPI) ester 2a (Table 1). Some potentially reactive functional groups, including alkyl chloride 3k and aryl bromide 3l were left intact under current conditions, offering opportunities for subsequent cross-coupling. Substrates with functional groups known to engage in transition-metal-catalyzed transformations such as aryl chlorides (3al), aryl bromides (3am) and aryl boronate esters (3an), delivered the desired product smoothly without competing reactivity. Heterocycle substrates, such as indole (3aq), was likewise suitable for this chemistry. The scope and chemoselectivity of this method in activating aldehydes in the presence of a wide array of reactive functional groups including ketones is quite broad, addressing an important limitation of classical methods for carbonyl additions
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