AsiaChem | Chemistry in Japan | December 2021 Volume 2 Issue 1

30 | December 2021 www.facs.website conventional single metal catalysis, which commonly proceeds at the ortho-position through directed C–H metalation, in which the carbonyl groups bind to the metal catalyst to promote C–H activation at the proximal ortho-position.24 Cooperative double activation catalysis thus offers unique opportunities for the promotion of C–H functionalization as well as control of the site-selectivity, which have been elusive by single-site catalysts. The acceleration and the control of the para-selectivity of the bulky Ni/Al catalysis system for C–H functionalization reactions has been extended to other metal-catalyzed C–H functionalizations. Ir-catalyzed arene C–H borylation has been established, and its utility and reliability have been developed over the last three decades.25 This is because the site-selectivity of the reaction can be controlled by steric factors in a highly predictable manner. For example, 1,3-di-substituted benzenes can be borylated selectively at the 5-position. However, controlling the site-selectivity can be difficult with certain arenes, such as mono-substituted and 1,2-di-substituted benzenes, because of the less-biased steric environments at the possible reaction sites; this issue has attracted great attention from synthetic organic chemists.26 We revealed that cooperative Ir/Al catalysis could provide high para-selectivity for the C–H borylation of benzamides.27 Again, the use of the bulky Al Lewis acid and an Ir catalyst bearing ligands with peripheral bulk was crucial (Scheme 8a). As in the case of cooperative Ni/Al catalysis, the Al catalysts play key roles in terms of steric repulsion and rate-acceleration to induce the para-selectivity through making the arene core electrophilic towards the Ir catalysts under much milder reaction conditions than those in single-center Ir catalysis. We could even achieve meta-selectivity in the arene C–H borylation using a catalyst with tethered Ir and Al centers (Scheme 8b).28 Notably, the benzene ring bearing the aminocarbonyl group was functionalized with high meta-selectivity exclusively over a phenyl substituent, which could also be borylated otherwise. The Ir/Lewis acid cooperative catalysis was also effective to achieve site-selective borylation of pyridine derivatives. The activation and functionalization of C–C bonds have attracted great attention in organic synthesis recently, as they could enable innovative transformations.29 The key to such transformations is the activation of the C–C bonds, which are commonly less kinetically and thermodynamically reactive. Successful and useful examples of C–C bond functionalization involving 3- and 4-membered compounds have been achieved via single site metal catalysts through the relief of ring strain as a major driving force to promote the C–C bond activation. Cooperative double activation catalysis has become a powerful strategy to expand the scope of C–C bond activation for organic synthesis. The C–CN bonds of nitriles are thermodynamically stable, but can reportedly be activated and functionalized by several transition metal catalysts.30 We expected that C–CN bond activation followed by the addition reaction of the organic and cyano fragments across unsaturated compounds, namely, the carbocyanation reaction, could be useful for organic synthesis, and initially performed the transformation using a single Ni catalyst. We then found that the scope of nitriles participating in this reaction could be significantly expanded using cooperative Ni/ Al catalysis.31 The cooperative double activation catalysis allows the activation of even acetonitrile to achieve the methylcyanation reaction (Scheme 9).32 Experimental and theoretical studies revealed that the cyano group coordinated to the Al Lewis acid at the N atom, while the p-bond bound to the Ni catalyst to significantly lower the barrier of the oxidative addition of the C–CN bonds. Cooperative transition metal/organic catalysis has also been developed to enable difficult C–H and C–C functionalizations that have been unavailable via single metal catalysts.33 A pioneering work was reported by Jun in 1997, who demonstrated the hydroacylation of alkenes via cooperative Rh/2-aminopicoline catalysis through formyl C–H bond activation (Scheme 10a).34 The amine catalyst reacts with aldehydes to give imines bearing a 3-methylpyridyl group, which serve as a coordinating directing group to bring the Rh catalyst close to the proximal formyl C–H bond, which undergoes oxidative addition to the Rh center. The ketone products are generated through the subsequent olefin insertion followed by C–C bond-forming reductive elimination. Hydroacylation via Rh catalysis alone has been limited to aldehyde and/ or alkene substrates bearing a coordinating functional group to prevent unwanted decarbonylation through its intramolecular coordination to the Rh center. The cooperative Rh/2-aminopicoline system has recently been further developed to achieve the direct a-alkylation of ketones with olefins (Scheme 10b).35 In this reaction, the enamine species bearing the pyridyl directing group is likely responsible for the directed C–H activation at the Rh center. Jun’s cooperative Rh/2-aminopicoline catalysis also effects the highly challenging catalytic C–C bond activation of ketones (Scheme 10c).36 Temporarily formed imines bearing the directing pyridyl group undergo the oxidative addition of the proximal C–C bond to the Rh(I) center. The reaction of phenylethyl ketones with 1-alkenes proceeds to afford alkyl ketones and styrene through C–C bond activation followed by exchange of the alkyl groups through b-H elimination. Cooperative double activation catalysis has recently been applied to the ring-expansion reaction of cyclopentanones through sequential C–C and C(sp2)–H bond activation (Scheme 10d).37 Conclusion In conclusion, the principles and representative examples of cooperative metal catalysis have been introduced, with a particular focus on new reactions that are difficult to achieve using conventional single metal catalysis. Taking advantage of cooperative synergistic catalysis, the scope and versatility of cross-coupling-type transformations have been significantly improved via the generation of nucleophilic organometallic Scheme 9: Cooperative double activation Ni/Al catalysis for C–C functionalization. Scheme 8: Cooperative double activation Ir/Al catalysis for siteselective C–H borylation.

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