The directed ortho metalation — Cross‐coupling symbiosis in heteroaromatic synthesis

Abstract

Thirty years after its discovery by Gilman and Wittig, the Directed ortho Metalation (DoM) reaction continues to march in synthetically useful paths. To offer evidence for this statement, this lecture review describes a new and general cumyl Directed Metalation Group (DMG) (Schemes 2–6) and a phosphine oxide DMG (Schemes 7 and 8). Aryl‐aryl cross‐coupling chemistry is highlighted by polymer support Suzuki‐Miyaura (Schemes 10 and 11) and an aryl O‐carbamate‐Grignard of value in the construction of naphthalenes (Scheme 12) and indoles (Scheme 13) and, for the latter class of compounds, in the generation of 4,5‐quinodimethane intermediates (Scheme 14) for the synthesis of corresponding annelated derivatives (Scheme 15). The marriage of DoM with the Negishi cross‐coupling reaction is demonstrated in general (Scheme 16). The concept of Directed remote Metalation (DreM) (Schemes 17 and 19) is applied to the synthesis of dibenzopyranones (Scheme 18), xanthones (Scheme 21), acridones, dibenzoazepinones, and oxindoles (Scheme 20). In this context, a carbanionic N‐to‐ortho‐C t‐Boc migration leading to anthranilate esters is also achieved (Scheme 20). For provision of diaryl ethers, diaryl sulfides, and diaryl amines, a new copper catalyst is introduced into the venerable Ullmann reaction (Scheme 22) and its extension by DoM, and cross‐coupling chemistry is indicated (Scheme 23). A recently evolving link to DoM, the Grubbs metathesis process is manifested in the total synthesis of two natural products (Schemes 25 and 26) and has anticipated use more broadly in heterocyclic synthesis. (Scheme 27).

The Synthesis and Applications of Heterocyclic Boronic Acids

“…91 In this example chlorine appears to function as an ortho-directing metallating group (DMG). 92 Scheme 24…”

“…Snieckus recently highlighted the inroads that his team had made into the use of polymer supported Suzuki coupling reactions 19,128 using the Merrifield resin bound bromobenzene-acetal Leznoff linker 129,130 148.…”

DirectedorthoMetalation−Boronation and Suzuki−Miyaura Cross Coupling of Pyridine Derivatives: A One-Pot Protocol to Substituted Azabiaryls

“…In context of modern transition metal-catalyzed reactions, the impact of new sp 2 −sp 2 bond synthetic protocols has revolutionized how chemists conceptualize aryl−aryl, aryl−heteroaryl, and heteroaryl−heteroaryl bond formation leading to wide adaptation of the Kumada−Corriu, Negishi, Suzuki−Miyaura, and Stille 6 cross coupling processes especially in pharmaceutical industry practice . The D o M strategy, when linked with the named cross coupling reactions by transmetalation ( 1 , Scheme ), provides considerable tactical advantage in the construction of polysubstituted aromatic and heteroaromatic compounds 1 The D o M-Cross Coupling Nexus …”

Pest und Geschrei in Dosen?

“…In general, the success of a dearomatization process is determined by the presence of certain type of substituents on the aromatic ring. For instance, the ozonolysis of arenes (the formation of primary ozonides appears to result from 1,3‐dipolar cycloadditions to aromatic CC bonds) is facilitated by electron‐releasing substituents,2 and in contrast, the addition of organolithium compounds effectively facilitates ozonolysis in the case of π‐deficient arenes that contain electron‐withdrawing groups (for example, see ref 3–5…”