Cobalt-Catalyzed, Room-Temperature Addition of Aromatic Imines to Alkynes via Directed C–H Bond Activation

Abstract

A quaternary catalytic system consisting of a cobalt salt, a triarylphosphine ligand, a Grignard reagent, and pyridine has been developed for chelation-assisted C-H bond activation of an aromatic imine, followed by insertion of an unactivated internal alkyne that occurs at ambient temperature. The reaction not only tolerates potentially senstitive functional groups (e.g., Cl, Br, CN, and tertiary amide), but also displays a unique regioselectivity. Thus, the presence of substituents such as methoxy, halogen, and cyano groups at the meta-position of the imino group led to selective C-C bond formation at the more sterically hindered ortho positions. Under acidic conditions, the hydroarylation products of dialkyl- and alkylarylacetylenes underwent cyclization to afford benzofulvene derivatives, while those of diarylacetylenes afforded the corresponding ketones in moderate to good yields. A mechanistic investigation into the reaction with the aid of deuterium-labeling experiments and kinetic analysis has indicated that oxidative addition of the ortho C-H bond is the rate-limiting step of the reaction. The kinetic analysis has also shed light on the complexity of the quaternary catalytic system.

Cobalt‐Catalyzed Addition of Arylzinc Reagents to Alkynes to Form ortho‐Alkenylarylzinc Species through 1,4‐Cobalt Migration

“…[16, 17a] An N-aryl imine group at the meta position also served as a directing group ([D]-3 jb). [17] In contrast, the reactions of 3,4-dimethoxy-and 3-tosyloxyphenylzinc reagents resulted in preferential metal migration to the less hindered ortho position (4 kb and 4 lb), presumably because coordination of the meta-oxygen atom was not feasible owing to the increased bulkiness [16] and/or the reduced Lewis basicity (for 4 lb). Regioselective migration to the C2-position was observed in the reaction of 3-thienyl-and 3-quinolinylzinc reagents (see the corresponding products 4 mb and 4 nb), while correlation of the regioselectivity to specific parameters such as acidity is not clear to date.…”

“…The present 1,2-difunctionalization protocol opens the way for the divergent synthesis of benzo-fused carbocycles through manipulation of the alkenyl and other functional groups as synthetic handles. The feasibility of this idea was readily demonstrated by three sets of transformations: 1) naphthalene synthesis (15) from 1-iodo-2-alkenylarene 4 ab through Sonogashira coupling followed by NIS-mediated iodocarbocyclization (Scheme 6 a), [21] 2) indene synthesis (17) from 1-benzoyl-2-alkenylarene 5 through phenyllithium addition followed by BF 3 -mediated cyclization (Scheme 6 b), and 3) fluorene synthesis (18) from 1-phenyl-2-alkenylarene 8 through Friedel-Crafts cyclization (Scheme 6 c). In summary, we have developed a cobalt-catalyzed addition reaction of an arylzinc reagent to an internal alkyne that involves 1,4-cobalt migration followed by cobalt-to-zinc transmetalation to afford an ortho-alkenylarylzinc species, which serves as a versatile synthetic intermediate.…”

Development of Cobalt-Catalyzed C–H Bond Functionalization Reactions

“…In the reaction of aromatic ketimines, alkoxy, cyano, and halogen functional groups on the meta position directed the CH activation to take place at their proximity to selectively afford sterically more congested alkenylation products (Scheme 6a). 17 While such secondary directing effects of the alkoxy and fluorine substituents have been observed in other transitionmetal-catalyzed CH functionalizations, 26 it is not the case for the cyano, chloro, and bromo substituents. Regardless of the arene substrate, the reaction of an unsymmetrical alkyne leads to CC bond formation at the sterically less hindered acetylenic carbon atom, as illustrated by the examples of the addition of N-pyrimidylindole (Scheme 6b).…”

“…This initial finding has triggered subsequent expansion of the scope of alkyne hydroarylation reactions. Thus far, aromatic ketimines, 17 aldimines, 18 α,β-unsaturated imines, 19 indoles bearing an N-pyrimidyl group, 20 and oxazole/thiazole derivatives 21 have been successfully used as substrates for the cobaltcatalyzed addition to alkynes (Scheme 5). Note that the reaction of an α,β-unsaturated imine is followed by 6π electrocyclization to afford a dihydropyridine derivative.…”

Cobalt-Catalyzed C-C Bond-Forming Reactions via Chelation-Assisted C-H Activation

“…Thus, an imine derived from an acetophenone derivative and p anisidine can be ef ciently alkenylated with the aid of a cobalt catalyst generated from CoBr 2 , P(3 ClC 6 H 4 ) 3 , tBuCH 2 MgBr, and pyridine (Scheme 5). 12 The reaction takes place at a distinctly lower temperature (i.e., room temperature) than is required for a related reaction using a rhodium(I) catalyst. 13 Exploration of the scope of this reaction clari ed some mechanistically and synthetically notable features.…”