Testing the limits of radical-anionic CH-amination: a 10-million-fold decrease in basicity opens a new path to hydroxyisoindolines via a mixed C-N/C-O-forming cascade.

An intramolecular C(sp3)-H amidation proceeds in the presence of t-BuOK, molecular oxygen, and DMF. This transformation is initiated by the deprotonation of an acidic N-H bond and selective radical activation of a benzylic C-H bond towards hydrogen atom transfer (HAT). Cyclization of this radical-anion intermediate en route to a two-centered/three-electron (2c,3e) C-N bond removes electron density from nitrogen. As this electronegative element resists such an "oxidation", making nitrogen more electron rich is key to overcoming this problem. This work dramatically expands the range of N-anions that can participate in this process by using amides instead of anilines. The resulting 107-fold decrease in the N-component basicity (and nucleophilicity) doubles the activation barrier for C-N bond formation and makes this process nearly thermoneutral. Remarkably, this reaction also converts a weak reductant into a much stronger reductant. Such "reductant upconversion" allows mild oxidants like molecular oxygen to complete the first part of the cascade. In contrast, the second stage of NH/CH activation forms a highly stabilized radical-anion intermediate incapable of undergoing electron transfer to oxygen. Because the oxidation is unfavored, an alternative reaction path opens via coupling between the radical anion intermediate and either superoxide or hydroperoxide radical. The hydroperoxide intermediate transforms into the final hydroxyisoindoline products under basic conditions. The use of TEMPO as an additive was found to activate less reactive amides. The combination of experimental and computational data outlines a conceptually new mechanism for conversion of unprotected amides into hydroxyisoindolines proceeding as a sequence of C-H amidation and C-H oxidation.

Coupling N-H Deprotonation, C-H Activation, and Oxidation: Metal-Free C(sp3)-H Aminations with Unprotected Anilines.

An intramolecular oxidative C(sp3)-H amination from unprotected anilines and C(sp3)-H bonds readily occurs under mild conditions using t-BuOK, molecular oxygen and N,N-dimethylformamide (DMF). Success of this process, which requires mildly acidic N-H bonds and an activated C(sp3)-H bond (BDE < 85 kcal/mol), stems from synergy between basic, radical, and oxidizing species working together to promote a coordinated sequence of deprotonation: H atom transfer and oxidation that forges a new C-N bond. This process is applicable for the synthesis of a wide variety of N-heterocycles, ranging from small molecules to extended aromatics without the need for transition metals or strong oxidants. Computational results reveal the mechanistic details and energy landscape for the sequence of individual steps that comprise this reaction cascade. The importance of base in this process stems from the much greater acidity of transition state and product for the 2c,3e C-N bond formation relative to the reactant. In this scenario, selective deprotonation provides the driving force for the process.

Changing the path of least resistance, or access to endo-dig products via a sequence of three exo-trig transition states: electronic effects in homoallyic ring expansion cascades of alkenyl isonitriles.

Chemoselective addition of radicals to isonitriles can be harnessed for initiating reaction cascades designed to overcome the stereoelectronic restrictions on homoallylic ring expansion in alkyne reactions and to develop a new general route for the preparation of N-heteroaromatics. This method utilizes alkenes as synthetic equivalents of alkynes by coupling homoallylic ring expansion to yield the formal "6-endo" products with aromatization via stereoelectronically assisted C-C bond scission. Detailed computational analysis of the individual steps of the homoallylic expansion sequence maps effects of substituents and structural constraints on this multi-step potential energy surface.

Coupling Radical Homoallylic Expansions with C-C Fragmentations for the Synthesis of Heteroaromatics: Quinolines from Reactions of o-Alkenylarylisonitriles with Aryl, Alkyl, and Perfluoroalkyl Radicals.

Selective addition of radicals to isonitriles can be harnessed for initiating reaction cascades designed to overcome the stereoelectronic restrictions on homoallylic ring expansion in alkyne reactions and to develop a new general route for the preparation of N-heteroaromatics. This method utilizes alkenes as synthetic equivalents of alkynes by coupling homoallylic ring expansion to yield the formal "6-endo" products with aromatization via stereoelectronically assisted C-C bond scission. Computational analysis of the homoallyic expansion potential energy surface reveals that the indirect 5-exo/3-exo/retro-3-exo path is faster than the direct 6-endo-trig closure, revealing the general exo-preference for the cyclization processes.

Double C-H amination by consecutive SET oxidations.

A new method for intramolecular C-H oxidative amination is based on a FeCl3-mediated oxidative reaction of anilines with activated sp(3) C-H bonds. The amino group plays multiple roles in the reaction cascade: (1) as the activating group in single-electron-transfer (SET) oxidation process, (2) as a directing group in benzylic/allylic C-H activation at a remote position, and (3) internal nucleophile trapping reactive intermediates formed from the C-H activation steps. These multielectron oxidation reactions proceed with catalytic amounts of Fe(iii) and inexpensive reagents.

Coupling cyclizations with fragmentations for the preparation of heteroaromatics: quinolines from o-alkenyl arylisocyanides and boronic acids.

Stereoelectronic restrictions on homoallylic ring expansion in alkyne cascades can be overcome by using alkenes as synthetic equivalents of alkynes in reaction cascades that are terminated by C-C bond fragmentation. Implementation of this approach using Mn(iii)-mediated reaction of o-alkenyl isocyanides and boronic acids leads to efficient synthesis of substituted quinolines.

Alkenes as alkyne equivalents in radical cascades terminated by fragmentations: overcoming stereoelectronic restrictions on ring expansions for the preparation of expanded polyaromatics.

Chemoselective interaction of aromatic enynes with Bu3Sn radicals can be harnessed for selective cascade transformations, yielding either Sn-substituted naphthalenes or Sn-indenes. Depending on the substitution at the alkene terminus, the initial regioselective 5-exo-trig cyclizations can be intercepted at the 5-exo stage via either hydrogen atom abstraction or C-S bond scission or allowed to proceed further to the formal 6-endo products via homoallylic ring expansion. Aromatization of the latter occurs via ß-C-C bond scission, which is facilitated by 2c,3e through-bond interactions, a new stereoelectronic effect in radical chemistry. The combination of formal 6-endo-trig cyclization with stereoelectronically optimized fragmentation allows the use of alkenes as synthetic equivalents of alkynes and opens a convenient route to α-Sn-substituted naphthalenes, a unique launching platform for the preparation of extended polyaromatics.

Exploring Anion-Induced Conformational Flexibility and Molecular Switching in a Series of Heteroaryl-Urea Receptors.

Anion binding studies of 1,10-phenanthroline- and 2-pyridyl-substituted urea-based receptors reveal that guest-dependent conformations exist in structural variants related to a previously investigated bipyridyl-based receptor. Dynamic conformational switching persists in a monofunctional pyridyl-urea receptor, and the preorganization provided by a phenanthroline-based analogue promotes convergence of anion coordinating groups to a single guest. Despite this predisposition for anion coordination, the conformational flexibility of the bipyridyl-based receptor provides the most selective motif for H2PO4- coordination. Furthermore, the two new phenanthrolyl- and pyridyl-receptors serve as models of the bipyridyl-based receptor, elucidating accurate stepwise association constants for 1:2 host/guest binding by this receptor, and suggest that oxoanions prefer the embrace of a "U" conformation in 1:1 complexes.