Kinetic and thermodynamic control of C(sp2)-H activation enables site-selective borylation.

Catalysts that distinguish between electronically distinct carbon-hydrogen (C-H) bonds without relying on steric effects or directing groups are challenging to design. In this work, cobalt precatalysts supported by N-alkyl-imidazole-substituted pyridine dicarbene (ACNC) pincer ligands are described that enable undirected, remote borylation of fluoroaromatics and expansion of scope to include electron-rich arenes, pyridines, and tri- and difluoromethoxylated arenes, thereby addressing one of the major limitations of first-row transition metal C-H functionalization catalysts. Mechanistic studies established a kinetic preference for C-H bond activation at the meta-position despite cobalt-aryl complexes resulting from ortho C-H activation being thermodynamically preferred. Switchable site selectivity in C-H borylation as a function of the boron reagent was thereby preliminarily demonstrated using a single precatalyst.

Photo- and Metal-Mediated Deconstructive Approaches to Cyclic Aliphatic Amine Diversification.

Described herein are studies toward the core modification of cyclic aliphatic amines using either a riboflavin/photo-irradiation approach or Cu(I) and Ag(I) to mediate the process. Structural remodeling of cyclic amines is explored through oxidative C-N and C-C bond cleavage using peroxydisulfate (persulfate) as an oxidant. Ring-opening reactions to access linear aldehydes or carboxylic acids with flavin-derived photocatalysis or Cu salts, respectively, are demonstrated. A complementary ring-opening process mediated by Ag(I) facilitates decarboxylative Csp3-Csp2 coupling in Minisci-type reactions through a key alkyl radical intermediate. Heterocycle interconversion is demonstrated through the transformation of N-acyl cyclic amines to oxazines using Cu(II) oxidation of the alkyl radical. These transformations are investigated by computation to inform the proposed mechanistic pathways. Computational studies indicate that persulfate mediates oxidation of cyclic amines with concomitant reduction of riboflavin. Persulfate is subsequently reduced by formal hydride transfer from the reduced riboflavin catalyst. Oxidation of the cyclic aliphatic amines with a Cu(I) salt is proposed to be initiated by homolysis of the peroxy bond of persulfate followed by α-HAT from the cyclic amine and radical recombination to form an α-sulfate adduct, which is hydrolyzed to the hemiaminal. Investigation of the pathway to form oxazines indicates a kinetic preference for cyclization over more typical elimination pathways to form olefins through Cu(II) oxidation of alkyl radicals.

C(sp2)-H Activation with Bis(silylene)pyridine Cobalt(III) Complexes: Catalytic Hydrogen Isotope Exchange of Sterically-Hindered C-H Bonds.

The bis(silylene)pyridine cobalt(III) dihydride boryl, trans-[ ptol SiNSi]Co(H)2BPin (ptolSiNSi = 2,6-[EtNSi(NtBu)2CAr]2 C5H3N, where Ar = C6H5CH3, and Pin =pinacolato) has been used as a precatalyst for the hydrogen isotope exchange (HIE) of arenes and heteroarenes using benzene-d 6 as the deuterium source. Use of D2 as the source of the isotope produced modest levels of deuterium incorporation and stoichiometric studies established modification of the pincer ligand through irreversible addition of H2 across the silylene leading to catalyst deactivation. High levels of deuterium incorporation were observed with benzene-d 6 as the isotope source and enabled low (0.5 - 5 mol%) loadings of the cobalt precursor. The resulting high activity for C-H activation enabled deuterium incorporation at sterically encumbered sites previously inaccessible with first-row metal HIE catalysts. The cobalt-catalyzed method was also compatible with aryl halides, demonstrating a kinetic preference for chemoselective C(sp2)-H activation over C(sp2)-X (X = Cl, Br) bonds. Monitoring the catalytic reaction by NMR spectroscopy established cobalt(III) resting states at both low and high conversions of substrate and the overall performance was inhibited by the addition of HBPin. Studies on precatalyst activation with cis-[ ptol SiNSi]Co(Bf)2H and cis-[ ptol SiNSi]Co(H)2Bf (where Bf = 2-benzofuranyl), support the intermediacy of bis(hydride)aryl cobalt intermediates as opposed to bis(aryl)hydride cobalt complexes in the catalytic HIE method. Mechanistic insights resulted in an improved protocol using [ ptol SiNSi]Co(H)3 NaBHEt3 as the precatalyst, ultimately translating onto higher levels of isotopic incorporation.

Computational Study of Key Mechanistic Details for a Proposed Copper (I)-Mediated Deconstructive Fluorination of N-Protected Cyclic Amines.

Using calculations, we show that a proposed Cu(I)-mediated deconstructive fluorination of N-benzoylated cyclic amines with Selectfluor® is feasible and may proceed through: (a) substrate coordination to a Cu(I) salt, (b) iminium ion formation followed by conversion to a hemiaminal, and (c) fluorination involving C-C cleavage of the hemiaminal. The iminium ion formation is calculated to proceed via a F-atom coupled electron transfer (FCET) mechanism to form, formally, a product arising from oxidative addition coupled with electron transfer (OA + ET). The subsequent ß-C-C cleavage/fluorination of the hemiaminal intermediate may proceed via either ring-opening or deformylative fluorination pathways. The latter pathway is initiated by opening of the hemiaminal to give an aldehyde, followed by formyl H-atom abstraction by a TEDA2+ radical dication, decarbonylation, and fluorination of the C3-radical center by another equivalent of Selectfluor®. In general, the mechanism for the proposed Cu(I)- mediated deconstructive C-H fluorination of N-benzoylated cyclic amines (LH) by Selectfluor® was calculated to proceed analogously to our previously reported Ag(I)-mediated reaction. In comparison to the Ag(I)-mediated process, in the Cu(I)-mediated reaction the iminium ion formation and hemiaminal fluorination have lower associated energy barriers, whereas the product release and catalyst re-generation steps have higher barriers.

Sequential Norrish-Yang Cyclization and C-C Cleavage/Cross-Coupling of a [4.1.0] Fused Saturated Azacycle.

Methods that functionalize the periphery of azacylic scaffolds have garnered increasing interest in recent years. Herein, we investigate the selectivity of a solid-state Norrish-Yang cyclization (NYC) and subsequent C-C cleavage/cross-coupling reaction of a strained cyclopropane-fused azacyclic system. Surprisingly, the NYC primarily furnished a single lactam constitutional and diastereo-isomer. The regioselectivity of the C-C cleavage of the α-hydroxy-ß-lactam moiety could be varied by altering the ligand set used in the coupling chemistry. Experimental and computational observations are discussed.

Key Mechanistic Features of the Silver(I)-Mediated Deconstructive Fluorination of Cyclic Amines: Multistate Reactivity versus Single-Electron Transfer.

Density functional calculations have provided evidence that a Ag(I)-mediated deconstructive fluorination of N-benzoylated cyclic amines (LH) with Selectfluor [(F-TEDA)(BF4)2] begins with an association of the reactants to form a singlet state adduct {[(LH)-Ag]-[F-TEDA]2+}. The subsequent formation of an iminium ion intermediate, [L+-Ag]-HF-[TEDA]+, is, formally, a Ag(I)-mediated hydride abstraction event that occurs in two steps: (a) a formal oxidative addition (OA) of [F-TEDA]2+ to the Ag(I) center that is attended by an electron transfer (ET) from the substrate (LH) to the Ag center (i.e., OA + ET, this process can also be referred to as a F-atom coupled electron transfer), followed by (b) H-atom abstraction from LH by the Ag-coordinated F atom. The overall process involves lower-lying singlet and triplet electronic states of several intermediates. Therefore, we formally refer to this reaction as a two-state reactivity (TSR) event. The C-C bond cleavage/fluorination of the resulting hemiaminal intermediate via a ring-opening pathway has also been determined to be a TSR event. A competing deformylative fluorination initiated by hemiaminal to aldehyde equilibration involving formyl H-atom abstraction by a TEDA2+ radical dication, decarbonylation, and fluorination of the resulting alkyl radical by another equivalent of Selectfluor may also be operative in the latter step.

Reactivity and Selectivity Controlling Factors in the Pd/Dialkylbiarylphosphine-Catalyzed C-C Cleavage/Cross-Coupling of an N-Fused Bicyclo α-Hydroxy-ß-Lactam.

Density functional theory was employed in order to elucidate the mechanism and factors that lead to the observed regioselectivity in the dialkylbiarylphosphine (Phos)/Pd-catalyzed C-C cleavage/cross-coupling of an N-fused bicyclo α-hydroxy-ß-lactam, 1. We have identified that (a) a complex [(1)(Cs2CO3)]-PdL(PhBr) forms prior to a "base-mediated oxidative addition"; (b) Cs-carbonate (rather than a halide) deprotonates the alcohol substrate in the lowest energy pathway en route to Pd-alcoholate formation; (c) reactions using Phos ligands bearing OCF3 and OCF2H substituents on the "B"-ring are predicted to be selective toward proximal ring opening of 1; (d) steric repulsion between the bottom "B"-ring of the Phos ligand and the piperidine moiety of 1 controls the regioselectivity of the C-C cleavage followed by cross-coupling; and (e) the α- vs ß-selective functionalization of the piperidine moiety in 1 is influenced by the bulkiness of the R2-substituent of the coupling partner. These studies will aid in the design of selective functionalizations of the piperidine moiety in 1.

A unified strategy to reverse-prenylated indole alkaloids: total syntheses of preparaherquamide, premalbrancheamide, and (+)-VM-55599.

A full account of our studies toward reverse-prenylated indole alkaloids that contain a bicyclo[2.2.2]core is described. A divergent route is reported which has resulted in the synthesis of preparaherquamide, (+)-VM-55599, and premalbrancheamide. An intramolecular Dieckmann cyclization between an enolate and isocyanate was used to forge the bicyclo[2.2.2]diazaoctane core that is characteristic of these molecules. The pentacyclic indole scaffold was constructed through a one-pot Hofmann rearrangement followed by Fischer indole synthesis. The utilization of our previously reported indole peripheral functionalization strategy also led to natural products including malbrancheamides B, C, stephacidin A, notoamides F, I and R, aspergamide B, and waikialoid A. Ultimately, the divergent route that we devised provided access to a wide range of prenylated indole alkaloids that are differently substituted on the cyclic amine core.

Synthesis of Bridged Bicyclic Amines by Intramolecular Amination of Remote C-H Bonds: Synergistic Activation by Light and Heat.

The construction of complex aza-cycles is of interest to drug discovery due to the prevalence of nitrogen-containing heterocycles in pharmaceutical agents. Herein we report an intramolecular C-H amination approach to afford value-added and complexity-enriched bridged bicyclic amines. Guided by density functional theory and nuclear magnetic resonance investigations, we determined the unique roles of light and heat activation in the bicyclization mechanism. We applied both light and heat activation in a synergistic fashion, achieving gram-scale bridged aza-cycle synthesis.

C-H/C-C Functionalization Approach to N-Fused Heterocycles from Saturated Azacycles.

Herein we report the synthesis of substituted indolizidines and related N-fused bicycles from simple saturated cyclic amines through sequential C-H and C-C bond functionalizations. Inspired by the Norrish-Yang Type II reaction, C-H functionalization of azacycles is achieved by forming α-hydroxy-ß-lactams from precursor α-ketoamide derivatives under mild, visible light conditions. Selective cleavage of the distal C(sp2)-C(sp3) bond in α-hydroxy-ß-lactams using a Rh-complex leads to α-acyl intermediates which undergo sequential Rh-catalyzed decarbonylation, 1,4-addition to an electrophile, and aldol cyclization, to afford N-fused bicycles including indolizidines. Computational studies provide mechanistic insight into the observed positional selectivity of C-C cleavage, which depends strongly on the groups bound to Rh trans to the phosphine ligand.

Author Correction: Deconstructive diversification of cyclic amines.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

C─C Cleavage Approach to C─H Functionalization of Saturated Aza-Cycles.

Saturated cyclic amines (aza-cycles) are ubiquitous structural motifs found in pharmaceuticals, agrochemicals, and bioactive natural products. Given their importance, methods that directly functionalize aza-cycles are in high demand. Herein, we disclose a fundamentally different approach to functionalizing cyclic amines which relies on C─C cleavage and attendant cross-coupling. The initial functionalization step is the generation of underexplored N-fused bicyclo α-hydroxy-ß-lactams under mild, visible light conditions using a Norrish-Yang process to affect α-functionalization of saturated cyclic amines. This approach is complementary to previous methods for the C─H functionalization of aza-cycles and provides unique access to various cross-coupling adducts. In the course of these studies, we have also uncovered an orthogonal, base-promoted opening of the N-fused bicyclo α-hydroxy-ß-lactams. Computational studies have provided insight into the origin of the complementary C─C cleavage processes.

Deconstructive diversification of cyclic amines.

Deconstructive functionalization involves carbon-carbon (C-C) bond cleavage followed by bond construction on one or more of the constituent carbons. For example, ozonolysis1 and olefin metathesis2,3 have allowed each carbon in C=C double bonds to be viewed as a functional group. Despite the substantial advances in deconstructive functionalization involving the scission of C=C double bonds, there are very few methods that achieve C(sp3)-C(sp3) single-bond cleavage and functionalization, especially in relatively unstrained cyclic systems. Here we report a deconstructive strategy to transform saturated nitrogen heterocycles such as piperidines and pyrrolidines, which are important moieties in bioactive molecules, into halogen-containing acyclic amine derivatives through sequential C(sp3)-N and C(sp3)-C(sp3) single-bond cleavage followed by C(sp3)-halogen bond formation. The resulting acyclic haloamines are versatile intermediates that can be transformed into various structural motifs through substitution reactions. In this way we achieve the skeletal remodelling of cyclic amines, an example of scaffold hopping. We demonstrate this deconstructive strategy by the late-stage diversification of proline-containing peptides.

Deconstructive fluorination of cyclic amines by carbon-carbon cleavage.

Deconstructive functionalizations involving scission of carbon-carbon double bonds are well established. In contrast, unstrained C(sp3)-C(sp3) bond cleavage and functionalization have less precedent. Here we report the use of deconstructive fluorination to access mono- and difluorinated amine derivatives by C(sp3)-C(sp3) bond cleavage in saturated nitrogen heterocycles such as piperidines and pyrrolidines. Silver-mediated ring-opening fluorination using Selectfluor highlights a strategy for cyclic amine functionalization and late-stage skeletal diversification, establishing cyclic amines as synthons for amino alkyl radicals and providing synthetic routes to valuable building blocks.