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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.

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 β-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.

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-β-lactam moiety could be varied by altering the ligand set used in the coupling chemistry. Experimental and computational observations are discussed.

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.

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-β-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 β-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.

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-β-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-β-lactams. Computational studies have provided insight into the origin of the complementary C─C cleavage processes.

The mechanism of permanganate-mediated dual C-H oxidation of complex diketopiperazines has been examined with density functional theory computations. The products of these oxidations are enabling intermediates in the synthesis of structurally diverse ETP natural products. We evaluated, for the first time, the impact of ion-pairing and aggregation states of the permanganate ion and counter-cations, such as bis(pyridine)-silver(I) (Ag+) and tetra- n-butylammonium (TBA+), on the C-H oxidation mechanism. The C-H abstraction occurs through an open shell singlet species, as noted previously, followed by O-rebound and a competing OH-rebound pathway. The second C-H oxidation proceeds with a second equivalent of oxidant with lower free energy barriers than the first C-H oxidation due to directing effects and the generation of a more reactive oxidant species after the first C-H oxidation. The success and efficiency of the second C-H oxidation are found to be critically dependent on the presence of an ion-paired oxidant. We used the developed mechanistic knowledge to rationalize an experimentally observed oxidation pattern for C3-indole-substituted diketopiperazine (+)-5 under optimal oxidation conditions: namely, the formation of diol (-)-6 as a single diastereomer and lack of the ketone products. We proposed two factors that may impede the ketone formation: (i) the conformational flexibility of the diketopiperazine ring, and (ii) hindrance of this site, making it less accessible to the ion-paired oxidant species.

C-H functionalization represents a promising approach for the synthesis of complex molecules. Instead of relying on modifying the functional groups present in a molecule, the synthetic sequence is achieved by carrying out selective reactions on the C-H bonds, which traditionally would have been considered to be the unreactive components of a molecule. A major challenge is to design catalysts to control both the site- and stereoselectivity of the C-H functionalization. We have been developing dirhodium catalysts with different selectivity profiles in C-H functionalization reactions with donor/acceptor carbenes as reactive intermediates. Here we describe a new dirhodium catalyst capable of the functionalization of non-activated primary C-H bonds with high levels of site selectivity and enantioselectivity.

Herein, we report the Cu‐complex catalyzed, native functional group‐assisted, and TFA/NMF additives promoted (phenylsulfonyl)difluoromethylation of vinylic C(sp2)−H bond of acrylamides. Using our in‐home designed reagent, this reaction enables the construction of the C(sp2)−CF2SO2Ph bond from simple C−H bond activation by copper catalysis under mild reaction conditions with total Z‐selectivity. The versatility of utilized fluorinated group was illustrated by its conversion into value‐added CF2 moieties as well as the remarkable =CHF residue. The performed experimental and computational mechanistic studies enabled to identify the true nature of active catalyst and substrate, as well as establish critical roles of TFA and NMF additives. In this reaction, the TFA acts as a promoter of the much‐needed CuII/CuII→CuIII/CuI disproportionation, while the NMF facilitates the following ligand exchange and C−C coupling processes. We ruled out the generation of radical intermediates and established the C−H activation to be irreversible and the rate‐determining step of the entire process. [ABSTRACT FROM AUTHOR]

Carbon-hydrogen (C-H) bonds have long been considered unreactive and are inert to traditional chemical reagents, yet new methods for the transformation of these bonds are continually being developed.sup.1-9. However, it is challenging to achieve such transformations in a highly selective manner, especially if the C-H bonds are unactivated.sup.10 or not adjacent to a directing group.sup.11-13. Catalyst-controlled site-selectivity--in which the inherent reactivities of the substrates.sup.14 can be overcome by choosing an appropriate catalyst--is an appealing concept, and substantial effort has been made towards catalyst-controlled C-H functionalization.sup.6,15-17, in particular methylene C-H bond functionalization. However, although several new methods have targeted these bonds in cyclic alkanes, the selectivity has been relatively poor.sup.18-20. Here we illustrate an additional level of sophistication in catalyst-controlled C-H functionalization, whereby unactivated cyclohexane derivatives can be desymmetrized in a highly site- and stereoselective manner through donor/acceptor carbene insertion. These studies demonstrate the potential of catalyst-controlled site-selectivity to govern which C-H bond will react, which could enable new strategies for the production of fine chemicals.Unactivated cyclohexane derivatives can be desymmetrized by site- and stereoselective C-H functionalization using carbene-insertion chemistry., Author(s): Jiantao Fu [sup.1] , Zhi Ren [sup.1] , John Bacsa [sup.1] , Djamaladdin G. Musaev [sup.1] [sup.2] , Huw M. L. Davies [sup.1] Author Affiliations:(1) Department of Chemistry, Emory [...]

Author(s): Kuangbiao Liao [1]; Thomas C. Pickel [1]; Vyacheslav Boyarskikh [1]; John Bacsa [1]; Djamaladdin G. Musaev [2]; Huw M. L. Davies (corresponding author) [1] The synthesis of complex organic [...]

Radical enhanced intersystem crossing (EISC) of organic chromophores is an important approach to generate a long-lived triplet state for various electronic and optoelectronic applications. However, structural factors and design rules to promote EISC are not entirely clear. In this work, we report a series of boron dipyrromethene (BODIPY) derivatives covalently linked with a 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO) radical with varying distances and topologies. We show that the incorporation of the TEMPO radical to BODIPY results in strong fluorescence quenching by up to 85% as a result of EISC and enhanced internal conversion. In BDP-2AR [2-(4-methyleneamino-TEMPO) BODIPY], a dyad with the shortest BODIPY–TEMPO through-bond distance, we observe the fastest EISC rate (τisc = 1.4 ns) and the longest triplet excited state lifetime (τT = 32 µs) compared to other distance and geometry variations. Contrary to previous reports and a general presumption, the BODIPY–TEMPO through-bond distance in this system does not play a significant role on the triplet formation rate and yield. Density functional theory suggests a folding of the TEMPO radical to form a sandwich-like structure with a BODIPY ring that leads to a decrease in the through-space distance, providing a new and an interesting insight for the radical enhanced intersystem. [ABSTRACT FROM AUTHOR]

The idea of carbon-hydrogen functionalization, in which C-H bonds are modified at will, represents a paradigm shift in the standard logic of organic synthesis; here, dirhodium catalysts are used to achieve highly site-selective, diastereoselective and enantioselective C-H functionalization of n-alkanes and terminally substituted n-alkyl compounds. Functionalization of unactivated C-H bonds Organic synthesis has traditionally relied heavily on the introduction and manipulation of functional groups, such as carbon-oxygen or carbon-halogen bonds. Much current research is focused on a potentially powerful alternative strategy in which carbon-hydrogen bonds, normally much less reactive and therefore resistant to functionalization, are somehow persuaded to be more easily modified. These authors report that it is possible to selectively functionalize an unactivated C-H bond by the use of well-defined catalysts to control the site selectivity, without the need for a directing or anchoring group present in the molecule. They use dirhodium catalysts to achieve diastereoselective and enantioselective C-H functionalization of n-alkanes and terminally substituted n-alkyl compounds. The reactions proceed in high yield and can be carried out on substrates containing other functional groups such as halides, silanes, and esters. The laboratory synthesis of complex organic molecules relies heavily on the introduction and manipulation of functional groups, such as carbon-oxygen or carbon-halogen bonds; carbon-hydrogen bonds are far less reactive and harder to functionalize selectively. The idea of C-H functionalization, in which C-H bonds are modified at will instead of the functional groups, represents a paradigm shift in the standard logic of organic synthesis.sup.1,2,3. For this approach to be generally useful, effective strategies for site-selective C-H functionalization need to be developed. The most practical solutions to the site-selectivity problem rely on either intramolecular reactions.sup.4 or the use of directing groups within the substrate.sup.5,6,7,8. A challenging, but potentially more flexible approach, would be to use catalyst control to determine which site in a particular substrate would be functionalized.sup.9,10,11. Here we describe the use of dirhodium catalysts to achieve highly site-selective, diastereoselective and enantioselective C-H functionalization of n-alkanes and terminally substituted n-alkyl compounds. The reactions proceed in high yield, and functional groups such as halides, silanes and esters are compatible with this chemistry. These studies demonstrate that high site selectivity is possible in C-H functionalization reactions without the need for a directing or anchoring group present in the molecule., Author(s): Kuangbiao Liao [sup.1] , Solymar Negretti [sup.1] , Djamaladdin G. Musaev [sup.2] , John Bacsa [sup.1] , Huw M. L. Davies [sup.1] Author Affiliations: (1) Department of Chemistry, Emory [...]

Transition metal‐catalyzed C−H bond oxidation of free carboxylic acid stands as an economic, selective, and efficient strategy to generate lactones, hydroxylated products, and acetoxylated products and attracts much of the chemists' attention. Herein, we performed a density functional theory study on the mechanism and selectivity in Pd‐catalyzed and MPAA ligand‐enabled C−H bond acetoxylation reaction. It was found that the ligand, base, and substrate are important in determining the reaction mechanism and the selectivity. The acetic anhydride additive is critical in leading the reaction to be acetoxylation, instead of the lactonization, through a facile σ‐bond metathesis mechanism that leads to the Pd‐OAc in‐termediate. Our study sheds light on the further development of transition metal‐catalyzed C−H bond oxidation reactions. [ABSTRACT FROM AUTHOR]