Selective functionalization of ubiquitous C(sp)-H bonds using visible light is a highly challenging yet desirable goal in organic synthesis. The development of such processes relies on both rational design and serendipitous discoveries from innovative tools such as screening technologies. Applying a mechanism-based screening strategy, we herein report photoredox-mediated hydrogen atom transfer catalysis for the selective activation of otherwise unactivated C(sp)-H bonds, followed by their trifluoromethylthiolation, which has high potential as a late-stage functionalization tool. The generality of this method is exhibited through incorporation of the trifluoromethylthio group in a large number of C(sp)-H bonds with high selectivity without the need for an excess of valuable substrate.

Dedicated to Professor Dieter Enders on the occasion of his 65th birthdaySince the first isolation and characterization of stable Nheterocyclic carbenes (NHCs) by Arduengo and co-workers in 1991, [1] these compounds have attracted great interest in various fields of chemistry. As molecules with divalent carbon atoms, NHCs (e.g., 1-3, Scheme 1) are not only of theoretical interest [2] but also of practical relevance as ligands in metal complexes [3] and as nucleophilic organocatalysts.[4]Despite the extensive use of NHCs as organocatalysts, quantitative investigations of their catalytic activities are rare.[5] Since the relative reactivities of different nucleophiles towards electrophiles correlate only poorly [6] with the corresponding Brønsted basicities (pK aH ), [7] we have recently employed benzhydrylium ions and structurally related quinone methides 4 (Table 1) with widely varying reactivities as reference compounds [8] to compare the nucleophilicities and Lewis basicities of various organocatalysts. [9] It was demonstrated that the rates of the reactions of carbocations and Michael acceptors with n-, p-, and snucleophiles can be described by the linear free-energy relationship in Equation (1), where electrophiles are charac-terized by one solvent-independent electrophilicity parameter E, and nucleophiles are characterized by two solventdependent parameters, the nucleophilicity parameter N, and a nucleophile-specific sensitivity parameter s N .[8]We now report on the use of the benzhydrylium methodology for characterizing the nucleophilicities of three representative NHCs (1 d, 2 d, and 3 e) and for comparing them with other nucleophilic organocatalysts.Representative combinations of the carbenes 1 d, 2 d, and 3 e with the reference electrophiles 4 a or 4 i showed the course of the reactions (Scheme 2). The products formed from 1 d and 2 d and the quinone methide 4 i in THF were subsequently treated with one equivalent of HBF 4 to generate the salts 5 a,b, which were isolated and characterized as described in the Supporting Information. Addition of the Enders carbene 3 e to the blue solution of the benzhydrylium tetrafluoroborate 4 a-BF 4 in THF at ambient temperature led to decolorization and formation of the adduct 5 c, which has been isolated and characterized by X-ray crystallography.

Equilibria for the reactions of benzhydryl cations (Ar2CH(+)) with phosphines, tert-amines, pyridines, and related Lewis bases were determined photometrically in CH2Cl2 and CH3CN solution at 20 °C. The measured equilibrium constants can be expressed by the sum of two parameters, defined as the Lewis Acidity (LA) of the benzhydrylium ions and the Lewis basicity (LB) of the phosphines, pyridines, etc. Least-squares minimization of log K = LA + LB with the definition LA = 0 for (4-MeOC6H4)2CH(+) gave a Lewis acidity scale for 18 benzhydrylium ions covering 18 orders of magnitude in CH2Cl2 as well as Lewis basicities (with respect to C-centered Lewis acids) for 56 bases. The Lewis acidities correlated linearly with the quantum chemically calculated (B3LYP/6-311++G(3df,2pd)//B3LYP/6-31G(d,p) level) methyl anion affinities of the corresponding benzhydrylium ions, which can be used as reference compounds for characterizing a wide variety of Lewis bases. The equilibrium measurements were complemented by isothermal titration calorimetry studies. Rates of SN1 solvolyses of benzhydryl chlorides, bromides, and tosylates derived from E(13-33)(+), i.e., from highly reactive carbocations, correlate excellently with the corresponding Lewis acidities and the quantum chemically calculated methyl anion affinities. This correlation does not hold for solvolyses of derivatives of the better stabilized amino-substituted benzhydrylium ions E(1-12)(+). In contrast, the correlation between electrophilic reactivities and Lewis acidities (or methyl anion affinities) is linear for all donor-substituted benzhydrylium ions E(1-21)(+), while the acceptor-substituted benzhydrylium ions E(26-33)(+) react more slowly than expected from their thermodynamic stabilities. The boundaries of linear rate-equilibrium relationships were thus defined.

Covalent organic frameworks (COFs) are promising hosts in heterogeneous catalysis. Herein, we report a dual metalation strategy in a single two-dimensional-COF TpBpy for performing a variety of C–N cross-coupling reactions. [Ir­(ppy)2(CH3CN)2]­PF6 [ppy = 2-phenylpyridine], containing two labile CH3CN groups, and NiCl2 are used as iridium and nickel-metal precursors, respectively, for postsynthetic decoration of the TpBpy COF. Moving from the traditional approach, we focus on the COF-backbone host for visible-light-mediated nickel-catalyzed C–N coupling reactions. The controlled metalation and recyclability without deactivation of both catalytic centers are unique with respect to previously reported coupling strategies. We performed various photoluminescence, electrochemical, kinetic, and Hammett correlation studies to understand the salient features of the catalyst and reaction mechanism. Furthermore, theoretical calculations delineated the feasibility of electron transfer from the Ir center to the Ni center inside the confined pore of the TpBpy COF. The dual metal anchoring within the COF backbone prevented nickel-black formation. The developed protocol enables selective and reproducible coupling of a diverse range of amines (aryl, heteroaryl, and alkyl), carbamides, and sulfonamides with electron-rich, neutral, and poor (hetero) aryl iodides up to 94% isolated yield. The reaction can also be performed on a gram scale. Furthermore, to establish the practical implementation of this approach, we have applied the synthetic strategy for the late-stage diversification of the derivatives of ibuprofen, naproxen, gemfibrozil, helional, and amino acids. The methodology could also be applied to synthesize pharmacophore N,5-diphenyloxazol-2-amine and Food and Drug Administration-approved drugs, including flufenamic acid, flibanserin, and tripelennamine.

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Being the third most abundant transition metal in the Earth’s crust (after iron and titanium) and less toxic, reactions catalyzed by manganese are becoming very important. A large number of manganese complexes have been synthesized using bidentate and tridentate ligands. Such manganese complexes display excellent catalytic activities for various important organic transformations, such as hydrogenation, dehydrogenation, dehydrogenative coupling, transfer hydrogenation reactions, etc. In this short review, recent developments of such manganese-catalyzed reactions are presented.1 Introduction2 Well-Defined Manganese-Complex-Catalyzed Hydrogenation Reactions2.1 Hydrogenation of Nitriles2.2 Hydrogenation of Aldehydes and Ketones2.3 Hydrogenation of Esters2.4 Hydrogenation of Amides2.5 Hydrogenation of Carbon Dioxide3 Manganese-Catalyzed Dehydrogenation Reactions3.1 Selective Dehydrogenation of Methanol3.2 Dehydrogenative N-Formylation of Amines by Methanol3.3 Dehydrogenative Coupling Reactions of Alcohols3.4 Imine Synthesis via Dehydrogenative Coupling of Alcohols and Amines3.5 Synthesis of N-Heterocycles via Dehydrogenative Coupling4 Manganese-Catalyzed Dehydrogenation–Hydrogenation Cascades4.1 N-Alkylation of Amines with Primary Alcohols4.2 α-Alkylation of Ketones with Primary Alcohols4.3 Transfer Hydrogenation of Ketones5 Conclusion

SummaryThe key steps in most organocatalytic cyclizations are the reactions of electrophiles with nucleophiles. Their rates can be calculated by the linear free-energy relationship log k(20 °C) = s N(E + N), where electrophiles are characterized by one parameter (E) and nucleophiles are characterized by the solvent-dependent nucleophilicity (N) and sensitivity (s N) parameters.Electrophilicity parameters in the range –10 < E < –5 were determined for iminium ions derived from cinnamaldehyde and common organocatalysts, such as pyrrolidines and imidazolidinones, by studying the rates of their reactions with reference nucleophiles. Iminium activated reactions of α,β-unsaturated aldehydes can, therefore, be expected to proceed with nucleophiles of 2 < N < 14, because such nucleophiles are strong enough to react with iminium ions but weak enough not to react with their precursor aldehydes. With the N parameters of enamines derived from phenylacetaldehyde and MacMillan’s imidazolidinones one can rationalize why only strong electrophiles, such as stabilized carbenium ions (–8 < E < –2) or hexachlorocyclohexadienone (E = –6.75), are suitable electrophiles for enamine activated reactions with imidazolidinones. Several mechanistic controversies concerning iminium and enamine activated reactions could thus be settled by studying the reactivities of independently synthesized intermediates.Kinetic investigations of the reactions of N-heterocyclic carbenes (NHCs) with benzhydrylium ions showed that they have similar nucleophilicities to common organocatalysts (e.g., PPh3, DMAP, DABCO) but are much stronger (100–200 kJ mol–1) Lewis bases. While structurally analogous imidazolylidenes and imidazolidinylidenes have comparable nucleophilicities and Lewis basicities, the corresponding deoxy Breslow intermediates differ dramatically in reactivity. The thousand-fold higher nucleophilicity of 2-benzylidene-imidazoline relative to 2-benzylidene-imidazolidine is explained by the gain of aromaticity during electrophilic additions to the imidazoline derivatives. O-Methylated Breslow intermediates are a hundred-fold less nucleophilic than deoxy Breslow intermediates.

Scheme 1. Mn-catalyzed hydrogen-autotransfer strategy for the a-alkylation of ketones with alcohols.