Contra-thermodynamic hydrogen atom abstraction in the selective C−H functionalization of trialkylamine N‑CH3 groups

We report a simple one-pot protocol that affords functionalization of N-CH3 groups in N-methyl-N,N-dialkylamines with high selectivity over N-CH2R or N-CHR2 groups. The radical cation DABCO+•, prepared in situ by oxidation of DABCO with a triarylaminium salt, effects highly selective and contra-thermodynamic C−H abstraction from N-CH3 groups. The intermediates that result react in situ with organometallic nucleophiles in a single pot, affording novel and highly selective homologation of N-CH3 groups. Chemoselectivity, scalability, and recyclability of reagents are demonstrated, and a mechanistic proposal is corroborated by computational and experimental results. The utility of the transformation is demonstrated in the late-stage site-selective functionalization of natural products and pharmaceuticals, allowing rapid derivatization for investigation of structure−activity relationships

An affordable, programmable and interactive continuous flow Photoreactor setup for undergraduate organic synthetic teaching labs

Photochemistry and continuous flow chemistry are synthetic technology platforms that have witnessed an increasing uptake by chemical industries interested in complex organic molecule synthesis. Simultaneously, automation and data science are prominent targets in organic synthesis and in chemical industries for streamlined workflows, meaning hardware-software interaction between operators and devices is crucial. Since undergraduate teaching labs at public-funded research Universities typically (i) lack budget for commercial, user-friendly continuous flow reactors and (ii) do not teach synthetic chemists how to program or interact with reactors, there is a disparity between the skills undergraduates are equipped with and the skills that future industries need. We report a teaching lab project where undergraduates assemble, program and execute a continuous flow photoreactor to realize a multigram-scale photoredox catalyzed oxidation reaction. A palladium-free synthetic access to the starting material was described to further cut costs. Not only does this exercise introduce useful skills in reactor design, programming and wet chemistry (both photochemical and thermal, both batch and flow), it also accommodates both the typical budget and afternoon timeslot (2-3 h) of a teaching lab and can be followed by thin-layer chromatography/color changes without necessarily requiring access to NMR facilities

Organophotocatalytic Mechanisms: Simplicity or Naïvety? Diverting Reactive Pathways by Modifications of Catalyst Structure, Redox States and Substrate Preassemblies

Photocatalysis is a powerful tool to assemble diverse chemical scaffolds, yet a bottleneck on its further development is the understanding of the multitude of possible pathways when practitioners rely only on oversimplified thermodynamic and optical factors. Recently, there is a growing number of studies in the field that exploit, inter alia, kinetic parameters and organophotocatalysts that are synthetically more programmable in terms of their redox states and opportunities for aggregation with a target substrate. Non-covalent interactions play a key role that enables access to a new generation of reactivities such as those of open-shell organophotocatalysts. In this review, we discuss how targeted structural and redox modifications influence the organophotocatalytic mechanisms together with their underlying principles. We also highlight the benefits of strategies such as preassembly and static quenching that overcome common reactivity issues (e. g., diffusion rate limits and energetic limits)

KOtBu : a privileged reagent for electron transfer reactions?

Many recent studies have used KOtBu in organic reactions that involve single electron transfer; in the literature, the electron transfer is proposed to occur either directly from the metal alkoxide or indirectly, following reaction of the alkoxide with a solvent or additive. These reaction classes include coupling reactions of halobenzenes and arenes, reductive cleavages of dithianes and SRN1 reactions. Direct electron transfer would imply that alkali metal alkoxides are willing partners in these electron transfer reactions, but the literature reports provide little or no experimental evidence for this. This paper examines each of these classes of reaction in turn, and contests the roles proposed for KOtBu; instead, it provides new mechanistic information that in each case supports the in situ formation of organic electron donors. We go on to show that direct electron transfer from KOtBu can however occur in appropriate cases, where the electron acceptor has a reduction potential near the oxidation potential of KOtBu, and the example that we use is CBr4. In this case, computational results support electrochemical data in backing a direct electron transfer reaction

Benzoates as photosensitization catalysts and auxiliaries in efficient, practical, light-powered direct C(sp3)–H fluorinations

Of the methods for direct fluorination of unactivated C(sp3)–H bonds, photosensitization of SelectFluor is a promising approach. Although many substrates can be activated with photosensitizing catalysts, issues remain that hamper fluorination of complex molecules. Alcohol- or amine-containing functional groups are not tolerated, fluorination regioselectivity follows factors endogenous to the substrate and cannot be influenced by the catalyst, and reactions are highly air-sensitive. We report that benzoyl groups serve as highly efficient photosensitizers which, in combination with SelectFluor, enable visible light-powered direct fluorination of unactivated C(sp3)–H bonds. Compared to previous photosensitizer architectures, the benzoyls have versatility to function both (i) as a photosensitizing catalyst for simple substrate fluorinations and (ii) as photosensitizing auxiliaries for complex molecule fluorinations that are easily installed and removed without compromising yield. Our auxiliary approach (i) substantially decreases the reaction's induction period, (ii) enables C(sp3)–H fluorination of many substrates that fail under catalytic conditions, (iii) increases kinetic reproducibility, and (iv) promotes reactions to higher yields, in shorter times, on multigram scales, and even under air. Observations and mechanistic studies suggest an intimate ‘assembly’ of auxiliary and SelectFluor prior/after photoexcitation. The auxiliary allows other EnT photochemistry under air. Examples show how auxiliary placement proximally directs regioselectivity, where previous methods are substrate-directed

Photocatalytic (Het)arylation of C(sp3)−H Bonds with Carbon Nitride

Polymeric graphitic carbon nitride materials have attracted significant interest in recent years and found applications in diverse light-to-energy conversions such as artificial photosynthesis, CO2 reduction or degradation of organic pollutants. However, their utilization in synthetic photocatalysis especially in the direct functionalization of C(sp3)−H bonds remains underexplored. Herein, we report mesoporous graphitic carbon nitride (mpg-CN) as a heterogeneous organic semiconductor photocatalyst for direct arylation of sp3 C−H bonds via a combination of hydrogen atom transfer and nickel catalysis. Our protocol has a broad synthetic scope (>70 examples including late-stage modification of densely functionalized bio-active molecules), is operationally simple, and shows high chemo- and regioselectivity. Facile separation and recycling of the mpg-CN catalyst in combination with its low preparation cost, innate photochemical stability and low toxicity are beneficial features overcoming typical shortcomings of homogeneous photocatalysis. Additionally, mechanistic investigations indicate that an unprecedented energy transfer process (EnT) from the organic semiconductor to the nickel complex is operating

Dual roles for potassium hydride in haloarene reduction : CSNAr and SET reduction via organic electron donors formed in benzene

Potassium hydride behaves uniquely and differently than sodium hydride towards aryl halides. Its reactions with a range of haloarenes, including designed 2,6-dialkylhaloarenes, were studied in THF and in benzene. In THF, evidence supports concerted nucleophilic aromatic substitution, CSNAr, and the mechanism originally proposed by Pierre et al. is now validated through DFT studies. In benzene, besides this pathway, strong evidence for single electron transfer chemistry is reported. Experimental observations and DFT studies lead us to propose organic super electron donor generation to initiate BHAS (base-promoted homolytic aromatic substitution) cycles. Organic donor formation originates from deprotonation of benzene by KH; attack on benzene by the resulting phenylpotassium generates phenylcyclohexadienylpotassium that can undergo (i) deprotonation to form an organic super electron donor or (ii) hydride loss to afford biphenyl. Until now, BHAS reactions have been triggered by reaction of a base, MOtBu (M = K, Na), with many different types of organic additive, all containing heteroatoms (N or O or S) that enhance their acidity and place them within range of MOtBu as a base. This paper shows that with the stronger base, KH, even a hydrocarbon (benzene) can be converted into an electron-donating initiator

One-pot functionalisation of N-substituted tetrahydroisoquinolines by photooxidation and tunable organometallic trapping of iminium intermediates

Nucleophilic trapping of iminium salts generated via oxidative functionalisation of tertiary amines is well established with stabilised carbon nucleophiles. The few reports of organometallic additions have limited scope of substrate and organometallic nucleophile. We report a novel, one-pot methodology that functionalises N-substituted tetrahydroisoquinolines by visible lightassisted photooxidation, followed by trapping of the resultant iminium ions with organometallic nucleophiles. This affords 1,2-disubstituted tetrahydroisoquinolines in moderate to excellent yields

Photosensitized direct C–H fluorination and trifluoromethylation in organic synthesis

The importance of fluorinated products in pharmaceutical and medicinal chemistry has necessitated the development of synthetic fluorination methods, of which direct C-H fluorination is among the most powerful. Despite the challenges and limitations associated with the direct fluorination of unactivated C-H bonds, appreciable advancements in manipulating the selectivity and reactivity have been made, especially via transition metal catalysis and photochemistry. Where transition metal catalysis provides one strategy for C-H bond activation, transition-metal-free photochemical C-H fluorination can provide a complementary selectivity via a radical mechanism that proceeds under milder conditions than thermal radical activation methods. One exciting development in C-F bond formation is the use of small-molecule photosensitizers, allowing the reactions i) to proceed under mild conditions, ii) to be user-friendly, iii) to be cost-effective and iv) to be more amenable to scalability than typical photoredox-catalyzed methods. In this review, we highlight photosensitized C-H fluorination as a recent strategy for the direct and remote activation of C-H (especially C(sp(3))-H) bonds. To guide the readers, we present the developing mechanistic understandings of these reactions and exemplify concepts to assist the future planning of reactions

Site-Selective C(sp3)–H Functionalizations Mediated by Hydrogen Atom Transfer Reactions via α-Amino/α-Amido Radicals

Amines and amides, as N-containing compounds, are ubiquitous in pharmaceutically-active scaffolds, natural products, agrochemicals, and peptides. Amides in nature bear a key responsibility for imparting three-dimensional structure, such as in proteins. Structural modifications to amines and amides, especially at their positions. to N, bring about profound changes in biological activity oftentimes leading to more desirable pharmacological profiles of small drug molecules. A number of recent developments in synthetic methodology for the functionalizations of amines and amides omit the need of their directing groups or pre-functionalizations, achieving direct activation of the otherwise relatively benign C(sp(3))-H bonds. to N. Among these, hydrogen atom transfer (HAT) has proven a very powerful platform for the selective activation of amines and amides to their alpha-amino and alpha-amido radicals, which can then be employed to furnish C-C and C-X (X = heteroatom) bonds. The abilities to both form these radicals and control their reactivity in a site-selective manner is of utmost importance for such chemistries to witness applications in late-stage functionalization. Therefore, this review captures contemporary HAT strategies to realize chemo- and regioselective amine and amide alpha-C(sp(3))-H functionalization, based on bond strengths, bond polarities, reversible HAT equilibria, traceless electrostatic-directing auxiliaries, and steric effects of in situ-generated HAT agents