C-H Functionalization of Heterocycles with Triplet Carbenes by means of an Unexpected 1,2-Alkyl Radical Migration.

The C-H functionalization of indole heterocycles constitutes a key strategy to leverage the synthesis of endogenous signaling molecules such as tryptamine or tryptophol. Herein, we report on the photocatalytic reaction of ethyl diazoacetate with indole, which shows an unusual solvent dependency. While C2-functionalization occurs under protic conditions, the use of aprotic solvents leads to a complete reversal of selectivity and exclusive C3-functionalization occurs. To rationalize for this unexpected reactivity switch, we have conducted detailed theoretical and experimental studies, which suggest the participation of a triplet carbene intermediate that undergoes initial C2-functionalization. A distinct cationic [1,2]-alkyl radical migration then leads to formation of C3-functionalized indole. We conclude with the application of this photocatalytic reaction to access oxidized tryptophol derivatives including gram-scale synthesis and derivatization reactions.

Azoxy Compounds-From Synthesis to Reagents for Azoxy Group Transfer Reactions.

The azoxy functional group is an important structural motif and represents the formally oxidized counterpart of the azo group. Azoxy compounds find numerous applications ranging from pharmaceuticals to functional materials, yet their synthesis remains underdeveloped with a main focus on the formation symmetric azoxy compounds. To overcome challenges in the synthesis of such unsymmetric azoxy compounds, we designed a process employing readily accessible nitroso compounds and iminoiodinanes. This method builds on the use of visible light irradiation to generate a triplet nitrene from iminoiodinanes, which is trapped by nitroso arenes to give access to sulfonyl-protected azoxy compounds with a good substrate scope and functional group tolerance. We further describe two applications of these sulfonyl-protected azoxy compounds as radical precursors in synthesis, where the whole azoxy group can be transferred and employed in C(sp3 )-H functionalization of ethers or 1,2-difunctionalization of vinyl ethers. All of the reactions occurred at room temperature under visible light irradiation without the addition of any photoredox catalysts and additives. Control experiments, mechanism investigations, and DFT studies well explained the observed reactivity.

Carbene Formation or Reduction of the Diazo Functional Group? An Unexpected Solvent-Dependent Reactivity of Cyclic Diazo Imides.

The control of the reactivity of diazo compounds is commonly achieved by the choice of a suitable catalyst, e.g. via stabilization of singlet carbenes or radical intermediates. Herein, we report on the light-promoted reactivity of cyclic diazo imides with thiols, where the choice of solvent results in two fundamentally different reaction pathways. In dichloromethane (DCM), a carbene is formed initially and engages in a cascade C-H functionalization/thiolation reaction to deliver indane-fused pyrrolidines in good to excellent yields. When switching to acetonitrile solvent, the carbene pathway is shut down and an unusual reduction of the diazo compound occurs under otherwise identical reaction conditions, where the aryl thiol acts as reductant. A combined set of experimental and computational studies was carried out to obtain mechanistic understanding and to support that indane formation proceeds via the insertion of a triplet carbene, while the reduction of diazo imides proceeds via an electron transfer process.

Photoredox-Enabled Self-(3+2) Cyclization of Vinyldiazo Reagents: Synthesis of Cyclopentenyl α-Diazo Compounds.

A photocatalytic self-(3+2) cycloaddition of vinyldiazo compounds is described, which provides cyclopentene derivatives with conservation of one diazo functional group. Experimental insights and density functional theory indicate that the reaction is triggered by an unusual single electron oxidation of vinyldiazo compounds, while the photolysis for the generation of free carbene species is not involved. The synthetic applications of the resulting cyclopentenyl α-diazo compounds were demonstrated based on the rich chemistry of the diazo functional group.

Rhodium-Catalyzed C-H Methylation and Alkylation Reactions by Carbene-Transfer Reactions.

In this combined computational and experimental study, the C-H functionalization of 2-phenyl pyridine with diazoalkanes was investigated. Initial evaluation by computational methods allowed the evaluation of different metal catalysts and diazoalkanes and their compatibility in this C-H functionalization reaction. With these findings, suitable reaction conditions for the C-H methylation reactions were quickly identified by using highly reactive TMS diazomethane and C-H alkylation reactions with donor/acceptor diazoalkanes, which is applied to a broad scope on alkylation reactions of 2-aryl pyridines with TMS diazomethane and donor/acceptor diazoalkane (51 examples, up to 98 % yield).

Proton or Carbene Transfer? On the Dark and Light Reaction of Diazoalkanes with Alcohols.

The formal alkylation reaction of OH groups with diazoalkanes under catalyst-free reaction conditions finds broad application in organic synthesis. However, even today, this reaction is mainly limited to the use of diazomethane as reaction partner. In this combined experimental and theoretical study, we aim at a fundamental understanding of the reaction of diazoalkanes with alcohols to make this transformation amenable to a generalized approach towards formal alkylation reactions of alcohols with diazoalkanes. Experimental and theoretical studies suggest a direct proton transfer only in exceptional cases. In a more general setting, such O-H functionalization proceed both under dark and photochemical conditions via a key hydrogen-bonded singlet carbene intermediate that undergoes a protonation-addition mechanism. We conclude with applications of this approach in O-H functionalization reactions of alcohols, including simple fluorinated, halogenated and aliphatic alcohols and showcase functional-group tolerance of this method in the reaction of biologically active and pharmaceutically relevant alcohols.

A Computational Study on the Photochemical O-H Functionalization of Alcohols with Diazoacetates.

In this computational study, we provide a detailed analysis of the underlying reaction mechanism and show that a singlet carbene is initially formed. Depending on the pKA of the alcohol, this singlet carbene can engage in direct protonation or enol formation to yield the O-H functionalization product. On the contrary, propargylic alcohols take up a dual role and form a complex with the carbene intermediate that leads to facile cyclopropenation reactions.

Visible-Light-Induced, Single-Metal-Catalyzed, Directed C-H Functionalization: Metal-Substrate-Bound Complexes as Light-Harvesting Agents.

C-H functionalization represents one of the most rapidly advancing areas in organic synthesis and is regarded as one of the key concepts to minimize the ecological and economic footprint of organic synthesis. The ubiquity and low reactivity of C-H bonds in organic molecules, however, poses several challenges, and often necessitates harsh reaction conditions to achieve this goal, although it is highly desirable to achieve C-H functionalization reactions under mild conditions. Recently, several reports uncovered a conceptually new approach towards C-H functionalization, where a single transition-metal complex can be used as both the photosensitizer and catalyst to promote C-H bond functionalization in the absence of an exogeneous photosensitizer. In this Minireview, we will provide an overview on recent achievements in C-H functionalization reactions, with an emphasis on the photochemical modulation of the reaction mechanism using such catalysts.

Photocatalytic gem-Difluoroolefination Reactions by a Formal C-C Coupling/Defluorination Reaction with Diazoacetates.

The photolysis of diazoalkanes to conduct singlet carbene transfer reactions of colored diazoalkanes has recently attracted significant interest in organic synthesis. Herein, we describe a photocatalytic approach that allows the access of triplet carbene intermediates via energy transfer to conduct highly efficient gem-difluoroolefination reactions with α-trifluoromethyl styrenes. The use of a tertiary amines proved pivotal to unlock this unusual reaction pathway and to prevent undesired cyclopropanation pathways. The amine further facilitates the ultimate abstraction of fluoride to yield gem-difluoroolefins (43 examples, up to 88 % yield), which is supported by experimental and theoretical mechanistic studies. We explored this synthesis method with a broad substrate scope, ranging from simple olefins and heterocyclic olefins towards the decoration of pharmaceutically relevant building blocks.

Hydrogen Bonding Networks Enable Brønsted Acid-Catalyzed Carbonyl-Olefin Metathesis.

Synthetic chemists have learned to mimic nature in using hydrogen bonds and other weak interactions to dictate the spatial arrangement of reaction substrates and to stabilize transition states to enable highly efficient and selective reactions. The activation of a catalyst molecule itself by hydrogen-bonding networks, in order to enhance its catalytic activity to achieve a desired reaction outcome, is less explored in organic synthesis, despite being a commonly found phenomenon in nature. Herein, we show our investigation into this underexplored area by studying the promotion of carbonyl-olefin metathesis reactions by hydrogen-bonding-assisted Brønsted acid catalysis, using hexafluoroisopropanol (HFIP) solvent in combination with para-toluenesulfonic acid (pTSA). Our experimental and computational mechanistic studies reveal not only an interesting role of HFIP solvent in assisting pTSA Brønsted acid catalyst, but also insightful knowledge about the current limitations of the carbonyl-olefin metathesis reaction.

Photoinduced Palladium-Catalyzed Dicarbofunctionalization of Terminal Alkynes.

Herein, a conceptually distinct approach was developed that allowed for the dicarbofunctionalization of alkynes at room temperature using simple, bench-stable alkyl iodides and a second molecule of alkyne as coupling partner. Specifically, the photochemical activation of palladium complexes enabled this strategic dicarbofunctionalization via addition of alkyl radicals from secondary and tertiary alkyl iodides and formation of an intermediate palladium vinyl complex that could undergo subsequent Sonogashira reaction with a second alkyne molecule. This alkylation-alkynylation sequence allowed the one-step synthesis of 1,3-enynes including heteroarenes and biologically active compounds with high efficiency without exogenous photosensitizers or oxidants and now opens up pathways towards cascade reactions via photochemical palladium catalysis.

Recent Perspectives on Rearrangement Reactions of Ylides via Carbene Transfer Reactions.

Among the available methods to increase the molecular complexity, sigmatropic rearrangements occupy a distinct position in organic synthesis. Despite being known for over a century sigmatropic rearrangement reactions of ylides via carbene transfer reaction have only recently come of age. Most of the ylide mediated rearrangement processes involve rupture of a σ-bond and formation of a new bond between π-bond and negatively charged atom followed by simultaneous redistribution of π-electrons. This minireview describes the advances in this research area made in recent years, which now opens up metal-catalyzed enantioselective sigmatropic rearrangement reactions, metal-free photochemical rearrangement reactions and novel reaction pathways that can be accessed via ylide intermediates.

Multi C-H Functionalization Reactions of Carbazole Heterocycles via Gold-Catalyzed Carbene Transfer Reactions.

Herein we describe a multiple C-H functionalization reaction of carbazole heterocycles with diazoalkanes. We show that gold catalysts play a distinct role in enabling a multiple C-H functionalization reaction to introduce up to six carbene fragments onto molecules containing multiple carbazole units or to link multiple carbazole units into a single molecule. A one-pot stepwise approach enables the introduction of two different carbene fragments to allow orthogonal deprotection and straightforward derivatization.

Visible light-promoted reactions with diazo compounds: a mild and practical strategy towards free carbene intermediates.

Carbenes are important intermediates in organic chemistry and have been widely applied in various types of organic reactions, ranging from cycloaddition reactions and sigmatropic rearrangements to C-H functionalizations, thus allowing the rapid construction of densely functionalized molecules. Over the past decades, remarkable progress has been achieved in metal-catalyzed carbene transfer reactions. Nevertheless, realizing these transformations under milder and/or greener conditions is still highly desirable. Only recently, visible light-promoted carbene transfer reactions of diazo compounds via free carbene intermediates have emerged as a practical, mild and powerful tool. In this tutorial review, we summarize the latest advances in the area, aiming at providing a clear overview on reaction design, mechanistic scenarios and potential future developments.

Photochemical Carbene Transfer Reactions of Aryl/Aryl Diazoalkanes-Experiment and Theory*.

Controlling the reactivity of carbene intermediates is a key parameter in the development of selective carbene transfer reactions and is usually achieved by metal complexes via singlet metal-carbene intermediates. In this combined experimental and computational studies, we show that the reactivity of free diaryl carbenes can be controlled by the electronic properties of the substituents without the need of external additives. The introduction of electron-donating and -withdrawing groups results in a significant perturbation of singlet triplet energy splitting of the diaryl carbene intermediate and of activation energies of consecutive carbene transfer reactions. This strategy now overcomes a long-standing paradigm in the reactivity of diaryl carbenes and allows the realization of highly chemoselective carbene transfer reactions with alkynes. We could show that free diaryl carbenes can be readily accessed via photolysis of the corresponding diazo compounds and that these carbenes can undergo highly chemoselective cyclopropenation, cascade, or C-H functionalization reactions. Experimental and theoretical mechanistic analyses confirm the participation of different carbene spin states and rationalize for the observed reactivity.

Diazoacetonitrile (N2 CHCN): A Long Forgotten but Valuable Reagent for Organic Synthesis.

Diazoacetonitrile (N2 CHCN) is a small reactive diazoalkane. It has been synthesized for the first time already in 1898 by Theodor Curtius, however, did not gain much recognition in organic synthesis until recently. Only in 2015, after introduction of in situ and flow protocols for the safe generation of diazoacetonitrile, it started gaining popularity. In this minireview, the synthetic properties and applications of this valuable reagent are discussed.

Stoichiometric Photochemical Carbene Transfer by Bamford-Stevens Reaction.

The photolysis of diazoalkanes is a timely strategy to conduct carbene-transfer reactions under mild and metal-free reaction conditions, and has developed as an important alternative to conventional metal-catalyzed carbene-transfer reactions. One of the major limitations lies within the rapidly occurring side reaction of the carbene intermediate with remaining diazoalkane molecules that result in the use of an excess of the reaction partner and thus impacts on the reaction efficiency. Herein, we describe a protocol that takes advantage of the in situ generation of donor-acceptor diazoalkanes by Bamford-Stevens reaction. Following this strategy, the concentration of the diazoalkane reaction partner can be minimized to reduce unwanted side reactions and to now conduct photochemical carbene transfer reactions under stoichiometric reaction conditions. We have explored this approach in the C-H and N-H functionalization and cyclopropanation reaction of N-heterocycles and could demonstrate the applicability of this method in 51 examples.

Catalytic Synthesis of Trifluoromethyl Cyclopropenes and Oligo-Cyclopropenes.

The synthesis of trifluoromethylated cyclopropenes is often associated with important applications in drug discovery and functional materials. In this report, we describe the use of readily available chiral rhodium(II) catalysts for a highly efficient asymmetric cyclopropenation reaction of fluorinated donor-acceptor diazoalkanes with a broad variety of aliphatic and aromatic alkynes. Further studies highlight the unique reactivity of fluorinated donor-acceptor diazoalkanes in the synthesis of oligo-cyclopropenes. Subsequent C-H functionalization of trifluoromethyl cyclopropenes furnishes densely substituted cyclopropene frameworks and also allows the alternative synthesis of bis-cyclopropenes.

Metal-Free Insertion Reactions of Silanes with Aryldiazoacetates.

Si-H insertion reactions represent an important method for the efficient construction of new C-Si bonds, and typically, they are conducted in the presence of metal catalysts. In this report, we describe a photochemical approach that now allows the insertion of carbenes into the Si-H bond of silanes under metal-free reaction conditions (23 examples, up to 83% yield).

Gold-Catalyzed Sigmatropic Rearrangement Reactions via Carbene Transfer Reactions.

Sigmatropic rearrangements are an important fundamental toolbox in organic synthesis to access complex molecular fragments. Yet, the rearrangement reactions of onium ylides via gold catalyzed carbene transfer reactions are relatively unexplored. Herein, we describe a gold-catalyzed sigmatropic rearrangement of sulfonium and selenium ylides (39 examples, up to 99% yield). Furthermore, we report on the limitations of sigmatropic rearrangement reactions of aryl allyl anilines, which deliver exclusively C-H functionalized products.