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.

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.

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).

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.

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.

Photochemical O-H Functionalization of Aryldiazoacetates with Phenols via Proton Transfer.

In this work, we report a thorough investigation of the reaction of phenols with aryldiazoacetates. Mechanistic studies using different spectroscopic methods and theoretical calculations suggest a hydrogen bond between phenol and aryldiazoacetates, which can be modulated by the phenol acidity. The pKA of phenol and therefore the hydrogen bond plays an important role in a subsequent photoinduced proton transfer reaction to give the formal O-H functionalization product of phenols.

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.

Gold-Catalyzed Carbazolation Reactions of Alkynes.

Herein, we report on a Au(I)-catalyzed reaction of alkynes with carbazoles that enables a one-step synthesis of vinyl carbazoles that are important molecules for applications as photoluminescent materials. This reaction proceeds under mild conditions at room temperature, without the need of external bases, and can be employed to a variety of aromatic and aliphatic alkynes in monohydroamination and poly-hydroamination reactions. We conclude with photophysical studies of the vinyl carbazole products, which feature distinct fluorescence properties.

C-H Functionalization via Iron-Catalyzed Carbene-Transfer Reactions.

The direct C-H functionalization reaction is one of the most efficient strategies by which to introduce new functional groups into small organic molecules. Over time, iron complexes have emerged as versatile catalysts for carbine-transfer reactions with diazoalkanes under mild and sustainable reaction conditions. In this review, we discuss the advances that have been made using iron catalysts to perform C-H functionalization reactions with diazoalkanes. We give an overview of early examples employing stoichiometric iron carbene complexes and continue with recent advances in the C-H functionalization of C(sp2)-H and C(sp3)-H bonds, concluding with the latest developments in enzymatic C-H functionalization reactions using iron-heme-containing enzymes.

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.

Photoinduced Proton-Transfer Reactions for Mild O-H Functionalization of Unreactive Alcohols.

Hexafluoroisopropanol is typically considered as an unreactive solvent and not as a reagent in organic synthesis. Herein, we report on a mild and efficient photochemical reaction of aryl diazoacetates with hexafluoroisopropanol that enables, under stoichiometric reaction conditions, the synthesis of fluorinated ethers in excellent yield. Mechanistic studies indicate there is a preorganization of hexafluoroisopropanol and the diazoalkane acts as an unreactive hydrogen-bonding complex. Only after photoexcitation does this complex undergo a protonation-substitution reaction to the reaction product. Investigations on the applicability of this photochemical transformation show that a broad variety of acidic alcohols can be subjected to this transformation and thus demonstrate the feasibility of this concept for O-H functionalization reactions (54 examples, up to 98 % yield).

Rhodium catalysed synthesis of seleno-ketals via carbene transfer reactions of diazoesters.

Herein, we report on rhodium catalysed carbene transfer reactions of diazoesters with diselenides that result in the formal insertion reaction of the carbene fragment into the Se-Se bond to give seleno-ketals in up to 96% yield (35 examples) via an ionic mechanism.

Rhodium-Catalyzed Carbene Transfer Reactions for Sigmatropic Rearrangement Reactions of Selenium Ylides.

The rearrangement of selenium ylides is even today almost unexplored, although it would provide access to important organoselenium compounds with broad downstream applications. In this report, the first systematic study of sigmatropic rearrangement reactions of selenium ylides using a simple rhodium catalyst with catalyst loadings as low as 0.01 mol % is described. Selenium oxide pyrolysis of the rearrangement products gives access to important 1,1-disubstituted butadienes.

Photochemical ring expansion reactions: synthesis of tetrahydrofuran derivatives and mechanism studies.

The reaction mechanism of oxygen and sulfur ylide mediated rearrangements is even today a matter of debate. In this report, we describe ring expansion reactions of oxetane and thietane heterocycles that allow probing the underlying reaction mechanism under metal-free, photochemical conditions. This ring expansion proves highly efficient and allows the synthesis of tetrahydrofuran and thiolane heterocycles under mild and operationally simple reaction conditions. These studies reveal marked differences in the stereoselectivity of the ring expansion of oxygen or sulfur ylides, which were further investigated computationally. DFT calculations show that carbenes react under ylide formation and that the corresponding ring expansion reactions proceed via a diradical pathway. The different bond lengths in free oxygen or sulfur ylide intermediates cause the distinctive stereochemical outcome.