Discovery of an α-amino C-H arylation reaction using the strategy of accelerated serendipity.

Introducing aryl- and heteroaryl moieties into molecular scaffolds are often key steps in the syntheses of natural products, drugs, or functional materials. A variety of cross-coupling methods have been well established, mainly using transition metal mediated reactions between prefunctionalized substrates and arenes or C-H arylations with functionalization in only one coupling partner. Although highly developed, one drawback of the established sp2-sp2 arylations is the required transition metal catalyst, often in combination with specific ligands and additives. Therefore, photoredox mediated arylation methods have been developed as alternative over the past decade. We begin our survey with visible light photo-Meerwein arylation reactions, which allow C-H arylation of heteroarenes, enones, alkenes, and alkynes with organic dyes, such as eosin Y, as the photocatalyst. A good number of examples from different groups illustrate the broad application of the reaction in synthetic transformations. While initially only photo-Meerwein arylation-elimination processes were reported, the reaction was later extended to photo-Meerwein arylation-addition reactions giving access to the photoinduced three component synthesis of amides and esters from alkenes, aryl diazonium salts, nitriles or formamides, respectively. Other substrates with redox-active leaving groups have been explored in photocatalyzed arylation reactions, such as diaryliodonium and triarylsulfonium salts, and arylsulfonyl chlorides. We discus some examples with their scope and limitations. The scope of arylation reagents for photoredox reactions was extended to aryl halides. The challenge here is the extremely negative reduction potential of aryl halides in the initial electron transfer step compared to, e.g., aryl diazonium or diaryliodonium salts. In order to reach reduction potentials over -2.0 V vs SCE two consecutive photoinduced electron transfer steps were used. The intermediary formed colored radical anion of the organic dye perylenediimide is excited by a second photon allowing the one electron reduction of acceptor substituted aryl chlorides. The radical anion of the aryl halide fragments under the loss of a halide ion and the aryl radical undergoes C-H arylation with biologically important pyrrole derivatives or adds to a double bond. Rhodamine 6G as an organic photocatalyst allows an even higher degree of control of the reaction. The dye is photoreduced in the presence of an amine donor under irradiation with green light (e.g., 530 nm), yielding its radical anion, which is a mild reducing reagent. The hypsochromic shift of the absorption of the rhodamine 6G radical anion toward blue region of the visible light spectrum allows its selective excitation using blue light (e.g., 455 nm). The excited radical anion is highly reducing and able to activate even bromoanisole for C-H arylation reactions, although only in moderate yield. Photoredox catalytic C-H arylation reactions are valuable alternatives to metal catalyzed reactions. They have an excellent functional group tolerance, could potentially avoid metal containing catalysts, and use visible light as a traceless reagent for the activation of arylating reagents.

Recent progress towards transition-metal-catalyzed arylative cyclization/annulation reactions with boronic acids

Detailed and generalized protocols are presented for the synthesis and subsequent purification of four palladium N-heterocyclic carbene complexes from benzimidazolium salts. Detailed and generalized protocols are also presented for testing the catalytic activity of such complexes in arylation and Suzuki-Miyaura cross-coupling reactions. Representative results are shown for the catalytic activity of the four complexes in arylation and Suzuki-Miyaura type reactions. For each of the reactions investigated, at least one of the four complexes successfully catalyzed the reaction, qualifying them as promising candidates for catalysis of many carbon-carbon bond-forming reactions. The protocols presented are general enough to be adapted for the synthesis, purification and catalytic activity testing of new palladium N-heterocyclic carbene complexes.

In recent years, diaryliodonium salts have been extensively exploited as green, efficient electrophilic arylation reagents in a large range of organic synthesis. These arylating reagents exhibit relatively high reactivity and good selectivity in many transformations. In this review, the synthetic methods towards diaryliodonium salts are described briefly, and the research progress in arylation reactions by using diaryliodoniums in C-C and carbonheteroatom bond formation, especially in enantioselective C-C bond formation and cascade reactions, in recent ten years is summarized and discussed in detail.

Despite significant progress in aliphatic decarboxylation, an efficient and general protocol for radical aromatic decarboxylation has lagged far behind. Herein, we describe a general strategy for rapid access to both aryl and alkyl radicals by photosensitized decarboxylation of the corresponding carboxylic acids esters followed by their successive use in divergent carbon-heteroatom and carbon-carbon bond-forming reactions. Identification of a suitable activator for carboxylic acids is the key to bypass a competing single-electron-transfer mechanism and "switch on" an energy-transfer-mediated homolysis of unsymmetrical σ-bonds for a concerted fragmentation/decarboxylation process.

Tandem photoelectrochemical and photoredox catalysis for efficient and selective aryl halides functionalization by solar energy

Design of solid‐supported metal catalysts (SSMCs) has made an increasingly important contribution to heterogeneous catalysis in terms of fundamental understanding and technological applications. For instance, industrial use of supported catalysts for oxidation, reduction, and C−C bond formation reactions is highly prevalent. The reason behind this is that such catalysts are economical, have high thermal stability, dispersion, high exposed surface area, and above all, high reusability (up to multiple subsequent cycles). Such characteristics make supported catalysts ideal for green synthesis. However, unlike homogeneous catalysis, heterogeneous catalysis is widely applied in crude oil refining, the pharmaceutical industry, water purification, natural product synthesis, and environmental catalysis. Carbon‐carbon bond formation reactions are frequently used in the organic synthesis using SSMCs. SSMCs are attractive to synthetic chemists due to their easy recovery and excellent stability compared to unsupported metal catalysts. However, the major drawback of SSMCs is related to metal sintering at elevated temperatures caused by weak interactions between the metal and solid support in SSMCs. This review highlights major advancements in SSMCs. Three commonly reported solid supports for metal catalysts, such metal oxides, carbonaceous materials, and polymeric compounds, are discussed. Moreover, a series of thermo‐ and photocatalyzed reactions, such as hydrogenation, carbon‐carbon bond formation, oxidation reactions and multicomponent reactions and the effect of variable supports towards activity and selectivity are demonstrated.

General and Efficient C–P Bond Formation by Quantum Dots and Visible Light

Isocyanides and tri-t-butylphosphine undergo a C–P bond-forming reaction under photocatalytic conditions. The resulting imidoyltrialkylphosphonium salts represent a new class of organophosphorus compounds that can be isolated by silica gel chromatography under air. This transformation exhibits broad functional group tolerance and affords a range of imidoylphosphonium salts in good to moderate yields. Mechanistic studies suggest a reaction pathway involving addition of a phosphine radical cation to the isocyanide, followed by single-electron reduction to form a phosphorus ylide intermediate. Furthermore, the imidoylphosphonium salts exhibit unique reactivity under reductive conditions, enabling their conversion to imidoylphosphines through elimination of a P-substituent.

The photocatalytic surface reactions of formaldehyde (HCHO) on rutile TiO2(110) surface were studied by means of thermal desorption spectroscopy and X-ray photoelectron spectroscopy and compared with its thermally catalytic surface reactions. Thermally catalytic surface reactions of formaldehyde on rutile TiO2(110) surface are dominated by the carbon–carbon bond formation reaction of HCHO adsorbed at oxygen vacancies to produce C2H4 via a diolate (−OCH2CH2O−) surface intermediate. During the photocatalytic surface reactions, HCHO adsorbed at the Ti5c sites of rutile TiO2(110) surface is photocatalytically oxidized to a transient formyl (HCO) species that facilely transforms to adsorbed formate (HCOO) species. HCOO species and HCHO adsorbed at oxygen vacancies undergo novel surface reactions to produce CO, C2H4, and CH3OH at elevated temperatures whose mechanisms were successfully identified. The healing of bridging oxygen vacancies on rutile TiO2(110) surface by preadsorption of water suppresses the oxygen vacancy-mediated coupling reaction of formaldehyde but does not affect its photocatalytic surface reactions. These results not only greatly deepen the fundamental understanding of photochemistry of formaldehyde on TiO2 surface but also demonstrate novel surface reactions of organic functional groups formed by the combined photocatalytic and thermally catalytic reactions of formaldehyde on oxide surfaces.

In modern synthetic organic chemistry, C-H bond activation has attracted the attention of researchers for various organic transformations, including C-C and C-X (X = N, O, S, and P) bond formation and heterocycle construction. For the purpose of C-C bond formation or annulation, C-H bond functionalization is more advantageous than conventional cross-coupling reactions owing to the non-requirement of pre-functionalized substrates, less waste generation, higher atom economy, low operational cost and direct incorporation of the desired functional group. Earlier, it was considered that transition metals and their coordinating directing groups are crucial for performing C-H activation reactions. Later, the hazardous effect of the metals on the environment and human health introduced metal-free organic reactions in the synthetic chemistry toolbox. Metal-free organic transformations are gradually becoming more preferred by both industry and academia for construction of bioactive molecules considering their advantages such as low operational cost, less number of steps for the synthesis, low risk of metal contamination-associated hazards, and less possibility of error in the results of biological evaluations. For achieving the mentioned advantages, two different sustainable practices (i.e., metal-free approaches and C-H bond activation) were combined into a new approach of sustainable synthesis, entitled "metal-free C-H bond activation approach". Although the C-H bond activation strategy is itself a sustainable approach, one or more sustainable approaches were also incorporated for synergism in the C-H functionalization protocol. In this review, we focus on metal-free C-C bond formation reactions carried out via a C-H activation approach. This review covers metal-free C-H alkylation, alkenylation, arylation, carbonylation, carbamoylation, alkynylation and cyanation reactions with emphasis on their reaction mechanisms.

Organometallic AlaM reagents for umpolung peptide diversification

A series of novel benzimidazolium salts (1–4) and their pyridine enhanced precatalyst preparation stabilization and initiation (PEPPSI) themed palladium N-heterocyclic carbene complexes [PdCl2(NHC)(Py)] (5–8), where NHC = 1-(N-methylphthalimide)-3-alkylbenzimidazolin-2-ylidene and Py = 3-chloropyridine, were synthesized and characterized by means of 1H and 13C{1H} NMR, UV–vis (for 5–8), ESI-FTICR-MS (for 2, 4, 6–8) and FTIR spectroscopic methods and elemental analysis. The synthesized compounds were tested in Suzuki–Miyaura cross-coupling (for 1–8) and arylation (for 5–8) reactions. As catalysts, they demonstrated a highly efficient route for the formation of asymmetric biaryl compounds even though they were used in very low loading. For example, all compounds displayed good catalytic activity for the C–C bond formation of 4-tert-butylphenylboronic acid with 4-chlorotoluene.

Over the past decade, photoredox catalysis has harnessed light energy to accelerate bond-forming reactions. We postulated that a complementary method for the redox-activation of small organic molecules in response to applied mechanical energy could be developed through the piezoelectric effect. Here, we report that agitation of piezoelectric materials via ball milling reduces aryl diazonium salts. This mechanoredox system can be applied to arylation and borylation reactions under mechanochemical conditions.

Selective modification of peptides and proteins is emerging as a promising strategy to develop novel mechanistic probes and prepare compounds with translational potential. While many methods to perform direct bioconjugation rely on reactions with dehydroalanine, an alternative strategy capitalizing on polarity reversal at the β carbon in amino acids can open access to a new type of diversification reactions characterized by absolute control of regio- and stereoselectivity. Here, we report that alanine carbastannatranes AlaSn can serve as a universal synthon in various C-C and C-heteroatom bond-forming reactions demonstrated in over 50 diverse examples. These reagents are compatible with peptide and protein manipulation techniques and undergo chemoselective conjugation in minutes when promoted by Pd(0). Despite their increased nucleophilicity and propensity to transfer the alkyl group, AlaSn operate at room temperature under buffered conditions (pH 6.5-8.5). We also show that AlaSn can be easily transformed into several canonical L- and D-amino acids in arylation, acylation, and etherification reactions. Furthermore, AlaSn can partake in macrocyclizations exemplified by the synthesis of medium size cyclic peptides with various topologies (7-13 membered macrocycles). Taken together, metalated alanine AlaSn demonstrate unparalleled scope and represent a new type of umpolung reagents suitable for structure-activity relationship studies and peptide diversification.