Regioselective Acceptorless Dehydrogenative Coupling of N‐Heterocycles toward Functionalized Quinolines,Phenanthrolines, and Indoles

A new strategy has been developed for the oxidant‐ and base‐free dehydrogenative coupling of N‐heterocycles at mild conditions. Under the action of an iridium catalyst, N‐heterocycles undergo multiple sp³ C H activation steps, generating a nucleophilic enamine that reacts in situ with various electrophiles to give highly functionalized products. The dehydrogenative coupling can be cascaded with Friedel–Crafts addition, resulting in a double functionalization of the N‐heterocycles.     

Regioselective Acceptorless Dehydrogenative Coupling of N‐Heterocycles toward Functionalized Quinolines,Phenanthrolines, and Indoles

A new strategy has been developed for the oxidant‐ and base‐free dehydrogenative coupling of N‐heterocycles at mild conditions. Under the action of an iridium catalyst, N‐heterocycles undergo multiple sp³ C? H activation steps, generating a nucleophilic enamine that reacts in situ with various electrophiles to give highly functionalized products. The dehydrogenative coupling can be cascaded with Friedel–Crafts addition, resulting in a double functionalization of the N‐heterocycles.     

Simple Sulfinate Synthesis Enables CH Trifluoromethylcyclopropanation

A simple method to convert readily available carboxylic acids into sulfinate salts by employing an interrupted Barton decarboxylation reaction is reported. A medicinally oriented panel of ten new sulfinate reagents was created using this method, including a key trifluoromethylcyclopropanation reagent, TFCS‐Na. The reactivity of six of these salts towards C? H functionalization was field‐tested using several different classes of heterocycles.     

Coordination Assisted Distal C−H Alkylation of Fused Heterocycles

Distal C?H bond functionalization of heterocycles remained extremely challenging with covalently attached directing groups (DG). Lack of proper site for DG attachment and inherent catalyst poisoning by heterocycles demand alternate routes for site selective functionalization of their distal C?H bonds. Utilizing non‐productive coordinating property to hold the heterocycle into the cavity of a template system in a host–guest manner, we report distal C?H alkylation (C‐5 of quinoline and thiazole, C‐7 of benzothiazole and benzoxazole) of heterocycles. Upon complexation with heterocyclic substrate, nitrile DG in template directs the metal catalyst towards close vicinity of the specific distal C?H bond of the heterocycles. Our hypothesized pathway has been supported by various X‐ray crystallographically characterized intermediates.     

Cu/Fe Catalyzed Intermolecular Oxidative Amination of Benzylic C−H Bonds

We report a Cu/Fe co‐catalyzed Ritter‐type C?H activation/amination reaction that allows efficient and selective intermolecular functionalization of benzylic C?H bonds. This new reaction is featured by simple reaction conditions, readily available reagents and general substrate scope, allowing facile synthesis of biologically interesting nitrogen containing heterocycles. The Cu and Fe salts were found to play distinct roles in this cooperative catalysis.     

Regioselective Synthesis of Quinazolinone‐/Phenanthridine‐Fused Heteropolycycles by Pd‐Catalyzed Direct Intramolecular Aerobic Oxidative C−H Amination from Aromatic Strained Amides

A new route for the expedient synthesis of specific regioisomer of quinazolinone‐ and phenanthridine‐fused heterocycles through a palladium‐catalyzed regioselective intramolecular oxidative C?H amination from cyclic strained amides of aromatic amido–amidine systems (quinazolinones) has been developed. The amine functionalization of an aromatic C?H bond from a strained amide nitrogen involved in aromaticity has been a challenging work so far. The fusion of two heterocyclic cores, quinazolinone and phenanthridine, can occur in two different ways (linear and angular), but under the conditions reported here, only linear type isomer is exclusively produced. This approach provides a variety of substituted quinazolinone‐ and phenanthridine‐fused derivatives in moderate to excellent yields. Moreover, such fused molecules show excellent fluorescent properties and have great potential to be a new type of fluorophores for the use in medicinal and material science.     

Simple Sulfinate Synthesis Enables C?H Trifluoromethylcyclopropanation

A simple method to convert readily available carboxylic acids into sulfinate salts by employing an interrupted Barton decarboxylation reaction is reported. A medicinally oriented panel of ten new sulfinate reagents was created using this method, including a key trifluoromethylcyclopropanation reagent, TFCS‐Na. The reactivity of six of these salts towards C H functionalization was field‐tested using several different classes of heterocycles.     

Modern Approaches to the Synthesis and Transformations of Practically Valuable Benzothiazole Derivatives

The review is devoted to modern trends in the chemistry of 2-amino and 2-mercapto substituted benzothiazoles covering the literature since 2015. The reviewed heterocycles belong to biologically active and industrially demanded compounds. Newly developed synthesis methods can be divided into conventional multistep processes and one-pot, atom economy procedures, realized using green chemistry principles and simple reagents. The easy functionalization of the 2-NH₂ and 2-SH groups and the benzene ring of the benzothiazole moiety allows considering them as highly reactive building blocks for organic and organoelement synthesis, including the synthesis of pharmacologically active heterocycles. The review provides a summary of findings, which may be useful for developing new drugs and materials and new synthetic approaches and patterns of reactivity.     

Classical‐Reaction‐Driven Stereo‐ and Regioselective C(sp3)–H Functionalization of Aliphatic Amines

A large variety of synthetic methods have been developed for the synthesis of functionalized aliphatic amines because of their broad spectrum of application. Metallic reagents/catalysts and/or toxic oxidants are involved in most of the cases. Direct C? H functionalization of aliphatic amines via their classical condensation reactions with suitable carbonyl compounds is advantageous because this method avoids hazardous metallic reagents, toxic oxidants and pre‐activation/pre‐functionalization step(s). In this account, the concept of direct C? H functionalization of aliphatic amines based on the classical condensation–isomerization–addition (CIA) strategy followed by recent contributions from our ongoing research in the field along with relevant examples from other groups are described. Successes in stereo‐ and regioselective C? C and C? O bond formation via direct α‐ as well as β‐C(sp³)–H functionalization are discussed.

     

Photochemical Functionalization of Heterocycles with EBX Reagents: C−H Alkynylation versus Deconstructive Ring Cleavage**

The development of novel methodologies for the functionalization of saturated heterocycles is highly desirable. Herein, we report a cheap and efficient photochemical method for the C−H functionalization of saturated O-heterocycles, as well as the deconstructive ring-cleavage of S-heterocycles, employing hypervalent iodine alkynylation reagents (ethynylbenziodoxolones, EBX). This photochemical alkynylation is performed utilizing phenylglyoxylic acid as the photoinitiator, leading to the corresponding products in good to high yields, under household fluorescent light bulb irradiation. When O-heterocycles were employed, the expected α-C−H alkynylation took place. In contrast, oxidative ring-opening to form a thioalkyne and an aldehyde was observed with S-heterocycles. Preliminary mechanistic experiments are presented to give first insights into this puzzling divergent reactivity.     

Tryptamine Synthesis by Iron Porphyrin Catalyzed C−H Functionalization of Indoles with Diazoacetonitrile

The functionalization of C?H bonds with non‐precious metal catalysts is an important research area for the development of efficient and sustainable processes. Herein, we describe the development of iron porphyrin catalyzed reactions of diazoacetonitrile with N‐heterocycles yielding important precursors of tryptamines, along with experimental mechanistic studies and proof‐of‐concept studies of an enzymatic process with YfeX enzyme. By using readily available FeTPPCl, we achieved the highly efficient C?H functionalization of indole and indazole heterocycles. These transformations feature mild reaction conditions, excellent yields with broad functional group tolerance, can be conducted on gram scale, and thus provide a unique streamlined access to tryptamines.     

Radical CH Functionalization of Heteroarenes under Electrochemical Control

Electrochemical reactions are shown to be effective for the C? H functionalization of a number of heterocyclic substrates that are recalcitrant to conventional peroxide radical initiation conditions. Monitoring reaction progress under electrochemical conditions provides mechanistic insight into the C? H functionalization of a series of heterocycles of interest in medicinal chemistry.     

Directing‐Group‐mediated C−H‐Alkynylations

C?C triple bonds are amongst the most versatile functional groups in synthetic chemistry. Complementary to the Sonogashira coupling the direct metal‐catalyzed alkynylation of C?H bonds has emerged as a highly promising approach in recent years. To guarantee a high regioselectivity suitable directing groups (DGs) are necessary to guide the transition metal (TM) into the right place. In this Focus Review we present the current developments in DG‐mediated C(sp²)?H and C(sp³)?H modifications with terminal alkynes under oxidative conditions and with electrophilic alkynylation reagents. We will discuss further modifications of the alkyne, in particular subsequent cyclizations to carbo‐ and heterocycles and modifications of the DG in the presence of the alkyne.     

Recent Advances in Organic Electrochemical C—H Functionalization

Organic electrochemistry has a rich history in organic synthesis and has been considered as a promising alternative to traditional chemical oxidants and reductants because it obviates the use of stoichiometric amount of dangerous and toxic reagents. In particular, the electrochemical C—H bonds functionalization is one of the most desirable approaches for the construction of carbon–carbon (C—C) and carbon–heteroatom (C—X) bonds. This review summarizes the substantial progress made in the last few years in C—H functionalization via organic electrochemistry. It is divided into sections on C—C, C—N, C—O, C—S, C–Halogen and C—P bond formation.     

C−H Bond Arylation of Pyrazoles at the β-Position: General Conditions and Computational Elucidation for a High Regioselectivity

Direct arylation of most five-membered ring heterocycles are generally easily accessible and strongly favored at the α-position using classical palladium-catalysis. Conversely, regioselective functionalization of such heterocycles at the concurrent β-position remains currently very challenging. Herein, we report general conditions for regioselective direct arylation at the β-position of pyrazoles, while C−H α-position is free. By using aryl bromides as the aryl source and a judicious choice of solvent, the arylation reaction of variously N-substituted pyrazoles simply proceeds via β-C−H bond functionalization. The β-regioselectivity is promoted by a ligand-free palladium catalyst and a simple base without oxidant or further additive, and tolerates a variety of substituents on the bromoarene. DFT calculations revealed that a protic solvent such as 2-ethoxyethan-1-ol significantly enhances the acidity of the proton at β-position of the pyrazoles and thus favors this direct β-C−H bond arylation. This selective pyrazoles β-C−H bond arylation was successfully applied for the straightforward building of π-extended poly(hetero)aromatic structures via further Pd-catalyzed combined α-C−H intermolecular and intramolecular C−H bond arylation in an overall highly atom-economical process.     

Overcoming the Limitations of C−H Activation with Strongly Coordinating N‐Heterocycles by Cobalt Catalysis

Strongly coordinating nitrogen heterocycles, including pyrimidines, oxazolines, pyrazoles, and pyridines, were fully tolerated in cobalt‐catalyzed C?H amidations by imidate assistance. Structurally complex quinazolines are thus accessible in a step‐economic manner. Our findings also establish the relative powers of directing groups in cobalt(III)‐catalyzed C?H functionalization for the first time.     

Diastereoselective Carbocyclization of 1,6‐Heptadienes Triggered by Rhodium‐Catalyzed Activation of an Olefinic CH Bond

The use of α,ω‐dienes as functionalization reagents for olefinic carbon–hydrogen bonds has been rarely studied. Reported herein is the rhodium(I)‐catalyzed rearrangement of prochiral 1,6‐heptadienes into [2,2,1]‐cycloheptane derivatives with concomitant creation of at least three stereogenic centers and complete diastereocontrol. Deuterium‐labeling studies and the isolation of a key intermediate are consistent with a group‐directed C? H bond activation, followed by two consecutive migratory insertions, with only the latter step being diastereoselective.     

光/电化学氧化诱导C–H键官能团化

C–H键活化及其官能团化一直被认为是合成化学的圣杯,光/电氧化诱导C–H键官能团化反应为追求更为绿色、原子经济性、步骤经济性更高的现代合成化学提供了新思路.我们借助可见光或电化学氧化诱导策略实现了直接C–H键官能团化,即底物无需预官能团化,无需外加氧化剂,可直接实现碳–碳以及碳–杂键的构建.通过光/电化学氧化诱导策略使得反应在更为温和的条件下进行,能够兼容更多官能团,并且为合成化学提供一条新的途径.近些年,该策略已经应用于不同化学环境C–H官能团化构建多种化学键.本文结合该领域的代表性工作,重点介绍本课题组近些年在光/电氧化诱导C–H键官能团化反应上的研究进展,并对这一领域的前景进行了展望.     

Organoselenium‐Catalyzed Regioselective C−H Pyridination of 1,3‐Dienes and Alkenes

An efficient approach for organoselenium‐catalyzed regioselective C−H pyridination of 1,3‐dienes to form pyridinium salts has been developed. This method was also successfully applied to direct C−H pyridination of alkenes. Fluoropyridinium reagents, or initially loaded pyridine derivatives, acted as pyridine sources in the pyridination reactions. The obtained pyridinium salts could be further converted under different conditions. This work is the first example of catalytic C‐2 direct C−H functionalization of 1,3‐dienes and the first case of organoselenium‐catalyzed C−H pyridination.     

Transition‐Metal‐Catalyzed Redox‐Neutral and Redox‐Green C–H Bond Functionalization

Transition‐metal‐catalyzed C–H bond functionalization has become one of the most promising strategies to prepare complex molecules from simple precursors. However, the utilization of environmentally unfriendly oxidants in the oxidative C–H bond functionalization reactions reduces their potential applications in organic synthesis. This account describes our recent efforts in the development of a redox‐neutral C–H bond functionalization strategy for direct addition of inert C–H bonds to unsaturated double bonds and a redox‐green C–H bond functionalization strategy for realization of oxidative C–H functionalization with O₂ as the sole oxidant, aiming to circumvent the problems posed by utilizing environmentally unfriendly oxidants. In principle, these redox‐neutral and redox‐green strategies pave the way for establishing new environmentally benign transition‐metal‐catalyzed C–H bond functionalization strategies.