Mechanistic Study on the Cleavage and Reorganization of C(sp3)?H and CN Bonds in Carbodiimides: Synthesis of 1,2‐Dihydrothiopyrimidines and 2,3‐Dihydropyrimidinthiones through Four‐Component Coupling

This study sheds light on the cleavage and reorganization of C(sp³)? H and C?N bonds of carbodiimides in a three‐component reaction of terminal alkynes, sulfur, and carbodiimides by a combination of methods including 1) isolation and X‐ray analysis of six‐membered‐ring lithium species 2‐S , 2) trapping of the oxygen‐analogues ( B‐O and D‐O ) of both four‐membered‐ring intermediate B‐S and ring‐opening intermediate D‐S , 3) deuterium labeling studies, and 4) theoretical studies. These results show that 1) the reaction rate‐determining step is [2+2] cycloaddition, 2) the C?N bond cleavage takes place before C(sp³)? H bond cleavage, 3) the hydrogen attached to C6 in 2‐S originates from the carbodiimide, and 4) three types of new aza‐heterocycles, such as 1,2‐dihydrothiopyrimidines, N‐acyl 2,3‐dihydropyrimidinthiones, and 1,2‐dihydropyrimidinamino acids are constructed efficiently based on 2‐S . All results strongly support the idea that the reaction proceeds through [2+2] cycloaddition/4π electrocyclic ring‐opening/1,5‐H shift/6π electrocyclic ring‐closing as key steps. The research strategy on the synthesis, isolation, and reactivity investigation of important intermediates in metal‐mediated reactions not only helps achieve an in‐depth understanding of reaction mechanisms but also leads to the discovery of new synthetically useful reactions based on the important intermediates.     

Copper‐Catalyzed C(sp3)−H/C(sp3)−H Cross‐Dehydrogenative Coupling with Internal Oxidants: Synthesis of 2‐Trifluoromethyl‐Substituted Dihydropyrrol‐2‐ols

The first oxidative C(sp³)−H/C(sp³)−H cross‐dehydrogenative coupling (CDC) reaction promoted by an internal oxidant is reported. This copper‐catalyzed CDC reaction of oxime acetates and trifluoromethyl ketones provides a simple and efficient approach towards 2‐trifluoromethyldihydropyrrol‐2‐ol derivatives in a highly diastereoselective manner by cascade C(sp³)−C(sp³) bond formation and cyclization. These products were further transformed into various significant and useful trifluoromethylated heterocyclic compounds, such as trifluoromethylated furan, thiophene, pyrrole, dihydropyridazine, and pyridazine derivatives. A trifluoromethylated analogue of an Aβ₄₂ lowering agent was also synthesized smoothly. Preliminary mechanistic studies indicated that this reaction involves a copper(I)/copper(III) catalytic cycle with the oxime acetate acting as an internal oxidant.     

Copper(I)‐Catalyzed Chemoselective Coupling of Cyclopropanols with Diazoesters: Ring‐Opening C−C Bond Formations

Reported herein is an exceptional chemoselective ring‐opening/C(sp³)−C(sp³) bond formation in the copper(I)‐catalyzed reaction of cyclopropanols with diazo esters. The conventional O−H insertion product is essentially suppressed by judicious choice of reaction conditions. DFT calculations provide insights into the reaction mechanism and the rationale for this unusual chemoselectivity.     

Amine‐Catalyzed Highly Regioselective and Stereoselective C(sp2)–C(sp2) Cross‐Coupling of Naphthols with trans‐α,β‐Unsaturated Aldehydes

A metal‐free C(sp²)–C(sp²) cross‐coupling approach to highly congested (E)‐α‐naphtholylenals from simple naphthols and enals is described. The mild reaction conditions with pyridine hydrobromideperbromide (PHBP) as the bromination reagent in the presence of piperidine or diphenylprolinol trimethylsilyl (TMS) ether as promoters enable the process in good yields and with high chemoselectivity, regioselectivity, and stereoselectivity. The process involves an unprecedented pathway of in situ regioselective 4‐bromination of 1‐naphthols and the subsequent unusual aromatic nucleophilic substitution of the resulting 4‐bromo‐1‐naphthols with the α‐C(sp²) of enals through a Michael‐type Friedel–Crafts alkylation–dearomatization followed by a cyclopropanation ring‐opening cascade process. The noteworthy features of this strategy are highlighted by the highly efficient creation of a C(sp²)–C(sp²) bond from readily available unfunctionalized naphthols and enals catalyzed by non‐metal, readily available cyclic secondary amines under mild reaction conditions.     

Intramolecular Metal‐Free Oxidative Aryl–Aryl Coupling: An Unusual Hypervalent‐Iodine‐Mediated Rearrangement of 2‐Substituted N‐Phenylbenzamides

Hypervalent‐iodine‐mediated oxidative coupling of the two aryl groups in either 2‐acylamino‐N‐phenyl‐benzamides or 2‐hydroxy‐N‐phenylbenzamides, with concomitant insertion of the ortho‐substituted N or O atom into the tether, has been described for the first time. This unusual metal‐free rearrangement reaction involves an oxidative C(sp²)? C(sp²) aryl–aryl bond formation, cleavage of a C(sp²)? C(O) bond, and a lactamization/lactonization. Furthermore, unsymmetrical diaryl compounds can be easily obtained by removing the tether within the cyclized product.     

Access to β‐Lactams by Enantioselective Palladium(0)‐Catalyzed C(sp3)H Alkylation

β‐Lactams are very important structural motifs because of their broad biological activities as well as their propensity to engage in ring‐opening reactions. Transition‐metal‐catalyzed C? H functionalizations have emerged as strategy enabling yet uncommon highly efficient disconnections. In contrast to the significant progress of Pd⁰‐catalyzed C? H functionalization for aryl–aryl couplings, related reactions involving the formation of saturated C(sp³)? C(sp³) bonds are elusive. Reported here is an asymmetric C? H functionalization approach to β‐lactams using readily accessible chloroacetamide substrates. Important aspects of this transformation are challenging C(sp³)? C(sp³) and strain‐building reductive eliminations to for the four‐membered ring. In general, the β‐lactams are formed in excellent yields and enantioselectivities using a bulky taddol phosphoramidite ligand in combination with adamantyl carboxylic acid as cocatalyst.     

Access to β‐Lactams by Enantioselective Palladium(0)‐Catalyzed C(sp3)?H Alkylation

β‐Lactams are very important structural motifs because of their broad biological activities as well as their propensity to engage in ring‐opening reactions. Transition‐metal‐catalyzed C H functionalizations have emerged as strategy enabling yet uncommon highly efficient disconnections. In contrast to the significant progress of Pd⁰‐catalyzed C H functionalization for aryl–aryl couplings, related reactions involving the formation of saturated C(sp³) C(sp³) bonds are elusive. Reported here is an asymmetric C H functionalization approach to β‐lactams using readily accessible chloroacetamide substrates. Important aspects of this transformation are challenging C(sp³) C(sp³) and strain‐building reductive eliminations to for the four‐membered ring. In general, the β‐lactams are formed in excellent yields and enantioselectivities using a bulky taddol phosphoramidite ligand in combination with adamantyl carboxylic acid as cocatalyst.     

A study of the planarity of the pyrrolone fragment in 2‐isopropyl‐2,3‐dihydro‐1H‐isoindol‐1‐one

Orthophthalaldehyde (o‐phthalaldehyde, OPA) is an aromatic dialdehyde bearing two electron‐withdrawing carbonyl groups. The reactions of OPA with primary amines are broadly applied for the synthesis of important heterocyclic compounds with biological relevance. A number of such reactions have been investigated recently and several structures of condensation products have been reported, however, the complex reaction mechanism is still not fully understood and comprises concurrent as well as consecutive reactions. The reaction products depend on the primary amine which reacts with OPA, the reaction environment (solvent) and the proportion of the reactants. The title molecule, C₁₁H₁₃NO, the product of the reaction of OPA with isopropylamine, contains a five‐membered pyrrole C₄N ring with a carbonyl substituent, which forms part of the isoindolinone unit. Though this pyrrole ring contains one C atom in the sp³‐hybridized state, it is fairly planar. The title molecule has been compared with similar structures retrieved from the Cambridge Structural Database in order to study this phenomenon. The planarity of this fragment has been explained by the presence of partially delocalized C—C, C—N and C—O bonds, and by an inner angle in the planar pentagonal ring (∼108°), which is close to the ideal tetrahedral value for the sp³‐hybridized state of the constituent C atom. Due to this propitious angle, this C atom can be present in states intermediate between sp³‐ and sp²‐hybridized in different structures, while still maintaining the planarity of the ring. There are only weak intermolecular C—H…O hydrogen bonds and C—H…π‐electron ring interactions in the structure. In particular, it is the pyrrole ring which is involved in these interactions.     

Cu‐Catalyzed [4+1] Annulation toward Indolo[2,1‐a]isoquinolines through Oxidative C(sp3)/C(sp2)−H Bond Bifunctionalization

A Cu‐catalyzed [4+1] annulation of N‐aryl‐1,2,3,4‐tetrahydroisoquinolines (N‐aryl THIQs) with α‐diazoketones has been established under oxidative conditions, leading to the construction of a series of indolo[2,1‐a]isoquinolines with generally good yields. The reaction enables dediazotized dicarbonylation of α‐diazoketones, creating direct C(sp³)/C(sp²)?H bond bifunctionalization to access tetracyclic aza‐heterocyclic skeletons.     

Regioselective Vinylation of Remote Unactivated C(sp3)−H Bonds: Access to Complex Fluoroalkylated Alkenes

Regioselective incorporation of a particular functional group into aliphatic sites by direct activation of unreactive C?H bonds is of great synthetic value. Despite advances in radical‐mediated functionalization of C(sp³)?H bonds by a hydrogen‐atom transfer process, the site‐selective vinylation of remote C(sp³)?H bonds still remains underexplored. Reported herein is a new protocol for the regioselective vinylation of unactivated C(sp³)?H bonds. The remote C(sp³)?H activation is promoted by a C‐centered radical instead of the commonly used N and O radicals. The reaction possesses high product diversity and synthetic efficiency, furnishing a plethora of synthetically valuable E alkenes bearing tri‐/di‐/mono‐fluoromethyl and perfluoroalkyl groups.     

Rhodium(I)‐Catalyzed Sequential C(sp)?C(sp3) and C(sp3)?C(sp3) Bond Formation through Migratory Carbene Insertion

A Rh^I‐catalyzed three‐component reaction of tert‐propargyl alcohol, diazoester, and alkyl halide has been developed. This reaction can be considered as a carbene‐involving sequential alkyl and alkynyl coupling, in which C(sp) C(sp³) and C(sp³) C(sp³) bonds are built successively on the carbenic carbon atom. The Rh^I‐carbene migratory insertion of an alkynyl moiety and subsequent alkylation are proposed to account for the two separate C C bond formations. This reaction provides an efficient and tunable method for the construction of all‐carbon quaternary center.     

Intramolecular C(sp3)–H Bond Oxygenation by Transition-Metal Acylnitrenoids

This study demonstrates for the first time that easily accessible transition-metal acylnitrenoids can be used for controlled direct C(sp³)-H oxygenations. Specifically, a ruthenium catalyst activates N-benzoyloxycarbamates as nitrene precursors towards regioselective intramolecular C−H oxygenations to provide cyclic carbonates, hydroxylated carbamates, or 1,2-diols. The method can be applied to the chemoselective C−H oxygenation of benzylic, allylic, and propargylic C(sp³)−H bonds. The reaction can be performed in an enantioselective fashion and switched in a catalyst-controlled fashion between C−H oxygenation and C−H amination. This work provides a new reaction mode for the regiocontrolled and stereocontrolled conversion of C(sp³)-H into C(sp³)−O bonds.     

Metal‐Free Radical [2+2+1] Carbocyclization of Benzene‐Linked 1,n‐Enynes: Dual C(sp3)?H Functionalization Adjacent to a Heteroatom

A new metal‐free oxidative radical [2+2+1] carbocyclization of benzene‐linked 1,n‐enynes with two C(sp³) H bonds adjacent to the same heteroatom is described. This method achieves two C(sp³) H oxidative functionalizations and an annulation, thus providing efficient and general access to a variety of fused five‐membered carbocyclic hydrocarbons.     

Transition‐metal‐free Chemoselective Oxidative C−C Coupling of the sp3 C−H Bond of Oxindoles with Arenes and Addition to Alkene: Synthesis of 3‐Aryl Oxindoles,and Benzofuro‐ and Indoloindoles

A transition‐metal (TM)‐free and halogen‐free NaOt Bu‐mediated oxidative cross‐coupling between the sp³ C−H bond of oxindoles and sp² C−H bond of nitroarenes has been developed to access 3‐aryl substituted and 3,3‐aryldisubstituted oxindoles in DMSO at room temperature in a short time. Interestingly, the sp³ C−H bond of oxindoles could also react with styrene under TM‐free conditions for the practical synthesis of quaternary 3,3‐disubstituted oxindoles. The synthesized 3‐oxindoles have also been further transformed into advanced heterocycles, that is, benzofuroindoles, indoloindoles, and substituted indoles. Mechanistic experiments of the reaction suggests the formation of an anion intermediate from the sp³ C−H bond of oxindole by tert ‐butoxide base in DMSO. The addition of nitrobenzene to the in‐situ generated carbanion leads to the 3‐(nitrophenyl)oxindolyl carbanion in DMSO which is subsequently oxidized to 3‐(nitro‐aryl) oxindole by DMSO.     

RhodiumIII/SilverI Relay Catalyzed C—H Aminomethylation with Imine Equivalents and Lewis Acid Catalyzed [4+2] Cycloaddition of Indoles with Triarylhexahydrotriazine†

A Rh^III/Ag^I relay‐catalyzed C(sp²)—H coupling of indoles with triarylhexahydrotriazine (THT) is reported in this context. Upon merging Rh^III‐catalyzed C(sp²)—H bond activation and silver promoted THT dissociation, an efficient indole's C3 aminomethylation protocol is uncovered, providing C3 aminomethyl indoles in good yields and exhibiting potential applications for the synthesis of complicated bioactive compounds. We revealed the C3‐selectivity of this reaction through a detailed mechanistic investigation. Meanwhile, during the examination of the reaction conditions, we discovered another [4+2] cycloaddition pathway to afford tetrahydro‐indolo[3,2‐c]quinoline scaffold products via silver or Lewis acid catalysis.     

Domino Pd0‐Catalyzed C(sp3)–H Arylation/Electrocyclic Reactions via Benzazetidine Intermediates

The Pd⁰‐catalyzed C(sp³)‐H arylation of 2‐bromo‐N‐methylanilides leads to unstable benzazetidine intermediates that rearrange to benzoxazines through 4π electrocyclic ring‐opening and 6π electrocyclization. The introduction of a bulky, non‐activatable amide group on the nitrogen atom was key to favor the challenging reductive elimination step and disfavor undesired reaction pathways.     

Rhodium(I)‐Catalyzed Sequential C(sp)C(sp3) and C(sp3)C(sp3) Bond Formation through Migratory Carbene Insertion

A Rh^I‐catalyzed three‐component reaction of tert‐propargyl alcohol, diazoester, and alkyl halide has been developed. This reaction can be considered as a carbene‐involving sequential alkyl and alkynyl coupling, in which C(sp)? C(sp³) and C(sp³)? C(sp³) bonds are built successively on the carbenic carbon atom. The Rh^I‐carbene migratory insertion of an alkynyl moiety and subsequent alkylation are proposed to account for the two separate C? C bond formations. This reaction provides an efficient and tunable method for the construction of all‐carbon quaternary center.     

Modular Stereoselective Synthesis of (1→2)‐C‐Glycosides based on the sp2–sp3 Suzuki–Miyaura Reaction

This work reports a modular and rapid approach to the stereoselective synthesis of a variety of α‐ and β‐(1→2)‐linked C‐disaccharides. The key step is a Ni‐catalyzed cross‐coupling reaction of D ‐glucal pinacol boronate with alkyl halide glycoside easily prepared from commercially available D ‐glucal. The products of this sp²–sp³ cross‐coupling reaction can be converted to glucopyranosyl, mannopyranosyl, or 2‐deoxy‐glucopyranosyl C‐mannopyranosides by one‐ or two‐step stereoselective oxidative–reductive transformations. To the best of our knowledge, we demonstrated the first synthetic application of a challenging sp²–sp³ Suzuki‐Miyaura cross‐coupling reaction in carbohydrate chemistry.     

Silver‐Catalyzed Oxidative C(sp3)−P Bond Formation through C−C and P−H Bond Cleavage

The silver‐catalyzed oxidative C(sp³)−H/P−H cross‐coupling of 1,3‐dicarbonyl compounds with H‐phosphonates, followed by a chemo‐ and regioselective C(sp³)−C(CO) bond‐cleavage step, provided heavily functionalized β‐ketophosphonates. This novel method based on a readily available reaction system exhibits wide scope, high functional‐group tolerance, and exclusive selectivity.     

Synthesis and Reactions of New Dithiolopyrroles

The title compounds were prepared starting from pyrrolinone 4 . Nucleophilic‐displacement and ring‐closure reactions yielded the dithiolopyrrole 5a , which formed salts with electrophiles ( 7, 8 ) as well as with bases. The crystal structure of 5a was determined. Oxidation of the dithioles 5a and 6a led to S(2)‐oxides ( 10a, 11a ) and the corresponding S(2)‐dioxides ( 10b, 11b ) depending on reaction conditions. The thiosulfinate 10a was converted by a ring‐opening/ring‐closure reaction sequence to the bicyclic sulfinamide 12 . The oxidative addition reactions of [Pt(η²‐C₂H₄) (PPh₃)₂] ( 14 ) with the disulfides 5a and 13 led to the dithiolatoplatinum(II) complexes 15 and 16 , respectively. Complex 16 was characterized structurally. The sulfenato‐thiolato complex 17 was synthesized via reaction of 14 with the thiosulfinate 10a . The thiosulfonato Pt^II complex 18 was prepared by an oxidative insertion of Pt⁰ into the C? S bond of the corresponding thiosulfonate 10b . Furthermore, complex 18 was characterized by single‐crystal X‐ray‐diffraction studies.