Heterogeneous copper‐catalyzed oxidative coupling of oxime acetates with sodium sulfinates: An efficient and practical synthesis of β‐keto sulfones

An efficient and practical route to β‐keto sulfones has been developed through heterogeneous oxidative coupling of oxime acetates with sodium sulfinates by using an MCM‐41‐supported Schiff base‐pyridine bidentate copper (II) complex [MCM‐41‐Sb,Py‐Cu (OAc)₂] as the catalyst and oxime acetates as an internal oxidant, followed by hydrolysis. The reaction generates a variety of β‐keto sulfones in good to excellent yields. This new heterogeneous copper (II) catalyst can be easily prepared via a simple procedure from readily available and inexpensive reagents and exhibits the same catalytic activity as Cu (OAc)₂. MCM‐41‐Sb,Py‐Cu (OAc)₂ is also easy to recover and is recyclable up to eight times with almost consistent activity.     

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.     

Metal Free Mono‐ and 2,3‐Bis‐sulfenylation of Indoles in Water with Sodium Sulfinates as a Sulfur Source

An iodine‐PPh₃ mediated sulfenylation of indoles in water with stable and odorless sodium sulfinates as the sulfur source is described. The reaction could afford monosulfenylated indoles in moderate to excellent yields under metal free conditions. Moreover, double C—H sulfenylation of indoles at 2‐ and 3‐positions has also been achieved by using excess sodium sulfinates under the optimized reaction conditions.     

Synthesis of Allyl Aryl Sulfone Derivatives from Baylis?Hillman Acetates in Water

Various phenyl and p‐tolyl allyl sulfone derivatives were prepared stereoselectively by reacting Baylis? Hillman acetates with sodium 4‐R‐benzenesulfinate (R=H, Me) in H₂O. The reaction was very efficient in providing the corresponding sulfone derivatives in good to excellent yields (Table).     

Heck‐Type Reactions of Imine Derivatives: A DFT Study

The mechanism of a recently discovered intramolecular Heck‐type coupling of oximes with aryl halides (Angew. Chem. Int. Ed. 2007 , 46, 6325) was systematically studied by using density functional methods enhanced with a polarized continuum solvation model. The overall catalytic cycle of the reaction was found to consist of four steps: oxidative addition, migratory insertion, β‐H elimination, and catalyst regeneration, whereas an alternative base‐promoted C? H activation pathway was determined to be less favorable. Migratory insertion was found to be the rate determining step in the catalytic cycle. The apparent activation barrier of migratory insertion of the (E)‐oxime was +20.5 kcal mol^?1, whereas the barrier of (Z)‐oxime was as high as +32.7 kcal mol^?1. However, (Z)‐oxime could isomerize to form the more active (E)‐oxime with the assistance of K₂CO₃, so that both the (E)‐ and (Z)‐oxime substrates could be transformed to the desired product. Our calculations also indicated that the Z product was predominant in the equilibrium of the isomerization of the imine double bond, which constituted the reason for the good Z‐selectivity observed for the reaction. Furthermore, we examined the difference between the intermolecular Heck‐type reactions of imines and of olefins. It was found that in the intermolecular Heck‐type coupling of imines, the apparent activation barrier of migratory insertion was as high as +35 kcal mol^?1, which should be the main obstacle of the reaction. The analysis also revealed the main problem for the intermolecular Heck‐type reactions of imines, which was that the breaking of a C?N π bond was much more difficult than the breaking of a C?C π bond. After systematic examination of a series of substituted imines, (Z)‐N‐amino imine and N‐acetyl imine were found to have relatively low barriers of migratory insertion, so that they might be possible substrates for intermolecular Heck‐type coupling.     

Electrosynthesis of Arylsulfonamides from Amines and Sodium Sulfinates Using H2O‐NaI as the Electrolyte Solution at Room Temperature

With H₂O as the solvent and NaI as the supporting electrolyte, a green and efficient electrochemical route has been developed to synthesize arylsulfonamides via I₂ electrogenerated in situ at a graphite anode to promote the reaction of sodium sulfinates with aromatic or aliphatic primary and secondary amines. The target products could be obtained in good to excellent yields at room temperature.     

Copper‐Catalyzed Site‐Selective Intramolecular Amidation of Unactivated C(sp3)H Bonds

The intramolecular dehydrogenative amidation of aliphatic amides, directed by a bidentate ligand, was developed using a copper‐catalyzed sp³ C? H bond functionalization process. The reaction favors predominantly the C? H bonds of β‐methyl groups over the unactivated methylene C? H bonds. Moreover, a preference for activating sp³ C? H bonds of β‐methyl groups, via a five‐membered ring intermediate, over the aromatic sp² C? H bonds was also observed in the cyclometalation step. Additionally, sp³ C? H bonds of unactivated secondary sp³ C? H bonds could be functionalized by favoring the ring carbon atoms over the linear carbon atoms.     

Catalytic Diastereoselective Tandem Conjugate Addition–Elimination Reaction of Morita–Baylis–Hillman C Adducts by C?C Bond Cleavage

Through the cleavage of the C? C bond, the first catalytic tandem conjugate addition–elimination reaction of Morita–Baylis–Hillman C adducts has been presented. Various S_N2′‐like C‐, S‐, and P‐allylic compounds could be obtained with exclusive E configuration in good to excellent yields. The Michael product could also be easily prepared by tuning the β‐C‐substituent group of the α‐methylene ester under the same reaction conditions. Calculated relative energies of various transition states by DFT methods strongly support the observed chemoselectivity and diastereoselectivity.     

Copper‐Catalyzed Intramolecular C(sp3)H and C(sp2)H Amidation by Oxidative Cyclization

The first copper‐catalyzed intramolecular C(sp³)? H and C(sp²)? H oxidative amidation has been developed. Using a Cu(OAc)₂ catalyst and an Ag₂CO₃ oxidant in dichloroethane solvent, C(sp³)? H amidation proceeded at a terminal methyl group, as well as at the internal benzylic position of an alkyl chain. This reaction has a broad substrate scope, and various β‐lactams were obtained in excellent yield, even on gram scale. Use of CuCl₂ and Ag₂CO₃ under an O₂ atmosphere in dimethyl sulfoxide, however, leads to 2‐indolinone selectively by C(sp²)? H amidation. Kinetic isotope effect (KIE) studies indicated that C? H bond activation is the rate‐determining step. The 5‐methoxyquinolyl directing group could be removed by oxidation.     

Selective Benzylic and Allylic Alkylation of Protic Nucleophiles with Sulfonamides through Double Lewis Acid Catalyzed Cleavage of sp3 Carbon–Nitrogen Bonds

The acid‐catalyzed benzylic and allylic alkylation of protic nucleophiles is fundamentally important for the formation of carbon? carbon and carbon? heteroatom bonds, and it is a formidable challenge for benzylic and allylic amine derivatives to be used as the alkylating agents. Herein we report a highly efficient benzylic and allylic alkylation of protic carbon and sulfur nucleophiles with sulfonamides through double Lewis acid catalyzed cleavage of sp³ carbon–nitrogen bonds at room temperature. In the presence of a catalytic amount of inexpensive ZnCl₂‐TMSCl (TMSCl: chlorotrimethylsilane), 1,3‐diketones, β‐keto esters, β‐keto amides, malononitrile, aromatic compounds, thiols, and thioacetic acid can couple with a broad range of tosyl‐activated benzylic and allylic amines to give diversely functionalized products in good to excellent yields and with high regioselectivity. Furthermore, the cross‐coupling reaction of 1,3‐dicarbonyl compounds with benzylic propargylic amine derivatives has been successfully applied to the one‐step synthesis of polysubstituted furans and benzofurans.     

Activation of CH Bonds through Oxidant‐Free Photoredox Catalysis: Cross‐Coupling Hydrogen‐Evolution Transformation of Isochromans and β‐Keto Esters

The direct and controlled activation of a C(sp³)?H bond adjacent to an O atom is of particular synthetic value for the conventional derivatization of ethers or alcohols. In general, stoichiometric amounts of an oxidant are required to remove an electron and a hydrogen atom of the ether for subsequent transformations. Herein, we demonstrate that the activation of a C?H bond next to an O atom could be achieved under oxidant‐free conditions through photoredox‐neutral catalysis. By using a commercial dyad photosensitizer (Acr⁺‐Mes ClO₄^?, 9‐mesityl‐10‐methylacridinium perchlorate) and an easily available cobaloxime complex (Co(dmgBF₂)₂?2 MeCN, dmg=dimethylglyoxime), the nucleophilic addition of β‐keto esters to oxonium species, which is rarely observed in photocatalysis, leads to the corresponding coupling products and H₂ in moderate to good yields under visible‐light irradiation. Mechanistic studies suggest that both isochroman and the cobaloxime complex quench the electron‐transfer state of this dyad photosensitizer and that benzylic C?H bond cleavage is probably the rate‐determining step of this cross‐coupling hydrogen‐evolution transformation.     

Visible‐Light‐Induced CS Bond Activation: Facile Access to 1,4‐Diketones from β‐Ketosulfones

A novel method for the synthesis of 1,4‐diketones from β‐ketosulfones was developed by means of a visible light‐induced C?S bond activation process. Symmetrical and unsymmetrical 1,4‐diketones can be easily prepared in moderate to good yields.     

Highly reusable support‐free copper(II) complex of para‐hydroxy‐substituted salen: Novel,efficient and versatile catalyst for C─N bond forming reactions

An air‐stable, highly active and versatile method for C─N bond forming reactions is reported. Under mild conditions using a highly reusable support‐free Cu(II)–salen complex, structurally diverse N ‐aryl‐substituted compounds were obtained via direct C─N bond forming reaction of HN‐heterocycles with aryl iodides or three‐component C─N bond forming reaction of 2‐bromobenzaldehyde, aniline derivatives and sodium azide in good to excellent yields. C─N bond forming reaction for benzimidazole derivatives was also performed in the presence of the catalyst under ambient conditions. A series of hybrid benzimidazoles bearing morpholine, tetrazole and quinoxaline backbones were produced using this method. All reactions were performed in short times under air. The Cu(II) catalyst could be reused up to eight times in the direct cross‐coupling reaction of 9H –carbazole with iodobenzene without any decrease in its catalytic activity.     

Intramolecular Ring-Expansion Reaction (RER) and Intermolecular Coordination of In Situ Generated Cyclic (Amino)(aryl)carbenes (cAArCs)

Cyclic (amino)(aryl)carbenes (cAArCs) based on the isoindoline core were successfully generated in situ by α-elimination of 3-alkoxyisoindolines at high temperatures or by deprotonation of isoindol-2-ium chlorides with sodium or copper(I) acetates at low temperatures. 3-Alkoxy-isoindolines 2 a , b-OR (R=Me, Et, iPr) have been prepared in high yields by the addition of a solution of 2-aryl-1,1-diphenylisoindol-2-ium triflate ( 1 a , b-OTf ; a : aryl=Dipp=2,6-diisopropylphenyl; b : Mesityl-, Mes=2,4,6-trimethylphenyl) to the corresponding alcohol (ROH) with NEt₃ at room temperature. Furthermore, the reaction of 2 a , b-OMe in diethyl ether with a tenfold excess of hydrochloric acid led to the isolation of the isoindol-2-ium chlorides 1 a , b-Cl in high yields. The thermally generated cAArC reacts with sulfur to form the thioamide 3 a . Without any additional trapping reagent, in situ generation of 1,1-diphenylisoidolin-3-ylidenes does not lead to the isolation of these compounds, but to the reaction products of the insertion of the carbene carbon atom into an ortho C−H bond of a phenyl substituent, followed by ring-expansion reaction; namely, anthracene derivatives 9-N(H)aryl-10-Ph-C₁₄H₈ 4 a , b ( a : Dipp; b : Mes). These compounds are conveniently synthesized by deprotonation of the isoindol-2-ium chlorides with sodium acetate in high yields. Deprotonation of 1 a-Cl with copper(I) acetate at low temperatures afforded a mixture of 4 a and the corresponding cAArC copper(I) chloride 5 a , and allowed the isolation and structural characterization of the first example of a cAArC copper complex of general formula [(cAArC)CuCl].     

Electrochemical Synthesis of Thienoacene Derivatives: Transition‐Metal‐Free Dehydrogenative C−S Coupling Promoted by a Halogen Mediator

The first electrochemical dehydrogenative C?S bond formation leading to thienoacene derivatives is described. Several thienoacene derivatives were synthesized by dehydrogenative C?H/S?H coupling. The addition of ⁿBu₄NBr, which catalytically promoted the reaction as a halogen mediator, was essential.     

Iron-catalyzed alkenylation of cyclic ethers via decarboxylative sp(C)–sp(C) coupling

An efficient Fe(acac)₃-catalyzed decarboxylative C(sp²)–C(sp³) coupling reaction via oxidation of C–H bond adjacent to an oxygen atom has been developed successfully, in which cyclic ethers are selectively transformed into the corresponding alkenylation products with good chemical yields and excellent stereoselectivities. The mechanism was studied and the reaction was supposed to proceed through a radical oxidative coupling process.     

Advances in Copper‐Catalyzed C?C Coupling Reactions and Related Domino Reactions Based on Active Methylene Compounds

Active methylene compounds are a major class of reaction partners for C? C bond formation with sp² C? X (X=halide) fragments. As one of the most‐classical versions of the Ullmann‐type coupling reaction, activated‐methylene‐based C? C coupling reactions have been efficiently employed in a large number of syntheses. Although this type of reaction has long relied on noble‐metal catalysis, the renaissance of copper catalysis at the end of last century has led to dramatic developments in Ullmann C? C coupling reactions. Owing to its low cost, abundance, as well as excellent catalytic activity, the exceptional atom economy of copper catalysis is gaining widespread attention in various organic synthesis. This review summarizes the advances in copper‐catalyzed intermolecular and intramolecular C? C coupling reactions that use activated methylene species as well as in tandem reactions that are initiated by this transformation.     

Photoinduced,Direct C(sp2)−H Bond Azo Coupling of Imidazoheteroarenes and Imidazoanilines with Aryl Diazonium Salts Catalyzed by Eosin Y

Herein, a greener approach to the eosin Y-Na₂ catalyzed, C(sp²)−H bond azo coupling of imidazoheteroarene with aryl diazonium salts is described, under acid free conditions. This direct photoredox process resulted in the corresponding azo products in good to excellent yields. Besides, this new approach could also be applicable to anilines, which is a poorly reactive substrate by other methods. The main features of this reaction are that it provides high yields and is gram-scalable and applicable to biologically relevant imidazoheteroarenes and -anilines.     

A novel synthesis of aryl methyl sulfones and β-hydroxysulfones from sodium sulfinates and di-tert-butyl peroxide in H2O medium

A novel and convenient synthetic route for aryl methyl sulfones and β-hydroxysulfones was developed via the radical reaction between sodium sulfinates and di-tert-butyl peroxide (DTBP). Without any catalysts and additives, the synthetic process could be smoothly carried out to afford the target products in good to excellent yields in H₂O medium, demonstrating its promising application. In the present system, H₂O could act not only as a green solvent but also as a reactant.     

Synthesis of 2-substituted benzofuran derivatives by the palladium-catalyzed intermolecular coupling of 2-fluoroallylic acetates with phenols

We investigated the intermolecular coupling reaction of 2-fluoroallylic acetates with simple phenols by the [Pd(C₃H₅)Cl]₂, DPPF, and KHMDS at 100 °C for 16 h, and succeeded in obtaining 2-substituted benzofuran derivatives in good to high yield through the C–F bond activation and intermolecular cyclization.