Site-selective,catalytic, and diastereoselective sp3 C–H hydroxylation and alkoxylation of vicinally functionalized lactams

The C–H bond functionalization of sp³ carbon centres presents a significant challenge due to the inert nature of hydrocarbons as well as the need to selectively functionalize one of the numerous aliphatic C–H bonds embodied in organic molecules. Here, we describe catalytic, diastereoselective, and site-selective sp³ C–H hydroxylation/alkoxylation protocols featuring dihydroisoquinolones, γ-, and δ-lactams, which bear vicinal stereocenters. The hydroxylation strategy utilizes oxygen, a waste-free oxidant and affords attractive fragments for potential drug discovery. Fe-catalyzed dehydrative coupling of the resulting tertiary alcohols with simple primary alcohols has led to the construction of highly versatile unsymmetrical dialkyl ethers.

Catalytic, diastereoselective, and site-selective sp³ C–H hydroxylation and alkoxylation protocols featuring lactams that bear vicinal stereocenters, is described.     

Copper-catalyzed aerobic decarboxylative coupling between cyclic α-amino acids and diverse C–H nucleophiles with low catalyst loading

An aerobic decarboxylative cross-coupling of α-amino acids with diverse C–H nucleophiles has been realized using Cu₂(OH)₂CO₃ (1 mol%) as the catalyst under air. This protocol enables highly efficient formation of various C(sp³)–C(sp³), C(sp³)–C(sp²) and C(sp³)–C(sp) bonds under simple conditions without the use of any ligand or extra oxidant, providing a practical approach to numerous nitrogen-containing compounds in good to excellent yields. The efficiency and practicability were also demonstrated by the gram-scale experiment and three-step synthesis of a Rad51 inhibitor.

An aerobic decarboxylative cross-coupling of α-amino acids was realized using 1 mol% Cu₂(OH)₂CO₃ catalyst under ligand free conditions.     

A walk around the application of nanocatalysts for cross-dehydrogenative coupling of C–H bonds

Cross-dehydrogenative coupling reactions between two unmodified C–H bonds are one of the most attractive and fundamental strategies for the construction of C–C bonds. As these reactions avoid pre-functionalization and de-functionalization of the substrates, they are cleaner, safer, and faster than traditional cross-coupling reactions. After the introduction of the modern area of cross-dehydrogenative coupling in 2003, many efforts have been devoted to the development of more efficient and selective catalytic systems for these appealing reactions. Among the different types of catalytic systems that have been investigated, nanostructured metal catalysts are highly attractive in view of their high catalytic performance, easy separability and good reusability. The purpose of this review is to focus on the application of nanocatalysts for cross-dehydrogenative coupling of C–H bonds with particular emphasis on the mechanistic aspects of the reactions. Specifically, we have structured this review based on the type of C–C bonds. Thus, the review is divided into six major sections: (i) C(sp³)–C(sp³) coupling; (ii) C(sp³)–C(sp²) coupling; (iii) C(sp³)–C(sp) coupling; (iv) C(sp²)–C(sp²) coupling; (v) C(sp²)–C(sp) coupling; and (vi) C(sp)–C(sp) coupling.

Cross-dehydrogenative coupling reactions between two unmodified C–H bonds are one of the most attractive and fundamental strategies for the construction of C–C bonds.     

Cobalt-catalyzed C(sp3)–H/C(sp2)–H oxidative coupling between alkanes and benzamides

A direct cobalt-catalyzed oxidative coupling between C(sp²)–H in unactivated benzamides and C(sp³)–H in simple alkanes, ethers and toluene derivatives was explored. This protocol achieves direct C–C formation without using alkyl or aryl halide surrogates and exhibits high practicality with ample substrate scope. The method provides a new way to construct linear and five- or six-membered ring moieties in bioactive molecules.

A direct cobalt-catalyzed oxidative coupling between C(sp²)–H in unactivated benzamides and C(sp³)–H in simple alkanes, ethers and toluene derivatives was explored.     

Methods for direct C(sp2)–H bonds azidation

Direct functionalization of C–H bonds has attracted great attention in recent years from the perspectives of atom and step economy. In this context, a variety of processes have been developed for the construction of synthetically and biologically important organic azides through the oxidative C–H bonds azidation. In this review, we have summarized recent progress in the direct azidation of C(sp²)–H bonds. The review is divided into three major sections: (i) direct azidation of aromatic C–H bonds; (ii) direct azidation of olefinic C–H bonds; and (iii) direct azidation of aldehydic C–H bonds. Mechanistic aspects of the reactions are considered and discussed in detail.

Direct functionalization of C–H bonds has attracted great attention in recent years from the perspectives of atom and step economy.     

Transition-metal-catalyzed remote C–H functionalization of thioethers

In the last decade, transition-metal-catalyzed direct C–H bond functionalization has been recognized as one of most efficient approaches for the derivatization of thioethers. Within this category, both mono- and bidentate-directing group strategies achieved the remote C(sp²)–H and C(sp³)–H functionalization of thioethers, respectively. This review systematically introduces the major advances and their mechanisms in the field of transition-metal-catalyzed remote C–H functionalization of thioethers from 2010 to 2021.

This minireview systematically introduces the major advances and their mechanisms in the field of transition-metal-catalyzed remote C–H functionalization of thioethers.     

Recent advances in photochemical and electrochemically induced thiocyanation: a greener approach for SCN-containing compound formation

Techniques utilizing photo- and electrochemically induced reactions have been developed to accelerate organic processes. These techniques use light or electrical energy (electron transfer) as a direct energy source without using an initiator or reagent. Thiocyanates are found in biologically active and pharmacological compounds and can be converted into various functional groups. It is one of the most prominent organic scaffolds. Significant development in photo- and electro-chemically induced thiocyanation procedures has been made in recent years for the conception of carbon-sulfur bonds and synthesis of pharmaceutically important molecules. This review discusses different photo- and electro-chemically driven thiocyanation C(sp³)–SCN, C(sp²)–SCN, and C(sp)–SCN bond conception processes that may be useful to green organothiocyanate synthesis. We focus on the synthetic and mechanistic characteristics of organic photo- and electrochemically accelerated C–SCN bond formation thiocyanation reactions to highlight major advances in this novel green and sustainable research field.

Techniques utilizing photo- and electrochemically induced reactions have been developed to accelerate organic processes.     

Oxidative cross-dehydrogenative coupling (CDC) via C(sp2)–H bond functionalization: tert-butyl peroxybenzoate (TBPB)-promoted regioselective direct C-3 acylation/benzoylation of 2H-indazoles with aldehydes/benzyl alcohols/styrenes

An efficient, cost-effective, transition-metal-free, oxidative C_(sp²)–H/C_(sp²)–H cross-dehydrogenative coupling via a C_(sp²)–H bond functionalization protocol for the regioselective direct C-3 acylation/benzoylation of substituted 2H-Indazoles 1a–m with substituted aldehydes 2a–q/benzyl alcohols 5a–e/styrenes 6a–e is reported. The operationally simple protocol proceeds in the presence of tert-butyl peroxybenzoate (TBPB) as an oxidant in chlorobenzene (PhCl) as a solvent at 110 °C for 24 h under an inert atmosphere, which furnished a diverse variety of substituted 3-(acyl/benzoyl)-2H-indazoles 3a–q/4a–l in up to 87% yields. The reaction involves a free-radical mechanism and proceeds via the addition of an in situ generated acyl radical (from aldehydes/benzyl alcohols/styrenes) on 2H-indazoles. The functional group tolerance, broad substrate scope, control/competitive experiments and gram-scale synthesis and its application to the synthesis of anti-inflammatory agent 11 and novel indazole-fused diazepine 13 further signify the versatile nature of the developed methodology.

An efficient transition-metal-free oxidative C_(sp²)–H/C_(sp²)–H cross-dehydrogenative coupling via C_(sp²)–H bond functionalization for regioselective C-3 acylation/benzoylation of 2H-indazoles with aldehydes/benzyl alcohols/styrenes is reported.     

Computational study on palladium-catalyzed alkenylation of remote δ-C(sp3)–H bonds with alkynes: a new understanding of mechanistic insight and origins of site-selectivity

Palladium-catalyzed alkenylation of δ-C(sp³)–H bonds with alkynes was conducted by density functional theory calculations. The present study shows that the dimeric Pd₂(OAc)₄ mechanism reproduces experimental observations well, including regioselectivity and provides a deep mechanistic insight complementing the monomeric Pd(OAc)₂ mechanism recently reported by Chen''s group. In addition, the economical heterodimeric Ni–Pd(OAc)₄ was predicted to be a potential species for such alkenylation of δ-C(sp³)–H bonds.

Palladium-catalyzed alkenylation of δ-C(sp³)–H bonds with alkynes was conducted by DFT calculations, showing that the dimeric Pd₂(OAc)₄ mechanism reproduces experimental observations well.     

Auxiliary-directed etherification of sp2 C–H bonds under heterogeneous metal–organic framework catalysis: synthesis of ethenzamide

An efficient protocol for 8-aminoquinoline assisted alkoxylation and phenoxylation of sp² C–H bonds under heterogeneous catalysis was developed. The optimal conditions employed Cu-MOF-74 (20%), K₂CO₃ base, pyridine ligand or dimethyl formamide solvent, and O₂ oxidant at 80 °C or 100 °C for 24 hours. Cu-MOF-74 revealed remarkably higher activity when compared with other previously commonly used Cu-MOFs in cross coupling reactions, supported copper catalysts, and homogeneous copper salts. The reaction scope with respect to coupling partners included a wide range of various substrates. Interestingly, the developed conditions are applicable for the synthesis of high-profile relevant biological agents from easily accessible starting materials. Furthermore, a leaching test confirmed the reaction heterogeneity and the catalyst was reused and recycled at least 8 times with trivial degradation in activity.

An efficient protocol for 8-aminoquinoline assisted alkoxylation and phenoxylation of sp² C–H bonds under heterogeneous catalysis was developed.     

PLS regression-based chemometric modeling of odorant properties of diverse chemical constituents of black tea and coffee

Tea and coffee are the most attractive non-alcoholic beverages used worldwide due to the odorant properties of diverse components present in these beverages. The aim of this work is to investigate the key structural features which regulate the odorant properties of constituents present in black tea and coffee using regression-based chemometric models. We have also investigated the key structural properties which create the odor difference between tea and coffee. We have employed different variable selection strategies to extract the most relevant variables prior to development of final partial least squares (PLS) models. The models were extensively validated using different validation metrics, and the results justify the reliability and usefulness of the developed predictive PLS models. The best PLS model captured the necessary structural information on relative hydrophobic surface area, heteroatoms with higher number of multiple bonds, hydrogen atoms connected to C³(sp³)/C²(sp²)/C³(sp²)/C³(sp) fragments, electron-richness, C–O atom pairs at the topological distance 10 and surface weighted charged partial negative surface areas for explaining the odorant properties of the constituents present in black tea. On the other hand, C–S atom pairs at the topological distance 1, C–C atom pairs at the topological distance 5, donor atoms like N and O for hydrogen bonds, hydrogen atoms connected to C³(sp³)/C²(sp²)/C³(sp²)/C³(sp) fragments and R–CX–X fragments (where, R represents any group linked through carbon and X represents any heteroatom (O, N, S, P, Se, and halogens)) are the key structural components captured by the PLS model developed from the constituents present in coffee. The developed models can thus be successfully utilized for in silico prediction of odorant properties of diverse classes of compounds and exploration of the structural information which creates the odor difference between black tea and coffee.

We investigate the key structural features regulating the odorant properties of constituents present in black tea and coffee, the most attractive non-alcoholic beverages.     

Direct synthesis of 2-oxo-acetamidines from methyl ketones,aromatic amines and DMF via copper-catalyzed C(sp3)–H amidination

A convenient method for the synthesis of 2-oxo-acetamidines from methyl ketones using aromatic amines and DMF as nitrogen sources is reported via copper-catalyzed C(sp³)–H amidination. Various methyl ketones react readily with aromatic amines and DMF, producing 2-oxo-acetamidines in yields of 47 to 92%. This protocol features the simultaneous formation of C–N and C N bonds using DMF and aromatic amines as two different nitrogen sources. It thus provides an efficient approach to construct acyclic amidines via three C(sp³)–H bond amidination. Based on the preliminary experiments, a plausible mechanism of this transformation is disclosed.

A convenient method for the synthesis of 2-oxo-acetamidines from methyl ketones using aromatic amines and DMF as nitrogen sources is reported via copper-catalyzed C(sp³)–H amidination.     

Role of O–H⋯O/S conventional hydrogen bonds in considerable Csp2–H blue-shift in the binary systems of acetaldehyde and thioacetaldehyde with substituted carboxylic and thiocarboxylic acids

Stable binary complexes of RCZOH⋯CH₃CHZ (R = CH₃, H, F; Z = O, S) are due to contributions from the O–H⋯O/S and C_sp²–H⋯O/S hydrogen bonds. The strength of C_sp²/O–H⋯O is 1.5 to 2 times greater than that of the C_sp²/O–H⋯S bond. The substitution of H(C_sp²) of HCZOH by CH₃ causes a decrease in complex stability, while the opposite trend occurs for the F atom. A very large red shift of the O–H stretching frequency in O–H⋯O/S bonds was observed. A surprising C_sp²–H blue shift up to 104.5 cm⁻¹ was observed for the first time. It is found that the presence of O–H⋯O/S hydrogen bonds and a decisive role of intramolecular hyperconjugation interactions in the complex cause a significant blue shift of the C_sp²–H covalent bonds. A striking role of O compared to the S atom in determining the blue shift of C_sp²–H stretching vibration and stability of binary complexes is proposed. The obtained results show that the ratio of deprotonation enthalpy and proton affinity could be considered as an index for the classification of the non-conventional hydrogen bond. SAPT2+ results show that the strength of RCSOH⋯CH₃CHS complexes is dominated by electrostatic and induction energies, while a larger contribution to the stability of remaining complexes is detected for the electrostatic component.

The presence of O–H⋯O/S conventional hydrogen bonds in the complex governs a significant blue shift of Csp_²–H bonds.     

Cobalt(ii)-catalyzed benzylic oxidations with potassium persulfate in TFA/TFAA

A cobalt-catalyzed C(sp³)–H oxygenation reaction to furnish aldehyde was herein reported. This transformation demonstrated high chemo-selectivity, and tolerated various methylarenes bearing electron-withdrawing substituents. This reaction provided rapid access to diverse aldehydes form methylarenes. Notably, TFA/TFAA was used for the first time as a mixed solvent in cobalt-catalyzed oxygenation of benzylic methylenes.

A Co-catalyzed C(sp³)–H oxygenation reaction to furnish diverse aldehydes from methylarenes in TFA/TFAA is reported. This transformation demonstrated high chemo-selectivity, and tolerated with various methylarenes bearing electron-withdrawing substituents.     

Copper(ii)-catalyzed and acid-promoted highly regioselective oxidation of tautomerizable C(sp3)–H bonds adjacent to 3,4-dihydroisoquinolines using air (O2) as a clean oxidant

A mild, efficient and eco-friendly method for the oxidation of 1-Bn-DHIQs to 1-Bz-DHIQs without concomitant excessive oxidation of 1-Bz-DHIQs to 1-Bz-IQs is very important for the syntheses of 1-Bz-DHIQ alkaloids and analogues. In this article, we developed a novel Cu(ii)-catalyzed and acid-promoted highly regioselective oxidation of tautomerizable C(sp³)–H bonds adjacent to the C-1 positions of various 1-Bn-DHIQs. It was observed that when 0.2 equiv. of Cu(OAc)₂·2H₂O was used as the catalyst, 3.0 equiv. of AcOH was used as the additive and air (O₂) was used as a clean oxidant, various 1-Bn-DHIQs could be efficiently oxidized to corresponding 1-Bz-DHIQs at 25 °C in DMSO. Especially, almost no concomitant excessive oxidation of 1-Bz-DHIQs to 1-Bz-IQs was observed during the above reaction. In addition, this method was successfully applied in the first total synthesis of the alkaloid canelillinoxine.

A novel Cu(ii)-catalyzed and acid-promoted highly regioselective oxidation of tautomerizable C(sp³)–H bonds adjacent to 1-Bn-DHIQs was developed. This method was successfully applied in the first total synthesis of canelillinoxine.     

The role of sp2 and sp3 hybridized bonds on the structural,mechanical, and electronic properties in a hard BN framework

A first-principles approach is used to systematically investigate the role of sp² and sp³ hybridized bonds on the structural, mechanical, and electronic properties in a new BN phase (denoted Hex-(BN)₁₂). Hex-(BN)₁₂ has the same number of sp² and sp³ hybridized atoms. The calculated cohesion energy, phonon frequencies, and elastic constants unambiguously confirm the structural stability of this compound. Due to the different types of hybridization and B–N covalent bonds with ionic characteristics, Hex-(BN)₁₂ has unequal bond lengths and bond angles in these hybrid orbitals. These cause the relative energetic stability to be slightly lower than c-BN and w-BN. The hardness of Hex-(BN)₁₂ is estimated to range from 33 to 40 GPa. The bond-breaking order under stress is sp³–sp³, sp²–sp³, and sp²–sp². DFT calculations with the gradient approximation (GGA) and HSE06 functional indicate the electronic structure contains an indirect band gap at 3.21 and 4.42 eV, respectively. The electronic states in the region near the Fermi level primarily arise from the 2p orbitals in sp²-hybridized atoms. In general, sp³ bonded B and N atoms guarantee higher mechanical properties, and sp² bonded atoms ensure ductility and even conductivity, although all changes vary with spatial structure. Hex-(BN)₁₂ can be obtained from multilayer yne-BN, and BN nanosheets, nanotubes and nanoribbons under pressure.

A first-principles approach is used to systematically investigate the role of sp² and sp³ hybridized bonds on the structural, mechanical, and electronic properties in a new BN phase (denoted Hex-(BN)₁₂).     

Cross-dehydrogenative coupling reactions between arenes (C–H) and carboxylic acids (O–H): a straightforward and environmentally benign access to O-aryl esters

Transition-metal catalyzed cross-dehydrogenative-coupling reactions encompass highly versatile and atom economical methods for the construction of various carbon–carbon and carbon–heteroatom bonds by combining two C(X)–H (X = heteroatom) bonds. Along this line, direct acyloxylation of C–H bonds with carboxylic acids has emerged as a powerful and green approach for the synthesis of structurally diverse esters. In this focus-review we will describe recent progress in direct esterification of aromatic C–H bonds with special emphasis on the mechanistic features of the reactions. Literature has been surveyed until the end of February 2019.

Transition-metal catalyzed cross-dehydrogenative-coupling encompass atom economical methods for the construction of various carbon–carbon and carbon–heteroatom bonds by combining two C(X)–H (X = heteroatom) bonds.     

A multi pathway coupled domino strategy: I2/TBHP-promoted synthesis of imidazopyridines and thiazoles via sp3, sp2 and sp C–H functionalization

I₂/TBHP-promoted, one-pot, multi pathway synthesis of imidazopyridines and thiazoles has been achieved through readily available ethylarenes, ethylenearenes and ethynearenes. I₂/TBHP as an initiator and oxidant is used to realize the C–H functionalization of this domino reaction. Simple and available starting materials, wide range of functional group tolerance, high potential for drug activity of the products and application in production are the advantageous features of this method.

One-pot, multi-pathway, and atom economic synthesis of imidazoles and thiazoles has been achieved. In the catalytic system, I₂/TBHP as an initiator and oxidant is used to realize sp³, sp² and sp C–H functionalization.     

Computational insights into Ir(iii)-catalyzed allylic C–H amination of terminal alkenes: mechanism,regioselectivity, and catalytic activity

Computational studies on Ir(iii)-catalyzed intermolecular branch-selective allylic C–H amination of terminal olefins with methyl dioxazolone have been carried out to investigate the mechanism, including the origins of regioselectivity and catalytic activity difference. The result suggests that the reaction proceeds through generation of active species, alkene coordination, allylic C–H activation, decarboxylation, migratory insertion, and protodemetalation. The presence of AgNTf₂ could thermodynamically promote the formation of catalytically active species [Cp*Ir(OAc)]⁺. Both the weaker Ir–C(internal) bond and the closer interatomic distance of N⋯C(internal) in the key allyl-Ir(v)-nitrenoid intermediate make the migratory insertion into Ir–C(internal) bond easier than into the Ir–C(terminal) bond, leading to branch-selective allylic C–H amidation. The high energy barrier for allylic C–H activation in the Co system could account for the observed sluggishness, which is mainly ascribed to the weaker coordination capacity of alkenes to the triplet Cp*Co(OAc)⁺ and the deficient metal⋯H interaction to assist hydrogen transfer.

DFT studies on Ir(iii)-catalyzed branch-selective allylic C–H amination of terminal olefins with methyl dioxazolone have been carried out to investigate the mechanism, including the origins of regioselectivity and catalytic activity difference.     

Highly economical and direct amination of sp3 carbon using low-cost nickel pincer catalyst

Developing more efficient routes to achieve C–N bond coupling is of great importance to industries ranging from products in pharmaceuticals and fertilizers to biomedical technologies and next-generation electroactive materials. Over the past decade, improvements in catalyst design have moved synthesis away from expensive metals to newer inexpensive C–N cross-coupling approaches via direct amine alkylation. For the first time, we report the use of an amide-based nickel pincer catalyst (1) for direct alkylation of amines via activation of sp³ C–H bonds. The reaction was accomplished using a 0.2 mol% catalyst and no additional activating agents other than the base. Upon optimization, it was determined that the ideal reaction conditions involved solvent dimethyl sulfoxide at 110 °C for 3 h. The catalyst demonstrated excellent reactivity in the formation of various imines, intramolecularly cyclized amines, and substituted amines with a turnover number (TON) as high as 183. Depending on the base used for the reaction and the starting amines, the catalyst demonstrated high selectivity towards the product formation. The exploration into the mechanism and kinetics of the reaction pathway suggested the C–H activation as the rate-limiting step, with the reaction second-order overall, holding first-order behavior towards the catalyst and toluene substrate.

Developing more efficient routes to achieve efficient C–N bond coupling is of great importance to industries ranging from products in pharmaceuticals and fertilizers to biomedical technologies and next-generation electroactive materials.