Photocatalytic α-Tertiary Amine Synthesis via C−H Alkylation of Unmasked Primary Amines

A practical, catalytic entry to α,α,α-trisubstituted (α-tertiary) primary amines by C−H functionalisation has long been recognised as a critical gap in the synthetic toolbox. We report a simple and scalable solution to this problem that does not require any in situ protection of the amino group and proceeds with 100 % atom-economy. Our strategy, which uses an organic photocatalyst in combination with azide ion as a hydrogen atom transfer (HAT) catalyst, provides a direct synthesis of α-tertiary amines, or their corresponding γ-lactams. We anticipate that this methodology will inspire new retrosynthetic disconnections for substituted amine derivatives in organic synthesis, and particularly for challenging α-tertiary primary amines.     

On-Surface Synthesis of One-Dimensional Carbon-Based Nanostructures via C−X and C−H Activation Reactions

The past decades have witnessed the emergence of low-dimensional carbon-based nanostructures owing to their unique properties and various subsequent applications. It is of fundamental importance to explore ways to achieve atomically precise fabrication of these interesting structures. The newly developed on-surface synthesis approach provides an efficient strategy for this challenging issue, demonstrating the potential of atomically precise preparation of low-dimensional nanostructures. Up to now, the formation of various surface nanostructures, especially carbon-based ones, such as graphene nanoribbons (GNRs), kinds of organic (organometallic) chains and films, have been achieved via on-surface synthesis strategy, in which in-depth understanding of the reaction mechanism has also been explored. This review article will provide a general overview on the formation of one-dimensional carbon-based nanostructures via on-surface synthesis method. In this review, only a part of the on-surface chemical reactions (specifically, C−X (X=Cl, Br, I) and C−H activation reactions) under ultra-high vacuum conditions will be covered.     

Synthesis of Some Novel α-Cyanoketene-N,S-acetals Derived from Secondary Aliphatic Amines and Their Use in Pyrazole Synthesis

New α-cyanoketene-N,S-acetals 2(a–g) and β-dialkylamine-α-cyanoacrylates 3(g–i) were synthesized in good to excellent yields by the reaction of ethyl 2-cyano-3,3-bis(methylthio)acrylate 1 with secondary aliphatic amines (i.e., N-methylalkyl- and N-ethylalkylamines), and pyrrolidine, in the presence of triethylamine, under reflux in ethanol, for 1–16 h, depending on the amine used. Five N-methylalkyl amines and pyrrolidine yielded exclusively mono-substituted N,S-acetals 2(a–f) in good yields. On the other hand, N-ethylbenzylamine gave a mixture of monosubstituted products including N,S-acetal 2g in 35% yield and the unexpected product ethyl 3-[benzyl(ethyl)amino]-2-cyanoacrylate 3g in 50% yield. N-Ethylcyclohexylamine and N-ethylbutylamine did not produce N,S-acetals and gave only the unexpected products ethyl 2-cyano-3-[cyclohexyl(ethyl)amino]acrylate 3h and ethyl 3-[butyl(ethyl)amino]-2-cyanoacrylate 3i in good yields. The α-cyanoketene-N,S-acetals 2(a–f), 2j, and 2k underwent cyclization with the binucleophile hydrazine in ethanol under reflux to afford substituted pyrazoles 4(a–f), 4j, and 4k in good yields.

[Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resources: Full experimental and spectral details.]     

Simple and Mild One-Pot Synthesis of Dipeptidyl Ureas via Carbamoyl Azides of α-N-Protected Amino Acids

A simple and mild one-pot synthesis of potentially bioactive α-N-protected dipeptidyl ureas is reported. The procedure involves the reaction between the carbamoyl azide of an α-N-protected amino acid and an α-amino acid methyl ester. The reaction is fast (3 h at 45 °C), regardless of the nature of both the reagents, and racemization free. The reported protocol represents a valid alternative to existing methods.

Enantioselective Silylation of Aliphatic C−H Bonds for the Synthesis of Silicon-Stereogenic Dihydrobenzosiloles

A rhodium(I)-catalyzed enantioselective silylation of aliphatic C−H bonds for the synthesis of silicon-stereogenic dihydrobenzosiloles is demonstrated. This reaction involves a highly enantioselective intramolecular C(sp³)−H silylation of dihydrosilanes, followed by a stereospecific intermolecular alkene hydrosilylation leading to the asymmetrically tetrasubstituted silanes. A wide range of dihydrosilanes and alkenes displaying various functional groups are compatible with this process, giving access to a variety of highly functionalized silicon-stereogenic dihydrobenzosiloles in good to excellent yields and enantioselectivities.     

Synthesis of Acyclic Aliphatic Amides with Contiguous Stereogenic Centers via Palladium-Catalyzed Enantio-, Chemo- and Diastereoselective Methylene C(sp3)−H arylation

The enantioselective desymmetrizing C−H activation of α-gem-dialkyl acyclic amides remains challenging because the availability of four chemically identical unbiased methylene C(sp³)−H bonds and increased rotational freedoms of the acyclic systems add tremendous difficulties for chemo- and stereocontrol. We have developed a method for the synthesis of acyclic aliphatic amides with α,β-contiguous stereogenic centers via Pd^II-catalyzed asymmetric arylation of unbiased methylene C(sp³)−H, in good yields and with high levels of enantio-, chemo- and diastereoselectivity (up to >99 % ee and >20:1 d.r.). Successive application of this method enables the sequential arylation of the gem-dialkyl groups with two different aryl iodides, giving a range of β-Ar¹-β′-Ar²-aliphatic acyclic amides containing three contiguous stereogenic centers with excellent diastereoselectivity.     

Iodine-Promoted Domino Oxidative Cyclization for the One-Pot Synthesis of Novel Fused Four-Ring Quinoxaline Fluorophores by sp3 C−H Functionalization

A method for the synthesis of novel fused four-ring quinoxaline skeleton has been described by an I₂ promoted sp³ C−H functionalization between 1,2,3,3-tetramethyl-3H-indolium iodides and 1,2-diamines. This transformation proceeds smoothly under metal- and peroxide-free conditions through a sequential iodination, oxidation, annulation and rearrangement. Moreover, 8,9-dichloro-5,12,12-trimethyl-2-(trifluoromethyl)-5,12-dihydroquinolino[2,3-b]quinoxaline showed good photophysical properties and was used in live cell imaging, indicating the potential value of this skeleton as a fluorophore in probes.     

Isoindolinone Synthesis via One-Pot Type Transition Metal Catalyzed C−C Bond Forming Reactions

Isoindolinone structure is an important privileged scaffold found in a large variety of naturally occurring as well as synthetic, biologically and pharmaceutically active compounds. Owing to its crucial role in a number of applications, the synthetic methodologies for accessing this heterocyclic skeleton have received significant attention during the past decade. In general, the synthetic strategies can be divided into two categories: First, direct utilization of phthalimides or phthalimidines as starting materials for the synthesis of isoindolinones; and second, construction of the lactam and/or aromatic rings by different catalytic methods, including C−H activation, cross-coupling, carbonylation, condensation, addition and formal cycloaddition reactions. Especially in the last mentioned, utilization of transition metal catalysts provides access to a broad range of substituted isoindolinones. Herein, the recent advances (2010–2020) in transition metal catalyzed synthetic methodologies via formation of new C−C bonds for isoindolinones are reviewed.     

Triton B–Mediated Mild,Convenient, and Efficient Method for the Selective Alkylation of Cyclic Secondary Amines and Thiols

Alkylation of cyclic secondary amines, thiols, and pyridazinones has been demonstrated with alkyl halides using Triton B as base and reaction medium.     

TEMPO-Mediated Selective Synthesis of Isoxazolines, 5-Hydroxy-2-isoxazolines,and Isoxazoles via Aliphatic δ-C(sp3)-H Bond Oxidation of Oximes

Selective synthesis of three different bioactive heterocycles; isoxazolines, 5-hydroxy-2-isoxazolines and isoxazoles from the same starting material using TEMPO (2,2,6,6-Tetramethylpiperidin-1-oxyl) as a radical initiator is reported. Selectivity was achieved using different oxidants with TEMPO. The reaction goes through a 1,5-HAT (hydrogen atom transfer) process resulting in products with good yields. This strategy offers a straightforward route to three different heterocycles from oximes via radical-mediated C(sp³)-H oxidation.     

One-Pot Dual C−C Coupling Reaction via Site Selective Cascade Formation by PdII-Cryptate of an Amino-Ether Heteroditopic Macrobicycle

Selectivity of aryl iodo over ethynyl iodo toward the Suzuki cross coupling reaction is explored by utilizing a palladium complex of amino-ether heteroditopic macrobicycle. Subsequently, unreacted ethynyl iodide undergoes homocoupling reaction in the same catalytic atmosphere, thereby representing a cascade dual C−C coupling reaction. Furthermore, this approach is extended for novel one-pot synthesis of unsymmetrical 1,3-diynes.     

Divergent Coupling of Benzocyclobutenones with Indoles via C−H and C−C Activations

Highly selective divergent coupling reactions of benzocyclobutenones and indoles, in which the chemoselectivity is controlled by catalysts, are reported herein. The substrates undergo C2(indole)–C8(benzocyclobutenone) coupling to produce benzylated indoles and benzo[b]carbazoles in the Ni- and Ru-catalyzed reactions. A completely different selectivity pattern C2(indole)–C2(benzocyclobutenone) coupling to form arylated indoles is observed in the Rh-catalyzed reaction. Preliminary mechanistic studies suggest C−H and C−C activations in the reaction pathway. Synthetic utility of this protocol is demonstrated by the selective synthesis of three different types of carbazoles from the representative products.     

Coupling of Methyl Ketones and Primary or Secondary Amines Leading to α-Ketoamides

A metal-free oxidative coupling of methyl ketones and primary or secondary amines to α-ketoamides has been developed. Four intermediates, α-iodoketone, α-aminoketone, iminium intermediate, and α-hydroxy amine have been identified through a series of control experiments. The atom-economic methodology can be scaled-up, tolerates a variety of functional groups, and is operationally simple.     

Synthesis of reversible PAD4 inhibitors via copper-catalyzed C−H arylation of benzimidazole

PAD4 is a promising epigenetic drug target for various cancers and immune diseases. In this work, we applied a Cu-catalyzed C–H arylation reaction of N-heteroarene to the synthesis of complex non-covalent PAD4 inhibitors bearing a bi-heteroaryl pharmacophore. This strategy allowed us to access various analogs of C_2-aryl substituted benzimidazoles from a common benzimidazole core and easily accessible aryl iodides. Preliminary SAR studies revealed the indole motif of GSK-484 is critical to its activity. Replacing the N-cyclopropylmethyl group to N-benzyl group on the indole ring of GSK-484 resulted in more than5-fold increase in cell killing efficacy against 4T1 cell line.     

Synthesis of Stannylated Aryl Imines and Amines via Aryne Insertion Reactions into Sn−N Bonds

The reaction of in situ generated arynes with stannylated imines to provide ortho-stannyl-aniline derivatives is reported. The readily prepared trimethylstannyl benzophenone imine is introduced as an efficient reagent to realize the aryne σ-insertion reaction. The imine functionality is an established N-protecting group and insertions proceed with good yields and good to excellent regioselectivities. The product anilines are valuable starting materials for follow-up chemistry thanks to the rich chemistry offered by the trimethylstannyl moiety.     

Ligand-Enabled β-Methylene C(sp3)−H Arylation of Masked Aliphatic Alcohols

Despite recent advances, reactivity and site-selectivity remain significant obstacles for the practical application of C(sp³)−H bond functionalization methods. Here, we describe a system that combines a salicylic-aldehyde-derived L,X-type directing group with an electron-deficient 2-pyridone ligand to enable the β-methylene C(sp³)−H arylation of aliphatic alcohols, which has not been possible previously. Notably, this protocol is compatible with heterocycles embedded in both alcohol substrates and aryl coupling partners. A site- and stereo-specific annulation of dihydrocholesterol and the synthesis of a key intermediate of englitazone illustrate the practicality of this method.     

Synthesis of Conjugated Polymers via Transition Metal Catalysed C−H Bond Activation

Transition metal catalysed C−H bond activation chemistry has emerged as an exciting and promising approach in organic synthesis. This allows us to synthesize a wider range of functional molecules and conjugated polymers in a more convenient and more atom economical way. The formation of C−C bonds in the construction of pi-conjugated systems, particularly for conjugated polymers, has benefited much from the advances in C−H bond activation chemistry. Compared to conventional transition-metal catalysed cross-coupling polymerization such as Suzuki and Stille cross-coupling, pre-functionalization of aromatic monomers, such as halogenation, borylation and stannylation, is no longer required for direct arylation polymerization (DArP), which involve C−H/C−X cross-coupling, and oxidative direct arylation polymerization (Ox-DArP), which involves C−H/C−H cross-coupling protocols driven by the activation of monomers’ C(sp²)−H bonds. Furthermore, poly(annulation) via C−H bond activation chemistry leads to the formation of unique pi-conjugated moieties as part of the polymeric backbone. This review thus summarises advances to date in the synthesis of conjugated polymers utilizing transition metal catalysed C−H bond activation chemistry. A variety of conjugated polymers via DArP including poly(thiophene), thieno[3,4-c]pyrrole-4,6-dione)-containing, fluorenyl-containing, benzothiadiazole-containing and diketopyrrolopyrrole-containing copolymers, were summarized. Conjugated polymers obtained through Ox-DArP were outlined and compared. Furthermore, poly(annulation) using transition metal catalysed C−H bond activation chemistry was also reviewed. In the last part of this review, difficulties and perspective to make use of transition metal catalysed C−H activation polymerization to prepare conjugated polymers were discussed and commented.     

Synthesis of Diverse Functionalized Quinoxalines by Oxidative Tandem Dual C−H Amination of Tetrahydroquinoxalines with Amines

The tandem dual C−H amination of tetrahydroquinoxalines with free amines under aerobic copper catalysis conditions has been demonstrated. The synthetic protocol proceeds with good substrate and functional group compatibility, mild reaction conditions, short reaction time, the use of the naturally abundant [Cu]/O₂ catalyst system, excellent chemoselectivity and synthetic efficiency, and with no need for the pre-installation of specific aminating agents, which offers a practical platform for the rapid and diverse synthesis of diaminoquinoxalines. Moreover, this work has shown the potential of single-electron-oxidation-induced C−H functionalization of N-heterocycles, and its application in the development of optoelectronic materials.     

Anionic Synthesis of Primary and Secondary Amine-Functionalized Polymers Using Imine Chemistry

There has been growing interest and research on new synthetic methods for thepreparation of well-defined polymers with chain-end functional groups[1～ 7] . Thesefunctional groups in polymers can participate in reversible ionic association;chainextension,branching,or crosslinking reactions with polyfunctional reagents;couplingand linking with reactive groups in other oligomer or polymer chains;and initiation ofpolymerization of other monomers[4～ 6] . The methodology of living anionic polyme-ri…     

Versatile Biocatalytic C(sp3)−H Oxyfunctionalization for the Site- Selective and Stereodivergent Synthesis of α- and β-Hydroxy Acids

C(sp³)−H oxyfunctionalization, the insertion of an O-atom into C(sp³)−H bonds, streamlines the synthesis of complex molecules from easily accessible precursors and represents one of the most challenging tasks in organic chemistry with regard to site and stereoselectivity. Biocatalytic C(sp³)−H oxyfunctionalization has the potential to overcome limitations inherent to small-molecule-mediated approaches by delivering catalyst-controlled selectivity. Through enzyme repurposing and activity profiling of natural variants, we have developed a subfamily of α-ketoglutarate-dependent iron dioxygenases that catalyze the site- and stereodivergent oxyfunctionalization of secondary and tertiary C(sp³)−H bonds, providing concise synthetic routes towards four types of 92 α- and β-hydroxy acids with high efficiency and selectivity. This method provides a biocatalytic approach for the production of valuable but synthetically challenging chiral hydroxy acid building blocks.