Alkene Carboarylation through Catalyst-Free,Visible Light-Mediated Smiles Rearrangement

A light-mediated Truce–Smiles arylative rearrangement is described that proceeds in the absence of any photocatalyst. The protocol creates two C−C bonds from simple starting materials, with the installation of an aryl ring and a difluoroacetate moiety across unactivated alkenes. The reaction proceeds via a radical mechanism, utilizing a light-mediated reduction of ethyl bromodifluoroacetate by N,N,N′,N′-tetramethylethylenediamine (TMEDA) to set up intermolecular addition to an unactivated alkene, followed by Truce–Smiles rearrangement.     

One-Pot Synthesis of N-Benzyl/Allyl-N-phenyl-2-benzothiazolamines from 1-(2-Iodophenyl)-3-phenylthioureas and Benzyl/Allyl Halides

A facile method for the copper-catalyzed synthesis of N-benzyl-N-phenyl-2-benzothiazolamines was explored. In the presence of CuI, N-phenylbenzothiazolamines was in situ generated from substituted 1-(2-iodophenyl)-3-phenylthioureas, which susequently underwent coupling with benzyl/allyl halides to give the desired N-benzyl/allyl-N-phenyl-2-benzothiazolamines fluently in a one-pot manner. The protocol features easy performance, easily available materials, good yield and broad substrates scope, showing potential synthetic value for the preparation of a variety of biologically or pharmaceutically active compounds.     

Reduction of N,N‐Dimethylcarboxamides to Aldehydes by Sodium Hydride–Iodide Composite

A new and concise protocol for selective reduction of N,N‐dimethylamides into aldehydes was established using sodium hydride (NaH) in the presence of sodium iodide (NaI) under mild reaction conditions. The present protocol with the NaH‐NaI composite allows for reduction of not only aromatic and heteroaromatic but also aliphatic N,N‐dimethylamides with wide substituent compatibility. Retention of α‐chirality in the reduction of α‐enantioriched amides was accomplished. Use of sodium deuteride (NaD) offers a new step‐economical alternative to prepare deuterated aldehydes with high deuterium incorporation rate. The NaH‐NaI composite exhibits unique chemoselectivity for reduction of N,N‐dimethylamides over ketones.     

Rhodium-Catalyzed C8-Alkenylation of Isoquinolones with Maleimides

An efficient Rh(III)-catalyzed C−H alkenylation of N-protected isoquinolone with maleimides is reported. The carbonyl group of isoquinolone acts as an inherent directing group. Various N-substituents in the maleimide, including alkyl, aryl, and even H and −OH, were well tolerated under the developed reaction condition. This protocol showed broad substrate scope, good selectivity, and excellent yields. Hammett plot is also drawn to check the effect of substituents on the reaction progress.     

Diversity Oriented Synthesis of Indoloazepinobenzimidazole and Benzimidazotriazolobenzodiazepine from N1‐Alkyne‐1,2‐diamines

A one‐pot protocol for the diversity oriented synthesis of two N‐polyheterocycles indoloazepinobenzimidazole and benzimidazotriazolobenzodiazepine from a common N¹‐alkyne‐1,2‐diamine building block is described. The approach involves sequential formation of benzimidazole through cyclocondensation and oxidation, which is followed by the formation of either an azepine ring (through alkyne activation and 6‐endo‐dig cyclization, 1,2‐migration with ring expansion, and re‐aromatization), or diazepine and triazole rings through 1,3‐dipolar cycloaddition.     

Palladium-Catalyzed Aminocarbonylation of Aryl Halides with N,N-Dialkylformamide Acetals

We developed a protocol for the palladium-catalyzed aminocarbonylation of aryl halides using less-toxic formamide acetals as bench-stable aminocarbonyl sources under neutral conditions. Various aryl (including heteroaryl) halides reacted with N,N-dialkylformamide acetals in the presence of a catalytic amount of tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct and xantphos to give the corresponding aromatic carboxamides at 90–140 °C without any activating agents or bases in up to quantitative chemical yield. This protocol was applied to aryl bromides, aryl iodides, and trifluoromethanesulfonic acid, as well as to relatively less-reactive aryl chlorides. A wide range of functionalities on the aromatic ring of the substrates were tolerated under the aminocarbonylation conditions. The catalytic aminocarbonylation was used to prepare the insect repellent N,N-diethyl-3-methylbenzamide as well as a synthetic intermediate of the dihydrofolate reductase inhibitor triazinate.     

Rh-Catalyzed Decarbonylative Cross-Coupling between o-Carboranes and Twisted Amides: A Regioselective,Additive-Free,and Concise Late-Stage Carboranylation

The convenient cross-coupling of sp² or sp³ carbons with a specific boron vertex on carborane cage represents significant synthetic values and insurmountable challenges. In this work, we report an Rh-catalyzed reaction between o-carborane and N-acyl-glutarimides to construct various B_cage−C bonds. Under the optimized condition, the removable imine directing group (DG) leads to B(3)− or B(3,6)−C couplings, while the pyridyl DG leads to B(3,5)−Ar coupling. In particular, an unexpected rearrangement of amide reagent is observed in pyridyl directed B(4)−C(sp³) formation. This scalable protocol has many advantages, including easy access, the use of cheap and widely available coupling agents, no requirement of an external ligand, base or oxidant, high efficiency, and a broad substrate scope. Leveraging the Rh^I dimer and twisted amides, this method enables straightforward access to diversely substituted and therapeutically important carborane derivatives at boron site, and provides a highly valuable vista for carborane-based drug screening.     

Expanding the Chemical Space of Non-Proteinogenic N4-Substituted Asparagine: Racemic,Enantioenriched, and Deuterated Derivatives

A site-selective carbamoylation strategy to access non-proteinogenic N⁴-modified asparagines has been described. The protocol is characterized by mild reaction conditions, high functional group compatibility, and a wide diversity of functionalized carbamoyl radicals making possible the access to peptides, pharmaceuticals, and natural N⁴-asparagine conjugates, as well as enantioenriched unnatural N⁴-asparagines. Besides that, deuterated analogues were achieved with the insertion of D₂O and enantioenriched derivatives could be obtained in 15 min in continuous-flow conditions.     

Exploring Synthetic Strategies for 1H-Indazoles and Their N-Oxides: Electrochemical Synthesis of 1H-Indazole N-Oxides and Their Divergent C−H Functionalizations

The selective electrochemical synthesis of 1H-indazoles and their N-oxides and the subsequent C−H functionalization of the 1H-indazole N-oxides are described. The electrochemical outcomes were determined by the nature of the cathode material. When a reticulated vitreous carbon cathode was used, a wide range of 1H-indazole N-oxides were selectively synthesized, and the electrosynthesis products were deoxygenated to N-heteroaromatics, owing to cathodic cleavage of the N−O bond via paired electrolysis, when a Zn cathode was used. The scope of this electrochemical protocol is broad, as both electron-rich and electron-poor substrates were tolerated. The potency of this electrochemical strategy was demonstrated through the late-stage functionalization of various bioactive molecules, making this reaction attractive for the synthesis of 1H-indazole derivatives for pharmaceutical research and development. Detailed mechanistic investigations involving electron paramagnetic resonance spectroscopy and cyclic voltammetry suggested a radical pathway featuring iminoxyl radicals. Owing to the rich reactivity of 1H-indazole N-oxides, diverse C−H functionalization reactions were performed. We demonstrated the synthetic utility of 1H-indazole N-oxides by synthesizing the pharmaceutical molecules lificiguat and YD (3); key intermediates for bendazac, benzydamine, norepinephrine/serotonin reuptake inhibitors, SAM-531, and gamendazole analogues; and a precursor for organic light-emitting diodes.     

Copper‐Catalyzed Reductive N‐Alkylation of Amides with N‐Tosylhydrazones Derived from Ketones

A CuI‐catalyzed reductive coupling of ketone‐derived N‐tosylhydrazones with amides is presented. Under the optimized conditions, an array of N‐tosylhydrazones derived from aryl–alkyl and diaryl ketones could couple effectively with a wide variety of (hetero)aryl as well as aliphatic amides to afford the N‐alkylated amides in high yields. The method represents the very few examples for reliably accessing secondary and tertiary amides through a reductive N‐alkylation protocol.     

Nickel-Catalyzed Amination of (Hetero)aryl Halides Facilitated by a Catalytic Pyridinium Additive

An efficient and operationally simple Ni-catalyzed amination protocol has been developed. This methodology features a simple Ni^II salt, an organic base and catalytic amounts of both a pyridinium additive and Zn metal. A diverse number of (hetero)aryl halides were coupled successfully with primary and secondary alkyl amines, and anilines in good to excellent yields. Similarly, benzophenone imine gave the corresponding N-arylation product in an excellent yield.     

Direct,Enantioselective, and Nickel(II) Catalyzed Reactions of N-Azidoacetyl Thioimides with Trimethyl Orthoformate: A New Combined Methodology for the Rapid Synthesis of Lacosamide and Derivatives

A direct and highly enantioselective reaction of N-azidoacetyl-1,3-thiazolidine-2-thione with trimethyl orthoformate catalyzed by Tol-BINAPNiCl₂ in the presence of TESOTf and 2,6-lutidine is reported. The heterocyclic scaffold can be easily removed by addition of a wide array of amines to give the corresponding enantiomerically pure 2-azido-3,3-dimethoxypropanamides in high yields. Appropriate manipulation of the N-benzyl amide derivative provides an efficient access to the antiepileptic agent lacosamide through a new enantioselective C−C bond-forming process. DFT computational studies uncover clues for the understanding of the remarkable stereocontrol of the addition of a nickel(II) enolate to a putative oxocarbenium intermediate from trimethyl orthoformate.     

Synthesis of novel N-aryl-N-(1H-tetrazol-5-yl)benzenesulfonamides in water

N-Aryl-N-(1H-tetrazol-5-yl)benzenesulfonamides were synthesized via an eco-friendly protocol using ZnBr₂-catalyzed [2 + 3] cycloaddition reaction of N-cyano-N-arylbenzenesulfonamides and sodium azide under reflux conditions in water. The products were obtained in excellent yields via an easy work-up procedure.     

N-Boc-Protected α-Amino Acids by 1,3-Migratory Nitrene C(sp3)−H Insertion

N-Boc-protected α-amino acids are synthesized in two steps from linear or branched carboxylic acid feedstocks. In the first step, the carboxylic acid is coupled with tert-butyl aminocarbonate (BocNHOH) to generate azanyl ester (acyloxycarbamate) RCO₂NHBoc. In the second step, this azanyl ester undergoes a stereocontrolled iron-catalyzed 1,3-nitrogen migration to generate the N-Boc-protected non-racemic α-amino acid. This straightforward protocol is applicable to the catalytic asymmetric synthesis of α-monosubstituted α-amino acids with aryl, alkenyl, and alkyl side chains. Furthermore, α,α-disubstituted α-amino acids are accessible in an enantioconvergent fashion from racemic carboxylic acids. The new method is also advantageous for the synthesis of α-deuterated α-amino acids. N-Boc-protected α-amino acids synthesized using this two-step protocol are ready-to-use building blocks.     

Syntheses,Crystal Structure and Reactivity of Tin(II) Bis[N‐(diphenylphosphanyl)(2‐pyridylmethyl)amide]

Metallation of N‐(diphenylphosphanyl)(2‐pyridylmethyl)amine with n‐butyllithium in toluene yields lithium N‐(diphenylphosphanyl)(2‐pyridylmethyl)amide ( 1 ), which crystallizes as a tetramer. Transamination of N‐(diphenylphosphanyl)(2‐pyridylmethyl)amine with an equimolar amount of Sn[N(SiMe₃)₂]₂ leads to the formation of monomeric bis(trimethylsilyl)amido tin(II) N‐(diphenylphosphanyl)(2‐pyridylmethyl)amide ( 2 ). The addition of another equivalent of N‐(diphenylphosphanyl)(2‐pyridylmethyl)amine gives homoleptic tin(II) bis[N‐(diphenylphosphanyl)(2‐pyridylmethyl)amide] ( 3 ). In these complexes the N‐(diphenylphosphanyl)(2‐pyridylmethyl)amido groups act as bidentate bases through the nitrogen bases. At elevated temperatures HN(SiMe₃)₂ is liberated from bis(trimethylsilyl)amido tin(II) N‐(diphenylphosphanyl)(2‐pyridylmethyl)amide ( 2 ) yielding mononuclear tin(II) 1,2‐dipyridyl‐1,2‐bis(diphenylphosphanylamido)ethane ( 4 ) through a C–C coupling reaction. The three‐coordinate tin(II) atoms of 2 and 4 adopt trigonal pyramidal coordination spheres.     

Cu2O/Cs2CO3/DMF: An efficient catalytic system for N-arylation of imidazole with aryl halides under ligand-free conditions

A ligand-free Cu-catalyzed protocol for the Ullmann-type N-arylation of N-containing heterocycles with aryl or heteroaryl iodides and bromides has been established. A broad range of functional groups is well tolerated on both of the cross-coupling partners, producing the desired products in good to excellent yields.     

Substituent chemical shifts of N‐arylsuccinanilic acids,N‐arylsuccinimides,N‐arylmaleanilic acids,and N‐arylmaleimides

NMR spectra of a series of N‐arylsuccinanilic acids, N‐arylsuccinimides, N‐arylmaleanilic acids, and N‐arylmaleimides were examined to estimate the electronic effect of the amide and imide groups on the chemical shifts of the hydrogen and carbon nuclei of the benzene ring. Copyright © 2009 John Wiley & Sons, Ltd.     

Amine Exchange Reactions in Ionic Liquid

An operationally simple, inexpensive, efficient, and environmentally friendly protocol for the amine exchange reactions of 3-N,N-dimethylaminopropiophenone and N,N-dimethylaminomethylferrocene with primary aryl amines is developed using the ionic liquid [bmim]PF ₆ as a solvent. The recovered ionic liquid can be reused for several cycles with constant activity.     

Synthesis,characterization, and polymerization of N-vinylarylamines

Several N-vinylarylamines have been prepared by direct N-vinylation of arylamine salts with acetylene at atmospheric pressure. Nuclear magnetic resonance (NMR) spectra of the various N-vinylarylamines were recorded and chemical shift assignments were made for the first time. The vinyl protons of the enamines generally exhibit an ABX pattern. The electron-rich monomers are sensitive to acid-catalyzed hydrolysis in a wet solvent. Polymerizations of the monomers were carried out at low temperatures with phosphorous pentafluoride as an initiator. It was found that PF₅ generated directly from thermal decomposition of p-chlorobenzenediazonium hexafluorophosphate is useful in the preparation of an extremely high-molecular-weight poly(N-vinylcarbazole) (M _w = 3 × 10⁶) with a narrow molecular weight distribution (MWD = 2.1). The polymerizability of N-vinylarylamines appears to vary with the amine functional groups of the monomers. N-vinylarylamine containing a planar amine moiety such as carbazole forms a higher-molecular-weight polymer than the monomers with the nonplanar bulky amine groups.     

Efficient Synthesis of 2-Methylene-3phosphorylalkanoates: Phosphorylation of Baylis–Hillman Bromides via an S N 2-S N 2′ Strategy

A novel synthesis of 2-methylene-3-phosphorylalkanoates under mild conditions is described. Thus, Balyis–Hillman bromides react with secondary phosphine oxides or H-phosphonites in the presence of DABCO via an S _N 2-S _N 2′ protocol to produce the target compounds in good yields.