Aniline Substrates Research Articles

Direct N‐Alkylation of Amines with Alcohols Catalyzed by N‐Heterocyclic Carbene Cobalt‐Pincer Catalyst under Mild Conditions

AbstractAlcohols are widely available and can be derived from renewable resources. Catalytic alcohol amination for N‐alky amine synthesis using the borrowing hydrogen strategy is an environmentally benign and prominent sustainable method, which produces water as the sole byproduct. However, expensive noble metals are generally employed for this transformation, while the nonprecious metal‐based catalysts were also known for this reaction and have attracted considerable attention recently. Herein, an efficient N‐alkylation of amines with alcohols using base‐metal cobalt catalysts is reported. This reaction is catalyzed by an N‐heterocyclic carbene cobalt‐pincer catalyst and the reaction operates simply and under mild conditions. Various alcohol and aniline substrates and functional groups including nitrile, ether, thioether and alkene could be well tolerated. Moreover, experimental studies and DFT calculations were also performed to illustrate the reaction mechanism. Our results suggest that the N‐alkylation reaction proceeds via a hydrogen autotransfer mechanism.

H2 O ⋅ B(C6 F5 )3 -Catalyzed para-Alkylation of Anilines with Alkenes Applied to Late-Stage Functionalization of Non-Steroidal Anti-Inflammatory Drugs.

Anilines are core motifs in a variety of important molecules including medicines, materials and agrochemicals. We report a straightforward procedure that allows access to new chemical space of anilines via their para-C-H alkylation. The method utilizes commercially available catalytic H2 O ⋅ B(C6 F5 )3 and is highly selective for para-C-alkylation (over N-alkylation and ortho-C-alkylation) of anilines, with a wide scope in both the aniline substrates and alkene coupling partners. Readily available alkenes are used, and include new classes of alkene for the first time. The mild reaction conditions have allowed the procedure to be applied to the late-stage-functionalization of non-steroidal anti-inflammatory drugs (NSAIDs), including fenamic acids and diclofenac. The formed novel NSAID derivatives display improved anti-inflammatory properties over the parent NSAID structure.

Rapid Access to Densely Functionalized Cyclopentenyl Sulfoximines through a Sc-Catalyzed Aza-Piancatelli Reaction.

Sulfoximines make up a class of compounds of growing interest for crop science and medicinal chemistry, but methods for directly incorporating them into complex molecular scaffolds are lacking. Here we report a scandium-catalyzed variant of the aza-Piancatelli cyclization that can directly incorporate sulfoximines as nucleophiles rather than the classical aniline substrates. Starting from 2-furylcarbinols and sulfoximines, the reaction provides direct access to 4-sulfoximinocyclopentenones, a new scaffold bearing cyclopentenone and sulfoximine motifs, both of interest for bioactive compounds.

Direct Alkylative Amination using 1-Allylsilatrane.

Homoallylic amines prepared via addition of allylsilanes often require preformed imine substrates, metal catalysts, fluoride activators, or use of protected amines. In this metal-free, air- and water-tolerant procedure, aromatic aldehyde and aniline substrates undergo direct alkylative amination using easily accessible 1-allylsilatrane.

Chemoenzymatic Synthesis of Phenol Diarylamine Using Non-Heme Diiron N-Oxygenase

Diarylamines are important moieties in organic materials and bioactive molecules. The traditional synthetic approach to diarylamines is metal catalysis in organic solvents. Herein, we report the chemoenzymatic synthesis of phenol diarylamines. Non-heme diiron N-oxygenase AzoC, which catalyzes the oxidization of amines to nitroso groups for azoxymycin biosynthesis in Streptomyces chattanoogensis, is engineered as a catalyst. This synthetic method tolerates a broad range of phenol and aniline substrates. The mechanistic study indicates that the enzymatically formed nitroso intermediate coupled to phenoxide facilitates the nonenzymatic diarylamine synthesis. Our study suggests that diarylamines can be enzymatically synthesized in aqueous solutions and highlights the synthetic potential of non-heme diiron N-oxygenases.

Magnetically Separable Visible Light-Active Ag0.75Ni0.25 Binary Alloy Nanoparticles as a Highly Efficient Photocatalyst for the Selective Oxidative Coupling of Aniline to Azobenzene.

Aniline wastes can be converted to useful pharmaceutical and industrial compounds like azobenzene. For this purpose, a bimetallic Ag0.75Ni0.25 alloy is designed in the nanoscale range resembling a fivefold twinned morphology using water as the solvent. These newly developed alloy nanoparticles (NPs) are employed for the first time as an efficient visible light-active photocatalyst for the oxidative homocoupling of aniline to azobenzene. Our catalytic protocol is highly sustainable for a large number of aniline substrates with a high yield of the product (up to 95%), which might be attributed to the combinational and superior properties achieved on alloy formation in comparison to the monometallic counterparts. High-electron density amines (p-anisidine) display greater photocatalytic proficiency than that of low-electron density amines (4-fluoroaniline). The developed photocatalyst is magnetically well-separable and can be reused for at least five catalytic cycles without appreciable loss in its activity.

Synthesis of 1,2-Fused/Disubstituted Benzimidazoles and Benzimidazolium Salts by I2-Mediated sp3 C-H Amination.

An intramolecular sp3 C-H amination reaction of aniline derivatives has been established. This reaction employs molecular iodine (I2) under transition-metal-free conditions and produces 1,2-fused or 1,2-disubstituted benzimidazoles. This operationally simple synthetic process works well with N-substituted aniline substrates, forming novel benzimidazolium frameworks. Under the optimal reaction conditions, a broad variety of 1,2-fused/disubstituted benzimidazoles and benzimidazolium salts, including several bioactive compounds, were synthesized from readily accessible precursors in an efficient and scalable fashion.

Palladium-Catalyzed para-C-H Arylation of Anilines with Aromatic Halides.

Controlling regioselectivity in C-H functionalizations is a key challenge in chemical method development. In arenes, functionalizations are most difficult to direct towards the C-H group furthest away from a substituent, in its para position. We herein demonstrate how the para-C-H arylation of anilines with non-activated aryl halides, elusive to date, is achieved by a base-assisted "metalla-tautomerism" approach. A proton is abstracted from the aniline substrate and replaced by an arylpalladium species, generated from the aryl halide coupling partner. In this step, the palladium is directed away from the N- to the tautomeric para-C-H position by a large phosphine ligand combined with a triphenylmethyl shielding group. The triphenylmethyl group is easily installed and removed, and can be recycled.

Highly Selective Catalyst‐Free Oxidative Synthesis of N‐Formamides from C2‐ and C3‐Feedstocks

AbstractThe application of bio‐derived feedstocks as building blocks in organic syntheses holds great value with goals of high product yield and minimizing carbon loss. As contribution to this effort, present work explores 5 different C2‐ and C3‐feedstocks (derived from biomass and conventional sources) such as glycerol (GLY), 1,3‐dihydroxyacetone (DHA), ethylene glycol (EG), glycolic acid (GLYAC) and glyoxal (GLYOX) as carbon sources for highly selective, catalyst‐free oxidative synthesis of N‐formamides from primary and secondary amines. Both DHA and GLYOX showed the best carbon efficiency through carbon source: amine ratio of 1 : 2, resulting in 100 % selectivity of N‐formanilide with tert‐butyl hydrogen peroxide (TBHP) as the oxidant. GLYOX was applied further for synthesizing a N‐formamide library of 21 substrates exemplifying substantial yields ranging from 68–98 %. Moreover, pilot scalability of this methodology achieved a yield of 87 % and 72 % for aniline substrate at 5‐gram scale using GLYOX and DHA respectively in 24 hours.

Microwave-Assisted, Metal- and Azide-Free Synthesis of Functionalized Heteroaryl-1,2,3-triazoles via Oxidative Cyclization of N-Tosylhydrazones and Anilines.

As the search for competent soft-Lewis basic complexants for separations continues to evolve toward identification of a chemoselective moiety for speciation of the minor actinides from the electronically similar lanthanides, synthetic methods must congruently evolve. Synthetic options to convergently construct unsymmetric heteroaryl donor complexants incorporating a 1,2,3-triazole from accessible starting materials for evaluation in separation assays necessitated the development of the described methodology. In this report, metal- and azide-free synthesis of diversely functionalized pyridyl-1,2,3-triazole derivatives facilitated by microwave irradiation was leveraged to prepare a novel class of tridentate ligands. The described work negates the incorporation of thermally sensitive and toxic organoazides by using N-tosylhydrazones and anilines as viable synthetic equivalents in an efficient 12 min reaction time. Adaptation to alternative synthons useful for drug discovery was also realized. Method discovery, optimization, N-tosylhydrazone and aniline substrate scope, as well as a preliminary mechanistic hypotheses supported by DFT calculations are reported herein.

Rhodium(I) Carbene-Promoted Enantioselective C-H Functionalization of Simple Unprotected Indoles, Pyrroles and Heteroanalogues: New Mechanistic Insights.

A rhodium(I)-diene catalyzed highly enantioselective C(sp2 )-H functionalization of simple unprotected indoles, pyrroles, and their common analogues such as furans, thiophenes, and benzofurans with arylvinyldiazoesters has been developed for the first time. This transformation features unusual site-selectivity exclusively at the vinyl terminus of arylvinylcarbene and enables a reliable and rapid synthetic protocol to access a distinctive class of diarylmethine-bearing α,β-unsaturated esters containing a one or two heteroarene-attached tertiary carbon stereocenter in high yields and excellent enantioselectivities under mild reaction conditions. Mechanistic studies and DFT calculations suggest that, compared to the aniline substrate, the more electron-rich indole substrate lowers the C-C addition barrier and alters the rate-determining step to the reductive elimination, leading to different isotope effect.

Rhodium(I) Carbene‐Promoted Enantioselective C−H Functionalization of Simple Unprotected Indoles, Pyrroles and Heteroanalogues: New Mechanistic Insights

AbstractA rhodium(I)‐diene catalyzed highly enantioselective C(sp2)−H functionalization of simple unprotected indoles, pyrroles, and their common analogues such as furans, thiophenes, and benzofurans with arylvinyldiazoesters has been developed for the first time. This transformation features unusual site‐selectivity exclusively at the vinyl terminus of arylvinylcarbene and enables a reliable and rapid synthetic protocol to access a distinctive class of diarylmethine‐bearing α,β‐unsaturated esters containing a one or two heteroarene‐attached tertiary carbon stereocenter in high yields and excellent enantioselectivities under mild reaction conditions. Mechanistic studies and DFT calculations suggest that, compared to the aniline substrate, the more electron‐rich indole substrate lowers the C−C addition barrier and alters the rate‐determining step to the reductive elimination, leading to different isotope effect.

One-Pot Synthesis of 2-Arylindole Derivatives under Transition-Metal-Free Conditions

AbstractA new and simple method for preparing 2-arylindole derivatives under transition-metal-free conditions has been developed. When N-(2-methyl-3-nitrophenyl)acetamide was treated with 2-fluorobenzaldehydes in the presence of Cs2CO3 in DMF at 60 °C, the desired indoles were typically obtained in moderate to good yields (up to 83%). When other aniline substrates were employed, only a Knoevenagel condensation occurred, giving the corresponding diarylethenes in moderate to excellent yields.

Boron-Catalyzed Hydroarylation of 1,3-Dienes with Arylamines.

Catalytic hydroarylation reactions of conjugated dienes are achieved using tris(pentafluorophenyl)borane as a Lewis acid catalyst under mild reaction conditions. This new protocol shows a broad substrate scope for the highly regioselective functionalization of sterically hindered aniline derivatives. Experimental and extensive density functional theory mechanistic studies show that the complex of residual water and B(C6F5)3 plays a crucial role in the aryl-assisted protonation of conjugated dienes, forming allyl cation intermediates that induce the facile electrophilic aromatic substitution of aniline substrates.

Sandmeyer-Type Reductive Disulfuration of Anilines.

A transition metal/ligand-free disulfuration of anilines with disulfur transfer reagents (dithiosulfonate or tetrasulfide) is reported herein. The reaction, which can be considered as a reductive disulfuration variation of the classic Sandmeyer reaction, is performed under mild conditions and exhibits broad scope across the aniline substrate and disulfur transfer reagent classes. The gram-scale synthesis of disulfides is successfully achieved through this method, rendering the approach highly valuable.

Synthesis of Rhodium and Iridium Complexes Supported by Bis(indolylphosphino)silyl Pincer Ligation: Competitive N–H and C–H Bond Activation by an Ir(I) Species

The synthesis of five-coordinate amido hydride PSiP pincer complexes of both RhIII and IrIII was pursued. The preparation of such complexes by a salt metathesis route was initially targeted to assess the synthetic viability of such species. Isolable anilido hydride complexes of both Rh and Ir proved accessible, and rare examples of thermally robust Ir alkylamido hydride complexes were found to be viable synthetic targets. The preparation of amido hydride species by N–H oxidative addition was also pursued. Toward this end, the generation of coordinatively unsaturated (iPr-PSiPInd)MI (M = Rh, Ir) species was investigated. Dehydrohalogenation of (iPr-PSiPInd)RhH(Cl) (1) under N2 afforded the isolable complex [(iPr-PSiPInd)Rh]2(μ-N2) (8a). While the N2 ligand could be displaced to afford (iPr-PSiPInd)RhL (L = PMe3, DMAP, H2NPh), such RhI species proved unreactive toward N–H oxidative addition of aniline. Dehydrohalogenation of (iPr-PSiPInd)IrH(Cl) (2) in benzene solution resulted in activation of the solvent to afford (iPr-PSiPInd)IrH(Ph) (11), which undergoes facile arene exchange with benzene-d6. In cyclohexane solution, treatment with aniline afforded a mixture of N–H and aniline sp2-C–H bond oxidative addition products, with the latter species being favored. Although the observation of arene exchange involving (iPr-PSiPInd)IrH(Ph) suggests that C–H bond oxidative addition is reversible, attempts to drive the reactivity with aniline in the direction of N–H bond oxidative addition were unsuccessful. This reactivity differs significantly from that of previously reported complexes supported by related PSiP ligation. Most notably, it appears that for (iPr-PSiPInd)Ir, products resulting from N–H- and C–H-oxidative addition of aniline substrates do not readily interconvert, although both are postulated to share a common intermediate of the type (iPr-PSiPInd)Ir(NH2Ph).

Catalytic Carbodiimide Guanylation by a Nucleophilic, High Spin Iron(II) Imido Complex.

Reduction of the three-coordinate iron(III) imido [Ph2B(tBuIm)2Fe═NDipp] (1) affords [Ph2B(tBuIm)2Fe═NDipp][K(18-C-6)THF2] (2), a rare example of a high-spin (S = 2) iron(II) imido complex. Unusually for a late metal imido complex, the imido ligand in 2 has nucleophilic character, as demonstrated by the reaction with DippNH2, which establishes an equilibrium with the bis(anilido) complex [Ph2B(tBuIm)2Fe(NHDipp)2][K(18-C-6)THF2] (3). In an unusual transformation, formal insertion of iPrN═C═NiPr into the Fe═N(imido) bond yields the guanidinate [Ph2B(tBuIm)2Fe(iPrN)2CNDipp][K(18-C-6)THF2] (4). Reaction of 4 with excess DippNH2 provides 3, along with the guanidine (iPrNH)2C═NDipp. As suggested by these stoichiometric reactions, 2 is an efficient catalyst for the guanylation of carbodiimides, converting a wide range of aniline substrates under mild conditions.

Sodium perborate mediated oxidation kinetics and mechanism of aniline and its substituents catalysed by Iron(III) phthalocyanine chloride

The present study is focused on the investigation of aniline and its substituents oxidation facilitated by sodium perborate in diluted acetic acid. The oxidation reaction follows first and second order with respect to sodium perborate (oxidant) and aniline (substrate) respectively. The rate of the reaction has been accelerated by enhancing the catalyst concentration. The oxidative reaction mechanism seemed to be a polar ionic mechanism with respect to the solvent. The product of the oxidation reaction was found to be azobenzene which was characterised using ultraviolet spectroscopy. The changes in the thermodynamic parameters such as activation entropy (ΔS # ), activation enthalpy (ΔH # ), free energy (ΔG # ), and activation energy (E a ) were computed for ortho-, meta-, and para -substituted anilines. The mechanism for the oxidative reaction has also been proposed along with isokinetic temperature.

Theoretical Study of the Mechanism of Catalytic Enanteoselective N-H and O-H Insertion Reactions.

Theoretical density functional theory (DFT) calculations were carried out to study bond insertion reactions using a copper(I)-Box-carbenoid as a bond activator. In order to understand the reaction mechanism where N-H and O-H bonds actively participate, the reaction force (RF) and activation strain model (ASM) were used. Results indicate that the first step of the reaction is barrierless for both bond insertions (N-H and O-H), and the second step of the insertion reaction in the phenol (O-H bond) is favored kinetically and thermodynamically with regard to the aniline substrate (N-H bond). The enantioselectivity is driven by the ligand of the catalyst by steric repulsion, favoring the formation of the R isomer. The analysis of the reaction force and ASM exhibited that the higher energy barrier in aniline is mainly due to a higher W2 contribution together with repulsive interactions, which hinders the insertion process.

Highly Site-Selective Formation of Perfluoroalkylated Anilids via a Protecting Strategy by Molybdenum Hexacarbonyl Catalyst.

Introducing a perfluoroalkyl group on the aromatic ring with high site selectivity remains a challenging area in organofluorine chemistry. We herein report a highly para-selective C-H perfluoroalkylation of aniline substrates using the molybdenum hexacarbonyl catalyst. Various substituted anilids derived from anilids were well-tolerated, affording the corresponding products in moderate to good yields. Preliminary mechanism studies and density functional theory calculations revealed the coordination of Mo catalyst with amides as the key factor to realize para selectivity.