Application of a C?C Bond‐Forming Conjugate Addition Reaction in Asymmetric Dearomatization of β‐Naphthols

A C C bond‐forming conjugate reaction was successfully applied to the enantioselective dearomatization of β‐naphthols. A C(sp2) C(sp3) bond is formed by using propargylic ketones as reactive partners. Good to excellent Z/E ratios and ee values were obtained by employing an in situ generated magnesium catalyst. Further transformations of the Z‐configured C C double bond in the products were achieved under mild reaction conditions. Moreover, the stereocontrolling element of this magnesium‐catalyzed dearomatization reaction was explored by computational chemistry.     

Unprecedented Dearomatized Spirocyclopropane in a Sequential Rhodium(III)‐Catalyzed C−H Activation and Rearrangement Reaction

An unprecedented dearomatized spirocyclopropane intermediate was discovered in a sequential Cp*Rh^III‐catalyzed C?H activation and Wagner–Meerwein‐type rearrangement reaction. How the oxidative O?N bond is cleaved and the role of HOAc were uncovered in this study. Furthermore, a Cp*Rh^III‐catalyzed dearomatization reaction of N‐(naphthalen‐1‐yloxy)acetamide with strained olefins was developed, affording a variety of spirocyclopropanes.     

Methyl 2‐benzamido‐4‐(3,4‐dimethoxyphenyl)‐5‐methylbenzoate and N‐{5‐benzoyl‐2‐[(Z)‐2‐methoxyethenyl]‐4‐methylphenyl}benzamide

Methyl 2‐benzamido‐4‐(3,4‐dimethoxyphenyl)‐5‐methylbenzoate, C₂₄H₂₃NO₅, (Ia), and N‐{5‐benzoyl‐2‐[(Z)‐2‐methoxyethenyl]‐4‐methylphenyl}benzamide, C₂₄H₂₁NO₃, (IIa), were formed via a Diels–Alder reaction of appropriately substituted 2H‐pyran‐2‐ones and methyl propiolate or (Z)‐1‐methoxybut‐1‐en‐3‐yne, respectively. Each of these cycloadditions might yield two different regioisomers, but just one was obtained in each case. In (Ia), an intramolecular N—H...O hydrogen bond closes a six‐membered ring. A chain is formed due to aromatic π–π interactions, and a three‐dimensional framework structure is formed by a combination of C—H...O and C—H...π(arene) hydrogen bonds. Compound (IIa) was formed not only regioselectively but also chemoselectively, with just the triple bond reacting and the double bond remaining unchanged. Compound (IIa) crystallizes as N—H...O hydrogen‐bonded dimers stabilized by aromatic π–π interactions. Dimers of (IIa) are connected into a chain by weak C—H...π(arene) interactions.     

A New Monomer for π‐Conjugated Polymers — Synthesis and Characterization of Bis((Z)‐5‐phenyl‐2‐phenylmethylidene‐1, 3‐dithiole‐4‐yl)monosulfane

Bis((Z)‐5‐phenyl‐2‐phenylmethylidene‐1, 3‐dithiole‐4‐yl)monosulfane ( 6 ), a molecule consisting of two diphenyldithiafulvene units connected by a sulfur bridge, was synthesized by the selective lithiation of (Z)‐4‐phenyl‐2‐phenylmethylidene‐1, 3‐dithiole ( 7a ) at the endocyclic double bond and by subsequent reaction of the lithiated intermediate with bis(phenylsulfonyl)sulfane. Since this reaction sequence proceeded with retention of configuration, of three possible isomers (E, E, Z, E, and Z, Z) only the Z, Z form was obtained. On the basis of the X‐ray structure analysis and the NMR‐spectroscopic characterization of 6 supplemented by the NMR parameters of (E)‐ and (Z)‐4‐phenyl‐2‐phenylmethylidene‐1, 3‐dithiole, it was demonstrated that two characteristic ⁵J coupling constants of the proton at the exocyclic double bond indicate the configuration (Z or E) of disubstituted dithiafuvene derivatives.     

Direct Asymmetric Dearomatization of 2‐Naphthols by Scandium‐Catalyzed Electrophilic Amination

Catalytic asymmetric aminative dearomatization of 1‐substituted 2‐naphthols was successfully implemented with electrophilic azodicarboxylates under the catalysis of chiral Sc^III/pybox complexes. This intermolecular reaction represents a hitherto unknown enantioselective C? N bond‐forming process through direct dearomatization of phenolic compounds to generate chiral nitrogen‐containing quaternary carbon stereocenters.     

Chemoselectivity of the Reactions of Diazomethanes with 5‐Benzylidene‐3‐phenylrhodanine

The reactions of 5‐benzylidene‐3‐phenylrhodanine ( 2 ; rhodanine=2‐thioxo‐1,3‐thiazolidin‐4‐one) with diazomethane ( 7a ) and phenyldiazomethane ( 7b ) occurred chemoselectively at the exocyclic C?C bond to give the spirocyclopropane derivatives 9 and, in the case of 7a , also the C‐methylated products 8 (Scheme 1). In contrast, diphenyldiazomethane ( 7c ) reacted exclusively with the C?S group leading to the 2‐(diphenylmethylidene)‐1,3‐thiazolidine 11 via [2+3] cycloaddition and a ‘two‐fold extrusion reaction’. Treatment of 8 or 9b with an excess of 7a in refluxing CH₂Cl₂ and in THF at room temperature in the presence of [Rh₂(OAc)₄], respectively, led to the 1,3‐thiazolidine‐2,4‐diones 15 and 20 , respectively, i.e., the products of the hydrolysis of the intermediate thiocarbonyl ylide. On the other hand, the reactions with 7b and 7c in boiling toluene yielded the corresponding 2‐methylidene derivatives 16, 21a , and 21b . Finally, the reaction of 11 with 7a occurred exclusively at the electron‐poor C?C bond, which is conjugated with the C?O group. In addition to the spirocyclopropane 23 , the C‐methylated 22 was formed as a minor product. The structures of the products (Z)‐ 8, 9a, 9b, 11 , and 23 were established by X‐ray crystallography.     

Synthesis of Functionalized α‐Vinyl Aldehydes from Enaminones

An efficient Rh^II‐catalyzed synthesis of functionalized α‐vinyl aldehydes with high E/Z stereoselectivity was developed. The reaction mediates the cyclopropanation of enaminones with vinyl carbenoids that are generated from cyclopropenes in situ to give the aminocyclopropane intermediates. Selective C?C bond cleavage of the cyclopropane intermediates leads to formation of α‐vinyl aldehyde derivatives with high E/Z selectivity. This method proceeds at room temperature under very mild reaction conditions and works with a broad substrate scope.     

4‐Ethynyl‐4‐hydroxycyclohexan‐1‐one and 4‐ethynyl‐4‐hydroxy‐2,3,5,6‐tetramethylcyclohexa‐2,5‐dien‐1‐one

The title compounds, C₈H₁₀O₂, (I), and C₁₂H₁₄O₂, (II), occurred as by‐products in the controlled synthesis of a series of bis­(gem‐alkynols), prepared as part of an extensive study of synthon formation in simple gem‐alkynol derivatives. The two 4‐(gem‐alkynol)‐1‐ones crystallize in space group P2₁/c, (I) with Z′ = 1 and (II) with Z′ = 2. Both structures are dominated by O—H?O=C hydrogen bonds, which form simple chains in the cyclo­hexane derivative, (I), and centrosymmetric dimers, of both symmetry‐independent mol­ecules, in the cyclo­hexa‐2,5‐diene, (II). These strong synthons are further stabilized by C[triple‐bond]C—H?O=C, C_methylene—H?O(H) and C_methyl—H?O(H) interactions. The direct intermolecular interactions between donors and acceptors in the gem‐alkynol group, which characterize the bis­(gem‐alkynol) analogues of (I) and (II), are not present in the ketone derivatives studied here.     

MgII‐Mediated Catalytic Asymmetric Dearomatization (CADA) Reaction of β‐Naphthols with Dialkyl Acetylenedicarboxylates

A Mg^II‐mediated catalytic asymmetric dearomatization (CADA) reaction of β‐naphthols has been developed. The reaction proceeds under ambient temperature and give a series of chiral trisubstituted olefins with good chemoselectivities, Z/E ratios, and excellent enantioselectivities. A fluorinated β‐naphthol was designed to generate chiral organofluorine skeletons through the current CADA reaction. Moreover, an interesting tandem cyclization reaction was observed in the following transformation process through an undiscovered intramolecular hydride transfer pathway.     

Rhodium(II)‐ or Copper(I)‐Catalyzed Formal Intramolecular Carbene Insertion into Vinylic C(sp2)−H Bonds: Access to Substituted 1H‐Indenes

A rhodium(II)‐ or copper(I)‐catalyzed formal intramolecular carbene insertion into vinylic C(sp²)−H bonds is reported herein. This method provides straightforward access to 1H ‐indenes with high efficiency and excellent functional‐group compatibility. Mechanistically, the reaction is proposed to involve the following sequence: metal carbene formation, intramolecular nucleophilic addition of the double bond to the electron‐deficient carbene carbon atom, dearomatization, and finally a 1,5‐H shift.     

Intramolecular Cooperative CC Bond Cleavage Reaction of 1,3‐Dicarbonyl Compounds with 2‐Iodoanilines to Give o‐(N‐Acylamino)aryl Ketones and Multisubstituted Indoles

A copper‐catalyzed C?C bond cleavage reaction of 1,3‐dicarbonyl compounds with 2‐iodoanilines was developed. In this process, the ortho effect played an important role in the reactivity and a new reaction pathway that involved a (2‐aminophenyl)‐bis‐(1,3‐dicarbonyl) copper species was clearly observed by a time‐course HRMS analysis of the reaction mixture. Unlike the previous reports, both the nucleophilic and electrophilic parts of the 1,3‐dicarbonyl compound were coupled with 2‐iodoaniline by C?C bond cleavage to form o‐(N‐acylamino)aryl ketones, which could be efficiently converted into multisubstituted indoles.     

Intramolecular [2+2] Photocycloaddition of 3‐ and 4‐(But‐3‐enyl)oxyquinolones: Influence of the Alkene Substitution Pattern,Photophysical Studies,and Enantioselective Catalysis by a Chiral Sensitizer

The intramolecular [2+2] photocycloaddition of four 4‐(but‐3‐enyl)oxyquinolones (substitution pattern at the terminal alkene carbon atom: CH₂, Z‐CHEt, E‐CHEt, CMe₂) and two 3‐(but‐3‐enyl)oxyquinolones (substitution pattern: CH₂, CMe₂) was studied. Upon direct irradiation at λ=300 nm, the respective cyclobutane products were formed in high yields (83–95 %) and for symmetrically substituted substrates with complete diastereoselectivity. Substrates with a Z‐ or E‐substituted terminal double bond showed a stereoconvergent reaction course leading to mixtures of regio‐ and diastereomers with almost identical composition. The mechanistic course of the photocycloaddition was elucidated by transient absorption spectroscopy. A triplet intermediate was detected for the title compounds, which–in contrast to simple alkoxyquinolones such as 3‐butyloxyquinolone and 4‐methoxyquinolone–decayed rapidly (τ≈1 ns) through cyclization to a triplet 1,4‐diradical. The diradical can evolve through two reaction channels, one leading to the photoproduct and the other leading back to the starting material. When the photocycloaddition was performed in the presence of a chiral sensitizer (10 mol %) upon irradiation at λ=366 nm in trifluorotoluene as the solvent, moderate to high enantioselectivities were achieved. The two 3‐(but‐3‐enyl)oxyquinolones gave enantiomeric excesses (ees) of 60 and 64 % at ?25 °C, presumably because a significant racemic background reaction occurred. The 4‐substituted quinolones showed higher enantioselectivities (92–96 % ee at ?25 °C) and, for the terminally Z‐ and E‐substituted substrates, an improved regio‐ and diastereoselectivity.     

Stereoselective Synthesis of 1,3‐Diaminotruxillic Acid Derivatives: An Advantageous Combination of CH‐ortho‐Palladation and On‐Flow [2+2]‐Photocycloaddition in Microreactors

The stereoselective synthesis of ε‐isomers of dimethyl esters of 1,3‐diaminotruxillic acid in three steps is reported. The first step is the ortho‐palladation of (Z)‐2‐aryl‐4‐aryliden‐5(4H)‐oxazolones 1 to give dinuclear complexes 2 with bridging carboxylates. The reaction occurs through regioselective activation of the ortho‐C?H bond of the 4‐arylidene ring in carboxylic acids. The second step is the [2+2]‐photocycloaddition of the C?C exocyclic bonds of the oxazolone skeleton in 2 to afford the corresponding dinuclear ortho‐palladated cyclobutanes 3 . This key step was performed very efficiently by using LED light sources with different wavelengths (465, 525 or 625 nm) in flow microreactors. The final step involved the depalladation of 3 by hydrogenation in methanol to afford the ε‐1,3‐diaminotruxillic acid derivatives as single isomers.     

Visible‐Light‐Induced Trifluoromethylation of Isonitrile‐Substituted Methylenecyclopropanes: Facile Access to 6‐(Trifluoromethyl)‐7,8‐Dihydrobenzo[k]phenanthridine Derivatives

A new visible‐light‐induced trifluoromethylation of isonitrile‐substituted methylenecyclopropanes is developed. A range of substituted 6‐(trifluoromethyl)‐7,8‐dihydrobenzo[k]phenanthridine derivatives are readily furnished by this newly developed tandem reaction with moderate to good yields. This reaction allows the direct formation of two six‐membered rings and three new C?C bonds, including the C?CF₃ bond, under visible light irradiation.     

Transition‐Metal‐Free Cross‐Coupling of Benzothiophenes and Styrenes in a Stereoselective Synthesis of Substituted (E,Z)‐1,3‐Dienes

A transition metal‐free one‐pot stereoselective approach to substituted (E,Z)‐1,3‐dienes was developed by using an interrupted Pummerer reaction/ligand‐coupling strategy. Readily available benzothiophene S‐oxides, which can be conveniently prepared by oxidation of the parent benzothiophenes, undergo Pummerer coupling with styrenes. Reaction of the resultant sulfonium salts with alkyllithium/magnesium reagents generates underexploited hypervalent sulfurane intermediates that undergo selective ligand coupling, resulting in dismantling of the benzothiophene motif and the formation of decorated (E,Z)‐1,3‐dienes.     

Asymmetric Desymmetrization via Metal‐Free C−F Bond Activation: Synthesis of 3,5‐Diaryl‐5‐fluoromethyloxazolidin‐2‐ones with Quaternary Carbon Centers

We disclose the first asymmetric activation of a non‐activated aliphatic C?F bond in which a conceptually new desymmetrization of 1,3‐difluorides by silicon‐induced selective C?F bond scission is a key step. The combination of a cinchona alkaloid based chiral ammonium bifluoride catalyst and N,O‐bis(trimethylsilyl)acetoamide (BSA) as the silicon reagent enabled the efficient catalytic cycle of asymmetric C_sp3?F bond cleavage under mild conditions with high enantioselectivities. The ortho effect of the aryl group at the prostereogenic center is remarkable. This concept was applied for the asymmetric synthesis of promising agrochemical compounds, 3,5‐diaryl‐5‐fluoromethyloxazolidin‐2‐ones bearing a quaternary carbon center.     

Amine‐Catalyzed Highly Regioselective and Stereoselective C(sp2)–C(sp2) Cross‐Coupling of Naphthols with trans‐α,β‐Unsaturated Aldehydes

A metal‐free C(sp²)–C(sp²) cross‐coupling approach to highly congested (E)‐α‐naphtholylenals from simple naphthols and enals is described. The mild reaction conditions with pyridine hydrobromideperbromide (PHBP) as the bromination reagent in the presence of piperidine or diphenylprolinol trimethylsilyl (TMS) ether as promoters enable the process in good yields and with high chemoselectivity, regioselectivity, and stereoselectivity. The process involves an unprecedented pathway of in situ regioselective 4‐bromination of 1‐naphthols and the subsequent unusual aromatic nucleophilic substitution of the resulting 4‐bromo‐1‐naphthols with the α‐C(sp²) of enals through a Michael‐type Friedel–Crafts alkylation–dearomatization followed by a cyclopropanation ring‐opening cascade process. The noteworthy features of this strategy are highlighted by the highly efficient creation of a C(sp²)–C(sp²) bond from readily available unfunctionalized naphthols and enals catalyzed by non‐metal, readily available cyclic secondary amines under mild reaction conditions.     

2,4‐Dinitrophenol‐Catalyzed α‐C(sp3)−H and C(sp)−H Bond Functionalization of Cyclic Amines and Alkynes: Highly Regio‐/Diastereoselective Synthesis of α‐Alkynyl‐3‐Amino‐2‐Oxindoles

A transition‐metal‐ and oxidant‐free DNP (2,4‐dinitrophenol)‐catalyzed atom‐economical regio‐ and diastereoselective synthesis of monofunctionalized α‐alkynyl‐3‐amino‐2‐oxindole derivatives by C?H bond functionalization of cyclic amines and alkynes with indoline‐2,3‐diones has been developed. This cascade event sequentially involves the reductive amination of indoline‐2,3‐dione by imine formation and cross coupling between C(sp³)?H and C(sp)?H of the cyclic amines and alkynes. This reaction offers an efficient and attractive pathway to different types of α‐alkynyl‐3‐amino‐2‐oxindole derivatives in good yields with a wide tolerance of functional groups. The salient feature of this methodology is that it completely suppresses the homocoupling of alkynes. To the best of our knowledge, this is the first example of a DNP‐catalyzed metal‐free direct C(sp³)?H and C(sp)?H bond functionalization providing biologically active α‐alkynyl‐3‐amino‐2‐oxindole scaffolds.     

An X‐ray crystallographic and density functional theory study of (3Z)‐4‐(5‐ethylsulfonyl‐2‐hydroxyanilino)pent‐3‐en‐2‐one and (3Z)‐4‐(5‐tert‐butyl‐2‐hydroxyanilino)pent‐3‐en‐2‐one

The Schiff base enaminones (3Z)‐4‐(5‐ethylsulfonyl‐2‐hydroxyanilino)pent‐3‐en‐2‐one, C₁₃H₁₇NO₄S, (I), and (3Z)‐4‐(5‐tert‐butyl‐2‐hydroxyanilino)pent‐3‐en‐2‐one, C₁₅H₂₁NO₂, (II), were studied by X‐ray crystallography and density functional theory (DFT). Although the keto tautomer of these compounds is dominant, the O=C—C=C—N bond lengths are consistent with some electron delocalization and partial enol character. Both (I) and (II) are nonplanar, with the amino–phenol group canted relative to the rest of the molecule; the twist about the N(enamine)—C(aryl) bond leads to dihedral angles of 40.5 (2) and −116.7 (1)° for (I) and (II), respectively. Compound (I) has a bifurcated intramolecular hydrogen bond between the N—H group and the flanking carbonyl and hydroxy O atoms, as well as an intermolecular hydrogen bond, leading to an infinite one‐dimensional hydrogen‐bonded chain. Compound (II) has one intramolecular hydrogen bond and one intermolecular C=O...H—O hydrogen bond, and consequently also forms a one‐dimensional hydrogen‐bonded chain. The DFT‐calculated structures [in vacuo, B3LYP/6‐311G(d,p) level] for the keto tautomers compare favourably with the X‐ray crystal structures of (I) and (II), confirming the dominance of the keto tautomer. The simulations indicate that the keto tautomers are 20.55 and 18.86 kJ mol⁻¹ lower in energy than the enol tautomers for (I) and (II), respectively.     

Tunable Electrochemical C−N versus N−N Bond Formation of Nitrogen‐Centered Radicals Enabled by Dehydrogenative Dearomatization: Biological Applications

Herein, an environmentally friendly electrochemical approach is reported that takes advantage of the captodative effect and delocalization effect to generate nitrogen‐centered radicals (NCRs). By changing the reaction parameters of the electrode material and feedstock solubility, dearomatization enabled a selective dehydrogenative C?N versus N?N bond formation reaction. Hence, pyrido[1,2‐a]benzimidazole and tetraarylhydrazine frameworks were prepared through a sustainable transition‐metal‐ and exogenous oxidant‐free strategy with broad generality. Bioactivity assays demonstrated that pyrido[1,2‐a]benzimidazoles displayed antimicrobial activity and cytotoxicity against human cancer cells. Compound 21 exhibited good photochemical properties with a large Stokes shift (approximately 130 nm) and was successfully applied to subcellular imaging. A preliminary mechanism investigation and density functional theory (DFT) calculations revealed the possible reaction pathway.