New Types of Reactivity of α,β‐Unsaturated N,N‐Dimethylhydrazones: Chemodivergent Diastereoselective Synthesis of Functionalized Tetrahydroquinolines and Hexahydropyrrolo[3,2‐b]indoles

The indium trichloride‐catalyzed reaction between aromatic imines and α,β‐unsaturated N,N‐dimethylhydrazones in acetonitrile afforded 1,2,3,4‐tetrahydroquinolines bearing a hydrazone function at C4 through a one‐pot diastereoselective domino process that involves the formation of two C? C bonds and the controlled generation of two stereocenters, one of which is quaternary. This reaction constitutes the first example of an α,β‐unsaturated dimethylhydrazone that behaves as a dienophile in a hetero Diels–Alder reaction. The related reaction between anilines, aromatic aldehydes, and methacrolein dimethylhydrazone in CHCl₃ with BF₃?Et₂O as catalyst afforded polysubstituted 1,2,3,3a,4,8b‐hexahydropyrrolo[3,2‐b]indoles as major products through a fully diastereoselective ABB′C four‐component domino process that generates two cycles, three stereocenters, two C? C bonds, and two C? N bonds in a single operation.     

3‐(p‐Chloro­phenyl)‐4‐phenyl‐4,5‐di­hydro­isoxazole‐5‐spiro‐2′‐1′,2′,3′,4′‐tetra­hydro­naphthalen‐1′‐one

In the title compound, C₂₄H₁₈ClNO₂, the phenyl ring and the tetralone moiety are approximately orthogonal to the isoxazoline ring. The isoxazoline ring adopts an envelope conformation, while the cyclo­hexenone ring of the tetralone moiety has an intermediate sofa/half‐chair conformation. In this structure, one C—H?N intermolecular and two C—H?O intramolecular hydrogen bonds occur; the H?A distances are 2.60, and 2.35 and 2.57 Å, respectively. The mol­ecules are held together by an intermolecular C—H?N hydrogen bond, forming a one‐dimensional chain along the [100] direction.     

Rh(III)‐Catalyzed Denitrogenative [4+2] Annulation of Benzamides and 3‐Diazoindolin‐2‐imines: Expedient Access to Indolo[2,3‐c] isoquinolin‐5‐ones

An effective and pragmatic strategy for the synthesis of structurally diverse indolo[2,3‐c]isoquinolin‐5‐ones has been developed via a Rh(III)‐catalyzed C?H activation and [4+2] annulation reaction of N‐methoxybenzamides and 3‐diazoindolin‐2‐imines. The reaction involves the efficient formation of two new (one C?C and one C?N) bonds under operationally simple conditions and has the benefits of a broad substrate scope.     

Synthesis of fused pyrimidines with N‐, S‐heterocyclic moieties by double‐annelation reaction

A variety of tri‐ and tetracyclic hetero systems were obtained by reaction of heteroaromatic ortho‐aminoesters or ortho‐aminonitriles with iminothioether, yielding double‐annelation of a thiazolo[3,2‐a]‐pyrimidine, pyrimido[2,l‐b]thiazine, imidazo[1,2‐a]pyrimidine, and pyrimido[1,2‐a]pyrimidine moieties in a one‐pot process.     

A Copper‐Catalyzed Aerobic [1,3]‐Nitrogen Shift through Nitrogen‐Radical 4‐exo‐trig Cyclization

A novel radical [1,3]‐nitrogen shift catalyzed by copper diacetate under an oxygen atmosphere (1 atm) has been developed for the construction of a diverse range of indole derivatives from α,α‐disubstituted benzylamine. In this reaction, oxygen was used as a clean terminal oxidant, and water was produced as the only by‐product. Five inert bonds were cleaved, and two C−N bonds and one C−C double bond were constructed in one pot during this transformation. This unique method demonstrated broad application protential for the late‐stage modification of biologically active natural products and drugs. Mechanistic investigations indicate that a unique 4‐exo ‐trig cyclization of an aminyl radical onto a phenyl ring is involved in the catalytic cycle.     

Cross‐Coupling of Organolithium with Ethers or Aryl Ammonium Salts by C−O or C−N Bond Cleavage

Various aryl‐, alkenyl‐, and/or alkyllithium species reacted smoothly with aryl and/or benzyl ethers with cleavage of the inert C?O bond to afford cross‐coupled products, catalyzed by commercially available [Ni(cod)₂] (cod=1,5‐cyclooctadiene) catalysts with N‐heterocyclic carbene (NHC) ligands. Furthermore, the coupling reaction between the aryllithium compounds and aryl ammonium salts proceeded under mild conditions with C?N bond cleavage in the presence of a [Pd(PPh₃)₂Cl₂] catalyst. These methods enable selective sequential functionalizations of arenes having both C?N and C?O bonds in one pot.     

Zirconium‐Mediated Multicomponent Reactions of 1,3‐Butadiynes with Ylidenemalononitriles to Form Functionalized 1,8‐Naphthyridine and Cyclopenta[b]pyridine Derivatives

Zirconocene‐mediated multicomponent reactions of 1,3‐butadiynes with ylidenemalononitriles in the absence or presence of CuCl have been developed. In the absence of CuCl, 1,3‐butadiyne couples with three molecules of ylidenemalononitriles to yield azazirconacycles bearing a hexahydro‐1,8‐naphthyridine skeleton with high stereoselectivity. In the presence of CuCl, cyclopenta[b]pyridine or cyclopenta[b]quinolin‐1‐one derivatives are obtained via transmetalation of Zr?C bond to Cu?C bond as the key reaction step. These domino‐type reactions proceed with high chemo‐, regio‐ and/or stereoselectivities, and allowing the formation of multiple C?N and C?C bonds in a single operation.     

Synthesis of N‐Arylated 1,2‐Dihydroheteroaromatics Through the Three‐Component Reaction of Arynes with N‐Heteroaromatics and Terminal Alkynes or Ketones

The reaction of benzynes with N‐heteroaromatics including quinolines, isoquinolines, and pyridines and various terminal alkynes or ketones with an α‐hydrogen in the presence of KF and 18‐crown‐6 in THF at room temperature for 8 h gave various N‐arylated 1,2‐dihydroheteroaromatics in good to moderate yields. Some of these product structures are found in various naturally occurring and biologically active heterocyclic compounds. The reaction involves an unusual multiple construction of new C? C, C? N, and C? H bonds and the cleavage of a C? H bond in one pot. It is likely that the three‐component coupling proceeds through the nucleophilic addition of quinoline to benzyne, which generates a zwitterionic species. The latter then attracts a proton from terminal alkyne (or ketone) to generate an N‐arylated quinolinium cation and an acetylide anion. Further reaction of these two ions provides the final substituted 1,2‐dihydroquinolines. In the reaction, the terminal alkyne acts first as a proton donor and then as a nucleophile. The application of a three‐component coupling reaction product, 1,2‐dihydro‐2‐pyridinyl alkyne in a stereospecific [4+2] Diels–Alder cycloaddition reaction with N‐phenyl maleimide to give an isoquinuclidine derivative, an important core present in various natural products, is demonstrated.     

A Flexible Copper(I)‐Complexed [4]Rotaxane Containing Two Face‐to‐Face Porphyrinic Plates that Behaves as a Distensible Receptor

A new cyclic [4]rotaxane composed of two flexible bis‐macrocycles and two rigid axles is described. Each bis‐macrocycle consists of two rings attached to antipodal meso positions of a central Zn porphyrin through single C? C bonds. Each ring incorporates a 2,9‐diphenyl‐1,10‐phenanthroline chelation site. The axles contain two coplanar bidentate sites derived from the 2,2′‐bipyridine motif. The building blocks were assembled by using a one‐pot threading‐and‐stoppering reaction, which afforded the [4]rotaxane in 50 % yield. The “gathering‐and‐threading” effect of copper(I) was utilised in the formation of a [4]pseudorotaxane, which was immediately converted to the corresponding [4]rotaxane by a quadruple CuAAC stoppering reaction. The rotaxane contains two face‐to‐face zinc porphyrins, which allowed the coordination of ditopic guest substrates. The rotaxane host showed remarkable flexibility and was able to adjust its conformation to the guest size. It can be distended and accommodate rod‐like guests of 2.6 to 15.8 Å in length.     

One‐pot Sequential Reactions Featuring a Copper‐catalyzed Amination Leading to Pyrido[2′,1′:2,3]imidazo[4,5‐c]quinolines and Dihydropyrido[2′,1′:2,3]imidazo[4,5‐c]quinolines

Tetracyclic skeletons combining an imidazo[1,2‐a]pyridine moiety with a quinoline framework such as pyrido[2′,1′:2,3]imidazo[4,5‐b]quinoline are stimulating increasing interests since they are close isosteres of a series of powerful antiproliferative compounds. In this paper, we report a novel methodology for the synthesis of pyrido[2′,1′:2,3]imidazo[4,5‐c]quinolines through one‐pot sequential reactions of commercially available or readily obtainable 2‐aminopyridines, 2‐bromophenacyl bromides, aqueous ammonia, and aldehydes. Moreover, dihydropyrido[2′,1′:2,3]imidazo[4,5‐c]quinolines could also be obtained in a similar manner by using various ketones as the substrates in place of aldehydes. Notably, the whole procedure combines condensation/amination/cyclization reactions in one pot to give complex compounds in a simple and practical manner. Compared with literature methods, the synthetic strategy reported herein has the advantages of readily available starting materials, structural diversity of products, good functional group tolerance, and obviation of step‐by‐step operations.     

Cascade Nitration/Cyclization of 1,7‐Enynes with tBuONO and H2O: One‐Pot Self‐Assembly of Pyrrolo[4,3,2‐de]quinolinones

Here we describe the one‐pot construction of the pyrrolo[4,3,2‐de]quinolinone scaffold by a cascade nitration/cyclization sequence of 1,7‐enynes with tBuONO and H₂O. The cascade proceeds through alkene nitration, 1,7‐enyne 6‐exo‐trig cyclization, C? H nitrations, and redox cyclization, and exhibits excellent functional group tolerance. The mechanism was investigated using in situ high‐resolution mass spectrometry (HR‐MS).     

Supramolecular structures of 5‐[3‐(4‐methyl­phenyl)‐ and 5‐[3‐(4‐chloro­phenyl)‐2‐propenyl­idene]‐2,2‐di­methyl‐1,3‐dioxane‐4,6‐dione

2,2‐Di­methyl‐5‐[3‐(4‐methyl­phenyl)‐2‐propenyl­idene]‐1,3‐di­ox­ane‐4,6‐dione, C₁₆H₁₆O₄, crystallizes in the triclinic space group , with two mol­ecules in the asymmetric unit. These mol­ecules and a centrosymmetrically related pair, linked together by weak C—H?O hydrogen bonds, form a tetramer. 5‐[3‐(4‐Chloro­phenyl)‐2‐propenyl­idene]‐2,2‐di­methyl‐1,3‐dioxane‐4,6‐dione, C₁₅H₁₃ClO₄, also crystallizes in the triclinic space group , with one mol­ecule in the asymmetric unit. Centrosymmetrically related mol­ecules are linked together by weak C—H?O hydrogen bonds to form dimers which are further linked by yet another pair of centrosymmetrically related C—H?O hydrogen bonds to form a tube which runs parallel to the a axis.     

A Hydrazone‐Based exo‐Directing‐Group Strategy for β C−H Oxidation of Aliphatic Amines

Described is a new hydrazone‐based exo‐directing group (DG) strategy developed for the functionalization of unactivated primary β C?H bonds of aliphatic amines. Conveniently synthesized from protected primary amines, the hydrazone DGs are shown to site‐selectively promote the β‐acetoxylation and tosyloxylation via five‐membered exo‐palladacycles. Amines with a wide scope of skeletons and functional groups are tolerated. Moreover, the hydrazone DG can be readily removed, and a one‐pot C?H acetoxylation/DG removal protocol was also discovered.     

Microwave‐assisted Domino Cyclization for the Synthesis of Novel Spiro‐benzo[a]phenazine Annulated Heterocycles Catalyzed by a Basic Ionic Liquid

An efficient and green strategy for the improved synthesis of a biologically and pharmaceutically interesting multi‐functionalized diverse novel spiro‐benzo[a ]phenazine annulated heterocycles was developed with the assistance of microwave irradiation. A sequential one‐pot, two‐step domino reaction starting from 2‐hydroxynaphthalene‐1,4‐dione, benzene‐1,2‐diamines, a cyclic carbonyl compound, and 1,3‐indandione in the presence of a basic ionic liquid (1‐butyl‐3‐methylimidazolium hydroxide) as an expedient, ecofriendly and reusable catalyst afforded the corresponding novel spiro[benzo[a ]indeno[2′,1′:5,6]pyrano[2,3‐c ]phenazine] derivatives with high yield under solvent‐free conditions. This domino Knoevenagel–Michael annulation reaction provided five new bonds (two C–C, two CN, and one C–O) and two new rings through multiple operations in a single flask.     

Direct Synthesis of Benzofuro[2,3‐b]pyrroles through a Radical Addition/[3,3]‐Sigmatropic Rearrangement/Cyclization/Lactamization Cascade

A straightforward synthetic method for the construction of benzofuro[2,3‐b]pyrrol‐2‐ones by a novel domino reaction through a radical addition/[3,3]‐sigmatropic rearrangement/cyclization/lactamization cascade has been developed. The domino reaction of O‐phenyl‐conjugated oxime ether with an alkyl radical allows the construction of two heterocycles with three stereogenic centers as a result of the formation of two C?C bonds, a C?O bond, and a C?N bond in a single operation, leading to pyrrolidine‐fused dihydrobenzofurans, which are not easily accessible by existing synthetic methods. Furthermore, asymmetric synthesis of benzofuro[2,3‐b]pyrrol‐2‐one derivatives through a diastereoselective radical addition reaction to a chiral oxime ether was also developed.     

A Facile,Atom‐Economical,and One‐Pot Pseudo Four‐Component Synthesis of Isoxazolylspiro[diindeno[1,2‐b;2′,1′‐e]pyridine‐11,3′‐indoline]‐2′,10,12‐triones Catalyzed by pTSA

A facile, atom‐economical, and one‐pot pseudo four‐component method for the synthesis of isoxazolylspiro[diindeno[1,2‐b ;2′,1′‐e ]pyridine‐11,3′‐indoline]‐2′,10,12‐trione derivatives ( 14 ) is described. Prominent advantages of this new method are operational simplicity, excellent yields with high purity, short reaction time, easy workup, and mild conditions.     

Iron‐Catalyzed Oxidative C−C and N−N Coupling of Diarylamines and Synthesis of Spiroacridines

We describe iron‐catalyzed intermolecular oxidative coupling reactions of diarylamines to form substituted 2,2′‐bis(arylamino)biaryl compounds, tetraarylhydrazines, and 5,6‐dihydrobenzo[c ]cinnolines with the same hexadecafluorinated iron–phthalocyanine catalyst. The mild formation of C−C or N−N bonds was controlled by the use of acidic or basic additives. In contrast to most iron‐catalyzed dehydrogenative coupling reactions, ambient air could be used as the sole oxidant. Moreover, iron(III) chloride hexahydrate promoted a one‐pot coupling and subsequent intramolecular dearomative coupling to give 10H ‐spiro[acridine‐9,1′‐cyclohexa‐2′,5′‐dien‐4′‐ones].     

Facile One‐Pot Synthesis of [1, 2, 3]Triazolo[1, 5‐a]Pyridines from 2‐Acylpyridines by Copper(II)‐Catalyzed Oxidative NN Bond Formation

An efficient and simple method for the synthesis of various [1, 2, 3]triazolo[1, 5‐a]pyridines has been established. The method involves a copper(II)‐catalyzed oxidative N?N bond formation that uses atmospheric oxygen as the terminal oxidant following hydrazonation in one pot. The use of ethyl acetate as the solvent dramatically promotes the oxidative N?N bond‐formation reaction and enables the application of oxidative cyclization in the efficient one‐pot reaction. A mechanism for the reaction was proposed on the basis of the results of a spectroscopic study.     

Rhodium(III)‐Catalyzed Tandem [2+2+2] Annulation–Lactamization of Anilides with Two Alkynoates via Cleavage of Two Adjacent C−H or C−H/C−O bonds

An electron‐deficient Cp^E rhodium(III) complex bearing a cyclopentadienyl ligand with two ethyl ester substituents catalyzes the tandem [2+2+2] annulation–lactamization of acetanilides with two alkynoates via cleavage of adjacent two C?H bonds to give densely substituted benzo[cd]indolones. The reactions of meta‐methoxy‐substituted acetanilides with two alkynoates also provided benzo[cd]indolones via cleavage of adjacent C?H/C?O bonds. Furthermore, 3,5‐dimethoxyacetanilides reacted with two alkynoates to give dearomatized spiro compounds.     

Assembling an isomer grid: the isomorphous 4‐, 3‐ and 2‐fluoro‐N′‐(4‐pyridyl)benzamides

The three title isomers, 4‐, (I), 3‐, (II), and 2‐fluoro‐N′‐(4‐pyridyl)benzamide, (III), all C₁₂H₉FN₂O, crystallize in the P2₁/c space group (No. 14) with similar unit‐cell parameters and are isomorphous and isostructural at the primary hydrogen‐bonding level. An intramolecular C—H...O=C interaction is present in all three isomers [C...O = 2.8681 (17)–2.884 (2) Å and C—H...O117–118°], with an additional N—H...F [N...F = 2.7544 (15) Å] interaction in (III). Intermolecular amide–pyridine N—H...N hydrogen bonds link molecules into one‐dimensional zigzag chains [graph set C(6)] along the [010] direction as the primary hydrogen bond [N...N = 3.022 (2), 3.049 (2) and 3.0213 (17) Å]. These are augmented in (I) by C—H...π(arene) and cyclic C—F...π(arene) contacts about inversion centres, in (II) by C—F...F—C interactions [C...F = 3.037 (2) Å] and weaker C—H...π(arene)/C—H...F contacts, and in (III) by C—H...π(arene) and C=O...O=C interactions, linking the alternating chains into two‐dimensional sheets. Typical amide N—H...O=C hydrogen bonds [as C(4) chains] are not present [N...O = 3.438 (2) Å in (I), 3.562 (2) Å in (II) and 3.7854 (16) Å in (III)]; the C=O group is effectively shielded and only participates in weaker interactions/contacts. This series is unusual as the three isomers are isomorphous (having similar unit‐cell parameters, packing and alignment), but they differ in their interactions and contacts at the secondary level.