Dearomative Photocatalytic Construction of Bridged 1,3-Diazepanes

The construction of diverse sp³-rich skeletal ring systems is of importance to drug discovery programmes and natural product synthesis. Herein, we report the photocatalytic construction of 2,7-diazabicyclo[3.2.1]octanes (bridged 1,3-diazepanes) via a reductive diversion of the Minisci reaction. The fused tricyclic product is proposed to form via radical addition to the C4 position of 4-substituted quinoline substrates, with subsequent Hantzsch ester-promoted reduction to a dihydropyridine intermediate which undergoes in situ two-electron ring closure to form the bridged diazepane architecture. A wide scope of N-arylimine and quinoline derivatives was demonstrated and good efficiency was observed in the construction of sterically congested all-carbon quaternary centers. Computational and experimental mechanistic studies provided insights into the reaction mechanism and observed regioselectivity/diastereoselectivity.     

Acyl Migration versus Epoxidation in Gold Catalysis: Facile,Switchable, and Atom‐Economic Synthesis of Acylindoles and Quinoline Derivatives

We report a switchable synthesis of acylindoles and quinoline derivatives via gold‐catalyzed annulations of anthranils and ynamides. α‐Imino gold carbenes, generated in situ from anthranils and an N,O‐coordinated gold(III) catalyst, undergo electrophilic attack to the aryl π‐bond, followed by unexpected and highly selective 1,4‐ or 1,3‐acyl migrations to form 6‐acylindoles or 5‐acylindoles. With the (2‐biphenyl)di‐tert‐butylphosphine (JohnPhos) ligand, gold(I) carbenes experienced carbene/carbonyl additions to deliver quinoline oxides. Some of these epoxides are valuable substrates for the preparation of 3‐hydroxylquinolines, quinolin‐3(4H)‐ones, and polycyclic compounds via facile in situ rearrangements. The reaction can be efficiently conducted on a gram scale and the obtained products are valuable substrates for preparing other potentially useful compounds. A computational study explained the unexpected selectivities and the dependency of the reaction pathway on the oxidation state and ligands of gold. With gold(III) the barrier for the formation of the strained oxirane ring is too high; whereas with gold(I) this transition state becomes accessible. Furthermore, energetic barriers to migration of the substituents on the intermediate sigma‐complexes support the observed substitution pattern in the final product.     

Regioselective Photocyclizations of Di(quinolinyl)arylamines and Tri(quinolinyl)amine with Emission Color Changes and Photoreaction‐Induced Self‐Assemblies

Bis[2,4‐di(trifluoromethyl)quinoline‐7‐yl]amine ( 1 ), bis[2,4‐di(trifluoromethyl)quinoline‐7‐yl]methylamine ( 2 ), bis[2,4‐di(trifluoromethyl)quinoline‐7‐yl]phenylamine derivatives, Q₂NPhX; X=NO₂ ( 3 a ), I ( 3 b ), H ( 3 c ), OMe ( 3 d ), and NH₂ ( 3 e ), tris[2,4‐di(trifluoromethyl)quinoline‐7‐yl]amine ( 4 ), and bis[2,4‐di(pentafluoroethyl)quinoline‐7‐yl]‐4‐nitrophenylamine ( 5 ) were prepared as functional fluorophores. On irradiating the solution samples, 1 showed no noticeable alteration, whereas 2 , 3 a – d , and 4 showed emission color changes from yellowish green to blue, indicating that a photoreaction took place. Analyses of the photoproduct based on absorption and emission spectra, ¹H NMR spectra, and X‐ray crystallography indicated that photocyclization reactions occurred regioselectively and quantitatively to form bent–bent dipyridocarbazoles. In 3 a – d , the reaction rates depended on the solvent polarity and the substituent on the benzene ring. The photoreactions were accelerated with decreasing solvent polarity and with increasing electron‐withdrawing character of the substituents. The photocyclization of triquinolineamine 4 was faster than that of 3 a in all solvents. The results of semiempirical quantum‐chemical PM6 calculations suggested that the observed regioselective photocyclization could be explained by stabilization of the excited triplet transition state for the bent–bent form because of the molecular geometry with the CH?NQ hydrogen bonds. The solution of 5 in MeOH displayed photoreaction‐induced self‐assembly behavior to form twisted tape‐like fibers of width 200 nm, as determined by TEM imaging.     

Facile Construction of Quinoline‐2‐carboxylate Esters through Aerobic Oxidation of Alkyl 4‐Anilinocrotonates Induced by a Radical Cation Salt

A facile construction of quinoline‐2‐carboxylate esters through an aerobic oxidation of alkyl 4‐anilinocrotonates is described. In the presence of dioxygen, sp³ C−H bonds in 4‐anilinocrotonates can easily be oxidized by using a catalytic amount of a radical cation salt, providing a radical intermediate. After further oxidation and domino cyclization, the desired quinoline derivatives were afforded in high yields. This reaction provides a new way to construct the pharmaceutically relevant quinoline skeleton, avoiding harsh reaction conditions and tedious starting material synthesis.     

Synthesis and Cyclization of 8‐Formyl‐2‐(phenoxymethyl)quinoline‐3‐carboxylic Acids

A facile synthesis of a series of new quinoline‐8‐carbaldehyde compounds, namely 8‐formyl‐2‐(phenoxymethyl)quinoline‐3‐carboxylic acids ( 4a – 4h ) and 13‐oxo‐6,13‐dihydro[1]benzoxepino[3,4‐b]quinoline‐8‐carbaldehyde ( 5a – 5g ) is described, involving the one‐pot synthesis reaction of ethyl 2‐(chloromethyl)‐8‐formylquinoline‐3‐carboxylate ( 3 ) with substituted phenols followed by the intramolecular cyclization reaction via the treatment with polyphosphoric acid (PPA). Quinoline‐8‐carbaldehydes 4a – 4h and 5a – 5g are novel and their structures were supported by IR, ¹H NMR, ¹³C NMR, MS and elemental analysis.     

Synthesis of novel quinoline analogues of nimesulide: An unusual observation

Reduction of nimesulide followed by treating the N‐acyl derivative of resulting arylamine with Vilsmeier‐Haack reagent provided novel 2‐chloro‐3‐formylquinoline derivatives. The construction of quinoline ring using Vilsmeier‐Haack reagent afforded an unexpected compound, N‐(2‐chloro‐3‐formyl‐7‐phenoxy quinolin‐6‐yl)formamide, in addition to the expected product. The structure of this unexpected quinoline derivative was established via single‐crystal X‐ray analysis and its formation could be explained by an unprecedented N‐S bond cleavage under Vilsmeier‐Haack reaction conditions. The 2‐chloro‐3‐formylquinoline derivatives obtained were converted to a number of corresponding Schiff bases with potential pharmacological importance. J. Heterocyclic Chem., 2011.     

Formation of Metal‐Assisted Stable Double Helices in Dimers of Cyclic Bis‐Tetrapyrroles that Exhibit Spring‐Like Motion

Bidipyrrin‐bridged macrocycles, prepared from Ni^II‐bridged dipyrrin‐based nanorings by intramolecular oxidative biaryl coupling reactions, yielded [2+4]‐type Zn^II‐assisted stable twisted‐ring dimers comprising two double helices. These [2+4]‐type metal complexes can be optically resolved by chiral HPLC and exhibit tunable electronic and optical properties as a result of spring‐like motions. The double helices behave as glue to connect two macrocycles and as the screws of hinges to form thermally responsive synchronized spring systems.     

Bromenium‐Catalysed Tandem Ring Opening/Cyclisation of Vinylcyclopropanes and Vinylcyclobutanes: A Metal‐Free [3+2+1]/[4+2+1] Cascade for the Synthesis of Chiral Amidines and Computational Investigation

We present a detailed study of a [3+2+1] cascade cyclisation of vinylcyclopropanes (VCP) catalysed by a bromenium species (Br^δ+? X^δ?) generated in situ, which results in the synthesis of chiral bicyclic amidines in a tandem one‐pot operation. The formation of amidines involves the ring‐opening of VCPs with Br? X, followed by a Ritter‐type reaction with chloramine‐T and a tandem cyclisation. The reaction has been further extended to vinylcyclobutane systems and involves a [4+2+1] cascade cyclisation with the same reagents. The versatility of the methodology has been demonstrated by careful choice of VCPs and VCBs to yield bicyclo[4.3.0]‐, ‐[4.3.1]‐ and ‐[4.4.0]amidines in enantiomerically pure form. On the basis of the experimental observations and DFT calculations, a reasonable mechanism has been put forth to account for the formation of the products and the observed stereoselectivity. We propose the existence of a π‐stabilised homoallylic carbocation at the cyclopropane carbon as the reason for high stereoselectivity. DFT studies at B3LYP/6‐311+G** and M06‐2X/6‐31+G* levels of theory in gas‐phase calculations suggest the ring‐opening of VCP is initiated at the π‐complex stage (between the double bond and Br? X). This can be clearly perceived from the solution‐phase (acetonitrile) calculations using the polarisable continuum model (PCM) solvation model, from which the extent of the ring opening of VCP was found to be noticeably high. Studies also show that the formation of zero‐bridge bicyclic amidines is favoured over other bridged bicyclic amidines. The energetics of competing reaction pathways is compared to explain the product selectivity.     

Synthesis and Photophysical Properties of Doubly β‐to‐β Bridged Cyclic ZnII Porphyrin Arrays

A series of doubly β‐to‐β bridged cyclic Zn^II porphyrin arrays were prepared by a stepwise Suzuki–Miyaura coupling reaction of borylated Zn^II porphyrin with different bridge groups. The coupling of the building block of β,β′‐diboryl Zn^II porphyrin 1 with different bridges provided the doubly β‐to‐β carbazole‐bridged Zn^II porphyrin array 3 , the fluorene‐bridged Zn^II porphyrin array 5 , the fluorenone‐bridged Zn^II porphyrin array 7 , and the three‐carbazole‐bridged Zn^II porphyrin ring 8 . The structural assignment of 3 was confirmed by the X‐ray diffraction analysis, which revealed a highly symmetrical and remarkably bent syn‐form structure. The incorporation of bridge units with different electronic effects results in different photophysical properties of the cyclic Zn^II porphyrin arrays. Comprehensive photophysical studies demonstrate that the electron‐withdrawing bridge fluorenone has the largest electronic interaction with the Zn^II porphyrin unit among the series, thus resulting in the highest two‐photon absorption cross‐section values (σ⁽²⁾) of 6570±60 GM for 7 . The present work provides a new strategy for developing porphyrin‐based optical materials.     

Carbamoyl Radical‐Mediated Synthesis and Semipinacol Rearrangement of β‐Lactam Diols

In an approach to the biologically important 6‐azabicyclo[3.2.1]octane ring system, the scope of the tandem 4‐exo‐trig carbamoyl radical cyclization—dithiocarbamate group transfer reaction to ring‐fused β‐lactams is evaluated. β‐Lactams fused to five‐, six‐, and seven‐membered rings are prepared in good to excellent yield, and with moderate to complete control at the newly formed dithiocarbamate stereocentre. No cyclization is observed with an additional methyl substituent on the terminus of the double bond. Elimination of the dithiocarbamate group gives α,β‐ or β,γ‐unsaturated lactams depending on both the methodology employed (base‐mediated or thermal) and the nature of the carbocycle fused to the β‐lactam. Fused β‐lactam diols, obtained from catalytic OsO₄‐mediated dihydroxylation of α,β‐unsaturated β‐lactams, undergo semipinacol rearrangement via the corresponding cyclic sulfite or phosphorane to give keto‐bridged bicyclic amides by exclusive N‐acyl group migration. A monocyclic β‐lactam diol undergoes Appel reaction at a primary alcohol in preference to semipinacol rearrangement. Preliminary investigations into the chemo‐ and stereoselective manipulation of the two carbonyl groups present in a representative 7,8‐dioxo‐6‐azabicyclo[3.2.1]octane rearrangement product are also reported.     

In Pursuit of the PO2+ Cation. The Reaction of KPO2F2 and SbF5 leads to an Eight‐membered Antimony‐Oxygen‐Phosphorus‐bridged Ring

The reaction of KPO₂F₂ with the strong Lewis acid SbF₅ was studied as a potential pathway to the unknown PO₂⁺ cation. The resulting product has the desired PO₂SbF₆ composition but consists of an eight‐membered, antimony‐oxygen‐phosphorus‐bridged ring that was characterized by vibrational and NMR spectroscopy, ab initio methods, and a single crystal x‐ray diffraction study. The preferred formation of the ring and its mechanism are discussed.     

Total Synthesis of Gelsedilam by Means of a Thiol‐Mediated Diastereoselective Conjugate Addition–Aldol Reaction

The total synthesis of gelsedilam, which features a highly diastereoselective thiol conjugate addition–intramolecular aldol reaction to install the strained and caged [3.2.2] bridged ring system and highly efficient NiCl₂/NaBH₄‐mediated four‐step transformation in one‐pot to construct its five‐membered lactam ring is reported. The synthesis requires only 18 linear steps from the known compounds, providing useful strategies for the construction of the intricate ring system in the synthesis of related gelsedine‐type alkaloids.     

An Efficient Method for the Synthesis of Laquinimod

Laquinimod, 5‐chloro‐1,2‐dihydro‐N‐ethyl‐4‐hydroxy‐1‐methyl‐2‐oxo‐N‐ phenyl‐3‐quinoline carboxamide, is an oral drug in clinical trials for the treatment of multiple sclerosis. An efficient synthetic method for laquinimod from 2‐amino‐6‐chlorobenzoic acid via four steps was established. The overall yield of laquinimod is up to 82% as compared with 70% reported in literature. It has also been demonstrated that green reagent dimethyl carbonate is not suitable for the N‐methylation of 5‐chloroisatoic anhydride owing to the ring‐cleavage reaction induced by the generated methanol. The ring‐cleavage by‐products were isolated and characterized by ¹H‐NMR and ¹³C‐NMR. In addition, in the study of laquinimod derivatives, we found that 5‐chloro‐1,2‐dihydro‐N‐ethyl‐4‐hydroxy‐1‐methyl‐2‐oxo‐N‐phenyl‐3‐quinoline carboxamide (laquinimod) was obtained in much higher yield than 7‐chloro‐1,2‐dihydro‐N‐ethyl‐4‐hydroxy‐1‐methyl‐2‐oxo‐N‐phenyl‐3‐quinoline carboxamide under the same reaction conditions, and it is possibly attributed to a neighboring group effect.     

A Systematic Study on the Synthesis of n‐Butyl Substituted 8‐Aminoquinolines

A systematic study on the synthesis of 8‐aminoquinoline derivatives with an n‐butyl group at each alternate position of the quinoline ring was carried out. Skraup Reaction and its Doebner–von Miller variation were used to obtain most of the quinoline ring except for the 2‐butyl‐8‐aminoquinolines and 4‐butyl‐8‐aminoquinolines where the commercially available methylquinoline derivatives were used as precursors. The structures of the synthesized compounds were characterized by FTIR, ¹H‐NMR, COSY, ¹³C‐NMR and HRMS spectra.     

Gold‐Catalyzed Cyclization of Furan‐Ynes bearing a Propargyl Carbonate Group: Intramolecular Diels–Alder Reaction with In Situ Generated Allenes

Gold‐catalyzed cyclization of various furan‐ynes with a propargyl carbonate or ester moiety results in the formation of a series of polycyclic aromatic ring systems. The reactions can be rationalized through a tandem gold‐catalyzed 3,3‐rearrangement of the propargyl carboxylate moiety in furan‐yne substrates to form an allenic intermediate, which is followed by an intramolecular Diels–Alder reaction of furan and subsequent ring‐opening of the oxa‐bridged cycloadduct. It was found that the steric and electronic properties of phosphine ligands on the gold catalyst had a significant impact on the reaction outcome. In the case of 1,5‐furan‐yne, the cleavage of the oxa‐bridge in the cycloadduct with concomitant 1,2‐migration of the R¹ group occurs to furnish anthracen‐1(2H)‐ones bearing a quaternary carbon center. For 1,4‐furan‐yne, a facile aromatization of the cycloadduct takes place to give 9‐oxygenated anthracene derivatives.     

Microwave Assisted Synthesis and Antimicrobial Potential of Quinoline‐Based 4‐Hydrazide‐Hydrazone Derivatives

Quinoline is a benzo‐fused pyridine which is a therapeutically important heterocycle in medicinal chemistry research and new drug development. A series of 12 new hydrazide‐hydrazone motifs bearing quinoline core 4a–l was successfully synthesized by microwave irradiation technique. The synthesis involved four steps strategies which was initiated by ring‐opening synthetic modification of isatin to quinoline‐4‐carboxylic acid through Pfitzinger approach. The structure of the reactive intermediates 1, 2, and 3 as well as the targeted quinoline 4a–l were confirmed by the result of physicochemical parameters and spectroscopic means which include FTIR, UV, ¹H and ¹³C NMR as well as DEPT 135 NMR. The in vitro antimicrobial screening of the targeted hydrazide‐hydrazones 4a–l alongside with gentamicin (clinical standard) against six microorganisms was determined using agar diffusion. The result from the MIC test showed that this series of hydrazide‐hydrazones exhibited remarkable efficacy as antimicrobial agents with 4e being the most active antibacterial agent with MIC value ranging from 3.13 to 0.39 μg/mL on the six organisms tested.     

An Unusual Ring‐Contraction/Rearrangement Sequence for Making Functionalized Di‐ and Triquinanes

A novel ring contraction/rearrangement sequence leading to functionalized 2,8‐oxymethano‐bridged di‐ and triquinane compounds is observed in the reaction of various substituted 1‐methyl‐4‐isopropenyl‐6‐oxabicylo[3.2.1]octan‐8‐ones with Lewis acids. The reaction is novel and is unprecedented for the synthesis of di‐ and triquinane frameworks.     

Functionalization of Intramolecular Frustrated Lewis Pairs by 1,1‐Carboboration with Conjugated Enynes

The vicinal P/B frustrated Lewis pair (FLP) Mes₂PCH₂CH₂B(C₆F₅)₂ undergoes 1,1‐carboboration reactions with the Me₃Si‐substituted enynes to give ring‐enlarged functionalized C₃‐bridged P/B FLPs. These serve as active FLPs in the activation of dihydrogen to give the respective zwitterionic [P]H⁺/[B]H^? products. One such product shows activity as a metal‐free catalyst for the hydrogenation of enamines or a bulky imine. The ring‐enlarged FLPs contain dienylborane functionalities that undergo “bora‐Nazarov”‐type ring‐closing rearrangements upon photolysis. A DFT study had shown that the dienylborane cyclization of such systems itself is endothermic, but a subsequent C₆F₅ migration is very favorable. Furthermore, substituted 2,5‐dihydroborole products are derived from cyclization and C₆F₅ migration from the photolysis reaction. In the case of the six‐membered annulation product, a subsequent stereoisomerization reaction takes place and the resultant compound undergoes a P/B FLP 1,2‐addition reaction with a terminal alkyne with rearrangement.     

Modified Riemschneider Reaction of 3‐Thiocyanatoquinolinediones

The Riemschneider reaction of 3‐thiocyanatoquinoline‐2,4(1H,3H)‐diones with conc. H₂SO₄ was investigated. Using different reaction conditions, 13 types of reaction products were isolated. Compounds bearing a Me, Et, or Bu group at C(3) afforded mainly [1,3]thiazolo[5,4‐c]quinoline‐2,4‐diones and 1,9b‐dihydro‐9b‐hydroxythiazolo[5,4‐c]quinoline‐2,4‐diones. In the case of the 3‐Bu derivatives of the starting compounds, C‐debutylation was also observed. If a Bn group is present at C(3), rapid C‐debenzylation of the starting thiocyanates occurred, yielding [1,3]oxathiolo[4,5‐c]quinoline‐2,4‐diones, and mixtures of mono‐, di‐, and trisulfides derived from 4‐hydroxy‐3‐sulfanylquinoline‐2‐ones. The reaction mechanism of all of the transformations is discussed. All new compounds were characterized by IR, ¹H‐ and ¹³C‐NMR, and EI and ESI mass spectra, and in some cases, ¹⁵N‐NMR spectra were also used to characterize new compounds.     

冠醚桥接苯并菲二聚体合成的新途径

本研究借鉴合成冠醚的Willianmson反应,通过缓慢滴加二氯乙醚合成了重要中间体乙氧基醚链接的苯并菲二聚体,且避免了2,3-二羟基四戊烷氧基苯并菲自身成环反应所导致单一冠醚苯并菲的生成.进一步以该中间体为原料,通过缩合反应,最终得到了冠醚桥接苯并菲二聚体,并用1H NMR,13C NMR和MALDI-TOF质谱对产物的结构和纯度进行了表征.