Concise Synthesis of [1,1′‐Biisoquinoline]‐4,4′‐diol via a Protecting Group Strategy and Its Application for Potential Liquid‐Crystalline Compounds

The [1,1′‐biisoquinoline]‐4,4′‐diol ( 4a ), which was obtained as hydrochloride 4a ?2 HCl in two steps starting from the methoxymethyl (MOM)‐protected 1‐chloroisoquinoline 8 (Scheme 3), opens access to further O‐functionalized biisoquinoline derivatives. Compound 4a ?2 HCl was esterified with 4‐(hexadecyloxy)benzoyl chloride ( 5b ) to give the corresponding diester 3b (Scheme 4), which could not be obtained by Ni‐mediated homocoupling of 6b (Scheme 2). The ether derivative 2b was accessible in good yield by reaction of 4a ?2 HCl with the respective alkyl bromide 9 under the conditions of Williamson etherification (Scheme 4). Slightly modified conditions were applied to the esterification of 4a ?2 HCl with galloyl chlorides 10a – h as well as etherification of 4a ?2 HCl with 6‐bromohexyl tris(alkyloxy)benzoates 11b , d – h and [(6‐bromohexyl)oxy]‐substituted pentakis(alkyloxy)triphenylenes 14a – c (Scheme 5). Despite the bulky substituents, the respective target 1,1′‐biisoquinolines 12, 13 , and 15 were isolated in 14–86% yield (Table).     

Asymmetric Synthesis of (R)‐1‐Alkyl‐Substituted Tetrahydro‐ß‐carbolines Catalyzed by Strictosidine Synthases

Stereoselective methods for the synthesis of tetrahydro‐ß‐carbolines are of significant interest due to the broad spectrum of biological activity of the target molecules. In the plant kingdom, strictosidine synthases catalyze the C?C coupling through a Pictet–Spengler reaction of tryptamine and secologanin to exclusively form the (S)‐configured tetrahydro‐ß‐carboline (S)‐strictosidine. Investigating the biocatalytic Pictet–Spengler reaction of tryptamine with small‐molecular‐weight aliphatic aldehydes revealed that the strictosidine synthases give unexpectedly access to the (R)‐configured product. Developing an efficient expression method for the enzyme allowed the preparative transformation of various aldehydes, giving the products with up to >98 % ee. With this tool in hand, a chemoenzymatic two‐step synthesis of (R)‐harmicine was achieved, giving (R)‐harmicine in 67 % overall yield in optically pure form.     

A [4+1] Cyclative Capture Approach to 3H‐Indole‐N‐oxides at Room Temperature by Rhodium(III)‐Catalyzed CH Activation

The rhodium(III)‐catalyzed [3+2] C? H cyclization of aniline derivatives and internal alkynes represents a useful contribution to straightforward synthesis of indoles. However, there is no report on the more challenging synthesis of pharmaceutically important N‐hydroxyindoles and 3H‐indole‐N‐oxides. Reported herein is the first rhodium(III)‐catalyzed [4+1] C? H oxidative cyclization of nitrones with diazo compounds to access 3H‐indole‐N‐oxides. More significantly, this reaction proceeds at room temperature and has been extended to the synthesis of N‐hydroxyindoles and N‐hydroxyindolines.     

Ruthenium‐Catalyzed meta‐Selective CH Bromination

The first example of a transition‐metal‐catalyzed, meta‐selective C? H bromination procedure is reported. In the presence of catalytic [{Ru(p‐cymene)Cl₂}₂], tetrabutylammonium tribromide can be used to functionalize the meta C? H bond of 2‐phenylpyridine derivatives, thus affording difficult to access products which are highly predisposed to further derivatization. We demonstrate this utility with one‐pot bromination/arylation and bromination/alkenylation procedures to deliver meta‐arylated and meta‐alkenylated products, respectively, in a single step.     

Ortho‐Functionalized Aryltetrazines by Direct Palladium‐Catalyzed C−H Halogenation: Application to Fast Electrophilic Fluorination Reactions

A general catalyzed direct C?H functionalization of s‐tetrazines is reported. Under mild reaction conditions, N‐directed ortho‐C?H activation of tetrazines allows the introduction of various functional groups, thus forming carbon–heteroatom bonds: C?X (X=I, Br, Cl) and C?O. Based on this methodology, we developed electrophilic mono‐ and poly‐ortho‐fluorination of tetrazines. Microwave irradiation was optimized to afford fluorinated s‐aryltetrazines, with satisfactory selectivity, within only ten minutes. This work provides an efficient and practical entry for further accessing highly substituted tetrazine derivatives (iodo, bromo, chloro, fluoro, and acetate precursors). It gives access to ortho‐functionalized aryltetrazines which are difficult to obtain by classical Pinner‐like syntheses.     

Enantioselective Synthesis and Physicochemical Properties of Libraries of 3‐Amino‐ and 3‐Amidofluoropiperidines

The enantioselective syntheses of 3‐amino‐5‐fluoropiperidines and 3‐amino‐5,5‐difluoropiperidines were developed using the ring enlargement of prolinols to access libraries of 3‐amino‐ and 3‐amidofluoropiperidines. The study of the physicochemical properties revealed that fluorine atom(s) decrease(s) the pK_a and modulate(s) the lipophilicity of 3‐aminopiperidines. The relative stereochemistry of the fluorine atoms with the amino groups at C3 on the piperidine core has a small effect on the pK_a due to conformationnal modifications induced by fluorine atom(s). In the protonated forms, the C?F bond is in an axial position due to a dipole–dipole interaction between the N?H⁺ and C?F bonds. Predictions of the physicochemical properties using common software appeared to be limited to determine correct values of pK_a and/or differences of pK_a between cis‐ and trans‐3‐amino‐5‐fluoropiperidines.     

Pd‐ and Cu‐Catalyzed Stereo‐ and Regiocontrolled Decarboxylative/CH Fluoroalkenylation of Heteroarenes

Pd/Cu‐catalyzed decarboxylative/direct C?H alkenylations of heteroarenes with α‐fluoroacrylic acid is reported. This method offers step‐economical and stereocontrolled access to valuable heteroarylated monofluoroalkenes as both Z and E isomers, which are known to be useful in the synthesis of fluorinated biomolecules.     

Cobalt‐Catalyzed Electrophilic Amination of Aryl‐ and Heteroarylzinc Pivalates with N‐Hydroxylamine Benzoates

Aryl‐ and heteroarylzinc pivalates can be aminated with O‐benzoylhydroxylamines at 25 °C within 2–4 h in the presence of 2.5–5.0 % CoCl₂?2 LiCl to furnish the corresponding tertiary arylated or heteroarylated amines in good yields. This electrophilic amination also provides access to diarylamines and aryl(heteroaryl)amines. A new tuberculosis drug candidate (Q203) was prepared in six steps and 56 % overall yield by using this cobalt‐catalyzed amination as the key step.     

Palladium‐Catalyzed Dearomative syn‐1,4‐Oxyamination

A palladium‐catalyzed dearomative syn‐1,4‐oxyamination protocol using non‐activated arenes has been developed. This one‐pot procedure utilizes arenophile chemistry, and the corresponding para‐cycloadducts are treated with oxygen nucleophiles via formal allylic substitution, providing direct access to syn‐1,4‐oxyaminated products. The reaction conditions permit a range of arenes, as well as different O‐nucleophiles, such as oximes and benzyl alcohols. Moreover, this process was established in an asymmetric fashion, delivering products with high enantioselectivity. The dearomatized products are amenable to a multitude of further derivatizations ranging from olefin chemistry to C?H activation, giving rise to a diverse set of new functionalities. Overall, this dearomative functionalization offers rapid and controlled formation of molecular complexity, enabling straightforward access to functionalized small molecules from simple and readily available arenes.     

Access to P‐ and Axially Chiral Biaryl Phosphine Oxides by Enantioselective CpxIrIII‐Catalyzed C−H Arylations

An enantioselective C?H arylation of phosphine oxides with o‐quinone diazides catalyzed by an iridium(III) complex bearing an atropchiral cyclopentadienyl (Cp^x) ligand and phthaloyl tert‐leucine as co‐catalyst is reported. The method allows access to a) P‐chiral biaryl phosphine oxides, b) atropo‐enantioselective construction of sterically demanding biaryl backbones, and also c) selective assembly of axial and P‐chiral compounds in excellent yields and diastereo‐ and enantioselectivities. Enantiospecific reductions provide monodentate chiral phosphorus(III) compounds having structures and biaryl backbones with proven importance as ligands in asymmetric catalysis.     

Application of D‐chiro‐Inositol as a Chiral Template for the Diels?Alder Reaction

The Diels? Alder reaction can reliably provide the expected endo‐product in the presence of secondary orbital overlap. It can be considerably more difficult to access a single enantiomer of the exo‐product. In this paper, a D ‐chiro‐inositol derivative is used as a chiral tether to facilitate the regio‐, diastereo‐, and enatioselective cycloaddition between cinnamic acid and hexa‐3,5‐dienoic acid. The Diels? Alder reaction between these two substrates, or their respective esters, does not occur under thermal conditions. Because of the ease of removal of the chiral tether from the resulting cyclohexene, this approach could provide a viable technique to access otherwise unavailable systems.     

An ortho‐lithiated derivative of protected phenylboronic acid: an approach to ortho‐functionalized arylboronic acids and 1,3‐dihydro‐1‐hydroxybenzo[c][2,1]oxaboroles

2‐(2′‐Bromophenyl)‐6‐butyl‐[1,3,6,2]dioxazaborocan, prepared readily by the esterification of 2‐bromophenylboronic acid with N‐butyldiethanolamine (BDEA), undergoes Br/Li exchange using BuLi/THF at ? 78 °C. A resulting intermediate proved useful in synthesis of various ortho‐functionalized arylboronic acids. Specifically, reactions with benzaldehydes provide a convenient access to 1,3‐dihydro‐1‐hydroxy‐3‐arylbenzo[c][2,1]oxaboroles that exhibit a remarkably high rotational barrier around the C? aryl bond. In addition, the molecular structure of sterically hindered 1,3‐dihydro‐1‐hydroxy‐3‐(2′, 6′‐dimethoxyphenyl)benzo[c][2,1]oxaborole is reported. Copyright © 2007 John Wiley & Sons, Ltd.     

Synthesis and characterization of fluorene‐based oligomers and polymers incorporating N‐arylphenothiazine‐S,S‐dioxide units

A series of 3,7‐bis(9,9‐di‐n‐hexylfluoren‐2‐yl)‐N‐arylphenothiazine‐S,S‐dioxide trimers and (9,9‐di‐n‐octylfluorene‐2,7‐diyl‐co‐N‐arylphenothiazine‐S,S‐dioxide) co‐polymers, with varying ratios of phenothiazine‐S,S‐dioxide units, have been prepared in good yields by palladium‐catalyzed cross‐coupling reactions. The materials are deep blue emitters and show no solvatochromism or evidence for an intramolecular charge‐transfer state. The photoluminescence quantum yields of the trimers are ?_PL 15–30% in solution and 14–25% in films. The polymers demonstrated very high values in solution (?_PL 74–84%) and ?_PL values in films of 28–47%. The estimated HOMO energy levels are between ?5.64 and ?5.62 eV for the polymers with 15% incorporation of the phenothiazine‐S,S‐dioxide units. An analogous N‐arylphenothiazine co‐polymer shows significantly red shifted absorption and emission. Solution electrochemical data and density functional theory calculations are also presented. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Synthesis of meta‐Terphenyl‐2,2′′‐diols by Anodic C−C Cross‐Coupling Reactions

The anodic C?C cross‐coupling reaction is a versatile synthetic approach to symmetric and non‐symmetric biphenols and arylated phenols. We herein present a metal‐free electrosynthetic method that provides access to symmetric and non‐symmetric meta‐terphenyl‐2,2′′‐diols in good yields and high selectivity. Symmetric derivatives can be obtained by direct electrolysis in an undivided cell. The synthesis of non‐symmetric meta‐terphenyl‐2,2′′‐diols required two electrochemical steps. The reactions are easy to conduct and scalable. The method also features a broad substrate scope, and a large variety of functional groups are tolerated. The target molecules may serve as [OCO]^3? pincer ligands.     

Pd(0)‐Catalyzed Direct C−H Functionalization of 2‐H‐4‐Benzylidene Imidazolones: Friendly and Large‐Scale Access to GFP and Kaede Protein Fluorophores

The first one‐pot synthesis of N‐substituted 2‐H‐4‐benzylidene imidazolones and their subsequent palladium‐catalyzed and copper‐assisted direct C2?H arylation and alkenylation with aryl‐ and alkenylhalides are described. This innovative synthesis is step‐economical, azide‐free, high yielding, highly flexible in the introduction of a variety of electronically different groups, and can be operated on large‐scale. Moreover, the method allows direct access to C2‐arylated or alkenylated imidazolone‐based green fluorescent protein (GFP) and Kaede protein fluorophores, including ortho‐hydroxylated models.     

Generation and Rearrangement of N,O‐Dialkenylhydroxylamines for the Synthesis of 2‐Aminotetrahydrofurans

A new diastereoselective route to 2‐aminotetrahydrofurans has been developed from N,O‐dialkenylhydroxylamines. These intermediates undergo a spontaneous C?C bond‐forming [3,3]‐sigmatropic rearrangement followed by a C?O bond‐forming cyclization. A copper‐catalyzed N‐alkenylation of an N‐Boc‐hydroxylamine with alkenyl iodides, and a base‐promoted addition of the resulting N‐hydroxyenamines to an electron‐deficient allene, provide modular access to these novel rearrangement precursors. The scope of this de novo synthesis of simple nucleoside analogues has been explored to reveal trends in diastereoselectivity and reactivity. In addition, a base‐promoted ring‐opening and Mannich reaction has been discovered to covert 2‐aminotetrahydrofurans to cyclopentyl β‐aminoacid derivatives or cyclopentenones.     

Synthesis of Novel Imidazo[1,2‐a]pyridin‐2‐amines from Arylamines and Nitriles via Sequential Addition and I2/KI‐Mediated Oxidative Cyclization

A novel and practical strategy for the construction of imidazo[1,2‐a]pyridin‐2‐amine frameworks has been developed. The present sequential approach involves addition of arylamines to nitriles and I₂/KI‐mediated oxidative C?N bond formation without purification of the intermediate amidines. This operationally simple synthetic process provides a facile access to a variety of new 2‐amino substituted imidazo[1,2‐a]pyridines and related heterocyclic compounds in an efficient and scalable fashion.     

Oxidative Coupling of Anionic Abnormal N‐Heterocyclic Carbenes: Efficient Access to Janus‐Type 4,4′‐Bis(2H‐imidazol‐2‐ylidene)s

The oxidative coupling of anionic imidazol‐4‐ylidenes protected at the C2 position with [MnCp(CO)₂] or BH₃ led to the corresponding 4,4′‐bis(2H‐imidazol‐2‐ylidene) complexes or adducts, in which the two carbene moieties are connected through a single C?C bond. Subsequent acidic treatment of the later species led to the corresponding 4,4′‐bis(imidazolium) salts in good yields. The overall procedure offers practical access to a novel class of Janus‐type bis(NHC)s. Strikingly, the coplanarity of the two NHC rings within the mesityl derivative 4,4′‐bis(IMes), favored by steric hindrance along with stabilizing intramolecular C?H???π aryl interactions, allows the alignment of the π‐systems and, as a direct consequence, significant electron communication through the bis(carbene) scaffold.     

Synthesis of N,N‐Dialkylamino‐nor‐Dihydroxanthene‐Hemicyanine Fused Near‐Infrared Fluorophores and Their First Water‐Soluble and/or Bioconjugatable Analogues

The effective synthesis of extended conjugated N ,N ‐dialkylamino‐nor ‐dihydroxanthene‐based fluorophores is described from diversely functionalized salicylic aldehydes. The access to these original fluorescent derivatives proceeded in two steps through a one‐pot construction of the unusual nor ‐dihydroxanthene (nor ‐DHX) scaffold followed by a diversification step providing a wide variety of nor ‐DHX‐hemicyanine fused dyes emitting in the range of 730–790 nm. The versatility of our approach has enabled a further extension to the late‐stage introduction of negatively/positively charged polar groups onto their terminal nitrogen heterocyclic subunit, thereby giving access to the first water‐soluble and/or bioconjugatable members of this emerging class of NIR fluorophores. Our water‐solubilizing method is easily implementable, and the nor ‐DHX‐hemicyanine skeleton maintains satisfying fluorescence quantum yields (5–20 %) under physiological conditions. Finally, the bioconjugation ability of fluorescent derivatives bearing a free carboxylic acid was demonstrated through the covalent labeling of a model protein, namely, bovine serum albumin.     

Application of carbon arc‐generated Mo‐ and W‐based catalyst systems to the ROMP of norbornene

This study focuses on the application of the carbon arc‐generated molybdenum‐ and tungsten‐based catalyst systems, MoCl₅? C and WCl₆? C, to effect ring‐opening metathesis polymerization (ROMP) of bicyclo[2.2.1]hept‐2‐ene (norbornene). The results are compared with those previously obtained by the electrochemically generated MoCl₅? ē? Al? CH₂Cl₂ and WCl₆? ē? Al? CH₂Cl₂ systems. The polymer products are characterized using ¹H and ¹³C NMR, gel permeation chromatography, differential scanning calorimetry and thermo gravimetric analysis. According to NMR spectra analyses, the molybdenum‐based catalyst system produced polynorbornene with ca 48% cis structure whereas tungsten system produced ca 56% cis structure polynorbornene and in both cases the polynorbornene had a blocky distribution. Copyright © 2009 John Wiley & Sons, Ltd.