Palladium‐Catalyzed,tert‐Butyllithium‐Mediated Dimerization of Aryl Halides and Its Application in the Atropselective Total Synthesis of Mastigophorene A

A palladium‐catalyzed direct synthesis of symmetric biaryl compounds from aryl halides in the presence of tBuLi is described. In situ lithium–halogen exchange generates the corresponding aryl lithium reagent, which undergoes a homocoupling reaction with a second molecule of the aryl halide in the presence of the palladium catalyst (1 mol %). The reaction takes place at room temperature, is fast (1 h), and affords the corresponding biaryl compounds in good to excellent yields. The application of the method is demonstrated in an efficient asymmetric total synthesis of mastigophorene A. The chiral biaryl axis is constructed with an atropselectivity of 9:1 owing to catalyst‐induced remote point‐to‐axial chirality transfer.     

Palladium‐Catalyzed,tert‐Butyllithium‐Mediated Dimerization of Aryl Halides and Its Application in the Atropselective Total Synthesis of Mastigophorene A

A palladium‐catalyzed direct synthesis of symmetric biaryl compounds from aryl halides in the presence of tBuLi is described. In situ lithium–halogen exchange generates the corresponding aryl lithium reagent, which undergoes a homocoupling reaction with a second molecule of the aryl halide in the presence of the palladium catalyst (1 mol %). The reaction takes place at room temperature, is fast (1 h), and affords the corresponding biaryl compounds in good to excellent yields. The application of the method is demonstrated in an efficient asymmetric total synthesis of mastigophorene A. The chiral biaryl axis is constructed with an atropselectivity of 9:1 owing to catalyst‐induced remote point‐to‐axial chirality transfer.     

Palladium-catalyzed reactions of arylindium reagents prepared directly from aryl iodides and indium metal

Treatment of aryl iodides with indium metal in the presence of lithium chloride leads to the formation of an organoindium reagent capable of participating in cross-coupling reactions under transition-metal catalysis. Combination with aryl halides in the presence of 5 mol % Cl2Pd(dppf) furnishes biaryl compounds in good yields; similarly, reaction with acyl halides or allylic acetates/carbonates in the presence of 5-10 mol % palladium catalyst leads to arylketones and allylic substitution products, respectively, in moderate yields. The reactions are tolerant of the presence of protic solvents, and approximately 85% of the indium metal employed can be recovered by reduction of the residual indium salts with zinc(0).     

4‐(2‐Hydroxyphenyl)‐2‐phenyl‐2,3‐dihydro‐1H‐1,5‐benzodiazepine and the 2‐(2,3‐dimethoxyphenyl)‐, 2‐(3,4‐dimethoxyphenyl)‐ and 2‐(2,5‐dimethoxyphenyl)‐substituted derivatives

The 1,5‐benzodiazepine ring system exhibits a puckered boat‐like conformation for all four title compounds [4‐(2‐hydroxyphenyl)‐2‐phenyl‐2,3‐dihydro‐1H‐1,5‐benzodiazepine, C₂₁H₁₈N₂O, (I), 2‐(2,3‐dimethoxyphenyl)‐4‐(2‐hydroxyphenyl)‐2,3‐dihydro‐1H‐1,5‐benzodiazepine, C₂₃H₂₂N₂O₃, (II), 2‐(3,4‐dimethoxyphenyl)‐4‐(2‐hydroxyphenyl)‐2,3‐dihydro‐1H‐1,5‐benzodiazepine, C₂₃H₂₂N₂O₃, (III), and 2‐(2,5‐dimethoxyphenyl)‐4‐(2‐hydroxyphenyl)‐2,3‐dihydro‐1H‐1,5‐benzodiazepine, C₂₃H₂₂N₂O₃, (IV)]. The stereochemical correlation of the two C₆ aromatic groups with respect to the benzodiazepine ring system is pseudo‐equatorial–equatorial for compounds (I) (the phenyl group), (II) (the 2,3‐dimethoxyphenyl group) and (III) (the 3,4‐dimethoxyphenyl group), while for (IV) (the 2,5‐dimethoxyphenyl group) the system is pseudo‐axial–equatorial. An intramolecular hydrogen bond between the hydroxyl OH group and a benzodiazepine N atom is present for all four compounds and defines a six‐membered ring, whose geometry is constant across the series. Although the molecular structures are similar, the supramolecular packing is different; compounds (I) and (IV) form chains, while (II) forms dimeric units and (III) displays a layered structure. The packing seems to depend on at least two factors: (i) the nature of the atoms defining the hydrogen bond and (ii) the number of intermolecular interactions of the types O—H...O, N—H...O, N—H...π(arene) or C—H...π(arene).     

Synthesis and Mesomorphic Behavior of 3‐Alkyl‐2,5‐ bis[p‐(hexa‐2,4‐dienoyloxy)phenyl]‐Thiophene Derivatives

3‐Alkyl‐2,5‐bis[p‐(hexa‐2,4‐dienoyloxy)phenyl]‐thiophene derivatives were synthesized by using Kumada coupling and Suzuki coupling reactions as key steps. The thermotropic liquid crystalline behavior of these compounds was investigated by optical polarized microscopy, monotropic nematic mesophases were observed in such compounds.     

Annosqualine: a Novel Alkaloid from the Stems of Annona squamosa

Annosqualine (=(10′bR)‐1′,5′,6′,10′b‐tetrahydro‐9′‐hydroxy‐7′,8′‐dimethoxyspiro[cyclohexa‐2,5‐diene‐1,2′‐pyrrolo[2,1‐a]isoquinoline]‐3′,4‐dione; 1 ), a novel alkaloid with an unprecedented skeleton, and a new amide, dihydrosinapoyltyramine (=3‐(4‐hydroxy‐3,5‐dimethoxyphenyl)‐N‐[2‐(4‐hydroxyphenyl)ethyl]propanamide; 2 ), were isolated from the stems of Annona squamosa L., together with six known alkaloids. The structures of all compounds were elucidated spectroscopically by means of optical rotation, ¹H‐, ¹³C‐, and 2D‐NMR, and by EI‐MS, or by comparison with the spectral data of authentic samples. A possible biogenetical pathway towards annosqualine ( 1 ) is proposed.     

Deprotonative Metalation of Substituted Benzenes and Heteroaromatics Using Amino/Alkyl Mixed Lithium–Zinc Combinations

Different homoleptic and heteroleptic lithium–zinc combinations were prepared, and structural elements obtained on the basis of NMR spectroscopic experiments and DFT calculations. In light of their ability to metalate anisole, pathways were proposed to justify the synergy observed for some mixtures. The best basic mixtures were obtained either by combining ZnCl₂ ? TMEDA (TMEDA=N,N,N′,N′‐tetramethylethylenediamine) with [Li(tmp)] (tmp=2,2,6,6‐tetramethylpiperidino; 3 equiv) or by replacing one of the tmp in the precedent mixture with an alkyl group. The reactivity of the aromatic lithium zincates supposedly formed was next studied, and proved to be substrate‐, base‐, and electrophile‐dependent. The aromatic lithium zincates were finally involved in palladium‐catalyzed cross‐coupling reactions with aromatic chlorides and bromides.     

Buchwald–Hartwig Amination of Nitroarenes

The Buchwald–Hartwig amination of nitroarenes was achieved for the first time by using palladium catalysts bearing dialkyl(biaryl)phosphine ligands. These cross‐coupling reactions of nitroarenes with diarylamines, arylamines, and alkylamines afforded the corresponding substituted arylamines. A catalytic cycle involving the oxidative addition of the Ar−NO₂ bond to palladium(0) followed by nitrite/amine exchange is proposed based on a stoichiometric reaction.     

Biocatalytic Dynamic Kinetic Resolution for the Synthesis of Atropisomeric Biaryl N‐Oxide Lewis Base Catalysts

Atropisomeric biaryl pyridine and isoquinoline N‐oxides were synthesized enantioselectively by dynamic kinetic resolution (DKR) of rapidly racemizing precursors exhibiting free bond rotation. The DKR was achieved by ketoreductase (KRED) catalyzed reduction of an aldehyde to form a configurationally stable atropisomeric alcohol, with the substantial increase in rotational barrier arising from the loss of a bonding interaction between the N‐oxide and the aldehyde. Use of different KREDs allowed either the M or P enantiomer to be synthesized in excellent enantiopurity. The enantioenriched biaryl N‐oxide compounds catalyze the asymmetric allylation of benzaldehyde derivatives with allyltrichlorosilane.     

Palladium‐Catalyzed Cyclization Reaction of o‐Haloanilines,CO2 and Isocyanides: Access to Quinazoline‐2,4(1H,3H)‐diones

Quinazoline‐2,4(1H,3H)‐diones are core structural subunits frequently found in many biologically important compounds. The reaction of 2‐​aminobenzonitrile and CO₂, which was frequently studied, only provided N3‐unsubstituted quinazoline‐2,4(1H,3H)‐dione compounds. Herein we report palladium‐catalyzed cyclization reactions of o‐haloanilines, CO₂ and isocyanides to prepare N3‐substituted quinazoline‐2,4(1H,3H)‐diones. Electron‐rich o‐bromoanilines participated in the cyclization reaction using Cs₂CO₃ at high temperature, and electron‐deficient o‐bromoaniline or o‐iodoaniline substrates conducted the reaction using CsF as base to deliver corresponding quinazoline‐2,4(1H,3H)‐dione products in good yields.     

Synthese von neuen (Phenylalkyl)aminen zur Untersuchung von Struktur–Aktivitätsbeziehungen. Mitteilung 2

Synthesis of Novel (Phenylalkyl)amines for the Investigation of Structure–Activity Relationships. Part 2¹). 4‐Thio‐Substituted [2‐(2,5‐Dimethoxyphenyl)ethyl]amines (=2,5‐Dimethoxybenzeneethanamines) The 4‐substituted [2‐(2,5‐dimethoxyphenyl)ethyl]amines (=2,5‐dimethoxybenzeneethanamines) and its α‐methyl analogs are known to act as potent 5‐HT_2A/C ligands, which have, depending on their 4‐substituent, agonistic or antagonistic character. Generally, compounds with a small lipophilic substituent typically are agonists and those with a larger lipophilic substituent predominantly antagonists or at least partial agonists. Since little is known about the transition and more information is needed about the structural requirements of the 4‐substituent to control the functional activity, 12 novel 4‐thio‐substituted [2‐(2,5‐dimethoxyphenyl)ethyl]amines were synthesized and spectroscopically characterized. Thus 2,5‐dimethoxybenzenethiol ( 7 ) was converted to the thioether derivatives 8a – l with several alkyl, fluoroalkyl, alkenyl, and benzyl halides. Subsequent Vilsmeier‐formylation afforded the benzaldehydes 9a – l , condensation with MeNO₂ the nitroethenyl derivatives 10a – l , and reduction with AlH₃ the desired (2‐phenylethyl)amines 11a – l .     

Synthesis,structural studies and antimicrobial evaluation of nickel (II) complexes of NNS tridentate thiosemicarbazone based ligands

Synthesis and characterization of three nickel complexes [NiCl(L¹)] 1 , [NiCl(L²)] 2 and [NiCl(L³)] 3 are described {HL¹ = 4‐(2,5‐dimethoxyphenyl)‐1‐((pyridin‐2‐yl)methylene)thiosemicarbazide, HL² = 4‐(3‐nitrophenyl)‐1‐((pyridin‐2‐yl)methylene)thiosemicarbazide and HL³ = 4‐(2,4‐dimethoxyphenyl)‐1‐((pyridin‐2‐yl)methylene)thiosemicarbazide} and among the tridentate ligands HL³ is reported for the first time. The structures of the complexes were assigned based on CHNS microanalysis, spectroscopic (IR & UV–Vis.) data and solution conductivity studies. The absence of any magnetism for the complexes proved their square planar geometry. Single crystals of complex 1 were grown and analyzed by XRD analysis which confirmed the complex planarity as each Ni atom connects to three (two nitrogen and one sulfur) atoms from the thiosemicarbazone ligand and an additional chlorine atom. Packing of the complex 1 in the crystal lattice was proved to stabilize via intermolecular hydrogen bonds. Antimicrobial activities of 1 – 3 were studied in vitro against fungal and bacterial species and, in several instances, the complexes possessed improved antibacterial behavior in comparison to chloramphenicol.     

Concise and stereoselective synthesis of 2,5- and 2,4-disubstituted thiazole amino acid subunits for synthesizing thiazole-containing peptides

A concise, highly stereoselective synthesis of 2,4- and 2,5-disubstituted thiazole amino acids was developed. These are important building blocks for various biologically active thiazole-containing natural peptides and their regioisomeric analogues. The fundamental reactions are diastereoselective addition of (4- or 5-bromothiazol-2-yl)lithium to N-tert-butanesulfinyl imine with subsequent Pd-catalyzed phenoxycarbonylation.     

A Convenient Alumination of Functionalized Aromatics by Using the Frustrated Lewis Pair Et3Al and TMPMgCl⋅LiCl

A straightforward and efficient alumination of functionalized arenes by using the frustrated Lewis pair Et₃Al and TMPMgCl ? LiCl (TMP=2,2,6,6‐tetramethylpiperidyl) has been developed. In particular, halogenated electron‐rich aromatics can be smoothly functionalized by using the frustrated Lewis pair Et₃Al and TMPMgCl ? LiCl. Compared with previously described alumination methods, this procedure avoids extensive cooling and the need for an excess of base. This in situ procedure has proven to be most practical and allows for regio‐ and chemoselective metalation of a wide range of aromatics with sensitive functional groups (CONEt₂, CO₂Me, CN, OCONMe₂) or halogens (F, Cl, Br, I). The resulting aromatic aluminates, which were characterized by using NMR spectroscopy, were subjected to allylations, acylations, and palladium‐catalyzed cross‐coupling reactions after transmetalation to zinc. It was shown that the nature of the Zn salt used for transmetalation is crucial. Thus, compared with ZnCl₂ (2 equiv), the use of Zn(OPiv)₂ (2 equiv; OPiv=pivalate) allows the subsequent quenching reactions to be performed with only a slight excess of electrophile (1.2 equiv) and provides interesting functionalized aromatics in good yields.     

Formation of Tri‐ and Tetranuclear Titanacycles through Decamethyltitanocene‐Mediated Intermolecular C–C Coupling of Dinitriles

The reactions of [Cp*₂Ti(η²‐Me₃SiC₂SiMe₃)] (Cp*=η⁵‐pentamethylcyclopentadienyl) with various dicyano compounds were investigated. Nitrile–nitrile C? C couplings result in multinuclear complexes owing to the bifunctionality of the substrates. Applying 1,3‐ or 1,4‐dicyanobenzene led to tri‐ and tetranuclear complexes of the rare 1‐metalla‐2,5‐diaza‐cyclopenta‐2,4‐dienes. These are potential catalysts and were tested in the ring‐opening polymerization of ε‐caprolactone. The reaction with adiponitrile as alkyl dinitrile afforded a trinuclear 1‐metalla‐2,5‐diaza‐cyclopent‐3‐ene through additional protonation of the nitrogen atoms. The structure and bonding of the products were investigated by X‐ray crystallography and DFT analysis to understand the molecular organization in the macrocycles.     

Design,Synthesis, and Structural Elucidation of New Pyridine and Thienopyridine Derivatives

New series of 3‐cyanopyridine scaffolds were prepared from the reaction of 3‐(4‐bromophenyl)‐1‐(3,4‐dimethoxyphenyl)prop‐2‐en‐1‐one with active nitriles, including malononitrile and 2‐cyanothioacetamide. The newly prepared 6‐(4‐bromophenyl)‐4‐(3,4‐dimethoxyphenyl)‐2‐thioxo‐1,2‐dihydropyridine‐3‐carbonitrile was used as a scaffold for the preparation of new series of condensed thienopyridines by its reactions with active halo compounds, namely, ethyl chloroacetate, chloroacetonitrile, phenacyl bromide, chloroacetone, and 2‐chloro‐N‐arylacetamide. The structures of the synthesized compounds were elucidated by the elemental analysis, spectral data and chemically by their preparations with other pathways.     

Synthesis of 3,4‐Dihalogenated Furan‐2‐(5 H)‐ones by Electrophilic Cyclization of 4‐Hydroxy‐2‐alkynoates

Functionalized 3,4‐dihalogenated furan‐2(5 H)‐ones can be readily prepared in moderate to good yields by treating 4‐hydroxy‐4‐arylbut‐2‐ynoate derivatives with ICl, IBr, and I₂. Both halogen atoms of the electrophile are incorporated in the product. The resulting halides can further afford polycyclic aromatic compounds using known palladium‐catalyzed coupling reactions.     

Efficient initiators for the ring‐opening polymerization of L‐lactide: Synthesis and characterization of NNO‐tridentate Schiff‐base zinc complexes

A series of efficient catalysts, based on zinc alkoxides coordinated with NNO‐tridentate Schiff‐base ligands (L¹H‐L⁶H), for ring opening polymerization of L ‐lactide have been prepared. The reactions of diethyl zinc (ZnEt₂) with L¹H‐L⁶H yielded [(μ‐L)ZnEt]₂ ( 1a–6a ), respectively. Further reaction of compounds 1a–6a with benzyl alcohol (BnOH) produced the corresponding compounds of [LZn(μ‐OBn)]₂ ( 1b–6b), respectively. X‐ray crystal structural studies reveal that all of these compounds 1a–6a are dimeric bridging through the phenolato oxygen atoms of the Schiff‐base ligand. However, the molecular structures of 1b–6b show a dimeric character bridging through the benzylalkoxy oxygen atoms. Ring‐opening polymerization of L ‐lactide, initiated by 1b–6b , proceeds rapidly with good molecular weight control and yields polymer with a very narrow molecular weight distribution. Experimental results show that the substituents on the imine carbon of the NNO‐ligand affect the reactivity of zinc complexes dramatically. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 6466–6476, 2008     

Scalable,Stereocontrolled Formal Syntheses of (+)‐Isoschizandrin and (+)‐Steganone: Development and Applications of Palladium(II)‐Catalyzed Atroposelective C−H Alkynylation

Dibenzocyclooctadiene lignans are an interesting class of molecules because of their unique structure based on an axially chiral biaryl moiety as well as their significant biological activity. Herein, we describe the development of a palladium‐catalyzed atroposelective C?H alkynylation and its application in gram‐scale, stereocontrolled formal syntheses of (+)‐isoschizandrin and (+)‐steganone. tert‐Leucine was identified as an efficient, catalytic transient chiral auxiliary. A wide range of enantiomerically enriched biaryl compounds were prepared by this approach in good yields (up to 99 %) with excellent enantioselectivity (up to >99 % ee).     

Pd-catalyzed decarboxylative couplings of arenecarboxylic acids with aryl iodides

The combination of palladium chloride with BINAP shows high efficiency in the decarboxylative cross-coupling reactions of arenecarboxylic acids with aryl iodides. The reactions proceed smoothly to generate the corresponding biaryl compounds in good to excellent yields.