Synthesis of Functionalized trans‐A2B2‐Porphyrins Using Donor–Acceptor Cyclopropane‐Derived Dipyrromethanes

meso‐Substituted trans‐A₂B₂‐porphyrins bearing specific patterns of substituents are crucial building blocks in porphyrin‐based biomimetic systems and molecular materials and can be used for the construction of well‐defined porphyrin‐based architectures. A new stepwise and rational synthesis of functionalized trans‐A₂B₂‐porphyrins is reported in which for the first time donor–acceptor‐substituted cyclopropane precursors (d–a cyclopropanes) are exploited. The three presented d–a cyclopropanes are readily accessible in a multi‐gram scale and serve as aldehyde equivalents in the reaction with an excess of pyrrole to afford the corresponding dipyrromethanes (DPMs). The three DPMs were synthesized in yields of 60–74%. They are stable in purified form in the absence of light and air and were subsequently condensed with a wide range of aliphatic and aromatic aldehydes bearing electron‐donating or electron‐withdrawing substituents followed by oxidation to form the corresponding trans‐A₂B₂‐porphyrins. Fourteen functionalized porphyrins were synthesized in yields of 14–31%, indicating the broad scope of the synthetic procedure. The possibility to introduce key functional groups is emphasized, which enables subsequent modification of these porphyrins with moieties inducing biological activity. Modification of the tetrapyrroles may occur by addition to one of the porphyrin peripheral double bonds, the use of substituents of the aryl groups or via the methoxycarbonyl group at two of the meso‐substituents. Three examples of porphyrins were converted into the corresponding 7,8‐dihydroxychlorins by osmium‐mediated dihydroxylation and one of the resulting chlorins was subjected to saponification to give a highly polar chlorin dicarboxylic acid. A 4‐bromophenyl‐substituted d–a cyclopropane was prepared by rhodium‐catalyzed cyclopropanation and then transformed into a DPM which was subsequently condensed to a porphyrin. Its Zn complex allowed a Heck reaction to afford the functionalized bis(alkenyl)‐substituted trans‐A₂B₂‐Zn‐porphyrin.     

Palladium‐Catalysed Regioselective Sequential C‐5 and C‐2 Direct Arylations of 3‐Acetylpyrroles with Aryl Bromides

The PdCl(C₃H₅)(dppb)/KOAc system was found to be effective for the direct regioselective C‐5 arylation of 3‐acetylpyrroles with ortho‐substituted aryl bromides. This procedure has been found to be tolerant to a variety of functional groups at C‐2 of the aryl bromide such as methyl, formyl, nitrile, nitro, hydroxymethyl, chloro, fluoro or trifluoromethyl. The sequential direct C‐5 arylation followed by C‐2 arylation of such 3‐substituted pyrroles allows the synthesis of 2,5‐diaryl‐3‐acetylpyrroles in high yields.     

5‐(Piperidin‐4‐yl)‐3‐Hydroxypyrazole: A Novel Scaffold for Probing the Orthosteric γ‐Aminobutyric Acid Type A Receptor Binding Site

A series of bioisosteric N₁‐ and N₂‐substituted 5‐(piperidin‐4‐yl)‐3‐hydroxypyrazole analogues of the partial GABA_AR agonists 4‐PIOL and 4‐PHP have been designed, synthesized, and characterized pharmacologically. The unsubstituted 3‐hydroxypyrazole analogue of 4‐PIOL ( 2 a ; IC₅₀～300 μM ) is a weak antagonist at the α₁β₂γ₂ GABA_AR, whereas substituting the N₁‐ or N₂‐position with alkyl or aryl substituents resulted in antagonists with binding affinities in the high nanomolar to low micromolar range at native rat GABA_ARs. Docking studies using a α₁β₂γ₂ GABA_AR homology model along with the obtained SAR indicate that the N₁‐substituted analogues of 4‐PIOL and 4‐PHP, 2 a – k , and previously reported 3‐substituted 4‐PHP analogues share a common binding mode to the orthosteric binding site in the receptor. Interestingly, the core scaffold of the N₂‐substituted analogues of 4‐PIOL and 4‐PHP, 3 b – k , are suggested to flip 180° thereby adapting to the binding pocket and addressing a cavity situated above the core scaffold.     

Lewis Acid‐Mediated Transformations of trans‐2‐Aroyl‐3‐aryl‐ cyclopropane‐1,1‐dicarboxylates into 2‐Pyrones and 1‐Indanones

trans‐2‐Aroyl‐3‐arylcyclopropane‐1,1‐dicarboxylates upon treatment with aluminium(III) chloride (AlCl₃) underwent ring‐opening, fragmentation, recombination and lactonization to give highly substituted 2‐pyrones. Alternatively, when treated with titanium(IV) chloride (TiCl₄), the cyclopropane diesters underwent a Nazarov cyclization to afford 1‐indanones with high diastereoselectivity.

     

Studies on Electrophilic Interaction of 2,3‐Allenols with Electrophilic Halogen Reagents: Selective Synthesis of 2,5‐Dihydrofurans, 3‐Halo‐3‐alkenals,or 2‐Halo‐2‐alkenyl Ketones

The reaction of primary 2,3‐allenols with iodine (I₂) afforded 2,5‐dihydrofurans while that of readily available 1‐aryl or 1‐methyl substituted 2,3‐allenols with bromine (Br₂), N‐bromosuccinimide (NBS), I₂ or N‐iodosuccinimide (NIS) formed the not easily available but synthetically useful 3‐halo‐3‐alkenals and 2‐halo‐2‐alkenyl ketones with good selectivity and yields via a sequential electrophilic interaction of X⁺ with the allene moiety, 1,2‐aryl or 1,2‐proton shift, and H⁺ elimination process.     

Beziehungen zwischen algistatischer Aktivität und physikalisch‐chemischen Eigenschaften von 5‐Amino‐1‐aryl‐1H‐tetrazolen

A series of 20 5‐amino‐1‐aryl‐1H‐tetrazoles was synthesized by diazotation of corresponding 1‐amino‐3‐aryl‐guanidines and tested for growth‐inhibiting activity against autotrophic Chlorella vulgaris cultures. In the used tests the different algae growth was quantified by photometric measurements at 680 nm. From obtained dosage‐effectivity relationships the reciprocal values of isoeffective concentrations c ₅₀ were derived and defined as activity parameters A in QSAR (quantitative structure‐activity relationship) studies. It could be shown that the algistatitic activity (log A) of the tested heterocycles strongly depends on hydrophobicity described by their octan‐1‐ol/water partition coefficients (log P). The calculated linear relationships between log A and log P can be significantly improved by separate treatment of meta‐/para‐ and ortho‐substituted compounds or using an indicator variable to describe the lower activity of ortho‐substituted 5‐ami‐no‐1‐aryl‐1H‐tetrazoles in common regression equations. The results are discussed and compared with analogous QSAR found for earlier tested series of N‐heterocycles and compounds with urea structure.     

Chemical structure of poly(β‐cyclodextrin‐co‐citric acid)

We synthesized water‐insoluble polymers, poly(β‐cyclodextrin‐co‐citric acid)s, by heating a mixture of citric acid, cyclodextrin (CD), and Na₂HPO₄ as a catalyst with a 6 : 1 : 2 molar ratio at 160, 170, and 180°C for 10 and 20 min. The chemical composition of the polyesters was determined by high pressure liquid chromatography (HPLC) analysis of the polymer hydrolysates. The crosslinking mechanisms and thermal degradation of the polymers were also investigated. The polyesters contained 30–35% citric acid, 1–4% unsaturated carboxylic acids (i.e., itaconic, cis‐aconitic, trans‐aconitic, and mesaconic acids), and 60–70% CD, whereas about 40% of them were able to form inclusion complexes. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Highly trans‐1,4‐specific polymerization of 1,3‐butadiene catalyzed by [2,6‐bis{(4S)‐ (−)‐isopropyl‐2‐oxazolin‐2‐yl}pyridine] chromium complex activated with modified methylaluminoxane

Chromium complexes with N,N,N‐tridentate ligands, LCrCl₃ (L = 2,6‐bis{(4S)‐(?)‐isopropyl‐2‐oxazolin‐2‐yl}pyridine ( 1 ), 2,2′:6′,2″‐terpyridine ( 2 ), and 4,4′,4″‐tri‐tert‐butyl‐2,2′:6′,2″‐terpyridine ( 3 )), were prepared. The structures of 1 and 2 were determined by X‐ray crystallography. Upon activation with modified methylaluminoxane (MMAO), 1 catalyzed the polymerization of 1,3‐butadiene, while 2 and 3 was inactive. The obtained poly(1,3‐butadiene) obtained with 1 ‐MMAO was found to have completely trans‐1,4 structure. The 1 ‐MMAO system also showed catalytic activity for the polymerization of isoprene to give polyisoprene with trans‐1,4 (68%) and cis‐1,4 (32%) structure. Copyright © 2011 Society of Chemical Industry     

Synthesis of 3,4‐Disubstituted Quinolin‐2‐(1H)‐ones via Palladium‐Catalyzed Decarboxylative Arylation Reactions

The Pd‐catalyzed decarboxylative cross‐coupling reaction of 4‐substituted quinolin‐2(1H)‐one‐3‐carboxylic acids with (hetero)aryl halides is described. With palladium(II) bromide and triphenylarsine ligand as the catalyst system, a variety of 4‐substituted 3‐(hetero)aryl quinolin‐2(1 H)‐ones and related heterocycles, such as 4‐substituted 3‐arylcoumarins can be prepared in good to excellent yields.     

Directed sequential synthesis of conjugated linoleic acid isomers from Δ7, 9 to Δ12, 14

Position and configuration isomers of conjugated linoleic acid (CLA), from 7, 9‐ through 12, 14‐C18:2, were synthesized by directed sequential isomerizations of a mixture of rumenic (cis‐9, trans‐11 C18:2) and trans‐10, cis‐12 C18:2 acids. Indeed, the synthesized conjugated fatty acids cover the range of unsaturated systems as found in milk fat CLA. The two‐step sequence consisted in initial sigmatropic rearrangement of cis/trans CLA isomers at 200 °C for 13 h under inert atmosphere (Helium, He), followed by selenium‐catalyzed geometrical isomerization of double bonds at 120 °C for 20 h under He. Product analysis was achieved by gas‐liquid chromatography using a 120 m polar capillary column coated with 70% cyanoalkylpolysiloxane equivalent polymer. Migration of conjugated systems was geometrically controlled as follows: the cis‐C_n, trans‐C_n+2 double bond system was rearranged through a pericyclic [1, 5] sigmatropic mechanism into a trans‐C_n‐1, cis‐C_n+1 unsaturated system, while the trans‐C_n, cis‐C_n+2 double bond system was rearranged through a similar pericyclic mechanism into a cis‐C_n+1, trans‐C_n+3 unsaturated system. Selenium‐catalyzed geometrical isomerization under mild conditions then allowed cis/trans double bond configuration transitions, resulting in the formation of all cis, all trans, cis‐trans and trans‐cis isomers. A sequential combination of the two reactions resulted in a facile controlled synthesis of CLA isomers, useful for the chromatographic identification of milk fat CLA, as well as for the preparation of CLA standard mixture.     

Synthesis and characterization of conducting copolymer of Trans‐1‐(4‐methyl‐3′‐thienyl)‐2‐(ferrocenyl)ethene with EDOT

Ferrocene‐substituted conducting polymer namely poly(trans‐1‐(4‐methyl‐3′‐thienyl)‐2‐(ferrocenyl)ethene‐co‐3,4‐ethylenedioxythiophene) [P(MTFE‐co‐EDOT)] was synthesized and its electrochromic properties were studied. Monomer, MTFE, was obtained using 2‐(ferrocenyl)ethene and 3‐methyl‐4‐bromothiophene. The structure of monomer was determined via Fourier transform infrared spectroscopy (FTIR), ¹H‐NMR, and ¹³C‐NMR techniques. The copolymer was synthesized using this monomer and EDOT. The resulting copolymer P(MTFE‐co‐EDOT) was characterized by cyclic voltammetry, FTIR, scanning electron microscopy, atomic force microscopy, and UV–vis spectroscopy. The conductivity measurements of copolymer and PEDOT were accomplished by the four‐probe technique. Although poly(trans‐1‐(4‐methyl‐3′‐thienyl)‐2‐(ferrocenyl)ethene) [P(MTFE)] reveals no electrochromic activity, its copolymer with EDOT has two different colors (violet and gray). Band gap (E_g) and λ_max of P(MTFE‐co‐EDOT) were determined. © 2012 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

Gold(I)‐Catalyzed Intramolecular Hydroamination of N‐Allylic N′‐Arylureas to form Imidazolidin‐2‐ones

Treatment of N‐allylic N′‐arylureas with a catalytic 1:1 mixture of di‐tert‐butyl‐o‐biphenylphoshphine gold(I) chloride and silver hexafluorophosphate (1 mol%) in chloroform at room temperature led to 5‐exo‐hydroamination to form the corresponding imidazolidin‐2‐ones in excellent yield. In the case of N‐allylic ureas that possessed an allylic alkyl, benzyloxymethyl, or acetoxymethyl substituent, gold(I)‐catalyzed 5‐exo‐hydroamination leads to formation of the corresponding trans‐3,4‐disubstituted imidazolidin‐2‐ones in excellent yield with ≥50:1 diastereoselectivity.     

Ferrocenyl‐Aryl Based trans‐Chelating Diphosphine Ligands: Synthesis,Molecular Structure and Application in Enantioselective Hydrogenation

Potentially trans‐chelating diphosphine ligands based on a ferrocenyl‐aryl backbone were synthesised in a four‐step sequence and the molecular structures in the solid state of two representatives were determined by X‐ray diffraction. High throughput screening of these ligands in rhodium‐, ruthenium‐ and iridium‐mediated hydrogenations of a variety of alkenes and ketones revealed that these ligands can deliver high enantioselectivity for alkenes (up to 98% ee) but are less selective when ketones are used as the substrates. The coordination behaviour of one ligand in its square planar palladium and platinum dichloride complexes was studied by ³¹P NMR and only trans‐chelated complexes, together with oligomeric by‐products, were observed. Reaction with the (p‐cymene)ruthenium dichloride dimer, [RuCl₂(p‐cymene)]₂, resulted in a mixture of diastereomeric complexes.     

A New Chiral P,N‐Ligand Derived from 1‐Phenylphospholane‐2‐carboxylic Acid (Phenyl‐P‐proline) for Palladium‐Catalyzed Asymmetric Allylic Substitution Reactions

New types of P,N‐ligands, cis‐ and trans‐ 3 , containing a tetrahydroisoquinoline skeleton as an N‐donor were synthesized from (1R,2S)‐1‐phenylphospholane‐2‐carboxylic acid (phenyl‐P‐proline, 1 ). The cis isomer, cis‐ 3 , was found to act as an excellent ligand in palladium‐catalyzed asymmetric allylic substitution reactions. The reactions of 1,3‐diphenyl‐2‐propenyl acetate ( 5 ) with several nucleophiles in the presence of [Pd(π‐allyl)Cl]₂, cis‐ 3 (Pd : ligand=1 : 2), and a base afforded the desired products in high yields with high enantioselectivity. It was suggested that these ligands did not serve as P,N‐bidentate ligands but as P‐monodentate ligands in these reactions.     

Palladium(II)‐Catalyzed 1,4‐Addition of Arylboronic Acids to β‐Arylenones for Enantioselective Synthesis of 4‐Aryl‐4H‐chromenes

The enantioselective 1,4‐addition of arylboronic acids to β‐arylenones to give β‐diaryl ketones was carried out at 0–25 °C in the presence of a dicationic palladium(II) catalyst, [Pd(S,S‐chiraphos)(PhCN)₂](SbF₆)₂. Addition of a silver salt such as silver tetrafluoroborate [AgBF₄] or silver hexafluoroantimonate [AgSbF₆] (5–10 mol %) was effective to achieve high enantioselectivities at low temperatures (92–99 % ee) and to reduce the catalyst loading to 0.05 mol %. The protocol provided a simple access to 4‐aryl‐4H‐chromenes. Optically active chromenes were synthesized with up to 99 % ee via dehydration of the 1,4‐adducts between arylboronic acids and β‐(2‐hydroxyaryl)‐α,β‐unsaturated ketones.     

Synthesis, σ Receptor Affinity,and Pharmacological Evaluation of 5‐Phenylsulfanyl‐ and 5‐Benzyl‐Substituted Tetrahydro‐2‐benzazepines

In accordance with a novel strategy for generating the 2‐benzazepine scaffold by connecting C6–C1 and C3–N building blocks, a set of 5‐phenylsulfanyl‐ and 5‐benzyl‐substituted tetrahydro‐2‐benzazepines was synthesized and pharmacologically evaluated. Key steps of the synthesis were the Heck reaction, the Stetter reaction, a reductive cyclization, and the introduction of diverse N substituents at the end of the synthesis. High σ₁ affinity was achieved for 2‐benzazepines with linear or branched alk(en)yl residues containing at least an n‐butyl substructure. The butyl‐ and 4‐fluorobenzyl‐substituted derivatives, (±)‐5‐benzyl‐2‐butyl‐2,3,4,5‐tetrahydro‐1H‐2‐benzazepine ( 19 b ) and (±)‐5‐benzyl‐2‐(4‐fluorobenzyl)‐2,3,4,5‐tetrahydro‐1H‐2‐benzazepine ( 19 m ), show high selectivity over more than 50 other relevant targets, including the σ₂ subtype and various binding sites of the N‐methyl‐D ‐aspartate (NMDA) receptor. In the Irwin screen, 19 b and 19 m showed clean profiles without inducing considerable side effects. Compounds 19 b and 19 m did not reveal significant analgesic and cognition‐enhancing activity. Compound 19 m did not have any antidepressant‐like effects in mice.     

Regioselective Synthesis of β‐Aryl Enaminones and 1,4,5‐ Trisubstituted 1,2,3‐Triazoles from Chalcones and Benzyl Azides

A highly regioselective synthesis of β‐aryl enaminones and 1,4,5‐trisubstituted 1,2,3‐triazoles from chalcones and benzyl azides based on reaction solvent selection is reported. In the presence of a catalytic amount of Ce(OTf)₃, reactions of chalcones with benzyl azides in DMF at 100 °C afforded densely substituted Z‐β‐aryl enaminones in good to excellent yields, whereas treatment of chalcones with benzyl azides in toluene at 100 °C selectively produced 1,4,5‐trisubstituted 1,2,3‐triazoles in excellent yields.

     

Arabinosylated phenolics obtained from SO2‐steam‐pretreated sugarcane bagasse

A pentose‐rich hydrolysate fraction obtained by extraction of steam‐pretreated sugarcane bagasse was analysed with regard to dissolved phenolics. The liquid obtained after steam pretreatment (2% SO₂ (w/w) at 190 °C for 5 min) was divided into two parts: one containing dissolved compounds originating from hemicellulose (with xylose as the dominating compound), and the other containing predominantly dissolved compounds originating from lignin. Using nuclear magnetic resonance, the main dissolved compounds originating from lignin were identified as the glycosylated aromatics, 5‐O‐(trans‐feruloyl)‐L‐Arabinofuranose and 5‐O‐(trans‐coumaroyl)‐L‐Arabinofuranose, together with p‐coumaric acid and small amounts of more common free phenolics such as p‐hydroxybenzaldehyde, p‐hydroxybenzoic acid and vanillin. The phenolic compounds were analysed and quantified using reversed‐phase high‐performance liquid chromatography. The findings show that SO₂ steam explosion opened up new degradation pathways during lignin degradation. Copyright © 2012 Society of Chemical Industry     

Palladium‐Catalyzed Synthesis of (Z)‐3‐Arylthioacrylic Acids and Thiochromenones

The three‐component reaction of aryl halides, sodium sulfide pentahydrate (Na₂S⋅5 H₂O), and propiolic acid in the presence of 2.5% bis(triphenylphosphine)palladium chloride [Pd(PPh₃)₂Cl₂], 5% 1,4‐bis(diphenylphosphino)butane (dppb) and 2 equivalents of 1,8‐diazabicycloundec‐7‐ene (DBU) produces stereoselectively (Z)‐3‐arylthioacrylic acids in good yields. A study of the reaction pathway suggested that the C S bond formation between aryl halides and Na₂S⋅5 H₂O proceeded first, and the resulting intermediate reacted with propiolic acid to produce the desired product. In addition, when the resulting product was treated with acid, the respective thiochromenones were formed in good yields.     

1,2,5, 6‐Tetrazocines from Nitrile Imines and tert‐Butyl Isocyanide

tert‐Butyl isocyanide ( 2 ) reacts with acceptor‐substituted nitrile imines to give derivatives of tetrahydro‐1,2,5,6‐tetrazocines 3 along with substituted 5‐hydrazonoyl‐1,2,4‐triazoles 4 . Replacement of 2 with aryl or sec‐alkyl isocyanides leads to substituted a‐hydrazonoamides ( 6B ) rather than to analogues of 3 ; removal of the acceptor group in 1 is likewise detrimental. — The structure of 3 has been established by means of an X‐ray diffraction analysis of 3d .