New efficient route to dissymmetric 2,4-di(het)aryl-pyrido[3,2-d]pyrimidines via regioselective cross-coupling reactions

The first access to dissymmetric 2,4-di(het)aryl-pyrido[3,2-d]pyrimidines III is reported. Two mild alternative routes led to the rarely targeted compounds from 2,4-dichloro- and 2-chloro-4-isopropylsulfanyl-pyrido[3,2-d]pyrimidine by two successive palladium-catalyzed reactions involving an original regioselective chlorine discrimination. Alternatively, type III compounds were elaborated from 2 by C-2 chlorine further displacement of the C-4 isopropylsulfanyl group, which acted as a temporary C-4 protecting group. These results open the way to innovative synthesis strategies of various bis-functionalized pyrimidine series.     

New findings in the alkylation and N-deprotection of (4S)-4-methyl-2-benzyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-diones

Alkyl halides behave differently to benzyl halides in C-1 alkylation of the title compounds. The syn and anti 1,4-disubstituted diastereomers thus obtained show different regioselectivity by further alkylation leading to the 1,4,4- and 1,1,4-trisubstituted compounds, respectively. Alkylation is always directed anti with respect to the bulkier substituent at C-1 or C-4. Debenzylation attempts on 2-benzyl-derivatives 1b by treatment with HCOOH and C/Pd or H₂/C–Pd/MeOH/H⁺ led to C-1 oxidised or 7,8,9,10-tetrahydro-derivatives. Deprotection of 2-p-methoxybenzyl- and 2-(2,4-dimethoxybenzyl)-derivatives with CAN and with TFA/anisole, respectively, was successful, but in the latter case epimerization at C-1 occurred.     

Highly selective synthesis of 4(5)-aryl-, 2,4(5)-diaryl-, and 4,5-diaryl-1H-imidazoles via Pd-catalyzed direct C-5 arylation of 1-benzyl-1H-imidazole

Highly selective, practical, and efficient protocols for the preparation of 4(5)-aryl-1H-imidazoles 2, 2,4(5)-diaryl-1H-imidazoles 3, and 4,5-diaryl-1H-imidazoles 1 are described. A key step of these protocols is the regioselective synthesis of 5-aryl-1-benzyl-1H-imidazoles 9 by Pd-catalyzed direct C-5 arylation of commercially available 1-benzyl-1H-imidazole (8) with aryl halides. The three-step synthesis of compounds 3 from 8 also involves the Pd-catalyzed and Cu-mediated direct C-2 arylation of imidazoles 9 with aryl halides under base-free and ligandless conditions. On the other hand, the four-step synthesis of imidazoles 1 from 8 also involves the regioselective bromination of compounds 9 and a Suzuki reaction of the resulting 5-aryl-1-benzyl-4-bromo-1H-imidazoles 11 with arylboronic acids 5 under phase-transfer conditions, followed by N-debenzylation.     

Synthesis of 7H-indolo[2,3-c]quinolines: study of the Pd-catalyzed intramolecular arylation of 3-(2-bromophenylamino)quinolines under microwave irradiation

D-ring substituted 5-methyl-5H-indolo[2,3-c]quinolines (4) have been synthesized in three steps starting from commercially available 3-bromoquinoline (5) and 2-bromoanilines (6). The methodology consists of two consecutive palladium-catalyzed reactions: a selective Buchwald-Hartwig amination followed by a regioselective intramolecular Heck-type reaction. The latter step has been investigated under microwave irradiation. Heating at 180 °C allows to seriously reduce the catalyst loading and get a full conversion to reaction product in 10 min. In addition, the former simplifies the purification.     

Stereoselective synthesis of sugar-based β-lactam derivatives: docking studies and its biological evaluation

Highly diastereoselective synthesis of cis-β-lactams via [2+2] cycloaddition reactions of sugar-imine derivative possessing free hydroxyl groups at C-2 and C-3 positions and ketenes is described. exo-Approach of sugar-imine with ketene leads to the stereoselective formation of cis product and it is facilitated by hydrogen bonding interaction of C2–OH with carbonyl group of ketene. Docking studies show that these derivatives are having greater affinity towards PBP and it has been validated by in vivo studies. Among the different sugar-based azetidine-2-ones, compounds 6a and 6d were superior in activity to the commercial antibiotic tetracycline.     

Preparation of 2,2′-anhydronucleosides: regio- and stereoselective modifications of the base and sugar moieties

2′-Deoxy-2′-iodonucleosides 4–9, obtained from suitably protected furanoid glycals 1 and 2 with different silylated pyrimidine bases, were transformed into the corresponding 2,2′-anhydronucleosides 10–15 with inversion of the configuration at C-2′, by heating in DMF with n-dibutyltin oxide. Regio- and stereospecific opening at C-2′ of the 2,2′-ring in compounds 10, 11, and 12 with sodium azide afforded the related 2′-azido-2′-deoxynucleosides 16, 17 and 18, respectively. Action of sodium hydroxide on 12 caused the regioselective opening of the above-mentioned ring at C-2 with retention of the configuration at C-2′ giving 19. Compound 19 could be transformed straightforwardly into 18 by well-established methodology. On the other hand, compound 15 could be transformed into the related 2′,3′-anhydronucleoside 23 by a regio- and stereoselective addition at N-3–C-2′ of allyl bromide concomitant with 2,2′-ring opening and inversion of the configuration at C-2′ to afford the intermediate 2′-bromo-2′-deoxynucleoside 21, which was subsequently treated with sodium methoxide giving 23.     

Diastereoselective Friedel–Crafts reaction of α-trifluoromethyl imines derived from chiral amines

The Friedel–Crafts reactions of chiral N-(2,2,2-trifluoroethylidene)-1-arylethylamines 1a and 1b with various electron-rich aromatic compounds were examined. The reactions proceeded readily at room temperature in the presence of BF₃·Et₂O. Substituted products 2–12 were obtained in low to very high stereoselectivities (up to 100% d.e.). The absolute configuration of compound 12 was determined by X-ray analysis. Moreover, the chiral auxiliary from compounds 3 and 12 was selectively removed by palladium-catalyzed hydrogenolysis.     

Regioselective palladium-catalyzed phenylation of ethyl 4-oxazolecarboxylate

The efficient and regioselective palladium-catalyzed C-2 arylation of ethyl 4-oxazolecarboxylate 1 with phenyliodide is described. The different parameters (solvent, base, ligand and catalyst) for the optimal conditions of this arylation process have been screened.     

Preparation and characterization of symmetrical bis[4-chloro-2-pyrimidyl] dichalcogenide (S, Se, Te) and unsymmetrical 4-chloro-2-(arylchalcogenyl) pyrimidine: X-ray crystal structure of 4-chloro-2-(phenylselanyl) pyrimidine and 2-(p-tolylselanyl)-4-chloropyrimidine

Synthesis of a novel class of multinucleate pyrimidine chalcogen (S/Se/Te) derivatives has been successfully attempted for the first time by the selective substitution of chlorine at the C-2 position of 2,4-dichloropyrimidine with nucleophilic dichalcogenide anion E₂²⁻ (E = S, Se, Te) to afford bis[4-chloro-2-pyrimidyl] dichalcogenide. The highly electrophilic nature of 2,4-dichloropyrimidine compared to aryl chlorides has been further exploited to prepare a variety of 4-chloro-2-(arylchalcogenyl) pyrimidine compounds by substituting the chlorine exclusively at the C-2 position of 2,4-dichloropyrimidine with a variety of chalcogen bearing aryl anions ArE⁻ (Ar = phenyl, 1-naphthyl, p-tolyl, 4,6-dimethyl-2-pyrimidyl, 2-pyridyl, 4-methyl-2-pyridyl). All the newly prepared symmetrical and unsymmetrical pyrimidyl chalcogen compounds have been thoroughly characterized with the help of various spectroscopic techniques viz., NMR (¹H, ¹³C, ⁷⁷Se), FT-IR and mass spectrometry (in representative cases). The crystal structures of 4-chloro-2-(phenylselanyl) pyrimidine and 2-(p-tolylselanyl)-4-chloropyrimidine have been determined by X-ray crystallography.     

A substituent directed regioselective synthesis of aryl/pyronyl pendant unusual adipate and tetrahydronaphthalene

An efficient regioselective synthesis of pyronyl pendant ethyl methylthiocarbonylalkanoates 5 has been delineated from the base catalyzed reaction of suitably functionalized 2-pyranone 1 and 2-carbethoxycycloalkanones 2, 6 through successive substitution and regioselective ring opening by in situ generated mercaptide ion. To assess the effect of C-4 substituent on regioselectivity, reactions of 6-aryl-3-cyano-4-(piperidin-1-yl)-2-oxopyran 8 with 2-carbethoxycyclohexanone 6a and 2-carbethoxy-2-methylcyclohexanone 6b were carried out separately under analogous reaction conditions but the compounds isolated were identical and characterized as 4-aryl-8-methyl-2-piperidin-1-yl-5,6,7,8-tetrahydronaphthalene-1-carbonitriles 9. Ethyl 2-(5-amino-4′-bromo-4,6-dicyanobiphenyl-3-yl)-5-methylsulfanylcarbonylpentanoate 10 has also been prepared through base catalyzed ring transformation of ethyl 2-[6-(4-bromophenyl)-3-cyano-2-oxo-2H-pyran-4-yl]-5-methylsulfanylcarbonylpentanoate 5d by malononitrile in DMF.     

On the reaction of chlorodithiophosphoric acid pyridiniumbetaine with polyfunctional nucleophiles: Part II. Reaction with thiosemicarbazide derivatives

Chlorodithiophosphoric acid pyridiniumbetaine, PyPS₂Cl (I), reacts with thiosemicarbazide derivatives (RNH)(H₂NNMe)CS, R= iso-propyl, tert-butyl, in acetonitrile in the absence of any HCl-acceptor to form new compounds with a five-membered heterocycle, i.e. 5-iso-propylamino-4-methyl-2-sulfido-2-thioxo-1,3,4,2λ⁵-thiadiazaphospholan-5-onium (II) or 5-tert-butylamino-4-methyl-2-sulfido-2-thioxo-1,3,4,2λ⁵-thiadiazaphospholan-5-onium (III). The triethylammonium salt of 1,3-bis-(N-methyl-N′-tert-butyl-thioureido)-2,4-disulfido-2,4-dithioxo-1,3-diaza-2λ⁵,4λ⁵-diphosphetidine (IV) is formed when the reaction is carried out in the presence of triethylamine. The prepared compounds were characterized by ³¹P NMR, FT-IR spectroscopies, mass spectrometry and the molecular structures of II, III and IV were determined by X-ray crystallography.     

Study of substituent effects on rotational isomers and monomer–dimer equilibria of the 3-carboxy group in 4-substituted (R)-2-(3,4-methylenedioxyphenyl)-6-isopropyloxy-2H-chromen-3-carboxylic acids in dilute CCl4 and CHCl3 solutions by FTIR spectroscopy

FTIR spectra of the title carboxylic acids (I–III) with 4-substituents (H, CH₃ or C₆H₅) and their related compounds IV–VI with 4-(substituted phenyl) groups were measured in dilute CCl₄ and CHCl₃ solutions. The concentration dependence of FTIR spectra of I–IV was also measured in these solutions. These spectra were subjected to curve analysis in order to quantitatively identify the rotational isomers of 3-carboxy group attributable to steric hindrance of the 4-substituents. For I, II and III–VI, two, four and five ν(CO) bands were observed for their carboxy groups, respectively, indicative of monomer–dimer equilibrium and two and three kinds of rotational isomers for II and III–VI, respectively. Compounds III–VI were found to form intra-molecular hydrogen bonds between the trans-type of the 3-carboxy group and the π-electrons in the 4-benzene ring. We have worked out a method to estimate the association constant (K) of complicated monomer–dimer equilibria such as II–VI. The K values of I–IV decrease remarkably in the order of H (I), C₆H₅ (III), CH₃ (II) and C₆H₄-p-OCH₃ (IV) in CCl₄ and I, II, III and IV in CHCl₃; these orders are discussed.     

Kinetics of hydrolysis of the geminal alkoxy-NNO-azoxy compounds in sulfuric acid

The kinetics of hydrolysis of two alkoxy-NNO-azoxy compounds with geminal position of N₂O₂ groups, di(methoxy-NNO-azoxy)methane (I) and di(methyl-NON-azoxy)formal (II), as well as isomeric geminal nitramine, 2,4-dinitro-2,4-diazapentane (III) in 64.16% H₂SO₄ were studied by a manometric method. The relative rates of the hydrolysis at 80°C of compounds I?CIII and methoxy-NNO-azoxymethane (IV) were found to be equal to 4.2:77:??50000:1. The limiting stage of hydrolysis of compound I is the attack of the nucleophile on the carbon atom of the MeO group of the protonated molecule I by S _N2 mechanism. According to the parameters of the Arrhenius equation the hydrolysis of compound II proceeds more probably by the S _N1     

Complexation of N-Allyl Derivatives of Morpholinium with Copper(I) Halides: Synthesis and Crystal Structure of [C4H8ON(C3H5)2]+[Cu4Cl5]–, [C4H8ONH(C3H5)]+[CuBr2]–, and [C4H8ONH(C3H5)]+[CuBr1.41Cl0.59]–

The compounds [C₄H₈ON(C₃H₅)₂]⁺[Cu₄Cl₅]^– (I), [C₄H₈ONH(C₃H₅)]⁺[CuBr₂]^– (II), and [C₄H₈ONH(C₃H₅)]⁺[CuBr_1.41Cl_0.59]^– (III) were prepared for the first time by ac electrochemical synthesis from mono- and di-N-allyl derivatives of morpholinium and copper(I) halides in ethanol solution and structurally characterized. In the structure of I π-complex, the centrosymmetric Cu₈Cl₁₀ fragments are associated into layers perpendicular to the b axis. The N,N"-diallylmorpholinium cation functions as a bridge, which coordinates two copper atom of the adjacent inorganic fragments by both allyl groups. The trigonal-pyramidal surrounding of the Cu(I) atom, as well as the distorted tetrahedral coordination sphere of Cu(2), involves three chlorine atoms and the C=C bond, whereas the planar trigonal surrounding of the Cu(3) atom and trigonal-pyramidal surrounding of the Cu(4) atom involve only chlorine atoms. In the isostructural II and III σ-complexes, the edge-shared CuX₄ tetrahedra form the infinite copper-halide chains running along the a axis. The inorganic fragments and organic N-allylmorpholinium cations are united into the three-dimensional crystal structures by N–H···X and C–H···X (X = Cl, Br) hydrogen bonds.     

Vercytochalasins A and B: Two unprecedented biosynthetically related cytochalasins from the deep-sea-sourced endozoic fungus Curvularia verruculosa

Vercytochalasins A (1) and B (2), two biosynthetically related cytochalasins featuring novel structure and substituents, were isolated from the endozoic fungus Curvularia verruculosa which was associated with the deep-sea squat lobster Shinkaia crosnieri collected from the cold seep environment in South China sea. Their structures were elucidated by detailed interpretation of NMR spectroscopic and mass spectrometric data. The absolute configurations were confirmed by NOESY experiments as well as by DP4+ and ECD calculations. Differed from common cytochalasins, compound 1 is an uncommon secocytochalasin featuring the ester group cleaved between C-9 and C-23, and incorporating an additional oxygenated C4 unit which coupled with C-20 and C-22 to form a new substituted cyclohexenone moiety, while compound 2 contains an unusual 2?hydroxy-3-oxobutan-2-yl unit at C-22. Both compounds are distinctive from the commonly described cytochalasins. Compound 1 exhibited potent activity against angiotensin-I-converting enzyme (ACE) whereas compound 2 showed antibacterial activity. Molecular docking simulations were performed to explore the intermolecular interaction of compounds 1 and 2 with ACE.     

Synthesis and stereochemistry of highly crowded N-benzylpiperidones

A series of N-benzylated 3,5-diakyl-2,6-diarylpiperidin-4-ones 4–8 were conveniently synthesized in significant yields of 68–88% by N-benzylation of the corresponding 2,6-diaryl-3,5-dimethylpiperidin-4-ones 1–3 using different benzyl bromides. Initially, the new piperidone 2,6-bis(4-ethoxyphenyl)-3,5-dimethylpiperidin-4-one 3 was synthesized by the condensation of 1:1:2 M ratio of 3-pentanone, ammonium acetate and para-ethoxybenzaldehyde in ethanolic medium. All the synthesized new compounds 3–8 were characterized by their analytical and spectral (IR, ¹H and ¹³C NMR) interpretations. The stereochemistry of the new piperidone 3 was elucidated as chair conformation with an equatorial orientation of all substituents, suggested by its vicinal couplings from ¹H NMR spectrum. To investigate the impact on piperidone stereochemistry as well as NMR chemical shifts, all the N-benzylated products 4–8 were compared with their corresponding precursors, and as a result, it is clearly established that all the synthesized N-benzyl piperidones exist in the chair conformation with an equatorial orientation of all the substituents at C-2, C-3, C-5, C-6 and N. Contrary to the probability all N-benzylated compounds retain the same conformation and configuration as their precursors, however, a remarkable change on the chemical shifts are observed. For the further unambiguous confirmation of stereochemistry, the 1-benzyl-3,5-dimethyl-2,6-diphenylpiperidin-4-one 4 was examined by single-crystal X-ray diffraction. The compound 4, C₂₆H₂₇NO, crystallized in a P-1 space group under triclinic system with unit cell dimensions a, b, c (Å) and α, β, γ (°) of 10.156(2), 11.002(2), 11.348(4) and 116.74(4), 100.81(3), 100.17(3), respectively.     

Site-selective oxidation of unactivated C–H sp3 bonds of oleanane triterpenes by Streptomyces griseus ATCC 13273

The oxidization of unactivated C–H bonds is of great interests in the structural modification of pentacyclic triterpenes. Herein we discovered the unique capability of Streptomyces griseus ATCC 13273 to catalyze the site-selective oxidation of C-29 methyl group to carboxyl group over a range of oleanane triterpenes, oleanolic acid (1), hederagenin (2), echinocystic acid (3), quillaic acid (4) and senegenin (5). Along with this reaction the hydroxylation on C-24 and C-21 were also discovered on some substrates. As a result, eight new compounds (1c, 2a～5a and 2b～4b) among the ten metabolites were isolated. The anti-inflammatory activities of these compounds were evaluated against lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophages, and the products with hydroxyl group on C-21 (1c, 2b and 5a) showed significantly enhanced activities with the IC₅₀ values of 1.230, 0.078 and 0.015 μM, respectively. Thus S. griseus ATCC 13273 was further proved as a useful biocatalyst to expand the structural diversity of oleanane triterpenes for medicinal chemistry research.     

Cross-metathesis of allyl halides with olefins bearing amide and ester groups

An investigation was conducted to determine whether the cross-metathesis (CM) of allyl halides tolerates amide groups. The results show that the ruthenium-based complexes I–III serve as poor catalysts for the CM of allyl halides with olefins that contain an N,N-dimethylamide group. In contrast, the Grubbs–Hoveyda–Blechert second generation catalyst (III) efficiently promotes these processes with olefins bearing a Weinreb amide group. Lastly, a reinvestigation of the ester group tolerance of the allyl halide CM with unsaturated esters demonstrated that III serves as an efficient catalyst for these reactions.     

Novel pyrrolo[2,3-d]pyrimidine derivatives: Design,synthesis, structure elucidation and in vitro anti-BVDV activity

The progression of drug resistance of viral infection justifies the discovering of new anti-viral agents. Thus, a novel series of pyrrolopyrimidine derivatives 5–7 and 9–18 were designed, synthesized and fully characterized by IR, mass spectroscopy, NMR, and elemental analysis. The structure of 4,6-dichloro-pyrrolo[2,3-d]pyrimidine 10 elucidated by single crystal X-ray diffraction. Herein, we reported the first pyrrolo[2,3-d]pyrimidine compounds with trichloromethane at position 2 of the pyrimidine ring. As initial biological activity screening, evaluation of the pyrrolo[2,3-d]pyrimidine compounds as anti-BVDV (Bovine Viral Diarrhea Virus) was examined. The compounds 11, 13, 16 and 17 exhibited excellent activity as a potent inhibitor against BVDV. Structure activity relationship showed that the pyrrolo[2,3-d]pyrimidine molecules presenting hydrogen atom or trichloromethyl group on C2 and chlorine, sulfur, pyrrolidine or methoxy groups on C4 of the pyrimidine ring showed high activity as anti-BVDV in comparison with the compounds which have Cl or CH₃ on C2 position.     

Synthesis and structures of organoantimony and organobismuth derivatives of 4-sulfophenol and 2,4-disulfophenol

Tetraphenylbismuth 4-hydroxybenzenesulfonate (I) and tetraphenylantimony 4-hydroxybenzenesulfonate (II) are synthesized in yields up to 80% by the reaction of pentaphenylbismuth and pentaphenylantimony, respectively, with 4-sulfophenol. Compounds I and II are also prepared by the ligand redistribution reaction from pentaphenyl compounds of bismuth and antimony and triphenylbismuth bis(4-hydroxybenzenesulfonate) and triphenylantimony bis(4-hydroxybenzenesulfonate), respectively, in yields up to 87%. The recrystallization of compounds I and II from water gives crystalline hydrates Ph₄BiOSO₂C₆H₄(OH-4) · H₂O (III) and Ph₄SbOSO₂C₆H₄(OH-4) · H₂O (IV). Pentaphenylbismuth and pentaphenylantimony react with 2,4-disulfophenol in acetone, regardless of the ratio of the starting reactants, to form bis(tetraphenylbismuth) 4-hydroxybenzene-1,3-disulfonate (V) and bis(tetraphenylantimony) 4-hydroxybenzene-1,3-disulfonate (VI) in yields up to 74%. According to X-ray diffraction data, coordination of the bismuth atoms in compound I is trigonal-bipyramidal with the axial oxygen atom of the 4-hydroxybenzenesulfonate group (Bi···O 2.764 Å). In compound II, coordination of the Sb atom is tetrahedral (CSbC angles 106.2°–112.3°). In crystal III, the distances between the central atom and the nearest oxygen atoms of the arenesulfonate group and the hydrate water molecule are 3.094 and 3.125 Å, respectively. Crystals V and VI consist of doubly charged anions of 2,4-disulfophenol and several distorted tetrahedral cations of tetraphenylbismuthonium (CBi(1)C, CBi(2)C angles and Bi(1)-C, Bi(2)-C bond lengths vary in the intervals 102.1°–122.7°, 105.4°–114.0° and 2.103–2.230, 2.187–2.209 Å, respectively) and tetraphenylantimonium (CSb(1)C, CSb(2)C angles and Sb(1)-C, Sb(2)-C bond lengths 106.3°–112.2°, 101.3°–122.4° and 2.095–2.110, 2.092–2.123 Å, respectively). The Bi(1) and Sb(2) atoms are coordinated by one of the oxygen atoms of the 2,4-disulfophenol anions (distances Bi(1)···O(3) 2.803, Sb(2)···O(1), 2.704 Å).