Sonogashira cross-couplings of dehydroamino acid derivatives and phenylacetylenes

Several phenylacetylenes were coupled under Sonogashira cross coupling conditions with the methyl esters of N-(tert-butoxycarbonyl)-(E)-beta-bromo or beta, beta-dibromodehydroalanine to give respectively beta-substituted or beta,beta-bis-substituted dehydroalanines. The beta-substituted dehydroalanines were obtained in good to high yields (60-90%) under the usual Sonogashira conditions (1 equiv. of the phenylacetylene, 1 mol% Pd(PPh3)4, 2 mol% CuI 18 equiv. NEt3 in acetonitrile, 24h at rt) with maintenance of the stereochemistry. The beta,beta-bis-substituted dehydroalanines were in turn obtained in moderate to good yields (44-63%) requiring modified Sonogashira conditions (4 equiv. of the phenylacetylene,10 mol% PdCl2(PPh3)2, 20 mol% CuI, 1.4 equiv. Cs2CO3, 2h at reflux of acetonitrile). In the latter reactions some phenylacetylene dimer and the (E)-isomer of the mono substituted coupled products were also isolated in some extent. The Sonogashira products which were obtained from the 4-bromophenylacetylene were reacted with functionalized benzo[b]thiophenes under C-C or C-N palladium-catalyzed cross-coupling conditions. Preliminary fluorescence studies were performed for mono and disubstituted 4-aminophenylacetylenic dehydroamino acids and for the benzo[b]thiophene derivatives. The results showed that some of the dehydroalanines prepared can be used as fluorescent probes.Fundação para a Ciência e Tecnologia - POCTI/99/QUI/32689, SFRH/BD/4709/2001

8-[2-Chloro-5-(trifluoromethyl)phenyl]-4H-[1,2,4]oxadiazolo-[3,4-c][1,4]benzoxazin-1-one

8-Bromo-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazin-1-one 1 (NS2028) reacts with [2-chloro-5-(trifluoromethyl)phenyl]boronic acid 2 (2 equiv), Pd(OAc)2 (10 mol%) and KOAc (4 equiv) in acetonitrile heated to ca. 110 °C (sealed tube) for 12 hours to give 8-[2-chloro-5-(trifluoromethyl)phenyl]-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazin-1-one 4 in 64% yield

Synthesis of diarylamines in the benzo[b]thiophene series bearing electron donating or withdrawing groups by Buchwald–Hartwig C–N coupling

Diarylamines in the benzo[b]thiophene series bearing electron donating or withdrawing groups, were prepared by Buchwald– Hartwig C–N coupling in moderate to high yields. The conditions used were Pd(OAc)2 (3 mol%), BINAP as ligand (4 mol%) and Cs2CO3 as base (1.4 equiv.), in toluene at 1008C, being 6-bromo or amino benzo[b]thiophenes coupled, respectively, with substituted anilines or phenylbromides. The 6-aminobenzo[b]thiophene derivatives were also prepared by palladium catalyzed C–N coupling of the corresponding 6-bromo compounds with benzophenone imine, followed by acidic hydrolysis of the imino derivatives. When 4-nitrobromobenzene and 4-bromobenzonitrile were used as coupling components, triarylamines were also isolated in small amounts. The presence of a fluorine atom on the phenylbromide highly increases the diarylamine yield

Ligand-Free Palladium-Catalyzed Oxyarylation of Dihydronaphthal­enes and Chromenequinone with o-Iodophenols and 3-Iodolawsone in PEG-400: An Efficient Synthesis of 5-Carbapterocarpans and Pterocarpanquinones

Dihydronaphthalenes were oxyarylated with o-iodophenols, in PEG-400 at 140 or 170 °C, leading regio- and stereoselectively to 5-carbapterocarpans. By using Pd(OAc)2 (5–10 mol%) as precatalyst and Ag2CO3 (1.1 equiv) as base (conditions A), products were obtained in good to excellent chemical yields, in 5–30 minutes, irrespective of the pattern of substitution the starting materials. Alternatively, when p-hydroxyacetophenone oxime derived palladacycle (1 mol%) was used as precatalyst, and dicyclohexylamine (2 equiv) was used as base (silver-free, conditions B), the corresponding adducts were obtained in moderate to good yields, in 0.5 to 4 hours. Finally, the oxyarylation of dihydronaphthalenes­ and chromenquinone with o-iodophenols and 3-iodolawsone in PEG-400 under conditions A led regio- and stereoselectively to the formation of carbapterocarpanquinones and pterocarpanquinones in moderate yield.Financial support from Brazilian agencies CAPES-DGU (Project 200/09), CNPq, FAPERJ and UFRJ are acknowledged. Spanish MICINN (Projects PHB2008-0037-PC, CTQ2007-62771/BQU, CTQ2010-20387, Consolider INGENIO 2010 CSD2007-00006), FEDER, Generalitat Valenciana (Project PROMETEO/2009/038), and the University of Alicante are acknowledged

Palladium(II) organic synthetic methodology

This dissertation is divided into four papers. The focus of all four papers is the development of useful palladium(II)-catalyzed organic synthetic methodology;Paper One discusses the development and application of conditions for the palladium(II)-catalyzed cyclization of alkenoic acids to unsaturated lactones. Using these conditions acyclic and cyclic, aliphatic or aromatic, 4- or 5-alkenoic acids cyclize in high yields to 5- or 6-membered unsaturated lactones using 5 mol% Pd(OAc)[subscript]2, 2 equiv. of NaOAc, DMSO as the solvent, and 1 atmosphere of O[subscript]2;Paper Two discusses the development and application of conditions for the palladium(II)-catalyzed cyclization of N-substituted olefinic amines. The conditions which were so successful in the cyclization of alkenoic acids also proved successful in the cyclization of acyclic and cyclic, aliphatic or aromatic 4- or 5-olefinic tosylamides in moderate to high yields to the corresponding 5- or 6-membered unsaturated nitrogen heterocycles;Paper Three discusses the development of conditions which allow the exclusive formation of benzopyran in 41% yield from 2-allylphenol using 5 mol% Pd(OAc)[subscript]2, 2 equiv. of Na[subscript]2CO[subscript]3 and 9:1 DMSO/H[subscript]2O as the solvent system under an oxygen atmosphere;Paper Four discusses the development and application of conditions which allow for the conversion of enol silyl ethers and acetals to the corresponding [alpha],[beta]-unsaturated carbonyl systems. These reaction conditions entail using 10 mol% Pd(OAc)[subscript]2 and DMSO under an oxygen atmosphere

A synthetic approach to palmerolides via Negishi cross coupling. The challenge of the C15-C16 bond formation

The esterification of fragment C1-C8 (2) with fragment C16-C23 (3) to give iodo derivative 4, followed by a Pd-catalysed coupling with a C9-C15 fragment (7 or 8), may provide a common precursor of most palmerolides. Ligands and reaction conditions were exhaustively examined to perform the C15-C16 bond formation via Negishi reaction. With simple models, pre-activated Pd-Xantphos and Pd-DPEphos complexes were the most efficient catalysts at RT. Zincation of the C9-C15 fragment (8) and cross coupling with 4 required 3 equiv of t-BuLi, 10 mol % of Pd-Xantphos and 60 °C

Cross-linked low molecular weight glycopeptide-mediated gene delivery: Relationship between DNA metabolic stability and the level of transient gene expression in vivo

DNA co-condensates were formed by reacting [ 125 I]DNA with an admixture of a high-mannose glycopeptide (Man9-CWK 18 ) and either of two poly(ethylene glycol) peptides (PEG-VS-CWK 18 or PEG-SS-CWK 18 ) followed by cross-linking with 6–50 mol equiv of glutaraldehyde. [ 125 I]DNA co-condensates were administered intravenously in mice to determine the influence of peptide DNA formulation parameters on specific targeting to Kupffer cells. Optimal targeting to Kupffer cells required the combined use of 50 mol % Man9-CWK 18 and PEG-CWK 18 to mediate specific recognition by the mannose receptor to Kupffer cells. The cellular uptake of cross-linked Man9-CWK 18 /PEG-CWK 18 DNA co-condensates was receptor mediated since Kupffer cell targeting was inhibited by pre-administration of Man-bovine serum albumin (BSA) but not BSA. An optimized formulation targeted 60% of the dose to the liver, with 80% of the liver-targeted DNA localized to Kupffer cells. Cross-linking with either 6, 15, or 50 mol equiv of glutaraldehyde led to a corresponding decrease in the metabolism rate of DNA in liver as measured by half-live- of 4, 6, and 39 h, respectively. Tail vein dosing of 50 Μg of DNA co-condensates cross-linked with 6 mol equiv of glutaraldehyde produced detectable levels of human Α 1 -antitrypsin in blood after 12 h, which peaked at day six and persisted for 10 days. The level of human Α 1 -antitrypsin was elevated two-fold each day when dosing with DNA co-condensates cross-linked with 15 mol equiv of glutaraldehyde, revealing a correlation between the metabolic stability of the DNA in liver and level of gene expression. In addition to possessing greater metabolic stability, DNA co-condensates cross-linked with 50 mol equiv of glutaraldehyde, but lacking a targeting ligand, avoided rapid liver uptake and possessed a prolonged pharmacokinetic half-life, providing insight into a means to target DNA condensates to peripheral tissues. © 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:2010–2022, 2001Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34505/1/1152_ftp.pd

Single crystal growth and physical properties of the layered arsenide BaRh_2As_2

Single crystals of BaRh_2As_2 have been synthesized from a Pb flux. We present the room temperature crystal structure, single crystal x-ray diffraction measurements as a function of temperature T, anisotropic magnetic susceptibility \chi versus T, electrical resistivity in the ab-plane \rho versus T, Hall coefficient versus T and magnetic field H, and heat capacity C versus T measurements on the crystals. The single crystal structure determination confirms that BaRh_2As_2 forms in the tetragonal ThCr_2Si_2 type structure (space group I4/mmm) with lattice parameters a = b = 4.0564(6)\AA and c = 12.797(4) \AA. Band structure calculations show that BaRh_2As_2 should be metallic with a small density of states at the Fermi energy N(E_ F) = 3.49 states/eV f.u. (where f.u. \equiv formula unit) for both spin directions. \rho(T) data in the ab-plane confirm that the material is indeed metallic with a residual resistivity \rho(2K) = 29 \mu \Omega cm, and with a residual resistivity ratio \rho(310K)/\rho(2K) = 5.3. The observed \chi(T) is small (\sim 10^{-5} cm^3/mol) and weakly anisotropic with \chi_{ab}/\chi_ c \approx 2. The C(T) data indicate a small density of states at the Fermi energy with the low temperature Sommerfeld coefficient \gamma = 4.7(9) mJ/mol K^2. There are no indications of superconductivity, spin density wave, or structural transitions between 2K and 300K. We compare the calculated density of states versus energy of BaRh_2As_2 with that of BaFe_2As_2.Comment: Accepted for publication in Phys. Rev.