Preparation of Pseudo-Arsonolipids: Dl-2,3-Diacyloxybutane-1,4-Bis(Arsonic Acids)

Abstract

The title pseudo-arsonolipid with palmitoyl side chain has been prepared in ～70% yield from its parent DL-2,3-dihydroxybutane-1,4-bis(arsonic acid) after reduction of the As(V) to As(III) by thiophenol, acylation with palmitoyl chloride in the presence of pyridine and catalytic amounts of 4-(dimethylamino)pyridine, and reoxidation of As(III) to As(V) by hydrogen peroxide. In CDCl₃/CD₃OD esterification of the –AsO₃H₂ groups was detected by ¹H NMR.     

Synthesis of new condensed thieno[2,3-b]pyridines containing pyrimidine and imidazole rings

Two different convenient methods have been developed for the synthesis of condensed thieno[2,3-b]pyridines. The intramolecular cyclization of 3-amino-2-hydrazinocarbonyl-7,7-dimethyl-7,8-dihydo-5H-pyrano[3,4-e]-thieno[2,3-b]pyridine was carried out to give 7,7-dimethyl-2-oxo-1,2,6,7-tetrahydro-9H-pyrano[3′,4′-e]-imidazo[4″,5″∶2,3]thieno[5,4-b]pyridine, which is the first representative of a new heterocyclic system.     

syn-2,3-Disubstituted-2,3-dihydro-1,4-benzoxathiin rings: preparation from quinone ketals and 2-mercaptoethanols

A general method for the preparation of syn-2,3-disubstituted-2,3-dihydro-1,4-benzoxathiin rings from 2-mercaptoethanols and quinone ketals is presented. This ring system is produced by Michael addition of a 2-mercaptoethanol to a quinone ketal, followed by cyclization of the initial Michael adduct, and subsequent aromatization to afford a syn-2,3-disubstituted-1,4-benzoxathiin in fair to good chemical yield. Several chiral syn-2,3-disubstituted-2,3-dihydro-1,4-benzoxathiin rings were prepared with this method from enantioenriched 2-mercaptoethanols. No loss of enantiopurity was observed.     

Stereocontrolled Oxidative Additions upon 1,4-Dihydropyridines: Synthesis of Hexahydrofuro[2,3-b]pyridine and Hexahydropyrano[2,3-b]pyridine Derivatives

trans-α-Alkoxy-β-halotetrahydropyridines are synthesized in a very efficient single step by stereocontrolled N-halosuccinimide (NXS)–promoted alcohol addition to the enamine group in N-alkyl-1,4-dihydropyridines. These compounds are cyclized using sodium cyanoborohydride in the presence of 2,2′-azobis(2-methylpropionitrile), azabisisobutyronitrile (AIBN) (cat.), and tributylstannane (cat.), affording hexahydrofuro[2,3-b]pyridine and hexahydropyrano[2,3-b]pyridine derivatives. The cyclized product undergoes ring-opening reaction by a nucleophile in the presence of Lewis acid to afford highly functionalized tetrahydropyridines.     

Novel analogues of 3-substituted-2,3-dihydro-1,4-dioxino[2,3-b]pyridines: modifications in the dioxane ring

The synthesis of a series of novel analogues of the 3-substituted-2,3-dihydro-1,4-dioxino[2,3-b]pyridine core, modified in the non-aromatic ring, is described. Due to the presence of a versatile hydroxymethyl group in their structure, these novel scaffolds are attractive intermediates for the preparation of potential new therapeutic agents.     

Regioselective synthesis of 2,3-dihydrospiro[1,4]dioxino[2,3-b]pyridine derivatives

2-Chloropyridines and an aryl bromide underwent palladium-catalyzed intramolecular C-O bond forming reactions to provide 2,3-dihydrospiro[1,4]dioxino[2,3-b]pyridine derivatives and a benzodioxin, regioselectively.     

Synthesis of 2,3-dioxo-2,3-dihydro-4-methyl-6-chloro-1H-pyrrolo[2,3-b]pyridine and its 1-α-L-arabinopyranoside

A new type of isatin analog-2,3-dioxo-2,3-dihydro-4-methyl-6-chloro-1H-pyrrolo[2,3-b]pyridine — was obtained by oxidation of 4-methyl-6-chloro-1H-pyrrolo(2,3-b]pyridine. Condensation of L-arabinose with 4-methyl-6-chloro-2,3-dihydropyrrolo[2,3-b]pyridine and subsequent acetylation and dehydrogenation gave 1-(2,3,4-tri-O-acetyl--L-arabinopyranosyl)-4-methyl-6-chloropyrrolo[2,3-b]pyridine, which served as the starting compound for the synthesis of 1--L-arabinopyranosyl-4-methyl-6-chloropyrrolo[2,3-b]pyridine. Oxidation of 1-(2,3,4-tri-O-acetyl-L-arabinopyranosyl)-4-methyl-6-chloropyrrolo[2,3-b]pyridine gave 1-(2,3.4-tri-O-acetyl--L-arabinopyranosyl)-2,3-dioxo-2,3-dihydro-4-methyl-6-chloropyrrolo [2,3-b]pyridine.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1083–1086, August, 1977.     

Influence of electronic and steric factors on 2,3-dihydroimidazo[1,2-a]pyridine-based enantioselective acylation catalysts

The catalytic activity and enantioselectivity of chiral 2,3-dihydroimidazo[1,2-a]pyridine (DHIP) derivatives was examined as a function of the steric environment of the nucleophilic nitrogen and the electronic properties of the pyridine ring. 2-Phenyl-6-trifluoromethyl-DHIP (CF₃-PIP) was confirmed to be the best catalyst in this series. In addition, three second-generation catalysts derived from the 1,2-dihydroimidazo[1,2-a]quinoline (DHIQ) core were tested and proved to be considerably more active than CF₃-PIP.     

Synthesis of 6-methylfuro[2,3-b]pyridine

The Claisen condensation of ethyl 2-ethoxy-6-methylpyridine-3-carboxylate with ethyl acetate gave ethyl 2-ethoxy-6-methylnicotinoylacetate, which was converted to 3-bromo-acetyl-6-niethyl-2-pyridone by heating with bromine in 48% hydrobromic acid. The cyclization of the bromoacetylpyridone by the action of silver oxide in methanol gave 3-oxo-6-methyl-2,3-dihydrofuro[2,3-b]pyridine, which was reduced to 3-hydroxy-6-methyl-2,3-dihydrofuro[2,3-b]pyridine with lithium aluminum hydride in dimethoxyethane. Acetylation of the latter gave its acetate, the pyrolysis of which in vacuo gave 6-methylfuro[2,3-b]-pyridine.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1544–1546, November, 1972.     

Furopyridines. I. Synthesis of furo[2,3-c]pyridine

The parent framework of furo[2,3-c]pyridine has been synthesized. 3-Furoic acid chloride ( 2 ) was reduced with bis(triphenylphosphine) copper(1) tetrahydroborate to afford 3-furaldehyde ( 3 ) which was condensed with malonic acid to give β-(3-furyl)acrylic acid ( 4 ). The acrylic acid 4 was converted to the acid azide ( 5 ), which in turn was cyclized to give furo[2,3-c]pyridin-7(6H)-one ( 6 ) by heating at 180° in diphenylmethane. The pyridone 6 was chlorinated with phosphorus oxychloride, followed by reduction with zinc and acetic acid to give furo[2,3-c]pyridine ( 8 ).     

Chemistry of thienopyridines. XIX. Further studies on chlorination and S-oxidation in the thieno[2,3-b] pyridine system

Treatment of thieno [2,3-b] pyridine (1a) with chlorine gas in chloroform (plus water) gave a mixture of two 2,3-dichloro-2,3-dihydrothieno[2,3-b] pyridine 1-oxides [trans-syn (IIa), and cis-anti (IIb)) [and 2,3,3-trichloro-2,3-dihydrothieno[2,3-b]pyridine syn-1-oxide (IVa), as well as a non-isolated fourth product (prohably the anti isomer of IVa) and sometimes a small amount of thieno[2,3-b]pyridine 1,1-dioxide (III). Treatment of Ia in a solvent (water, chloroform-water, or THF-water) with sulfuric acid and sodium hypochlorite gave a mixture of IIb and III. Effects of variations of reaction conditions on the composition of the product mixture were ascertained through chemical isolation and/or pmr analysis. Products formed were rationalized in terms of the chlorine-water-hypochlorous acid equilibrium, plus attack of chlorine variously at positions 1 (S-atom), 2, and 3 of 1a, but of hypochlorous acid only at position 1. Thermal and chromatographic limitations on isolation procedures for some of the products were established. Stereochemistries of IIa, IIb, and IVa were assigned by means of pmr spectrometry with the aid of the shift reagent Eu(fod)₃. Spin-spin couplings between the proton at position 2 and those at positions 4 and 6 were observed at high resolution. In exploratory runs, 5-ethyl-la was converted into isolable 2,3-dichloro-5-ethyl-2,3-dihydrothieno[2,3-b]pyridine 1-oxide, and 5-acetyl-Ia yielded 3-chloro-5-acetylthieno] 2,3-b]pyridine. Mass spectral fragmentation patterns for the various products are presented.     

Smiles rearrangement for the synthesis of 5-amino-substituted [1]benzothieno[2,3-b]pyridine

The Smiles rearrangement was successfully applied to 4-hydroxybenzo[b]thiophene furnishing a facile entry to the 4-amino derivative. The rearrangement was extended to 5-methoxy-4-methoxycarbonyl[1]benzothieno[2,3-b]pyridine obtained via aza-Wittig/electrocyclization reaction of novel N-(4-methoxybenzothiophen-2-yl)iminomethyldiphenylphosphorane with methyl trans-4-oxo-2-pentenoate. The preparation of a novel 5-amino-4-methoxycarbonyl[1]benzothieno[2,3-b]pyridine, which is of interest as a potential secondary peptide structure mimic, was successfully achieved.     

A new synthesis of 3-hydroxy-2,3-dihydro-1,4-benzodioxin-2-carboxamides and 3-aminomethylene-1,4-benzodioxin-2(3H)-one derivatives

The 1,4-benzodioxin-2-carboxylic esters or carboxamides react with nucleophilic amines to give access to 3-hydroxy-2,3-dihydro-1,4-benzodioxin-2-carboxamides and 3-aminomethyn-1,4-benzodioxin-2(3H)-one precursors of potential therapeutical compounds. The basic environment (K₂CO₃ or amine) facilitates the process.     

One-pot synthesis of furo[2,3-h]quinoline and furo[2,3-h]isoquinoline derivatives using Fischer carbene complex

A new route for the synthesis of furo[2,3-h]quinoline and furo[2,3-h]isoquinoline derivatives have been explored through the coupling of carbene complexes with pyridine-bridged enynes. This reaction process, involving the annulation of both furan and benzene ring on to a pre-existing pyridine ring is highly efficient in the presence of triphenylphosphine as ligand additive.     

Analogues of the Quararibea metabolite chiral enolic-γ-lactone from (2S,3S)- and (2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acids

Reaction of dialkyl (2S,3S)- or (2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylates with POCl₃ in pyridine followed by diazomethane resulted in the isolation of dialkyl 2S-4-methoxy-5-oxo-2,5-dihydro-2,3-furandicarboxylates, which are analogues of the Quararibea metabolite chiral enolic-γ-lactone (3-hydroxy-4,5-(R)-dimethyl-2(5H)-furanone). An unusual α-hydroxylation of γ-butyrolactone takes place involving POCl₃ in pyridine. When the dehydration was facilitated with methanesulfonyl chloride in triethylamine, instead of POCl₃, aromatic dialkyl 5-[(methylsulfonyl)oxy]-2,3-furandicarboxylates were obtained.     

Synthesis of tetrahydropyrido[2,3-b]pyrazine scaffolds from 2,3,5,6-tetrafluoropyridine derivatives

Reactions between N,N′-dimethylethylene diamine and a range of 2,3,5,6-tetrafluoropyridine derivatives provided ready access to the corresponding tetrahydropyrido[2,3-b]pyrazine systems if the substituent located at the 4-position of the pyridine ring was either hydrogen or an electron withdrawing substituent. In contrast, the presence of electron donating substituents at the 4-position made the formation of ring-fused products much more difficult. The two-step sequential nucleophilic substitution procedures from pentafluoropyridine gave convenient and adaptable methodology for the synthesis of polyfunctional tetrahydropyrido[2,3-b]pyrazine scaffolds of interest to the life science discovery arenas.     

Chemistry of thienopyridines. XXVI. Synthesis of 6-(γ-diethylaminopropylamino)thieno[2,3-b]pyridine

6-(γ-Diethylaminopropylamino)thieno[2,3-b]pyridine ( 3b ) was obtained (58% yield) from copper-promoted aminodechlorination of 6-chlorothieno[2,3-b]pyridine at 168°. A mechanistic rationalization for the reaction and the mass spectral fragmentation pattern for 3b are presented.     

Disruption of Crystal Packing in Thieno[2,3-b]pyridines Improves Anti-Proliferative Activity

3-Amino-2-arylcarboxamido-thieno[2,3-b]pyridines have been shown to have anti-proliferative activity, but are also known to have poor solubility. This has been previously proposed to be due to their extensive planarity, which allows for intermolecular stacking and crystal packing. We herein report the synthesis of fifteen novel thieno[2,3-b]pyridines that have incorporated bulky, but easily cleavable, ester and carbonate functional groups in an effort to decrease crystal packing. The addition of these ‘prodrug-like’ moieties into the thieno[2,3-b]pyridine resulted in compounds with increased activity against HCT-116 colon cancer cells and the triple-negative breast cancer cell line MDA-MB-231.     

Polymethine dyes — Benzofuro[2,3-b]pyridine and selenonaphtheno[2,3-b]pyridine derivatives

Polymethine dyes — benzofuro[2,3-b]pyridine and selenonaphtheno[2,3-b]pyridine derivatives — were synthesized, and their spectral properties are discussed. Replacement of a vinylene group by an oxygen or selenium atom in one benzene ring of the 2-benzo[h]quinoline residue in the cyanines causes a large bathochromic shift of the absorption maxima of the dyes as compared with replacement by a sulfur atom. The dyes derived from benzofuro[2,3-b]pyridine derivatives are more deeply colored than the derivatives of both thionaphtheno[2,3-b]-pyridine and selenonaphtheno[2,3-b]pyridine.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp.1611–1614, December, 1972.     

Synthesis of new compounds containing the 2,3-dihydro[1,4]dioxino[2,3-b]pyridine heterocyclic system as a substructure

2,3-Dihydro-spiro[1,4]dioxino[2,3-b]pyridine-3,3′-pyrrolidine (8A) and 2,3-dihydro-spiro[1,4]dioxino[2,3-b]pyridine-3,4′-piperidine (9A) have been synthesized from 2-chloro-3-pyridinol. The corresponding 2,3′ (8B) and 2,4′ (9B) isomers were obtained via the Smiles rearrangement, while 9B was also selectively synthesized from 2-nitro-3-pyridinol. The separation of the isomers A and B under the sulfamide form was carried out by flash column chromatography. Subsequent transformations of the corresponding dioxinopyridine derivatives were described.