Alkoxy Carbonyl Research Articles

Activator-regulated chemodivergent deoxygenative- and alkoxy-carbonylation of alcohols with boronic acids

A method for the chemodivergent deoxygenative- and alkoxy-carbonylation of alcohols with boronic acids via palladium catalysis has been developed. Manipulation of the divergent selectivities depend on simply changing the choice of activators. While a carbodiimide activator promoted the formation of ketones through deoxygenative carbonylation, selectivity for esters via alkoxy carbonylation was observed with an azo activator. Notably, in addition to the broad substrate scope, this base-free strategy enables the use of highly base-sensitive boronic acid substrates. This study contributes to the art of chemoselectivity control in carbonylation chemistry.

Synthesis and Evaluation of Self-Assembling Properties of 3-(3,5-Difluoro-3,5-bis((alkoxy)carbonyl)-2,6-dioxoheptan-4-yl)-1-methylpyridin-1-ium Iodides

A synthesis of 3-(3,5-difluoro-3,5-bis((alkoxy)carbonyl)-2,6-dioxoheptan-4-yl)-1-methylpyridin-1-ium iodides with ethyl or nonyl ester groups at positions 3 and 5 was performed. Treatment of the corresponding 2’,6’-dimethyl-1’,4’-dihydro-[3,4’-bipyridine]-3’,5’-dicarboxylates with Selectfluor® followed by quaternization of pyridine moiety in the obtained dialkyl 2,4-diacetyl-2,4-difluoro-3-(pyridin-3-yl)pentanedioates with methyl iodide gave the desired 3-(3,5-difluoro-3,5-bis((alkoxy)carbonyl)-2,6-dioxoheptan-4-yl)-1-methylpyridin-1-ium iodides. This type of compound would be useful as synthetic lipids for further development of the delivery systems. The obtained target compounds were fully characterized by 1H NMR, 19F NMR, 13C NMR, HRMS, IR and UV data. The estimation of self-assembling properties and characterization of the nanoparticles obtained by ethanol solution injection in an aqueous media were performed by dynamic light scattering (DLS) measurements. DLS measurement data showed that 3-(3,5-difluoro-3,5-bis((nonyloxy)carbonyl)-2,6-dioxoheptan-4-yl)-1-methylpyridin-1-ium iodide created liposomes with the average diameter of 300–400 nm and polydispersity index (PDI) value around 0.30–0.40, while 3-(3,5-difluoro-3,5-bis((ethyloxy)carbonyl)-2,6-dioxoheptan-4-yl)-1-methylpyridin-1-ium iodide formed a heterogeneous sample with PDI value 1, which was not prospective for delivery system development.

O-Alkyl S-(Pyridin-2-yl)carbonothiolates: Operationally Simple and Highly Nitrogen-Selective Reagents for Alkoxy Carbonylation of Amino Groups

Amino groups are selectively protected in good yields by reaction with O-alkyl S-(pyridin-2-yl)carbonothiolates in an appropriate solvent at room temperature in air. Even glucosamine, which contains multiple hydroxyl groups, is selectively N-protected in methanol.

C(sp3)-H dehydrogenation and C(sp2)-H alkoxy carbonylation of inactivated cyclic amines towards functionalized N-heterocycles.

A novel and efficient synthesis of tetrahydropyridine (THP)-, dihydropyrrole (DHP)-, or tetrahydroazepine (THA)-3-carboxylates via cascade reactions of inactivated cyclic amines with CO and alcohols is presented. To our knowledge, this should be the first example in which functionalized N-heterocycles were prepared directly from Pd-catalyzed C(sp3)-H dehydrogenation and C(sp2)-H carbonylation of saturated cyclic amines. Moreover, the DHP-3-carboxylates thus obtained could readily undergo an oxidative aromatization to give pyrrole-3-carboxylates by using O2 as a green oxidant. Notable features of the methods developed herein include simple substrates, high efficiency and excellent atom-economy, mild reaction conditions, and broad substrate scope.

Design, synthesis and biological evaluation of diaziridinyl quinone isoxazole hybrids

A series of novel diaziridinyl quinone isoxazole hybrids (9a-9j) were synthesized starting from 2, 5-dimethoxy acetophenone 1 via Claisen reaction, cyclisation, alkoxy carbonylation, hydrolysis, oxidation and aziridine insertion. All the compounds were screened for antimicrobial, anti-biofilm and cytotoxic activities. Among the screened compounds, the compound 9h showed good antibacterial and anti-biofilm activities with MIC value of 3.9, 3.9, 3.9 and 7.8 μg/mL, respectively, and IC50 values of 1.9, 2.5, 2.8 and 5.1 μM, respectively, against Staphylococcus aureus MTCC 96, S. aureus MLS-16 MTCC 2940, Bacillus subtilis MTCC 121 and Klebsiella planticola MTCC 530, and also exhibited potent antifungal activity against Candida albicans MTCC 227, C. albicans MTCC 854 and Candida krusei MTCC 3020 equipotent to standard miconazole (MIC value 7.8 μg/mL). All the synthesized compounds exhibited promising cytotoxicity against A549 and PC3 cell lines (IC50 values between 1 and 4 μM). Compounds 9b and 9j exhibited IC50 value of 0.5 μM which was similar to that of Mitomycin C against PC3 cell line.

Heterocycles Synthesis at Carbonylation of Acetylenic Compounds

The carbonylation of unsaturated hydrocarbons, alcohols, organic halides and other substrates catalyzed by transition metals, salts of transition metals and organometallic complexes is a wide used synthesis method of new carbonyl, carboxyl and alkoxy carbonyl containing compounds including creation or modificationt of heterocycles. The data about synthesis of heterocycles at carbonylation of acetylenic compounds have been appeared at last 20 years and are demonstrated in our review. Introduction of carbon monoxide in the catalytic reactions of acetylenic compounds permits to obtain in oneput process the diverse heterocycles, having carbonyl, carboxyl or alkoxycarbonyl substitutes or containing these fragments inside of heterocycles.

Synthesis of new derivatives of 2-chloro-3-formyl-1,8-naphthyridine

A simple and regioselective synthesis of 2-chloro-3-formyl-1,8-naphthyridine, through Vilsmeier-Haack cyclization of N -(pyridin-2-yl)acetamide has been reported. The reaction of 2-chloro-3-formyl-1,8-naphthyridine is also investigated and new series of 1,8-naphthyridine derivatives such as 3-chloro-4-(2-chloro-1,8-naphthyridine-3-yl)-1-(phenylamino)azetidin-2-one, 3-chloro-4-(2-chloro-1,8-naphthyridin-3yl)-1-((4-nitrophenyl) amino)-azetidin-2-one and 3-chloro-4-(2-chloro-1,8-naphthyridine-3-yl)-1-((2,4-dinitrophenyl) amino)-azetidin-2-one have been prepared. The formyl group in the 1,8-naphthyridine is subjected to further transformation into alkoxy carbonyl (NIS-K 2 CO 3 /alcohol) to afford 3-alkoxy carbonyl-1,8-naphthyridine and new hetero cyclic compounds such as oxadiazolo, thiadiazolo-thion and triazolo-thion have been prepared. The reaction between 2-chloro-3-formyl-1,8-naphthyridine and sodium sulphide in DMF produced 2-mercapto-3-formyl-1,8-naphthyridine. Some of the prepared compounds were found to have good biological activity against Staphylococcus aureus and Staphylococcus epidermidis.

Synthesis of intermediate compounds with P-N bond from (thio)carbamates and chlorodioxaphospholanes and -phosphorinanes and their reactivity

A variety of 2-( N -alkoxy(thio)carbonyl alkyl(aryl)amino)-1,3,2-dioxaphospholanes and phosphorinanes were prepared from chlorodioxaphospholanes and phosphorinanes. Their structures were determined by IR, Mass and NMR spectroscopy. These compounds were employed in direct reactions with elemental sulphur and methylester of chloroacetic acid giving potentially physiologically active N -phosphorylated carbamates with P(O)-N and P(S)N bonds.

Synthesis and the Intestinal Glucosidase Inhibitory Activity of 2-Aminoresorcinol Derivatives toward an Investigation of Its Binding Site

2-Aminoresorcinol is a potent and selective intestinal glucosidase inhibitor. Unlike the majority of glucosidase inhibitors, it shows an uncompetitive mode of inhibition. In this study, we tested the intestinal glucosidase inhibitory activity of various 2-aminoresorcinol derivatives. We found that structural changes, in amino and two phenolic hydroxyl groups had a negative impact on inhibitory activity, but methylation of the phenolic hydroxyl group was found to maintain its activity and replacement of the aromatic ring with an acyl or alkoxy carbonyl group at the 4th position also retained its activity. This enable us to design a molecular probe for further study of the inhibition mechanism of 2-aminoresorcinol.

Helically π-Stacked Thiophene-Based Copolymers with Circularly Polarized Fluorescence: High Dissymmetry Factors Enhanced by Self-Ordering in Chiral Nematic Liquid Crystal Phase

Novel derivatives of polythiophenes and their phenylene copolymers were synthesized by introducing chiral alkoxy carbonyl substituents into their side chains. Most of these polymers showed enantiotropic main-chain liquid crystallinity at high temperatures and across a wide range of elevated temperatures. They exhibited fluorescence that ranged in color from blue to orange in chloroform solutions and from blue to red in films. The bisignate Cotton effect was observed in the π–π* transition region of the circular dichroism (CD) spectra of the polymers consisting of three aromatic rings in the repeating unit, which was attributed to the formation of a polymer assembly with an interchain helically π-stacked structure. The dependence of UV–vis absorption and CD spectra on the concentration and temperature of the solution indicated that the polymer assembly exists, even in dilute concentration at room temperature, but it dissociated into single polymers at high temperatures. Additionally, the polymer films exhibited an enhanced Cotton effect caused by the strengthening of the helical π-stacking in the polymer assembly. Both the polymer solutions and films generated circularly polarized fluorescence with values for gem, the dissymmetry factor, on the order of 10–3 and 10–2, respectively. Values for gem as high as 10–1 were obtained by annealing the polymer films at temperatures corresponding to the liquid crystalline region and were due to the self-ordering of their chiral nematic phases. Furthermore, a mixture of red, green, and blue fluorescent polymers generated a unique, circularly polarized white luminescence not only in solution but also in the cast film prepared by dispersing the mixture in an excess of polystyrene.

Ruthenium imidazole oxime carbonyls and their activities as CO-releasing molecules

Carbon monoxide has been found to possess various beneficial effects in living organisms. To study the effects of CO further and to develop potential pharmaceutical agents, a meaningful method for delivering CO to the target organ is needed. It has been found that under physiological conditions various metal carbonyl complexes release carbon monoxide. In this study six novel ruthenium carbonyl complexes Ru(IMOX)(CO)(2)(COOR)Cl(1) (IMOX: imidazolecarbaldehyde oxime, R: Me, Et) were prepared and tested as carbon monoxide releasing molecules (CORMs). Synthesis of the complexes was performed under mild conditions in alcoholic solutions. The ability to release CO was tested spectrophotometrically by following the transformation of deoxymyoglobin to carbonmonoxy myoglobin. All of the complexes studied were found to release CO. Compared to formerly studied ruthenium-based CORMs these complexes offer a way for slower CO release.

ChemInform Abstract: Synthesis of 1,3-Di[alkoxy(aryloxy)carbonyl]-2-oxo-2,3-dihydroindoles.

Abstract Two protocols have been developed for the synthesis of 1,3-di[alkoxy(aryloxy)carbonyl]-2-oxo-2,3-dihydroindoles starting from the corresponding N,O-diacyl derivatives obtained by treatment of 2-oxindoles with chloroformic acid esters and triethylamine. The first is rearrangement of N,O-diacylated compounds in the presence of 4-dimethylaminopyridine to give N,C(3)-diacylated products with identical acyl groups in the two positions. The second involves O-deacylation of the N,O-diacylated compounds, followed by O-acylation and rearrangement resulting N,C(3)-diacylated 2-oxindoles with different acyl groups in the two positions.

Addition of Hypophosphorous Acid to N,N′-Terephthalylidene-bis[1-(alkoxycarbonyl)alkylamines

The preparation of 1,4-phenylene-bis[1-(alkoxycarbonyl)alkylamino-methanephosphonous acids] by the addition of hypophosphorous acid to terephthalylidene-bis[1-(alkoxycar bonyl)alkylamines] is described. Despite expectations, no chiral assistance of the amino acid ester moiety is observed.

Microwave-Assisted Carbonylation and Cyclocarbonylation of Aryl Iodides under Ligand Free Heterogeneous Catalysis

Carbonylation reaction is a very effective transformation for the synthesis of esters, amides, and heterocyclic compounds. Heterogeneous catalyzed carbonylation reactions can be carried out using the association of Pd/C and microwave dielectric heating. Alkoxy carbonylation can be performed with stoichiometric amounts of different primary and secondary alcohols in DMF in the presence of DBU as the base. Analogously, iodobenzene, CO, and amines can be transformed into the corresponding amides in good yields after a simple filtration to remove the catalyst. Pd/C was also successfully employed in microwave-assisted cyclocarbonylation of o-iodoaniline with acyl chlorides to give benzoxazinones. Pd/C can be recycled two times without a considerable difference in the reaction yields.

Enantiomeric resolution of biomarkers in space analysis: Chemical derivatization and signal processing for gas chromatography–mass spectrometry analysis of chiral amino acids

The work compares two GC–MS methods for enantioselective separation of amino acids as suitable candidate for stereochemical analysis of chiral amino acids on board spacecrafts in space exploration missions of solar system body environments. Different derivatization reagents are used: a mixture of alkyl chloroformate–alcohol–pyridine to obtain the alkyl alkoxy carbonyl esters and a mixture of perfluorinated alcohols and anhydrides to form perfluoroacyl perfluoroalkyl esters. 20 proteinogenic amino acids were derivatized with the two procedures and submitted to GC–MS analysis on a Chirasil- l-Val stationary phase. The results were then compared in terms of the enantiomeric separation achieved and intensity of MS response. The combination of methyl chloroformate (MCF) and heptafluoro-1-butanol (HFB) allows separation of 14 enantiomeric pairs, five of which display a resolution ( R s ≥ 1.2) supposed to be sufficient to quantify the enantiomeric excess. Three mixtures of trifluoroacetic (TFAA) and heptafluorobutyric (HFBA) anhydrides were combined with the corresponding perfluorinated alcohols – TFE (2,2,2-trifluoro-1-ethanol) and HFB (2,2,3,3,4,4,4-heptafluoro-1-butanol) – to give three different reagents (TFAA–TFE, TFAA–HFB, HFBA–HFB): the derivatives obtained show separation of the same number of proteinogenic amino acids (14 of 20) at a temperature lower than column bleeding limit (200 °C) and 8 of them give a separation with R s ≥ 1.2. Linearity study and limit of detection ( X LOD) computation show that both methods are suitable for quantitative determination of several amino acid diastereomers at trace level ( X LOD ≈ 0.5 nmol as derivatized quantity). Both the procedures were coupled with automatic data handling to increase their suitability for space analysis: the simplified data treatment is especially helpful to handle the low quality data recovered from space experiments and labor and time are saved, as imposed by the space experiments requiring a rapid delivery of the results. To achieve this aim, a chemometric approach based on the computation of the Autocovariance Function (ACVF) was applied to extract information on the enantiomeric pairs present in the sample and the enantioseparation achieved on the chiral column.

Synthesis and Bioactivity of Some New 2‐(Alkoxy carbonyl alkyl)‐6‐bromo‐3,4‐dihydro‐3‐(α‐methyl benzyl)‐2‐oxo‐benzo[e] [2H‐1,3,2‐oxazaphosphinine] Derivatives

AbstractSynthesis of some new 2‐(alkoxy carbonyl alkyl)‐6‐bromo‐3,4‐dihydro‐3‐(α‐methyl benzyl)‐2‐oxo‐3‐benzo‐ [e][2H‐1,3,2‐oxazaphosphinine] derivatives was accomplished through a two step process, which involves the condensation of 2‐[(α‐methylbenzyl amino)methyl]‐4‐bromophenol (1) with phosphorus oxychloride in equimolar quantities in the presence of triethylamine in dry toluene in 50–55 °C producing the corresponding intermediate (2), and subsequent reaction with the amino acid alkyl ester in dry tetrahydrofuran in the presence of triethylamine at different temperatures. They exhibited significant antibacterial and fungal activity.

Gas chromatography–mass spectrometry analysis of amino acid enantiomers as methyl chloroformate derivatives: Application to space analysis

This work describes a GC–MS method for enantioselective separation of amino acids. The method is based on a derivatization reaction which employs a mixture of alkyl chloroformate–alcohol–pyridine, as reagents to obtain the N( O, S)-alkyl alkoxy carbonyl esters of amino acids. Various reaction parameters are investigated and optimized to achieve a reproducible derivatization procedure suitable for separation of amino acid enantiomers on Chirasil- l-Val chiral stationary phase. In particular, the following topics are investigated for 20 proteinogenic amino acids: (i) the proper reagent and reaction conditions to obtain the highest derivative yield; (ii) the amino acid reactivity and the MS properties of the obtained derivatives; (iii) the linearity and sensitivity of the analytical method; (iv) the retention behavior of the derivatives and their enantiomeric separation on the Chirasil- l-Val chiral stationary phase. By combining the resolution power of the Chirasil- l-Val column and the high selectivity of the SIM MS detection mode, the described procedure enables the enantiomeric separation and quantification of 16 enantiomeric pairs of amino acids. The procedure is simple and fast and reproducible. It displays a wide linearity range at ppb detection limits for quantitative determinations: these properties make this derivatization method a suitable candidate for amino acid GC–MS analysis on board of the spacecrafts in space exploration missions of solar system body environments.

New Routes to Oxindole Derivatives

A new, practical synthesis of the antirheumatic oxindole derivative, tenidap, has been elaborated. The new approach has initiated studies on the mechanism of the acylation reactions of oxindoles. Methods have been developed for the synthesis of 1-[alkoxy(or aryloxy)carbonyl]- and 1,3-di[alkoxy(or aryloxy)carbonyl]oxindoles starting from oxindoles. The route designed for tenidap has provided a facile access to several analogues, too.

Kinetics and Mechanism of the Cobalt(III) Tetraammine Complex-Promoted Hydrolysis of 4-Nitrophenyl Glycinate

Abstract The kinetics of the hydrolysis of 4-nitrophenyl glycine ester (PNPG) catalysed by [Co(OH)(trien)(OH2)]2+, [Co(OH)(tren)(OH2)]2+ and [Co(OH)(en)2(OH2)]2+ complexes has been studied spectrophotometrically in weakly basic aqueous media (pH = 6.5 to 7.4). Kinetic experiments were carried out as a function of the pH, complex concentration and temperature. The rate of hydrolysis increases linearly with the complex concentration with a trend to wards rate saturation, suggesting the formation of associative species in a pre-equilibrium step. The pseudo-first order rate constant, kobs, increases rapidly with a decrease in the hydrogen-ion concentration. The complexes promote the hydrolysis of 4-nitrophenyl glycinate significantly, and the acceleration rate is about 400–600. An attack of external OH- on the chelated ester is suggested as a probable mechanism for the hydrolysis. The lower rate enhancements observed in the present study could probably be ascribed to a weaker cobalt(III) alkoxy carbonyl interaction in the chelate, owing to a decreased nucleophilicity of the carbonyl oxygen in the p-nitrophenyl ester. The activation parameters for all three complex-promoted reactions are found to be comparable, thus suggesting a common mechanism operative in all complex catalysed reactions.

Site-recognition of one of the two alkoxy carbonyl groups present in the dienophile for Diels–Alder reaction

Recognition of one alkoxy carbonyl group from the two in a molecule by a Lewis acid was investigated using 1a– e in the Diels–Alder reaction with diene 6 . Combination of 1a and BF 3·OEt 2 provided the highest efficiency to afford 7a , thus showing evidence for the site-selective coordination of BF 3·OEt 2 to the MOM-oxy carbonyl group in 1a . Furthermore, the generality and high reactivity of this combination were confirmed with dienes 11– 14 .