HFIP-mediated 2-aza-Cope rearrangement: metal-free synthesis of α-substituted homoallylamines at ambient temperature.

An efficient metal-free strategy for the synthesis of α-substituted homoallylamine derivatives has been developed via a 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP)-promoted 2-aza-Cope rearrangement of aldimines, generated in situ by condensation of aldehydes with easily accessible 1,1-diphenylhomoallylamines. This reaction provides rapid access to α-substituted homoallylamines with excellent functional group tolerance and yields. The reaction takes place at room temperature and no chromatographic purification is required for product isolation.

Comparative Study of the Vibrational Optical Activity Techniques in Structure Elucidation: The Case of Galantamine.

The absolute configuration of the alkaloid galantamine was studied using a range of solution-state techniques; nuclear magnetic resonance (NMR), vibrational circular dichroism (VCD), and Raman optical activity (ROA). While the combined use of NMR and VCD does provide a fast, high-resolution methodology for determining the absolute configuration of galantamine, both techniques were needed in concert to achieve this goal. ROA, on the other hand, proved to be sensitive enough to assign the full absolute configuration without relying on other techniques.

Lewis acidic FeCl promoted 2-aza-Cope rearrangement to afford α-substituted homoallylamines in dimethyl carbonate.

The iron(iii)-catalyzed efficient strategy for the synthesis of α-substituted homoallylamines was accomplished a cationic 2-aza-Cope rearrangement of aldimines, generated by condensation of commercially available aldehydes and easily synthesizable 1,1-diphenylhomoallylamines. This reaction features a broad substrate scope with high yields and is conducted in an eco-friendly solvent, dimethyl carbonate.

Synthesis and antitubercular activity of 1- and 3-substituted benzo[g]isoquinoline-5,10-diones.

In this study, a small library of twenty benzo[g]isoquinoline-5,10-diones were synthesized in a novel straightforward approach, starting from 2-methyl-1,4-naphthoquinone (vitamin K). An intramolecular Heck reaction of a N-vinylacetamide was a crucial step in the synthetic route, at which the combination of cesium carbonate and a bulky, electron rich trialkylphosphine (tBuCy2P.HBF4) provided high 6-endo-trig selectivity.

The Use of Calcium Carbide as Acetylene Source in a Three-Component Coupling with ω-Chlorinated Ketones and Primary Amines.

Calcium carbide was used in a Cu -catalysed three-component coupling with ω-chlorinated ketones and primary amines to generate terminal 2-alkynyl-N-heterocycles. The formation of an imine and the subsequent intramolecular substitution results in an active electrophilic iminium species, which can be alkynylated by in situ formed copper acetylide. A number of aliphatic primary (functionalised) amines and aliphatic or aromatic alkynes together with different alkyl- or aryl-substituted γ- or δ-chloroketones could be used.

Synthesis of highly functionalized 1,6-dihydropyridines via the Zn(OTf)-catalyzed three-component cascade reaction of aldimines and two alkynes (IA-coupling).

A zinc(ii) triflate catalyzed three component synthesis of 1,6-dihydropyridines, involving aldimines, alkynes and electron-deficient dimethyl acetylenedicarboxylate (DMAD), in good to excellent yields has been described. Besides a range of different N-substituents, a variety of both aromatic and aliphatic alkynes could be used. The application of electron-deficient propiolates instead of DMAD resulted in regiospecific incorporation of the ester functionality on the 1,6-dihydropyridine ring.

Copper(I)-Catalyzed Ketone, Amine, and Alkyne Coupling for the Synthesis of 2-Alkynylpyrrolidines and -piperidines.

A Cu(I)-catalyzed coupling of a ω-chloro ketone, a primary amine, and an alkyne is described. This protocol allows for the synthesis of α-quaternary carbons in 2-alkynyl-substituted N-heterocycles. The key step is the in situ generation of a cyclic ketiminium species, which has enhanced reactivity for alkynylation compared to acyclic ketiminium species.

Base metal-catalyzed benzylic oxidation of (aryl)(heteroaryl)methanes with molecular oxygen.

The methylene group of various substituted 2- and 4-benzylpyridines, benzyldiazines and benzyl(iso)quinolines was successfully oxidized to the corresponding benzylic ketones using a copper or iron catalyst and molecular oxygen as the stoichiometric oxidant. Application of the protocol in API synthesis is exemplified by the alternative synthesis of a precursor to the antimalarial drug Mefloquine. The oxidation method can also be used to prepare metabolites of APIs which is illustrated for the natural product papaverine.

Stereochemistry of the Brivaracetam Diastereoisomers.

The stereochemistry of all four stereoisomers of brivaracetam was determined using vibrational circular dichroism (VCD) spectroscopy. By comparing experimentally obtained VCD spectra and computationally simulated ones, the absolute configurations can be confidently assigned without prior knowledge of their relative stereochemistry. Neither the corrected mean absolute errors analysis of the nuclear magnetic resonance (NMR) data, nor the matching of experimental and calculated infrared spectra allowed the diastereoisomers to be distinguished.

Mechanism of the Cu-catalyzed benzylic oxygenation of (aryl)(heteroaryl)methanes with oxygen.

A mechanistic study of the copper-catalyzed oxidation of the methylene group of aryl(di)azinylmethanes was performed. Initial reaction rates were measured making use of IR reaction monitoring and a kinetic analysis of the reaction was executed. The reaction proved to be first order in oxygen concentration.

New short and general synthesis of three key Maillard flavour compounds: 2-Acetyl-1-pyrroline, 6-acetyl-1,2,3,4-tetrahydropyridine and 5-acetyl-2,3-dihydro-4H-1,4-thiazine.

A new general synthetic route towards three key Maillard flavour compounds, namely 2-acetyl-1-pyrroline, 6-acetyl-1,2,3,4-tetrahydropyridine and 5-acetyl-2,3-dihydro-4H-1,4-thiazine, was developed. The key step in the process is the methylenation reaction of azaheterocyclic carboxylic esters by means of dimethyltitanocene, giving rise to intermediate vinyl ethers which can be considered as excellent and stable precursors for the title compounds, as a simple acidic treatment of these precursors suffices to release the characteristic Maillard flavours.

Stereochemistry of the tadalafil diastereoisomers: a critical assessment of vibrational circular dichroism, electronic circular dichroism, and optical rotatory dispersion.

The stereochemistry of all four stereoisomers of tadalafil is determined using vibrational circular dichroism (VCD), electronic circular dichroism (ECD), and optical rotatory dispersion (ORD) spectroscopy. By comparing experimentally obtained VCD spectra to computationally simulated ones, the absolute configuration of the enantiomeric pair (6R, 12aR)/(6S, 12aS) can be confidently assigned without prior knowledge of their relative stereochemistry. IR and NMR spectra are used to aid the assignment of the relative stereochemistry.

Lewis acid mediated vinyl-transfer reaction of alkynes to N-alkylimines by using the N-alkyl residue as a sacrificial hydrogen donor.

A variety of N-alkyl-α,α-dichloroaldimines were vinylated by terminal acetylenes in the presence of Lewis acids such as In(OTf)3 or BF3 ⋅OEt2 and hexafluoroisopropanol (HFIP) as an additive. The reaction proceeds at ambient temperature and leads to geometrically pure allylic β,β-dichloroamines. This approach is complementary to previously reported transition-metal-catalyzed vinyl-transfer methods, which are not applicable to aliphatic imines and are restricted to imines that contain an electron-withdrawing nitrogen substituent.

Synthesis of aryl(di)azinyl ketones through copper- and iron-catalyzed oxidation of the methylene group of aryl(di)azinylmethanes.

Sustainable Oxidations: an oxidation method to transform aryl(di)azinylmethanes into aryl(di)azinyl ketones is described. Base metals (copper and iron) as catalysts in combination with O(2) as the oxidant are used, which makes this method sustainable. The utility of this method is illustrated by the synthesis of 6-(4-methylbenzoyl)pyridine-2-carbaldehyde, which is an intermediate in the preparation of the drug Acrivastine.

Synthesis of 3-methoxyazetidines via an aziridine to azetidine rearrangement and theoretical rationalization of the reaction mechanism.

The synthetic utility of N-alkylidene-(2,3-dibromo-2-methylpropyl)amines and N-(2,3-dibromo-2-methylpropylidene)benzylamines was demonstrated by the unexpected synthesis of 3-methoxy-3-methylazetidines upon treatment with sodium borohydride in methanol under reflux through a rare aziridine to azetidine rearrangement. These findings stand in contrast to the known reactivity of the closely related N-alkylidene-(2,3-dibromopropyl)amines, which are easily converted into 2-(bromomethyl)aziridines under the same reaction conditions. A thorough insight into the reaction mechanism was provided by both experimental study and theoretical rationalization.

Synthesis of 1-substituted 1,2,3,4-tetrahydrobenz[g]isoquinoline-5,10-diones.

1,2-Disubstituted 1,2,3,4-tetrahydrobenz[g]isoquinoline-5,10-diones are prepared for the first time through an activated Pictet-Spengler reaction of the corresponding imines of 2-(1,4-dimethoxynaphth-2-yl)ethylamine in the presence of an acyl chloride and AlCl(3) followed by an oxidation with silver(II) oxide in nitric acid. Depending on the reaction conditions the N-trichloroacetyl protecting group could be cleaved off, converted to an N-methoxycarbonyl group or transformed to an N-(2-oxoacetamide) moiety. The synthesized 1,2-disubstituted 1,2,3,4-tetrahydrobenz[g]isoquinoline-5,10-diones constitute a new class of quinones, which has not been reported yet.

Siderophore-mediated iron acquisition in the entomopathogenic bacterium Pseudomonas entomophila L48 and its close relative Pseudomonas putida KT2440.

Pseudomonas entomophila L48 is a recently identified entomopathogenic bacterium which, upon ingestion, kills Drosophila melanogaster, and is closely related to P. putida. The complete genome of this species has been sequenced and therefore a genomic, genetic and structural analysis of the siderophore-mediated iron acquisition was undertaken.

Synthesis of benzo[f]isoindole-4,9-diones.

A synthesis of benzo[f]isoindole-4,9-diones 1 is presented starting from the reaction of 2,3-bis(bromomethyl)-1,4-dimethoxynaphthalene 15 with primary amines affording 2,3-bis(aminomethyl)-1,4-dimethoxynaphthalenes 14, which could be converted by CAN-mediated oxidation in one step to benzo[f]isoindole-4,9-diones 1. An alternative synthesis of benzo[f]isoindole-4,9-diones 1 starts from 2,3-bis(bromomethyl)-1,4-naphthoquinone 9 via 2,3-dihydrobenzo[f]isoindoles 10 which spontaneously oxidize.

Thioquinolobactin, a Pseudomonas siderophore with antifungal and anti-Pythium activity.

Under conditions of iron limitation Pseudomonas fluorescens ATCC 17400 produces two siderophores, pyoverdine, and a second siderophore quinolobactin, which itself results from the hydrolysis of the unstable molecule 8-hydroxy-4-methoxy-2-quinoline thiocarboxylic acid (thioquinolobactin). Pseudomonas fluorescens ATCC 17400 also displays a strong in vitro antagonism against the Oomycete Pythium, which is repressed by iron, suggesting the involvement of a siderophore(s). While a pyoverdine-negative mutant retains most of its antagonism, a thioquinolobactin-negative mutant only slowed-down Pythium growth, and a double pyoverdine-, thioquinolobactin-negative mutant, which does not produce any siderophore, totally lost its antagonism against Pythium.

Detailed investigation of the production of the bread flavor component 6-acetyl-1,2,3,4-tetrahydropyridine in proline/1,3-dihydroxyacetone model systems.

The production of 6-acetyl-1,2,3,4-tetrahydropyridine (ATHP), an important Maillard flavor component, in the reaction of L-(-)-proline and 1,3-dihydroxyacetone was investigated as a function of different reaction conditions. The two major side products from the reaction were identified as 5-acetyl-6-methyl-2,3-dihydro-1H-pyrrolizine and 5-acetyl-6-hydroxymethyl-2,3-dihydro-1H-pyrrolizine, the last one being a new compound described here for the first time. A maximum yield of ATHP of 2.

Genotoxicity of melanoidin fractions derived from a standard glucose/glycine model.

Genotoxic compounds can act at various levels in the cell (causing gene, chromosome, or genome mutations), necessitating the use of a range of genotoxicity assays designed to detect these different types of mutations. The production of melanoidins during the processing and cooking of foods is associated with changes in their nutritional character, and the discovery of mutagenic substances in pyrolyzed protein and amino acids has raised concern about the safety of these foods. The aim of this work was to test melanoidin fractions in three different in vitro assays (Ames test, Vitotox test, and micronucleus test).

Characterization of model melanoidins by the thermal degradation profile.

Different types of model melanoidins were thermally degraded, with subsequent identification of the volatiles produced, to obtain and compare the thermal degradation profile of various melanoidins. At first, the volatiles produced from heated glucose/glycine standard melanoidins were compared with glucose/glutamic acid and L-(+)-ascorbic acid/glycine standard melanoidins. In the headspace of heated glucose/glycine melanoidins, mainly furans, were detected, accompanied by carbonyl compounds, pyrroles, pyrazines, pyridines, and some oxazoles.

Flavor release in the presence of melanoidins prepared from L-(+)-ascorbic acid and amino acids.

High-molecular-weight (HMW) water-soluble melanoidins were prepared from model systems of L-(+)-ascorbic acid-glycine, L-(+)-ascorbic acid-lysine, L-(+)-ascorbic acid-glutamic acid, and glucose-glycine using a very recently approved standard protocol. The amount of HMW water-soluble melanoidins prepared from L-(+)-ascorbic acid was over 5-15 times higher than the amount obtained from glucose. The study of the release of a model flavor compound, namely isoamyl acetate, from melanoidins by solid-phase microextraction (SPME) showed that SPME is a suitable technique for the analysis of flavor release from melanoidin-containing solutions.

Thermal degradation studies of glucose/glycine melanoidins.

Nondialyzable and water-insoluble melanoidins, isolated from a glucose/glycine model reaction mixture, which was prepared in a standardized way according to the guidelines of the COST Action 919, were heated at different temperatures ranging from 100 to 300 degrees C. Among the volatile compounds, which were analyzed by SPME and GC-MS, pyrazines, pyridines, pyrroles, and furans were detected. In general, total amounts of volatile compounds increased with the temperature.

Synthesis of 4,4-Disubstituted beta-Lactams by Regiospecific Electrophile- and Silver-Induced Ring Expansion of 2,2-Disubstituted 1-Methoxycyclopropylamines.

2,2-Disubstituted 1-methoxycyclopropylamines underwent regiospecific ring expansion to 1,4,4-trisubstituted 2-azetidinones by N-chlorination with tert-butyl hypochlorite and subsequent rearrangement with silver tetrafluoroborate. Upon thermolysis, 4,4-disubstituted beta-lactams suffer a characteristic ring opening to afford beta,gamma-unsaturated carboxylic amides. The reduction of 1,4,4-trisubstituted 2-azetidinones with lithium aluminum hydride afforded 1,2,2-trisubstituted azetidines.