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. The synthetic utility of the current method is further demonstrated by the transformation of the obtained benzophenone ketimines into N-unprotected homoallylamines, an α-amino alcohol and an α-amino amide.

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 anti-tubercular activity against Mycobacterium tuberculosis H37Ra and acute cytotoxicity against J774 A.1 macrophages were studied. From the structure activity relationship, it could be derived that in general the substitution of position 3 yielded analogs with a higher antitubercular potency. Among these, two analogs, 27a and 27b, showed remarkable activity with minimal inhibition concentrations of respectively 28.92 µM and 1.05 µM, and acute cytotoxic concentrations of >128 µM and 34.85 µM. In addition, the analogs and their possible metabolites were evaluated using a Vitotox™ assay to study the possibility of genotoxicity. Results indicated that none of the evaluated analogs and their possible metabolites showed early signs of genotoxicity.

Synthesis of highly functionalized 1,6-dihydropyridines via the Zn(OTf)2-catalyzed three-component cascade reaction of aldimines and two alkynes (IA2-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. The reaction proceeds via a cascade reaction involving nucleophilic addition of the metal acetylide to the imine, followed by the addition of the intermediately formed propargylic amine to the electron-deficient alkyne and subsequent 6-endo dig cyclization.

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 ß,ß-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. In the present approach, terminal alkynes were used as a source of the vinyl residue, and the N-alkyl moiety of the imine acts as a sacrificial hydrogen donor. The additional advantage of this methodology is the fact that no external toxic or hazardous reducing agents or molecular hydrogen has to be used. This new methodology nicely combines a C(sp(2) )C(sp) bond formation, hydride transfer, and an unusual cleavage of an unactivated CN bond, thereby giving rise to functionalized primary allylic amines. A detailed experimental study supported by DFT calculations of the mechanism has been done.

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.

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. P. entomophila produces two siderophores, a structurally new and unique pyoverdine and the secondary siderophore pseudomonine, already described in P. fluorescens species. Structural analysis of the pyoverdine produced by the closely related P. putida KT2440 showed that this strain produces an already characterised pyoverdine, but different from P. entomophila, and no evidence was found for the production of a second siderophore. Growth stimulation assays with heterologous pyoverdines demonstrated that P. entomophila is able to utilize a large variety of structurally distinct pyoverdines produced by other Pseudomonas species. In contrast, P. putida KT2440 is able to utilize only its own pyoverdine and the pyoverdine produced by P. syringae LMG 1247. Our data suggest that although closely related, P. entomophila is a more efficient competitor for iron than P. putida.

Lewis acidic FeCl3 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 via a cationic 2-aza-Cope rearrangement of aldimines, generated in situ 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, i.e. dimethyl carbonate.

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.

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.

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.

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. Heating of L-(+)-ascorbic acid/glycine melanoidins resulted in relatively more N-heterocycles, while from glucose/glutamic acid melanoidins no N-heterocycles were formed. In a second part, a chemical treatment was applied to glucose/glycine melanoidins prior to the thermal degradation. Acid hydrolysis was performed to cleave glycosidically linked sugar moieties from the melanoidin skeleton. Nonsoluble glucose/glycine melanoidins were also subjected to an oxidation. The results indicate that the thermal degradation profile is a useful tool in the characterization of different types of melanoidins.

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). These melanoidin fractions were produced from the condensation of glucose with glycine and their separation was conducted by dialysis. The crude reaction mixture (before dialysis) and both the LMW and HMW fractions obtained by dialysis showed no genotoxicity in these assays, despite being tested at concentrations much higher than those naturally found in food products. The LMW fraction, however, showed toxicity at these high concentrations. The volatile fraction produced in this reaction showed genotoxicity only in the Vitotox test, at high concentrations.