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Aseries of 1-(2-aryloxy-2-phenylethyl)-1,2,3-triazole derivatives (Miconazole analogs) was obtained via copper catalyzed azide-alkyne cycloaddition as the key step. The synthesized compounds were evaluated for antimicrobial activity against Candida genus strains as well as filamentous fungi (Mucor hiemalis, Aspergillus fumigatus and Rhizopus oryzae). A 1-(2-aryloxy-2-phenylethyl)-1,2,3-triazole derivative exhibited remarkable selectivity comparable to that of Itraconazole against Rhizopus oryzae.

Chalcones are aromatic ketones found in nature as the central core of many biological compounds. They have a wide range of biological activity and are biogenetic precursors of other important molecules such as flavonoids. Their pharmacological relevance makes them a privileged scaffold, advantageous for seeking alternative therapies in medicinal chemistry. Due to their structural diversity and ease of synthesis, they are often employed as building blocks for chemical transformations. Chalcones have a carbonyl conjugated system with two electrophilic centers that are commonly used for nucleophilic additions, as described in numerous articles. They can also participate in Diels-Alder reactions, which are [4+2] cycloadditions between a diene and a dienophile. This microreview presents a chronological survey of studies on chalcones as dienes and dienophiles in Diels-Alder cycloadditions. Although these reactions occur in nature, isolation of chalcones from plants yields very small quantities. Contrarily, synthesis leads to large quantities at a low cost. Hence, novel methodologies have been developed for [4+2] cycloadditions, with chalcones serving as a 2π or 4π electron system.

A series of highly potent antihyperlipidemic agents constituted by a fibrate-based structure was recently reported by our group, whose synthesis started from isovanillin derivatives. In the interest of evaluating the bioisosteric effect of the vanillin-based isomers on their antihyperlipidemic activity, the present study focuses on the synthesis of 5-acyl-1-phenoxyacetic methyl esters 5a–c and their saturated side-chain 5-alkyl-1-phenoxyacetates 6a–c. Their strong in vivo effect was associated with the inhibition of HMG-CoA reductase. Since 1,2-dihydroquinolines inhibit this enzyme, a series of such heterocycles (9a–d) was prepared by our efficient regioselective, one-step, solvent-free method. Apart from showing hypolipidemic activity in vivo, some of the compounds displayed antifungal, antioxidant and cytotoxic activity in vitro. The binding mode of four compounds at the active site of HMGRh was examined with docking simulations, observing an interaction with most of the amino acids targeted by simvastatin.

A small series of 4′-substituted 1,3-bis-1,2,3-triazol-1-yl-propan-2-ol compounds was prepared via CuAAC click reaction of 1,3-diazido-2-propanol and various alkynes R. Antifungal evaluation of these molecules revealed important activity against some yeast strains, and one compound (R = Ph) displayed antifungal activity comparable with that of fluconazole standard.

The synthesis of novel of 4,5,6,7-tetrahydrobenzoxazol-2-ones is herein reported. They were obtained in moderate to good yields by a highly regio- and stereoselective Diels-Alder cycloaddition of N-substituted exo-oxazolidin-2-one dienes with chalcones or bis-chalcones as dienophiles.

Long range 5J and 6J (1H 19F) spin-spin coupling constants for a set of nine biarylic fluorinated derivatives were determined by 1H NMR experiments. The quantitation of these long-range 5J and 6J (1H 19F) coupling can be found through the measure of the residual coupling-signals obtained after the selective decoupling process. The information obtained for the NMR spectra was confirmed through computational studies.

A library of novel benzylic 1,2,3-triazole-4-carboxamides (3a-m) were obtained with acceptable yields via a one-pot procedure. The series of compounds was screened for fungicidal activity and evaluated in vitro against four filamentous fungi and four Candida species. The former consisted of Aspergillus fumigatus, Trichosporon cutaneum, Rhizopus oryzae and Mucor hiemalis, and the latter C. krusei, C. albicans, C. utilis and C. glabrata. According to the in vitro assays, 3d and 3e were the most efficient fungicidal agents (of all the test compounds) against R. oryzae, even better than the reference drug (itraconazole). Thus, 3d and 3e represent important scaffolds that can be modified to increase antifungal activity. Additionally, they are candidates for complementary studies on the inhibition of clinical infections produced by Rhizopus spp. strains. Resumen. Se obtuvo una librería de nuevos bencil 1,2,3-triazoles-4-carboxamidas (3a-m) con rendimientos aceptables mediante un procedimiento one-pot. La serie de compuestos se seleccionó para determinar la actividad fungicida llevando a cabo una evaluación in vitro contra cuatro hongos filamentosos y cuatro especies de Candida. Los primeros consistieron en Aspergillus fumigatus, Trichosporon cutaneum, Rhizopus oryzae y Mucor hiemalis, mientras que para las segundas especies, esta fueron C. krusei, C. albicans, C. utilis y C. glabrata. Según los ensayos in vitro, 3d y 3e fueron los agentes fungicidas más eficaces (de todos los compuestos de prueba) contra R. oryzae, incluso mejores que el fármaco de referencia (itraconazol). Por tanto, 3d y 3e representan importantes núcleos que podrían modificarse para aumentar la actividad antifúngica, siendo excelentes candidatos para estudios complementarios sobre la inhibición de infecciones clínicas producidas por Rhizopus spp.

Novel oxazolidin-2-one-linked 1,2,3-triazole derivatives (4a-k) were synthesized by straightforward and versatile azide-enolate (3 + 2) cycloaddition. The series of compounds was screened for antifungal activity against four filamentous fungi as well as six yeast species of Candida spp. According to their efficiency and breadth of scope, they can be ordered as 4k > 4d > 4h > 4a, especially in relation to the activity displayed against Candida glabrata ATCC-34138, Trichosporon cutaneum ATCC-28592 and Mucor hiemalis ATCC-8690, i.e. compounds 4d, 4h and 4k showed excellent activity against C. glabrata (MIC 0.12, 0.25 and 0.12 μg mL-1, respectively), better than that of itraconazole (MIC 1 μg ml-1). The activity of compound 4d (MIC = 2 μg mL-1) was higher than that observed for the standard antifungal drug (MIC = 8 μg mL-1) against Trichosporon cutaneum, while compound 4k displayed an excellent antimycotic activity against Mucor hiemalis (MIC = 2 μg mL-1vs. 4 μg mL-1 for itraconazole). In addition, we describe herein a novel mild and eco-friendly synthetic protocol for obtaining β-ketosulfones (adducts to afford compounds 4a-k) from α-brominated carbonyls in an aqueous nanomicellar medium at room temperature.

The exploration of azide-enolate cycloaddition in the synthesis of novel Rufinamide analogs is reported for the first time. A very simple procedure involving the use of β-ketonitriles as dipolarophiles afforded 5-aril/heteroayl Rufinamide derivatives in two steps.

A small library of diverse 1,1-diaryl-2-(1,2,3)triazol-1-yl-ethanol derivatives was designed and prepared from CuAAC reaction as the key step. The molecular structure of some representative compounds was unambiguously determined from X-ray diffraction studies. In addition, synthesized 1,2,3-triazoles were evaluated for activity against filamentous fungi (Mucor hiemalis, Aspergillus fumigatus, Trichosporon cutaneum, and Rhizopus oryzae) and yeasts that belong to the genus Candida. Two compounds showed high activity against C. utilis (MIC 0.5 $$\upmu \mathrm{{g/mL}}$$ ) and A. fumigatus (MIC 4 $$\upmu \mathrm{{g/mL}}$$ ) which is close to itraconazole used as reference compound. 1,1-diaryl-2-(1,2,3)triazol-1-yl-ethanol analogues to flutriafol were prepared from CuAAC reaction and the molecular structure of some representative compounds was unambiguously determined from X-ray diffraction studies. Some of these 1,2,3-triazoles displayed activity against filamentous fungi and Candida yeasts, especially C. utilis and A. fumigatus.

A simple procedure to prepare 1,5-disubstituted 1,2,3-triazoles efficiently from alkyl/aryl azides and β-ketophosphonates in the presence of KOH by an azide–enolate 1,3-dipolar cycloaddition in good yields was developed.

We report that the benzyl azido group is directly converted to carbonyls in good yields through a rapid hydrolysis (basic conditions) of benzylideneamides generated readily/efficiently in situ under a very simple procedure involving conventional reagents.

Four novel miconazole analogues ( 8 – 11 ) were synthetized and evaluated for activity against four filamentous fungi ( Mucor hiemalis , Aspergillus fumigatus , Trichosporon cutaneum , and Rhizopus oryzae ) and eight species of Candida as yeast specimens. Compounds 9 and 10 showed very good activity when evaluated in yeast (MIC 0.112 and 0.163 μg/mL) compared to the reference compound, itraconazole (MIC 0.067 μg/mL). The best antifungal activity in filamentous strains was shown by compound 9 . Hence compounds 9 and 10 represent new leads for further pharmacomodulation in this series.

The preparation of 1,4,5-trisubstituted 1,2,3-triazoles by the coupling of three components (alkyl halides, sodium azide, and active ketones) through an azide–enolate [3+2] cycloaddition (Dimroth cycloaddition) has been developed for the first time. A wide variety of halides (including chlorides, bromides, and iodides as well as primary and secondary derivatives) have demonstrated the versatility of this method, which is based on a one-pot system under mild reaction conditions.

A simple one-pot procedure has been developed to efficiently prepare 1,4,5-trisubstituted 1,2,3-triazoles from benzylic alcohols. The presence of diphenylphosphoryl azide (DPPA) and active ketones allows for an azide–enolate [3+2] cycloaddition by use of DBU.

The reaction of benzylic azides (I) and (III) with NaH leads to intermediate benzylideneamides, which react with water to afford aldehydes (II) and ketones (IV), respectively.

A simple procedure to prepare 1,5-disubstituted 1,2,3-triazoles efficiently from alkyl/aryl azides and β-ketophosphonates in the presence of KOH by an azide–enolate 1,3-dipolar cycloaddition in good yields was developed.

A new method for the synthesis of 4-oxazolin-2-ones by a one-pot MW-promoted condensation of α-ketols and isocyanates is reported. An alternative thermal approach using the same starting materials is also described. These cyclic enamides were efficient nucleophiles, reacting with Michael acceptors and prenyl bromide to give a variety of polycyclic structures bearing one or two quaternary stereocenters. The selectivity of the products depended on the reaction conditions and on the electrophile used.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

An efficient and simple synthesis of highly substituted 9-ethoxy-3-phenyl-3H-fluorene[3,2-d]oxazol-2-(4H,9H,10H)-one derivatives 10a−f by a tandem [4 + 2] cycloaddition/cyclopentannulation process of Fischer (arylethynyl)(ethoxy)carbene complexes (CO)5M═C(C≡CC6H4-R)OCH2CH3 (1a, M = Cr, R = H; 1b, M = Cr, R = p-CH3; 1c, M = Cr, R = p-OCH3; 1d, M = W, R = H; 1e, M = W, R = p-CH3; 1f, M = W, R = p-OCH3) with exo-2-oxazolidinone dienes 7a−d is described. A study of reactivity as well as regio- and stereoselectivity in a tandem process of the Fischer carbene complexes 1 with the exo-heterocyclic dienes 7 was carried out. The cycloadditions were found to be highly regioselective, favoring the para cycloadducts, and highly stereoselective, giving the trans diastereoisomers. The stereochemical assignment of the cycloadducts was supported by NOE measurements, and the derivatives 10b,c,e were further characterized by single crystal X-ray diffraction. A rationalization of the regioselectivity was carried out through...

Seven miconazole analogs involving 1,4,5-tri and 1,5-disubstituted triazole moieties were synthesized by azide-enolate 1,3-dipolar cycloaddition. The antifungal activity of these compounds was evaluated in vitro against four filamentous fungi, including Aspergillus fumigatus, Trichosporon cutaneum, Rhizopus oryzae, and Mucor hiemalis as well as three species of Candida spp. as yeast specimens. These pre-clinical studies suggest that compounds 4b, 4d and 7b can be considered as drug candidates for future complementary biological studies due to their good/excellent antifungal activities.

A convenient one-pot procedure for the [3 + 2] cycloaddition reaction of in situ generated organic azides with enolates to produce triazoles in good yields is presented.

While (Ia) gives the exo-adduct (IIIa) as the single product, (Ib)—(Id) and (V) give exo/endo mixtures.

DBU promoted [3 + 2] cycloaddition of in situ generated azides and enolates gives highly functionalized triazoles under mild conditions.

The rhodium(II)-catalysed reaction of the diazoketone derived from 5-(4-methoxybenzoyl)-2,3-dihydropyrrolizin-1-carboxylic acid (anirolac) did not give the expected intramolecular cyclisation product but afforded the 2,3-dihydropyrrolizin-1-one only an elimination product. X-ray studies confirmed the structure.

A new method for the synthesis of 4-oxazolin-2-ones by a one-pot MW-promoted condensation of α-ketols and isocyanates is reported. An alternative thermal approach using the same starting materials is also described. These cyclic enamides were efficient nucleophiles, reacting with Michael acceptors and prenyl bromide to give a variety of polycyclic structures bearing one or two quaternary stereocenters. The selectivity of the products depended on the reaction conditions and on the electrophile used.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

An efficient and simple synthesis of highly substituted 9-ethoxy-3-phenyl-3H-fluorene[3,2-d]oxazol-2-(4H,9H,10H)-one derivatives 10a−f by a tandem [4 + 2] cycloaddition/cyclopentannulation process of Fischer (arylethynyl)(ethoxy)carbene complexes (CO)5M═C(C≡CC6H4-R)OCH2CH3 (1a, M = Cr, R = H; 1b, M = Cr, R = p-CH3; 1c, M = Cr, R = p-OCH3; 1d, M = W, R = H; 1e, M = W, R = p-CH3; 1f, M = W, R = p-OCH3) with exo-2-oxazolidinone dienes 7a−d is described. A study of reactivity as well as regio- and stereoselectivity in a tandem process of the Fischer carbene complexes 1 with the exo-heterocyclic dienes 7 was carried out. The cycloadditions were found to be highly regioselective, favoring the para cycloadducts, and highly stereoselective, giving the trans diastereoisomers. The stereochemical assignment of the cycloadducts was supported by NOE measurements, and the derivatives 10b,c,e were further characterized by single crystal X-ray diffraction. A rationalization of the regioselectivity was carried out through...

The rhodium(ll)-catalysed reaction of the diazoketone derived from 5-(4-methoxybenzoyl)-2,3-dihydropyrrolizin-1-carboxylic acid (anirolac) did not give the expected intramolecular cyclisation product but afforded the 2,3-dihydropyrrolizin-1-one only an elimination product. X-ray studies confirmed the structure.

Caffeine is one of the most widely consumed, naturally occurring, mild, and central nervous system stimulants. Its synthesis, by the N-methylation (SN2 substitution) of theobromine is described as an experiment for the undergraduate organic chemistry laboratory. The N-methylation of theobromine is rapid and efficient and its progress is monitored by TLC using authentic standards. The undergraduate student also is able to observe the effect of temperature on the rate of the N-methylation reaction.