Metal catalyzed multicomponent syntheses of secondary propargylamides and oxazoles from silylimines, acid chlorides, and alkynes

Copper(I) and zinc(II) catalyzed routes to construct secondary propargylamides in one-pot procedures from aldehydes, LiN(TMS)₂, acid chlorides, and alkynes are described. This reaction has been subsequently used to provide a one-pot synthesis of oxazoles from four simple building blocks.     

Triflic anhydride-mediated synthesis of oxazoles

N-Acyl amino acid esters undergo triflic anhydride-mediated cyclodehydration to form oxazoles and bisoxazoles in a simple one-pot transformation.     

A new synthesis of oxazoles

Oxazoles are prepared from the ketoximes in a single pot sequence.     

TBHP/I2-mediated domino oxidative cyclization for one-pot synthesis of polysubstituted oxazoles

A facile type of one-pot, transition-metal-free domino process was developed for the synthesis of oxazoles. Thus, a variety of polysubstituted oxazoles were easily synthesized via t-BuOOH/I(2)-mediated domino oxidative cyclization from readily available starting materials under mild conditions.     

Asymmetric synthesis of propargylamides via 3,3'-disubstituted binaphthol-modified alkynylboronates

[reaction: see text] Alkynylboronates derived from 3,3'-disubstituted-2,2'-binaphthols react with various N-acylimines to give the expected chiral propargylamides with up to 99% ee. This new methodology was applied to the first enantioselective synthesis of the antitubulin agent (-)-N-acetylcolchinol.     

A silver-mediated one-step synthesis of oxazoles

A silver-mediated one-step procedure to 2,4-disubstituted and 2,4,5-trisubstituted oxazoles has been developed. The method is complementary to existing technologies, yet provides advantages with regard to simplicity, efficiency, and performance. The silver product can be readily recycled, thus minimizing waste.     

One-pot synthesis of oxazoles using isocyanide surrogates

We wish to present herein a simple one-pot synthesis of 2,5-disubstituted oxazoles, starting from benzyl halides and acyl chlorides. The in situ formation of isocyanides, followed by the addition of an acyl chloride in the presence of a base leads to the desired oxazoles in good yields.     

A versatile synthesis of 2,4-substituted oxazoles

A variety of five-membered ring oxazoles have been synthesised with complete regiocontrol and without the requirement for ring oxidation via a reaction sequence based on a vinyl sulfonamide template.     

PIFA-mediated oxidative cycloisomerization of 2-propargyl-1,3-dicarbonyl compounds: divergent synthesis of furfuryl alcohols and furfurals

PhI(OCOCF₃)₂ (PIFA) in the presence of trifluoroacetic acid (TFA) in CH₂Cl₂ efficiently promotes the oxidative cycloisomerization of 2-propargyl 1,3-dicarbonyl compounds to give 4,5-disubstituted furfuryl alcohols. PIFA in hexafluoroisopropanol (HFIP) or PIFA-BF₃·OEt₂ in CH₂Cl₂ bring about the direct formation of furfurals from 2-propargyl 1,3-dicarbonyl compounds. In a few cases, PhIO is suitable for the direct formation of furfurals.     

Gold-catalysed synthesis of amino acid-derived 2,5-disubstituted oxazoles

Amino acid-derived propargylic amides are cyclised in a one-pot, Au(III)-catalysed operation to yield 5-bromomethyl oxazoles. These compounds are further elaborated to bis-heterocycles, dipeptide mimics and more.     

Gold-catalyzed oxazoles synthesis and their relevant antiproliferative activities

Nine 5-aryl-2-methyloxazole derivatives were synthesized via gold-catalyzed alkyne oxidation. All of the compounds have been screened for their antiproliferative activities against MCF-7 cell （human breast carcinoma）, A549 cell （human lung carcinoma） and Hela cell （human cervical carcinoma） lines in vitro. The results revealed that compounds 1b, 1c and 1d exhibited strong inhibitory activities against the MCF-7 cell lines （with ICso values of 4.6, 9.7 and 2.2 μmol/L, respectively）.     

Copper(II)-mediated oxidative cyclization of enamides to oxazoles

The copper(II)-mediated oxidative cyclization of enamides to oxazoles is reported. A range of 2,5-disubstituted oxazoles were prepared in moderate to good yields in two steps from simple amide and alkyne precursors.     

Fully automated continuous flow synthesis of 4,5-disubstituted oxazoles

[Structure: see text] A multipurpose mesofluidic flow reactor capable of producing gram quantities of material has been developed as an automated synthesis platform for the rapid on-demand synthesis of key building blocks and small exploratory libraries. The reactor is configured to provide the maximum flexibility for screening of reaction parameters that incorporate on-chip mixing and columns of solid supported reagents to expedite the chemical syntheses.     

5-(hydroxymethyl)oxazoles: versatile scaffolds for combinatorial solid-phase synthesis of 5-substituted oxazoles

A scheme combining the preparation of building blocks in solution followed by solid-phase combinatorial chemistry has been developed to side-chain diversify 5-(hydroxymethyl)oxazole scaffold (1) into aryl ethers, thioethers, sulfones, sulfonamides, and carboxamides. Protected heterocyclic scaffolds 2 were linked to the solid phase and N-terminal derivatized using active ester chemistry, providing chemset 4?1-4,1-4?. The free side-chain hydroxyl of 4 was smoothly converted to aryl ethers 6 under Mitsunobu conditions, with a broad range of substituted phenols. Alternatively, quantitative conversion of hydroxyl to bromide followed by displacement with alkyl and aryl thiols gave thioethers 8. Thioethers were optionally oxidized to sulfones 9. Bromide displacement by azide, followed by reduction to amine and acylation with a range of carboxylic acids and sulfonyl chlorides gave carboxamides 11 and sulfonamides 13, respectively. Crude purity at typically >90% was observed for each of the five modifications detailed. A series of 20 compounds, exemplifying each modification, was reprepared, purified, and fully characterized.     

Efficient synthesis of multi-substituted oxazoles under solvent-free microwave irradiation

A new and efficient method for the synthesis of multi-substituted oxazoles from various carbonyl compounds has been developed using sequential treatment of carbonyl compounds with HDNIB and amides such as acetamide or benzamide under solvent-free microwave irradiation conditions.     

PdCl2-catalyzed oxidative cycloisomerization of 3-cyclopropylideneprop-2-en-1-ones

A novel PdCl(2)-catalyzed oxidative cycloisomerization of 3-cyclopropylideneprop-2-en-1-ones, providing a facile synthesis of highly strained functionalized 2-alkylidenecyclobutanones via furan-fused cyclobutene intermediates, is reported. An interesting route to 2(3H)-furanones with a spiro-cyclopropane unit from the obtained 2-alkylidenecyclobutanones via a ring-contraction rearrangement reaction is also realized.     

Trifluoroacetic anhydride-mediated solid-phase version of the Robinson-Gabriel synthesis of oxazoles

A traceless solid-phase synthesis of oxazoles 4 via Robinson-Gabriel reaction of solid-supported alpha-acylamino ketones 2 has been achieved. The reaction requires that the cyclization precursor be linked to a benzhydrylic-type linker (compounds 2) and that trifluoroacetic anhydride be used as the cyclodehydrating agent. The solvent has a dramatic effect on the latter reaction, which goes to completion and follows a cyclative-type mechanism only when an ethereal solvent is used. Different synthetic routes have been investigated toward assembling compounds 2. The most straightforward one, which we have validated more extensively, comprises the reaction of Merrifield alpha-methoxyphenyl (MAMP) resin with an alpha-amino ketone to form compounds 1, which are, in turn, acylated. Other methodologies and strategies allowing for the synthesis of compounds 1 that have been investigated include direct alkylation of Rink amide resin; reductive amination of the latter with alpha-keto aldehydes; reaction of MAMP resin with alpha-amino alcohols, followed by oxidation; and protection of Rink amide resin with either 2,4-dinitrosulfonyl or allyl group, followed by alkylation and removal of protecting group. In addition, we disclose a novel variant of the Ugi four-component reaction that allows for the preparation of compounds 2 in a single synthetic step.     

A Ru catalyzed divergence: oxidative cyclization vs cycloisomerization of bis-homopropargylic alcohols

During the course of investigating the development of catalytic reactions involving ruthenium vinylidene intermediates, a novel divergence of reactivity was discovered. The oxidative cyclization of bis-homopropargylic alcohols with Ru(+2) complexes as catalysts and N-hydroxysuccinimide as oxidant, which requires formation of a ruthenium vinylidene intermediate, is complicated by the simple electrophilically initiated direct attack of the hydroxyl group on a pi-complex of the alkyne and ruthenium. A catalytic system composed of CpRu[(p-CH(3)O(6)H(4))(3)P](2)Cl and excess (p-CH(3)O-C(6)H(4))(3)P directs the reaction toward the oxidative cyclization to form delta-lactones in good yields. Significantly, a simple switch of catalyst to CpRu[(p-FC(6)H(4))(3)P](2)Cl redirects the reaction to a cycloisomerization to form dihydropyrans in good yields. The synthetic utility of the oxidative cyclization is illustrated by the synthesis of oviposition attractant pheromone of the mosquito Culex pipens. The utility of the cycloisomerization to dihydropyrans is demonstrated by an iterative process leading to the antiviral agent narbosine B. A rationale for this dramatic switch by simple ligand modification is proposed.     

One-pot Friedel-Crafts/Robinson-Gabriel synthesis of oxazoles using oxazolone templates

[reaction: see text] We report herein a one-pot synthesis of 2,4,5-trisubstituted oxazoles via a Friedel-Crafts/Robinson-Gabriel synthesis using a general oxazolone template. Treatment of the oxazolone template with a range of aromatic nucleophiles provided the highly substituted oxazoles in good yields.