Synthesis of trifluoromethylated 2H-azirines through Togni reagent-mediated trifluoromethylation followed by PhIO-mediated azirination.
ABSTRACT: The reaction of enamine compounds with the Togni reagent in the presence of CuI afforded ?-trifluoromethylated enamine intermediates, which were converted directly to biologically interesting trifluoromethylated 2H-azirines by an iodosobenzene (PhIO)-mediated intramolecular azirination in a one-pot process.
Project description:2H-Azirines are versatile coupling partners for the synthesis of N-heterocycles. Herein, we present our studies on the reactivity of Cp2Ti(BTMSA) (1; BTMSA = bis(trimethylsilyl)acetylene) with a variety of azirines. In all the cases examined, the initial organometallic products formed are diazatitanacyclohexenes, presumably formed via oxidative addition of Ti(II) into the C-N bond of the azirine to form an azatitanacyclobutene intermediate, followed by C?N insertion of a second equivalent of azirine into the Ti-C bond to form the observed products. Diazatitanacyclohexene 3, bearing phenyl substituents and derived from 2,3-diphenyl-2H-azirine, fragments to form an azabutadiene and nitrile, which is shown to be catalytic in the presence of excess 2,3-diphenyl-2H-azirine. H-substituted complex 8, derived from 3-phenyl-2H-azirine, decomposes via protonolysis of the Cp ligands. In contrast, the methyl-substituted diazatitanacyclohexene 10, derived from 2-methyl-3-phenyl-2H-azirine, is thermally robust. Attempts to trap the putative azatitanacyclobutene intermediate with an alkyne were unsuccessful, resulting instead in the formation of titanacyclopentadiene (12) from coupling of alkyne with BTMSA. Initial reactivity studies found that 10 could be protonolyzed with AcOH to form mixtures of pyrrole and aziridine products, whereas reacting 10 with MeOH results solely in the formation of 2,4-dimethyl-3,5-diphenyl-1H-pyrrole.
Project description:Copper-mediated trifluoromethylation of unsaturated organotrifluoroborates with the Langlois reagent (NaSO2CF3) and TBHP allows the introduction of trifluoromethyl groups into a variety of organic substructures. The reactions are easy to set up, the conditions are mild and general, and the process provides access to trifluoromethylated alkynes, alkenes, arenes, and heteroarenes in fair to good yields.
Project description:We herein describe an unprecedented 1,2-bis(trifluoromethylation) of arynes with [CuCF3] in the presence of an oxidant DDQ. The method allows the rapid construction of a new class of 1,2-bis(trifluoromethyl)arenes in one-step from aryne precursors under mild conditions. Its synthetic utility has been demonstrated in the preparation of bis(trifluoromethylated) molecules with potential pharmaceutical and materials science applications. Mechanistic studies indicated the presence of an o-trifluoromethyl aryl radical intermediate via CF3 group transfer from [CuCF3] to the aryne.
Project description:An efficient palladium-catalyzed Heck-type reaction of secondary trifluoromethylated alkyl bromides has been developed. The reaction proceeds under mild reaction conditions with high efficiency and excellent functional group tolerance, even towards formyl and hydroxy groups. Preliminary mechanistic studies reveal that a secondary trifluoromethylated alkyl radical is involved in the reaction.
Project description:Chiral aziridines are structure units found in many biologically active compounds and are important building blocks in organic synthesis. Herein, by merging nucleophilic generation through copper(I)-catalyzed decarboxylation and activation of poorly electrophilic 2H-azirines through protonation with carboxylic acids, an asymmetric decarboxylative Mannich reaction between α,α-disubstituted cyanoacetic acids and 2H-azirines is uncovered, which leads to generation of chiral aziridines containing vicinal tetrasubstituted and acyclic quaternary stereogenic carbon centers in good to excellent diastereo- and enantioselectivities. At last, transformations of the produced chiral aziridine are successfully carried out to deliver synthetically useful compounds.
Project description:A new approach toward the asymmetric synthesis of optically active trifluoromethylated amines was enabled by an unprecedented, highly enantioselective catalytic isomerization of trifluoromethyl imines with a new chiral organic catalyst. Not only aryl but also alkyl trifluoromethylated amines could be obtained in high enantioselectivities.
Project description:Strained azirinium ylides derived from 2H-azirines and ?-diazoketones under Rh(II)-catalysis can undergo either irreversible ring opening across the N-C2 bond to 2-azabuta-1,3-dienes that further cyclize to 2H-1,4-oxazines or reversibly undergo a 1,5-cyclization to dihydroazireno[2,1-b]oxazoles. Dihydroazireno[2,1-b]oxazoles derived from 3-aryl-2H-azirines and 3-diazoacetylacetone or ethyl diazoacetoacetate are able to cycloadd to acetyl(methyl)ketene generated from 3-diazoacetylacetone under Rh(II) catalysis to give 4,6-dioxa-1-azabicyclo[3.2.1]oct-2-ene and/or 5,7-dioxa-1-azabicyclo[4.3.1]deca-3,8-diene-2-one derivatives. According to DFT calculations (B3LYP/6-31+G(d,p)), the cycloaddition can involve two modes of nucleophilic attack of the dihydroazireno[2,1-b]oxazole intermediate on acetyl(methyl)ketene followed by aziridine ring opening into atropoisomeric oxazolium betaines and cyclization. Azirinium ylides generated from 2,3-di- and 2,2,3-triaryl-substituted azirines give rise to only 2-azabuta-1,3-dienes and/or 2H-1,4-oxazines.
Project description:3-Aryl-2H-azirines react with acylketenes, generated by thermolysis of 5-arylfuran-2,3-diones, to give bridged 5,7-dioxa-1-azabicyclo[4.4.1]undeca-3,8-diene-2,10-diones and/or ortho-fused 6,6a,12,12a-tetrahydrobis[1,3]oxazino[3,2-a:3',2'-d]pyrazine-4,10-diones. The latter compounds, with a new heterocyclic skeleton, are the result of the coupling of two molecules of azirine and two molecules of acylketene and can be prepared only from 3-aryl-2H-azirines having no electron-withdrawing groups in the aryl substituent. Calculations at the DFT B3LYP/6-31G(d) level for the various routes of bis[1,3]oxazino[3,2-a:3',2'-d]pyrazine skeleton formation revealed a new domino reaction of 3-aryl-2H-azirines occurring in the presence of furandiones: acid-catalyzed dimerization to dihydropyrazine followed by consecutive cycloaddition of the latter to two molecules of acylketenes.
Project description:RBF3 K is a chemist's BFF: A metal-free synthetic route to unprecedented organoboron compounds bearing an ?-trifluoromethyl substituent, employing a variety of trifluoroborate (RBF3 K) starting materials, is reported. These substrates represent the first isolated ?-trifluoromethylated alkylboron building blocks, and these reagents lead to a variety of useful bench-stable, synthetic intermediates. Pin=pinacol.
Project description:We report the synthesis, characterization, and reactivity of [LFe3 (PhPz)3 OMn(s PhIO)][OTf]x (3: x=2; 4: x=3), where 4 is one of very few examples of iodosobenzene-metal adducts characterized by X-ray crystallography. Access to these rare heterometallic clusters enabled differentiation of the metal centers involved in oxygen atom transfer (Mn) or redox modulation (Fe). Specifically, 57 Fe Mössbauer and X-ray absorption spectroscopy provided unique insights into how changes in oxidation state (FeIII2 FeII MnII vs. FeIII3 MnII ) influence oxygen atom transfer in tetranuclear Fe3 Mn clusters. In particular, a one-electron redox change at a distal metal site leads to a change in oxygen atom transfer reactivity by ca. two orders of magnitude.