protocol-for-synthesis-ortho-trifluoromethoxylated-aniline

Protocol for the Synthesis of <em>Ortho</em>-trifluoromethoxylated Aniline Derivatives

Molecules bearing trifluoromethoxy (OCF3) group often show desired pharmacological and biological properties. However, facile synthesis of ...

State University of New York at Stony Brook

Catalytic hydrogenation of 1,3-enynes 1a-7a in the presence of ethyl pyruvate and related activated ketones using chirally modified cationic rhodium catalysts results in reductive coupling to afford dienylated alpha-hydroxy esters 1b-7b and 3c-3f with exceptional levels of regio- and enantiocontrol. These studies represent the first highly enantioselective direct catalytic reductive couplings of alkynes to ketones. As illustrated by the conversion of 6b to 6c-6h, the diene containing the side chain of the coupling products is subject to diverse chemo- and regioselective manipulation. Reductive coupling of enyne 6a and ethyl pyruvate using elemental deuterium provides the monodeuterated product deuterio-6b, consistent with a catalytic mechanism involving alkyne-carbonyl oxidative coupling followed by hydrogenolytic cleavage of the resulting oxametallacycle, as corroborated by ESI-MS analysis.

Highly enantioselective direct reductive coupling of conjugated alkynes and alpha-ketoesters via rhodium-catalyzed asymmetric hydrogenation.

Iridium-catalyzed C-C bond forming hydrogenation: direct regioselective reductive coupling of alkyl-substituted alkynes to activated ketones.

Hydrogen-mediated C-C bond formation: a broad new concept in catalytic C-C coupling.

Allylic amines via iridium-catalyzed C-C bond forming hydrogenation: imine vinylation in the absence of stoichiometric byproducts or metallic reagents.

Hydrogenation of alkynes in the presence of carbonyl compounds and imines using cationic rhodium(I) and iridium(I) precatalysts enables the formation of allylic alcohols and allylic amines, respectively. Through the use of hydrogenation catalysts modified by chiral ligands, allylic alcohols and allylic amines may be generated in highly optically enriched forms. Hydrogenative fragment couplings of this type circumvent the use of preformed organometallic reagents and avoid the generation of stoichiometric byproducts.

Enantiomerically enriched allylic alcohols and allylic amines via C-C bond-forming hydrogenation: asymmetric carbonyl and imine vinylation.

Enantioselective iridium-catalyzed imine vinylation: optically enriched allylic amines via alkyne-imine reductive coupling mediated by hydrogen.

Protocols for highly enantioselective carbonyl allylation from the alcohol or aldehyde oxidation level are described based upon transfer hydrogenative C-C coupling. Exposure of allyl acetate to benzylic alcohols 1a-i in the presence of an iridium catalyst derived from [IrCl(cod)]2 and (R)-BINAP delivers products of C-allylation 2a-i. Employing isopropanol as terminal reductant, exposure of allyl acetate to aryl aldehydes 3a-i in the presence of an iridium catalyst derived from [IrCl(cod)]2 and (-)-TMBTP delivers identical products of C-allylation 2a-i. In all cases examined, exception levels of enantioselectivity are observed. Thus, enantioselective carbonyl allylation is achieved from the alcohol or aldehyde oxidation level in the absence of any preformed allylmetal reagents. These studies define a departure from preformed organometallic reagents in carbonyl additions that transcend the boundaries of oxidation level.

Enantioselective iridium-catalyzed carbonyl allylation from the alcohol or aldehyde oxidation level using allyl acetate as an allyl metal surrogate.

Under the conditions of ruthenium-catalyzed transfer hydrogenation employing 2-propanol as the terminal reductant, 1,1-disubstituted allenes 1a- h engage in reductive coupling to paraformaldehyde to furnish homoallylic alcohols 2a- h. Under identical transfer hydrogenation conditions, 1,1-disubstituted allenes engage in reductive coupling to aldehydes 3a- f to furnish homoallylic alcohols 4a- n. In all cases, reductive coupling occurs with branched regioselectivity to deliver homoallylic alcohols bearing all-carbon quaternary centers.

Ruthenium catalyzed C-C bond formation via transfer hydrogenation: branch-selective reductive coupling of allenes to paraformaldehyde and higher aldehydes.

Under the conditions of transfer hydrogenation employing an iridium catalyst generated in situ from [Ir(cod)Cl]2, chiral phosphine ligand (R)-BINAP or (R)-Cl,MeO-BIPHEP, and m-nitrobenzoic acid, allyl acetate couples to allylic alcohols 1a-c, aliphatic alcohols 1d-l, and benzylic alcohols 1m-u to furnish products of carbonyl allylation 3a-u with exceptional levels of asymmetric induction. The very same set of optically enriched carbonyl allylation products 3a-u are accessible from enals 2a-c, aliphatic aldehydes 2d-l, and aryl aldehydes 2m-u, using iridium catalysts ligated by (-)-TMBTP or (R)-Cl,MeO-BIPHEP under identical conditions, but employing isopropanol as a hydrogen donor. A catalytically active cyclometallated complex V, which arises upon ortho-C-H insertion of iridium onto m-nitrobenzoic acid, was characterized by single-crystal X-ray diffraction. The results of isotopic labeling are consistent with intervention of symmetric iridium pi-allyl intermediates or rapid interconversion of sigma-allyl haptomers through the agency of a symmetric pi-allyl. Competition experiments demonstrate rapid and reversible hydrogenation-dehydrogenation of the carbonyl partner in advance of C-C coupling. However, the coupling products, which are homoallylic alcohols, experience very little erosion of optical purity by way of redox equilibration under the coupling conditions, although isopropanol, a secondary alcohol, may serve as terminal reductant. A plausible catalytic mechanism accounting for these observations is proposed, along with a stereochemical model that accounts for the observed sense of absolute stereoinduction. This protocol for asymmetric carbonyl allylation transcends the barriers imposed by oxidation level and the use of preformed allyl metal reagents.

Enantioselective iridium-catalyzed carbonyl allylation from the alcohol or aldehyde oxidation level via transfer hydrogenative coupling of allyl acetate: departure from chirally modified allyl metal reagents in carbonyl addition.

An enantioselective propargylation of aldehydes using an allenylzinc reagent generated in situ via a zinc-iodine exchange reaction is described. The enantioselectivity is controlled by addition of a catalytic amount of readily accessible and highly tunable amino alcohol ligand L13. A wide range of aldehydes can be propargylated to afford valuable and versatile homopropargyl alcohols in good to excellent yields with high levels of enantiopurity.

Ligand-accelerated enantioselective propargylation of aldehydes via allenylzinc reagents.

An amine-N-oxide-ligated palladium complex, in conjunction with a silver cocatalyst, catalyzes imidation of arenes by the reagent N-fluorobenzenesulfonimide. The reaction enables imidation of a variety of arenes at or below room temperature, requires no coordinating directing group on the substrate, and gives synthetically useful yields with only 1 equiv of arene. Mechanistic data implicate an unusual mechanism devoid of commonly invoked organometallic intermediates: oxidation of the Pd catalyst occurs as the turnover-limiting step, while C-H bond functionalization occurs subsequently at a high oxidation state of the catalyst.

Pd-catalyzed aryl C-H imidation with arene as the limiting reagent.

Aryl trifluoromethoxylation by a two-step sequence of O-trifluoromethylation of N-aryl-N-hydroxylamine derivatives and intramolecular OCF3  migration is presented. This protocol allows easy access to a wide range of synthetically useful ortho-OCF3 aniline derivatives. In addition, it utilizes bench-stable reagents, is operationally simple, shows high functional-group tolerance, and is amenable to gram-scale as well as one-pot synthesis. A reaction mechanism of a heterolytic cleavage of the NOCF3 bond followed by recombination of the resulting nitrenium ion and trifluoromethoxide is proposed for the OCF3 -migration reaction.

Trifluoromethoxylation of arenes: synthesis of ortho-trifluoromethoxylated aniline derivatives by OCF3 migration.

Leustroducsin B exhibits a large variety of biological activities and unique structural features. An efficient and highly convergent total synthesis of Leustroducsin B was achieved in 17 longest linear and 39 total steps by disconnecting the molecule into three fragments having similar levels of complexity. These pieces were connected via a highly efficient chelate-controlled addition of a vinyl zincate to an α-hydroxy ketone and a silicon-mediated cross-coupling. The stereochemistry of the central and western fragments was set catalytically in high yields and excellent de by a zinc-ProPhenol-catalyzed aldol reaction and a palladium-catalyzed asymmetric allylic alkylation.

Article	Year
Highly enantioselective direct reductive coupling of conjugated alkynes and alpha-ketoesters via rhodium-catalyzed asymmetric hydrogenation. Journal of the American Chemical Society\| PubMed ID: 16417351	2006
Iridium-catalyzed C-C bond forming hydrogenation: direct regioselective reductive coupling of alkyl-substituted alkynes to activated ketones. Journal of the American Chemical Society\| PubMed ID: 17212400	2007
Hydrogen-mediated C-C bond formation: a broad new concept in catalytic C-C coupling. The Journal of organic chemistry\| PubMed ID: 17288361	2007
Allylic amines via iridium-catalyzed C-C bond forming hydrogenation: imine vinylation in the absence of stoichiometric byproducts or metallic reagents. Journal of the American Chemical Society\| PubMed ID: 17571894	2007
Enantiomerically enriched allylic alcohols and allylic amines via C-C bond-forming hydrogenation: asymmetric carbonyl and imine vinylation. Accounts of chemical research\| PubMed ID: 17784728	2007
Enantioselective iridium-catalyzed imine vinylation: optically enriched allylic amines via alkyne-imine reductive coupling mediated by hydrogen. Journal of the American Chemical Society\| PubMed ID: 17914825	2007
Enantioselective iridium-catalyzed carbonyl allylation from the alcohol or aldehyde oxidation level using allyl acetate as an allyl metal surrogate. Journal of the American Chemical Society\| PubMed ID: 18444616	2008
Ruthenium catalyzed C-C bond formation via transfer hydrogenation: branch-selective reductive coupling of allenes to paraformaldehyde and higher aldehydes. Organic letters\| PubMed ID: 18533665	2008
Enantioselective iridium-catalyzed carbonyl allylation from the alcohol or aldehyde oxidation level via transfer hydrogenative coupling of allyl acetate: departure from chirally modified all... Journal of the American Chemical Society\| PubMed ID: 18841896	2008
Ligand-accelerated enantioselective propargylation of aldehydes via allenylzinc reagents. Organic letters\| PubMed ID: 21391717	2011
Pd-catalyzed aryl C-H imidation with arene as the limiting reagent. Journal of the American Chemical Society\| PubMed ID: 23998528	2013
Trifluoromethoxylation of arenes: synthesis of ortho-trifluoromethoxylated aniline derivatives by OCF3 migration. Angewandte Chemie (International ed. in English)\| PubMed ID: 25358501	2014
A Highly Convergent Total Synthesis of Leustroducsin B. Journal of the American Chemical Society\| PubMed ID: 26313159	2015

Ming-Yu Ngai

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