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1.
Angew Chem Int Ed Engl ; 63(12): e202319773, 2024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38279666

RESUMO

We report herein the development of palladium-catalyzed deacylative deuteration of arylketone oxime ethers. This protocol features excellent functional group tolerance, heterocyclic compatibility, and high deuterium incorporation levels. Regioselective deuteration of some biologically important drugs and natural products are showcased via Friedel-Crafts acylation and subsequent deacylative deuteration. Vicinal meta-C-H bond functionalization (including fluorination, arylation, and alkylation) and para-C-H bond deuteration of electro-rich arenes are realized by using the ketone as both directing group and leaving group, which is distinct from aryl halide in conventional dehalogenative deuteration.

2.
J Org Chem ; 88(11): 7070-7074, 2023 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-37191073

RESUMO

We report herein the synthesis of exo-chalcogenated methylene chroman-3-ones via palladium-catalyzed intramolecular acyl-chalcogenation of alkyne with thio- and selenoesters. Chalcogen containing tetrasubstituted alkenes are obtained stereoselectively. This protocol tolerates various functional groups and heterocycles, affording the chroman-3-one products in moderate-to-good yields.

3.
J Org Chem ; 87(10): 6807-6811, 2022 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-35507767

RESUMO

We report herein the synthesis of 1,3-enynes via palladium-catalyzed cross-coupling between enone derivatives and alkynylsilanes. The employment of an appropriate pyridine-oxazoline ligand is the key to the C-C cleavage and the high E/Z stereoselectivity. This protocol features broad substrate scope and wide functional-group tolerance, affording the desired products in moderate-to-good yields. Late-stage diversification of natural product ß-ionone further demonstrated the synthetic utility of this protocol.


Assuntos
Paládio , Catálise , Ligantes , Paládio/química
4.
J Org Chem ; 85(6): 4475-4481, 2020 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-32077291

RESUMO

Here, we report O-methyl S-aryl thiocarbonates as a versatile esterification reagent for palladium-catalyzed methoxycarbonylation of arylboronic acid in the presence of copper(I) thiophene-2-carboxylate (CuTC). The reaction condition is mild, and a variety of substituents including sensitive -Cl, -Br, and free -NH2 could be tolerated. Further applications in the late-stage esterification of some pharmaceutical drugs demonstrate the broad utility of this method.

5.
Nature ; 515(7527): 389-93, 2014 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-25383516

RESUMO

In directed C-H activation reactions, any nitrogen or sulphur atoms present in heterocyclic substrates will coordinate strongly with metal catalysts. This coordination, which can lead to catalyst poisoning or C-H functionalization at an undesired position, limits the application of C-H activation reactions in heterocycle-based drug discovery, in which regard they have attracted much interest from pharmaceutical companies. Here we report a robust and synthetically useful method that overcomes the complications associated with performing C-H functionalization reactions on heterocycles. Our approach employs a simple N-methoxy amide group, which serves as both a directing group and an anionic ligand that promotes the in situ generation of the reactive PdX2 (X = ArCONOMe) species from a Pd(0) source using air as the sole oxidant. In this way, the PdX2 species is localized near the target C-H bond, avoiding interference from any nitrogen or sulphur atoms present in the heterocyclic substrates. This reaction overrides the conventional positional selectivity patterns observed with substrates containing strongly coordinating heteroatoms, including nitrogen, sulphur and phosphorus. Thus, this operationally simple aerobic reaction demonstrates that it is possible to bypass a fundamental limitation that has long plagued applications of directed C-H activation in medicinal chemistry.


Assuntos
Carbono/química , Química Farmacêutica/métodos , Compostos Heterocíclicos/química , Hidrogênio/química , Ar , Amidas/química , Catálise , Nitrogênio/química , Oxidantes/química , Paládio/química , Fósforo/química , Enxofre/química
6.
Angew Chem Int Ed Engl ; 59(34): 14388-14393, 2020 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-32463551

RESUMO

The coupling of aromatic electrophiles (aryl halides, aryl ethers, aryl acids, aryl nitriles etc.) with nucleophiles is a core methodology for the synthesis of aryl compounds. Transformations of aryl ketones in an analogous manner via carbon-carbon bond activation could greatly expand the toolbox for the synthesis of aryl compounds due to the abundance of aryl ketones. An exploratory study of this approach is typically based on carbon-carbon cleavage triggered by ring-strain release and chelation assistance, and the products are also limited to a specific structural motif. Here we report a ligand-promoted ß-carbon elimination strategy to activate the carbon-carbon bonds, which results in a range of transformations of aryl ketones, leading to useful aryl borates, and also to biaryls, aryl nitriles, and aryl alkenes. The use of a pyridine-oxazoline ligand is crucial for this catalytic transformation. A gram-scale borylation reaction of an aryl ketone via a simple one-pot operation is reported. The potential utility of this strategy is also demonstrated by the late-stage diversification of drug molecules probenecid, adapalene, and desoxyestrone, the fragrance tonalid as well as the natural product apocynin.

7.
Angew Chem Int Ed Engl ; 58(38): 13335-13339, 2019 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-31290577

RESUMO

A rhodium(III)-catalyzed domino annulation of simple olefins with diazo oxindoles to give spirooxindole pyrrolone products is described. This reaction can be formally viewed as the result of an anomalous tandem C-H activation, carbene insertion, Lossen rearrangement, and a nucleophilic addition process. The potential utility of this reaction was further demonstrated by the late-stage diversification of drug molecules.

8.
Angew Chem Int Ed Engl ; 56(19): 5317-5321, 2017 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-28393446

RESUMO

One long-standing issue in directed C-H functionalization is that either nitrogen or sulfur atoms present in heterocyclic substrates may bind preferentially to a transition-metal catalyst rather than to the desired directing group. This competitive binding has largely hindered the application of C-H functionalization in late-stage heterocycle drug discovery. Reported here is the use of an oxazoline-based directing group capable of overriding the poisoning effect of a wide range of heterocycle substrates. The potential use of this directing group in pharmaceutical drug discovery is illustrated by diversification of Telmisartan (an antagonist for the angiotensin II receptor) through copper-mediated C-H amination, hydroxylation, thiolation, arylation, and trifluoromethylation.

9.
J Am Chem Soc ; 138(7): 2146-9, 2016 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-26855140

RESUMO

Pd-catalyzed α-olefinic C-H activation of simple α,ß-unsaturated olefins has been developed. 4-imino-ß-lactam derivatives were readily synthesized via activation of α-olefinic C-H bonds with excellent cis stereoselectivity. A wide range of heterocycles at the ß-position are compatible with this reaction. The product of 4-imino-ß-lactam derivatives can be readily converted to 2-aminoquinoline which exists extensively in pharmaceutical drugs and natural products.

10.
Angew Chem Int Ed Engl ; 55(2): 785-9, 2016 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-26611496

RESUMO

A quinoline-based ligand effectively promotes the palladium-catalyzed borylation of C(sp(3))-H bonds. Primary ß-C(sp(3))-H bonds in carboxylic acid derivatives as well as secondary C(sp(3))-H bonds in a variety of carbocyclic rings, including cyclopropanes, cyclobutanes, cyclopentanes, cyclohexanes, and cycloheptanes, can thus be borylated. This directed borylation method complements existing iridium(I)- and rhodium(I)-catalyzed C-H borylation reactions in terms of scope and operational conditions.


Assuntos
Compostos de Boro/química , Paládio/química , Catálise , Ligação de Hidrogênio , Ligantes
11.
J Org Chem ; 80(17): 8843-8, 2015 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-26259687

RESUMO

A Cu(II)-mediated ortho-C-H hydroxylation using a removable directing group has been developed. The reaction exhibits considerable functional group tolerance. The use of O2 as an oxidant is crucial for the reactivity. Water is also found to significantly improve this reaction.

12.
J Am Chem Soc ; 136(9): 3354-7, 2014 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-24527701

RESUMO

A Cu(OAc)2-mediated C-H amidation and amination of arenes and heteroarenes has been developed using a readily removable directing group. A wide range of sulfonamides, amides, and anilines function as amine donors in this reaction. Heterocycles present in both reactants are tolerated, making this a broadly applicable method for the synthesis of a family of inhibitors including 2-benzamidobenzoic acids and N-phenylaminobenzoates.

13.
J Am Chem Soc ; 136(33): 11590-3, 2014 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-25087720

RESUMO

Cu(II)-promoted ortho alkynylation of arenes and heteroarenes with terminal alkynes has been developed to prepare aryl alkynes. A variety of arenes and terminal alkynes bearing different substituents are compatible with this reaction, thus providing an alternative disconnection to Sonogashira coupling.


Assuntos
Alcinos/química , Alcinos/síntese química , Derivados de Benzeno/química , Cobre/química , Alquilação , Estrutura Molecular
14.
Angew Chem Int Ed Engl ; 53(39): 10439-42, 2014 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-25100616

RESUMO

The direct ortho-trifluoromethylation of arenes, including heteroarenes, with TMSCF3 has been accomplished by a copper(II)-promoted C-H activation reaction which completes within 30 minutes. Mechanistic investigations are consistent with the involvement of C-H activation, rather than a simple electrophilic aromatic substitution (SE Ar), as the key step.


Assuntos
Cobre/química , Hidrocarbonetos Fluorados/química , Silanos/química , Carbono/química , Catálise , Flúor/química , Compostos Heterocíclicos/química , Hidrogênio/química , Paládio/química
15.
Org Lett ; 26(11): 2260-2265, 2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38452482

RESUMO

Herein, we report the C-H cyanation of indoles via a palladium-catalyzed directed C-CN activation reaction using aryl nitrile as a cyano source. The employment of the phenoxy-oriented group is the key to the cleavage of the C-CN bond. This protocol features a broad substrate scope, good efficiency, and high regioselectivity. Furthermore, the practical application of this protocol was showcased in the late-stage functionalization and synthesis of indole derivatives, which were derived from drugs and natural products, through the process of cyanation.

16.
J Am Chem Soc ; 135(20): 7567-71, 2013 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-23614807

RESUMO

A combination of weakly coordinating auxiliaries and ligand acceleration allows for the development of both ortho- and meta-selective C-H olefination of phenol derivatives. These reactions demonstrate the feasibility of directing C-H functionalizations when functional groups are distal to target C-H bonds. The meta-C-H functionalization of electron-rich phenol derivatives is unprecedented and orthogonal to previous electrophilic substitution of phenols in terms of regioselectivity. These methods are also applied to functionalize α-phenoxyacetic acids, a fibrate class of drug scaffolds.


Assuntos
Alcenos/química , Compostos Organometálicos/química , Paládio/química , Fenóis/síntese química , Acetatos/síntese química , Acetatos/química , Catálise , Estrutura Molecular , Fenóis/química
17.
Chem Commun (Camb) ; 59(22): 3269-3272, 2023 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-36820796

RESUMO

Herein, we report an efficient synthetic method for polysubstituted pentafulvenes via palladium-catalyzed deacetylative [2+2+1] annulation of enones with alkynes. Aryl-, alkenyl-, and alkyl-substituted α,ß-enones were suitable substrates, affording the pentafulvene products in moderate to good yields. This protocol shows excellent compatibility with sensitive halides, free hydroxyl groups, and heterocycles. One-pot gram-scale synthesis and further applications in the late-stage modification of natural products demonstrate the synthetic utility of this method.

18.
Org Lett ; 25(29): 5406-5410, 2023 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-37458387

RESUMO

Herein, we report the transformation of aromatic acids to indole-fused seven- and eight-membered azaheterocycles. Two C-C bonds are formed via the cleavage of one C-C bond and two C-H bonds. The incorporation of indole moieties into bioactive pharmaceuticals and natural products to construct a medium-sized polyfused heterocycle demonstrates the synthetic utility of the protocol.

19.
J Am Chem Soc ; 134(1): 134-7, 2012 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-22148883

RESUMO

The development of a Pd-catalyzed oxidative ortho-C-H borylation with N-arylbenzamides is reported. A modified dibenzylideneacetone (dba) ligand, a weak base, and a strong oxidant are critical for obtaining good yields. The reaction is tolerant of electron-deficient and electron-rich benzamides derived from readily available benzoic acids. The borylated products can be converted to various synthons via diverse transformations.


Assuntos
Benzeno/química , Boro/química , Carbono/química , Hidrogênio/química , Paládio/química , Catálise
20.
J Am Chem Soc ; 134(29): 11948-51, 2012 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-22780303

RESUMO

A Pd(II)-catalyzed trifluoromethylation of ortho C-H bonds with an array of N-arylbenzamides derived from benzoic acids is reported. N-Methylformamide has been identified as a crucial promoter of C-CF(3) bond formation from the Pd center. X-ray characterization of the C-H insertion intermediate has revealed a rare coordination mode of acidic amides as directing groups and the origin of their capacity in directing C-H activation.


Assuntos
Benzamidas/química , Benzoatos/química , Formamidas/química , Paládio/química , Catálise , Halogenação , Metilação , Modelos Moleculares , Oxirredução
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