Gold Catalysis: Selectivity Problems in Hydroarylations with Pyrroles

Hashmi, A. Stephen K.; Salathé, Ralph; Frey, Wolfgang

doi:10.1002/ejoc.200601062

Cited by 45 publications

(23 citation statements)

References 29 publications

(12 reference statements)

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“…It should be noted that intermolecular hydroarylation with substituted pyrroles was less investigated, possibly due to the difficulty of controlling the regioselectivity. 12,20 To clarify the reaction mechanism, we tried the following control experiments (Scheme 6). It was found that the desired product 2a was not observed upon stirring 1a and acetophenone under the standard reaction conditions, implying that the reaction did not proceed via hydration of alkyne followed by condensation with α-amino ketone.…”

Section: * S Supporting Informationmentioning

confidence: 99%

Synthesis of Multiple-Substituted Pyrroles via Gold(I)-Catalyzed Hydroamination/Cyclization Cascade

Chen

Xie

et al. 2015

Org. Lett.

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A gold-catalyzed cascade hydroamination/cyclization reaction of α-amino ketones with alkynes to form substituted pyrroles has been developed. The method offers several advantages such as high regioselectivity with the tested cases, wide functional group tolerance, and easily accessible starting materials. The synthetic utility of the obtained pyrrole products was demonstrated by their efficient transformations to 2-vinylated pyrroles via gold-catalyzed intermolecular hydroarylation.

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Section: * S Supporting Informationmentioning

confidence: 99%

Synthesis of Multiple-Substituted Pyrroles via Gold(I)-Catalyzed Hydroamination/Cyclization Cascade

Chen

Xie

et al. 2015

Org. Lett.

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“…We also expect that, using this protocol, substrates such as bromoindoles could lead to the formation of bromocarbazoles, which could subsequently be cross-coupled. 14 A tentative mechanism to explain the formation of carbazole 2 is given in Scheme 5. 15 The carbophilic gold catalyst activates alkyne 1 to form a -complex intermediate 1I.…”

Section: Scheme 1 Synthetic Plan For Carbazolementioning

confidence: 99%

Synthesis of Carbazoles by Gold(I)-Catalyzed Carbocyclization of 2-(Enynyl)indoles

Praveen¹,

Perumal²

2011

Synlett

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A new synthetic protocol for carbazoles through gold(I)-catalyzed intramolecular hydroarylation of (Z)-2-(enynyl)indoles was achieved in good yields. The requisite (Z)-2-(enynyl)indoles were synthesized stereoselectively by trimethylgallium-promoted, Z-selective Wittig olefination of N-alkylindole-2-carboxaldehydes with propargyl ylides. Substrates possessing both alkyl as well as aromatic groups are well tolerated under these reaction conditions.Carbazoles are important heterocyclic scaffolds that serve as key components in a variety of natural products and biologically active molecules. 1 Thus, it is not surprising that several synthetic approaches to these molecules have been described in the literature. 2 In contrast, recent work has focused on the development of transition-metal-catalyzed methods for the synthesis of carbazoles. 3 Of particular value are Rh(II)-catalyzed synthesis of carbazoles from biaryl azides, 3a Pd(II)-catalyzed cyclization of 2-phenylacetanilides, 3b Pd(II)-catalyzed cross-coupling reaction of 2-iodoanilines with silylaryl triflates, 3c Pd(II)-catalyzed oxidative cyclization of 3-(3¢-alkenyl)indoles, 3d Pd(0)-catalyzed cross-coupling of alkynes and N-(3-iodophenyl)anilines, 3e Pd(0)-catalyzed tandem Suzuki cross-coupling/S N Ar of aniline-derived boronic ester with 1,2-dihalobenzene, 3f Pd(II)-catalyzed oxidative C-H bond amination of biaryls, 3g and Pt(II)-catalyzed cyclization of 1-(indol-2-yl)-2,3-allenols. 3h Typically, these protocols involve the use of palladium catalysts. While these reactions are often useful, a catalytic protocol that accomplishes the intramolecular carbocyclization of 2-(enynyl)indoles remains to be developed (Scheme 1). We felt that such transformations promise to facilitate selective construction of carbon-carbon bonds at the later stages in the synthesis of drug molecules and/or natural products. As part of our ongoing interest in the synthesis of novel heterocyclic compounds 4 under transition-metal catalysis, 4b-h we herein report the synthesis of carbazoles via gold-catalyzed 5 intramolecular carbocylization of 2-(enynyl)indoles.Recently, gold-catalyzed intramolecular hydroarylation of indole-tethered propargyl esters 6a and propargyl amines 6b have been disclosed. Both of these methods involve the use of 3-substituted indole derivatives. We were interested in the cyclization of 2-substituted indole derivatives, since the C3 of indole is more nucleophilic. Our initial investigations focused on the synthesis of the requisite 2-(enynyl)indoles by Wittig olefination of N-alkylindole-2-carboxaldehydes 7 3 with propargyl ylides 8 4. These substrates were synthesized in good yields by standard procedures (Scheme 2). To develop the general synthesis of 2-(enynyl)indoles, Wittig reaction of model substrates 3a and 4a promoted by n-BuLi (1.5 equiv, -10°C,THF) was performed (Scheme 3). Scheme 1 Synthetic plan for carbazoleThe desired enynl product was obtained in 92% yield as a mixture of E-and Z-isomers in a 45:55 ratio. The isomers were separated by column chro...

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“…It should be noted that chemoselectivity is a well-known problem in gold-catalysed reactions with pyrroles, because the mono-alkylated product is more nucleophilic than the startingp yrrole, and this can result in multiple alkylations. [35] Remarkably,t his chemoselectivity issue was not observed under our conditions. To our surprise, however,n or egioselectivity was observed between reactiona tt he a and b positiono ft he pyrrole (3cl/3cl'',1 :1, entry 12).…”

Section: Resultsmentioning

confidence: 56%

“…Although N ‐methylpyrrole 2 l was reported to be unreactive under Gagné’s original conditions, the reaction proceeded under our optimised protocol with a reasonable yield (58 %), good allene regioselectivity (>20:1), and excellent chemoselectivity (entry 12). It should be noted that chemoselectivity is a well‐known problem in gold‐catalysed reactions with pyrroles, because the mono‐alkylated product is more nucleophilic than the starting pyrrole, and this can result in multiple alkylations . Remarkably, this chemoselectivity issue was not observed under our conditions.…”

Section: Resultsmentioning

confidence: 99%

Gold(I)‐Catalysed Hydroarylation of 1,3‐Disubstituted Allenes with Efficient Axial‐to‐Point Chirality Transfer

Sutherland

Kinsman

Angiolini

et al. 2018

Chemistry A European J

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Hydroarylation of enantioenriched 1,3-disubstituted allenes has the potential to proceed with axial-to-point chirality transfer to yield enantioenriched allylated (hetero)aryl compounds. However, the gold-catalysed intermolecular reaction was previously reported to occur with no chirality transfer owing to competing allene racemisation. Herein, we describe the development of the first intermolecular hydroarylations of allenes to proceed with efficient chirality transfer and summarise some of the key criteria for achieving high regio- and stereoselectivity.

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Gold Catalysis: Selectivity Problems in Hydroarylations with Pyrroles

Cited by 45 publications

References 29 publications

Synthesis of Multiple-Substituted Pyrroles via Gold(I)-Catalyzed Hydroamination/Cyclization Cascade

Synthesis of Multiple-Substituted Pyrroles via Gold(I)-Catalyzed Hydroamination/Cyclization Cascade

Synthesis of Carbazoles by Gold(I)-Catalyzed Carbocyclization of 2-(Enynyl)indoles

Gold(I)‐Catalysed Hydroarylation of 1,3‐Disubstituted Allenes with Efficient Axial‐to‐Point Chirality Transfer

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