An Annulative Approach to Highly Substituted Indoles:  Unusual Effect of Phenolic Additives on the Success of the Arylation of Ketone Enolates

Rutherford, Jennifer L.; Rainka, Matthew P.; Buchwald, Stephen L.

doi:10.1021/ja0288993

Cited by 184 publications

(56 citation statements)

References 14 publications

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“…According to the above-mentioned general procedure, the following indole derivatives were obtained and their m.p., 1 H-and 13 C-NMR were identical to those described in the literature. 2-Phenyl-1H-indole (entry 1, Table 2, in 68 and 66% yield), [26] 2-(4 -methyl)phenyl-1H-indole (entry 2, Table 2, in 67 and 62% yield), [27] 2-(4 -fluoro)phenyl-1H-indole (entry 3, Table 2, in 62 and 68% yield), [27] 2-(4 -methoxy)phenyl-1H-indole (entry 4, Table 2, in 65 and 58% yield), [28] 2,3,4,9-tetrahydro-1H-carbazole (entry 5, Table 2, in 98 and 92% yield), [29] 6,11-dihydro-5H-benzo[a]carbazole (entry 6, Table 2, in 69 and 65% yield), [30] 2-ethyl-3-methyl-1H-indole (entry 7, Table 2, in 81 and 80% yield), [31] 5-methyl-2-phenyl-1H-indole (entry 8, Table 2, in 70% yield), [27] 5-methyl-2-(4 -methyl)phenyl-1H-indole (entry 9, Table 2, in 72% yield), [32] 5-methyl-2-(4 -fluoro)phenyl-1H-indole (entry 10, Table 2, in 77% yield), [33] 6-methyl-2,3,4,9-tetrahydro-1H-carbazole (entry 11, Table 2, in 92% yield), [31] 8-methyl-6,11-dihydro-5H-benzo[a]carbazole (entry 12, Table 2, in 69% yield), [34] 8-methyl-5,10-dihydroindeno[1,2-b]indole (entry 13, Table 2, in 57% yield), [35] 4-methyl-2-phenyl-1H-indole (entry 14, Table 2, in 61 and 55% yield), [36] 5-methyl-2,3,4,9-tetrahydro-1H-carbazole (entry 16, Table 2, in 87 and 80% yield), [37] 2-(pyridin-4-yl)-1H-indole (entry 18, Table 2, in 86% yield). [38] According to the same procedure, 4-methyl-2-(4 -fluoro)phenyl-1H-indole (entry 15, …”

Section: General Procedures For Annulation Reaction Of O-haloanilines mentioning

confidence: 99%

Well‐defined NHCPd complex‐mediated intermolecular direct annulations for synthesis of functionalized indoles (NHC = N‐hetero‐cyclic carbene)

Jin

Guo

Qiu

et al. 2011

Applied Organom Chemis

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As alternatives to the common tertiary phosphine/Pd systems, well-defined N-heterocyclic carbene-Pd complexes have been proven to be highly efficient precatalysts for intermolecular direct annalution of o-haloanilines and ketones at lower catalyst loadings. A highly efficient and practical protocol for synthesis of functionalized indoles was developed using (IPr)Pd(acac)Cl as catalyst. Both o-bromoanilines and o-chloroanilines gave rise to efficient coupling under the reaction conditions. Related to acyclic ones, cyclic ketones coupled more effectively with o-haloanilines. With [Pd(IPr) 2 ] as catalyst, the base-sensitive groups including OH and CO 2 H groups could be tolerated.

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Section: General Procedures For Annulation Reaction Of O-haloanilines mentioning

confidence: 99%

Well‐defined NHCPd complex‐mediated intermolecular direct annulations for synthesis of functionalized indoles (NHC = N‐hetero‐cyclic carbene)

Jin

Guo

Qiu

et al. 2011

Applied Organom Chemis

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“…However, these standard conditions could not be used with many ketones, as significant a-arylation of the substrate was observed. [10] However, if KOAc was replaced with K 3 PO 4 in the first step, then the biaryl species was obtained in good yield (Table 5, entry 8). These methods represent the first processes for the direct synthesis of symmetrical and unsymmetrical biaryl compounds from two aryl chlorides.…”

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confidence: 98%

Palladium‐Catalyzed Borylation of Aryl Chlorides: Scope, Applications, and Computational Studies

2007

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Aryl boronic acids and esters are versatile reagents for organic synthesis that are utilized in the preparation of various carbon-oxygen, carbon-nitrogen, and carbon-carbon bonds. [1] In addition, the use of organoboranes for crosscoupling processes is particularly attractive owing to their high stability and low toxicity. However, boronic acids and esters usually are prepared via intermediate alkyl and aryllithium compounds or Grignard reagents, processes that are not compatible with numerous functional groups. [2] Furthermore, the use of aryl iodides or bromides is often necessary, while the more readily available aryl chlorides [3] are often unsuitable precursors.In recent years, the development of a variety of transitionmetal-catalyzed processes has allowed for the preparation of aryl boronate esters under milder conditions.[4] In particular, numerous palladium-catalyzed methods have emerged for the conversion of aryl iodides, bromides, and triflates to the corresponding pinacol or catechol boronate esters.[5] However, only two reports [6] can be found in which unactivated aryl chlorides are suitable coupling partners, and these methods have several disadvantages: 1) High quantities of palladium catalysts (5-6 mol %) are required for many substrates. 2) Long reaction times (24-48 h) are necessary. 3) Limited substrate scope and functional-group tolerance (e.g. few or no examples with ortho substituents, phenols, and anilines) is exhibited. Herein, we report an active catalyst composed of Pd and dialkylphosphinobiphenyl ligands 1 or 2 that efficiently converts aryl chlorides to pinacol boronate esters and allows, for the first time, the direct "one-pot" synthesis of symmetrical and unsymmetrical biaryl compounds from two aryl chlorides. In addition, computational studies are presented that provide insight into the efficacy of biaryl monophosphine ligands in the palladium-catalyzed borylation process.We began by optimizing the reaction parameters. We found that a variety of dialkylphosphinobiphenyl ligands could be employed to afford highly active catalysts for the borylation of 4-n-butylchlorobenzene (Table 1). In each instance, the desired aryl boronate ester was obtained in good or excellent yield. The optimum system, based upon [Pd 2 dba 3 ] and XPhos (1), allowed for the use of relatively low quantities of catalyst and provided a quantitative yield of product in just two hours (Table 1, entry 6). We found KOAc to be the optimum base, although a variety of inorganic bases could be utilized. However, the use of K 3 PO 4 or fluoride bases, despite resulting in full conversion of the aryl chloride, also led to the formation of approximately 15-20 % of the homocoupling product 4,4'-n-butylbiphenyl.To illustrate the activity of the catalyst, the borylation of an electron-rich aryl chloride, 4-chloroanisole, was examined (Scheme 1). The best previous result for the transformation of this substrate combination required 5 mol % [Pd(dba) 2 ] and a 24-h reaction time to obtain a 86 % yield of the pinacol boronate est...

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“…[15] Although weak bases (e.g., K 3 PO 4 and Cs 2 CO 3 ) have been used in some Pd-catalyzed arylation [8,16,17] and alkenylation [3,4a, b] reactions, PhOK could play an additional role in these processes as can be seen in Buchwalds work, where phenol is used as a catalytic additive in some a-arylation reactions of ketone enolates. In line with Buchwalds proposal, [18] we thought that the intermediacy of a palladium phenoxide complex, which both stabilizes an otherwise unstable intermediate and facilitates the enolization by coordinating the carbonyl group, could be the most plausible explanation of the key role of phenoxide in these reactions.…”

mentioning

confidence: 72%

Palladium‐Catalyzed Intramolecular Coupling of Amino‐Tethered Vinyl Halides with Ketones, Esters, and Nitriles Using Potassium Phenoxide as the Base

2004

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Vinyl halides undergo intramolecular coupling with amino-tethered ketones, esters, and nitriles in the presence of a palladium catalyst and potassium phenoxide as the base. This reaction constitutes a useful methodology for the synthesis of monocyclic, bridged, and spirocyclic nitrogen-containing compounds.Keywords: alkenylation; enolates; homogeneous catalysis; nitrogen heterocycles; palladium During the past decade there has been a growing interest in the palladium-catalyzed coupling reactions of aryl and vinyl halides with enolates and related anions. However, while the reactions of aryl halides have been extensively studied, and it is now possible to introduce an aromatic unit to a broad range of enolate-type nucleophiles, [1] the coupling reactions involving vinyl halides have received little attention and deal almost exclusively with the a-alkenylation of ketone enolates.The first examples of such palladium-catalyzed coupling reactions involving vinyl halides were reported by Piers at the beginning of the 1990s, when he described the intramolecular alkenylation of ketone enolates and then applied the reaction to the synthesis of the diterpenoid crinipellin B.[2] Some years later, another example of this coupling process was reported by Cook in the context of the total synthesis of the alkaloid (þ)-vellosimine, [3] and we reported our studies on the synthesis of nitrogen heterocycles by the Pd(0)-catalyzed intramolecular coupling of amino-tethered vinyl halides and ketone enolates.[4] Later on, Buchwald described the intermolecular vinylation of ketone enolates. [5] Finally, it is worth mentioning that isolated examples of the alkenylation reaction have also been reported in the studies of the Pd(0)-catalyzed intermolecular arylation of ester [6] and alanine-derived azlactone [7] enolates.In our previous work, we established that the use of Pd(PPh 3 ) 4 (0.2 equivs.) and KO-t-Bu (1.5 equivs.) in THF at reflux effectively promotes the intramolecular coupling of amino-tethered vinyl halides and ketones to afford bridged, condensed, and monocyclic nitrogen-containing compounds.[4] However, for some substrates side reactions such as the elimination of HX leading to alkynes which may undergo subsequent coupling with the starting vinyl halides to afford dimeric compounds, and dealkylation at the nitrogen, resulted in low or moderate yields of the cyclization products.[4b]As these side reactions can mainly be attributed to the use of a strong base, a more general protocol for the intramolecular a-alkenylation of ketones could be found if, instead of KO-t-Bu, a milder base was used. In this context, it should be noted that the intramolecular coupling of amino-tethered vinyl halides and ketones was also accomplished in some cases by using Cs 2 CO 3 as the base, although these reaction conditions were only suitable for the construction of five-membered ring systems and afforded moderate or low yields. [4b] Continuing our studies on this palladium chemistry, [8] we have recently reported that both vinyl an...

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An Annulative Approach to Highly Substituted Indoles: Unusual Effect of Phenolic Additives on the Success of the Arylation of Ketone Enolates

Cited by 184 publications

References 14 publications

Well‐defined NHCPd complex‐mediated intermolecular direct annulations for synthesis of functionalized indoles (NHC = N‐hetero‐cyclic carbene)

Well‐defined NHCPd complex‐mediated intermolecular direct annulations for synthesis of functionalized indoles (NHC = N‐hetero‐cyclic carbene)

Palladium‐Catalyzed Borylation of Aryl Chlorides: Scope, Applications, and Computational Studies

Palladium‐Catalyzed Intramolecular Coupling of Amino‐Tethered Vinyl Halides with Ketones, Esters, and Nitriles Using Potassium Phenoxide as the Base

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