Palladium-Catalyzed C−N(sp<sup>2</sup>) Bond Formation:  <i>N</i>-Arylation of Aromatic and Unsaturated Nitrogen and the Reductive Elimination Chemistry of Palladium Azolyl and Methyleneamido Complexes

Mann, Grace; Hartwig, John F.; Driver, and Michael S.; Fernández-Rivas, Carolina

doi:10.1021/ja973524g

Cited by 348 publications

(166 citation statements)

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“…We were pleased that no N-phenylindole was observed under these simple conditions, which is consistent with the requirement for bulky σ-donor ligands at the palladium metal for the N-arylation to proceed. 13 Also, the importance of CsOAc base should be noted-it is too weak to deprotonate the indole N-H bond or other protic substituents, while it seems to facilitate the palladation step.…”

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confidence: 99%

Phosphine-Free Palladium-Catalyzed C−H Bond Arylation of Free (N−H)-Indoles and Pyrroles

2007

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This paper describes a phosphine-free palladium-catalyzed method for direct C-arylation of free (N-H)-indoles and pyrroles with iodo-and bromoarene donors. Employing commercially available materials, this new and operationally simple procedure provides a rapid entry to a wide range of Carylated (N-H)-indoles including derivatives of tryptamine. In the course of this study, a profound halide effect was uncovered, affecting both the efficiency and regioselectivity of indole arylation.Many natural products and pharmaceuticals contain C-arylated azole core structures. Although palladium-catalyzed cross-coupling reactions provide an efficient entry to these compounds, such protocols require the preparation of functionalized heteroarenes (e.g., boronates and halides). 1 For this reason, considerable effort has been directed toward the development of Carylation reactions of azole and related heteroarenes via direct C-H bond functionalization of the parent heteroarenes. 2 Despite significant progress in this area, C-arylation of free (N-H)-indoles and pyrroles with haloarene donors remains an unsolved problem. One approach relies on the protection of the amine functionality prior to the palladium-catalyzed arylation step, either by formation of azole magnesium3 , 4 or azole zinc salts,5 or by installing the SEM protecting group [SEM = 2-(trimethylsilyl)-ethoxymethyl].6 Direct C-arylation of free indoles and pyrroles has recently been described with a rhodium catalyst and a mild base. 7 However, this system did not tolerate hindered substrates containing a substituent in the 3-position of indole or in the 2-position of the haloarene donor. [8][9][10] As part of our continuing efforts in the broad area of C-H bond functionalization, 11 we herein describe the development of a simple phosphine-free palladium catalytic system for the direct C-arylation of free indoles and pyrroles. This protocol not only obviates the protection of the N-H function, but also accommodates both ortho-substituted aryl donors and 3-substituted indoles, including tryptamine derivatives. On a strategic level, this method (as well as other catalytic C-H functionalization reactions) provides new approaches to complex heteroarenes, advantages of which are particulalry apparent in the context of preparation of a series of compounds, wherein established multistep methods become inefficient. 11 We have previously reported a catalytic system [Pd(OAc) with free (N-H)-indoles, closer examination revealed that the efficiency could be improved by increasing the substrate concentration. Specifically, the yield was nearly tripled, from 6% to 16% of 2-phenylindole, when the indole concentration was increased from 1.25 to 5.0 M (Table 1, entries 1 and 2). In addition to this concentration effect, we also found that phosphine ligands inhibited the reaction. 12 A representative collection of phosphine and carbene ligands, frequently used in arylation coupling chemistry, was examined (Table 1, entries 3-7). While the presence of the IPr carbene ligand had ...

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Phosphine-Free Palladium-Catalyzed C−H Bond Arylation of Free (N−H)-Indoles and Pyrroles

2007

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“…One post-cleavage methylation has also been reported (Scheme 17). 16 On the other hand, palladium 33,34 or copper-catalysed 35 Narylations reported in solution have not been reported on solid phase so far. Maybe, in the future, these reactions will be adapted to solid-phase chemistry and also alkylations or acylations with groups that have a directing effect toward C-2 lithiation.…”

Section: Modification Of Indoles By Substitution At Nitrogenmentioning

confidence: 99%

Synthetic approaches towards indoles on solid phase recent advances and future directions

2003

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Section: Modification Of Indoles By Substitution At Nitrogenmentioning

confidence: 99%

Synthetic Approaches Towards Indoles on Solid Phase. Recent Advances and Future Directions

2003

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Palladium-Catalyzed C−N(sp²) Bond Formation: N-Arylation of Aromatic and Unsaturated Nitrogen and the Reductive Elimination Chemistry of Palladium Azolyl and Methyleneamido Complexes

Cited by 348 publications

References 18 publications

Phosphine-Free Palladium-Catalyzed C−H Bond Arylation of Free (N−H)-Indoles and Pyrroles

Phosphine-Free Palladium-Catalyzed C−H Bond Arylation of Free (N−H)-Indoles and Pyrroles

Synthetic approaches towards indoles on solid phase recent advances and future directions

Synthetic Approaches Towards Indoles on Solid Phase. Recent Advances and Future Directions

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Palladium-Catalyzed C−N(sp2) Bond Formation: N-Arylation of Aromatic and Unsaturated Nitrogen and the Reductive Elimination Chemistry of Palladium Azolyl and Methyleneamido Complexes

Cited by 348 publications

References 18 publications

Phosphine-Free Palladium-Catalyzed C−H Bond Arylation of Free (N−H)-Indoles and Pyrroles

Phosphine-Free Palladium-Catalyzed C−H Bond Arylation of Free (N−H)-Indoles and Pyrroles

Synthetic approaches towards indoles on solid phase recent advances and future directions

Synthetic Approaches Towards Indoles on Solid Phase. Recent Advances and Future Directions

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Palladium-Catalyzed C−N(sp²) Bond Formation: N-Arylation of Aromatic and Unsaturated Nitrogen and the Reductive Elimination Chemistry of Palladium Azolyl and Methyleneamido Complexes