Synthesis of Diverse 2,3-Dihydroindoles, 1,2,3,4-Tetrahydroquinolines, and Benzo-Fused Azepines by Formal Radical Cyclization onto Aromatic Rings

Clive, Derrick L. J.; Peng, Jianbiao; Fletcher, Stephen P.; Ziffle, Vincent E.; Wingert, David A.

doi:10.1021/jo7026307

Cited by 19 publications

(7 citation statements)

References 30 publications

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“…The indoline moiety can be found in numerous biologically active alkaloid natural products and pharmaceuticals . Recently, highly efficient indoline-based organic dyes for dye-sensitized solar cells have also been developed …”

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confidence: 99%

Synthesis of Indolines via a Domino Cu-Catalyzed Amidation/Cyclization Reaction

Minatti

Buchwald

2008

Org. Lett.

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A highly efficient one-pot procedure for the synthesis of indolines and their homologues based on a domino Cu-catalyzed amidation/nucleophilic substitution reaction has been developed. Substituted 2-iodophenethyl mesylates and related compounds afforded the corresponding products in excellent yields. No erosion of optical purity was observed when transforming enantiomerically pure mesylates under the reaction conditions.The indoline moiety 1 can be found in numerous biologically active alkaloid natural products 2 and pharmaceuticals. 3 Recently, highly efficient indoline-based organic dyes for dye-sensitized solar cells have also been developed. 4Since our earlier reports on the Pd-catalyzed intramolecular amination reactions for the formation of indolines, 5 a variety of intramolecular transition metal-catalyzed amination and amidation processes have emerged for the synthesis of N-protected indolines (Scheme 1, eq. 1). 6,7,8 More versatile routes toward the synthesis of the indoline core incorporate an intermolecular Pd-catalyzed amidation or amination reaction as part of a sequential or domino process (Scheme 1, eq. 2 and 3). 9 Although, this strategy represents a significant improvement in the modular synthesis of indolines, several drawbacks limit the reported methods. Specifically, certain methods only allow access to 3-substituted, 9a 2-substituted 9c or nonsubstituted 9d,e indolines, and the Pd-catalyzed C-C/C-N coupling of bromoalkylamines with an aryl iodide requires ortho-substituted aryl iodides and a para-nitrophenyl-protected amine. 9f We felt that a one-pot procedure for the synthesis of indolines that overcomes these limitations would be highly desirable.Herein, we report the development of a general domino Cu-catalyzed amidation/nucleophilic substitution process for the synthesis of substituted indolines and their homologues (Scheme 1, eq. 4). 10We began our investigation with 1-iodo-2-(2-iodoethyl)benzene (1a) and tert-butylcarbamate (2a) as the model substrates to examine the reaction conditions, which we previously reported for the Cu-catalyzed amidation of aryl halides (Table 1) [5 mol % CuI, 20 mol % N,N′-dimethylethylenediamine (DMEDA), Cs 2 CO 3 in THF]. 7a,11 Only low conversion of 1a was observed at room temperature after 16 h. At 80 °C, however, full conversion and up to 37% of the N-Boc-protected indoline 3a were obtained, along with 23% of 2-N-Boc-styrene (4a). Systematic variation of the solvent, base, and diamine-ligand did not increase the yield of the desired product, although varying amounts of the products 4a and 5a were observed ( Variation of the nucleofuge proved to be crucial. Switching from the phenethyl iodide 1a to the phenethyl chloride 1b or the phenethyl mesylate 1c resulted in exclusive formation of the desired product 3a in high yields (87% and 89%, respectively).Under the optimized reaction conditions 2-iodophenethyl mesylate (1c) reacted equally efficiently with other commonly used carbamates 2b-c and amides 2d and yielded the corresponding N-protected indo...

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confidence: 99%

Synthesis of Indolines via a Domino Cu-Catalyzed Amidation/Cyclization Reaction

Minatti

Buchwald

2008

Org. Lett.

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“…It was particularly striking to us that the arene unprecedentedly stabilizes the primary carbon cation through a neighboring participation in the mechanism proposed by Tellitu et al To resolve the confusion, we synthesized the corresponding pyrrolidine through an alternative approach (Scheme 4). The amination of para -methoxyaryliodide with 2-hydroxymethylpyrrolidine in the presence of Cs 2 CO 3 and a catalytic amount of copper iodide in DMF afforded 13a in 60% isolated yield [47]. To our surprise, the proton NMR of 13a was distinct from that of the originally proposed 13 by Tellitu et al [46].…”

Section: Resultsmentioning

confidence: 90%

Study on the total synthesis of velbanamine: Chemoselective dioxygenation of alkenes with PIFA via a stop-and-flow strategy

Liu¹,

Zheng²,

Liu³

et al. 2013

Beilstein J. Org. Chem.

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SummaryA “stop-and-flow” strategy was developed for the chemoselective dioxygenation of alkenes with a PIFA-initiated cyclization. This method is conceived for the desymmetrization of seco-diene, and a series of substituted 5-hydroxymethyl-γ-lactones were constructed after hydrolysis. This strategy also differentiates terminally substituted alkenes and constitutes a potentially novel synthetic approach for the efficient synthesis toward velbanamine.

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“…Remarkably, this method allows an easy access to nitrogen-containing heterocycles structurally related with alkaloids such as dihydroindoles 10 , tetrahydroisoquinolines 13 , and dihydroindolones 17 . Those benzo-fused nitrogen heterocyclic systems are of significant interest as potential pharmaceutical agents due to their action as enzyme inhibitors, receptor ligands, and hormone release promotors. − …”

Section: Resultsmentioning

confidence: 99%

Ti/Ni-Mediated Inter- and Intramolecular Conjugate Addition of Aryl and Alkenyl Halides and Triflates

et al. 2014

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In this work, we show that the unique combination of a nickel catalyst and Cp2TiCl allows the direct conjugate addition of aryl and alkenyl iodides, bromides, and to a lesser extent, chlorides and triflates to α,β-unsaturated carbonyls at room temperature, without requiring the previous formation of an organometallic nucleophile. The reaction proceeds inter- and intramolecularly with good functional group compatibility, which is key for the development of free protecting group methodologies. Carbo- and heterocycles of five- and six-membered rings are obtained in good yields. Moreover, some insights about the mechanism involved have been obtained from cyclic voltammetry, UV-vis, and HRTEM measurements.

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Synthesis of Diverse 2,3-Dihydroindoles, 1,2,3,4-Tetrahydroquinolines, and Benzo-Fused Azepines by Formal Radical Cyclization onto Aromatic Rings

Cited by 19 publications

References 30 publications

Synthesis of Indolines via a Domino Cu-Catalyzed Amidation/Cyclization Reaction

Synthesis of Indolines via a Domino Cu-Catalyzed Amidation/Cyclization Reaction

Study on the total synthesis of velbanamine: Chemoselective dioxygenation of alkenes with PIFA via a stop-and-flow strategy

Ti/Ni-Mediated Inter- and Intramolecular Conjugate Addition of Aryl and Alkenyl Halides and Triflates

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