Efficient Nickel-Mediated Intramolecular Amination of Aryl Chlorides

Omar‐Amrani, Rafik; Thomas, Antoine; Brenner, Éric; Schneider, Raphaël; Fort, Yves

doi:10.1021/ol034659w

Cited by 194 publications

(91 citation statements)

References 35 publications

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“…A wide variety of functional groups, such as ethers, acetals, halogens, esters, and siloxy or alkyl groups were tolerated on the aryl ring (entries 1-3) and in positions R 2 and R 3 (entries [4][5][6][7][8]. In all cases, the reaction proceeded smoothly and the corresponding substituted indolines were obtained in excellent yield.…”

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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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