3-Nitroindoles Serving as N-Centered Nucleophiles for Aza-1,6-Michael Addition to para-Quinone Methides

An unprecedented N-alkylation of 3-nitroindoles with para-quinone methides was developed for the first time. Using potassium carbonate as the base, a wide range of structurally diverse N-diarylmethylindole derivatives were obtained with moderated to good yields via the protection group migration/aza-1,6-Michael addition sequences. The reaction process was also demonstrated by control experiments. Different from the previous advances where 3-nitrodoles served as electrophiles trapping by various nucleophiles, the reaction herein is featured that 3-nitrodoles is defined with latent N-centered nucleophiles to react with ortho-hydrophenyl p-QMs for construction of various N-diarylmethylindoles.

[1]  Zhi‐Bing Dong,et al.  Recent Advances in Indole Synthesis and the Related Alkylation , 2023, Asian Journal of Organic Chemistry.

[2]  H. Görls,et al.  Latent Pronucleophiles in Lewis Base Catalysis: Enantioselective Allylation of Silyl Enol Ethers with Allylic Fluorides. , 2023, Chemistry.

[3]  L. Ye,et al.  Chiral Brønsted acid-catalyzed asymmetric intermolecular [4 + 2] annulation of ynamides with para-quinone methides , 2023, Science China Chemistry.

[4]  Dong-qiang Zhang,et al.  Direct Catalytic Asymmetric and Regiodivergent N1- and C3- Allenylic Alkylation of Indoles. , 2023, Angewandte Chemie.

[5]  Jian‐Qiang Zhao,et al.  Diastereoselective synthesis of polycyclic indolines via dearomative [4 + 2] cycloaddition of 3-nitroindoles with ortho-aminophenyl p-quinone methides. , 2023, Organic and biomolecular chemistry.

[6]  Lijuan Bai,et al.  Facile construction of dibenzodioxo[3.3.1]nonanes bearing spirocyclohexadienones via domino [4 + 2] cycloaddition/C(sp3)-H oxidative dehydrogenation coupling reactions. , 2022, Organic and biomolecular chemistry.

[7]  Junling Zhao,et al.  Chiral Phosphoric Acid‐Catalyzed Chemo‐ and Enantioselective N‐Alkylation of Indoles with Imines , 2022, Advanced Synthesis & Catalysis.

[8]  Kaikai Wang,et al.  Recent Progress of Electron‐Withdrawing‐Group‐Tethered Arenes Involved Asymmetric Nucleophilic Aromatic Functionalizations , 2022, Advanced Synthesis & Catalysis.

[9]  F. Shi,et al.  Organocatalytic Atroposelective Synthesis of Indole Derivatives Bearing Axial Chirality: Strategies and Applications. , 2022, Accounts of chemical research.

[10]  Jian‐Qiang Zhao,et al.  Organocatalyzed asymmetric dearomative 1,3-dipolar cycloaddition of 2-nitrobenzofurans and N-2,2,2-trifluoroethylisatin ketimines. , 2022, Chirality.

[11]  Kaizhi Li,et al.  Dearomatization of Nitro(hetero)arenes through Annulation , 2022, European Journal of Organic Chemistry.

[12]  Xin-Meng Chen,et al.  Ag-Catalyzed Asymmetric Interrupted Barton-Zard Reaction Enabling the Enantioselective Dearomatization of 2- and 3-Nitroindoles. , 2022, Organic letters.

[13]  Jinshan Li,et al.  HFIP-catalyzed highly diastereoselective formal [4 + 2] cyclization to synthesize difluorinated multisubstituted chromans using difluoroenoxysilanes as C2 synthons , 2021, Chinese Chemical Letters.

[14]  Jing Sun,et al.  Diastereoselective synthesis of spiro[chromane-3,3'-indolines] and spiro[chromane-3,2'-indenes] via DBU promoted formal [4 + 2]cycloaddition reaction , 2021, Green Synthesis and Catalysis.

[15]  Jian‐Qiang Zhao,et al.  Catalytic asymmetric dearomative [4 + 2] annulation of 2-nitrobenzofurans and 5H-thiazol-4-ones: stereoselective construction of dihydrobenzofuran-bridged polycyclic skeletons , 2021, Organic Chemistry Frontiers.

[16]  Beeraiah Baire,et al.  Recent Dearomatization Strategies of Benzofurans and Benzothiophenes , 2021 .

[17]  Zhinong Gao,et al.  A Metal-Free Reductive N-Alkylation of Indoles with Aldehydes. , 2021, Organic letters.

[18]  J. Legros,et al.  Reactivity of 3-nitroindoles with electron-rich species. , 2020, Chemical communications.

[19]  F. Shi,et al.  Progresses in organocatalytic asymmetric dearomatization reactions of indole derivatives , 2020, Organic Chemistry Frontiers.

[20]  Y. Zou,et al.  Organocatalytic and enantioselective [4+2] cyclization between hydroxymaleimides and ortho-hydroxyphenyl para-quinone methide-selective preparation of chiral hemiketals. , 2020, Chemical communications.

[21]  Dmitri Trubitsõn,et al.  Enantioselective Catalytic Synthesis of N-alkylated Indoles , 2020, Symmetry.

[22]  S. Tu,et al.  Recent developments in 1,6-addition reactions of para-quinone methides (p-QMs) , 2020, Organic Chemistry Frontiers.

[23]  M. Bandini,et al.  Recent Advances in the Catalytic Functionalization of “Electrophilic” Indoles , 2020 .

[24]  R. Zare,et al.  Chemoselective N-alkylation of Indoles in Aqueous Microdroplets. , 2019, Angewandte Chemie.

[25]  Jian‐Qiang Zhao,et al.  Catalytic asymmetric [4+2] cycloaddition of 1-((2-aryl)vinyl)naphthalen-2-ols with in situ generated ortho-quinone methides for the synthesis of polysubstituted chromanes. , 2019, Chemical communications.

[26]  Y. Zi,et al.  Enantioselective Synthesis of Pyrrolizin-1-ones via Lewis Base Catalyzed N-Allylation of N-Silyl Pyrrole Latent Nucleophiles. , 2019, The Journal of organic chemistry.

[27]  Mi Yan,et al.  Indole: A privileged scaffold for the design of anti-cancer agents. , 2019, European journal of medicinal chemistry.

[28]  Y. Zi,et al.  Latent Nucleophiles in Lewis Base Catalyzed Enantioselective N-Allylation of N-Heterocycles. , 2019, Angewandte Chemie.

[29]  A. Bahamonde,et al.  Enantioselective N-Alkylation of Indoles via an Intermolecular Aza-Wacker-Type Reaction. , 2019, Journal of the American Chemical Society.

[30]  Guang-Jian Mei,et al.  Catalytic Asymmetric [4+2] Cyclization of para ‐Quinone Methide Derivatives with 3‐Alkyl‐2‐vinylindoles , 2018, Advanced Synthesis & Catalysis.

[31]  G. Zhong,et al.  Chiral phosphoric acid catalyzed enantioselective N-alkylation of indoles with in situ generated cyclic N-acyl ketimines. , 2018, Chemical communications.

[32]  N. Szymczak,et al.  The Difluoromethyl Group as a Masked Nucleophile: A Lewis Acid/Base Approach. , 2018, Journal of the American Chemical Society.

[33]  Pengfei Zhang,et al.  Recent Advances in the Catalytic Enantioselective Reactions of para-Quinone Methides. , 2018, Chemistry, an Asian journal.

[34]  O. Silakari,et al.  Indoles as therapeutics of interest in medicinal chemistry: Bird's eye view. , 2017, European journal of medicinal chemistry.

[35]  Jianwei Sun,et al.  Catalytic Asymmetric N-Alkylation of Indoles and Carbazoles through 1,6-Conjugate Addition of Aza-para-quinone Methides. , 2017, Angewandte Chemie.

[36]  K. Rissanen,et al.  Organocatalytic Domino Oxa-Michael/1,6-Addition Reactions: Asymmetric Synthesis of Chromans Bearing Oxindole Scaffolds. , 2016, Angewandte Chemie.

[37]  S. Manju,et al.  Indoles - A promising scaffold for drug development. , 2016, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[38]  K. Scheidt,et al.  Emerging Roles of in Situ Generated Quinone Methides in Metal-Free Catalysis. , 2016, The Journal of organic chemistry.

[39]  D. MacMillan,et al.  Native functionality in triple catalytic cross-coupling: sp3 C–H bonds as latent nucleophiles , 2016, Science.

[40]  Alexander H Sandtorv.  Transition Metal-Catalyzed CH Activation of Indoles , 2015 .

[41]  R. Dalpozzo.  Strategies for the Asymmetric Functionalization of Indoles: An Update , 2015 .

[42]  G. Bartoli,et al.  Organocatalytic strategies for the asymmetric functionalization of indoles. , 2010, Chemical Society reviews.

[43]  M. Hamann,et al.  Marine indole alkaloids: potential new drug leads for the control of depression and anxiety. , 2010, Chemical reviews.

[44]  M. Bandini,et al.  Catalytic functionalization of indoles in a new dimension. , 2009, Angewandte Chemie.

[45]  M. Zeng,et al.  Chiral Brønsted acid catalyzed Friedel-Crafts alkylation reactions. , 2009, Chemical Society reviews.

[46]  E. Barreiro,et al.  From nature to drug discovery: the indole scaffold as a 'privileged structure'. , 2009, Mini reviews in medicinal chemistry.

[47]  Jeffrey T. Kuethe,et al.  Practical methodologies for the synthesis of indoles. , 2006, Chemical reviews.

[48]  Jian‐Qiang Zhao,et al.  Higher-order [10+2] cycloaddition of 2-alkylidene-1-indanones enables the dearomatization of 3-nitroindoles: an access to polycyclic cyclopenta[b]indoline derivatives , 2022, Organic Chemistry Frontiers.

[49]  M. Somei,et al.  Simple indole alkaloids and those with a non-rearranged monoterpenoid unit. , 2005, Natural product reports.