Direct Catalytic Enantioselective Benzylation from Aryl Acetic Acids

Journal of the American Chemical Society, Journal Year: 2018, Volume and Issue: 140(50), P. 17418 - 17422

Published: Nov. 18, 2018

We demonstrate that metal-catalyzed enantioselective benzylation reactions of allylic electrophiles can occur directly from aryl acetic acids. The reaction proceeds via a pathway in which decarboxylation is the terminal event, occurring after stereoselective carbon–carbon bond formation. This mechanistic feature enables without generation highly basic nucleophile. Thus, process has broad functional group compatibility would not be possible employing established protocols.

Language: Английский

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Highly Diastereo- and Enantioselective Synthesis of Quinuclidine Derivatives by an Iridium-Catalyzed Intramolecular Allylic Dearomatization Reaction

CCS Chemistry, Journal Year: 2019, Volume and Issue: 1(1), P. 106 - 116

Published: April 1, 2019

Open AccessCCS ChemistryRESEARCH ARTICLE1 Apr 2019Highly Diastereo- and Enantioselective Synthesis of Quinuclidine Derivatives by an Iridium-Catalyzed Intramolecular Allylic Dearomatization Reaction Lin Huang, Yue Cai, Hui-Jun Zhang, Chao Zheng, Li-Xin Dai Shu-Li You Huang State Key Laboratory Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute Organic University Chinese Academy Sciences, 200032 (China) , Cai Zhang Zheng *Corresponding author: E-mail Address: [email protected] Collaborative Innovation Chemical Science Engineering, Tianjin https://doi.org/10.31635/ccschem.019.20180006 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Asymmetric construction quinuclidine derivatives has been realized iridium-catalyzed allylic dearomatization reaction. The catalytic system, derived from [Ir(cod)Cl]2 the Feringa ligand, tolerates a broad range substrates. A large array can be obtained under mild conditions good excellent yields (68%–96%), diastereoselectivity (up >20/1 dr), enantioselectivity >99% ee). These products feature versatile functional group diversity undergo diverse transformations. model that accounts origin stereoselectivity proposed based on density theory (DFT) calculations. Download figure PowerPoint Introduction Quinuclidine, also named 1-azabicyclo[2.2.2]octane, exists number naturally occurring compounds, biologically active agents, privileged catalysts ligands asymmetric catalysis (Figure 1).1–6 In particular, quinine, kind cinchona alkaloid, recognized as medication treatment malaria babesiosis.7,8 are widely utilized homogeneous or heterogeneous various processes such Morita–Baylis–Hillman reactions,4 Sharpless dihydroxylation reactions,5 phase-transfer reactions.6 Therefore, development synthetic approaches efficient novel is great significance. Figure 1 | Selected natural molecules containing scaffolds. this regard, efforts have devoted new methods toward preparation derivatives.9 Traditionally, scaffolds constructed second-order nucleophilic substitution (SN2) reaction condensation piperidine derivatives.10–12 However, most these reactions racemic chiral auxiliary-assisted processes. formed conveniently introducing substituents into ring,13 but scope method rather limited available source starting materials. Catalytic emerged powerful tool transformation planar aromatic compounds highly enantio-enriched three-dimensional molecules.14–49 our ongoing investigate transition-metal-catalyzed reactions, several straightforward protocols access spiroindolenine spiroindoline were revealed.50–53 Recently, we reported unprecedented synthesis indole-annulated, medium-sized ring tetrahydro-γ-carboline- hexahydroazepino[4,3-b]indole-derived carbonates via cascade Ir-catalyzed dearomatization/retro-Mannich/hydrolysis (Scheme 1a).54 Notably, intermediate I was reactive could not isolated. We envisaged if tetrahydro-β-carboline-derived employed protocol, retro-Mannich should avoided due existence two methylene groups between indole nitrogen atom. As consequence, interesting indolenine-fused 2 might afforded major 1b). Herein, report derivatives. Scheme design plan study. Results Our study commenced with evaluation using tetrahydro-β-carboline derivative 1a substrate system consisting iridium precursor [2 mole percent (mol %)] phosphoramidite ligand (4 mol %) tetrahydrofuran (THF) at 50 °C (Table 1).55–85 First, influence ( L1–L8) considered Cs2CO3 (100 base (entries 1–8). L1)86 occurred smoothly (entry 1), delivering product 2a yield (74%) moderate dr value (5.2/1). both diasteroisomers enantiopurity (95% generated L2 Alexakis L3),87 respectively, lead comparable diasteroisomers. dropped slightly 3). addition, Me-THQphos L4) BHPphos L5) developed less terms 4 5). Further more L6–L8) only gave poor 6–8). order improve reaction, bases including DBU, K3PO4, K2CO3, KOAc, NaOAc tested 9–13). found best choice concerning (74%), (7.9/1 ee isomer 96% minor isomer) 13). When no used, completed even after 48 h 14). Inspired work Hartwig co-workers,88 effect counteranion complex examined adding silver salts AgOAc, AgSO3Me, AgOTf, AgBF4 15–18). To delight, all cases, single diastereoisomer. Of particular note, absence base, AgOAc give almost same results 19), while AgSO3Me just 20). Finally, optimal determined described entry 19, where desired isolated 86% ee. Table Optimization Conditionsa Entry L Base Time (h) Yield (%)b drc (major) (%)d (minor) L1 3 74 5.2/1 95 82 4.4/1 94 L3 76 2.9/1 97 4e L4 14 24 8.8/1 / 5e L5 18 5.0/1 6 L6 1.4/1 96 99 7 L7 19 >99 8 L8 42 28 3.0/1 89 85 9 DBU 73 93 10 K3PO4 80 5.4/1 11 K2CO3 6.0/1 12 KOAc 4.5/1 13 7.9/1 23 4.0/1 15f 16g 17h 68 71 18i 83 19/1 91 19f (86j) 20g 6.7/1 Notes: aReaction conditions: (0.2 mmol), (2 %), (2.0 mL) °C. Catalyst prepared nPrNH2 activation.60bCombined diastereoisomers proton nuclear magnetic resonance (1H NMR) analysis CH2Br2 (0.1 mmol) internal standard. cDetermined 1H NMR crude mixtures. dDetermined high-performance liquid chromatography (HPLC) stationary phase. eIn refluxing dioxane. fWith (8 %). gWith hWith AgOTf iWith jIsolated yield. Under optimized conditions, tethered explored examine generality 2). Substrates bearing varied 4-, 5-, 6-position moiety proceed their corresponding yields, diastereo- 2a–2l, 68%–92% 14/1 dr, 88%–96% values lower when seven-substituted indole-derived substrates used 2m, 72% yield, 6/1 95% ee; 2n, 16/1 88% electronic property does show notable influence. either electron-withdrawing (F Cl) electron-donating (Me, MeO, BnO) well tolerated. Moreover, tryptophan-derived substrates, which contain one center ring, underwent smoothly, affording 2o–2q, 91%–96% 8/1 dr). relatively 2q probably caused mismatch R configuration 1q (S,S,Sa)- transition state. gem-dimethyl carboline 2r combined (94%) (>99% [major isomer] 99% [minor isomer]), (1.8/1 carbonate skipped (m = 2), target proceeded well. diastereomeric ratios despite high enantiomeric purity 2s, 71% 94% isomer], 1.1/1 dr; 2t, 69% 1.5/1 stereochemistry 2p (4R,4aR,11S) (4R,4aR,11R) established Overhauser enhancement spectroscopy X-ray crystallographic analysis, respectively.89 absolute other (major isomers) assigned analogy. Substrate scope. activation.60 Combined reported. analysis. Enantiomeric excess (ee) generally exhibit 20/1 It known catalyst Feringa-type control position. utilized, Si-face position allowed attacked. it facial selectivity prochiral nucleophile determines obtained. At stage, calculations90 (M06-2X/SDD/6-31G**) shed some light selectivity. formation selected Two states, TS-2a-( Si ) Re ), leading (4R,4aR) (4R,4aS) 2a, located calculated Gibbs free energy than 1.2 kcal/mol, agreement experimental results. structure relative positively charged allyl electron-rich –synclinal [defined dihedral angle D (Ca–Cb–Cc–Cd), below]. favorable interaction overlapped parts exist help stabilize On hand, antiperiplanar conformation, thus, stabilization expected structure. believe inherent preference 2a.91 noted, strength weak nonbonding sensitive external perturbations. reasonable different solvents counter anions Ir-catalyst employed. Optimized structures Si, Si) Re) (in kcal/mol). (a) (b) side views; (c) (d) Newman projection along forming Cb–Cc bond. associated Ir omitted clarity. green pink, respectively. additional introduced certain positions significantly 2r, 1.8/1 Similar computational investigations applied models. shown 4, difference competitive states TS-2r-( isomers reduced 0.8 kcal/mol. geometric similar ). (–synclinal) (antiperiplanar). causes stronger steric repulsion formal case, exemplified closer hydrogen atom pairs (B[H1⋯H4] 2.15 Å, B(H3⋯H4) 2.09 B[H5⋯H6] 2.10 Å) compared (B[H2⋯H4] 2.37 B[H3⋯H4] 2.16 2.06 Å). brought about overlap diminished energetic gap reduces. situation elongated tether very For state TS-2s'-( keep (–synclinal), strain must suffered bridged cyclic conformation require strong strain.92 minimized 0.3 5 short, qualitatively reproduced trend observed three kinds largely originates beneficial states. will lowered stabilizing neutralized operating Synthetic applications demonstrate utility newly gram-scale carried out. standard 1p 3.76 mmol scale 76% (0.85 g) Gram-scale herein readily transformations Subjecting Pd/C-catalyzed hydrogenation 87% dr. Reduction sodium cyanoborohydride furnished 77% meantime, imine easily converted enamine reacting methyl chloroformate. Transformations products. 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Language: Английский

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Iridium‐Catalyzed Asymmetric Allylic Aromatization Reaction

Angewandte Chemie International Edition, Journal Year: 2019, Volume and Issue: 58(31), P. 10493 - 10499

Published: May 13, 2019

Abstract Described herein is an asymmetric allylic aromatization (AAAr) strategy that employs readily accessible equivalents of benzylic nucleophiles in iridium‐catalyzed substitution reactions with the concomitant formation aromatic rings by aromatization. The optimized reaction conditions involving a catalyst derived from commercially available iridium precursor and Carreira ligand are compatible 4‐ or 5‐methyloxazoles, 5‐methylthiazoles, 5‐methylfurans, 2‐ 3‐methylbenzofurans, 3‐methylbenzothiophene, 3‐methylindole, 1‐methylnaphthalene, methylbenzene. This provides straightforward accesses to valuable heterocyclic compounds, bearing homobenzylic stereogenic center, enantiopure form would be difficult access otherwise. versatility was showcased further elaboration products into useful building blocks drug analogue.

Language: Английский

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Ni-Catalyzed dehydrogenative coupling of primary and secondary alcohols with methyl-N-heteroaromatics

Organic Chemistry Frontiers, Journal Year: 2018, Volume and Issue: 5(22), P. 3250 - 3255

Published: Jan. 1, 2018

Here we report the first base-metal catalyzed dehydrogenative coupling of primary (aromatic, heteroaromatic, and aliphatic) secondary alcohols with methyl-N-heteroaromatics to form various C(sp³)-alkylated N-heteroaromatics.

Language: Английский

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Recent trends in catalytic sp³ C–H functionalization of heterocycles

Organic & Biomolecular Chemistry, Journal Year: 2020, Volume and Issue: 18(4), P. 606 - 617

Published: Jan. 1, 2020

In this mini-review, we attempt to highlight gaps in existing techniques for sp³ C–H activation adjacent heterocycles.

Language: Английский

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Iridium and a Brønsted acid cooperatively catalyzed chemodivergent and stereoselective reactions of vinyl benzoxazinones with azlactones

Chemical Communications, Journal Year: 2019, Volume and Issue: 55(9), P. 1283 - 1286

Published: Jan. 1, 2019

Under cooperative catalysis of iridium and a Brønsted acid, different C4-substituted azlactones react with vinyl benzoxazinones via formal [4+2] cycloaddition or substitution reaction in chemo- stereoselective mode.

Language: Английский

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Asymmetric Formal Nucleophilic o-Cresolylation with Morita–Baylis–Hillman Carbonates of 2-Cyclohexenones via Palladium Catalysis

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(22), P. 9564 - 9569

Published: May 27, 2022

Here we report an asymmetric formal nucleophilic o-cresolylation reaction with the Morita-Baylis-Hillman (MBH) carbonates from 2-cyclohexanones and diverse aldehydes under palladium catalysis, by in situ generation of electron-neutral HOMO-raised η2-Pd(0)-dienone complexes via oxidative insertion/π-σ-isomerization/β-H elimination activation sequence. The subsequent umpolung vinylogous addition to a variety imines is realized upon Pd(0)-mediated π-Lewis base finally furnishing o-cresolylated products followed another cascade π-σ-isomerization/β-H elimination/aromatization process. Moderate excellent diastereo- enantioselectivity are achieved for substantial substrate assemblies employing newly designed bulky chiral phosphonamidite ligand, resultant multifunctional can be facilely elaborated access enantioenriched architectures. In addition, catalytic pathway finely illuminated control experiments.

Language: Английский

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Iridium‐Catalyzed Asymmetric Allylic Substitution of Methyl Azaarenes

Angewandte Chemie International Edition, Journal Year: 2022, Volume and Issue: 61(20)

Published: March 3, 2022

Abstract Herein, an Ir‐catalyzed asymmetric allylic substitution reaction of methyl azaarenes is described. Azaarenes such as (benzo)thiazole, oxazole, benzoimidazole, pyridine, and (iso)quinoline are all tolerated. The corresponding chiral azaarene derivatives obtained in good yields with high enantioselectivity (up to 96 % yield 99 ee). utilization the Knochel reagent TMPZnBr⋅LiBr warrants situ formation benzylic nucleophiles without additional activating reagents. 1 H NMR studies suggested a two‐fold function this reaction. synthetic utility method has been showcased by concise enantioselective synthesis allosteric protein kinase modulator.

Language: Английский

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Borane-Catalyzed Enantioselective α-Alkylation of Unactivated 2-Alkylbenzoxazoles with Electron-Deficient Olefins

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(35), P. 24663 - 24669

Published: Aug. 20, 2024

Chiral borane–catalyzed reactions have recently emerged as a powerful tool for the enantioselective production of chiral scaffolds. In this study, we demonstrated first time that bisborane catalyst can be used α-functionalization 2-alkylazaarenes; specifically, accomplished unprecedented highly α-alkylation unactivated 2-alkylbenzoxazoles with electron-deficient olefins. The strong Lewis acidity and steric bulk were essential to observed reactivity selectivity.

Language: Английский

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Iridium‐Catalyzed Enantioselective Synthesis of Pyrrole‐Annulated Medium‐Sized‐Ring Compounds

Angewandte Chemie International Edition, Journal Year: 2017, Volume and Issue: 56(35), P. 10545 - 10548

Published: June 30, 2017

Abstract Enantioselective synthesis of pyrrole‐annulated medium‐sized‐ring compounds by an iridium‐catalyzed allylic dearomatization/retro‐Mannich/hydrolysis sequence is presented. Various substituted seven‐ and eight‐membered‐ring products were obtained under mild reaction conditions with moderate to good yields excellent enantioselectivity. Additionally, these contain a scaffold widely distributed in natural biologically active compounds. The current method provides convenient way for accessing such pyrrole‐anuulated

Language: Английский

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