CCS Chemistry, Год журнала: 2020, Номер 3(1), С. 652 - 664

Опубликована: Май 19, 2020

Open AccessCCS ChemistryRESEARCH ARTICLE1 Jan 2021Visible-Light-Mediated Synthesis of Cyclobutene-Fused Indolizidines and Related Structural Analogs Min Zhu, Xu-Lun Huang, Hao Xu, Xiao Zhang, Chao Zheng Shu-Li You Zhu State Key Laboratory Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute Organic University Chinese Academy Sciences, 200032 School Physical Science Technology, ShanghaiTech University, 201210 , Huang Xu Zhang *Corresponding author(s): E-mail Address: [email protected] https://doi.org/10.31635/ccschem.020.202000254 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Expedient assembly unprecedented molecular scaffolds from readily accessible starting materials a sustainable fashion is highly pursued modern organic chemistry. Herein, the first catalytic intramolecular dearomative [2 + 2] cycloaddition indoles or pyrroles with alkynes achieved via visible-light-mediated energy-transfer catalysis. This method enables synthesis cyclobutene-fused indolizidines, which are otherwise challenging access, high yields exclusive selectivity. The reaction profiles well documented by density functional theory (DFT) calculations. In addition, this protocol can be extended cyclobutane-fused indolizidines related structural analogs. Diverse elaborations products achieved. Download figure PowerPoint Introduction Expansion chemical space construction holds significant position chemistry, due its great potential drug discovery molecules.1–7 regard, there demand expeditious strategies generate previously architectures, particularly desirable if an atom-economic environmental-friendly fashion.8–11 found large number alkaloid natural that display diverse biological pharmacological activities (Scheme 1, top).12–18 Driven their therapeutic potential, numerous methods such as radical cyclizations, aza-Michael cross-coupling, multistep syntheses have been developed access indolizidine-based libraries.19–33 Despite achievements, incorporation pharmaceutically relevant components on still pursued. On other hand, all-carbon four-membered rings including cyclobutanes cyclobutenes privileged cores frequently encountered products, pharmaceuticals, agrochemicals middle).34–42 Owing rigid structures well-defined spatial arrangements, they also recognized promising templates discovery.3,43,44 assemble indolizidine motifs together might but rather strained fused polycyclic contiguous tertiary quaternary stereogenic centers often embedded therein. particular, cyclobutenes, even more than corresponding cyclobutanes, value it offers chances into functionalized valuable skeletons.45–48 Scheme 1 | Visible-light-mediated Dearomatization reactionsa received considerable attention recent years thanks possibility constructing three-dimensional architectures directly functionalizing available aromatic compounds.49–59 To end, we envisioned tethered alkyne moiety enabling strategy complete atom step economy. However, date, only isolated reports intermolecular substituted specialized alkynes, dimethyl acetylenedicarboxylate (DMAD) electronically biased ynenamides, where stoichiometric amount strong acid was required.60–62 Notably, photocycloaddition DMAD under irradiation ultraviolet light. Nevertheless, reactions suffer narrow substrate scope poor functional-group tolerance. More importantly, resultant cycloadducts were easily sensitized again converted ring-opening compounds UV conditions.63–66 Thus, development mild process allows cycloadditions using nonactivated desirable. emergence visible-light catalysis has provided new opportunity reactions.67–91 Strikingly, studies shown advantages rapid selective generation complexity, those difficult environmentally friendly conditions. groups Glorius,87,90,91 Meggers,88 Bach89 made important contributions field.87–91 Our laboratory reported tetracyclic spiroindolines catalysis.92 these examples mainly involve alkenes.93 sharp contrast, no precedent visible-light-induced attributed diminished reactivity relative alkenes, ring strain products.94,c Based considerations, discovered blue LEDs, designed indole-tethered proceeded smoothly rationally chosen iridium-based photosensitizers based calculated triplet–singlet energy gaps [ΔG(T1 − S0)].95,96 A wide synthesized (up 98%) diastereoselectivity (>20∶1 dr). involvement diradical species excited states detailed profile explored controlled experiments DFT applicable involved downstream synthetic transformations. report results study bottom). Experimental Method Indole derivative 1a (54.0 mg, 0.2 mmol) photosensitizer V (4.4 0.004 dry DMSO (20 mL) added flame-dried tube. mixture degassed three freeze–pump–thaw cycles. After thoroughly degassed, vial sealed positioned approximately 5 cm 24 W LEDs. Then stirred at room temperature indicated time (monitored thin layer chromatography) argon atmosphere. Afterward, concentrated rotary evaporation. residue purified silica gel column chromatography (PE/EtOAc = 10/1) afford desired product 2a. experimental details characterization Supporting Information. Results Discussion Optimization conditions launched evaluation terminal (Table 1). Upon exposure (2 mol%) MeOH temperature. benzindolizidine 2a delivered single isomer 53% NMR yield after 12 h (entry Further revealed profound solvent effect outcomes (entries 2–7), optimal (84%) obtained 7). structure configuration determined X-ray crystallographic analysis. series transition-metal-based I– VI further examined 8–12). clear correlation between ΔG(T1 S0) values photosensitizer96 efficiency emerged. Only having similar higher triplet state energies compared (54.6 kcal/mol), III (49.2 IV (57.8 (60.8 (63.5 kcal/mol),97,98 could promote reaction. has, (or shorter time) observed. oxidation/reduction potentials outcomes. Control verified both visible light essential 13 14). Collectively, suggest proceed through mechanism electron transfer (vide infra). Table Reaction Conditionsa Entry Photosensitizer Solvent Time (h) Yield (%)b 53 2 CH2Cl2 58 3 acetone 66 4 THF 36 0 DMF 6 CH3CN 80 7 10 89 (84c) 8 I 9 II 11 88 13d – 14e aReaction conditions: solution (0.2 (c 0.01 M) irradiated LEDs argon. bNMR cIsolated parenthesis. dAbsence photosensitizer. eIn dark. Substrate With optimized hand 7, 1), 2). variety C2-substituted indole substrates produced benzindolizidines ( 2a–2d; R2 CO2Et, CO2Me, Ph, p-FC6H4) good excellent (79–98%). aryl group C2 proved beneficial 2c 2d) because decrease substrates. 1c dropped 52.3 kcal/mol. C3-substituted tolerated. energies, exemplified 1e (59.9 required utilization reach reasonable 2e– 2g (R1 COMe, CN; 21–57%). substituents positions did not affect significantly. general, bearing electron-withdrawing C5 C6 slightly 2j–2m; R3 5-F, 5-Cl, 5-Br, 6-Cl; 79–86%) electron-donating 2h 2i; 5-OMe 5-Me; 70–75%). When linkage employed, seven-membered lactam incorporated 2n (34%). Remarkably, 7-azaindole compatible reaction, producing pyridine-fused compound 2o 49% yield. broadened pyrrole-derived Although absence benzene raised pyrrole lack resonance stabilization unpaired electrons [the 1p 58.4 kcal/mol], 2p–2r) moderate (44–58%) VI. all cases, cyclobutene when switching C3 indoles, dimerization observed instead. scope. asolution h. bVI used. internal next considered 3). bromo-substituted 3a underwent smoothly, leading 4a 89% phenyl- benzoyl-substituted 3b 3c relatively sluggish presence V, respectively. 4b 4c decreased (43%) coformation unidentified side products. Examination that, instead ring, conjugated ynone moieties would light, 59.9 kcal/mol 3c. contrast styrene enone 4b; 50.9 4c; 51.7 kcal/mol). undesired photo-induced transformations unavoidable. Reactions alkynes. Mechanistic shed combined theoretical investigations conducted (see Information details). Stern–Volmer quenching suggested mechanism. then patterns spin population triplet-state 1a-T1 kcal/mol) 3c-T1 quite different, facile kinetic exited cases. As Figure bond-formation event occurs transition TS1 (65.4 TS3 (62.7 minor energetic barriers (10.8 1a-T1, 2.8 3c-T1), indicating fast formation C–C bond upon excitation. subsequent inversion radical–radical recombination open-shell singlet TS2 (44.0 TS4 (39.0 respectively, energetically insignificant. Finally, overall thermodynamically favorable. Gibbs free lower 5.1 3.3 kcal/mol, All agree efficient experimentally. Optimized key intermediates (in ground state. Calculated (U)B3LYP/6-31 G** level theory. densities isosurface purple (Isovalue 0.03) pink –0.03). Underlined Mulliken populations certain atoms. forming bonds highlighted yellow dashes. Values brown distances angstrom. E CO2Et. Extension (benz)indolizidines expected, analogs 4).60,99–104 Various –CO2Me, –CO2Et, –CO2tBu, –C6H5, 4-FC6H4– tolerated derivatives 5a– 5e), delivering 6a– 6e continuous centers—including one—in 80–99% amenable without 2-substituent 6f; 27% 6g; 35%). dearomatization 3-substituted 6h– 6k) tested. We delighted find commonly functionalities aldehyde 5h), ester 5i), ketone 5j), cyano 5k) remained intact during processes center 6k; 85–97%). Substrates possessing either 5l: 6-MeO; 5m: 5-Me) 5n: 5-F; 5o: 5-Cl; 5p: 5-Br) reacted give 6l– 6p (81–99%). 5q prolonged carbon chain aza-indole 5r suitable substrates, 6q 92% 6r 98% yield, illustrative example, structurally distinct 6s constructed 78% simply introducing olefin-tethered link 5s).93,b (benz)indolizidines. (5→6): (1 0.1 bReaction (7→8): 5r) c48 dV e6 Similarly, current method.105–107 Under modified conditions, different substitution esters 7a: –CO2Et; 7b: –CO2Me), ketones 7c: –COCH3; 7d– 7i: –COAr), sensitive 7j: –CHO) accommodated. 8a– 8j 43–87% all-cis-fused configuration. various irrespective electronic properties 7e: 4-MeO; 7f: 4-F; 7g: 3-Cl; 7h: 3-Br; 2-Me) efficiently phenyl ketones. Furthermore, 2-CO2Et additional 3-position 7k– 7n) providing two vicinal ones—in 8k– 8n; 75–85%). Lastly, pyrrolo[1,2-a]azepine feasible 8o; 37%). Gram-scale utility evaluated 5). First, gram-scale 1a, 5i, 5p performed standard giving 2a, 6i, (0.70 g), (1.10 (0.89 showed comparable mmol-scale (a, Subjecting Pd/C-catalyzed hydrogenation cyclobutane 6a (eq treatment LiOH, hydrolyzed deliver carboxylic 80% Cyclopropanation Et2Zn/CH2I2 produce Epoxidation m-CPBA occurred affording 75% 4). confirmed pentacyclic afforded diastereoselectivity. showcase molecules increased complexity. Moreover, 8a C(sp3)-rich 97% amide 6i reduced simultaneously LiAlH4, 54% 6). illustration, palladium-catalyzed Suzuki coupling bromo-containing 4-MeOC6H4B(OH)2 furnish 14 82% 7), demonstrating external functionality (e.g., 4-MeOC6H4−) late stage. (a) Pd/C (10%), H2 atm), MeOH, rt. (b) LiOH (3.0 equiv), THF/H2O (1/1). (c) Et2Zn (8.0 CH2I2 toluene. (d) (4.0 NaHCO3 CH2Cl2. Conclusion conclusion, sustainable, by-product-free approach expedient capitalizes carbon–carbon multiple iridium complexes photosensitizers, heterocycles stereocenters regio- optimization guided established Notable features include broad scope, tolerance groups, operationally simple procedure. Importantly, demonstrated capacity scale-up late-stage functionalizations demonstrates utilities pharmaceutical agrochemical research. Footnotes For selected reviews reactions, see references Roche Porco,49 You.50 b During preparation paper, Oderinde co-workers93 olefin C2-position scaffolds. c Successful cyclization limited. 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