Synthesis of Dihydroisoquinoline and Dihydropyridine Derivatives via Asymmetric Dearomative Three-Component Reaction

CCS Chemistry, Год журнала: 2021, Номер 4(6), С. 2000 - 2008

Опубликована: Июнь 9, 2021

Open AccessCCS ChemistryRESEARCH ARTICLE6 Jun 2022Synthesis of Dihydroisoquinoline and Dihydropyridine Derivatives via Asymmetric Dearomative Three-Component Reaction Guihua Pan, Changli He, Min Chen, Qian Xiong, Weidi Cao Xiaoming Feng Pan Key Laboratory Green Chemistry Technology, Ministry Education, College Chemistry, Sichuan University, Chengdu 610064 , He Chen Xiong *Corresponding authors: E-mail Address: [email protected] https://doi.org/10.31635/ccschem.021.202101060 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail We report the first asymmetric three-component nucleophilic addition/dearomative [4+2] cycloaddition/isomerization cascade transient dipoles generated from N-heteroarenes allenoates with methyleneindolinones in presence chiral N,N′-dioxide/metal complexes. This tandem reaction enabled rapid access versatile polycyclic N-heterocycles good excellent enantioselectivities under mild conditions spite strong background reaction, including 1,2-dihydroisoquinoline, 1,2-dihydropyridine derivatives, others. Meanwhile, a series control experiments were conducted elucidate mechanism roles additives. Download figure PowerPoint Introduction Nitrogen-containing heterocyclic compounds represent largest most diverse family organic compounds, which play crucial role numerous pharmaceuticals agrochemicals.1–4 A recent analysis U.S. Food Drug Administration (U.S. FDA) approved drugs reveals that 59% small-molecule contain at least one N-heterocycle.2 As significant subset such hydroisoquinoline hydropyridine motifs are particularly interesting.1 For instance, skeletons prevalent bioactive alkaloids drug molecules, as crystamidine ( A), jamtine B), haiderine C), emetine D) (Scheme 1a).5–11 Note also hydropyridines useful synthetic intermediates for synthesis complex nitrogenous natural products pharmaceutical targets12–15 exemplified by practical influenza (–)-oseltamivir (Tamiflu, E).13 Therefore, development expeditious entries especially enantioenriched ones containing peripheral functional groups, would make great contribution discovery new molecules or drugs. Scheme 1 | (a b) Representative biologically active N-heterocyclic catalytic dearomative reaction. Dearomatization strategy multicomponent fashion represents efficient methods construction natural-product-like structures,16–21 can easily achieve extended molecular complexity diversity simple starting materials high atomic economy. Huisgen 1,4-dipoles heteroarenes (such pyridine, quinolone, isoquinoline) electrophilic π-systems acetylenic esters, allenoates, diazoesters) broadly explored topic dearomatization chemistry (poly)cyclic N-heterocycles.22–26 Among these activated π-systems, allenoates27–29 an important reagent have been less explored. Only Nair's30,31 Shi's32 groups reported reactions isoquinoline, allenoate, α,β-unsaturated compound ketone, respectively. key 1,4-dipole was involved through addition isoquinoline 1,3-diester substituted allene, subsequently intercepted trapping component cycloaddition, affording derivatives low moderate yields diastereoselectivities. To best our knowledge, enantioselective version this field is still challenge, may be attributed highly reactive short-lived zwitterions, giving rise difficulty stereocontrol.33–35 Inspired performance N,N′-dioxide-based Lewis acid catalysts showed activation stereocontrol methyleneindolinone bidentate coordination,36–39 we proposed stereoselective sequential involving allenoate could realized careful choice type ligand metal salt. Herein, present N-heteroarenes, N,N′-dioxide-Mg(II) complexes 1b). The bicyclic aromatic (isoquinoline, quinoline, phthalazine, phenanthridine), successfully varied, well more challenging monocyclic pyridine because its increased resonance stabilization possibility poisoning system.20,26 result, wide range afforded results conditions. Experimental Methods General procedure 2a oven-dried tube added Mg(OTf)2 (3.2 mg, 0.01 mmol, 10 mol %), L3-Pi c H (4.9 1b (33.1 0.10 mmol) N2 atmosphere. Tetrahydrofuran (THF; 0.5 mL) added, mixture stirred 35 °C 30 min. Then concentrated vacuo, CH2Cl2 (1.0 H2O (0.5 μL) added. Subsequently, (12.9 3a (22.1 0.12 20 air 2 h, then Et3N (0.05 50 %) another h. directly subjected flash column chromatography on silica gel (eluent: petroleum ether/dichloromethane/diethyl ether = 7∶1∶1) afford product 4b. 5a L3-PrEt2Me (4.7 THF 4-phenylpyridine (15.5 3b (18.7 36 (petroleum ether/dichlorometane/ethyl acetate 6:1:1 4∶1) 6a. Results Discussion In initial study, employed 1a electrophile trap intermediate, formed diethyl allenedicarboxylate 3a, optimize (Table 1). preliminary screening, when carried out without ligand/metal salt complex, desired 4a obtained 63% yield diastereoselectivity (2.6∶1 dr), revealing existence 1, entry Next, several salts coordinating N,N′-dioxide L3-PiPr2 tested °C. L3-PiPr2/Mg(OTf)2 promote give 60% yield, >19∶1 diastereomeric ratio (dr), 38% enantiomeric excess (ee) along small amount exocyclic alkene Int-4a (entry 2). When changed into Ni(OTf)2 Zn(OTf)2, but racemic (entries 3 4). surprise, rare-earth used, Y(OTf)3 Yb(OTf)3, nearly optically pure opposite configuration 5 6). Combined previous work40 (see Supporting Information), thought YIII YbIII led deprotection (N-Boc) kinetic resolution process N,N′-dioxide. Subsequent investigation ligands gave better than L3-Pr L3-Ra 7–9). Lowering temperature slightly improved enantioselectivity lower 10). used instead dipolarophile reducing concentration, 4b 73% >19:1 dr 94% ee 12). It should noted accelerate transformation Int-4b higher 13 see Information). reduced reactivity precluded Thus, optimized established 14, 92% dr, ee). Table Optimization Conditions Construction Chiral 1,2-Dihydroisoquinolinesa Entry Metal Salt Ligand T (°C) Yield (%)b drc (%)c — 63 2.6∶1 0 60 38 82 11∶1 4 Zn(OTf)2 54 −99 6 Yb(OTf)3 31 7 81 86 8 77 57 9 64 75 69 18∶1 90 11d 71 91 12d–e 73 94 13d–f 88 14d–g 92 aUnless otherwise noted, all (0.10 mmol), Ligand/metal (1:1, bIsolated yield. cDetermined high-performance liquid (HPLC) supercritical-fluid (SFC) using stationary phase. dPerformed (0.12 mmol). eIn mL). fAt (50 gH2O With hand, substrate scope synthesizing 1,2-dihydroisoquinoline examined Changing ester group iso-propyl steric methyl, ethyl, benzyl, bulkier tert-butyl 2-adamantyl group, diastereoselectivities basically maintained 4a– 4f, 65–92% 10:1–>19:1 85–95% 3-ethylthioester, 3-heteroaromatic ring, 3-benzoyl group-substituted tolerated delivering 4g– 4l (63–80% 71–99% electron-donating substituents (R2) phenyl ring oxindole smoothly converted corresponding cycloaddition 4m– 4q 64–77% 73–99% ee. By comparison, substrates bearing electron-withdrawing yielded π-system 4r– 4t, 54–75% 82–84% variations isoquinolines studied. Generally, different (both -withdrawing C4, C5, C6, C8 positions) reacted form dihydroisoquinoline 4u– 4ad) 52–86% (10:1–>19:1 dr) (78–96% Functional (cyano, nitro) attached precursors amides amines 4w 4ab). investigated effect 4ag isopropyl value 4ag, 86% absolute 4x determined (2′S, 3R, 11b′R) single-crystal X-ray diffraction analysis.a Substrate Scope μL), H/Mg(OTf)2 1H NMR spectroscopy, HPLC SFC bPerformed turned attention nitrogen-containing heterocycles, allenoate.31 Under aforementioned conditions, 4-phenyl 6a results. Upon switching prolonging time h adding base, 77% single diastereomer Information S7). pyridines 3). C4 positions delivered products, exhibited 6b 6c vs 6d). 3-substituted pyridines, diastereo- preserved. However, regioselective situation observed annulation step significantly affected hindrance electronic effect. 3-methyl, 3-chloro, 3-bromo, 3-iodo-substituted took place preferentially hindered C6 position 6e– 6h). Nonetheless, regioselectivity 3-chloride 3-bromo-pyridine 6f/ 6f′ 1.7:1, 6g/ 6g′ 4.8:1). (3-OMe) occurred C2 position, while 6j (3-CN). 3,5-disubstituted lie substituents. 3-bromo-5-fluoropyridine 5k) employed, normal selective 6k 78% 96% ee, 3-bromo-5-methylpyridine 5l). worth noting special selectivity has rarely respect pyridinium salts, pyridine-bearing groups.41–43 1,2-Dihydropyridine Derivativesa L3-PrEt2Me/Mg(OTf)2 (1∶1, (rr) spectroscopy crude product. view utility N-heterocycles, other kinds N-heteroaromatic 3-Methoxy 6-bromoquinolines transformed 8a 8b, enantioselectivitivities obtained, albeit yields. Phthalazine 8c 35% 91% Phenanthridine well, 8d poor (26% 47% Benzimidazole, benzothiazole, benzoxazole did not proceed Investigation Other Heteroaromatic Compoundsa 24 acetanilide internal standard. cPerformed 48 show current system, scale-up 4d performed. shown 2a, 1d (2.5 (3.0 83% 93% Moreover, derivatizations conducted. oxidized m-CPBA generate expected epoxide 9a Treatment Pd/C 60-bar hydrogen pressures, hexahydropyridine derivative 9b 62% 2b). 8′S, 9a′R) N-Ts protected 9b′ Information).b system capable behaving diene Diels–Alder reactions.12,13 example, react dimethyl but-2-ynedioate bridged 9d stereoselectivity 9d, 23% Gram-scale derivatization. get insight mechanism, out. First, deuterium-labelling performed clarify 1,3-H shift process. equiv D2O 75% deuterated [D]- being observed. Furthermore, deuterium-labeled [D2]-3a (88% equivalent amounts [D2]-4a 80.5% D. Even days, completely final products. These two deuterium experiment consistent intramolecular analyzed 3b). obvious Int-6a transferred went (a–c) Control mechanism. Based work,30–32,44–46,c possible pathway 3c). Initially, zwitterion Int-1 situ 2a) diethylallenedicarboxylate 3a). β-Si face H/Mg(II) shielded neighboring cyclohexyl ligand, simultaneous Si/β-Re attack based diastereoselectivities, Int-4b. Nevertheless, step-wise addition/ring closure cannot ruled out.25 Finally, base accelerated [1,3]-hydrogen furnish isomerized Conclusion described dearomatizing zwitterions N,N′-dioxide/Mg(OTf)2 catalyst. (up 99% ee), 1,2-dihydroquinolines, 1,2-dihydropyridines, so on. additives elucidated experiments. cycle explain origin stereoinduction. 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Visible-light-induced organophotocatalytic and singlet oxygen-initiated domino construction of 1,4-dihydropyridines, C-3 functionalized spiro[indoline-3,4′-pyridines] and C-11 functionalized spiro[indeno-[1,2-b]quinoxaline-11,4′-pyridines]

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Язык: Английский

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Язык: Английский

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The iron-catalyzed [4 ​+ ​2] annulation of α,β-unsaturated ketoxime acetates with enaminones has been developed, providing efficient access to highly substituted pyridines in moderate good yields. Notable features the present strategy include low-cost catalytic system, simple and mild reaction condition wide substrate scope. Mechanistic studies reveal that FeCl2 may directly serve as a Lewis acid activate for nucleophilic addition.

Язык: Английский

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The copper-catalyzed [4 + 2] annulation of α,β-unsaturated ketoxime acetates with 1,3-dicarbonyl compounds for the synthesis three classes structurally diverse pyridines has been developed. This method employs as C2 synthons and enables multifunctionalized electron-withdrawing groups in moderate to good yields. mechanistic investigation suggests that reactions proceed through an ionic pathway.

Язык: Английский

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Язык: Английский

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The solvent-free preparation of unsymmetrical N-aryl-5,6-unsubstituted-1,4-dihydropyridines (DHPs) by ball-milling was investigated. Three different mechanochemical domino reactions (one-pot/one step or stepwise) were studied, the process parameters underlying any modulated and differences with solution-based mechanistic pathways disclosed. selection most suitable method driven physical state both reactants intermediates, while final 1,4-DHP directed choice catalyst (Lewis vs Brønsted) type work-up to recover products (by column chromatography precipitation in water). results herein described are unprecedented arena synthetic methods access diversely substituted 1,4-DHPs, an N-heterocyclic scaffold relevant medicinal purposes.

Язык: Английский

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A heterocycle is an important structural scaffold of many organic compounds found in pharmaceuticals, materials, agrochemicals, and biological processes. Azacycles are one the most common motifs a have variety applications, including pharmaceuticals. Therefore, azacycles received significant attention from scientists methods synthesizing been developed because their efficient synthesis plays vital role production useful compounds. In this review, we summarize recent approaches to preparing via different as well describe plausible reaction mechanisms.

Язык: Английский

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Abstract Alkaloids are structurally complex pharmacologically valuable natural products, the synthesis of which attracts attention world scientific community. This review summarizes and highlights recent advancements in total different family alkaloids (such as Lycopodium, Manzamine, Indole, Amaryllidaceae, well other alkaloids) from transformations α,β‐unsaturated aldehydes.

Язык: Английский

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Язык: Английский

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