An Unconventional <i>trans</i> - <i>exo</i> -Selective Cyclization of Alkyne-Tethered Cyclohexadienones Initiated by Rhodium(III)-Catalyzed C–H Activation via Insertion Relay

Open AccessCCS ChemistryRESEARCH ARTICLE1 May 2021An Unconventional trans-exo-Selective Cyclization of Alkyne-Tethered Cyclohexadienones Initiated by Rhodium(III)-Catalyzed C–H Activation via Insertion Relay Yun-Xuan Tan†, Xing-Yu Liu†, Shuo-Qing Zhang†, Pei-Pei Xie, Xin Wang, Kai-Rui Feng, Shao-Qian Yang, Zhi-Tao He, Hong, Ping Tian and Guo-Qiang Lin Tan† The Research Center Chiral Drugs, Innovation Institute Traditional Chinese Medicine, Shanghai University 201203 CAS Key Laboratory Synthetic Chemistry Natural Substances, for Excellence in Molecular Synthesis, Organic Chemistry, Academy Sciences, 200032 †Y.-X. Tan, X.-Y. Liu, S.-Q. Zhang contributed equally to this work.Google Scholar More articles author , Liu† Zhang† Department Zhejiang University, Hangzhou 310027 Xie Google Wang Feng Yang He *Corresponding authors: E-mail Address: [email protected] or Hong Engineering Jiao Tong 200240 https://doi.org/10.31635/ccschem.020.202000339 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd favoritesTrack Citations ShareFacebookTwitterLinked InEmail Different from the established trans-endo-selective cyclization alkyne-tethered electrophiles that involve an E/Z isomerization process, herein, authors present a novel strategy allow trans-exo-selective arylative 1,6-enynes. Through initiation rhodium(III)-catalyzed activation, diverse range N-heterocyclic directing groups, including pyridine, pyrazole, imidazo[1,2-a]pyridine, benzoxazole, benzothiazole, purine, was feasible cascade transformation, exhibiting high efficiency (up 92% yield), broad substrate scope, excellent functional group compatibility. Moreover, modification natural products pharmaceutical compounds also demonstrated showcase its synthetic utility. Based on density theory (DFT) calculations, key three-membered ring intermediate through insertion relay, rather than direct alkenyl rhodium species, controlled stereochemical outcome cyclization. subsequent ring-opening protonation more favored rotamer led exclusive trans-exo-selectivity. Download figure PowerPoint Introduction Transition metal-catalyzed reactions have received significant attention modern organic synthesis become reliable, efficient, step-economical prepare carbo- heterocyclic skeletons, which widely exist products, drug molecules, materials.1–3 Substances containing two potential electrophilic sites would be suitable substrates construction heterocycles selective organometallic species. In view appealing reactivity alkynes,4,5 transition been extensively investigated over past decades.6–20 As shown Scheme 1a, elementary cis-insertion alkyne species usually adopts following ways: α-insertion β-insertion. electronic sterically unbiased alkynes undertake cis-β-insertion form intermediates I, can subsequently cyclize cis-exo-fashion furnish conventional II possessing exocyclic double bond (Scheme Path A). This cis-exo-cyclization pathway well studied various (aldehyde, ketone, imine, ester, isocyanate, nitrile, alkene, alkyne, etc.) using rhodium,6–10 palladium,11–13 other metals14–20 as catalysts. On hand, bearing aryl silyl groups at R1 substituents prefer choose α-position offer metal III 1a). Obviously, cis-cyclization does not occur due geometric constraints. issue first resolved et al.21 nickel-catalyzed nitriles could react with arylboronic acids undergo B). words, bypassed constraints nickel intermediates.22 Concurrently, independent study Clarke al.23 disclosed elegant enantioselective cyclic 1,3-diketones cyclohexadienones acids. They further extended formal allylic phosphates,24 malonate esters,25 amides.26 Later, Ranjith Kumar al.27 reported azides Recently, Petrone al.28 discovered palladium-catalyzed hydrohalogenation 1,6-enynes, crucial E-to-Z vinyl–palladium (Pd) involved step. Thus, both palladium catalyze process cis-α-insertion trans-endo-cyclization 1 | electrophiles. Despite these notable advances, has never uncovered best our knowledge, probably because occurs easily. Therefore, it is quite necessary develop new favor trans-exo-cyclization electrophiles, result, trans-exocyclic accordingly obtained, compensating capacity currently known methods.21–43 Herein, we terminal (1,6-enynes). reaction proceeds pathway44: regioselective arylrhodium generates V, undergoes VI 1b, C). Generally, remains difficult challenging process. Experimental Section A dried Schlenk flask charged (Cp*RhCl2)2 (6.18 mg, 5 mol %), NaBArF4 (42.5 24 2 (0.2 mmol, 1.0 equiv), 4 6 (0.4 2.0 then backfilled argon. Then anhydrous 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP; mL) added. After mixture stirred 60 °C 8 h, filtered, washed ethyl acetate (EtOAc) (10 mL × 3), concentrated vacuo. residue purified flash silica gel chromatography afford desired product 3, 5, 7. For details, please see Supporting Information. Results Discussion Very recently, manganese(I)-catalyzed (1,6-enynes) 2-arylpyridine.45 general, cis-exo-selective 3aa′ obtained major together small amount 3aa [ 3aa:3aa′ = 15∶85, 2, Eq. (1)]. formation attracted special encouraged us explore potentially trans-exo-selectivity Preliminary findings. continuing interest initiated activation,46–48 commenced screen post-transition catalysts transformation [Scheme (2)]. To delight, exclusively (15% yield) observed when conducted catalyst AgSbF6 additive ( 100∶0). yield improved 30% switching [Cp*Rh(MeCN)3](SbF6)2, revealing importance cationic complex. These exciting preliminary findings prompted propose tentative mechanism elaborating 3). First, five-membered rhodacycle A, generated underwent 2a seven-membered B. Next, similar reversible isomerization21–44 between B F occurred rhodium-carbenoid carbocation D. During neighboring pyridine stabilize D pyridinium E. Finally, intramolecular conjugate addition afforded 3aa. Although product, cannot excluded generate 3 proposed mechanism. With above considerations mind, optimization reaction, selected results are summarized Table 1. aprotic solvents, tetrahydrofuran (THF), dimethylformamide (DMF), toluene, 1,2-dichloroethane (DCE) gave albeit low (Table 1, Entries 1−6), except CH3CN Entry 4, 3aa: 2.5∶1). Screening several protic such MeOH, 2,2,2-trifluoroethan-1-ol (TFE), HFIP, enhanced 7−11), HFIP solvent giving up 60% 10), attributed fact possesses dielectric constant nucleophilicity, strongly affect stabilization cation intermediates.49 use cosolvent, 1,4-dioxane water (1∶1), satisfactory yields 7). Lowering temperature did impair 12). Considering important role counter anions Cp*Rh(III)-catalyzed reactions,50 replaced [Cp*Rh(MeCN)3](SbF6)2 combination NaBArF4. increased 82% 13). Reducing loading 1a erosion 14 15). Under optimized conditions, reinvestigated Cp*Co(III)- Cp*Ir(III)-complexes, no 16 17), consistent studies 2. Reaction Condition Optimizationa Catalyst Additive Solvent Temperature (°C) Yield (%)b / Dioxane 100 30 THF DMF 15 28 2.5∶1) Toluene 18 DCE 7 Dioxane/H2O 1∶1 52 MeOH 9 TFEc 38 10 HFIPd 11 HFIP/H2O 35 12 59 13 (Cp*RhCl2)2e NaBArF4f 82(77)g (Cp*RhCl2)2h 45 15i 63 (Cp*IrCl2)2j 0 17 Cp*Co(CO)I2k aReactions were carried out mmol), (1.0 under Ar atmosphere, h. bDetermined 1H NMR analysis unpurified mixtures CH2Br2 internal standard. cTFE 2,2,2-trifluoroethan-1-ol. dHFIP 1,1,1,3,3,3-hexafluoropropan-2-ol. e(Cp*RhCl2)2 (5 %) used instead [Cp*Rh(MeCN)3](SbF6)2. fNaBArF4 sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, (24 used. gYield isolated h(Cp*RhCl2)2 (2.5 (12 i mmol) j(Cp*IrCl2)2 kCp*Co(CO)I2 optimal conditions began scope rhodium-catalyzed 1,6-enynes screened alkyl, benzyl, phenyl proceeded smoothly moderate (33−77%), affording 3aa–3ae). It noteworthy steric hindrance big influence 3ab vs 3ac). Furthermore, aryl-bromide, aryl-cyanide, alkyl-cyanide, ether, halogens (Cl Br), imide, amine, tolerated well, corresponding 78% 3af–3ao). addition, easily available 2p, 2q, 2r derived coumarin, estrone, dehydrocholic acid, applied successfully providing 3ap–3ar). Substrate Scope 1,6-Enynes Pyridinesa A: Reactions performed °C, bYield 3. cNPhth N-phthaloyl. d B: dioxane (0.5 mL), H2O different 2-arylpyridines methyl-substituted examined 2). Various halogen (F, Cl, aldehyde, cyanide para-position rings, compatible 3ba–3ia). relative configuration 3ha undoubtedly confirmed X-ray crystallography. ester meta-position ring, activation selectively less hindered position, only single good 3ja). However, 1k methoxyl provided regioisomers 3ka). para-substitutions all obvious effects observed, electron-withdrawing (cyano nitro) leading lower 3la–3pa). 2-phenyl 5-substituted 1q 3qa). Notably, thiophene 3ra overall trend 2-arylpyridines, neutral electron-donating either aryls pyridines, higher those group. fully support catalytic cycle, benzyl-carbocation ion Subsequently, started evaluate pyrazolyl, imidazo[1,2-a]pyridyl, benzoxazolyl, benzothiazolyl, purinyl, acceptable (33–76%), 5aa– 5la). cyclopropyl allyl survived 5ka stereochemistry 5ea unambiguously Encouraged compatibility next focused molecules. Both estrone- phenylalanine-derived 6a 6b 7aa 7ba). Similarly, fenofibrate clofibrate derivatives amenable 7ca 7da). importantly, commercially substances 1-phenyl-1H-pyrazole 2-phenylpyridine substructure, pyraclostrobin (fungicide), GSK1292263 (GPR119 agonist), atazanavir (HIV-1 protease inhibitor), practicable without requiring pretreatments 7ea– 7ga). Heterocycle, sulfone, hydrazine, amide, even exposed hydroxyl demonstrating remarkable once again. Other Directing Groups Late-Stage Modification Functional Moleculesa C: b cYield dDr value determined NMR. eIsolated gram-scale experiment. gain insight into uncommon series mechanistic experiments 4). deuterium-labeling out. When pentadeuterated [D5]-1a) itself subjected standard deuterium loss ortho-positions [D5]-1a detected. treated min, minor hydrogen/deuterium (H/D) exchange recycled [D4]-3aa 4a). indicated step might faster reversed H/D exchange. intermolecular kinetic isotope effect (KIE) experiment KIE 1.38 implied cleavage rate-determining 4b).51 Intermolecular competition 1c 1h reacting 2a. electron-rich preferentially transformed, suggesting arene-coordination essential 4c).52,53 cyclometalated Cp*Rh(III) complexes C1 C2 prepared Rhodacycle complex relatively 4d, 1). combined employed, significantly suggested go cyclorhodium Mechanistic experiments. Afterwards, control understand unusual trans-selectivity reaction. (Z)-product (E)-product 3ff individually recovered material, stability (Z)- (E)-isomers 4e). Several parallel temperatures cases 4f). supply radical inhibitors, 2,2,6,6-tetramethyl-1-piperinedinyloxy (TEMPO) 2,6-bis(1,1-dimethylethyl)-4-methyl-phenol (BHT), apparent ratio 4g).54–59 upon treatment C-linked 2s observed. Instead, cis-protonation took place produce E-olefin 8as 4h). previous report,23 achieved alkenyl-metal bypass isomerization. We explored calculations (for details about computational studies, Information).60–65 DFT-computed free-energy profiles generation Figure structures states From di-cationic int1, acts Brønsted base deprotonate arene TS2, must overcome 15.7 kcal mol−1 barrier. resulting int3 coordinates give int5, undertakes facile TS6 irreversibly int7. Int7 isomerizes int8 coordination enone moiety, followed TS9 bicyclic int10. efficient possible int7 Information S1), corroborates Z-product int10, styrene moiety requires barrier 13.5 mol−1, favoring int12. Int12 stable int14 coordination. Due sequential insertions, original π-bonds converted σ-bonds int14, allows rotation equilibrium int16 TS15. Owing stereochemistry-determining TS17 opens leads product-coordinated int18, olefin defined Z-form. Int18 ligand liberate regenerate catalytically active int1. changes whole resting state step, 24.9 TS17. Gibbs diagrams pathways Relative configurations clarification. Optimized states. Trivial hydrogens omitted clarity. trans/cis selectivity competitive equilibrated (Figure eventually produces alternative TS19 int20, E-product 3aa′. Our reveal 3.9 preference TS17, supports Z-product. E/Z-selectivity related intrinsic stabilities int16), since energy differences int16) determining TS19). Competition (Z-product) (E-product). hydrogen