Fluorine Effects for Tunable C–C and C–S Bond Cleavage in Fluoro-Julia–Kocienski Intermediates

Open AccessCCS ChemistryRESEARCH ARTICLE1 Jun 2021Fluorine Effects for Tunable C–C and C–S Bond Cleavage in Fluoro-Julia–Kocienski Intermediates Lei Kang†, Yongjia Lin†, Zeng Gao, Jinlong Zhang, Huameng Yang, Qian, Qian Peng Gaoxi Jiang Kang† State Key Laboratory Oxo Synthesis Selective Oxidation, Center Excellence Molecular Synthesis, Suzhou Research Institute of LICP, Lanzhou Chemical Physics (LICP), Chinese Academy Sciences, 730000 Element-Organic Chemistry, College Nankai University, Tianjin 300071 †L. Kang Y. Lin contributed equally to this work.Google Scholar More articles by author , Lin† University Beijing 100049 Gao Google Zhang Yang *Corresponding authors: E-mail Address: [email protected] https://doi.org/10.31635/ccschem.020.202000320 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd favoritesTrack Citations ShareFacebookTwitterLinked InEmail Classical Julia–Kocienski fluoroolefination represents an indispensable platform the construction monofluoroalkenes. Nevertheless, its complex multistep mechanistic manifold along with unrevealed intrinsic “fluorine effect” nucleophilic reactions might be responsible difficult control original stereoselectivity is thus often ambiguous predict. Herein, a novel strategy involving defined fluorine effect new reaction mechanism was developed tunable bond cleavage, providing versatile avenue highly stereoselective easily scalable diverse Density functional theory (DFT) investigations indicate substituents can activate leading α-elimination antiphase orbital interaction. The rate-limiting step were calculated via four-membered transition states ring strain. Both sterically eclipsed repulsion secondary interaction affect stereoselectivity. Download figure PowerPoint Introduction In recent decades, organofluorine chemistry has played important role many aspects pure applied since unique significantly modify chemical entities’ physical, chemical, biological properties1–8 and, sometimes, completely change transformation behavior.9–14 Fluorine substitution on carbanion centers will decrease carbanion’s nucleophilicity, or “negative effect,” which been successfully used organic reactions.15,16 Increasing lead lowered thermal stability carbanions caused fluoride ion that control. Among these, reactivity adjacent carbon atoms yet undisclosed (Scheme 1a). Therefore, further investigation utilization exploit reactions, especially realize activation contiguous C–C/C–X bonds, should streamline synthesis fluorine-containing compounds are achieve traditional methods. As stable bioisostere amide monofluoroalkenes vitally exploitation pharmacologically active candidates material science applications.17 part “olefination toolbox,” classical fluoro-Julia–Kocienski olefinations provide powerful nonselective Z/E simultaneous cleavage two special heteroaryl (benzothiazal-2-yl, pyridin-2-yl, 1-phenyl-1H-tetrazol-5-yl, etc.) electron-deficient aromatic sulfone implanted into starting advance assistant unit released sulfur dioxide 1b).18–20 Highly monofluoroalkenes, trisubstituted ones, still remains formidable challenge due larger steric hindrance minimal energy difference between inseparable stereoisomeric forms.21 Besides metal catalyzed, site-selective defluorinative coupling gem-difluoroalkenes, scarce currently limited 1-aryl-2,2-difluoroalkenes,22–29 metal-free breakthrough achieved Hu group.30,31 They realized smart stepwise extraction independent workup procedure from one-pot Julia–Kocienski-type mixture separate Z E monofluoroisomers. Basically, differences (334 kJ/mol) (276 kJ/mol),32 more favorable. issue, best our knowledge, atom-economical survival sulfonyl group through produce useful (α-fluoro)vinyl sulfones33–36 preferentially selective conversion unprecedented. we employ intermediates, 1c). This method features wide substrate scope, independence conventional groups, exclusive stereoselectivity, complement desulfonated fluoroolefinations. substituent strain rate-determining steps reaction. Scheme 1 | (a) carbanions, (b) fluoroolefination, (c) current strategy. Experimental Method General reactions: dry 5 mL screw cap tube equipped Teflon-coated magnetic stirring bar charged anhydrous Na2SO4 (100 mg), α-fluoro-sulfonylones (1.0 equiv, 0.1 mmol), 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (1.2 0.12 mmol Cs2CO3 as base), aldehyde mmol) 0.5 MeCN. Then stirred heated at 60–80 °C 12 h. After completion monitored thin-layer chromatography (TLC), until materials disappeared, solvent removed vacuum. crude product purified flash column silica gel petroleum ether (PE)/ethyl acetate (EA) = 15∶1 series monofluoroalkene compounds. details characterization methods available Supporting Information. Results Discussion sulfones careful optimization conditions (see Information), proved range readily furnished high yields excellent (E)-stereoselectivity (all E/Z ratio > 50∶1) 2-fluoro-1-phenyl-2-(phenylsulfonyl)ethan-1-one 1a different kinds aldehydes 2 (Table 1). Aromatic 2a– p compatible deliver desired products 3aa– ap good regardless substituted electrical properties rings. Aliphatic 2q– t, even polyformaldehyde 2u, also applicable reaction, assembling corresponding (E)-monofluoroalkenes 3aq– au satisfactory outcomes. Gratifyingly, substrates various heterocyclic such pyridine ( 2v), benzo[b]thiophene 2w), furan 2x), chiral pyrrolidine 2y), imidazole 2z), well tolerated smoothly provided 3av– az 70–92% yields. It noted natural (R)-citronellal 2za) myrac 2zb), furanose 2zc), converted relevant 80–95% Olefinic isomerization observed 2r 2z conjugated (1-fluoroallyl)sulfonyl iso- 3ar 3az. amplified up gram scale without appreciable decreases Accordingly, both 3am 3aq isolated 91% 0.95 g, respectively. Table Substrate Generality Aldehydesa aUnless indicated otherwise, carried out mmol. equiv), DBU MeCN (0.5 mL) 80 bUse (2.0 equiv) instead 60 24 cat room temperature We then investigated scope α-fluoro-β-keto-sulfones 1. shown 2, α-fluoro-β-phenylacetyl bearing 1b–n), ortho-pyridyl 1o), 2-methyl-furanyl 1p), aliphatically benzyl 1q), methyl 1r), cyclohexyl 1s), bulky tertiary butyl groups 1t), reacted 2m, generating 3bm–tm E-selectivity. Other leaving acyl amenable Based benzenesulfonyl substitution, phenylacetyl reactive 1a, 1u, 1v). yield could increased 78% 95% when para-OMe 1u) replaced 1v) group. Pivaloyl 1w) acetyl 1x) α-fluoro-sulfones effective giving 57% 86% yields, Scope α-Fluoro-β-Keto-Sulfonesa demonstrated 3, interesting complementary contradistinctive protocol above decarbonylative fluoro-olefinations, found desulfonation 2-fluoro-1-phenyl-2-((trifluoromethyl)sulfonyl)ethan-1-one 1y employed react 2m afforded 4a higher (89%) than olefination process 1z 1za). With treatment variety aldehydes, adducts 4b–f 80–91% 2za), 2zc) suitable process, 4g–i 3 Aldehyde Desulfonation Processa DFT calculations mentioned earlier, gain insight propose plausible based experiments 2). abstracted hydrogen base obtain intermediate IN1. Oxygen anion IN2 produced addition IN1 2-fluorobenzaldehyde 2m. When R trifluoromethyl, proceeds β-O elimination b-TS2, step. trifluoromethylsulfonate produces vinylcarbonyl 4a. methyl, benzoyl 1,3-migration a-TS2 form a-IN3, where Compared trifluoromethylsulfonate, it release benzoyloxy unit. a-IN3 subsequently undergoes a-TS3 only 7.6 kcal/mol barrier, vinylsulphonyl 3rm. Figures SMD-M06-2X/6–31G(d,p)//6–311+G(d,p) level introduced understand competed C–C/C–S olefins dependent −CH3 −CF3 (for computational details, see Information).37–40 functionals B3LYP-D3 ω-B97XD gave comparable results selected key Information 9-S2). Calculated intermediates C-C/C-S pathways each other C-C rotations facile supporting scan a-IN2 Figure S2. isomer IN2-1 obtained Energy profile pathway a-IN1. low barrier Cα–Cβ rotation omitted clarity, supported While state a-TS2, E-olefin, 8.7 a-TS2-3 cleavage. addition, a-TS2-1 a-TS2-2 Z-isomer illustrated dashed line over 4 suggesting final (E)- 3rm kinetically thermodynamically favorable stereospecific. b-TS2 4.7 b-TS2-2 Z-olefins. (Z)- irreversible stable. Additional substitutions carbonyl calculated, all them experiment, S3 details. Our predicts controlled slight change, substitutions. Plausible calculations. Selectivity Computational analysis conducted reveal classified four Schemes S3–S5 Frontier study how atom promotes (Figure 3).41,42 Yu co-workers43 frontier molecular (FMO) describe electrophilicity nucleophilicity issues discuss issues. analysis. HOMO a-TS2-H. Distortion–interaction a-TS2-3. geometry a-TS2-1. Dihedral angle values given degrees, Z-isomer, adding 180°. (d) NPA charge b-TS2-3. kcal/mol. distance Å. control, effects 3a). relative 9.4 According these highest occupied (HOMO) orbitals, find interacts site antiphase, resulting bond. A lower gap lowest unoccupied (LUMO) rather a-TS2-H (6.03 vs. 6.50 eV) 0.47 eV (10.8 kcal/mol) gives barriers kcal/mol, implying FMO contributions. atom, there in-phase interactions neighboring stabilize orbital. facilitates interaction, consistent dissociation (BDE) a-IN1 a-IN1-H.44,45,a Further using nonfluorinated counterparts 1x 3) afford selectivity reasonably support effect. Controlled experiment Versus For oxygen anionic moiety nucleophilically attacks states, respectively (Figures 3b). LUMO indicates trends accept anions regioselectivity moieties decomposed parts: There distortion energies parts states. concluded 8.0 mainly derived a-IN1, about 30.7 a-TS2-3, forming C4–O1 S–O1 vital anion. 1.42 Å shorter Considering 0.11 radius atoms, 0.17 another one.46,47 suggested C4 O1 S trifluoromethyl b-IN1. Stereoselectivity Z- E-olefins inspection affording stereoisomer (E)-olefins 3c) shows dihedral ∠C3–C2–C1–F E-isomer 15.1° closer coplanar olefin, 21.3° smaller likely because aryl sulfonate Z-isomer. showed trend (E)-isomer, distances F···O F···Ar able support. Substitution Comparing b-TS2-3, 3d). Due electron withdrawing capacities −CF3, negative C2 accumulated b-TS2-3 according nature population (NPA) charge. Also, strong ability interact late a-IN3. stabilized 2.5 free compared −SO2CH3 with−SO2CH3 feasible C2–C4 However, containing −SO2CF3 −SO2CH3, indicating LUMOs contribute S4). Conclusions have (E)-(α-fluoro)vinyl (Z)-α-fluoroenones. results, constrained plays promoting orbitals modes fluorine, chemoselectivity Z/E-olefin slightly changing sulfones. interactions, repulsion, uncovered explain rationalize selectivity. anticipated multisubstituted accurate C–X understanding fluorosulfones may facilitate development insights available. Conflict Interest authors declare no competing financial interests. Acknowledgments gratefully acknowledge National Natural Science Foundation China (nos. 21602231, 21890722, 21702109, 11811530637), Sciences “Light West China” Program, Jiangsu Province BK20160396 BK20191197), Municipality 18JCYBJC21400 19JCJQJC62300), Innovation Project Postgraduate Students (no. 2019YJSB081) Fundamental Funds Central Universities [Nankai (nos.63191515 63196021)] generous Footnote Regarding heterolytic type, 6.0 aIN1-H, substrate. And BDE imply weak References Kirsch P.Modern Fluoroorganic Chemistry; Wiley-VCH: Weinheim, Germany, 2004. 2. Chambers R. D.Fluorine Organic Blackwell: Oxford, U.K., 3. Soloshonok V. A.Fluorine-Containing Synthons; American Society: Washington, DC, 2005. 4. Uneyama K.Organofluorine 2006. 5. Müller K.; Faeh C.; Diederich F.Fluorine Pharmaceuticals: Looking Beyond Intuition.Science2007, 317, 1881–1886. 6. Purser S.; Moore P. 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