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One-Pot Fluorination and Organocatalytic Robinson molecules Communication CommunicationOne-pot Fluorination and Organocatalytic Robinson One-potAnnulation Fluorination for Asymmetric and Organocatalytic Synthesis of Mono-Robinson and AnnulationDifluorinated for CyclohexenonesAsymmetric Synthesis of Mono- and Difluorinated Cyclohexenones Xin Huang 1,*, Weizhao Zhao 1, Xiaofeng Zhang 2, Miao Liu 2, Stanley N. S. Vasconcelos 3 and Wei Zhang 2,* Xin Huang 1,*, Weizhao Zhao 1, Xiaofeng Zhang 2, Miao Liu 2, Stanley N. S. Vasconcelos 3 and Wei1 ZhangCollege 2,* of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua 321004, China; [email protected] 1 College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua 321004, China; 2 Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Boulevard, [email protected] Boston, MA 02125, USA; [email protected] (X.Z.); [email protected] (M.L.) 2 Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Boulevard, Boston, 3 Departamento de Farmácia, Universidade de São Paulo, Av. Prof. Lineu Prestes, 580 São Paulo, MA 02125, USA; [email protected] (X.Z.); [email protected] (M.L.) SP 05508-000, Brazil; [email protected] 3 Departamento de Farmácia, Universidade de São Paulo, Av. Prof. Lineu Prestes, 580 São Paulo, * Correspondence: [email protected] (X.H.); [email protected] (W.Z.); SP 05508-000, Brazil; [email protected] Tel.: +1-617-287-6147 (W.Z.); Fax: +1-617-287-6030 (W.Z.) * Correspondence: [email protected] (X.H.); [email protected] (W.Z.); Tel.: +1-617-287-6147 (W.Z.); Fax: +1-617-287-6030 (W.Z.) Received: 4 August 2018; Accepted: 31 August 2018; Published: 4 September 2018 Received: 4 August 2018; Accepted: 31 August 2018; Published: 4 September 2018 Abstract: A one-pot fluorination and organocatalytic Robinson annulation sequence has been Abstract:developed A one-pot for asymmetric fluorination synthesis and oforganocatalytic 6-fluoroyclohex-2-en-1-ones Robinson annulation and 4,6-difluorocyclohex-2-en- sequence has been developed1-ones. The for reactionsasymmetric promoted synthesis by of cinchona 6-fluoroyc alkaloidlohex-2-en-1-ones amine afforded and products 4,6-difluorocyclohex-2-en- bearing two or three 1-ones.stereocenters The reactions in good promoted to excellent by cinchona yields with alkaloid up to amine 99% ee afforded and 20:1 products dr. bearing two or three stereocenters in good to excellent yields with up to 99% ee and 20:1 dr. Keywords: organocatalysis; fluorination; α-fluoro-β-keto ester; Michael addition; Robinson Keywords:annulation; organocatalysis; cyclohexenone fluorination; α-fluoro-β-keto ester; Michael addition; Robinson annulation; cyclohexenone 1. Introduction 1. IntroductionThe development of new synthetic methods for organofluorine compounds is an active topic inThe organic development and medicinal of new synthetic chemistry. methods Introduction for organofluorine of fluorine compounds atom(s) could is an haveactive significanttopic in organicimpact and on medicinal molecules’ chemistry. biological Introduction activity, bioavailability, of fluorine atom(s) and metabolic could have property significant [1–4 ].impact Shown on in molecules’Figure1 arebiological bioactive activity, fluorinated bioavailability, cyclohexenones and metabolic [ 5] including property intermediate [1–4]. Shown for in antitumor Figure 1 agentare bioactiveCOTC (Figurefluorinated1A) [cyclohexenon6], aromatasees inhibitor[5] including (Figure intermediate1B) [ 7], and for retinalantitumor protein agent bacteriorhodopsin COTC (Figure 1A)(Figure [6], aromatase1C) [8]. inhibitor (Figure 1B) [7], and retinal protein bacteriorhodopsin (Figure 1C) [8]. FigureFigure 1. Bio-active 1. Bio-active fluorinated fluorinated cyclohexenones. cyclohexenones. TheThe β-ketoesterβ-ketoester scaffold scaffold is a isversatile a versatile synthon synthon for being for beingboth electrophilic both electrophilic and nucleophilic and nucleophilic sites [9].sites The [9 ].asymmetric The asymmetric Michael Michael addition addition reactions reactions of α-fluoro- of α-fluoro-β-ketoβ-keto esters esters [10–15] [10– 15and] and other other monofluorinatedmonofluorinated nucleophiles nucleophiles [16–19] [16–19 ]is is an an attractive topic.topic. TheseThese nucleophiles nucleophiles have have been been used used to reactto reactwith with nitroolefins nitroolefins [10,11 [10,11,13,14,16,17],,13,14,16,17], N-alkyl N-alkyl maleimides maleimides [12,15], [12,15], chalcones chalcones [18], and [18],α,β-unsaturated and α,β- unsaturated aldehydes [19]. Beside the Michael addition reactions, some Michael addition-initiated Molecules 2018, 23, 2251; doi:10.3390/molecules23092251 www.mdpi.com/journal/molecules Molecules 2018, 23, x; doi: www.mdpi.com/journal/molecules Molecules 2018, 23, 2251 2 of 7 Molecules 2018, 23, x 2 of 7 aldehydes [19]. Beside the Michael addition reactions, some Michael addition-initiated reactions reactionsinvolving involvingα-fluoro- α-fluoro-β-ketoβ esters-keto esters have have also also been been reported reported [20 [20–22].–22]. ThoseThose reactions reactions include include Michael/aldolMichael/aldol (Robinson) (Robinson) [20], [20], Michael/Michael/aldol Michael/Michael/aldol [21], [21], and and Michael/aza-Henry/lactamization sequencessequences [22] [22 ]for for the the construction construction of of cyclohexen cyclohexenones,ones, cyclohexanones, cyclohexanones, and and 2-piperidinones 2-piperidinones bearing bearing multiplemultiple stereocenters. stereocenters. AsAs part part of of our our recent recent effort effort on on the the sy synthesisnthesis of of organofluorine organofluorine compounds compounds using using αα-fluoro--fluoro-ββ-keto-keto estersesters [23–25], [23–25], we we have have reported reported a aone-pot one-pot fluorination/Robinson fluorination/Robinson annu annulationlation sequence sequence for for fluorinated fluorinated cyclohexenonescyclohexenones 1 1(Scheme (Scheme 11A)A) [ [23],23], RobinsonRobinson annulation/dehydrofluorination/aromatizationannulation/dehydrofluorination/aromatization sequencesequence for for phenols phenols 2 (Scheme 2 (Scheme 1B)1 B)[24], [ 24 and], andpyridines pyridines [25]. [We25]. envisioned We envisioned that in that the inpresence the presence of an organocatalyst,of an organocatalyst, such as such cinchona as cinchona alkaloid alkaloid primary primary amine amine cat-1cat-1, the, the one-pot one-pot asymmetric asymmetric synthesis synthesis couldcould be be developed developed for for the the preparation preparation of of monofluorocyclohexenones monofluorocyclohexenones 3 3 and and difluorocyclohexenones difluorocyclohexenones 4 4 (Scheme(Scheme1 1C).C). SchemeScheme 1.1. RobinsonRobinson annulation-based annulation-based one-pot one-pot synthesis. synthesis. 2.2. Results Results and and Discussions Discussions AA number number of of six six organocatalysts organocatalysts were were screened screened fo forr the the asymmetric asymmetric Robinson Robinson annulation annulation reaction reaction ofof chalcone chalcone 6a6a andand αα-fluoro--fluoro-ββ-ketoester-ketoester 5a5a (Table(Table 1,1 ,entries entries 1–6). 1–6). It It was was found found that that the the reaction reaction with with 2020 mol% mol% of of cat-1cat-1 gavegave the desireddesired productproduct3a 3ain in 79% 79% yield yield with with 5:1 5:1 dr dr and and 99% 99% ee (entryee (entry 1), while 1), while other othercatalysts catalysts did notdid givenot give good good results. results. Acidity Acidity of the of reaction the reaction system system plays plays an important an important role in role amine in aminecatalysis catalysis for lowering for lowering the LUMO the LUMO energy ofenergy iminium of iminium ions [26]. ions Thus, [26]. an investigationThus, an investigation of the reactions of the in reactions in the presence of different acids was carried out. The best result was achieved by adding the presence of different acids was carried out. The best result was achieved by adding CF3C6H4CO2H CFto3C afford6H4CO3a2Hin to 89% afford yield 3a with in 89% 9:1 yield dr and with 99% 9:1 ee dr (entry and 99% 10). Weee (entry lowered 10). the We reaction lowered temperature the reaction to temperature−20 ◦C which to − slightly20 °C which increased slightly the increased dr to 12:1, the but dr significantly to 12:1, but decreasedsignificantly the decreased yield to 51% the (entry yield to 13). 51%Because (entry we 13). failed Because to get we the fa crystaliled to of get3 for the X-ray crystal structure of 3 for analysis, X-ray structure the absolute analysis, configuration the absolute of 3a configurationwas deduced of based 3a was on deduced the information based on reported the information in the literature reported [27 in]. Thethe literatureS-amine catalyst [27]. The promoted S-amine a catalyst promoted a highly selective Re-face attack at the Michael acceptor. We believed that our reactions also catalyzed by the S-amine cat-1 could have the same stereochemistry outcome. Molecules 2018, 23, 2251 3 of 7 Moleculeshighly 2018 selective, 23, x Re-face attack at the Michael acceptor. We believed that our reactions also catalyzed3 of 7 by the S-amine cat-1 could have the same stereochemistry outcome. TableTable 1. 1.ScreeningScreening of ofcatalysts catalysts for for the the Robinson Robinson annulation annulation a. a. Entry Cat Additive Yield (%) b dr c ee (%) d Entry Cat Additive Yield (%) b dr c ee (%) d 1 cat-1 C6H5CO2H 79 5:1 99 2 1cat-2 cat-1C6H5CO2HC 6H5CO2HNR 79 5:1- 99 - 2 cat-2 C H CO H NR - - 3 cat-3 C6H5CO2H 6 5 2 NR - - 3 cat-3 C6H5CO2H NR - - 4 cat-4 C6H5CO2H NR - - 4 cat-4 C6H5CO2H NR - - 5 cat-5 C6H5CO2H trace - - 5 cat-5 C6H5CO2H trace - - 6 cat-6 C6H5CO2H 27 3:1 85 6 cat-6 C6H5CO2H 27 3:1 85 7 7cat-1 cat-1 None None42 42 5:15:1 92 92 8 8cat-1 cat-1 AcOH AcOH52 52 6:16:1 92 92 9 9cat-1 cat-1 TsOH TsOH45 45 5:15:1 95 95 10 10cat-1 cat-1CF3C6H4COCF2H3C 6H4CO2H 8989 9:19:1 99 99 11 11cat-1 cat-1CCl3CO2HCCl 3CO2H75 75 8:18:1 90 90 cat-1 12 12cat-1 CF3CO2H CF3CO2H77 77 8:18:1 90 90 13e cat-1 CF C H CO H 51 12:1 99 13e cat-1 CF3C6H4CO2H3 6 4 2 51 12:1 99 a b c 1 a ReactionReaction of of 0.1 0.1 mmol mmol of 5a5aand and 0.15 0.15 mmol mmol of 6aof in6a 0.5 in mL0.5 ofmL MeCN.
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