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Solvent-Free Selective Condensations Based on the Formation of the Olefinic

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Solvent-Free Selective Condensations Based on the Formation of the Olefinic catalysts Article Solvent-Free Selective Condensations Based on the Formation of the Olefinic (C=C) Bond Catalyzed by Organocatalyst Heyuan Song 1,2, Ronghua Jin 1, Fuxiang Jin 1, Meirong Kang 1, Zhen Li 1,* and Jing Chen 1,* 1 State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, China; [email protected] (H.S.); [email protected] (R.J.); [email protected] (F.J.); [email protected] (M.K.) 2 Graduate school, University of Chinese Academy of Sciences, Beijing 100049, China * Correspondence: [email protected] (Z.L.); [email protected] (J.C.); Tel.: +86-931-496-8056 (Z.L.); +86-931-496-8068 (J.C.); Fax: +86-931-496-8129 (Z.L. & J.C.) Academic Editors: Aurelio G. Csákÿ and Keith Hohn Received: 6 June 2016; Accepted: 14 July 2016; Published: 20 July 2016 Abstract: Pyrrolidine and its derivatives were used to catalyze aldol and Knoevenagel condensations for the formation of the olefinic (C=C) bond under solvent-free conditions. The 3-pyrrolidinamine showed high activity and afforded excellent yields of α,β-unsaturated compounds. The aldol condensation of aromatic/heterocyclic aldehydes with ketones affords enones in high conversion (99.5%) and selectivity (92.7%). Good to excellent yields of α,β-unsaturated compounds were obtained in the Knoevenagel condensation of aldehydes with methylene-activated substrates. Keywords: aldol condensation; Knoevenagel condensation; organocatalysis; solvent-free condition; ketone; aldehyde 1. Introduction The formation of a new olefinic (C=C) bond, which is one of the most fundamental transformations in organic synthesis, is well represented by aldol and Knoevenagel condensations. This transformation is generally achieved in the presence of a strong acid or base such as HCl [1,2], p-toluenesulfonic acid [3], and potassium or sodium hydroxide [4,5]; the drawbacks of poor chemoselectivity and yield, heavy corrosion, difficulty in separation and recovery, and disposal of the spent catalyst have limited the development of these methods. To overcome the disadvantages caused by liquid acids or bases, tremendous efforts toward developing highly efficient and environmentally friendly catalysts have been made in recent years. In this endeavor, the development of organocatalysts is among the most important advances. Organocatalysis have some favorable properties, such as mild reaction conditions, being environmentally friendly, and the allowing for the facile recovery of catalysts [6]. Organic small molecules, especially proline and its structural analogues, as catalysts in the aldol condensation reactions [7–19] and Knoevenagel condensations [20–22] have been reported. As a rule, the major products of most aldol condensations are β-hydroxy ketones; also, the organic solvents employed in these reactions, such as DMSO and DMF, are not environmentally friendly. Recently, it was found that pyrrolidine and piperidine can catalyze the aldol condensation reactions in aqueous medium for the formation of β-hydroxy ketones, and the selectivity for enones is too low [23]. Herein, we report the results of an investigation on the feasibility of the application of cyclic secondary amines as catalysts in aldol and Knoevenagel condensations for the formation of α,β-unsaturated compounds without solvent (Scheme1). Pyrrolidine with two active centers exhibited good catalytic activity which allowed us to develop a new method for the formation of olefinic (C=C) bonds catalyzed by organocatalysts. Catalysts 2016, 6, 106; doi:10.3390/catal6070106 www.mdpi.com/journal/catalysts Catalysts 2016, 6, 106 2 of 8 Catalysts 2016, 6, 106 2 of 8 activeactive centerscenters exhibitedexhibited goodgood catalyticcatalytic activityactivity whichwhich allowedallowed usus toto developdevelop aa newnew methodmethod forfor thethe Catalysts 2016, 6, 106 2 of 8 formationformation ofof olefinicolefinic (C=C)(C=C) bondsbonds catalyzedcatalyzed byby organocatalysts.organocatalysts. OO O O OO ++ R1 R2 R1 R2 RR ++ R R'R' R NH Aldol condensation R1 R2 R2 R1 O NH Aldol condensation R1 R2 R2 R1 O n n R1, R2 = H, allyl, Ph, etc. R1, R2 = H, allyl, Ph, etc. R H one step R H one step R3 R3 R = Ar, Furyl, etc. + R3 R4 R = Ar, Furyl, etc. + R3 R4 R' = H, NH , OH, R' = H, NH 2, OH, RR4 COOH,2 allyl, etc. RR4 COOH, allyl, etc. KnoevenagelKnoevenagel condensationcondensation n = 1 or 2. R3, R4 = CN, COOCH3, COOC2H5, etc. n = 1 or 2. R3, R4 = CN, COOCH3, COOC2H5, etc. SchemeScheme 1. 1. CondensationCondensation reactionreaction of of aromatic/heterocyclic aromatic/heterocyclic aldehydesaldehydes aldehydes withwith with ketonesketones ketones oror or methylenemethylene methylene-‐‐ activatedactivated substrates substrates catalyzed catalyzed by by cyclic cyclic secondary secondary amines. amines. 2.2. ResultsResults Results andand and DiscussionDiscussion Discussion Originally,Originally, a a probe probe reaction reaction of of furaldehydefuraldehyde (10 (10 mmol) mmol) and and butanone butanone (60 (60 mmol) mmol) was was carried carried out out atat 60 60 °C˝°CC underunder solventsolvent solvent-free‐‐freefree conditionsconditions catalyzedcatalyzed byby thesethese cyclic cyclic secondary secondary aminesamines (4(4 mol mol %) %) and and the the resultsresults are are shown shown in in Table Table 1 1.1.. Pyrrolidine PyrrolidinePyrrolidine and andand its itsits derivatives derivativesderivatives exhibited exhibitedexhibited highhighhigh activityactivityactivity (Table(Table(Table1 1,,1, entries entriesentries 1–4),1–4), in in particular particular 3 3-pyrrolidinamine3‐‐pyrrolidinaminepyrrolidinamine and and 3 3-pyrrolidinol3‐‐pyrrolidinolpyrrolidinol were were very very effective. effective. The The best best conversion conversion of of furaldehydefuraldehyde (99.5%)(99.5%) andand selectivity selectivity forfor enones enones (92.7%) (92.7%) werewere obtained obtained over over 3 3-pyrrolidinamine3‐‐pyrrolidinaminepyrrolidinamine inin 1 1 h (Table(Table1 1,,1, entry entryentry 1), 1),1), affording affordingaffording an 83.0%anan 83.0%83.0% isolated isolatedisolated yield yieldyield of 1a ofof. The 1a1a.. conversion TheThe conversionconversion (94.6%) (94.6%)(94.6%) and selectivity andand selectivityselectivity (87.7%) (87.7%)decreased(87.7%) decreaseddecreased slightly whenslightlyslightly 3-pyrrolidinol whenwhen 33‐‐pyrrolidinolpyrrolidinol was used waswas as a usedused catalyst asas a (Tablea catalystcatalyst1, entry (Table(Table 2). As1,1, entryentry for pyrrolidine, 2).2). AsAs forfor pyrrolidine,apyrrolidine, moderate conversionaa moderatemoderate of conversionconversion 80.2% and ofof selectivity 80.2%80.2% andand of selectivityselectivity 62.2% were ofof 62.2%62.2% achieved werewere (Table achievedachieved1, entry (Table(Table 3). We 1,1, entryentry also L 3).investigated3). WeWe alsoalso investigated theinvestigated activity of thetheL-proline, activityactivity which ofof L‐‐proline,proline, was inferior whichwhich in behaviorwaswas inferiorinferior in this inin reaction behaviorbehavior compared inin thisthis reactionreaction to other comparedfive-memberedcompared toto otherother pyrrolidine fivefive‐‐memberedmembered rings. We pyrrolidinepyrrolidine determined rings.rings. the pH WeWe of determineddetermined the 4 mol % thethe aqueous pHpH ofof solution thethe 44 molmol of pyrrolidine%% aqueousaqueous solutionandsolution its derivatives. ofof pyrrolidinepyrrolidine The andand alkalinity itsits derivatives.derivatives. order of theTheThe four alkalinityalkalinity cyclic order secondaryorder ofof thethe amines fourfour cycliccyclic is: pyrrolidine secondarysecondary (13.23) aminesamines > L is:3-pyrrolidinamineis: pyrrolidinepyrrolidine (13.23)(13.23) (12.62) >> 33‐‐pyrrolidinaminepyrrolidinamine > 3-pyrrolidinol (12.62)(12.62) (12.35) >> > 33‐‐Lpyrrolidinolpyrrolidinol-proline (7.28). (12.35)(12.35) The >> result L‐‐prolineproline suggested (7.28).(7.28). The thatThe result cyclicresult suggestedaminessuggested with thatthat moderate cycliccyclic aminesamines alkalinity withwith and moderatemoderate two active alkalinityalkalinity centers andand exhibited twotwo activeactive high centerscenters activity. exhibitedexhibited Plausible highhigh pathways activity.activity. PlausiblearePlausible shown pathwayspathways in Scheme areare2 shownshownand we inin consider SchemeScheme 22 that andand the wewe ratio considerconsider of the thatthat aldol thethe ratioratio condensation ofof thethe aldolaldol was condensationcondensation promoted wasbywas the promotedpromoted hydrogen byby bonding thethe hydrogenhydrogen between bondingbonding the amino betweenbetween group thethe or theaminoamino hydroxy groupgroup group oror thethe of hydroxy 3-pyrrolidinaminehydroxy groupgroup ofof or33‐‐ pyrrolidinamine3-pyrrolidinolpyrrolidinamine and oror the 33‐‐pyrrolidinolpyrrolidinol aldehyde [24 andand,25 ]. thethe aldehydealdehyde [24,25].[24,25]. O O OO O O X NH + X NH R + ++ R R H R1 R2 H R1 R2 R H R1 R2 H R1 R2 - H2O - H2O XX NN HH OO R1 R2 R1 R2 RR X = NH, or O X = NH, or O Scheme 2. A plausible pathway of the aldol condensation catalyzed by 3‐pyrrolidinamine or 3‐ SchemeScheme 2. 2. AA plausible plausible pathway pathway of of the the aldol aldol condensation condensation catalyzed catalyzed by by3‐pyrrolidinamine 3-pyrrolidinamine or 3 or‐ pyrrolidinol. pyrrolidinol.3-pyrrolidinol. CatalystsCatalysts 20162016, 6, 6106, 106 3 of3 of8 8 CatalystsCatalystsCatalysts 2016 2016 2016, 6, ,6 ,106 ,6 106, 106 3 3of 3of 8 of 8 8 CatalystsCatalystsCatalysts 20162016 2016,,, 66,,, 1066106,
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