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 of aromatic/heterocyclic with 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; ; solvent-free condition; ;

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 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 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 3 or3‐‐ 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, 106 33 ofof3 8of8 8 OtherOtherOther cyclic cycliccyclic secondary secondarysecondary amines aminesamines could couldcould also alsoalso catalyze catalyzecatalyze the thethe aldol aldolaldol condensation; condensation;condensation; the thethe reaction reactionreaction of ofof OtherOtherOtherOtherOther cycliccyclic cycliccyclic cyclic secondarysecondary secondarysecondary secondary aminesamines aminesamines amines couldcould couldcould could alsoalso alsoalso also catalyzecatalyze catalyzecatalyze catalyze thethethe thethe aldolaldol the aldolaldol aldol condensation;condensation; condensation;condensation; condensation; thethethe thethe reactionreaction thereactionreaction reaction ofof of of furaldehydefuraldehydefuraldehyde and andand butanonebutanonebutanone waswaswas performedperformedperformed ininin thethethe presence presencepresence ofofof indoline, indoline,indoline, piperidine,piperidine,piperidine, ororor 1,2,3,4 1,2,3,41,2,3,4‐‐‐ furaldehydefuraldehydefuraldehydefuraldehydefuraldehydeof furaldehyde andand andand butanonebutanone andbutanonebutanone butanone waswas waswas performedperformed performed wasperformed performed ininin in inthethethe thethe presencepresence in presencepresence the presenceofof of ofindoline,indoline,indoline, indoline,indoline, of indoline,piperidine,piperidine, piperidine,piperidine, piperidine, oror or or1,2,3,41,2,3,4 1,2,3,41,2,3,4‐‐‐ or‐‐ tetrahydroquinolinetetrahydroquinolinetetrahydroquinoline (Table (Table(Table 1, 1,1, entries entriesentries 5–7). 5–7).5–7). Their TheirTheir catalytic catalyticcatalytic activities activitiesactivities seem seemseem to toto be bebe extremely extremelyextremely inferior inferiorinferior to toto tetrahydroquinolinetetrahydroquinolinetetrahydroquinolinetetrahydroquinolinetetrahydroquinoline1,2,3,4-tetrahydroquinoline (Table(Table(Table (Table(Table 1,1, 1,entries1,entries (Table entriesentries 15–7).5–7)., 5–7). entries5–7). TheirTheir TheirTheir 5–7). catalyticcatalytic catalyticcatalytic Their activitiesactivities activities catalyticactivities seemseem seem activitiesseem tototo to betobe be be extremelyextremely seem extremelyextremely to be inferiorinferiorinferior inferior extremelyinferior tototo to to thatthatthat of ofof 3 3‐3pyrrolidinamine.‐‐pyrrolidinamine.pyrrolidinamine. thatthatthatthatthatinferior ofof of 3of3‐‐‐ pyrrolidinamine. 3pyrrolidinamine.3‐‐ topyrrolidinamine.pyrrolidinamine. that of 3-pyrrolidinamine.

TableTableTable 1. 1.1. Catalytic CatalyticCatalytic activity activityactivity of ofof different differentdifferent cyclic cycliccyclic secondary secondarysecondary amines aminesamines on onon the thethe aldol aldolaldol condensation condensationcondensation of ofof TableTableTableTableTable 1.1. 1.1.CatalyticCatalytic Catalytic CatalyticCatalytic activityactivity activityactivity ofofof differentof ofdifferentdifferent differentdifferent cyclic cycliccyclic cycliccyclic secondary secondarysecondary secondarysecondary amines aminesamines aminesamines on the onon aldol on on thethe the condensationthe aldolaldol aldolaldol condensationcondensation condensationcondensation of furaldehyde ofof of of Tablefuraldehyde 1. Catalytic and butanone. activity of different cyclic secondary amines on the aldol condensation of furaldehydefuraldehydefuraldehyde and and and butanone. butanone. butanone. furaldehydefuraldehydefuraldehydefuraldehydeand butanone. andand and butanone.butanone. butanone. OO OO OHOH OO O OO OOOO OHOHOOO OO Cat.Cat. OO OO O OO O OO OHOHOHOO OO OO OO Cat.Cat. OO + OOO + OO O+O+O Cat.Cat.Cat. OO O ++ OO ++ OO O OO O++ ++ ++ + ++ OO O++ + + + OOOO O 1a1a 2a2a 3a3a 1a1a 2a2a 3a3a 1a1a1a 2a2a2a 3a3a3a Sele./% Sele./%Sele./%Sele./% a Sele./%Sele./%Sele./% Entry a a Catalysts Time/h Furaldehyde Con./% Sele./%Sele./% 1a + EntryEntry a a a a CatalystsCatalysts Time/hTime/h FuraldehydeFuraldehyde Con./% Con./% 1a1a + + EntryEntryEntryEntry aa CatalystsCatalystsCatalystsCatalysts Time/hTime/hTime/hTime/h FuraldehydeFuraldehydeFuraldehyde Con./% Con./%Con./% 1a1a 2a2a 3a3a 1a1a 1a+ ++ Entry Catalysts Time/h Furaldehyde Con./% 1a1a 2a2a 3a3a 1a2a + 1a1a1a 1a 2a2a 2a 3a3a 3a 3a 2a2a 1a 2a + 2a 2a2a 2a NHNH22 NHNHNHNH22 NH22 2 1 1 h 99.5 88.9 3.8 1.1 92.7 1 1 1 1 1h 1 h h 99.599.599.5 88.988.988.9 3.83.83.8 1.11.11.1 92.792.792.7 11 1 1 111 h hh1 h 99.5 99.599.5 88.988.9 88.988.9 3.83.8 3.81.11.11.1 1.1 92.792.792.7 92.7 NNN NHNHNN NHH HHH OH OHOHOH OHOHOH 2 1 h 94.6 87.2 0.5 3.2 87.7 2 2 2 1 1h 1 h h 94.694.694.6 87.287.287.2 0.50.50.5 3.23.23.2 87.787.787.7 22 2 2 N 111 h hh1 h 94.6 94.694.6 87.287.2 87.287.2 0.50.5 0.53.23.23.2 3.2 87.787.787.7 87.7 NNN NHNHN HHHHH H 3 1 h 80.2 62.2 0.0 4.2 62.2 3 3 3 N 1 1h 1 h h 80.280.280.2 62.262.262.2 0.00.00.0 4.24.24.2 62.262.262.2 33 3 3 NNN 111 h hh1 h 80.2 80.280.2 62.262.2 62.262.2 0.00.0 0.04.24.24.2 4.2 62.262.262.2 62.2 NHNHN HHHH H 1 h 26.3 62.5 0.8 7.5 63.3 11 h 1h 1 h h 26.3 26.326.3 62.5 62.562.562.5 0.80.8 0.80.8 7.57.5 7.5 63.363.363.3 63.3 OHOH 11 hh1 h 26.326.326.3 62.562.562.5 0.80.80.8 7.57.57.5 63.363.363.3 44 N OHOHOHOHOH 44 4 4 NNN OH 4 NHNHN HHHHH OO 202020 h h h 97.897.897.8 65.965.965.9 4.54.54.5 12.912.912.9 70.470.470.4 H OOOOO 202020 h 20 h20h hh 97.8 97.897.897.8 65.965.9 65.965.965.9 4.54.5 4.54.5 12.912.912.9 12.9 70.470.470.470.4 70.4 O 20 h 97.8 65.9 4.5 12.9 70.4

55 202020 h h h 29.2 29.2 4.6 4.64.6 00 0 73.073.0 73.0 4.64.6 4.6 5 5 N 2020 h h 29.229.2 4.64.6 0 0 73.073.0 4.64.6 55 5 NNN 2020 20 hh h 29.229.229.2 4.64.64.6 00 0 73.073.073.0 4.64.64.6 NHNHN HHHH H

66 6 20202020 h h h h 42.4 42.442.4 60.0 60.060.060.0 6.76.76.7 6.713.313.313.3 13.3 66.766.766.7 66.7 66 66 N 2020 20 h20h hh 42.442.442.442.4 60.060.060.060.0 6.76.76.76.7 13.313.313.313.3 66.766.766.766.7 6 NNN 20 h 42.4 60.0 6.7 13.3 66.7 NHNHN HHHH H

77 7 202020 h h h 37.137.137.1 13.913.913.9 11.111.111.1 8.38.38.3 25.025.025.0 77 7 77 N 202020 h 20 h20h hh 37.1 37.137.137.1 13.913.9 13.913.913.911.111.1 11.111.1 8.38.38.3 8.3 25.025.025.025.0 25.0 7 NNN 20 h 37.1 13.9 11.1 8.3 25.0 NHNHN HHHHH a a H Reactiona Reactiona conditions: conditions: Amount Amount of of catalyst catalyst is is 4 4 mol mol %, %, butanone/furaldehyde butanone/furaldehyde = = 6:1 6:1 (mol (mol ratio), ratio), 60 60 °C. °C. aa aReaction Reactiona conditions: conditions: Amount Amount of of catalyst catalyst is is 4 4mol mol %, %, butanone/furaldehyde butanone/furaldehyde = =6:1 6:1 (mol (mol ratio), ratio), ˝60 60 °C. °C. a ReactionReaction ReactionReaction conditions:conditions: conditions: conditions: AmountAmount Amount Amount ofof of catalystcatalyst ofcatalyst catalyst isisis 4is4 is mol mol4 4 mol mol %,%, %, %, butanone/furaldehydebutanone/furaldehyde butanone/furaldehyde = = 6:1 6:1= 6:1 (mol(mol (mol ratio), ratio),ratio),ratio), ratio), 60 6060 C. 60 °C.°C.°C. °C. ToToTo optimize optimizeoptimize the thethe aldol aldolaldol condensation condensationcondensation conditions conditionsconditions of ofof furaldehyde furaldehydefuraldehyde and andand butanone, butanone,butanone, the thethe effects effectseffects of ofof ToToTo To optimizeoptimize optimizeoptimize thethethe thethe aldolaldol aldolaldol condensationcondensation condensationcondensation conditionsconditions conditionsconditions ofof of offuraldehydefuraldehydefuraldehyde furaldehydefuraldehyde andand andand butanone,butanone, butanone,butanone, thethethe thethe effectseffects effectseffects ofof of of catalystcatalystcatalyst To loading, loading,loading, optimize the thethe the molar molarmolar aldol condensation ratio ratioratio of ofof butanone butanonebutanone conditions to toto furaldehyde, furaldehyde,furaldehyde, of furaldehyde the thethe and reaction reactionreaction butanone, temperature, temperature,temperature, the effects and ofandand catalyst the thethe catalystcatalystcatalystcatalyst loading,loading,loading, loading,loading, thethethe thethe molarmolar molarmolar ratioratio ratioratio ofof of ofbutanonebutanone butanonebutanone tototo to tofuraldehyde,furaldehyde,furaldehyde, furaldehyde,furaldehyde, thethethe thethe reactionreaction reactionreaction temperature,temperature,temperature, temperature,temperature, andand andand thethethe thethe reactionreactionreactionloading, time timetime the were molarwerewere also alsoalso ratio investigated investigatedinvestigated of butanone with towithwith furaldehyde, 3 3‐3pyrrolidinamine‐‐pyrrolidinaminepyrrolidinamine the reaction as asas the the temperature,the catalyst, catalyst,catalyst, and and and the the the results reactionresultsresults are areare time reactionreactionreactionreaction timetimetime timetime werewere werewere alsoalso alsoalso investigatedinvestigatedinvestigated investigatedinvestigated withwith withwith 33‐ ‐‐ pyrrolidinamine3pyrrolidinamine3‐‐pyrrolidinaminepyrrolidinamine asas as asthethethe thethe catalyst,catalyst, catalyst,catalyst, andand andand thethethe thethe resultsresults resultsresults areare areare summarizedsummarizedsummarizedwere also investigated in inin Table TableTable 2. 2.2. withThe TheThe catalyst 3-pyrrolidinamine catalystcatalyst loading loadingloading had hadhad as thea a agreat great catalyst,great effect effecteffect and on onon the the thethe results reaction. reaction.reaction. are summarized When WhenWhen the thethe percent percent inpercent Table 2 . summarizedsummarizedsummarizedsummarized ininin in inTableTable TableTable 2.2. 2.The2.The TheThe catalystcatalyst catalystcatalyst loadingloadingloading loadingloading hadhad hadhad aa greatagreata greatgreat effecteffect effecteffect onon on on thethethe thethe reaction.reaction. reaction.reaction. WhenWhen WhenWhen thethethe thethe percentpercent percentpercent contentcontentcontentThe catalyst of ofof 3 3‐3pyrrolidinamine‐‐pyrrolidinaminepyrrolidinamine loading had a greatincreased increasedincreased effect from fromfrom on the 1 1 1mol mol reaction.mol % %% to toto 4 When4 4mol molmol % %% the (Table (Table(Table percent 2, 2,2, entries entriesentries content 1–3), 1–3),1–3), of 3-pyrrolidinamine the thethe conversion conversionconversion contentcontentcontentcontent ofof of 3of3‐‐‐ pyrrolidinamine 3pyrrolidinamine3‐‐pyrrolidinaminepyrrolidinamine increasedincreasedincreased increasedincreased fromfromfrom fromfrom 11 mol mol 11 molmol %% % toto%to to 4to4 mol mol 44 molmol %% % (Table(Table%(Table (Table(Table 2,2, entries2,entries2, entriesentries 1–3),1–3), 1–3),1–3), thethethe thethe conversionconversion conversionconversion ofofof furaldehydeincreased furaldehydefuraldehyde from increased increasedincreased 1 mol % from tofromfrom 4 mol44.9% 44.9%44.9% % (Tableto toto 99.8%, 99.8%,99.8%,2, entries and andand a a 1–3), afurther furtherfurther the increase conversion increaseincrease to toto 5 of 5 5mol mol furaldehydemol % %% resulted resultedresulted increased in inin a a a99.7% 99.7%99.7% from ofof of furaldehydeoffuraldehydefuraldehyde furaldehydefuraldehyde increasedincreasedincreased increasedincreased fromfromfrom fromfrom 44.9%44.9% 44.9%44.9% tototo to 99.8%,to99.8%, 99.8%,99.8%, andand andand aa furtherfurther furtheraa furtherfurther increaseincreaseincrease increaseincrease tototo to 5to5 mol mol55 molmol %% % resulted%resulted resultedresulted ininin in aina 99.7% 99.7%aa 99.7%99.7% conversionconversionconversion44.9% to (Table 99.8%, (Table(Table 2, and2,2, entry entryentry a further 4). 4).4). The TheThe increase selectivity selectivityselectivity to for 5 forfor mol enones enonesenones % resulted showed showedshowed in a a amaximum maximum 99.7%maximum conversion with withwith the thethe (Tablemolar molarmolar2 percent , percentpercent entry 4). conversionconversionconversionconversion (Table(Table(Table (Table(Table 2,2, 2,entry2,entry entryentry 4).4). 4). 4). TheThe TheThe selectivityselectivity selectivityselectivity forforfor forfor enonesenones enonesenones showedshowed showedshowed aa maximum maximumaa maximummaximum withwith withwith thethethe thethe molarmolar molarmolar percentpercent percentpercent contentcontentcontentThe selectivity of ofof the thethe 3 3‐3 forpyrrolidinamine‐‐pyrrolidinaminepyrrolidinamine enones showed increases. increases. aincreases. maximum Hence, Hence,Hence, with the the thethe molar optimal optimaloptimal percent amount amountamount content of ofof ofcatalyst catalystcatalyst the 3-pyrrolidinamine is isis 4 4 4 mol molmol %. %.%. contentcontentcontentcontent ofof of ofthethethe thethe 33 ‐‐‐ pyrrolidinamine3pyrrolidinamine3‐‐pyrrolidinaminepyrrolidinamine increases.increases.increases. increases.increases. Hence,Hence, Hence,Hence, thethethe thethe optimaloptimal optimaloptimal amountamount amountamount ofof of ofcatalystcatalyst catalystcatalyst isisis isis44 mol4mol4 molmol %.%. %. %. IncreasingIncreasingIncreasingincreases. the thethe Hence, molar molarmolar theratio ratioratio optimal of ofof butanone butanonebutanone amount to toto offuraldehyde furaldehydefuraldehyde catalyst is 4is isis mol propitious propitiouspropitious %. Increasing for forfor the thethe thereaction reactionreaction molar (Table (Table(Table ratio of2, 2,2, entries butanone entriesentries IncreasingIncreasingIncreasingIncreasingIncreasing thethethe thethe molarmolar molarmolar ratioratio ratioratio ofof of butanoneofbutanone butanonebutanone tototo to furaldehydetofuraldehydefuraldehyde furaldehydefuraldehyde isisis ispropitiousispropitious propitiouspropitious forforfor forfor thethethe thethe reactionreaction reactionreaction (Table(Table(Table (Table(Table 2,2, 2,entries2,entries entriesentries 3,3,3, 5–8) to 5–8)5–8) furaldehyde because becausebecause the thethe is excess propitiousexcessexcess of ofof one oneone for of ofof the the thethe reaction reactants reactantsreactants (Table makes makesmakes2, entries the thethe equilibrium equilibriumequilibrium 3, 5–8) because shift shiftshift thetowards towardstowards excess the thethe of product one productproduct of the 3,3, 3,5–8)3,5–8) 5–8)5–8) becausebecause becausebecause thethethe thethe excessexcess excessexcess ofof of ofoneone oneone ofof of ofthethethe thethe reactantsreactants reactantsreactants makesmakes makesmakes thethethe thethe equilibriumequilibrium equilibriumequilibrium shiftshift shiftshift towardstowardstowards towardstowards thethethe thethe productproduct productproduct side.side.reactants The The dependence dependence makes the of equilibriumof the the conversion conversion shift of towards of furaldehyde furaldehyde the product and and the the side. selectivity selectivity The dependence for for enones enones of on theon the the conversion reaction reaction of side.side.side.side.side. TheThe The TheThe dependencedependence dependence dependencedependence ofof of of theofthe the thethe conversionconversion conversion conversionconversion ofof of of furaldehydeoffuraldehyde furaldehyde furaldehydefuraldehyde andand and andand thethe the thethe selectivityselectivity selectivity selectivityselectivity forfor for forfor enonesenones enones enonesenones onon on on on thethe the thethe reactionreaction reaction reactionreaction side.temperaturetemperature The dependence was was investigated investigated of the conversion in in the the range range of furaldehydeof of 40–60 40–60 °C °C (Table and(Table the 2, 2, selectivityentries entries 3, 3, 9). 9).for The Theenones results results on showed theshowed reaction that that temperaturetemperaturetemperaturetemperaturetemperature waswas was waswas investigatedinvestigated investigated investigatedinvestigated inin in in theinthe the thethe rangerange range rangerange ofof of of 40–60of40–60 40–60 40–6040–60 °C°C °C °C °C (Table(Table (Table (Table(Table 2,2, 2, 2,entries2,entries entries entriesentries 3,3, 3, 3,9).3,9). 9). 9). 9). TheThe The TheThe resultsresults results resultsresults showedshowed showed showedshowed thatthat that thatthat temperaturewithwith the the temperature temperature was investigated increase increase infrom from the 40 range40 °C °C to toof 60 6040–60 °C, °C, the the°C conversion(Table conversion 2, entries and and selectivity 3,selectivity 9). The resultsincreased increased showed from from 85.3%that 85.3% withwithwithwith the the thethe temperature temperature temperaturetemperature increase increase increaseincrease from from fromfrom 40 40 4040 °C °C °C°C to to to to60 60 6060 °C, °C, °C,°C, the the thethe conversion conversion conversionconversion and and andand selectivity selectivity selectivityselectivity increased increased increasedincreased from from fromfrom 85.3% 85.3% 85.3%85.3% with thethe temperaturetemperature increaseincrease fromfrom 40 °C toto 60 °C, thethe conversion and selectivity increasedincreased fromfrom 85.3%

Catalysts 2016, 6, 106 4 of 8 furaldehyde and the selectivity for enones on the reaction temperature was investigated in the range of 40–60 ˝C (Table2, entries 3, 9). The results showed that with the temperature increase from 40 ˝C to 60 ˝C, the conversion and selectivity increased from 85.3% to 99.8% and 83.3% to 87.0%, respectively. The reaction was also influenced by the reaction time (Table2, entries 3, 10–11). When the reactants were stirred for 1 h, the conversion of furaldehyde could reach 99.5%, and the selectivity for enones could reach 92.7%, suggesting the high efficiency of the organocatalysts.

Table 2. Effect of different reaction conditions using 3-pyrrolidinamine as the catalyst.

Amount of Sele./% a Butanone/Furaldehyde/mol ˝ Furaldehyde Entry Temp./ C Time/h Catalyst/mol Ratio Con./% % 1a 2a 3a 1a + 2a 1 1 6:1 60 2 44.9 84.9 1.4 4.1 86.3 2 2 6:1 60 2 81.6 79.5 2.4 4.7 81.9 3 4 6:1 60 2 99.8 85.0 2.0 3.8 87.0 4 5 6:1 60 2 99.7 82.1 3.7 5.2 85.8 5 4 2:1 60 2 50.8 79.4 0.0 7.5 79.4 6 4 3:1 60 2 74.9 78.8 0.0 7.2 78.8 7 4 4:1 60 2 94.0 78.7 2.2 6.0 80.9 8 4 8:1 60 2 100 85.7 3.4 3.4 89.1 9 4 6:1 40 2 85.3 80.2 3.1 5.2 83.3 10 4 6:1 60 0.5 90.9 81.8 2.3 4.5 84.1 11 4 6:1 60 1 99.5 88.9 3.8 1.1 92.7

The applicability of this catalytic system for the reaction of other aromatic/heterocyclic aldehydes and different ketones was also studied and the results were summarized in Table3. The reaction of acetone with furaldehyde affords aldol adducts in good conversion but the selectivity for enone is only 51.4% (Table3, entry 1). The cyclic donor cyclohexanone gave product 1d, with 90.4% conversion and 90.9% selectivity (Table3, entry 2). When acetophenone reacted with furaldehyde at 60 ˝C for 1 h, the conversion was only 56.3% while the selectivity for 1c could reach 100%. Once the reaction time was prolonged to 20 h, the conversion of furaldehyde could be increased by up to 86.2% (Table3, entry 3). To elaborate the synthetic utility further, aromatic aldehydes were also used. The results indicated that aromatics containing electron-donating substituents such as -OCH3 and -CH3 gave corresponding enones with 98.8%–100% conversion and 96.2%–96.8% selectivity within 1 h at 40 ˝C (Table3, entries 4, 5). When benzaldehyde, which does not have any substituents on the aromatic rings, was used as the reactant, 98.6% conversion and 96.0% selectivity for 1e and 2e were also obtained, respectively (Table3, entry 6). The aldol condensation of nitro-substituted aromatic aldehyde with butanone was also successful but the catalytic activity was slightly inferior (Table3, entry 7). Thus, the feasibility of the 3-pyrrolidinamine catalyzing the aldol condensation of butanone with aromatic aldehydes is dependent on the electrophilicity of the respective aldehydes, and electron-rich aldehydes favor the formation of enones, which is consistent with a previous study [23]. Catalysts 2016, 6, 106 4 of 8

to 99.8% and 83.3% to 87.0%, respectively. The reaction was also influenced by the reaction time (Table 2, entries 3, 10–11). When the reactants were stirred for 1 h, the conversion of furaldehyde could reach 99.5%, and the selectivity for enones could reach 92.7%, suggesting the high efficiency of the organocatalysts.

Table 2. Effect of different reaction conditions using 3‐pyrrolidinamine as the catalyst.

Amount of Butanone/ Sele./% Furaldehyde Entry a Catalyst/ Furaldehyde/ Temp./°C Time/h Con./% 1a 2a 3a 1a + 2a mol % mol Ratio 1 1 6:1 60 2 44.9 84.9 1.4 4.1 86.3 2 2 6:1 60 2 81.6 79.5 2.4 4.7 81.9 3 4 6:1 60 2 99.8 85.0 2.0 3.8 87.0 4 5 6:1 60 2 99.7 82.1 3.7 5.2 85.8 5 4 2:1 60 2 50.8 79.4 0.0 7.5 79.4 6 4 3:1 60 2 74.9 78.8 0.0 7.2 78.8 7 4 4:1 60 2 94.0 78.7 2.2 6.0 80.9 8 4 8:1 60 2 100 85.7 3.4 3.4 89.1 9 4 6:1 40 2 85.3 80.2 3.1 5.2 83.3 10 4 6:1 60 0.5 90.9 81.8 2.3 4.5 84.1 11 4 6:1 60 1 99.5 88.9 3.8 1.1 92.7 The applicability of this catalytic system for the reaction of other aromatic/heterocyclic aldehydes and different ketones was also studied and the results were summarized in Table 3. The reaction of acetone with furaldehyde affords aldol adducts in good conversion but the selectivity for enone is only 51.4% (Table 3, entry 1). The cyclic donor cyclohexanone gave product 1d, with 90.4% conversion and 90.9% selectivity (Table 3, entry 2). When acetophenone reacted with furaldehyde at 60 °C for 1 h, the conversion was only 56.3% while the selectivity for 1c could reach 100%. Once the reaction time was prolonged to 20 h, the conversion of furaldehyde could be increased by up to 86.2% (Table 3, entry 3). To elaborate the synthetic utility further, aromatic aldehydes were also used. The results indicated that aromatics containing electron‐donating substituents such as ‐OCH3 and ‐CH3 gave corresponding enones with 98.8%–100% conversion and 96.2%–96.8% selectivity within 1 h at 40 °C (Table 3, entries 4, 5). When benzaldehyde, which does not have any substituents on the aromatic rings, was used as the reactant, 98.6% conversion and 96.0% selectivity for 1e and 2e were also obtained, respectively (Table 3, entry 6). The aldol condensation of nitro‐substituted aromatic aldehyde with butanone was also successful but the catalytic activity was slightly inferior (Table 3, entry 7). Thus, the feasibility of the 3‐pyrrolidinamine catalyzing the aldol condensation of butanone with aromatic aldehydes is dependent on the electrophilicity of the respective aldehydes, and Catalysts 2016, 6, 106 5 of 8 electron‐rich aldehydes favor the formation of enones, which is consistent with a previous study [23].

Table 3. AldolAldol condensation condensation of of aromatic/heterocyclic aromatic/heterocyclic aldehydes aldehydes with with ketones ketones catalyzed catalyzed by by3‐ pyrrolidinamine.3-pyrrolidinamine. O O O OH O OH O Cat. RCHO+ R + R + R + R

R1 R2 R1 R2 R2 R1 R1 R2 R2 R1 1a~h 2a~h 3a~h 4a~h

b: R = furyl, R1 = H, R2 = H c: R = furyl, R1 = H, R2 = Ph d: R = furyl, R1, R2 = -(CH2)3- e: R = phenyl, R1 = H, R2 = CH3 f: R = p-methoxyphenyl, R1 = H, R2 = CH3 g: R = p-methylphenyl, R1 = H, R2 = CH3 h: R = p-nitrophenyl, R = H, R = CH 1 2 3 Reaction Aldehyde Sele./% a Entrya Ketone Aldehyde Reaction Aldehyde Sele./% CatalystsEntry 2016, 6,Ketone 106 Aldehyde Conditions Con./% 1 2 3 4 1 +5 2of 8 CatalystsCatalystsCatalystsCatalysts 2016 2016, ,20166 6 ,2016 ,106 106, 6 , ,6 106, 106 Conditions Con./% 55 of of 8 8 5 5of of 8 8 CatalystsCatalystsCatalysts 2016 2016, 2016,,6 6, ,,106 106, 6 , 106 1 2 3 455 of 1 of +8 85 2 of 8 OO OO O 1 OO O OO OO ˝ 60 °C/1 h 99.4 51.4 39.2 51.4 1 1 11 1 OO O60 60C/160 °C/1 °C/1 h6060 h °C/1h °C/1 h h 99.499.499.4 99.499.4 51.451.4 51.451.4 39.239.2 39.2 39.239.2 51.4 51.4 51.4 51.4 11 1 O O 6060 °C/1 °C/160 h °C/1h h 99.499.4 99.4 51.451.4 51.4 39.239.2 39.2 51.451.4 51.4 OO OO OO O OO O O OO O O O 2 O OO ˝ 60 °C/1 h 90.4 90.9 1.4 90.9 22 22 2 OO O60 60C/160 °C/1 °C/1 h6060 h °C/1h °C/1 h h 90.490.490.4 90.490.4 90.990.9 90.990.9 1.41.4 1.4 1.41.4 90.9 90.9 90.9 90.9 22 2 O 6060 °C/1 °C/160 h °C/1h h 90.490.4 90.4 90.990.9 90.9 1.41.4 1.4 90.990.9 90.9 OO OO OO O

O O 60 ˝C/1 h 56.3 100 0 0 0 100 OOO O 60 °C/1 h 56.3 100 0 0 0 100 O O O 6060 °C/1 °C/16060 h °C/1h °C/1 h h 56.356.3 56.356.3 100100 100100 00 0 00 00 0 0 0100 1000 100100 3 OO OO 6060 °C/1 °C/160 h °C/1h h 56.356.3 56.3 100100 100 00 0 00 00 0 0 100100 100 33 33 3 OO O ˝ 33 3 O 60 C/20 h 86.2 100 0 0 0 100 3 O O 60 °C/20 h 86.2 100 0 0 0 100 OOO O 6060 °C/20 °C/206060 °C/20h h°C/20 h h 86.286.2 86.286.2 100100 100100 00 0 00 00 0 0 0100 1000 100100 O O 6060 °C/20 °C/2060 °C/20 h h h 86.286.2 86.2 100100 100 00 0 00 00 0 0 100100 100

O O O O OO O OO OO 4 4 OO O OO O40 °C/140 h °C/1 h 100 100 81.7 81.715.0 15.01.3 1.30.4 0.496.7 96.7 44 4 4 ˝ 404040 °C/1 °C/1 °C/140 h h °C/1h h 100100100 100 81.781.781.7 81.715.015.015.0 15.01.31.31.3 0.41.30.40.4 0.496.796.796.7 96.7 4 44 H3COH3CO 40 C/140 h°C/140 °C/1h h 100100 100 81.781.7 81.7 15.015.0 15.0 1.31.3 1.30.4 0.4 0.496.7 96.7 H3HCOCO3H3CO HH3CO3COH CO 3 3 O O O OO OO OO OO 5 5 OO O OO O 40 °C/140 h °C/1 h 98.8 98.8 83.1 83.113.1 13.11.2 1.20.5 0.596.2 96.2 5 5 55 40 ˝C/14040 °C/1 h°C/140 h °C/1h h 98.898.898.8 98.8 83.183.183.1 83.1 13.113.113.1 13.11.2 1.21.2 0.51.20.5 0.5 0.596.296.2 96.2 55 5 H3C H3C 4040 °C/1 °C/140 h °C/1h h 98.898.8 98.8 83.183.1 83.113.113.1 13.11.21.2 1.20.50.5 0.596.296.2 96.2 H3HCC 3H3C HH3C3C H3C 3 OO OO O O 6 OO O O OO 40 °C/1 h 98.6 80.6 15.4 1.2 0.6 96.0 66 66 6 O OO O40 ˝40C/140 °C/1 °C/1 h4040 h °C/1h °C/1 h h 98.698.698.6 98.698.6 80.680.6 80.680.615.4 15.4 15.415.41.21.2 1.2 1.20.60.61.2 0.6 0.696.00.696.0 96.0 96.0 66 6 4040 °C/1 °C/140 h °C/1h h 98.698.6 98.6 80.680.6 80.615.415.4 15.41.21.2 1.20.60.6 0.696.096.0 96.0 6 40 °C/1 h 98.6 80.6 15.4 1.2 0.6 96.0

OO OO O O 7 OO O OOO O 40 °C/1 h 95.7 39.7 47.2 5.2 4.7 86.9 77 7 7 O O O˝4040 °C/1 °C/14040 h °C/1h °C/1 h h 95.795.7 95.795.7 39.739.7 39.739.747.247.2 47.247.25.25.2 5.24.74.75.2 4.786.94.786.9 86.986.9 77 77 40 C/14040 °C/1 h°C/140 h °C/1h h 95.795.795.7 95.7 39.739.739.7 39.7 47.247.247.2 47.25.2 5.2 5.24.74.7 4.7 4.786.986.9 86.9 7 O2N O2N 40 °C/1 h 95.7 39.7 47.2 5.2 4.7 86.9 OO2NNO2 2N OO22NNO2N a a 2 a Reactiona Reactiona conditions: conditions: Amount Amount of catalyst of catalyst is 4 mol is 4 %,mol ketone/aldehyde %, ketone/aldehyde = 6:1 =(mol 6:1 (molratio). ratio). a Reactiona Reaction Reactiona conditions: conditions: conditions: Amount Amount Amount of catalyst of of catalyst catalyst is 4 molis is 4 4mol%, mol ketone/aldehyde %, %, ketone/aldehyde ketone/aldehyde = 6:1 = (mol =6:1 6:1 (mol ratio).(mol ratio). ratio). a Reaction Reactiona Reaction Reactionconditions: conditions: conditions: conditions: Amount Amount Amount Amount of of catalyst catalyst of of catalyst catalyst is isis 4 4 mol ismolis 4 4 mol %, mol%, ketone/aldehyde %,ketone/aldehyde %, ketone/aldehyde ketone/aldehyde = = =6:1 6:1 6:1 =(mol (mol (mol6:1 (molratio). ratio). ratio). ToTo obtainobtainToTo obtain obtain moremore more more insightinsight insight insight intointo into the theinto catalytic catalyticthe the catalytic catalytic possibilitiespossibilities possibilities possibilities ofof 33 ‐ ‐ofpyrrolidinamine,pyrrolidinamine, of 3 ‐3pyrrolidinamine,‐pyrrolidinamine, wewe investigated investigatedwe we investigated investigated thethe the the ToTo obtain obtainTo obtain more more more insight insight insight into into into the the catalytic thecatalytic catalytic possibilities possibilities possibilities of of 3 3 ‐of‐pyrrolidinamine,pyrrolidinamine, 3‐pyrrolidinamine, we we investigated investigatedwe investigated the the the KnoevenagelKnoevenagelKnoevenagelKnoevenagel condensationscondensations condensations condensations ofof a a of seriesseriesof a aseries series ofof aldehydes aldehydesof of aldehydes aldehydes withwith with methylenewithmethylene methylene methylene‐‐activatedactivated‐activated‐activated substratessubstrates substrates substrates forfor theforthe for the the KnoevenagelKnoevenagelKnoevenagel condensationscondensations condensations ofof a a of seriesseries a series ofof aldehydes aldehydesof aldehydes withwith with methylenemethylene methylene‐‐activatedactivated‐activated substratessubstrates substrates forfor theforthe the synthesissynthesis ofTo α obtain ,ofβ‐ α αunsaturated,,β‐ moreunsaturated insight compounds. compounds. into the catalyticGood Good to excellent possibilities to excellent yields of yields 3-pyrrolidinamine,were were observed observed in all wein cases. all investigated cases. As can As can the synthesissynthesissynthesissynthesissynthesis of of of α α α, β‐, ofβ‐of,β‐unsaturated α αunsaturatedunsaturated,,β‐β‐unsaturatedunsaturated compounds. compounds. compounds. compounds.compounds. Good Good Good GoodGood to to to excellent excellent excellent toto excellentexcellent yields yields yields yieldsyields were were were were wereobserved observed observed observedobserved in in in all all all in incases. cases. cases. allall cases.cases. As As As can can can AsAs cancan synthesisbeKnoevenagel seen of from α,β‐ Tableunsaturated condensations 4, the condensation compounds. of a series ofGood furaldehyde of aldehydes to excellent with with yields methylene-activated were observed or dimethyl in all substrates cases. malonate As can for was the bebebe seen seen beseenbe seenfrom fromseen from from Table fromTable Table Table Table4, 4, 4,the the the4, 4,condensation condensationthe condensationthe condensation condensation of of of furaldehyde furaldehyde furaldehydeof of furaldehyde furaldehyde with with with with malononitrile malononitrilewith malononitrile malononitrile malononitrile or or or dimethyl dimethyl ordimethyl or dimethyl dimethyl malonate malonate malonate malonate malonate was was was was was bebe seen seensynthesisbe seen from from from Table Table of α Table, β4, 4,-unsaturated the the 4, condensationthecondensation condensation compounds. of of furaldehyde furaldehyde of furaldehyde Good towith with excellent with malononitrile malononitrile malononitrile yields were or or dimethyl dimethyl or observed dimethyl malonate malonate in malonate all cases. was was was As veryveryvery fast fastvery (within fast(within fast (within (within 10 10 min) min) 10 10 min) using min)using using using1 1 mol mol 1 1mol% % mol 3 3‐ ‐%pyrrolidinaminepyrrolidinamine % 3 ‐3pyrrolidinamine‐pyrrolidinamine as as the the as as catalyst. catalyst.the the catalyst. catalyst. The The yieldThe yield The yield of yieldof 5c 5c of was ofwas 5c 5c wasfound found was found found veryveryvery fast fast (within fast (within (within 10 10 min) min) 10 min) using using using 1 1 mol mol 1 mol% % 3 3‐ ‐%pyrrolidinaminepyrrolidinamine 3‐pyrrolidinamine as as the the as catalyst. thecatalyst. catalyst. The The Theyield yield yield of of 5c 5c of was was 5c wasfound found found to beto can94.5% be be 94.5% seenwhen fromwhen the Table condensationthe 4condensation, the condensation was wasdone done of with furaldehyde with malononitrile malononitrile with malononitrile(Table (Table 4, entry 4, orentry dimethyl1). As 1). forAs malonate thefor the tototo be bebetoto 94.5% 94.5% 94.5%bebe 94.5%94.5% when whenwhen whenwhen the thethe condensation condensationthethecondensation condensationcondensation was waswas wasdonewas donedone done done with withwith withwith malononitrile malononitrilemalononitrile malononitrilemalononitrile (Table (Table(Table (Table(Table 4, 4,4, entry entry entry 4,4, entryentry 1). 1).1). As As As1).1). for forAsforAs the theforforthe thethe to dimethylbewas 94.5% very malonate,when fast (within the thecondensation 10 yield min) of using thewas corresponding 1 done mol %with 3-pyrrolidinamine malononitrile product was (Table as92.5% the 4, catalyst. (Tableentry 1).4, The entryAs yieldfor 2). the ofThe 5c dimethyldimethyldimethyldimethyldimethyl malonate,malonate, malonate, malonate, malonate, thethe the yieldthe yield theyield yield yieldofof of the the of theof correspondingthe corresponding thecorresponding corresponding corresponding productproduct product product product waswas was was 92.5%92.5%was 92.5% 92.5% 92.5% (Table(Table (Table (Table (Table 4,4, 4, entry entry 4, entry4, entry entry 2).2). 2). TheThe 2). The2). The The dimethyldimethylwasdimethyl found malonate,malonate, malonate, to be the 94.5%the theyieldyield when yield ofof the thetheof condensation thecorrespondingcorresponding corresponding was productproduct done product with waswas was malononitrile 92.5%92.5% 92.5% (Table(Table (Table (Table 4,4, entry entry4,4 ,entry entry 2).2). TheThe2). 1). The As condensationcondensationcondensationcondensation ofof furaldehydefuraldehyde of of furaldehyde furaldehyde withwith with diethylwithdiethyl diethyl diethyl malonatemalonate malonate malonate tooktook took 11took hh to to1 1h achieve achieve h to to achieve achieve aa 96.8%96.8% a a96.8% 96.8% yieldyield yield ofyieldof 5a5a of (Tableof(Table 5a 5a (Table (Table 4,4, 4, 4, condensationcondensationcondensation of of furaldehyde furaldehyde of furaldehyde with with with diethyl diethyl diethyl malonate malonate malonate took took took 1 1 h h to 1to h achieve achieve to achieve a a 96.8% 96.8% a 96.8% yield yield yield of of 5a 5a of (Table (Table 5a (Table 4, 4, 4, entryentry for3). the Thereafter,3). dimethyl Thereafter, we malonate, westudied studied the the yield thescope ofscope theof corresponding theof the3‐pyrrolidinamine–catalyzed 3‐pyrrolidinamine–catalyzed product was 92.5% Knoevenagel (Table Knoevenagel4, entry 2). entryentryentryentryentry 3).3).3). Thereafter,Thereafter,3).3).Thereafter, Thereafter,Thereafter, wewewe studiedwestudiedwestudied studiedstudied thethethe scopethethescopescope scopescope ofofof the thetheofof 3thethe3‐3‐pyrrolidinamine–catalyzed‐pyrrolidinamine–catalyzedpyrrolidinamine–catalyzed 33‐‐pyrrolidinamine–catalyzedpyrrolidinamine–catalyzed KnoevenagelKnoevenagelKnoevenagel KnoevenagelKnoevenagel entrycondensationThe 3). condensation Thereafter, towards ofwe various furaldehyde studied aromatic the with scope aldehydes diethyl of the malonate with 3‐pyrrolidinamine–catalyzed diethyl took malonate. 1 h to achieve Aromatic a 96.8% Knoevenagelaldehydes yield with of 5a condensationcondensationcondensationcondensationcondensation towardstowards towards towards towards variousvarious various various various aromaticaromatic aromatic aromatic aromatic aldehydesaldehydes aldehydes aldehydes aldehydes withwith with with diethylwithdiethyl diethyl diethyl diethyl malonate.malonate. malonate. malonate. malonate. AromaticAromatic Aromatic Aromatic Aromatic aldehydesaldehydes aldehydes aldehydes aldehydes withwith with with with condensationcondensation(Tablecondensation4, entry towardstowards towards 3). Thereafter, variousvarious various aromaticaromatic we aromatic studied aldehydesaldehydes aldehydes the scope withwith of with diethyldiethyl the diethyl 3-pyrrolidinamine–catalyzed malonate.malonate. malonate. AromaticAromatic Aromatic aldehydesaldehydes aldehydes Knoevenagel withwith with electronelectronelectronelectron‐‐donatingdonating‐donating‐donating or or ‐ ‐withdrawingwithdrawing or or ‐ ‐withdrawing ‐withdrawing substituents substituents substituents substituents reacted reacted reacted reacted efficiently efficiently efficiently efficiently and and relativelyand relatively and relatively relatively quickly quickly quickly quickly with with with diethyl diethylwith diethyl diethyl electronelectronelectron‐‐donatingdonating‐donating or or ‐ ‐ ‐withdrawing withdrawingor ‐withdrawing substituents substituents substituents reacted reacted reacted efficiently efficiently efficiently and and andrelatively relatively relatively quickly quickly quickly with with with diethyl diethyl diethyl malonate,malonate,condensation giving giving condensation towards condensation various products products aromatic 5d–5h 5d aldehydes in–5h high in high yields. with yields. We diethyl observed We malonate.observed a significant a Aromatic significant yield aldehydes yield (91.8%) (91.8%) with malonate,malonate,malonate,malonate,malonate, giving giving giving givinggiving condensation condensation condensation condensationcondensation products products products productsproducts 5d 5d 5d––5h–5h 5d5h5d in in– –in5h 5hhigh high high inin highyields. highyields. yields. yields.yields. We We We observed observed WeobservedWe observedobserved a a asignificant significant significant aa significantsignificant yield yield yield yield yield(91.8%) (91.8%) (91.8%) (91.8%)(91.8%) malonate,inelectron-donating the reaction giving ofcondensation benzaldehyde or -withdrawing products with substituentsdiethyl 5d–5h malonatein high reacted yields. (Table efficiently We 4, observedentry and 4). relativelyThe a significant reactivity quickly yield increased with (91.8%) diethyl with ininin the the thein inreaction reactionthe reactionthe reaction reaction of of of benzaldehyde benzaldehyde benzaldehydeof of benzaldehyde benzaldehyde with with with with diethyl diethylwith diethyl diethyl diethyl malonate malonate malonate malonate malonate (Table (Table (Table (Table (Table 4, 4, 4,entry entry entry4, 4, entry 4).entry 4). 4). The The 4).The 4). reactivity Thereactivity Thereactivity reactivity reactivity increased increased increased increased increased with with with with with inin the themalonate,in reaction reactionthe reaction givingof of benzaldehyde benzaldehyde of benzaldehyde condensation with with products with diethyl diethyl diethyl malonate 5dmalonate– 5hmalonatein high(Table (Table (Table yields. 4, 4, entry entry 4, We entry 4). 4). observed The The 4). Thereactivity reactivity a reactivity significant increased increased increased yield with with (91.8%) with thethe increasingincreasingthethe increasing increasing electronelectron electron electron densitydensity density density ofof thethe of of benzene benzenethe the benzene benzene ringring ring which whichring which which dependsdepends depends depends onon the the on on substituted substitutedthe the substituted substituted groupsgroups groups groups (Table(Table (Table (Table thethe increasing theincreasing increasing electron electron electron density density density of of the the of benzene thebenzene benzene ring ring ring which which which depends depends depends on on the theon substituted thesubstituted substituted groups groups groups (Table (Table (Table 4,4, entriesentries4,4, entries entries 5–7).5–7). 5–7). The5–7).The Thecondensation condensationThe condensation condensation ofof nitrobenzaldehydenitrobenzaldehyde of of nitrobenzaldehyde nitrobenzaldehyde withwith with diethylwithdiethyl diethyl diethyl malonatemalonate malonate malonate waswas was moremorewas more more difficultdifficult difficult difficult 4,4, entriesentries4, entries 5–7).5–7). 5–7). TheThe The condensationcondensation condensation ofof nitrobenzaldehyde nitrobenzaldehydeof nitrobenzaldehyde withwith with diethyldiethyl diethyl malonatemalonate malonate waswas was moremore more difficultdifficult difficult comparedcomparedcomparedcompared to to that that to to thatof of that benzaldehyde benzaldehyde of of benzaldehyde benzaldehyde (Table (Table (Table (Table 4, 4, entry entry 4, 4, entry entry8). 8). 8). 8). comparedcomparedcompared to to that that to thatof of benzaldehyde benzaldehyde of benzaldehyde (Table (Table (Table 4, 4, entry entry 4, entry 8). 8). 8).

TableTableTable Table 4.4. KnoevenagelKnoevenagel 4. 4. Knoevenagel Knoevenagel condensationcondensation condensation condensation ofof aromatic/heterocyclicaromatic/heterocyclic of of aromatic/heterocyclic aromatic/heterocyclic aldehydesaldehydes aldehydes aldehydes withwith with methylenemethylenewith methylene methylene‐‐activatedactivated‐activated‐activated TableTableTable 4.4. KnoevenagelKnoevenagel 4. Knoevenagel condensationcondensation condensation ofof aromatic/heterocyclicaromatic/heterocyclic of aromatic/heterocyclic aldehydesaldehydes aldehydes withwith with methylenemethylene methylene‐‐activatedactivated‐activated substratessubstratessubstratessubstrates catalyzed catalyzed catalyzed catalyzed by by 3 3‐ by‐pyrrolidinamine.pyrrolidinamine. by 3 ‐3pyrrolidinamine.‐pyrrolidinamine. substratessubstratessubstrates catalyzed catalyzed catalyzed by by 3 3 ‐by‐pyrrolidinamine.pyrrolidinamine. 3‐pyrrolidinamine. R R3 Cat. Cat. R33 R3 3 Cat. Cat.Cat. RR33 R R Cat.Cat.Cat. 3 3 RCHORCHO+ R3+ RR3 R4 R4 RCHORCHORCHO++RR3+3 3RR4 R4 4 RCHORCHORCHO++ RR+33 R3 RR44 R4 RRRR4 4 RRRRRR4 4 4 RRRRRR444 5a~h5a~h5a~h5a~h4 4 5a~h5a~h5a~h R = R3 == RCOOC4 = COOCH 2H5 a: R =a: furyl, R = furyl, R3R3 = =RR 34R43 = = =COOC R 4COOC4 = COOC22H5H5 2 2H5 5 a:a: R R = a: =furyl, furyl,R = furyl, RR33 = R= RR R 34= 4 = = R= RCOOC COOC 4= = COOCH COOC22HH552H5 b:a:a: R R Rb:= a:= =furyl, R furyl,Rfuryl, = = furyl, furyl, R3 =3 RR34 =4 =RCOOCH R4 = =COOCH COOCH32 5 3 b: R b:=b: furyl,R R = =furyl, furyl, RRR3 3= = =R R R43 4= = =COOCH COOCH COOCH4 3 3 3 b:b: R R b:= = furyl, Rfuryl, = furyl, RR 3=3 R=R 3R 34== 4= RCN= R 4COOCH 4= = CN COOCH33 3 c: b:R =Rc: furyl, =R furyl, = furyl, R3R3 = =RR 34R43 = = =CN R 4CN4 = CN c:c: R R = c: =furyl, furyl,R = furyl, RR33 = R= RR R 34= 4 = = R= RCN CN 4= = COOC CN H d:c:c: R R Rd:= =c: =phenyl, R furyl,Rfuryl, = = phenyl, furyl, R3 =3 RR34 =4 =RCOOC R4 = =COOC COOC2H5 2HH5 d: R d:=d: phenyl,R R = =phenyl, phenyl, RRR3 3= = =R R R43 4= = =COOC COOC COOC4 2H2HH5 5 2 5 d:d: R R d:= = phenyl,Rphenyl, = phenyl, RR 3=3 R=R 3R 34== 4= RCOOC= R 4COOC 4= = COOC COOCH22H552H2H55 e: d:R =Re: p-hydroxybenyl, =R phenyl, = p-hydroxybenyl, R3R3 = =RR 34R43 = = =COOC R 4COOC4 = COOC22H5H5 2 2H5 5 e:e: R R = e: =p-hydroxybenyl, p-hydroxybenyl,R = p-hydroxybenyl,RR33 = R= RR R 34= 4 = = R= RCOOC COOC 4= = COOC COOC22HH55H2H5 f:e: e: R R Rf:= =e: =p-methoxyphenyl, R p-hydroxybenyl,Rp-hydroxybenyl, = = p-methoxyphenyl, p-hydroxybenyl,R3 =3 RR34 =4 =RCOOC R4 = =COOC COOC2H25 52HH5 f: Rf: =f: p-methoxyphenyl,R R = =p-methoxyphenyl, p-methoxyphenyl,RRR3 3= = =R R R43 4= = =COOC COOC COOC4 2H2HH5 5 2 5 f:f: R R f:= = p-methoxyphenyl, Rp-methoxyphenyl, = p-methoxyphenyl,RR 3=3 R=R 3R 34== 4= RCOOC= R 4COOC 4= = COOC COOCH22H552H2H55 g:f: R R=g: p-methylphenyl, =R p-methoxyphenyl, = p-methylphenyl, R3R3 = =RR 34R43 = = =COOC R 4COOC4 = COOC22H5H5 2 2H5 5 g:g: R R = g: =p-methylphenyl, p-methylphenyl,R = p-methylphenyl,RR33 = R= RR R 34= 4 = = R= RCOOC COOC 4= = COOC COOC22HH55H2H5 h:g:g: R R Rh:= g:= =p-nitrophenyl, R p-methylphenyl, Rp-methylphenyl, = = p-nitrophenyl, p-methylphenyl,RR3 = 3= R RR34 = 4= =RCOOC COOC R4 = =COOC COOC2HH25 52HH5 h:h: R R h:=h: = p-nitrophenyl,R p-nitrophenyl,R = =p-nitrophenyl, p-nitrophenyl, RR3 3 = = RR R43 4 == = RCOOC COOC4 = COOC2 2HH5 5 2H5 h:h: R R h:= = p-nitrophenyl,Rp-nitrophenyl, = p-nitrophenyl, R33 = R344 = COOC4 22H55 2 5 EntryEntry a aa AldehydeAldehyde MethyleneMethylene‐Activated‐Activated Substrates SubstratesTime TimeProduct Product Yield/% Yield/% EntryEntry aEntry a a AldehydeAldehydeAldehyde MethyleneMethyleneMethylene‐Activated‐Activated‐Activated Substrates Substrates SubstratesTimeTimeTimeProductProductProduct Yield/% Yield/% Yield/% EntryEntryEntry a a a AldehydeAldehydeAldehyde MethyleneMethyleneMethylene‐‐ActivatedActivated‐Activated Substrates Substrates SubstratesTimeTimeTimeProductProductProduct Yield/% Yield/% Yield/%

Catalysts 2016, 6, 106 5 of 8

O O 1 60 °C/1 h 99.4 51.4 39.2 51.4 O O O 2 60 °C/1 h 90.4 90.9 1.4 90.9 O

O O 60 °C/1 h 56.3 100 0 0 0 100 3 O 60 °C/20 h 86.2 100 0 0 0 100

O O 4 40 °C/1 h 100 81.7 15.0 1.3 0.4 96.7 H CO 3

O O 5 40 °C/1 h 98.8 83.1 13.1 1.2 0.5 96.2 H C 3 O O 6 40 °C/1 h 98.6 80.6 15.4 1.2 0.6 96.0

O O 7 40 °C/1 h 95.7 39.7 47.2 5.2 4.7 86.9 O2N a Reaction conditions: Amount of catalyst is 4 mol %, ketone/aldehyde = 6:1 (mol ratio). To obtain more insight into the catalytic possibilities of 3‐pyrrolidinamine, we investigated the Knoevenagel condensations of a series of aldehydes with methylene‐activated substrates for the synthesis of α,β‐unsaturated compounds. Good to excellent yields were observed in all cases. As can be seen from Table 4, the condensation of furaldehyde with malononitrile or dimethyl malonate was very fast (within 10 min) using 1 mol % 3‐pyrrolidinamine as the catalyst. The yield of 5c was found to be 94.5% when the condensation was done with malononitrile (Table 4, entry 1). As for the dimethyl malonate, the yield of the corresponding product was 92.5% (Table 4, entry 2). The condensation of furaldehyde with diethyl malonate took 1 h to achieve a 96.8% yield of 5a (Table 4, entry 3). Thereafter, we studied the scope of the 3‐pyrrolidinamine–catalyzed Knoevenagel condensation towards various aromatic aldehydes with diethyl malonate. Aromatic aldehydes with Catalysts 2016, 6, 106 6 of 8 electron‐donating or ‐withdrawing substituents reacted efficiently and relatively quickly with diethyl malonate, giving condensation products 5d–5h in high yields. We observed a significant yield (91.8%) inin the the reaction reaction of of benzaldehyde benzaldehyde with with diethyl diethyl malonate malonate (Table (Table 4, entry4, entry 4). The 4). Thereactivity reactivity increased increased with thewith increasing the increasing electron electron density density of the ofbenzene the benzene ring which ring whichdepends depends on the onsubstituted the substituted groups groups (Table 4,(Table entries4, entries 5–7). 5–7).The condensation The condensation of nitrobenzaldehyde of nitrobenzaldehyde with with diethyl diethyl malonate malonate was was more more difficultdifficult comparedcompared to that of benzaldehyde (Table 4 4,, entry entry 8). 8).

Table 4.4. Knoevenagel condensation ofof aromatic/heterocyclicaromatic/heterocyclic aldehydes with methylene-activatedmethylene‐activated substratessubstrates catalyzed catalyzed by 3 3-pyrrolidinamine.‐pyrrolidinamine. R Cat. 3 RCHO+ R3 R4 RR4 Catalysts 2016, 6, 106 5a~h 5 of 8 a: R = furyl, R3 = R4 = COOC2H5 R = R = COOCH O b:O R = furyl, 3 4 3 1 c: R = furyl,60 °C/1 h R99.43 = R4 = CN 51.4 39.2 51.4 O d: R = phenyl, R3 = R4 = COOC2H5 R = R = COOC H O e: R = p-hydroxybenyl, 3 4 2 5 f: R = p-methoxyphenyl, R3 = R4 = COOC2H5 O R3 = R4 = COOC2H5 2 g: R = p-methylphenyl,60 °C/1 h 90.4 90.9 1.4 90.9 h: R = p-nitrophenyl, R3 = R4 = COOC2H5 O Catalysts 2016, 6, 106 Entry a Aldehyde Methylene‐Activated Substrates Time Product Yield/%5 of 8 CatalystsCatalysts 20162016,, 66,, 106106a 66 ofof 88 CatalystsCatalysts 2016, 6 2016,OEntry 106, 6, 106 Aldehyde Methylene-Activated Substrates Time Product5 Yield/% of 8 6 of 8 60 °C/1 h 56.3 100 0 0 0 100 O O 3 O N N bb OO N N 1 1O1 b O 60 °C/1 h CC99.4 1051.4 min10 min39.294.5 51.4 94.5 1 b O 60 °C/20 Nh CC86.2N 100 10 min0 0 94.50 100 1 1 OOO 60 °C/1 h CC99.4 51.410 min 39.294.5 51.4 Catalysts 2016, 6, 106 O 5 of 8 OO O OO OO 4 Obb OO 40 °C/1 h O O100 81.7 15.0 1.3 0.4 96.7 22 b 10 min10 min92.5 92.5 O2 b O 10 min 92.5 2 O2 H3CO O 60 H°C/1CO h 90.4OCH 90.910 min 1.492.5 90.9 OO O H33CO OCH33 12 O 60 °C/1H CO h 99.490.4OCH 51.490.9 39.21.4 51.490.9 3 O O 3 O O O O O O OO O O 5 O33 O 40 °C/1 h 98.8 83.1 11 hh13.1 1 h 1.2 96.896.80.5 96.2 96.8 O O3 H C C H O OC H 1 h 96.8 3OO 60 °C/1C22H55 hO 56.3OC 22H55 100 0 0 0 100 O O O C2H5O OC2H5 32 O 60 °C/1 h O O90.456.3 100 90.9 0 0 1.4 0 90.9100 2 O OOO 60 °C/1 h O O90.4 90.9 1.4 90.9 3 4 O O O O 2 h 91.8 6 44 6040 °C/20 °C/1 hh 86.298.6 80.6100 2 h15.4 02 h 1.20 91.80.60 96.0100 91.8 4 O CC2HH5OO OCOC2HH5 2 h 91.8 60 °C/20C2 H5 hO 86.2OC 2 H5 100 0 0 0 100 OO O 2 5 2 5 O OO OO 4 O OOO 4060 °C/1 h O O56.3100 81.7100 15.00 1.30 0.40 96.7100 5 H CO OOO 0.5 h 98.6 734 5 3 40 °C/1 h 95.7100 39.781.7 0.5 47.215.0h 5.21.3 98.64.70.4 86.996.7 5 5 CC2HH5OO OCOC2HH5 0.50.5 h h98.6 98.6 HOHOH3COO 2 5 2 5 HOO2NO 60 °C/20C2H 5hO 86.2OC 2H5 100 0 0 0 100 O O a O O O 5 ReactionO conditions: AmountO ofO catalyst40 °C/1is 4 hmol O %, ketone/aldehydeO98.8 83.1 = 6:113.1 (mol 1.2 ratio). 0.5 96.2 O6 O O O O 1 h 90.2 5 6 H3C 40 °C/1 h 98.8 83.1 1 h13.1 1.2 90.20.5 96.2 4 6 6 40 C°C/1H Oh 100OC H 81.7 1 15.0h1 h 1.3 90.20.4 96.7 90.2 H COH C C22H55O OC22H55 To obtain more insightH3COH3CO3 into the catalytic possibilitiesC H O of 3‐pyrrolidinamine,OC H we investigated the H3 CO3 2 5 2 5 O 3 O Knoevenagel6 condensations of a seriesO of aldehydes40 °C/1 h OOwithOO methylene98.6 80.6‐activated15.4 substrates1.2 0.6 for96.0 the O OOO O O synthesis56 of α,β‐77unsaturated compounds.O Good40 to°C/1 excellent h yields98.698.8 were80.683.1 observed22 hh15.413.1 2 h in1.2 all 91.7 91.7cases.0.60.5 As96.096.2 91.7 can 5 7 40 C°C/1H Oh 98.8OC H 83.1 2 13.1h 1.2 91.70.5 96.2 H3CH3C C22H55O OC22H55 be seen from Table 4, theH3 condensationC3 of furaldehydeC2H5O with malononitrileOC2H5 or dimethyl malonate was O H3C O 7 O 40 °C/1 h 95.7 39.7 47.2 5.2 4.7 86.9 very fast (withinO 10 min) using 1 mol %OO 3‐pyrrolidinamineOO asOO the catalyst. The yield of 5c was found 7 8 O2N O O 40 °C/1 h O O95.7 39.7 47.22 h 5.2 4.7 86.9 69.9 to be6 94.5% when88 the condensation was done40 °C/1 with h malononitrile98.6 (Table80.6 22 hh4,15.4 entry 1.2 1).69.969.90.6 As for96.0 the 8 O2N C H O OC H 2 h 69.9 a O N C22H55O OC22H55 Reaction conditions: O22N Amount of catalyst isC 4H molO %, ketone/aldehydeOC H = 6:1 (mol ratio). dimethyl malonate,a theO yieldN of the corresponding 2 5 product was2 5 92.5% (Table 4, entry 2). The Reactiona Reaction conditions: conditions:2 Amount Amount of catalystcatalyst is is 4 mol4 mol %, %, methylene-activated ketone/aldehyde substrate/aldehyde = 6:1 (mol ratio). = 6:1 (mol ratio), aa ReactionO conditions: Amount ofO catalyst is 4 mol %, methylene‐activated substrate/aldehyde = 6:1 condensationTo obtain aReaction of40 more ˝furaldehydeC. conditions:b insightAmount ofinto Amountwith catalyst the diethyl iscatalytic of 1 molcatalyst malonate %. possibilities is 4 mol took %, 1 ofmethylene h 3to‐pyrrolidinamine, achieve‐activated a 96.8% substrate/aldehyde yieldwe investigated of 5a (Table = the6:1 4, 7 Reaction conditions:b Amount of catalyst40 °C/1is 4 hmol %, methylene95.7 ‐activated39.7 47.2 substrate/aldehyde 5.2 4.7 86.9 = 6:1 entryTo 3). obtain(mol(mol Thereafter, ratio),ratio), more 4040 insight °C.°C.we Ob AmountAmountNstudied into the ofof thecatalyticcatalystcatalyst scope isis possibilities 11 molmolof %.the%. 3‐ ofpyrrolidinamine–catalyzed 3‐pyrrolidinamine, we investigated Knoevenagel the Knoevenagel(mol condensations ratio), 40 °C.O b2 NAmount of a series of catalyst of aldehydes is 1 mol %. with methylene‐activated substrates for the Knoevenagel condensations of a series of aldehydes with methylene‐activated substrates for the synthesiscondensation3. of Experimentala αReaction ,towardsβ‐unsaturated conditions: various Section compounds. Amountaromatic of aldehydes catalyst Good to is excellent4 with mol %,diethyl ketone/aldehyde yields malonate. were observed =Aromatic 6:1 (mol in ratio). allaldehydes cases. As with can synthesis3. Experimental of α,β‐unsaturated Section compounds. Good to excellent yields were observed in all cases. As can beelectron seen3.3. Experimental Experimentalfrom‐donating Table or 4, ‐Section thewithdrawingSection condensation substituents of furaldehyde reacted with efficiently malononitrile and relatively or dimethyl quickly malonate with diethyl was be seenTo fromobtainThe Table more reactions 4, insight the condensation were into carried the catalytic outof furaldehyde in apossibilities 25 mL round-bottomed with of malononitrile 3‐pyrrolidinamine, flask or equipped dimethyl we investigated with malonate a magnetic was the stirrer. verymalonate, fast TheThe(within giving reactionsreactions 10condensation min) werewere using carriedcarried products1 mol outout % inin 35d ‐ aapyrrolidinamine – 25255h mLmL in high roundround yields.‐‐bottomedbottomed as Wethe observedcatalyst. flaskflask equippedequipped The a significant yield withwith of 5c aayield magneticmagnetic was (91.8%) found stirrer.stirrer. Knoevenagelvery fastIn (withinThe a typical condensationsreactions 10 experiment, min) were using carriedof 1 aldehydea mol series out % 3inof‐ (10pyrrolidinamine a aldehydes25 mmol), mL round ketone with‐bottomed as ormethylene the active catalyst. flask methylene‐activated equipped The yield group substrates with of (605c a magneticwas mmol) for found the and stirrer. toin thebeInIn reaction 94.5% aa typicaltypical when of experiment,experiment, benzaldehyde the condensation aldehydealdehyde with diethyl (10(10was mmol),mmol), done malonate ketoneketonewith (Table malononitrile oror activeactive 4, entry methylenemethylene 4). (Table The reactivity groupgroup4, entry (60(60 increased1). mmol)mmol) ˝As for andand with the amineamine synthesisto beIn 94.5% (2.8a typicalof mmol) α when,β‐ unsaturatedexperiment, were the condensation charged compounds.aldehyde into the was (10 flask, Good mmol),done then to with ketoneexcellent the sealedmalononitrile or yieldsactive reactor methylenewere was(Table observed heated 4, group entry at in 40–60 (60all 1). cases.mmol) AsC for forAs and 10 canthe min–20amine h. dimethylthe increasing(2.8(2.8 mmol)mmol) malonate, electron werewere chargedchargedthe density yield intointo ofof thethethethe benzeneflask, flask,corresponding thenthen ring thethe which sealedsealed product depends reactorreactor was waswason 92.5% the heatedheated substituted (Table atat 40–6040–60 4, groupsentry °C°C forfor 2). (Table1010 The min–20min–20 bedimethyl seen(2.8 Afterfrom mmol)malonate, Table reaction, were 4, the thecharged the condensationyield round-bottomed intoof thethe flask,correspondingof furaldehyde flask then wasthe sealed cooled withproduct malononitrile reactor to roomwas was92.5% temperature. heated or (Tabledimethyl at 40–60 4, The malonateentry final°C for 2). products 10 wasThe min–20 were condensation4, entriesh.h. AfterAfter 5–7). reaction,reaction, of The furaldehyde condensation thethe roundround with‐‐bottomedbottomed diethylof nitrobenzaldehyde flaskflaskmalonate waswas cooled cooledtook with1 totoh toroomroom diethyl achieve temperature.temperature. malonate a 96.8% yieldTheThewas finalfinal ofmore 5a productsproducts (Tabledifficult 4, werewere verycondensation fasth. Afteridentified (within reaction, of furaldehyde10 and min) quantitativelythe using round with 1‐ bottomedmol diethyl analyzed % 3‐ pyrrolidinamine malonateflask by was gas tookcooled chromatography/mass 1 as hto tothe room achieve catalyst. temperature. a 96.8%The spectrometry yield yield The of finalof 5c 5a was (GC/MS) products (Table found 4, (Agilent were entrycomparedidentifiedidentified 3). Thereafter,to that andand of quantitativelyquantitatively benzaldehyde we studied analyzedanalyzed (Table the scope4, byby entry gasgas of chromatography/mass8).chromatography/mass the 3‐pyrrolidinamine–catalyzed spectrometryspectrometry (GC/MS)(GC/MS)Knoevenagel (Agilent(Agilent toentry beidentified 94.5%3).7890A/5975C, Thereafter, when and quantitativelythe Santa wecondensation studied Clara, analyzed CA, the was USA) scope done by and gas ofwith GC chromatography/massthe (Agilent malononitrile 3‐pyrrolidinamine–catalyzed 6890 equipped (Table spectrometry 4, with entry a SE-54 1).Knoevenagel (GC/MS) As capillary for the(Agilent column, condensation7890A/5975C,7890A/5975C, towards SantaSanta various Clara,Clara, aromaticCA,CA, USA)USA) aldehydes andand GCGC (Agilent(Agilent with diethyl 68906890 equippedequippedmalonate. withwith Aromatic aa SESE‐‐54 54aldehydes capillarycapillary with column,column, dimethylcondensation7890A/5975C, malonate, towards Santa the various Clara,yield aromatic ofCA, the USA) corresponding aldehydes and GC (Agilentwith product diethyl 6890 was malonate.equipped 92.5% Aromaticwith (Table a SE 4, ‐aldehydes54 entry capillary 2). withThe column, electronSantaSantaTable‐donating Clara,Clara,4. Knoevenagel CA, CA,or ‐ withdrawing USA),USA), condensation respectively.respectively. substituents of aromatic/heterocyclic AA knownknown reacted amountamount efficiently aldehydes ofof andfuranidinefuranidine relatively with methylenewaswas quickly addedadded‐activated with asas andiethylan internalinternal condensationelectronsubstratesSanta‐donating Clara, ofcatalyzed furaldehyde orCA, ‐withdrawing byUSA), 3‐pyrrolidinamine. with respectively. diethylsubstituents malonate A known reacted took amountefficiently 1 h to achieveof andfuranidine relatively a 96.8% was quicklyyield added of with5a as(Table diethylan internal 4, malonate,standardstandard giving toto thethe condensation productproduct mixturemixture products beforebefore 5d– thethe5h in GCGC high analysis.analysis. yields. We observed a significant yield (91.8%) entrystandard 3). Thereafter, to the product we studied mixture the before scope the ofGC theanalysis. 3‐pyrrolidinamine–catalyzed Knoevenagel malonate, giving11 condensation products1313 5d–5h in high yields.3 We observed a significant yield (91.8%) in the reactionTheThe H Hof‐‐ NMRNMRbenzaldehyde spectraspectra andand with CdiethylC‐‐NMRNMR malonate spectraspectra inin (Table CDCD33ODOD 4, entry werewere 4). recordedrecordedR 3The reactivity onon anan AvanceincreasedAvance TMTM with IIIIII‐ ‐400400 condensationThe towards1H‐NMR various spectra aromatic and 13C‐ NMRaldehydes spectra with inCat. diethylCD3OD malonate.were recorded Aromatic on an aldehydes Avance TM with III ‐400 thecondensationin the increasingMHz reaction NMR towards ofelectron spectrometer benzaldehyde variousdensity (Bruker, aromatic ofwith the diethyl benzene Switzerland) aldehydes malonate ring withwhich using (Table diethyl dependstetramethylsilane 4, entry malonate. on 4). the The substitutedAromatic reactivity (TMS) as aldehydes increasedgroupsinternal (Table standard. with MHz NMR spectrometerRCHO (Bruker,(Bruker, Switzerland)+ R3 R4 using tetramethylsilanetetramethylsilane (TMS)(TMS) as internalinternal standard. electronthe increasingMHz‐donating NMR electron spectrometer or ‐withdrawing density (Bruker,of the substituents benzene Switzerland) ring reacted which using efficiently depends tetramethylsilaneRR and on relativelythe substituted (TMS) quickly as groups internal with diethyl (Table standard. 4, entriesChemicalChemical 5–7). shiftsshifts The arearecondensation reportedreported inin of partsparts nitrobenzaldehyde perper millionmillion (ppm,(ppm, with δδ)) and anddiethyl referencedreferenced malonate4 toto CDCD was33ODOD more ((δδ == difficult3.333.33).). 3 malonate,4, entriesChemical 5–7).giving1 shiftsThe condensation condensation are reported products inof parts nitrobenzaldehyde 5d per–5h million in high (ppm, yields. with δ We) anddiethyl5a~h observed referenced malonate a significant to CDwasOD more yield (δ =difficult (91.8%) 3.33). compared1a to: 11 Hthat‐NMR of benzaldehyde (400 MHz, CD (Table3OD): 4, δ entry1.12 (t, 8). J = 12.0 Hz, 3H), 2.69 (q, J = 20.0 Hz, 2H ), 6.57 (q, J = 1a: H1 ‐NMR (400 MHz, CD3OD): δ 1.12 (t, J = 12.0 Hz, 3H), 2.69 (q, J = 20.0 Hz, 2H ), 6.57 (q, J = incompared the reaction1a to: that Hof‐ NMRbenzaldehyde of benzaldehyde (400 MHz,a: R with = CD furyl,(Table diethyl3OD): 4, δ entrymalonate 1.12 8).(t, JR (Table=3 =12.0 R4 =Hz,4, COOC entry 3H),2 4).H 2.695 The (q, reactivity J = 20.0 Hz,increased 2H ), 6.57 with (q, J = 4.04.0 Hz,Hz, 1H),1H), 6.626.62 (d,(d, JJ == 16.016.0 Hz,Hz, 1H),1H), 6.826.82 (d,(d, JJ == 4.0R4.0 = Hz,Hz, R =1H),1H), COOCH 7.417.41 (d,(d, JJ == 16.016.0 Hz,Hz, 1H),1H), 7.657.65 (d,(d, JJ == 4.04.0 the increasing4.0 Hz, 1H), electron 6.62 (d, density J = b:16.0 Rof = Hz,the furyl, benzene1H), 6.82 ring (d, J which = 4.03 Hz, depends4 1H), 7.41 on3 the(d, substitutedJ = 16.0 Hz, groups1H), 7.65 (Table (d, J = 4.0 Table 4. Knoevenagel1313 condensation 3of aromatic/heterocyclicR = R = aldehydesCN with methylene‐activated Hz,Hz, 1H),1H), CC‐‐NMRNMR (100(100 c:MHz,MHz, R = furyl, CDCD33OD):OD): δδ 7.22,7.22, 33.22,33.22,3 4112.28,112.28, 115.75,115.75, 122.63,122.63, 129.03,129.03, 145.29,145.29, 151.05,151.05, 4, entriesTableHz, 1H), 5–7).4. Knoevenagel 13 TheC‐NMR condensation (100 condensation MHz, of CD nitrobenzaldehyde of3OD): aromatic/heterocyclic δ 7.22, R33.22, = Rwith =112.28, aldehydesCOOC diethyl 115.75,H malonate with 122.63, methylene was 129.03, more‐activated 145.29, difficult 151.05, 201.79.201.79.substrates catalyzed by 3‐pyrrolidinamine.d: R = phenyl, 3 4 2 5 comparedsubstrates201.79. to that catalyzed of benzaldehyde by 3‐pyrrolidinamine.e: R = p-hydroxybenyl, (Table 4, entry 8). R3 = R4 = COOC2H5 R = R = COOC HR f: R = p-methoxyphenyl, Cat.3 4 2 53 4.4. ConclusionsConclusions g: R = p-methylphenyl, R3 = R4 = COOC2HR53 Table 4. Knoevenagel condensationRCHO of+ aromatic/heterocyclicR3 R4 Cat. aldehydes with methylene‐activated Table4. Conclusions 4. Knoevenagel condensationh: R = p-nitrophenyl, of aromatic/heterocyclicR3 = R4 = aldehydesCOOC2H5 with methylene‐activated RCHO+ R3 R4 RR4 substratesInIn conclusion,conclusion, catalyzed webywe 3 havehave‐pyrrolidinamine. demonstrateddemonstrated thatthat pyrrolidinepyrrolidine andand itsits derivativesderivatives catalyzecatalyze thethe aldolaldol andand EntryIn conclusion, a Aldehyde we have demonstratedMethylene that‐Activated pyrrolidine SubstratesRR5a~h and itsTime4 derivativesProduct catalyze Yield/% the aldol and KnoevenagelKnoevenagel condensationscondensations forfor thethe formationformation ofof olefinicolefinic (C=C)(C=C)5a~h bondsbonds underunder solventsolvent‐‐freefree conditions.conditions. a: R = furyl, R3 = R4 = COOC2HR53 Knoevenagel condensations for the formation of olefinicCat. (C=C) bonds3 under solvent‐free conditions. TheThe 33‐‐pyrrolidinaminepyrrolidinamine showedshowedb:a: R = furyl, highhigh activityactivity andand affordedRafforded3 = R4 = goodCOOCHCOOCgood toto2H 3 excellentexcellent5 yieldsyields ofof α α,,β‐β‐unsaturatedunsaturated RCHO+ R3 R The 3‐pyrrolidinamine RCHOshowedc:b: RR == furyl,furyl, high+ activity3 Rand4 R afforded3 = R4 = CNCOOCH good to3 excellent yields of α,β‐unsaturated compounds.compounds. TheThe electronelectron‐‐richrich aromaticaromatic aldehydesaldehydes areare favoredfavoredRR forfor 4thethe reactivity.reactivity. TheThe presentpresent studystudy compounds. The electrond:c: R‐rich = furyl,phenyl, aromatic aldehydesR3 = are R4 =favored COOCCN 2 Hfor54 the reactivity. The present study 5a~h providesprovides anan environmentallyenvironmentallye:d: RR == friendlyp-hydroxybenyl,friendlyphenyl, andand highhigh‐‐Ryieldingyielding3 = R4 = syntheticCOOCsynthetic2H5 methodologymethodology forfor procuringprocuring α α,,β‐β‐ provides an environmentally friendly and highR‐yielding = R = COOC syntheticH methodology for procuring α,β‐ unsaturated compounds.f:a:e: R = p-hydroxybenyl,furyl,p-methoxyphenyl, R3 = R4 = COOC2H5 unsaturated compounds. R = R = COOCCOOCHH unsaturated compounds.g:b:f: RR == p-methylphenyl,furyl,p-methoxyphenyl, R3 = R4 = COOCCOOCH2H35 R = R = COOCCN H h:c:g: R = furyl,p-methylphenyl,p-nitrophenyl, R3 = R4 = COOCCN 2H5 Acknowledgements: This work was supported byR the = R National = COOC NaturalH Science Foundation of Acknowledgements: Thisd:h: workR = phenyl,p-nitrophenyl, was supported byR3 thethe= R 4National = COOC 2NaturalH5 Science Foundation of Acknowledgements:Entry a Aldehyde This work wasMethylene supported‐Activated Rby =the R Substrates National= COOC HNaturalTime ProductScience Yield/% Foundation of China (Project No. 21473225).e: R = p-hydroxybenyl, R3 = R4 = COOC2H5 ChinaEntry (Project a No. 21473225).Aldehyde Methylene‐ActivatedR = R Substrates = COOC HTime Product Yield/% China (Project No. 21473225).f: R = p-methoxyphenyl, R3 = R4 = COOC2H5 R = R = COOC H g: R = p-methylphenyl, R3 = R4 = COOC2H5 R = R = COOC H h: R = p-nitrophenyl, R3 = R4 = COOC2H5

Entry a Aldehyde Methylene‐Activated Substrates Time Product Yield/%

Catalysts 2016, 6, 106 7 of 8

Santa Clara, CA, USA), respectively. A known amount of furanidine was added as an internal standard to the product mixture before the GC analysis. 1 13 The H-NMR spectra and C-NMR spectra in CD3OD were recorded on an Avance TM III-400 MHz NMR spectrometer (Bruker, Switzerland) using tetramethylsilane (TMS) as internal standard. Chemical shifts are reported in parts per million (ppm, δ) and referenced to CD3OD (δ = 3.33). 1 1a: H-NMR (400 MHz, CD3OD): δ 1.12 (t, J = 12.0 Hz, 3H), 2.69 (q, J = 20.0 Hz, 2H ), 6.57 (q, J = 4.0 Hz, 1H), 6.62 (d, J = 16.0 Hz, 1H), 6.82 (d, J = 4.0 Hz, 1H), 7.41 (d, J = 16.0 Hz, 1H), 7.65 (d, 13 J = 4.0 Hz, 1H), C-NMR (100 MHz, CD3OD): δ 7.22, 33.22, 112.28, 115.75, 122.63, 129.03, 145.29, 151.05, 201.79.

4. Conclusions In conclusion, we have demonstrated that pyrrolidine and its derivatives catalyze the aldol and Knoevenagel condensations for the formation of olefinic (C=C) bonds under solvent-free conditions. The 3-pyrrolidinamine showed high activity and afforded good to excellent yields of α,β-unsaturated compounds. The electron-rich aromatic aldehydes are favored for the reactivity. The present study provides an environmentally friendly and high-yielding synthetic methodology for procuring α,β-unsaturated compounds.

Acknowledgments: This work was supported by the National Natural Science Foundation of China (Project No. 21473225). Author Contributions: J.C. and H.S. conceived and designed the experiments; H.S., R.J., F.J. and M.K. performed the experiments and analyzed the data; H.S. and L.Z. wrote the paper and proofread the manuscript. Conflicts of Interest: The authors declare no conflict of interest.

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