molecules
ArticleArticle Two-StepTwo-Step One-PotOne-Pot ReductiveReductive AminationAmination ofof FuranicFuranic AldehydesAldehydes UsingUsing CuAlOCuAlOxx Catalyst in a Flow Reactor
AlexeyAlexey L.L. NuzhdinNuzhdin*, * Marina, Marina V. V.Bukhtiyarova Bukhtiyarova and and Valerii Valerii I. I.Bukhtiyarov Bukhtiyarov Boreskov Institute of Catalysis SB RAS, 630090 Novosibirsk, Russia; [email protected] (M.V.B.); Boreskov Institute of Catalysis SB RAS, 630090 Novosibirsk, Russia; [email protected] (M.V.B.); [email protected] (V.I.B.) [email protected] (V.I.B.) * Correspondence: [email protected]; Tel.: +7-383-3269-410 * Correspondence: [email protected]; Tel.: +7-383-3269-410 Received: 26 26 September September 2020; 2020; Accepted: Accepted: 15 October 15 October 2020; Published:2020; Published: 17 October date 2020
Abstract:Abstract: AminomethylhydroxymethylfuranAminomethylhydroxymethylfuran derivatives derivatives are are well well known known compounds compounds which which are used are inused the in pharmaceutical the pharmaceutical industry. industry. Reductive Reductive amination amination of 5-hydroxymethylfurfural of 5-hydroxymethylfurfural (HMF) derived(HMF) fromderived available from available non-edible non-edible lignocellulosic lignocellulosic biomass is biomass an attractive is an method attractive for method the synthesis for the of synthesis this class of compounds.this class of compounds. In the present In the study, present the synthesisstudy, the of synthesis N-substituted of N-substitu 5-(hydroxymethyl)-2-furfurylted 5-(hydroxymethyl)- amines2-furfuryl and amines 5-(acetoxymethyl)-2-furfuryl and 5-(acetoxymethyl)-2-furfur amines wasyl performedamines was by performed two-step process, by two-step which includesprocess, thewhich condensation includes the of furaniccondensation aldehydes of furanic (HMF andaldehydes 5-acetoxymethylfurfural) (HMF and 5-acetoxymethylfurfural) with primary amines with in methanolprimary amines on the firstin methanol step and on the the reduction first step of an obtainedd the reduction imines with of obtained hydrogen imines in a flow with reactor hydrogen over CuAlOin a flowx catalyst reactor derivedover CuAlO fromx layeredcatalyst doublederived hydroxide from layered on thedouble second hydroxide step. This on processthe second does step. not requireThis process isolation does and not purification require isolation of intermediate and purification imines andof intermediate can be used imines to synthesize and can a numberbe used ofto aminomethylhydroxymethylfuranssynthesize a number of aminomethylhydroxymethylfurans in good to excellent yield. in good to excellent yield.
Keywords: reductive amination;amination; 5-hydroxymethylfurfural;5-hydroxymethylfurfural; 5-acetoxymethylfurfural;5-acetoxymethylfurfural; Cu-basedCu-based catalyst; Cu-AlCu-Al mixedmixed oxide;oxide; primaryprimary amines;amines; imineimine hydrogenation;hydrogenation; flowflow reactorreactor
1. Introduction N-Substituted 5-(hydroxymethyl)-2-furfuryl5-(hydroxymethyl)-2-furfuryl amines amines are are an an important important class class of of compounds compounds due due to theirto their usage usage in in pharmaceutical pharmaceutical industry industry for for production production of of calcium calcium antagonists, antagonists, muscarinicmuscarinic agonists, cholinergic agents,agents, carcinogenesiscarcinogenesis inhibitors,inhibitors, etc.etc. (for (for instance, instance, anti-hepatitis anti-hepatitis B B virus drug andand antihypertensives, Scheme 11))[ [11–3].–3]. Generally, Generally, these these structures are prepared by aa Mannich-typeMannich-type reaction startingstarting fromfrom furfuralfurfural alcoholalcohol (or(or furfural),furfural), formaldehyde,formaldehyde, andand primaryprimary amines.amines. However, harsh reaction conditions are usually required, that leads to a low yield of the target product [4–6]. [4–6]. Meanwhile, reductivereductive amination amination of of 5-hydroxymethylfurfural 5-hydroxymethylfurfural (HMF) (HMF) derived derived from from available available non-edible non- lignocellulosicedible lignocellulosic biomass biomass is an attractive is an attractive method method for the for synthesis the synthesis of this of type this of type amines of amines [3,7–11 [3,7–11].].
OH O O R2 O HN N O O O N R3 R 1 N H Anti-hepatitis B Anti-hypertensive Scheme 1. Examples1. Examples of N-substituted of N-substituted 5-(hydroxymethyl)-2-furfuryl 5-(hydroxymethyl)-2-furfuryl amines with pharmaceutical amines activity. with pharmaceutical activity. In general, the reductive amination of HMF is realized in the presence of noble metal-based catalystsIn general, such as the dichlorobis(2,9-dimethyl-1,10-phenanthroline) reductive amination of HMF is realized in ruthenium(II)the presence complexof noble [metal-based7], Pd/C[8], Aucatalysts/TiO2 [such3], and as Pddichlorobis(2,9-dimethyl-1,10-phenanthroline) nanoparticles immobilized in a MOF/polymer ruthenium(II) composite [9 complex] using batch [7], Pd/C reactors. [8], Au/TiO2 [3], and Pd nanoparticles immobilized in a MOF/polymer composite [9] using batch reactors. Molecules 20202020,, 2525,, 4771;x; doi: doi: FOR10.3390 PEER/molecules25204771 REVIEW www.mdpi.com/journwww.mdpi.com/journalal/molecules/molecules Molecules 2020, 25, 4771 2 of 7
Molecules 2020, 25, x FOR PEER REVIEW 2 of 7 However, the high price and limited availability of precious metals are stimulated interest in catalysts basedHowever, on earth-abundant the high price and elements. limited availability Chieffi et of al. pr studiedecious metals the reductive are stimulated amination interest of in HMFcatalysts over carbon-supportedbased on earth-abundant Fe-Ni catalyst elements. under Chieffi flow conditions.et al. studied However, the reductive the amines amination used of were HMF limited over to 3-aminopropanolcarbon-supported and Fe-Ni alanine catalyst sodium under and flow the conditions. yield of the However, target aminomethylhydroxymethylfuran the amines used were limited to 3-aminopropanol and alanine sodium and the yield of the target aminomethylhydroxymethylfuran (AMHMF) derivatives did not exceed 78% [11]. (AMHMF) derivatives did not exceed 78% [11]. In our previous study [12], an environmentally friendly procedure has been developed for the In our previous study [12], an environmentally friendly procedure has been developed for the synthesis of secondary amines through a two-step one-pot reductive amination of aromatic aldehydes synthesis of secondary amines through a two-step one-pot reductive amination of aromatic with primary amines. The condensation of benzaldehyde derivatives (or furfural) with amines in aldehydes with primary amines. The condensation of benzaldehyde derivatives (or furfural) with methanolamines atin roommethanol temperature at room temperature gives imines, gives which imin arees, then which hydrogenated are then hydrogenated in a flow reactor in a flow using reactor Cu-Al mixed oxide (denoted hereafter as CuAlO ) derived from layered double hydroxide (LDH). In present using Cu-Al mixed oxide (denoted hereafterx as CuAlOx) derived from layered double hydroxide work,(LDH). we In investigated present work, the we effi investigatedciency of this the procedure efficiency forof this reductive procedure amination for reductive of furanic amination aldehydes of (HMFfuranic and aldehydes 5-acetoxymethylfurfural) (HMF and 5-acetoxymethylfurfural with primary amines) with via hydrogenation primary amines of thevia intermediatehydrogenation imines of overthe CuAlO intermediatex catalyst imines in a over flow CuAlO reactor.x catalyst in a flow reactor.
2. Results2. Results and and Discussion Discussion MethanolMethanol is is a suitablea suitable solvent solvent for for the the synthesissynthesis ofof N-substitutedN-substituted 5-(hyd 5-(hydroxymethyl)-2-furfurylroxymethyl)-2-furfuryl amines,amines, since since it isit ais good a good solvent solvent for bothfor both the condensationthe condensation of aromatic of aromatic aldehydes aldehydes with primarywith primary amines andamines hydrogenation and hydrogenation of imines of [10 imines,12,13]. [10,12,13]. We found We that found the reactionthat the ofreaction HMF withof HMF aniline with in aniline low water in methanollow water (0.02 methanol wt% H 2(0.02O) occurs wt% H at2O) room occurs temperature at room temperature with imine with yield imine of 98% yield (Table of 98%1, entry (Table 1) and1, timeentry dependence 1) and time of dependence imine yield of let imine us to yield see let that us equilibrium to see that equilibrium concentrations concentrations are reached are withinreached 2 h (Supplementarywithin 2 h (Supplementary Materials, Figure Materials, S1). The Figure use ofS1). ethanol The use instead of ethanol of methanol instead leadsof methanol to a decrease leads to in a the yielddecrease of imine in 1atheto yield 70% of (Table imine1, entry1а to 2).70% Simultaneously, (Table 1, entry the 2). yield Simultaneo of 1a inusly, isopropanol the yield isof only 1а in 31% underisopropanol the same is reactiononly 31% conditions under the (Tablesame reaction1, entry conditions 3). (Table 1, entry 3).
1 TableTable 1. 1. CondensationCondensation of of 5-hydroxymethylfurfural 5-hydroxymethylfurfural (HMF) (HMF) with with aniline aniline1. .
Entry Solvent Yield, % 2 1 Methanol 98 Entry Solvent Yield, % 2 2 Ethanol 70 31 Methanol Isopropanol 98 31
1 2 Ethanol 70 2 Reaction conditions: HMF (0.05 M), aniline (0.05 M), batch reactor, T = 25 ◦C, 2 h. GC yields. 3 Isopropanol 31 The1 Reaction reaction conditions: mixtures HMF obtained (0.05 M), by aniline condensation (0.05 M), of batch HMF reactor, with primaryT = 25 °C, amines2 h. 2 GC were yields. further hydrogenated over CuAlOx catalyst in a flow reactor at 100 ◦C and H2 pressure of 10 bar. Before each The reaction mixtures obtained by condensation of HMF with primary amines were further catalytic run, the CuO phase of CuAlOx was reduced in situ by hydrogen to metallic copper particles [12, ° 14].hydrogenated The average over size CuAlO of copperx catalyst crystallites in a flow in reactor the reduced at 100 sampleC and H was2 pressure about of 7 nm 10 bar. [14] Before that is each much catalytic run, the CuO phase of CuAlOx was reduced in situ by hydrogen to metallic copper particles smaller than in case of the supported Cu/Al2O3 catalysts with high copper content. Thus, CuAlOx [12,14]. The average size of copper crystallites in the reduced sample was about 7 nm [14] that is much material prepared by calcination of LDH precursor is a promising non-noble metal catalyst for smaller than in case of the supported Cu/Al2O3 catalysts with high copper content. Thus, CuAlOx hydrogenation reactions [12,14,15]. material prepared by calcination of LDH precursor is a promising non-noble metal catalyst for The hydrogenation of imine 1a, which is obtained by condensation of HMF and aniline in methanol, hydrogenation reactions [12,14,15]. leads to the formation of AMHMF derivative 2a with the yield of 97% (Table2, entry 1). In addition The hydrogenation of imine 1a, which is obtained by condensation of HMF and aniline in to 2amethanol,, undesired leads bis-(hydroxymethyl)furan to the formation of AMHMF3 wasderivative observed 2a with among the yield the reaction of 97% (Table products. 2, entry The 1). use In of ethanoladdition or isopropanolto 2a, undesired instead bis-(hydroxymethyl)furan of methanol leads to a3 strongwas observed drop in among the yield the of reaction the target products. product (TableThe2 use, entries of ethanol 2 and or 3) isopropanol due to the instead much lower of methanol yield of leads imine to a in strong the first drop stage in the (Table yield1 ).ofAs the a target result, a greaterproduct amount (Table 2, of entries HMF 2 is and hydrogenated 3) due to the tomuch3. Raising lower yield the concentrationof imine in the offirst reactants stage (Table in methanol 1). As toa 0.2 result, M reduces a greater the amount yield to of 94% HMF (Table is hydrogenated2, entry 4). However,to 3. Raising an the increase concentration of reaction of reactants temperature in methanol to 0.2 M reduces the yield to 94% (Table 2, entry 4). However, an increase of reaction
Molecules 2020, 25, x FOR PEER REVIEW 3 of 7
temperature to 120 °C at high reactant concentration leads to rise of the imine hydrogenation rate and allows synthesizing 2a with the yield of 98% (Table 2, entry 5). The effect of primary amine structure on the formation of AMHMF derivatives was investigated by reductive amination of HMF with different aromatic and aliphatic amines over CuAlOx catalyst (Table 2, entries 1 and 6−16). Formation of 2b, 2c, and 2e with the excellent yield (95−97%) is observed for aromatic amines containing electron-donating substituent (CH3 and OCH3) in meta- and para- position (Table 2, entries 6, 7, and 9). It means that the rates of imine formation in the condensation of HMF with these compounds are similar to that in the reaction of HMF with aniline while using o- toluidine gives lower rate of imine formation due to steric hindrance created by methyl group in ortho-position [12]. A much longer period of time (16 h) is needed for the condensation of HMF with o-toluidine at the first stage to obtain 2d with the yield of 88% by imine hydrogenation over the CuAlOx catalyst at the second stage (Table 2, entry 8). Introduction of F and Cl substituent in the para-position of aniline slightly decreases the yield of Molecules 2020, 25, 4771 3 of 7 compounds 2 to 93−94% (Table 2, entries 10 and 11). At the same time, in the case of p-bromoaniline the significant drop in the yield of the target product to 60% was observed while imine amount in the final mixture was increased (Table 2, entry 12). It is worth to mention that reaction was performed at to 120 ◦C at high reactant concentration leads to rise of the imine hydrogenation rate and allows ° synthesizing110 C that2a is withhigher the than yield in case of 98% of other (Table aromatic2, entry amines. 5). This result can be explained by the steric hindranceThe effect created of primary by bulk aminey Br substituent structure on during the formation the diffusion of AMHMF of imine to derivatives active sites was of CuAlO investigatedx [12]. by It should be noted that hydrodehalogenated product practically did not form during the reaction. reductive amination of HMF with different aromatic and aliphatic amines over CuAlOx catalyst (Table2, The position of electron-withdrawing substituent in aromatic amine has a strong effect on the entries 1 and 6–16). Formation of 2b, 2c, and 2e with the excellent yield (95–97%) is observed for reaction. The imine formation rate in the condensation of HMF with m-chloroaniline is much lower aromatic amines containing electron-donating substituent (CH and OCH ) in meta- and para-position than with p-chloroaniline. As a result, the reaction of HMF with3 m-chloroaniline3 for 3 h on the first (Tablestage2, entriesleads 6,to 7,formation and 9). It of means 2i in that a low the ratesyield of(Table imine 2, formation entry 13). in theHowever, condensation carrying of out HMF the with thesecondensation compounds of are HMF similar and m to-chloroaniline that in the reaction for 16 h of allows HMF obtaining with aniline 2i in while 95% yield using (Tableo-toluidine 2, entry gives lower14). rate At the of iminesame time, formation o-chloroaniline due to steric gave hindrancea moderate createdyield of by2j (52%) methyl after group the reaction in ortho -positionwith HMF [ 12]. A muchon the longer first stage period for 16 of timeh (Table (16 2, h) entry is needed 15). Th forese the observations condensation are explai of HMFned withby a decreaseo-toluidine in the at the firstnucleophilic stage to obtain properties2d with of thechloroanilines yield of 88% in bythe iminefollowing hydrogenation order: p-chloroaniline over the CuAlO> m-chloroanilinex catalystat > the secondo-chloroaniline. stage (Table 2, entry 8). IntroductionThus, the yield of F andof 2 is Cl determined substituent by in the the iminepara-position formation of at aniline the first slightly stage. Higher decreases yield the of yield the of compoundsintermediate2 to imine 93–94% provides (Table higher2, entries yield 10 of and AMHMF 11). At derivative. the same In time, the case in the of caseprimary of pamines-bromoaniline with theweak significant nucleophilic drop in properties the yield ( ofo-toluidine, the target m product-chloroaniline, to 60% o was-chloroaniline), observed while a longer imine condensation amount in the finaltime mixture (16 h) wasis required increased to obtain (Table compound2, entry 12). 2 with It is a worth higher to yield. mention that reaction was performed at Using aliphatic hexylamine gave a slightly lower yield of AMHMF derivative than aniline (Table 110 ◦C that is higher than in case of other aromatic amines. This result can be explained by the steric 2, entries 1 and 16) that can be explained by instability of intermediate imines containing alkyl hindrance created by bulky Br substituent during the diffusion of imine to active sites of CuAlO [12]. substituent [16]. x It should be noted that hydrodehalogenated product practically did not form during the reaction. Table 2. Two-step one-pot reductive amination of HMF with primary amines 1. Table 2. Two-step one-pot reductive amination of HMF with primary amines 1.
2 Yield,Yield, % 2 % EntryEntry RR StepStep 1, h 1, hT, ◦CT, °C 2 2 11 2 23 34 4 1 PhPh 3 3 100 100 2a 2a n.d. 97 97 3 n.d. 3 n.d. 3 2 3 PhPh 3 3 100 100 2a 2a n.d. 74 74 26 26n.d. n.d. 3 4 Ph 3 100 2a n.d. 67 33 n.d. 3 4 Ph 3 100 2a n.d. 67 33 n.d. 4 5 Ph 3 100 2a 3 94 3 <0.5 5 54 5 PhPh 3 3 120 100 2a 2a 13 94 98 3 <<0.51 0.5 5 56 p-CHPh3C 6H4 3 3 100 120 2b2a n.d.1 98 97 <1 30.5 n.d. 76 pm-CH-CH3CC6HH4 33 100 100 2c2b n.d. 97 96 3 n.d. 4 n.d. 8 o-CH3C6H4 16 100 2d n.d. 88 12 <0.5 7 m-CH3C6H4 3 100 2c n.d. 96 4 n.d. 9 p-CH3OC6H4 3 100 2e n.d. 95 5 n.d. 10 p-FC6H4 3 100 2f n.d. 94 6 n.d. 11 p-ClC6H4 3 100 2g n.d. 93 7 n.d. 12 p-BrC6H4 3 110 2h 22 60 16 1 13 m-ClC6H4 3 100 2i n.d. 55 45 n.d. 14 m-ClC6H4 16 100 2i n.d. 95 4 1 15 o-ClC6H4 16 100 2j n.d. 52 42 6 16 n-hexyl 3 100 2k n.d. 93 7 n.d.
1 Reaction conditions: HMF (0.05 M), primary amine (0.05 M), CuAlOx catalyst (165 mg), 10 bar H2, liquid flow rate 1 1 2 1 3 of 0.5 mL min− , hydrogen flow rate of 30 mL min− . The product yields were determined by H-NMR. Ethanol was used as a solvent. 4 Isopropanol was used as a solvent. 5 Reactant concentrations were 0.2 M.
The position of electron-withdrawing substituent in aromatic amine has a strong effect on the reaction. The imine formation rate in the condensation of HMF with m-chloroaniline is much lower than with p-chloroaniline. As a result, the reaction of HMF with m-chloroaniline for 3 h on the first stage leads to formation of 2i in a low yield (Table2, entry 13). However, carrying out the condensation of HMF and m-chloroaniline for 16 h allows obtaining 2i in 95% yield (Table2, entry 14). At the same time, o-chloroaniline gave a moderate yield of 2j (52%) after the reaction with HMF on the first stage for Molecules 2020, 25, x FOR PEER REVIEW 4 of 7
8 o-CH3C6H4 16 100 2d n.d. 88 12 <0.5 9 p-CH3OC6H4 3 100 2e n.d. 95 5 n.d. Molecules 2020, 25, 4771 10 p-FC6H4 3 100 2f n.d. 94 6 n.d. 4 of 7 11 p-ClC6H4 3 100 2g n.d. 93 7 n.d. 12 p-BrC6H4 3 110 2h 22 60 16 1 16 h (Table2, entry 15).13 These m observations-ClC6H4 are3 explained100 by2i a decreasen.d. 55 in45 the n.d. nucleophilic properties of chloroanilines in the14 followingm-ClC order:6H4 p-chloroaniline16 100 > m2i-chloroaniline n.d. 95 4 > o-chloroaniline. 1 Thus, the yield of152 is determinedo-ClC6H4 by the16 imine100 formation 2j n.d. at the52 first 42 stage. 6 Higher yield of the intermediate imine provides16 highern-hexyl yield of3 AMHMF 100 derivative. 2k n.d. In93 the case 7 n.d.of primary amines with 1 weak nucleophilic Reaction conditions: properties HMF (o -toluidine,(0.05 M), primarym-chloroaniline, amine (0.05 M), oС-chloroaniline),uAlOx catalyst (165 amg), longer 10 bar condensation H2, liquid flow rate of 0.5 mL min−1, hydrogen flow rate of 30 mL min−1. The product yields were time (16 h) is required to obtain compound 2 with a higher yield. determined by 1H-NMR. 3 Ethanol was used as a solvent. 4 Isopropanol was used as a solvent. 5 UsingReactant aliphatic concentrations hexylamine were gave 0.2 M. a slightly lower yield of AMHMF derivative than aniline (Table2, entries 1 and 16) that can be explained by instability of intermediate imines containing alkyl substituent [16]. The time-on-streamThe time-on-stream measurements measurements for for reductive reductive amination amination of HMFof HMF with with aniline aniline over over the the CuAlO x catalystСuAlO werex catalyst performed were for~3performed h (Supplementary for~3 h (Supplemen Materials,tary Materials, Figure S3).Figure The S3). yield The ofyield2a (97%)of 2a (97%) remained unchangedremained meaning unchanged that meaning the catalyst that the exhibits catalyst good exhibits stability good duringstabilitythe during reaction the reaction [12,14 ].[12,14]. 5-Acetoxymethylfurfural (AMF), which can be prepared from carbohydrates without isolating 5-Acetoxymethylfurfural (AMF), which can be prepared from carbohydrates without isolating HMF, is less reactive, more stable and easily extracted from the aqueous reaction mixture. Therefore, HMF, is less reactive, more stable and easily extracted from the aqueous reaction mixture. Therefore, AMF represents a good substitute for HMF [17–19]. Similar to HMF, AMF reacts with aniline in AMFmethanol represents to a goodform substituteimine with for the HMF yield [17 –of19 ].98 Similar% (Supplementary to HMF, AMF Materi reactsals, with Figure aniline S2). in methanolThe to formhydrogenation imine with of theimines yield obtained of 98% by (Supplementary condensation of AMF Materials, with different Figure amines S2). Thewas carried hydrogenation out on of iminesthe obtained СuAlOx catalyst by condensation at lower temperature of AMF with of 80 di °Cff erentthan in amines case of wasHMF carried in order out to avoid on the the CuAlO reductionx catalyst at lowerof the temperature acetoxymethyl of 80 group.◦C than It was in case found ofHMF that reductive in order toamination avoid the of reduction AMF with of aniline the acetoxymethyl and its group.derivatives It was found containing that reductiveCH3 group amination in para- and of meta- AMF positions with aniline leads to and the itsformation derivatives of N-substituted containing CH3 group5-(acetoxymethyl)-2-furfuryl in para- and meta- positions amines leads to6a–c the with formation the yields of N-substituted about 99% 5-(acetoxymethyl)-2-furfuryl(Table 3, entries 1−3). aminesIntroduction6a–c with of the methyl yields substituent about 99% in ortho (Table-position3, entries of aniline 1–3). decreases Introduction the yield of methyl of compound substituent 6 to in 96% (Table 3, entry 4). It is worth to mention that condensation of AMF with o-toluidine was ortho-position of aniline decreases the yield of compound 6 to 96% (Table3, entry 4). It is worth to performed for 16 h while temperature of following hydrogenation of obtained imine was raised to 90 mention that condensation of AMF with o-toluidine was performed for 16 h while temperature of °C. In the case of anilines with CH3O, F, and Cl substituents in para-position, AMHMF derivatives 6e, following6f, and hydrogenation 6g were obtained of obtainedwith the yield imine of was 99, raised>98 and to 97%, 90 ◦ C.respectively In the case (Table of anilines 3, entries with 5−7). CH 3O, F, andSimultaneously, Cl substituents the inreactionpara-position, of AMF with AMHMF m-chloroaniline derivatives for 16 6eh at, 6f the, andfirst stage,6g were followed obtained by imine with the yieldhydrogenation of 99, >98 and at 97%, 80 °C, respectively allows synthesizing (Table3 ,6h entries with the 5–7). yield Simultaneously, of 96% (Table 3, theentry reaction 8). In contrast of AMF to with m-chloroanilinearomatic amines, for 16 hexylamine h at the first gives stage, only followed 82% yiel byd of imine the AMHMF hydrogenation derivative at 80due◦C, to allowshydrogenation synthesizing 6h withof acetyl the yield group of in 96% 6i (Table (Table 3,3 entry, entry 9). 8). In contrast to aromatic amines, hexylamine gives only 82% yield of the AMHMF derivative due to hydrogenation of acetyl group in 6i (Table3, entry 9). Table 3. Two-step one-pot reductive amination of 5-Acetoxymethylfurfural (AMF) with primary amines 1. Table 3. Two-step one-pot reductive amination of 5-Acetoxymethylfurfural (AMF) with primary amines 1.
2 Yield,Yield, % 2 % Entry RR StepStep 1, h1, h 6 6 55 6 67 78 89 9 1 PhPh 3 3 6a6a n.d.n.d. 99 99 <0.5 <0.5<1
1 Reaction conditions: AMF (0.05 M), primary amine (0.05 M), CuAlOx catalyst (165 mg), 80 ◦C, 10 bar H2, liquid flow 1 1 2 1 rate of 0.5 mL min− , hydrogen flow rate of 30 mL min− . The product yields were determined by H-NMR. 3 4 T = 90 ◦C. Compound 2k was also formed. Molecules 2020, 25, 4771 5 of 7
3. Materials and Methods
3.1. Chemicals Aniline (99.8%), o-toluidine (99%), m-toluidine (99%), p-toluidine (99%), p-anisidine (99%), o-chloroaniline (>98%), m-chloroaniline (99%), p-chloroaniline (98%), p-fluoroaniline (98%), p-bromoaniline (>99%), n-hexylamine (99%), and 5-(acetoxymethyl)-2-furaldehyde (97%) from Acros Organics (Geel, Belgium), as well as 5-hydroxymethylfurfural (99%) from Sigma-Aldrich (St Louis, MO, USA), were used without additional purification. Methanol (99.8%) from J.T. Baker (Phillipsburg, NJ, USA), ethanol (99.9%) from J.T. Baker and isopropanol (99.5%) from Acros Organics were employed as a solvent.
3.2. Catalyst Preparation Cu-Al layered double hydroxide was prepared by co-precipitation method at pH 9.0 and temperature of 70 ◦C using the mixture of copper (II) nitrate and aluminum nitrate as starting material 2 3+ 3+ 2+ and solution containing NaOH and Na2CO3 ([CO3 −]/[Al ] = 0.86, [OH−] = 1.6([Al ] + [Cu ]) as precipitant agent. The aging of the obtained suspension was performed at 70 ◦C for 4 h. Afterwards, the precipitate was filtered, washed with hot water and dried at 110 ◦C for 14 h. The as-prepared LDH was calcined at 650 ◦C for 4 h to obtain desired CuAlOx catalyst [11,13] containing 47.2 wt% of Cu and 19.9 wt% of Al. The texture properties of CuAlOx were found to be as follows: BET specific surface 2 1 3 1 area—68 m g− and total pore volume—0.15 cm g− .
3.3. Characterization Techniques The Cu and Al content was measured by atomic absorption spectroscopy on an Optima 4300 DV instrument (Perkin Elmer, Waltham, MA, USA). Textural characteristics were determined from nitrogen adsorption–desorption isotherms (77 K) obtained on a Micromeritics ASAP 2400 analyzer (Micromeritics, Norcross, GA, USA).
3.4. General Procedure for Reductive Amination of Furanic Aldehydes with Primary Amines Depending on the nucleophilic properties of the amine, the solution of furanic aldehyde (0.05 M) and primary amine (0.05 M) in methanol was kept at 25 ◦C for 3 or 16 h. Then, the reaction mixture was mixed with H2 and pumped through the flow reactor packed with the CuAlOx material. Catalytic experiments were performed in H-Cube Pro setup (Thalesnano, Budapest, Hungary) equipped with a 30 mm CatCart cartridge (CatCart®30, 0.30 mL empty volume) [11,13]. Before the catalytic run, the catalyst (0.165 g of 250–500 µm particles) was reduced by a mixture of hydrogen with methanol at 1 120 ◦C for 1 h (pressure of 10 bar, flow rates of methanol and H2 were 0.5 and 30 mL min− , respectively). Afterwards, the reaction mixture was pumped through the reactor instead of pure solvent, and this point in time was chosen as the starting point of the experiment. The reaction was carried out at temperature of 80–120 ◦C, H2 pressure of 10 bar, liquid feed rate of 1 1 0.5 mL min− and hydrogen flow rate of 30 mL min− (inlet H2/substrate molar ratio was 54). The use of a large excess of H2 in the reaction medium is necessary to avoid the influence of external mass transfer on the reaction progress [13]. The performance of the catalyst was evaluated by analysis of the samples taken in the interval of 30–33 min from the beginning of the experiment. The composition of 1 the reaction products was determined using H NMR spectroscopy in CDCl3. The error in determining the yield is 1%. ± 4. Conclusions The two-step one-pot reductive amination of furanic aldehydes, including non-catalytic condensation of HMF (or AMF) with primary amines and the subsequent flow hydrogenation of the obtained imine over Cu-based catalyst derived from layered double hydroxide, was successfully Molecules 2020, 25, 4771 6 of 7 performed using methanol as a solvent. This inexpensive and environmentally friendly process can be utilized to obtain a wide range of N-substituted 5-(hydroxymethyl)-2-furfuryl amines and 5-(acetoxymethyl)-2-furfuryl amines in good to excellent yields (up to 98 and 99%, respectively). The proposed approach is a new method for the synthesis of aminomethylhydroxymethylfuran derivatives which can be used as pharmaceuticals or their precursors.
Supplementary Materials: The following are available online, Figure S1: The time dependence of imine yield in the condensation of HMF (0.05 M) and aniline (0.05 M) at room temperature; Figure S2: The time dependence of imine yield in the reaction between AMF (0.05 M) and aniline (0.05 M) in methanol at room temperature; Figure S3: Time dependence of 2a yield in the two-step one-pot reductive amination of HMF (0.05 M) with aniline (0.05 M) at 1 100 ◦C; H-NMR spectra of the final reaction mixtures. Author Contributions: A.L.N. planned and designed the experiments, performed the catalytic activity tests, and wrote the manuscript. M.V.B. performed the catalyst synthesis and revised the manuscript. V.I.B. supervised the project. All authors discussed the results and approved the final version of the manuscript. Funding: The work was supported by the Russian Science Foundation (grant no. 20-43-05002). Conflicts of Interest: The authors declare no conflict of interest.
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