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: