catalysts
Article Application of Heterogeneous Catalysts in the First Steps of the Oseltamivir Synthesis
José M. Fraile * ID and Carlos J. Saavedra ID Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), Facultad de Ciencias, CSIC—Universidad de Zaragoza, E-50009 Zaragoza, Spain; [email protected] * Correspondence: [email protected]
Received: 17 November 2017; Accepted: 12 December 2017; Published: 17 December 2017
Abstract: The first steps of oseltamivir synthesis from quinic acid involve acetalization and ester formation. These reactions are catalyzed by either acids or bases, which may be accomplished by heterogeneous catalysts. Sulfonic solids are efficient acid catalysts for acetalization and esterification reactions. Supported tetraalkylammonium hydroxide or 1,5,7-triazabicyclo[4.4.0]dec-5-ene are also efficient base catalysts for lactone alcoholysis and in this work, these catalysts have been applied in two alternative synthetic routes that lead to oseltamivir. The classical route consists of an acetalization, followed by a lactonization, and then a lactone alcoholysis. This achieves a 66% isolated yield. The alternative route consists of esterification followed by acetalization and is only efficient when an acetone acetal is used.
Keywords: heterogeneous catalysis; acetalization; lactonization; esterification; sulfonic solids; oseltamivir
1. Introduction Pharmaceutical molecules are quintessentially specialty chemicals with structural complexity that require multistep synthetic routes [1]. In addition to atom economy, other parameters such as step [2,3] and pot [4] economy have to be considered in assessments of synthetic routes. The option to carry out multistep chemical transformations in one pot would be of great interest for the synthesis of pharmaceuticals [5]. Heterogeneous catalysts are viable options [6] as multifunctional heterogeneous catalysts and furthermore, different solids can be used to support sites that would otherwise be mutually incompatible in one reaction system [7]. Oseltamivir is one of the most important anti-influenza drugs, and has interesting synthetic approaches, with various routes having from four to 25 steps [8]. The highest overall yield and step economy is provided by a route beginning with (−)-shikimic acid [9] (Scheme1), which is a natural product obtained from the Chinese star anise (Illicium verum). Hence, its availability and price generate a bottleneck for this synthesis, and in fact, the shortage of Tamiflu in 2005 during the avian flu pandemic is attributed to this problem. Intensive research has been carried out to develop total synthesis of oseltamivir using commercially available starting materials. In some cases, the synthetic route starts from cyclic materials, as in Shibasaki’s [10] and Zutter’s [11] methods, in which one of the key steps is the desymmetrization of a meso intermediate, or Trost’s synthesis [12], using an asymmetric allylic alkylation as key step. In other cases, one of the key steps is the formation of the cyclohexene ring, for example through an asymmetric Diels–Alder reaction, as in Corey’s [13] and Fukuyama’s [14] methods. In all cases, the synthetic pathway involves several (nine to 14) steps. Some synthetic methods from sugars have been described [15,16], and are even more complicated. Very recently, the construction of the oseltamivir ring has been described in a three-component reaction system using highly efficient asymmetric organocatalysis [17].
Catalysts 2017, 7, 393; doi:10.3390/catal7120393 www.mdpi.com/journal/catalysts Catalysts 2017, 7, 393 2 of 14 Catalysts 2017, 7, 393 2 of 14 construction of the oseltamivir ring has been described in a three‐component reaction system using Catalystsconstruction2017, 7 ,of 393 the oseltamivir ring has been described in a three‐component reaction system using2 of 14 highly efficient asymmetric organocatalysis [17]. highly efficient asymmetric organocatalysis [17].
SchemeScheme 1. 1.General General routes routes to to oseltamivir oseltamivir from from ( −(−)-shikimic)‐shikimic andand ((−))-quinic‐quinic acids. acids. Scheme 1. General routes to oseltamivir from (−)‐shikimic and (−)‐quinic acids. For the moment, the most scalable route to oseltamivir involves (−)‐quinic acid as the starting For the moment,moment, thethe mostmost scalablescalable routeroute toto oseltamiviroseltamivir involvesinvolves ((−−))-quinic‐quinic acid as the startingstarting material (Scheme 1), as it shares a good number of steps with the well‐known shikimic acid route. material (Scheme 11),), asas itit sharesshares aa goodgood numbernumber ofof stepssteps withwith thethe well-knownwell‐known shikimicshikimic acidacid route.route. The first step of the oseltamivir syntheses, starting from (−)‐quinic acid (1) [18,19], consists of the The firstfirst stepstep ofof thethe oseltamiviroseltamivir syntheses,syntheses, startingstarting fromfrom ((−−))-quinic‐quinic acid ( 1))[ [18,19],18,19], consists of thethe acetalization of the two cis hydroxyl groups in positions 3 and 4 with acetone, with concomitant acetalization of the two cis hydroxyl groups in positions 3 and 44 withwith acetone,acetone, withwith concomitantconcomitant lactonization of the carboxylic group and the cis hydroxyl at carbon 5, catalyzed by p‐toluenesulfonic lactonization of the carboxylic group and the cis hydroxyl at carbon 5, catalyzed by p-toluenesulfonic‐toluenesulfonic acid, leading to the acetal–lactone (2a) (Scheme 2). The lactone ring is then opened by a reaction with acid, leading to the acetal–lactone (2a)) (Scheme(Scheme2 2).). The The lactone lactone ring ring is is then then opened opened by by a a reaction reaction with with EtONa/EtOH, to obtain the acetal–ester (3ab). Notably, there is a pent‐3‐yl group in the final product EtONa/EtOH, to to obtain obtain the the acetal–ester acetal–ester ( (3ab3ab).). Notably, Notably, there there is a pent pent-3-yl‐3‐yl group in the final final product that requires a transacetalization step. A weak point of this route is the use of dimethyl acetonide that requiresrequires a a transacetalization transacetalization step. step. A A weak weak point point of of this this route route is the is the use use of dimethyl of dimethyl acetonide acetonide [20], [20], and this could be circumvented if the acetalization were carried out directly with pentan‐3‐one and[20], thisand couldthis could be circumvented be circumvented if the if acetalizationthe acetalization were were carried carried out out directly directly with with pentan-3-one pentan‐3‐one to to get (2b), and subsequently (3bb) as the acetal–ester product (Scheme 2). Alternatively, there could getto get (2b (2b), and), and subsequently subsequently (3bb (3bb) as) as the the acetal–ester acetal–ester product product (Scheme (Scheme2 ).2). Alternatively, Alternatively, there there could could be a viable route via an initial esterification step, leading to the ethyl quinate (4b), with subsequent be a viable route via anan initialinitial esterificationesterification step, leading to the ethylethyl quinatequinate (4b),), withwith subsequentsubsequent acetalization (Scheme 2). acetalization (Scheme2 2).). In this manuscript, both alternatives starting from (−)‐quinic acid (referred to henceforth as In thisthis manuscript,manuscript, bothboth alternativesalternatives startingstarting fromfrom ((−−))-quinic‐quinic acid (referred to henceforth as “quinic acid”) will be studied using heterogeneous catalysts, as well as the possibility to carry out the “quinic“quinic acid”)acid”) willwill bebe studiedstudied usingusing heterogeneousheterogeneous catalysts,catalysts, asas wellwell asas thethe possibility to carry out the transformation in one pot. As the methyl ester has been also described in other synthetic pathways, transformation in one pot. As the methyl ester has been also described in other synthetic pathways, the series of methyl esters (3aa, 4a) will be also explored. the series of methyl esters ((3aa,, 4a)) willwill bebe alsoalso explored.explored.
Scheme 2. Possible routes from (−)‐quinic acid to the acetal–esters (3). SchemeScheme 2.2. PossiblePossible routesroutes fromfrom ((−−))-quinic‐quinic acid acid to to the the acetal–esters acetal–esters ( (3).).
Catalysts 2017, 7, 393 3 of 14 Catalysts 2017, 7, 393 3 of 14
2. Results Catalysts 2017 and , 7Discussion , 393 3 of 14
2.1.2. Single Results Step and One: Discussion Acetal Formation from Quinic Acid
2.1.The Single firstfirst Step step step One: described described Acetal in Formation the in Gileadthe fromGilead [18 ]Quinic and [18] Hoffmann-La Acid and Hoffmann Roche‐La [9 ,19Roche] routes [9,19] is the routes acetalization is the ofacetalization quinic acid of with quinic 2,2-dimethoxypropane acid with 2,2‐dimethoxypropane in acetone catalyzed in acetone by catalyzedp-toluenesulfonic by p‐toluenesulfonic acid (PTSA) (Schemeacid (PTSA)The3). first(Scheme step 3). described in the Gilead [18] and Hoffmann‐La Roche [9,19] routes is the acetalization of quinic acid with 2,2‐dimethoxypropane in acetone catalyzed by p‐toluenesulfonic acid (PTSA) (Scheme 3).
SchemeScheme 3.3. AcetalizationAcetalization ofof ((−−))-quinic‐quinic acid. acid.
Scheme 3. Acetalization of (−)‐quinic acid. Many sulfonic sulfonic solids solids have have been been described described as ascatalysts catalysts for foracid acid-catalyzed‐catalyzed procedures procedures [21–23], [21– and23], andseveral several of them of them were were chosen chosen (Figure (Figure 1) as1 )potentially as potentially interesting interesting alternatives alternatives for forPTSA: PTSA: Many sulfonic solids have been described as catalysts for acid‐catalyzed procedures [21–23], and Amberlyst IR‐15 [24]: macroreticular sulfonated polystyrene–divinylbenzene with 20% cross‐ • several of them were chosen (Figure 1) as potentially interesting alternatives for PTSA: Amberlystlinking degree. IR-15 [24]: macroreticular sulfonated polystyrene–divinylbenzene with 20% cross-linkingDeloxanAmberlyst ASP degree.I/9IR‐ [25]:15 [24]: alkyl macroreticular sulfonic polysiloxane. sulfonated polystyrene–divinylbenzene with 20% cross‐ • DeloxanSAClinking‐13 [26]: ASP degree. nafion–silica I/9 [ 25]: alkyl composite, sulfonic polysiloxane. with perfluoroalkyl sulfonic groups. • SAC-13sulfonatedDeloxan [26 ]:ASPhydrothermal nafion–silica I/9 [25]: alkyl composite,carbon sulfonic (SHTC): with polysiloxane. perfluoroalkylprepared from sulfonic glucose groups. under mild conditions and • sulfonatedSAC‐13 [26]:with hydrothermal nafion–silica sulfuric acid carbon composite, [27] (SHTC):that contains with prepared perfluoroalkyl arylsulfonic from glucose sulfonic groups under groups.and has mild shown conditions improved and sulfonatedactivitysulfonated in different with hydrothermal sulfuric esterification acid carbon [27 ]reactions that (SHTC): contains [28,29]. prepared arylsulfonic from groupsglucose and under has mild shown conditions improved and activitysulfonated in different with sulfuric esterification acid [27] reactions that contains [28,29]. arylsulfonic groups and has shown improved activity in different esterification reactions [28,29].
Figure 1. Sulfonic solids used as acid catalysts.
The results obtained withFigure allFigure the 1. sulfonic Sulfonic1. Sulfonic solids catalysts solids used used are as acidascollected acid catalysts. catalysts. in Table 1.
The results obtained with all the sulfonic catalysts are collected in 1Table 1. The results obtained withTable all 1. the Results sulfonic of the catalysts acetalization are collected of quinic inacid. Table 1. With 3.5 eq of 2,2-dimethoxypropane (DMP)2 heated at reflux3 in acetone, all the solid catalysts, with Entry KetoneTable 1. CatalystResults of theT acetalization(°C) DMP of quinicTime (h)acid. 1Yield (%) the exception of Amberlyst1 Acetone IR-15, led to yieldsPTSA of the56 acetal–lactone Yes 2a higher3 (86–91%,83 entries 3, 7 and 9) than that obtained2Entry with PTSA(R =Ketone Me) (83%, entryIRCatalyst‐15 1). The2 56 reactionT (°C) YesDMP is significantly3 Time3 (h) slowerYield48 in (%) the absence of DMP (entries 4, 8 and1 10), orAcetone with DMP at PTSA room temperature56 Yes (entry 48 11)3 or in73 a solvent83 other than acetone (entry 12).3 2 (R = Me) DeloxanIR‐15 56 56 YesYes 3 3 91 48 In the case of4 pentan-3-one, the dimethyl acetal56 is not commerciallyNo 3 available48 10 and 73 the reactions that 5 3 Deloxan 25 56 YesYes 68 3 63 91 lead to 2b were carried out in the ketone heated at reflux. Given its higher boiling point, the reaction 6 4 66 56 Yes No4 3 3 11 10 was faster and yields of over 90% were obtained after only 24 h (entries 13 and 14). 7 5 SAC‐13 56 25 YesYes 3 68 86 63 8 6 56 66 NoYes 4 3 3 15 11 7 SAC ‐13 56 Yes 24 3 40 86 8 56 No 72 3 64 15 9 SHTC 56 Yes 3 24 90 540 10 56 No 3 72 9 64 9 SHTC 56 Yes 3 90 5 10 56 No 3 9
Catalysts 2017, 7, 393 4 of 14
Table 1. Results of the acetalization of quinic acid. 1
Catalysts 2017, 7, 393 4 of 14 Entry Ketone Catalyst 2 T(◦C) DMP 3 Time (h) Yield (%) 1 Acetone PTSA 56 Yes24 364 83 2 (R = Me) IR-15 56 Yes48 380 48 11 25 Yes 24 4882 73 3 Deloxan 56 Yes 3 91 12 66 Yes 4 3 61 4 56 No 3 10 13 Pentan‐3‐one Deloxan 101 No 24 100 5 25 Yes 68 63
614 (R = Et) SHTC 101 66 NoYes 4 24 391 11
7 SAC-13 56 Yes48 3100 86 1 Reaction8 conditions: quinic acid (1 mmol), catalyst 56 (0.01 Nommol), ketone 3 (4 mL); 152 PTSA: p‐ toluenesulfonic acid; SHTC: sulfonated hydrothermal carbon; 3 DMP:24 addition 40 of 2,2‐ dimethoxypropane (3.5 mmol); 4 with tetrahydrofuran (4 mL) as solvent instead72 of acetone; 64 5 average 9 SHTC 56 Yes 3 90 5 yield of two experiments. 10 56 No 3 9 24 64 With 3.5 eq of 2,2‐dimethoxypropane (DMP) heated at reflux in acetone,48 all the 80 solid catalysts, with the exception11 of Amberlyst IR‐15, led to yields 25 of the acetal–lactone Yes 2a 24 higher (86%–91%, 82 entries 4 3, 7 and 9) than12 that obtained with PTSA (83%, entry 66 1). TheYes reaction is 3significantly 61 slower in the absence of DMP13 (entriesPentan-3-one 4, 8 and 10),Deloxan or with DMP 101 at room Notemperature 24 (entry 11) 100 or in a solvent 14 (R = Et) SHTC 101 No 24 91 other than acetone (entry 12). 48 100 In the case of pentan‐3‐one, the dimethyl acetal is not commercially available and the reactions 1 Reaction conditions: quinic acid (1 mmol), catalyst (0.01 mmol), ketone (4 mL); 2 PTSA: p-toluenesulfonic that leadacid; to SHTC: 2b were sulfonated carried hydrothermal out in the carbon; ketone3 heatedDMP: additionat reflux. of Given 2,2-dimethoxypropane its higher boiling (3.5 mmol);point, the 4 5 reactionwith was tetrahydrofuran faster and (4yields mL) as of solvent over instead90% were of acetone; obtainedaverage after yield only of two24 h experiments. (entries 13 and 14).
2.2. Single Step Two: Lactone Alcoholysis The second step is the lactone alcoholysis to give the acetal–ester 3 (Scheme 44).). ThisThis reactionreaction isis in fact a transesterification,transesterification, which could be catalyzed by acids or bases, and the two types of solid catalysts were tested.
Scheme 4. Alcoholysis of acetal–lactones 2.
In the two acid‐catalyzed reactions with ethanol (Table 2), the lactone ethanolysis was quite In the two acid-catalyzed reactions with ethanol (Table2), the lactone ethanolysis was quite efficient, with yields of esters around 74%–77% (entries 1 and 3), but unfortunately, the side efficient, with yields of esters around 74%–77% (entries 1 and 3), but unfortunately, the side transacetalization reaction was also very efficient, and the main product was in both cases the ethyl transacetalization reaction was also very efficient, and the main product was in both cases the ethyl quinate 4b, with a small amount of lactone 5 [30]. At room temperature (entries 2 and 4), the reaction quinate 4b, with a small amount of lactone 5 [30]. At room temperature (entries 2 and 4), the reaction was very slow. was very slow. Three heterogeneous basic catalysts were tested (Figure 2): Amberlite IRA‐400 [31] (quaternary Three heterogeneous basic catalysts were tested (Figure2): Amberlite IRA-400 [ 31] (quaternary ammonium hydroxide) and 1,5,7‐triazabicyclo[4.4.0]dec‐5‐ene (TBD), supported on either ammonium hydroxide) and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), supported on either polystyrene polystyrene (TBD‐PS [32]) or silica (TBD‐SiO2 [33]). Their activities were compared with (TBD-PS [32]) or silica (TBD-SiO [33]). Their activities were compared with tetramethylammonium tetramethylammonium hydroxide2 and TBD, which are the homogeneous counterparts. Only the hydroxide and TBD, which are the homogeneous counterparts. Only the lactone 2a and the ethyl lactone 2a and the ethyl ester 3ab were detectable in the reaction mixtures. While heated at reflux in ester 3ab were detectable in the reaction mixtures. While heated at reflux in ethanol, the 2a/3ab ethanol, the 2a/3ab ratio was around 40:60, which seems to be the equilibrium position under those ratio was around 40:60, which seems to be the equilibrium position under those conditions. At lower conditions. At lower temperature, the reaction is not so easily reversible, and 86% yield can be temperature, the reaction is not so easily reversible, and 86% yield can be obtained with TBD-PS after obtained with TBD‐PS after only 24 h at 0 °C (entry 10). The homogeneous catalysts (entries 11–14) only 24 h at 0 ◦C (entry 10). The homogeneous catalysts (entries 11–14) lead to similar or worse results, lead to similar or worse results, showing the positive effect of immobilization on the activity, together with the simple work‐up of the reaction mixture when using heterogeneous catalysts. In the case of 3bb, 84% yield can be also obtained with TBD‐PS at 0 °C (entry 17). Finally, the methyl ester 3aa can also be obtained from 2a and methanol with very high yield (96%) at 0 °C after 48 h (entry 18).
Catalysts 2017, 7, 393 5 of 14 showing the positive effect of immobilization on the activity, together with the simple work-up of the reaction mixture when using heterogeneous catalysts. In the case of 3bb, 84% yield can be also obtained with TBD-PS at 0 ◦C (entry 17). Finally, the methyl ester 3aa can also be obtained from 2a and methanol with very high yield (96%) at 0 ◦C after 48 h (entry 18).
Table 2. Results of the alcoholysis of acetal–lactones 2. 1
T Time Yield (%) Entry Reaction Catalyst (◦C) (h) 2 3 4 5 1 2a + EtOH SAC-13 78 24 13 1 76 10 2 25 24 87 0 6 7 3 SHTC 78 24 17 2 72 9 4 25 24 82 0 9 9 5 IRA-400 78 5 42 58 - - 6 TBD-SiO2 78 4 40 60 - - 7 25 4 69 31 - - 19 45 55 - - 8 −20 48 21 79 - - 9 TBD-PS 78 4 36 64 - - 10 0 4 60 40 - - 24 14 86 - - 48 10 90 2 -- 11 Me4NOH 78 24 39 61 - - 12 0 24 30 70 - - 48 30 70 - - 13 TBD 78 24 42 58 - - 14 0 24 42 58 - - 48 43 57 - - 15 2b + EtOH TBD-SiO2 78 4 48 52 - - 16 TBD-PS 78 4 44 56 - - 17 0 4 29 71 - - 24 16 84 - - 48 14 86 2 -- 18 2a + MeOH TBD-PS 0 24 31 69 - - 48 4 96 2 -- 1 Reaction conditions: lactone 2 (1 mmol), alcohol (4 mL) and catalyst (0.01 mmol of acid or 0.1 mmol of base); 2 average yields of two experiments. Catalysts 2017, 7, 393 5 of 14
Figure 2. Solids used as base catalysts.
2.3. One-Pot Acetalization andTable Lactone 2. Results Alcoholysis: of the alcoholysis Single Acid of acetal–lactones Catalyst 2. 1 T Time Yield (%) In spiteEntry of the transacetalizationReaction Catalyst problems detected with acid catalysts, the direct one-pot synthesis of acetal–esters 3 (Scheme5) was tried with the sulfonic(°C) solids,(h) using2 2,2-dimethoxypropane3 4 5 in a 1:1 mixture (v/v1) of acetone2a + EtOH and the correspondingSAC‐13 alcohol78 (Table24 3). 13 1 76 10 2 25 24 87 0 6 7 3 SHTC 78 24 17 2 72 9 4 25 24 82 0 9 9 5 IRA‐400 78 5 42 58 ‐ ‐ 6 TBD‐SiO2 78 4 40 60 ‐ ‐ 7 25 4 69 31 ‐ ‐ 19 45 55 ‐ ‐ 8 –20 48 21 79 ‐ ‐ 9 TBD‐PS 78 4 36 64 ‐ ‐ 10 0 4 60 40 ‐ ‐ 24 14 86 ‐ ‐ 48 10 90 2 ‐ ‐ 11 Me4NOH 78 24 39 61 ‐ ‐ 12 0 24 30 70 ‐ ‐ 48 30 70 ‐ ‐ 13 TBD 78 24 42 58 ‐ ‐ 14 0 24 42 58 ‐ ‐ 48 43 57 ‐ ‐ 15 2b + EtOH TBD‐SiO2 78 4 48 52 ‐ ‐ 16 TBD‐PS 78 4 44 56 ‐ ‐ 17 0 4 29 71 ‐ ‐ 24 16 84 ‐ ‐ 48 14 86 2 ‐ ‐ 18 2a + MeOH TBD‐PS 0 24 31 69 ‐ ‐ 48 4 96 2 ‐ ‐ 1 Reaction conditions: lactone 2 (1 mmol), alcohol (4 mL) and catalyst (0.01 mmol of acid or 0.1 mmol of base); 2 average yields of two experiments.
2.3. One‐Pot Acetalization and Lactone Alcoholysis: Single Acid Catalyst In spite of the transacetalization problems detected with acid catalysts, the direct one‐pot synthesis of acetal–esters 3 (Scheme 5) was tried with the sulfonic solids, using 2,2‐dimethoxypropane in a 1:1 mixture (v/v) of acetone and the corresponding alcohol (Table 3).
Catalysts 2017, 7, 393 6 of 14 CatalystsCatalysts 20172017,, 77,, 393393 66 ofof 1414
Scheme 5. One‐step formation of dimethyl acetal and ester from quinic acid using 2,2‐ Scheme 5. OneOne-step‐step formation formation of ofdimethyl dimethyl acetal acetal and andester ester from from quinic quinic acid acidusing using 2,2‐ dimethoxypropane. dimethoxypropane.2,2-dimethoxypropane. The reaction with ethanol led to five reaction products, two lactones in the form of acetal (2a) The reactionTable 3. Resultswith ethanol of the one-step led to five formation reaction of dimethyl products, acetal two and lactones ester from in the quinic form acid. of 1acetal (2a) andand freefree hydroxylshydroxyls ((55),), twotwo ethylethyl estersesters withwith acetalacetal ((3ab3ab)) andand freefree quinatequinate ((4b4b),), asas wellwell asas thethe quinicquinic acidacid acetalacetal ((6a6a).). TotalTotal conversionconversion ofof quinicquinic acidacid waswas obtainedobtainedYield inin (%) mostmost cases,cases, butbut thethe productproduct distribution was Entryquite differentAlcohol dependingCatalyst on the catalyst. However, the acetal–ester 3ab, the desired distribution was quite different depending on the catalyst.2a However, 3 4 the acetal–ester 5 6 3ab, the desired product, was not obtained with a significant yield. On the contrary, ethyl quinate 4b was the major product, was not obtained with a significant2 yield. On the contrary, ethyl quinate 4b was the major product because of1 the transacetalization EtOH Deloxan of 2a with56 ethanol 8 in the 9 presence 7 of the 20 acid catalyst. product because of2 the transacetalization IR-15 of 2a with 54 ethanol 0 in the 32 presence 6 of the 8 acid catalyst. 3 SAC-13 38 3 38 10 11 1 TableTable 3.3. ResultsResults4 ofof thethe oneone‐‐stepstep SHTC formationformation ofof 46 dimethyldimethyl 0 acetalacetal andand 24 esterester 12 fromfrom quinicquinic3 3 acid.acid. 1 5 MeOH Deloxan 41 25Yield (%) 23 7 4 6Entry Alcohol IR-15 Catalyst 35 Yield 9 (%) 45 10 1 Entry Alcohol Catalyst 2a 3 4 5 6 7 SAC-13 382a 263 4 265 6 7 3 2 811 EtOHEtOH SHTC DeloxanDeloxan 39 2 5656 088 99 4977 2020 12 0 2 IR‐15 54 0 32 6 8 1 Reaction conditions: quinic2 acid (1 mmol),IR 2,2-dimethoxypropane‐15 54 0 32 (3.5 6 mmol), 8 catalyst (0.01 mmol) in acetone/alcohol (4 mL, 1:1 v/v),33 heated at reflux,SACSAC 24‐‐13 h;13 2 average3838 33 yields 3838 of two1010 experiments;1111 3 the remaining 3 15% corresponds to unconverted44 quinic acid. SHTCSHTC 4646 00 2424 1212 33 3 55 MeOHMeOH DeloxanDeloxan 4141 2525 2323 77 44 6 IR‐15 35 9 45 10 1 The reaction with ethanol6 led to five reactionIR‐15 products, 35 two9 45 lactones 10 in1 the form of acetal (2a) and 7 SAC‐13 38 26 26 7 3 free hydroxyls (5), two ethyl7 esters with acetalSAC (3ab‐13 ) and38 free26 quinate26 7 (4b3), as well as the quinic acid 88 SHTCSHTC 3939 00 4949 1212 00 acetal1 (6a). Total conversion of quinic acid was obtained in most cases, but the product distribution 1 ReactionReaction conditions:conditions: quinicquinic acidacid (1(1 mmol),mmol), 2,22,2‐‐dimethoxypropanedimethoxypropane (3.5(3.5 mmol),mmol), catalystcatalyst (0.01(0.01 mmol)mmol) was quite different depending on the catalyst. However, the2 acetal–ester 3ab, the desired product,3 was inin acetone/alcoholacetone/alcohol (4(4 mL,mL, 1:11:1 v/v),v/v), heatedheated atat reflux,reflux, 2424 h;h; 2 averageaverage yieldsyields ofof twotwo experiments;experiments; 3 thethe not obtained with a significant yield. On the contrary, ethyl quinate 4b was the major product because remainingremaining 15%15% correspondscorresponds toto unconvertedunconverted quinicquinic acid.acid. of the transacetalization of 2a with ethanol in the presence of the acid catalyst. Methanol is much more reactive than ethanol and consequently, the results are quite different. MethanolMethanol isis muchmuch moremore reactivereactive thanthan ethanolethanol andand consequently,consequently, thethe resultsresults areare quitequite different.different. In fact, the yield of the desired acetal–ester 3aa was significant, around 25% with both Deloxan and InIn fact,fact, thethe yieldyield ofof thethe desireddesired acetal–esteracetal–ester 3aa3aa waswas significant,significant, aroundaround 25%25% withwith bothboth DeloxanDeloxan andand SAC-13 (entries 5 and 7), although the yield of free ester 4a was also important in all the cases. SACSAC‐‐1313 (entries(entries 55 andand 7),7), althoughalthough thethe yieldyield ofof freefree esterester 4a4a waswas alsoalso importantimportant inin allall thethe cases.cases. Finally, the reaction of quinic acid in a 1:1 mixture of ethanol and pentan-3-one (Scheme6) was Finally,Finally, thethe reactionreaction ofof quinicquinic acidacid inin aa 1:11:1 mixturemixture ofof ethanolethanol andand pentanpentan‐‐33‐‐oneone (Scheme(Scheme 6)6) waswas tried with the same acid catalysts (Table4). The yields of the compounds with the acetal group triedtried withwith thethe samesame acidacid catalystscatalysts (Table(Table 4).4). TheThe yieldsyields ofof thethe compoundscompounds withwith thethe acetalacetal groupgroup ((3bb3bb (3bb and 6) were very low, showing the lower stability of the pentanone acetal. In view of the problems andand 66)) werewere veryvery low,low, showingshowing thethe lowerlower stabilitystability ofof thethe pentanonepentanone acetal.acetal. InIn viewview ofof thethe problemsproblems associated with the use of acid catalysts in the alcoholysis step, the sequential acetalization followed associatedassociated withwith thethe useuse ofof acidacid catalystscatalysts inin thethe alcoholysisalcoholysis step,step, thethe sequentialsequential acetalizationacetalization followedfollowed by alcoholysis was tested with two different catalysts. byby alcoholysisalcoholysis waswas testedtested withwith twotwo differentdifferent catalysts.catalysts.
SchemeScheme 6.6. One-stepOneOne‐‐stepstep formationformation of of diethyldiethyl acetal acetal andand ethylethyl esterester fromfrom quinicquinic acidacid usingusing pentan-3-onepentanpentan‐‐33‐‐oneone andand ethanol. ethanol.
Catalysts 2017, 7, 393 7 of 14
Table 4. Results of the one‐step formation of diethyl acetal and ethyl ester from quinic acid. 1
Yield (%) Catalyst 2b 3bb 4b 5 Deloxan 27 3 43 24 IR‐15 34 2 47 17 SAC‐13 20 10 53 17 SHTC 67 0 29 4 1 Reaction conditions: quinic acid (1 mmol), catalyst (0.01 mmol) in pentan‐3‐one/ethanol (4 mL, 1:1 v/v), heated at reflux, 24 h. Catalysts 2017, 7, 393 7 of 14 2.4. One‐Pot Sequential Process with One Acid and One Base Catalyst: Acetalization and Lactone Alcoholysis
In theTable sequential 4. Results process of the one-step (Scheme formation 7), the offirst diethyl acetalization acetal and reaction ethyl ester was from carried quinic acid.out under1 the optimal conditions determined in the individual test, and once the reaction mixture was cooled at 0 Yield (%) °C, the basic catalyst TBDCatalyst‐PS and ethanol were added. As can be seen in the results (Table 5), the alcoholysis is less efficient under these2b new conditions. 3bb A significant 4b amount 5 of acetal–lactone 2a (53% with Deloxan, entryDeloxan 1, and 38% with 27 SHTC, entry 3 2) remained 43 unreacted 24 even after 48 h, and the conversion of 2b wasIR-15 even lower under 34 the same conditions 2 (entries 47 5 and 17 8), giving 13% of acetal– ester 3bb as the best resultSAC-13 (entry 8). The 20 filtration 10 of the acid 53catalyst before 17 addition of the basic catalyst and ethanol (entrySHTC 3) did not improve 67 the results, 0 demonstrating 29 that 4 the presence of the acid 1 catalystReaction was not conditions: the reason quinic for acid this (1 mmol), lower catalyst efficiency. (0.01 mmol) The in combination pentan-3-one/ethanol of a ketone (4 mL, 1:1andv/ va), base heated catalyst at reflux, 24 h. may produce an aldol condensation as side reaction, as already detected in previous work [7]. Furthermore, about one‐half of the converted 2a was transformed to a previously undetected 2.4. One-Pot Sequential Process with One Acid and One Base Catalyst: Acetalization and Lactone Alcoholysis new product, which was identified as the compound 7 (entries 1–3), which must arise from the simultaneousIn the sequential presence process of acetone/DMP (Scheme7 and), the a firstbasic acetalization catalyst. In fact, reaction when was the carriedacetone/DMP out under mixture the optimalwas evaporated conditions prior determined to the addition in the individualof ethanol test,and andTBD once‐PS (entry the reaction 4), the mixture conversion was of cooled acetal– at ◦ 0lactoneC, the 2a basic was catalystsignificantly TBD-PS improved and ethanol and the were compound added. As7 was can not be seenobtained. in the The results simultaneous (Table5), thepresence alcoholysis of the acid is less catalyst efficient and under ethanol these did new produce conditions. a partial A transacetalization significant amount to ofthe acetal–lactone ethyl quinate 2a4b.(53% The partial with Deloxan, transacetalization entry 1, and was 38% also with observed SHTC, when entry pentan 2) remained‐3‐one was unreacted evaporated even before after 48 the h, andaddition the conversion of TBD‐PS ofand2b ethanolwas even (entry lower 6). under In view the of same the incompatibility conditions (entries of reagents 5 and 8), and giving catalysts 13% of acetal–esterthe two reaction3bb assteps, the bestthe acid result catalyst (entry 8).was The filtered filtration and ofpentan the acid‐3‐one catalyst was evaporated before addition before of the basicaddition catalyst of ethanol and ethanol and TBD (entry‐PS 3)to did the notcrude improve mixture the (entries results, 7 demonstrating and 9). As expected, that the the presence reaction of theselectively acid catalyst formed was the not acetal–ester the reason 3bb for, thiswith lower up to efficiency. a 76% yield The after combination 96 h (entry of 9), a showing ketone and that a pure base catalystacetal–lactone may produce 2b behaves an aldol much condensation better than asthe side crude reaction, one for as the already base‐catalyzed detected in lactone previous alcoholysis. work [7].
Scheme 7. OneOne-pot‐pot sequential acetalization of quinic acid and lactone alcoholysis.
Furthermore,Table 5. Results about of the one-half one‐pot of sequential the converted acetalization2a was of transformedquinic acid and to lactone a previously alcoholysis. undetected 1 new product, which was identified as the compound 7 (entries 1–3), which must arise from the Acid Time (h) Yield (%) simultaneous presenceEntry of acetone/DMPKetone and a basic catalyst. In fact, when the acetone/DMP mixture was evaporated prior to the addition of ethanolCatalyst and TBD-PS1st 2nd (entry2 4), the3 conversion4b 7a of acetal–lactone 1 Acetone Deloxan 4 24 54 21 ‐ 19 2a was significantly improved and the compound 7 was not obtained. The simultaneous presence of 48 53 26 ‐ 16 the acid catalyst and ethanol did produce a partial transacetalization to the ethyl quinate 4b. The partial 2 SHTC 4 24 41 28 ‐ 31 2 transacetalization was also observed when pentan-3-one was48 evaporated 38 32 ‐ before the30 addition of TBD-PS and ethanol (entry 6).3 In view of the incompatibilitySHTC 3 4 of reagents24 48 and23 ‐ catalysts28 of the two reaction steps, the acid catalyst was filtered and pentan-3-one was120 evaporated 25 46 before ‐ the29 addition of ethanol and TBD-PS to the crude4 mixture (entriesSHTC 7 and 4 9). As4 expected,24 19 the 65 reaction 16 ‐ selectively formed the acetal–ester 3bb, with up to a 76% yield after 96 h (entry48 9), showing11 49 that40 ‐ pure acetal–lactone 2b behaves much better than the crude one for the base-catalyzed lactone alcoholysis. Catalysts 2017, 7, 393 8 of 14
Table 5. Results of the one-pot sequential acetalization of quinic acid and lactone alcoholysis. 1
Time (h) Yield (%) Entry Ketone Acid Catalyst 1st 2nd 2 3 4b 7a 1 Acetone Deloxan 4 24 54 21 - 19 48 53 26 - 16 2 SHTC 4 24 41 28 - 31 2 48 38 32 - 30 3 SHTC 3 4 24 48 23 - 28 120 25 46 - 29 4 SHTC 4 4 24 19 65 16 - 48 11 49 40 - Catalysts 2017, 7, 393 8 of 14 5 Pentan-3-one Deloxan 24 24 100 - - - 48 85 - 7 5 - 6 5 Pentan‐3‐oneDeloxan Deloxan4 2424 24 24 100 53 ‐ ‐ ‐ 23 24 - 5 7 Deloxan 6 2448 24 85 47 ‐ 537 ‐ - - 6 Deloxan 4 24 2448 53 35 23 6524 ‐ - - 87 SHTCDeloxan 6 24 48 24 24 47 87 53 ‐ ‐ 13 - - 48120 35 87 65 ‐ ‐ 13 - - 9 8 SHTCSHTC5 4848 24 24 87 46 13 ‐ ‐ 54 - - 12048 87 29 13 ‐ ‐ 71 - - 9 SHTC 5 48 2496 46 24 54 ‐ ‐ 76 - - 1 Reaction conditions: quinic acid (1 mmol), acid catalyst (0.01 mmol),48 ketone29 (471 mL), ‐ ‐ at reflux. In the case of the reaction with acetone, 2,2-dimethoxypropane (3.5 mmol) was also96 added. 24 The second76 ‐ ‐ reaction was carried out at 0 ◦C after addition of TBD-PS (0.1 mmol) and ethanol (4 mL); 2 average yields of two experiments; 3 the acid catalyst 1is Reaction filtered before conditions: adding ethanolquinic andacid TBS-PS; (1 mmol),4 the acid ketone catalyst is evaporated (0.01 mmol), under vacuum ketone before(4 mL), adding at reflux. ethanol In andthe caseTBS-PS; of 5thelactone reaction5 was with also obtained acetone, in 8%;2,2‐dimethoxypropane6 the acid catalyst is filtered (3.5 mmol) and the pentan-3-onewas also added. is evaporated The second under vacuum before adding ethanol and TBS-PS. reaction was carried out at 0 °C after addition of TBD‐PS (0.1 mmol) and ethanol (4 mL); 2 average yields of two experiments; 3 the acid catalyst is filtered before adding ethanol and TBS‐PS; 4 the ketone 2.5. Single Step Three: Esterification of Quinic Acid is evaporated under vacuum before adding ethanol and TBS‐PS; 5 lactone 5 was also obtained in 8%; 6In the view acid catalyst of the problemsis filtered and encountered the pentan‐3 in‐one the is evaporated sequential under process vacuum of acetalization before adding followed ethanol by alcoholysis,and TBS‐ anotherPS. strategy was conceived by changing the sequence order. This new sequence consists of an initial esterification of quinic acid to the corresponding quinate 4 (Scheme8) and then 2.5.the acetalizationSingle Step Three: of this Esterification ester. Again, of Quinic the main Acid advantage would be the possibility of using a single acid catalystIn view andof the thus, problems the individual encountered esterification in the stepsequential was studied process (Table of acetalization6). followed by alcoholysis,Both ethyl another quinate strategy4b and was lactone conceived5 were by obtainedchanging inthe ethanol sequence (entries order. 1–4), This but new the sequence lactone consistsunderwent of an a slow initial acid-catalyzed esterification alcoholysis, of quinic acid leading to the to corresponding more than a 90% quinate yield of4 (Scheme ethyl quinate 8) and4 thenwith theSHTC acetalization (entry 4). Theof this higher ester. reactivity Again, the of methanol main advantage led to a would faster alcoholysis be the possibility reaction of and, using in a general, single acidhigher catalyst methyl and ester thus, (4a the) yields individual were obtained esterification in shorter step was reaction studied times (Table (entries 6). 5–6).
Scheme 8. EsterificationEsterification of quinic acid.
Table 6. Results of the esterification of quinic acid with ethanol or methanol. 1
Yield (%) Entry Alcohol Catalyst Time (h) 4 5 1 EtOH Deloxan 3 19 12 24 72 25 2 48 81 19 68 87 13 2 Deloxan 3 24 83 17 3 SAC‐13 24 65 22 4 SHTC 24 82 9 48 90 10 72 93 7 5 MeOH Deloxan 48 94 6 6 SHTC 24 93 7 1 Reaction conditions: quinic acid 1 (1 mmol), ethanol or methanol (4 mL), and catalyst (0.01 mmol) heated at reflux; 2 average yields of two experiments; 3 0.02 mmol of catalyst.
Both ethyl quinate 4b and lactone 5 were obtained in ethanol (entries 1–4), but the lactone underwent a slow acid‐catalyzed alcoholysis, leading to more than a 90% yield of ethyl quinate 4 with SHTC (entry 4). The higher reactivity of methanol led to a faster alcoholysis reaction and, in general, higher methyl ester (4a) yields were obtained in shorter reaction times (entries 5–6).
Catalysts 2017, 7, 393 9 of 14
Table 6. Results of the esterification of quinic acid with ethanol or methanol. 1
Yield (%) Entry Alcohol Catalyst Time (h) 4 5 1 EtOH Deloxan 3 19 12 24 72 25 2 48 81 19 68 87 13 2 Deloxan 3 24 83 17 3 SAC-13 24 65 22 4 SHTC 24 82 9 48 90 10 72 93 7 5 MeOH Deloxan 48 94 6 6 SHTC 24 93 7 1 Reaction conditions: quinic acid 1 (1 mmol), ethanol or methanol (4 mL), and catalyst (0.01 mmol) heated at reflux; 2 average yields of two experiments; 3 0.02 mmol of catalyst.
2.6. Sequential Process with One or Two Acid Catalysts: Esterification and Acetalization The sequence of esterification with ethanol followed by acetalization was then tried with both acetone and pentan-3-one (Scheme9). In the first case, DMP was used to efficiently promote Catalyststhe acetalization 2017, 7, 393 reaction. Two efficient catalysts for the direct esterification of quinic acid9 with of 14 ethanol—Deloxan and SHTC—were chosen to act as the single catalyst for both reactions or to be 2.6.combined Sequential as catalysts Process with for theOne first or Two and Acid second Catalysts: reactions. Esterification The results and are Acetalization gathered in Table7. The combinationsequence of esterification of Deloxan for with the ethanol esterification followed with by ethanol, acetalization and SHTC was for then acetalization tried with withboth acetone andand DMP,pentan was‐3‐one tested (Scheme (entry 1).9). AIn long the reactionfirst case, time DMP was was used used in the to first efficiently reaction promote to reach the acetalizationhighest conversion reaction. of Two quinic efficient acid, whereas catalysts room for the temperature direct esterification and moderate of quinic time acid was with used ethanol— for the Deloxansecond reaction. and SHTC—were The acetalization chosen to of act ethyl as the quinate single4b catalystwas slower for both than reactions acetalization or to be of combined quinic acid. as catalystsIn fact, after for 24the h, first 13% and of 4b secondremained reactions. unconverted. The results Moreover, are gathered the acetal–lactone in Table 7. 2a was also obtained (up toThe 24% combination yield), indicating of Deloxan that lactonizationfor the esterification can also with be producedethanol, and from SHTC the ester. for acetalization Longer reaction with acetonetimes did and not DMP, change was the tested result. (entry In the 1). absenceA long reaction of DMP, time the acetalization was used in wasthe first slower reaction (entry to 2), reach but the lactonizationhighest conversion occurred of quinic in a similar acid, whereas ratio. The room use oftemperature SHTC as the and only moderate catalyst time for both was reactionsused for theimproves second both reaction. conversion The acetalization and selectivity of ethyl to 3ab quinate(74% 4b yield, was entry slower 4), than but the acetalization best result of was quinic obtained acid. withIn fact, Deloxan after 24 as h, the13% only of 4b catalyst remained (entry unconverted. 3), with almost Moreover, complete the acetal–lactone conversion of 2a4b wasand also 83% obtained yield of (upthe acetal–esterto 24% yield),3ab indicating. that lactonization can also be produced from the ester. Longer reaction timesWhen did not acetalization change the was result. carried In the out absence at higher of DMP, temperature the acetalization (acetone reflux), was slower conversion (entry was 2), but higher the lactonizationbut selectivity occurred was much in lowera similar due ratio. to an The extensive use of lactonization SHTC as the (entries only catalyst 5 and 6). for On both the reactions contrary, ◦ improvesa decrease both in reaction conversion temperature and selectivity to 0 C to (entries 3ab (74% 7 and yield, 8) improves entry 4), the but selectivity the best result with was respect obtained to the withdesired Deloxan acetal–ester as the when only catalyst SHTC is (entry the acetalization 3), with almost catalyst, complete but 83% conversion was the maximum of 4b and yield 83% (entryyield of 7) theobtained acetal–ester in any 3ab case..
Scheme 9. Sequential esterification esterification and acetalization of quinic acid.
Table 7. Sequential esterification and acetalization of quinic acid with two acid catalysts. 1
Acid Acetalization Yield (%) Acid Esterification Time Entry catalyst Ketone T Time catalyst 1 (h) 4b 3 2 5 2 (°C) (h) 1 Deloxan 70 SHTC Acetone 25 15 29 56 15 0 24 13 63 24 0 2 Deloxan 70 SHTC Acetone 2 25 40 27 57 16 0 3 Deloxan 3 70 ‐ Acetone 25 40 3 83 14 0 4 SHTC 3 96 ‐ Acetone 25 40 11 74 15 0 5 Deloxan 3 70 ‐ Acetone 56 40 7 49 44 0 6 SHTC 3 96 ‐ Acetone 56 40 0 9 91 0 7 Deloxan 70 SHTC Acetone 0 70 0 83 17 0 8 Deloxan 3 70 ‐ Acetone 0 40 10 76 14 0 Pentan‐3‐ 9 Deloxan 70 SHTC 25 70 64 24 3 9 one Pentan‐3‐ 10 Deloxan 3 70 ‐ 25 78 79 9 2 10 one Pentan‐3‐ 11 SHTC 48 Deloxan 25 78 41 39 4 16 one Pentan‐3‐ 12 SHTC 48 SHTC 25 78 44 35 13 8 one Pentan‐3‐ 13 SHTC 48 Deloxan 40 68 47 14 33 6 one Pentan‐3‐ 14 SHTC 48 SHTC 40 20 62 12 20 6 one 68 41 14 38 7 Pentan‐3‐ 15 SHTC 48 SHTC 101 24 2 0 82 16 one
Catalysts 2017, 7, 393 10 of 14
Table 7. Sequential esterification and acetalization of quinic acid with two acid catalysts. 1
Acid Esterification Acid Acetalization Yield (%) Entry Ketone catalyst 1 catalyst 2 Time (h) T(◦C) Time (h) 4b 3 2 5 1 Deloxan 70 SHTC Acetone 25 15 29 56 15 0 24 13 63 24 0 2 Deloxan 70 SHTC Acetone 2 25 40 27 57 16 0 3 Deloxan 3 70 - Acetone 25 40 3 83 14 0 4 SHTC 3 96 - Acetone 25 40 11 74 15 0 5 Deloxan 3 70 - Acetone 56 40 7 49 44 0 6 SHTC 3 96 - Acetone 56 40 0 9 91 0 7 Deloxan 70 SHTC Acetone 0 70 0 83 17 0 8 Deloxan 3 70 - Acetone 0 40 10 76 14 0 9 Deloxan 70 SHTC Pentan-3-one 25 70 64 24 3 9 10 Deloxan 3 70 - Pentan-3-one 25 78 79 9 2 10 11 SHTC 48 Deloxan Pentan-3-one 25 78 41 39 4 16 12 SHTC 48 SHTC Pentan-3-one 25 78 44 35 13 8 13 SHTC 48 Deloxan Pentan-3-one 40 68 47 14 33 6 14 SHTC 48 SHTC Pentan-3-one 40 20 62 12 20 6 68 41 14 38 7 15 SHTC 48 SHTC Pentan-3-one 101 24 2 0 82 16 1 Reaction conditions: quinic acid (1 mmol), first acid catalyst (0.01 mmol), ethanol (4 mL), reflux. After the indicated time, the catalyst was filtered off, the ethanol was evaporated under reduced pressure and the second catalyst (0.01 mmol), ketone (4 mL) and DMP (3.5 mmol, only in the case of acetone) were added. In the case of pentan-3-one, 3 mL of ketone and 1 mL of ethanol were added in the second step, due to the lack of solubility of 4b in pure pentan-3-one. Temperature and time as indicated in the table; 2 in the absence of DMP; 3 as the two reactions were catalyzed by the same solid, the evaporation of ethanol was the only treatment after the first reaction.
Finally, the formation of the most interesting acetal–ester 3bb was tried by the same methodology. The ethyl quinate 4b was not soluble in pure pentan-3-one and a small amount of ethanol was added in the second step to allow solubilization of the substrate. At room temperature (entries 9–12), the lack of ketal in the medium and the lower reactivity of the ketone made the reaction less efficient than in the case of acetone, and the yields of 3bb were low in all cases. Moreover, lactones 2b and 5 were also formed. At higher reaction temperatures (entries 13–15), the conversions were improved, but the lactonization side reaction occurred to a more significant level.
2.7. Process at Gram Scale After the exploration of all the possibilities, the optimal procedure to get the acetal–ester of interest 3bb was to use a sequential two-step process using an acid catalyst for the acetalization with pentan-3-one, with concomitant lactonization, followed by a base-catalyzed ethanolysis of the lactone in the way described in Table5. The chosen scale was 10 mmol of quinic acid (1.92 g) and the first reaction was carried out in pentan-3-one heated at reflux for 24 h, with Deloxan as the catalyst. After the catalyst filtration and evaporation of the ketone, the crude product was dissolved in ethanol, cooled to 0 ◦C and made to react using TBD-PS as the catalyst. This reaction was monitored by 1H NMR, was observed during the course of seven days, and led to a 73% yield for 3bb. Catalyst filtration and purification by column chromatography led to 1.89 g of pure 3bb (66% isolated yield), and thus illustrates the potential of this methodology for preparative purposes. Although the recovery of the catalysts was not the primary objective of the work, the gram-scale synthesis permits one to test this aspect. Moreover, the use of the sequential method allows one to recover and reuse each catalyst separately, with the possibility of optimizing the number of runs for each one [34,35]. In this case, both catalysts were recovered and reused under the same conditions without any further pre-treatment. The analysis of the final reaction mixture showed a yield of 57%, slightly lower than in the first reaction, indicating a certain degree of deactivation. Further work would be necessary to identify the origin of this deactivation in order to optimize the recovery and reuse of this catalytic system. Catalysts 2017, 7, 393 11 of 14
3. Materials and Methods See the Supplementary Materials for a full description of the catalysts and the general reaction methods.
3.1. Acetalization of Quinic Acid (1) A mixture of quinic acid (192 mg, 1 mmol) and the acid catalyst (0.01 mmol) in acetone (4 mL) was heated at reflux for the required time. In some reactions, 2,2-dimethoxypropane (430 µL, 364 mg, 3.5 mmol) was also added to the mixture. After cooling to room temperature the catalyst was filtered off and the acetone was evaporated under reduced pressure. The yield of acetal–lactone 2a was determined by 1H NMR [36,37] using mesitylene as an internal standard. The acetalization with pentan-3-one was carried out under the same conditions to obtain acetal–lactone 2b [38].
3.2. Alcoholysis of Acetal–Lactones (2) A mixture of the acetal–lactone (2a or 2b, 1 mmol) and the catalyst (0.01 mmol of acid catalyst or 0.1 mmol of basic catalyst) in alcohol (methanol or ethanol, 4 mL) was stirred at the required temperature for the required time. After allowing the reaction to reach room temperature the catalyst was filtered off and the solvent was evaporated under reduced pressure. Yields of the different products were determined by 1H NMR, using mesitylene as an internal standard.
3.3. One-Pot Acetalization and Lactone Alcoholysis with a Single Acid Catalyst A mixture of quinic acid (192 mg, 1 mmol), 2,2-dimethoxypropane (430 µL, 364 mg, 3.5 mmol) and the acid catalyst (0.01 mmol) in an acetone/alcohol 1:1 (v/v) mixture (4 mL) was heated at reflux for 24 h. After cooling to room temperature, the catalyst was filtered off and the acetone was evaporated under reduced pressure. Yields of the different products obtained (2, 3, 4 and 5) were determined by 1H NMR, using mesitylene as an internal standard. The reaction with pentan-3-one was carried out in the same way, without 2,2-dimethoxypropane.
3.4. One-Pot Acetalization and Lactone Alcoholysis with One Acid and One Basic Catalyst A mixture of quinic acid (192 mg, 1 mmol), 2,2-dimethoxypropane (430 µL, 364 mg, 3.5 mmol) and the acid catalyst (0.01 mmol) in acetone (4 mL) was heated at reflux for 4 h. Then the reaction mixture was cooled to 0 ◦C, TBD-PS (0.1 mmol) and ethanol (4 mL) were added and the reaction was stirred at 0 ◦C for at least 24 h. The catalysts were filtered off and the solvent was evaporated under reduced pressure. Yields of the different products obtained (2a, 3ab, and 6) were determined by 1H NMR using mesitylene as an internal standard. In the case of pentan-3-one, the first reaction was carried out without 2,2-dimethoxypropane and it was heated for either 24 or 48 h. The second reaction was carried out in the same way as for acetone.
3.5. Esterification of Quinic Acid A mixture of quinic acid (192 mg, 1 mmol) and the acid catalyst (0.01 mmol) in alcohol (4 mL) was heated at reflux for the required time. After cooling at room temperature, the catalyst was filtered off and the solvent was evaporated under reduced pressure. Yields of ester 4 [39–41] and lactone 5 [30] were determined by 1H NMR using mesitylene as an internal standard.
3.6. Sequential Esterification and Acetalization with Two Acid Catalysts A mixture of quinic acid (192 mg, 1 mmol) and the acid catalyst (0.01 mmol) in ethanol (4 mL) was heated at reflux for the required time. The catalyst was filtered off and the solvent was eliminated under reduced pressure. The ketone (4 mL) (in the case of the acetalization with pentan-3-one, 3 mL of pentan-3-one and 1 mL of EtOH) and the second acid catalyst (0.01 mmol) were added and the reaction was heated at the required temperature. 2,2-Dimethoxypropane (430 µL, 364 mg, 3.5 mmol) Catalysts 2017, 7, 393 12 of 14 was also added when acetone was used in the acetalization step. The catalyst was filtered off and the ketone was evaporated under reduced pressure. Yields of all the products were determined by 1H NMR using mesitylene as an internal standard.
4. Conclusions The acetal–esters derived from quinic acid (3aa, 3ab and 3bb) can be prepared using heterogeneous catalysis through two different synthetic routes. The desired pentanone acetal ethyl ester 3bb has been prepared on a gram scale with an isolated yield of 66% by a sequential procedure consisting of two reaction steps: the sulfonic acid-catalyzed acetalization and the base-catalyzed alcoholysis of the acetal lactone 2b. The second synthetic route involves an acid-catalyzed esterification of quinic acid followed by the acetalization, catalyzed either by the same acid or by a different solid. Although this route is effective for the isopropylidene derivative 3ab, the acetalization with pentan-3-one is much less efficient due to the competitive lactonization under the reaction conditions. These results demonstrate the potential of heterogeneous catalysts for multistep synthesis of pharmaceutical intermediates.
Supplementary Materials: catalyst descriptions, preparation details and full spectroscopic description of compounds 2a, 2b, 3aa, 3ab, 3bb, 4a, 4b, 5, 6 and 7, including improved assignation of 1H- and 13C-NMR signals. It is available online at www.mdpi.com/2073-4344/7/12/393/s1. Acknowledgments: This work was made possible by the financial support of the Spanish Ministerio de Economía y Competitividad (project CTQ2014-52367-R) and the Gobierno de Aragón (E11 Group co-financed by the European Regional Development Funds). Author Contributions: José M. Fraile conceived and designed the experiments; Carlos J. Saavedra performed the experiments; José M. Fraile and Carlos J. Saavedra analyzed the data; José M. Fraile wrote the paper. Conflicts of Interest: The authors declare no conflict of interest.
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