Knoevenagel Reaction of Unprotected Sugars Marie-Christine Scherrmann Abstract The Knoevenagel reaction of unprotected sugars was investigated in the 1950s using zine chloride as promoter.The so-called Garcia Gonzalez reaction had been alm st forgotten for 50 ye cid beha ars,until the emerge ence of new water tolerant catalysts ha or. The reactic thus invest aed optimal condition ave been foun to prepare trihydroxyla from pentose or B-tetrahydrofuranylfuran from hexoses with non-cyclic B-keto ester or B-diketones.Other valuable compounds such as B-linked tetrahydrobenzo furanyl glycosides or hydroxyalkyl-3.3,6,6.-tetramethyl-3,4.5.6.7,9-hexahydro-1H- xanthene-1.8(2H)-dione can be obtained using cyclic B-dicarbonylic derivatives Apart from one report in the 1950s,the Knoevenagel reaction of unprotected carbohydrate in basic condition has been studied only in the mid-1980s to prepare etones. non 8.C yco The efficient method ited to prepare such compounds s found an industrial development in cosmetics Keywords Acetylacetates,2-Amino-2-deoxyaldoses,Barbituric acids,C-Glyco- sides,Dimedone,Furans,Garcia-Gonzalez reaction,Green chemistry,Hexoses, Meldrum's acid,Penta-2,4-dione,Pentoses,Pyrroles,Reactions in water,Tetrahy- drofuranylfurans Contents 4 Conclusion References........................................ .15 M.-C.Scherrmann Institut de Chimie Moleculaire et des Materiaux d'Orsay.UMR 8182 Universite Paris-Sud 11. 914050sayC mann@u-psud.fr
Top Curr Chem (2010) 295: 1–18 DOI: 10.1007/128_2010_49 # Springer‐Verlag Berlin Heidelberg 2010 Published online: 23 March 2010 Knoevenagel Reaction of Unprotected Sugars Marie-Christine Scherrmann Abstract The Knoevenagel reaction of unprotected sugars was investigated in the 1950s using zinc chloride as promoter. The so-called Garcia Gonzalez reaction had been almost forgotten for 50 years, until the emergence of new water tolerant catalysts having Lewis acid behavior. The reaction was thus reinvestigated and optimal conditions have been found to prepare trihydroxylated furan derivatives from pentose or b-tetrahydrofuranylfuran from hexoses with non-cyclic b-keto ester or b-diketones. Other valuable compounds such as b-linked tetrahydrobenzofuranyl glycosides or hydroxyalkyl-3,3,6,6,-tetramethyl-3,4,5,6,7,9-hexahydro-1Hxanthene-1,8(2H)-dione can be obtained using cyclic b-dicarbonylic derivatives. Apart from one report in the 1950s, the Knoevenagel reaction of unprotected carbohydrate in basic condition has been studied only in the mid-1980s to prepare C-glycosyl barbiturates from barbituric acids and, later on, from non-cyclic b-diketones, b-C-glycosidic ketones. The efficient method exploited to prepare such compounds has found an industrial development in cosmetics. Keywords Acetylacetates, 2-Amino-2-deoxyaldoses, Barbituric acids, C-Glycosides, Dimedone, Furans, Garcı´a-Gonzalez reaction, Green chemistry, Hexoses, Meldrum’s acid, Penta-2,4-dione, Pentoses, Pyrroles, Reactions in water, Tetrahydrofuranylfurans Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 2 Condensation Under Acidic Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 3 Condensation Under Basic Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 4 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 M.-C. Scherrmann Institut de Chimie Mole´culaire et des Mate´riaux d’Orsay, UMR 8182 Universite´ Paris-Sud 11, 91405 Orsay Cedex, France e-mail: marie-christie.scherrmann@u-psud.fr
M.-C.Scherrmann 1 Introduction The Knoevenagel condensation is a simple and easy to perform reaction for carbon- carbon bond formation by reacting carbonyl co nds and activated methylene [1.2].Variou e hee mo ses 26].Lewis acids ha in this rea e example ng the us C )10 ee MgBr2.OEt2 [11],Mg(CIO)2[12],or lanthanide salts [13. 14.Recent efforts hav been focused on the search for solid catalyst to facilitate their recovery by simple filtration.These systems include modified silica [15-20]or other modified oxide matrices [21,221.hydrotalcites [23-25].zeolites [26-31],ion exchange resin [32]. or nitrogen containing carbon nanotubes [33].Organocatalysis has become a subiect of interest in recent vears because the use of a substoichiometric an of an organic co und to accelerate the actions is me friend omp ared to metallic catalysis 34).Th h i m of the organ catalyzed cac s the con ing imini as shown by Knoeve nagel h elf use organocatalysts [4.36-38].including dendrimeric structures [39.40],has been investigated. The reaction could also be promoted using alternative activation conditions such as high pressure [41].ultrasound [39-46],or microwaves [6,47-51].Although a wide range of solvents has been used,it could also be carried out in neat conditions These solvent-free experiments have been carried out with variou romoters such rchlorate alts [21 lanthan de [141 z olites [28.291.othe org talysts [4.371 metim wave heating【 30 and support-free been reported [55].Despite the fact that the Knoevenagel reaction involves dehy dration,it is surprisingly favored in water [5,18,26.40,49,51-61],the most abundant liquid on Earth,which is very cheap,nontoxic,and can be used in large amounts without associated hazards.Water is able to promote reaction owing to its polarity and hydrophobic effects [62-65].Some cases of uncatalyzed Knoevenagel condensations have been reported in this medium 166.671. lonic liguids are also alte idered as en mostl he of their lack of vapor pr and d the e po 168.691.Base talyzed K hed ir n th se.The solvent and promoter are coupled is a real breakthrough in the field and some of them have been used in the Knoevenagel condensation 174-811. Polyethylene glycols and their monomethyl ethers are inexpensive,thermally stable.recoverable,and nontoxic,and can be used as green solvents for various transformations 1821 including knoevenagel condensations 183-851 evieo on the Koeveneppliedp The tected s ars.It has been divided int conditions) vhich the arguments are treated in chrono logical orde
1 Introduction The Knoevenagel condensation is a simple and easy to perform reaction for carbon– carbon bond formation by reacting carbonyl compounds and activated methylene [1, 2]. Various promoters have been found to be efficient for this reaction, the most conventional being soluble bases [2–6]. Lewis acids have been found to be effective in this reaction, some examples being the use of TiCl4 [7, 8], Ti(OiPr)4 [9, 10], MgBr2.OEt2 [11], Mg(ClO4)2 [12], or lanthanide salts [13, 14]. Recent efforts have been focused on the search for solid catalyst to facilitate their recovery by simple filtration. These systems include modified silica [15–20] or other modified oxide matrices [21, 22], hydrotalcites [23–25], zeolites [26–31], ion exchange resin [32], or nitrogen containing carbon nanotubes [33]. Organocatalysis has become a subject of interest in recent years because the use of a substoichiometric amount of an organic compound to accelerate the reactions is more environmentally friendly compared to organometallic catalysis [34]. The mechanism of the organocatalyzed reaction involves the corresponding iminium intermediate as the acceptor as shown by Knoevenagel himself in 1898 using piperidine [35]. The use of other organocatalysts [4, 36–38], including dendrimeric structures [39, 40], has been investigated. The reaction could also be promoted using alternative activation conditions such as high pressure [41], ultrasound [39–46], or microwaves [6, 47–51]. Although a wide range of solvents has been used, it could also be carried out in neat conditions. These solvent-free experiments have been carried out with various promoters such as perchlorate salts [12], lanthanum chloride [14], zeolites [28, 29], other solid catalysts [19, 21, 50, 52–54], and organocatalysts [4, 37], sometimes under microwave heating [49, 50]. A solvent-, catalyst-, and support-free procedure has also been reported [55]. Despite the fact that the Knoevenagel reaction involves dehydration, it is surprisingly favored in water [5, 18, 26, 40, 49, 51–61], the most abundant liquid on Earth, which is very cheap, nontoxic, and can be used in large amounts without associated hazards. Water is able to promote reaction owing to its polarity and hydrophobic effects [62–65]. Some cases of uncatalyzed Knoevenagel condensations have been reported in this medium [66, 67]. Ionic liquids are also alternative reaction media considered as green, mostly because of their lack of vapor pressure and the possibility of reuse [68, 69]. Basecatalyzed Knoevenagel reactions have been described in these media [70–73]. The development of task specific ionic liquids in which the solvent and promoter are coupled is a real breakthrough in the field and some of them have been used in the Knoevenagel condensation [74–81]. Polyethylene glycols and their monomethyl ethers are inexpensive, thermally stable, recoverable, and nontoxic, and can be used as green solvents for various transformations [82] including Knoevenagel condensations [83–85]. The present review is focused on the Knoevenagel reaction applied to unprotected sugars. It has been divided into two parts (acidic and basic conditions) in which the arguments are treated in chronological order. 2 M.-C. Scherrmann
Knoevenagel Reaction of Unprotected Sugar 3 2 Condensation Under Acidic Conditions The condensation of unprotected reducing sugars with 1.3-dicarbonylic compounds under acidic conditions was reported in the 1950s by Garcia Gonzalez.His group has extensively studied the zinc chloride promoted reaction in methanol leading to polyhydroxylated furans [86].The ZnCl-catalyzed Knoevenagel reaction in alco- holic solvents has been used recently as the first step of the syntheses of a cytotoxic ound [871.of selective inhibitors of L-fucosidases [881 of E-and P-selectin and peptidomimetics and of furan mino acid analog of Dand L-serine [91].The so-called Garcia Gonzalez reacti n was reinvestigate in order to improve yields using milder conditions.Misra and Agnihotri obtained good results for the reaction of various aldoses and pentane-2,4-dione (1)or ethyl acetoacetate(2)using cerium(III)chloride in aqueous solution [92](Scheme 1).The mechanism of this transformation involves an acid-promoted Knoevenagel conden- sation of the 1,3-dicarbonylic compound followed by an attack of OH-2 of the sugar moiety (ie..R.or Ra)on the ketone and then aromatization to furan affording the trihydroxyalkyl-substituted furans 3 or 4 from pentoses.When the starting sugar is a he ose (R=CH2OH),the intern ediate furans 3 or 4 undergo a cyclization to B- ofuranylfur derivatives5or6 In this process only the configurations at C-3 and C-4 were retained,so tha the same trihydroxylated furan derivatives 3b or 4b were obtained from D-ribose (9)and D-arabinose (8)(Scheme 1,Table 1).These compounds were diastereoi- somers of the products 3a or 4a obtained from D-xylose(7).When starting from 81-93% 8驰 -2H,0 OH B R=8驰 8驰 Scheme 1 Synthesis of trihydroxyalkyl-substituted furans derivatives 3or 4 from D-pentose and C-furyl glycosides 5 or 6 from D-hexoses In 92].the Authors might have inverted the compounds obtained from or Darabinose m D-xylo d by Nagarapu et al.[941.A
2 Condensation Under Acidic Conditions The condensation of unprotected reducing sugars with 1,3-dicarbonylic compounds under acidic conditions was reported in the 1950s by Garcia Gonzalez. His group has extensively studied the zinc chloride promoted reaction in methanol leading to polyhydroxylated furans [86]. The ZnCl2-catalyzed Knoevenagel reaction in alcoholic solvents has been used recently as the first step of the syntheses of a cytotoxic compound [87], of selective inhibitors of L-fucosidases [88] of E- and P-selectin ligands [89], of glyco- and peptidomimetics [90], and of furan amino acid analogs of D- and L-serine [91]. The so-called Garcia Gonzalez reaction was reinvestigated in order to improve yields using milder conditions. Misra and Agnihotri obtained good results for the reaction of various aldoses and pentane-2,4-dione (1) or ethyl acetoacetate (2) using cerium(III) chloride in aqueous solution [92] (Scheme 1). The mechanism of this transformation involves an acid-promoted Knoevenagel condensation of the 1,3-dicarbonylic compound followed by an attack of OH-2 of the sugar moiety (i.e., R2 or R3) on the ketone and then aromatization to furan affording the trihydroxyalkyl-substituted furans 3 or 4 from pentoses. When the starting sugar is a hexose (R7 ¼ CH2OH), the intermediate furans 3 or 4 undergo a cyclization to btetrahydrofuranylfuran derivatives 5 or 6. In this process, only the configurations at C-3 and C-4 were retained, so that the same trihydroxylated furan derivatives 3b or 4b were obtained from D-ribose (9) and D-arabinose (8) (Scheme 1, Table 1). These compounds were diastereoisomers of the products 3a or 4a obtained from D-xylose (7).1 When starting from O OH R6 R5 O O R O R5 R6 R3 R1 R2 R7 OH R4 R O O CeCl3 + 1 R = CH3 2 R = OC2H5 R7 = CH2OH or InCl3 cat. 81-93% R4 R5 R3 R6 OH R7 OH O R O OH – 2 H2O R4 R5 R3 R6 R7 OH O O R H2O 3 R = CH3 4 R = OC2H5 5 R = CH3 6 R = OC2H5 Scheme 1 Synthesis of trihydroxyalkyl-substituted furans derivatives 3 or 4 from D-pentose and C-furyl glycosides 5 or 6 from D-hexoses 1 In [92], the Authors might have inverted the compounds obtained from D-ribose or D-arabinose with those obtained from D-xylose. This error has been reproduced by Nagarapu et al. [94]. A debate of a hypothetic epimerization at C-1’ has been engaged [91]. Knoevenagel Reaction of Unprotected Sugars 3
M.-C.Scherrmann Table 1 Reaction of aldoses with pentane-2.4-dione (1)or ethyl acetoacetate (2) D-Aldose 1.3-Dicarbonylic Product Catalyst Yield (% References compound D-Xylose (7) 3a CeCl3.7H2O 92] =R=R=R=H 2 4a D-Arabinose(8)1 36 CeCls.7H2O -R-Rs-R-H 2 4 D-Ribose(9) 1 36 CeCls.7H2O K团 93 D-Glucose(10) 1 高 CeCls.7H2O 93 92 R:=R,=R=OH I93] 2 R-CHOH 6a 98 D-Mannose (11) 1 g InCl Ri-R-R-OH InCls 2 R-CH-OH 6a D-Galactose (12) 1 % CeCl2.7H2O 92 92 R:=R,=R,=OH [93 2 =CH-OH 6 13.7H0 hexoses (R=CH2OH),the cyclization to B-tetrahydrofuranylfuran derivatives 5 or 6 only maintained the configurations at C-4 and C-5 of the starting sugar.As a result,D-glucose (10)and D-mannose (11)afforded the same compounds 5a or 6a, diastereoisomers of the products 5b or 6b obtained from D-galactose (12). Later on,Yadav et al.reported the same reaction catalyzed by indium(III) chloride [93],and similar yields were obtained. vater gave similar results [94](see tnote 1) Bartoli et al.have extensively studied the combination of CeCl3.7H2Oand Nal in order to increase the activity of the catalytic system [13,95].They studied the condensation of D-glucose(10)and pentane-2.4-dione(1)and showed that 5a could be obtained in 95%yield by using SiO2 supported CeCl3.7H2O-NaI system in solvent-free conditions [96]. Cyclic B-dicarbonyl compounds have also been used in this reaction.Yadav and colleagues reported that when the InCla catalyzed reaction between D-glucose and cyclohexane-1.3-dione (13)or dimedone (14)was carried out in CHaCN the B-linked te glycosides 15 stereoche stry of the glycosidic experiments and was in good agreement with previously reported results.Sato and
hexoses (R7 ¼ CH2OH), the cyclization to b-tetrahydrofuranylfuran derivatives 5 or 6 only maintained the configurations at C-4 and C-5 of the starting sugar. As a result, D-glucose (10) and D-mannose (11) afforded the same compounds 5a or 6a, diastereoisomers of the products 5b or 6b obtained from D-galactose (12). Later on, Yadav et al. reported the same reaction catalyzed by indium(III) chloride [93], and similar yields were obtained. The reaction was applied with success to unprotected reducing disaccharides [92, 93]. The use of iron(III) chloride in ethanol–water gave similar results [94] (see footnote 1). Bartoli et al. have extensively studied the combination of CeCl3.7H2O and NaI in order to increase the activity of the catalytic system [13, 95]. They studied the condensation of D-glucose (10) and pentane-2,4-dione (1) and showed that 5a could be obtained in 95% yield by using SiO2 supported CeCl3.7H2O-NaI system in solvent-free conditions [96]. Cyclic b-dicarbonyl compounds have also been used in this reaction. Yadav and colleagues reported that when the InCl3 catalyzed reaction between D-glucose and cyclohexane-1,3-dione (13) or dimedone (14) was carried out in CH3CN, the b-linked tetrahydrobenzofuranyl glycosides 15 or 16 were obtained [93] (Scheme 2). The stereochemistry of the glycosidic linkage was proved by NMR experiments and was in good agreement with previously reported results. Sato and Table 1 Reaction of aldoses with pentane-2,4-dione (1) or ethyl acetoacetate (2) D-Aldose 1,3-Dicarbonylic compound Product Catalyst Yield (%) References D-Xylose (7) R2=R3=R6=OH R1=R4=R5=R7=H 1 3a CeCl3.7H2O 90 [92] InCl3 85 [93] 2 4a CeCl3.7H2O 85 [92] InCl3 81 [93] D-Arabinose (8) R1=R4=R6=OH R1=R3=R5=R7=H 1 3b CeCl3.7H2O 90 [92] InCl3 87 [93] 2 4b CeCl3.7H2O 76 [92] InCl3 82 [93] D-Ribose (9) R2=R4=R6=OH R1=R3=R5=R7=H 1 3b CeCl3.7H2O 84 [92] InCl3 85 [93] 2 4b CeCl3.7H2O 80 [92] InCl3 81 [93] D-Glucose (10) R2=R3=R6=OH R1=R4=R5=H R7=CH2OH 1 5a CeCl3.7H2O 93 [92] InCl3 93 [93] 2 6a CeCl3.7H2O 87 [92] InCl3 83 [93] D-Mannose (11) R1=R3=R6=OH R2=R4=R5=H R7=CH2OH 1 5a InCl3 93 [93] 2 6a InCl3 85 [93] D-Galactose (12) R2=R3=R5=OH R1=R4=R6=H R7=CH2OH 1 5b CeCl3.7H2O 92 [92] InCl3 90 [93] 2 6b CeCl3.7H2O 82 [92] InCl3 83 [93] 4 M.-C. Scherrmann
Knoevenagel Reaction of Unprotected Sugars -F o-glucose (10) 8R8 18R:86 Scheme Synthesis of glycosides from ucos ribose (9) 袖ahtncmeaayoincanegaa coworkers explored the use of Sc(OTf)3 as the promoter in water for the same reaction and described a product having an a-linkage [97].Unfortunately.as Yadav's group characterized their compounds as diacetylated derivatives,the restingly,the use of Sc(T) cal data was not possible as the dihydroben ofuran-4(5H)-on promoter 9).wh yalky!-3.3.6.0 5anthene-12-dions (5)in sood yiel '-mont) hydro [97](Scheme 3). The different selectivity between Sc-mont and Sc(OTf)has been rationalized by the mechanism of the transformation.While the Sc(OTf)3 catalyzed reaction in water afforded 17 through the classical mechanism,when Sc3+-mont is ndare reacing when coordinated to the Se center in thesiic mont,giving rise to the addition of two molecules of dimedone
coworkers explored the use of Sc(OTf)3 as the promoter in water for the same reaction and described a product having an a-linkage [97]. Unfortunately, as Yadav’s group characterized their compounds as diacetylated derivatives, the comparison of the spectroscopic and optical data was not possible. Interestingly, the use of Sc(OTf)3 as the promoter gave hydroxyalkyl-6,7- dihydrobenzofuran-4(5H)-one derivatives 17 from D-ribose (9), whereas scandium cation-exchanged montmorillonite (Sc3+-mont) afforded hydroxyalkyl-3,3,6,6,- tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione (18) in good yield [97] (Scheme 3). The different selectivity between Sc3+-mont and Sc(OTf)3 has been rationalized by the mechanism of the transformation. While the Sc(OTf)3 catalyzed reaction in water afforded 17 through the classical mechanism, when Sc3+-mont is used the compounds are reacting when coordinated to the Sc center in the silicate layer of Sc3+-mont, giving rise to the addition of two molecules of dimedone O HO OH HO O O HO OH OH O O R R InCl3 CH3CN 13 R = H 14 R = CH3 + O R R 15 R = H 81% 16 R = CH3 85% D-glucose ( 10) OH Scheme 2 Synthesis of tetrahydrobenzofuranyl glycosides from D-glucose O O Sc(OTf)3 O HO O OH OH 14 17 18 + Sc3+ –mont. 78% 86% O OH HO OH HO H2O H2O HO HO HO HO O O O D-ribose ( 9) Scheme 3 Reaction of D-ribose with dimedone catalyzed by scandium cation-exchanged montmorillonite or scandium triflate Knoevenagel Reaction of Unprotected Sugars 5