ricci2010 chitosan aerogel a recyclable heterogeneous organocatalyst for the symmetric direct aldol reaction in water

View Article Online / Journal Homepage / Table of Contents for this issue COMMUNICATION www.rsc.org/chemcomm | ChemComm Chitosan aerogel: a recyclable, heterogeneous organocatalyst for the asymmetric direct aldol reaction in waterwz Published on 12 August 2010 Downloaded by Laurentian University on 01/06/2013 23:58:54 Alfredo Ricci,*a Luca Bernardi,a Claudio Gioia,a Simone Vierucci,a Mike Robitzerb and Franc¸oise Quignard*b Received 20th May 2010, Accepted 2nd July 2010 DOI: 10.1039/c0cc01502d Aerogel microspheres of chitosan, an abundant biopolymer obtained from marine crustaceans, have been successfully applied to catalyze the asymmetric aldol reaction in water, providing the products in high yields and with good stereoselectivity (up to 93% ee) and recyclability (up to runs) Yields were favourably affected by additives such as DNP and stearic acid The development of heterogeneous catalytic systems for fine chemical synthesis has become recently a major area of research The ability to utilise heterogeneous catalysts in the liquid phase can aid considerably in the separation, recovery and reuse of catalysts, and can afford the clean separation of products from the reaction mixture thus making a major impact on the environmental performance of a synthesis The majority of these novel catalysts are based on silica and display many advantageous properties like high surface area, good accessibility and easy anchoring of organic groups to provide catalytic centres but are of poor stability in aqueous basic conditions.1 The most recent efforts, however, are being driven by a shift from the petrochemical-based or inorganic feedstock toward biological materials Therefore, an increasingly important key role is being played by the use of biopolymers for use as polymeric supports for catalysis Chitosan derived by extensive deacetylation of chitin can be considered as a natural polyamine.2,3 The flexibility of this material, its insolubility in the vast majority of solvents along with its inherent chirality (Fig 1) and its tendency to act as an absorbent of metals,4–8 but also as a support for chiral organic frameworks9 make chitosan an excellent candidate for building heterogeneous catalysts.10 In contrast with these reports the direct use of chitosan in base catalysis has been very poorly explored Chitosan hydrogel has been used as a green and Fig Chitosan monomer a Department of Organic Chemistry ‘‘A Mangini’’, University of Bologna, V Risorgimento 4, 40136 Bologna, Italy E-mail: ricci@ms.fci.unibo.it; Fax: +39 051 2093654; Tel: +39 0512093635 b Institut Charles Gerhardt-Montpellier, Mate´riaux Avance´s pour la Catalyse et la Sante´, UMR5253 CNRS-ENSCM-UM2-UM1, rue de l’Ecole Normale, 34296 Montpellier, France E-mail: quignard@enscm.fr; Fax: +33 467 163 470; Tel: +33 467 163 460 w Dedicated to Prof Carmen Na´jera on the occasion of her 60th birthday z Electronic supplementary information (ESI) available: Experimental details See DOI: 10.1039/c0cc01502d 6288 | Chem Commun., 2010, 46, 6288–6290 recyclable catalyst for aldol and Knoevenagel reactions.11 Some of us have shown that chitosan microspheres obtained under supercritical conditions could be used as a catalyst for the synthesis of monoglyceride by fatty acid addition to glycidol.12 Indeed aerogel formulation of chitosan affords high surface area materials (up to 350 m2 gÀ1) with high accessibility to the functional groups (up to 5.2 mmol gÀ1 NH2).13 The lack of literature reports dealing with the heterogeneous asymmetric organocatalysis displayed by polysaccharides prompted us to undertake a detailed study of the evaluation of the chitosan potential in this new frontier area of organocatalytic reactions To this purpose and considering the polyamino structure of this renewable natural material, we focused on the field in which primary amine organocatalysis14 has emerged in the past few years Accordingly, to evaluate the putative chitosan catalytic activity, the direct aldol reaction,15 one of the most important carbon–carbon bond forming reactions,16 was investigated in the presence of water17 without any organic cosolvent, by using supercritical CO2 dried chitosan as the catalyst (Table 1).13 Initial tests were performed in the prototype reaction between p-nitrobenzaldehyde and cyclohexanone as the pronucleophile aimed at establishing the optimized reaction conditions (Table 1) A catalytic loading of 22 mol%, referred to the estimated amount of the free amino group functions, afforded, with acceptable reaction rates and in high yields, the expected product 1a The aqueous medium being necessary for the reaction to occur, no substantial variations were noticed on varying the amount of water (compare entries 1–3) We were delighted to see that high enantiomeric excess up to 84% ee for the major diastereoisomer and up to 60% for the minor were obtained (entry 2) with an anti/syn ratio in the range of : This is to the best of our knowledge the first report on the capability of chitosan to act as an asymmetric organocatalyst under heterogeneous conditions A lower catalyst loading caused a substantial drop of the conversion without affecting however the enantioselectivity Moreover, comparison with the monomeric glucosamine (entry 9) highlighted the superiority of the polymeric bio-material as catalyst with respect to the monomeric aminosugar In the direct aldol reaction the amine-catalyzed version usually proceeds via an enamine intermediate15 whose formation is catalysed by acids matched with the basicity of the amine In line with these assumptions, when the reaction between cyclohexanone and p-nitrobenzaldehyde was performed in the presence of 20 mol% of 2,4-dinitrophenol (DNP, pKa = 4.11), a substantial increase of the enantiomeric excess to 92% was observed that however diminished in the presence of 10 mol% of the additive (entries 4–5) This This journal is  c The Royal Society of Chemistry 2010 View Article Online Published on 12 August 2010 Downloaded by Laurentian University on 01/06/2013 23:58:54 Table Direct aldol reaction of cyclohexanone with p-nitrobenzaldehyde catalyzed by chitosan: optimisation of the reaction conditionsa Entry H2O/mL Catalyst Additive (mol%) Time/h Yieldb (%) anti/sync eed (%) 0.3 0.5 1.0 0.5 0.5 0.5 0.5e 0.5e 0.5 Chitosan aerogel None None None DNP (10) DNP (20) Stearic acid (20) None DNP (20) None 48 48 48 24 24 48 48 24 48 75 85 80 78 85 88 75 70 38 70/30 70/30 69/31 74/26 76/24 69/31 68/32 75/25 58/42 80 84 85 86 92 93 80 87 50 Chitosan hydrogel Glucosamine (50) (60) (50) (55) (75) (54) (53) (75) (28) a Conditions: chitosan 4.5 mg (corresponding to 22 mol% free amino units with respect to aldehyde), p-nitrobenzaldehyde (0.10 mmol), cyclohexanone (2.0 mmol), H2O b Isolated yield after chromatography on silica gel c Determined by 1H NMR spectroscopy on the crude mixture d Determined by chiral-phase HPLC analyses, results in parentheses refer to the minor diastereomer e This figure does not take into account the amount of H2O in the hydrogel beads employed, evaluated in ca 0.05 mL improvement could not be observed when a weaker acid such as p-nitrophenol (pKa = 7.2) was employed Worth noting also a long chain carboxylic acid like stearic acid increased reactivity and enantioselectivity up to 93% ee (entry 6) in spite of its lower acidity (pKa = 10.15) Although the mechanism through which fatty acids improve yields and stereoselectivity is presumably complex, the possibility exists that the liquid organic donor and the acceptor form an emulsion with the fatty acid in water18 and because of this aggregation the organic molecules could be favourably driven towards the intermediate enamine formation Finally, replacing chitosan Table aerogel with hydrogel the reaction performed in the presence of DNP led to slightly diminished yields and to some erosion of the enantioselectivity (entries and 8) With respect to the recently reported chitosan-supported L-proline complex9 the natural polysaccharide leads to comparable results even though the diastereoselectivity appears to be lower With the optimised set of conditions in hand, the scope of the direct aldol reaction was inspected using several ketone donors and p-nitrobenzaldehyde and isatin as the acceptors (Table 2) In most cases, reactions afforded the aldol products with good diastereoselectivities and in fairly high yields and Scope of the aldol reaction catalysed by chitosan aerogela Additiveb Time/h 1-Yieldc (%) anti/synd eee (%) 10 11 None Nonef DNP Stearic acid None Nonef DNP DNPf Stearic acid None DNP 48 48 24 48 48 48 24 24 48 48 24 1a-85 1a-86 1a-85 1a-88 1b-90 1b-86 1b-90 1b-88 1b-83 1c-76 1c-78 70/30 70/30 76/24 69/31 32/68 33/65 36/64 40/60 33/67 66/34 70/30 84 (60) 83(62) 92 (75) 93 (54) 69 (90) 65(70) 68(90) 66(70) 65(83) 70(30) 72(24) 12 13 14 None Nonef DNP 48 24 24 1d-86g 1d-60g 1d-89g 98/2g 95/5g 97/3g 80(27)g 76(30)g 77(30)g 15h 16h 17h None DNP Stearic acid 48 48 48 1e-95g 1e-97i 1e-97i — — — 25g 25 Entry Acceptor Donor Product a Conditions: chitosan aerogel 13.5 mg (corresponding to 22 mol% free amino units with respect to the acceptor), aldol acceptor (0.30 mmol), ketone donor (6.0 mmol), H2O (1.5 mL or 0.90 mL), additive b 20 mol% c Isolated yield after chromatography on silica gel d Determined by H NMR spectroscopy on the crude mixture Relative configurations assigned by comparison with literature data or analogy See ESIw e Determined by HPLC analyses, results in parentheses refer to the minor diastereomer Absolute configurations assigned by comparison with literature data or by analogy See ESIw f Natural chitosan from a commercial source was used g After crystallisation h 12.0 mmol of acetone were used i Conversion This journal is  c The Royal Society of Chemistry 2010 Chem Commun., 2010, 46, 6288–6290 | 6289 Published on 12 August 2010 Downloaded by Laurentian University on 01/06/2013 23:58:54 View Article Online enantioselectivities for the major anti diastereomer Besides cyclohexanone (entries 1–4, and 12–14) other donors like hydroxyacetone (entries 5–9), tetrahydro-4H-pyran-4-one (entries 10–11) and acetone (entries 15–17) were used in these reactions In particular, the reaction with water miscible acetone yielded the product 1e in good yields but not in synthetically useful enantioselectivities, a result which parallels previous literature reports.19 Using isatin as the acceptor system (entries 12–14) allowed the formation in very high yields and good enantioselectivity of the oxindole 1d having a structural moiety of high interest in medicinal chemistry.20 The contrasting diastereoselectivity observed when cyclohexanone and hydroxyacetone were used as donors can be rationalised with the models shown in Scheme Following the generally accepted mechanistic picture,14,21 cyclohexanone condenses with chitosan primary amine to give E-enamine A, whereas hydroxyacetone results predominantly in Z-enamine B stabilised by an intramolecular hydrogen bond These enamines then react with the incoming aldehyde, likely activated by a hydrogen-bond with the 4-hydroxy group in intermediates C and D, affording as the major products the corresponding antiand syn-aldol adducts, respectively However, the possibility of additional hydrogen-bond interactions between substrates and other hydroxyl moieties (of the same or adjacent saccharide units) cannot be ruled out The efficacy of chitosan aerogel in terms of its reusability as an organocatalyst in the aldol reaction between cyclohexanone and p-nitrobenzaldehyde was finally tested After completion of the reaction and decantation of the organic/aqueous layer the aerogel did not seem macroscopically affected and could be reused for at least more additional runs displaying the same Scheme Table Proposed reaction pathway Recyclability of chitosan aerogel catalysta Cycle Yieldb (%) anti/sync eed (%) 85 80 82 87 70/30 67/33 69/31 65/35 84 82 80 83 a Conditions: chitosan aerogel 13.5 mg (corresponding to 22 mol% free amino units with respect to aldehyde), p-nitrobenzaldehyde (0.30 mmol), cyclohexanone (6.0 mmol), H2O (1.5 mL), 48 h Then after phase separation, the beads were washed with H2O and reused b Isolated yield after chromatography on silica gel c Determined by H NMR spectroscopy on the crude mixture d Determined by chiral stationary phase HPLC Refers to the major anti diastereomer 6290 | Chem Commun., 2010, 46, 6288–6290 efficiency and stereoselectivity (Table 3) The use of powdered chitosan from a commercial source (entries 2, 6, 8, 13 in Table 2) led to results to some extent comparable to those with the aerogel and hydrogel but the formation of a slurry in the reaction medium prevented the easy recycle and recovery of the catalyst as a solid-like heterogeneous phase In summary, we have developed the first direct asymmetric aldol reaction that can be performed in the presence of water using as a heterogeneous organocatalyst chitosan, a renewable feedstock material The simple and environmentally friendly experimental procedure and the recycling of the catalytic system highlight good assets of this catalytic protocol Further studies focusing on a wider scope of these catalyzed asymmetric transformations are currently in progress We acknowledge financial support from ‘Stereoselezione in Sintesi Organica Metodologie e Applicazioni’ 2007 Notes and references F Cozzi, Adv Synth Catal., 2006, 348, 1367 R A A Muzzarelli, Chitin, Pergamon Press, Oxford, 1977; G A F Roberts, Chitin Chemistry, Macmillan, London, 1992 (a) M N V Ravi Kumar, React Funct Polym., 2000, 46, 1; (b) K Kurita, H Ikeda, Y Yoshida, M Shimojoh and M Harata, Biomacromolecules, 2002, 3, (a) J J E Hardy, S Hubert, D J Macquerrie and A J Wilson, Green Chem., 2004, 6, 53; (b) V Calo`, A Nacci, A Monopoli, L Fornaro, L Sabbatini, N Cioffi and N Ditaranto, Organometallics, 2004, 23, 5154 (a) F Quignard, A Choplin and A Domard, Langmuir, 2000, 16, 9106; (b) P Buisson and F Quignard, Aust J Chem., 2002, 55, 73 W Sun, C.-G Xia and H.-W Wang, New J Chem., 2002, 26, 755 A V Kucherov, N V Kramareva, E D Finashima, A E Koklin and L M Kustova, J Mol Catal A: Chem., 2003, 198, 377 M Chtchigrovsky, A Primo, P Gonzalez, K Molvinger, M Robitzer, F Quignard and F Taran, Angew Chem., Int Ed., 2009, 48, 5916 H Zhang, W Zhao, J Zou, Y Liu, R Li and Y Cui, Chirality, 2009, 21, 492 10 For a comprehensive review see: D J Macquarrie and J J E Hardy, Ind Eng Chem Res., 2005, 44, 8499 11 K R Reddy, K Rajgopal, C U Maheswari and M L Kantam, New J Chem., 2006, 30, 1549 12 R Valentin, K Molvinger, F Quignard and D Brunel, New J Chem., 2003, 27, 1690 13 F Quignard, R Valentin and F Di Renzo, New J Chem., 2008, 32, 1300 14 (a) S Mukherjee, J W Yang, S Hoffmann and B List, Chem Rev., 2007, 107, 5471; (b) P Melchiorre, M Marigo, A Carlone and G Bartoli, Angew Chem., Int Ed., 2008, 47, 6138; (c) S Bertelsen and K A Jørgensen, Chem Soc Rev., 2009, 38, 2178; (d) D W C MacMillan, Nature, 2008, 455, 304 15 (a) A Co´rdova, W Zou, I Ibrahem, E Reyes, M Engqvist and W.-W Liao, Chem Commun., 2005, 3586; (b) A Co´rdova, W Zou, P Dziedzic, I Ibrahem, E Reyes and Y Xu, Chem.–Eur J., 2006, 12, 5383; (c) L.-W Xu, J Luo and Y Lu, Chem Commun., 2009, 1807 and references therein 16 Modern Aldol Reactions, ed R Mahrwald, Wiley-VCH, Weinheim, 2004, vol and 17 (a) E A C Davie, S M Mennen, Y Miller and S J Xu, Chem Rev., 2007, 107, 5759; (b) A P Brogan, T J Dickerson and K D Janda, Angew Chem., Int Ed., 2006, 45, 100; (c) Y Hayashi, Angew Chem., Int Ed., 2006, 45, 8103; (d) J Paradowska, M Stodulski and J Mlynarski, Angew Chem., Int Ed., 2009, 48, 4288 18 N Mase, N Noshiro, A Moyuka and K Takabe, Adv Synth Catal., 2009, 351, 2791 19 N Mase, Y Nakai, N Ohara, H Yoda, K Takabe, F Tanaka and C F Barbas III, J Am Chem Soc., 2006, 128, 734 20 M Raj, N Veerasamy and V K Singh, Tetrahedron Lett., 2010, 51, 2157 21 S S V Ramasastry, H Zhang, F Tanaka and C F Barbas III, J Am Chem Soc., 2007, 129, 288 This journal is  c The Royal Society of Chemistry 2010 ... catalyst as a solid-like heterogeneous phase In summary, we have developed the first direct asymmetric aldol reaction that can be performed in the presence of water using as a heterogeneous organocatalyst. .. and other hydroxyl moieties (of the same or adjacent saccharide units) cannot be ruled out The efficacy of chitosan aerogel in terms of its reusability as an organocatalyst in the aldol reaction. .. organic donor and the acceptor form an emulsion with the fatty acid in water1 8 and because of this aggregation the organic molecules could be favourably driven towards the intermediate enamine formation