Preparation of Chitosan-supported Urea Materials and their Application in Some Organocatalytic Procedures

1 Preparation of chitosan-supported urea materials and 1 their application in some organocatalytic procedures 2 3 Gonzalo de Gonzalo,a,* Antonio Franconetti,a,b* Rosario Fernández,a 4 José M. Lassaletta,c Francisca Cabrera-Escribanoa 5 6 a Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, C/ 7 Profesor García González 1, 41012 Sevilla, Spain. 8 b Departament de Química. Universitat Autònoma de Barcelona. 08193 Cerdanyola del 9 Vallès, Spain 10 c Instituto de Investigaciones Químicas (CSIC-US) and Centro de Innovación en Química 11 Avanzada (ORFEO-CINQA), Avda. Américo Vespucio, 49, 41092 Sevilla, Spain. 12 13 E-mail addresses: [email protected] (G. de Gonzalo); [email protected] (A. 14 Franconetti) 15 *Corresponding author. Phone number: +34 95459997; Fax number: +34 954624960 16 17 2 Abstract 18 An efficient and mild procedure was developed for the preparation of three chitosan- 19 supported ureas containing electron-withdrawing groups. These catalysts were 20 characterized and employed as organocatalysts in different transformations, including the 21 enantioselective cyanosilylation of α-ketoesters and aldehydes, the asymmetric addition 22 of formaldehyde tert-butyl hydrazone to prochiral α-ketoesters and a Friedel-Crafts 23 reaction. Several parameters that can affect the activity and selectivity of the reactions 24 were analysed. The supported catalysts can be reused for more than 10 cycles with only 25 a small loss in their properties. Finally, theoretical DFT calculations were carried out to 26 interpret the results of the catalysed reactions. 27 Highlights 28 - Chitosan-based ureas are easily prepared by a mild and efficient procedure 29 - Chitosan-supported ureas catalyse valuable chemical reactions in a range of yields 30 - These heterogeneous catalysts are robust and can be employed for several catalytic 31 cycles 32 Keywords 33 Chitosan-supported ureas; Organocatalysis; Cyanosilylation; Chiral tertiary alcohols; 34 Heterogeneous catalysis; DFT calculations. 35 Chemical compounds 36 Acetophenone (PubChem CID: 7410); Ethyl benzoylformate (PubChem CID: 15349); 37 Ethyl 2-oxo-4-phenybutyrate (PubChem CID: 562087); Benzaldehyde (PubChem CID: 38 240); 4-Chlorobenzaldehyde (PubChem CID: 7726); Trimethylsilyl cyanide (PubChem 39 CID: 82115); Indole (PubChem CID: 798); tert-Butylhydrazine hydrochloride (PubChem 40 CID: 81889); trans-β-Nitrostyrene (PubChem CID: 5284459); p-Nitrophenol (PubChem 41 CID: 980). 42 Abbreviations 43 CS: Chitosan; DFT: Density functional theory; FTBH: Formaldehyde tert-butyl 44 hydrazone; HOBt: 1-Hydroxybenzotriazole hydrate; TBME: tert-Butyl methyl ether; 45 TMSCN: Trimethylsilyl cyanide. 46 47 3 1. Introduction 48 In asymmetric synthesis, chiral catalysts usually include small organic molecules and 49 metal complexes. In particular, organocatalysis avoids the use of metal complexes, with 50 chiral organic scaffolds being responsible for asymmetric induction. Since the beginning 51 of the present century, this technique has experienced great development for the 52 preparation of optically active molecules (Berkessel & Groger, 2005; Bertelsen & 53 Jorgensen, 2009; List, 2009; Dalko, 2013; Rossi, Benaglia, Massolo, & Raimondi, 2014). 54 Catalysis through hydrogen-bond interactions falls within the category of non- 55 covalent organocatalysis. The hydrogen bond represents a well-known interaction of high 56 interest, as it is a strong force with a crucial role for maintaining the structure of a vast 57 number of different molecules (Gilli, & Gilli, 2016; Sweetman et al., 2014). This bond 58 has been employed as an assisting force in catalytic procedures in organic synthesis 59 (Dekamin, Karimi, & Farahmand, 2012; Pihko, 2009). Among the different molecules 60 that can perform hydrogen bond interactions, ureas, thioureas, and more recently 61 squaramides (Alemán, Parra, Jiang, & Jorgensen, 2011), are the most employed, due to 62 their ability to establish a double hydrogen-bond interaction with the substrates. Since the 63 initial studies on ureas and thioureas as organocatalysts, both of them have been widely 64 employed in several catalytic procedures for the preparation of valuable compounds 65 (Kotke, & Schreiner, 2009). Recently, bifunctional hydrogen bond catalysts have been 66 widely investigated to perform asymmetric processes via a dual activation of both the 67 reaction’s nucleophile and electrophile components (Sonsona, Marques-López, & 68 Herrera, 2016). 69 Organocatalysts are, in general, robust, inexpensive, non-toxic and easily available, 70 whereas organocatalyzed processes are conducted under mild reaction conditions and in 71 the absence of metals (Hernández & Juaristi, 2012). The preparation of supported 72 organocatalysts represents a valuable tool in asymmetric catalysis. In addition, supported 73 organocatalysts facilitate product recovery and purification (Gruttaduria, Giacalone, & 74 Noto, 2008; Munirathinam, Huskens, & Verboom, 2015). 75 Chitosan is a non-toxic, biocompatible, and biodegradable linear polysaccharide of 76 randomly distributed β(1→4) linked D-glucosamine (>60%) and N-acetyl-D- 77 glucosamine. It is obtained from the alkaline deacetylation of chitin and has emerged as 78 a valuable polymer with several applications (Ravi Kumar, Muzzarelli, Muzzarelli, 79 Sashiwa, & Domb, 2004), such as solvent sensing (Jatunov et al., 2015), non-lineal optics 80 (Franconetti, Contreras-Bernal, Prado-Gotor, & Cabrera-Escribano, 2015), chiral 81 recognition of enantiomers (Jafari, Tashkhourian, & Absalan, 2018), including 82 carbamates (Bai, et al., 2017) and ureidyl derivatives (Wang, Xi, Chen, Huang, & Bai, 83 2017), and catalysis (Dekamin, Azimoshan, & Ramezani, 2013; El Kadib, 2015; Mahé, 84 Brière, & Dez, 2015). From a catalytic perspective, chitosan can be used following two 85 strategies, that is, directly as a heterogeneous catalyst or as a platform supporting the 86 corresponding organocatalyst. For the first strategy, native chitosan hydrogels have 87 proved to be an effective catalyst for Knoevenagel reactions (Franconetti, Domínguez- 88 4 Rodríguez, Lara-García, Prado-Gotor, & Cabrera-Escribano, 2016), aldol reactions and 89 Henry reactions, among others (Kühbeck, Saidulu, Reddy, & Díaz-Díaz, 2012). Chitosan 90 derivatives have also served as a valuable support for several types of organocatalysts 91 (Chtchigrovsky, et al. 2009). Thus, cycloadditions of carbon dioxide and epoxides to 92 obtain cyclic carbonates (Zhao, et al., 2007), Michael additions for the preparation of 93 different functionalized heterocycles (Khalil, & Al-Matar, 2013), and aldol reactions 94 (Zhang et al., 2009), have been developed by employing different types of organocatalysts 95 supported on chitosans. Very recently, chitosan-supported thioureas have been employed 96 in the aza-Henry reaction between N-Boc-protected imines and nitroalkanes (Andrés, 97 González, Maestro, Pedrosa, & Valle, 2017). 98 Due to the interest of supported organocatalytic systems, we hypothesized that 99 chitosan could be a used as suitable support for hydrogen-boding catalysts in different 100 interesting reactions without loss of its activity. These novel organocatalysts can be 101 considered a greener alternative to that supported on synthetic resins. As chitosan is able 102 to act itself as base catalyst, it should be crucial to demonstrate that these reactions 103 selectively proceed through hydrogen-bonding activation. 104 In the present work, we report the simple preparation and perfect characterization of 105 a set of chitosan-supported ureas. These materials were effectively employed as robust 106 hydrogen-bonding organocatalysts in three different reactions: the cyanosilylation of α- 107 ketoesters and aldehydes, the addition of formaldehyde tert-butyl hydrazone to α- 108 ketoesters and a Friedel-Crafts process. In addition, the catalytic results are supported by 109 DFT calculations, which were performed to explain the role of the substituent on the 110 hydrogen bond donor capability of these catalysts. 111 2. Materials and Methods 112 2.1 Materials and methods 113 Low molecular weight chitosan (CS 1) [HPLC/SEC (g·mol-1) Mn = 48675; Mw = 87875] 114 with a DD (Fernández-Megía, Novoa-Carballal, Quiñoá, & Riguera, 2005) of 84% and 115 polydispersity index of 1.81, and medium molecular weight chitosan (CS 2) were 116 purchased from Sigma-Aldrich. Acetophenone (1a), ethyl benzoylformate (2a), ethyl 4- 117 cyanobenzoylformate (3a), benzaldehyde (5a), 4-chlorobenzaldehyde (6a), trimethylsilyl 118 cyanide, acetone cyanohydrin, tert-butylhydrazine hydrochloride, trans-β-nitrostyrene, 119 p-nitrophenol, and 1-hydroxybenzotriazole hydrate were also purchased from Sigma- 120 Aldrich. Ethyl 2-oxo-4-phenylbutyrate (4a) was obtained from Alfa Aesar. Indole (8) was 121 a product from TCI Europe. 122 Formaldehyde tert-butyl hydrazone (FTBH) was prepared according to literature 123 procedure (Lehn, Javed, & Hoffman, 2007). The physical and spectral properties of the 124 synthesized compounds (R)-5,6b, (R)-5,6c, (R)-5,6d (Li, He, Qin, Feng, & Zhang, 2004), 125 (R)-7 (Crespo-Peña et al., 2012) and 9 (Herrera, Sgarzani, Bernardi, & Ricci, 2005) are 126 in accord with those reported. The absolute configurations of chiral compounds (R)-7, 127 (R)-5d and (R)-6d were established by comparing the HPLC chromatograms with the 128 5 patterns described in previous experiments for the known configurations (Li et al., 2004; 129 Crespo-Peña et al., 2012). The spectra were recorded in CDCl3 at [1H NMR (300, 400 or 130 500 MHz); 13C NMR (75, 100 or 125 MHz)] with the solvent peak used as the internal 131 reference (7.26 and 77.0 ppm for 1H and 13C, respectively). Column chromatography was 132 performed on silica gel (Merck Kieselgel 60). Analytical TLC was performed on 133 aluminium backed plates (1.5 × 5.0 cm) precoated (0.25 mm) with silica gel (Merck, 134 Silica Gel 60 F254). The compounds were visualized by exposure to UV light or by 135 dipping the plates in solutions of KMnO4 or vanillin stains followed by heating. Unless 136 otherwise noted, analytical grade solvents and commercially available reagents were used 137 without further purification. HPLC analyses for the determination of the optical purities 138 were performed on a Waters 2695 Instrument equipped with a Waters 996 Photodiode 139 Array Detector. 140 2.2. Synthesis of chitosan-supported ureas I-III 141 To a homogenous solution of chitosan CS (100 mg) in an acetic acid aqueous mixture 1:1 142 MeOH:H2O (50 mL) at a pH value around 6.0, an excess of the corresponding isocyanate 143 was added. The reaction was allowed to stand at room temperature and its completion 144 was noted by TLC (MeOH as eluent) absorption UV (254 nm) at the origin, corresponding 145 to the polymer that incorporated the aromatic unit. After completion, the resulting 146 heterogeneous mixture was precipitated by adding 4.0 M NaOH until pH 9.0 was reached. 147 The obtained solid was filtered and then exhaustively washed with H2O, MeOH, CH2Cl2 148 and acetone, affording the corresponding pure chitosan-supported urea. 149 N-(3-Trifluoromethylphenylcarbamoyl)chitosan I: Application of the general procedure 150 to CS 1 (200 mg) and 3-trifluoromethylphenyl isocyanate (250 µL, 1.8 mmol), after 120 151 h (pH 6.0), afforded compound I (177 mg) as a white solid (Franconetti, et al., 2016). 152 DS: 0.14. IR: 3364, 2920, 1655, 1595, 1558, 1420, 1374, 1335, 1256, 1150, 1059, 1026 153 and 893 cm-1. 1H NMR (500 MHz, AcOD/D2O): δ 7.75 (br s, H-2’’), 7.57 (br s, H-4’’ or 154 H-6’’), 7.50 (br s, H-6’’ or H-4’’), 7.38 (br d, J = 7.3 Hz, H-5’’), 5.70 (br s, H-1’), 4.95 155 (br s, H-1), 4.11-3.53 (br m, H-3, H-4, H-5, H-6 and H-6’), 3.26 (br s, H-2) and 2.09 (br 156 s, NHCOCH3, overlapped with AcOD). 157 N-[3,5-Bis(trifluoromethyl)phenylcarbamoyl]chitosan, II: Application of the general 158 procedure to CS 1 (400 mg) and 3,5-bis(trifluoromethyl)phenyl isocyanate (951 µL, 5.5 159 mmol), after 96 h (pH 6.3), afforded compound II (358 mg) as a white solid. DS: 0.06. 160 IR: 3368, 3299, 2871, 1663, 1560, 1417, 1371, 1313, 1246, 1149, 1062, 1026 and 896 161 cm-1. 1H NMR (500 MHz, AcOD/D2O): δ 8.23 (br s, H-2’’ or H-6’’), 8.00 (br s, H-6’’ or 162 H-2’’), 7.64 (br s, H-4’’), 5.69 (br s, H-1’), 4.95 (br s, H-1), 4.18-3.53 (br m, H-3, H-4, 163 H-5, H-6 and H-6’), 3.26 (br s, H-2) and 2.09 (br s, NHCOCH3, overlapped with AcOD). 164 N-(3-Trifluoromethylphenylcarbamoyl)chitosan, III: Application of the general 165 procedure to CS 2 (200 mg) and 3-trifluoromethylphenyl isocyanate (250 µL, 1.8 mmol), 166 after 120 h (pH 6.3), afforded compound III (173 mg) as a white solid. DS: 0.02. IR: 167 3288, 2879, 1638, 1543, 1394, 1314, 1155, 1060, 1028 and 897 cm-1. 1H NMR (500 MHz, 168 6 AcOD/D2O): δ 7.75 (br s, H-2’’), 7.57 (br s, H-4’’ or H-6’’), 7.50 (br s, H-6’’ or H-4’’), 169 7.39 (br d, J = 7.3 Hz, H-5’’), 5.60 (br s, H-1’), 4.95 (br s, H-1), 4.20-3.50 (br m, H-3, H- 170 4, H-5, H-6 and H-6’), 3.26 (br s, H-2) and 2.09 (br s, NHCOCH3, overlapped with 171 AcOD). 172 2.3. Characterization of chitosan-supported ureas 173 NMR spectra (500 MHz) were acquired on a Bruker Avance III spectrometer equipped 174 with a 5 mm CryoProbe TCI using a 1:0.85 AcOD/D2O solution. Degrees of N- 175 substitution (DS) were calculated from the relative integral value of 1H NMR spectra as 176 follows: 177 DS = [(IAr/n)/(IH2-H6/6)] 178 Where IAr is the relative area of the ureidyl moiety peaks (3 for compound II or 4 for 179 compounds I and III) and IH2-H6 corresponds to the integral for protons H-2 to H-6 of the 180 pyranose ring. 181 To confirm effective substitution into the polymer backbone, diffusion-filtered 1H NMR 182 experiments were carried out applying a standard gradient pulse (Bruker pulse program 183 ledbpgps2) (Wu, Chen, & Johnson, 1995). 184 Finally, infrared spectra were recorded on a Jasco FT/IR-4100 spectrophotometer 185 applying 30 scans per sample at a resolution of 4 cm-1. 186 2.4 General procedure for the organocatalyzed cyanosilylation of α-ketoesters 1-6a in 187 the presence of trimethylsilyl cyanide. 188 Trimethylsilyl cyanide (99 μL, 0.75 mmol) was added to a solution of ketones or 189 aldehydes 1-6a (0.5 mmol) and the corresponding chitosan-based urea I-III (15 mg) in 190 the proper solvent (0.5 mL) at the specified temperature. The mixture was stirred for the 191 time established (TLC monitoring). The catalyst was filtered and washed twice with the 192 corresponding solvent. To the crude reaction, 1.0 mL of a saturated solution of NH4Cl 193 was added, and the mixture was extracted with EtOAc (2 × 5 mL). The organic phase was 194 washed with 5.0 mL of a saturated solution of NaCl, dried with Na2SO4, and the solvents 195 were removed under reduced pressure. The residue was purified by column 196 chromatography using 8:2 n-hexane/EtOAc for compounds 2-4b and 9:1 n- 197 hexane/EtOAc for products 5,6b, affording the corresponding O-protected cyanohydrins 198 2-4b and (R)-5,6b. 199 Ethyl 2-cyano-2-phenyl-2-[(trimethylsilyl)oxy]acetate, 2b, was synthesized from ethyl 200 benzoylformate 2a using catalyst II at -30 ºC in toluene. Yellow pale oil. 1H NMR (300 201 MHz, CDCl3): δ 7.69-7.66 (m, 2H), 7.43-7.41 (m, 3H), 4.31-4.18 (m, 2H), 1.26 (t, 3JHH = 202 8.1 Hz,), 0.21 (s, 9H); 13C NMR (74.5 MHz, CDCl3): δ 167.2 (C=O), 134.2 (CAr), 129.2 203 (2 × CHAr), 128.1 (2 × CHAr), 124.8 (CHAr), 116.4 (CºN), 72.1 (C), 64.2 (CH2), 12.9 204 (CH3), 0.0 (3 × Si-CH3); HRMS: m/z calcd. for C14H19NNaO3Si (M+ + Na): 300.1026; 205 found: 300.1032. 206 7 Ethyl 2-cyano-2-(4-cyanophenyl)-2-[(trimethylsilyl)oxy]acetate, 3b: Prepared from ethyl 207 4-cyanobenzoylformate 3a, using catalyst II in toluene at -30 ºC. Yellow pale oil. 1H 208 NMR (300 MHz, CDCl3): δ 7.65-7.60 (m, 2H), 7.58-7.55 (m, 2H), 4.15-4.03 (m, 2H), 209 1.10 (t, 3JHH = 7.8 Hz, 3H), 0.15 (s, 9H); 13C NMR (74.5 MHz, CDCl3): δ 165.5 (C=O), 210 140.7 (CAr), 131.8 (2 × CHAr), 125.7 (2 × CHAr), 117.2 (CºN), 116.6 (CºN), 113.1 (CAr), 211 73.6 (C), 63.3 (CH2), 13.1 (CH3), 0.0 (3 × Si-CH3); HRMS: m/z calcd. for 212 C15H18N2NaO3Si (M+ + Na): 325.0984; found: 325.0980. 213 Ethyl 2-cyano-4-phenyl-2-[(trimethylsilyl)oxy]butanoate, 4b, was prepared starting from 214 ethyl 2-oxo-4-phenylbutyrate 4a in the presence of catalyst II in toluene at -30 ºC. Yellow 215 pale oil. 1H NMR (300 MHz, CDCl3): δ 7.22-7.20 (m, 2H), 7.19-7.10 (m, 3H), 4.23-4.15 216 (m, 2H), 2.77-2.71 (m, 2H), 2.23-2.17 (m, 2H) 1.26 (t, 3JHH = 8.0 Hz, 3H), 0.20 (s, 9H); 217 13C NMR (74.5 MHz, CDCl3): δ 167.0 (C=O), 139.0 (CAr), 127.8 (2 × CHAr), 127.6 (2 × 218 CHAr), 125.6 (CHAr), 117.3 (CºN), 72.1 (C), 62.4 (CH2), 41.4 (CH2), 29.1 (CH2), 13.3 219 (CH3), 0.0 (3 × Si-CH3). HRMS: m/z calcd. for C16H23NNaO3Si (M+ + Na): 328.1339; 220 found: 328.1342. 221 2.5 General procedure for the hydrolysis of the O-protected cyanohydrins 2-6b. Synthesis 222 of 2-6c. 223 The corresponding cyanohydrin trimethylsilyl ether 2-6b (0.2 mmol) was dissolved in 224 THF (2.0 mL), and then 1.0 N HCl (2.0 mL) was added dropwise to the mixture. The 225 reaction was stirred at room temperature for 4 h and the aqueous phase was then extracted 226 with Et2O (2 × 5mL). The combined organic layers were dried with Na2SO4 and the 227 solvent was eliminated under reduced pressure to obtain the free cyanohydrins 2-6c. 228 Compounds 2-4c were directly employed to measure the optical purities. In case of 229 cyanohydrins 5,6c a further acetylation step was required to determine the enantiomeric 230 excesses. The optical purities of cyanohydrins 2-4c were determined using a Chiralpak 231 ADH-H column (25 cm × 0.46 cm) from Daicel (95:5 n-hexane/i-PrOH, 1.0 mL/min, 30 232 ºC). 233 (-)-Ethyl 2-cyano-2-hydroxy-2-phenylacetate, (-)-2c: Yellow pale oil. 1H NMR (300 234 MHz, CDCl3): δ 7.58-7.55 (m, 2H), 7.37-7.35 (m, 3H), 4.33-4.18 (m, 2H), 1.20 (t, 3JHH = 235 8.0 Hz, 3H); 13C NMR (74.5 MHz, CDCl3): δ 168.1 (C=O), 134.9 (CAr), 129.9 (2 × CHAr), 236 128.9 (2 × CHAr), 125.6 (CHAr), 117.1 (CºN), 72.7 (C), 65.0 (CH2), 13.7 (CH3); HRMS: 237 m/z calcd. for C11H11NNaO3 (M+ + Na): 228.0631; found: 228.0635. HPLC data: tr (-) = 238 12.5 min., tr (+) = 13.7 min. [α]D25: - 15.6 (c 1.0, CHCl3, 24% ee). 239 (-)-Ethyl 2-cyano-2-hydroxy-2-(4-cyanophenyl)acetate, (-)-3c: Yellow pale oil. 1H 240 NMR (300 MHz, CDCl3): δ 7.74-7.66 (m, 4H), 4.37 (br s, 1H, OH), 4.15-4.03 (m, 2H), 241 1.10 (t, 3JHH = 8.0 Hz, 3H); 13C NMR (74.5 MHz, CDCl3): δ 167.0 (C=O), 139.5 (CAr), 242 132.7 (2 × CHAr), 126.6 (2 × CHAr), 117.8 (CºN), 116.3 (CºN), 114.1 (CAr), 72.1 (C), 243 65.8 (CH2), 13.7 (CH3); HRMS: m/z calcd. for C12H10N2NaO3 (M+ + Na): 253.0589; 244 found: 253.0592. HPLC data: tr (-) = 28.4 min., tr (+) = 34.7 min. [α]D25: - 17.2 (c 1.45, 245 CHCl3, 28% ee). 246 8 (-)-Ethyl 2-cyano-2-hydroxy-4-phenylbutanoate, (-)-4c: Yellow pale oil. 1H NMR (300 247 MHz, CDCl3): δ 7.33-7.30 (m, 2H), 6.98-6.95 (m, 3H), 4.38-4.29 (m, 2H), 2.84-2.78 (m, 248 1H), 2.69-2.63 (m, 1H), 2.31-2.20 (m, 2H), 1.28 (t, 3JHH 8.1 Hz, 3H); 13C NMR (74.5 249 MHz, CDCl3): δ 167.1 (C=O), 137.4 (CAr), 128.6 (2 × CHAr), 127.7 (2 × CHAr), 127.3 250 (CHAr), 116.4 (CºN), 69.7 (C), 65.4 (CH2), 40.1 (CH2), 29.2 (CH2), 13.7 (CH3); HRMS: 251 m/z calcd. for C13H15NNaO3 (M+ + Na): 256.0944; found: 256.0950. HPLC data: tr (-) = 252 11.2 min., tr (+) = 18.1 min. [α]D25: - 5.9 (c 0.70, CHCl3, 21% ee). 253 2.6 General procedure for the acetylation of free cyanohydrins 5c and 6c. 254 Free cyanohydrins 5-6c (0.1 mmol) were dissolved in CH2Cl2 (2 mL), and pyridine (16 255 µL, 0.2 mmol), 4-dimethylaminopyridine (catalytic) and acetic anhydride (19 µL, 0.2 256 mmol) were added dropwise. The reaction was stirred at room temperature for 1 h, and 257 the crude mixture was washed with 1.0 N HCl (2 × 5 mL). The organic layer was dried 258 with Na2SO4 and the solvents were evaporated to give the corresponding acetates 5-6d, 259 which were used without further purification for the determination of the enantiomeric 260 excesses using a Chiracel OD (25 cm × 0.46 cm) column from Daicel (99:1 n-hexane/i- 261 PrOH, 1.0 mL/min, 30 ºC). HPLC data: Cyanohydrin 5d: tr (R) = 12.4 min., tr (S) = 13.6 262 min; Cyanohydrin 6d: tr (R) = 14.8 min., tr (S) = 17.0 min. 263 2.7. General procedure for the catalytic enantioselective reaction of formaldehyde tert- 264 butyl hydrazone (1) with α-ketoester 2a. 265 Formaldehyde tert-butyl hydrazone (134 μL, 1.2 mmol) was added to a solution of ethyl 266 benzoylformate (2a) (106 mg, 0.6 mmol) and the chitosan-based urea I-III (15 mg) in the 267 proper solvent (0.6 mL) at the specified temperature. The mixture was stirred for the time 268 established. After that, the catalyst was filtered and washed with the corresponding 269 solvent (2 × 2 mL). The solvent was then removed under reduced pressure and the crude 270 reaction mixture was purified by column chromatography using 6:1 toluene/EtOAc as 271 eluent, in order to afford the corresponding azomethyl alcohol (R)-7. The enantiomeric 272 excess of this compound was determined with a Chiralpak AD-H column (98:2 n- 273 hexane/i-PrOH, 1.0 mL/min, 30 ºC), tr (R) = 13.0 min., tr (S) = 19.2 min. 274 (R)-Ethyl-3-[2-(tert-butyl)hydrazono]-2-hydroxy-2-phenylpropanoate, (R)-7: Colourless 275 oil. 1H NMR (300 MHz, CDCl3): δ 7.66 (d, 3JHH = 7.2 Hz, 2H), 7.36 (t, 3JHH = 7.2 Hz, 276 3H), 7.30 (d, 3JHH = 7.2 Hz, 1H), 4.71-4.63 (m, 1H), 4.27-4.20 (m, 2H), 4.04 (s, 1H), 277 4.03-3.95 (m, 1H), 1.26 (t, 3JHH = 7.5 Hz, 3H), 1.18 (s, 9H); 13C NMR (74.5 MHz, CDCl3): 278 δ 172.1 (C=O), 139.8 (CAr), 128.3 (2 × CHAr), 128.0 (2 × CHAr), 125.9 (CHAr), 77.8 (C), 279 75.1 (C), 68.3 (CH2), 62.0 (CH2), 26.5 (CH3), 14.1 (CH3); HRMS calcd. for C15H23N2O3 280 (M+): 278.1630; found: 278.1624. 281 2.8. General procedure for the Friedel-Crafts reaction between indole and trans-β- 282 nitrostyrene. 283 To a solution of trans-β-nitrostyrene (30 mg, 0.2 mmol) and the corresponding chitosan- 284 supported urea I-III (15 mg) in the selected solvent (0.6 mL), indole 8 (35 mg, 0.3 mmol) 285 9 was added in one portion. The test tube was stirred at the chosen temperature for the times 286 established. After the reaction finished (monitoring by TLC), the catalyst was filtered and 287 the solvent was evaporated under reduced pressure. The obtained residue was purified by 288 column chromatography (8:2 n-hexane-EtOAc). The enantiomeric excess of product 9 289 was measured using a Chiralpack AD-H column (9:1 n-hexane/i-PrOH, 1.0 mL/min, 30 290 ºC), tr = 24.7 min., and 27.2 min. 291 (±)-3-(2-nitro-1-phenylethyl)-1H-indole, (±)-9: Colourless oil. 1H NMR (300 MHz, 292 CDCl3): δ 8.05 (br s, 1H), 7.43-7.03 (m, 10H), 5.21 (t, 3JHH = 8.0 Hz, 1H), 5.00 (m, 1H), 293 4.93 (m, 1H); 13C NMR (74.5 MHz, CDCl3): δ 139.2 (CAr), 137.9 (CAr), 128.9 (CAr), 127.8 294 (2 x CHAr), 127.6 (2 × CHAr), 124.7 (CHAr), 122.7 (CHAr), 121.6 (CHAr), 120.0 (CHAr), 295 118.9 (CHAr), 114.5 (CAr), 111.4 (CHAr), 79.5 (CH2), 41.6 (CH); HRMS: calcd. for 296 C16H14N2O2 (M+): 266.1055; found: 266.1049. 297 2.9. Computational details 298 Theoretical calculations were computed employing the program Gaussian 09 (Frisch et 299 al, 2009). All DFT optimizations were performed without symmetry restrictions using the 300 hybrid Minnesota functional M06-2X (Zhao et al, 2006a, b, 2008) at 6-31++G(d,p) level 301 of theory. Analyses of frequencies were carried out revealing that all optimized structures 302 were minima (no imaginary frequencies). Monomers of methyl 2-deoxy-2-(3- 303 trifluoromethylphenylureide)-4-O-methyl-β-D-glucopyranoside and methyl 2-deoxy-2- 304 [3,5-di-(trifluoromethyl)phenylureide]-4-O-methyl-β-D-glucopyranoside were used as 305 models for chitosan-based catalysts I and II in which hydroxyl functions at C-1 and C-4 306 positions were methylated to simulate the β(1→4) glycosidic linkage. 307 Binding energies (kcal mol-1) for non-covalent interactions were calculated at the same 308 level of theory as follows: 309 310 ΔEbind = Esystem – Ecarbohydr – EAr 311 312 Where Esystem corresponds to the interaction between the catalyst model and the 313 corresponding aromatic ring, whereas Ecarbohydr and EAr are the energy for single optimized 314 structures for the catalyst and the aromatic acceptor, respectively. 315 316 3. Results and Discussion 317 The synthesis of chitosan-based ureas I-III (Scheme 1) was carried out under 318 homogeneous conditions as was previously described in the experimental section, starting 319 from native chitosans and the corresponding 3-mono- or 3,5-bistrifluoromethylphenyl 320 isocyanate. In this context, the electron-deficient isocyanates can even react with the polar 321 reaction solvents (H2O and MeOH) and, therefore, an excess of these reactants was 322 needed. Chitosans with different molecular weights and degrees of deacetylation were 323 used for the preparation of ureidyl derivatives I-III. Thus, catalysts I (R = H) and II (R = 324 CF3) were obtained from the low molecular weight chitosan (DD = 84 %), whereas 325 material III was prepared from medium molecular weight chitosan (DD = 81 %). 326 16 In this study, 4-chlorobenzaldehyde (6a) was also tested as substrate in the 474 cyanosilylation catalysed by I and II at -30 ºC. Catalyst II showed higher activity than I, 475 with 90% yield after 6 h (entry 6), although the processes took place with low selectivity 476 (ee = 15%). The reaction of 6a with TMSCN catalysed by unmodified chitosan CS 1 led 477 to 28% yield of racemate 6b after 36 h (entry 7), indicating again that the urea-driven 478 hydrogen-bond catalysis was the main force in these processes. On the other hand, the 479 effect of a non-silylated cyanide source was studied. Thus, hydrocyanation of 6a 480 catalysed by II was conducted with 1.5 equivalents of acetone cyanohydrin in toluene at 481 -30 ºC. The advantage of using this reagent was that the final free cyanohydrin (R)-6c 482 was directly obtained, which made the hydrolysis step unnecessary. This reaction 483 occurred with very low yield (13% after 9 h) and 10% ee, as shown in entry 8. 484 Table 2. Chitosan-based ureas catalysed preparation of (R)-cyanohydrins 5c and 6c 485 starting from aromatic aldehydes 5a and 6a. 486 Entry Chitosan Catalyst Aldehyde Solvent T (ºC) time (h) Yield (%)a ee (%)b 1 I 5a Toluene 4 7 95 ≤3 2 II 5a Toluene 4 7 95 ≤3 3 I 5a Toluene -30 22 53 19 4c II 5a Toluene -30 8 92 14 5 I 6a Toluene -30 22 70 9 6c II 6a Toluene -30 6 90 15 7 CS 1 6a Toluene -30 36 28 ≤3 8e II 6a Toluene -30 9 13 10 a Isolated yield 487 b Determined by HPLC on the O-acetylated derivatives 5-6d. 488 c Optimal reaction conditions explored for this substrate (also see Table S2). 489 e Reaction performed employing 1.5 equivalents of acetone cyanohydrin as cyanide source. 490 491 3.2. Chitosan-supported ureas catalysed addition of formaldehyde tert-butyl hydrazone 492 to α-ketoesters. 493 Formaldehyde tert-butyl hydrazone has been widely employed as a versatile carbon 494 nucleophile in organocatalyzed additions to electrophilic compounds (Crespo-Peña et al., 495 2012; Monge et al., 2013; Retamosa, Matador, Monge, Lassaletta, & Fernández, 2016; 496 Carmona et al., 2017), in order to obtain the corresponding optically active azomethyl 497 alcohols (Scheme 4a, azo compounds, R–N=N–R′). These compounds constitute an 498 important family of molecules with a wide variety of applications in organic chemistry 499 (Patai, 1997). 500 17 501 Scheme 4. Reactions catalysed by chitosan-based ureas: a) Synthesis of (R)-azo 502 compound (R)-7 by addition of formaldehyde tert-butyl hydrazone to ethyl 503 benzoylformate 2a, and b) Organocatalyzed Friedel-Crafts alkylation between indole 8 504 and trans-b-nitrostyrene. 505 Thus, it was also decided to evaluate the chitosan-supported ureas as heterogeneous 506 catalysts for the addition of this hydrazone to ethyl benzoylformate 2a as model substrate. 507 The homogenous counterpart of this reaction has been performed using a (R)-BINAM- 508 derived bis-urea, achieving (R)-7 with a 90% ee after 42 hours at -30 ºC (Crespo-Peña et 509 al., 2012). The first experiment was conducted with catalyst II in toluene at 4 ºC. As 510 shown in Table 3, after 22 h, a 58% yield of the racemic azomethyl alcohol 7 was obtained 511 (entry 1). At this temperature, the reaction in the absence of catalyst led to 28% of the azo 512 compound, which can partially explain the absence of selectivity. Thereby, the reactions 513 were carried out at -30 ºC in toluene. Under these conditions, no background reaction was 514 observed after 24 h. Ureas I and III led to (R)-7 with yields around 20% (entries 3 and 5, 515 respectively), whereas catalyst II afforded the azo compound with 33% yield and 16% 516 ee. The use of TBME as solvent allowed increasing the yield up to 42% (entry 6), 517 although the optical purity of 7 remained very similar. The use of acetonitrile as solvent 518 (entry 7) afforded (R)-7 with higher yield and only 10% ee, whereas the process 519 performed in EtOAc showed low activity (entry 8). The reactions catalysed by chitosan 520 II in toluene and TBME were also conducted at -45 ºC (entries 9 and 10). The reaction 521 catalysed by TBME led to 41% of (R)-7 with 24% ee after 48 h, whereas toluene showed 522 lower performance (32% yield, 20% ee). 523 Table 3. Chitosan-based ureas catalysed addition of FTBH to ethyl benzoylformate 2a. 524 Entry Chitosan Catalyst Solvent T (ºC) time (h) Yield (%)a ee (%)b 1 II Toluene 4 22 58 ≤3 2 None Toluene 4 22 28 ≤3 3c I Toluene -30 24 23 15 18 4 II Toluene -30 24 33 16 5 III Toluene -30 24 20 7 6 II TBME -30 24 42 19 7 II CH3CN -30 24 47 10 8 II EtOAc -30 24 23 15 9 II Toluene -45 48 32 20 10d II TBME -45 48 41 24 a Isolated yield. 525 b Determined by HPLC. 526 c No reaction in the absence of catalyst was observed after 24 h. 527 d Optimal reaction conditions explored for this substrate (also see Table S2). 528 529 3.3. Catalytic Friedel-Crafts alkylation of indole catalysed by chitosan-based ureas. 530 The addition of aromatic compounds to electron-deficient alkenes is a kind of Friedel- 531 Crafts alkylation (Scheme 3b), a synthetic process of great interest in organic chemistry. 532 The catalytic version of this reaction has been reported using metal catalysts (Bandini, 533 Melloni, & Umani-Ronchi, 2004) and organocatalysts (Herrera, Sgarzani, Bernardi, & 534 Ricci, 2005), being obtained the final adduct 9 with 82% ee and good conversion when 535 employing an homogeneous thiourea derived from 1-indanol as catalyst at -24 ºC. 536 In order to evaluate the performance of the chitosan-based catalyst II for Friedel-Craft 537 reactions, we have investigated the model reaction between indole (8) and trans-b- 538 nitrostyrene (Table 4). Since no product was observed at 0 ºC after 72 h, the reactions 539 were performed at 25 ºC in different organic solvents. Adduct 9 was obtained with 47% 540 yield after 48 h in TBME, whereas the use of CH2Cl2, CH3CN or toluene led to slightly 541 lower yields (from 45% to 37%), and the reaction in EtOAc afforded the final product 542 with only 25% yield (entry 6). At this temperature, the reaction in the absence of catalyst 543 yielded 17% of 9 after 65 h, which can explain to a certain extent the lack of selectivity. 544 Table 4. Catalyzed Friedel-Crafts alkylation of indole by trans-b-nitrostyrene in the 545 presence of chitosan-supported urea II. 546 Entry Chitosan Catalyst Solvent T (ºC) time (h) Yield (%)a ee (%)b 1 II Toluene 0 72 ≤3 -- 2 II Toluene 25 48 37 ≤3 3c II TBME 25 48 47 ≤3 4 II CH2Cl2 25 48 43 ≤3 5 II CH3CN 25 48 45 ≤3 6 II EtOAc 25 48 25 ≤3 7 None Toluene 25 65 17 ≤3 a Isolated yield. 547 b Determined by HPLC. 548 c Optimal reaction conditions explored for this substrate (also see Table S2). 549 550 3.4 Theoretical calculations for mechanistic considerations 551 19 In order to understand the mechanism of the cyanosilylation reaction of benzaldehyde 5a 552 catalysed by chitosan-based ureas, theoretical calculations were performed. The 553 optimization process of models for chitosan-supported ureas I and II based on methyl 2- 554 deoxy-2-(3-trifluoromethylphenylureide)-4-O-methyl-β-D-glucopyranoside and methyl 555 2-deoxy-2-[3,5-di-(trifluoromethyl)phenylureide]-4-O-methyl-β-D-glucopyranoside 556 provided minima (no imaginary frequencies) in which the gauche-trans rotamer was the 557 most stabilized one. Initial screening applying the B3LYP functional revealed a non- 558 covalent interaction between aromatic rings. Therefore, this study was carried out 559 applying the M06-2X functional at 6-31++G(d,p) level of theory. 560 The outcomes (Figure S2) brought to light a π-π interaction for the interplay between 561 models (for I and II) and benzaldehyde 5a, as well as the corresponding hydrogen 562 bonding between both moieties. Binding energies are indicative of higher stabilization for 563 model II with respect to compound I (ΔE = 0.9 kcal mol-1), with only one electron- 564 withdrawing trifluoromethyl group. Despite being a similar structure from a geometrical 565 point of view, a deep analysis showed slight but significant equilibrium distances (ΔR = 566 0.06 Å, Table S3) between centroids. 567 In fact, we suggest that the improved catalytic behaviour of chitosan-supported urea II is 568 due to the fact that these π-π interactions govern the stabilization of the corresponding 569 aldehyde, slightly modulated by dual hydrogen bonding between the carbonyl group and 570 -NH- hydrogen bond donors. 571 4. Conclusions 572 Making use of the unique properties of chitosan as a valuable support, a set of chitosan- 573 supported ureas containing electron-withdrawing groups in their structure was easily 574 synthesised and characterized. These organocatalysts were tested in three different 575 reactions involving asymmetric C-C bond formation: cyanosilylation of α-ketoesters and 576 aldehydes, addition of formaldehyde tert-butyl hydrazone to an activated carbonyl 577 compound and a Friedel-Crafts reaction. The optimal reaction conditions for each 578 reaction are summarized in Table S2. All three chitosan-supported ureas I-III catalyzed 579 these processes with moderate to good activities, with the highest activities being 580 achieved for catalyst II, which presented a 3,5-bistrifluoromethylphenyl group in its 581 structure. Different parameters were analysed to obtain the highest yields and optical 582 purities, although a further optimization procedure should be performed in terms of the 583 catalysts selectivity, as the enantiomeric excesses of the compounds synthesized are still 584 much lower when compared with non-supported organocatalysts. It has to be considered 585 that the heterogeneous chitosan-based ureas employed in this paper present a different 586 structure to the optimized homogeneous organocatalysts for each one of the catalytic 587 processes described. 588 As a proof of concept, catalyst II was employed in the cyanosilylation of ethyl 589 benzoylformate for 13 cycles without changes in selectivity and only a slight loss in its 590 activity. This chitosan-supported urea seems to be an affordable and robust hydrogen- 591 20 bonding catalyst that can improve the product isolation of the organocatalyzed reactions, 592 as only a simple filtration is required to separate the catalyst from the final product. This 593 work represents one of the first examples in which chitosans support hydrogen bond 594 catalysts. 595 Acknowledgements 596 The authors thank the Junta de Andalucía (FQM 142, FQM 263 and Projects P09-AGR- 597 4597 and 2012/FQM 10787) and MINECO (CTQ2016-78703-P and CTQ2016-76908- 598 C2-1,2-P) for financial support. G. de Gonzalo also thanks MINECO (Ramón y Cajal 599 Program) for financial support. The authors also thank the Servicio de Resonancia 600 Magnética Nuclear, CITIUS, and the Center of Supercomputing of Galicia (CESGA) for 601 their facilities. 602 AUTHOR INFORMATION 603 Corresponding author. 604 E-mail address: [email protected] (G. de Gonzalo); [email protected] (A. 605 Franconetti) 606 References 607 Alemán, J., Parra, A., Jiang, H., & Jørgensen, K. A. (2011) Squaramides: Bridging from 608 molecular recognition to bifunctional organocatalysis. Chemistry- A European Journal, 609 17, 6890-6899. 610 Andrés, J. M., González, F., Maestro, A., Pedrosa, R., & Valle, M. 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