Preparation of chitosan-supported urea materials and their application in some organocatalytic procedures

Article abstract of DOI:10.1016/j.carbpol.2018.07.009

An efficient and mild procedure was developed for the preparation of three chitosan-supported ureas containing electron-withdrawing groups. These catalysts were characterized and employed as organocatalysts in different transformations, including the enan

Full text of DOI:10.1016/j.carbpol.2018.07.009

Accepted Manuscript
Title: Preparation of chitosan-supported urea materials and
their application in some organocatalytic procedures
Authors: Gonzalo de Gonzalo, Antonio Franconetti, Rosario
´
´
Fernandez, Jose M. Lassaletta, Francisca Cabrera-Escribano
PII:
S0144-8617(18)30790-2
DOI:
Reference:
https://doi.org/10.1016/j.carbpol.2018.07.009
CARP 13809
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Accepted date:
11-1-2018
3-7-2018
3-7-2018
´
Please cite this article as: de Gonzalo G, Franconetti A, Fernandez R, Lassaletta
JM, Cabrera-Escribano F, Preparation of chitosan-supported urea materials and their
application in some organocatalytic procedures, Carbohydrate Polymers (2018),
https://doi.org/10.1016/j.carbpol.2018.07.009
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Preparation of chitosan-supported urea materials and
their application in some organocatalytic procedures
Gonzalo de Gonzalo,a,* Antonio Franconetti,a,b* Rosario Fernández,a
José M. Lassaletta,c Francisca Cabrera-Escribanoa
a Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, C/
Profesor García González 1, 41012 Sevilla, Spain.
b Departament de Química. Universitat Autònoma de Barcelona. 08193 Cerdanyola del
Vallès, Spain
c Instituto de Investigaciones Químicas (CSIC-US) and Centro de Innovación en Química
Avanzada (ORFEO-CINQA), Avda. Américo Vespucio, 49, 41092 Sevilla, Spain.
E-mail addresses: gdegonzalo@us.es (G. de Gonzalo); Antonio.Franconetti@uab.cat (A.
Franconetti)
*Corresponding author. Phone number: +34 95459997; Fax number: +34 954624960
1

Highlights
- Chitosan-based ureas are easily prepared by a mild and efficient procedure
- Chitosan-supported ureas catalyse valuable chemical reactions in a range of yields
- These heterogeneous catalysts are robust and can be employed for several catalytic
cycles
Chemical compounds
Acetophenone (PubChem CID: 7410); Ethyl benzoylformate (PubChem CID: 15349);
Ethyl 2-oxo-4-phenybutyrate (PubChem CID: 562087); Benzaldehyde (PubChem CID:
240); 4-Chlorobenzaldehyde (PubChem CID: 7726); Trimethylsilyl cyanide (PubChem
CID: 82115); Indole (PubChem CID: 798); tert-Butylhydrazine hydrochloride (PubChem
CID: 81889); trans-β-Nitrostyrene (PubChem CID: 5284459); p-Nitrophenol (PubChem
CID: 980).
2

1. Introduction
In asymmetric synthesis, chiral catalysts usually include small organic molecules and
metal complexes. In particular, organocatalysis avoids the use of metal complexes, with
chiral organic scaffolds being responsible for asymmetric induction. Since the beginning
of the present century, this technique has experienced great development for the
preparation of optically active molecules (Berkessel & Groger, 2005; Bertelsen &
Jorgensen, 2009; List, 2009; Dalko, 2013; Rossi, Benaglia, Massolo, & Raimondi, 2014).
Catalysis through hydrogen-bond interactions falls within the category of non-
covalent organocatalysis. The hydrogen bond represents a well-known interaction of high
interest, as it is a strong force with a crucial role for maintaining the structure of a vast
number of different molecules (Gilli, & Gilli, 2016; Sweetman et al., 2014). This bond
has been employed as an assisting force in catalytic procedures in organic synthesis
(Dekamin, Karimi, & Farahmand, 2012; Pihko, 2009). Among the different molecules
that can perform hydrogen bond interactions, ureas, thioureas, and more recently
squaramides (Alemán, Parra, Jiang, & Jorgensen, 2011), are the most employed, due to
their ability to establish a double hydrogen-bond interaction with the substrates. Since the
initial studies on ureas and thioureas as organocatalysts, both of them have been widely
employed in several catalytic procedures for the preparation of valuable compounds
(Kotke, & Schreiner, 2009). Recently, bifunctional hydrogen bond catalysts have been
widely investigated to perform asymmetric processes via a dual activation of both the
reaction’s nucleophile and electrophile components (Sonsona, Marques-López, &
Herrera, 2016).
Organocatalysts are, in general, robust, inexpensive, non-toxic and easily available,
whereas organocatalyzed processes are conducted under mild reaction conditions and in
the absence of metals (Hernández & Juaristi, 2012). The preparation of supported
organocatalysts represents a valuable tool in asymmetric catalysis. In addition, supported
organocatalysts facilitate product recovery and purification (Gruttaduria, Giacalone, &
Noto, 2008; Munirathinam, Huskens, & Verboom, 2015).
Chitosan is a non-toxic, biocompatible, and biodegradable linear polysaccharide of
randomly distributed β(1→4) linked D-glucosamine (>60%) and N-acetyl-D-
glucosamine. It is obtained from the alkaline deacetylation of chitin and has emerged as
a valuable polymer with several applications (Ravi Kumar, Muzzarelli, Muzzarelli,
Sashiwa, & Domb, 2004), such as solvent sensing (Jatunov et al., 2015), non-lineal optics
(Franconetti, Contreras-Bernal, Prado-Gotor, & Cabrera-Escribano, 2015), chiral
recognition of enantiomers (Jafari, Tashkhourian, & Absalan, 2018), including
carbamates (Bai, et al., 2017) and ureidyl derivatives (Wang, Xi, Chen, Huang, & Bai,
2017), and catalysis (Dekamin, Azimoshan, & Ramezani, 2013; El Kadib, 2015; Mahé,
Brière, & Dez, 2015). From a catalytic perspective, chitosan can be used following two
strategies, that is, directly as a heterogeneous catalyst or as a platform supporting the
corresponding organocatalyst. For the first strategy, native chitosan hydrogels have
proved to be an effective catalyst for Knoevenagel reactions (Franconetti, Domínguez-
Rodríguez, Lara-García, Prado-Gotor, & Cabrera-Escribano, 2016), aldol reactions and
Henry reactions, among others (Kühbeck, Saidulu, Reddy, & Díaz-Díaz, 2012). Chitosan
derivatives have also served as a valuable support for several types of organocatalysts
3

(Chtchigrovsky, et al. 2009). Thus, cycloadditions of carbon dioxide and epoxides to
obtain cyclic carbonates (Zhao, et al., 2007), Michael additions for the preparation of
different functionalized heterocycles (Khalil, & Al-Matar, 2013), and aldol reactions
(Zhang et al., 2009), have been developed by employing different types of organocatalysts
supported on chitosans. Very recently, chitosan-supported thioureas have been employed
in the aza-Henry reaction between N-Boc-protected imines and nitroalkanes (Andrés,
González, Maestro, Pedrosa, & Valle, 2017).
Due to the interest of supported organocatalytic systems, we hypothesized that
chitosan could be used as suitable support for hydrogen-boding catalysts in different
interesting reactions. These kinds of organocatalysts could be considered a greener
alternative to those supported on synthetic resins. In addition, as chitosan is able to act
itself as base catalyst, it should be crucial to demonstrate that these reactions selectively
proceed through hydrogen-bonding activation.
In the present work, we report the simple preparation and perfect characterization of
a set of chitosan-supported ureas. These materials were effectively employed as robust
hydrogen-bonding organocatalysts in three different reactions: the cyanosilylation of α-
ketoesters and aldehydes, the addition of formaldehyde tert-butyl hydrazone to α-
ketoesters and a Friedel-Crafts process. In addition, the catalytic results are supported by
DFT calculations, which were performed to explain the role of the substituent on the
hydrogen bond donor capability of these catalysts.
2. Materials and Methods
2.1 Materials and methods
Low molecular weight chitosan (CS 1) [HPLC/SEC (g·mol-1) Mn = 48675; Mw = 87875]
with a DD (Fernández-Megía, Novoa-Carballal, Quiñoá, & Riguera, 2005) of 84% and
polydispersity index of 1.81, and medium molecular weight chitosan (CS 2) were
purchased from Sigma-Aldrich. Acetophenone (1a), ethyl benzoylformate (2a), ethyl 4-
cyanobenzoylformate (3a), benzaldehyde (5a), 4-chlorobenzaldehyde (6a), trimethylsilyl
cyanide, acetone cyanohydrin, tert-butylhydrazine hydrochloride, trans-β-nitrostyrene,
p-nitrophenol, and 1-hydroxybenzotriazole hydrate were also purchased from Sigma-
Aldrich. Ethyl 2-oxo-4-phenylbutyrate (4a) was obtained from Alfa Aesar. Indole (8) was
a product from TCI Europe.
Formaldehyde tert-butyl hydrazone (FTBH) was prepared according to literature
procedure (Lehn, Javed, & Hoffman, 2007). The physical and spectral properties of the
synthesized compounds (R)-5,6b, (R)-5,6c, (R)-5,6d (Li, He, Qin, Feng, & Zhang, 2004),
(R)-7 (Crespo-Peña et al., 2012) and 9 (Herrera, Sgarzani, Bernardi, & Ricci, 2005) are
in accord with those reported. The absolute configurations of chiral compounds (R)-7,
(R)-5d and (R)-6d were established by comparing the HPLC chromatograms with the
patterns described in previous experiments for the known configurations (Li et al., 2004;
Crespo-Peña et al., 2012). The spectra were recorded in CDCl3 at [1H NMR (300, 400 or
13
500 MHz); C NMR (75, 100 or 125 MHz)] with the solvent peak used as the internal
reference (7.26 and 77.0 ppm for 1H and 13C, respectively). Column chromatography was
performed on silica gel (Merck Kieselgel 60). Analytical TLC was performed on
aluminium backed plates (1.5 × 5.0 cm) precoated (0.25 mm) with silica gel (Merck,
4

Silica Gel 60 F254). The compounds were visualized by exposure to UV light or by
dipping the plates in solutions of KMnO4 or vanillin stains followed by heating. Unless
otherwise noted, analytical grade solvents and commercially available reagents were used
without further purification. HPLC analyses for the determination of the optical purities
were performed on a Waters 2695 Instrument equipped with a Waters 996 Photodiode
Array Detector.
2.2. Synthesis of chitosan-supported ureas I-III
To a homogenous solution of chitosan CS (100 mg) in an acetic acid aqueous mixture 1:1
MeOH:H2O (50 mL) at a pH value around 6.0, an excess of the corresponding isocyanate
was added. The reaction was allowed to stand at room temperature and its completion
was noted by TLC (MeOH as eluent) absorption UV (254 nm) at the origin, corresponding
to the polymer that incorporated the aromatic unit. After completion, the resulting
heterogeneous mixture was precipitated by adding 4.0 M NaOH until pH 9.0 was reached.
The obtained solid was filtered and then exhaustively washed with H2O, MeOH, CH2Cl2
and acetone, affording the corresponding pure chitosan-supported urea.
N-(3-Trifluoromethylphenylcarbamoyl)chitosan I: Application of the general procedure
to CS 1 (200 mg) and 3-trifluoromethylphenyl isocyanate (250 µL, 1.8 mmol), after 120
h (pH 6.0), afforded compound I (177 mg) as a white solid (Franconetti, et al., 2016).
DS: 0.14. IR: 3364, 2920, 1655, 1595, 1558, 1420, 1374, 1335, 1256, 1150, 1059, 1026
and 893 cm-1. 1H NMR (500 MHz, 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’’), 7.38 (br d, J = 7.3 Hz, H-5’’), 5.70 (br s, H-1’), 4.95
(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
s, NHCOCH3, overlapped with AcOD).
N-[3,5-Bis(trifluoromethyl)phenylcarbamoyl]chitosan, II: Application of the general
procedure to CS 1 (400 mg) and 3,5-bis(trifluoromethyl)phenyl isocyanate (951 µL, 5.5
mmol), after 96 h (pH 6.3), afforded compound II (358 mg) as a white solid. DS: 0.06.
IR: 3368, 3299, 2871, 1663, 1560, 1417, 1371, 1313, 1246, 1149, 1062, 1026 and 896
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
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,
H-5, H-6 and H-6’), 3.26 (br s, H-2) and 2.09 (br s, NHCOCH3, overlapped with AcOD).
N-(3-Trifluoromethylphenylcarbamoyl)chitosan, III: Application of the general
procedure to CS 2 (200 mg) and 3-trifluoromethylphenyl isocyanate (250 µL, 1.8 mmol),
after 120 h (pH 6.3), afforded compound III (173 mg) as a white solid. DS: 0.02. IR: 3288,
1
2879, 1638, 1543, 1394, 1314, 1155, 1060, 1028 and 897 cm-1. H NMR (500 MHz,
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’’),
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-
4, H-5, H-6 and H-6’), 3.26 (br s, H-2) and 2.09 (br s, NHCOCH3, overlapped with
AcOD).
2.3. Characterization of chitosan-supported ureas
NMR spectra (500 MHz) were acquired on a Bruker Avance III spectrometer equipped
with a 5 mm CryoProbe TCI using a 1:0.85 AcOD/D2O solution. Degrees of N-
substitution (DS) were calculated from the relative integral value of 1H NMR spectra as
follows:
5

DS = [(IAr/n)/(IH2-H6/6)]
Where IAr is the relative area of the ureidyl moiety peaks (3 for compound II or 4 for
compounds I and III) and IH2-H6 corresponds to the integral for protons H-2 to H-6 of the
pyranose ring.
To confirm effective substitution into the polymer backbone, diffusion-filtered 1H NMR
experiments were carried out applying a standard gradient pulse (Bruker pulse program
ledbpgps2) (Wu, Chen, & Johnson, 1995).
Finally, infrared spectra were recorded on a Jasco FT/IR-4100 spectrophotometer
applying 30 scans per sample at a resolution of 4 cm-1.
2.4 General procedure for the organocatalyzed cyanosilylation of α-ketoesters 1-6a in
the presence of trimethylsilyl cyanide.
Trimethylsilyl cyanide (99 μL, 0.75 mmol) was added to a solution of ketones or
aldehydes 1-6a (0.5 mmol) and the corresponding chitosan-based urea I-III (15 mg) in the
proper solvent (0.5 mL) at the specified temperature. The mixture was stirred for the time
established (TLC monitoring). The catalyst was filtered and washed twice with the
corresponding solvent. To the crude reaction, 1.0 mL of a saturated solution of NH4Cl
was added, and the mixture was extracted with EtOAc (2 × 5 mL). The organic phase was
washed with 5.0 mL of a saturated solution of NaCl, dried with Na2SO4, and the solvents
were removed under reduced pressure. The residue was purified by column
chromatography using 8:2 n-hexane/EtOAc for compounds 2-4b and 9:1 n-
hexane/EtOAc for products 5,6b, affording the corresponding O-protected cyanohydrins
2-4b and (R)-5,6b.
Ethyl 2-cyano-2-phenyl-2-[(trimethylsilyl)oxy]acetate, 2b, was synthesized from ethyl
1
benzoylformate 2a using catalyst II at -30 ºC in toluene. Yellow pale oil. H NMR (300
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
=
8.1 Hz,), 0.21 (s, 9H); 13C NMR (74.5 MHz, CDCl3): δ 167.2 (C=O), 134.2 (CAr), 129.2
(2 × CHAr), 128.1 (2 × CHAr), 124.8 (CHAr), 116.4 (CN), 72.1 (C), 64.2 (CH2), 12.9
(CH3), 0.0 (3 × Si-CH3); HRMS: m/z calcd. for C14H19NNaO3Si (M+ + Na): 300.1026;
found: 300.1032.
Ethyl 2-cyano-2-(4-cyanophenyl)-2-[(trimethylsilyl)oxy]acetate, 3b: Prepared from ethyl
1
4-cyanobenzoylformate 3a, using catalyst II in toluene at -30 ºC. Yellow pale oil. H
NMR (300 MHz, CDCl3): δ 7.65-7.60 (m, 2H), 7.58-7.55 (m, 2H), 4.15-4.03 (m, 2H),
1.10 (t, 3JHH = 7.8 Hz, 3H), 0.15 (s, 9H); 13C NMR (74.5 MHz, CDCl3): δ 165.5 (C=O),
140.7 (CAr), 131.8 (2 × CHAr), 125.7 (2 × CHAr), 117.2 (CN), 116.6 (CN), 113.1 (CAr),
73.6 (C), 63.3 (CH2), 13.1 (CH3), 0.0 (3 × Si-CH3); HRMS: m/z calcd. for
C15H18N2NaO3Si (M+ + Na): 325.0984; found: 325.0980.
Ethyl 2-cyano-4-phenyl-2-[(trimethylsilyl)oxy]butanoate, 4b, was prepared starting from
ethyl 2-oxo-4-phenylbutyrate 4a in the presence of catalyst II in toluene at -30 ºC. Yellow
pale oil. 1H NMR (300 MHz, CDCl3): δ 7.22-7.20 (m, 2H), 7.19-7.10 (m, 3H), 4.23-4.15
(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);
13C NMR (74.5 MHz, CDCl3): δ 167.0 (C=O), 139.0 (CAr), 127.8 (2 × CHAr), 127.6 (2 ×
CHAr), 125.6 (CHAr), 117.3 (CN), 72.1 (C), 62.4 (CH2), 41.4 (CH2), 29.1 (CH2), 13.3
6

(CH3), 0.0 (3 × Si-CH3). HRMS: m/z calcd. for C16H23NNaO3Si (M+ + Na): 328.1339;
found: 328.1342.
2.5 General procedure for the hydrolysis of the O-protected cyanohydrins 2-6b. Synthesis
of 2-6c.
The corresponding cyanohydrin trimethylsilyl ether 2-6b (0.2 mmol) was dissolved in
THF (2.0 mL), and then 1.0 N HCl (2.0 mL) was added dropwise to the mixture. The
reaction was stirred at room temperature for 4 h and the aqueous phase was then extracted
with Et2O (2 × 5mL). The combined organic layers were dried with Na2SO4 and the
solvent was eliminated under reduced pressure to obtain the free cyanohydrins 2-6c.
Compounds 2-4c were directly employed to measure the optical purities. In case of
cyanohydrins 5,6c a further acetylation step was required to determine the enantiomeric
excesses. The optical purities of cyanohydrins 2-4c were determined using a Chiralpak
ADH-H column (25 cm × 0.46 cm) from Daicel (95:5 n-hexane/i-PrOH, 1.0 mL/min, 30
ºC).
1
()-Ethyl 2-cyano-2-hydroxy-2-phenylacetate, ()-2c: Yellow pale oil. H NMR (300
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
=
8.0 Hz, 3H); 13C NMR (74.5 MHz, CDCl3): δ 168.1 (C=O), 134.9 (CAr), 129.9 (2 × CHAr),
128.9 (2 × CHAr), 125.6 (CHAr), 117.1 (CN), 72.7 (C), 65.0 (CH2), 13.7 (CH3); HRMS:
m/z calcd. for C11H11NNaO3 (M+ + Na): 228.0631; found: 228.0635. HPLC data: tr () =
12.5 min., tr (+) = 13.7 min. [α]D25: - 15.6 (c 1.0, CHCl3, 24% ee).
1
()-Ethyl 2-cyano-2-hydroxy-2-(4-cyanophenyl)acetate, ()-3c: Yellow pale oil. H
NMR (300 MHz, CDCl3): δ 7.74-7.66 (m, 4H), 4.37 (br s, 1H, OH), 4.15-4.03 (m, 2H),
1.10 (t, 3JHH = 8.0 Hz, 3H); 13C NMR (74.5 MHz, CDCl3): δ 167.0 (C=O), 139.5 (CAr),
132.7 (2 × CHAr), 126.6 (2 × CHAr), 117.8 (CN), 116.3 (CN), 114.1 (CAr), 72.1 (C),
65.8 (CH2), 13.7 (CH3); HRMS: m/z calcd. for C12H10N2NaO3 (M+ + Na): 253.0589;
found: 253.0592. HPLC data: tr () = 28.4 min., tr (+) = 34.7 min. [α]D25: - 17.2 (c 1.45,
CHCl3, 28% ee).
()-Ethyl 2-cyano-2-hydroxy-4-phenylbutanoate, ()-4c: Yellow pale oil. 1H NMR (300
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,
3
13
1H), 2.69-2.63 (m, 1H), 2.31-2.20 (m, 2H), 1.28 (t, JHH 8.1 Hz, 3H); C NMR (74.5
MHz, CDCl3): δ 167.1 (C=O), 137.4 (CAr), 128.6 (2 × CHAr), 127.7 (2 × CHAr), 127.3
(CHAr), 116.4 (CN), 69.7 (C), 65.4 (CH2), 40.1 (CH2), 29.2 (CH2), 13.7 (CH3); HRMS:
m/z calcd. for C13H15NNaO3 (M+ + Na): 256.0944; found: 256.0950. HPLC data: tr () =
11.2 min., tr (+) = 18.1 min. [α]D25: - 5.9 (c 0.70, CHCl3, 21% ee).
2.6 General procedure for the acetylation of free cyanohydrins 5c and 6c.
Free cyanohydrins 5-6c (0.1 mmol) were dissolved in CH2Cl2 (2 mL), and pyridine (16
L, 0.2 mmol), 4-dimethylaminopyridine (catalytic) and acetic anhydride (19 L, 0.2
mmol) were added dropwise. The reaction was stirred at room temperature for 1 h, and
the crude mixture was washed with 1.0 N HCl (2 × 5 mL). The organic layer was dried
with Na2SO4 and the solvents were evaporated to give the corresponding acetates 5-6d,
which were used without further purification for the determination of the enantiomeric
excesses using a Chiracel OD (25 cm × 0.46 cm) column from Daicel (99:1 n-hexane/i-
7

PrOH, 1.0 mL/min, 30 ºC). HPLC data: Cyanohydrin 5d: tr (R) = 12.4 min., tr (S) = 13.6
min; Cyanohydrin 6d: tr (R) = 14.8 min., tr (S) = 17.0 min.
2.7. General procedure for the catalytic enantioselective reaction of formaldehyde tert-
butyl hydrazone (1) with α-ketoester 2a.
Formaldehyde tert-butyl hydrazone (134 μL, 1.2 mmol) was added to a solution of ethyl
benzoylformate (2a) (106 mg, 0.6 mmol) and the chitosan-based urea I-III (15 mg) in the
proper solvent (0.6 mL) at the specified temperature. The mixture was stirred for the time
established. After that, the catalyst was filtered and washed with the corresponding
solvent (2 × 2 mL). The solvent was then removed under reduced pressure and the crude
reaction mixture was purified by column chromatography using 6:1 toluene/EtOAc as
eluent, in order to afford the corresponding azomethyl alcohol (R)-7. The enantiomeric
excess of this compound was determined with a Chiralpak AD-H column (98:2 n-
hexane/i-PrOH, 1.0 mL/min, 30 ºC), tr (R) = 13.0 min., tr (S) = 19.2 min.
(R)-Ethyl-3-[2-(tert-butyl)hydrazono]-2-hydroxy-2-phenylpropanoate, (R)-7: Colourless
1
3
oil. H NMR (300 MHz, CDCl3): δ 7.66 (d, 3JHH = 7.2 Hz, 2H), 7.36 (t, JHH = 7.2 Hz,
3
3H), 7.30 (d, JHH = 7.2 Hz, 1H), 4.71-4.63 (m, 1H), 4.27-4.20 (m, 2H), 4.04 (s, 1H),
4.03-3.95 (m, 1H), 1.26 (t, 3JHH = 7.5 Hz, 3H), 1.18 (s, 9H); 13C NMR (74.5 MHz, CDCl3):
δ 172.1 (C=O), 139.8 (CAr), 128.3 (2 × CHAr), 128.0 (2 × CHAr), 125.9 (CHAr), 77.8 (C),
75.1 (C), 68.3 (CH2), 62.0 (CH2), 26.5 (CH3), 14.1 (CH3); HRMS calcd. for C15H23N2O3
(M+): 278.1630; found: 278.1624.
2.8. General procedure for the Friedel-Crafts reaction between indole and trans-β-
nitrostyrene.
To a solution of trans-β-nitrostyrene (30 mg, 0.2 mmol) and the corresponding chitosan-
supported urea I-III (15 mg) in the selected solvent (0.6 mL), indole 8 (35 mg, 0.3 mmol)
was added in one portion. The test tube was stirred at the chosen temperature for the times
established. After the reaction finished (monitoring by TLC), the catalyst was filtered and
the solvent was evaporated under reduced pressure. The obtained residue was purified by
column chromatography (8:2 n-hexane-EtOAc). The enantiomeric excess of product 9
was measured using a Chiralpack AD-H column (9:1 n-hexane/i-PrOH, 1.0 mL/min, 30
ºC), tr = 24.7 min., and 27.2 min.
1
(±)-3-(2-nitro-1-phenylethyl)-1H-indole, (±)-9: Colourless oil. H NMR (300 MHz,
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),
4.93 (m, 1H); 13C NMR (74.5 MHz, CDCl3): δ 139.2 (CAr), 137.9 (CAr), 128.9 (CAr), 127.8
(2 x CHAr), 127.6 (2 × CHAr), 124.7 (CHAr), 122.7 (CHAr), 121.6 (CHAr), 120.0 (CHAr),
118.9 (CHAr), 114.5 (CAr), 111.4 (CHAr), 79.5 (CH2), 41.6 (CH); HRMS: calcd. for
C16H14N2O2 (M+): 266.1055; found: 266.1049.
2.9. Computational details
Theoretical calculations were computed employing the program Gaussian 09 (Frisch et
al, 2009). All DFT optimizations were performed without symmetry restrictions using the
hybrid Minnesota functional M06-2X (Zhao et al, 2006a, b, 2008) at 6-31++G(d,p) level
of theory. Analyses of frequencies were carried out revealing that all optimized structures
were minima (no imaginary frequencies). Monomers of methyl 2-deoxy-2-(3-
8

trifluoromethylphenylureide)-4-O-methyl-β-D-glucopyranoside and methyl 2-deoxy-2-
[3,5-di-(trifluoromethyl)phenylureide]-4-O-methyl-β-D-glucopyranoside were used as
models for chitosan-based catalysts I and II in which hydroxyl functions at C-1 and C-4
positions were methylated to simulate the β(1→4) glycosidic linkage.
Binding energies (kcal mol-1) for non-covalent interactions were calculated at the same
level of theory as follows:
Abstract
An efficient and mild procedure was developed for the preparation of three chitosan-
supported ureas containing electron-withdrawing groups. These catalysts were
characterized and employed as organocatalysts in different transformations, including the
enantioselective cyanosilylation of α-ketoesters and aldehydes, the asymmetric addition
of formaldehyde tert-butyl hydrazone to prochiral α-ketoesters and a Friedel-Crafts
reaction. Several parameters that can affect the activity and selectivity of the reactions
were analysed. The supported catalysts can be reused for more than 10 cycles with only
a small loss in their properties. Finally, theoretical DFT calculations were carried out to
interpret the results of the catalysed reactions.
Abbreviations
CS: Chitosan; DFT: Density functional theory; FTBH: Formaldehyde tert-butyl
hydrazone; HOBt: 1-Hydroxybenzotriazole hydrate; TBME: tert-Butyl methyl ether;
TMSCN: Trimethylsilyl cyanide.
Keywords: Chitosan-supported ureas; Organocatalysis; Cyanosilylation; Chiral tertiary
alcohols; Heterogeneous catalysis; DFT calculations.
ΔEbind = Esystem – Ecarbohydr – EAr
Where Esystem corresponds to the interaction between the catalyst model and the
corresponding aromatic ring, whereas Ecarbohydr and EAr are the energy for single optimized
structures for the catalyst and the aromatic acceptor, respectively.
3. Results and Discussion
The synthesis of chitosan-based ureas I-III (Scheme 1) was carried out under
homogeneous conditions as was previously described in the experimental section, starting
from native chitosans and the corresponding 3-mono- or 3,5-bistrifluoromethylphenyl
isocyanate. In this context, the electron-deficient isocyanates can even react with the polar
reaction solvents (H2O and MeOH) and, therefore, an excess of these reactants was
needed. Chitosans with different molecular weights and degrees of deacetylation were
used for the preparation of ureidyl derivatives I-III. Thus, catalysts I (R = H) and II (R =
CF3) were obtained from the low molecular weight chitosan (DD = 84 %), whereas
material III was prepared from medium molecular weight chitosan (DD = 81 %).
Applying the conditions described above, a DS average between 0.02 and 0.14 for these
1
derivatives was calculated using H NMR spectra. DS values for each compound were
easily controlled by modification of the pH value of the reaction medium. For instance, it
was observed in compound I that a higher pH value induced a higher DS (with a
9

maximum of 0.14) due to an increase of the nucleophilic properties of the unprotonated
amino groups.
Scheme 1. Synthesis of chitosan supported-ureas I-III. Different repeating units of
these materials are shown as molar fractions (y values are obtained from the
corresponding DS parameters)
It is necessary to note that 1H NMR spectra for catalysts I and III showed signals at 7.75,
7.57, 7.50 and 7.38 ppm, corresponding to the C-H protons of the ureidyl moiety, whereas
only three signals at 8.23, 8.00 and 7.65 ppm were observed for the bis-3,5-
trifluoromethyl moiety in catalyst II. From a NMR point of view, the effective attachment
into the polymer backbone arises from two key points: (a) a broadening of signals takes
place after the incorporation, and (b) ureidyl 1H NMR peaks continue to be observed upon
application of a diffusion gradient. Indeed, diffusion-filtered NMR experiments (Figure
1) provided a routine tool to corroborate any substitution on chitosan. In addition, FTIR
spectra brought to light exclusively the N-substitution pattern on the basis of the
absorbance peak ratios A1025/A1061 that remained unchanged.
Figure 1. 1H NMR diffusion-filtered experiment for chitosan-supported urea II in
AcOD/D2O at 500 MHz.
10

On the other hand, from a microscopic perspective, it is known that unmodified chitosan
usually has a very low surface area (Kühbeck, et al., 2012). Measurements of N2
absorption isotherms for catalysts I-III show that the introduction of ureidyl moieties did
not modify the porous surface area (see Table S1, Supplementary data), as it was similar
to that of native chitosan. In addition, these materials were also morphologically
characterized by Field Emission Scanning Electron Microscopy (FESEM). The obtained
FESEM images (see Fig. S1, Supplementary data) reveal an amorphous structure with a
heterogeneous distribution of pore sizes in agreement with those calculated by absorption
isotherms.
3.1. Chitosan-supported ureas for the organocatalyzed cyanosilylation of carbonyl
compounds
The asymmetric cyanosilylation of aldehydes and ketones is a process of great interest in
organic synthesis (Kurono, & Ohkuma, 2016), as optically active cyanohydrins are
versatile building blocks which can be converted into several valuable compounds
(Gregory, 1999). Several methodologies have been developed for the preparation of chiral
cyanohydrins, including the use of hydrogen bond catalysts. Different ureas and thioureas
have been employed, achieving the best results generally in the presence of Jacobsen type
(thio)ureas (Zuend, & Jacobsen, 2007) or cinchona-based catalysts (Kong, Fan, Wu, &
Miao, 2012). Both families of compounds are bifunctional organocatalysts, presenting in
addition to the (thio)urea moiety an amine group that is able to activate the cyanide
nucleophile. The use of silyl cyanides as cyanation reagents has gained great interest in
the last few years, as these compounds present good reactivity and they do not show
volatility and toxicity issues due to hydrogen cyanide (Dekamin, & Mokhtari, 2012). In
addition, the obtained O-silylated cyanohydrins can be easily hydrolysed by treatment
with a diluted aqueous solution of HCl in organic solvents.
Scheme 2. Organocatalyzed cyanosilylation of carbonyl compounds 1-6a by chitosan
supported ureas I-III.
Firstly, the cyanosilylation of acetophenone (1a) with TMSCN was carried out in the
presence of the three chitosan-supported urea catalysts I-III, although no reaction was
observed after long reaction times (72 h) at room temperature. Thereby, it was decided to
test activated ketones, such as α-ketoesters, in which the presence of an electron-
withdrawing group makes the carbonyl group more reactive. The addition of 1.5
equivalents of TMSCN to ethyl benzoylformate 2a was performed at room temperature
in the presence of catalyst II. Under these conditions, a very high yield of the racemic O-
11

silylated cyanohydrin 2b was obtained after 22 h (Table 1, entry 1), whereas no reaction
was observed in the absence of catalyst.
The cyanosilylation of 2a catalysed by both chitosans I and II was also performed at 4
ºC. The results for cyanosilylation reactions highlight that catalyst II is more active than
catalyst I. Despite this fact, the O-silylated cyanohydrin 2b was obtained with very low
optical purity (entries 2 and 3), regardless of the catalyst employed. Thereby, the reaction
temperature was further decreased to -10 ºC (results shown in entries 4 and 5). At this
temperature, longer reaction times were required to obtain high conversions, whereas the
enantiomeric excesses of 2b were close to 15% with both catalysts. The O-protected
cyanohydrin 4b was obtained from the aliphatic ketoester 4a (as the reactive centre was
linked to an aliphatic carbon atom) with a similar result (86% yield and 12% ee, entry 6)
using chitosan-based urea II. In order to improve the selectivity of the process, reactions
were conducted at -30 ºC. After 30 h, catalyst I yielded 87% of 2b with a slightly higher
optical purity (ee=20%), while catalyst II afforded the O-silylated cyanohydrin with 84%
yield and 24% ee after 24 h (entry 8). Medium molecular weight chitosan III showed
much lower activity and selectivity (entry 9). We have also conducted a cyanosilylation
employing unmodified low molecular weight chitosan CS 1, in order to verify whether
this chitosan was able to catalyse the process. After 24 h, only 5% yield was observed
(entry 10), indicating that most of the cyanohydrin formed was due to the urea-driven
hydrogen-bond catalysis. A further decrease in the reaction temperature to -45 ºC led to
obtain 2b, with 61% yield after 40 h and a minimal effect on the final product optical
purity (entry 11).
Other parameters were studied in the urea II-catalysed cyanosilylation of 2a at -30 ºC.
Reactions carried out in TBME, CH2Cl2 or MeCN led to slightly higher yields than in
toluene (more than 90% for both solvents). When using TBME, 2b was recovered with
22% ee, while both CH2Cl2 and CH3CN afforded the cyanohydrin with lower optical
purities. When the reaction was performed in EtOAc, a low yield was achieved, whereas
the enantiomeric excess of 2b was similar to that of toluene. Since it has been described
that the presence of small amounts of alcohols or phenols helps to generate cyanide as the
active nucleophile (Kong et al., 2012), the use of different additives was also tested. Thus,
addition of TMSCN to 2a was carried out in toluene with 10 mol% of p-nitrophenol;
however, as shown in entry 16, no improvements in neither activity nor selectivity were
observed. 1-Hydroxybenzotriazole hydrate (HOBt) was also employed as additive in this
reaction, leading to a loss in activity, with the final product being obtained almost as a
racemic mixture, as shown in entry 17. This additive is commonly used for the activation
of carbonyl groups (Franconetti, Jatunov, Borrachero, Gómez-Guillén, & Cabrera-
Escribano, 2013). Nevertheless, HOBt proved to be capable of forming chitosan-based
water-soluble salts (Fangkangwanwong, Akshi, Kida, & Chirachanchai, 2006), which is,
for the purpose of this study, an undesired process that could explain the loss in activity.
The reactions catalysed by chitosan II at -30 ºC in toluene were extended to other α-
ketoesters. The 4-cyanophenyl derivative 3b was obtained with a higher yield compared
to its phenyl analogue (entry 18) and 28% ee after 24 h, whereas the reaction using
aliphatic substrate 4a led to both lower activity and selectivity (entry 19) in the formation
of the chiral O-silylated cyanohydrin 4b.
12

Table 1. Asymmetric cyanosilylation of α-ketoesters 2-4a catalysed by chitosan-
supported ureas.
Entry
Chitosan
Catalyst
Substrate Solvent
T (ºC)
time (h) Yield (%)a ee (%)b
1
2
3
4
5
6
7
8
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
TBME
CH2Cl2
CH3CN
EtOAc
Toluene
Toluene
Toluene
Toluene
25
4
4
22
22
22
24
24
24
30
24
30
24
40
24
24
24
24
24
24
24
24
95
85
94
78
91
86
87
84
67
5
61
92
92
90
70
88
72
95
68
≤3
6
II
I
II
I
II
II
I
II
III
CS 1
II
II
II
II
II
II
II
II
II
2a
2a
2a
2a
2a
4a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
3a
4a
11
13
15
12
20
24
6
≤3
27
22
15
12
18
22
21
28
21
-10
-10
-10
-30
-30
-30
-30
-45
-30
-30
-30
-30
-30
-30
-30
-30
9
10
11
12c
13d
14
15
16d
17e
18c
19c
a Isolated yield
b Determined by HPLC.
c Optimal reaction conditions explored for this substrate (also see Table S2).
d Reaction carried out in the presence of 10 mol% of p-nitrophenol as additive.
e Reaction performed with 10 mol% of HOBt hydrate as additive.
The feasibility of the heterogeneous chitosan-supported urea II system was studied in the
catalysed cyanosilylation of substrate 2a in toluene at 4 ºC. After 24 h, the reaction was
completed and the urea was filtered off and washed several times with toluene. The
recovered catalyst was then employed for a further reaction. The results are summarized
in Figure 2. During the first five cycles, catalyst II maintained high activity, which made
it possible to obtain 2b with almost quantitative yield. From the sixth cycle, although a
slight loss in urea activity was observed, even after 13 reactions this catalyst showed high
robustness, affording 73% conversion of the O-silylated cyanohydrin. Regarding the
catalyst selectivity, it was maintained throughout each of the cycles performed.
13

Figure 2. Chitosan-supported urea II recycling study on the cyanosilylation of prochiral
α-ketoester 2a with 1.5 equivalents of TMSCN in toluene at 4 ºC.
The organocatalyzed cyanosilylation of aromatic aldehydes was also tested with a set of
benzaldehydes. These compounds have been selectively cyanosilylated in presence on
different homogeneous hydrogen bond catalysts, being possible to obtain the O-silylated
cyanohydrins with excellent optical purities (Kurono, & Ohkuma, 2016), but no
heterogenous version of this procedure has been reported. Reactions using benzaldehyde
as model substrate (5a, Table 2) were initially conducted at 4 ºC in toluene using chitosans
I and II. After 7 h, 95% of racemic cyanohydrin (±)-5b was isolated with both catalysts.
In view of these results, reactions were carried out at -30 ºC. The use of catalyst I afforded
53% yield of cyanohydrin (R)-5b after 22 h (entry 3), whereas only 8 h were required to
achieve 92% yield in the presence of chitosan II, as shown in entry 4. For both catalysts,
the optical purities of the final product were around 15-20% ee. A possible mechanism
for the R-selective cyanosilylation of 5a to yield (R)-5b in the presence of catalyst II is
proposed in Scheme 3.
14

Scheme 3. Proposed mechanism for the TMSCN addition to benzaldehyde (5a) catalysed
by catalyst II.
The cyanosilylation of benzaldehyde (5a) followed a mechanism similar to those
previously described (Kong, Fan, Wu, & Miao, 2012; Dekamin, Azimoshan, &
Ramezani, 2013). Benzaldehyde is coordinated to the urea moiety through a hydrogen
bonding interaction. The nucleophilic attack of cyanide (CN), which is also coordinated
to the chitosan through the O-Si interaction in the TMSCN, from the Re face of the
aldehyde, leads to the formation of the R-configured enantiomer as the major product.
Cyanide attack to the Si face is partially restricted by the polysaccharide chain, which
also serves as chiral auxiliary. After this, cyanohydrin (R)-5b is released and a new
catalytic cycle will start again.
In this study, 4-chlorobenzaldehyde (6a) was also tested as substrate in the
cyanosilylation catalysed by I and II at -30 ºC. Catalyst II showed higher activity than I,
with 90% yield after 6 h (entry 6), although the processes took place with low selectivity
(ee = 15%). The reaction of 6a with TMSCN catalysed by unmodified chitosan CS 1 led
to 28% yield of racemate 6b after 36 h (entry 7), indicating again that the urea-driven
hydrogen-bond catalysis was the main force in these processes. On the other hand, the
effect of a non-silylated cyanide source was studied. Thus, hydrocyanation of 6a
catalysed by II was conducted with 1.5 equivalents of acetone cyanohydrin in toluene at
15

-30 ºC. The advantage of using this reagent was that the final free cyanohydrin (R)-6c
was directly obtained, which made the hydrolysis step unnecessary. This reaction
occurred with very low yield (13% after 9 h) and 10% ee, as shown in entry 8.
Table 2. Chitosan-based ureas catalysed preparation of (R)-cyanohydrins 5c and 6c
starting from aromatic aldehydes 5a and 6a.
Chitosan
Catalyst
Yield
(%)a
Entry
Aldehyde Solvent
T (ºC) time (h)
ee (%)b
1
2
3
4c
Toluene
Toluene
Toluene
Toluene
4
4
-30
-30
7
7
22
8
95
95
53
92
≤3
≤3
19
14
I
II
I
5a
5a
5a
5a
II
5
Toluene
Toluene
Toluene
Toluene
-30
-30
-30
-30
22
6
36
9
70
90
28
13
9
I
II
6a
6a
6a
6a
6c
7
15
≤3
10
CS 1
II
8e
a Isolated yield
b Determined by HPLC on the O-acetylated derivatives 5-6d.
c Optimal reaction conditions explored for this substrate (also see Table S2).
e Reaction performed employing 1.5 equivalents of acetone cyanohydrin as cyanide source.
3.2. Chitosan-supported ureas catalysed addition of formaldehyde tert-butyl hydrazone
to α-ketoesters.
Formaldehyde tert-butyl hydrazone has been widely employed as a versatile carbon
nucleophile in organocatalyzed additions to electrophilic compounds (Crespo-Peña et al.,
2012; Monge et al., 2013; Retamosa, Matador, Monge, Lassaletta, & Fernández, 2016;
Carmona et al., 2017), in order to obtain the corresponding optically active azomethyl
alcohols (Scheme 4a, azo compounds, R–N=N–R′). These compounds constitute an
important family of molecules with a wide variety of applications in organic chemistry
(Patai, 1997).
Scheme 4. Reactions catalysed by chitosan-based ureas: a) Synthesis of (R)-azo
compound (R)-7 by addition of formaldehyde tert-butyl hydrazone to ethyl
16

benzoylformate 2a, and b) Organocatalyzed Friedel-Crafts alkylation between indole 8
and trans--nitrostyrene.
Thus, it was also decided to evaluate the chitosan-supported ureas as heterogeneous
catalysts for the addition of this hydrazone to ethyl benzoylformate 2a as model substrate.
The homogenous counterpart of this reaction has been performed using a (R)-BINAM-
derived bis-urea, achieving (R)-7 with a 90% ee after 42 hours at -30 ºC (Crespo-Peña et
al., 2012). The first experiment was conducted with catalyst II in toluene at 4 ºC. As
shown in Table 3, after 22 h, a 58% yield of the racemic azomethyl alcohol 7 was obtained
(entry 1). At this temperature, the reaction in the absence of catalyst led to 28% of the azo
compound, which can partially explain the absence of selectivity. Thereby, the reactions
were carried out at -30 ºC in toluene. Under these conditions, no background reaction was
observed after 24 h. Ureas I and III led to (R)-7 with yields around 20% (entries 3 and 5,
respectively), whereas catalyst II afforded the azo compound with 33% yield and 16%
ee. The use of TBME as solvent allowed increasing the yield up to 42% (entry 6),
although the optical purity of 7 remained very similar. The use of acetonitrile as solvent
(entry 7) afforded (R)-7 with higher yield and only 10% ee, whereas the process
performed in EtOAc showed low activity (entry 8). The reactions catalysed by chitosan
II in toluene and TBME were also conducted at -45 ºC (entries 9 and 10). The reaction
catalysed by TBME led to 41% of (R)-7 with 24% ee after 48 h, whereas toluene showed
lower performance (32% yield, 20% ee).
Table 3. Chitosan-based ureas catalysed addition of FTBH to ethyl benzoylformate 2a.
Chitosan
Catalyst
Entry
Solvent
T (ºC)
time (h)
Yield (%)a
ee (%)b
1
2
3c
4
Toluene
Toluene
Toluene
Toluene
4
4
-30
-30
22
22
24
24
58
28
23
33
≤3
≤3
15
16
II
None
I
II
5
Toluene
TBME
CH3CN
EtOAc
Toluene
-30
-30
-30
-30
-45
24
24
24
24
48
20
42
47
23
32
7
III
II
II
II
II
6
7
8
9
19
10
15
20
10d
TBME
-45
48
41
24
II
a Isolated yield.
b Determined by HPLC.
c No reaction in the absence of catalyst was observed after 24 h.
d Optimal reaction conditions explored for this substrate (also see Table S2).
3.3. Catalytic Friedel-Crafts alkylation of indole catalysed by chitosan-based ureas.
The addition of aromatic compounds to electron-deficient alkenes is a kind of Friedel-
Crafts alkylation (Scheme 3b), a synthetic process of great interest in organic chemistry.
The catalytic version of this reaction has been reported using metal catalysts (Bandini,
Melloni, & Umani-Ronchi, 2004) and organocatalysts (Herrera, Sgarzani, Bernardi, &
17

Ricci, 2005), being obtained the final adduct 9 with 82% ee and good conversion when
employing an homogeneous thiourea derived from 1-indanol as catalyst at -24 ºC.
In order to evaluate the performance of the chitosan-based catalyst II for Friedel-Craft
reactions, we have investigated the model reaction between indole (8) and trans--
nitrostyrene (Table 4). Since no product was observed at 0 ºC after 72 h, the reactions
were performed at 25 ºC in different organic solvents. Adduct 9 was obtained with 47%
yield after 48 h in TBME, whereas the use of CH2Cl2, CH3CN or toluene led to slightly
lower yields (from 45% to 37%), and the reaction in EtOAc afforded the final product
with only 25% yield (entry 6). At this temperature, the reaction in the absence of catalyst
yielded 17% of 9 after 65 h, which can explain to a certain extent the lack of selectivity.
Table 4. Catalyzed Friedel-Crafts alkylation of indole by trans--nitrostyrene in the
presence of chitosan-supported urea II.
Chitosan
Catalyst
Entry
Solvent
T (ºC)
time (h)
Yield (%)a
ee (%)b
1
2
3c
4
5
6
7
Toluene
Toluene
TBME
CH2Cl2
CH3CN
EtOAc
0
72
48
48
48
48
48
65
≤3
37
47
43
45
25
17
--
II
II
II
II
II
II
None
25
25
25
25
25
25
≤3
≤3
≤3
≤3
≤3
Toluene
≤3
a Isolated yield.
b Determined by HPLC.
c Optimal reaction conditions explored for this substrate (also see Table S2).
3.4 Theoretical calculations for mechanistic considerations
In order to understand the mechanism of the cyanosilylation reaction of benzaldehyde 5a
catalysed by chitosan-based ureas, theoretical calculations were performed. The
optimization process of models for chitosan-supported ureas I and II based on methyl 2-
deoxy-2-(3-trifluoromethylphenylureide)-4-O-methyl-β-D-glucopyranoside and methyl
2-deoxy-2-[3,5-di-(trifluoromethyl)phenylureide]-4-O-methyl-β-D-glucopyranoside
provided minima (no imaginary frequencies) in which the gauche-trans rotamer was the
most stabilized one. Initial screening applying the B3LYP functional revealed a non-
covalent interaction between aromatic rings. Therefore, this study was carried out
applying the M06-2X functional at 6-31++G(d,p) level of theory.
The outcomes (Figure S2) brought to light a π-π interaction for the interplay between
models (for I and II) and benzaldehyde 5a, as well as the corresponding hydrogen
bonding between both moieties. Binding energies are indicative of higher stabilization for
model II with respect to compound I (ΔE = 0.9 kcal mol-1), with only one electron-
withdrawing trifluoromethyl group. Despite being a similar structure from a geometrical
point of view, a deep analysis showed slight but significant equilibrium distances (ΔR =
0.06 Å, Table S3) between centroids.
18

In fact, we suggest that the improved catalytic behaviour of chitosan-supported urea II is
due to the fact that these π-π interactions govern the stabilization of the corresponding
aldehyde, slightly modulated by dual hydrogen bonding between the carbonyl group and
-NH- hydrogen bond donors.
4. Conclusions
Making use of the unique properties of chitosan as a valuable support, a set of chitosan-
supported ureas containing electron-withdrawing groups in their structure was easily
synthesised and characterized. These organocatalysts were tested in three different
reactions involving asymmetric C-C bond formation: cyanosilylation of α-ketoesters and
aldehydes, addition of formaldehyde tert-butyl hydrazone to an activated carbonyl
compound and a Friedel-Crafts reaction. The optimal reaction conditions for each
reaction are summarized in Table S2. All three chitosan-supported ureas I-III catalyzed
these processes with moderate to good activities, with the highest activities being
achieved for catalyst II, which presented a 3,5-bistrifluoromethylphenyl group in its
structure. Different parameters were analysed to obtain the highest yields and optical
purities, although a further optimization procedure should be performed in terms of the
catalysts selectivity, as the enantiomeric excesses of the compounds synthesized are still
much lower when compared with non-supported organocatalysts. It has to be considered
that the heterogeneous chitosan-based ureas employed in this paper present a different
structure to the optimized homogeneous organocatalysts for each one of the catalytic
processes described.
As a proof of concept, catalyst II was employed in the cyanosilylation of ethyl
benzoylformate for 13 cycles without changes in selectivity and only a slight loss in its
activity. This chitosan-supported urea seems to be an affordable and robust hydrogen-
bonding catalyst that can improve the product isolation of the organocatalyzed reactions,
as only a simple filtration is required to separate the catalyst from the final product. This
work represents one of the first examples in which chitosans support hydrogen bond
catalysts.
Acknowledgements
The authors thank the Junta de Andalucía (FQM 142, FQM 263 and Projects P09-AGR-
4597 and 2012/FQM 10787) and MINECO (CTQ2016-78703-P and CTQ2016-76908-
C2-1,2-P) for financial support. G. de Gonzalo also thanks MINECO (Ramón y Cajal
Program) for financial support. The authors also thank the Servicio de Resonancia
Magnética Nuclear, CITIUS, and the Center of Supercomputing of Galicia (CESGA) for
their facilities.
AUTHOR INFORMATION
Corresponding author.
E-mail address: gdegonzalo@us.es (G. de Gonzalo); Antonio.Franconetti@uab.cat (A.
Franconetti)
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