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Chitosan: a highly efficient renewable and recoverable

Cite this: Green Chem., 2013, 15, 811 bio-polymer catalyst for the expeditious synthesis of
α-amino nitriles and imines under mild conditions†
Published on 16 January 2013 on http://pubs.rsc.org | doi:10.1039/C3GC36901C

Mohammad G. Dekamin,* Mojtaba Azimoshan and Leila Ramezani

Commercial chitosan – without any post-modification with active Bronsted or Lewis acid centers – was
found to be a highly efficient renewable and recoverable bio-polymer catalyst for the rapid and con-
Received 27th November 2012,
venient synthesis of α-amino nitriles or imines from aromatic aldehydes and amines under mild reaction
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Accepted 16th January 2013

conditions at room temperature in high to quantitative yields. The α-amino nitrile derivatives were pre-
DOI: 10.1039/c3gc36901c
pared through the Strecker reaction using trimethylsilyl cyanide (TMSCN) and catalyzed by chitosan as a
www.rsc.org/greenchem heterogeneous bifunctional organocatalyst.

Introduction
In recent years, development of new processes that minimize
pollution in chemical synthesis has received considerable
attention due to growing environmental concerns. In this
respect, heterogeneous catalysis has emerged as a useful tool
to reduce waste production with regard to simplicity of the pro-
cesses, lower contamination of the products with the active cata-
lytic species, avoiding the use of toxic solvents, separation and Scheme 1 Chemical structure of chitosan (1a) and chitin (1b).
recycling of the catalysts, and potential to apply continuous
flow versus batch configuration on technical scales.1,2 For this
purpose, metallic species or other catalytic active centers have cosmetics, water treatment, membranes, fuel cells, hydrogels,
been often immobilized on inorganic materials such as SiO2, adhesives, and surface conditioners. Indeed, chitosan as a
Al2O3, ZrO2, TiO2 or MgF2, synthetic organic polymers or their linear polyamine is the most important derivative of chitin,
hybrid materials.1–5 Further development of this strategy has the second most abundant natural polymer in the world after
resulted in exploring nano-ordered heterogeneous catalysts.6–8 celloluse. Chitin itself is a byproduct of the fishery industry
On the other hand, biopolymers such as starch,9 cellulose,10 (Scheme 1).12
chitosan2 or wool11 have been used as a support in hetero- The presence of free NH2 groups in chitosan and its insolu-
geneous catalytic systems very recently. However, extensive pro- bility in most organic compounds and pure water explains the
gress in designing more sustainable chemical processes takes greater potential of chitosan than chitin for use in different
place if biopolymers themselves without any post-modification areas of the chemical industry including heterogeneous cata-
can be used as heterogeneous catalysts. In this context, chito- lysis. Since chitosan has both hydroxyl and amino groups, it can
san can play a major role as a natural, biodegradable, and bio- be modified chemically into many forms and can participate
compatible polymer. Literature survey shows that a wide range in different types of chemical reactions as a suitable support
of applications have been reported for chitosan in different for different catalytic species.2,13 Furthermore, the use of small
fields such as medicine, drug delivery, food packaging, natural or synthetic organic molecules, namely organocata-
lysis, has provided attractive alternatives to the more traditional
metal-catalyzed variants and in many cases has obviated the
Pharmaceutical and Biologically-Active Compounds Research Laboratory, need for prior activation of the reaction components in sepa-
Department of Chemistry, Iran University of Science and Technology, rate steps, especially for asymmetric transformations in recent
Tehran 16846-13114, Iran. E-mail: mdekamin@iust.ac.ir
† Electronic supplementary information (ESI) available: Experimental details, IR
years.14 Hence, chitosan, as a natural poly-glucosamine, can
and 1H NMR spectral data for some of the prepared imines. See DOI: be explored without any post-modification, as a mild bifunc-
10.1039/c3gc36901c tional heterogeneous catalyst in organic synthesis. In this

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regard, chitosan contains both amino groups and primary

and secondary hydroxyl groups in higher concentrations
(Scheme 1). Therefore, it can activate the electrophilic and
nucleophilic components of the reactions by hydrogen
bonding and lone pairs, respectively. These requirements are
fully met in the multicomponent Strecker reaction of carbonyl
compounds and amines with trimethylsilyl cyanide (TMSCN).
The Strecker reaction between a carbonyl compound, an
amine and a cyanide source is widely regarded as the first multi- Scheme 2 The Strecker reaction of carbonyl compounds and amines with
component reaction (MCR).15 Some of the most important TMSCN catalyzed by chitosan (A), synthesis of imines by chitosan (B).
advantages of the MCRs are generating structural complexity
in a one-pot reaction, selectivity, convergence, atom efficiency
heterogeneous catalyst, for the one-pot three-component
and simplicity.16 The Strecker reaction is one of the most
Published on 16 January 2013 on http://pubs.rsc.org | doi:10.1039/C3GC36901C

Strecker reaction of aldehydes and aromatic amines under

straightforward methods for the synthesis of α-amino acids on
solvent-free conditions at room temperature (Scheme 2A).
both lab and technical scale even 160 years after its initial
Also, the corresponding imines, as Strecker reaction intermedi-
introduction. Indeed, the resulting bi-functional α-amino
ates, were easily prepared and isolated under the same reac-
nitriles are very important intermediates in organic synthesis
tion conditions in EtOH (Scheme 2B).
due to the rich chemistry of the cyano group (CN) which can
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Imines also called Schiff bases or azomethines are very

produce α-amino acids,17,18 diamines and various nitrogen
important compounds in biological systems and demonstrate
containing heterocycles such as thiadiazoles and imidazoles.19
anti-bacterial effects against E. coli, antiviral, antioxidant,
Furthermore, the Strecker reaction is a key step in the prep-
anticancer, enzymatic reductive and antitumor activities.32a–e
aration of pharmaceuticals such as saframycin A,20 ecteinasci-
Imines are also used as catalysts in oxygenation of alkenes,
din 74321 and phthalascidin.22 The classical Strecker reaction
hydrolysis of amino acid esters, electrochemical studies and
generally requires HCN or alkali metal cyanides such as KCN
decomposition of polymers.33a–d There are various methods
or NaCN as cyanide sources.23–25 To overcome problems
for the synthesis of imines such as reaction of aldehydes or
associated with those cyanide sources in terms of safety and
ketones with amines, oxygen removal from carbonyl com-
producing the alkaline solutions after completion of the reac-
pounds,34 reaction of nitriles with organometallic com-
tion,8 a variety of other cyanide sources such as Bu3SnCN,26a
pounds,35 amines dehydrogenation,36 direct synthesis from
K2[Fe(CN)6],26b Zn(CN)2,26c Et2AlCN,26d (EtO)2P(O)CN,26e
alcohols in the presence of amines,37a,b and aryl or alkenyl
CH3(OH)(CN)CH3,26f and TMSCN26g have been developed.
halides amination.38 However, the most convenient method
Among these alternative cyanide sources for nucleophilic
for imine synthesis is the reaction of aldehyde and ketones
addition to different electrophiles, trimethylsilyl cyanide
with amines in the presence of Lewis or Bronsted acid catalytic
(TMSCN) is a promising one, because it is an effective, easily-
systems.39,40
handled, and relatively safe cyanation reagent. However,
TMSCN requires a catalyst for its activation to transfer the
cyanide ion to electrophiles including imines in the Strecker
reaction. Therefore, the Strecker reaction of carbonyl com- Results and discussion
pounds and amines with TMSCN has been investigated for a
variety of Lewis or Bronsted acid homogeneous26g–j and hetero- Synthesis of α-amino nitriles catalyzed by chitosan
geneous catalysts so far.8 In comparison to homogeneous cata- According to our previous studies concerning the Strecker reac-
lysts such as Fe(Cp)2PF6,27a InI3,27b RhI3,27c Cu(OTf )2,27d I2,27e tion catalyzed by the modified nano-ordered MCM-41 solid
BiCl3,27f La(NO3)3·6H2O, GdCl3·6H2O,27g NiCl2,27h Ga(OTf )3,27i acid catalysts including MCM-41-SO3H and B-MCM-41,8 the
GaCl3,27j CeCl3,27k Pr(OTf )3,27l RuCl3,27m FeCl3,27n p-toluenesul- reaction of 4-chlorobenzaldehyde (2a), aniline (3a) and TMSCN
fonic acid,27o a few heterogeneous catalytic systems such as Sn- (mol ratio 1 : 1 : 1.2) was investigated, as a model reaction, to
montmorillonite,28a Co/SBA-15,28b,c Zr-MCM-41,28d B-MCM-41 optimize the conditions in the presence of chitosan (1a). The
and MCM-41-SO3H,8a,b xanthan sulfuric acid10 and cellulose results are summarized in Table 1. It is noteworthy that only a
sulfuric acid,28e nano-sized TiO2,29 and PEG-OSO3H30 have trace amount of the desired α-amino nitrile 4a was formed in
been introduced in recent years. All these heterogeneous cata- the absence of chitosan even after 24 h (Table 1, entry 1) at
lysts require transition metal cations27a–l,28a–d,29 or strong room temperature. However, we were delighted to observe that
Bronsted acid8a,27m–o,28e,30 centers. Therefore, the development the model reaction afforded the desired α-amino nitrile 4a in
of milder catalysts is still in great demand. In continuation of good to high yields using catalytic amounts of chitosan in
our ongoing research to develop mild and efficient catalytic EtOH (Table 1, entries 2–4). No cyanosilylation product was
systems for addition of the cyanide anion to electrophiles such observed in the reaction mixture.14b,31a–f Interestingly, the
as carbonyl compounds14b,31a–f and imines,8 herein we wish to model reaction in the presence of chitosan afforded the
report commercially available chitosan without any post-modi- desired product 4a under solvent-free conditions in high to
fication (1a), as a renewable and recoverable bifunctional quantitative yields and less reaction time compared to the

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Table 1 Screening of chitosan (1a) loading for the three-component Strecker group of chitosan (1a) by the trimethylsilyl (TMS) group,31g as
reaction of 4-chlorobenzaldehyde (2a) and aniline (3a) with TMSCNa a byproduct of the Strecker reaction promoted with TMSCN.
These observations were confirmed by the appearance of
characteristic sharp peaks of Si–O–C and Si–CH3 vibrations at
1157–1018, 850–827 and 752 cm−1 in the FT IR spectrum of
the recycled catalysts after the first to third runs (see ESI†).41
On the other hand, the high hygroscopic property of chitosan
Amount of or its protected derivatives has been documented.42 Therefore,
Entry chitosan (1a)/mg Solvent Time/min Yieldb/%
a part of the catalytic activity of 1a can be interpreted based on
1 — EtOH 24 h Trace its affinity toward water as another byproduct of the Strecker
2 12 EtOH 20 91 reaction. Both physical adsorption and chemical absorption
3 6 EtOH 45 76
4 4 EtOH 60 64 may be responsible for this property (Scheme 3).
5 12 — 2 98 Encouraged by these results, the optimized conditions were
Published on 16 January 2013 on http://pubs.rsc.org | doi:10.1039/C3GC36901C

6 6 — 3 95 applied to other aromatic carbonyl compounds (2b–2k) and

7c 6 — 4 95
8d 6 — 5 88 amines (3a–c) for the synthesis of other α-amino nitrile deriva-
9e 6 — 5 76 tives 4. The results are summarized in Table 2. Both aromatic
a carbocyclic and heterocyclic aldehydes containing electron-
Reaction conditions: 1 mmol of 4-chlorobenzaldehyde, 1 mmol of
aniline and 1.2 eq. of TMSCN at room temperature. b Isolated yield. withdrawing and electron-donating groups were involved in
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c
The recycled catalyst 1a after the first run was used. d The recycled the optimized reaction conditions. The reaction time for the
catalyst 1a after the second run was used. e The recycled catalyst 1a Strecker reaction catalyzed by chitosan (1a) is generally shorter
after the third run was used.
compared to previous methodologies that require a Bronsted
or Lewis acid center in the structure of their catalysts.8,27–30
reaction in EtOH (Table 1, entries 5–6). Therefore, 6 mg of chito- Interestingly, solid products 4a–l precipitated out of the reac-
san per 1 mmol of 2a was used as optimized catalyst loading tion mixture. On the other hand, the catalyst is not soluble in
under solvent-free conditions in the next experiments for water and boiling EtOH. Therefore, it was simply separated
investigating the reusability of the catalyst in the model reac- from the desired products during their recrystallization from
tion (Table 1, entries 7–9). The catalytic efficiency of 1a showed EtOH or usual work-up.8 However, an interesting feature was
a gradual decrease after the second run when it was recycled. observed for the Strecker reaction catalyzed by chitosan (1a) in
This might be attributed to gradual silylation of the hydroxyl complete contrast to the heterogeneous or homogeneous

Scheme 3 Preferable mechanism for the Strecker reaction of carbonyl compounds (2) and amines (3) with TMSCN or formation of imines 5 catalyzed by chitosan 1a.

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Table 2 Three-component Strecker reaction of different aldehydes 2 and amines 3 with TMSCN catalysed by chitosan (1a) under optimized conditionsa

Entry Aldehyde Amine Products Time/min Yieldb/% Mp MpRef

1 4-(Cl)C6H4CHO 2a Aniline 3a 3 95 109–111 110–1128

2 2-(Cl)C6H4CHO 2b Aniline 3a 12 93 67–70 63–6627a

3 4-(CN)C6H4CHO 2c Aniline 3a 48 92 109–111 108–1108

Published on 16 January 2013 on http://pubs.rsc.org | doi:10.1039/C3GC36901C

4 PhCHO 2d Aniline 3a 10 95 80–82 80–8210

5 4-(Me)C6H4CHO 2e Aniline 3a 3 96 78–80 77–7810

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6 4-(MeO)C6H4CHO 2f Aniline 3a 5 95 98–100 94–9727a

7 Furfural 2g Aniline 3a 6 93 64–67 67–698

8 Thiophen-2-carbaldehyde 2h Aniline 3a 55 92 95–97 98–1008

9 Vaniline 2i Aniline 3a 12 h 80 109–110 106–10826i

10 PhCHO 2d p-Toluidine 3b 7 95 107–109 104–1068

11 4-(Me)C6H4CHO 2f p-Toluidine 3b 4 93 104–106 10327a

12 4-(NO2)C6H4CHO 2j p-Toluidine 3b 7h 75 83–85 85–878

13 4-(NO2)C6H4CHO 2j Aniline 3a 60 80 Oil Oil8

14c PhCHCHCHO 2k Aniline 3a 90 85 103–104 105–10626k

15 Furfural 2g p-Toluidine 3b 8h — — —

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Table 2 (Contd.)

Entry Aldehyde Amine Products Time/min Yieldb/% Mp MpRef

16 Thiophen-2-carbaldehyde 2h p-Toluidine 3b 7h — — —

17 4-Fluorobenzaldehyde 2l Aniline 3a 8h — — —

18 PhCH2CH2CHO 2m Aniline 3a 9h — — —
Published on 16 January 2013 on http://pubs.rsc.org | doi:10.1039/C3GC36901C

19 Octanal 2n Aniline 3a 8h — — —

a b
Reaction conditions: 1 mmol aldehyde, 1 mmol amine, 1.2 eq. TMSCN, 6 mg chitosan, solvent-free conditions, r.t. Isolated yields. c The
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corresponding imine intermediate was identified as the final reaction product.

catalytic systems developed by us8 or other research activate both imine and TMSCN to produce α-amino nitriles 4
groups.27–30 Indeed, the nature of substituents on the aromatic through hydrogen bonding and expanding of the d-orbital of
ring of the aldehyde does not determine the overall trend of the silicon atom in TMSCN (intermediate IV), respectively. In a
the reactivity. As shown in Table 2, the reaction was completed similar pathway, TMSCN can be activated by the water mole-
smoothly to afford those α-amino nitriles 4 which are solid cules produced as imine formation byproduct (intermediate
(entries 1–12). It is noteworthy that only α-amino nitrile 4e V). It should be noted that formation of imines 5 from alde-
which is an oil at r.t. was prepared under the optimized reac- hydes 2 and amines 3 and subsequent addition of the cyanide
tion conditions (Table 2, entry 13). Furthermore, the imine anion from complexes IV or V to afford the corresponding
intermediate 5d was observed in the reaction of (E)-cinnam- α-amino nitriles 4 is faster than direct cyanation of carbonyl
aldehyde (2k) and aniline with TMSCN (entry 14). Also, 3-phenyl compounds.14b,31a–f
propanal (2m) and octanal (2n), which on reaction with To show the efficiency of the chitosan biopolymer for the
aniline and TMSCN give oily products, were not involved in Strecker reaction, Table 3 compares some of the obtained
the reaction (entries 18–19). On the other hand, altering the results in this study with those methodologies which have
amine component to benzyl amine (3c) did not afford the cor- been reported using heterogeneous catalysts containing active
responding desired products 4 in all the studied cases using Lewis or Bronsted acid centers.7,8,10,28,30 It is obvious that a
aldehydes 2a, 2d and 2e. Benzyl amine usually produces oily superior methodology in terms of the use of a renewable bio-
products in the Strecker reaction.8,26b This feature might be polymeric catalyst without any post-modification, catalyst
attributed to the strength of hydrogen bonding in the α-amino loading and a short reaction time in most cases has been
nitriles 4 or its corresponding imine 5 (Scheme 3) to interact developed.
with the hydroxyl and amine groups in the chitosan structure,
and symmetry effects in their solid lattice.
According to the obtained results and our previous studies Synthesis of imines (5) catalyzed by chitosan (1a)
on the Strecker reaction,8 cyanosilylation of carbonyl com- Since imines 5 are known as the Strecker reaction intermedi-
pounds with TMSCN, and protection of the hydroxyl group in ates,8 after our observation of the reaction of cinnamaldehyde,
alcohols and phenols with hexamethyldisilazane (HMDS),14b,31 aniline and TMSCN (Table 2, entry 14) which afforded the cor-
a plausible mechanism for the Strecker reaction catalyzed by responding imine, we decided to investigate the imine for-
chitosan (1a) is shown in Scheme 3. The free hydroxyl and mation from carbonyl compounds 2 and amines 3 in the
amino groups distributed on the surface of chitosan in high presence of chitosan (1a) under similar conditions. The results
concentrations activate the carbonyl group of the aldehydes (2) of this part of our studies on the synthesis of imines 5 are
through hydrogen bonding for nucleophilic attack of amines summarized in Table 4. In contrast to the Strecker reaction in
(3) to produce the corresponding imine 5. Furthermore, both which on addition of TMSCN the reaction mixture liquefies
physical adsorption and chemical absorption of the produced completely at room temperature, the reaction did not go to
water can be considered as a driving force for promoting the completion when at least one of the reaction components was
imine formation in its equilibrium with the carbonyl com- a solid. Therefore, a minimum amount of EtOH was added to
pound (2) and amine (3) or even intermediate II. In the next the reaction mixture to dissolve the produced melts and to
step, the hydroxyl groups on the surface of chitosan can facilitate their stirring.

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Table 3 Comparison of the catalytic efficiency of chitosan with other heterogeneous catalysts for the synthesis of α-amino nitriles 4a and 4da

Entry Catalyst Solvent Catalyst loading/mg Time/min Yielda/% Ref

1 Chitosan a
— 6 3 95 This work
2 Chitosanb — 6 10 95 This work
3 Cellulose sulfuric acidb CH3CN 100 45 94 28d
4 XSAb CH3CN 100 65 97 10
5 Sn-montmorillonitea — 10 6 90 28a
6 Sn-montmorilloniteb — 10 6 96 28a
7 MCM-41-SO3Ha EtOH 96% 5 30 98 8a
8 MCM-41-SO3Hb EtOH 96% 5 70 97 8a
9 PEG-OSO3Ha H2O 180 10 92 30
10 PEG-OSO3Hb H2O 180 10 91 30
11 B-MCM-41a EtOH 96% 50 90 98 8b
12 B-MCM-41b EtOH 96% 50 2h 96 8b
Ga-TUDa —
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13 20 30 92 7
14 Ga-TUDb — 20 30 95 7
15 PVP-SO2 a CH2Cl2 100 6h 89 4
16 PVP-SO2 b CH2Cl2 100 — 86 4
a b
4-Chlorobenzaldehyde (1 mmol), aniline (1 mmol) and TMSCN (1.2 eq.) were used at r.t. Benzaldehyde (1 mmol), aniline (1 mmol) and
TMSCN (1.2 mmol) were used at r.t.
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Table 4 Preparation of different imines 5 by the reaction of corresponding aldehydes 2 and amines 3 catalysed by chitosan (1a)a

Entry Aldehyde (2) Amine (3) Products Time/min Yieldb/% Mp/°C MpRef

1 4-(Cl)C6H4CHO 2a Aniline 3a 1 85 62–64 63–6543

2 4-(OH)C6H4CHO 2o Aniline 3a 3 96 190–192 193–19444

3 2-(OH)C6H4CHO 2p Aniline 3a 180 90 52–54 50–5226i

4 PhCHCHCHO 2k Aniline 3a 0.5 70 98–100 100–10245

5 4-(Cl)C6H4CHO 2a p-Toluidine 3b 190 75 124–126 127–12945

6 4-(NO2)C6H4CHO 2j p-Toluidine 3b 120 65 111–113 11646

7 3-(NO2)C6H4CHO 2q p-Toluidine 3b 20 85 89–91 89–9047

8 4-(MeO)C6H4CHO 2f p-Toluidine 3b 10 85 93–94 93–9448

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Table 4 (Contd.)

Entry Aldehyde (2) Amine (3) Products Time/min Yieldb/% Mp/°C MpRef

9 4-(Me)C6H4CHO 2e p-Toluidine 3b 30 80 84–86 8949

10 4-(OH)C6H4CHO 2o p-Toluidine 3b 300 85 210–211 21350

11 PhCHO 2d p-Toluidine 3b 480 78 55–57 5250

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12 PhCHCHCHO 2k p-Toluidine 3b 1 88 72–74 76–7745

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13 Furfural 2g p-Toluidine 3b 420 50 45–47 42–4451

14 2-(OH)C6H4CHO 2p p-Toluidine 3b 5 70 89–90 9444

15 Vaniline 2i p-Toluidine 3b 60 68 111–113 11652

16 4-(OH)C6H4CHO 2o Benzylamine 3c 300 56 213–215 208–21053

17 3-(NO2)C6H4CHO 2q Benzylamine 3c 60 90 60–62 62–6454

18 2-(OH)C6H4CHO 2p Benzylamine 3c 360 73 30–32 27–2955

19 4-(NO2)C6H4CHO 2j Benzylamine 3c 300 70 50–52 5656

a
Reaction conditions: 1 mmol aldehyde, 1 mmol amine and 6 mg chitosan in EtOH (0.5 mL) at r.t. b Isolated yields.

Experimental section obtained using a Bruker DRX-500 AVANCE spectrometer.

Analytical TLC was carried out using Merck 0.2 mm silica gel
General 60 F-254 Al plates.
All chemicals were purchased from Merck or Aldrich and used
as received except for benzaldehyde for which a freshly dis- General procedure for the synthesis of α-amino nitriles 4
tilled sample was used. Chitosan (MW = 600 000–800 000 catalysed by chitosan (1a)
Dalton) was purchased from Acros Organics and used without A mixture of aldehyde 2 (1 mmol), amine 3 (1 mmol), TMSCN
any post-modification. Melting points were determined using (1.2 eq., 0.15 mL) and 6 mg chitosan (1a) was stirred under
an Electrothermal 9100 apparatus and are uncorrected. FT-IR solvent-free conditions at room temperature. After completion
spectra were recorded as KBr pellets on a Shimadzu FT of the reaction, as indicated by precipitation of solid products
IR-8400S spectrometer. 1H NMR (500 MHz) spectra were from the liquid reaction mixture and TLC experiments

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using authentic samples,8 the reaction mixture was recrystal- 5 (a) A. Kirschning, H. Monenschein and R. Wittenberg,
lized from EtOH 96% (5 mL) to afford pure desired α-amino Angew. Chem., Int. Ed., 2001, 40, 650–679; (b) E. Kemnitz,
nitriles 4. S. Wuttke and S. M. Coman, Eur. J. Inorg. Chem., 2011,
4773–4794.
General procedure for the synthesis of imines 5 catalysed by 6 (a) A. Corma, Chem. Rev., 1997, 97, 2373–2419; (b) D. T. On,
chitosan (1a) D. Desplantier-Giscard, C. Danumah and S. Kaliaguine,
A mixture of aldehyde 2 (1 mmol), amine 3 (1 mmol) and 6 mg Appl. Catal., A, 2003, 253, 545–602; (c) A. Taguchi and
chitosan was dissolved in 0.5 mL of EtOH 96%. The obtained F. Schuch, Microporous Mesoporous Mater., 2005, 77, 1–45;
mixture was stirred at room temperature for the times indi- (d) A. Corma and D. Kumar, Stud. Surf. Sci. Catal., 1998,
cated in Table 4. After completion of the reaction, as indicated 117, 201–222; (e) A. Molnar and R. Bulcsu, Curr. Org.
by precipitation of solid products from the liquid reaction Chem., 2006, 10, 1697–1726.
mixture and by TLC experiments using authentic samples,8 7 (a) B. Karmakar, A. Sinhamahapatra, A. Panda, J. Banerji
the crude product was recrystallized from EtOH 96% (5 mL) to and B. Chowdhury, Appl. Catal., A, 2011, 392, 111–117;
Published on 16 January 2013 on http://pubs.rsc.org | doi:10.1039/C3GC36901C

afford pure desired imines 5. (b) K. Iwanami, H. Seo, J. C. Choi, T. Sakakura and
H. Yasuda, Tetrahedron, 2010, 66, 1898–1901; (c) B. Karimi
and A. Safari, J. Organomet. Chem., 2008, 693, 2967–2970.
Conclusion 8 (a) M. G. Dekamin and Z. Mokhtari, Tetrahedron, 2012, 68,
922–930; (b) M. G. Dekamin, J. Mokhtari and Z. Karimi, Sci.
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In summary, a new, simple, efficient and environmentally Iran. Trans. C: Chem. Chem. Eng., 2011, 18, 1356–1364;
benign method for the synthesis of α-amino nitriles and (c) M. R. Naimi-Jamal, E. Ali and M. G. Dekamin, Sci. Iran.
imines by the use of renewable and heterogeneous chitosan Trans. C: Chem. Chem. Eng., 2013, DOI: 10.1016/j.
biopolymer without any post-modification has been described. scient.2013.02.007.
Low catalyst loading, clean reaction profiles, the use of a one- 9 V. Budarin, J. H. Clark, F. E. I. Deswarte, J. J. E. Hardy,
pot and multi-component procedure for the synthesis of A. J. Hunt and F. M. Kerton, Chem. Commun., 2005,
α-amino nitriles, reusability of the catalyst and operational 2903–2905.
simplicity are the important features of this methodology. 10 A. Shaabani and A. Maleki, Appl. Catal., A, 2007, 331, 149–
151.
11 S. Wu, H. Ma, X. Jia, Y. Zhong and Z. Lei, Tetrahedron,
Acknowledgements 2011, 67, 250–256.
We are grateful for financial support from The Research 12 (a) G. A. Dee, O. Rhode and R. Wachter, Cosmet. Toiletories,
Council of Iran University of Science and Technology (IUST), 2001, 116, 39–44; (b) K. R. Reddy, K. Rajgopal,
Iran (Grant No. 160/1085). C. U. Maheswari and M. L. Kantam, New J. Chem., 2006, 30,
1549–1552.
13 (a) D. Klemm, F. Kramer, S. Moritz, T. Lindström,
Notes and references M. Ankerfors, D. Gray and A. Dorris, Angew. Chem., Int. Ed.,
2011, 50, 5438–5466; (b) H. Honarkar and M. Barikani,
1 (a) J. H. Clark and C. N. Rhodes, Clean Synthesis Using Monatsh. Chem., 2009, 140, 1403–1420; (c) K. Landfester,
Porous Inorganic Solid Catalysts and Supported Reagents, Angew. Chem., Int. Ed., 2009, 48, 4488–4507.
Royal Society of Chemistry, Cambridge, UK, 2000; 14 (a) J. T. Mohr, M. R. Krout and B. M. Stoltz, Nature, 2008,
(b) J. M. Thomas and W. J. Thomas, Principles and Practice 455, 323–332; (b) M. G. Dekamin, Z. Karimi and
of Heterogeneous Catalysis, VCH, Weinheim, 1997; M. Farahmand, Catal. Sci. Technol., 2012, 2, 1375–1381;
(c) K. Wilson and J. H. Clark, Pure Appl. Chem., 2000, 72, (c) E. Guibal, Prog. Polym. Sci., 2005, 30, 71–109;
1313–1320. (d) S. Y. Park, K. S. Marsh and J. W. Rhim, J. Food Sci.,
2 M. Chtchigrovsky, A. Primo, P. Gonzalez, K. Molvinger, 2002, 67, 194–197; (e) B. List, R. A. Lerner and C. F. Barbas,
M. Robitzer, F. Quignard and F. Taran, Angew. Chem., Int. J. Am. Chem. Soc., 2000, 122, 2395–2396.
Ed., 2009, 48, 5916–5920, and references cited therein. 15 E. Guibal, Prog. Polym. Sci., 2005, 30, 71–109.
3 (a) G. Zhu, C. Wang, Y. Zhang, N. Guo, Y. Zhao, R. Wang, 16 B. Ganem, Acc. Chem. Res., 2009, 42, 463–472.
S. Qiu, Y. Wei and R. H. Baughman, Chem.–Eur. J., 2004, 17 Y. M. Shafran, V. S. Bakulev and V. S. Mokrushin, Russ.
10, 4750–4754; (b) Q. F. Zhang, T. C. H. Lam, X. Y. Yi, Chem. Rev., 1989, 58, 148–162.
E. Y. Y. Chan, W. Y. Wong, H. H. Y. Sung, I. D. Williams 18 M. B. Smith and J. March, March’s Advanced Organic Chem-
and W. H. Leung, Chem.–Eur. J., 2005, 11, 101–111; istry, John Wiley, New York, 5th edn, 2001, ch. 16, p. 1240.
(c) J. H. Clark, M. G. Dekamin and F. M. Moghaddam, 19 S. K. De and R. A. Gibbs, Tetrahedron Lett., 2004, 45, 7407–
Green Chem., 2002, 4, 366–368. 7408.
4 G. A. Olah, T. Mathew, C. Panja, K. Smith and 20 (a) Y. Mikami, K. Takahashi, K. Yazawa, T. Arai,
G. K. S. Prakash, Catal. Lett., 2007, 114, 1–7, and references M. Namikoshi, S. Iwasaki and S. Okuda, J. Biol. Chem.,
cited therein. 1985, 260, 344–348; (b) R. O. Duthaler, Tetrahedron, 1994,

818 | Green Chem., 2013, 15, 811–820 This journal is © The Royal Society of Chemistry 2013
 View Article Online

Green Chemistry Paper

50, 1539–1650; (c) E. J. Martinez and E. J. Corey, Org. Lett., Synth. Commun., 2005, 35, 961–966; (m) S. K. De, Synth.
1999, 1, 75–77; (d) A. G. Myers and D. W. Kung, Org. Lett., Commun., 2005, 35, 653–656; (n) M. M. Heravi,
2000, 2, 3019–3022. M. Ebrahimzadeh, H. A. Oskooie and B. Baghernejad,
21 (a) E. J. Martinez, T. Owa, S. L. Schreiber and E. J. Corey, Chin. J. Chem., 2010, 28, 480–482; (o) C. S. Reddy and
Proc. Natl. Acad. Sci. U. S. A., 1999, 96, 3496–3501; M. Raghu, Indian J. Chem., Sect. B: Org. Chem. Incl. Med.
(b) C. R. Razafindrabe, S. Aubry, B. Bourdon, Chem., 2008, 47, 1572–1577.
M. Andriantsiferana, S. P. Rostaing and M. Lemaire, Tetra- 28 (a) J. Wang, Y. Masui and M. Onaka, Eur. J. Org. Chem.,
hedron, 2000, 66, 9061–9066. 2010, 1763–1771; (b) F. Rajabi, S. Ghiassian and
22 (a) K. L. Rinehart, T. G. Holt, N. L. Fregeau, P. A. Keifer, M. R. Saidi, Green Chem., 2010, 12, 1349–1352; (c) F. Rajabi,
G. R. Wilson, T. J. Perun, J. R. Sakai, A. G. Thompson, S. Nourian, S. Ghiassian, A. M. Balu, M. R. Saidi,
J. G. Stroh and L. S. Shield, J. Nat. Prod., 1990, 53, 771–792; J. C. Serrano-Ruiz and R. Luque, Green Chem., 2011, 13,
(b) K. L. Rinehart, T. G. Holt, N. L. Fregeau, J. G. Stroh, 3282–3289; (d) Z. Derikvand and F. Derikvand,
P. A. Keifer, F. Sun, L. H. Li and D. G. Martin, J. Org. Chem., Chin. J. Catal., 2011, 32, 532–535; (e) A. Shaabani,
Published on 16 January 2013 on http://pubs.rsc.org | doi:10.1039/C3GC36901C

1990, 55, 4512–4515; (c) E. J. Corey, D. Y. Gin and A. Maleki, M. R. Soudi and H. Mofakham, Catal. Commun.,
R. S. Kania, J. Am. Chem. Soc., 1996, 118, 9202–9203. 2009, 10, 945–949.
23 A. Strecker, Ann. Chem. Pharm., 1850, 75, 27–45. 29 S. M. Baghbanian, M. Farhang and R. Baharfar, Chin.
24 D. Enders and J. P. Shilvock, Chem. Soc. Rev., 2000, 29, 359– Chem. Lett., 2011, 22, 555–558.
373. 30 M. Shekouhy, Catal. Sci. Technol., 2012, 2, 1010–1020.
Downloaded by Duke University on 27 February 2013

25 (a) S. Kobayashi and H. Ishitani, Chem. Rev., 1999, 99, 31 (a) M. G. Dekamin, S. Sagheb-Asl and M. R. Naimi-Jamal,
1069–1094; (b) P. Vachal and E. N. Jacobsen, J. Am. Chem. Tetrahedron Lett., 2009, 50, 4063–4066; (b) M. G. Dekamin,
Soc., 2002, 124, 10012–10014. S. Javanshir, M. R. Naimi-Jamal, R. Hekmatshoar and
26 (a) S. J. Zuend, M. P. Coughlin, M. P. Lalonde and J. Mokhtari, J. Mol. Catal. A: Chem., 2008, 283, 29–32;
E. N. Jacobsen, Nature, 2009, 461, 968–470; (b) L. Zheng, (c) M. G. Dekamin and Z. Karimi, J. Organomet. Chem.,
M. Yuanhong, X. Jun, S. Jinghong and C. Hongfang, Tetra- 2009, 694, 1789–1794; (d) M. G. Dekamin, R. Alizadeh and
hedron Lett., 2010, 51, 3922–3926; (c) S. Shah and B. Singh, M. R. Naimi-Jamal, Appl. Organomet. Chem., 2010, 24, 229–
Tetrahedron Lett., 2012, 53, 151–156; (d) S. Nakamura, 235; (e) M. G. Dekamin, J. Mokhtari and M. R. Naimi-
N. Sato, M. Sugimoto and T. Toru, Tetrahedron: Asymmetry, Jamal, Catal. Commun., 2009, 10, 582–585;
2004, 15, 1513–1516; (e) S. Harusawa, Y. Hamada and (f) M. G. Dekamin, M. Farahmand, S. Javanshir and
T. Shioiri, Tetrahedron Lett., 1979, 20, 4663–4666; M. R. Naimi-Jamal, Catal. Commun., 2008, 9, 1352–1355;
(f) S. Sipos and I. Jablonkai, Tetrahedron Lett., 2009, 50, (g) M. G. Dekamin, N. Yazdaninia, J. Mokhtari and
1844–1846; (g) B. A. B. Prasad, A. Bisai and V. K. Singh, M. R. Naimi-Jamal, J. Iran. Chem. Soc., 2011, 8, 537–544.
Tetrahedron Lett., 2004, 45, 9565–9567; (h) G. Brahmachari 32 (a) C. G. Saxena and S. V. Shrivastava, J. Indian Chem. Soc.,
and B. Banerjee, Asian J. Org. Chem., 2012, 1, 251–258; 1987, 68, 685–686; (b) M. A. S. Aslam, S. U. Mahmood,
(i) L. X. Cheng, J. J. Tang, H. Luo, X. L. Jin, F. Dai, J. Yang, M. Shahid, A. Saeed and J. Iqbal, Eur. J. Med. Chem., 2011,
Y. P. Qian, X. Z. Li and B. Zhou, Bioorg. Med. Chem. Lett., 46, 5473–5479; (c) Z. Guo, R. Xing, S. Liu, Y. Huahua,
2010, 20, 2417–2420; ( j) J. J. Eisch and T. Dluzniewski, P. Wang, C. Li and P. C. Li, Bioorg. Med. Chem. Lett., 2005,
J. Org. Chem., 1989, 54, 1269–1274. 15, 4600–4603; (d) P. Phatak, V. S. Jolly and K. P. Sharma,
27 (a) N. U. H. Khan, S. Agrawal, R. I. Kureshy, S. H. R. Abdi, Orient. J. Chem., 2000, 16, 493–494; (e) G. C. Ferreira,
S. Singh, E. Suresh and R. V. Jasra, Tetrahedron Lett., 2008, P. J. Neame and H. A. Dailey, Protein Sci., 1993, 2, 1959–1965.
49, 640–644; (b) Z. L. Shen, S. J. Ji and T. P. Loh, Tetra- 33 (a) A. Nishinaga, T. Yamada, H. Fujisawa and K. Ishizaki,
hedron, 2008, 64, 8159–8163; (c) A. Majhi, S. S. Kim and J. Mol. Catal. A: Chem., 1998, 48, 249–264;
S. T. Kadam, Tetrahedron, 2008, 64, 5509–5514; (b) H. Chakraborty, N. Paul and M. N. Rahman, Transition
(d) S. Abhimanyu, A. S. Paraskar and A. Sudalai, Tetra- Met. Chem., 1994, 19, 524–526; (c) Y. D. Zhao, D. W. Pang,
hedron Lett., 2006, 47, 5759–5762; (e) L. Royer, S. K. De and Z. Zong, J. K. Cheng, Z. F. Luo, C. J. Feng, H. Y. Shen and
R. A. Gibbs, Tetrahedron Lett., 2005, 46, 4595–4597; X. C. Zhung, Huaxue Xuebao, 1998, 56, 178–183;
(f) S. K. De and R. A. Gibbs, Tetrahedron Lett., 2004, 45, (d) S. Kumar, D. N. Dhar and P. N. Saxena, J. Sci. Ind. Res.,
7407–7408; (g) M. Narasimhulu, T. S. Reddy, K. C. Mahesh, 1994, 68, 181–187.
S. M. Reddy, A. V. Reddy and Y. Venkateswarlu, J. Mol. 34 A. F. M. Iqbal, J. Org. Chem., 1972, 37, 2791–2793.
Catal. A: Chem., 2007, 264, 288–292; (h) S. K. De, J. Mol. 35 F. J. Weiberth and S. S. Hall, J. Org. Chem., 1987, 52, 3901–
Catal. A: Chem., 2005, 225, 169–171; (i) G. K. S. Prakash, 3904.
T. Mathew, C. Panja, S. Alconcel, H. Vaghoo, C. Do and 36 K. C. Nicolaou, C. J. N. Mathison and T. Montagnon,
G. A. Olah, Proc. Natl. Acad. Sci. U. S. A., 2007, 104, 3703– Angew. Chem., Int. Ed., 2003, 42, 4077–4082.
3706; ( j) D. Kumar, A. Saini and S. S. Jagir, Rasayan 37 (a) H. Sun, F. Z. Su, J. Ni, Y. Cao, H. Y. He and K. N. Fan,
J. Chem., 2008, 1, 639–647; (k) M. A. Pasha, Angew. Chem., Int. Ed., 2009, 48, 4390–4393; (b) K. Serk,
A. Nanjundaswamy and V. P. Jayashankara, Synth. S. Kim, S. Park, W. Bosco, R. K. Chidrala and J. Park, J. Org.
Commun., 2007, 37, 4371–4380; (l) S. K. De and R. A. Gibbs, Chem., 2009, 74, 2877–2879.

This journal is © The Royal Society of Chemistry 2013 Green Chem., 2013, 15, 811–820 | 819
 View Article Online

Paper Green Chemistry

38 J. Barluenga, F. Aznar and C. Valdés, Angew. Chem., Int. Ed., R. Pitombo and B. Polakiewicz, Braz. Arch. Biol. Technol.,
2004, 116, 347–349. 2006, 49, 665–668.
39 (a) A. K. Chakraborti, S. Bhagat and S. Rudrawar, Tetra- 43 K. A. T. E. Saitou, Bull. Chem. Soc. Jpn., 1969, 42, 2693–2694.
hedron Lett., 2004, 45, 7641–7644; (b) J. H. Billman and 44 J. S. Bennett, K. L. Charles, M. R. Miner, C. F. Heuberger,
K. M. Tai, J. Org. Chem., 1958, 23, 535–539; E. J. Spina, M. F. Bartels and T. Foreman, Green Chem.,
(c) B. P. Branchaud, J. Org. Chem., 1983, 48, 3531–3538; 2009, 11, 166–168.
(d) R. S. Varma, R. Dahiya and S. Kumar, Tetrahedron Lett., 45 Y. M. S. A. Al-Kahraman, H. M. F. Madkour, D. Ali and
1997, 38, 2039–2042; (e) G. Liu, D. A. Cogan, T. D. Owens, M. Yasinzai, Molecules, 2010, 15, 660–671.
T. P. Tang and J. A. Ellman, J. Org. Chem., 1999, 64, 1278– 46 Z. Galewski, Mol. Cryst. Liq. Cryst., 1990, 191, 211–218.
1284; (f) R. Dalpozzo, A. D. Nino, M. Nardi, B. Russo and 47 M. Á. Vázquez, M. Landa, L. Reyes, R. Miranda, J. Tamariz
A. Procopio, Synthesis, 2006, 1127–1132. and F. Delgado, Synth. Commun., 2004, 34, 2705–2718.
40 (a) J. R. Wang, Y. Fu, B. B. Zhang, X. Cui, L. Liu and 48 R. A. Champa, Mol. Cryst. Liq. Cryst., 1973, 19, 233–247.
Q. X. Guo, Tetrahedron Lett., 2006, 47, 8293–8297; 49 A. S. Hirwe, R. L. Metcalf and I. P. Kapoor, J. Agric. Food
Published on 16 January 2013 on http://pubs.rsc.org | doi:10.1039/C3GC36901C

(b) J. S. M. Samec and J. E. Bäckvall, Chem.–Eur. J., 2002, 8, Chem., 1972, 20, 818–824.
2955–2961; (c) Y. Zheng, K. Ma, H. Li, J. Li, J. He, X. Sun, 50 K. Tanaka and R. Shiraishi, Green Chem., 2000, 2, 272–273.
R. Li and J. Ma, Catal. Lett., 2009, 128, 465–474; 51 I. Kraicheva, A. Bogomilova, I. Tsacheva, G. Momekov and
(d) L. Ravishankar, S. A. Patwe, N. Gosarani and A. Roy, K. Troev, Eur. J. Med. Chem., 2009, 44, 3363–3367.
Synth. Commun., 2010, 40, 3177–3180. 52 J. Schmeyers, F. Toda, J. Boy and G. Kaupp, J. Chem. Soc.,
Downloaded by Duke University on 27 February 2013

41 E. Pretsch, P. Bühlmann and C. Affolter, Structure Determi- Perkin Trans. 2, 1998, 989–993.
nation of Organic Compounds: Tables of Spectral Data, 53 H. R. Snyder and J. R. Demuth, J. Am. Chem. Soc., 1956, 78,
Springer, Berlin, 3rd edn, 2000, p. 304. 1981–1984.
42 (a) K. Kurita, T. Kojima, Y. Nishiyama and M. Shimojoh, 54 C. G. Overberger, N. P. Marullo and R. G. Hiskey, J. Am.
Macromolecules, 2000, 33, 4711–4716; (b) M. Lavertu, Z. Xia, Chem. Soc., 1961, 83, 1374–1378.
A. N. Serreqi, M. Berrada, A. Rodrigues, D. Wang, 55 S. Inoue, Chem. Pharm. Bull., 1967, 15, 1540–1556.
M. D. Buschmann and A. Gupta, J. Pharm. Biomed. Anal., 56 V. Madan and L. B. Clapp, J. Am. Chem. Soc., 1969, 91,
2003, 32, 1149–1158; (c) K. D. Mello, L. Bernusso, 6078–6083.

820 | Green Chem., 2013, 15, 811–820 This journal is © The Royal Society of Chemistry 2013