L-Proline nitrate: A recyclable and green catalyst for the synthesis of highly functionalized piperidines

Article abstract of DOI:10.1039/c5ra08022c

The synthesis of highly functionalized piperidines has been strategically accessed via organo-catalytic three components (in situ five components) reaction of an amine, aldehyde and 1,3-dicarbonyl compound. This imine based multi-component reaction was realized using fully green l-proline nitrate as recyclable room temperature ionic liquid. Recycling of the catalyst was possible up to five runs without loss of catalyst activity. Smaller E-factor (0.255) and process mass intensity (PMI = 3.35), high atom-economy (AE = 89.5%) and reaction mass efficiency (RME = 79.66%) demonstrates the higher environmental compatibility and sustainability of this protocol. DFT calculations showed that the l-proline catalyzed reaction proceeds by three pathways; (i) via proline enamine pathway, (ii) proline mediated aniline enamine pathway or (iii) the pathway involving iminium activation of the aldehyde to provide the Knoevenagel product. This journal is

Full text of DOI:10.1039/c5ra08022c

View Article Online
View Journal
RSC Advances
This article can be cited before page numbers have been issued, to do this please use: N. R. Agrawal, S.
P. Bahekar, P. B. Sarode, S. S. Zade and H. S. Chandak, RSC Adv., 2015, DOI: 10.1039/C5RA08022C.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. This Accepted Manuscript will be replaced by the edited,
formatted and paginated article as soon as this is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/advances

Page 1 of 16
RSC Advances
View Article Online
DOI: 10.1039/C5RA08022C
L-Proline Nitrate: A Recyclable and Green Catalyst for the Synthesis of Highly
Functionalized Piperidines
Nikita R Agrawal, Sandeep P Bahekar, Prashant B Sarode, Sanjio S Zade, and Hemant S
Chandak
Graphical Abstract
Multi-component synthesis of highly functionalized piperidines has been demonstrated using
‘fully green’ -proline nitrate as recyclable room temperature ionic liquid. Recycling of the
L
catalyst was possible up to five runs without loss of catalyst activity. Smaller E-factor (0.255)
and process mass intensity (PMI = 3.35), high atom-economy (AE = 89.5%) and reaction
mass efficiency (RME = 79.66%) demonstrates the higher environmental compatibility and
sustainability of this protocol.

RSC Advances
Page 2 of 16
View Article Online
DOI: 10.1039/C5RA08022C
L-Proline Nitrate: A Recyclable and Green Catalyst for the Synthesis of Highly
Functionalized Piperidines†
Nikita R Agrawal,a,c Sandeep P Bahekar,a Prashant B Sarode,a Sanjio S Zade,b and Hemant S
Chandaka,*
a
Department of Chemistry, G. S. Science, Arts and Commerce College, Khamgaon 444303, India
Fax: (+)91-7263-253844, E-mail: chemants@gmail.com (Hemant S Chandak)
b
Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER)
Kolkata, Mohanpur 741246, India.
†
Electronic Supplementary Information (ESI) available: Calculation of Green chemistry metrics and spectral
characterisation of the selected compounds are available in supplementary information.
c
Present Address: Department of Chemistry, Govt. V.I.S.H., Amravati 444602, India

Page 3 of 16
RSC Advances
View Article Online
DOI: 10.1039/C5RA08022C
L-Proline Nitrate: A Recyclable and Green Catalyst for the Synthesis of Highly
Functionalized Piperidines
Abstract: The synthesis of highly functionalized piperidines has been strategically accessed
via organo-catalytic three components (in situ five components) reaction of a amine,
aldehyde and 1,3-dicarbonyl compound. This imine based multi-component reaction was
realized using fully green -proline nitrate as recyclable room temperature ionic liquid.
L
Recycling of the catalyst was possible up to five runs without loss of catalyst activity.
Smaller E-factor (0.255) and process mass intensity (PMI = 3.35), high atom-economy (AE =
89.5%) and reaction mass efficiency (RME = 79.66%) demonstrates the higher
environmental compatibility and sustainability of this protocol. DFT calculations showed that
the L-proline catalyzed reaction proceeds by three pathways; (i) via proline enamine pathway,
(ii) proline mediated aniline enamine pathway or (iii) the pathway involving iminium
activation of the aldehyde to provide the Knoevenagel product.
Keywords: functionalised piperidines; multicomponent reactions; DFT calculations; green
chemistry metrics; L-proline nitrate.

RSC Advances
Page 4 of 16
View Article Online
DOI: 10.1039/C5RA08022C
Introduction:
In the context of sustainability, ionic liquids (ILs) attracted great attention of the chemists in
recent years.1,2 Commonly used ionic liquids, based on imidazolium cations and fluorinated
anions are synthetic chemicals and therefore are not as green as desired. This demands the
development of bio-degradable ILs replacing the synthetic quaternary nitrogen cations such
as alkylammonium, dialkylimidazolium and pyridinium ions by bio-renewable ions. Use of
bio-renewable natural compounds as starting materials for the preparation of the ions in ILs is
a promising ongoing approach.3 Amino acids which represent the natural chiral pool, offers a
best choice as a source of quaternary nitrogen cation. Among the various amino acids, proline
plays a vital role in iminium and enamine catalysis.4
Piperidine and its derivatives bestowed supreme importance in the heterocyclic as
well as pharmaceutical arena.5 Many natural products6,7 possessing piperidine scaffold
interestingly exhibit anti-hypertensive,8 anti-bacterial,9 anti-convulsant and anti-inflammatory
activities.10 Boehm et al. in 1943 reported the first multicomponent reaction (MCR) between
and amine, aldehyde and 1,3-dicarbonyl to synthesize functionalised piperidines.11 Apart
from some Lewis and Brönsted acid catalysts,12 a few organocatalysts which include wet
picric
acid,13
p-toluenesulfonic
acid,14
bromodimethylsulfonium
bromide,15
tetrabutylammonium tribromide (TBATB),16 and thiourea oxide 17 have been reported for this
MCR. Mishra and co-workers have reported proline and trifluoroacetic acid (TFA) as dual
L-
catalytic system for this MCR.18 However, proline and TFA as dual catalytic system suffer
L-
from major drawbacks such as catalyst loadings (20% of each), longer reaction time, tiresome
isolation and purification procedure and non-recyclability of the catalyst. Recently, Shaterian
and Azizi used imidazolium and guanidinium acidic ionic liquid for the synthesis of
functionalized piperidines.19 Although recyclability and shorter reaction time makes their
protocol superior than the others but the use of chemicals like imidazole and guanidine as a

Page 5 of 16
RSC Advances
View Article Online
DOI: 10.1039/C5RA08022C
source of quaternary nitrogen is still a matter of serious concern which deprives the green
essence of the protocol.
To the best of our knowledge, there is only one report for the use of -proline nitrate
L
IL as catalyst. Kou et al. used it as a catalyst and solvent for Diels–Alder reaction.20 Despite
of having advantageous properties, the catalytic potential of -proline nitrate has not been
L
utilized yet by the synthetic organic chemists. In this context, we evaluated the catalytic
efficiency of -proline based acidic IL in the MCR involving Aza-Diels-Alder cycloaddition
L
of imine to enamine. We achieved this pseudo five component MCR using 10 mol % of -
L
proline nitrate ionic liquid as a fully green catalyst in methanol at ambient temperature
leading to the formation of highly functionalised piperidines (Scheme 1).
Scheme 1 L-Proline nitrate IL catalysed synthesis of highly functionalised piperidines
Results and discussion
Mechanistically, multicomponent synthesis of functionalized piperidines involves Aza Diels-
Alder cycloaddition of Knovenagel adduct (C) and imine (D) (Scheme 2).
O
NH
O
O
NH
N
O
Aza DA
(C)
+
N
(D)
Scheme 2 Aza Diels-Alder reaction between Knovenagel adduct and imine
In order to investigate the role of proline in this reaction, DFT study (at
B3LYP/631G(d)) was performed on the key reaction steps. We have considered

RSC Advances
Page 6 of 16
View Article Online
DOI: 10.1039/C5RA08022C
computationally the pathways of formation of tautomer of diene (C). In these reaction
pathways, we have found that the addition of enamine to benzaldehyde is the rate
determining step (RDS). As solvent (methanol) supposed to play important role on the
mechanism, solvent effects of methanol were taken into account using polar continuum
model (PCM) calculations on the optimized geometries. A transition state for the formation
of enamine from methylacetoacteate with aniline is compared to that with -proline. The
L
activation barrier for the formation of enamine with -proline is 6.2 kcal mol-1 which is 7.2
L
kcal mol-1 lower than that with aniline. Again L-proline is considered to catalyse this reaction
by two pathways- either via proline enamine pathway or proline mediated aniline enamine
pathway as shown in the Figure 1 and Figure S1. Both the pathways have less activation
energy (8.9 and 11.9 kcal mol-1 for pathway b and proline mediated aniline enamine pathway)
for the rate determining steps than that of in absence of proline (21.7 kcal mol-1 for pathway
a). Thus L-proline catalyzes the reaction either by forming enamine with acetoacetate ester in
the first step (pathway b) or by facilitating the proton transfer through its molecular
framework (Figure S1). In addition to this, we have considered the pathway involving
iminium activation of the aldehyde to provide the Knoevenagel product (Figure S2).
However, this pathway has similar energy profile compared to that of pathway a.

Page 7 of 16
RSC Advances
View Article Online
DOI: 10.1039/C5RA08022C
a) Energetics of uncatalysed reaction
b) Energetics of the reaction via L-proline enamine pathway
Figure 1. DFT investigation of formation of enamines and Knoevenagel adducts
These considerations from DFT calculation and the role of proline in iminium and
enamine catalysis, prompted us to employ a fully green -proline based acidic IL for the
L

RSC Advances
Page 8 of 16
View Article Online
DOI: 10.1039/C5RA08022C
synthesis of functionalised piperidines. -Proline nitrate was prepared by treating -proline
L
L
with nitric acid using the reported procedure.20 Initially, the reaction of benzaldehyde, aniline
and methyl acetoacetate was screened with various potential catalysts (Table 1). In presence
of - proline nitrate, the reaction proceeds smoothly giving corresponding highly diversified
L
piperidines in good yields. Thus, encouraged with these results, we focused on the
optimization reaction conditions as shown in Table1. The finest result was accomplished in
the presence of 10 mol% of the catalyst in methanol medium at ambient temperature (Table1,
entry 6). Optimal amount of catalyst is advisable since lower (5 mol%, Table1, entry 8) as
well as higher amounts (upto 30 mol %) did not put any desirable impact on the yield of
products even after the longer reaction time. Additionally, the effect of different solvents
such as ethanol and CH3CN was also investigated, and was found to be insignificant (Table 1,
entry 5 and 7). Methanol was found to be the best choice as a solvent, used directly without
rigorous drying. Methanol can dissolve all starting materials and the product formed is nearly
insoluble in it. This allows us to isolate the desired product straightforwardly by filtration.
Table 1: Screening of different organo-catalysts for the MCR of benzaldehyde, aniline and
methyl acetoacetate.(a)
Entry Catalyst
Condition
Time Yield (%)(b)
(h)
1
2
3
None
Methanol
Methanol
Methanol
24
30
24
Trace
37
Succinic acid (10 mol %)
L- Ascorbic acid (10 mol %)
40

Page 9 of 16
RSC Advances
View Article Online
DOI: 10.1039/C5RA08022C
4
5
6
7
L-Proline+TFA (20 mol %)
L-Proline nitrate (10 mol %)
L-Proline nitrate (10 mol %)
L-Proline nitrate (10 mol %)
L-Proline nitrate (5 mol %)
Acetonitrile
Ethanol
17
8
70 (ref 18)
69
90
79
59
Methanol
Acetonitrile
Methanol
8
8
8
24
(a)
General reaction conditions: methylacetoacetate (1.75 mmol), aniline (3.5 mmol), benzaldehyde (3.5
mmol), rt.
Isolated yield.
(b)
The green chemistry metrics like E-factor, atom-economy, process mass intensity and
reaction mass efficiency concepts have been widely embraced by the chemical industry and
the academic community.21 This optimised protocol has favourable green chemistry metrics
such as smaller E-factor (0.255) and process mass intensity (PMI = 3.35); higher atom-
economy (AE = 89.5%) and reaction mass efficiency (RME = 79.66%) (see ESI for details of
the calculations).
The generality and scope of this optimized protocol was tested with various
aldehydes, anilines and 1,3-dicarbonyls. The outputs are summarized in Table 2. In all cases
we achieved high yields of the products. Among the various aldehydes, aromatic aldehydes
with electron donating as well as electron withdrawing group reacts smoothly giving high
yields of functionalised piperidines. As evident from Table 2, aromatic aldehydes with nitro-
and methoxy substituent did offer only moderate yield of the product.22 Aromatic amines
with chloro substitution also entered smoothly in the play and gives good to high yields of
functionalised piperidines (Table 2, 4u-4x). The R3 group of 1,3-dicarbonyl compounds has
little or no effect on reaction. This observation is in line with the previous report.15

RSC Advances
Page 10 of 16
View Article Online
DOI: 10.1039/C5RA08022C
Table 2: Scope of -proline nitrate catalysed five component reaction for the synthesis of
L
functionalised piperidines(a)
NH
N
O
NH
N
O
NH
N
O
O
NH
N
O
NH
N
OMe
OMe
OMe
OMe
OMe
Cl
iPr
iPr
MeO
OMe
F
F
Cl
4e 79% (10 h)b
62% (12 h)
4d
4c 75% (12 h)
4a 90% (8 h)
4b 81% (10 h)
NH
N
O
NH
O
NH
O
NH
N
O
NH
O
OMe
OMe
OMe
OMe
OEt
Cl
OMe
Cl
MeO
MeO
N
N
N
OMe
O2
N
NO2
HO
OH
OMe
OMe
4i 78% (14 h)c
4g 66% (14 h)
4f 77% (10 h)
4h 78% (10 h)
4j 80% (8 h)
NH
N
O
NH
N
O
NH
N
O
NH
N
O
NH
N
O
OEt
OEt
OEt
OEt
OEt
MeO
OM
e
MeO
OM
e
Cl
Cl
F
F
MeO
OMe
iPr
iPr
OMe
OMe
4n 80% (10 h)d
4k 69% (10 h)
87% (12 h)
4l
4m 72% (12 h)
4o 72% (10 h)
NH
N
O
NH
N
O
O
NH
N
O
NH
N
NH
N
O
OEt
Cl
OEt
OEt
OEt
OEt
Cl
O2
N
NO
2HO
Br
Br
OH
4r 65% (13 h)b
4s 88% (8 h)
64% (14 h)
4p
4q 88% (12 h)
4t 87% (12 h)
Cl
Cl
Cl
Cl
NH
N
O
NH
N
O
NH
O
NH
N
O
NH
N
O
OEt
OEt
Ph
N
MeO
OMe
MeO
OMe
Cl
Cl
Cl
Cl
Cl
4u 63% (13 h)
Cl
4v 76% (12 h)
4y 63% (8 h)
4w 75% (11 h)
67% (12 h)
4x
(a)
General reaction conditions: 1,3-dicarbonyl (1.75 mmol), amine (3.5 mmol), aldehyde (3.5 mmol),
L-proline nitrate (10 mol%), methanol (0.5 mL), rt.
(b)
(c)
(d)
Diastereotropic ratio = syn: anti :: 10: 91 (as evident from 1H NMR)
Diastereotropic ratio = syn: anti :: 13: 87 (as evident from 1H NMR)
Diastereotropic ratio = syn:anti :: 09: 91 (as evident from 1H NMR)
1
Synthesized functionalised piperidines are characterized by IR, H-NMR, and 13C-
NMR spectra. The IR spectrum of the compounds perfectly indicates the conjugation of the

Page 11 of 16
RSC Advances
View Article Online
DOI: 10.1039/C5RA08022C
carbonyl and olefinic groups, exhibiting the absorption band at around 1648-1573 cm-1. The
ESIMS (mass spectra) of the compounds showed molecular ion peaks at their respective m/e.
In the 1H NMR spectrum, the proton attached to C-2 of the piperidine ring was observed as
singlet at around δ 6.01-6.46 ppm or it come into view along with the multiplets of aromatic
protons ranging from δ 6.35 to 7.50 ppm. The methylene protons of carbethoxy group
appeared as multiplet at around δ 4.15-4.41ppm. The only exchangeable secondary amine
proton (NH) connected at C-4 appeared as broad singlet at around δ10.29 ppm. The multiplet
pertaining to the methylene protons, triplet of methyl group of carbethoxy moiety and signals
of secondary amino group have been observed at two different chemical shifts in a few
cases.23 The 13C NMR spectra showed requisite number of distinct resonances in agreement
with the proposed structure. The anti stereochemistry of the product was also confirmed by
single crystal X-ray analysis of the product 4o.
Figure 2 ORTEP diagram of compound 4o (CCDC 1047298)
The ease with which product was isolated from the reaction mixture prompted us to
think about the recovery of the catalyst from residue. To recover the catalyst, initially
methanol was removed under reduced pressure. Proline nitrate IL is soluble in water (or

RSC Advances
Page 12 of 16
View Article Online
DOI: 10.1039/C5RA08022C
ethanol or acetone) and is insoluble in ethyl acetate (or chloroform or benzene). The careful
examination of the solubility properties suggests two ways to recover the catalyst- (1) to
dissolve all the components of residue except catalyst in ethyl acetate or chloroform and (2)
to dissolve catalyst in water and remove the rest of the residue by filtration. The first method
was ruled out as washing with the volatile organic compound creates waste stream. We
preferred the second possibility, and taking the advantage of the solubility of the IL in water,
the residue was washed with a little amount of water to get an aqueous solution of the catalyst
as a filtrate. Water from the filtrate was removed under reduced pressure and the last traces of
water were removed by forming azeotrope with a very little amount of toluene to get the
catalyst which was then available for the next run.
Conclusion
Scope, optimization, and application of the L-proline nitrate catalyzed pseudo five component
reaction leading to the formation of functionalized piperidines have beendescribed herein. Of
the several important improvements, a few are: (1) It is the first -proline nitrate ionic liquid
L
catalysed synthesis of functionalised piperidines. (2) The reaction has operational simplicity
and uses aninexpensive, nontoxic and biocompatible catalyst. (3) Simple purification of
product without the use of column chromatography. (4) The formation of highly
distereoselective products with generally high yield. (5)Higher atom economy (AE) and
reaction mass efficiency (RME). (6) Lower E factor and process mass intensity (PMI).
DFT calculations showed that the -proline can act as catalyst in three catalytic
L
pathways which proceed either via- (i) formation of proline enamine or (ii) formation of
proline mediated aniline enamine or (iii) proline mediated iminium activation of the aldehyde
to provide the Knoevenagel product. These three pathways are significantly lower in
energetics than that of uncatalyzed reaction. We have developed green protocol using a ‘fully
green’ -proline nitrate ionic liquid for the synthesis of functionalised piperidines. Additional
L

Page 13 of 16
RSC Advances
View Article Online
DOI: 10.1039/C5RA08022C
attributes of this procedure over previous processes are minimal usage of organic
solvent,simple work-up procedure, recyclability and biocompatibility of the catalyst. The
green chemistry metrics calculations reveals smaller E-factor (0.255) and process
massintensity (PMI = 3.35), high atom-economy (AE = 89.5%) and reaction mass efficiency
(RME = 79.66%), approves the higher environmental compatibility and sustainability of this
protocol.
Experimental
General procedure for the synthesis of functionalised piperidines
A mixture of 1,3-dicarbonyl (1.75 mmol), amine (3. 5 mmol), aldehyde (3.5 mmol)
and L-proline nitrate (31.2 mg, 0.175 mmol) in MeOH (0.5 mL) was stirred at room
temperature for an appropriate time (Table 2). After completion of the reaction, as indicated
by TLC, solid obtained was filtered under suction to get product of sufficient purity. To
recover the catalyst, initially methanol was removed under reduced pressure and residue was
washed with a little quantity of water to get an aqueous solution of the catalyst as a filtrate.
Water from the filtrate was removed under reduced pressure and the last traces of water were
removed by forming azeotrope with a very little amount of toluene to get the catalyst which
was then available for the next run.
Computational Details
All calculations were performed using Gaussian 09 programme.24 The geometries involved in
the key reaction steps were fully optimized by using a hybrid25 Becke three-parameter
26
exchange density functional with the LYP correlation functional (B3LYP)
and the 6-
31G(d) basis set (B3LYP/6-31G(d) method). Transition states were located by using the TS
routine. At the same level frequency calculations were performed for all stationary points to
differentiate them as minima or saddle points. The energies of optimized structures were
corrected using unscaled zero-point vibrational energies (ZPVEs). Gas phase values were

RSC Advances
Page 14 of 16
View Article Online
DOI: 10.1039/C5RA08022C
corrected by using single-point calculations on gas phase optimized geometries for methanol
as a solvent with the Polarized Continuum Model (PCM) at the same level of theory.27
Acknowledgment
Authors are thankful to UGC New Delhi, India (F. No. 41-335 / 2012 (SR) dt.13.07.2012) for
the financial support.
References
1
2
B. Kirchner and B. Clare, Ionic liquids, Springer Science & Business Media, 2009.
P. Wasserscheid and T. Welton, Ionic liquids in synthesis, Wiley Online Library,
2008.
3
4
S. T. Handy, Chem. Eur. J., 2003, 9, 2938-2944.
(a) B. List, Synlett, 2001, 2001, 1675-1686; (b) B. List, Tetrahedron, 2002, 58, 5573-
5590.
5
(a) N. G. Kozlov and A. P. Kadutskii, Tetrahedron Lett., 2008, 49, 4560-4562; (b) S.
G. Gladstone, W. G. Earley, J. K. Acker and G. S. Martin, Tetrahedron Lett., 2009,
50, 3813-3816; (c) S. G. Davies, P. M. Roberts and A. D. Smith, Org. Biomol. Chem.,
2007, 5, 1405-1415; (d) S. V. Karthikeyan, S. Perumal and K. K. Balasubramanian,
Tetrahedron Lett., 2007, 48, 6133-6136; (e) J. Esquivias, R. G. Arrayás and J. C.
Carretero, J. Am. Chem. Soc., 2007, 129, 1480-1481; (f) X.-F. Zhu, J. Lan and O.
Kwon, J. Am. Chem. Soc., 2003, 125, 4716-4717; (g) A. Takemiya and J. F. Hartwig,
J. Am. Chem. Soc., 2006, 128, 6042-6043; (h) M. Amat, O. Bassas, M. A. Pericàs, M.
Pastó and J. Bosch, Chem. Commun., 2005, 1327-1329; (i) R. Martín, C. Murruzzu,
M. A. Pericas and A. Riera, J. Org. Chem., 2005, 70, 2325-2328; (j) P. Li, L.-J. Liu
and J.-T. Liu, Org. Biomol. Chem., 2011, 9, 74-77; (k) D. P. Harrison, M. Sabat, W.
H. Myers and W. D. Harman J. Am. Chem. Soc., 2010, 132, 17282-17295.
C. Viegas, V. da S. Bolzani, M. Furlan, E. J. Barreiro, M. C. M. Young, D. Tomazela
and M. N. Eberlin J. Nat. Prod., 2004, 67, 908-910.
6
7
8
P. M. Dewick, Medicinal Natural Products: A Biosynthetic Approach, 2nd ed., Wiley:
New York, 2002, pp. 307-316.
S. Petit, J. Nallet, M. Guillard, J. Dreux, R. Chermat, M. Poncelet, C. Bulach, P.
Simon, C. Fontaine and M. Barthelmebs, Eur. J.Med. Chem., 1991, 26, 19-32.

Page 15 of 16
RSC Advances
View Article Online
DOI: 10.1039/C5RA08022C
9
Y. Zhou, V. E. Gregor, B. K. Ayida, G. C. Winters, Z. Sun, D. Murphy, G. Haley, D.
Bailey, J. M. Froelich and S. Fish, Bioorg. Med. Chem. Lett., 2007, 17, 1206-1210.
10 H. Bin, A. M. Crider and J. P. Stables, Eur. J. Med. Chem., 2001, 36, 265-286.
11 T. Boehm and W. Stöcker, Archiv der Pharmazie, 1943, 281, 62-77.
12 (a) InCl3: P. A. Clarke, A. V. Zaytsev and A. C. Whitwood, Synthesis, 2008, 3530-
3532; b) Iodine: A. T. Khan, M. M. Khan and K. K. Bannuru, Tetrahedron, 2010, 66,
7762-7772; c) CAN: H.-J. Wang, L.-P. Mo and Z.-H. Zhang, ACS Comb. Sci., 2011,
13, 181-185; d) ZrOCl2.8H2O: S. Mishra and R. Ghosh, Tetrahedron Lett., 2011, 52,
2857-2861; e) BF3.SiO2: R. Ramachandran, S. Jayanthi and Y. T. Jeong, Tetrahedron,
2012, 68, 363-369; f) Bi(NO3)3.5H2O: G. Brahmachari and S. Das, Tetrahedron Lett.,
2012, 53, 1479-1484; g) LaCl3.7H2O: B. Umamahesh, V. Sathesh, G. Ramachandran,
M. Sathishkumar and K. Sathiyanarayanan, Catal. Lett., 2012, 142, 895-900; h) VCl3:
S. Pal, L. H. Choudhury and T. Parvin, Mol. Divers., 2012, 16, 129-143; i)
NiCl2.6H2O: M. R. M. Shafiee, B. H. Najafabadi and M. Ghashang, J. Chem. Res.,
2012, 36, 336-339.
13 C. Mukhopadhyay, S. Rana, R. J. Butcher and A. M. Schmiedekamp, Tetrahedron
Lett., 2011, 52, 5835-5840.
14 S. S. Sajadikhah, M. T. Maghsoodlou, N. Hazeri, S. M. Habibi-Khorassani and S. J.
Shams-Najafi, Monatsh. Chem., 2012, 143, 939-945.
15 A. T. Khan, T. Parvin and L. H. Choudhury, J. Org. Chem., 2008, 73, 8398-8402.
16 A. T. Khan, M. Lal and M. M. Khan, Tetrahedron Lett., 2010, 51, 4419-4424.
17 S. Verma, S. Kumar, S. L. Jain and B. Sain, Org. Biomol. Chem., 2011, 9, 6943-6948.
18 M. Misra, S. K. Pandey, V. P. Pandey, J. Pandey, R. Tripathi and R. P. Tripathi,
Bioorg. Med. Chem., 2009, 17, 625-633
19 H. R. Shaterian and K. Azizi, J. Mol. Liq., 2013, 180, 187-191.
20 G.-H. Tao, L. He, W.-S. Liu, L. Xu, W. Xiong, T. Wang, Y. Kou, Green Chemistry,
2006, 8, 639-646.
21 (a) F. I. McGonagle, H. F. Sneddon, C. Jamieson and A. J. Watson, ACS Sustainable
Chem. Eng., 2014, 2, 523-532. (b) A. D. Curzons, D. J. Constable, D. N. Mortimer
and V. L. Cunningham, Green Chemistry, 2001, 3, 1-6.
22 We found that the present protocol is not suitable for the aliphatic aldehydes.

RSC Advances
Page 16 of 16
View Article Online
DOI: 10.1039/C5RA08022C
23 Two signals due to secondary NH, CH2 (H5a and H5b) and CH3 were observed in case
of the compound 4e, 4i and 4n. These compounds are obtained as diasteromeric
mixtures.
24 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,M. A. Robb, J. R.
Cheeseman, G. Scalmani, V. Barone,B. Mennucci, G. A. Petersson, H. Nakatsuji, M.
Caricato,X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng,J. L.
Sonnenberg, M. Hada, M. Ehara, K. Toyota,R. Fukuda, J. Hasegawa, M. Ishida, T.
Nakajima, Y. Honda,O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery, Jr,J. E.
Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd,E. Brothers, K. N. Kudin, V. N.
Staroverov, R. Kobayashi,J. Normand, K. Raghavachari, A. Rendell, J. C. Burant,S.
S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam,M. Klene, J. E. Knox, J. B.
Cross, V. Bakken, C. Adamo,J. Jaramillo, R. Gomperts, R. E. Stratmann, O.
Yazyev,A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski,R. L. Martin, K.
Morokuma, V. G. Zakrzewski, G. A. Voth,P. Salvador, J. J. Dannenberg, S. Dapprich,
A. D. Daniels,O. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox,
Gaussian 09, Revision C.01, Gaussian Inc.,Wallingford CT, 2010.
25 (a) R. G. Parr and R. G. P. W. Yang, Density-functional theory of atoms and
molecules, Oxford university press, 1989; (b) W. Koch, M. C. Holthausen and M. C.
Holthausen, A chemist's guide to density functional theory, Wiley-Vch Weinheim,
2001.
26 (a) C. Lee, W. Yang and R. Parr, Phys. Rev. B, 1988, 37, 785-789; b) A. D. Becke, J.
Chem. Phys., 1993, 98, 5648-5652.
27 M. Cossi, V. Barone, R. Cammi and J. Tomasi, Chem. Phys. Lett., 1996, 255, 327-
335.