Synthesis of hexahydroquinoline (HHQ) derivatives using ZrOCl2·8H2O as a potential green catalyst and optimization of reaction conditions using design of experiment (DOE)

Article abstract of DOI:10.1039/c5ra16102a

In this investigation, hexahydroquinoline (HHQ) derivatives were synthesized via a one-pot reaction using dimedone, β-ketoester, ammonium acetate, and different aryl aldehydes. ZrOCl₂·8H₂O was used as a potential green catalyst, it i

Full text of DOI:10.1039/c5ra16102a

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Synthesis of hexahydroquinoline (HHQ) derivatives using ZrOCl2.8H2O as a
potential green catalyst and optimization of reaction condition using design of
experiment (DOE)
Ardeshir Khazaeia,*, Negin Sarmastia, Jaber Yousefi Seyfb,*, Mahsa Tavasolia
aFaculty of Chemistry, BuꢀAli Sina University, Hamedan, 6517838683, Iran
bDepartment of Chemical Engineering, Tarbiat Modares University, P.O. Box 14115ꢀ143, Tehran, Iran
In this investigation, hexahydroquinoline (HHQ) derivatives were synthesized by oneꢀpot
reaction using dimedone, bꢀketoester, ammonium acetate, and with different aryl aldehyde.
ZrOCl2.8H2O was used as the potential green catalysts, commercially available solid material,
with low toxicity, low cost, ease of handling, and high activity. The reaction condition was
optimized using response surface method (Central Composite Design (CCD)) with three
replicates at a central point. Optimization showed that optimum temperature and catalyst amount
◦
◦
are 83.75 C and 0.15 mol%, respectively. Loss of reaction yield after 83.75 C is related to the
formation of a new crystalline phase of ZrOCl2.8H2O. The fitted quadratic polynomial model to
the experimental yield could well predict the experimental reaction yield. Ecofriendly reaction
condition, easy workup procedure, the reusability of the catalyst, short reaction times with
high yields are some advantages of this work.

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Introduction
Multicomponent reactions (MCRs) are oneꢀpot reactions which more than two starting material
reacts together, where most of the starting materials atoms present in the target molecule.1 MCRs
are atom economic, effective, convergent, and show a high bondꢀformingꢀindex (BFI) (several
nonꢀhydrogen atom bonds are formed in oneꢀpot reaction).2 So, MCRs are often more useful
than conventional sequential multistep synthesis.
One of the most important and conventional MCR is the dihydropyridine (DHP) synthesis which
is attributed to Arthur Hantzsch which discovered in 1881.3 Due to the versatility and the general
stability of the products, Hantzsch method has remained the most common method for the
synthesis of 1,4ꢀdihydropyridines. First, Dihydropyridines were discovered to be active part of
nicotinamide adenine dinucleotide (NADH), the essential reducing coenzyme in animals.
Finally, nifedipine (a DHP derivative) came to market as a calcium channel modulating agent.4
Although DHPs were primarily developed as cardiovascular agents, but they are vasodilator,
antihypertensive, bronchodilator, antiatherosclerotic, hepatoprotective, antitumor, antimutagenic,
geroprotective, and antidiabetic agents.5 Their widespread pharmacological properties have
interested the researchers to find new derivatives which are more effective, selective, stable, and
perhaps with different modes of action.6 Modification of DHP ring and its substitutes is a
combinatorial chemistry that makes it possible to prepare a large number of compounds which
can be analyzed by structure activity relationship to design better DHPs.7, 8 One of possible
structural scaffold modifications of DHP is incorporating fused ring to DHPs, that leads to
hexahydroquinoline (HHQ) derivatives, which are successfully explored by the Safak’s group.9

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HHQs clearly show the remarkable potential of novel dihydropyridine derivatives as sources of
valuable drug candidates. HHQs derivatives possess a variety of biological activities, such as
vasodilatory, bronchodilatory, antiatherosclerotic, antitumor, geroprotective, hepatoprotective,
and antidiabetic property.10, 11
Without using any catalyst, transformation of starting material to HHQs derivatives has long
reaction times, harsh reaction conditions, and large quantities of organic solvents and commonly
gives low yields. So, various catalysts such as Lewis acids,12, 13 bases,14, 15 salts,16 and ionic
liquids17, 18 have been used to solve mentioned problems. Although some of these are successful,
but most of them are expensive, toxic, and are difficult to be separated from the reaction
medium. Therefore, it is important to apply an effective catalyst that does not have the
above mentioned problems. So, we have reported a clean, ecofriendly, facile, and rapid
solventꢀfree reaction for the synthesis of HHQs derivatives in the presence of ZrOClꢀ
2.8H2O. This is a commercially available solid material, with low toxicities (LD50 ZrOCl2.8H2O
oral rate= 2950 mg/kg), low costs, ease of handling, high activity. The zirconium (IV)
compounds are ecofriendly and potential green catalysts or reagents which are used in many
organic reactions under mild condition with excellent yield.18, 19 It should be noted that, many of
the chemists optimize their reactions using one variable at a one time (OVAT). Optimization by
OVAT method is valid only when the variables have not cross interaction.20 In this study
optimization of the reaction condition was done by design of experiments.
Experimental
Materials

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All chemicals were purchased from Merck and Fluka Chemical Companies. The products were
identified by 1H,13C NMR, mass analysis and melting points as well as IR spectra. The
1
corresponding spectral data have been reported in the Experimental section. The H,13C NMR
(500 MHz) was recorded on a Bruker Avance DPXꢀ400 FTꢀNMR spectrometer (δ in
ppm). Mass spectra were recorded on a Shimadzu GC MSꢀQP 1000 EX 85 apparatus.
Melting points were recorded on a Büchi Bꢀ545 apparatus in open capillary tubes.
Infrared spectrum of products was recorded by Perkin Elmer PEꢀ1600ꢀFTIR. Progress of the
reactions was monitored by TLC using silica gel SIL G/UV 254 plates.
General procedure for Preparation of HHQs
ZrOCl2.8H2O (0.0451 g, 14 mol%) as a catalyst, was added to a mixture of dimedone (0.28 g,
2mmol), aryl aldehyde (2 mmol), betaꢀketoester (2 mmol) and ammonium acetate (0.185 g, 2.4
mmol) in a test tube, then the resulting mixture was firstly stirred magnetically, and after
solidification of the reaction mixture with a small rod, at 90◦C. After completion of the reaction,
as monitored by TLC, the reaction mixture was cooled to room temperature. Then, ethyl acetate
(25 mL) was added, stirred and refluxed for 3 min. The solid catalyst was collected by filter
paper and separated from the solution of product and remaining starting materials. The crude
product was purified by recrystallization from ethyl acetate as a less toxic Class III solvent.21 The
reaction is shown in the Fig. 1.

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O
Ar
O
O
Zr
O
Zr
O
O
O
Cl
O
Cl
Cl
Cl
N
H
O
O
O
O
Zr
Cl
Ar
H
Cl
Solvent-free
84
C
15% mol
Fig. 1 Preparation of hexahydroquinoline at optimum condition using ZrOCl2.8H2O as the clean and ecofriendly
catalyst.
Results and discussion
First, to find reaction condition for the synthesis of HHQs derivatives, reaction of aryl
aldehydes, dimedone (5,5ꢀdimethylcyclohexaneꢀ1,3ꢀdione), ethyl acetoacetate and ammonium
acetate was selected as a representative reaction. The reaction was carried out is various solvents
with ZrOCl2.8H2O as a catalyst to investigate the effect of solvent on the reaction time. In
addition, the reaction was carried out with catalyst in the solventꢀfree condition. From time and
yield point of view, the reaction in solventꢀfree condition is more efficient than in the presence of
solvents. The results are given in the Table 1.
Table 1 Time and yield of the model reaction with and without solvent
in the presence of ZrOCl2.8H2O as a catalyst.
Entry
Solvent
Time (min)
Yielda (%)
50 oC
1
ꢀꢀꢀ
5
96
2
3
4
5
6
7
EtOAc
CH2Cl2
H2O
nꢀHexane
Acetonitrile
EtOH
25
60
60
60
15
60
93
95
50
80
95
86
aIsolated yield.

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Therefore, the solventꢀfree method is more efficient (entry 1) and can be selected for the
representative reaction. In other hand, Lewis acids catalyst such as ZrOCl2.8H2O, ZrO2, and
FeCl3 were applied to investigate the effect of various catalyst on the reaction (Table 2). As it
given in Table 2, ZrOCl2.8H2O (10 mole %) as a catalyst, leads to higher yield and shorter
reaction time.
Table 2 Effect of different catalysts on the time and yield of the reaction.
Entry
Catalyst
Amount of catalyst (mol %)
Time (min) Yielda (%)
1
2
3
10
10
10
5
15
20
96
90
85
ZrOCl2.8H2O
ZrO2
FeCl3
aIsolated yield.
Statistical analysis and the model fitting
The Central Composite Design (CCD) as a response surface method, with three replicates at
central point was employed to fitting the experimental data to a polynomial model Two main
.
factors that can affect the yield of the reaction are temperature (X1) and amount of catalyst (X2).
These variables were coded to three levels of +1, 0, and 1. The levels of the variables and the
corresponding response values (reaction yield) are shown in Table 3.
Table 3 Levels of the experimental variables and the corresponding response values
of the CCD.
Independent variables
Dependent
variable
X1 (temperature)
Runs Coded levels Actual
X2 (amount of catalyst)
Coded
levels
Actual
levels
Yield
levels
1
2
3
4
5
6
7
8
9
0
+1
ꢀ1
0
75.00
100.00
50.00
75.00
75.00
50.00
50.00
100.00
100.00
0
0
ꢀ1
0
ꢀ1
+1
0
+1
ꢀ1
0.10
0.10
0.05
0.10
0.05
0.15
0.10
0.15
0.05
92.00
85.00
67.00
91.00
88.00
73.00
67.00
93.00
73.00
0
ꢀ1
ꢀ1
+1
+1

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10
11
0
0
75.00
75.00
0
+1
0.10
0.15
93.00
95.00
Table 4 Analysis of variance for the response
surface quadratic model for yield
Source
pꢀval. prob.>F
Model (yield)
0.0003
0.0004
0.0015
0.0223
<0.0001
0.9852
X1
X2
X1X2
2
X12
X2
Reaction yield was used as the dependent variables and to investigate the effect of variables on
the reaction yield, all of the runs (reactions) of Table 3 were stopped after 2 minutes. Analysis of
variance (ANOVA) shows that quadratic can well predict the experimental data (Table 4). The pꢀ
values show that the model is significant from a statistical point of view. The smaller the pꢀvalue,
the more significant the term. The coefficient of determination (R2) for yield is 0.9813 with the
derived model, which demonstrates that theoretical values are in good agreement with the
experimental data. Polynomial response surface models for time and yield based on significant
levels and actual values are resulted from experimental design:
2
1
2
2
Y Yield = ꢀ59.37+3.73X ꢀ102.10X +2.8X X ꢀ0.025X +10.53X
(1)
(
)
1
2
1 2
It can be seen from coefficient of equation (1) that X2 (amount of catalyst) has a greater impact
on the reaction yield than X1 (temperature) and there is a considerable interaction between X1
and X2. Generally, the terms that have minus and plus sign have negative and positive effect on
yield, respectively. The magnitude of the effect of X is related to the value of coefficients in Y.
Fig. 2 represents the contour and three dimensional of reaction yield versus temperature and

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amount of catalyst. As it is shown in Fig. 2, by increasing the amount of catalyst, the reaction
yield increases, but as temperature increase, a maximum point can be seen in the reaction yield.
This behavior can be related to the dehydration/decomposition of ZrOCl2.8H2O at temperature
◦
above 85 C. Using differential thermal analysis (DTA) and thermogravimetric analysis
(TGA),22ꢀ24 a broad endothermic feature is evident in the DSC curve for zirconyl chloride
octahydrate up to about 55 °C, which reflects the removal of weakly held water molecules
(lattice waters) from the crystal between 25 and 55°C. The integrity of the tetranuclear zirconyl
cations appears to be unaffected within this temperature range.25 Above 55 °C, a prominent
exothermic peak centered about 73°C and a minor exothermic maximum about 85°C has been
observed, which indicate an increase in the degree of structural ordering (crystallization). TG
data has been revealed the removal of the third lattice and one of the four coordinatively bound
water molecules, respectively, by 73 and 90°C. Thus, the removal of these two water molecules
results in the formation of a new crystalline phase. For the formation of the tetrahydrate a
reduction of the Zr coordination number from eight to seven has been proposed.26 Two wellꢀ
separated endothermic peaks has been observed above 110°C (125 and 175 °C), which indicate a
significant reduction in crystallinity of the compound (melting). Melting might be initiated by the
removal of chloride counterions above 100°C.24
Based on above discussion, yield reduction at temperatures above 85 °C can be related to the
removal of the third lattice and one of the four coordinatively bound water molecules, new
crystalline phase formation, and changes the Zr coordination number ion from eight to seven. It
can be deduced that tetranuclear zirconyl cations are the actual catalytic species. In other hand,
these finding is good agreement with our previous research that the maximum yield of the

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reaction in the presence of ZrOCl2.8H2O as a catalyst was obtained at 60 watt of microwave
power.27
To investigate the connectivity between the decomposition/dehydration of ZrOCl2.8H2O and
its catalytic activity, 0.075 gr of catalyst was heated for 30 minutes. The catalyst was weighed
before and after heating. Then the reaction was carried out in room temperature with the
decomposed/dehydrated catalyst. Infrared spectra, weight of the catalyst before and after the
heating, and reaction yield are provided in the Table 5.
Table 5 The effect of temperature on the dehydration/decomposition of the ZrOCl2.8H2O
Heating
Weight Weight Yield
temperature
Image
IR spectra
(before) (after)
(%)
(◦C)
50
0.075
0.075
0.075
0.075
0.075
0.075
0.075
0.0616
0.0556
0.0495
0.0407
0.0347
0.0341
0.0338
70
75
96
90
76
65
51
32
100
125
150
200
250

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Fig. 2 The contour and three dimensional of reaction yield versus temperature and amount of the catalyst
Optimization of reaction condition and validation of the model
Optimization of the equation (1) as the constrained problem showed that optimum reaction
conditions are X1=83.75 and X2=0.15. At these optimum conditions corresponding maximum
yield is 99.21%. The validity of the model for predicting reaction yield was tested using the
optimum condition. The predicted and experimental optimum responses are shown in Table 6.
Table 6. Predicted and experimental value of responses at the
optimum condition
Optimum
Optimum variables
Optimum response
Time (min) Yield (%)
X1
X2
Predicted
Exprimental
83.75
85.00
0.15
0.15
1
1
99.21
97.00
A mean value of 97.00% (N=3) and with deviation of 2.27% for yield was obtained from
experimental results deviation in that are in good agreement with predicted responses. This
shows that one can using equation (1) predict the experimental yield with an acceptable

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deviation. In order to investigate the effect of ZrOCl2 as a catalyst on the reaction yield, the
optimum condition was repeated without catalyst (X1=85.00 and X2=0.15). Result shows that the
presence of ZrOCl2 is a key factor to decrease reaction time to reach a specified yield (Table 7).
Table 7. Checking optimum condition without catalyst
Variables
response
X1
X2
Time (min)
Yield (%)
With catalyst
Without catalyst
85.00
85.00
0.14
0.14
<1
>25
96
94
Using Optimal condition
After optimization of the reaction conditions, the efficiency and applicability of the method were
studied by the reaction of dimedone, ethyl acetoacetate and ammonium acetate with different
aryl aldehyde derivatives in the presence of ZrOCl2.8H2O. The results are given in Table 8. As
Table 8 shows, hexahydroquinonine derivatives could be obtained in high to excellent yields
(75.41ꢀ95.82%) within short reaction times (40ꢀ180 Sec.). Benzaldehyde derivatives, including
electronꢀreleasing, electronꢀwithdrawing substituents or halogens on the 2’, 3’, 4’, 5’, and 6’
position and aromatic rings with heteroatoms were successfully tested in this reaction condition
(Table 8, compounds 1ꢀ15). Using optimum condition, less reaction time and almost equal
reaction yield can be obtained to the amounts reported in the literatures.28ꢀ37

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Table 8. Time, yield, and melting point of products using optimal condition.
A=time (Sec.), B=yield (%),C=melting point (◦C)
A
B
C
40
97
60
81
50
60
91
85
257ꢀ259 [33]
Cl
219ꢀ222 [35]
205ꢀ207 [28]
233ꢀ235 [29]
O
O
O
N
H
A
B
C
90
80
150
90
244ꢀ245 [33]
180
89
243ꢀ245 [35]
40
86
231ꢀ234 [36]
228ꢀ230 [32]
A
B
C
40
84
80
98
60
90
180
80
251ꢀ253 [37]
264ꢀ265 [35]
204ꢀ206 [34]
205ꢀ207 [31]
O
O
O
N
H
A
B
C
60
87
232ꢀ233 [28]
100
79
242ꢀ243 [30]
60
86
246ꢀ248 [33]
a Yield refers to isolated product.
Molar ratio: dimedone, ethyl acetoacetate, aldehyde, ammonium acetate (1:1:1:1.2)
Reaction condition: temperature (85 ◦C), catalyst (0.14 mole)
Proposed mechanism
A possible mechanism (Scheme 2) is given in the Fig. 3 which is supported by the literature.34
ZrOCl2 is a Lewis acid catalyst that catalyzes Knoevenagel type coupling of aldehydes with
active methylene compounds (direction 2 and 5) and Michael type addition reactions (direction 3

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and 7). To investigate the possible mechanism and the proper role of ZrOCl2, Infrared (IR)
technique was used. After 20 seconds at the optimum reaction condition, two intermediate were
detected and separated by the plate. The possible structure of these intermediate were identified
and characterized by FTꢀIR. Details of collected data were summarized in supporting
information.
O
Ar
NH4OAC
O
Cl
Zr
H
O
Cl
NH3
HOAC
Ar
O
O
O
1
5
O
O
NH2
ZrOCl2.8H2O
4
2
O
O
Ar
O
O
2
3
O
Ar O
Path 1
Path 2
NH2
O
N
H
Ar
O
O
2
O
H
7
O
8 H2N
.
2
l
C
O
8
ZrOCl2.8H2O
O
O
r
Z
Ar
O
O
H N
2
O
2
6
O
HOAC
NH3
Zr
Cl
O
O
Cl
H
O
O
Ar
NH4OAC
Fig. 3 The possible mechanism for the synthesis of hexahydroquinolines derivatives catalyzed by ZrOCl2
Regeneration of the catalyst
ZrOCl2.8H2O catalyst is a yellowish solid. First, 0.15 mole of ZrOCl2.8H2O were added to the
◦
reaction mixture at optimum reaction temperature (85 C), after the reaction was complete (40
◦
seconds), 25 ml ethyl acetate was added to the reaction mixture at 50 C and was mixed for 5

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minutes. All of the unreacted reagents and product were extracted to ethyl acetate, but
ZrOCl2.8H2O remained unsolved. After the filtration and drying, the ZrOCl2.8H2O was
regenerated to use in the next reaction cycle. Decrease in the reaction yield to the number of
reaction cycles is shown in Fig 4.
Reaction Temperature=358.15 K
100
yield (%)
90
80
70
60
50
40
30
20
10
0
time (sec)
1
2
3
4
Number of cycles
Fig. 4 Decrease in the reaction yield to the number of reaction cycles (at optimized reaction
condition)
Conclusion
In conclusion, we have introduced ZrOCl2.8H2O as an efficient, cheap and recyclable catalyst
under solventꢀfree condition for the oneꢀpot multiꢀcomponent reaction to synthesis of
hexahydroquinoline derivatives. Optimization of the reaction condition was studied by the
central composite design (CCD). It was shown that by increasing the amount of catalyst, the
reaction yield increases, but as temperature increase, a maximum point can be seen in the
reaction yield. This behavior can be related to the dehydration/decomposition of ZrOCl2.8H2O at
temperature above 85 ◦C. The quadratic model was best fitted (coefficient of
determination=0.90) to the experimental data. Predicting response values using the obtained

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model were in a good agreement with the experimental results. The promising points for
the presented protocol were efficiency, high yields, short reaction times, cleaner reaction
profile and simplicity.
Acknowledgement
The authors gratefully acknowledge partial support of this work by the Research Affairs Office
of BuꢀAli Sina University (Grant number 32ꢀ1716 entitled development of chemical methods,
reagents and molecules), Center of Excellence in Development of Chemical Method (CEDCM),
Hamedan, I. R. Iran.
Supporting Information
Supplementary data associated with this article can be found, in the online version, at
**********.
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DOI: 10.1039/C5RA16102A
O
Ar
O
O
Zr
O
Zr
O
O
O
Cl
Cl
O
Cl
Cl
N
H
O
O
O
O
Zr
Cl
H
Ar
Cl
Solvent-free
84 C
15% mol