SECTION – IV USE OF ZWITTERIONIC-TYPE MOLTEN SALT FOR THE SYNTHESIS OF N-SUBSTITUTED DECAHYDROACRIDINE-1, 8-DIONES IN WATER- METHANOL
SECTION – IV
USE OF ZWITTERIONIC-TYPE MOLTEN SALT FOR THE SYNTHESIS
OF N-SUBSTITUTED DECAHYDROACRIDINE-1, 8-DIONES IN WATER-
METHANOL
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
I.4.1 INTRODUCTION
Acridine (C13H9N) is a nitrogen containing heterocycle, which is structurally related to
anthracene with one of the central CH groups replaced by nitrogen.
N
Fig 1
Acridine systems have attracted considerable attention due to their potential
pharmacological activity. Industrial applications for acridine and its derivatives are well known
since the 19th century when they were first used as pigments and dyes.1-3 During the early 20th
century their pharmacological properties were evaluated. At this time, proflavin was used as a
topical antibacterial and antifungal agent.4 From 1940’s till date, the acridines (eg., quinacrine,
pyronaridine and acranil) have been used as anti-malarial drugs.5 The first acridine-based
therapeutic agents specifically designed for cancer treatment were developed during the 1970’s.
These efforts led to the development of m-amsacrine, a 9-anilinoacridine introduced into clinical
use in 1976.6 Accordingly, this acridine has been clinically utilized as a single agent or in
combination with other anti-neoplastic drugs in the treatment of acute nonlymphocytic,
lymphocytic,7, 8 and acute myeloid9,10 leukemias.
Acridine and its hydro derivatives have high and more biological activities like anti-
malerial,11,12 antitumor,13 anti-cancer,14 antileishmanial activities,15 DNA-binding and DNA
photo damaging ability,16 antimicrobial activity,17,18 potassium channel blockers.19 The antitumor
and anti infectious activities of acridines are mainly related to their capacity to reversibly bind
with DNA.20 Due to their planar polycyclic structure, they have been shown to intercalate
between DNA double-strands, to interfere with DNA regulatory enzymes such as topoisomerase
I and II and to disrupt DNA functions in cells.21 Some acridine derivatives with their biological
activities are shown in Fig 2.
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
N
NO2NH
(H3C)N
NCl
O
HN
NHHN
Mepacrine
Amtimalarial drug
Nitracrine
Antitumor
Fig 2
General synthetic strategies for the synthesis of acridine include Bernthsen’s method,
Pfitzinger’s method, Friedlander’s method, Ullman’s method and Goldberg’s method. The above
mentioned strategies have been modified by different researchers to obtain diversely
functionalized acridines.
N-substituted decahydroacridine-1, 8-diones are polyfunctionalized 1,4-dihydropyridine
(DHP) type derivatives. The chemical modifications on the DHP ring, such as different
substituents22 or heteroatoms,23 have allowed the study of the extended structure and activity
relationship and also provided some insight into the molecular interactions at the receptor level.
Therefore, N-substituted decahydroacridine-1,8-diones are increasingly receiving attention due to
their resemblance in properties with those of 1,4-dihydropyridines. As a consequence, the
synthesis of these privileged heterocyclic compounds has gained special attention.
I.4.2 SYNTHESIS OF N-SUBSTITUTED DECAHYDROACRIDINE-1, 8-DIONES: A
BRIEF REVIEW
Efforts have been directed to develop different synthetic strategies for this privileged
structure of N-substituted decahydroacridine-1, 8-diones and a short review of these work are
summarized here before going to our attempt.
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
Margarita Suarez et al24 synthesized N-substituted decahydroacridine-1,8-diones by
reaction of aromatic aldehyde, dimedone and ammonium acetate using two types of alumina
(neutral or basic) as mineral solid supports, DMF as energy transfer medium under microwave
irradiation. They synthesized only five products and the yields were very poor (scheme 1).
NH
O O
O
O CHO
+ +DMF, MW
Alumina
NH4OAc
Scheme 1
2
In 2002, Shu-Jiang Tu and his coworkers25 reported another method for the synthesis of
N-substituted decahydroacridine-1,8-diones under microwave irradiation without solid supports
and energy transfer medium with comparatively higher yields. They used ammonium
bicarbonate instead of ammonium acetate (scheme 2).
NH
O O
O
O CHO
+ + NH4CO3
MW
Scheme 2
2
The results are listed in Table 1.
Entry Ar Time (min) Yield (%)
1
2
3
4
5
6
7
8
C6H5
2 Cl-C6H4
4 Cl-C6H4
4- (CH3)NC6H4
3- O2NC6H4
3,4- (OCH3)C6H3
3,4- (OCH2O)C6H3
4- CH3OC6H5
5
4
4
7
4
6
6
7
90
85
92
91
83
89
91
89
Table 1. synthesis of N-substituted decahydroacridine-1, 8-diones
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
Tong-Shou Jin and his co-workers26 reported a synthesis of N-substituted
decahydroacridine-1, 8-diones by one pot four component reaction of aromatic aldehyde, 5,5-
dimethyl-1,3-cyclohexanedione and p-toluidine in water under refluxing conditions. They used
p-dodecylbenezenesulfonic acid (DBSA) as a Bronsted acid-surfactant-combined catalyst
(scheme 3).
N
O O
O
O NH2 CHODBSA
+ + Wate, Reflux2
Scheme 3
They examined various types of catalyst for the reaction and concluded that DBSA was
the good catalyst even better than surfactant- type Lewis acid, Sc(DS)3 (entry 4). While TsOH
(entry 1), which has a shorter alkyl chain than DBSA does, gives only a little amount of the
product. This result indicates that the long alkyl chain of DBSA is indispensable for efficient
catalysis probably due to the formation of hydrophobic colloidal particles in water. A carboxyl
acid having a long alkyl chain, lauric acid, was much less effective (entry 6) than DBSA,
suggesting that the strong acidity of DBSA is essential for the catalysis. Effects of various
catalysts in water are given in Table 2.
Entry Catalyst(mol%) Time(h) Yield(%)
1
2
3
4
5
6
6
6
6
6
6
6
13.2
67.8
76.8
78.3
87
26.8
TsOH (10)
DBSO (10)+TsOH (10)
DBSO (30) + TsOH (10)
Sc(DS)3 (10)
DBSA (10)
C11H23COOH
Table 2. The reaction in the presence of various catalysts in water
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
The brief results are shown in Table 3.
Entry Ar Product Yield (%)
Table 3. synthesis of N-substituted decahydroacridine-1, 8-diones
1
2
3
4
5
C6H5 4a
4b
4g
4h
4i
78.9
87
90.2
89.3
90.3
4-ClC6H4
4-OHC6H4
4-OCH3C6H4
4-CH3C6H4
In 2006, Biswanath Das et al27 presented a novel and efficient method for the synthesis of
1,8-dioxo-decahydroacridines in high yields employing Amberlyst-15 as a heterogeneous solid
acid in CH3CN as solvent under reflux conditions. They recovered the catalyst and reused for
three consecutive times with a minimum variation of the yields of the products (scheme 4).
N
O O
O
O NH2 CHOAmberlyst-15
+ +CH3CN, Reflux
Scheme 4
2
Jianji Wang and his group28 developed an environmental friendly methodology for one-
pot reaction of aldehyde, 5,5-dimethyl- 1,3-cyclohexandione and ammonium bicarbonate for the
preparation of acridine-1,8-dione promoted by a catalytic amount of cerium(III) chloride
heptahydrate (CeCl3·7H2O) by using the ionic liquid, 1-butyl-3-methyl-imidazolium
tetrafluoroborate ([bmim][BF4]) as solvent at 55 oC (scheme 5).
NH
O O
O
OCHO
+ + NH4HCO3
CeCl3. 7H2O
[bmim][BF4]
Scheme 5
2
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
They investigated the reaction by using some traditional organic solvents, such as
anhydrous ethanol, THF, CH2Cl2, and CH3CN and showed that through similar operational
procedure under similar reaction conditions, reactions carried out in these organic solvents only
gave the corresponding product in rather disappointingly low yields compared with the case
when [bmim][BF4] was used.
In 2008, Xiang-Shan Wang et al29 synthesized a series of 3,3,6,6-tetramethyl-9,10-
diaryl-1,2,3,4,5,6,7,8,9,10-decahydroacridine-1,8-diones 3,3,6,6-tetramethyl-9-aryl
1,2,3,4,5,6,7,8,9,10-decahydroacridine- 1,8-diones by three component reaction of aldehydes,
5,5-dimethyl-1,3-cyclohexanedione and aromatic amines or ammonium acetate in [bmim]Br at
90 oC (scheme 6).
NH
Ar1
O OO
O
+ 2[bmim][Br]
Ar2NH2
NH4OAc
Ar1CHO
N
Ar1
O O
Ar2
90oC
Scheme 6
Synthesis of 1,8-dioxodecahydroacridines have been developed by Srivari Chandrasekhar
et al30 in 2008. The synthesis proceeds via a three-component reaction of a mixture 1,3-dione, an
aldehyde and an amine under solvent-free conditions catalyzed by tris(pentafluorophenyl) borane
[B(C6F5)3] (scheme 7).
N
R1
O O
R2
O
O
+ +R1CHO R
2NH2
B(C6F5)3, (3 mol%)
neat, R.T.
Scheme 7
2
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
They have carried out the reaction by using other common Lewis acids, such as
BF3·OEt2, AlCl3 and ZnCl2. Among the tested catalysts, B(C6F5)3 was found to be mildest and
most effective in terms of yield (90%).
Entry Acid catalyst (3 mol%) Time (h) Yield (%)
1
2
3
4
BF3. OEt
AlCl3
ZnCl2
B(C6F5)3
2
3
2
1.5
58
63
78
90
Table 4. Reaction of 1,3-Cyclohexanedione with Benzaldehyde and Aniline
in the Presence of Different Lewis Acid Catalysts
In 2009, K. Venkatesan et al31 have developed a simple but very effective protocol for
the one pot synthesis of 1,8-dioxo-decahydroacridine derivatives using L-proline as catalyst.
They have suggested that 10 mol% L-proline in refluxing ethanol (65 oC) is sufficient to get
excellent yield. A wide range of structurally diverse aldehydes underwent the reaction to give the
acridine derivatives (scheme 8).
N
O O
O
ONH2
CHO
Proline+ +
R2
R1
R2
R1
R2
R1
R3
R4
65oC, 5-6 h
aq. Ethanol
R4
R3
Scheme 8
2
In the same year, Balalaie Saeed et al32 introduced a procedure for the synthesis of 1,8-
dioxo-decahydroacridine derivatives in aqueous media via a one-pot three component reaction of
dimedone, aromatic aldehydes, ammonium acetate in the presence of ammonium chloride or
Zn(OAc)2•2H2O or L-proline (scheme 9).
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
NH
O O
O
O
+ +H2O, Reflux
A
NH4OAcArCHO
A: NH4Cl, Zn(OAC)2, L- Proline
Ar
2
Scheme 9
The results have been described in Table 5.
Product Ar
Yield (%)
4a
4b
4c
4d
4e
4f
4g
4Br-C6H4
4Cl-C6H4
4- MeCONH-C6H4
3- O2N-C6H4
4-NO2-C6H4
4-CF3-C6H4
86
93
87
95
94
93
96
L- proline Zn(OAC)2NH4Cl
4CN-C6H4
82 84
88 91
84 86
97 94
96 93
89 90
96 93
Table 5. Synthesis of 1,8-dioxo-decahydroacridine derivatives in the presence of
ammonium chloride or Zn(OAc)2• 2H2O or L-proline in water at reflux condition.
Da-Qing Shi et al33 developed a one-pot three-component reaction of aromatic aldehydes,
aromatic amines, and 5,5-dimethyl-1,3-cyclohexanedione using sodium 1-dodecanesulfonate
(SDS) as the catalyst in aqueous media to give 1,8-dioxo-decahydroacridine derivatives. The key
intermediates along with the acridine derivatives were obtained under the present reaction
conditions (scheme 10).
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
N
R1
O O
R2
O
O
+ +R1CHO R
2NH2
H2O, SDS
90oC, 6-18h
R1
O O
OHNHR
2
+
Scheme 10
2
Later on, Wei Shen, Li-Min Wang and his co-workers34 prepared Brønsted acidic
imidazolium salts containing perfluoroalkyl tails and served as effective catalyst for three-
component one-pot synthesis of 1,8-dioxo-9,10-diaryldecahydroacridines in water in good to
excellent yields (scheme 11).
N
O O
O
ONH2
CHO
Catalyst+ +
H2O, Reflux
2
R1
R2
NN
NNH
+
+SO3HC8F17
SO3H
C8F17
SO3-
2
Catalyst:
Scheme 11
The effect of electron and the nature of substituents on the ring of both aromatic
aldehydes and amine did not show expected strong effects in terms of yields under these reaction
conditions. A brief result has been displayed in Table 6.
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
Entry R1
R2
Product Yield (%)
1
2
3
4
5
6
H
4- CH3
4- OCH3
4- Cl
3- NO2
3,4- Cl2
4- CH3
4- CH3
4- CH3
4- CH3
4- CH3
4- CH3
4a
4b
4c
4d
4e
4f
86
87
84
86
91
81
Table 6. Synthesis of different 1,8-dioxo-9,10-diaryl-decahydroacridines
in the presence of catalyst in water.
Although the methodology is quite good enough but the preparation procedure of the
catalyst is difficult and the reaction occurs at reflux condition and the perfluoroalkyl compounds
are quite expensive.
Khodabakhsh Niknam et al35 introduced silica bonded N-propyl sulfamic acid (SBNPSA)
as a solid acid catalyst for the synthesis of 1,8-dioxo-decahydroacridines in short reaction times
in ethanol under reflux conditions. A number of commercially available aromatic aldehydes have
condensed with dimedone and aryl amines under reflux conditions (scheme 12).
N
O O
O
O
+ +Ethanol, Reflux
SBNPSA
2 Ar1NH2ArCHO
Ar
Ar1
Scheme 12
Mazaahir Kidwai and Divya Bhatnagar36 used polyethylene glycol (PEG) as an
inexpensive, non-toxic and effective medium for the one pot synthesis of N-substituted
decahydroacridine-1,8-diones in the presence of ceric ammonium nitrate (CAN) as the catalyst.
The solvent system can be recovered and reused. They investigated the best reaction conditions
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
by using different amounts of CAN at different temperatures as shown in Table 7 and concluded
that 5 mol% catalysts at 50oC was the optimized conditions (scheme 13).
N
O O
O
ONH2
CHO
PEG 400+ +
R2
R1
R2
R1
R2
R1
R3
R4
CAN (5mol%)
50oC, 4h
R4
R3
Scheme 13
2
Catalytic activity evaluation Effect of temperatures
Entry CAN(mol%) Time(h) Yield(%) Entry Temperature(oC) Time(h) Yield(%)
1
2
3
4
1
2
3
4
0
2
5
10
8
6
4
3
83
94
98
67
25
50
65
80
6
4
3.5
3
98
98
93
78
Table 7. catalytic activity evaluation and effect of temperature for the synthesis of Nsubstituted
decahydroacridine-1,8-diones
Antar A. Abdelhamid and his group37 in 2011 reported a synthesis of acridinedione
derivatives under microwave irradiation of an ethanolic solution of a mixture of dimedone,
appropriate aromatic aldehydes and amino alcohols in a stoichiometric ratio 2:1:1, respectively,
for 10 min followed by evaporation of the solvent under vacuum afforded the formation of the
desired product as solid (scheme 14).
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
N
O O
O
O CHO
+ +
R1
R2
NH2
HO
R
MW
R= H, CH3R
1= OH, R
2= H
R1= OH, R
2= Br
3a; R= H, R1= OH, R
2= H
3b; R= H, R1= OH, R
2= Br
3c; R= CH3, R1= OH, R
2= H
Scheme 14
OH
R
2
In 2012, Ghodsi Mohammadi Ziarani et al 38 have developed a method using sulfonic
acid functionalized silica as an efficient solid acid catalyst in the synthesis of 1,8-dioxo-
decahydroacridines from aromatic aldehydes, an amine and a dimedone under solvent free
conditions (scheme 15).
N
O O
RO
O CHO
+ +Xsolvent free
X
RNH2 or NH4OAC
R= H or R
SiO2-Pr-SO3H
Scheme 15
2
In the same year, K. R. Moghadam and his coworkers39 prepared a homogeneous ionic
liquid of 0.5 mol% Mg(BF4)2 doped in [BMIm]BF4 from a mixture of MgCl2 and [BMIm]Cl and
employed in development of a method for the synthesis of 1,8-dioxo-decahydroacridines
(scheme 16).
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
NH
O O
O
O
+ +
80°C
NH4OAcArCHO
Ar[BMIm][BF4]- Mg(BF4)2
Scheme 16
2
They have showed that in the absence of the ionic liquid, the yields of reactions were
traced even at 80oC and longer reaction time. The reaction was carried out at variable
temperatures and alternatively in closely related ionic liquids and the best result was obtained
with 1 mL of [BMIm][BF4]–0.5 mol% Mg(BF4)2 at 80 oC. The results of temperature variation
are summarized in Table 8.
Entry Ionic liquid Temperature(oC) Time Yield(%)
1
2
3
4
5
6
7
8
9
10
11
12
[Bmim][BF4]–0.5 mol% Mg(BF4)2
[Bmim][BF4]–0.5 mol% Mg(BF4)2
[Bmim][BF4]–0.5 mol% Mg(BF4)2
[Bmim][BF4]–0.5 mol% Mg(BF4)2
[Bmim][BF4]–0.5 mol% Mg(BF4)2
[Bmim][BF4]–0.5 mol% Mg(BF4)2
[Bmim][BF4]–0.5 mol% Mg(BF4)2
[Bmim][BF4]–0.5 mol% Mg(BF4)2
[Bmim][BF4]
[Bmim][Cl]
[Bmim][BF4]–0.5 mol% MgCl2
Neat
20
30
40
50
60
70
80
90
80
80
80
80
12 h
10 h
7 h
3 h
1.5 h
40 min
15 min
15 min
12 h
12 h
4 h
12 h
Trace
15
25
42
68
80
87
67
-
-
51
45
Table 8. optimization of reaction conditions for the model reactants, 5,5-dimethyl-
1,3-cyclohexanedione and 4-chlorobenzaldehyde
Sheshanath V. Bhosale and his group40 developed an environmental friendly protocol for
the synthesis of 1,8-dioxodecahydroacridines via cyclocondensation of aldehyde, amine and
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
cyclic diketone in the presence of MoO3/SiO2 as recyclable solid acid catalyst in THF as solvent
at reflux temperature (scheme 17).
N
O ONH2 CHO
+ +THF, Reflux
MoO3 /SiO2
Scheme 17
2
O
O
They explored the use of variety of solvents to optimize the present reaction conditions
and found that THF is the best solvent in terms of product yield as well as reaction time as
compare to other polar and non polar solvents. The results are summarized in Table 9.
Entry Solvent Time (h) Yield (%)
1
2
3
4
5
Ethanol
DMF
Toluene
THF
Acetonitrile
6
5
6
4
5
60
75
79
92
84
Table 9. Solvent Screening for the Synthesis of N-substituted
decahydroacridine-1,8-diones by Using MoO3/SiO2
Mei Hong and Guomin Xiao41 reported an efficient, eco-friendly and simple procedure
for the synthesis of 1,8-dioxo-decahydroacridines through one-pot condensation reaction of
aromatic aldehyde, 5,5-dimethyl- 1,3-cyclohexanedion and different aromatic amine or
ammonium acetate in the presence of a catalytic amount of FSG supported Hf(NPf2)4 as a stable
and recyclable catalyst under water–ethanol (1:1, v/v) at reflux. This protocol was found to be
applicable to obtain a diverse range of 1,8-dioxo-9-aryl-decahydroacridine derivatives in 49–
83% isolated yields and the catalyst was recycled for three cycles (scheme 18).
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
N
O O
R3
OCHO
+ +R1
C2H5OH- H2O, Reflux
R1
R2NH2 or NH4OAC
R3= H or R
2
(FSG-Hf(NPf2)4)
Scheme 18
2O
Very recently, J. S. Ghomi et al 42
established an efficient and novel methodology for the
synthesis of 1,8-dioxo-decahydroacridines via one-pot MCRs of aldehydes, dimedone and
aromatic by using nano-Fe3O4.. The reaction was carried out under solvent free conditions at 120
oC (scheme 19).
N
O O
O
O
+ +Solvent- free, 120
oC
Ar1NH2ArCHO
Ar
Ar1
nano-Fe3O4
Scheme 19
2
They have studied the reaction by using several nanoparticles including Mn3O4, CuO,
CaO, MgO and Fe3O4 under various reaction conditions. The optimized conditions were obtained
when the reaction was carried out in the presence of 10 mol% nano-Fe3O4 under solvent-free
conditions at 120 oC as shown in table (Table 10, entry 8).
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
Entry Catalyst Catalyst(mol %) Solvent Time (min) Yield(%)
1
2
3
4
5
6
7
8
9
10
11
Mn3O4
CuO
CaO
MgO
Fe3O4
Fe3O4
Fe3O4
Fe3O4
Fe3O4
Fe3O4
Fe3O4
20
20
20
20
20
20
20
20
15
10
5
EtOH
EtOH
EtOH
EtOH
EtOH
DMF
Toluene
Solvent- free
Solvent- free
Solvent- free
Solvent- free
120
150
200
180
60
140
300
25
25
25
35
55
45
30
40
75
45
25
85
85
85
80
Table 10. Optimization of model reaction by using various catalysts, solvents and
amount of magnetic nanoparticles.
The brief results are summarized in Table 11.
Entry Ar Ar1 Time (min) Yield(%) m.p (
oC)
1
2
3
4
5
6
7
8
9
Ph Ph
o-MeC6H4 Ph
p-MeC6H4 Ph
m-NO2C6H4 Ph
p-NO2C6H4 Ph
p-BrC6H4 Ph
p-NO2C6H4 p-MeC6H4
Ph p-OMeC6H4
p-CNC6H4 p-OMeC6H4 15 90 233–235
18 88 215–216
10 90 272-274
20 90
25 85 254–255
40 75 225–227
35 80 260–262
20 88 298–299
15 90 288–290
254–256
Table 11. One-pot synthesis of 1,8-dioxo-decahydroacridines catalyzed by nano-Fe3O4.
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
I.4.3 CONCLUSION
From the above discussion, it is cleared that the synthesis of 1,8-dioxo-
decahydroacridines derivatives have attracted considerable interest among the synthetic organic
chemist even in recent year. Although, a variety of procedures have been developed for synthesis
of 1,8-dioxo-decahydroacridines synthesis, many of these methodologies suffer from one or
more disadvantages such as the use of expensive reagents, which are difficult to recover and
recycle, longer reaction times, high temperature, tedious separation procedures and use of
organic solvents which are a threat to the environment due to their pyrophoric nature, volatility,
and poor recovery. Ionic liquids which have been used for the synthesis of such compounds
require tedious preparation procedure and their environmental impact is still in debate. Thus,
there is a need for an improved procedure.
I.4.4 PRESENT WORK
In continuation of our effort to walk around for better methodologies in organic
synthesis43
, we have improved the methodology for synthesis of 1,8-dioxo-decahydroacridines
derivatives. We have developed a mild, efficient and room-temperature protocol for one-pot
synthesis of N-substituted decahydroacridine-1,8-diones derivatives by the multi-component
reaction of dimedone, amine and aldehyde (scheme 20). We have used Zwitterionic-Type
Molten Salt- 4-(1-imidazolium) butane sulfonate as an excellent catalyst as makes the processes
clean, safe, eco-friendly and inexpensive.
N
O O
O
O NH2 CHO
Zwitterionic salt : HN NSO3
Zwitterionic salt (10 mol%)
+ +Water-Methanol, RT
Scheme 20
2
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
To optimize the reaction conditions, the reaction of benzaldehyde, dimedone and aniline
was selected as a model to examine the effects of the catalyst (0-15 %) in presence of different
solvents at room temperature. The best result was achieved by carrying out the reaction with
1:2:1 mole ratios of benzaldehyde, dimedone and aniline in presence of 10 mol% zwitterionic
salt at room-temperature for 20 min (Table 1). We have examined the effect of mixture of
methanol and water (1:1). The reaction in presence of only water or methanol decreases the yield
considerably (15-20 %). Higher amount of the catalyst or higher temperature did not improve the
results to a great extent.
Entry Catalyst (mol%) Temperature ( 0
C) Time (min) Yield (%)
1 R. T. 20
2 5 20 72
3 20
4 15 20 95
5 20 20 96
6 15 80 20 97
10 100 20 967
10
-
96
Table 12. optimization of catalyst loading and temperature
<10
Solvent
Water- Methanol(1:1)
Water- Methanol(1:1)
Water- Methanol(1:1)
Water- Methanol(1:1)
Water- Methanol(1:1)
Water- Methanol(1:1)
Water- Methanol(1:1)
8 10 Water 20 65
9 10 Methanol 20 70
R. T.
R. T.
R. T.
R. T.
R. T.
R. T.
In a general experimental procedure, a mixture of aldehyde (1 mmol), dimedone (2
mmol) and aniline (1 mmol) was taken in a round bottom flask with 3 ml of water-methanol
(1:1) in presence of 10 mol% molten salt. The reaction mixture was stirred at room-temperature
for a certain period of time as required to complete (TLC). After completion, the solid residue
was isolated through filtration and it was recrystallized from ethanol to obtain the pure product
as solid. In general reactions are very clean and no isolable side products were found. A wide
range of structurally diverse aromatic aldehydes and amines underwent condensation by this
procedure to provide substituted acridine derivatives in good yields. The results are summarized
in Table 13.
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
Entry Dicarbonyl Aldehyde Amine Time (min) Yield (%)a
2
O
O
CHO
OCH3
NH2
40 90
3
O
O
CHO
Br
NH2
30 89
4
O
O
CHO
NO2
NH2
20 95
5
O
O
CHO
Cl
NH2
CH3
30 92
6
O
O
CHO
OCH3
NH2
CH3
30 88
7
O
O
CHO
OH
NH2
CH3
45 87
8
O
O
94
Table 13: Preparation of N-substituted decahydroacridine-1,8-diones in Water-Methanol
Ref
36
42
36
34
34
27
NH2
CH3
CHO
NO2
20 27
9
O
O
CHO NH2
CH3
15 95
10
O
O
CHO
OO
NH2
CH3
40 89
34
_
1
O
O
CHO
30 95 36
a : isolated yield
NH2
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
Entry dicarbonyl aldehyde amine Time (min) Yield(%)a
12
O
O
CHO
OCH3
NH2
NO2
40 86
13
O
O
CHO
OCH3
NH2
Cl
60 80
27
29
Table 13 : Contd....
14
O
O
CHO NH2
20 96
15
O
O
CHO
OCH3
NH2
25 96
16
O
O
CHO
Cl
NH2
20 95
17
O
O
CHO
NO2
NH2
15 94
36
36
36
36
O
O
CHO
OCH3
CH2NH2
20 95 2711
Ref
a: isolated yield
As evident from the results, this procedure is uniformly effective for both aniline and
benzyl amine. The aliphatic aldehydes such as iso-butyraldehyde, and
cyclohexanecarboxaldehyde were subjected under the reaction conditions but no desired
products were isolated. Aromatic aldehydes with both activating and deactivating groups such as
OMe (entry 2, 6, 11, 12, 13, 15), Cl (entry 3, 5, 16), OH (entry 7) and NO2 (entry 4, 8, 17)
reacted to afford the corresponding products. The scope of the reaction was examined to explore
the reactivity of simple cyclohexane 1,3-dione (Entry 14-17) with different aldehyde and
aniline under the similar reaction conditions.
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
A mechanistic rationale portraying the probable sequence of events is given in Fig 3.
O
O
O
O
OO
O O
NH2
O O
ON
O O
OHN
N
O O
HON
O O
H
O
HN NS
H OO
O
O OH
Molten Salt
Fig 3
I.4.5 CONCLUSION
In conclusion, We have demonstrated herein that imidazole-based zwitterionic-type
molten salt is an excellent catalyst for the synthesis of N-substituted decahydroacridine-1,8-
diones through a multicomponent condensation reaction of dimedone, aromatic aldehydes and
amines under water- methanol at room temperature. To the best of knowledge, this is the first
report on the synthesis of N-substituted decahydroacridine-1,8-diones by zwitterionic-type
molten salt. The non-hazardous experimental conditions, high yields, easy work-up, non
chromatographic purification procedure, inexpensive reagents, use of metal-free catalyst and
environmentally friendly nature are the notable advantages of this procedure. Thus, it provides a
better and more practical alternative to the existing methodologies.
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
I.4.6 EXPERIMENTAL
General: 1H and
13C NMR spectra were recorded using CDCl3 solution at ambient
temperature on a spectrometer operating at 300, 400 MHz for 1H and 75, 100 MHz for
13C NMR
spectra recorded on a Chemical shift were recorded as δ values in parts per million (ppm), and
were indirectly referenced to trimethylsilane (TMS) via the solvent signal. Coupling constant are
given in Hz. IR spectra were recorded on a FT-IR spectrometer. IR spectra of solid products
were recorded in KBr and thin plates for liquid products. Melting points were determined on a
glass disk with an electrical bath and are uncorrected. TLC was done on silica gel coated glass
slide (Merck, Silica gel G for TLC). Silica gel (60-120 mesh, SRL, India) and Petroleum ether
(60-80 0C) was used for column chromatography. All solvents were dried and distilled before
use. Commercially available substrates were freshly distilled before the reaction. Solvents,
reagents and chemicals were purchased from Aldrich, Fluka, Merck, SRL, Spectrochem and
Process Chemicals. The synthesis of zwitterionic-type molten salt, 4-(1-imidazolium) butane
sulfonate (IBS) was carried out using a method similar to that reported.43
General procedure for the synthesis of N-substituted decahydroacridine-1,8-diones:
A mixture of aldehyde, dimedone and amine was taken in a round bottom flask with 3 ml
of water-methanol (1:1) in presence of 10 mol% molten salt. The reaction mixture was stirred at
room-temperature for appropriate time. After completion, the solid residue was isolated through
filtration and it was recrystallized from ethanol to obtain the pure product as solid.
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
Melting point and Spectral data of N-substituted decahydroacridine-1,8-diones presented
in order of their entries in table 13.
3,3,6,6-Tetramethyl-9,10-diphenyl-3,4,6,7,9,10-hexahydro-2H,5H-acridine-1,8-dione (entry
1)36
:
N
O O
White solid; m.p. 256–258 oC;
IR (KBr): 1234, 1361, 1454, 1662, 2963 cm-1
;
1H NMR (200 MHz, CDCl3): δ 0.82 (s, 6H), 0.97 (s, 6H), 1.79 (d, J = 16.0 Hz, 2H), 2.03 (d, J =
16.0 Hz, 2H), 2.10 (q, J = 14.0 Hz, 4H), 5.22 (s, 1H), 7.07 (dt, J = 8.0, 2.0 Hz, 1H), 7.20-
7.28(m, 2H), 7.39 (dd, J = 8.0, 2.0 Hz, 2H), 7.60–7.48-7.61 (m, 3H).
9-(4-Methoxy-phenyl)-3,3,6,6-tetramethyl-10-phenyl-3,4,6,7,9,10-hexahydro-2H,5H-
acridine-1,8-dione (entry 2)36
:
N
O O
OCH3
Light yellow solid; m.p. 223–225 °C;
IR (KBr): 1227, 1366, 1572, 1644, 2875, 2952 cm-1
;
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
1H NMR (400 MHz, CDCl3): δ 0.63 (s, 6H), 0.76 (s, 6H), 1.62-1.66 (m, 2H), 1.88-2.00 (m, 6H),
3.57 (s, 3H), 5.06 (s, 1H), 6.62 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.8 Hz,
2H), 7.37-7.40 (m, 3H);
13C NMR (100 MHz, CDCl3): δ 26.8, 29.7, 31.9, 32.4, 41.8, 50.2, 55.1, 113.5, 114.8, 128.8,
129.4, 138.8, 139.1, 149.6, 157.7, 195.9.
3,3,6,6-Tetramethyl-9-(4-Bromo)-10-phenyl 1,2,3,4,5,6,7,8,9,10decahydroacridine-1,8-dione
(entry 3)36
:
N
O O
Br
White solid; m.p. 253-254 °C;
IR (KBr): 1276, 1301, 1453, 1577, 1594, 1639, 2871, 2956 cm-1
;
1H NMR (400 MHz, CDCl3): δ 0.80 (s, 6H), 0.94 (s, 6H), 1.80-1.84 (m, 2H), 2.06-2.22 (m, 6H),
5.24 (s, 1H), 7.23 (d, J = 8.8 Hz, 2H), 7.31-7.38 (m, 4H), 7.57 (d, J = 7.6 Hz, 3H);
13
C NMR (100 MHz, CDCl3): δ 26.8, 29.8, 32.4, 32.6, 41.8, 50.2, 114.2, 119.8, 129.6, 129.8,
131.2, 138.9, 145.4, 150.0, 195.8.
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
3,3,6,6-Tetramethyl-9-(3-nitro-phenyl)-10-phenyl-3,4,6,7,9,10-hexahydro-2H,5H acridine-
1,8-dione (entry 4)36
:
N
O O
NO2
Yellow solid; m.p. 277–279 oC;
IR (KBr):1350, 1433, 1579, 1645, 1660, 2947, 3066 cm-1
;
1H NMR (200 MHz, CDCl3): δ 0.86 (s, 6H), 0.97 (s, 6H), 1.71(d, J = 16.0 Hz, 2H), 2.03 (d, J =
16.0 Hz, 2H), 2.17 (brs, 4H), 3.77 (s, 3H), 5.15 (s, 1H), 6.79 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0
Hz, 2H), 7.61 (dd, J = 8.0, 2.0 Hz, 1H), 7.99 (t, J = 8.0 Hz, 1H), 8.13 (d, J = 2.0 Hz, 1H),
8.43(dd, J = 8.0, 2.0 Hz, 1H).
3,3,6,6-Tetramethyl-1,8-dioxo-9-(4-chlorophenyl)-10-(4-methylphenyl) decahydroacridine
(entry 5)34
:
N
O O
Cl
CH3
White solid; m.p. 269- 271 oC;
IR (KBr): 1222, 1363, 1516, 1576, 1640, 2873, 2957 cm-1
;
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
1H NMR (400 MHz, CDCl3): δ 0.80 (s, 6H), 0.97 (s, 6H), 1.80 (d, J = 17.4 Hz, 2H), 2.05–2.21
(m, 6H), 2.51 (s, 3H), 5.17 (s, 1H), 7.08 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 7.9 Hz, 2H), 7.39 (t, J =
8.4 Hz, 4H).
13C NMR (75 MHz, CDCl3): δ 23.4, 26.7, 29.6, 32.3, 32.9, 41.7, 50.1, 113.5, 116.56, 123.5,
128.8, 129.7, 138.2, 146.2, 148.1, 150.3, 152.9, 195.6.
3,3,6,6-Tetramethyl-1,8-dioxo-9-(4-methoxyphenyl)-10-(4-methylphenyl)-
decahydroacridine (entry 6)34
:
N
O O
OCH3
CH3
White solid; m.p. 279-283 oC;
IR (KBr): 1310, 1360, 1424, 1466, 1511, 1575, 1640, 2841, 2959 cm-1
;
1H NMR (400 MHz, CDCl3): δ 0.83 (s, 6H), 0.93 (s, 6H), 1.81 (d, J = 18.0 Hz, 2H), 2.01–2.19
(m, 6H), 2.51 (s, 3H), 3.77 (s, 3H), 5.19 (s, 1H), 6.77 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 7.2 Hz,
2H), 7.31 (t, J = 4.8 Hz, 4H).
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
9-(4-Hydroxy-phenyl)-3,3,6,6-tetramethyl-10-p-tolyl-3,4,6,7,9,10-hexahydro-2H,5H-
acridine-1,8-dione (entry 7)27
:
N
O O
CH3
OH
White solid; m.p. 350–352 °C;
IR (KBr): 1309, 1371, 1512, 11553, 1581, 1663, 2850, 2983, 3026, 3369 cm–1
;
1H NMR (400 MHz, CDCl3): δ 0.83 (s, 6H), 0.96 (s, 6H), 1.84 (d, J = 17.6 Hz, 2H), 2.05 (d, J =
17.6 Hz, 2H), 2.16 (q, J = 16.4 Hz, 4H), 2.53 (s, 3H), 5.19 (s, 1H), 5.36 (s, 1H), 7.09 (d, J = 6.0
Hz, 2H), 7.21–7.31 (m, 4H), 7.36 (d, J = 6.0 Hz, 2H).
3,3,6,6-Tetramethyl-1,8-dioxo-9-(3-nitrophenyl)-10-(4-methylphenyl)decahydroacridine
(entry 8)27
:
N
O O
CH3
NO2
White solid; m.p. 283-284
oC;
IR (KBr): 1535, 1578, 1640, 2870, 2980, 3020 cm-1
;
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
1H NMR (400 MHz, CDCl3): δ 0.81 (s, 6H), 0.95 (s, 6H), 1.83 (d, J = 16.0 Hz, 2H), 2.04–2.21
(m, 6H), 2.51 (s, 3H), 5.34 (s, 1H), 7.17 (d, J = 6.4 Hz, 2H), 7.23–7.32 (m, 4H), 7.38 (d, J = 6.4
Hz, 2H).
3,3,6,6-Tetramethyl-1,8-dioxo-9-benzene-10-(4-methylphenyl)-decahydroacridine (entry
9)34
:
N
O O
CH3
White solid; m.p. 260-262
oC;
IR (KBr): 1301, 1396, 1490, 1586, 1597, 1649, 2876, 2929, 2983, 3078 cm–1
;
1H NMR (400 MHz, CDCl3): δ 0.80 (s, 6H), 0.91 (s, 6H), 1.87 (d, J = 16.0 Hz, 2H), 2.05–2.21
(m, 6H), 2.50 (s, 3H), 5.27 (s, 1H), 7.00 (d, J = 6.4 Hz, 2H), 7.11–7.21 (m, 5H), 7.39 (d, J = 6.4
Hz, 2H).
3, 3, 6, 6, tetramethyl-1, 8 – dioxo – 9 - (piperonal) -10-(4-methyl-phenyl) decahydro-acridine (entry 10):
N
O O
CH3
OO
Yellow solid; m.p. 192-194
oC;
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
IR (KBr): 1363, 1481, 1602 cm-1
;
1H NMR (300 MHz, CDCl3): δ 0.82 (s, 6H), 0.94 (s, 6H), 1.85 (s, 2H), 2.03 (s, 2H), 2.21 (d, J =
4.8 Hz, 4H), 2.48 (s, 3H), 5.17 (s, 1H), 5.87 (s, 2H), 6.68 (d, J = 7.8 Hz, 1H), 6.88 (d, J = 9.0
Hz, 2H), 6.94 (s, 1H), 7.08 (d, J = 7.8 Hz, 2H), 7.33 (d, J = 7.5 Hz, 2H);
13C NMR (75 MHz, CDCl3): δ 21.2, 26.7, 29.1, 32.1, 40.7, 50.1, 50.6, 100.4, 107.7, 108.6, 114.4,
120.8, 136.1, 139.4, 140.5, 145.4, 147.1, 149.9, 162.1.
10-Benzyl-9-(4-methoxy-phenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahydro-2H,5H-acridine-1,8-dione (entry 11)
27
N
O O
OCH3
Yellow viscous liquid;
IR (KBr): 1420, 1467, 1516, 1577, 1639, 2846, 2962 cm-1
;
1H NMR (200 MHz, CDCl3): δ 0.97 (s, 6H), 1.12 (s, 6H), 1.87- 2.30 (m, 8H), 3.79 (s, 3H), 4.87
(s, 2H), 5.29 (s, 1H), 6.73 (d, J = 8.0 Hz, 2H), 6.87-6.92 (m, 2H), 7.17-7.31 (m, 5H).
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
9-(4-Methoxy-phenyl)-3,3,6-trimethyl-10-(3-nitro-phenyl)-3,4,6,7,9,10-hexahydro-2H,5H-acridine-1,8-dione (entry 12)
27:
N
O O
OCH3
NO2
Yellow solid; m. p. 276–278 oC;
IR (KBr): 1535, 1576, 1639, 2868, 2982, 3018 cm-1
;
1H NMR (200 MHz ,CDCl3): δ 0.85 (s, 6H), 0.97 (s, 6H), 1.74 (d, J = 16.0 Hz, 2H), 2.04 (d, J
= 16.0 Hz, 2H), 2.17 (brs, 4H), 3.79 (s, 3H), 5.19 (s, 1H), 6.73 (d, J = 8.0 Hz, 2H), 7.25 (d, J =
8.0 Hz, 2H), 7.59 (dd, J = 8.0, 2.0 Hz, 1H), 7.83 (t, J = 8.0 Hz, 1H), 8.11 (d, J = 2.0 Hz, 1H),
8.43 (dd, J = 8.0, 2.0 Hz, 1H).
3,3,6,6-Tetramethyl-9-(4-methoxyphenyl)-10-(4-chlorophenyl)-1,2,3,4,5,6,7,8,9,10-decahydroacridine-1,8-dione (entry 13)
29:
N
O O
OCH3
Cl
Solid; m.p. 269-271°C;
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
IR (KBr): 1299, 1361, 1439, 1473, 1491, 1508, 1578, 1641, 2837, 2953, 3052 cm-1
;
1H NMR (200 MHz, DMSO-d6): δ 0.77 (s, 6H), 0.87 (s, 6H), 1.73 (d, J = 17.0 Hz, 2H), 2.01 (d,
J = 16.0 Hz, 2H), 2.16 (d, J = 16.0 Hz, 2H), 2.19 (d, J = 17.2 Hz, 2H), 3.61 (s, 3H), 4.99 (s, 1H,),
6.80 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 8.8 Hz, 2H), 7.39-7.54 (m, 2H), 7.69 (d, J = 8.8 Hz, 2H).
9,10-Diphenyl-3,4,6,7,9,10-hexahydro-2H,5H-acridine-1,8-dione (entry 14)
36:
N
O O
White solid; m.p. 273–275 °C;
IR (KBr): 2937, 1637, 1352, 1267, 1221, 1180, 713 cm–1
;
1H NMR (200 MHz, CDCl3): δ 1.57-2.53 (m, 12H), 5.31 (s, 1H), 7.17-7.79 (m, 10H);
13C NMR (75 MHz, CDCl3): δ 22.3, 27.9, 33.17, 37.0, 116.1, 125.9, 127.9, 128.0, 130.0, 131.1,
139.2, 147.0, 152.0, 196.1.
9-(4-Methoxy-phenyl)-10-phenyl-3,4,6,7,9,10-hexahydro-2H,5H-acridine-1,8-dione (entry
15)36
:
N
O O
OCH3
Yellow solid; m.p. 268–271 °C;
IR (KBr): 1289, 1357, 1512, 1559, 1601, 1637, 2897 cm–1
;
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
1H NMR (200 MHz, CDCl3): δ 1.63-2.41 (m, 12H), 3.77 (s, 3H), 5.29 (s, 1H), 6.79 (d, J = 8.8
Hz, 2H), 7.23- 7.44 (m, 4H), 7.41-7.63 (m, 3H);
13C NMR (75 MHz, CDCl3): δ 21.3, 27.9, 31.5, 37.1, 54.9, 112.8, 116.0, 129.4, 130.0, 140.1,
140.4, 152.0, 159.0, 196.3.
9-(4-Chloro-phenyl)-10-phenyl-3,4,6,7,9,10-hexahydro-2H,5H-acridine-1,8-dione (entry 16)
36:
N
Cl
O O
White solid; m.p. 292–295
oC;
IR (KBr): 1422, 1517, 1563, 1599, 1643, 2886 cm-1
;
1H NMR (300 MHz, CDCl3): δ 2.30–1.59 (m, 12H), 5.21 (s, 1H), 6.97–7.56 (m, 9H).
9-(3-Nitro-phenyl)-10-phenyl-3,4,6,7,9,10-hexahydro-2H,5H-acridine-1,8-dione
(entry17)36
:
N
O O
NO2
White solid; m.p. 278–280
oC;
IR (KBr): 1352, 1429, 1519, 1601, 1639, 2896 cm-1
;
1H NMR (300 MHz, CDCl3): δ 2.83–1.33 (m, 12H), 5.32 (s, 1H), 6.49–7.91 (m, 9H).
SOME IMPORTANT 1H &
13C NMR SPECTRA
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
N
O O
OCH3
CH3
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
N
O O
OCH3
CH3
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
REFERANCES:
1. Albert A. the Acridines, second ed. Edward Arnold Ltd, London, 1996.
2. Ramamurthy, S. P. N.; Shanmugasundaram, P.; Ramakrishana, V. T. J. Org. Chem. 1996,
61, 5083.
3. Ramamurthy, S. P. N.; Shanmugasundaram, P.; Ramakrishana, V. T. Acta.
Specttrochemica 1998, 54, 245.
4. Albert, A.; The Acridines; St. Martin’s Press: New York, 1966, 403.
5. Greenwood, D. J. Antimicrob. Chemother 1995, 36, 857.
6. Grove, W. R.; Fortner, C. I.; Wiernik, P. H. Clin. Pharm. 1982, 1, 320.
7. Van Mouwerik, T. J.; Caines, P. M.; Ballentine, R. Drug Intell. Clin. Pharm. 1987, 21,
330.
8. Jehn, U. Bone Marrow Transplant 1989, Suppl. 3, 53.
9. Harousseau, J. -L.; Cahn, J. -Y.; Pignon, B.; Witz, F.; Milpied, N.; Delain, M.; Lioure,
B.; Lamy, T.; Desablens, B.; Guilhot, F.; Caillot, D.; Abgrall, J.-F.; Francois, S.; Briere,
J.; Guyotat, D.; Casassus, P.; Audhuy, B.; Tellier, Z.; Hurteloup, P.; Herve, P. Blood
1997, 90, 2978.
10. Brown, P.; Hoffmann, T.; Hansen, O. P.; Boesen, A. M.; Gronbaek, K.; Hippe, E.;
Leukemia 1997, 11, 37.
11. Girault, S., Grellier, P., Berecibar, A.; Maes, L., Mouray, E., Lemiere, P., Debreu, M.;
Davioud-Charvet, E.; Sergheraet, C. J. Med. Chem. 2000, 43, 2646.
12. Gay, F., Traoré, B., Zanoni, J., Danis, M.; Fribourg-Blanc, A. Transactions of the Royal
Society of Tropical Medicine and Hygiene 1996, 90, 516.
13. Sánchez, I., Reches, R., Henry, D., Pierre, C., Maria, R.; Pujol, D. European Journal of
Medicinal Chemistry 2006, 41, 340.
14. Sondhi, S. M.; Singh, J.; Rani, R.; Gupta, P. P.; Agrawal, S. K.; Saxena, A. K. Eur. J.
Med. Chem. 2010, 45, 555.
15. Carole, D., Michel, D., Julien, C., Florence, D., Anna, N. J., Séverine, D., Gérard T.;
Pierre, G. Pierre Bioorganic & Medicinal Chemistry 2005, 13, 5560.
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
16. Yang, P., Yang, Q., Qian, X., Tong, L.; Li, X. Journal of Photochemistry and
Photobiology B: Biology 2006, 84, 221.
17. Crémieux, A., Chevalier, J., Sharples, D., Berny, H., Galy, A. M., Brouant, P., Galy, J. P.
Barbe.; J. Research in Microbiology 1995, 146, 73.
18. Shaikh, B. M., Konda, S. G., Mehare, A. V., Mandawad, G. G., Chobe, S. S.; Dawan, B.
S. Der Pharma Chemica 2010, 2, 25.
19. Gunduz, M. G., Dogan, A. E., Simsek, R., Erol, K.; Safak, C. Med. Chem. Res. 2009, 18,
317.
20. Lerman, L. S. J. Mol. Biol. 1961, 3, 18.
21. (a) Topcu, Z. J. Clin. Pharm. Ther. 2001, 26, 40; (b) Jelic, S.; Nikolic-Tomasevic, Z.;
Kovcin, V.; Milanovic, N.; Tomasevic, Z.; Jovanivic, V.; Vlajic, M. J. Chemother. 1997,
9, 364.
22. Eisner, U.; Kuthan, J. Chem. Rev. 1972, 72, 1.
23. Chorvat, R. J.; Rorig, K. J. J. Org. Chem. 1988, 53, 5779.
24. Suarez, M.; Loupy, A.; Salfran, E.; Moran, L.; Rolando, E. Heterocycles 1999, 51, 21.
25. Tu, S. J.; Lu, Z.; Daqing Shi, D.; Yao, C.; Gao, Y.; Guo, C. Synthetic commun. 2002, 14,
2181.
26. Jin, T. S.; Zhang, J. S.; Guo, T. T.; Wang, A. Q.; Li, T. S. Synthesis 2004, 2001.
27. Das, B.; Thirupathi, P.; Mahender, I.; Reddy, V. S.; Rao,Y. K. Journal of Molecular
Catalysis A: Chemical 2006, 247, 233.
28. Fan, X.; Li, Y.; Zhang, X.; Qu, G.; Wang, J. Heteroatom Chemistry 2007, 18, 786.
29. Shi, D.-Q.; Ni, S.-N.; Fang, Y.; Shi, J.-W.; Dou, G.-L.; Li, X.-Y.; Wang, X.-S. J.
Heterocycl.Chem. 2008, 45, 653.
30. Chandrasekhar, S.; Rao, Y. S.; Sreelakshmi, L.; Mahipal, B.; Reddy, C. R. Synthesis
2008, 11, 1737.
31. Venkatesan, K.; Pujari, S. S.; Srinivasan, K. V. Synthetic Commun. 2009, 39, 228.
32. Saeed, B.; Fatemeh, C.; Fatemeh, D.; Reza, B. H. Chinese Journal of Chemistry 2009,
27, 1953.
33. Shi, D. Q.; Shi, J. W.; Yao, H. Synthetic Commun. 2009, 39, 664.
Chapter I Section IV
---------------------------------------------------------------------------------------------------------------------
34. Shen, W.; Wang, Li -M.; Tian, H.; Tang, J.; Yu, J. J. Journal of Fluorine Chemistry
2009, 130, 522.
35. Rashedian, A. F.; Saberib, D.; Niknam, K.; Journal of the Chinese Chemical Society
2010, 57, 998.
36. Kidwai, M.; Bhatnagar, D. Tetrahedron Lett. 2010, 51, 2700.
37. Abdelhamid, A. A.; Mohamed, S. K.; Maharramov, A. M.; Khalilov, A. N.;
Allahverdiev, M. A. Journal of Saudi Chemical Society 2011 (in press).
38. Ziarani, G. M.; Badiei, A.; Hassanzadeh, M.; Mousavi, S. Arabian Journal of Chemistry
2011 (in press).
39. Moghadam, K.; Azimi, S. C. Journal of Molecular Catalysis A: Chemical 2012, 465, 363.
40. Patil, V. S.; Nandre, K. P.; Kalyankar, M. B.; Nalage, S. V.; Ghule, N. V.; Bhosale, S.
V.; Bhosale, S. V. Current Catalysis 2012, 1, 73.
41. Hong, M.; Xiao, G. Journal of Fluorine Chemistry 2012, 144, 7.
42. Ghasemzadeh, M. L.; Ghomi, J. S.; Molaei, H. C. R. Chimie. 2012, 15, 969.
43. (a) Kundu, D.; Debnath, R. K.; Majee, A.; Hajra, A. Tetrahedron Lett. 2009, 50, 6998;
(b) Kundu, D.; Majee, A.; Hajra, A. Catal.Commun. 2010, 11, 1157; (c) Rahman, M.;
Bagdi, A. K.; Majee, A.; Hajra, A. Tetrahedron Lett. 2011, 52, 4437; (d) Kundu, D.;
Majee, A.; Hajra, A. Chemistry-An Asian Journal 2011, 6, 243; (e) Urinda, S.; Kundu,
D.; Majee, A.; Hajra, A. J. Het. atom. 2009, 20, 232; (f) Kundu, D.; Majee, A.; Hajra,
A. Tetrahedron Lett. 2009, 50, 2668. (g) Santra, S.; Majee, A.; Hajra, A. Tetrahedron
Lett. 2012, 53, 1974.