SECTION – IV USE OF ZWITTERIONIC-TYPE MOLTEN SALT FOR ...

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

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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.


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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.


---------------------------------------------------------------------------------------------------------------------

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


---------------------------------------------------------------------------------------------------------------------

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


---------------------------------------------------------------------------------------------------------------------

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


---------------------------------------------------------------------------------------------------------------------

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


---------------------------------------------------------------------------------------------------------------------

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).


---------------------------------------------------------------------------------------------------------------------

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).


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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.


---------------------------------------------------------------------------------------------------------------------

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


---------------------------------------------------------------------------------------------------------------------

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).


---------------------------------------------------------------------------------------------------------------------

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).


---------------------------------------------------------------------------------------------------------------------

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]

[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


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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).


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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).


---------------------------------------------------------------------------------------------------------------------

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.


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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


---------------------------------------------------------------------------------------------------------------------

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)







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.


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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


---------------------------------------------------------------------------------------------------------------------

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.


---------------------------------------------------------------------------------------------------------------------

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.


---------------------------------------------------------------------------------------------------------------------

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.


---------------------------------------------------------------------------------------------------------------------

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

;


---------------------------------------------------------------------------------------------------------------------

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.


---------------------------------------------------------------------------------------------------------------------

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

;


---------------------------------------------------------------------------------------------------------------------

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

;


(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).


---------------------------------------------------------------------------------------------------------------------

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

;


---------------------------------------------------------------------------------------------------------------------


(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

;


(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;


---------------------------------------------------------------------------------------------------------------------

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).


---------------------------------------------------------------------------------------------------------------------

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;


---------------------------------------------------------------------------------------------------------------------

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

;


---------------------------------------------------------------------------------------------------------------------

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


---------------------------------------------------------------------------------------------------------------------


---------------------------------------------------------------------------------------------------------------------

N

O O

OCH3

CH3


---------------------------------------------------------------------------------------------------------------------

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