SYNTHESIS AND CHARACTERIZATION OF HETEROCYCLES UNDER GREEN

CONDITIONS

Oissertation

/

SUBMITTED FOR THE AWARD Of THE DEGREE OF

M&atst of ^^Haaop^v

€^tmiftttp

By Saima 'Tarannum

DEPARTMENT OF CHEMISTRY ALIGARH MUSLIM UNIVERSITY

ALIGARH ( INDIA) 2012

2 4 NOV 2014

DS4363

<Dr. Ztba % Siddiqid M.PhJl., Ph.D.

Associate Professor

DEPARTMENT OF CHEMISTRY ALIGARH MUSLIM UNIVERSITY

ALIGARH-202002 (INDIA)

Ph. (Off) 0571-2703515 (Mob) 09412653054

E-Mail: siddiqui_zeba@yahoo.co.in

Certificate This is to certify that the dissertation entitled "Synthesis ani

characterization of heterocycles under green conditions" submitted for tjfjie

award of the degree of master of philosophy (M.Phil.) in chenitstry td Xligarh

Muslim University, Aligarh, is a record of bonafide research work carried out

by Ms. Saima tarannum under my guidance. It is fiirther certified that the

dissertation embodies the work of candidate himself and has not been

submitted for any degree either of this or any other University. The present

work is suitable for the submission for the above mentioned purpose.

Dr. Zeba N. Siddi^ui

(Supervisor)

Res: C-23, Al-Hamd Apartment, Badar bagh, Civil Lines, Aligarh-202002

Contents Page No.

Acknowledgements

Preface 1-3

*> Theoretical 4-15

*> Discussion 16-40

<• Experimental 41-50

*> Bibliography 51-58

A cknowledgements

First and foremost all praise is due to Allah, the Lord of the world, the

Beneficent, the Merciful. I am paying all my thanks to Almighty Allah who

provided me an opportunity and ability to accomplish this task into a practical

one.

It is the best opportunity to express my profound sense of gratitude,

indebtedness and sincere thanks to respectable Dr. Zeba N. Siddiqui, Associate

Professor, Department of Chemistry, Aligarh Muslim University, Aligarh for

her keen interest, fervent guidance, valuable suggestions, gentle criticism,

empirical approach, encouragement, futuristic vision and her inexhaustible

source of inspiration for this study. Indeed, it is proud privilege for me to learn

from her as research supervisor.

With due reverence. I am extremely grateful to Chairman, Department of

Chemistry, A.M.U., Aligarh for providing research facilities in the department.

I am thankful to University Sophisticated Instrument Facility (USIF) and

Department of Applied Physics, Aligarh Muslim University, Aligarh, for providing

the SEM and XRD facilities. Thanks also to SAIF (Sophisticated Analytical

Instrument Facility), Punjab University, Chandigarh, for providing NMR and ESI

iviass opectra.

I would like to express my heartfelt thanks for the care and concern shown by

my lab colleagues Ms. Farheen, Tabassum Khan, Kulsum and Mr. Nayeem

Ahmed for timely discussion, suggestions and help in completing the task.

Completion of research work is never a "one man show' but a collective effort

of several well wishers. My special thanks are also due to my friends who

ahvays stood rock solid by tny shoulders, boost my moral and confidence and

gave me care and affection viz., Tanvir, Rozy, Saad and Maaz.

Heartiest respect and indebtedness are offered to my affectionate and beloved

sisters for their affection, blessing, encouragement, support and care

throughout my studies. Without their prayers and support I would not have been

able to achieve my goal in time. I want to take this opportunity to offer my

gratitude with great honour and respect towards my father Mr. Azimul Hague

and my beloved mother Late Mrs. Nikhat Azim whose blessings have proven

beacon for the ship of my carrier, I pray to Allah that I may live up to their

expectations.

Saima Tarannum

Preface

The aim of present research is to develop green methodology for the

synthesis of biologically important heterocyclic compounds. Herein,

we descibe an efficient and green method for the synthesis of

bis(indolyl)methanes at room temperature under solvent-free condition

using xanthan sulfuric acid (XSA) as an eco-freindly catalyst. The

prevalence of this motif in natural and bioactive products continues to

be a vector in the development of new methodology to fmd useful

compounds. Grinding of different aldehydes with indole in presence of

catalyst (XSA) provided excellent yields of bisindolylmethanes. All the

synthesized com.pounds were characterized by spectroscopic studies

and the catalyst was characterized by FT-IR spectra, SEM-EDX, XRD

and DSC. The remarkable features of this green, new methodology are

remarkable decrease in reaction time, increased yield of products, clean

reaction profile, simple experimental and easier work-up procedures.

H,C.

42a X=CI

42b X=N3

42e R=H 42(1 R=CH3 42e R=CI

42f

42g

42 h

THEORETICAL

Theoretical

Indoles are convenient starting materials for the synthesis of series of

compounds with promising practical uses. Indole and its derivatives are

known as important intermediates in organic synthesis and

pharmaceutical chemistry.' Substituted indoles are capable of binding

to many receptors with high affinity. Since, the 3-position of indole is

the prefeiTed site for electrophilic substitution reactions, 3-alkyl or acyl

indoles are versatile intermediates for the synthesis of a wide range of

indole derivatives. Therefore, the synthesis and selective

functionalization of indoles have been the focus of active research over

the years. These compounds exhibit various physiological properties

and pharmacological activities such as anticancer,'^ anti-inflammatory,"*

anti-psychotic,^ anticonvulsant, antiproliferative,^ antimicrobial,^

antifungal,^ anti-HIV'° and cytotoxic'' activities. Some important

reactions of indole are given below:

1. Michael addition of indole with electron deficient olefins

Michael reaction of indole with a,(3-unsaturated carbonyl

compounds provide easy access to 3-substituted indoles, which

are important building blocks for the synthesis of biologically

relevant compounds and natural products.

Adapa et al reported a simple and direct method for the synthesis

of 3-alkylated indoles (3, 5) involving the conjugate addition of

indole (1) to unsaturated compounds (2, 4) in the presence of

Bi(OTf)3as catalyst.'^(Scheme 1)

Scheme 1

2. Syntheses of Bis(indolyl)pyrazine and Bis(indolyl)pyrazinone

Several pyrazine compounds have been proved to be potent

antitumor agents.'^ Pyrazinone linked with two indolyl groups

show antiviral activities. 3,6-Bis(3'-indolyl)pyrazine (7) and

3,5-bis(3'-indolyl)-2(lH)pyrazinone (11) were designed and

synthesized from indole by Jiang et al. ^

Reaction of indole with chloroacetyl chloride in toluene

containing pyridine followed by treatment with sodium azide in

refluxing aqueous acetone afforded the azidoketone (6) which

was hydrogenated over Pd/C in methanol containing a few drops

of glacial acetic acid at room temperature to offer 3, 5-bisindolyl

pyrazine (Scheme 2).

CICHjCOCI.Py, toluene ^

NaNj, acetone/H20, reflux

H2,Pd/C MeOH, AcOH

Scheme 2

Azidoketone (6) was hydrogenated over Pd/C in methanol

containing conc.HCl to afford 3-(a-aminoacetyl)indole

hydrochloride salt (9) which react with 3-indolylglyoxylic

chloride (8) in CH2CI2 and EtsN to form compound (10). Central

pyrazinone ring was successfully constructed by treatment of

(10) in excess of ammonia at 60-80° C under 50 psi pressure

(Scheme 3).

ClCHiCOCl.Py, toluene

NaNv acctone/IbO, rellux

H2, Pd/C

MeOH, HCl

O

NHi

Scheme 3

3. Mannich-Type Reaction of Indole

Indole, being an integral part of many natural products of

therapeutic importance, possesses potentially reactive sites for a

variety of chemical reactions to generate molecular diversity.

Prajapati et al reported the synthesis of 3-[3'-(aryUminomethyl)

benzopyranyl J indoles (14) by the reaction of indole (1) with 3-

formyl chromone (12) and /?-anisidine (13) in presence of

indium triflate as catalyst'^ (Scheme 4).

o X H O

+

o HnN

12

In(0Tf)3 CH3CN, heat

PCHi

13

.OCH.

4, Synthesis of Triazoles

Scheme 4

Triazoles and their derivatives are found to be associated with

various biological activities such as anticonvulsant, 17

20 antifungal, anticancer, anti-inflammatory and antibacterial

properties. 21

Liu et al reacted indole (1) with l-aryl-3-(2-aryl-l,2,3-triazol-4-

yl)propan-1-one (15) using Bronsted acid ionic liquid

[Sbmim][HS04] as catalyst to form 1,2,3-triazole derivative

ai ( 1 6 r (Scheme 5).

^^^^^

Sbmim(HS04)

CH3CN or Solvent-free

Scheme 5

5. Synthesis of 3-substituted indolyl-propionates (Yonemitsu

Reaction)

Yonemitsu et al. was the first group to report the successful three

component reaction of indole (1) with Meldrum's acid (18).

Subsequent decarboxylative ethanolysis of adduct led to ethyl 3-

substituted indolyl-propionate (20) used as intermediate in

23 synthesis of complex indole alkaloids" (Scheme 6)

10

RCHO +

17 o^^a

18

CH3CN, rt

,OEt

HtOH, Py

Cu, heat [f T ^ ° u N

H

20

R = alkyl, aryl

Scheme 6

Yonemitsu reaction was successfully applied and extended to

various complexes of alkyl- or phenyl-ring-substituted indole

derivatives, which proved to be a useful method in the synthesis

of complex indole alkaloid precursors.

Catalyzing the reaction with TiCU/EtsN or TiCl2 (0-iPr)2/Et3N

gives only Yonemitsu product (23) but with TiCU/EtsN and

extended reaction time, the tricyclic cyclopenta[Z)]indole (24) is

the dominant product. It appears that the intermolecular

Friedel-Crafts reaction of (23) is efficiently catalyzed with TiCU

to yield the tricyclic compound (24) (Scheme 7).

11

CH,

H3C CHO

21

O O TiCl4, EtjN

OMe CH2CI2 rt

22

CH3 CO,Me

,CH,

23

C C M e

Scheme 7

6. Synthesis of indolyl chromanes

Perumal reported an efficient approach in which a three

component condensation of salicaldehyde derivatives (26),

malononitrile (25) and indole, catalyzed by InCls or L-proline to

25 form indolyl chromanes (27) (Scheme 8)

Scheme 8

R = H, Br

12

7. Synthesis of p-indolylketones

A method for the synthesis of (3-indolylketones (30) in good

yields via condensation of indole (1), aromatic aldehydes (29),

and deoxybenzoin (28) with ultrasonic irradiation was described

by Shen et al *" (Scheme 9). This one-pot process proceeds

smooth and efficient in alkaline ethanolic solution.

Ph.

28

ArCHO +

29

NaOH, EtOH

Scheme 9

8. Synthesis of indole-3-propionic acids

Adamo et al report the reaction of isoxazole (31), aldehydes (32)

and indole (1) in the presence of BuLi to form indole

derivatives (33) which easily hydrolyzed in aqueous alkaline

media in a one-pot process to form valuable compounds such as

indole-3-propionic acids (34) in good yield (Scheme 10).

13

piperidine, THF

BuLi

. X P—N

HN

RCHO

32

piperidine, THF

BuLi, NaOH (aq)

HOOC

33 34

X = H, CI, NO2, CH3, OMe

Scheme 10

9. Synthesis of indolyl-isoquinolines

Yadav discovered coupling of indole (1) to isoquinoline (35)

which are activated by dimethyl acetylenedicarboxylate at room

temperature without a catalyst to produce indolyl-isoquinoline 28

(36) (Scheme 11). When a terminal acetylene and methyl

propiolate are used the major product is an indolyl compound

(37).

14

35

-COOMe

N CH.Ci,, rt

Scheme 11

10. Synthesis of indolyldihydropyridines

H 36

COOMe

R = COOMe

37

COOMe

R = H

Lavilla et al reported the reaction of pyridine in the presence of

acetyl chloride and a proton sponge to react with nucleophile

29 such as indole (1) to convert into N-acyl dihydropyridine (39).

Subsequent treatment of (39) with alkaline methanol

successfully yields (indolyl)dihydropyridine (40) in high yield

(Scheme 12).

Scheme 12

15

DISCUSSION

Discussion

Important tasks of modern chemistry are preservation of the

environment and the development of new methods and technologies.

In recent year, much effort has been directed towards the development

of new organic transformations under environmentally friendly

conditions. Solvent-free organic syntheses are very important from the

• 5 1

point of view of green chemistry. In view of the emerging importance

of environmental awareness in chemical and pharmaceutical industries,

development of new solid-phase (solvent-free) reactions and

transferring solution-phase reactions to solid-phase are subjects of

recent interest in the context of generating libraries of molecules for the

discovery of biologically active leads and also for the optimization of

drug candidates.

Replacement of conventional toxic and pollutant Bronsted and Lewis

acid catalysts with environmentally benign and reusable solid

heterogeneous catalysts is active area of current research. Using solid

acid catalyst have some advantages such as lower of equipments, ease

of products separation, recycling of the catalyst and environmental

16

•J "1

acceptability as compared to liquid acid catalyst. Carbon-based solid

acid catalyst has many advantages. It is insoluble in common organic

solvents, causes low corrosion and environmentally benign. Also the

products could be easily separated from the reaction mixture and the

catalyst is recoverable without decreasing its activity. Because of

their stronger acidity, they generally exhibit higher catalytic activity

than conventional catalysts.

Indoles are convenient starting materials for the synthesis of series of

compounds with promising practical uses. These compounds exhibit

various physiological properties as well as pharmacological activities.

Bis(indolyl)methanes and bis(indolyl)ethanes are important derivatives

of indole. Bis(indolyl)methanes are the most active cruciferous

substances for promoting beneficial estrogen metabolism in women

and men. * They are also effective in the prevention of cancer due to

their ability to modulate certain cancer causing estrogen metabolites.

Moreover, these compounds may normalize abnormal cell growth

associated with cervical dysplasia. Several methods have been reported

in the literature for the synthesis of bis(indolyl)methanes using protic

acids and Lewis acids including FeCls, ^ CuBr2, zeolite,"* ion

exchange resins,"*' antimony sulphate,"*^ AgBF4,'*^ PPh3-HC104,'*'* silica

17

supported sodium hydrogen sulfate and amberlyst-15,'^^

tetrabutylammonium tribromide/^ Yb-amberlist/^ ZnO," ^ NBS" ,

KIISO.,,'*' InFs,'' ZrCU,' MgS04," p-TsOH,^^ H3P04-Si02/^ metal

hydrogen sulfates, *' aminosulfonic acid,^^PCl5,^^ boric acid, ^ iodine,^

P205-Si02,'^' sulfamic acid, ^ PEG-SO3H," silica sulfuric acid,^* and

cellulose sulfuric acid^ . Many of the methods used have disadvantages

such as long reaction periods, use of hazardous solvents, use of

expensive reagents or preformed reagents, poor yields of products and

are not environmental friendly. For these reasons, there is a great effort

to replace the conventionally catalysts by eco-friendly and green

process catalysts.

Among natural biopolymers, xanthan is the most abundant bacterial

exopolysaccharide, being produced through fermentation. It has been

widely studied during the past several decades because it is a

biodegradable material and a renewable resource. Its unique properties

make it an attractive alternative to conventional organic or inorganic

supports in catalytic applications. ^"^^ It is very stable under a wide

range of temperatures and pH values. Recently, xanthan sulfuric acid

(XSA) has emerged as a promising biopolymeric solid-support acid

catalyst for acid catalyzed reactions, such as the synthesis of 3,4-

18

dihydropyrimidin-2(lH)-ones,*'^ thiadiazolo benzimidazoles''° and 4,4'-

71

(arylmethylene)bis(lH-pyrazol-5-ols) .

It is therefore, of interest to examine the behaviour of xanthan sulfuric

acid (XSA) as catalyst for synthesis of bisindolylmethanes. To the best

of our Icnowledge, condensation of different aldehydes and indoles in

the presence of a catalytic amount of xanthan sulfuric acid for the

synthesis of bisindolylmethanes has not been reported in literature.

Herein, we describe the use of xanthan sulfuric acid as a mild, highly

efficient, and recyclable solid acid catalyst for the synthesis of

bisindolylmethanes by the reaction of indole with different

heterocyclic/aromatic aldehydes under solvent-free condition in

excellent yields. The compounds were identified on the basis of

spectral data. The catalyst was recyclable up to four cycles. The

structure and morphology of the catalyst was established for the first

time with the help of powder XRD, differencial scannig calorimetry

(DSC), scanning electron microscopy (SEM) and energy dispersion

analytical X-ray (EDX).

19

Xanthan Gum

Xanthan gum is an extracellular polysaccharide secreted by the micro­

organism Xanthomonas campestris. X. campestris was originally

isolated from the cabbage plant, where it is responsible for black rot

disease. It is a widely used biopolymer in the food and pharmaceutical

industries and is often used for the purposes of thickening, suspending,

79

stabilising and gelling. Xanthan gum is also used in many other fields

such as petroleum production, pipe line cleaning, enhanced oil

recovery, textile printing and dyeing, ceramic glazes, slurry explosives

and in cosmetics . Xanthan is produced on an industrial scale by

fermentation, in a well-aerated and principally carbohydrate medium

containing other trace elements. It is precipitated from the fermentation

broth using isopropyl alcohol, then dried and milled.'"^

Structure of Xanthan

Xanthan consists of pentasaccharide repeating subunit consisting of

two D-glucopyranosyl units, two D-mannopyranosyl units and a D-

glucopyranosyluronic acid unit as determined by methylation analysis

and uronic acid degradation. The molecule has a (1^4) linked (3-D-

glucopyranosyl backbone, as is found in cellulose, but with a

trisaccharide side chain attached to the 0-3 position on alternate

20

glucosyl units. The side chain is constructed such that the D-

glucuronosyl unit is flanked by mannosyl units as shown in (Fig. 1). In

solution the side chains wrap around the backbone thereby protecting

the labile (1,4) linkages from attack. It is thought that this protection is

responsible for the stability of the gum under adverse conditions.

CH7OH

M+^Na, K, l/jCa

0

R = II C CH3

or

Fig. 1. Structure of xanthan gum

21

Synthesis of Xanthan Sulfuric acid

Xanthan sulfuric acid was synthesized from xanthan gum and

chiorosuifonic acid as shown in Scheme 13.

CISO3H ^/\nj\/\j\/\r>j'—OH >- yy\/\J\nj\r\j\r—O—SO3H

-HCI xsA Sch

erne 13

Characterization of the catalyst

FT-IR Spectrum of Xanthan Sulfuric Acid (XSA)

The FT-IR spectrum of the catalyst showed absorption bands at 1263

and 1374 cm"' for symmetric and asymmetric stretching vibrations of

the SO2 group respectively. Another stretching absorption band at 599

to 659 cm'' attributed to S-O functional group. The spectrum (Fig. 2)

also showed a strong broad band for OH stretching absorption in the

range of 3261 to 3467 cm"'. ^

22

...r ««*•*• rtiwif

' mm/t

£.'•<•* H c i u l

•

>

Ut.,n. .rs«,.

H * ^ V% »«• i-^fi >

!)p;

<M»ttr MM«l.>

A cm% m ^ Y^^ %

\

, i|«te»»

' ^ ^ i:i

^w-*

i

>

o

o

8

X

o o

23

Powder X-ray diffraction (XRD) analysis of the catalyst (XSA)

The structure of the prepared catalyst was identified by powder XRD.

X-ray patterns of the catalyst was recorded at 20 = 20-80° range (Fig.

3). The sharp peaks centred at 20 angle confirmed the formation of

xanthan sulfuric acid (XSA) as crystalline compound.

500

400-

>-

W 300

t-z

~ 200-

100-

—1 ' 1— 20 30

UW Vt*' k»»^AiwJ L M A - . ^ ' V ^ \

40 —\ ' r-50 60

70

_2e^degreg) i Fig. 3. The powder XRD pattern of fresh catalyst.

SEM-EDX analysis of the catalyst

To study the surface morphology of the catalyst, SEM micrographs of

the catalyst was employed. The SEM images of the catalyst (Fig. 4)

showed an even distribution of sulfuric acid molecules on the surface

of the xanthan gum.

24

Fig. 4. The SEM images of freshly synthesized catalyst (XSA) at

different magnifications

Further, EDX analysis (Fig. 5) of the catalyst showed the presence of

S, O and C elements suggesting the formation of expected catalytic

system.

Fig. 5. EDX analysis of the catalyst (XSA).

DSC analysis of catalyst (XSA)

DSC analysis (Fig. 6.) of the catalyst (XSA) was performed in the

temperature range of 20-300° C at a constant heating rate of 10° C/min

25

in the nitrogen atmosphere. The DSC curve shows an irreversible

endothermic transition in the region of 100-136° C, which may be due

to loss of water molecule from polymer matrix. This analysis also

shows that the catalyst is stable upto 270° C, after which it shows some

exothermic transition.

'9—1 a I u.' r ' DSC mW

lrmn«mi«wli)<ie«««r«,0«t«.c»aniHMi>,

of i—«„- ,„ ..

SXXh

000

-5.0O

10055 200.00 T«(np IQ

300.00

Fig. 6. DSC of catalyst (XSA)

26

Syn til esis of Bis in dolylmeth an es

111 the present study, synthesis of bis(indo!yi)iTiethanes were made by

the eondensation of indole (1) with different aldehydes (41a-h) using

xanthan sulfuric acid as recyclable solid acid catalyst (Scheme 14). The

clectrophilic substitution reactions of indole with various aldehydes

proceeded smoothly to afford the corresponding bis(indolyl)methanes

in good to excellent yields. The results are summarized in Table 1.

o

Ar ' > l

41

H,C H,C,

'I \ N ^ '

Ph

41a

N // \

N - ^ ^N3

41b

O

O

41c

H3C.

O

•^o

41d

n 41e

S

41f

V ^ 41h

Scheme 14

27

Table 1. XSA catalyzed synthesis of bis(indolyl)methanes.

Entr\

42a

Aldehyde

Hic; r i io

// ^

\r^ Ci

Product I i m c

(mill)

25

"vicicF' (%)

92

42b

42c

42d

42e

421

H.C Clio

H,C

N I

N-,

Clio

CI 10

CI lU

\ / ^ ' X l i U

20

30

25

35

30

86

88

90

86

84

28

4--ti

42h

i 'HO

\ \

!!

.x:iio

<i

35

8 b

90

Reaction progress monitored by TLC. Isolated yield

Since the 3-position of indole is the preferred site for electrophilic

reactions, substitution occurred exclusively at this position, and N-

substituted products were not detected in the reaction mixture.

The structural assignment of all the compounds (42a-h) was done by

elemental and spectroscopic data (IR, NMR and MS). The IR spectrum

(Fig. 7) of the newly synthesized compound (42a) exhibited strong

absorption bands at 3467 and 3400 cm'' for two NH groups of indole

moiety. The proton nuclear magnetic resonance spectroscopy (Fig. 8)

exhibited sharp singlets at 5 1.98 and 5.87 for three methyl and one

methinc protons (11 ) respectively. Thirteen aromatic protons (five

protons of a phenyl group of pyrazole moiety and ten protons of indole

unit) were discernible as muliiplct at o 6.80-7.57. Two NH protons of

29

• itrtiH a Sin)

: 3 .

5

X

I

iMica'irtHi) UCWt«'MiM><

iKmm-Kifttl

PS

? •

i

1

t4-l

o s o

«/)

^ r-m fa

o o

( f i - ^ W i ^ ^ I -

>

innis'nimti i >

0)

It

K

o a o o

CI «S s

30

• ) • U

i I I !

!i:';ni;;

I

i'i ;j 1:1 . (

1 u I it i) M i ; .0 i.;p:

i , ; in-ri i;K,.,„.,t l i ! i . , : i , : , i . < o i . i » 1

t 8 '"

, I ill-I'll''. I ! ','.

II I

' l l i l ' h •

:•• I ' i

i ' l ' m ' H ' l i j

•' MllJ

I, i l l I •

: ; ' , i i l '

I ! :'i

n i l ' !

I I I ' . ! •

i i ' i i i

111 iii

! 11.1 '

• I ' l ' i l ' '

'I II 'II ' •

V

- ^ ^

-iiff

- ^ . 1 1 1 ) • K

fB

00

^1

F^

s

O pa

U CD

w

00

C7N

do

32

indole moiety were present as singlet at 8 10.47, The '"'C NMR

speetrum showed signals at 6 13.4 and 29,6 for methyl and methine

carbon respectively. Other carbon signals appeared at their appropriate

positions and discussed in experimental section. Fuitlier, evidence for

the formation of 42a was obtained by mass spectrum (Fig. 9) which

showed molecular ion peak at m/z 436.

A plausible mechanism for the formation of 42a in the presence of

XSA has been shown in Scheme 15.

o ihC

// w //

N

Ph

41a

M3C

-XSA

// // N

N" !-i

© ,XSA

H \

N

Ph

H.C.

42a Scheme 15. Proposed mechanism for the formation of 42a.

34

Catalytic Reaction

To study the appropriate reaction condition for the synthesis of

bisindolyhtiethancs, the condensation of aldehyde and indole was

examined in the presence of catalyst, xanthan sulfuric acid (XSA)

under various reaction conditions. The reaction of 5-chioro-3-methyl-l-

phenylpyrazole-4-carboxaldehyde (Immol) with indole (2 mmol) in the

presence of xanthan sulfuric acid was used as a model reaction.

Effect of different catalysts

In order to emphasize the efficiency of XSA in comparison with other

catalysts, the model reaction was carried out with various catalysts such

as L-proline, Zn (L-proline)2 , zinc acetate, sulfamic acid, NiCl2 and

AICI3 (Table 2). It was observed that L-proline and Zn (L-proline)2

could not catalyze the reaction (Table 2, entries 1, 2). When the

reaction was performed with sulfamic acid reaction was completed

after long time period with impure product (Table 2, entry 3). Using

Zinc acetate, reaction was completed relatively in shorter time period

but with moderate yield of the product (Table 2, entry 4). With NiCL

and AICI3 only trace amounts of the product were obtained (Table 2,

entries 5, 6).When XSA was used as catalyst, reaction completed in

shorter reaction time with excellent yield of product (Table 2, entry 7).

35

Table 2. The screening of different catalvsts on the model reaction.

:nli-v Cataivst Time Yield (%)

L-proline

o

3

4

5

6

7

Zn (' I - n r n h n e V-,

Sulfamic acid

Zinc acetate

NiCl.

AICI3

XSA

-

2h

40 min

1 h

50 min

25 min

60

72

trace

trace

92

Effect of solvents

In order to study solvent effect, the model reaction was carried out

in different orotic and aprotic solvents such as CII3COOH, MeOH,

BtOH, (CH3)2CHOH, CH2CI2 and CH3CN. When the reaction was

performed in EtOIi, MeOH and (CH3)2CHOH, lower yield of the

product was obtained after longer time period (Table 3, entries 4, 5,

6). Using CH3COOH reaction was completed relatively in shorter time

period with impure product (Table 3, entry 3). In CH2CI2 and

CM3CN, again only trace amounts of the product was obtained (Table

3, entries 7, 8). When the reaction was carried out under grinding

36

condition, both ihe yield and reaction time were significantly improved

(Table 3, entry 1). fn comparison with the solvent-free condition,

model reaction was also performed under sol vent-free heating^ It was

observed that reaction was completed relatively in shorter time period

but the product was obtained in lower yield (Table 2, entry 2).

Table 3. Comparative study for the synthesis of bisindolylmethanes

using solution conditions versus the solvent-free method.

lintry Solvent Temperature Time Yield(%)

Grinding RT 25 min 92

Solvent-free TOT 35 min 48

CH.COOH RT 3 h mixture

EtOH RT 7 h 7:

5

7

8

MeOH

(Cll3)2CI

CH2CI2

CH3CN

lOH RT

RT

RT

8 h

23 h

43 h

46 h

64

54

36

28

Loading of the catalyst

Model reaction was carried out using different amounts (60, 100, 140,

180, 200 and 220 mg) of XSA for the optimization of the catalyst. It

37

was {bund thai 200 mg of catalyst is sufficient for the fruitful

conipleiion of reaction. !t was found that when reaction was carried out

without use of catalyst, it required longer reaction time for completion

with the formation of by-products (Table 4, entry 7). As the amount of

the catalyst increased, reduction in time period and enhancement in the

product yield was observed. Maximum yield of the product (92 %) and

shorter time period (25 mm) for the completion of reaction was

observed when amount of the catalyst was 200 mg. Further, increase in

the amount of the catalyst reduced the time period but yield of the

product was lowered (Table 4, entry 6).

Table 4. Effect of catalyst loading on the synthesis of

bisindolylmethane.

Entry Catalyst (mg) Time Yield(%)

60 4 h 35

2

3

4

5

6

7

100

140

180

200

220

none

2.5 h

2h

1 h

25 min

20 min

10 h

42

65

84

92

90

20

38

Recycling study of catalyst

Recycling studies were carried out in order to evaluate the catalytic

activity of xanthan sulfuric acid (XSA). "Fhus, in a model reaction

indole, aldehyde and xanthan sulfuric acid (XSA) were ground together

in a mortar with a pesile at room temperature tor specified time period.

On completion of reaction, chloroform was added and the reaction

mixture filtered. Fhe recovered catalyst was washed with chloroform

thoroughly (4x10 ml), dried in oven at 80° C for 2 h and used for the

subsequent cycles. I' he same procedure was applied for all recycling

studies. The results (Table 5) revealed that catalyst exhibited good

catalytic activity up to four consecutive cycles.

Table 5. Recycling studies of catalyst for the model reaction.

Catalyst recycle Time Yield (%)

I 25 min 92

II 25 min 92

III 25 min 92

IV 25 min 92

V 40 min 84

'fhe recovered catalyst was identified by powder XRD (Fig. 10) and

SHM analysis (Fig. 11). It was observed that peaks remained the same

39

and also no change in the morphology of the catalyst was obsereved as

compared to the fresh catalyst.

> 1-(0

g 1-

z

600-)

500-

400-

300-

200-

100-

0 - jJL ^ L A A , * ^ . ^ . - — L — - < * ^ I — I — ' — I — 20 30

— I — 40 50

2d(degree)

—r-60

—r~ 70 80

Fig. 10. The powder XRD pattern of recovered catalyst after four

runs

Fig. 11. SEM image of the recovered catalyst after four runs.

40

EXPERIMENTAL

Experimental

(iencral

Mching points of all synthesized compounds were taken in a Riechert

rhermover instrument and are uncorrected. The IR spectra (KBr) were

recorded on Pericin Elmer RXI spectrometer. ' l i NMR and ' \ : NMR

spectra were recorded on a Bruker DRX-300 and Bruker Avance II 400

spectrometer using tetramethylsilane (TMS) as an internal standard and

DMSO-o'^/CDCls as solvent. ESI-MS were recorded on a Quattro II

(BSI) spectrometer. Elemental analyses (C, H and N) were conducted

using the Elemental vario EL III elemental analyzer and their results

were found to be in agreement with the calculated values. 3-

Formylchromone, 5-chloro-3-methyl-1 -phenylpyrazole-4-

carboxaldehyde and 5-azido-3-methyl-l-phenylpyrazole-4-

carboxaldehyde were synthesized by reported procedures. ' " The

catalyst (Xanthan sulfuric acid) was synthesized by the reported

procedure. Other chemicals were of commercial grade and used

without further purification. The homogeneity of the compounds was

checked by thin layer chromatography (ILC) on glass plates coated

with silica gel G254 (E. Merck) using chloroform-methanol (3:1)

41

mixture as mobile phase and visualized using iodine vapors. X-ray

difiraclograms (XRD) of tlie caialyst were recorded in the 20 range of

20-80" with scan rate of 4°/ min on a Rigaku Minifax X-ray

dilTractometcr with Ni-filtered Cu Ka radiation at a wavelength of

1.54060"' A, The SEM-EDX characterization of the catalyst was

performed on a JEOL JSM-6510 scanning electron microscope

equipped with energy dispersive X-ray spectrometer operating at 20

kV. DSC data was obtained with DSC-60 shimadzu instrument.

Preparation of catalyst (XSA)

fo a magnetically stirred mixture of xanthan (5.0 g) in CHCI3 (15 mL),

chlorosulfonic acid (1.00 g) was added dropwise at 0° C during 2 h.

IICl gas was removed from the reaction vessel immediately. After

completion of the addition, the mixture was stirred for 3 h. Then, the

mixture was filtered and washed with methanol (25 mL) and dried at

room temperature to obtain xanthan sulfuric acid as white powder (5.30

g)-

General Procedure for the Synthesis of 5-chloro-3-methyl-l-

phenylpyrazoIe-4-carboxaldehyde (41a)7*^

Compound 41a is synthesized by the formylation of 3-methyl-l-

phcnyl-pyrazol-5(4//)-one using Vilsmeier-Haack reagent

(DMF/POCI3). 3-methyl-l-phenyl-pyrazolin-5-one was dissolved in

42

DiVlf- (Imol) and added POCI3 in excess. The reaction was stirred at

(i(}-10° C for 8 hours. The completion of the reaction mixture was

checked b\' 'FLC. The reaction mixture was poured into 200 ml of

crushed ice water and neutraUzed with 5% NaOH solution. The

yellowish white solid obtained was fiitered, washed with cold water

and dried.

General Procedure for the Synthesis of 5-azid[o-3-methyl-l-

phenylpyrazole-4-carboxaIdehyde (41 b).

To a well stirred solution of sodium azide (3mmol) in 10 ml of DMSO

was added, the appropriate chloroformyl pyrazole (Immol). The

reaction mixture darkens and temperature was slowly rised to 60 °C for

1 hour. After being cooled to room temperature the reaction mixture

was poured into 20 ml of cold water. The solid obtained was filtered,

washed with cold water and dried.

General procedure for the synthesis of bisindolylmethanes (42a-h)

A mixture of indole (2 mmol), aldehyde (1 mmol) and xanthan sulfuric

acid (200 mg) were ground together in a mortar with a pestle at room

temperature for specified period. On completion of reaction (as

monitored by TLC) chloroform (20 mL) was added and the reaction

mixture filtered. The catalyst was washed with chloroform several

times. Solvent was evaporated under reduced pressure to obtain the

43

product in almost pure form which was futther purified by

crvslallization from suitable solvents.

44

Spectroscopic data

4-lBis(indol-3-\i)methyll-5-cltloro-3-metliyl-l-phenylpynizole (42a)

Peach crystalline solid

MP : 210-212° C.

IR (KBr) v,,,J cm"' : 3467 and 3400 (NH), 1596 and

1541(C=C)

' H N M R (DMSO-dfi, 300 MHz) : 61.98 (s, 3H, CH3), 5.87 (s, IH,

Ha), 6.80-7.57 (m, 13Ar-

H+2Hb), 10.47 (s ,2H,NH).

"C NMR (300 MHz) : 5148.58, 138.35, 136.75,

128.78, 127.48, 126.64, 124.37,

123.64, 121.00, 118.92, 118.34,

115.40, 111.41,29.66, 13.45.

ESI-MS :M^436(m/z).

Anal. Calcd (C27H21N4CI) : C, 74.38; H, 4.82; N, 12.84 %;

Anal. Found (C27H21N4CI) : C, 73.37; 4.85, N, 12.82 %

4-lBis('mdol-3-yl)methyl]-5-azido-3-methyl-l-phenylpyrazole (42b)

Brown crystalline solid

MP : 220-222° C

45

IR (KBr) v,,,,,/ cm - : 342! and 3374 (NH), 1 542 and

1521 (C=C).

11 NMR (DMSO-d,, 300 MHz) : 61.98 (s, 3H, CH3), 5.87 (s, IH,

Ha), 6.80-7.57 (13 Ar-H +2Hh),

-^ T T "V TT -IV.^-/ (S, Zti, l^Jrl).

"C NMR (300 MHz) : 5146.58, 134.75, 133.95,

126.36, 125.24, 124.28,

123.80, 122.32, 120.86, 118.35,

117.66, 114.82, 110.35, 30.72,

14.26.

ESI-MS : M^ 443 (m/z)

Anal. Calcd (C27H21N7) : C, 73.20; H, 4.74; N, 22.12 %;

Anal. Found (C27H21N7) : C, 73.24; H, 4.77; N, 22.09 %

3-[Bis(indol-3-yl)methyl]chromone (42c)

Yellow crystalline solid

MP : 236-240° C.

IR (KBr) Vmax/ cm"' : 3389 and 3226 (NH), 1635

(CO), 1571 (C=C).

'lINMR(DMSO-d(„300MHz) : 56.08 (s, IH, Ha), 6.88-8.13

(m, 9Ar-H +2Hb +Hc +Hd +He),

10.69 (s,2H,NH).

46

•'CNMR(300MlIz) : 5176.25, 156.08, 154.53,

136.94, 133.34, 126.75, 125.52,

123.77, 123.69, 121.13, 118.96,

118.11, 115.94, 111.47,29.39.

L'.:ii-ivi>, ; ivi jyu un/z).

Anal. Calcd (CsoHigNsO.) : C, 80.07; H, 4.62; N, 7.18 %;

Anal. Found (C26H,8N202) : C, 80.11; H, 4.65; N, 7.2i %

3-[Bis(indol-3-yl)metliyl]-6-methylchromone (42d)

Yellow crystalline solid

MP : 244-246° C.

IR (KBr) v,™^/cm'' : 3289 and 3146 (NH), 1646

(CO), 1619 (C=C).

'li NMR (DMS0-d6, 300 MHz) : 52.35 (s, 3H, CH3), 6.42(s,lH,

Ha), 6.89-8.74 (m, 9Ar-H +

2Hb+ He + Hd +Hc), 10.27 (s,

IH, NH), 11.90(s, IH, NH).

13 C NMR (300 MHz) : 5175.64, 162.23, 156.34,

151.26, 135.71, 133.82, 128.62,

127.52, 124.46, 122.85, 121.24,

117.88, 116.74, 115.56, 113.60,

20.82.

47

[•:S1-MS : M'404 (m/z).

Anal. Calcd (C2-Ib)N:0:) : C. 80.27; H, 4.95; N, 6.93 %;

Anal. Found (C27H20N2O2) : C, 80.29; H, 4.92; N, 6.89 %

3-lBis(indol-3-yl)metltyl]-6-chlorochromone (42e)

Yellow crvstalline solid

MP : 240-242° C.

IR (KBr) v,„a.v' cnV' : 3304 (NH), 1640 (CO), i 604

(C=C).

'HNMR(DMSO-d(„300MHz) : 56.47 (s, IH, Ha), 7.03-8.23

(m,9Ar-H+2Hb+H,+Hd+He),

12.04(s, 2H, NH).

' Y NMR (300 MHz) : 8178.46, 165.32, 158.21,

150.60, 134.17, 128.26, 126.81,

124.24, 123.87, 121.66, 118.23,

117.65, 115.82, 112.28,25.62.

I-:SI-MS : M^ 424 {m/z).

Anal. Calcd (CjeHiTNsOzCi) : C, 73.59; H, 4.01; N, 6.60 %;

Anal. Found (CsfJii^NsOzCl) : C, 73.62; H, 4.03; N, 6.63 %

J, 3 '-(Thiophen-2-ylmetltylene)his(indole) (42f)

Brown crystalline solid

MP : 148-150° C.

48

IR (KBr) Vnuix/ cm' 3404 and 3384 (NH).

]545(C=C).

NMR (DMSO-de„ 300 MHz) : 86.09 (s, IH, Ha), 6.87-7,37 (m.

llAr-H+2Hb), 10.49 (s, 2H,

NK).

T NMR (300 MHz) 5149.35. 136.61. 126.37,

126.13, 124.55, 123.26, 120.95,

118.30, 118.25, 111.37,35.14.

liSl-MS M" 328 {m/z).

Anal. Calcd (C.iHieNzS) C, 76.83; H, 4.88; N, 8.53%;

Anal. Found (CsiH.fiNsS) C, 76.80; H, 4.83; N, 8.61 %

Tr'is(lH-indol-3-yl)methane (42g)

Brown crystalline solid

MP : 230-232° C.

IR (KBr) v,,,J cm" 3396 and 3054 (NH), 1553

(C=C).

' H NMR (DMS0-d6, 300 MHz) : 56.03 (s, IH, Ha), 6.81-8.04 (m,

13Ar-H+Hb), 10.46 (s, 3H, NH).

'Y" NMR (300 MHz) : 5136.75, 126.91, 123.36,

120.70, 118.49, 111.23,31.16.

;:Sl-MS :M"361 {m/z).

49

Anal. Calcd {C25II(9N3) : C, 83.17; H, 5.26; N, 1 1,63 %;

Anal, Found (Cz.H.oNO : C 83.14; H, 5.21; N, 11.61 %

J,3 '-Bis(indolyl)phenylmethanes (42h)

[3rown crystalline solid

N4P ; 124-126° C.

IR (KBr) v,™x/cm"' ; 3404 and 3194 (NH), 1603

(C-C).

'11 NMR (DMSO-dc, 300 MHz) : 55.88 (s, IH, Ha), 6.65-7.39

(m, 13Ar-H + 2Hb), 7.89 (s, 2H,

NH).

' T NMR (300 MHz) : 5144.68, 136.75, 128.41,

127.89, 126.74, 125.72, 123.70,

120.92, 119.21, 118.31, 118.21,

111.30,39.89.

r^SI-MS : M^ 322 {m/z).

Anal. Calcd (C.^HIKN.) : C, 85.79; H, 5.59; N, 8.69 %;

Anal. Found (CzsHisNj) : C, 85.82; H, 5.53; N, 8.64 %

50

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