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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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