Abstract
ABSTRACT
The Thesis entitled “Chemical Investigation on Natural and Synthetic Heterocyclic
Compounds” consists of three chapters.
CHAPTER- I
Chemical Investigation on Caesalpinia pulcherrima and Synthesis of
Homoisoflavonoids
Chemical Investigation on Caesalpinia pulcherrima
PART- A
INRODUCTION
Caesalpinia is a genus of the family Leguminosae. The species belong to this genus
are evergreen and deciduous trees, and shrubs grown as an ornamental plant. Various
species of Caesalpinia are known for their medicinal properties. The metabolites
obtained from different species of Caesalpinia are also chemically interesting. These
metabolites are of varied types, viz., different kinds of diterpenoids, flavonoids,
homoisoflavonoids and peltogynoids. The constituents of Caesalpinia species are thus
both chemically and biologically interesting.
The present investigation relates to the isolation and characterization of four naturally
new homoisofalvonoids from Caesalpinia Pulcherrima. These constituents belong to the
homoisofalvonoids which are relatively common in nature. The structures of the new
molecules have been confirmed by its 1D and 2D NMR (1H-1H COSY, HMQC, HMBC
and NOESY), mass spectroscopic studies and comparison with the structurally related
compounds in the literature.
The following compounds were isolated from the plant Caesalpinia Pulcherrima.
OMe
5
6
4a
O
4
7
MeO
O
5
3
2
8
1'
O
8a O
3'
1
6'
CP-I
4
6
2'
4'
7
MeO
10
1'
3
8a
O
CP-II
i
6'
4'
5'
1
O
5'
OMe
3'
2
8
2'
9
4a
OMe
Abstract
O
O
MeO
O
O
CP-III
O
O
MeO
OMe
O
HO
OMe
OMe
O
CP-IV
CP-V
O
O
HO
O
O
CP-VI
O
O
OH
HO
OH
OMe
O
HO
OH
O
CP-IX
CP-VIII
OMe
5'
8
MeO
7
1
8a
O 2
4a
5
OH
4
2'
OMe
O
CP-X
ii
OMe
4'
3'
1'
3
6
MeO
6'
OH
Abstract
Table- 1: Compounds isolated from Caesalpinia pulcherrima.
Compound
code
Compound name
Compound nature
Remarks
CP-I
5,7-Dimethoxy-3,4-methylenedioxy
Colorless powder
Known
compound
flavanone
CP-II
CP-III
7-Methoxy-3-(3-hydroxy-4-methoxy
Light yellow amorphous
Naturally New
benzylidene)chroman-4-one
powder
7-Methoxy-3-(4-methoxy
Light yellow amorphous
Known
benzylidene)chroman-4-one
powder
compound
Yellow amorphous powder
Naturally New
Yellow amorphous powder
Known
(7-O-methyl bonducellin)
CP-IV
7-Methoxy-3-(3,4-methylenedioxy
benzylidene)chroman-4-one
CP-V
7-Hydroxy-3-(2,4-dimethoxy
compound
benzylidene)chroman-4-one (2methoxy bonducellin)
CP-VI
7-Hydroxy-3-(3,4-methylenedioxy
Yellow solid
Naturally New
Yellow needles
Known
benzylidene) chroman-4-one
CP-VII
7-Hydroxy-3-(4-methoxy
benzylidene)
compound
chroman-4-one (bonducellin)
CP-VIII
CP-IX
7-Methoxy-3-(3-hydroxy-4-methoxy
Light yellow amorphous
benzylidene)chroman-4-one
powder
7-Hydroxy-3-(3,4-dihydroxy
Yellow solid
enzylidene)chroman-4-one (sappanone
Naturally New
First report
from the species
A)
3,6,7,4,5-Pentamethoxy-5,3CP-X
Yellow solid
dihydroxyflavone
First report from
the species
iii
Abstract
Synthesis of Homoisoflavonoids
PART- B
We extended our work to synthesis of isolated homoisoflavonoids from Caesalpinia
pulcerrima
and
of
known
homoisoflavonoids
from
Caesalpina
sappan
and
Hoffmanosseggia intricate. These are related to flavonoids and occur as natural
products and exhibit various biological properties. These compounds have been reported
to possess antifugal, hyposholesterolemic, antimutagenic, antiviral and antioxidant
activities. Synthesis of these compounds is based on condensation of 4-chromanones
with appropriate aromatic aldehydes in the presence of acidic or basic catalyst.
Retrosynthesis of some homoisoflavonoids is displayed below.
Scheme- 1
O
O
O
condensation
R
RO
O
2
+
RO
H
R
2
O
2
1
cyclization
O
HO
O
Cl
4
C-C formation
+
RO
OH
Cl
3
RO
OH
5
Accordingly we first prepared the 2′,4′-dihydroxy-3-chloropropiophenone 6 starting
from commercial available resorcinol 5 by reaction with 3-chloropropionic acid 4 using
trifluromethane sulphonic acid. We mainly focused on the synthesis of
7-
hydroxychroman-4-one 7, a key intermediate in the synthesis of homoisoflavonoids. In
the previous reports yields of this intermediate were less, reaction times were long and
more number of steps were involved. To over come the problems, we prepared this
intermediate through the reaction of resorcinol with 3-chloropropionic acid using
trifluromethane sulphonic acid to afford 2′,4′-dihydroxy-3-chlosropropiophenone 6, which
was cyclized using aqueous sodium hydroxide to give 7-hydroxy-4-chromanone 7 in
iv
Abstract
high yields (63% for two steps) (Scheme- 2). Formation of the product was confirmed by
its 1H NMR and mass spectra.
Scheme- 2
O
O
OH
HO
HO
5
Cl
CF3SO3H
+
80 oC
Cl
HO
30 min
4
2M NaOH
OH
2h
6M H2SO4
6
O
O
HO
7
Scheme- 3
O
O
H
OMe
HO
O
OMe
O
OMe
8
OMe
O
H
OMe
HO
O
O
OH
H
OMe
9
O
OH
O
OH
Piperdine
O
HO
70- 80 oC
2h
HO
O
O
O
10
OH
H
7
OH
O
HO
O
H
O
O
11
O
O
HO
O
OH
H
O
12
HO
O
O
OH
OMe
v
OH
O
13
OMe
Abstract
The piperdine catalyzed condensation of 7-hydroxy-4-chromanone 7 with 4-methoxy,
2,4-dimethoxy, 3,4-dihydroxy, 4-hydroxy, 3,4-methylenedioxy and 3-hydroxy-4-methoxy
benzaldyhydes afforded 8 (bonducellin), 9 (2-methoxy bonducellin) 10, (sappanone A),
11, 12 and 13 in 68, 63, 58, 65, 60 and 69% yields respectively (Scheme- 3).
The condensation of 7-methoxy-4-chromanone 14, which was obtained from
methylation of 7-hydroxy-4-chromanone 7 using iodomethane and K2CO3 with
appropriate substituted benzyldehydes, 4-methoxy, 3,4-methylenedioxy and 3,4dimethoxy benzaldehydes using piperdine gave compounds 15, 16 and 17 in 65%, 68%
and 66% yields respectively (Scheme- 4). Formation of the products was confirmed by
their 1H NMR and mass spectra.
Scheme- 4
O
O
MeO
O
O
16
O
piperdine
O
H
70- 80oC
2h
O
O
H
O
O
O
CH3I
OMe
acetone
O
HO
7
K2CO3
reflux
MeO
O
2h
piperdine
O
70- 80oC
2h
14
OMe
H
OMe
70- 80oC
2h
O
OMe
MeO
OMe
O
17
vi
MeO
OMe
O
15
Abstract
Bonducellin 8 was photoisomerized to isobonducellin 18 using medium pressure
mercury lamp in 48% (Scheme- 5). The spectral data (IR, NMR, and MS) of
isobonducellin were identical with those of natural product. Bonducellin and 2′-methoxy
bonducellin was converted into corresponding dihydrobonducellin 19 (95%) and dihyro2′-methoxybonducellin 20 (92%) respectively using Pd/C hydrogenation in methanol
(Scheme- 5). Formation of the products was confirmed by its 1H NMR and mass
spectra.
Scheme- 5
O
O
benzene
MeOH
OMe 3 h HO
O
19
HO
O
HO
Pd/ C
H2
hv, 4 h
OMe
O
O
8
18
OMe
OMe
O
OMe
O
Pd/ C
H2
HO
MeOH
3h
OMe
O
OMe
O
HO
9
20
The retro synthetic approach to the compounds intricatinol and intricatin are delineated
in Scheme- 6.
Scheme- 6
O
O
O
+
O
RO
OR
1
OMe
O
RO
21
H
OR
1
OMe
23
22
O
HO
O
Cl
4
+
OH
RO
OR
Cl
1
24
RO
OH
OR
1
25
vii
Abstract
The homoisoflavonoid, intricatinol (isolated from H. intricata) was synthesized from
7,8-dihydroxy-4-chromanone 28, a key intermediate obtained by the reaction of
pyrogallol 26 with 3-chloropropionic acid 4 in the presence of trifluromethane sulphonic
acid followed by cyclization with aqueous NaOH in 58% yield. Piperdine catalyzed
condensation of 7,8-dihydroxy-4-chromanone 28 with 4-methoxy benzaldehyde afforded
intracatinol 29 in 63% yield.
Finally we attempted to synthesize the intricatin (isolated from H. intricata). The
selective methylation of intricatinol 29 with dimethyl sulphate using NaHCO3 as a base
gave intricatin 30 in 48% yield and dimethylated product 31 in 18% yields. The formation
of the products was confirmed by their 1H NMR and mass spectra.
Scheme- 7
O
O
CF3SO3H
+
OH
HO
HO
Cl
OH
oC
80
30 min
HO
Cl
OH
4
26
OH
2M NaOH
2h
6M H2SO4
O
27
HO
O
OH 28
O
Piperdine
H
O
MeO
MeO
O
OH
O
OMe
2h
23
O
OMe
DMS
30
+
NaHCO3
36 h
r. t.
O
MeO
70- 80oC
OMe
O
HO
OH
29
OMe
31
Another method for synthesis of intricatin involved 7-methoxy-8-hydroxy-4chromanone 34, it can be obtained from the reaction of 3-methoxy catacohol 32 with 3chloropropionic acid 4 using trifluoromethane sulphonic acid followed by cyclization with
aqueous NaOH. 7-Methoxy-8-hydroxy-4-chromanone 34 and 4-methoxy benzaldehyde
viii
Abstract
23 condensed together in the presence of piperdine to afford intricatin 30 in 58% yields.
Formation of the products was confirmed by its 1H NMR and mass spectra.
Scheme- 8
O
O
CF3SO3H
+
MeO
HO
OH
Cl
80 oC
MeO
30 min
OH
32
OH
2M NaOH
2h
Cl
6M H2SO4
OH
4
O
33
MeO
O
OH
34
O
Piperdine
H
MeO
70- 80oC
2h
23
O
MeO
OMe
O
OH
30
CHAPTER- II
Chemical Investigation on Orthosiphon glabratus and Synthesis of Chromene
and Chromenochalcone
Chemical Investigation on Orthosiphon glabratus
PART- A
INTRODUCTION
Various species of Orthosiphon are known for their medicinal properties. The
metabolites obtained from different species of Orthosiphon are also chemically
interesting. These metabolites are of varied types, viz., different kinds of diterpenoids,
monoterpene,
polychiral
furano
pyrones,
flavonoids,
saponins
and
chromene
compounds. The constituents of Orthosiphon species are thus both chemically and
biologically interesting.
ix
Abstract
The present investigation relates to the isolation and characterization of twelve
compounds from Orthosiphon glabratus which was not investigated earlier. These
constituents belong to the chromenochalcones, chromenes, polychiral furano pyrones
and flavonoids. The structures of the new molecules have been confirmed by its 1D and
2D NMR (1H-1H COSY, HMQC, HMBC and NOESY) and mass spectroscopic studies
and by comparison with the structurally related compounds reported in the literature.
Table 2: Compounds isolated from Orthosiphon glabratus
Compound
Compound name
Compound nature
Remarks
1-(5-Hydroxy-2,2-dimethyl-2H-
Light yellow amorphous powder
New compound
White crystals
First report from the
species
code
OG-I
chromen-6-yl)-3-(2,3,4trimethoxyphenyl)-propenone
OG-II
6-Acetyl-7-hydroxy-2,2-dimethyl
chromene (eupatoriochromene )
OG-III
3,5,7,4′-Tetramethoxy flavanoid
Colorless solid
First report from the
species
OG-IV
3,5-Dihydroxy-7,3′,4′-trimethoxy
Pale yellow solid
First report from the
species
flavanoid (casticin)
OG-V
OD-1
Viscous mass
First report from the
species
OG-VI
OD-VII
Viscous mass
First report from the
species
OG-VII
3,4-Dihydro-6-acetyl-(5-O-prenyl)-
Colorless viscous
New compound
Yellow solid
First report from the
species
Yellow needles
First report from the
species
2,2-dimethylchromene
OG-VIII
1-(5-Hydroxy-2,2-dimethyl-2Hchromen-6-yl)-3-(4-methoxyphenyl)propenone
(pongachalcone-I)
OG-IX
1-(5-Hydroxy-2,2-dimethyl-2Hchromen-6-yl)-3-(3-hydroxy-4methoxyphenyl) -propenone
(pongachalcone-II)
OG-X
8-Hydroxy-6,7-dimethoxy coumarine
Pale yellow solid
First report from the
species
OG-XI
3-Methoxy-4-hydroxy cinnamic acid
Colorless amorphous powder
First report from the
species
x
Abstract
(ferulic acid)
OG-XII
3-Hydroxy -4-methoxy cinnamic acid
Colorless solid
First report from the
species
(Isoferulic acid)
O
OH
4
10
3
H3 C
OMe
13
5
6 11
H3 C
9
61
7
8
1
OMe
31
12
2
O
21
11
41 OMe
51
OG-I
31
21
O
4
5
3
H3C
10
H3C 9
1
8
MeO
7
6 11
2
1
7
8
61
4
6
12
51
2
OH
OMe
3
5
O
11
O
OMe
O
OG-III
OG-II
41
51
61
31
OH
21
11
OMe
14
O
O
O
MeO
4
3
OH
O
6
O
O
O H
1
11
H
8
7
9
OH
H
OG-V
OG-IV
xi
H
10
5
2
OMe
H
12
H3 C13
OMe
41
H
OCOCH3
Abstract
4'
O
O
OH
1'
H
H
O H
H
3'
O
O
2'
4
5
4a
3
H3 C
OH
O
O
5'
H
OCOCH3
H3 C
2
10
H
9
OG-VI
OH
7
8a
O
H3 C
12
11
6
8
1
OG-VII
O
H3 C
O
H3 C
OMe
OG-VIII
MeO
O
OH
4a
3
7
OH
MeO
H3 C
O
H3 C
OG-IX
O
1
HO 4
9
O
1
OG-X
O
7
5
8a
8
OH
OMe
6
4
5
6
OH
OH
8
2
3
MeO
OMe
OH
OG-XI
xii
OG-XII
2
O
Abstract
Synthesis of Chromene and Chromenochalones
PART- B
We extended our work to syntheses of isolated chromenochalcones, chromenes,
ferulic
acid
and
isoferulic
acid
from
Orthosiphon
glabratus
and
of
known
chromenochalcones from Pongamia glabra and Loncocarpus utilus. These are related to
flavanoids and occur as natural products and exhibit various biological activities These
compounds have been reported to possess anticancer, antiinflammantory, antimitotic,
antitubercular, cardiovascular, cell differentiation inducing nitric oxide regulation
modulatory, antimalarial, antileishmanial, antihyperglycemic, antioxidant, antifeedant and
antimicrobial activities. Synthesis of these compounds is based on condensation of
acetylated chromenes with appropriate aromatic aldehydes in the presence of acidic or
basic catalyst.
The retro synthetic approach to the chromenochalcones is delineated (Scheme- 9).
Scheme- 9
OH
O
35
O
OH
R
O
O
+
O
R
36
O
O
+
H
H
OH
HO
37
38
Accordingly we first prepared the 6-acetyl-5-hydroxy-2,2-dimethyl chromene 36
starting from commercial available resacetophenone with 3-methyl-2-butenal using
pyridine. We are mainly focused on the synthesis of 6-acetyl-5-hydroxy-2,2-dimethyl
chromene, a key intermediate in the synthesis of chromenochalcones (Scheme- 10).
Because in the previous reports yields of this intermediate were less, reaction times
xiii
Abstract
were long and involves more number of steps. Along with 6-acetyl-5-hydroxy-2,2dimethyl chromene 36 the minor product 6-acetyl-7-hydroxy-2,2-dimethyl chromene 37
was also obtained in 6% yield. The BF3.Et2O catalyzed condensation of 6-acetyl-5hydroxy-2,2-dimethyl
chromene
with
4-methoxy,
3-hydroxy-4-methoxy,
3,4-
methylenedioxy, 2-hydroxy-3-methoxy and 2,3,4-trihydroxy benzaldyhydes afforded 40,
41, 42, 43 and 44 in 78, 83, 84, 81 and 83% yields respectively (Scheme- 11).
Scheme- 10
O
OH
O
O
+
H
H
O
OH
HO
+
O
2h
38
37
36 94%
Pyridine
O
OH
39 6%
Scheme- 11
O
OH
O
H
MeO
O
OMe
40
O
OH
HO
O
H
OH
MeO
OH
O
BF3.Et2O
Dioxane
O
O
O
OMe 41
OH
O
O
H
O
O
150 min
O
O
36
OH
O
MeO
OH
O
42
OH
H
OMe
O
43
OMe O
MeO
OH
H
O
OMe
OMe
MeO
O
OMe
44
xiv
Abstract
We have subjected the molecule 6-acetyl-5-hydroxy-2,2-dimethyl chromene 45 to
catalytic hydrogenation in presence of 10% Pd/C catalyst in methanol to afford the
desired
3,4-dihydro-6-acetyl-5-hydroxy-2,2-dimethyl
chromene
46
in
93%
yield
(Scheme- 12).
O-prenyl-3,4-dihydro-6-acetyl-5-hydroxy-2,2-dimethyl chromene 47 was obtained
from prenylation of 3,4-dihydro-6-acetyl-5-hydroxy-2,2-dimethyl chromene 46 using
prenylbromide and K2CO3 in acetone under reflux condition (Scheme- 12). The
prenylation of 6-acetyl-5-hydroxy-2,2-dimethyl chromene also proceeded in similar
conditions to form the corresponding O-prenyl product 45 (Scheme- 12).
Scheme- 12
O
O
OH
Br
K2CO3
O
45
Acetone
reflux
2h
O
O
OH
H2
Pd/C
MeOH
O
O
2 -3 h
46
36
Br
K2CO3
Acetone
reflux
2h
O
O
O
47
The ferulic acid and its analogues are well-known as antioxidants and prevent
oxidative damage of DNA by several mechanisms. In addition, these are also known to
exhibit antiinfalammatory, antiprolferative, antiviral and immunoprotective properties.
The ferulic acid and its esters are currently under development as a new drug candidate
for the treatment of the dementia.
xv
Abstract
The retrosythetic approach is delineated in Scheme- 13.
Scheme- 13
O
H
O
RO
O
1
RO
1
OR
48
50
OR
OH FGI
OCH2CH3
RO
+
O
Wittig Reaction
1
OR
Ph3P
49
OCH2CH3
51
FGI
O
PPh3 +
Br
OCH2CH3
52
We were also interested to synthesis ferulic acid and its regioisomer isolated from
Orthosihon glabratus. We started the synthesis of ferulic acid (56) from commercially
available 3-methoxy benzaldehyde 54, which was subjected to homologation by C-2
Wittig olefination using C-2 Wittig salt (Ph3P=CHCOOEt) in distilled benzene at reflux
condition for 1.2 h to afford E and Z α, β-unsaturated esters 55a and 55b in combined
yield of 98% (Scheme- 14). The trans isomer was found to be major (94%). Hydrolysis
of ethyl ester 55a using 20% methanolic KOH under reflux for 2 h, followed by
neutralization with aq. HCl afforded the desired ferulic acid 56 in excellent yield (91%)
(Scheme- 14).
xvi
Abstract
Scheme- 14
O
PPh3 +
Br
O
O
Benzene
OCH2 CH3
52
Br - Ph3P
+
r.t., 12 h
53
CH2Cl
OCH2 CH3
Ph3P
OCH2 CH3
aq. NaOH
51
+
O
Benzene
H
reflux, 1.2 h
HO
OMe
O
54
O
O
OH
aq. NaOH
HO
OCH2 CH3
HO
OMe
HO
OMe
56
EtO
+
OMe
55b
55a
The synthesis of isoferlic acid 59 was started from commercially available 4-methoxy3-hydroxy benzaldehyde 57, which was subjected to homologation by C-2 Wittig
olefination using C-2 Wittig salt (Ph3P=CHCOOEt) in distilled benzene at reflux condition
for 1.2 h to afford E and Z α, β-unsaturated ester 58a and 58b in combined yield of 98%
(Scheme- 15). The trans isomer was found to be major (94%). Hydrolysis of 58a using
20% methanolic KOH under reflux for 2 h, followed by neutralization with aq. HCl afford
the desired ferulic acid 59 in excellent yield (93%) (Scheme- 15).
Scheme- 15
O
O
Ph3P
O
H
OCH2 CH3
+
Benzene
MeO
MeO
OH
51
OCH2 CH3
reflux, 1.2 h
57
+
O
O
OH
59
OCH2 CH3
aq. NaOH
6NHCl
MeO
OH
58b
OH
58a
MeO
OH
xvii
Abstract
CHAPTER- III
Development of New Synthetic Methodologies for Formation of Heterocyclic
Compounds
PART- A
Heterogeneous catalysts-an overview
In the 20th century, a seemingly very different type of catalysis, heterogeneous
catalysis, became the foundation for much of the chemical industry. It plays a central
role in generating the feed stocks for making the synthetic materials that we use every
day, from fuels to fertilizers. New experimental techniques have brought fresh insights
into this form of catalysis, and it now seems that there are more similarities between
enzymes and heterogeneous catalysts than initially meets the eye.
An extensive application of heterogeneous catalysis in synthetic chemistry can help
to achieve new selective reactions, to lower the waste production, and, finally, to render
more attractive the synthetic process from both the environmental and also the
economic point of view, in agreement with some parameters of the “ideal synthesis”.
Generally the classical synthetic methodologies involve expensive reagents and
catalysts, which are not easily available and require harsh reaction conditions. Thus
there is a need to replace such reagents and catalysts. Recently there is also a much
greater demand on organic chemists for innovation of new mild synthetic methodologies
in view of the stipulations laid down by the environmental systems. The threat to
ecological and environmental synthesis due to the damages caused by the chemicals
has put forward a new area of the so called “Green Chemistry”.
PART- B
PRESENT WORK
3.0 Development of New Synthetic Methodologies
Different improved processes are now being discovered to carry out the reactions
efficiently and conveniently with readily available inexpensive materials. During the
present study utilizing heterogeneous as well as homogeneous catalysts some important
synthetic methodologies have been developed for synthesis of heterocyclic compounds.
xviii
Abstract
3.1. An efficient synthesis of 1,8-dioxo-octahydroxanthenes using heterogeneous
catalysts
Xanthenes and benzoxanthenes have received much attention because of their wide
range of therapeutic and biological properties, such as antibacterial, antiviral, and antiinflammatory activities. Furthermore, these compounds have emerged as sensitizers in
photodynamic therapy and are used as leuco-dyes and in laser technology.
Heterogeneous catalysts have gained interesting attraction in recent years due to
economic and environmental considerations. These catalysts are generally inexpensive
and easily available. They can conveniently be handled and removed from the reaction
mixture, thus making the experimental procedure simple and eco-friendly.
We have observed that 5,5-dimethyl-1,3-cyclohaxanedione 60 can easily undergo the
condensation with aromatic aldehydes 61 in the presence of silica supported sodium
hydrogen sulfate (NaHSO4.SiO2) or silica chloride to from 1,8-dioxo-octahydroxanthene
derivative 62 (Scheme- 16). The mixture of 60 and 61 was refluxed in CH3CN using
either of these two catalysts. Earlier, compound 62 was not synthesized using a
heterogeneous catalyst.
Scheme- 16
O
+ ArCHO
O
60
NaHSO4.SiO2
or
silica chloride
CH3CN
6.0-6.5h reflux
O
Ar
O
O
90-98%
62
61
15 Examples
We have developed a convenient and efficient method for the synthesis of 1,8-dioxooctahydroxanthenes utilizing two heterogeneous catalysts, NaHSO4.SiO2 and silica
chloride. The simple experimental work-up, high yields and applications of inexpensive
catalysts are the advantages of the present procedure.
xix
Abstract
3.2: Amberlyst-15: An efficient reusable heterogeneous catalyst for the synthesis
of 1,8-dioxo-octahydroxanthenes and 1,8-dioxodecahydroacridines
Acridine derivatives containing the 1,4-dihydropyridine unit belong to a special class
of compounds, not only because of their interesting chemical and physical properties but
also owing to their immense utility in the pharmaceutical and dye industries; they are
also well-known therapeutic agents.
Here we have observed that Amberlyst-15 is an efficient heterogeneous catalyst for
the synthesis of 1,8-dioxo-octahydroxanthenes 62 and 1,8-dioxo-decahydroacridines 63.
The former were prepared from a mixture of 5,5-dimethyl-1,3-cyclohexanedione 60 and
aromatic aldehydes 61 by heating in CH3CN under reflux in the presence of the catalyst
while the latter from this mixture along with amines under the similar reaction conditions
(Scheme- 17).
Scheme- 17
O
Ar
Amberlyst-15
O
O
O
O
ArCHO
CH3CN, reflux
5.0h
O
RNH2, Amberlyst-15
+
O
CH3CN, reflux
4.5-6.5 h
N
R
R=Aryl,Alkyl
90-96%
62
Ar
81-94%
61
60
63
15 Examples
We have developed a novel and efficient method for the synthesis of 1,8-dioxooctahydroxanthenes and 1,8-dioxo-decahydroacridines in high yields employing
Amberlyst-15 as a heterogeneous solid acid. The application of an inexpensive, easily
available and reusable catalyst makes this method simple, clean, practical and
economically viable. The method is an easy access to functionalized xanthenes and
acridines.
3.3. Efficient synthesis of 3-alkyl indoles through regioselective ring opening of
epoxides catalyzed by sulfated zirconia
Indole derivatives are key structural motifs in many pharmacologically and biologically
active compounds and as well as in many natural products. 3-Alkylindoles have
significant medicinal importance and they can be prepared by Friedel- Crafts alkylation
of indoles using epoxides.
xx
Abstract
During the development of useful synthetic methodologies we observed that the
styrene epoxide 64 can be opened smoothly with indole 65 in the presence of sulfated
zirconia in CH2Cl2 to afford the corresponding 3-alkylindoles 66 at room temperature
(Scheme- 18).
Scheme- 18
R
O
R3
R2
+
N
R
Sulfated
zirconia
CH2Cl2
R1
OH
R3
r. t
3- 4.5 h
N
R2
R1
64
42- 83%
65
66
15 Examples
Sulfated zirconia has been used here for the first time as an efficient catalyst for the
preparation of alkylated nitrogen heterocycles at room temperature from various
epoxides and nitrogen heterocycles. The mildness of the conversion, simple
experimental procedure, impressive regioselectivity and reusability of the catalyst are the
notable advantages of the present method.
3.4. Selective acetylation of alcohols, phenols and amines and selective
deprotection of aromatic acetates using silica supported phosphomolybdic acid
Protection of functional groups is highly essential in organic synthesis. The alcohols,
phenols and amines are frequently protected as acetates, which are generally prepared
by reaction with Ac2O in the presence of pyridine. (Dimethylamino) pyridine (DMAP) and
4-pyrrolidino pyridine (PPY) are also known to catalyze the acetylation of alcohols.
We have observed that silica supported phosphomolybdic acid is very suitable to
catalyze the acetylation of alcohols and phenols with acetic anhydride to form the
corresponding acetates at room temperature (Scheme- 19). The chemo selectivity of
the present acetylation method is remarkable. An alcoholic hydroxyl group can
conveniently be acetylated keeping intact the phenolic hydroxyl group in a molecule.
xxi
Abstract
Scheme- 19
O
O
R1
R2
R1
Ac2O
R2
PMA.SiO2
HO
O
R3
Neat, r. t.
2.5- 3.0 h
AcO
O
R3
68- 72%
67
68
31 Examples
Phenolic hydroxy groups are present in several bioactive naturally occurring
compounds. Hence protection and subsequent deprotection of this group is necessary
for multistep transformations and synthesis of these compounds. We have observed that
silica supported phosphomolybdic acid is a highly efficient catalyst for chemoselective
deprotection of aromatic acetates in methanol at room temperature within 2-3 h. Several
aromatic acetates underwent deprotection in the presence of the catalyst to produce the
corresponding parent phenols (Scheme- 20).
Scheme- 20
CH3O
CH3O
O
O
O
PMA. SiO2
OAc
AcO
O
O
O
O
O
r. t., Methanol
2.0 h
OCH3
OAc
HO
OCH3
98%
69
70
19 Examples
In conclusion, we have developed a simple and efficient method for acetylation of
alcohols, phenols and amines with Ac2O using silica supported phosphomolybdic acid as
a heterogeneous catalyst. The catalyst has also been applied for deprotection of
aromatic acetates. The salient features of this protocol include operational simplicity,
mild reaction conditions, short reaction times, excellent yields, application of an
inexpensive heterogeneous catalyst, compatibility with other hydroxyl and amine
protecting groups, high chemoselectivity and monoprotection of symmetrical diols.
xxii
Abstract
3.5. (Bromodimethyl) sulfonium bromide catalyzed aza- Diels- Alder reaction: A
highly efficient synthesis of tetrahydroquinolines
The substituted 1,2,3,4-tetrahydroquinoline derivatives are important class of
compounds in the field of medicinal chemistry, as these compounds possess a broad
range of biological properties. Tetrahydroquinoline moiety is also a component of many
bioactive natural products. Hence, there has been a considerable interest in the
development of new and efficient methodologies for the synthesis of tetrahydroquinoline
derivatives. The aza-Diels-Alder reaction provides a convenient method for the
preparation of these compounds. The imines derived from aromatic amines act as
heterodynes and undergo imino-Diels-Alder reactions with various dienophiles.
Here we have observed that (bromodimethyl)sulfonium bromide catalyzed efficiently
the reaction of arylamines with enol ethers to form the substituted 1,2,3,4tetrahydroquinoline derivatives at room temperature (Scheme- 21).
Scheme- 21
H
O
( )n
H
N
H
R
+
NH2
R
Me2S+BrBr ( )n
O
n= 0, 1
71
OH
endo 73a
+
CH3CN
r. t., 1.5- 2.5 h
H
O
( )n
72
H
N
H
R
n= 0, 1
OH
exo 73b
78- 91 %
15 Examples
In conclusion, (bromodimethyl)sulfonium bromide (Me2S+BrBr–) catalyzed facile
preparation of 1,2,3,4-tetrahydroquinolines from anilines and cyclic enol ethers has been
conveniently achieved in excellent yields and with high diastereoselectivity under mild
reaction conditions.
xxiii
Abstract
3.6. Convenient and facile cross-Aldol condensation catalyzed by Amberlyst-15 or
molecular iodine: An efficient synthesis of ,-bis(substituted benzylidene)
cycloalkanones
The
benzylidene
derivatives
are
intermediates
of
various
pharmaceuticals,
agrochemicals and perfumes. They are frequently used for the synthesis of bioactive
pyrimidene compounds. They also find applications in the preparation of nonlinear
optical materials and liquid –crystalline polymers.
Here during development of important synthetic methodologies we have discovered
that Amberlyst-15 and molecular Iodine are two efficient catalysts for cross-Aldol
condensation of aromatic aldehydes 74 with cyclic ketones 75 (Scheme- 22).
Scheme- 23
o
2 Ar-CHO
Amberlyst- 15
or
I2
+
( )n
n =1, 2
74
o
Ar
Ar
CH2Cl2 r.t.
3.0- 8.0h
75
( )n
n =1, 2
89-95%
76
22 Examples
Cross-Aldol condensation was also carried out using aromatic aldehydes 74 and 4chromanone 77 (Scheme- 23). 3-(Substituted benzylidenes)-4-chromanones 78 were
obtained in high yields.
Scheme- 23
O
O
Ar-CHO
Amberlyst- 15
or
I2
+
O
CH2Cl2
6.0h
74
77
r.t.
Ar
O
85-90%
78
5 Examples
In conclusion we developed a simple and efficient protocol for cross-Aldol
condensation of aromatic aldehydes with cyclic ketones including 4-chromanones using
Amberlyst-15 or molecular I2 at room temperature. The notable features of this procedure
are cleaner reaction profile, mild reaction conditions, operational simplicity, short
reaction times and excellent yields.
xxiv