Synthesis of Substituted BenzoylFumarate Derivatives against
Mycobacterium Tuberculosis
1. INTRODUCTION
1.1 Mycobacterium Tuberculosis
Mycobacterium tuberculosis (Mtb) is a notorious pathogen whose increasing resistance to
antibiotics and heightened lethality in combination with AIDS makes it a major health concern
worldwide. 1In 2012, the World Health Organization reported almost nine million new cases of
TB, 1.3 million deaths due to TB and 0.3 million deaths resulting from a co-infection with HIV
and TB. 2It commonly affects the lungs and it is transmitted from person to personvia droplets
from the throat and lungs of people with the active respiratory disease. In healthy people,
infection with Mycobacterium tuberculosis often causes no symptoms, since the person's
immune system acts to “wall off” the bacteria. 3
Schematic representation of different stages of Mycobacterium tuberculosis infection is
shown in the Figure 1.4 The cycle starts by transmission of the disease from pulmonary TB
infected people to healthy individual as they expel bacteria in air, through coughing or sneezing.
Interestingly, out of these infected people only small portion (5%)of individual will go on to
develop TB to such as those with poor immune system such as person infected by HIV(50%),
Diabetes patients , who can take chemotherapy and the population with deprived nutrition are
also vulnerable to develop TB. Another fact about TB is that men are more susceptible to
develop TB than women.5
1
Figure 1: Different stages of M.Tuberculosis infection
1.2 Anti-TB Drugs and Their Drawbacks
Anti-tuberculosis (TB) drugs are classified into five groups based on evidence of
efficacy, potency, drug class and experience of use.6First-line anti-TB drugs (Group 1) are
currently recommended in a four-drug combination for the treatment of drug-susceptible TB.
Second-line anti-TB drugs (Groups 2, 3 and 4) are reserved for drug-resistant TB. Third-line
anti-TB drugs (Group 5) have unclear efficacy or undefined roles.
First-line anti-TB drugs
Group 1. Oral: isoniazid, rifampicin, pyrazinamide, ethambutol, rifapentine or rifabutin.
Second-line anti-TB drugs
Group 2. Injectable aminoglycosides: streptomycin, kanamycin, amikacin. Injectable
polypeptides: capreomycin, viomycin.
Group 3. Oral and injectable fluoroquinolones: ciprofloxacin, levofloxacin, moxifloxacin,
ofloxacin, gatifloxacin.
Group 4. Oral: para-aminosalicylic acid, cycloserine, terizidone, ethionamide, prothion-amide
,thioacetazone, linezolid.
2
Third-line anti-TB drugs
Group 5.Clofazimine, linezolid, amoxicillin plus clavulanate, imipenem plus cilastatin,
clarithromycin.
Although infections with drug sensitive strains can be effectively cured with a 6 to 9 month
regimen of multiple antibiotics, the inability to deliver and complete appropriate courses of
therapy on a global level has led to the selection of resistant strains over the past 50 years.
Especially alarming is the upsurge in cases of multidrug-resistant tuberculosis (MDR-TB).7 The
selection and spread of multiple drug resistant Mtb continued for decades leading to selection
and spread of two operationally distinct forms, multiple drug resistant(MDR-TB resistant to
isoniazid and rifampicin) and extensively drug resistant (XDR-TB resistant to isoniazid,
rifampicin, a fluoroquinolone and at least one of the inject able second-line agents). In this
regard, the structures of the usually available anti TB drugs and their side effects are provided in
the following section (Figure 2 , Table 1 ).
Figure 2: Structures of Anti-TB drugs
3
Table 1: Anti-TB drugs and their side effects
DRUGS
SIDE EFFECTS
Rifampicin
Decreased appetite
Pyrazinamide
Nausea, Abdominal pain
Pyrazinamide
Joint pains
Isoniazid
Burning sensation in the feet
Rifampicin
Orange/Red urine
Rifampicin /Pyrazinamide/ Rifampicin
Itching, Skin rash
Streptomycin
Deafness
Streptomycin
Dizziness
Most anti TB drugs
Discoloration of eye
Most anti TB drugs
Vomiting
Ethambutol
Visual impairments
Rifampicin
Low urine output
2. HISTORICAL BACKGROUND OF 1,4-DIPOLAR CYCLOADDITION
Cycloaddition reactions constitute an important class of carbon-carbon as well as carbonheteroatom bond forming process in synthetic organic chemistry. Generally cycloaddition
reactions are considered to be concerted processes, with the simultaneous formation of two
new ϭ-bonds, via a cyclic transition state. Apart from the well-known Hetero Diels-Alder
reactions,81,4-dipolar
cycloaddition9
constitutes
a potentially versatile process
for
the
construction of six membered heterocycles.
A l,4-dipole is defined as a system 'a-b-c-d', in which ‘a’ has an unfilled electron
shell and carries a formal positive charge and ‘d’ is an anionic center with a free electron
pair. It is only the internal octet stabilisation with the help of a lone pair on ‘b’ that makes the
l,4-dipole capable of existence(Figure 3).
4
Figure3
The l,4-dipole is usually generated in situby the reaction of an electrophile (c=d)
with a nucleophilic (a=b) double bond. The combination of such a l,4-dipole with a multiple
bond system (e=f) termed as dipolarophile is referred to as l,4-dipolar cycloaddition (Figure
4).
Figure4
The l,4-dipolar cycloaddition reaction proceeds via a two-step addition mechanism in
which the two new σ bonds are formed one after the other. The l,4-dipole combines only
with those dipolarophiles which themselves display pronounced electrophilic or nucleophilic
reactivity.
The history of 1,4-dipolar cycloaddition dates back to 1932, when Diels and Alder reacted
pyridine with dimethyl acetylenedicarboxylate (DMAD) and obtained a 1:2 adduct whose
structure was established as a 4H-quinolizine much later by the extensive investigations of
Acheson and co-workers(Scheme 1).10 Many nitrogen containing heterocyclic compounds
undergo analogous reactions with DMAD; these can be designated as 1,4-dipolar cycloaddition
reactions.11
5
Scheme 1
One of the earlier reports from Huisgen has shown that the l,4-dipole generated from
aldimine and DMAD undergoes l,4-dipolar cycloaddition with second molecule of DMAD
to form the cycloadduct(Scheme 2).12
Scheme 2
The evidence for a similar 1,4-dipolar intermediate in the reaction of PTAD with l-phenyl4-vinylpyrazole
was
provided
by
its
trapping
with acetone, affording tetrahydro-
oxadiazine(Scheme 3).11
Scheme 3
6
Ghosezet al. reported an interesting intramolecular cyclisation of the 1,4-dipole
derived from enamine and N-phenylketenimine resulting in a one-pot synthesis of 4aminoquinoline derivatives in good yields(Scheme 4).13
Scheme 4
An unusual intramolecular cyclisation of 1,4-dipole derived from N-acylimidazole
and DMAD resulting in the formation of imidazo[1,2-a]pyridine ring system was observed
by Knolker14(Scheme 5).
Scheme 5
3. AIM OF PRESENT INVESTIGATION
New TB drugs needed because of the complexity, toxicity and high cost of the current
anti TB drug regimens and the major problem of them is the resistance. Besides this the
interaction of these drugs with the viral drugs taken by HIV positive people create major
7
problems, means that there is an urgent need for new anti TB drugs.The present study aims to
synthesize some new organic compounds with drug likeness.
Recent studies showed that one of the derivatives, dimethyl 2-(4-methylbenzoyl) fumarate
displayed anti-tuberculosis activity against M.tb.H37Rv with MIC value of 25.
To improve the anti-tuberculosis activity of the benzoyl fumarate moiety, we undertook the
synthesis of differently substituted benzoyl fumarates and their synthetic transformation to
biologically significant motifs by incorporating indole molecule.
4. RESULTS AND DISCUSSION
4.1 Reaction of Pyridine and DMAD with Aldehydes
Benzoyl fumarates and its corresponding acids are known to be important precursors for
the synthesis of many agro chemicals, drugs and organic transformations. Nair et al. reported the
synthesis of benzoyl fumarates by one pot reaction between dimethyl acetylene dicarboxylate
(DMAD) and aldehyde in presence of catalytic amount of pyridine (Scheme 6). 15
Scheme 6:Reaction of DMAD with aldehyde
The reaction of 4-bromobenzaldehyde with DMAD in presence of catalytic amount of
pyridine (20 mol%) in THF at -10
o
C followed by warming to room temperature
affordeddimethyl 2-(4-bromobenzoyl)fumarate72 % yield(Scheme 7).
8
Scheme 7
The structure of the product was elucidated by spectroscopic techniques. In IR spectrum,
a sharp band at 1714 cm-1 was assigned to the ester carbonyl ,while the absorption at 1669 cm-1
was attributed to the benzoyl carbonyl. The 1H NMR spectrum displayed two methoxy groups as
singlets at δ 3.66 and 3.79 and the olefinic proton was observed as a singlet at δ 7.08.In the
13
C
NMR spectrum, the two ester carbonyls were observed at δ 163.9 and 163.2, while the benzoyl
carbonyl was discernible at 190.8. The two methoxy carbons were observed at δ 53.2 and 52.4.
By utilizing this methodology, we have synthesized differently substituted Dimethyl
benzoyl fumarates by reacting various substituted aromatic aldehydes and the results are shown
in Table 2
Table 2: Synthesis of substituted benzoyl fumerates
Entry
Aldehyde
Product
Yield (%)
1
72
2
67
9
3
68
4
61
Mechanistic Consideration:
Mechanistically, the reaction may be raionalised to involve the initial addition of pyridine
to DMAD to form the 1,4-dipole and the addition of the latter to the aldehyde carbonyl, yielding
the 4+2 cycloadduct. The latter then undergoes a [1, 3]- H shift and ϭ-bond rotation, followed by
the elimination of pyridine, resulting in the formation of 2-benzoyl fumarate(Scheme 8).
Scheme 8
10
4.2 Reaction of substituted benzoyl fumerates with indole and substituted indole
Indole derivatives are very important heterocyclic compounds in the drug-discovery studies.
They represent a very important class of molecules that play a major role in cell biology and are
potential naturally occurring products. There has been an increasing interest in the use of indole
derivatives as bioactive molecules against microbes, cancer cells and various kinds of disorder in
the human body.16
Ahmed Kamal et al. synthesized of 3, 3-diindolyl oxyindoles efficiently catalyzed by FeCl3
and their in vitro evaluation for anticancer activity (Scheme 9).17
Scheme 9:3, 3diindolyloxylindoles: Anticancer agent
Lebohoet al. synthesised 2- and 3-aryl indoles and these compounds show excellent
antibacterial and antifungal activity. They also synthesized the 3-arylindoles from the
corresponding 3-bromoindoles using Suzuki-Miyaura reactions These synthesized 2- and 3arylindoles displayed potent antimicrobial activity, against the Gram-positive micro-organism
Bacillus cereus (Scheme 10).18
Scheme 10
11
4.2.a Reaction of dimethyl 2-(4-bromobenzoyl) fumarate with indole
The reaction of dimethyl 2-(4-bromobenzoyl) fumarate and indole in presence of Sc(OTf)3 in
CH3CN at room temperature for 4 h, afforded theMichael addition product as an inseparable
mixture of diastereomersin a total yield of 52 % (dr =1: 0.84)(Scheme 11).
Scheme 11
The structure of the product was elucidated by various spectroscopic techniques. In IR
spectrum , a sharp band at 1733 cm-1 was assigned to the ester carbonyl ,while the absorption at
1598 cm-1 was attributed to the benzoyl carbonyl (Figure 5).
Figure 5
The 1H NMR spectrum it was seen that the protons attached to the chiral carbon of
diastereomers resonated at δ 5.4, 5.24, 4.93 and 4.85. From proton NMR integration, the ratio of
two of these protons were found as 1:0.84. This clearly indicates the presence of two
diasteroisomers. Similarly the methoxy groups are 3.74, 3.72, 3.63, 3.35 seen as singlets
and
the proton near to nitrogen in indole was observed as a singlet at δ 8.35 and 8.28 for the other
diastereomer(Figure 6) .
12
Figure 6
In the
13
C NMR spectrum, the two ester carbonyls were observed at δ 168.5 and 167.6,
while the benzoyl carbonyl was discernible at 173.3.And the two methoxy carbons were
observed at δ 52.8and 54.9 (Figure 7).
13
Figure 7
The structure was further supported by high resolution mass spectral analysis which was showed
a molecular ion peak[C21H18BrNO5Na] at 466.02744 (Figure 8).
14
Figure 8
4.2.bReaction of dimethyl 2-(4-chlorobenzoyl) fumarate with indole
The reaction of dimethyl 2-(4-cholorobenzoyl) fumarate and indole in presence of
Sc(OTf)3in CH3CN at room temperature for 4 h, afforded 1,4-addition product in 54 % yield as
diastereomer (dr =1: 0.63) (Scheme 12).
Scheme 12
The structure of the product was elucidated by spectroscopic techniques. In IR spectrum,a sharp
band at 1727 cm-1 was assigned to the ester carbonyl ,while the absorption at1679 cm-1 was
attributed to the benzoyl carbonyl. The 1H NMR spectrum it was seen that the protons attached
to the chiral carbon of diastereomers resonated at δ 5.45, 5.27, 4.99 and 4.89. From proton NMR
integration, the ratio of two of these protons were found as 1:0.63. This clearly indicates the
15
presence of two diasteroisomers. Similarly the methoxy groups are 3.86, 3.75, 3.71, 3.63 seen
as singlets
and the proton near to nitrogen in indole was observed as a singlet at δ 7.77 and
7.81 for the other diastereomer.In the 13C NMR spectrum, the two ester carbonyls were observed
at δ 167.2 and 166.5, while the benzoyl carbonyl was discernible at 184.7.And the two methoxy
carbons were observed at δ 56.8and 53.9.The structure was further supported by high resolution
mass spectral analysis which was showed a molecular ion peak [C21H18ClNO5]+ at 399.17.
4.2.c Reaction of dimethyl 2-(4-fluorobenzoyl) fumarate with indole
Similarly, the reaction of dimethyl 2-(4-fluorobenzoyl) fumarate and indole in presence
of Sc(OTf)3 in CH3CN at room temperature for 4 h, afforded 1,4-addition product in 56 % yield
as a mixture of diastereomers (dr = 1: 0.93)(Scheme 13).
Scheme 13
The structure
of the product was elucidated by spectroscopic techniques. In IR spectrum, a
sharp band at 1739 cm-1was assigned to the ester carbonyl, while the absorption at1686 cm-1 was
attributed to the benzoyl carbonyl.The 1H NMR spectrum it was seen that the protons attached to
the chiral carbon of diastereomers resonated at δ 5.44, 5.29, 4.98 and 4.88. From proton NMR
integration, the ratio of two of these protons were found as 1:0. 93. This clearly indicates the
presence of two
diasteroisomers. Similarly the methoxy
groups are 3.86, 3.75, 3.74, 3.73
seen as singletsand the proton near to nitrogen in indole was observed as a singlet at δ 7.83 and
7.76 for the other diastereomer.In the 13C NMR spectrum, the two ester carbonyls were observed
at δ 168.5 and 167.6, while the benzoyl carbonyl was discernible at 181. 8.And the two methoxy
carbons were observed at δ 57.8 and53.9.The structure was further supported by high resolution
mass spectral analysis which was showed a molecular ion peak [C21H18FNO5Na]+ at 406.1078
4.2.dReaction of dimethyl 2-(4-methylbenzoyl) fumarate with indole
16
When dimethyl 2-(4-methylbenzoyl) fumaratewas treatedwith indole in presence of
Sc(OTf)3 in CH3CN at room temperature for 4 h, 1,4-addition product was obtained as an
inseparable mixture of diastereomersin 53 % yield(dr= 1: 0.71)(Scheme 14).
Scheme 14
The structure of the product was elucidated by spectroscopic techniques. In IR spectrum,a sharp
band at 1721 cm-1was assigned to the ester carbonyl,while the absorption at1678 cm-1 was
attributed to the benzoyl carbonyl.In1H NMR spectrum it was seen that the protons attached to
the chiral carbon of diastereomers resonated at δ 5.37, 5.23, 4.91 and 4.83. From proton NMR
integration, the ratio of two of these protons were found as 1:0.71. This clearly indicates the
presence of two diasteroisomers. Similarly the methoxy groups are 3.79, 3.74, 3.72, 3.63 seen
as singlets
and the proton near to nitrogen in indole was observed as a singlet at δ 7.93 and
7.81 for the other diastereomer.In the 13C NMR spectrum, the two ester carbonyls were observed
at δ 167.7 and 165.6, while the benzoyl carbonyl was discernible at 181. 4. And the two methoxy
carbons were observed at δ 57.6 and 54.9.The structure was further supported by high resolution
mass spectral analysis which was showed a molecular ion peak [C22H21NO5Na]+ at 402.16.
4.2.eReaction of dimethyl 2-(4-bromobenzoyl) fumarate with 5-fluoroindole
The reaction of dimethyl 2-(4-bromobenzoyl) fumarate and 5-fluoroindole in presence of
Sc(OTf)3 in CH3CN at room temperature for 4 h, afforded 1,4-addition product in 54 % yield as
diastereomer (dr=1: 0.82)(Scheme 15) .
Scheme 15
The structure of the product was elucidated by spectroscopic techniques.In IR spectrum,a sharp
band at 1730 cm-1was assigned to the ester carbonyl,while the absorption at1568 cm-1 was
17
attributed to the benzoyl carbonyl.The 1H NMR spectrum, it was seen that the protons attached
to the chiral carbon of diastereomers resonated at δ 5.4, 5.24, 4.93 and 4.85. From proton NMR
integration, the ratio of two of these protons were found as 1:0.82. This clearly indicates the
presence of two diasteroisomers. Similarly the methoxy groups are 3.86, 3.74, 3.72, 3.63seen
as singlets
and the proton near to nitrogen in indole was observed as a singlet at δ 7.96 and
7.85 for the other diastereomer.In the 13C NMR spectrum, the two ester carbonyls were observed
at δ 168.5 and 167.6, while the benzoyl carbonyl was discernible at 181.4.The two methoxy
carbons were observed at δ 57.8and 54.9. The structure was further supported by high resolution
mass spectral analysis which was showed a molecular ion peak [C21H17BrFNO5]+at 463.14.
4.2.fReaction of dimethyl 2-(4chlorobenzoyl) fumarate with 5-fluoroindole
The reaction of dimethyl 2-(4-cholorobenzoyl) fumarate and 5-fluoroindole in presence
of Sc(OTf)3 in CH3CN at room temperature for 4 h, afforded 1,4-addition product in 52 % yield
as diastereomer (dr=1: 0.74)(Scheme 16).
Scheme 16
The structure of the product was elucidated by spectroscopic techniques.In IR spectrum ,a
sharp band at 1732 cm-1 was assigned to the ester carbonyl ,while the absorption at1686 cm-1 was
attributed to the benzoyl carbonyl.In1H NMR spectrum it was seen that the protons attached to
the chiral carbon of diastereomers resonated at δ 5.39, 5.23, 4.91 and 4.83. From proton NMR
integration, the ratio of two of these protons were found as 1:0.74. This clearly indicates the
presence of two diasteroisomers. Similarly the methoxy groups are 3.74, 3.72, 3.64, 3.38 seen
as singlets and the proton near to nitrogen in indole was observed as a singlet at δ 7.84 and 7.69
for the other diastereomer.In the 13C NMR spectrum, the two ester carbonyls were observed at δ
167.2 and 166.5, while the benzoyl carbonyl was discernible at 184.7.The two methoxy carbons
were observed at δ 56.8and 53.9. The structure was further supported by high resolution mass
spectral analysis which was showed a molecular ion peak [C21H17ClFNO5Na] at 440.08.
18
4.2.gReaction of dimethyl 2-(4-fluorobenzoyl) fumarate with 5-fluoroindole
The reaction of dimethyl 2-(4-fluorobenzoyl) fumarate and 5-fluoroindole in presence of
Sc(OTf)3 in CH3CN at room temperature for 4 h, afforded 1,4-addition product in 52 % yield as
diastereomer (dr=1: 0.86)(Scheme 17) .
Scheme 17
The structure of the product was elucidated by spectroscopic techniques.In IR spectrum,a sharp
band at 1727 cm-1was assigned to the ester carbonyl ,while the absorption at1592 cm-1 was
attributed to the benzoyl carbonyl.The 1H NMR spectrum it was seen that the protons attached to
the chiral carbon of diastereomers resonated at δ 5.4, 5.23, 4.91 and 4.83. From proton NMR
integration, the ratio of two of these protons were found as 1:0.86. This clearly indicates the
presence of two diasteroisomers. Similarly the methoxygroups are 3.75, 3.72, 3.65, 3.38 seen
as singlets
and the proton near to nitrogen in indole was observed as a singlet at δ 8.12 and
7.77 for the other diastereomer.In the 13C NMR spectrum, the two ester carbonyls were observed
at δ 167.5 and 166.6, while the benzoyl carbonyl was discernible at 181.6.The two methoxy
carbons were observed at δ 57.8and 54.9. The structure was further supported by high resolution
mass spectral analysis which was showed a molecular ion peak [C21H17F2NO5Na]+ at 424.09.
4.2.hReaction of dimethyl 2-(4-methylbenzoyl) fumarate with 5-fluoroindole
The reaction of dimethyl 2-(4-methylbenzoyl) fumarate and 5-fluoroindole in presence of
Sc(OTf)3 in CH3CN at room temperature for 4 h, afforded 1,4-addition product in 51 % yield as
diastereomer (dr=1: 0.81)(Scheme 18) .
Scheme 18
19
The structure of the product was elucidated by spectroscopic techniques.In IR spectrum ,a sharp
band at 1733 cm was assigned to the ester carbonyl ,while the absorption at1678 cm was
attributed to the benzoyl carbonyl.In1H NMR spectrum, it was seen that the protons attached to
the chiral carbon of diastereomers resonated at δ 5.4, 5.22, 4.93 and 4.85. From proton NMR
integration, the ratio of two of these protons was found as 1:0.81. This clearly indicates the
presence of two diasteroisomers. Similarly the methoxy groups are 3.83, 3.74, 3.62, 3.37 seen
assingletsand the proton near to nitrogen in indole was observed as a singlet at δ 8.43 and 7.89
for the other diastereomer.In the 13C NMR spectrum, the two ester carbonyls were observed at δ
168.5 and 167.6, while the benzoyl carbonyl was discernible at 181.8.The two methoxy carbons
were observed at δ 57.8and 54.9. The structure was further supported by high resolution mass
spectral analysis which was showed a molecular ion peak [C22H20FNO5]+ at 399.17.
The 1,4-conjugate addition reaction of indolewas found to be general with benzoyl
fumarates containing both electron withdrawing and electron donating groups and the results
obtained are shown in table 3.
Table 3.Michael addition products of indole with benzoyl fumarates
Entry
Benzoyl Fumerates
Product
Yield (%)
1
52
dr= (1: 0.84)
2
54
dr= (1: 0.63)
3
56
dr= (1: 0.93)
20
4
53
dr=(1: 0.71)
5
54
dr= (1: 0.82)
6
52
dr=(1: 0.74)
7
52
dr=(1: 0.86)
8
51
dr=(1: 0.81)
Mechanistic Pathway:
Activation of enone by the lewis acid generates cationic intermediate A, which
undergoes nucleophilic 1,4-conjugate addition results in the formation of intermediate B.
Further proton abstraction at C-3 position of indolefurnishes the product.
21
Scheme 19
4.3. Reductionof dimethyl 2-(4-bromobenzoyl) fumarate with Palladium Carbon
The reaction of dimethyl 2-(4-methylbenzoyl) fumarate with palladium carbon and
EtOAc as the solvent at room temperature for 4 hrs, afforded a product which was characterized
as dimethyl 2-(4-methylbenzoyl)-3-(1H-indol-3-yl) succinate in 53% yield(Scheme 20).
Scheme 20
The structure of the product was elucidated by spectroscopic techniques. In IR
spectrum, a sharp band at 1733 cm-1 was assigned to the ester carbonyl, while the absorption at
1686 cm-1 was attributed to the benzoyl carbonyl. The 1H NMR spectrum displayed two
methoxy groups as singlets at δ 3.83and 3.64 and the hydrogenated protons were observed at
δ 4.8 and 3.06 (Figure 9).
22
Figure 9
In the 13C NMR spectrum, the two ester carbonyls were observed at δ 164.0 and 163.6,
while the benzoyl carbonyl was discernible at 191.4.And the two methoxy carbons were
observed at δ 53.1and 52.3 (Figure 10).
23
Figure 10
5. CONCLUSION
In summary, we have synthesized a series of benzoyl fumaratesby pyridine catalyzed
reaction of DMAD with variousaldehydes for screening the anti-tuberculosis activity. To further
improve the activity of synthesized compounds, we have incorporated biolologically significant
indole moiety to benzoyl fumaratesby lewis acid catalyzed 1,4- conjugate addition reaction.
Furthermore hydrogenation of enone moiety of benzoyl fumarate was carried out in presence of
Pd/C.
24
6. EXPERMENTAL DETAILS
All the chemicals were of the best grade commercially available and were used without further
purification. All the solvents were purified according to standard procedures; dry solvents were
obtained according to the literature methods stored over molecular sieves. All reactions were
monitored by TLC (silica gel 60 F254, 0.25mm, Merck), visualization was effected with uv
and/or by staining with Enholm yellow solution. Gravity column chromatography was performed
using 100-200 mesh silica gel, mixtures of hexane –ethyl acetate were used for elution. Melting
point was determined on Buchi melting point apparatus and is uncorrected. Proton nuclear
magnetic
resonance
spectra
( 1H
NMR)were
recorded
on
Bruker
AV
500
spectrophotometers(CDCl3 as solvent).Chemical shifts for 1H NMR spectra are reported as δ in
units of parts per million(ppm) downfield from SiMe4(δ0.0) and relative to the signal
chloroform-d(δ
7.25,singlet).Multiplities
were
given
as:
s(singlet);
d(doublet)
of
;
t
(triplet);dd(double doublet);m(multiplet).Coupling constants are reported as J value in Hz.
Carbon nuclear magnetic resonance spectra(13C NMR) are reported as in δ in units of parts per
million(ppm) downfield from SiMe4(δ0.0)and relative to the signal of chloroformd(77.03,triplet).Mass spectra were recorded under ESI/HRMS at 61800 resolution using Thermo
scientific Exactive mass spectrometer.IR spectra were recorded on Brucker Alpha FT-IR
spectrometer.
6.1 Dimethyl 2-(4-bromobenzoyl) fumarate
A solution of 4-bromobenzaldehyde (200 mg, 1.0809 mmol) and DMAD ( 0.1328,
1.4234 mmol) in THF (5 mL) under an argon atmosphere was cooled to 0 oC - 10 °C. To
this, pyridine (20 mol%) was added, and the reaction mixture was stirred for 4 h at room
temperature. The solvent was
then removed under
vacuum,
and
the
residue
on
chromatographic separation on silica gel column using hexane-ethyl acetate (88:12) gave a
colourless crystalline solid (254 mg, 72%).
Mp: 223 oC
25
IR (neat) υmax: 2952, 2396, 1932, 1714, 1669, 1577, 1481,
1436, 1397, 1359, 1260, 1199, 1065, 1007, 965, 936, 894, 836,
784 cm-1.
1H
NMR [500 MHz, CDCl3/CCl4, 7:3 (v/v)]: δ 7.74 (d, J = 8
Hz, 2H), 7.63 (d, J = 8.5 Hz, 2H), 7.08 (s, 1H), 3.79 (s, 3H),
3.66 (s, 3H)
13C
NMR (125 MHz, CDCl3): δ 190.8, 163.9, 163.2, 134.8,
134.3, 132.4 132.1, 130.9, 130.6, 130.0, 129.1, 53.2, 52.4
HRMS(EI) Calcd. for [C13H11BrO5]+: 326.9789 Found:
326.9874
6.2 Dimethyl 2-(4-chlorobenzoyl) fumarate
A solution of 4-chlorobenzaldehyde (200 mg, 1.664 mmol) and DMAD ( 0.244 ml,
1.996 mmol) in THF (5 mL) under an argon atmosphere was cooled to 0 – 10 °C. To this,
pyridine (20 mol%) was added, and the reaction mixture was stirred for 4 h at room
temperature. The solvent was
then removed under
vacuum,
and
the
residue
on
chromatographic separation on silica gel column using hexane- ethyl acetate (88:12) gave a
colourless crystalline solid (132 mg, 67 %).
Mp: 1470C
IR (neat) υmax: 2956, 1723,1679, 1596, 1503, 1439, 1352, 1235,
1153, 1081, 1015, 974, 944, 911, 849, 789 cm-1.
1H
NMR [500 MHz, CDCl3/CCl4, 7:3 (v/v)] : δ 7.80 (d, J = 8.5
Hz, 2H), 7.44 (d, J = 8.5 Hz, 2H), 7.07 (s, 1H), 3.78 (s, 3H), 3.64
26
(s, 3H)
NMR:13C NMR (125 MHz, CDCl3): δ 190.6, 163.9, 163.2,
l3C
134.6, 134.4, 133.1, 132.4, 132.1, 130.7, 129.7,129.1, 53.6, 52.3
HRMS(EI) Calcd. for [C13H11ClO5]+: 282.02950, Found:
282.0213
6.3 Dimethyl 2-(4-fluoro-benzoyl) fumarate
A solution of 4-fluorobenzaldehyde (200 mg, 0.93mmol) and DMAD ( 0.114ml, 0.93
mmol) in THF (5 mL) under an argon atmosphere was cooled to 0 -10 °C. To this,
pyridine (20 mol%) was added, and the reaction mixture was stirred for 4 h at room
temperature. The solvent was
then removed under
vacuum,
and
the
residue
on
chromatographic separation on silica gel column using hexane-ethyl acetate (88:12) gave
yellow viscous liquid (285 mg, 66 %).
IR (neat) υmax : 2957, 1739, 1687, 1596, 1503, 1439, 1352, 1235,
1153, 1081, 1015, 974, 944, 921, 849, 789 cm-1.
1H
NMR [500 MHz, CDCl3/CCl4, 7:3 (v/v)]: δ 7.89 (d, J = 9 Hz,
2H), 7.16 (d, J = 8.5 Hz, 2H), 7.073 (s, 1H), 3.75 (s, 3H), 3.69 (s,
3H)
13C
NMR (125 MHz, CDCl3): δ 191.8, 167.5, 163.6, 134.7, 133.4,
132.5, 132.1, 130.8, 130.0, 129.7, 128.6, 52.3, 49.6
HRMS(EI) Calcd. for [C13H11FO5]+: 266.0590, Found: 266.0514
6.4 Dimethyl 2-(4-methylbenzoyl) fumarate
A solution of tolualdehyde (200 mg, 1.664 mmol) and DMAD ( 0.204 ml, 1.664
mmol) in THF(5 mL) under an argon atmosphere was cooled to 0 -10 °C. To this,
27
pyridine (20 mol%) was added, and the reaction mixture was stirred for 4 h at room
temperature. The solvent was
then removed under
vacuum,
and
the
residue
on
chromatographic separation on silica gel column using hexane-ethyl acetate (88: 12) gave a
colourless crystalline solid (135 mg, 61 %).
IR(neat)υmax:2953,2917,2871,2847,1726,1678,1606,1436,
1311, 1250, 1203, 1170, 1108, 1016, 973, 836, 787.
1H
NMR [500 MHz, CDCl3/CCl4, 7:3(v/v)] :δ 7.77 (d, J =
8Hz, 2H), 7.28 (d, J = 8.5Hz, 2H),7.07 (s,1H) 3.79 (s, 3H),
3.64 (s, 3H), 2.44 (s, 3H)
13C
NMR (125 MHz, CDCl3): δ 192.8, 171.5, 168.9, 134.6,
134.2, 133.6, 132.0, 130.4, 130.0, 129.8, 129.6, 52.6, 49.2,
32.8
HRMS (EI)Calcd. for
[C14H14O5]+: 263.0841, Found:
263.0743
6.5 Dimethyl 2-(4-bromobenzoyl)-3-(1H-indol-3-yl) succinate
To the mixture of dimethyl 2-(4-bromobenzoyl) fumarate (30mg, 0.0917mmol) and indole (10.74 mg,
0.0917 mmol) , Scandiumtriflate (2.25mg,0.0045 mmol) was added. To this the solvent CH3CN (3mL)
was added under argon atmosphere, and the reaction mixture was stirred at room temperature for 4 hours.
Then the solvent was removed under vacuum, and the residue on chromatographic separation on
silica gel column using hexane-ethyl acetate (75:25) gave a colourlessviscous liquid ( 21 mg,52 %).
IR (neat) υmax : 3638,35432,2915,1736,1684,1156,736
H NMR [500 MHz, CDCl3/CCl4, 7:3(v/v)]: δ7.37(s, 1H), 7.35(d, J
1
=6.5Hz, 2H), 7.22(d,J= 7.5Hz, 2H), 7.17 (d, J=10Hz, 2H) 7.14 (dd,
28
J=8Hz, 1H), 7.12(dd,J=3.5Hz, 1H),5.43(d, J=11.5Hz,1H),5.26(d,
J=11.5Hz,1H), 4.99(d, J=11.5Hz,1H), 4.88(d, J=11.5Hz,1H) 3.87(s,
3H), 3.76(s, 3H),3.75(s,3H),3.71(s,3H),
13
C NMR (125 MHz, CDCl3): δ182.8, 165.5, 163.6, 138.9, 137.1,
136.2,134.4, 132.6, 128.9, 127.6, 126.8, 125.9, 125.4, 123.7, 123.1,
122.8, 121.5,120.8,120.6, 56.6, 54.5
HRMS (EI)Calcd. For [C21H18BrNO5Na]: 466.0428, Found:
466.0274
6.7 Dimethyl 2-(4-chlorobenzoyl)-3-(1H-indol-3-yl) succinate
To the mixture of dimethyl 2-(4-chlorobenzoyl) fumarate (30 mg, 0.1063 mmol) and indole
(12.45 mg,0.1063 mmol) ,Scandium triflates(2.61 mg,0.0053 mmol) was added. To this
the
solvent CH3CN (3 mL) was added under argon atmosphere, and the reaction mixture was stirred
at room temperature for 4hours. The solvent was then removed under vacuum, and the residue
on chromatographic separation on silica gel column using hexane-ethyl acetate (75:25)
gave a colourless viscous liquid ( 23 mg, 54%).
29
IR (neat) υmax : 3563, 3443, 2954, 1727, 1679, 1144,
734
1H
NMR [500 MHz, CDCl3/CCl4, 7:3(v/v)]: δ 7.77(s,
1H), 7.73(d, J =9 Hz, 2H), 7.37(d, J= 8Hz, 2H), 7.21(d,
J=10 Hz, 2H), 7.17 (dd, J=7 Hz, 1H), 7.14(dd, J=9 Hz,
1H),5.45(d, J=11.5Hz,1H),5.27(d, J=11.5Hz,1H), 4.99(d,
J=11.5Hz,1H), 4.89(d, J=11.5Hz,1H)3.86(s, 3H), 3.75(s,
3H) ,3.71(s,3H), 3.63(s, 3H)
13C
NMR (125 MHz, CDCl3): δ 184.7,167.2, 166.5,
138.9, 137.1, 136.5,134.2, 131.4, 128.7, 127.6, 127.1,
126.5, 125.3, 123.7,123,2, 122.8, 122.4,121.3,120.2,
56.8, 53.9
HRMS (EI)Calcd. For [C21H18ClNO5]+: 399.09, Found:
399.17
6.7 Dimethyl 2-(4-fluorobenzoyl)-3-(1H-indol-3-yl) succinate
To the mixture of dimethyl 2(4-fluorobenzoyl) fumarate (30 mg, 0.1872 mmol) and indole ( 13.
16 mg, 0.1872 mmol), Scandiumtriflate (2.75 mg,0.0093 mmol) was added. To this the solvent
CH3CN (3 mL) was added under argon atmosphere, and the reaction mixture was stirred at room
temperature for 4 hours. The solvent was then removed under vacuum, and the residue on
chromatographic separation on silica gel column using hexane-ethyl acetate (75:25) gave a
colourless viscous liquid ( 24 mg, 56 %).
30
IR (neat) υmax : 3548,2954,2917,2852, 1739,1686, 1501,
1455, 1375, 1237, 1163,1013, 846, 744,587,543
1H
NMR [500 MHz, CDCl3/CCl4, 7:3(v/v)]: δ 7.76 (s, 1H), 7.75
(d, J =9 Hz, 2H), 7.37(d, J= 8.5 Hz, 2H), 7.21(d, J=7 Hz, 2H),
7.18 (dd, J=7 Hz, 1H), 7.14 (dd, J=7.5 Hz, 1H), 5.44(d,
J=10Hz,1H),5.29(d, J=10Hz,1H), 4.98(d, J=10Hz,1H),
4.88(d,J=10Hz,1H) 3.86 (s, 3H), 3.75 (s, 3H),
3.74(s,3H),3.73(s,3H)
13C
NMR (125 MHz, CDCl3): δ 181.8, 168.5, 167.6, 139.9,
136.1, 136.0,134.7, 130.4, 129.8, 129.6, 128.6, 126.1, 125.8,
123.5,123,2, 122.6, 122.5,120.3,120.2, 57.8, 53.9
HRMS (EI)Calcd. For [C21H18FNO5Na]: 383.1234, Found:
406.1078
6.8 Dimethyl 2-(4-methylbenzoyl)-3-(1H-indol-3-yl) succinate
To the mixture of dimethyl 2-(4-methylbenzoyl) fumarate (30 mg,0.1144 mmol) and indole
(25.28 mg,0.1144 mmol) ,the Lewis acid scandium triflate (4.60 mg, 0.0057 mmol) was added.
To this the solvent CH3CN (3 mL) was added under argon atmosphere, and the reaction mixture
was stirred at room temperature for 4 hours. The solvent was then removed under vacuum, and
the residue on chromatographic separation on silica gel column using hexane-ethyl acetate
(75:25) gave a colourless viscous liquid ( 23 mg, 53 %).
IR (neat) υmax : 3410,2924, 2855,
1721,1678,1628,1581,1482,1448,1347,1257,11
31
78,1015,971,854,797, 752, 709, 603,581
1H
NMR [500 MHz, CDCl3/CCl4, 7:3(v/v)]: δ
7.81(s, 1H), 7.50 (d, J =8 Hz,2H), 7.49 (d, J=
9.5 Hz, 2H), 6.90 (d, J=8 Hz, 2H), 6.83 (dd,
J=6.5 Hz, 1H),6.81(dd, J=6.5 Hz, 1H) 5.37(d,
J=11Hz,1H),5.23(d, J=11.5Hz,1H), 4.91(d,
J=11.5Hz,1H), 4.83(d, J=11.5Hz,1H)3.79(s, 3H),
3.72 (s, 3H) ,3.74(s,3H), 3.63(s,3H),2.43(s,
3H)
13C
NMR (125 MHz, CDCl3): δ 181.4, 167.7,
165.6, 139.9, 136.1, 136.0, 134.7, 130.4, 132.1,
129.8, 129.6, 128.6, 126.1, 125.8, 123.5, 123,2,
122.6, 122.5, 120.3, 120.2, 57.6, 54.9, 27.4
HRMS (EI)Calcd. For [C22H21NO5Na]:
402.16, Found: 402.16
6.9 Dimethyl 2-(4-bromobenzoyl)-3-(5-fluoro-1H-indol-3-yl) succinate
To the mixture of dimethyl 2-(4-bromobenzoyl) fumarate (50 mg,0.152 mmol) and 5fluoroindole (20.64 mg,0.152 mmol) ,the Lewis acid scandium triflate (3.73 mg, 0.0076 mmol)
was added. To this
the solvent CH3CN (3 mL) was added under argon atmosphere, and the
reaction mixture was stirred at room temperature for overnight. The solvent was then removed
under vacuum, and the residue on chromatographic separation on silica gel column using
hexane-ethyl acetate (75:25) gave a colourless crystalline solid ( 38 mg, 54 %)
IR (neat) υmax : 2912,
1730,1721,1598,1678,1161,781,531
1H
NMR [500 MHz, CDCl3/CCl4, 7:3(v/v)]: δ
7.81(s, 1H), 7.39 (d, J =7.5 Hz, 2H), 7.29(d, J=
6.5 Hz, 2H), 7.14 (d, J=5.5 Hz, 1H), 6.99 (d,
32
J=8.5Hz, 1H), 6.97(s, 1H) 5.4(d,
J=11.5Hz,1H),5.24(d, J=11.5Hz,1H), 4.93(d,
J=11.5Hz,1H), 4.85(d, J=11.5Hz,1H), 3.86 (s,
3H), 3.74 (s, 3H) ,3.72(s,3H),3.63(s,3H)
13C
NMR (125 MHz, CDCl3): δ 181.8, 168.5,
167.6, 139.9, 136.1, 136.0, 134.7, 130.4,132.1,
129.8, 129.6, 128.6, 126.1, 125.8, 123.5,123,2,
122.6, 57.8, 54.9
HRMS (EI)Calcd. For [C21H17BrFNO5]+:
461.03, Found: 463.14
6.10 Dimethyl 2-(4-cholorobenzoyl)-3-(5-fluoro-1H-indol-3-yl) succinate
To the mixture of dimethyl 2-(4-chlorobenzoyl) fumarate (50 mg, 0.1771 mmol) and 5fluoro indole (21.74 mg, 0.1771 mmol) ,the Lewis acid scandium triflate (3.63 mg, 0.1015
mmol) was added. To this the solvent CH3CN (3 mL) was added under argon atmosphere, and
the reaction mixture was stirred at room temperature for overnight. The solvent was then
removed under vacuum, and the residue on chromatographic separation on silica gel
column using hexane-ethyl acetate (90:10) gave a colourless crystalline solid ( 36 mg, 52
%)
33
IR
(neat)
υmax
:
2961,1732,1686,1258,1164,1085,1011,791,693
,623,568
1H
NMR [500 MHz, CDCl3/CCl4, 7:3(v/v)]: δ
7.67(s, 1H), 7.62(d, J =8.5Hz, 2H), 7.42(d, J=
9Hz, 2H), 7.14(d, J=5Hz, 1H), 6.97 (d, J=7Hz,
1H), 6.92(s,1H), 5.39(d, J=11Hz,1H),5.23(d,
J=11.5Hz,1H),
4.91(d,
J=11.5Hz,1H)
3.74(s,
J=11.5Hz,1H),
3H),
3.72(s,
4.83(d,
3H)
,3.64(s,3H),3.38(s,3H)
13C
NMR (125 MHz, CDCl3): δ 184.7,167.2,
166.5, 138.9, 137.1, 136.5,134.2, 131.4, 128.7,
127.6, 127.1, 126.5, 125.3, 123.7,123,2, 122.8,
122.4,121.3,120.2, 56.8, 53.9
HRMS (EI)Calcd. For
[C21H17ClFNO5Na]:
440.02, Found: 440.08
6.11 Dimethyl 2-(4-fluorobenzoyl)-3-(5-fluoro-1H-indol-3-yl) succinate
34
To the mixture of dimethyl 2-fluorobenzoyl fumarate (50mg,0.1872mmol) and 5-fluroroindole
(25.28mg,0.1872mmol) ,the Lewis acid scandium triflate(4.60mg,0.0093mmol) was added. To
this
the solvent CH3CN (3mL) was added under argon atmosphere, and the reaction mixture
was stirred at room temperature for overnight. The solvent was then removed under vacuum,
and the residue on chromatographic separation on silica gel column using hexane-ethyl
acetate (75:25) gave a colourless crystalline solid ( 41 mg, 52 %).
IR (neat) υmax:
2956,2918,1727,1680,1592,1485,1438,1233,1154,1095,10
07,935,840,794,661,548
1H
NMR [500 MHz, CDCl3/CCl4, 7:3(v/v)]: δ 7.77(s, 1H),
7.70(d, J =8.5Hz, 2H), 7.29(d, J= 8.5Hz, 2H), 7.45(d,
J=7.5Hz, 1H), 7.28 (d, J=8Hz, 1H), 7.20(s, 1H) 5.4(d,
J=11.5Hz,1H),5.23(d, J=11.5Hz,1H), 4.91(d,J=11Hz,1H),
4.83(d,J=11.5Hz,1H),3.75(s,3H),3.72(s, 3H), 3.65(s, 3H)
,3.38(s, 3H)
13C
NMR (125 MHz, CDCl3): δ 181.6, 167.5, 166.6,
138.9, 136.7, 136.2,134.5, 130.4,132.1, 129.8, 129.6,
128.6, 126.1, 125.8, 123.5,123,2, 122.6, 122.5,120.3,120.2,
57.8, 54.9
HRMS (EI)Calcd. For [C21H17F2NO5Na]: 424.05, Found:
424.09
35
6.12 Dimethyl 2-(4-methylbenzoyl)-3-(5-fluoro-1H-indol-3-yl) succinate
To the mixture of dimethyl 2-(4-methylbenzoyl) fumarate (50mg, 0.190mmol) and5-fluoro
indole
(25.75mg,0.190mmol) ,the Lewis acid scandium triflate(4.69mg,0.0095mmol) was
added. To this the solvent CH3CN (3mL) was added under argon atmosphere, and the reaction
mixture was stirred at room temperature for 4 hours. The solvent was then removed under
vacuum, and the residue on chromatographic separation on silica gel column using
hexane-ethyl acetate (75:25) gave a colourless crystalline solid ( 39mg, 51.44%)
IR (neat) υmax:
3385,2920,2849,1733,1678,1599,1505,1435,12
F
O
CO2Me
04,1100,1009,968,844,810,745,593
1H
NMR [500 MHz, CDCl3/CCl4, 7:3(v/v)]: δ
7.89(s, 1H), 7.50(d, J =8Hz, 2H), 7.49(d, J=
CO2Me
H3C
9Hz, 2H), 6.90(d, J=8Hz, 1H), 6.83(d,
NH
J=6.5Hz, 1H), 6.80(s,1H),5.40(d,
J=11.5Hz,1H),5.22(d, J=11.5Hz,1H), 4.93(d,
J=11.5Hz,1H), 4.85(d,
J=11.5Hz,1H),3.83(s,3H),3.74 (s, 3H), 3.62 (s,
3H) ,3.37(s,3H), 2.46(s,3H)
13C
NMR (125 MHz, CDCl3): δ 181.8, 173.3,
173.0, 168.5, 167.6, 139.9, 136.1, 136.0,134.7,
36
130.4,132.1, 129.8, 129.6, 128.6, 126.1, 125.8,
123.5,123,2, 122.6, 122.5,120.3,120.2, 57.8,
54.9.
HRMS (EI)Calcd. For [C22H20FNO5]+:
397.13, Found:399.17.
6.13 Dimethyl 2-(4-bromobenzoyl )succinate
To the solution of dimethyl2-(4-bromobenzoyl) fumarate (50mg, 0.153mmol), dissolved in dry
ethyl acetate, catalytic amount of Pd/C was added and stirred under hydrogen atmosphere for4
hours. After passing through the celite column, solvent was removed under vacuum. And the
residue on chromatographic separation on silica gel column using hexane-ethyl acetate
(90:10) gave a pale yellow solid ( 28 mg, 56 %).
Mp: 223oC
IR (neat) υmax: 2954,1733, 168,1583,1437,
1401,1329,1215,1160,1104,1071,1005,949,916,840,764,690,
611
1H
NMR [500 MHz, CDCl3/CCl4, 7:3(v/v)]: δ 7.75(d, J
=8Hz, 2H), 7.62(d, J= 8.5Hz, 2H), 4.8(t, J=8Hz, 1H), 3.06
(d, J=8Hz, 2H), 3.66(s, 3H), 3.12(s, 3H)
13C
NMR (125 MHz, CDCl3): δ 191.4, 164.0, 163.6, 145.4,
144.7, 133.3, 130.2, 129.5128.8 53.1, 52.3 ,21.8, 21.6
HRMS (EI)Calcd. For [C13H13BrO5]+: 327.99, Found:
327.11
37
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