1
AN EFFICIENT ROUTE TO ACYLATION USING TFAAH3PO4 AND ITS APPLICATION TO THE SYNTHESIS OF
DERIVATIVES OF NSAIDS
A SYNOPSIS
Submitted
in the partial fulfillment of the requirements for
the award of the degree of
DOCTOR OF PHILOSOPHY
in
FACULTY OF CHEMISTRY
By
P. BINDU
[Reg. No: 0603PH0497]
RESEARCH AND DEVELOPMENT CELL
JAWAHARLAL NEHRU TECHNOLOGICAL UNIVERSITY
HYDERABAD
KUKATPALLY, HYDERABAD
INDIA
August, 2012
2
CONTENT
CHAPTER 1:
A brief review of different acylating techniques with
their merits and de-merits
CHAPTER 2:
Part A: TFAA-H3PO4 mediated synthesis of 2-acyl
thiophenes with their merits and de-merits
Part B: TFAA-H3PO4 mediated synthesis of 2-acyl
furans with their merits and de-merits
CHAPTER 3:
TFAA-H3PO4 mediated synthesis of
benzothiophene
compounds
with
significance
2-acylated
biological
CHAPTER 4:
TFAA-H3PO4 mediated synthesis of 1,2-diaryl-1-eth
anones from naproxen & ibuprofen
CHAPTER 5:
Part A : TFAA-H3PO4 mediated synthesis ester
derivatives of piroxicam with their merits and demerits
Part B : Cyclodehydrated product of piroxicam:
Abnormal observation
LIST OF PUBLICATIONS
LIST OF SYMPOSIUM PRESENTATIONS
3
Chapter 1 A brief
review of different acylating techniques with
their merits and de-merits
Electrophilic aromatic substitution (acylation reaction) is one of the
most important reactions in synthetic organic chemistry. Such reactions
are used for the synthesis of important intermediates that can be used as
precursors for the production of pharmaceutical, agrochemical & industrial
products. However, many commercial processes to produce such materials
still rely on technology that was developed many years ago. This leads to
serious environmental threat. Hence, it is a widely recognized fact that
there is a growing need for more environmentally friendly processes in the
chemical industry. The trend towards what has become known as ‘green
chemistry’ or ‘sustainable technology’ is therefore growing. Green chemistry
is a shift from traditional concepts of process efficiency, which generally
concentrate on molar yields of chemical products, to ones that take into
account elimination of waste at source & avoidance of use of toxic
materials.
Acylation can be broadly divided into following categories
1) Acylation on ‘C’ 2) Acylation on ‘O’ and 3) Acylation on ‘N’
In our thesis we basically concentrated on ‘C’-acylation to a larger extent
and ‘O’-acylation to limited extent. Acylating techniques can be broadly
classified in to the following categories
1) Catalytic homogenous acylations
2) Catalytic heterogenous acylations
3) Non-conventional acylations
4
Each of these categories is widely discussed to the extent of the
scope of green synthesis in each technique. However, each of these
techniques more or less has their own disadvantages. For example, the
simplest and convincing method for the synthesis of acylated compounds
would be Friedel-Crafts acylation which again has its own disadvantages
like use of excess AlCl3 which led to the formation of environmentally
harmful gaseous HCl. Also, this procedure involves a) the use of moisture
sensitive acyl chloride, b) requirement of large volume of chlorinated
solvent, c) the formation of aluminium waste that needs to be disposed off
and d) formation of unknown side products is very common in this
reaction. Overall, the use of this method in large scale preparation might
result major drawbacks. To overcome these difficulties, we have focused on
the alternative methods available in the literature that could direct a
straight forward preparation of acylated compounds via C-C bond forming
reactions as a key synthetic step. It has been previously reported that the
use of mixed anhydrides of trifluoroacetic acid for aromatic acylation was
useful alternative to the Friedel-Crafts acylation process and a variety of
aromatic and aliphatic carboxylic acids were employed successfully. We
envisioned that the use of a similar strategy could be useful for the Lewis
acid/transition metal free synthesis of various aromatic ketones.
Herein we report a new, green, one-pot, regio-selective, simple &
straight forward synthesis of various aromatic ketones possesing biological
significance.
5
When various arenes or heteroarenes are treated with different acids
in the presence of TFAA-H3PO4 catalytic system, their corresponding
aromatic ketones (C-acylated products) are obtained in good yields. Also,
compounds having phenolic group are acylated under similar conditions to
form their respective esters (O-acylated products).
Chapter 2
Part A: TFAA-H3PO4 mediated synthesis of 2-acyl
thiophenes with their merits and de-merits
Part B: TFAA-H3PO4 mediated synthesis of 2-acyl
furans with their merits and de-merits
Thiophene (Part A) & furan (Part B) derivatives possessing a –COAr
group at C-2 are of particular interest because of their valuable
pharmacological properties. Though there are many methods in literature
to synthesize these compounds, we basically focused on a new method
which is not only eco-friendly but also regio-selective in most of the cases.
When heteroaromatic arene like thiophene (1) or furan (4) was
treated with an acid (2) in the presence of TFAA-H3PO4 catalytic system at
rt-80 °C, regio-selective 2-acylated thiophene (3) and furan (5) compounds
were obtained in very good yield (Scheme 1 & 2).
Scheme 1
R
S
1
H + HO
n
O
2
R
TFAA / H3PO4
rt -80oC
n
S
O
3
6
Scheme 2
R
O
H + HO
4
R
TFAA / H3PO4
n
O
2
rt-80oC
n
O
O
5
Thus we could acylate thiophene and furan initially with simple acids and
later extended the same to some NSAIDs like ibuprofen, indomethacin,
mefenamic acid. In order to extend its scope and explore in the
pharmacologically potential areas, we took the aid of docking studies to
understand which NSAID based thiophene and furan derivatives would be
useful for different medical purposes. Our effort was directed towards
identification of potential
inhibitors possessing
balanced selectivity.
Accordingly, these compounds were docked in both COX-1 and COX-2
enzymes and their interactions along with binding energies were analyzed.
Based on the binding energy data, it was evident that all the compounds
interacted well with both the COX isoforms. However, indomethacin
showed better affinity towards COX-2 & was predicted to be COX-2
selective when compared to others.
However, the same NSAIDs with furan showed less affinity towards
COX-1 as well as COX-2 proteins. Hence they can be said to be nonselective towards COX isoforms.
7
Chapter 3
TFAA-H3PO4 mediated
synthesis of
benzothiophene
compounds
with
significance
2-acylated
biological
The successful synthesis of regio-selective acylation on monocyclic
thiophene and furan molecules inspired us to experiment the same with a
bicyclic system and explore its extent of application. For this we have
selected benzothiophene, considering its derivatives to have wide range of
applicability
in
the
field
of
pharmacy.
Especially,
benzothiophene
derivatives having an acyl group as one of the substituents on the five
membered ring have immense medicinal value due to their promising
pharmacological properties. For example, raloxifen, tamoxifen etc.
Herein, we describe an efficient, simple and eco-friendly method for the
preparation of acyl benzothiophenes (7 & 8) that involves the first use of
benzothiophene (6) in the aromatic acylation mediated
by mixed
anhydrides of trifluoroacetic acid and H3PO4 at 25-30 °C (Scheme 3).
Scheme 3
COR
S
6
RCOOH
2
H3PO4
TFAA
25-30oC
COR
S
7
S
8
In spite of our sincere effort, attempt to prepare a single regioisomer, as
was obtained earlier with acylation of thiophene and furan, was not
obtained. Instead, a mixture of 2- and 3- acylatedbenzothiophene (7 & 8)
were always isolated in every case. In fact, an attempt to prepare a single
8
regioisomer by varying all the reaction parameters failed, perhaps due to
the high reactivity of the benzothiophene ring under the conditions studied.
A similar observation was seen in the literature. The isolated solid mixture
was found to have more of the 3-isomer (8) than the 2-isomer (7). Due to
this drawback, we did not further proceed the reaction with any NSAIDs
like in the case of thiophene.
Chapter 4
We,
TFAA-H3PO4 mediated synthesis of 1,2-diaryl-1ethanones from naproxen & ibuprofen
by
now
could
analyze
the
functionality
of
the
Lewis
acid/transition-metal free synthesis via C-C bond forming reaction in
detail. Hence we envisioned to exploit its application in the pharmaceutical
field which could be a great help in the future. In this context, literature
survey shows that 1,2-diaryl-1-ethanones are recently attracting the
attention due to their usefulness as synthetic templates in the development
of selective COX-2 inhibitors, such as BIA3-202. The class 2-aryl propanoic
acids are known for their anti-inflammatory properties. Some of the drugs
which belong to this category are naproxen, ketoprofen, ibuprofen,
fenoprofen, flubiprofen, loxoprofen etc. All of them are NSAID’s. We have
aimed to synthesize various 1,2-diaryl-1-ethanones from few of the 2-aryl
propanoic
acids
like
naproxen
&
ibuprofen
exploiting
the
Lewis
acid/transition metal free synthesis via C-C bond forming reaction.
Notably, the use of various arylacetic acids has been explored in the
literature, the use of α-substituted arylacetic acids were not examined.
Hence forth, we describe an efficient and simple one step method for the
9
preparation of (11) that involves the first time use of α-methyl substituted
naphthyl acetic acid (9) in the aromatic acylation process (Scheme 4). We
tried to convert naphthalene-2-yl acetic acid (9) in to various 2-naphthalen2-yl-1-aryl ethanones (11), and phenyl-2-yl-acetic acid (12) in to various 2phenyl-2-yl-1-aryl ethanones (13) (Scheme 5), using wide range of arenes
or heteroarenes (10).
Scheme 4
Me
Me
RH
COOH
MeO
10
9
R
H3PO4
(CF3CO)2O
reflux, 2h
O
MeO
11
Scheme 5
O
HO
O
Me
Me
RH
10
Me
Me
12
R
TFAA
H3PO4
Me
Me
13
One of the striking feature and advantage of this method was that the
present acylation of mono-substituted benzenes generated only paraisomer and not ortho isomer. Hence this method was said to be regioselective. It does not require the usage of excess arene. Since TFAA can be
recycled and reused, it could be economical. Moreover it is an operationally
simple method.
Later, from the respective ketones (11), it’s derivatives like oximes
10
(14, Scheme 6), hydrazones (15, Scheme 7), were prepared.
Scheme 6
Me
Me
R
MeO
NH2OH
R
Pyridine
MeO
EtOH
O
11
NOH
14
Scheme 7
Me
R
Me
R
O
MeO
11
Chapter 5
2,4-DNP
MeO
H2SO4
MeOH
N
NH
O2N
15
NO2
Part A : TFAA-H3PO4 mediated synthesis of ester
derivatives of piroxicam with their merits and demerits
Part B : Cyclodehydrated product of piroxicam:
Abnormal observation
In the journey of our continuous effort in synthesizing biologically
potential molecules, we shifted our focus towards another NSAID by name
“Piroxicam” after a phenomenal success with the drugs “Naproxen” and
“Ibuprofen”.
Since, studies on piroxicam indicate that enolic hydroxyl group plays
a key role in the observed physio-chemical and pharmacological properties
exhibited by piroxicam. Hence, it could be understanding that, derivatizing
this group (enolic OH group) via alkylation or acylation is expected to
11
change all the properties of piroxicam. These derivatives possessing
masked enolic OH group are stable under gastric conditions and lowers
gastrointestinal irritation. However, they are satisfactorily labile towards
hydrolysis to allow release of 16, preferably during or immediately after
absorption from gastrointestinal track. While, a large number of piroxicam
derivatives have been explored for the generation of appropriate prodrugs,
we observed that only limited studies have been reported in the case of acyl
derivatives. Due to our continuous interest in the chemical modifications of
existing cyclooxygenase inhibitors we determine to synthesize derivatives of
piroxicam, by converting them to their corresponding esters (aryl
carboxylate
esters),
followed
by
evaluation
of
their
chemical
and
pharmacological properties. In our previous chapters, we have reported the
use of TFAA-H3PO4 as an efficient catalyst system for C-acylation. Thus, we
aimed to test the scope of the catalyst system (TFAA-H3PO4), and the extent
to which it would favour O-acylation. Herein we report a mild, single-step
and metal-free process for the synthesis of 17 via TFAA-H3PO4 mediated
direct acylation of piroxicam (16, 1,2-benzothiazine-3-carboxamide-4hydroxy-2-methyl-N-(2-pyridyl)-1,1-dioxide). Thus,we describe the first
TFAA-H3PO4 mediated direct O-acylation of piroxicam, using a free
carboxylic acid (2), such reaction is often carried out using acid chlorides
or anhydrides (Scheme 8).
12
Scheme 8
O
OH O
N
N H
S
Me
O O
R
N
RCOOH
16
O
TFAA
H3PO4
2
O
N
S
O O
17
N
H
Me
N
Thus, this methodology illustrates the usefulness of TFAA-H3PO4 as
an efficient coupling agent for the direct esterification of aromatic hydroxyl
group with free carboxylic acid. This methodology is advantageous as it
does not require the use of any inert or anhydrous atmosphere and works
well at moderate refluxing temperatures providing the O-acylated products
in good to excellent yields in a less time period. Because of operational
simplicity, clean and mild reaction conditions and shorter reaction time the
present metal-free process would find wide application in such situations.
Abnormal observation (Part B)
The reaction with piroxicam (16) and various acids (2) in the
presence of TFAA-H3PO4 afforded ester derivatives of piroxicam (17) in
major quantities, but we always found a trace amount of side product with
the same Rf value in each and every case. This drew our attention towards
that compound. When carefully isolated through column chromatography
and analyzed the compound was found to be a cyclodehydrated product of
piroxicam (19, Scheme 9).
13
Scheme 9
OH O
N
N N
N H
S
Me
O O
16
RCOOH
N
TFAA
H3PO4
2
O
17
Major
(Expected
product)
N
S
Me
O O
18
Minor
(Un expected
product)
When the details of this compound were traced in literature, it was
interesting to find out that it was supposed to be one of the metabolites of
piroxicam especially found in dogs and monkeys. It was also reported to
have no efficient preparatory method. Hence we shifted our focus in
exploring a proper method for the synthesis of compound (18). For this we
started with the basic method employed for the preparation of any ester i.e.
treating an enol with acid chloride. The main focus was eyed on the side
product that could likely to be formed (18) along with the expected acylated
product, the ester (17). The formation of this unknown product (18) was
found to be significant particularly when piroxicam (16) was reacted with
benzoyl chloride (Scheme 10).
Scheme 10
O
Ph
16
O
O
PhCOCl
Et3N, CHCl3
N
S
O O
17
N
H
Me
N
N
+
N
O
N
S
Me
O O
18
Cyclised
Product
Initially, the reaction was carried out for 6h using benzoyl chloride and
14
triethylamine, 1.0 equivalent each, when 17 was isolated as a major
product. However, by increasing the reaction time from 6h to 24h and
using 2.0 equivalent of each of these reagents, we were able to generate the
other product 17 in significant quantity. After separating from the Obenzoylated compound 17 the unexpected product 18 was characterized by
various spectral data. The comparison of the present proton NMR data with
the reported one remained inconclusive mainly due to the difference in
MHz of the NMR instrument used and solvent for the preparation of NMR
sample. In order to confirm the structure beyond doubt its structure was
finally confirmed unambiguously via X-ray single crystal data (Figure 1,
CCDC 695425).
Figure1 ORTEP Diagram of compound 18
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LIST OF PUBLICATIONS
1. “Novel naproxen derivatives: Lewis acid / transition-metal free
synthesis via C-C bond forming reaction”, S. Pal, P. Bindu, P.R.
Venna, P.K. Dubey, Letters in Organic Chemistry, 2007, 38, 51,
292.
2. “Transition-metal/Lewis
acid
free
synthesis
of
acylbenzothiophenes via C-C bond forming reaction”, S. Pal, M.A.
Khan, P. Bindu, P.K. Dubey, Beilstein Journal of Organic
Chemistry, 2007, 3, 35.
3. “Synthesis and structure analysis of cyclodehydration product of
piroxicam: A metabolite detected in dogs and monkeys”, S. Pal, P.
Bindu, P.K. Dubey, S. Chakraborty, A.K. Mukherjee, European
Journal of Medicinal Chemistry, 2009, 44, 8, 3368.
4. “TFAA-H3PO4 mediated C-2 acylation of thiophene: A direct
synthesis of known and novel thiophene derivatives”, P. Bindu,
S.R. Naini, K.S. Rao, P.K. Dubey, S. Pal,Journal of Heterocyclic
Chemistry, in press, 2012.
16
LIST OF SYMPOSIUM PRESENTATIONS
1.
“Green synthesis of naproxen derivatives via C-C bond forming
reaction”, S. Pal, P. Bindu, P.R. Venna, P.K. Dubey, Poster
presented in international symposium on “Current perspectives in
Organic Chemistry”, December
7-9,
2006,
IACS,
Jadavpur,
Kolkata,700032, W.B, India.
2.
“Synthesis and structure confirmation of cyclodehydration product
of piroxicam: A metabolite detected in dogs and monkeys”, P.
Bindu, P.K. Dubey, S. Chakraborty, A.K. Mukherjee, S. Pal, Poster
(PP 38), presented in international symposium on “Recent
advances in chemical research”, February 6-7, 2009, Department
of Chemistry, University college of science, O.U, Hyderabad, A.P,
India.
3.
“Environmentally benign synthesis of derivatives of piroxicam via
transition metal and lewis acid free acylation”, P. Bindu, K.S. Rao,
S.N.Reddy, P.K. Dubey, S. Pal, Poster (PB74) presented in
international conference on “recent advances in drug discovery”,
October 22-24, 2010, University College
of Pharmaceutical
Sciences, Kakatiya University, Warangal, A.P, India.
4.
“Green synthesis of acyl derivatives of ibuprofen”, P. Bindu, K.S.S.
Praveena, S.R. Naini, P.K. Dubey, Poster presented in national
seminar on “Recent trends in Pharmaceutical Chemistry”, January
30-31, 2011, Krishna University, Machilipatnam, A.P, India.
5.
“TFAA-H3PO4 mediated C-2 acylation of thiophene; A direct
17
synthesis of known and novel thiophene derivatives”, P. Bindu,
S.R. Naini, K.S. Rao, P.K. Dubey, S. Pal, Poster presented in
national seminar on “Recent trends in Pharmaceutical Chemistry”,
January 30-31, 2011, Krishna University, Machilipatnam, A.P,
India.
6.
“A straight forward synthesis of known and novel thiophene
derivatives via C-2 acylation of thiophene”, P. Bindu, S.R. Naini,
K.S. Rao, P.K. Dubey, S. Pal, Poster presented in Symposium on
“The Role of women in Chemistry”, September 24, 2011, St. Ann’s
college for women, Mehdipatnam, Hyderabad, A.P, India.
7.
“Environmentally
benign
synthesis
of
NSAID
based
2-acyl
derivatives of furan via transition metal and lewis acid free
acylation”, P. Bindu, K.S. Rao, S.R. Naini, P.K. Dubey, S. Pal,
Poster presented in national seminar on “Recent Advances in
Heterocyclic Chemistry (NSRAHC)”, November 4-5, 2011, JNTUH
College of Engineering, Hyderabad, A.P, India.