TFAA/H3PO4-Mediated C-2 acylation of thiophene: A direct synthesis of known and novel thiophene derivatives of pharmacological interest

Article abstract of DOI:10.1002/jhet.1106

A number of aliphatic and aromatic carboxylic acids were reacted with thiophene in the presence of trifluoroacetic anhydride and H₃PO ₄ to give a variety of acylated thiophenes in good to excellent yields. The methodology was used to prepare known nonsteroidal anti-inflammatory drug-based novel compounds of potential pharmacological significances. Molecular modeling studies were carried out by using nonsteroidal anti-inflammatory drug-based thiophene derivatives to assess their cyclooxygenase inhibiting potential in silico. On the basis of docking studies followed by subsequent in vitro assay, indomethacin-based thiophene derivative was identified as a novel cyclooxygenase-2 inhibitor with balanced selectivity.

Full text of DOI:10.1002/jhet.1106

586
TFAA/H3PO4-Mediated C-2 Acylation of Thiophene: A Direct Synthesis
of Known and Novel Thiophene Derivatives of Pharmacological Interest
Vol 51
a
a
b
a
P. Bindu,a,b Shravan Reddy Naini, K. Shanmukha Rao, P. K. Dubey, and Sarbani Pal
*
aDepartment of Chemistry, MNR Degree and PG College, Kukatpally, Hyderabad 500072, India
bJNT University, Kukatpally, Hyderabad 500072, India
*
E-mail: sarbani277@yahoo.com
Received March 10, 2011
DOI 10.1002/jhet.1106
Published online 26 November 2013 in Wiley Online Library (wileyonlinelibrary.com).
S
TFAA
H
COX-2
H3PO4
R
O
S
+
R
MeO
rt - 80 o
C
Me
HO
S
n
n
N
O
O
Cl
O
NSAID based
thiophene derivative
A number of aliphatic and aromatic carboxylic acids were reacted with thiophene in the presence of
trifluoroacetic anhydride and H3PO4 to give a variety of acylated thiophenes in good to excellent yields. The
methodology was used to prepare known nonsteroidal anti-inflammatory drug-based novel compounds of
potential pharmacological significances. Molecular modeling studies were carried out by using nonsteroidal
anti-inflammatory drug-based thiophene derivatives to assess their cyclooxygenase inhibiting potential in silico.
On the basis of docking studies followed by subsequent in vitro assay, indomethacin-based thiophene derivative
was identified as a novel cyclooxygenase-2 inhibitor with balanced selectivity.
J Heterocyclic Chem., 51, 586 (2014).
INTRODUCTION
[26], or Ph4BiNa [27]; (g) thiophene-2-carbonyl fluoride with
Ph2Zn [28]; (h) 2-bromothiophene [29,30] or thiophen-2-
ylmagnesium bromide [31] or trimethyl(thiophen-2-yl)stan-
nane [32] or dithiophen-2-ylmercury [33] with benzoyl
chloride; (i) thiophen-2-aldehyde with iodobenzene [34]; and
(j) 1-methyl-3-(N-methylthiophene-2-carboxamido)-1H-imi-
dazol-3-ium iodide with PhMgBr [35]. Most of these meth-
ods, however, require the use of a transition metal or other
catalyst and cumbersome preparation of unstable or mois-
ture-sensitive starting materials or special reagents. Some of
these catalysts are either expensive or not readily available
and therefore not suitable for use in large scale synthesis.
Moreover, in many cases, these methodologies were found to
be specific for the syntheses of a particular compound and there-
fore are not general in nature. Nevertheless, the simplest and
widely used method for the preparation of 2-aroyl thiophenes
is Friedel–Crafts acylation reaction between thiophene and
benzoyl chloride [36–40] and AlCl3 being the main catalyst,
although the use of other catalysts, for example, SnCl4, ZnCl2,
Yb(OTf)3, (TMP)2CuCl, P2O5, TiCl4, silica gel, iron silicate,
and iodine, has also been explored. This methodology is also
associated with several drawbacks such as requirement of
stoichiometric amount of environmentally harmful AlCl3 and
moisture-sensitive acid chloride. Although the direct use of
benzoic acid in place of benzoyl chloride has been explored
in the presence of various catalysts [13,41,42], these methodol-
ogies however were not developed as general methods for the
preparation of compounds represented by C (Figure 1). Thus
Thiophene derivatives possessing a –COAr group at C-2
are of particular interest because of their valuable pharmaco-
logical properties. For example, (RS)-2-[4-(2-thienylcarbonyl)
phenyl]propanoic acid (A, Figure 1) or suprofen, an nonsteroi-
dal anti-inflammatory drug (NSAID) marketed under the trade
name of Profenal, is presently used to prevent miosis during
and after ophthalmic surgery [1]. Similarly, [2,3-dichloro-4-
(2-thienylcarbonyl)phenoxy]acetic acid (B, Figure 1) or
tienilic acid that belongs to this class is a diuretic drug that
possesses uric acid-lowering (uricosuric) properties and was
formerly marketed for the treatment of hypertension [2].
Because of their medicinal value, we became interested to
synthesize a library of thiophene derivatives C (Figure 1)
related to A and B for their potential pharmacological applica-
tions. An impressive number of methods have been reported
for the synthesis of 2-aroyl thiophenes. Some of these include
the reaction of the following: (a) thiophene with benzoic anhy-
dride [3–8], (trichloromethyl)benzene [9], t-butylbenzoate
[10], pyridin-2-yl benzoate [11], (1H-imidazol-1-yl)(phenyl)
methanone [12], or PhCO2POF2 [13]; (b) thiophene-2-
boronic acid with benzoic anhydride [14–17]; (c) 2-iodothio-
phene with carbon monoxide and phenyl boronic acid or PhLi
[18–20]; (d) tributyl(thiophen-2-yl)stannane with Ph2TeCl2
[21] or Ph2IBF4 and carbon monoxide [22]; (e) thiophen-2-
boronic acid with benzoyl chloride [23]; (f) thiophene-2-
carbonyl chloride with phenyl boronic acid [24,25], Ph3Bi
© 2013 HeteroCorporation

May 2014
TFAA/H3PO4-Mediated C-2 Acylation of Thiophene
587
O
CO2H
R
A number of carboxylic acids were reacted with thiophene
to give a variety of thiophene derivatives possessing an acyl
group at the C-2 position of the thiophene ring (entries 4–13,
Table 1). Whereas 2.0 h was found to be optimum for
benzoic acid (entry 3, Table 1), the reaction time, however,
varied depending on the nature of acids used. For
example, aromatic acids containing electron-donating groups
(e.g., Me, Cl, or OMe) on the benzene ring required relatively
shorter reaction time (entries 4–7 and 9, Table 1) than those
containing electron-withdrawing groups (e.g., NO2, entry 8,
Table 1). The use of simple aliphatic acids was also found
to be effective, and the reaction was completed within 1.5 h
(entries 10 and 11, Table 1). All the thiophene derivatives
synthesized were isolated in good to excellent yields, and
formation of no side products were detected during the
acylation process. To expand the generality and scope of this
process, we examined the reaction of thiophene with few
highly functionalized carboxylic acids, for example, ibupro-
fen, indomethacin, and mefenamic acid (entries 12–14,
Table 1). Although the reaction proceeded smoothly at room
temperature, it took longer time to give the desired product in
good yield. However, the reaction was completed within
2.0 h when carried out at 80ꢀC, and the corresponding
thiophene based products (3j–3l) were isolated in 78–90%
CO2H
S
n
S
Cl
S
O
O
Cl
O
C; R = aryl, heteroaryl
B
A
n = 0,1
Figure 1. Thiophene-based drugs suprofen (A), tienilic acid (B), and the
proposed library (C).
a direct, general, and convenient method was required to
prepare C that could eventually help us to build a diver-
sity-based compound library. Herein, we report a new,
one-pot, and simple synthesis of thiophene-based
compound 3 (C in Figure 1) directly from thiophene (1)
and various carboxylic acids (2) via a C–C bond-forming
reaction (Scheme 1).
RESULTS AND DISCUSSION
Chemistry.
The use of TFAA/H3PO4 as an efficient
catalyst system for C–C bond forming reaction between a
carboxylic acid and arenes has been studied earlier [43–45].
Accordingly, we have reported TFAA/H3PO4-mediated
smooth C-acylation of arenes and heteroarenes [46,47].
However, exploring this methodology for the preparation of
compound 3 and related studies have not been reported
earlier. We anticipated that this methodology could be
developed as a general route for accessing thiophene-based
compound library represented by C.
Benzoic acid 2a (2; R = Ph, n= 0, Scheme 1) was initially
chosen as an acid partner to establish the optimized reaction
conditions for the present C-acylation of thipohene (1).
Results of this study are summarized in Table 1. Thus, the acid
2a (1.0 mol) was reacted with thiophene 1 (1.0 mol) in the
presence of commercially available 85% H3PO4 (1.0 mol)
and TFAA (4.0 mol) at room temperature. The yield of the
product, that is, 2-benzoyl thiophene 3a (3; R =Ph, n=0,
Scheme 1), was examined at different interval of time and
was found to be 51, 70, and 92% after 5, 15, and 120 min,
respectively (entries 1–3, Table 1). Further increase in time
did not improve the product yield. The use of lower quantity
of TFAA and H3PO4 was also examined and found to be less
productive as the progress of the reaction was slow and the
product yield was decreased significantly. The isolated
product 3a was well characterized by NMR, IR, and MS
and compared with the reported data. Having established the
optimum reaction condition, we then decided to examine the
reaction of 1 with other carboxylic acids (2b–2l).
1
yields. The H NMR spectrum of compound 3k is shown
in Figure 2. Notably, all these acids used are well-known
NSAIDs and have been in patient’s use for the treatment of
diseases related to pain and inflammation. Thus, the novel
thiophene derivatives prepared from these acids are not only
expected to have potential medicinal value but also might
play important role as precursors in the synthesis of various
thiophene-based bioactive molecules.
A
probable mechanism for TFAA/H3PO4-mediated
reaction of carboxylic acids with thiophene is shown in
Scheme 2 [43–45]. Thus, phosphoric acid that plays the
role of a covalent catalyst leads to the generation of acyl
bis(trifluoroacetyl)phosphate T-2 from the acylation precur-
sor acyl trifluoroacetate T-1 generated in situ [43]. The
acyl bis(trifluoroacetyl)phosphate T-2 then acetylates the
(hetero)arene ring in the presence of phosphoric acid to
afford the products 3. Thiophene being an electron-rich
heterocyclic ring facilitates the acylation step greatly after
activation of T-2 by phosphoric acid as a proton source. It
is worthy to mention that excess of TFAA and TFA (trifluor-
oacetic acid generated during the reaction) can be removed
by distillation during a large scale synthesis [48] of com-
pound 3, and the recovered TFA can be converted back to
TFAA via dehydration, thereby eliminating the acid waste.
Scheme 1. Preparation of thiophene derivatives from thiophene and
Docking studies and pharmacology.
Having prepared
carboxylic acids.
NSAID-based thiophene derivatives 3j–3l, we decided to
assess their potential for cyclooxygenase (COX)-inhibiting
properties in silico. COX, which catalyzes the first step
of biosynthesis of prostanoids, exists in two isoforms,
that is, a constitutive form called COX-1 responsible for
R
R
TFAA / H3PO4
rt
HO
H
+
S
n
n
S
O
O
2
1
3
Journal of Heterocyclic Chemistry
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588
P. Bindu, S. R. Naini, K. Shanmukha Rao, P. K. Dubey, and S. Pal
Vol 51
physiological production of prostaglandins and an
inducible form, known as COX-2, which is involved in
the processes of inflammation [49]. Classical NSAIDs
such as 2j–2l are nonselective inhibitors of COX, and
their long-term use leads to the side effects particularly
ulceration. Thus, a number of selective COX-2 inhibitors
were developed, and few were launched in the market,
for example, celecoxib and rofecoxib [50]. However, the
Table 1
TFAA/H3PO4-mediated synthesis of thiophene derivatives (3) from thiophene (1) and various carboxylic acids (2).a
Entry
1
Carboxylic acid (2)
Time (h)
5 min
Product (3)
% Yieldb
51
OH
O
S
2a
O
3a
2
3
4
2a
2a
15 min
2.0
2.0
3a
3a
70
92
93
OH
Me
Me
O
S
2b
O
3b
5
2.0
80
OH
O
S
Me
2c
Me
O
3c
6
7
2.0
2.0
87
81
OH
O
Cl
Cl
S
2d
O
3d
OH
O
S
Cl
2e
Cl
O
3e
8
9
2.5
1.5
79
85
O2N
OH
O
O2N
S
2f
O
O
3f
OH
O
MeO
MeO
S
2g
3g
10
11
MeCO2H 2h
1.5
1.5
94
89
Me
Et
S
O
3h
EtCO2H 2i
S
O
3i
(Continued)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2014
TFAA/H3PO4-Mediated C-2 Acylation of Thiophene
589
Table 1
(Continued)
Entry
12
Carboxylic acid (2)
Time (h)
2.0
Product (3)
% Yieldb
83c
Me
Me
O
Me
Me
Me
Me
S
OH
3j
O
2j
13
2.0
90c
OH
S
O
MeO
Me
O
MeO
N
Me
O
N
Cl
2k
O
Cl
3k
14
2.0
78c
Me
Me
HO
Me
Me
NH
O
H
S
N
O
2l
3l
aAll the reactions were carried out using thiophene 1 (1.0 mol), acid 2 (1.0 mol), 85% H3PO4 (1.0 mol), and TFAA (4.0 mol) at room temperature.
bIsolated yield.
cThe reaction was carried out at 80ꢀC.
Figure 2. 1H NMR (400 MHz) spectrum of compound 3k in DMSO-d6.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

590
P. Bindu, S. R. Naini, K. Shanmukha Rao, P. K. Dubey, and S. Pal
Vol 51
Scheme 2. Probable mechanism for TFAA/H3PO4-mediated reaction of carboxylic acids with thiophene.
R
R
R
TFAA
F3COCO
F3COCO
TFAA
F3C
O
O
HO
n
P
n
n
O
O
H3PO4
O
O
O
T-2
T-1
2
R
S
S
n
O
H3PO4
3
withdrawal of rofecoxib in 2004 followed by valdecoxib in
2005 has raised several safety-related questions including
the one that inhibitors possessing high selectivity towards
COX-2 have any real benefits. Nevertheless, our effort was
directed towards the identification of potential inhibitors
possessing balanced selectivity. Accordingly, compounds
3j–3l were docked in both COX-1 and COX-2 proteins,
and their interactions along with binding energies were
analyzed. On the basis of the binding energy data presented
in Table 2, it was evident that all the compounds interacted
well with both the COX isoforms. However, compound 3k
showed better affinity towards COX-2 in comparison with
3j and 3l, although it interacted with COX-1 as well. Thus,
3k was predicted to be COX-2 selective, whereas 3j and 3l
appeared to be nonselective inhibitors of COX isozymes.
The interaction of 3k with COX-1 and COX-2 is shown
in Figures 3 and 4, respectively. Its interaction with COX-1
was mainly contributed by a hydrogen bonding between
the indole C═O group with the –NH group of the
Arg120 residue of COX-1. In contrast, no such H-bonding
was observed when 3k was docked with COX-2 protein,
and the overall interaction was mainly contributed by
hydrophobic and van der Waals type of interactions.
Prompted by this observation, compound 3k was tested
against human COX-2 (expressed in sf9 insect cells using
baculovirus) and COX-1 (ram seminal vesicles) enzymes
in vitro [51]. At the concentration of 30 mM, this compound
showed fourfold selectivity for COX-2 (80% inhibition)
over COX-1 (20% inhibition). The moderate COX-2 selec-
tivity shown by 3k could be beneficial as this might lead to
the identification of COX-2 inhibitors with better safety
profile. Nevertheless, the present study indicated that a
new class of thiophene-based inhibitor could be generated
Table 2
Binding energy of compounds 3j–3l after docking with COX-1 and COX-2.
Binding energy (kcal/mol)
Compound
COX-1
COX-2
3j
3k
3l
À10.42
À8.48
À9.35
À11.08
À10.61
À11.31
Figure 3. Docking of 3k with the COX-1 protein (color figure can be viewed
Figure 4. Docking of 3k with the COX-2 protein (color figure can be viewed
in the online issue, which is available at www.interscience.wiley.com).
in the online issue, which is available at www.interscience.wiley.com).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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TFAA/H3PO4-Mediated C-2 Acylation of Thiophene
591
stirring at room temperature. The mixture was then stirred
according to the conditions (e.g., temperature and time)
indicated in Table 1. After completion of the reaction, the
mixture was poured into ice-cold water (50 mL) with vigorous
stirring. The mixture was filtered when solid was separated. The
residue was washed with petroleum ether (2 Â 5 mL), dried, and
purified by column chromatography on silica gel (EtOAc/
petroleum ether as eluting solvent) to give the desired product.
In case of liquid product, the mixture was extracted with EtOAc
(3 Â 20 mL). The organic layers were collected, combined,
washed with cold water (2 Â 25 mL), dried, and purified by
column chromatography on silica gel (EtOAc/petroleum ether as
eluting solvent) to give the desired product.
Phenyl(thiophen-2-yl)methanone (3a). Light brown solid;
mp 54–55ꢀC (petroleum ether, lit. [52] 54–55ꢀC); MS m/z 140
(M+, 100%); IR nmax/cmÀ1 (KBr): 3097, 3050, 1626, 1594,
1575; 1H NMR (CDCl3, 400 MHz) d 7.98 (d, 2H, J = 8.8 Hz),
7.73–7.72 (m, 1H), 7.64–7.40 (3H, m), 7.24 (d, J=3.4Hz, 1H), 6.60
(dd, 1H, J = 3.4 and 1.5Hz); 13C NMR (CDCl3, 100 MHz) 187.6,
143.8, 138.5, 134.2, 133.5, 131.9, 128.9, 128.2, 127.6.
via C-2 acylation of thiophene ring, and their COX
inhibiting properties as well as COX-2 selectivity could
be modulated via proper modifications in the acyl group.
Moreover, because of the absence of carboxylic acid
moiety, these compounds may exhibit favorable pharmaco-
logical properties than the parent NSAIDs.
CONCLUSIONS
In conclusion, a direct and facile synthesis of thiophene
derivatives has been achieved via TFAA/H3PO4-mediated
C-2 acylation of thiophene ring with the use of both
aliphatic and aromatic carboxylic acids. The present one-
pot method being simple and straightforward is easy to
handle and does not involve the use of unstable/moisture-
sensitive acid chlorides or expensive reagents/catalysts.
The generality and scope of this methodology has been
demonstrated in synthesizing novel acylated thiophenes
derived from well-known NSAIDs. The methodology is
expected to be superior to the classical Friedel–Crafts
acylation technique and other multistep synthesis and
therefore would find application for the preparation of
thiophene-based library of compounds with desired diver-
sity. Molecular modeling studies were carried out using
NSAID-based thiophene derivatives synthesized to assess
their COX-inhibiting potential in silico. On the basis of
docking studies followed by subsequent in vitro assay, in-
domethacin-based thiophene derivative was identified as a
novel COX-2 inhibitor with balanced selectivity. Overall,
this is the first report on synthesis, docking studies, and
in vitro pharmacological evaluation of NSAID-based
thiophene derivatives that may show favorable pharmaco-
logical properties than the parent NSAIDs.
(Thiophen-2-yl)(p-tolyl)methanone (3b).
Off-white solid;
mp 70–71ꢀC (ethanol, lit. [53] 72–75ꢀC); MS m/z 203 (M+,
100%); IR nmax/cmÀ1 (KBr): 3026, 2913, 1627, 1603, 1569; H
1
NMR (CDCl3, 400 MHz) d 7.78 (d, J = 7.7 Hz, 2H), 7.69 (d,
J = 4.8 Hz, 1H), 7.64 (d, J = 4.0 Hz, 1H), 7.29 (d, J = 8 Hz, 2H),
7.15 (dd, J = 4.8 and 4.0 Hz, 1H), 2.44 (s, 3H); 13C NMR
(CDCl3, 100 MHz) 187.4, 144.1, 142.9, 136.0, 133.3, 129.3,
128.9, 127.7, 127.6, 21.4.
(Thiophen-2-yl)(o-tolyl)methanone (3c).
Light yellow
solid; mp 145–146ꢀC (ethanol, lit. [41] 145–147ꢀC); MS m/z
203 (M+, 100%); IR nmax/cmÀ1 (KBr): 3026, 2913, 1627, 1603,
1569; 1H NMR (CDCl3, 400MHz) d 8.1 (d, J = 5.9 Hz, 1H),
7.45–7.37 (m, 3H), 7.30–2.23 (m, 2H), 7.11 (dd, J = 4.8 Hz,
4.0 Hz, 1H); 2.44 (s, 3H).
(4-Chlorophenyl)(thiophen-2-yl)methanone (3d). Off white
solid; mp 98–100ꢀC (ethanol, lit. [52] 99–100ꢀC); MS m/z 223
(M+, 100%); IR nmax/cmÀ1 (KBr): 1629, 1586; 1H NMR (CDCl3,
400 MHz) d 7.82 (d, J = 8.4 Hz, 2H); 7.75 (dd, J = 4.9 Hz, 1.1Hz,
1H); 7.63 (dd, 1H, J = 3.7 Hz, 1.1 Hz); 7.48 (d, J = 8.4 Hz, 2H);
7.18 (dd, J = 4.9Hz, 3.7Hz, 1H); 13C NMR (CDCl3, 100 MHz)
186.4, 143.3, 138.7, 136.7, 134.2, 133.9, 130.4, 128.6, 127.7.
(2-Chlorophenyl)(thiophen-2-yl)methanone (3e). Light brown
oil [54]; MS m/z 223 (M+, 100%); IR nmax/cmÀ1 (KBr): 1629, 1586;
1H NMR (CDCl3, 400 MHz) d 7.76 (dd, 1H, J= 4.9 Hz, 1.1 Hz, 1H);
7.49–7.34 (m, 5H); 7.12 (dd, J= 4.7 Hz, 4.0 Hz, 1H).
EXPERIMENTAL
Chemistry.
Melting points were all determined by open
glass capillary method on a Sisco melting point apparatus
(Thana, Maharashtra, India) and are uncorrected. IR spectra were
recorded on a PerkinElmer spectrometer in KBr pellets. 1H
NMR and 13C NMR spectra were recorded on a Varian 400-
(4-Nitrophenyl)(thiophen-2-yl)methanone (3f). Pale yellow
solid; mp 172–173ꢀC (EtOH, lit. [55] 173–174ꢀC); MS m/z 233
MHz spectrometer using CDCl3 as
a
solvent with
1
(M+, 100%); IR nmax/cmÀ1 (KBr): 1629, 1590, 1510; H NMR
tetramethylsilane as internal reference (TMS, d = 0.00). Elemental
analyses were performed using Varian 3LV analyzer series CHN
analyzer. Mass spectra were recorded on a Jeol JMCD-300
instrument. All solvents used were commercially available and
distilled before use. All reactions were monitored by TLC on pre-
(CDCl3, 400 MHz) d 8.37 (d, 2H, J = 8.7 Hz), 8.20 (d, 1H,
J = 4.2 Hz), 8.0 (d, 2H, J = 8.6 Hz), 7.73 (d, 1H, J = 2.80 Hz),
7.30 (t, 1H, J = 3.9 Hz).
(4-Methoxyphenyl)(thiophen-2-yl)methanone (3g).
Light
brown solid; mp 65–66ꢀC (ethanol, lit. [56] 69–72ꢀC) MS m/z
219 (M+, 100%); IR nmax/cmÀ1 (KBr): 3109, 3009, 2969, 1628,
1601; 1H NMR (CDCl3, 400 MHz) d 7.90 (d, J = 8.8 Hz, 2H),
7.68 (d, J = 5.1 Hz, 1H), 7.64 (d, J = 3.7 Hz, 1H), 7.16
(dd, J = 4.7 and 3.7 Hz, 1H), 6.98 (d, J = 8.4 Hz, 2H), 3.90
(s, 3H, OCH3); 13C NMR (CDCl3, 100 MHz) 186.3, 163.2,
143.9, 133.4, 132.8, 131.4, 131.1, 127.5, 113.8, 55.3.
coated silica gel plates (60
F
254; Merck). Column
chromatography was performed on a 100–200 mesh silica gel
(SRL, India) with the use of 10- to 20-fold excess (by weight) of
the crude product. The organic extracts were dried over anhydrous
Na2SO4. Ibuprofen, indomethacin, and mefenamic acid and all the
carboxylic acids used are commercially available.
General method for the preparation of compound 3. To a
mixture commercially available acid 2 (4.42 mmol) in TFAA
(2.5 mL, 17.7 mmol), thiophene 1 (4.42 mmol) was added
dropwise followed by 85% H3PO4 (4.42 mmol) with vigorous
1-(Thiophen-2-yl)ethanone (3h).
Light brown gum [57];
1
MS m/z 126 (M+, 100%); IR nmax/cmÀ1 (KBr): 1660; H NMR
(CDCl3, 400 MHz) 7.69 (dd, 1H, J = 5.0 and 1.4 Hz), 7.63 (dd,
Journal of Heterocyclic Chemistry
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Vol 51
1H, J = 3.5 and 1.4 Hz), 7.12 (dd, 1H, J = 5.0 and 3.5 Hz), 2.56 (s,
3H); 13C NMR (CDCl3, 100 MHz) 190.7, 144.5, 132.6, 128.2,
133.8, 26.8.
Tris pH 8.0, 3-mM EDTA, 15-mM hematin, 150 units enzyme,
and 8% DMSO. The mixture was pre-incubated at 25ꢀC for
15 min before initiation of enzymatic reaction in the presence of
compound/vehicle. The reaction was initiated by the addition of
100-mM arachidonic acid and 120-mM TMPD. The enzyme
activity was measured by estimation of the initial velocity of
TMPD oxidation over the first 25 s of the reaction followed from
an increase in absorbance at 603 nM.
1-(Thiophen-2-yl)propan-1-one (3i). Light brown oil [41];
1
MS m/z 140 (M+, 100%); IR nmax/cmÀ1 (KBr): 1665; H NMR
(CDCl3, 400 MHz) 7.72 (dd, 1H, J = 3.8 and 1.2 Hz), 7.66 (dd,
1H, J = 5.0 and 1.2 Hz), 7.12 (dd, 1H, J = 5.0 and 3.8 Hz), 2.89
(q, J = 7.2 Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3,
100 MHz) 193.7, 144.1, 133.6, 131.2, 128.3, 32.52, 8.51.
2-(4-Isobutylphenyl)-1-(thiophen-2-yl)propan-1-one (3j).
MS m/z 273 (M+, 100%); IR nmax/cmÀ1 (KBr): 1659; 1H
NMR (CDCl3, 400 MHz) d 7.67 (d, 1H, J = 3.7 Hz); 7.55 (d,
1H, J = 4.8 Hz); 7.22 (d, 2H, J = 8.1 Hz); 7.08–7.02 (m, 3H);
4.47 (q, 1H, J = 7.0 Hz); 2.41 (d, 2H, J = 7.3 Hz); 1.81–1.79
(m, 1H); 1.52 (d, 3H, J = 7.0 Hz); 0.87 (d, 6H, J = 6.6 Hz);
elemental analysis found C, 74.66; H, 7.31; Calcd for
C17H20SO; C, 74.96; H, 7.40.
Acknowledgments. The authors thank Mr. M. N. Raju, the chairman
of the MNR Educational Trust, for the constant support and
encouragement.
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