A high speed parallel synthesis of 1,2-diaryl-1-ethanones via a clean-chemistry C-C bond formation reaction

Article abstract of DOI:10.1016/S0040-4020(03)00407-1

In this report, we describe the parallel as well as conventional synthesis of 1,2-diaryl-1-ethanones via environmentally benign acylation of arenes with in situ generated arylacetyl trifluoroacetates. A wide variety of arylacetic acids I participated in trifluoroacetic anhydride/phosphoric acid mediated C-C bond formation reaction when reacted with arenes of type II to give 1,2-diaryl-1-ethanones III in good to excellent yield. Under the solvent-free conditions these chemical transformations that normally require longer reaction time can be performed within minutes in good yield.

Full text of DOI:10.1016/S0040-4020(03)00407-1

Tetrahedron 59 (2003) 3283–3290
A high speed parallel synthesis of 1,2-diaryl-1-ethanones via a
clean-chemistry C–C bond formation reactionq
*
Venugopal Rao Veeramaneni, Manojit Pal and Koteswar Rao Yeleswarapu
*
Chemistry—Discovery Research, Dr Reddy’s Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500050, India
Received 27 November 2002; revised 11 February 2003; accepted 14 March 2003
Abstract—In this report, we describe the parallel as well as conventional synthesis of 1,2-diaryl-1-ethanones via environmentally benign
acylation of arenes with in situ generated arylacetyl trifluoroacetates. A wide variety of arylacetic acids I participated in trifluoroacetic
anhydride/ phosphoric acid mediated C–C bond formation reaction when reacted with arenes of type II to give 1,2-diaryl-1-ethanones III in
good to excellent yield. Under the solvent-free conditions these chemical transformations that normally require longer reaction time can be
performed within minutes in good yield. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
The COX-2 inhibitors are known to be useful for the
treatment of inflammation and other related diseases with
reduced gastrointestinal side effects, when compared to
traditional NSAIDs (non-steroidal anti-inflammatory
drugs). In connection with our work on the development
of cyclooxygenase (COX-2) inhibitors,7 we planned to
synthesize various heterocycles with a central ring of the
1,2-diaryl-heterocycle class.7,8 Therefore, we needed a wide
variety of appropriately functionalized 1,2-diaryl-1-etha-
nones III (Fig. 2, Ar1 and Ar2 represents diverse aryl
groups). Due to their enormous importance, especially in
pharmaceutical research, several methodologies have been
developed by researchers from academia and industry for
the synthesis of 1,2-diaryl-1-ethanones.9 Among the
methods available in the literature for the synthesis of III,
the simplest involves Friedel–Crafts acylation6b of arenes
using arylacetyl chloride or acid. This method involves the
use of stoichiometric amounts of AlCl3 or ZnCl2–POCl3
1,2-Diaryl-1-ethanones are versatile intermediates1 for the
synthesis of pavine, isopavine and protoberberine groups of
alkaloids,1a as well as valuable synthons of various
bioactive molecules1c,d in the field of new drug discovery.
This is exemplified by the development of several
pyridinyloxazoles as CSBP (p38) kinase inhibitors,2 2,4,5-
triarylimidazole as IL-1 biosynthesis inhibitors3a or
acetylene analogues3b and estrogen receptor-b potency-
selective ligands. They are also useful as potent and
selective inhibitors of catechol-O-methyltransferase.4
A
member of this class BIA 3-202, is currently under clinical
development for the treatment of Parkinson’s disease. 1,2-
Diaryl-1-ethanones have recently attracted attention due to
their usefulness as synthetic templates in the development of
selective COX-2 inhibitors5,6 such as Valdecoxib,5b DuP
6976a (Fig. 1) etc.
Figure 1. Structure of BIA 3-202 and some COX-2 selective inhibitors.
q DRF Publication No. 193.
Keywords: 1,2-diaryl-1-ethanone; trifluoroacetic anhydride; phosphoric acid; acylation.
*
Corresponding authors. Tel.: þ91-40-3045438; fax: þ91-40-3045007; manojitpal@drreddys.com; koteswarraoy@drreddys.com
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00407-1

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V. R. Veeramaneni et al. / Tetrahedron 59 (2003) 3283–3290
with 3 equiv. of arene (II) in a solvent such as acetonitrile in
the presence of 85% phosphoric acid and excess trifluoro-
acetic anhydride at 508C for 30–180 min, 1,2-diaryl-1-
ethanones (III) were obtained as the major product in good
to excellent yields (Method A, Scheme 1). However, we
have observed that either III or the corresponding enolester
of trifluoroacetate (V) was formed as the exclusive product
when the reaction was performed at 258C for 1 min in the
absence of solvent (Methods B and C, Scheme 1). Here, in
this report, we disclose our preliminary findings on a simple
and rapid entry to 1,2-diaryl-1-ethanones from readily
available starting materials using parallel synthesis tech-
niques. Results of our acylation reaction are summarized in
Table 1.
Figure 2. Synthetic strategy for the development of new COX-2 inhibitor.
mixture, which leads to the formation of environmentally
harmful gaseous HCl, especially when applied to large-scale
synthesis. Non-availability of starting material is another
major drawback of this protocol, as in most cases,
preparation of the arylacetyl chloride is cumbersome due
to their moisture-sensitive nature and tendency to decom-
pose. Use of other reagents such as BF3·Et2O or CF3SO3H in
a modified Friedel–Crafts acylation processes has been
examined and reported to be inefficient for the synthesis of
III.9b,d To overcome all these difficulties we focused our
attention on the development of an alternative method that
could be utilized for the straightforward preparation of III.
As can be seen from Table 1 the solvent free acylation
reaction (Scheme 1, Method B) tolerated a variety of
substituents on Ar2. A substituent like the methoxy or
methylsulfanyl group was found to be highly effective
(entries 1, 2, 5 and 7), compared to weak electron donating
groups such as ethyl or methyl (entries 4 and 6).
Interestingly, only mono acylation was observed in the
case of biphenyl (entry 3). The molar ratio of reactants,
trifluoroacetic anhydride (TFAA) and phosphoric acid was
optimized to achieve maximum yield and was found to be a
1:1.2:1.2:4 ratio of I, II, H3PO4 and TFAA. The use of
excess TFAA (6 equiv.) led to the formation of the enol
trifluoroacetate ester V (9 and 10) as the exclusive product
(Scheme 2). This could be converted to the corresponding
ketone III (2 and 7, Scheme 2) in methanol in the presence
of K2CO3 in high yield. The acylation reaction was carried
out at 258C for 1 min and was found to be vigorous and
exothermic. Any increase in the reaction temperature led to
the generation of dark colored unidentified material. The
acylation reaction, as well as yield of products was not
2. Results and discussion
The use of acyl trifluoroacetate,10 generated in situ from a
carboxylic acid and trifluoroacetic anhydride (TFAA), for
aromatic acylation has been reported very recently.11 This
method has been viewed as a useful alternative, especially
for large scale preparation, to the Friedel–Crafts acylation
process. Surprisingly, despite its application for the
synthesis of a variety of aromatic ketones,11 use of this
methodology for the synthesis of III remained undisclosed.
We therefore, assayed the applicability and scope of this
protocol for the synthesis of 1,2-diaryl-1-ethanones of our
interest. Accordingly, when arylacetic acids (I) were treated
Scheme 1. Reagents and conditions: Method A: H3PO4, (CF3CO)2O, acetonitrile, 508C, 30–180 min; Method B: H3PO4, (CF3CO)2O, 258C, 1 min; Method C:
H3PO4, (CF3CO)2O (excess), 258C, 0.5 min.
Table 1. Synthesis of 1,2-diaryl-1-ethanones (III) via acylation of arenes (II) with arylacetic acids (I)
Entry no.
I Ar1
II Ar2–H
Compound no.a
Yield (%)b III
Method B
Method A
Parallel synthesis (Method B)
1
2
3
4
5
6
7
8
Phenyl
2-Methylanisole
Thioanisole
Biphenyl
Ethylbenzene
Anisole
Toluene
1
2
3
4
5
6
7
8
91
97
52
38
80
40
71
46
–
92c
–
–
–
–
74
41
90
93
55
42
77
44
75
45
4-Methoxyphenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Thioanisole
1,3-Dimethoxybenzene
Method A: I (1 equiv.), II (3 equiv.), 85% H3PO4 (1 equiv.) and TFAA (4 equiv.) in acetonitrile at 508C for 30 min. Method B: Reactions were carried out by
using I (1 equiv.), II (1.2 equiv.), 88–93% H3PO4 (1.2 equiv.) and TFAA (4 equiv.) at 258C for 1.0 min.
a
b
c
1
Identified by H NMR, IR, Mass.
Isolated yields of pure product.
Reaction was carried out at 808C for 180 min.

V. R. Veeramaneni et al. / Tetrahedron 59 (2003) 3283–3290
3285
Scheme 2. Reagents and conditions: (a) Method C, yield 50–60%; (b) K2CO3, MeOH, 258C, 1 min, yield 93–95%.
affected by the presence of atmospheric oxygen or moisture.
Therefore, this method allows reactions in open flasks
thereby avoiding the risk of high-pressure development.
study however, remained inconclusive and therefore further
investigation is in progress to confirm the possibility of
formation of other isomer as a side product. The structures
of the enolesters (9 and 10) were established from spectro-
scopic data12 (carbonyl stretching frequencies in the region
of 1800–1790 cm21 in IR spectra). The crude enolesters
isolated from the reaction mixture was found to exist as a
mixture of both Z and E-isomer in a ratio of Z/E¼3:1. In the
1H NMR spectra the olefinic hydrogen of Z-isomer was at d
6.77 or 6.71 as a singlet, which appeared in a more up field
region i.e. d 7.02 or 6.90 in the case of E-isomer.12b
Stereochemistry (E or Z) of the double bond in the case of
major isomer of 10 was assigned based on their NOESY1D
spectral data. The NOESY1D spectrum of this isomer
showed a cross peak between o-hydrogens of both the aryl
groups (d 7.46 and 7.42) and olefinic hydrogen (6.77 d)
indicating the syn orientation of the hydrogen and the aryl
moiety across the double bond.
A brief study was carried out on Method A also (entries 2, 7
and 8, Table 1) where the reactions were usually performed
at 50–808C. External heating was necessary to initiate the
reaction in such cases. Duration of the reaction time varied
from 30 to 180 min and any reduction of reaction time was
also found to be less effective. Acetonitrile was used as
solvent due to its water miscible nature. However, use of
other solvent like THF, dioxane was also investigated and
found to be less effective.
Comparisons of reaction times for both procedures (Method
A and B) clearly indicate that the rate of acylation is
accelerated from hours to minutes in the absence of solvent
(entries 2, 7 and 8, Table 1). For example, acylation of
thioanisole using 4-methoxyphenylacetic acid in the
presence of acetonitrile requires 180 min at 808C for 98%
completion (entry 2, Table 1). However, the same conver-
sion can be achieved in a shorter time (1 min) at a lower
temperature (258C) in the absence of acetonitrile. Thus,
Method B enjoys distinct advantages over Method A as it
requires less reaction time, milder reaction conditions and
does not require any solvent. Moreover, Method A yielded
side products as detected in few cases. These were identified
as enol-ester IV of the corresponding ketone and arylacetic
acid.
The reaction mechanism11c for Method A could be
envisaged as shown in Scheme 3. The role of phosphoric
acid has been viewed as a covalent catalyst which leads to
the generation of arylacetyl bis(trifluoroacetyl)phosphate
VII from the acylation precursor acyl trifluoroacetate VI
generated in situ. Since VII participates in faster acylation
reaction with arenes11c than VI, it acetylates the aromatic
substrate to afford the desired ketone III. The formation of
minor product IV in the case of Method A could be
accounted for by the enolization of ketone III under the
acidic reaction conditions followed by O-acylation13a,b in
the presence of either mixed anhydride VI or the phosphate
VII. However, the reason for dramatic rate enhancement in
the absence of solvent (Method B) is not fully understood.
In situ generation of activated dicationic intermediates13c
could be a possible reason for such an observation.
Interestingly, a highly exothermic and vigorous reaction
All the ketones synthesized (1–8) were well characterized
1
by the H NMR, Mass and IR spectra (carbonyl stretching
frequencies in the region of 1680–1660 cm21) and the pure
materials were found to be a single regioisomer. NMR
spectra of crude materials were also inspected in several
cases for the detection of other possible regioisomers. This
Scheme 3.

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V. R. Veeramaneni et al. / Tetrahedron 59 (2003) 3283–3290
Scheme 4. Reagents and conditions: (a) Method B in Scheme 1; (b) Oxonee, acetone–H2O (2:1), 1 h, 84%; (c) NH2NHCO2Et, p-toluenesulfonic acid
(catalytic amount), toluene, reflux, 24 h, 72% (d) SOCl2, reflux, 3 h, 51%.
was observed when hydrochloric acid was used in place of
orthophosphoric acid. Further investigation is in progress
to clarify whether the reaction follows a similar
mechanistic sequence (Scheme 3) in the absence of solvent
(Method B).
potential platelet aggregation inhibitory activity16a as well
as selective COX-2 inhibitor16b whereas 5 was used for the
synthesis of human neutrophile elastase inhibitor.16c
However, we have a long term interest in the palladium
mediated17a synthesis of benzofurans17b,c (VIII, Scheme 5)
due to their immense biological significance and therefore,
ketone 5 and 6 was converted to the 2,3-diarylbenzofuran
(IX, Scheme 5) under palladium catalysis.17d
Parallel synthesis strategy has been shown to provide an
attractive lead development tool for the refinement of
biological activity.14 The strategy has been utilized
successfully to generate a library of heterocycles by several
laboratories. For example preparation of a series of thiazoles
using this strategy has been reported recently.14b We
therefore, utilized this approach for the synthesis of a
number of novel compounds having potential biological
interest as well as synthetic analogues of existing bioactive
molecules. To demonstrate the feasibility of this approach in
the present case the substrates (I and II) in Table 1 were
subjected to eight simultaneous reactions according to the
conditions described in Method B. This parallel acylation of
arenes was carried out using a Buchi Syncorew Reactor/
Polyvap where reaction temperature and time could be
monitored with accuracy. After workup the individual
ethanones were isolated in good yields (Table 1). In many
cases (entries 1, 2, 5 and 7, Table 1), products appeared as
solid and were found to be analytically pure after usual
work-up. However, pure products were isolated in other
cases where crystallization of the crude products was
required for further purification.
3. Conclusion
In summary, we have described an efficient synthesis of
symmetrically/unsymmetrically substituted 1,2-diaryl-1-
ethanones via acylation of arenes with in situ generated
arylacetyl trifluoroacetates. Advantages of the present
protocol are: (i) ready availability of the starting materials
and mild reaction conditions, (ii) environmentally safe as
the protocol is free from the use of inorganic Lewis acids as
well as chlorinated hydrocarbons as solvent, (iii) simple
operational procedure. The protocol is certainly superior to
the classical Friedel–Crafts acylation technique and other
multi step synthesis. Acylation rate can be accelerated by
omitting the use of solvent thereby reducing the reaction
time from hours to minutes. This high-speed transformation
was utilized for the parallel synthesis of 1,2-diaryl-1-
ethanones leading to the compounds of potential biological
importance. Further studies on substrate tolerability, reac-
tion mechanism and application of this methodology in
organic synthesis as well as in the lead discovery arena are
under investigation.
With 1,2-diaryl-1-ethanones (III) that were readily avail-
able, synthesis of various diaryl heterocycles was investi-
gated. Thus diphenyl-1,2,3-thiadiazole 13,15a,b a potent and
selective COX-2 inhibitor developed by Merck as a novel
anti-inflammatory agent, and its analogues were prepared by
treating III e.g. 11 obtained from 7, with ethyl carbazate
(followed by several steps) according to the procedure
described in the literature (Scheme 4).15b,c Similarly, ketone
2 has been utilized for the synthesis of compound having
4. Experimental
4.1. General methods
All the solvents used were commercially available and
Scheme 5. Reagents and conditions: (a) HCuCR1 (R1¼aryl), (PPh3)2PdCl2; Ref. 17b,c; (b) 5 or 6, Pd(OAc)2, PPh3, Cs2CO3; Ref. 17d.

V. R. Veeramaneni et al. / Tetrahedron 59 (2003) 3283–3290
3287
distilled before use. Reactions were monitored by thin layer
chromatography (TLC) on silica gel plates (60 F254;
Merck), visualizing with ultraviolet light or iodine spray.
Flash chromatography was performed on silica gel (SRL
230–400 mesh) using distilled petroleum ether, ethyl
acetate, dichloromethane, chloroform and methanol. 1H
and 13C NMR spectra were determined in CDCl3, DMSO-d6
or MeOH-d4 solution on Varian Gemini 200 or 500 MHz
spectrometers. Proton chemical shifts (d) are relative to
tetramethylsilane (TMS, d¼0.00) as internal standard and
expressed in ppm. Spin multiplicities are given as s
(singlet), d (doublet), t (triplet) and m (multiplet) as well
as b (broad). Coupling constants (J) are given in Hertz.
Infrared spectra were recorded on a Perkin–Elmer 1650 FT-
IR spectrometer. UV spectra were recorded on Shimadzu
UV 2100S UV–Vis recording spectrophotometer. Melting
points were determined using Buchi melting point B-540
apparatus and are uncorrected. Thermal analysis data was
generated with the help of Shimadzu DSC-50 detector. MS
spectra were obtained on a HP-5989A mass spectrometer.
Purity was determined by HPLC (AGIL-AUTO) using the
condition specified in each case: column, mobile phase
(range used), flow rate (ranges used), detection wavelength,
retention times. Microanalyses were performed using
Perkin–Elmer 2400 C H N S/O analyzer. Arenes and
arylacetic acids are commercially available and used
without further purification.
Method C. Preparation of 9 and 10 was carried out using
appropriate arylacetic acid (7.35 mmol), thioanisole
(8.82 mmol), 88–93% orthophosphoric acid (8.82 mmol)
and trifluoroacetic anhydride (44.10 mmol) according to the
procedure described in Method B. The crude product
isolated from the reaction mixture was found to be a
mixture of both Z and E-isomer in a ratio of Z/E¼3:1. They
were separated by column chromatography. However, we
were unable to prepare analytically pure E-isomer which
was found to be contaminated with Z-isomer.
4.2.1. 1-(4-Methoxy-2-methyl-phenyl)-2-phenyl-etha-
none (1). Light yellow powder, mp 135–1368C (ethanol,
lit.18a 1368C); IR: nmax (KBr, cm21): 1669, 1605; 1H NMR
(200 MHz, CDCl3): d 7.88 (d, J¼8.6 Hz, 1H), 7.83 (s, 1H),
7.36–7.26 (m, 5H), 6.83 (d, J¼8.3 Hz, 1H), 4.23 (s, 2H,
CH2), 3.88 (s, 3H, OCH3), 2.24 (s, 3H, CH3); Mass (CI
method, I-butane): 241 (Mþ1, 100). Elemental analysis
found C, 79.68; H, 6.73; C16H16O2 requires C, 79.97; H,
6.71%.
4.2.2. 2-(4-Methoxy-phenyl)-1-(4-methylsulfanyl-
phenyl)-ethanone (2). Light yellow solid, mp 119.58C
(ethanol, lit.18b 121–1238C); IR: nmax (KBr, cm21): 1681,
1586; 1H NMR (200 MHz, CDCl3): d 7.92 (d, J¼8.3 Hz, 2H),
7.24–7.03 (m, 4H), 6.87 (d, J¼8.4 Hz, 2H), 4.19 (s, 2H, CH2),
3.79 (s, 3H, OCH3), 2.52 (s, 3H, SCH3); Mass (CI method, I-
butane): 273 (Mþ1, 100). Elemental analysis found C, 70.46;
H, 5.90; C16H16O2S requires C, 70.56; H, 5.92%.
4.2. Synthesis of 1,2-diaryl-1-ethanones
Method A (typical procedure). Preparation of 2. A solution
of 4-methoxyphenylacetic acid (3.65 g, 21.97 mmol), thio-
anisole (8.18 g, 65.86 mmol) and 85% phosphoric acid
(2.10 g, 21.97 mmol) in anhydrous acetonitrile (80 mL) was
stirred at 508C. To this mixture was added a solution of
trifluoroacetic anhydride (12.30 mL, 87.88 mmol) in
anhydrous acetonitrile (40 mL) rapidly with vigorous
stirring at 508C. The mixture was stirred for 1 h at the
same temperature and poured into ice-cold water (200 mL)
with stirring. The solid separated was filtered off, washed
with water (3£30 mL) followed by petroleum ether
(2£15 mL). Compound 2 was isolated in 92% yield as
light yellow solid.
4.2.3. 1-Biphenyl-4-yl-2-phenyl-ethanone (3). White
solid, mp 152–1538C (ethanol, lit.18c 1518C); IR: nmax
(KBr, cm21): 1678; 1H NMR (200 MHz, CDCl3): d 8.10 (d,
J¼8.3 Hz, 2H), 7.69 (d, J¼8.3 Hz, 2H), 7.66–7.13 (m,
10H), 4.34 (s, 2H); Mass (CI method, I-butane): 273 (Mþ1,
100). Elemental analysis found C, 88.41; H, 5.82; C20H16O
requires C, 88.20; H, 5.92%.
4.2.4. 1-(4-Ethyl-phenyl)-2-phenyl-ethanone (4). Light
yellow solid, mp 62–638C (ethanol, lit.18d 628C); IR: nmax
1
(KBr, cm21): 1680, 1608; H NMR (200 MHz, CDCl3): d
7.97 (d, J¼8.4 Hz, 2H), 7.33–7.07 (m, 7H), 4.25 (s, 2H,
CH2), 2.72 (q, J¼7.0 Hz, 2H, CH2), 1.26 (t, J¼7.1 Hz, 3H,
CH3); Mass (CI method, I-butane): 225 (Mþ1, 100).
Elemental analysis found C, 85.60; H, 7.22; C16H16O
requires C, 85.68; H, 7.19%.
Method B (parallel synthesis). Parallel synthesis was carried
out using eight reaction flasks simultaneously each contain-
ing the appropriate arene and arylacetic acid. To a mixture
of phenylacetic acid (7.35 mmol), arene (8.82 mmol) and
88–93% orthophosphoric acid (8.82 mmol) was added
trifluoroacetic anhydride (29.52 mmol) rapidly with vigor-
ous stirring at 258C. The mixture turned into a dark colored
solution and a vigorous exothermic reaction was observed.
The mixture was stirred for 1 min at the same temperature
and poured into ice-cold water (50 mL) with stirring. In
many cases products appeared as solid, and the filtered
solid, after washing with cold hexane (2£10 mL), was often
analytically pure. However, oily mass separated in other
cases was extracted with ethylacetate (3£20 mL). Organic
layers collected, combined, washed with water (3£30 mL),
dried over anhydrous sodium sulfate and concentrated under
vacuum to give the crude product. Crystallization of the
crude product from appropriate solvent afforded desired
product.
4.2.5. 1-(4-Methoxy-phenyl)-2-phenyl-ethanone (5).
Light brown solid, mp 1358C (petroleum ether, lit.18e
1358C); IR: nmax (KBr, cm21): 1680, 1600; 1H NMR
(200 MHz, CDCl3): d 8.01 (d, J¼8.9 Hz, 2H), 7.33–7.27
(m, 5H), 6.94 (d, J¼8.9 Hz, 2H), 4.25 (s, 2H, CH2), 3.87 (s,
3H, OCH3); Mass (CI method, I-butane): 227 (Mþ1, 100).
Elemental analysis found C, 79.67; H, 6.22; C15H14O2
requires C, 79.62; H, 6.24%.
4.2.6. 2-Phenyl-1-p-tolyl-ethanone (6). White solid, mp
110–1118C (ethanol, lit.18f 109.6–111.18C); IR: nmax (KBr,
cm21): 1681, 1603; 1H NMR (200 MHz, CDCl3): d 7.93 (d,
J¼8.1 Hz, 2H), 7.41–7.25 (m, 7H), 4.28 (s, 2H, CH2), 2.42
(s, 3H, CH3); Mass (CI method, I-butane): 211 (Mþ1, 100).
Elemental analysis found C, 85.61; H, 6.82; C15H14O
requires C, 85.68; H, 6.71%.

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V. R. Veeramaneni et al. / Tetrahedron 59 (2003) 3283–3290
4.2.7. 1-(4-Methylsulfanyl-phenyl)-2-phenyl-ethanone
(7). Light yellow solid, mp 1018C (ethanol, lit.18g 99.4–
99.88C); IR: nmax (KBr, cm21): 1664, 1598; 1H NMR
(200 MHz, CDCl3): d 7.92 (d, J¼8.6 Hz, 2H), 7.32–7.14
(m, 7H), 4.24 (s, 2H, CH2), 2.49 (s, 3H, SCH3); Mass (CI
method, I-butane): 243 (Mþ1, 100). Elemental analysis
found C, 74.41; H, 5.81; C15H14OS requires C, 74.35; H,
5.82%.
method, I-butane): 375 (Mþ, 100). Elemental analysis found
C, 77.11, H, 5.90; C24H22O4 requires C, 76.99, H, 5.92.
4.3. Cleavage of enolesters (V)
General procedure. A mixture of enolester 9 or 10 (2 mmol)
and K2CO3 (303 mg, 2.2 mmol) in methanol (2 mL) was
stirred at 258C for 1 min and the mixture was diluted with
cold water (10 mL) with vigorous stirring. Solid separated
was filtered, washed with water (2£2 mL) followed by
petroleum ether (2£2 mL) and dried under vacuum to afford
pure product (2 or 7).
4.2.8. 1-(2,4-Dimethoxy-phenyl)-2-phenyl-ethanone (8).
White solid, mp 55–568C (ethanol, lit.18h 568C); IR: nmax
1
(KBr, cm21): 1664, 1598; H NMR (200 MHz, CDCl3): d
7.83 (d, J¼8.9 Hz, 1H), 7.30–7.23 (m, 5H), 6.55 (dd,
J¼8.9, 2.2 Hz, 1H), 6.46 (d, J¼2.2 Hz, 1H), 4.30 (s, 2H,
CH2), 3.91 (s, 3H, OCH3), 3.86 (s, 3H, OCH3); Mass (CI
method, I-butane): 257 (Mþ1, 100). Elemental analysis
found C, 74.88; H, 6.28; C16H16O3 requires C, 74.98; H,
6.29%.
4.3.1. Preparation of 1-(4-methylsulfonylphenyl)-2-
phenyl-1-ethanone (11). To a suspension of 1-(4-methyl-
sulfanyl-phenyl)-2-phenyl-ethanone
(7)
(0.59 g,
2.43 mmol) in acetone (20 mL), water (10 mL) was added
Oxone (2.48 g, 4.03 mmol) and the mixture was stirred at
258C for 1 h. After completion of the reaction, acetone was
removed under low vacuum and the resulting mixture was
diluted with cold water (20 mL). The mixture was then
extracted with EtOAc (3£20 mL). Organic layers collected,
combined, washed with cold water (2£30 mL), dried over
anhydrous Na2SO4, filtered and concentrated to give the title
compound in 84% yield (0.56 g). Mp 165–1668C (lit.18g
164.5–1668C); 1H NMR (200 MHz, CDCl3): d 8.16 (d,
J¼8.3 Hz, 2H), 8.03 (d, J¼8.3 Hz, 2H), 7.31–7.26 (m, 5H),
4.32 (s, 2H, CH2), 3.06 (s, 3H, SO2CH3); Mass (CI method,
I-butane): 274 (Mþ, 100).
4.2.9. (Z)-2-(4-Methoxyphenyl)-1-(4-methylsulfanyl-
phenyl)-1-ethenyl 2,2,2-trifluoroacetate (9). Semi solid;
1
60% yield; IR: nmax (KBr, cm21): 1789, 1607; H NMR
(200 MHz, CDCl3): d 7.43 (d, J¼8.9 Hz, 2H), 7.40 (d,
J¼8.3 Hz, 2H), 7.26 (d, J¼8.3 Hz, 2H), 6.90 (d, J¼8.9 Hz,
2H), 6.71 (s, 1H, –CHvC), 3.83 (s, 3H, OCH3), 2.50 (s, 3H,
SCH3); Mass (CI method, I-butane): 369 (Mþ1, 100).
Elemental analysis found C, 58.57, H, 4.11; C18H15F3O3S
requires C, 58.69, H, 4.10.
(E)-2-(4-Methoxyphenyl)-1-(4-methylsulfanylphenyl)-1-
ethenyl 2,2,2-trifluoroacetate. Gum; 1H NMR
(200 MHz, CDCl3): d 7.42 (d, J¼8.9 Hz, 2H), 7.38 (d,
J¼8.3 Hz, 2H), 7.25 (d, J¼8.3 Hz, 2H), 7.02 (s, 1H,
–CHvC), 6.88 (d, J¼8.9 Hz, 2H), 3.82 (s, 3H, OCH3), 2.49
(s, 3H, SCH3).
4.3.2. Preparation of N 1-[1-(4-methanesulfonyl-phenyl)-
2-phenyl-ethylidene]-hydrazinocarboxylic acid ethyl
ester (12). A mixture of 11 (0.68 g, 2.5 mmol), ethyl
carbazate (0.28 g, 2.8 mmol) and p-toluenesulfonic acid
(10 mg) in toluene (20 mL) was refluxed with the
simultaneous removal of water for 24 h. The mixture was
cooled and the solid appeared was filtered. The residue
washed with toluene (3 mL) followed by hexane (2£3 mL)
to afford the title compound in 72% yield (0.65 g). 1H NMR
(200 MHz, CDCl3): d 8.00 (d, J¼8.3 Hz, 2H), 7.88 (d,
J¼8.3 Hz, 2H), 7.30–7.25 (m, 5H), 6.43 (bs, D2O exch.,
1H, NH), 4.25–4.15 (m, 2H, OCH2), 4.04 (s, 2H, CH2), 3.05
(s, 3H, SO2CH3) 1.30–1.23 (t, J¼7.3 Hz, 3H, CH3); Mass
(CI method, I-butane): 361 (Mþ, 100). Elemental analysis
found C, 59.71; H, 5.49; N, 7.89; C18H20N2O4S requires C,
59.98; H, 5.59; N, 7.77%.
4.2.10. (Z)-1-(4-Methylsulfanylphenyl)-2-phenyl-1-
ethenyl 2,2,2-trifluoroacetate (10). Semi solid; 50%
yield; IR: nmax (KBr, cm21): 1801, 1600; 1H NMR
(500 MHz, CDCl3): d 7.46 (d, J¼7.6 Hz, 2H), 7.42 (d,
J¼8.3 Hz, 2H), 7.39–7.04 (m, 5H), 6.77 (s, 1H, –CHvC),
2.51 (s, 3H, SCH3); Mass (CI method, I-butane): 339 (Mþ1,
100). Elemental analysis found C, 60.15, H, 3.91;
C17H13F3O2S requires C, 60.35, H, 3.87.
(E)-1-(4-Methylsulfanylphenyl)-2-phenyl-1-ethenyl 2,2,2-
trifluoroacetate. Gum; 1H NMR (200 MHz, CDCl3): d
7.49–7.13 (m, 9H), 6.91 (s, 1H, –CHvC), 2.50 (s, 3H,
SCH3).
4.3.3. Preparation of 4-(4-methylsulfonylphenyl)-5-
phenyl-[1,2,3]-thiadiazole (13). A mixture of 12 (400 mg,
1.12 mmol) and SOCl2 (4 mL) was refluxed for 3 h. The
excess SOCl2 was removed under vacuum and the residue
was purified by column chromatography using 3:2
petroleum ether–EtOAc as eluant to give the desired
product in 51% yield (180 mg). Mp 153–1548C (lit.15a
4.2.11. (Z)-1-(4-Methylsulfanylphenyl)-2-phenyl-1-
1
ethenyl-2-phenylacetate (IVa). Semi solid; 9% yield; H
NMR (200 MHz, CDCl3): d 7.90 (d, J¼8.5 Hz, 2H), 7.35–
7.13 (m, 12H), 6.77 (s, 1H, –CHvC), 3.69 (s, 2H), 2.51 (s,
3H, SCH3); Mass (CI method, I-butane): 361 (Mþ, 100).
Elemental analysis found C, 76.81, H, 5.57; C23H20O2S
requires C, 76.64, H, 5.59.
1
154–1558C); IR: nmax (KBr, cm21): 1605, 1527; H NMR
(200 MHz, CDCl3): 8.1 (d, J¼8.4 Hz, 2H), 7.99 (d,
J¼8.4 Hz, 2H), 7.51–7.47 (m, 5H), 3.06 (s, 3H, SO2CH3);
Mass (CI method, I-butane): 317 (Mþ, 100).
4.2.12. (Z)-1-(2,4-Dimethoxyphenyl)-2-phenyl-1-ethenyl-
1
2-phenylacetate (IVb). Semi solid; 10% yield; H NMR
(200 MHz, CDCl3): d 7.80 (d, J¼8.7 Hz, 1H), 7.34–7.10
(m, 10H), 6.76 (s, 1H, –CHvC), 6.57–6.47 (m, 2H), 3.90
(s, 3H, OCH3), 3.87 (s, 3H, OCH3), 3.68 (s, 2H); Mass (CI
4.4. General method for the synthesis17d of 3,4-diaryl
benzofurans (IX)
A mixture of 1,2-dibromobenzen (2 mmol), Pd(OAc)2

V. R. Veeramaneni et al. / Tetrahedron 59 (2003) 3283–3290
3289
6. (a) Leblanc, Y.; Gauthier, J. Y.; Ethier, D.; Guay, J.; Mancini,
J.; Riendeau, D.; Tagari, P.; Vickers, P.; Wong, E.; Prasit, P.
Bioorg. Med. Chem. Lett. 1995, 5, 2123–2128. (b) Carter, J. S.;
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Drug Dev. Res. 2000, 51, 273–286.
(0.10 mmol), PPh3 (0.4 mmol) and Cs2CO3 (4 mmol) in
o-xylene (5 mL) was heated to reflux under nitrogen
atmosphere with stirring. After 2 h the mixture was cooled
to room temperature and ketone 5 or 6 (2 mmol) was added
it. The mixture was again heated to reflux with stirring for
6 h. After completion of the reaction, the mixture was
cooled to room temperature and then directly transferred to
a silica gel column. The product was isolated by eluting the
column using 1–10% EtOAc–petroleum ether.
7. (a) Pal, M.; Rao, Y. K.; Rajagopalan, R.; Misra, P.; Kumar,
P. M.; Rao, C. S. World Patent Application WO 01/90097,
November 29, 2001; Chem. Abstr. 2002, 136, 5893.
(b) Pattabiraman, V. R.; Padakanti, P. S.; Veeramaneni,
V. R.; Pal, M.; Yeleswarapu, K. R. Synlett 2002, 947–951.
(c) Padakanti, S.; Veeramaneni, V. R.; Pattabiraman, V. R.;
Pal, M.; Yeleswarapu, K. R. Tetrahedron Lett. 2002, 43,
8715–8719. (d) Pal, M.; Veeramaneni, V. R.; Srinivas, P.;
Murali, N.; Akhila, V.; Premkumar, M.; Rao, C. S.; Misra, P.;
Ramesh, M.; Yeleswarapu, K. R. Indian J. Chem. 2003, 42B,
593–601. (e) Pal, M.; Veeramaneni, V. R.; Nagabelli, M.;
Kalleda, S. R.; Misra, P.; Casturi, S. R.; Yeleswarapu, K. R.
Presented at the International Symposium on Drug
Discovery and Process Research (DDPR-2003), Shivaji
University, Kolhapur, India, January 23–25, 2003; Paper
number O-5.
4.4.1. 2-(4-Methylphenyl)-3-phenylbenzo[b]furan (IXa).
Pale yellow solid; 67% yield; mp 96–978C (lit.17d
97–97.58C).
4.4.2. 2-(4-Methoxyphenyl)-3-phenylbenzo[b]furan
(IXb). White solid; 51% yield; mp 978C (lit.17d 98.5–998C).
Acknowledgements
The authors would like to thank Dr A. Venkateswarlu, Dr
R. Rajagopalan and Professor J. Iqbal for their constant
encouragement and the Analytical Department specially Dr
J. Moses Babu for spectral support.
8. (a) Pal, M.; Batchu, V. R.; Khanna, S.; Yeleswarapu, K. R.
Tetrahedron 2002, 58, 9933–9940. (b) Pal, M.; Veeramaneni,
V. R.; Yeleswarapu, K. R. Presented at the symposium on
Current Perspective in Organic Chemistry (CPOC-2002),
Indian Association for the Cultivation of Science, Kolkata,
India, January 24–25, 2002; Paper number 6.
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