Ortho-carboxylate effects in copper-mediated nucleophilic substitution of halothiophenecarboxylic acids and halobenzoic acids with sodium bisulphite

Article abstract of DOI:10.1002/jccs.201190140

Ortho-carboxylate effects in Ullmann type nucleophilic substitution reactions were found to be much more pronounced as compared to those of other substituent and steric factors. In this study, we propose an ortho halogen assisted intramolecular oxidative addition-reductive elimination mechanism that fits our experimental observations. Experimental data has been generated with halothiophenecarboxylic acids and halobenzoic acids by performing copper-mediated nucleophilic substitution with scant referred sodium bisulphite as nucleophile under aqueous conditions. The novel mechanism was used to establish a new and improved process for preparation of monopotassium salts of 3-sulphothiophene-2-carboxylic acid, 2-sulphobenzoic acid, and 5-sulphothiophene-2-carboxylic acid. These monopotassium salts are critical intermediates and building blocks in the preparation of several therapeutically valuable drugs. The differences in reactivity between the halogens, chlorine and bromine was utilized to prepare aryl ethers including 2-acetyl-3- phenoxythiophene and 2-acetyl-3-(m-tolyloxy)thiophene that have not been reported in literature so far.

Full text of DOI:10.1002/jccs.201190140

884
Journal of the Chinese Chemical Society, 2011, 58, 884-892
Ortho-carboxylate Effects in Copper-mediated Nucleophilic Substitution
of Halothiophenecarboxylic Acids and Halobenzoic Acids with Sodium
Bisulphite
Govindarajan K. Ramaswamy,ab* Thanigaiarasu Mohanasundaram,a
Murugesan Velayuthamb and Balasubramanian K. Kuppuswamya
aShasun Research Centre, Shasun Pharmaceuticals Limited, Vandaloor-Kelambakkam Road, 27,
Keelakottaiyur Chennai-600048, Tamilnadu, India
bAnna University, College of Engineering Guindy, Chennai 600025, Tamilnadu, India
Received April 16, 2011; Accepted June 21, 2011; Published Online June 30, 2011
Ortho-carboxylate effects in Ullmann type nucleophilic substitution reactions were found to be much
more pronounced as compared to those of other substituent and steric factors. In this study, we propose an
ortho halogen assisted intramolecular oxidative addition-reductive elimination mechanism that fits our
experimental observations. Experimental data has been generated with halothiophenecarboxylic acids
and halobenzoic acids by performing copper-mediated nucleophilic substitution with scant referred so-
dium bisulphite as nucleophile under aqueous conditions. The novel mechanism was used to establish a
new and improved process for preparation of monopotassium salts of 3-sulphothiophene-2-carboxylic
acid, 2-sulphobenzoic acid, and 5-sulphothiophene-2-carboxylic acid. These monopotassium salts are
critical intermediates and building blocks in the preparation of several therapeutically valuable drugs. The
differences in reactivity between the halogens, chlorine and bromine was utilized to prepare aryl ethers in-
cluding 2-acetyl-3-phenoxythiophene and 2-acetyl-3-(m-tolyloxy)thiophene that have not been reported
in literature so far.
Keywords: Ortho-carboxylate effect; Ullmann type nucleophilic substitution; Intramolecular oxida-
tive addition-reductive elimination; Sodium bisulphite.
INTRODUCTION
Unraveling the mechanism of modified Ullmann re-
of the aryl halide.1 Studies have indicated that such cou-
pling reactions exhibit ortho-effects, a term by which we
refer to the activation of chelating groups such as -NHCOR,
-COOH, ortho to the aromatic halide.1,3-5 The ortho car-
boxylate effects are pronounced even though the electronic
substituent effects and ortho-alkyl steric effects are not.6
Paine and Couture reported significant rate enhancements
attributed to the ortho carboxylate effect in the Ullmann
type nucleophilic substitution reaction.7
actions has been of great interest to the scientific commu-
nity ever since it was found that addition of relatively cheap
ligands (diamines, amino alcohols, diketones, diols) made
these reactions more efficient with catalyst amounts as low
as 1 mol% or even lower.1 These mechanisms require far
milder conditions for known transformations compared to
pre-existing methods. They also opened new avenues to
heterocycle preparation and asymmetric synthesis.2 It
seems reasonable to expect that the mechanism of Ullmann
type coupling reactions will vary, depending on the identity
of the substrates, ancillary ligands and/or the reaction con-
ditions. However, it has been established via several pro-
posed mechanisms that the reaction between copper pre-
cursor complex and the nucleophile precedes the activation
Scheme I Ullmann type coupling reaction
* Corresponding author. Tel: +91-44-47406215; Fax: +91-44-47406190; E-mail: gkr@shasun.com

Ortho-carboxylate Effect in Ullmann Reaction of Bromothiophenes
J. Chin. Chem. Soc., Vol. 58, No. 7, 2011 885
Alkyl-3-chlorosulphonylthiophene-2-carboxylates
are often used as key intermediates having several applica-
tions including preparation of therapeutically valuable
drugs. They are also key intermediates in a range of active
pharmaceutical ingredients (APIs),8-14 and are prepared
from the corresponding monopotassium salt of 3-sulpho-
thiophene-2-carboxylic acids. These monopotassium salts
are prepared according to Scheme I, via copper mediated
nucleophilic substitution reaction with sodium bisulphite,
followed by acidification and treatment with KCl.
RESULTS AND DISCUSSIONS
The reaction conditions for copper mediated nucleo-
philic substitution of halogen by sodium bisulphite using
3-bromothiophene-2-carboxylic acid (1b) were optimized
and it was chosen to be the model compound as described
in the Experimental section (General procedure). A
number of Lewis acid catalysts were screened including
copper(I) chloride, silver nitrate, zinc chloride, nickel sul-
phate, lanthanum triflate, ytterbium triflate and palla-
dium(II) acetate, palladium(II) acetate with ligand 2,2¢-
bis(diphenylphosphino)-1,1¢-binaphthyl (BINAP). Of the
several Lewis acids and salts examined, cuprous chloride
has been found to exhibit the best catalytic activity in fa-
cilitating nucleophilic substitution. Some copper species
were found to be essential to catalyze this reaction, as the
substitution did not take place in the absence of a copper
catalyst.
In this study we compare the rates of reaction of halo-
thiophenecarboxylic acids and halobenzoic acids with so-
dium bisulphite in the quest to understand the ortho-car-
boxylate effects in copper mediated nucleophilic substitu-
tion reactions. Within the family of halothiophenecarbox-
ylic acids, we present interesting results from comparing
3-chloro and 3-bromo thiophene analogs. The specific re-
agents discussed in this paper are labeled in Fig. 1. This in-
vestigation led to a new and improved process for the syn-
thesis of monopotassium salt of 3-sulphothiophene-2-car-
boxylic acid (3a) and ortho-sulfobenzoic acid (4g). Fur-
ther, we also present synthetic routes for monopotassium
salt of 5-sulphothiophene-2-carboxylic acid (3c), 2-acetyl-
3-phenoxythiophene (5a) and 2-acetyl-3-(m-tolyloxy)thio-
phene (5b). Finally we show that this experimental data
validates our proposal of ortho-halogen assisted intramo-
lecular oxidative addition – reductive elimination mecha-
nism based on which these synthetic routes were devel-
oped.
Experiments with exclusively copper salts such as
copper(I) chloride, copper(I) bromide, copper(I) iodide,
copper(II) chloride, copper(II) triflate and copper in the
form of copper bronze revealed that cuprous chloride ex-
hibits better catalytic activity compared to the rest. Iso-
meric halothiophenecarboxylic acids and halobenzoic ac-
ids were subjected to Ullmann-type nucleophilic substitu-
tion (outlined in Scheme I) by sodium bisulphite under
standard condition (Table 1).
Monopotassium salts 3a prepared from 3-chlorothio-
phene-2-carboxylic acid 1a typically require heating in au-
toclave at 140 °C for 16 hours which is quite drastic.8 We
Fig. 1. Thiophenecarboxylic acids, halobenzoic acids and other derivatives.

886 J. Chin. Chem. Soc., Vol. 58, No. 7, 2011
Ramaswamy et al.
Table 1. HPLC reaction monitoring results
Starting
material
(SM)
HPLC Monitoring results*
Entry
Remarks
Time
SM
Product
1
2
3
4
1a
1b
1c
1d
3 h
2 h
3 h
3 h
4 h
0.5
1 h
3 h
3 h
3 h
3 h
3 h
3 h
95.4
Nil
3.5
88.6
19.6
73.6
88.3
73.4
94.1
3.2
Very little reaction
Fast reaction
75.9
21.1
5.1
Slow reaction
Faster than 1c
5
1e
4a
4b
4c
4d
4e
4f
1.1
Faster reaction. More side product 1f is observed
Very fast reaction
6
Nil
7
86.6
89.4
75.6
99.7
99.9
22.8
Very little reaction
Very little reaction
Slow reaction
8
10.3
22.7
Nil
9
10
11
12
No reaction
Nil
No reaction
1b
62.3
2V water replaced by 2V of ethanol under standard conditions.
Product has formed.
13
14
1g
1h
3 h
3 h
96.1
98.2
Nil
Nil
2V water replaced by 2V of ethanol under standard conditions.
No reaction.
2V water replaced by 2V of ethanol under standard conditions.
No reaction
15
16
1a
1b
2 min
2 min
95.6
4.9
2.85
68.8
Microwave conditions, 80 °C, and 100W- No reaction
Microwave conditions 80 °C, 100W, Product has formed. Better
conversion as compared to 1a.
* Yield is based on HPLC area percentage
discovered that bromo-acid 1b undergoes cross coupling
with sodium bisulphite under relatively milder conditions
viz., 100 °C for 3 h under reflux conditions, as compared to
chloro analog 1a and thereby leading to a safe and scalable
process for the preparation of 3a.
conversion in the case of 1c (Table 1, entry 3), while 1d ex-
hibited a better reactivity, leading to 73% conversion in 3 h
(Table 1, entry 4). We find that our results are consistent
with data published by Luker et. al in the case of Pd cata-
lyzed amination of electron deficient halothiophenes.16 Be-
tween 1b and 2-bromothiophene-3-carboxylic acid 1e, 1e
displayed higher reactivity (Table 1, entry 5) but at the
same time led to more hydro debromination product in
comparison to that of 1b. The order of reactivity of iso-
meric bromothiophene carboxylic acids, was found to be
1e > 1b > 1d >> 1c. Interestingly, the reaction of 2-bromo-
benzoic acid 4a, with sodium bisulphite (Table 1, entry 6)
was faster compared to that of 1b.
Molecule 4g, monopotassium salt of 2-sulphobenzoic
acid, is a useful intermediate for the preparation of com-
pounds with various applications.15 Synthesis cited in liter-
ature start from ortho-chlorobenzoic acid 4d via an
Ullmann type nucleophilic substitution reaction with so-
dium sulphite, which requires conditions of 175 °C, under
pressure in an autoclave for 24 h. However, our synthesis
of 4g starting from bromo acid 4a required milder condi-
tions viz., 100 °C for 2 h under reflux conditions.
The meta isomer 4b (Table 1, entry 7) and para iso-
mer 4c (Table 1, entry 8) did not undergo substitution under
standard conditions. Similarly amongst the three isomeric
chlorobenzoic acids 4d-4f (Table 1, entry 9, 10 & 11), only
ortho-chloro isomer 4d displayed some reactivity which
was very low (23% conversion) compared to 4a (>94%
conversion). In the case of 4e and 4f there was hardly any
reaction. In both ortho-bromo and ortho-chloro series,
The chloro acid 1a underwent only 4% reaction (Ta-
ble 1, entry 1) under the standard conditions. The mono po-
tassium salt 3a (Table 1, entry 2, product) was isolated and
characterized by spectral data. The molecule 3c (Table 1,
entry 4 product) was obtained from 5-bromothiophene-2-
carboxylic acid 1d under standard conditions and was char-
acterized by spectral data. We have observed only 20%

Ortho-carboxylate Effect in Ullmann Reaction of Bromothiophenes
J. Chin. Chem. Soc., Vol. 58, No. 7, 2011 887
Table 2. HPLC reaction monitoring of (Scheme II)
halobenzoic acids exhibited higher reactivity compared to
corresponding halothiophene carboxylic acids towards
Monitoring results
HPLC area %
copper mediated nucleophilic substitution reaction with so-
dium bisulphite. To the best of our knowledge, such a com-
parative study of Ullmann type nucleophilic substitution of
halobenzoic acids and halothiophene carboxylic acids with
sodium bisulphite has not been reported in literature. The
rate spread in the case of 4a and 4c was several folds
greater compared to that of 1b and 1d. The bromides exhib-
ited higher reactivity compared to the chlorides both in
halobenzoic acids and halothiophene carboxylic acids. Un-
der identical conditions, only 1b (Table 1, entry 12) was
found to be reactive while 3-bromo-2-acetylthiophene 1g
(Table 1, entry 13) and methyl-3-bromo-2-thiophenecar-
boxylate 1h (Table 1, entry 14) did not undergo substitu-
tion. This reveals that substituent effect due to vicinal car-
boxylic acid group has an accelerating effect on the rate of
the reaction. The high reactivity of 1b over 1a was also ob-
served under microwave conditions (Table 1, entry 15 and
16).
Entry
1
SM
Remarks
h
SM
Pdt
1i
8
16
22
8
95
57
3.2
41
Very slow
reaction.
16.2
45.3
15.6
3.9
81.9
53.4
82.8
94
2
3
1j
Slow reaction.
Enhanced rate.
16
8
1g
16
0.2
95
terized by NMR spectral data. To the best of our knowl-
edge, these aryl ethers are not reported in literature. Inter-
estingly, when the cross coupling reaction was performed
with sodium sulphite (pH of the reaction mixture was
around 10.5) instead of sodium bisulphite, but without ad-
justing the pH to 7.5, the reaction proceeded very well in 2
h resulting in complete consumption of starting material
with 97.1% product formation, as monitored by HPLC.
This observation indicates that the actual nucleophile
might be the sulphite anion even in the case of reaction with
sodium bisulphite at pH 7.5-7.7.
The higher reactivity of bromo substituent when com-
pared to chloro analogs in copper mediated cross coupling
reactions was also observed in the preparation of phenolic
ethers (Scheme II). The reaction with sodium phenoxide, in
the case of bromo ketone 1g was much faster compared to
chloro ketone 1j. After 8 h of reaction the bromo ketone 1g
showed 94.9% conversion (by HPLC area %) with 3.9% of
starting material. Under identical conditions the reaction
with 1j showed only 53.4% conversion, with 45.3% of
starting material. Under these conditions, 3-bromothio-
phene 1i was hardly reactive (Table 2), the order of reactiv-
ity being 1g >> 1j > 1i. Following this procedure, the aryl
ethers, 5a and 5b, were prepared from 1g and were charac-
PROPOSED MECHANISM
Copper assisted nucleophilic substitution of aromatic
halides can take place in a variety of ways.17 Un-catalyzed
pathways or Lewis acid promoted SNAr, or ipso substitu-
tion, proceeding through addition-elimination mechanism
can be ruled out on the basis of the following observations:
i) Chloro analogs displayed very poor reactivity compared
to the bromo analogs; ii) Other Lewis acids did not bring
about coupling reaction and only Cu(I) was found to be an
effective catalyst; iii) ‘ortho-carboxylate effects’ causes
high reactivity of ortho bromo carboxylic acid salts.
Elimination addition mechanism via an aryne inter-
mediate can also be ruled out as there is no scope for forma-
tion of any hetero aryne intermediate in the case of 1b and
1e.18 Any aryne intermediate generated by decarboxylative
debromination cannot give rise to the observed products
viz., ortho-sulfocarboxylic acids. Among the classes of
mechanism that have been proposed in literature,1,17,19 there
are two conceivable ones involving 1) radical intermedi-
ates involving SRN1 pathway, and 2) oxidative addition-re-
duction elimination. When Ullmann type nucleophilic sub-
stitution of 1b with sodium bisulphite under standard con-
Scheme II Preparation of aryl ethers

888 J. Chin. Chem. Soc., Vol. 58, No. 7, 2011
Ramaswamy et al.
dition was performed in the presence of radical scavengers
like molecular Oxygen or Tempo20 we observed that part of
sodium bisulphite was destroyed by these agents leading to
incomplete reaction but the desired product was also
formed. Interestingly, we found that p-dinitro benzene
could not be used as radical scavenger in this reaction, as it
was getting reduced to form p-nitro aniline under the reac-
tion conditions. However when the experiment was per-
formed in the presence of reagents like 2,6-di-tert-butyl-
4-methyl phenol (BHT) or Tetrahydrofuran (THF) that are
commonly employed as radical quenchers to probe SRN1
mechanism,21 the nucleophilic substitution reaction was
not inhibited and expected product was formed. This obser-
vation clearly rules out SRN1 mechanistic pathway. Our
findings parallels the observations of Cirigotts, Ritch and
Taylor who noted that silver nitrate, zinc chloride nickel
chloride, Pd(II) chloride were completely ineffective cata-
lysts for condensation of 2-bromobenzoic acid with ben-
zoyl acetone in ethanolic sodium hydroxide.22 They had
observed that catalysis by some copper species was essen-
tial for this reaction.
thiophene-2-carboxyli acid 1c with sodium bisulphite, was
significantly very slow. The observed reactivity 1b > 1d >>
1c cannot be accounted for by SRN1 mechanism. Also the
‘ortho-carboxylate effect’ observed in the case of 1b can-
not be rationalized on the basis of SRN1 mechanism. We ex-
amined cyclic voltammeter data which revealed that bromo
derivatives are reduced at more positive potential com-
pared to chloro analogs (Fig. 2 and Fig. 3). The cathode
peak potential for the C-Br bond reduction of 1b and 1g are
observed at -1.882 V and -1.955 V respectively whereas the
cathode peak potential for the C-Cl bond reduction of 1j
and 1a are observed at -1.957 V and -2.058 V respectively.
The results obtained from the above studies provided use-
ful information with respect to the mechanism of reaction.
The experimental findings are consistent with a cyclic
intramolecular oxidative addition-reductive elimination
mechanism operating in the case of 1b as depicted in
Scheme III and an intermolecular version in the case of 1d.
The intervention of oxidative addition-reductive elimina-
tion mechanism in Ullmann condensation was first pro-
posed by Cohen23 in 1974 and substantiated by follow-up
studies from others,19, 20, 24 indicating Cu(I) and Cu(III) are
intermediates in this type of reactions. The exceptionally
high catalytic activity of copper(I) thiophene-2-carbox-
ylate in Ullmann type nucleophilic substitution reactions
has been ascribed to the stabilization of the Cu(III) com-
plex formed in the oxidative addition step thereby driving
the equilibrium to the forward direction.24 The proposed
Bowman et. al investigated the mechanism with re-
spect to radical pathway and their experimental observa-
tions led to the inference that no aryl radicals are produced
under copper(I) catalyzed conditions.20 Further in contrast
to the 3-bromo and 5-bromo isomers, the cuprous chloride
catalyzed nucleophilic substitution reaction of 4-bromo
Fig. 2. Semi differentiated cyclic voltammogram of 1g
(solid line) and 1j (broken line) at a scan rate of
0.5 Vs-1. The supporting electrolyte is TBAP
(0.1 M) at glassy carbon electrode.
Fig. 3. Semi differentiated cyclic voltammogram of 1b
(solid line) and 1a (broken line) at a scan rate of
0.5 Vs-1. The supporting electrolyte is TBAP
(0.1 M) at glassy carbon electrode.

Ortho-carboxylate Effect in Ullmann Reaction of Bromothiophenes
J. Chin. Chem. Soc., Vol. 58, No. 7, 2011 889
mechanism (Scheme III) is consistent with the following
observations - 1) the reactivity order ArBr > ArCl parallels
the leaving group ability of the halide ion; 2) Couplings are
favored by electron withdrawing groups; 3) Coupling did
not take place in the absence of copper catalyst; 4) There is
a correlation between the cyclic voltametric data on cath-
odic potential and the leaving group ability of the halide; 5)
Free radical inhibitors like BHT or THF did not suppress
the reaction. From the observed order of reactivity, viz., 4a
>> 4b ³ 4c and 1e > 1b > 1d >> 1c, it is evident that the very
high reactivity exhibited by the ortho-bromo carboxylic ac-
ids 1b, 1e and 4a in comparison with other isomers is pri-
marily due to chelation of copper(I) carboxylate with the
adjacent bromine atom and also due to mesomeric interac-
tion of the bromine with the carboxylate group. This chela-
tion in the case of 1b, 1e and 4a, makes the oxidative addi-
tion step an intramolecular process and as a consequence
renders it more facile.
dative addition of Cu(I) ion to the C-Br bond in the case of
1b.24 The mesomeric effect evidently is more important
than simple chelation as revealed by the observed order of
reactivity 1b > 1d >> 1c. Though 1b is more reactive than
1d, the rather high reactivity exhibited 1d however cannot
be solely due to mesomeric interaction since it’s aromatic
counterpart p-bromobenzoic acid 4c did not display such
high reactivity compared to the ortho isomer 4a. An inter-
molecular oxidative addition promoted by thiophene-2-
carboxylate function in the case of 1d can account for the
observed higher rate order as compared to its aromatic ana-
log 4c where in such type of activation does not exist. The
reactivity of 1b < 1e and 4a, may be due to a possible chela-
tion of carboxylate copper with sulphur atom in the case of
1b (Scheme IV), while this sort of chelation does not exist
in the case of 1e and 4a.
Scheme IV Chelation with sulphur atom
Cyclic intramolecular oxidative addition-
reductive elimination mechanism
Scheme III
The first direct observation of Cu(I)-Cu(III) redox
steps relevant to Ullmann type coupling reaction has very
recently been provided by Alicia Casitas, Amanda King et.
al.25 The very high reactivity of bromo acid 1b compared to
those of bromo ester 1h and bromo ketone 1g again high-
lights the role of ortho-carboxylic acid group in tremen-
dously accelerating the Ullmann type nucleophilic substi-
tution reaction.
CONCLUSION
In summary for the first time we have carried out an
investigation on copper catalyzed nucleophilic substitution
by sodium bisulphite on halothiophenecarboxylic acids
and halobenzoic acids. This methodology provides a con-
venient route for the synthesis of aryl and heteroaryl sul-
fonic acids. This is particularly effective for the preparation
of aromatic and heteroaromatic ortho-sulfocarboxylic ac-
ids. Our study of reactivity of isomeric bromothiophene
carboxylic acids and isomeric bromobenzoic acids towards
this copper catalyzed nucleophilic substitution reaction
with sodium bisulphite has brought out the importance of
chelation as well as mesomeric effect in accelerating this
nucleophilic substitution reaction. The bromo acid 1b was
The mesomeric interaction of the bromine with the
carboxylate group serves as an additional driving force for
the oxidative addition in these cases. Thus mesomeric ef-
fect, high catalytic efficiency of copper(I) thiophene-2-car-
boxylate salts in Ullmann coupling reactions and chelation
resulting in proximity of copper species combindly pro-
vides an unusual driving force for the intramolecular oxi-

890 J. Chin. Chem. Soc., Vol. 58, No. 7, 2011
Ramaswamy et al.
used to achieve a scalable process for the preparation of 3a.
This concept was extended towards synthesis of aryl ethers
5a and 5b, which have so far not been reported in literature.
We have also proposed a mechanism based on halogen as-
sisted cyclic intramolecular oxidative addition–reductive
elimination to explain the greater reactivity of the ortho-
bromobenzoic acid, 2-bromo-thiophene-3-carboxylic acid
and 3-bromo-thiophene-2-carboxylic acid. We have, for
the first time, reported the comparative work between
thiophene and benzenoid systems and also proposed a ra-
tionale for the higher ortho-carboxylate effect in the case
of aromatic halocompounds as compared to thiophene
analogs.
NaOH (10% w/w). Sodium bisulphite aq. solution (1.15
equivalent of 37% w/w) was added. The pH was adjusted to
7.5-7.7 using aq. NaOH (30% w/w). 0.1 mole of cuprous
chloride was added to the reaction mass and the mixture
was heated to 100 °C. The reaction was monitored by
HPLC. (Mobile phase Methanol: Water: TFA: TEA =
1500:500:1:0.5 v/v; wavelength-254 nm, flow rate 1 mL
per minute). The reaction mass then worked up acidifica-
tion and isolation of the corresponding potassium salt by
treatment with KCl. The product was leeched with hot
acetone.
Monopotassium salt of 3-sulfo-thiophene-2-carboxylic
acid (3a) (Standard condition)
A solution of sodium bisulphite 118.6 g (1.14 mol in
320 mL DM water) was added to a clear solution of 3-bro-
mo thiophene-2-carboxylic acid 1b 207 g (1 mol), in aq. so-
dium hydroxide 40 g (1 mol in 400 mL of DM water) at
room temperature. The pH of the mixture was adjusted to
7.5-7.7 using aq sodium hydroxide (30% w/w, 62 g of so-
dium hydroxide dissolved in 206 mL DM water). After pH
adjustment, CuCl 10.35 g (0.1045 mol) was added and the
solution was refluxed at 100 °C. The reaction was moni-
tored by HPLC for the absence of bromo acid 1b. The reac-
tion was completed in 3 h. The mixture was cooled to room
temperature and filtered under vacuum. Con.HCl 124 mL
was added to the filtrate and the mass was heated to 90 °C.
Solid potassium chloride 218.2 g (2.92 mol) was added in
lots at 90 °C during 45 min. The reaction mixture was
maintained at this temperature for 1 h and was slowly
cooled to 0-5 °C. The reaction mixture was maintained at
0-5 °C for 12 h. The precipitated 3a was filtered under vac-
uum .The product was dried at 110 °C for 3 hour. The dried
material was heated with acetone (621 mL) under reflux for
30 min. The product was isolated by filtration and dried at
70 °C for 3 h to get monopotassium salt of 3-sulfo thio-
phene-2-carboxylic acid 3a 209 g (85%) of HPLC purity
EXPERIMENTAL SECTION
Materials and Methods
3-Bromothiophene-2-carboxylic acid 1b was pre-
pared from 3-bromothiophene purchased from M/s Modipro
India Pvt Ltd, Mumbai. 3-chlorothiophene-2-carboxylic
acid 1a was made from 3-chlorothiophene, purchased from
M/s Modipro India Pvt Ltd, Mumbai. All other reagents
and solvents were from commercial sources and used with-
out purification. HPLC – in process check analysis was car-
ried out using Phenomenex Luna C18, 25 cm ´ 4.6 mm; ID
5 µm or equivalent. Mobile phase Methanol: Water: TFA:
TEA = 1500:500:1:0.5 v/v; wavelength-254 nm, flow rate
1 mL per minute.
Melting points were taken in VEEGO-programmable
apparatus. FT IR spectra were recorded in the solid state as
KBr pellet using Perkin-Elmer instrument, scanning in the
range 4400-450 cm-1. GC-Mass analysis-QP2010-Shimadzu
instrument. LC-MS analysis – LCQ DECA XP PLUS-
Thermo Finnegan instrument Proton NMR and 13C NMR
spectra were measured in CDCl3 using Bruker, 300 MHz
instrument and the chemical shifts are reported in d ppm
relative to TMS. Microwave reactions were performed in
Discover Benchmate model instrument. Cyclic Voltametric
data was derived from IIT Madras. CH 660A Electrical
work station is used. Working electrode – Glassy carbon.
Reference electrode-Ag/Ag+. Counter electrode-Pt elec-
trode. Supporting electrode-Tetrabutylammonium per-
chlorate. Solvent-Acetonitrile. Scan rate-0.1 V/s.
General procedure for sodium bisulphite substitution
reaction
1
>99% mp >250 °C. H-NMR (300 MHz-DMSO-d6) d
7.828 (d, 1H, J = 4.8 Hz), 7.29 (d, 1H, J = 4.8 Hz), 14.83 (br
s OH). 13C NMR (300 MHz, DMSO-d6) d 129.63 (aromatic
CH), d 131.52 (aromatic CH), d 132.10 (aromatic Cq), d
147.73 (aromatic -Cq), d 161.01 (-COOH), DEPT spec-
trum. d 129.63 (aromatic CH), d 131.52 (aromatic CH).
Monopotassium salt of 5-sulfothiophene-2-carboxylic
acid (3c)
The substrate was dissolved in one equivalent of aq
Compound 3c was prepared from 5-bromo thio-

Ortho-carboxylate Effect in Ullmann Reaction of Bromothiophenes
J. Chin. Chem. Soc., Vol. 58, No. 7, 2011 891
phene-2-carboxylic acid 1d in an analogous manner. 2 g of
1d (9.66 mmol) gave 1.30 g (55%) of 3c. White solid, mp
2-Acetyl-3-(m-tolyloxy)thiophene 5b
Similar process followed as in 5a, Waxy solid Yield
>245 °C, HPLC purity 100%, 1H NMR (300 MHz, DMSO-
d6) d 7.14 (d, 1H, J = 3.67 Hz), 7.51 (d, 1H, J = 3.6 Hz),
13.414 (br s OH), 13C NMR (CDCl3) d 126.2 (CH), 132.2
(CH), 133.2 (Cq), 157.4 (Cq), 163.3 (C=O); DEPT spectra
d 126.2 (aromatic CH), d 132.2 (aromatic CH). LC-MS for
the peak at RT 3.0 in HPLC. (M-K)+ at m/z -207.3. HRMS-
Mass M+K -284.8706; Calc. mass = 284.8696.
55%.
1H-NMR (300 MHz,CDCl3) d 2.36 (s, 3H, -Ar.CH3),
d 2.595 (s, 3H, -CH3) d 6.615 (d, 1H, J = 5.7 Hz ), d 6.875
(d, 2H, J = 8.7 Hz), d 6.988 (d, 1H, J = 7.5 Hz), d 7.263 (t,
1H, J = 7.8 Hz), d 7.465 (d, 1H, J = 5.7 Hz).13C NMR
(CDCl3) d 21.3 (Ar CH3), 32.1 (CH3), 118.95 (Ar CH),
119.3 (Ar CH), 119.4 (Thiophene Cq), 120.23 (Ar CH),
132.2 (Ar CH), 126.4 (Thiophene CH), 127 (Ar Cq), 130
(Thiophene CH), 140 (Ar Cq), 156 (Thiophene Cq), 193.22
(C=O), HRMS-HRMS M+H-Mass-233.0634, Calc.mass-
233.0636.
Monopotassium salt of 2-sulfobenzoic acid (4g)
Compound 4g was prepared from 2-bromo benzoic
acid 4a. 2 g (9.95 mmol) of 4a gave 1.74 g (73%) of 4g.
White solid, mp >260 °C, 1H-NMR (300 MHz-DMSO-d6)
d 7.555 (m, 2H) d 7.718 (dd, 1H, J = 1.5 Hz, J = 1.2 Hz),
7.849 (dd, 1H, J = 1.2 Hz, J = 1.2 Hz), 14.10 (br s OH).
13C-NMR-(DMSO-d6) d in ppm, 126.56 (aromatic CH),
129.58 (aromatic CH), 130.63 (aromatic Cq), 130.68 (aro-
matic CH), 130.77 (aromatic CH), 144.08 (aromatic Cq)
and 167.74 (carbonyl C), DEPT spectrum d in ppm 126.56,
129.58, 130.68, 130.77 (aromatic CH).
ACKNOWLEDGMENTS
The authors thank Shasun Pharmaceuticals Limited
for the financial support, laboratory infrastructure and
quality control facilities. We acknowledge Prof. M. V.
Sangaranarayan and Prof. A. Muthukrishnan at the De-
partment of Chemistry, IIT Madras, for cyclic voltametric
data.
2-Acetyl-3-phenoxythiophene 5a from 2-acetyl-3-bro-
mothiophene 1g
Cuprous chloride (0.48 g, 4.85 mmol) and phenol
(1.37 g, 14.58 mmol) were added sequentially to a solution
of 1g (1 g, 4.87 mmol) in dry pyridine (30 mL). Sodium hy-
dride (0.6 g, 15 mmol, 60% dispersion in mineral oil) was
then added slowly under nitrogen atmosphere. The reaction
mixture was heated to reflux and monitored by HPLC, for
reaction completion. Pyridine was removed under reduced
pressure. The residue was diluted with ether (50 mL) and
washed with 1N NaOH (3 ´ 30 mL), 1N HCl (2 ´ 30 mL)
and 1N NaOH (30 mL). The organic layer was dried over
anhydrous sodium sulfate. The solvent was removed under
vacuum. The residue was chromatographed (hexane/3%
ethyl acetate), to get 10b, colorless liquid, yield 0.66 g
(3.01 mmol 62%).
1H-NMR (300 MHz, CDCl3) d 2.601 (s, 3H, CH3), d
6.617 (d, 1H, J = 5.4 Hz), d 7.081 (d, 2H, J = 8.1 Hz), d
7.168 (t, 1H, J1 = 7.2 Hz, J2 = 14.2 Hz), d 7.368 (t, 2H, J1 =
7.8 Hz, J2 = 15.6 Hz), d 7.474 (d, 1H, J = 5.4 Hz).
13C NMR (CDCl3) d 24.23 (CH3), 118.95 (Ar CH),
120.05 (Ar CH), 124.58 (Thiophene CH), 125 (Ar Cq), 127
(Thiophene Cq), 130 (Ar CH), 132.13 (Thiophene CH),
159.13 (Ar Cq), 190.22 (C=O), HRMS-M+H; Mass
219.0481, Calc.mass-219.0480.
REFERENCES
1. Sperotto, E.; van Klink, G. P. M.; van Koten, G.; de Vries, J.
G. Dalton Trans. 2010, 39, 10338.
2. Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108,
3054.
3. Mei, X.; August, A. T.; Wolf, C. J. Org. Chem. 2006, 71, 142.
4. Cai, Q.; Zou, B.; Ma, D. Angew. Chem. 2006, 118, 1298.
5. Zeng, L.; Fu, H.; Qiao, R.; Jiang, Y.; Zhao, Y. Adv. Synth.
Catal. 2009, 351, 1671.
6. McKillop, A.; Bruggink, A. Tetrahedron 1975, 31(20), 2607.
7. Paine, A. J.; Couture, C. Can. J. Chem. 1985, 63, 111.
8. Binder, D.; Hromatka, O. J. Med. Chem. 1987, 30, 678.
9. Hromatka, O.; Binder, D. U. S. Patent 4,028,373, 1977.
(Chem. Abst. 1976, 85, 5612).
10. Binder, D.; Hromatka, O.; U. S. Patent 4,090,020, 1978.
(Chem. Abst. 1979, 90, 204119).
11. Hromatka, O.; Binder, D. U. S. Patent 4,224,445, 1980
(Chem Abst. 1980, 93, 220761).
12. George, L. U. S. Patent 4,659,369, 1987 (Chem. Abst. 1986,
105, 37500a).
13. Lawrence, M.; Setescak, L.; Linda, L. U. S. Patent
4,560,701, 1985 (Chem. Abst. 1985, 103, 123293a).
14. Okun, I.; Keller, K. M.; Brock, T.; Kogan, T. P.; Stavros, F.;
Chan, M. F.; Mong, S.; Raju, B.; Dixon, R. A.; Wu, C. J.
Med. Chem. 1997, 40(11), 1690. (Phase III studies are ongo-

892 J. Chin. Chem. Soc., Vol. 58, No. 7, 2011
Ramaswamy et al.
ing).
Lett. 1984, 25(59), 5821.
15. Sik, K. G.; Ho, C. D. Chem. Abstr. 2010, 152, 548099.
16. Lucker, T. J.; Beaton, H. G.; Whiting, M.; Mete, A.;
Cheshire, D. R. Tetrahedron Lett. 2000, 41(40), 7731.
17. Lindley, J. Tetrahedron 1984, 40(9), 1433.
18. Guo, D.; Huang, H.; Xu, J.; Jiang, H.; Liu, H. Org. Lett.
2008, 10(20), 4513.
21. Cohen, T.; Cristea, I. J. Am. Chem. Soc. 1976, 98(3), 748.
22. Cirigotts, K. A.; Ritch, E.; Taylor, W. C. Aust. J. Chem. 1974,
27, 2209.
23. Cohen, T.; Wood, J.; Dietz, A. G. Tetrahedron Lett. 1974,
15(40), 3555.
24. Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996,
118(11), 2748.
19. Cristau, H. J.; Cellier, P. P.; Spindler, J. F.; Taillefer, M.
Chem. Eur. J. 2004, 10, 5607.
25. Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.;
Ribas, X. Chem. Sci. 2010, 1, 326.
20. Bowman, W. R.; Heaney, H.; Smith, P. H. G. Tetrahedron