Molecular recognition: Studies on the synthesis of some bis thiophene carboxamide derivatives as ditopic receptors for long chain dicarboxylic acids

Article abstract of DOI:10.1016/S0040-4020(01)00676-7

New molecular receptors 6, 7 and 8 with diphenyl ether/diphenyl sulphide as spacer having functional groups complementary to long chain dicarboxylic acids have been developed. Binding studies with different dicarboxylic acids showed high association constants with the receptor 6.

Full text of DOI:10.1016/S0040-4020(01)00676-7

TETRAHEDRON
Pergamon
Tetrahedron 57 42001) 7213±7219
Molecular recognition: studies on the synthesis of some bis
thiophene carboxamide derivatives as ditopic receptors for long
chain dicarboxylic acids
Jayanta K. Ray,p Susmita Gupta, Dipanjan Pan and Gandhi K. Kar
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
Received 4 April 2001;revised 30 May 2001;accepted 20 June 2001
AbstractÐNew molecular receptors 6, 7 and 8 with diphenyl ether/diphenyl sulphide as spacer having functional groups complementary to
long chain dicarboxylic acids have been developed. Binding studies with different dicarboxylic acids showed high association constants with
the receptor 6. q 2001 Elsevier Science Ltd. All rights reserved.
The science of assembling heterocyclic rings has made
enormous strides in recent years. The proper arrangement
of such assemblies has generated novel molecular species
such as molecular clefts, molecular knots, heterohelicenes,
molecular cavities.1 Supramolecular chemistry2±5 based on
molecular recognition has added a new dimension to
chemistry and stereochemistry and is a fast growing subject.
It has potential application in different areas like 4i) drug
design and targeted drug delivery,6 4ii) synthesis of enzyme
models and arti®cial enzymes,7 4iii) development of
molecular sensors8 etc. During the last decade, considerable
efforts directed toward modeling biological non-covalent
binding in chemical systems, resulted in the synthesis of
numerous arti®cial receptors and also the development of
innovative approaches for the generation of selective non-
covalent binders.9 Both mono- and dicarboxylic acids and
carboxylates are important targets in the area of molecular
recognition because a large number of antibiotics, anal-
gesics, anti-in¯ammatory agents and other biologically
active molecules, e.g. folic acid, bile acid, prostaglandin,
billirubin, etc. contain the carboxylic acid moiety. Di- and
tri-carboxylates are essential components of numerous
metabolic processes, including for instance, the citric acid
glyoxalate cycle.10 The binding of carboxyl or carboxylate
groups is involved in many biological recognition process
such as peptide recognition11 by Vancomycin 4in which
amide-carboxylate binding is crucial) and biotin dependent
carboxylate catalyzed reactions 4which proceed through a
carboxylated enzyme complex intermediate in which the
covalently bound biotinyl prosthetic group acts as a mobile
carboxyl carrier between the remote catalytic sites).12
Thus the host±guest complexation studies of the carboxylic
acids and their derivatives with suitable receptors are of
prime importance to mimic the biochemical process. As a
result of this during the last decade, a large number of
synthetic receptors, with hydrogen bonding groups, have
been designed by various workers13±15 to recognize suitable
mono- and bis- dicarboxylic acids and their derivatives. The
hydrogen bonding groups include, simple amides and
phosphamides,12 urea derivatives,13,14 and amides derived
from amino pyridines.15 We have designed one of the
more promising types of ditopic receptor molecule in the
form of clip shaped forceps where the oxygen/sulphur atom
is the pivot directing the guest molecule through the array of
benzene and thiophene rings having amide functionalities at
the end for proper complementary hydrogen bonding.
Here we report the synthesis and their binding studies of
some bisthiophene-5-carboxamide derivatives 64a,b) and
74a,b) and 84a,b) as novel receptors for long chain dicar-
boxylic acids, where diphenyl ether or diphenyl sulphide
moiety has been used as a spacer between the two-thiophene
units. The molecules are designed for the selective recogni-
tion of dicarboxylic acids. Based on DTMM16 energy
minimization calculation, it has been found that suberic
acid, benzene-1,3-dipropanoic acid and benzene-1,3-dibuta-
noic acid may ®t into the cavities of our designed receptors.
The distances between the two amide protons and the two
pyridine nitrogen atoms in receptor 6a are 12.51 and
Ê
14.59 A, respectively 4Fig. 1) while the distances between
Ê
the amide protons for 7a and 8a are 12.42 and 16.02 A,
respectively.
The compounds have been synthesized in six steps
starting from diphenylether 41a) or diphenylsulphide 41b).
Friedel Craft acylation of 1a with an excess of acetyl
Keywords: dicarboxylic acids;diphenyl ether;diphenyl sulphide;host±
guest complexation.
Corresponding author. E-mail: jkray@chem.iitkgp.ernet.in
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020401)00676-7

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J.K.Ray et al./ Tetrahedron 57 $2001) 7213±7219
in turn was prepared from diphenyl sulphide 41b) using
Friedel Craft's acylation reaction as used for the synthesis
of 2a.
The bis-chloroaldehydes 3a or 3b separately on condensa-
tion with ,2 equiv. of methyl thioglycolate/Et3N in pyri-
dine followed by ring closure with 50% KOH produced the
bis thiophene-5-carboxylic ester derivatives 4a and 4b,
respectively. Subsequent hydrolysis with aqueous ethanolic
KOH produced bis acid 5 in 64±69% yield. Reaction of the
bis acids 45) with oxalyl chloride afforded the bis acid
chloride derivative which on subsequent treatment with
two equivalents of 2-amino pyridine and Et3N in CH2Cl2
resulted in the formation of the receptor 6 in moderate
yield. Following a similar sequence, reaction of 5 with
o-anisidine or n-butyl amine afforded the bisthiophene
carboxamide derivatives 7 and 8, respectively. All the
compounds have been characterized by the usual spectro-
scopic methods as well as by analysis. In addition the
structure of compound 4a and 4b has also been con®rmed
by X-ray crystallographic studies 4Fig. 2).17
Figure 1. DTMM energy minimised structure of receptor 6a.
chloride/anhydrous AlCl3 produced the diketone 2a in 90%
yield 4Scheme 1).
The diketone 2a on treatment with POCl3/DMF at 0±58C
for 4±5 days afforded the bis-chloroaldehyde 4,40-bis
41-chloro-2-formylethenyl)phenylether 43a) as a light
yellow solid in excellent yield. Under identical condition
compound 3b was obtained in 78% yield from 2b, which
Association constants 4Ka)14 for different dicarboxylic acids
with receptor 6a or 6b were evaluated by NMR titration18 in
Scheme 1. Reagents and conditions: 4i) CH3COCl, anhyd. AlCl3, CS2, rt, overnight then re¯ux, 2 h. 4ii) POCl3, DMF, 0±58C, 5 days. 4iii) Methyl
thioglycolate, pyridine, Et3N, 508C, 45 min, then KOH 450%), 20 min. 4iv) KOH, EtOH±H2O, re¯ux, 5±6 h. 4v) Oxalyl chloride, DMF 4cat.), CH2Cl2, rt,
overnight. 4vi) 2-Aminopyridine, Et3N, CH2Cl2, rt, 24 h, then re¯ux, 2 h. 4vii) o-Anisidine, Et3N, CH2Cl2, rt, 24 h, then re¯ux, 2 h. 4viii) n-Butylamine, Et3N,
CH2Cl2, rt, 24 h.

J.K.Ray et al./ Tetrahedron 57 $2001) 7213±7219
7215
Figure 2. ORTEP diagrams of compound 4a and 4b derived from X-ray crystallographic data.
dry CDCl3 at 298 K by adding increasing amounts of guest
in dry CDCl3 containing ,2% DMSO-d6 4Table 1). From
the 1H NMR spectra, it was observed that the NH resonance
of 6a and 6b showed a down®eld chemical shift upon addi-
tion of the guest. But the effect of addition of these acids to
the receptor 7a, 7b, 8a or 8b led to no change of NH reso-
nance. Thus receptor 6a form strong complexes 4Fig. 3) with
all three dicarboxylic acids 4Ka 102±103 M21) 4Table 1)
however complexation between receptor 6a and suberic
acid was found to be maximum 4Kaˆ5.87£103 M21). This
was expected as in receptor 6a, suberic acid is well arranged
with hydrogen bonding sites into the cavity compared to
other dicarboxylic acids 4as per DTMM energy minimiza-
tion study, Fig. 4). Receptor 6b also forms strong host±
guest complex with these acids 4Ka from 102±103 M21
)
4Table 1) though the binding of 6b with the guest carboxylic
acids are slightly lower as compared to that of host 6a.
However, receptors 7 or 8 could not take part in recognition
even though they have four binding centers, it has no basic
hydrogen bonding acceptor site 4as in 6) in the form of
amidopyridine. Thus, once again it is proved that the posi-
tioning of pyridine amides by a suitable spacer is important
for binding dicarboxylic acids.
Table 1. Binding constants of receptor 6 and dicarboxylic acids
Dicarboxylic acid
Receptor Association
constant Ka at 258C,
4at 258C),
DGa
kcal mol21
M21
Suberic acid
6a
6b
5.87£103
25.12
24.75
3.14£103
Benzene-1,3-dipropanoic acid 6a
6b
2.34£103
1.79£103
24.58
24.42
1H NMR titrations with the host 6 were carried out by
increasing addition of a solution of the guest dicarboxylic
Benzene-1,3-dibutanoic acid
6a
6b
7.45£102
23.90
23.69
5.26£102
a
DG was calculated from the relation DGˆ2RT ln Ka.
Figure 4. DTMM energy minimised structure of receptor 6a with suberic
acid.
Figure 3. Possible mode of complexation of 64a,b) with suberic acid.

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J.K.Ray et al./ Tetrahedron 57 $2001) 7213±7219
Figure 7. Fluorescence titration spectra of 6a at excitation at 330 nm with
suberic acid at 258C.
1
Figure 5. H NMR titration curve for suberic acid with receptor 6a.
Figure 8. Fluorescence titration spectra of 6b at excitation at 330 nm with
suberic acid at 258C.
1
Figure 6. H NMR titration curve for suberic acid with receptor 6b.
of receptor 6 was excited at 330 nm with the emission
being monitored at 433 and 435 nm, respectively for 6a
and 6b.
acid 4in dry CDCl3 containing about 2% of DMSO-d6) to a
solution of 6 4in dry CDCl3) followed by recording the NMR
spectra after each addition. Such addition was continued
until the complexation is completed, i.e. no further change
of the amide proton was observed. The chemical shift for the
amide protons of 6a and 6b at the saturation point was
dˆ9.43 and 9.36 ppm, respectively. The change in
chemical shift 4Dd) values were calculated by subtracting
the chemical shift at each titration point from the chemical
shift value of pure host. Thus a titration curve of Dd vs
concentration ratio of guest [G] and host [H] is plotted
4Figs. 5 and 6).
Here also a higher af®nity for suberic acid was noted with a
considerable change in the ¯uorescence intensity 4Figs. 7
and 8). Binding constant 4Ka)19 was calculated from the
titration curve 4a plot of emission intensity against the
concentration of suberic acid) and was found to be
3.45£103 and 1.47£103 M21, respectively for receptor 6a
and 6b. Results are consistent with the binding data obtained
1
from H NMR titration experiments.
Thus, we have succeeded in the synthesis of an arti®cial
receptor based on pivotal ether or thioether linkage, hinged
with two symmetrical arms of p-substituted phenyl with
thiophene moiety as core structure;by ®ne tuning these
molecules with amide functionalities, we are able to demon-
strate that these synthetic receptors can form strong
complexes with appropriate dicarboxylic acids. Although
there are many reports of amido pyridine derivatives as
carboxylic acid binders,15 to our knowledge, this type of
host without rigid spacer units has not been previously
investigated.
Integration of the proton signals of the 1:1 complex in the 1H
NMR spectrum as well as the break in the titration curve
4Fig. 5) 4Dd vs [G]/[H])18 at 1.0 establishes a 1:1 stoichio-
metry for the dicarboxylic acid with 6. We have also studied
the ¯uorescence spectra of the host molecules 6 and also the
in¯uence of the guest molecules in spectral shifts. The
¯uorescence titrations were carried out by successive
addition of guest solution 4in CHCl3 containing 2% dry
DMSO) to the solution of receptor 4in CHCl3). The solution

J.K.Ray et al./ Tetrahedron 57 $2001) 7213±7219
7217
1. Experimental
thus obtained was recrystallized from CH2Cl2±diethyl ether
mixture to furnish 3 as a yellow solid.
1.1. General
1.3.1. 4,40-Bis '1-chloro-2-formylethenyl)phenylether
'3a). Yellow solid, mp 120±1218C, yield 85%;IR 4KBr)
All melting points are uncorrected and recorded in one-side
open glass capillaries using a sulphuric acid bath. Solvents
and reagents were used as obtained from commercial
suppliers or puri®ed according to standard procedures.
NMR spectra were recorded on 200, 300 and 500 MHz
nmax 1665 cm21
;
1H NMR 4CDCl3) d 6.63 4d, 2H,
Jˆ6.8 Hz), 7.10 4dd, 4H, Jˆ2.5, 8.8 Hz), 7.78 4dd, 4H,
Jˆ2.5, 8.8 Hz), 10.21 4d, 2H, Jˆ6.8 Hz) ppm;MS 4 m/z)
351 43.3, M1212), 349 416.3, M12), 347 427.9, M1),
312 49.3, M2Cl), 219 48.4), 190 49.9), 167 435.5), 165
4100), 137 411.5). Anal. Calcd for C18H12O3Cl2: C, 62.25;
H, 3.46. Found: C, 62.11, H, 3.32.
Ê
Bruker spectrometer in CDCl3 4dried with 4 A molecular
sieves) or DMSO-d6 as solvent with TMS as an internal
standard. Coupling constant 4J) values are given in Hz. IR
spectra were recorded on a Perkin±Elmer 800 machine.
Mass spectral and elemental analysis values were obtained
from CDRI, Lucknow. Yields of the products refer to
spectroscopically homogeneous substances.
1.3.2. 4,40-Bis '1-chloro-2-formylethenyl)phenylsulphide
'3b). Yellow solid, mp 120±1228C, yield 78%;IR 4KBr)
;
nmax 1672 cm21 1H NMR 4CDCl3) d 6.67 4d, 2H,
Jˆ6.8 Hz), 7.42 4dd, 4H, Jˆ2.0, 8.8 Hz), 7.72 4dd, 4H,
Jˆ2.0, 8.8 Hz), 10.22 4d, 2H, Jˆ6.8 Hz). Anal. Calcd for
C18H12O2SCl2: C, 59.50;H, 3.31. Found: C, 59.25;H, 3.12.
1.2. Genearal method for the synthesis of 2 'a, b)
To a stirred solution of 1 434 mmol) and acetyl chloride
47.3 mL, 102 mmol) in dry carbon disul®de 475 mL),
anhydrous AlCl3 418.2 g, 136 mmol) was added in four
batches at 0±58C. The reaction mixture was allowed to
reach room temperature gradually and then stirred at this
temperature overnight. Then it was re¯uxed for 2 h, cooled
to room temperature and poured in crushed ice with stirring.
The aqueous layer was extracted with CHCl3. The organic
layer was successively washed with water and then dried
over anhydrous Na2SO4. Removal of solvent afforded the
crude product 2. The crude product thus obtained was
recrystallized from CHCl3±petroleum ether 460±808C)
mixture to furnish the diketone as a white solid in
71±90% yield.
1.4. General procedure for the preparation of 4 'a, b)
To a stirred solution of chloroaldehyde 3 40.58 mmol) and
methyl thioglycolate 40.11 mL, 1.27 mmol) in 3±4 mL
pyridine at 08C, triethylamine 40.24 mL, 1.73 mmol) was
added dropwise. The reaction mixture was gradually
allowed to attain room temperature and then stirred at
45±508C for an additional 30 min. Then it was cooled to
10±158C and 6 mL 50% KOH 4aq.) was added to it. Stirring
was continued at 10±158C for 20 min more. The reaction
mixture was then poured into ice water and extracted with
dichloromethane. The organic layer was successively
washed with dil HCl and water and then dried over
anhydrous Na2SO4. Removal of solvent followed by puri®-
cation with column chromatography 4silica gel/benzene)
afforded 4 in 75±78% yield.
1.2.1. 4,40-Diacetylphenyl ether '2a). White solid, mp 89±
918C;yield 90%;IR 4KBr)
nmax 1679 cm21 1H NMR
;
4CDCl3) d 2.60 4s, 6H), 7.08 4dd, 4H, Jˆ1.9, 6.9 Hz),
7.98 4dd, 4H, Jˆ1.9, 6.9 Hz) ppm. Anal Calcd for
C16H14O3: C, 75.59;H, 5.51. Found: C, 75.31;H, 5.36.
1.4.1. 4,40-Bis '5-carbomethoxy-2-thienyl)phenylether
'4a). Light yellow solid, yield 75%;mp 203±205 8C;IR
1
4KBr) nmax 1715 cm21; H NMR 4CDCl3) d 3.90 4s, 6H),
7.08 4dd, 4H, Jˆ1.9, 6.8 Hz), 7.23 4d, 2H, Jˆ3.9 Hz), 7.62
4dd, 4H, Jˆ1.9, 6.8 Hz), 7.76 4d, 2H, Jˆ3.9 Hz) ppm;MS
4m/z) 450 4100, M1), 419 429, M2OCH3), 392 422.4), 348
411.8), 289 49.4), 233 49.6), 193 411.6), 158 434), 148 414.7).
Anal. Calcd for C24H18O5S2: C, 64.00;H, 4.00. Found: C,
63.82;H, 3.84.
1.2.2. 4,40-Diacetylphenylsulphide '2b). White solid, mp
1
88±908C;yield 71%;IR 4KBr) nmax 1674 cm21; H NMR
4CDCl3) d 2.59 4s, 6H), 7.41 4ddd merged to td, 4H, Jˆ1.9,
8.5 Hz), 7.90 4ddd merged to td, 4H, Jˆ1.9, 8.5 Hz) ppm.
Anal. Calcd for C16H14O2S: C, 71.11;H, 5.18. Found: C,
70.85;H, 4.89.
1.4.2. 4,40-Bis '5-carbomethoxy-2-thienyl)phenylsul-
phide '4b). Light yellow solid, mp 178±1798C 4CHCl3±
petroleum ether, 60±808C), yield 78%;IR 4KBr) nmax
1.3. General method for the synthesis of 3 'a, b)
1
1700 cm21; H NMR 4CDCl3) d 3.90 4s, 6H), 7.28 4d, 2H,
To an ice cooled solution of DMF 43 mL), POCl3 40.66 mL,
7.24 mmol) was added dropwise and stirred at 08C for
10 min. To this stirred solution at 0±58C, a solution of the
ketone 2 41.8 mmol) in DMF 42±3 mL) was injected slowly.
Stirring was continued at 0±58C for 2 h and then left in the
fridge 4,48C) for ®ve days with occasional shaking. Then
the reaction mixture was decomposed with an excess of
ice-cold sodium acetate solution and extracted with
CH2Cl2. The organic layer was washed with water,
NaHCO3 45%) solution and ®nally thoroughly with water
and then dried 4anhydrous Na2SO4). Removal of solvent
under reduced pressure afforded compound 3 as a reddish
brown oil, which solidi®ed on standing. The crude product
Jˆ4.0 Hz), 7.39 4ddd merged to td, 4H, Jˆ2.0, 8.6 Hz), 7.58
4ddd merged to td, 4H, Jˆ2.0, 8.6 Hz), 7.75 4d, 2H,
Jˆ4.0 Hz) ppm. 13C NMR 4CDCl3): 52.49, 124.07,
127.14, 131.74, 132.48, 132.63, 134.68, 136.42, 150.38,
162.78. MS 4m/z): 466 4100, M1), 436 46.3), 364 420.3),
233 413.8), 218 429.7), 202 477.2), 166 450.9), 130 417.3).
Anal Calcd for C24H18O4S3: C, 61.80;H, 3.86. Found: C,
61.54;H, 3.75.
1.5. General method for the preparation of bis acid 5 'a, b)
To a solution of bisester 4 40.93 mmol) in 50 mL of ethanol,

7218
J.K.Ray et al./ Tetrahedron 57 $2001) 7213±7219
KOH 4209 mg, 3.72 mmol) in 10 mL of water was added
and re¯uxed for 4 h. Excess ethanol was distilled off and the
residue was diluted with water, extracted with ethyl acetate
to remove neutral matter 4if any). The aqueous part was
treated with active charcoal and ®ltered while hot. Acidi®-
cation of the cold ®ltrates with cold and dilute HCl precipi-
tated the desired product, which was isolated by ®ltration,
washed well with water and dried to produce 5 in 51±64%
yield.
4brm, 2H), 7.33 4d, 2H, Jˆ3.9 Hz), 7.41 4brd, 4H,
Jˆ8.3 Hz), 7.61 4brd, 4H, Jˆ8.3 Hz), 7.65 4d, 2H,
Jˆ3.9 Hz), 7.73±7.79 4m, 2H), 8.32±8.34 4brm, 4H), 8.50
4brs, 2H) ppm. Anal Calcd for C32H22N4O2S3: C, 65.08;H,
3.73;N, 9.49. Found: C, 64.85;H, 3.54;N, 9.31.
1.7. General method for the preparation of 7 'a, b)
The acid 5 40.71 mmol) in CH2Cl2 420 mL) on reaction with
oxalyl chloride 40.31 mL, 3.55 mmol) and DMF 4catalytic)
at room temperature afforded the bis acid chloride which on
subsequent stirring with o-anisidine 40.16 mL, 1.42 mmol)
and triethylamine 40.3 mL, 2.13 mmol) in CH2Cl2 450 mL)
at room temperature overnight and then re¯uxing 43 h)
afforded 7 as a brownish-yellow solid after the usual work
up. This was further puri®ed by column chromatography
[SiO2/petroleum ether 460±808C)±benzene, 1:1] to furnish
the bis amide 7 in 15±33% yield.
1.5.1. 4,40-Bis-'5-carboxy-2-thienyl)phenylether '5a).
Yellow solid;mp 233±235 8C;yield 64%;IR 4KBr) nmax
1
1672 cm21; H NMR 4DMSO-d6) d 7.13 4dd, 4H, Jˆ1.9,
6.8 Hz), 7.51 4d, 2H, Jˆ3.9 Hz), 7.70 4d, 2H, Jˆ3.9 Hz),
7.77 4dd, 4H, Jˆ1.9, 6.8 Hz) ppm;MS 4 m/z) 406 45, M216),
378 424.5, M2CO2), 336 424.4), 335 449.4), 333 43.9,
M2CO2±COOH), 323 46.6), 296 461.5), 295 410.6), 279
432.5), 241 416.1), 175 454.2), 158 422.3), 147 454.1).
1.5.2. 4,40-Bis-'5-carboxy-2-thienyl)phenylsulphide '5b).
Yellow solid;mp 237±240 8C;yield 51%;IR 4KBr) nmax
1.7.1.
4,40-Bis[5-'2-methoxyanilido)-2-thienyl]phenyl-
ether '7a). Yellow solid;yield 15%;mp 202±204 8C;IR
1
1673 cm21; H NMR 4DMSO-d6) d 7.35±7.93 4m, 12H),
4KBr) nmax 1649, 3362, 3428 4br) cm21; H NMR 4CDCl3)
1
12.68±13.0 4broad hump, 2H). 4The compound was poorly
soluble in DMSO-d6). Anal Calcd for C22H14O4S3: C, 60.27;
H, 3.19. Found: C, 60.15;H, 3.02.
d 3.94 4s, 3H), 3.95 4s, 3H), 6.92±7.18 4m, 8H), 7.27 4d, 2H,
Jˆ4.0 Hz), 7.59 4d, 2H, Jˆ4.0 Hz), 7.65 4brd, 4H,
Jˆ8.6 Hz), 8.41±8.49 4m, 4H), 9.96 4brs, 2H) ppm. Anal.
Calcd for C36H28N2O5S2: C 68.35;H, 4.43;N, 4.43. Found:
C, 68.15;H, 4.25;N, 4.23.
1.6. General method for the preparation of 6 'a, b)
1.7.2. 4,40-Bis[5-'2-methoxyanilido)-2-thienyl]phenylsul-
phide '7b). Yellow solid;yield 33%;mp 192±194 8C;IR
4KBr) nmax 1658, 3334, 3367 4br) cm21; 1H NMR 4CDCl3) d
3.95 4s, 6H), 6.92 4brd, 2H, Jˆ7.9 Hz), 7.01±7.09 4m, 4H),
7.59 4d, 2H, Jˆ4.0 Hz), 7.31 4d, 4H, Jˆ4.0 Hz), 7.39±7.45
4m, 4H), 7.58 4d, 2H, Jˆ4.0 Hz), 7.59±7.64 4m, 4H), 8.41
4brs, 2H), 8.44±8.52 4m, 2H) ppm. Anal Calcd for
C36H28N2O4S3: C, 66.67;H, 4.32;N, 4.32. Found: C,
66.41;H, 4.15;N, 4.18.
To a suspension of the bis acid 40.5 mmol) in dry CH2Cl2
430 mL), oxalyl chloride 40.2 mL, 2.25 mmol) and dry DMF
4catalytic) was added and stirred at room temperature for
7 h. Solvent was then removed under reduced pressure to
furnish the acid chloride as an orange brown solid. It was
used without further puri®cation and was immediately
dissolved in 50 mL of dry CH2Cl2 and cooled to 0±58C.
Now to this stirred solution at 0±58C was added dropwise
a solution of 2-amino pyridine 494 mg, 1.0 mmol) and
triethylamine 40.17 mL, 1.25 mmol) in CH2Cl2 4100 mL).
The mixture was stirred at room temperature for 24 h and
then re¯uxed further for 2 h. The reaction mixture was then
cooled to room temperature, decomposed with ice water and
extracted thoroughly with ethyl acetate. The organic layer
was washed successively with water, 10% NaHCO3
solution, ®nally with water for several times and dried
4anhydrous Na2SO4). Removal of solvent followed by puri-
®cation with preparative TLC 4silica gel/benzene±ethyl
acetate 2:1) furnished the bisamide 6 in 18±21% yield.
1.8. General method for the preparation of 8 'a, b)
To a cooled 40±58C) stirred solution of the bis acid chloride
4prepared from 100 mg of 5 following the procedure as
described under 6) in CH2Cl2 430 mL), a solution of
n-butyl amine 40.1 mL, 0.96 mmol) and Et3N 40.15 mL,
1.08 mmol) was added. The mixture was stirred at room
temperature overnight. The reaction mixture was then
decomposed with ice water and extracted with dichloro-
methane. The organic layer was washed successively with
5±10% ice cold 1N HCl, water, 10% NaHCO3 solution and
®nally again with water for several times. After drying
4anhydrous Na2SO4) solvent was distilled out to furnish
the bisamide 8 as yellow to light yellow solid.
1.6.1. 4,40-Bis[5-pyridine-2-aminocarboxyl)-2-thienyl]-
phenylether '6a). Light yellow solid;yield 21%;mp
220±2228C 4CHCl3±petroleum ether, 60±808C);IR 4KBr)
n
max 1696, 3398 4br) cm21; 1H NMR 4CDCl3) d 7.00±7.02
4brd, 2H, Jˆ7.2 Hz), 7.03 4dd, 4H, Jˆ1.9, 8.6 Hz), 7.21 4d,
2H, Jˆ3.9 Hz), 7.58 4dd, 4H, Jˆ1.9, 8.6 Hz), 7.59 4d, 2H,
Jˆ3.9 Hz), 7.70 4m, 2H), 8.24 4brd, 2H, Jˆ4.3 Hz), 8.27 4d,
2H, 8.4 Hz), 8.45 4brs, 2H) ppm. Anal Calcd for
C32H22N4O3S2: C, 66.90;H, 3.83;N, 9.76. Found: C,
66.72;H, 3.67;N, 9.57.
1.8.1. 4,40-Bis'5-n-butylaminocarboxyl-2-thienyl)phenyl
ether '8a). Light yellow solid;mp 187±188 8C;yield
43%;IR 4KBr) nmax 1634, 3356 4br) cm21 1H NMR
;
4CDCl3) d 0.96 4t, 6H, Jˆ7.0 Hz), 1.31±1.50 4m, 4H),
1.46±1.67 4m, 4H), 3.23±3.30 4m, 2H), 3.39±3.49 4m,
2H), 5.94 4br, 2H), 7.06 4brd, 4H, Jˆ8.7 Hz), 7.20 4d, 2H,
Jˆ3.9 Hz), 7.43 4d, 2H, Jˆ3.9 Hz), 7.60 4brd, 4H,
Jˆ8.7 Hz). MS 4m/z) 532 42.0, M1), 517 41.5, M215),
504 41.9, M2CO), 476 46.8, M2C4H8), 450 4100), 452
414.3), 434 416.4), 433 436.2), 419 422.5), 393 424.3).
1.6.2. 4,40-Bis[5-pyridine-2-aminocarboxyl)-2-thienyl]-
phenylsulphide '6b). Pale yellow solid;yield 18%;mp
186±1888C 4CHCl3±petroleum ether, 60±808C);IR 4KBr)
nmax 1655, 3435 4br) cm21; 1H NMR 4CDCl3) d 7.06±7.10

J.K.Ray et al./ Tetrahedron 57 $2001) 7213±7219
7219
Hamilton, A. D. J.Am.Chem.Soc.
1991, 113, 9265.
Anal. Calcd for C30H32O3N3S2: C, 67.67;H, 6.02;N, 5.26.
Found: C, 67.51;H, 5.82;N, 5.07.
4d) Etter, M. C.;Adamond, D. A. J.Chem.Soc,. Chem.
Commun. 1990, 589. 4e) Haldar, M. K.;Kar, G. K.;Ray,
J. K. Synlett 1997, 1057.
1.8.2. 4,40-Bis'5-n-butylaminocarboxyl-2-thienyl)phenyl
sulphide '8b). Yellow solid;mp 168±170 8C;yield 41%;
10. Stryer, L. Bio chemistry;3rd ed.;Freeman, W.H.: New York,
1988.
1
IR 4KBr) nmax 1647, 3442 4br) cm21; H NMR 4CDCl3) d
0.97 4t, 6H, Jˆ7.1 Hz), 1.29±1.44 4m, 4H), 1.45±1.65 4brm,
4H), 3.15±3.33 4m, 2H), 3.39±3.49 4m, 2H), 5.94 4br, 2H),
7.20 4d, 2H, Jˆ3.9 Hz), 7.24±7.31 4m, 4H), 7.43 4d, 2H,
Jˆ3.9 Hz), 7.53±7.60 4m, 4H) ppm. Anal Calcd for
C30H32O2N3S3: C, 64.05;H, 5.69;N, 7.47. Found: C,
63.80;H, 5.43;N, 7.22.
11. 4a) Frederics, J.;Yang, J.;Geib, S. J.;Hamilton, A. D. Proc.
Indian Acad.Sci.$Chem.Sci) 1994, 106, 923. 4b) Antanio, E.;
Galan, A.;Lehn, J. M.;Mendoza, J. J.Am.Chem.Soc. 1989,
111, 4994.
12. Moss, J.;Lam, M. D. Adv.Enzymol. 1971, 35, 3221.
13. Mussons, M. L.;Raposo, C.;Crego, M.;Anaya, J.;Caballero,
M. C.;Moran, J. R. Tetrahedron Lett. 1994, 35, 7061.
14. Kelly, T. R.;Kim, M. H. J.Am.Chem.Soc. 1994, 116, 7072.
15. 4a) Tellado, F. G.;Goswami, S.;Chang, S.;Geib, S. J.;
Acknowledgements
Hamilton, A. D. J.Am.Chem.Soc.
1990, 112, 7393.
Financial support from the CSIR, New Delhi is gratefully
acknowledged.
4b) Karle, I. L.;Ranganathan, D.;Haridas, V. J.Am.Chem.
Soc. 1997, 119, 2777. 4c) Goswami, S.;Ghosh, K.;Dasgupta,
S. J.Org.Chem. 2000, 65, 1907. 4d) Goswami, S.;Ghosh, K.;
Halder, M. Tetrahedron Lett 1999, 40, 1735. 4e) Cowart,
M. D.;Sucholeiki, I.;Bukownik, R. R.;Wilcox, C. S. J.Am.
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