Alkylation of azoles: Synthesis of new heterocyclic-based AT1- non-peptide angiotensin (II) receptor antagonists

Article abstract of DOI:10.1002/jhet.5570440302

(Chemical Equation Presented) Several novel analogues of Losartan 2 were synthesized as potential non-peptide angiotensin (II) receptor antagonists. In these non-peptide analogues, the tetrazole and the substituted imidazole rings of Losartan 2 were replaced, respectively, by a carboxylic acid function or its methyl ester and substituted triazole, imidazole or benzimidazole moieties. The biphenyl bromide precursor 3 (BPE) used to introduce the linker between the acid/ester function and the heterocyclic moiety was synthesized using Suzuki biphenyl coupling and then incorporated into the target molecule by simple nucleophilic substitution. The fixed N-aryl isomeric forms of several azole and benzimidazole tautomers were successfully separated by HPLC using 50% aqueous acetonitrile as eluent. Intermediate reaction products and final target compounds were fully characterized spectroscopically.

Full text of DOI:10.1002/jhet.5570440302

May-Jun 2007
515
Alkylation of Azoles: Synthesis of New Heterocyclic-Based AT1-
non-Peptide Angiotensin (II) Receptor Antagonists
Amal Al-Azmi,* Paulson George, and Osman M. E. El-Dusouqui
Department of Chemistry, Faculty of Science, University of Kuwait, P. O. Box 5969, 13060 Safat, Kuwait.
*Correspondent e-mail: alheqan@kuc01.kuniv.edu.kw
Received January 30, 2006
Br
Het
NaH, 16-crown-4,
solvent, reflux
Het
+
CO2CH3
CO2R
Het= triazoles; imidazoles;
benzimidazoles
R= CH3; H
Several novel analogues of Losartan 2 were synthesized as potential non-peptide angiotensin (II)
receptor antagonists. In these non-peptide analogues, the tetrazole and the substituted imidazole rings of
Losartan 2 were replaced, respectively, by a carboxylic acid function or its methyl ester and substituted
triazole, imidazole or benzimidazole moieties. The biphenyl bromide precursor 3 (BPE) used to introduce
the linker between the acid/ester function and the heterocyclic moiety was synthesized using Suzuki
biphenyl coupling and then incorporated into the target molecule by simple nucleophilic substitution. The
fixed N-aryl isomeric forms of several azole and benzimidazole tautomers were successfully separated by
HPLC using 50% aqueous acetonitrile as eluent. Intermediate reaction products and final target compounds
were fully characterized spectroscopically.
J. Heterocyclic Chem., 44, 515 (2007).
inhibitor being 1 (X = Cl, NO2) [3-8]. The most
successful among the non-peptide Ang II antagonists used
in antihypertensive therapy is Losartan 2 (Figure I).
INTRODUCTION
The renin-angiotensin system (RAS) cascade involves
initial conversion of renin into angiotensin I (Ang I)
followed by the formation of angiotensin II (Ang II)
through the agency of angiotensin converting enzymes
(ACE). The RAS cascade is essential in blood-pressure
regulation and electrolyte fluid transport processes and
consequently in antihypertensive therapy [1]. Hypertension
is the most common cardiovascular malady afflicting as
many as 50 million people in the USA alone [2].
RAS could be interrupted at the ACE stage with ACE
blockers or by use of Ang II receptor antagonists. Both
rennin and ACE inhibitors met with various difficulties in
application or due to side effects, and hence more
attention has been given to Ang II receptor antagonists.
These include peptide and non-peptide antagonists, the
first albeit weakly active non-selective, non-peptide
In the present work, we describe the different stages of
the synthesis of new heterocyclic-based biphenyl Losartan
analogues using substituted benzimidazoles and
heterocycles derived from diaminomaleonitrile (DAMN)
4, in addition to the techniques used to separate and
identify the isomeric fixed forms obtained by the
alkylation of tautomeric azoles with bromomethyl
derivatives of biphenyl ester
3 (BPE), and their
conversion into the corresponding carboxylic acid 3
(BPA) analogues by hydrolysis. It is envisaged that the
present heterocylic systems will induce and enhance the
potential for possible synthesis and application of
biologically active heterocyclic-based AT1-non-peptide
angiotensin (II) receptor antagonists.
Cl
N
R1
Bun
N
HOH2C
Cl
N
CO2R
CH2CO2H
n-Bu
N
X
N
N
3
HN
N
R = CH3 (BPE) or H (BPA)
R1 = Br
1
2
Figure I

516
A. Al-Azmi, P. George, and O. M. E. El-Dusouqui
Vol 44
then reacted with the biphenyl ester (BPE) 3 to yield the
alkylated derivatives 7a,b and the latter were hydrolyzed
with aqueous KOH into 8a,b, respectively (routes iii, iv,
Scheme I). The formation of 8a,b proceeded by con-
comitant hydrolysis of the ester group and the two cyano
RESULTS AND DISCUSSION
Diaminomaleonitrile (DAMN) 4 is a well known
precursor in the preparation of many heterocyclic
compounds [9]. The synthesis of imidazole derivatives, for
example 5a,b from 4 has been reported by several authors
[10-11]. We have prepared these imidazoles in pure forms
following the procedure reported by Rapoport et al. [11];
(route i, Scheme I). Alternatively, imidazoles 5 were
obtained when amides 6 (route ii, Scheme I) were refluxed
in the presence of NaH/DMF, the imidazoles 5a,b were
then decolorized by charcoal, and the yields were
comparable to those reported [11]. N-[2-Amino-1,2-dicya-
novinyl]acetamide or propanamide 6a,b were readily
prepared by direct reaction of 4 and the appropriate
anhydrides [8-12], or by dissolving the hydrochloride salts
of the corresponding amides in deionized water to furnish
6a,b in just a few minutes [12]. The imidazoles 5a,b were
1
functions of 7a,b as indicated by H/13C NMR spectra and
1
elemental analyses. The H NMR of 7a,b showed the
appearance of methylene protons as singlets at ꢀ 5.30 ppm
7a and ꢀ 5.31 ppm 7b, respectively. The hydrolysed
derivatives 8a,b showed also the presence of carboxylic
acid protons as broad singlets at ꢀ 7.5-13 ppm. The salts of
the alkylated imidazole derivatives 8a,b offered the
advantage of use in aqueous preparations.
1,2,3-Triazole-4,5-dicarbonitrile 9 was obtained via
diazotization of DAMN 4 following literature procedure
[13]. Two high intensity 13C NMR signals were observed
at 113.6 and 123.2 ppm, and a third very low intensity
peak at 128.4 ppm. Assuming that the highest intensity
NC
NC
NC
NC
N
N
N
N
NC
BPE
N
NC
NC
N
N
vi
N
N
N
+
NH
+
N
H
NC
v
BPE
10b
10a
9a
9b
NC NH2
vii
NC NH2
4
HO2C
N
HO2C
HO2C
N
BPA
N
N
+
N
HO2C
N
BPA
11b
11a
i
NC
NC
N
NC
NC
HO2C
N
N
N
N
iii
iv
R
R
R
N
H
HO2C
BPE
BPA
5 a R = CH3
b R = C2H5
7
a R = CH3
b R = C2H5
8
a R = CH3
b R = C2H5
ii
NC
NC
NHCOR
NH2
6 a R = CH3
b R= C2H5
i) triethyl orthoacetate/propionate (1.2-1.4 equiv.), NaOCH3, anisole, 2 hrs; ii) NaH (1 equiv.), DMF, reflux, 10-18 hrs; iii) NaH (1 equiv.), 3 (BPE,
R1= Br) (1 equiv.), cat. 16-crown-4ether, 1,4-dioxane, reflux, 18 hrs; iv) KOH (10%), reflux, 18 hrs; v) HCl/NaNO2, 0 °C, 1 hr; vi) NaH (1 equiv.), 3
(BPE, R1= Br) (1 equiv.), cat. 16-crown-4ether, toluene, reflux, 5 hrs; vii) KOH (10%), reflux, 18 hrs.
Scheme I

May-Jun 2007
New Heterocyclic-Based AT1-non-Peptide Angiotensin (II) Receptor Antagonists
517
peak at 113.6 is the result of an overlap of two signals, 9a
would be considered the predominant tautomer. However,
taken on their own, the two high intensity peaks would be
indicative of tautomer 9b. This tautomer is symmetric,
with its lone pair of electrons on (N) effectively delocalized
in the ring and partitioned over the two cyano groups.
Many studies showed that the tautomer relative ratio
In an attempt to assign the major and the minor isomers
of 10, the isomers were successfully separated using
preparative HPLC with 50% aqueous acetonitrile as eluent.
One of the HPLC fractions obtained as a pale yellow oil
showed 15 carbons in its 13C NMR spectrum corresponding
to the structure of the fixed isomer 10b derived from the
symmetric tautomer 9b. Based on this result and the
1
1
depends on temperature, solvent used in H NMR, and
analysis of both H and 13C NMR spectral data of the
concentration, 15N studies also supported the previous study
that 1H-1,2,3-triaozle exists in 66% in CDCl3, on the other
hand, the 2H tauotomer is favoured by 55% in d6-DMSO.
Another study in aqueous solution, showed that the 2H
isomer predominates by a factor of two lone pair repulsion
is the most probable cause. The study also revealed that the
tautomerism ratio is solvent dependant [14-15]. Alkylation
of 1,2,3-triazole-4,5-dicarbonitrile 9 gave a pale yellow oil,
isomeric mixture, isomer 10b is the major.
Alkylation of benzimidazole and benzotriazole with 3
(BPE, R1= Br) to prepare, respectively, the ester 12 and
13 analogues has already been reported [16]. Here, we
now present the results of the reaction of both 5-
methylbenzimidazole 14a and 2,5-dimethylbenzimidazole
14b with methyl 4'-(bromomethyl)biphenyl-2-carboxylate
3, first to prepare the esters 15 and then hydrolyse these
into the acids 16.
1
the H NMR spectrum of which revealed the presence of
two fixed isomeric forms of the ester 10 in approximately
1:2 ratio. The H NMR spectrum of the mixture showed
two methylene groups at ꢀ 5.75 ppm and ꢀ 5.80 ppm for the
major and the minor isomers, respectively. The same ratio
has been observed on hydrolysis of the mixture on reflux in
aqueous KOH solution to the corresponding acid forms 11.
The precursors 14a and b were prepared via reacting 4-
methyl-1,2-phenylenediamine with, respectively, formic
acid and acetic acid. The benzimidazole derivative 14a
reacted with 3 (route i, Scheme II) to yield a mixture of
the isomers 15a and 15c in a ratio of 9:1. HPLC was also
performed on the mixture to separate the two isomers.
1
N
X
N
BPE
12 X = CH
13 X = N
BPE
R
R
N
N
R
N
R1
N
i
R1
R1
+
N
H
N
H
BPE
14 a = R = CH3, R1 = H
b = R = R1 = CH3
15 a = R = CH3, R1 = H
b = R = R1 = CH3
15 c = R = CH3, R1 = H
d= R = R1 =CH3
ii
BPA
R
R
N
N
N
N
R1
R1
+
BPA
16 a = R = CH3, R1 = H
b = R = R1 = CH3
16 c = R = CH3, R1 = H
i) NaH (1 equiv.), 3 (BPE, R1= Br) (1 equiv.), toluene, reflux, 5 hrs; ii) KOH (10%), reflux, 18 hrs.
Scheme II

518
A. Al-Azmi, P. George, and O. M. E. El-Dusouqui
Vol 44
Method B. In a 50 mL round-bottomed flask a suspension of 4
(1.00 g, 9.26 mmol), and ethyl acetate (15.0 mL) was stirred at
room temperature. Acetyl chloride (0.73 g, 9.26 mmol) was then
added. An exothermic reaction took place with formation of white
fumes. TLC (9:1 v/v, CHCl3:EtOH) showed the reaction to be
complete within one hour. The reaction mixture was then filtered
and the solid so obtained washed with diethyl ether, and the
resultant yellow powder was then stirred in deionised water to
furnish 6a (1.2 g, 8.0 mmol, 86% yield). M.p. 164 °C [Found: C,
48.2; H, 4.0; N, 37.1; m/z (EI) M+ 108 (M-COCH3), 100%, 151
(M+1), 50% C6H6N4O requires: C, 48.0; H, 4.0; N; 37.3; M 150];
ꢀH 400 MHz (d6-DMSO, Me4Si) 1.93 (s, 3H, CH3), 7.19 (s, 2H,
NH2), 9.14 (s, 1H, NH); ꢀC 100 MHz (d6-DMSO, Me4Si) 169.4,
127.35, 117.7, 114.7, 90.2, 23.4; ꢁmax: (KBr) 3524, 3316, 3200,
2999, 2251, 2212, 1695, 1530, 1395, 1367, 1303, 992 cmꢀ1.
Synthesis of N-[2-Amino-1,2-dicyanovinyl]propanamide
(6b). A mixture of 4 (1.00 g, 9.26 mmol) and propanoic
anhydride (1.21 g, 9.3 mmol) was heated gently in a water bath
at 50 °C for 10 minutes. The precipitate formed was collected
by filtration and washed with petroleum ether to afford 6b as a
white powder (1.30 g, 7.93 mmol, 86% yield). M.p. 165 °C
[Found: C, 51.0; H, 4.9; N, 34.2; m/z (EI) (COCH2CH3), 57
100%, 164 M+, 15% C7H8N4O requires: C, 51.2; H, 4.8; N, 34.1;
M 164]; ꢀH 400 MHz (d6-DMSO, Me4Si) 1.00 (t, 3H, J 7.5 Hz,
CH3), 2.21 (q, 2H, J 7.5 Hz, CH2), 7.16 (s, 2H, NH2), 9.06 (s,
1H, NH); ꢀC 100 MHz (d6-DMSO, Me4Si) 173.1, 127.3, 117.9,
115, 90.6, 29.0, 10.0; ꢁmax: (KBr) 3410, 3319, 3217, 2978, 2879,
2251, 2212, 1669, 1638, 1523, 1383, 1292, 1072 cmꢀ1.
The fact that 15a is the major isomer can be attributed to a
steric effect favouring formation of the less bulky isomer.
Further, the influence of steric effects on the isomer ratios
of the reaction of 14 is clearly evident from the outcome of
the reaction of 14b with 3 (BPE, R1= Br)(route i, Scheme
II). Analysis of the product of this reaction indicated the
formation of only 15b, with no trace of its bulkier isomeric
form 15d. Hydrolysis of 15a,c mixture and 15b (route ii,
Scheme II) afforded 16a with no trace of 16c as shown by
1H NMR spectrum, and 16b in good yields.
CONCLUSION
A library of non-peptide angiotensin (II) receptor
antagonists is built for screening as potential agents in
antihypertensive therapy. The library now includes
several promising candidates. Formation of isomers can
be easily solved by separating them using highly
advanced techniques such as preparative HPLC.
Acknowledgements. The financial support of Kuwait
University received through research grant SC 04/02 and
SAF facilities through Projects GS 01/01 and GS 03/01
are gratefully acknowledged.
EXPERIMENTAL
Synthesis of 2-Methyl-1H-imidazole-4,5-dicarbonitrile (5a)
and 2-Ethyl-1H-imidazole-4,5-dicarbonitrile (5b).
General. Diaminomaleonitrile (DAMN) 4, 16-crown-4ether, 4-
tolylboronic acid and sodium hydride are from Aldrich, and 5-
methylbenzimidazole 14a, 2,5-dimethylbenzimidazole 14b, and
methyl 4'-(bromomethyl)biphenyl-2-carboxylate 3 (BPE, R1= Br)
used in this work were prepared according to literature procedures
[8,17-18]. 1H NMR spectra were recorded on a Bruker DPX 400
spectrometer at 400 MHz, and 13C NMR spectra were obtained
using a Bruker DPX 400 spectrometer at 100 MHz; TMS was used
as a reference. Mass spectra were from a VG Autospec Q
spectrometer with digital data output. Melting points were
determined on a Gallenkamp melting point apparatus and are
uncorrected. IR spectra were recorded on KBr disc using Perkin
Elmer 2000 FT Spectrophotometer. TLC was performed on 0.25
mm pre-coated silica gel plates (Merck). Substrates were separated
in pure form using Waters Preparative HPLC Delta Prep 4000
combining PrepLC Controller, PrepCL 4000 Series solvent delivery
unit, and an integral injector panel assembly within a simple, three-
level shelf. The detector used was a Water 2996 Photodiode Array
and variable path length flow cell for both analytical and preparative
work. HPLC columns used for the analysis and separation were
Supelco (25 cm length, 4.6 mm ID) and (25 cm length, 21.2 mm
ID) ABZ+, respectively. The mobile phase composition used in the
separation was 50:50 v/v [CH3CN:H2O].
Method A. A mixture of 4 (5.0 g, 46.3 mmol) and,
respectively, triethyl orthoacetate (9.75 g, 60.2 mmol) for 5a and
triethyl orthopropionate (9.79 g, 55.6 mmol) for 5b in anisole
(60 mL) was heated in a water bath at 100 °C, with distillation
of ethanol over a period of 2 hours. Sodium metal (0.18 g, 7.87
mmol) in methanol (5 mL) was then added, and heating was
continued until no more ethanol distillate was obtained. The
reaction mixture was filtered while hot, and then cooled to
afford 5a (4.3 g, 32.6 mmol, 70% yield) and 5b (4.5 g, 30.8
mmol, 67% yield).
Method B. A mixture of either 6a (0.5 g, 3.3 mmol) or 6b (0.5
g, 3.0 mmol) with an equimolar amount of NaH in DMF (15
mL) was refluxed for 10-18 hours. The mixture was then cooled
and poured into water. The pH was adjusted to 7 and the
resulting mixture was extracted with diethyl ether to yield 5a
(0.21 g, 1.6 mmol, 48% yield) and 5b (0.12 g, 0.82 mmol, 27%
yield). 5a: M.p. 228 °C [Found accurate mass: 132.0436; m/z
(EI) M+ 132, 100%, C6H4N4 requires: 132.0431; M 132]; ꢀH 400
MHz (d7-DMF, Me4Si) 2.49 (s, 3H, CH3), 12.8 (brs, 1H, NH); ꢀC
100 MHz (d7-DMF, Me4Si) 152.1, 115.9, 111.9, 79.8, 14.1; ꢁmax
:
(KBr) 3414, 3162, 3006, 2893, 2750, 2641, 2536, 2236, 1581,
1520, 1394, 1299, 1145, 1039, 920, 770 cm-1. 5b: M.p. 184 °C
[Found: C, 57.5; H, 4.1; N, 38.4; m/z (EI) M+ 147 (M+1), 100%,
C7H6N4 requires: C, 57.5; H, 4.1; N, 38.4; M 146]; ꢀH 400 MHz
(d7-DMF, Me4Si) 1.28 (t, 3H, J 7.7 Hz, CH3), 2.80 (q, 4H, J 7.6
Hz, CH2), 14.1 (brs, 1H, NH); ꢀC 100 MHz (d7-DMF, Me4Si)
157.0, 115.9, 112.1, 79.9, 22.3, 12.0; ꢁmax: (KBr) 3129, 2985,
2237, 1569, 1521, 1414, 1322, 1301, 1211, 1064, 1038 cmꢀ1.
Synthesis of methyl 4'-(4,5-dicyano-2-methylimidazol-1-
ylmethyl)-biphenyl-2-carboxylate (7a) and methyl 4'-(4,5-
dicyano-2-ethylimidazol-1-ylmethyl)biphenyl-2-carboxylate
Synthesis of N-[2-Amino-1,2-dicyanovinyl]acetamide (6a).
Method A. DAMN 4 (1.00 g, 9.26 mmol) was gently warmed
with acetic anhydride (2.0 mL) in which it dissolved readily. On
cooling, pale violet crystals were obtained. The crystals were
collected by filtration and washed with chloroform. The product
was refluxed with charcoal in ethanol, for 15 min, and
crystallised to give on cooling colourless needles 6a (1.37 g,
9.13 mmol, 99% yield).

May-Jun 2007
New Heterocyclic-Based AT1-non-Peptide Angiotensin (II) Receptor Antagonists
519
(7b). A mixture of either 5a (1.0 g, 7.6 mmol) or 5b (1.0 g, 6.8
mmol) with an equimolar amount of sodium hydride in 1,4-
dioxane (30 mL) was warmed for 5 minutes. After cooling, a
catalytic amount of 16-crown-4ether was added followed by
addition of an equimolar amount of 3 (BPE, R1= Br). After
refluxing the reaction mixture for 18 hours, the mixture was
cooled and then poured into water and extracted with
dichloromethane. Evaporation of dichloromethane gave the crude
7a and 7b as brown oils. Column chromatography (1:1, v/v,
EtOAc:CHCl3) furnished 7a (1.7 g, 4.8 mmol, 63% yield), and 7b
(1.5 g, 4.0 mmol, 60% yield). 7a: M.p. 124 °C [Found: C, 70.5; H,
4.7; N, 15.8; m/z (EI) M+ 356, 60%, (M-C6H3N4) 225, 100%,
C21H16N4O2 requires: C, 70.8; H, 4.5; N; 15.7; M 356]; ꢀH 400
MHz (CDCl3, Me4Si) 2.52 (s, 3H, CH3), 3.69 (s, 3H, OCH3), 5.30
(s, 2H, CH2), 7.18 (d, 2H, J 8 Hz, ArH), 7.33 (m, 3H, ArH), 7.45
(dt, 1H, J 0.88 Hz, J 7.5 Hz, ArH), 7.56 (dt, 1H, J 1 Hz, J 7.5 Hz,
ArH), 7.90 (d, 1H, J 8 Hz, ArH); ꢀC 100 MHz (CDCl3, Me4Si)
168.9, 151.4, 143.2, 142.0, 132.2, 132.1, 131.3, 131.2, 130.7,
130.2, 128.4, 127.3, 122.4, 113.3, 112.3, 109.1, 52.7, 50.6, 14.5;
ꢁmax: (KBr) 3438, 3001, 2839, 2231, 1724, 1516, 1416, 1256, 1087,
747 cm-1. 7b: M.p. 96 °C [Found: C, 71.3; H, 4.9; N, 15.2; m/z (EI)
M+ 370, 10%, (M-C7H5N4) 225, 100%, C22H18N4O2 requires: C,
71.3; H, 4.8; N; 15.1; M 370]; ꢀH 400 MHz (CDCl3, Me4Si) 1.36 (t,
3H, J 7.4 Hz, CH3), 2.74 (q, 2H, J 7.5 Hz, CH2), 3.68 (s, 3H,
OCH3), 5.31 (s, 2H, CH2), 7.17 (d, 2H, J 8 Hz, ArH), 7.33 (m, 3H,
ArH), 7.44 (dt, 1H, J 0.9 Hz, J 7.6 Hz, ArH), 7.55 (dt, 1H, J 1.0
Hz, J 7.6 Hz, ArH), 7.89 (d, 1H, J 7.4 Hz, ArH); ꢀC 100 MHz
(CDCl3, Me4Si) 169.0, 155.9, 143.2, 142.0, 132.3, 132.2, 131.3,
130.7, 130.6, 130.1, 128.4, 127.1, 122.5, 113.2, 112.5, 109.1, 52.7,
50.9, 21.6, 11.7; ꢁmax: (KBr) 3027, 2988, 2946, 2232, 1720, 1508,
1449, 1417, 1280, 1243, 1123, 1050, 818, 758 cm-1.
Synthesis of 1,2,3-triazole-4,5-dicarbonitrile (9).
Compound 4 (1.0 g, 9.26 mmol) was stirred in aquoeus HCl
(37%, 10 mL). The reaction mixture was cooled to 0 °C and a
solution of sodium nitrite (0.7 g, 10 mmol) in water (2 mL) was
added while stirring. After one hour, a clear solution was
formed which was extracted with diethyl ether to furnish 9 (0.77
g, 6.5 mmol, 70% yield). M.p. 145 °C [Found: C, 40.3; H, 0.81;
N, 59.2; m/z (EI) M+ 119, 100%, C4HN5 requires: C, 40.3; H,
0.84; N; 58.8; M 119]; ꢀH 400 MHz (d6-DMSO, Me4Si) 10.10 (s,
1H, NH); ꢀC 100 MHz (d6-DMSO, Me4Si) 128.4, 123.2, 113.6;
ꢁmax: (KBr) 3260, 2261, 1479, 1382, 1129, 791 cm-1.
Synthesis of isomeric methyl 4'-(4,5-dicyano-[1,2,3]triazol-
1-ylmethyl)biphenyl-2-carboxylate (10a) and methyl 4'-(4,5-
dicyano-[1,2,3]triazol-2-ylmethyl)biphenyl-2-carboxylate (10b).
A mixture of 9 (1.0 g, 8.4 mmol) and NaH (0.2 g, 8.3 mmol) in
toluene was heated gently for five minutes and allowed to cool
to room temperature. A catalytic amount of 16-crown-4ether
and an equimolar amount of methyl 4'-(bromomethylbiphenyl-2-
carboxylate 3 were then added and the mixture was refluxed for
five hours. After cooling to room temperature, the reaction
mixture was poured into water and extracted with toluene to
afford a brown oil. Column chromatography (65:35, v/v, hexane
: ethyl acetate) as an eluent yielded a mixture of 10a and 10b
(1.53 g, 4.5 mmol, 53% yield). [Found: C, 66.0; H, 3.9, N, 20.3;
m/z (EI) M+ 343, 100%, C19H13N5O2 requires: C, 66.4; H, 3.8; N;
1
20.4; M 343]; ꢀH 400 MHz (CDCl3, Me4Si): Mixture: 3.69 (s,
3H, OCH3), 5.75 (s, 2H, CH2), 5.80 (s, 2H, CH2), 7.32 (m, 3H,
ArH), 7.45 (m, 3H, ArH), 7.55 (tt, 1H, J 7.6 Hz, J 1.5 Hz, ArH),
7.90 (td, 1H, J 8.5 Hz, J 1.4 Hz, ArH). 10b (Major Isomer):
3.70 (s, 3H, OCH3), 5.75 (s, 2H, CH2), 7.32 (m, 3H, ArH), 7.44
(m, 3H, ArH), 7.55 (tt, 1H, J 1.5 Hz, J 7.6 Hz, ArH), 7.90 (d,
1H, J 7.7 Hz, ArH); ꢀC 100 MHz (CDCl3, Me4Si): Mixture:
168.90, 144.11, 143.70, 142.21, 142.00, 132.24, 132.22, 131.36,
131.34, 131.04, 130.80, 130.74, 130.65, 130.27, 130.21, 129.96,
129.92, 129.12, 128.99, 128.94, 128.44, 128.34, 126.39, 109.04,
108.88, 106.07, 61.73, 61.58, 55.98, 52.67. 10b (Major
Isomer): 168.92, 143.72, 142.20, 132.20, 131.36, 131.07,
130.74, 130.29, 129.92, 129.11, 128.34, 126.41, 108.87, 61.73,
52.65; ꢁmax: (KBr): Mixture: 3064, 2952, 2254, 1724, 1435,
1287, 1192, 1129, 1091, 911, 762 cm-1. 10b (Major Isomer):
3029, 2961, 2255, 1723, 1599, 1481, 1440, 1283, 1261, 1190,
1125, 1092, 1019, 912, 797 cm-1.
Synthesis of 4'-(2'-carboxy-[1,2,3]triazol-1-ylmethyl)bi-
phenyl-4,5-dicarboxylic acid (11a) and 4'-(2'-carboxy-[1,2,3]-
triazol-2-ylmethyl)biphenyl-,5-dicarboxylic acid (11b). An
isomeric mixture of 10a and 10b (1.0, 2.9 mmol) in KOH 10%
was refluxed for 18 hours. After cooling, the mixture was
neutralised with aqueous HCl, and an off-white solid started to
form. The solid was recrystallized from ethanol to give an
isomeric mixture of 11a and 11b (0.80 g, 2.0 mmol, 68% yield).
M.p. > 250 °C [Found: C, 53.2; H, 3.0; N, 10.6; m/z (EI) 135,
100%; (M-C4H2N3O4) 211, 80%, C18H13N3O6.HCl requires: C,
53.5; H, 3.4; N; 10.4; (M-HCl) 367]; ꢀH 400 MHz (CDCl3,
Me4Si) 5.75 (s, 2H, CH2, major isomer), 6.10 (s, 2H, CH2, minor
isomer), 7.27 (d, 1H, J 5 Hz, ArH), 7.33 (m, 4H, ArH), 7.44 (dt,
1H, J 1.22 Hz, J 7.5 Hz, ArH), 7.54 (m, 1H, ArH), 7.71 (dt, 1H, J
1.2 Hz, J 6 Hz, ArH), 12.8 (s, 1H, COOH); ꢀC 100 MHz (CDCl3,
Me4Si) 170.52, 162.20 (major isomer), 161.93 (minor isomer),
160.12, 143.73, 141.93, 144.45, 141.34, 136.44, 134.889, 133.51,
133.24, 131.94, 131.50, 130.57, 130.13, 129.71, 129.53, 128.99,
128.46, 128.39, 80.2, 59.3, 52.9; ꢁmax: (KBr) 3024, 2889, 2788,
1706, 1592, 1505, 1405, 1288, 1259, 1150, 1003, 861, 761 cmꢀ1.
Synthesis of 1-(2'-carboxybiphenyl-4-ylmethyl)-2-methyl-
1H-imidazole-4,5-dicarboxylic acid (8a) and 1-(2'-carboxy-
biphenyl-4-ylmethyl)-2-ethyl-1H-imidazole-4,5-dicarboxylic
acid (8b). A solution of either 7a (0.50 g, 1.4 mmol) or 7b (0.50
g, 1.35 mmol) with KOH 10% was refluxed for 18 hours. After
cooling the mixture was neutralised with aqueous HCl. The
precipitate that formed was collected by filtration and dried to
give 8a (0.32 g, 0.84 mmol, 60% yield), and 8b (0.34 g, 0.86
mmol, 64 % yield). 8a: M.p. 225 °C [Found: C, 62.8; H, 4.2; N,
7.5; m/z (EI) M+ 380, 10%, (M-C6H5N2O4) 211, 100%,
C20H16N2O6 requires: C, 63.1; H, 4.2; N; 7.4; M 380]; ꢀH 400
MHz (d6-DMSO, Me4Si) 2.50 (s, 3H, CH3), 5.94 (s, 2H, CH2),
7.22 (d, 2H, J 8.1 Hz, ArH), 7.30 (d, 2H, J 8.1 Hz, ArH), 7.35
(d, 1H, J 7.5 Hz, ArH), 7.44 (t, 1H, J 7.4 Hz, ArH), 7.55 (m, 2H,
CO2H, ArH), 7.71 (d, 1H, J 7.0 Hz, ArH), 8.30 (s < 1H, CO2H),
12.8 (brs, 1H, CO2H); ꢀC 100 MHz (d6-DMSO, Me4Si) 170.6,
160.3, 160.2, 148.5, 141.4, 141.3, 135.0, 133.3, 132.0, 131.4,
130.5, 130.1, 129.7, 128.4, 127.9, 127.6, 49.3, 12.2; ꢁmax: (KBr)
3477, 3024, 1725, 1700, 1592, 1547, 1514, 1444, 1381, 1322,
1233, 1131, 1005, 764 cmꢀ1. 8b: M.p. 215 °C [Found: C, 63.8;
H, 4.9; N, 7.3; m/z (EI) (M-C4H5O4) 277, 100%, C21H18N2O6
requires: C, 63.9; H, 4.6; N; 7.1; M 394]; ꢀH 400 MHz (d6-
DMSO, Me4Si) 1.05 (t, 3H, J 7.6 Hz, CH3), 2.90 (q, 2H, J 7.6
Hz, CH2), 6.98 (s, 1H, CH2), 7.20 (d, 2H, J 8.1 Hz, ArH), 7.30
(d, 2H, J 8.1 Hz, ArH), 7.35 (d, 1H, J 7.6 Hz, ArH), 7.44 (t, 1H,
J 7.6 Hz, ArH), 7.55 (dt, 1H, J 7.5 Hz, J 1.2 Hz, ArH), 7.71 (d,
1H, J 7.6 Hz, ArH), 12.8 (brs, 1H, CO2H); ꢀC 100 MHz (d6-
DMSO, Me4Si) 170.5, 160.4, 160.2, 152.5, 141.4, 141.2, 135.7,
133.2, 132.0, 131.5, 131.0, 130.2, 129.7, 128.4, 127.8, 127.3,
49.1, 19.3, 12.6; ꢁmax: (KBr) 3446, 3024, 2794, 1696, 1592,
1540, 1511, 1374, 1283, 1188, 1005, 767 cmꢀ1.

520
A. Al-Azmi, P. George, and O. M. E. El-Dusouqui
Vol 44
Synthesis of methyl 4'-(5-methyl-benzimidazol-1-yl-
(m, 3H, ArH), 7.70 (d, 1H, J 7.6 Hz, ArH), 8.59 (s < 1H, ArH),
8.68 (s < 1H, ArH), 12.73 (brs, 1H, COOH); ꢀC 100 MHz (d6-
DMSO, Me4Si) 170.7, 145.2, 144.8, 137.0, 132.9, 131.7,
131.4, 130.0, 129.7, 129.6, 128.3, 128.1, 128.0, 124.9, 124.2,
120.1, 111.4, 80.2, 48.1, 22.3; ꢁmax: (KBr) 3343, 2920, 1705,
1501, 1446, 1256, 1083, 804, 762 cm-1. 16b: M.p. > 250 °C
[Found: C, 77.3; H, 5.8; N, 7.8; m/z (EI) M+ 356, 40%, 211,
100%, C23H20N2O2 requires: C, 77.5; H, 5.6; N; 7.8; M 356];
ꢀH 400 MHz (d6-DMSO, Me4Si) 2.39 (s, 3H, CH3), 2.51 (s, 3H,
CH3), 5.48 (s, 2H, CH2), 6.97 (m, 1H, ArH), 7.12 (d, 2H, J 7.6
Hz ArH), 7.27 (m, 4H, ArH), 7.38 (m, 2H, ArH), 7.52 (t, 1H, J
7.5 Hz, ArH), 7.69 (d, 1H, J 7.6 Hz, ArH), 12.71 (brs, 1H,
COOH); ꢀC 100 MHz (CDCl3, Me4Si) 172.2, 151.6, 151.4,
142.6, 141.2, 134.2, 133.7, 132.3, 131.9, 131.0, 130.8, 128.0,
methyl)biphenyl-2-carboxylate (15a) and methyl 4'-(5-
methyl-benzimidazol-3-ylmethyl)biphenyl-2-carboxylate (15c)
and methyl 4'-(2,5-dimethyl-benzimidazol-1-ylmethyl)-
biphenyl-2-carboxylate (15b). On mixing equimolar amounts
of NaH and 14a (0.55 g, 4.2 mmol) or 14b (0.50 g, 3.4 mmol) in
toluene, a solid started to form after five minutes. This solution
was warmed up and kept warm for five minutes more, and then
allowed to cool to room temperature. Catalytic amount of 16-
crown-4ether and equimolar amount of biphenyl bromide 3 were
added and the mixture was refluxed for five hours. The resultant
reaction mixture was cooled to room temperature, then cold
water was added, and the mixture was extracted with toluene.
The solvent was evaporated to afford a mixture of 15a and 15c
(0.97 g, 2.7 mmol, 65% yield), and 15b (0.75 g, 2.0 mmol, 58%
yield). Mixture 15a, c: M. p. 105 °C [Found: C, 77.3; H, 5.7; N,
8.0; m/z (EI) M+ 356, 100%, C23H20N2O2 requires: C, 77.5; H,
5.6; N; 7.9; M 356].
126.8, 125.9, 125.7, 117.8, 110.4, 110.2, 47.7, 22.4, 22.0; ꢁmax
:
(KBr) 3423, 3027, 2920, 1681, 1517, 1411, 1302, 1243, 1136,
1005, 807, 747 cm-1.
ꢀH 400 MHz (CDCl3, Me4Si): Mixture: 2.48 (s, 3H, CH3), 3.65
(s, 3H, OCH3), 5.30 (s, 2H, CH2), 5.39 (s, 2H, CH2), 7.10 (m, 3H,
ArH), 7.28 (m, 3H, ArH), 7.40 (t, 1H, J 7.5 Hz, ArH), 7.52 (t, 1H,
J 7.5 Hz, ArH), 7.65 (s, 1H, ArH), 7.72 (d < 1H, J 8.7 Hz, ArH),
7.85 (d, 1H, J 7.7 Hz, ArH), 7.96 (s < 1H, ArH), 7.99 (s < 1H,
ArH). 15a (Major Isomer): 2.49 (s, 3H, CH3), 3.65 (s, 3H,
OCH3), 5.40 (s, 2H, CH2), 7.10 (m, 2H, ArH), 7.21 (m, 2H, ArH),
7.28 (m, 3H, ArH), 7.34 (t, 1H, J 7.6 Hz, ArH), 7.53 (t, 1H, J 7.5
Hz, ArH), 7.65 (s < 1H, ArH), 7.73 (s < 1H, ArH), 7.85 (d, 1H, J
7.7 Hz, ArH), 7.96 (s, 1H, ArH). ꢀC 100 MHz (CDCl3, Me4Si):
Mixture: 169.27, 144.17, 143.59, 143.26, 143.29, 142.40, 142.05,
142.01, 134.90, 134.67, 133.92, 132.47, 132.5 132.03, 131.86,
131.48, 131.29, 131.09, 130.56, 129.60, 128.04, 127.40, 127.34,
125.39, 124.75, 120.49, 120.33, 110.51, 110.30, 52.56, 52.53,
49.36, 49.12, 22.42, 22.12. 15a (Major Isomer): 169.28, 142.44,
141.19, 135.10, 133.75, 132.60, 132.03, 131.20, 130.57, 129.58,
128.03, 127.32, 125.20, 124.56, 120.78, 120.53, 110.45, 110.18,
52.54, 49.18, 22.26. Mixture: ꢁmax: (KBr) 3028, 2949, 1724,
1496, 1445, 1330, 1286, 1259, 1189, 1128, 1090, 911, 762, 731
cm-1. 15b: [Found: C, 76.0; H, 6.2; N, 7.3; m/z (EI) M+ 370, 90%;
(M-C9H9N2) 225, 100%, C24H22N2O2.0.5H2O requires: C, 75.9; H,
6.0; N; 7.3; M 370]; ꢀH 400 MHz (CDCl3, Me4Si) 2.48 (s, 3H,
CH3), 2.62 (s, 3H, CH3), 3.66 (s, 3H, OCH3), 5.37 (s, 2H, CH2),
7.07 (m, 4H, ArH), 7.17 (d < 1H, J 8.2 Hz, ArH), 7.26 (m > 1H,
ArH), 7.31 (m, 1H, ArH), 7.41 (t, 1H, J 7.5 Hz, ArH), 7.52 (m >
1H, ArH), 7.64 (d < 1H, J 8.0 Hz, ArH), 7.85 (d, 1H, J 7.7 Hz,
ArH); ꢀC 100 MHz (CDCl3, Me4Si) 169.3, 152.2, 151.9, 142.4,
135.2, 133.0, 132.6, 132.0, 131.2, 130.5, 129.6, 128.0, 126.5,
REFERENCES
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[3] Chiu, A. T.; Duncia, J. V.; McCall, D. E.; Wong, P. C.; Price,
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[4] Wong, P. C.; Price, W. A.; Chiu, A. T.; Thoolen, M. J. M .C.;
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124.5, 119.3, 119.0, 110.0, 109.7, 52.6, 47.5, 22.4, 22.1; ꢁmax
:
(KBr) 3392, 2948, 2922, 1723, 1622, 1519, 1446, 1401, 1284,
1250, 1189, 1127, 1089, 1048, 1005, 758 cmꢀ1.
Synthesis of 4'-(5-methyl-benzimidazol-1-ylmethyl)bi-
phenyl-2-carboxylic acid (16a) and 4'-(2,5-dimethyl-benzimi-
dazol-1-ylmethyl)biphenyl-2-carboxylic acid (16b). A mixture
of 15a and 15c (0.50 g, 1.40 mmol) or 15b (0.5 g, 1.32 mmol)
in aqeuoes KOH (10%, 10 mL) was refluxed for 18 hours.
After cooling, the mixture was neutralized with aqeuoes HCl.
A white precipitate was formed, which was filtered washed
and dried to afford 16a (0.36 g, 1.05 mmol, 75% yield), and
16b (0.33 g, 0.93 mmol, 70% yield). 16a: M.p. 233 °C [Found:
C, 77.0; H, 5.3; N, 8.3; m/z (EI) M+ 342, 100%, C22H18N2O2
requires: C, 77.1; H, 5.2; N; 8.1; M 342]; ꢀH 400 MHz (d6-
DMSO, Me4Si) 2.41 (s, 3H, CH3), 5.56 (s, 2H, CH2), 7.09 (m,
1H, ArH), 7.29 (m, 5H, ArH), 7.42 (t, 1H, J 7.4 Hz, ArH), 7.51