3-methoxalylchromone - A versatile reagent for the regioselective synthesis of 1-desazapurine

Article abstract of DOI:10.1055/s-0030-1258339

The reaction of 5-amino-1H-imidazoles with 3-methoxalylchromone provided a set of imidazo[4,5-b]pyridines (1-des-azapurines) bearing the CO₂Me substituent at the -position of the pyridine core. The corresponding acids were synthesized by subseq

Full text of DOI:10.1055/s-0030-1258339

PAPER
133
3-Methoxalylchromone – A Versatile Reagent for the Regioselective Synthesis
of 1-Desazapurine
R
egioselective Syn
m
thesis of 1-Desazap
y
urine tro Ostrovskyi,a Viktor O. Iaroshenko,*a,b,c Iftikhar Ali,a Satenik Mkrtchyan,a Alexander Villinger,a
Andrei Tolmachev,b,c Peter Langer*a,d
a
Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
Fax +49(381)4986412; E-mail: viktor.iaroshenko@uni-rostock.de; E-mail: iva108@googlemail.com
National Taras Shevchenko University, 62 Volodymyrska st., Kyiv-33, 01033, Ukraine
‘Enamine Ltd.’, 23 A. Matrosova st., 01103 Kyiv, Ukraine
b
c
Fax +380(44)5373253; E-mail: yaroshenko@enamine.net
Leibniz-Institut für Katalyse e. V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
d
Received 7 October 2010
O
N
Abstract: The reaction of 5-amino-1H-imidazoles with 3-methox-
alylchromone provided a set of imidazo[4,5-b]pyridines (1-des-
azapurines) bearing the CO2Me substituent at the a-position of the
pyridine core. The corresponding acids were synthesized by subse-
quent hydrolysis of the ester function. Being typical purine isos-
teres, 1-desazapurines are considered to be potent pharmacophores,
and are widely used in drug design and medicinal chemistry.
N
S
N
N
H
N
N
N
N
N
N
NH
Cl
N
Me
Me
N
Key words: 3-methoxalylchromone, 5-aminoimidazoles, imida-
zo[4,5-b]pyridines, 1-desazapurines, cyclocondensations
N
H
N
CCT 129202
L-158,809
Figure 1 Pharmacologically relevant imidazo[4,5-b]pyridines
The imidazopyridine moiety is an important pharmaco-
phore that has proven to be useful for a number of biologi-
cally relevant targets.1 Imidazo[4,5-b]pyridine, known as
1-desasapurine, is a common structural motif found in nu-
129202 had been reported to be a potent inhibitor of
Aurora-A.13
merous molecules that display antiviral, antifungal, anti- Being a core of purine-like scaffolds, imidazo[4,5-b]py-
bacterial, and antiproliferative activities. The potent ridines can serve as a base for the design and synthesis of
biological activity and the prevalence of 1-desazapurines potential adenosine deaminase (ADA) inhibitors.14 On the
in both natural products and pharmaceuticals has inspired other hand, pseudo-purines bearing a carbonyl function in
significant interest in the synthesis of these heterocycles.2 the 2-position of the purine/pseudo-purine skeleton, are
Compounds that belong to the imidazo[4,5-b]pyridin-2- considered as platforms for the mechanism-based design
one class have been shown to be nonsteroidal anti-inflam- and synthesis of potent inhibitors of inosine 5¢-monophos-
matory and analgesic agents,3–6 and to possess antidepres- phate dehydrogenase (IMPDH).15
sant,4–7 antiphlogistic,5–8 cardiotonic,6–9 hypotensive and
It is known that 3-acylchromones 1, and, especially, 3-
antiarrhythmic,7–10 and antisecretory activity.8–11 In addi-
formylchromones, can be considered as masked 1,3-di-
tion, certain members of this class have post-emergence
carbonyl compounds, with a masked 2-hydroxybenzoyl
fragment located at the 2-position, and they represent an
applications on broad-leaved plants.9–12
The parallel discovery of losartan and eprosartan, which important class of oxygen heterocyclic compounds. Be-
are potent and orally active nonpeptide Ang II antago- cause such chromones possess three electrophilic centers,
nists, has stimulated the design of a large number of con- their interaction with nucleophiles is sometimes difficult
geners.10 An outstanding position among the newly to predict.16 Previously, a number of preparative methods
developed cogenders of losartan is occupied by the imida- for pyrimidine syntheses were elaborated on the basis of
zo[4,5-b]pyridine moiety of compounds L-158,809 the mentioned 3-acylchromones and diverse amidines and
(Figure 1), L-158,338, and CR3210.11,12 These congeners guanidines.17
of losartan have been reported to show a subnanomolar
AT1 receptor affinity about one order of magnitude higher
than that of losartan and represents one of the most potent
nonpeptide Ang II antagonists so far developed. Previous-
We have recently developed a synthesis of the new build-
ing block 2 and studied its application for the preparation
of some fused pyridines (Scheme 1).18 Here, we commu-
nicate our new results on the application of 2 for the as-
sembly of functionalized 1-desazapurines bearing a
ly, the novel imidazo[4,5-b]pyridine derivative CCT
carbonyl moiety located at the 2-position of the 1-des-
azapurine skeleton.
SYNTHESIS 2011, No. 1, pp 0133–0141
Advanced online publication: 26.11.2010
x
x
.
x
x
.2
0
1
0
DOI: 10.1055/s-0030-1258339; Art ID: P15310SS
© Georg Thieme Verlag Stuttgart · New York

134
D. Ostrovskyi et al.
PAPER
O
O
N
CN
R
OMe
3
N
CN
N
N
i
O
1
i
+
NH
NH2
R = H, Me, CF3, CCl3
NH2
R
R
R
5a–j
OH
O
O
O
4a–j
6a–j
OMe
generated
in situ
ClCOCO2Me
Py
NMe2
O
O
2
Scheme 2 Reagents and conditions: (i) CH2Cl2, argon, reflux, 2 h.
Scheme 1 Synthesis of 3-methoxalylchromone 2
OH
Continuing our research in the field of electron-enriched
aminoheterocycles,19 we focused our attention on 3-acyl-
chromones as convenient intermediates in [3+3]-cyclo-
condensation reactions. Three available electrophilic
centers (carbon atoms C-2 and C-4 of the chromone moi-
ety and the methoxalyl carbonyl group), make these syn-
thons versatile building blocks. The interaction of
chromones with dinucleophiles usually leads to pyrone
ring opening, with subsequent formation of a new cyclic
structure.
N
i
O
2
+ 6a–j
N
CO2Me
N
R
7a–j
Scheme 3 Reagents and conditions: (i) CH2Cl2, reflux, 5 h.
Table 1 Yields of Imidazo[4,5-b]pyridines 7a–j and 10a–j
7, 10
R
7 (%)
48
10 (%)
69
3-Acylchromones 1 are readily available by reaction of 3-
(dimethylamino)-1-(2-hydroxyphenyl)propen-1-one with
a number of electrophiles.20 Recently, we have discovered
a synthetic route to hitherto unknown 2-unsubstituted 3-
methoxalylchromone (2) by reacting the corresponding
enaminone with methyl 2-chloro-2-oxoacetate under ba-
sic conditions (Scheme 1). Obtained in such a way, 2 was
led to react with a number of aminoheterocycles affording
a set of fused a-carboxymethylpyridines.18 Herein, we re-
port a route to imidazo[4,5-b]pyridines containing a
CO2Me residue located at the a-position of the pyridine
core and a 2-hydroxybenzoyl group at the b-position. Due
to their electron-withdrawing properties, the latter can sta-
bilize the g-hydrated pyridine moiety, which mimics the
transition state of adenosine mimetics and, thus, improves
potential inhibition characteristics.
a
b
c
d
e
f
t-Bu
allyl
44
75
c-Pr
47
86
c-Pent
46
82
c-Hex
51
87
4-MeOC6H4CH2
4-ClC6H4CH2
4-MeOC6H4CH2CH2
2-MeOC6H4CH2CH2
PhCH2CH2
50
88
g
h
i
44
74
45
73
50
81
j
54
90
Based on our successful experiences mentioned above, we
considered reacting 3-methoxalylchromone (2) with 5-
aminoimidazoles to give the corresponding imidazo[4,5-
b]pyridines. 5-Aminoimidazoles 6 were generated in situ
according to our previously described procedure.19h Pri-
mary aliphatic amines reacted with N-(cyanometh-
yl)formimidate to give 5, which could be transformed into
5-aminoimidazole by intramolecular cyclization
(Scheme 2).
All further attempts to achieve higher yields of the desired
products (extension of the reaction time, evaporation of
CH2Cl2 and heating of the residue in acetic acid) unfortu-
nately failed.
The structure of product 7a was independently confirmed
by an X-ray crystal structure analysis (Figure 2).21
3-Dichloroacetylchromone (8) could also be synthesized
by the same procedure used to generate 3-methoxalyl-
chromone (using dichloroacetylchloride).22 Following the
previously described strategy, we attempted to react 8
with 5-aminoimidazoles to give the corresponding
formyl-substituted 1-desazapurines. However, we could
First attempts to obtain 1-deasapurine derivatives by sim-
ple addition of 3-methoxalylchromone to the reaction
mixture and subsequent stirring under reflux resulted in
formation of the desired product 7a in 23% yield
(Scheme 3). Further improvement of the procedure not isolate the 1-desazapurines 9a or 9b in more than 15%
through preliminary cooling to 0 °C before the addition of yield under any of the reaction conditions applied
the starting materials and stirring at 0 °C for 20 minutes (Scheme 4).
before stirring under reflux, allowed the imidazo[4,5-
b]pydridines to be isolated in moderate yields (Table 1).
The formation of products 7 can be explained by conju-
gate addition of the enamine carbon atom of 6 to the dou-
ble bond of 2 to give intermediate A. Subsequent pyrone
Synthesis 2011, No. 1, 133–141 © Thieme Stuttgart · New York

PAPER
Regioselective Synthesis of 1-Desazapurine
135
ring opening delivers an intermediate of type B. Intramo-
lecular attack of the amino group on the carbonyl group
affords intermediate C, which undergoes elimination of
water to give pyridines 7 (Scheme 5).
All isolated compounds 7a–j were treated with a water/
methanol solution of potassium hydroxide to give, after
acidification with concentrated hydrochloric acid, the cor-
responding carboxylic acids 10a–j (Scheme 6). Bearing
an acidic proton, such carboxylic acid derivatives can
have larger binding constants with ADA, which could re-
sult in improved inhibition properties.
OH
OH
Figure 2 Molecular structure of compound 7a
N
N
N
N
O
O
i
CO2H
N
CO2Me
N
R
R
7a–j
10a–j
OH
CHCl2O
Scheme 6 Reagents and conditions: (i) (a) MeOH, KOH, reflux, 2
h; (b) concd HCl.
N
i
O
O
+
6
N
CHCl2
N
O
R
8
The structure of compound 10b was independently con-
firmed by X-ray structure analysis. Crystallized from
N,N-dimethylformamide, it exists in the form of a hydro-
gen-bonded dimer (Figure 3).21
9
a R = t-Bu (15%)
b R = PMB (12%)
Scheme 4 Reagents and conditions: (i) CH2Cl2, reflux, 7 h.
In summary, we have reported a convenient one-pot pro-
cedure that leads to previously unknown imidazo[4,5-
b]pyridine derivatives. Bearing two electron-withdrawing
groups, the products are of considerable interest as potent
ADA inhibitors. The synthetic applications as well as a
biological evaluation are currently being studied in our
laboratories.
OH
N
N
i
O
2
+
6a–j
CO2Me
N
R
7a–j
i
O
O
O
OH
CO2Me
N
N
O
N
CO2Me
N
H
OH
N
H2N
R
C
R
H
OH
O
O
O
O
O
H
CO2Me
N
CO2Me
N
N
R
N
R
H2N
H2N
B
A
Figure 3 Molecular structure of compound 10b and intermolecular
interactions
Scheme 5 Proposed cyclization mechanism
Synthesis 2011, No. 1, 133–141 © Thieme Stuttgart · New York

136
D. Ostrovskyi et al.
PAPER
Reactions were monitored by thin layer chromatography using UV
light to visualize the course of the reaction. Purification of reaction
products was carried out by flash chromatography on silica gel. Col-
umn chromatography was performed on silica gel (63–200 mesh,
Merck). Silica gel Merck 60F254 plates were used for TLC. Satis-
factory microanalysis obtained C 0.33; H 0.45; N 0.25.
Chemical yields refer to pure isolated substances. 1H and 13C NMR
spectra were obtained with a Bruker DPX-300 spectrometer. Chem-
ical shifts are reported in ppm from tetramethylsilane with the sol-
vent resonance as the internal standard. The following abbreviations
were used to designate chemical shift multiplicities: s = singlet,
d = doublet, t = triplet, q = quartet, h = heptet, m = multiplet,
br = broad.
(C-9), 146.5 (C-2), 149.7 (C-7), 159.9 (C-1¢), 165.56 (COOCH3),
198.2 (C=O).
MS (GS): m/z (%) = 337 (10) [M]+, 305 (12), 278 (100), 250 (11),
41 (11).
HRMS (EI): m/z [M + H]+ calcd for C18H15N3O4: 338.1135; found:
338.114.
Methyl 3-Cyclopropyl-6-(2-hydroxybenzoyl)-3H-imidazo[4,5-
b]pyridine-5-carboxylate (7c)
Yield: 0.55 g (47%); light-grey solid; mp 172–174 °C; Rf = 0.68
(EtOAc).
IR (ATR): 1704, 1628, 1485, 1443, 1337, 1298, 1265, 1237, 1141,
908, 759, 674, 628 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.22 (br m, 4 H, c-Pr), 3.74 (m,
Synthesis of Compounds 7a–j; General Procedure
3
3
To a Schlenk flask fitted with a reflux condenser, CH2Cl2 (2.5 mL),
primary amine (0.00345 mol), and methyl N-(cyanometh-
yl)formimidate (1; 0.338 g, 0.00345 mol) were added under an ar-
gon atmosphere at r.t. The reaction mixture was heated at reflux for
2 h then cooled down to r.t., and then to 0 °C with an ice bath. 3-
Methoxalylchromone (0.800 g, 0.00345 mol) was added and the
mixture was stirred at the same temperature for 15–20 min and then
heated at reflux for 5 h. When product formation was complete, the
solvent was evaporated to dryness and the residue was purified by
column chromatography (EtOAc) to give 7a–j as light-grey oily
gum, which crystallized within a few hours in air.
4 H, OCH3, c-Pr), 6.91 (t, J = 9.1 Hz, 1 H, H-4¢), 7.03 (d, J =
3
3
9.1 Hz, 1 H, H-2¢), 7.34 (d, J = 9.1 Hz, 1 H, H-5¢), 7.56 (t, J =
9.1 Hz, 1 H, H-3¢), 8.30 (s, 1 H, H-4), 8.79 (s, 1 H, H-2), 11.20 (s,
1 H, OH).
13C NMR (75 MHz, DMSO-d6): d = 5.7 (CH2), 25.6 (CH), 52.5
(OCH3), 117.4 (C-4¢), 119.2 (C-6¢), 121.7 (C-2¢), 127.3 (C-5), 131.6
(C-6), 132.0 (C-3¢), 135.8 (C-5¢), 136.2 (C-4), 140.8 (C-9), 147.8
(C-2), 149.6 (C-7), 159.9 (C-1¢), 165.6 (COOCH3), 198.2 (C=O).
MS (GS): m/z (%) = 337 (12) [M]+, 304 (14), 278 (97), 250 (16),
121 (10), 65 (10).
HRMS (EI): m/z [M]+ calcd for C18H15N3O4: 337.1057; found:
337.1050.
Methyl 3-tert-Butyl-6-(2-hydroxybenzoyl)-3H-imidazo[4,5-
b]pyridine-5-carboxylate (7a)
Yield: 0.58 g (48%); light-grey solid; mp 196–198 °C; Rf = 0.68
(EtOAc).
Methyl 3-Cyclopentyl-6-(2-hydroxybenzoyl)-3H-imidazo[4,5-
b]pyridine-5-carboxylate (7d)
Yield: 0.58 g (46%); light-grey solid; mp 161–163 °C; Rf = 0.71
(EtOAc).
IR (ATR): 1706, 1629, 1444, 1340, 1296, 1217, 1145, 911, 751, 626
cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.84 (s, 9 H, t-Bu), 3.72 (s,
3 H, OCH3), 6.91 (t, J = 9.2 Hz, 1 H, H-4¢), 7.02 (d, J = 9.2 Hz,
1 H, H-2¢), 7.36 (d, 3J = 9.2 Hz, 1 H, H-5¢), 7.55 (t, 3J = 9.2 Hz, 1 H,
H-3¢), 8.28 (s, 1 H, H-4), 8.80 (s, 1 H, H-2), 11.20 (s, 1 H, OH).
13C NMR (75 MHz, DMSO-d6): d = 28.5 (CH3), 52.6 (OCH3), 57.6
[C(CH3)3], 117.4 (C-4¢), 119.2 (C-6¢), 121.7 (C-2¢), 127.1 (C-5),
131.1 (C-6), 132.1 (C-3¢), 135.8 (C-5¢), 137.1 (C-4), 139.8 (C-9),
146.8 (C-2), 147.6 (C-7), 160.0 (C-1¢), 165.6 (COOCH3), 198.3
(C=O).
MS (GS): m/z (%) = 353 (11) [M]+, 322 (10), 294 (81), 266 (20),
238 (95), 209 (10), 121 (11).
HRMS (EI): m/z [M]+ calcd for C19H19N3O4: 353.1370; found:
353.1368.
IR (ATR): 2957, 1727, 1631, 1602, 1486, 1446, 1294, 1226, 1142,
910, 797, 754, 710 cm–1.
3
3
1H NMR (300 MHz, DMSO-d6): d = 2.01 (br m, 8 H, c-Pent), 3.72
(s, 3 H, OCH3), 5.12 (m, 1 H, CH), 6.90 (t, 3J = 9.2 Hz, 1 H, H-4¢),
3
3
7.03 (d, J = 9.2 Hz, 1 H, H-2¢), 7.34 (d, J = 9.2 Hz, 1 H, H-5¢),
7.55 (t, 3J = 9.2 Hz, 1 H, H-3¢), 8.31 (s, 1 H, H-4), 8.92 (s, 1 H, H-
2), 11.18 (s, 1 H, OH).
13C NMR (75 MHz, DMSO-d6): d = 23.6 (CH2), 32.2 (CH2), 52.5
(OCH3), 55.4 (CH), 117.4 (C-4¢), 119.2 (C-6¢), 121.7 (C-2¢), 127.3
(C-5), 131.4 (C-6), 132.1 (C-3¢), 135.8 (C-5¢), 136.1 (C-4), 140.6
(C-9), 146.6 (C-2), 148.1 (C-7), 160.0 (C-1¢), 165.5 (COOCH3),
198.3 (C=O).
MS (GS): m/z (%) = 365 (14) [M]+, 334 (10), 306 (97), 292 (11),
266 (21), 238 (34).
Methyl 3-Allyl-6-(2-hydroxybenzoyl)-3H-imidazo[4,5-b]pyri-
dine-5-carboxylate (7b)
Yield: 0.51 g (44%); light-grey solid; mp 163–165 °C; Rf = 0.7
(EtOAc).
HRMS (EI): m/z [M + H]+ calcd for C20H19N3O4: 366.1448; found:
366.1456.
Methyl 3-Cyclohexyl-6-(2-hydroxybenzoyl)-3H-imidazo[4,5-
b]pyridine-5-carboxylate (7e)
Yield: 0.66 g (51%); light-grey solid; mp 143–145 °C; Rf = 0.72
IR (ATR): 1709, 1628, 1608, 1483, 1445, 1374, 1280, 1255, 1235,
1203, 1145, 946, 907, 744, 672, 620 cm–1.
(hexane–EtOAc, 1:1).
1H NMR (300 MHz, DMSO-d6): d = 3.69 (s, 3 H, OCH3), 5.01 (d,
3
2
3J = 2.9 Hz, 2 H, CH2), 5.08 (dd, J1 = 15.3 Hz, J2 = 2.1 Hz, 1 H,
IR (ATR): 1715, 1630, 1605, 1447, 1377, 1295, 1252, 1240, 1214,
1141, 911, 796, 756, 674 cm–1.
=CH2(trans)), 5.25 (dd, 3J1 = 8.7 Hz, 2J2 = 2.1 Hz, 1 H, =CH2(cis)),
3
6.15 (m, 1 H, CH=), 6.88 (t, J = 9.1 Hz, 1 H, H-4¢), 7.00 (d,
1H NMR (300 MHz, DMSO-d6): d = 1.74 (br m, 11 H, Cy), 3.72 (s,
3
3J = 9.1 Hz, 1 H, H-2¢), 7.32 (d, J = 9.1 Hz, 1 H, H-5¢), 7.52 (t,
3
3 H, OCH3), 4.63 (m, 1 H, CH), 6.90 (t, J = 9.3 Hz, 1 H, H-4¢),
3J = 9.1 Hz, 1 H, H-3¢), 8.31 (s, 1 H, H-4), 8.78 (s, 1 H, H-2), 11.16
3
3
7.02 (d, J = 9.3 Hz, 1 H, H-2¢), 7.34 (d, J = 9.3 Hz, 1 H, H-5¢),
7.55 (t,3J = 9.3 Hz, 1 H, H-3¢), 8.30 (s, 1 H, H-4), 8.95 (s, 1 H, H-
2), 11.18 (s, 1 H, OH).
(s, 1 H, OH).
13C NMR (75 MHz, DMSO-d6): d = 45.3 (CH2), 52.6 (OCH3), 117.5
(C-4¢), 117.8 (=CH2), 119.3 (C-6¢), 121.7 (C-2¢), 127.5 (C-5), 131.5
(C-6), 132.1 (C-3¢), 132.9 (CH=), 135.7 (C-5¢), 135.8 (C-4), 141.0
13C NMR (75 MHz, DMSO-d6): d = 24.7 (CH2), 25.0 (CH2), 32.4
(CH2), 52.5 (OCH3), 53.6 (CH), 117.4 (C-4¢), 119.2 (C-6¢), 121.7
(C-2¢), 127.4 (C-5), 131.3 (C-6), 132.1 (C-3¢), 135.8 (C-5¢), 135.9
Synthesis 2011, No. 1, 133–141 © Thieme Stuttgart · New York

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Regioselective Synthesis of 1-Desazapurine
137
(C-4), 140.8 (C-9), 146.2 (C-2), 147.8 (C-7), 159.9 (C-1¢), 165.6
(COOCH3), 198.2 (C=O).
3J = 9.1 Hz, 1 H, H-3¢¢), 8.29 (s, 1 H, H-4), 8.57 (s, 1 H, H-2), 11.22
(s, 1 H, OH).
MS (GS): m/z (%) = 379 (13) [M]+, 346 (14), 320 (100), 302 (19),
266 (32), 238 (45), 207 (18).
HRMS (EI): m/z [M + H]+ calcd for C21H21N3O4: 380.1605; found:
380.1608.
13C NMR (75 MHz, DMSO-d6): d = 33.9 (CH2), 44.8 (CH2), 52.5
(OCH3), 54.9 (OCH3), 113.8 (C-2¢, C-6¢), 117.4 (C-4¢¢), 119.2 (C-
6¢¢), 121.6 (C-2¢¢), 127.3 (C-5), 129.5 (C-3¢, C-5¢), 129.6 (C-4¢),
131.3 (C-6), 132.0 (C-3¢¢), 135.8 (C-5¢¢), 135.8 (C-4), 140.7 (C-9),
146.6 (C-2), 149.6 (C-7), 157.9 (C-1¢), 160.0 (C-1¢¢), 165.5
(COOCH3), 198.3 (C=O).
Methyl 6-(2-Hydroxybenzoyl)-3-(4-methoxybenzyl)-3H-imida-
zo[4,5-b]pyridine-5-carboxylate (7f)
MS (GS): m/z (%) = 431 (14) [M]+, 429 (19), 372 (22), 310 (15),
Yield: 0.72 g (50%); light-grey solid; mp 165–166 °C; Rf = 0.68
(EtOAc).
134 (100), 91 (35), 65 (11).
HRMS (EI): m/z [M + H]+ calcd for C24H21N3O5: 432.1554; found:
IR (ATR): 1715, 1627, 1601, 1448, 1348, 1282, 1239, 1142, 1034,
904, 763 cm–1.
432.1558.
Methyl 6-(2-Hydroxybenzoyl)-3-(2-methoxyphenethyl)-3H-
imidazo[4,5-b]pyridine-5-carboxylate (7i)
Yield: 0.74 g (50%); light-grey solid; mp 138–140 °C; Rf = 0.75
(EtOAc).
1H NMR (300 MHz, DMSO-d6): d = 3.76 (s, 3 H, OCH3), 3.77 (s,
3
3 H, OCH3), 5.56 (s, 2 H, CH2), 6.92 (t, J = 8.8 Hz, 1 H, H-4¢¢),
6.98 (d, 3J = 6.3 Hz, 2 H, H-2¢, H-6¢), 7.06 (d, 3J = 8.8 Hz, 1 H, H-
2¢¢), 7.40 (m, 3 H, H-3¢, H-5¢, H-5“), 7.57 (t, 3J = 8.8 Hz, 1 H, H-3¢¢),
8.36 (s, 1 H, H-4), 8.92 (s, 1 H, H-2), 11.21 (s, 1 H, OH).
13C NMR (75 MHz, DMSO-d6): d = 46.0 (CH2), 52.9 (OCH3), 55.1
(OCH3), 114.1 (C-2¢, C-6¢), 117.4 (C-4¢¢), 119.2 (C-6¢¢), 121.6 (C-
2¢¢), 127.5 (C-5), 128.5 (C-4¢), 129.3 (C-3¢, C-5¢), 131.5 (C-6),
132.2 (C-3¢¢), 135.8 (C-5¢¢), 135.8 (C-4), 141.0 (C-9), 146.5 (C-2),
149.5 (C-7), 158.9 (C-1¢), 159.9 (C-1¢¢), 165.5 (COOCH3), 198.2
(C=O).
IR (ATR): 1713, 1626, 1601, 1497, 1443, 1380, 1285, 1249, 1142,
1034, 898, 747, 630 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 3.19 (t, 3J = 6.5 Hz, 2 H, CH2),
3.67 (s, 3 H, OCH3), 3.73 (s, 3 H, OCH3), 4.61 (t, 3J = 6.5 Hz, 2 H,
CH2), 6.78 (t, 3J = 6.2 Hz, 1 H, H-4¢), 6.91 (t, 3J = 9.4 Hz, 1 H, H-
4¢¢), 6.93 (d, 3J = 6.2 Hz, 1 H, H-2¢), 6.94 (d, 3J = 6.2 Hz, 1 H, H-5¢),
3
3
7.03 (d, J = 9.4 Hz, 1 H, H-2¢¢), 7.18 (t, J = 6.2 Hz, 1 H, H-3¢),
3
3
7.27 (d, J = 9.4 Hz, 1 H, H-5¢¢), 7.55 (t, J = 9.4 Hz, 1 H, H-3¢¢),
MS (GS): m/z (%) = 385 (67), 358 (39), 281 (11), 207 (19), 121
(100), 77 (10).
8.25 (s, 1 H, H-4), 8.49 (s, 1 H, H-2), 11.22 (s, 1 H, OH).
13C NMR (75 MHz, DMSO-d6): d = 30.2 (CH2), 43.3 (CH2), 52.5
(OCH3), 55.0 (OCH3), 110.5 (C-4¢), 117.4 (C-4¢¢), 119.2 (C-6¢¢),
120.1 (C-6¢), 121.6 (C-2¢¢), 125.5 (C-2¢), 127.0 (C-5), 128.1 (C-3¢),
130.0 (C-5¢), 131.1 (C-6), 132.0 (C-3¢¢), 135.7 (C-5¢¢), 135.8 (C-4),
140.5 (C-9), 146.7 (C-2), 149.6 (C-7), 157.2 (C-1¢), 160.0 (C-1¢¢),
165.5 (COOCH3), 198.4 (C=O).
HRMS (EI): m/z [M + H]+ calcd for C23H19N3O5: 418.1397; found:
418.1395.
Methyl 3-(4-Chlorobenzyl)-6-(2-hydroxybenzoyl)-3H-imida-
zo[4,5-b]pyridine-5-carboxylate (7g)
Yield: 0.64 g (44%); light-grey solid; mp 130–132 °C; Rf = 0.68
(EtOAc).
MS (GS): m/z (%) = 431 (15) [M]+, 400 (10), 372 (30), 134 (99),
119 (51), 91 (47), 65 (12).
HRMS (EI): m/z [M + H]+ calcd for C24H21N3O5: 432.1554; found:
IR (ATR): 1715, 1622, 1602, 1445, 1349, 1288, 1237, 1142, 904,
794, 752, 663 cm–1.
432.1559.
1H NMR (300 MHz, DMSO-d6): d = 3.76 (s, 3 H, OCH3), 5.66 (s,
2 H, CH2), 6.94 (t,3J = 8.9 Hz, 1 H, H-4¢¢), 7.06 (d, 3J = 8.9 Hz, 1 H,
H-2¢¢), 7.40 (d, 3J = 8.9 Hz, 1 H, H-5¢¢), 7.48 (m, 4 H, H-3¢, H-2¢, H-
5¢, H-6¢), 7.60 (t, 3J = 8.9 Hz, 1 H, H-3¢¢), 8.39 (s, 1 H, H-4), 8.97 (s,
1 H, H-2), 11.21 (s, 1 H, OH).
13C NMR (75 MHz, DMSO-d6): d = 45.7 (CH2), 52.5 (OCH3), 117.5
(C-4¢¢), 119.2 (C-6¢¢), 121.3 (C-2¢¢), 126.8 (C-5), 128.7 (C-2¢, C-6¢),
129.5 (C-3¢, C-5¢), 131.2 (C-6), 132.3 (C-3¢¢), 132.5 (C-4¢), 135.4
(C-5¢¢), 135.6 (C-1¢), 136.1 (C-4), 141.8 (C-9), 146.2 (C-2), 149.6
(C-7), 160.0 (C-1¢¢), 165.5 (COOCH3), 198.3 (C=O).
MS (EI): m/z (%) = 421 (10) [M]+, 390 (11), 362 (74), 125 (99), 89
(14), 65 (10).
HRMS (EI): m/z [M + H]+ calcd for C22H16ClN3O4: 422.0902;
found: 422.0904.
Methyl 6-(2-Hydroxybenzoyl)-3-phenethyl-3H-imidazo[4,5-
b]pyridine-5-carboxylate (7j)
Yield: 0.75 g (54%); light-grey solid; mp 142–144 °C; Rf = 0.78
(EtOAc).
IR (ATR): 1716, 1628, 1609, 1453, 1379, 1292, 1242, 1142, 1123,
1056, 907, 759, 700, 618 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 3.27 (t, 3J = 6.4 Hz, 2 H, CH2),
3
3
3.73 (s, 3 H, OCH3), 4.64 (t, J = 6.4 Hz, 2 H, CH2), 6.91 (t, J =
8.7 Hz, 1 H, H-4¢), 7.02 (d, 3J = 8.7 Hz, 1 H, H-2¢), 7.26 (br m, 6 H,
PhH, H-5¢), 7.55 (t, 3J = 8.7 Hz, 1 H, H-3¢), 8.29 (s, 1 H, H-4), 8.59
(s, 1 H, H-2), 11.21 (s, 1 H, OH).
13C NMR (75 MHz, DMSO-d6): d = 34.8 (CH2), 44.6 (CH2), 52.5
(OCH3), 117.5 (C-4¢¢), 119.2 (C-6¢¢), 121.7 (C-2¢¢), 126.6 (C-4¢),
127.3 (C-5), 128.4 (C-2¢, C-6¢), 128.6 (C-3¢, C-5¢), 131.3 (C-6),
132.1 (C-3¢¢), 135.8 (C-5¢¢), 135.9 (C-4), 137.8 (C-1¢), 140.8 (C-9),
146.6 (C-2), 149.6 (C-7), 160.0 (C-1¢¢), 165.5 (COOCH3), 198.3
(C=O).
MS (GS): m/z (%) = 401 (16) [M]+, 370 (10), 342 (100), 238 (28),
207 (12), 104 (49), 91 (11).
HRMS (EI): m/z [M + H]+ calcd. for C23H19N3O4: 402.1448; found:
402.1455.
Methyl 6-(2-Hydroxybenzoyl)-3-(4-methoxyphenethyl)-3H-
imidazo[4,5-b]pyridine-5-carboxylate (7h)
Yield: 0.67 g (45%); light-grey solid; mp 149–151 °C; Rf = 0.65
(EtOAc).
IR (ATR): 1717, 1626, 1610, 1453, 1380, 1288, 1237, 1144, 1033,
908, 761, 618 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 3.19 (t, 3J = 6.8 Hz, 2 H, CH2),
3.71 (s, 3 H, OCH3), 3.73 (s, 3 H, OCH3), 4.59 (t,3J = 6.8 Hz, 2 H,
3
3
CH2), 6.83 (d, J = 6.4 Hz, 2 H, H-2¢, H-6¢), 6.91 (t, J = 9.1 Hz,
Synthesis of Compounds 9a,b; General Procedure
To a Schlenk flask, fitted with a reflux condenser, CH2Cl2 (2.5 mL),
primary amine (0.00117 mol), and methyl N-(cyanometh-
3
3
1 H, H-4¢¢), 7.03 (d, J = 9.1 Hz, 1 H, H-2¢¢), 7.07 (d, J = 6.4 Hz,
2 H, H-3¢, H-5¢), 7.31 (d, 3J = 9.1 Hz, 1 H, H-5¢¢), 7.55 (t,
Synthesis 2011, No. 1, 133–141 © Thieme Stuttgart · New York

138
D. Ostrovskyi et al.
PAPER
yl)formimidate (1; 0.00117 mol) were added under an argon atmo-
sphere at r.t. The reaction mixture was heated at reflux for 2 h then
cooled to r.t. and then to 0 °C with an ice bath. 3-Dichloroacetyl-
chromone (0.300 g, 0.00117 mol) was added and the mixture was
stirred at the same temperature for 15–20 min and then heated at re-
flux for 7 h. The solvent was evaporated to dryness and the residue
was purified by column chromatography (EtOAc) to give 9 as green
crystals.
1H NMR (300 MHz, DMSO-d6): d = 1.83 (s, 9 H, t-Bu), 6.88 (t,
3
3J = 9.2 Hz, 1 H, H-4¢), 7.00 (d, J = 9.2 Hz, 1 H, H-2¢), 7.29 (d,
3J = 9.2 Hz, 1 H, H-5¢), 7.52 (t, 3J = 9.2 Hz, 1 H, H-3¢), 8.23 (s, 1 H,
H-4), 8.76 (s, 1 H, H-2), 11.41 (s, 1 H, OH), 13.33 (s, 1 H, COOH).
13C NMR (75 MHz, DMSO-d6): d = 28.5 (CH3), 57.5 [C(CH3)3],
117.4 (C-4¢), 119.2 (C-6¢), 121.3 (C-2¢), 126.7 (C-5), 130.9 (C-6),
132.3 (C-3¢), 135.9 (C-5¢), 136.9 (C-4), 140.6 (C-9), 146.5 (C-2),
147.3 (C-7), 160.5 (C-1¢), 166.5 (COOH), 199.3 (C=O).
MS (GS): m/z (%) = 321 (80), 294 (88), 266 (63), 237 (74), 220
(26), 205 (92), 190 (68), 177 (10), 145 (24), 117 (15), 157 (46).
HRMS (EI): m/z [M + H]+ calcd for C18H17N3O4: 340.1292; found:
340.1296.
{3-tert-Butyl-5-(dichloromethyl)-3H-imidazo[4,5-b]pyridine-6-
yl}(2-hydroxyphenyl)methanone (9a)
Yield: 0.067 g (15%); greenish solid; mp 189–191 °C; Rf = 0.62
(EtOAc).
IR (ATR): 2974, 1592, 1486, 1398, 1337, 1230, 1210, 1029, 803,
756, 644 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.88 (s, 9 H, t-Bu), 6.88 (t,
3J = 9.2 Hz, 1 H, H-4¢), 7.02 (d, 3J = 9.2 Hz, 1 H, H-2¢), 7.33 (s, 1 H,
CHCl2), 7.39 (d, 3J = 9.2 Hz, 1 H, H-5¢), 7.47 (t, 3J = 9.2 Hz, 1 H,
H-3¢), 8.18 (s, 1 H, H-4), 8.88 (s, 1 H, H-2), 11.06 (s, 1 H, OH).
13C NMR (75 MHz, DMSO-d6): d = 28.3 (CH3), 56.6 [C(CH3)3],
76.6 (CHCl2), 117.3 (C-4¢), 119.2 (C-6¢), 122.0 (C-2¢), 125.3 (C-5),
131.0 (C-6), 131.9 (C-3¢), 136.1 (C-5¢), 137.0 (C-4), 139.8 (C-9),
145.1 (C-7), 146.9 (C-2), 160.0 (C-1¢), 197.6 (C=O).
MS (GS): m/z (%) = 377 (11) [M]+, 342 (61), 294 (80), 286 (19),
250 (47), 238 (93), 222 (41), 140 (11), 57 (10).
HRMS (EI): m/z [M + H]+ calcd for C19H19N3O4: 378.0771; found:
378.0769.
3-Allyl-6-(2-hydroxybenzoyl)-3H-imidazo[4,5-b]pyridine-5-
carboxylic Acid (10b)
Yield: 0.22 g (75%); colourless solid; mp 249–250 °C.
IR (ATR): 1633, 1613, 1488, 1445, 1354, 1244, 1186, 1151, 901,
764, 674 cm–1.
3
1H NMR (300 MHz, DMSO-d6): d = 5.05 (d, J = 2.6 Hz, 2 H,
CH2), 5.10 (dd, 3J1 = 15.2 Hz, 2J2 = 2.1 Hz, 1 H, =CH2 (trans)), 5.28
(dd, 3J1 = 9.1 Hz, 2J2 = 2.1 Hz, 1 H, =CH2 (cis)), 6.20 (m, 1 H,
CH=), 6.88 (t, 3J = 9.4 Hz, 1 H, H-4¢), 7.03 (d, 3J = 9.4 Hz, 1 H, H-
2¢), 7.29 (d, 3J = 9.4 Hz, 1 H, H-5¢), 7.54 (t, 3J = 9.4 Hz, 1 H, H-3¢),
8.30 (s, 1 H, H-4), 8.79 (s, 1 H, H-2), 11.42 (s, 1 H, OH), 13.42 (s,
1 H, COOH).
13C NMR (75 MHz, DMSO-d6): d = 45.2 (CH2), 117.5 (C-4¢), 117.9
(=CH2), 119.2 (C-6¢), 121.4 (C-2¢), 127.0 (C-5), 131.4 (C-6), 132.3
(C-3¢), 133.0 (CH=), 135.6 (C-5¢), 135.9 (C-4), 141.7 (C-9), 146.2
(C-2), 149.4 (C-7), 160.5 (C-1¢), 166.3 (COOH), 199.2 (C=O).
{3-(4-Methoxybenzyl)-5-(dichloromethyl)-3H-imidazo[4,5-
b]pyridine-6-yl}(2-hydroxyphenyl)methanone (9b)
Yield: 0.062 g (12%); green solid; mp 172–175 °C; Rf = 0.66
(EtOAc).
MS (GS): m/z (%) = 305 (90), 276 (98), 260 (12), 250 (29), 237
(12), 156 (22), 92 (10), 41 (14).
HRMS (EI): m/z [M + H]+ calcd for C17H13N3O4: 324.0979; found:
324.0979.
IR (ATR): 1712, 1617, 1577, 1533, 1446, 1391, 1334, 1285, 1140,
1088, 1040, 918, 877 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 3.82 (s, 3 H, OCH3), 3.83 (s,
3-Cyclopropyl-6-(2-hydroxybenzoyl)-3H-imidazo[4,5-b]pyri-
dine-5-carboxylic Acid (10c)
Yield: 0.25 g (86%); colourless solid; mp 276–277 °C.
3
3 H, OCH3), 5.51 (s, 2 H, CH2), 6.91 (t, J = 9.0 Hz, 1 H, H-4¢¢),
6.95 (d, 3J = 5.7 Hz, 2 H, H-2¢, H-6¢), 7.06 (d, 3J = 9.0 Hz, 1 H, H-
2¢¢), 7.36 (m, 3 H, H-3¢, H-5¢, H-5¢¢), 7.42 (s, 1 H, CHCl2), 7.60 (t,
3J = 9.0 Hz, 1 H, H-3¢¢), 8.11 (s, 1 H, H-4), 8.48 (s, 1 H, H-2), 10.47
(s, 1 H, OH).
13C NMR (75 MHz, DMSO-d6): d = 46.4 (CH2), 53.0 (OCH3), 75.3
(CHCl2), 114.1 (C-2¢, C-6¢), 117.2 (C-4¢¢), 118.9 (C-6¢¢), 121.6 (C-
2¢¢), 126.9 (C-5), 128.4 (C-4¢), 129.1 (C-3¢, C-5¢), 130.0 (C-6),
132.4 (C-3¢¢), 135.2 (C-4), 136.1 (C-5¢¢), 141.7 (C-9), 146.5 (C-2),
148.2 (C-7), 157.9 (C-1¢), 160.1 (C-1¢¢), 198.0 (C=O).
MS (GS): m/z (%) = 443 (12) [M]+, 408 (38), 360 (80), 238 (86),
221 (23), 121 (96), 83 (13).
HRMS (EI): m/z [M + H]+ calcd. for C22H17Cl2N3O3: 444.3116;
found: 444.3120.
IR (ATR): 1682, 1627, 1485, 1450, 1343, 1297, 1234, 1148, 1028,
895, 760, 708 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.22 (br m, 4 H, c-Pr), 3.73 (m,
3
3
1 H, CH), 6.88 (t, J = 8 Hz, 1 H, H-4¢), 7.02 (d, J = 8.8 Hz, 1 H,
H-2¢), 7.27 (d, 3J = 8.8 Hz, 1 H, H-5¢), 7.54 (t, 3J = 8.8 Hz, 1 H, H-
3¢), 8.25 (s, 1 H, H-4), 8.76 (s, 1 H, H-2), 11.42 (s, 1 H, OH), 13.45
(s, 1 H, COOH).
13C NMR (75 MHz, DMSO-d6): d = 5.6 (CH2), 25.6 (CH), 117.5 (C-
4¢), 119.2 (C-6¢), 121.4 (C-2¢), 126.9 (C-5), 131.4 (C-6), 132.3 (C-
3¢), 135.9 (C-5¢), 136.1 (C-4), 141.8 (C-9), 147.6 (C-2), 149.4 (C-
7), 160.5 (C-1¢), 166.5 (COOH), 199.3 (C=O).
MS (GS): m/z (%) = 305 (91), 278 (78), 249 (34), 221 (13), 65 (10).
HRMS (EI): m/z [M + H]+ calcd for C17H13N3O4: 324.0979; found:
Synthesis of Compounds 10a–j; General Procedure
To a solution of the corresponding ester (300 mg) in MeOH (20
mL), KOH (30% in H2O, 2 equiv) was added. The mixture was
stirred at reflux temperature for 2 h then allowed to cool down. Con-
centrated HCl was added dropwise until the mixture became acidic.
The precipitate formed was filtered and washed with H2O (3 × 7
mL), then dried to give 10a–j as white crystals.
324.0977.
3-Cyclopentyl-6-(2-hydroxybenzoyl)-3H-imidazo[4,5-b]pyri-
dine-5-carboxylic Acid (10d)
Yield: 0.24 g (82%); colourless solid; mp 297–298 °C.
IR (ATR): 1693, 1626, 1486, 1453, 1344, 1293, 1227, 1148, 895,
763, 742, 670 cm–1.
3-tert-Butyl-6-(2-hydroxybenzoyl)-3H-imidazo[4,5-b]pyridine-
5-carboxylic Acid (10a)
Yield: 0.20 g (69%); colourless solid; mp 274–275 °C.
1H NMR (300 MHz, DMSO-d6): d = 2.02 (br m, 8 H, c-Pent), 5.12
(m, 1 H, CH), 6.88 (t, 3J = 9.0 Hz, 1 H, H-4¢), 7.00 (d, 3J = 9.0 Hz,
1 H, H-2¢), 7.33 (d, 3J = 9.0 Hz, 1 H, H-5¢), 7.55 (t, 3J = 9.0 Hz, 1 H,
H-3¢), 8.27 (s, 1 H, H-4), 8.91 (s, 1 H, H-2), 11.43 (s, 1 H, OH),
13.32 (s, 1 H, COOH).
IR (ATR): 1689, 1682, 1609, 1469, 1345, 1295, 1210, 1149, 898,
750 cm–1.
Synthesis 2011, No. 1, 133–141 © Thieme Stuttgart · New York

PAPER
Regioselective Synthesis of 1-Desazapurine
139
13C NMR (75 MHz, DMSO-d6): d = 23.5 (CH2), 32.1 (CH2), 55.4
(CH), 117.4 (C-4¢), 119.1 (C-6¢), 121.4 (C-2¢), 126.8 (C-5), 131.2
(C-6), 132.3 (C-3¢), 135.9 (C-5¢, C-4), 141.3 (C-9), 146.3 (C-7),
147.9 (C-2), 160.5 (C-1¢), 166.4 (COOH), 199.3 (C=O).
MS (GS): m/z (%) = 351 (11) [M]+, 332 (10), 292 (26), 282 (39),
171 (19), 69 (16).
(C-1¢), 135.9 (C-4), 141.7 (C-9), 146.4 (C-2), 149.4 (C-7), 160.5 (C-
1¢¢), 166.2 (COOH), 199.1 (C=O).
MS (EI): m/z (%) = 389 (50), 360 (37), 250 (10), 207 (19), 125
(100), 99 (10), 89 (22), 63 (12).
HRMS (EI): m/z [M + H]+ calcd for C21H14ClN3O4: 408.0746;
found: 408.0746.
HRMS (EI): m/z [M + H]+ calcd for C19H17N3O4: 352.1292; found:
352.1292.
6-(2-Hydroxybenzoyl)-3-(4-methoxyphenethyl)-3H-imida-
zo[4,5-b]pyridine-5-carboxylic Acid (10h)
3-Cyclohexyl-6-(2-hydroxybenzoyl)-3H-imidazo[4,5-b]pyri-
dine-5-carboxylic Acid (10e)
Yield: 0.25 g (87%); colourless solid; mp >300 °C.
Yield: 0.21 g, 73%); colorless solid; mp 252–255 °C.
IR (ATR): 1626, 1610, 1512, 1453, 1361, 1294, 1242, 1184, 1145,
1032, 893, 759, 713, 609 cm–1.
IR (ATR): 2930, 1627, 1607, 1488, 1447, 1353, 1295, 1225, 1184,
1148, 895, 743, 670 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.71 (br m, 11 H, Cy), 4.61 (m,
1 H, CH), 6.85 (t, 3J = 8.9 Hz, 1 H, H-4¢), 7.00 (d, 3J = 8.9 Hz, 1 H,
H-2¢), 7.27 (d, 3J = 8.9 Hz, 1 H, H-5¢), 7.51 (t, 3J = 8.9 Hz, 1 H, H-
3¢), 8.23 (s, 1 H, H-4), 8.90 (s, 1 H, H-2), 11.42 (s, 1 H, OH).
1H NMR (300 MHz, DMSO-d6): d = 3.21 (t,3J = 6.3 Hz, 2 H, CH2),
3.72 (s, 3 H, OCH3), 4.61 (t , 3J = 6.3 Hz, 2 H, CH2), 6.84 (d, 3J =
3
5.8 Hz, 2 H, H-2¢, H-6¢), 6.90 (t, J = 9.0 Hz, 1 H, H-4¢¢), 7.03 (d,
3J = 9.0 Hz, 1 H, H-2¢¢), 7.10 (d, 3J = 5.8 Hz, 2 H, H-3¢, H-5¢), 7.27
(d, 3J = 9.0 Hz, 1 H, H-5¢¢), 7.55 (t, 3J = 9.0 Hz, 1 H, H-3¢¢), 8.26 (s,
1 H, H-4), 8.57 (s, 1 H, H-2), 11.46 (s, 1 H, OH).
13C NMR (75 MHz, DMSO-d6): d = 24.7 (CH2), 25.1 (CH2), 32.3
(CH2), 53.4 (CH), 117.4 (C-4¢), 119.1 (C-6¢), 121.7 (C-2¢), 127.6
(C-5), 131.4 (C-6), 132.1 (C-3¢), 135.8 (C-5¢), 135.9 (C-4), 140.8
(C-9), 146.3 (C-2), 147.6 (C-7), 160.0 (C-1¢), 166.4 (COOH), 198.1
(C=O).
13C NMR (75 MHz, DMSO-d6): d = 33.9 (CH2), 44.9 (CH2), 54.9
(OCH3), 113.8 (C-2¢, C-6¢), 117.5 (C-4¢¢), 119.1 (C-6¢¢), 121.3 (C-
2¢¢), 126.8 (C-5), 129.6 (C-3¢, C-5¢), 129.6 (C-4¢), 131.2 (C-6),
132.3 (C-3¢¢), 135.7 (C-5¢¢), 135.9 (C-4), 141.3 (C-9), 146.3 (C-2),
149.4 (C-7), 157.9 (C-1¢), 160.5 (C-1¢¢), 166.3 (COOH), 199.4
(C=O).
MS (GS): m/z (%) = 365 (10) [M]+, 332 (11), 306 (22), 244 (35),
184 (10), 83 (16), 59 (10).
MS (GS): m/z (%) = 390 (27), 282 (20), 247 (52), 224 (10), 162
(82), 135 (95), 58 (14).
HRMS (EI): m/z [M + H]+ calcd for C23H19N3O5: 418.1397; found:
HRMS (EI): m/z [M + H]+ calcd for C20H19N3O4: 366.1448; found:
366.1452.
418.1399.
6-(2-Hydroxybenzoyl)-3-(4-methoxybenzyl)-3H-imidazo[4,5-
b]pyridine-5-carboxylic Acid (10f)
Yield: 0.26 g (88%); colourless solid; mp 286–288 °C.
6-(2-Hydroxybenzoyl)-3-(2-methoxyphenethyl)-3H-imida-
zo[4,5-b]pyridine-5-carboxylic Acid (10i)
Yield: 0.24 g (81%); colorless solid; mp 240–241 °C.
IR (ATR): 1714, 1606, 1511, 1456, 1295, 1238, 1142, 1032, 911,
772, 739 cm–1.
IR (ATR): 1632, 1485, 1453, 1296, 1235, 1181, 1147, 1035, 752,
710 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 3.74 (s, 3 H, OCH3), 5.54 (s,
2 H, CH2), 6.87 (t, 3J = 9.2 Hz, 1 H, H-4¢¢), 6.94 (d, 3J = 5.7 Hz, 2 H,
1H NMR (300 MHz, DMSO-d6): d = 3.19 (t, 3J = 6.4 Hz, 2 H, CH2),
3
3
3
3
H-2¢, H-6¢), 7.03 (d, J = 9.2 Hz, 1 H, H-2¢¢), 7.28 (d, J = 9.2 Hz,
1 H, H-5¢¢), 7.42 (d, 3J = 5.7 Hz, 2 H, H-3¢, H-5¢), 7.55 (t,
3J = 9.2 Hz, 1 H, H-3¢¢), 8.29 (s, 1 H, H-4), 8.89 (s, 1 H, H-2), 11.40
(s, 1 H, OH), 13.43 (s, 1 H, COOH).
3.67 (s, 3 H, OCH3), 4.59 (t, J = 6.4 Hz, 2 H, CH2), 6.77 (t, J =
6.0 Hz, 1 H, H-4¢), 6.92 (br m, 4 H, H-4¢¢, H-2¢, H-5¢, H-2¢¢), 7.18
(m, 2 H, H-3¢, H-5¢¢), 7.53 (t, 3J = 9.1 Hz, 1 H, H-3¢¢), 8.21 (s, 1 H,
H-4), 8.46 (s, 1 H, H-2), 11.43 (s, 1 H, OH), 13.37 (s, 1 H, COOH).
13C NMR (75 MHz, DMSO-d6): d = 46.0 (CH2), 55.1 (OCH3), 114.1
(C-2¢, C-6¢), 117.5 (C-4¢¢), 119.2 (C-6¢¢), 121.4 (C-2¢¢), 127.0 (C-5),
128.5 (C-4¢), 129.3 (C-3¢, C-5¢), 131.4 (C-6), 132.4 (C-3¢¢), 135.7
(C-5¢¢), 135.9 (C-4), 141.6 (C-9), 146.2 (C-2), 149.3 (C-7), 158.9
(C-1¢), 160.5 (C-1¢¢), 166.3 (COOH), 199.2 (C=O).
MS (EI): m/z (%) = 403 (23) [M]+, 385 (70), 370 (11), 358 (97), 342
(16), 121 (82), 91 (12), 77 (15).
13C NMR (75 MHz, DMSO-d6): d = 30.1 (CH2), 43.2 (CH2), 55.5
(OCH3), 110.6 (C-4¢), 117.5 (C-4¢¢), 119.1 (C-6¢¢), 120.1 (C-6¢),
121.3 (C-2¢¢), 125.5 (C-2¢), 126.6 (C-5), 128.1 (C-2¢), 130.0 (C-3¢),
131.0 (C-6), 132.2 (C-3¢¢), 135.6 (C-5¢¢), 135.9 (C-4), 141.3 (C-9),
146.5 (C-2), 149.3 (C-7), 157.2 (C-1¢), 160.5 (C-1¢¢), 166.4
(COOH), 199.4 (C=O).
MS (GS): m/z (%) = 417 (12) [M]+, 357 (61), 324 (15), 296 (20),
221 (13), 135 (96), 105 (18), 44 (10).
HRMS (EI): m/z [M + H]+ calcd for C23H19N3O5: 418.1397; found:
HRMS (EI): m/z [M + H]+ calcd for C22H17N3O5: 404.1241; found:
404.1236.
418.1400.
3-(4-Chlorobenzyl)-6-(2-hydroxybenzoyl)-3H-imidazo[4,5-
b]pyridine-5-carboxylic Acid (10g)
Yield: 0.21 g (74%); colorless solid; mp 299–300 °C.
6-(2-Hydroxybenzoyl)-3-phenethyl-3H-imidazo[4,5-b]pyridine-
5-carboxylic Acid (10j)
Yield: 0.26 g (90%); colorless solid; mp 229–231 °C.
IR (ATR): 1705, 1622, 1605, 1489, 1383, 1242, 1195, 1143, 910,
774, 740, 726 cm–1.
IR (ATR): 1625, 1483, 1454, 1360, 1290, 1254, 1184, 1145, 894,
701, 611 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 5.63 (s, 2 H, CH2), 6.88 (t,
3J = 9.0 Hz, 1 H, H-4¢¢), 7.03 (d, J = 9.0 Hz, 1 H, H-2¢¢), 7.30 (d,
1H NMR (300 MHz, DMSO-d6): d = 3.29 (t, 3J = 6.3 Hz, 2 H, CH2),
4.66 (t, 3J = 6.3 Hz, 2 H, CH2), 6.89 (t, 3J = 8.6 Hz, 1 H, H-4¢), 7.05
(d, 3J = 8.6 Hz, 1 H, H-2¢), 7.25 (br m, 6 H, PhH, H-5¢), 7.55 (t, 3J =
8.6 Hz, 1 H, H-3¢), 8.26 (s, 1 H, H-4), 8.59 (s, 1 H, H-2), 11.45 (s,
1 H, OH), 13.38 (s, 1 H, COOH).
13C NMR (75 MHz, DMSO-d6): d = 34.8 (CH2), 44.5 (CH2), 117.5
(C-4¢¢), 119.1 (C-6¢¢), 121.3 (C-2¢¢), 126.5 (C-4¢), 126.8 (C-5), 128.4
3
3J = 9.0 Hz, 1 H, H-5¢¢), 7.46 (m, 4 H, H-3¢, H-2¢, H-5¢, H-6¢), 7.54
3
(t, J = 9.0 Hz, 1 H, H-3¢¢), 8.31 (s, 1 H, H-4), 8.92 (s, 1 H, H-2),
11.40 (s, 1 H, OH).
13C NMR (75 MHz, DMSO-d6): d = 45.7 (CH2), 117.4 (C-4¢¢), 119.1
(C-6¢¢), 121.3 (C-2¢¢), 127.1 (C-5), 128.7 (C-2¢, C-6¢), 129.6 (C-3¢,
C-5¢), 131.6 (C-6), 132.3 (C-3¢¢), 132.6 (C-4¢), 135.6 (C-5¢¢), 135.7
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D. Ostrovskyi et al.
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(C-2¢, C-6¢), 128.6 (C-3¢, C-5¢), 131.2 (C-6), 132.3 (C-3¢¢), 135.7 (C-
5¢¢), 135.9 (C-4), 137.8 (C-1¢), 141.3 (C-9), 146.3 (C-2), 149.3 (C-
7), 160.5 (C-1¢¢), 166.3 (COOH), 199.3 (C=O).
(9) (a) Vaughn, J. R. Jr. U.S. Patent 2637731, 1953.
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U.S. Patent 3459759, 1969.
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M. J. Med. Chem. 1996, 39, 625. (b) Schmidt, B.; Schieffer,
B. J. Med. Chem. 2003, 46, 2261; and references therein.
(11) (a) Mantlo, N. B.; Chakravarty, P. K.; Ondeyka, D. L.; Siegl,
P. K. S.; Chang, R. S.; Lotti, V. J.; Faust, K. A.; Chen, T.-B.;
Schorn, T. W.; Sweet, C. S.; Emmert, S. E.; Patchett, A. A.;
Greenlee, W. J. J. Med. Chem. 1991, 34, 2919. (b) Kim, D.;
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(12) (a) Rizzo, M.; Ventrice, D.; Monforte, F.; Procopio, S.; De
Sarro, G.; Anzini, M.; Cappelli, A.; Makovec, F. J. Pharm.
Biomed. Anal. 2004, 35, 321. (b) Rizzo, M.; Anzini, M.;
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837.
MS (GS): m/z (%) = 369 (44), 237 (10), 104 (100), 91 (12).
HRMS (EI): m/z [M + H]+ calcd for C22H17N3O4: 388.1292; found:
388.1298
Acknowledgment
Financial support by the State of Mecklenburg-Vorpommern (scho-
larships for S.M. and D.O.), by the European Regional Develop-
ment Fund (EFRE), and by the State of Pakistan (HEC scholarship
for I.A.) is gratefully acknowledged. Funding for Dr. V.O.I by the
German Ministry of Education and Research (BMBF) is gratefully
acknowledged (grant No. 03IS2081A).
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141
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(21) Crystallographic data (excluding structure factors) for the
structures of 7a and 9b, reported in this paper, have been
deposited with the Cambridge Crystallographic Data Centre
as supplementary publication nos. CCDC 799366 for 7a and
CCDC 799367 for 9b. These data can be obtained free of
charge on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK; Fax: +44 (1223)336033; E-mail:
deposit@ccdc.cam.ac.uk, or via www.ccdc.cam.ac.uk/
data_request/cif
(22) Iaroshenko, V. O.; Mkrtchyan, S.; Ghazaryan, G.;
Hakopyan, A.; Maalik, A.; Supe, L.; Ostrovskyi, D.;
Villinger, A.; Tolmachev, A.; Sosnovskikh, V. Ya.; Langer,
P. manuscript in preparation.
Synthesis 2011, No. 1, 133–141 © Thieme Stuttgart · New York