Preparation of 1-alkyl-2-aryl-1H-imidazo[4,5-b]pyridines from 2-alkylamino-3-aminopyridines and aromatic aldehydes using air as an oxidant

Article abstract of DOI:10.3987/COM-05-10447

Attempted imine formation between 2-methoxyethylamino-3-aminopyridine (an exemplary 2-alkylamino-3-aminopyridine) and an array of aromatic aldehydes in methanol and ambient atmosphere led to the predominant formation of 1-methoxyethyl-2-aryl-1H-imidazo[4,

Full text of DOI:10.3987/COM-05-10447

HETEROCYCLES, Vol. 65, No. 9, 2005
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HETEROCYCLES, Vol. 65, No. 9, 2005, pp. 2189 - 2194
Received, 16th May, 2005, Accepted, 21st July, 2005, Published online, 26th July, 2005
PREPARATION OF 1-ALKYL-2-ARYL-1H-IMIDAZO[4,5-b]PYRIDINES
FROM
2-ALKYLAMINO-3-AMINOPYRIDINES AND AROMATIC
ALDEHYDES USING AIR AS AN OXIDANT
Mikhail Krasavin*, Vladimir V. Kobak, Tatiana Y. Bondarenko, and Dmitry
V. Kravchenko
Chemical Diversity Research Institute, 2a Rabochaya St., Khimki, Moscow Reg.,
114401 Russia
e-mail: myk@chemdiv.com
Abstract - Attempted imine formation between 2-methoxyethylamino-3-
aminopyridine (an exemplary 2-alkylamino-3-aminopyridine) and an array of
aromatic aldehydes in methanol and ambient atmosphere led to the predominant
formation of 1-methoxyethyl-2-aryl-1H-imidazo[4,5-b]pyridines. The reaction
was found to be of immediate preparative importance in the six cases studied.
INTRODUCTION
Our ongoing search for heterocyclic building blocks useful in construction of medicinally important
small molecules led us to investigate the synthesis of unsymmetrical 2,3-bis(dialkylamino)pyridines. The
latter have been reported as valuable intermediates en route to bioactive compounds among which
3
analgetics,1 antagonists for platelet activating factor,2 thromboxane A2, and angiotensin II4 as well as
hypoglycemic compounds5 are a few notable examples. Preparative methods described in the literature
for these diamine compounds include either sequential introduction of two different amino functionalities
via Pd-catalyzed amination of a dihalopyridine core,6 or LAH reduction of 2,3-bis(acylamino)pyridines.7
However, we found no account of a straightforward strategy (Scheme 1) that would include reductive
amination on the primary amino group2 of 2-alkylamino-3-aminopyridines (2) (easily accessible from
cheap 2-chloro-3-nitropyridine (1) in two high-yielding steps8) with intermediacy of respective imines
(3).
We therefore proceeded by mixing a model starting material (2a) with a set of aromatic aldehydes (4a-f)
in methanolic solution and monitoring the reaction progress while the solutions were being stirred in the
air (Scheme 2). As discussed below, the observed reaction followed a different route providing in all
cases substantial amounts of 1-methoxyethyl-2-aryl-1H-imidazo[4,5-b]pyridines (5a-f).

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R'
X
X
X
N
N
Y
z
NH2
Y
z
NO2
Cl
Y
z
R'CHO
-H2O
two steps
Ref. 8
N
NH
R
N
NH
R
3
2
1
Scheme 1. R, R' = alkyl, aryl, heteroaryl; X, Y, Z = any substituent, including a cycle
RESULTS AND DISCUSSION
The starting material (2a) was prepared from 2-chloro-3-nitropyridine (1) according to the well-
established two-step protocol.8 It was then brought in contact with methanolic solutions of aromatic
aldehydes (4a-f) in anticipation of the formation of a respective imine (3). However, in all cases TLC
analysis performed after 3 h indicated predominant formation of a slightly more polar product
(presumably different from the desired imine) that did not change when NaBH4 was subsequently added.
1
The reaction mixtures were worked up and the crude products were analyzed by H NMR spectroscopy
indicating the absence of signals of either aldimine proton9 or the benzylic methylene group. In all cases,
we purified the major reaction product by column chromatography and established its identity by 1H and
13C NMR spectroscopy (as well as MS) as 1-methoxyethyl-2-aryl-1H-imidazo[4,5-b]pyridines (5a-f)
(Scheme 2). Notably, the isolated yields of these pharmaceutically important10 heterocyclic compounds
were in the range 40-62% which clearly makes this environmentally benign transformation also
synthetically sound.
NH2
N
N
MeOH
rt, air
Ar-CHO
Ar
+
N
NH
N
2a
4a-f
5a-f
O
O
Ar =
O
O
c.
d.
b.
a.
O
O
O
O
O
f.
F
F
e.
Scheme 2

HETEROCYCLES, Vol. 65, No. 9, 2005
2191
Formation of 1H-imidazo[4,5-b]pyridines upon reacting 2,3-diaminopyridines with aldehydes has been
described in the literature.3,5,11-13 However, in all cases it required the use of elevated temperatures and
introduction of a specific oxidant such as elemental sulfur,11 iodine,3,5 copper(II) salts,12 or
nitrobenzene13 but we found no report on the use of air as a reactant in this type of cyclization at room
temperature.
Mechanistically, the formation of 1H-imidazo[4,5-b]pyridine nucleus could be justified as presented in
Scheme 3. The initially formed aldimine (3) exists in equilibrium with imidazoline (6). The latter, in
presence of an oxidant (such as air) is converted into the isolated 1H-imidazo[4,5-b]pyridines (5).
H+
H
NH2
N
R'
N
N
N
N
R'CHO
- H2O
H
air
R'
R
R'
N
N
NH
R
N
N
H
N
R
R
2
5
3
6
Scheme 3
In summary, we have established a new synthetic protocol to prepare pharmaceutically important 1H-
imidazo[4,5-b]pyridines from 2-alkylamino-3-aminopyridines in presence of air. This transformation
does not require the use of strong oxidants and elevated temperatures and clearly offers an attractive,
simple, and environmentally friendly alternative to previously reported methods.
EXPERIMENTAL
All reactions were run in oven-dried glassware in atmosphere of nitrogen. Melting points were measured
with a Büchi В-520 melting point apparatus and were not corrected. Analytical thin-layer
chromatography was carried out on EM Separations Technology F254 silica gel plates. Compounds were
1
visualized with short-wavelength UV light. H NMR and 13C NMR spectra were recorded on Bruker
DPX-300 spectrometers in DMSO-d6 using TMS as an internal standard. MS analyses were obtained on
a PE SCIEX API 150EX mass spectrometer. All solvents and reagents were obtained from commercial
sources and used without purification.
N2-(2-Methoxyethyl)pyridine-2,3-diamine (2a).
This material was prepared according to the literature procedure.8 To a solution of 2-chloro-3-
nitropyridine (25.0 g, 157.68 mmol) in anhydrous dioxane (250 mL) triethylamine (17.55 g, 173.44
mmol) and 2-methoxyethylamine (13.0 g, 173.45 mmol) were added and the mixture was heated at reflux
for 2 h. The progress of the reaction was followed by the appearance of yellow coloring and formation of
the precipitate, as well as by TLC control (chloroform-MeOH, 79:1). Upon completion, the reaction
mixture was cooled to rt, the solid triethylamine hydrochloride was filtered off, washed with dioxane,
and discarded. The combined filtrate and washings were concentrated in vacuo. The residue was

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dispersed in water (150 mL) and acidified with 4N aqueous HCl to pH 4.0. The resulting precipitate was
filtered off, washed with water, and air-dried to afford 30.3 g of 2-methoxyethylamino-3-nitropyridine as
bright-yellow solid: mp 70-71°C; 1H NMR (300 MHz, CDCl3): δ 8.47 (dd, J = 1.7, 4.5 Hz, 1H), 8.40 (dd,
J = 1.7, 8.5 Hz, 1H), 6.76 (dd, J = 4.5, 8.5 Hz, 1H), 3.73 (dt, Jd = 5.7 Hz, Jt = 5.6 Hz, 2H), 3.54 (t, J = 5.6
13
Hz, 2H), 3.29 (s, 3H); C NMR (75 MHz, DMSO-d6): δ 156.0, 151.9, 135.2, 127.5, 112.0, 70.1, 58.0,
40.1.
The latter (27.0 g) was dissolved in boiling ethanol (1L), the solution was cooled to 45ºC and transferred
into a pre-heated to 50ºC 2-L autoclave chamber. 10% Pd/C (2.7 g) was added and the mixture is
hydrogenated at 45ºC and 6 bar for 6 h. The mixture was then cooled to rt and the catalyst was filtered
off. The filtrate was concentrated in vacuo and the residue was dried in high vacuum. The
spectroscopically pure product (2a) (22.34 g, 97% for two steps) was obtained as dark oil: 1H NMR (300
MHz, CDCl3): δ 7.37 (dd, J = 1.7, 5.1 Hz, 1H), 6.68 (dd, J = 1.7, 7.4 Hz, 1H), 6.34 (dd, J = 5.1, 7.4 Hz,
1H), 5.55 (unresolved t, 1H), 4.66 (br s, 2H), 3.49 (m, 4H), 3.27 (s, 3H); 13C NMR (75 MHz, DMSO-d6):
δ 147.7, 134.9, 130.2, 117.6, 112.3, 71.0, 57.9, 40.4; LCMS m/z 168 (M + 1); Anal. Calcd for C8H13N3O:
C, 57.47; H, 7.84; N, 25.13. Found: C, 57.50; H, 7.88; N, 25.16.
General procedure: preparation of 3H-imidazo[4,5-b]pyridines (5a-f).
The amine (2a) (1.0 g, 5.98 mmol) and an aromatic aldehyde (6.00 mmol) in dry methanol (25 mL) were
stirred at rt13 for 12-24 h (or until full consumption of 3a was observed by TLC analysis). The solvent
was removed in vacuo and the residue was partitioned between dichloromethane and water. Organic
layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated. Chromatography on silica
gel (1Æ2.5% methanol in chloroform) provided analytically pure 3H-imidazo[4,5-b]pyridines (5a-f).
2-(4-Ethoxyphenyl)-3-(2-methoxyethyl)-3H-imidazo[4,5-b]pyridine (5a).
1
Yield 61.5%, mp 72-74ºC. H NMR (300 MHz, CDCl3): δ 8.35 (dd, J = 1.5, 4.7 Hz, 1H), 8.05 (dd, J =
1.5, 8.0 Hz, 1H), 7.85 (d, J = 8.9 Hz, 2H), 7.29 (dd, J = 4.7, 8.0 Hz, 1H), 7.10 (d, J = 8.9 Hz, 2H), 4.52 (t,
J = 5.5 Hz, 2H), 4.11 (q, J = 7.0 Hz, 2H), 3.76 (t, J = 5.5 Hz, 2H), 3.11 (s, 3H), 1.36 (t, J = 7.0 Hz, 3H);
13C NMR (75 MHz, DMSO-d6): δ 159.9, 154.3, 148.6, 143.1, 134.6, 130.8, 126.3, 122.1, 118.3, 114.6,
69.3, 63.2, 58.1, 43.0, 14.5; LCMS m/z 298 (M + 1); Anal. Calcd for C17H19N3O2: C, 68.67; H, 6.44; N,
14.13. Found: C, 68.65; H, 6.40; N, 14.11.
2-(3,4-Dimethylphenyl)-3-(2-methoxyethyl)-3H-imidazo[4,5-b]pyridine (5b).
Yield 62%, mp 56-59ºC. 1H NMR (300 MHz, CDCl3): δ 8.36 (dd, J = 1.3, 4.7 Hz, 1H), 8.06 (dd, J = 1.3,
8.0 Hz, 1H), 7.68 (br s, 1H), 7.62 (d, J = 7.7 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.30 (dd, J = 4.7, 8.0 Hz,
13
1H), 4.53 (t, J = 5.5 Hz, 2H), 3.73 (t, J = 5.5 Hz, 2H), 3.10 (s, 3H), 2.32 (s, 6H); C NMR (75 MHz,

HETEROCYCLES, Vol. 65, No. 9, 2005
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DMSO-d6): δ 154.5, 148.6, 138.5, 136.7, 134.6, 130.3, 129.7, 127.6, 126.6, 126.5, 118.3, 69.3, 58.0, 43.0,
19.3, 19.2; LCMS m/z 282 (M + 1); Anal. Calcd for C17H19N3O: C, 72.57; H, 6.81; N, 14.93. Found: C,
72.60; H, 6.84; N, 14.97.
2-Furan-2-yl-3-(2-methoxyethyl)-3H-imidazo[4,5-b]pyridine (5c).
Yield 53%, mp 39-40ºC. 1H NMR (300 MHz, CDCl3): δ 8.36 (dd, J = 1.3, 4.7 Hz, 1H), 8.05 (dd, J = 1.3,
8.1 Hz, 1H), 8.03 (m, 1H), 7.34 (d, J = 3.5 Hz, 1H), 7.30 (dd, J = 4.7, 8.1 Hz, 1H), 6.77 (dd, J = 1.9, 3.5
Hz, 1H), 4.75 (t, J = 5.6 Hz, 2H), 3.74 (t, J = 5.6 Hz, 2H), 3.16 (s, 3H); 13C NMR (75 MHz, DMSO-d6):
δ 148.0, 145.5, 144.7, 144.6, 143.7, 134.6, 126.5, 118.7, 113.6, 112.2, 70.0, 58.0, 42.6; LCMS m/z 244
(M + 1); Anal. Calcd for C13H13N3O2: C, 64.19; H, 5.39; N, 17.27. Found: C, 64.15; H, 5.36; N, 17.25.
3-(2-Methoxyethyl)-2-(3,4,5-trimethoxyphenyl)-3H-imidazo[4,5-b]pyridine (5d).
Yield 40%, mp 86-88ºC. 1H NMR (300 MHz, CDCl3): δ 8.37 (dd, J = 1.3, 4.7 Hz, 1H), 8.10 (dd, J = 1.3,
8.0 Hz, 1H), 7.32 (dd, J = 4.7, 8.0 Hz, 1H), 7.30 (s, 2H), 4.55 (t, J = 5.1 Hz, 2H), 3.87 (s, 6H), 3.86 (t, J =
13
5.1 Hz, 2H), 3.77 (s, 3H), 3.18 (s, 3H); C NMR (75 MHz, DMSO-d6): δ 154.3, 152.9, 148.6, 143.4,
139.0, 134.5, 126.6, 125.1, 118.5, 107.1, 69.6, 60.1, 58.3, 56.0, 43.7; LCMS m/z 344 (M + 1); Anal.
Calcd for C18H21N3O4: C, 62.96; H, 6.16; N, 12.24. Found: C, 62.97; H, 6.16; N, 12.26.
2-(3,4-Dimethoxyphenyl)-3-(2-methoxyethyl)-3H-imidazo[4,5-b]pyridine (5e).
Yield 41%, mp 70-72ºC. 1H NMR (300 MHz, CDCl3): δ 8.35 (dd, J = 1.1, 4.8 Hz, 1H), 8.07 (dd, J = 1.1,
7.9 Hz, 1H), 7.56 (s, 1H), 7.49 (dd, J = 1.7, 8.5 Hz, 1H), 7.30 (dd, J = 4.8, 8.1 Hz, 1H), 7.11 (d, J = 8.5
13
Hz, 1H), 4.54 (t, J = 5.3 Hz, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 3.81 (t, J = 5.3 Hz, 2H), 3.15 (s, 3H); C
NMR (75 MHz, DMSO-d6): δ 154.4, 150.3, 148.7, 148.6, 143.1, 134.6, 126.4, 122.2, 118.3, 112.8, 111.7,
69.5, 58.2, 55.6 (two peaks), 43.3; LCMS m/z 314 (M + 1); Anal. Calcd for C17H19N3O3: C, 65.16; H,
6.11; N, 13.41. Found: C, 65.12; H, 6.08; N, 13.39.
2-(3,4-Difluorophenyl)-3-(2-methoxyethyl)-3H-imidazo[4,5-b]pyridine (5f).
Yield 49%, mp 77-79ºC. 1H NMR (300 MHz, CDCl3): δ 8.41 (dd, J = 1.3, 4.7Hz, 1H), 8.11 (dd, J = 1.3,
7.9 Hz, 1H), 8.02 (ddd, J = 2.1, 7.7, 11.5 Hz, 1H), 7.77 – 7.82 (m, 1H), 7.66 (dt, Jd = 10.6, Jt = 8.3 Hz,
1H), 7.34 (dd, J = 3.2, 10.6 Hz, 1H), 4.53 (t, J = 5.5 Hz, 2H), 3.75 (t, J = 5.5 Hz, 2H), 3.11 (s, 3H); 13C
NMR (75 MHz, DMSO-d6): δ 152.3, 151.6 (dd, 2JC-F = 100.0 Hz, 3JC-F = 9.7 Hz), 148.3, 148.2 (dd, 2JC-F
= 97.1 Hz, 3JC-F = 12.0 Hz), 143.9, 134.4, 127.5 (dd, 3JC-F = 7.4 Hz, 4JC-F = 4.0 Hz), 127.0, 126.8 (dd, 3JC-
F = 6.3 Hz, 4JC-F = 2.9 Hz), 118.7, 118.4 (dd, 1JC-F = 293. Hz, 2JC-F = 48.0 Hz), 111.1 (dd, 1JC-F = 297.6.
Hz, 2JC-F = 52.1 Hz), LCMS m/z 290 (M + 1); Anal. Calcd for C15H13N3OF2: C, 62.28; H, 4.53; N, 14.53.
Found: C, 62.30; H, 4.55; N, 14.56.

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1
detecting the presence of respective characteristic signals in the H NMR spectrum of the reaction
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(4a): δ 8.60 (s, CH=N, rel. int. 1H), 6.21 (t, J = 5.1 Hz, NH-CH2, rel. int. 1H), 4.10 (d, J = 7.0 Hz,
OCH2CH3, rel. int. 2H), 3.27 (s, OCH3, rel. int. 3H), 1.35 (t, J = 7.0 Hz, OCH2CH3, rel. int. 3H). It
was present in rather small concentration (~ 10 mol. %) and could not be detected by TLC analysis
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