Synthesis of some new imidazo[4,5-B]pyridine derivatives using 2-cyanomethyl-1-methyl-1 H -imidazo[4,5-B]pyridine

Article abstract of DOI:10.1080/10426507.2011.631793

The reactions of 2-cyanomethyl-1-methyl-1H-imidazo[4,5-b]pyridine with isothiocyanates, nitroso compounds, acid chlorides, and thioglycolic acid were investigated. New imidazo[4,5-b]pyridine derivatives with various substituents in 2-position and derivati

Full text of DOI:10.1080/10426507.2011.631793

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Phosphorus, Sulfur, and Silicon and the
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Synthesis of Some New Imidazo[4,5-
B]Pyridine Derivatives Using 2-
Cyanomethyl-1-Methyl-1H-Imidazo[4,5-
B]Pyridine
b
L. Bukowski a , Zofia Zwolska b & Ewa Augustynowicz-Kopeć
a Department of Organic Chemistry, Medical University of Gdańsk,
Gdańsk, Poland
b Department of Microbiology, Institute of Tuberculosis and
Pulmonary Diseases, Warsaw, Poland
Version of record first published: 30 May 2012
To cite this article: L. Bukowski, Zofia Zwolska & Ewa Augustynowicz-Kopeć (2012): Synthesis of Some
New Imidazo[4,5-B]Pyridine Derivatives Using 2-Cyanomethyl-1-Methyl-1H-Imidazo[4,5-B]Pyridine,
Phosphorus, Sulfur, and Silicon and the Related Elements, 187:7, 879-887
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Phosphorus, Sulfur, and Silicon, 187:879–887, 2012
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2011.631793
SYNTHESIS OF SOME NEW IMIDAZO[4,5-B]PYRIDINE
DERIVATIVES USING 2-CYANOMETHYL-1-METHYL-1H-
IMIDAZO[4,5-B]PYRIDINE
L. Bukowski,1 Zofia Zwolska,2 and Ewa Augustynowicz-Kopec´2
1Department of Organic Chemistry, Medical University of Gdan´sk, Gdan´sk, Poland
2Department of Microbiology, Institute of Tuberculosis and Pulmonary Diseases,
Warsaw, Poland
GRAPHICAL ABSTRACT
Abstract The reactions of 2-cyanomethyl-1-methyl-1H-imidazo[4,5-b]pyridine with isothio-
cyanates, nitroso compounds, acid chlorides, and thioglycolic acid were investigated. New
imidazo[4,5-b]pyridine derivatives with various substituents in 2-position and derivatives of the
new pyrrolo[2ꢁ,1ꢁ:2,3]imidazo[4,5-b]pyridine ring system were synthesized. The compounds
obtained were tested in vitro for their tuberculostatic activity.
Keywords
b]pyridine; thioamides; tuberculostatic activity
α-Cyanoketones; imidazo[4,5-b]pyridine; pyrrolo[2ꢁ,1ꢁ:2,3]imidazo[4,5-
INTRODUCTION
Only a few imidazo[4,5-b]pyridine derivatives have been reported; they exhibit di-
verse bioactivities and some of them have been applied in pharmacotherapy.1 In continuation
of our interest in the chemistry and biological properties of imidazo [4,5-b]pyridine deriva-
tives,2,3 we synthesized and tested some new derivatives of this heterocycle. Previously, we
Received 9 August 2011; accepted 29 September 2011.
Address correspondence to L. Bukowski, Department of Organic Chemistry, Medical University of Gdan´sk,
Al. Gen. Hallera 107, 80-416, Gdan´sk, Poland. E-mail: agadub@gumed.edu.pl
879

880
L. BUKOWSKI ET AL.
have investigated the reactions of some isothiocyanates with 2-cyanomethylimidazo[4,5-
b]pyridine and with 2-cyanomethyl-3-methyl-3H-imidazo [4,5-b]pyridine.4,5 Since some
of carbothioamides obtained there5 showed a significant activity against Mycobacterium
tuberculosis, we decided to synthesize isomeric compounds starting from 2-cyanomethyl-
1-methyl-1H-imidazo[4,5-b]pyridine 1 and check whether the position of the CH3 group
in the imidazo[4,5-b]pyridine ring has an influence on the tuberculostatic activity. Here, we
also describe the synthesis of some new imidazo[4,5-b]pyridine derivatives obtained from
the reaction of nitrile 1 with some nitroso compounds, acid chlorides, and thioglycolic acid.
RESULTS AND DISCUSSION
As starting compound for the syntheses the previously reported6 2-cyanomethyl-1-
methyl-1H-imidazo[4,5-b]pyridine 1 was used. Reaction of this compound with isothio-
cyanates in the presence of potassium hydroxide gave the not isolated adduct 2, which
upon acidifying with 1N hydrochloric acid yielded the N-substituted thiocarboxamides
4–9. Reaction of the intermediate 2 with 1,2-dibromoethane or 1,3-dibromopropane gave
the compounds 10–13. When 1 is reacted with methyl- or phenylisothiocyanate in the
presence of sulfur the thiazolyl-imidazo[4,5-b]pyri-dines 14 and 15 are obtained.
Unexpectedly, the IR spectra of compounds 4–9 showed the presence of a conjugated
nitrile group, υ = 2180 cm−1, which suggested that these compounds may exist in two
tautomeric forms A or B (thiol or thione form, Scheme 1). This fact was also suggested
1
by the H NMR spectra of these compounds, in which no signal for a methine proton
(CH CN) was observed. The absence of this signal also confirmed the complete conversion
of compounds 4–9 into the isomers A or B (or a mixture thereof). As in the 13C NMR
spectrum of compound 4, a signal at 189.0 ppm was observed (which is typical for a thione
carbon atom7,8), it can be concluded that compounds 4–9 exist in the thione form B.
Scheme 1

SYNTHESIS OF SOME NEW IMIDAZO[4,5-B]PYRIDINE DERIVATIVES
881
CH3
CH3 NH2
N
R
S
O
COOH
CH2
SH
N
N
N
RNCS
S
1
S
S
N
N
N
N
22
14,15
O
O
R
C
=
ArCHO
N
r
Cl
A
CH3
CH3
N
CH3
N
O
CN
N
CN
N
C
R
NAr
N
S
N
N
N
N
N
O
CH
Ar
18–21
16,17
23–25
CH3
CH3
N
N
CN
OH
CN
C R
C
R
N
N
H
N
N
O
B
A
Ar
R
R(Ar)
Cl
23
24
25
–CH2 Cl
–CH3
14
15
18
19
CH3
CH3
N
16
17
20
21
Cl
OCH3
OCH3
CH3
CH3
–CH2O
N
Scheme 2
We also investigated the reactions of nitrile 1 with some nitroso compounds, with
some acid chlorides as well as with thioglycolic acid (Scheme 2). From these reac-
tions the enamines 16 and 17, the α-cyanoketones 18–21 and the thiazolo-imidazo[4,5-
b]pyridine 22 were obtained. Utilizing the reactivity of the CH2 group of com-
pound 22 in reactions with some aromatic aldehydes (p-chlorobenzaldehyde, p-N,N-
dimethylaminobenzaldehyde, 3,4-dimethoxy-benz-aldehyde), the compounds 23–25 were
synthesized.
The IR spectra of compounds 18–21 show the presence of a band at 2180 cm−1
characteristic for a conjugated nitrile group, which suggests that these compounds may
exist in two tautomeric forms A or B. This possibility was also supported by the 1H NMR
spectra of these compounds, in which no signal for the methine proton (CH CN) was
observed. The absence of this signal also confirmed the complete conversion of compounds
18–21 into the isomers A or B (or a mixture thereof). Due to the presence of a signal for an
>NH proton at about 13 ppm, it may be concluded that compounds 18–21 have in fact the
structure A. In addition, the 13C NMR spectrum of compound 18 shows a signal at 185.1
ppm typical of a carbonyl carbon atom8 thus also confirming the structure A.
While determinin◦g the melting point of compound 18, a vigorous decomposition was
observed at about 225 C. Subsequently, the sample was recrystallized and melted again

882
L. BUKOWSKI ET AL.
Table 1 1H and 13C NMR data of some of the new compounds
δ (ppm), J (Hz)
Solvent
CDCl3
4
3.26 (d, J = 4.7, 3H, NHCH3), 4.00 (s, 3H, NCH3), 7.24 (m, 1H, C(6)H), 7.51 (d, J = 8.2,
1H, C(7)H), 8.3 (d, J = 5.0, 1H, C(5)H)
13C NMR: 32.6, 32.7, 64.7, 116.3, 119.0, 120.6, 126.0, 143.4, 144.7, 153.6, 189.0
3.36 (d, J = 4.8, 4H, (CH2)2), 3.49 (s, 3H, NCH3), 3.87 (s, 3H, NCH3), 7.14 (dd, J1 = 4.8,
J2 = 7.0, 1H, C(6)H), 7.38 (d, J = 6.7, 1H, C(7)H), 8.40 (d, J = 3.6, 1H, C(5)H)
3.68 (s, 3H, NCH3), 3.82 (s, 3H, NCH3), 7.19 (dd, J1 = 4.8, J2 = 5.4, 1H, C(6)H), 7.94
(d, J = 7.8, 1H, C(7)H), 8.01 (s, 2H, NH2), 8.30 (d, J = 4.4, 1H, C(5)H)
4.16 (s, 3H, NCH3), 7.41 (m, 3H, Ar H), 7.49 (dd, J1 = 5.8, J2 = 4.4, 1H, C(6)H), 7.57
(t, J = 7.8, 2H, Ar H), 8.27 (d, J = 7.8, 1H, C(7)H), 8.62 (d, J = 5, 1H, C(5)H)
3.94 (s, 3H, NCH3), 4.50 (s, 2H, CH2Cl), 7.42 (dd, J1 = 5.4, J2 = 7.8, 1H, C(6)H), 8.19
(d, J = 8.3, 1H, C(7)H), 8.36 (d, J = 4.3, 1H, C(5)H), 13.45 (s, 1H, NH)
13C NMR: 32.2, 46.5, 64.3, 119.0, 119.6, 120.1, 125.7, 143.1, 144.6, 185.1
3.69 (s, 3H, NCH3), 3.85 (s, 2H, CH2 ), 6.14 (s, 2H, CH2 ), 7.12 (dd, J1 = 5.3, J2
= 7.8, 1H, C(6)H), 7.83 (d, J = 7.8, 1H, C(7)H), 8.25 (d, J = 4.4, 1H, C(5)H)
3.78 (s, 3H, NCH3), 6.40 (s, 1H, CH), 7.20 (dd, J1 = 4.8, J2 = 4.7, 1H, C(6)H), 7.53 (s,
1H, CH), 7.75 (m, 4H, Ar H), 7.95 (d, J = 1.3, 1H, C(7)H), 8.31 (d, J = 1.3, 1H,
C(5)H), 12.2 (br s, 1H, Ar OH)
10
14
16
18
CDCl3
DMSO-d6
DMSO-d6
DMSO-d6
22
23
DMSO-d6
DMSO-d6
26
30
DMSO-d6
DMSO-d6
3.85 (s, 3H, CH3), 4.52 (s, 2H, CH2), 7.33 (dd, J1 = 5, J2 = 7, 1H, C(3)H), 8.04 (d, J = 7.
1H, C(4)H), 8.23 (d, J = 5, 1H, C(2)H)
3.45 (s, 3H, NCH3), 3.86 (s, 3H, NCH3), 4.62 (s, 2H, CH2), 7.28 (dd, J1 = 4.7, J2 = 8.1H,
C(6)H), 8.03 (d, J = 7, 1H, C(7)H), 8.38 (d, J = 6, 1H, C(5)H)
at about 320 ◦C. This observation suggested the possibility of a cyclization. This was con-
firmed experimentally: a sample of compound 18 was heated at 250 ◦C for about 5 min (until
the decomposition was complete) and the product obtained after cooling was recrystallized
1
and investigated. Based on the IR, H NMR, and MS spectra, we established that com-
pound 18 loses a molecule of HCl at its melting temperature and undergoes intramolecular
cyclization to yield a new heterocyclic system, pyrrolo[2ꢁ,1ꢁ: 2,3]imidazo[4,5-b]pyridine 26
(Scheme 3). It is worth to note that according to 1H NMR data compound 23 exists in the
isomeric enole form (Table 1).
Scheme 3
In a further set of experiments, reaction of hydrazide 3 with methyl-, phenyl-, or
p-chlorophenyl isothiocyanate yielded the corresponding acyl-thiosemicarbazides 27–29.
Their cyclization in alkaline medium allowed us to prepare the 1,2,4-triazole derivatives
30–32.

SYNTHESIS OF SOME NEW IMIDAZO[4,5-B]PYRIDINE DERIVATIVES
883
Scheme 4
MICROBIOLOGY
The new compounds were tested in vitro for their tuberculostatic activity against My-
cobacterium tuberculosis H37Rv and two “wild” strains isolated from tuberculotic patients:
the 210 strain resistant to isoniazide (INH), p-aminosalicylic acid (PAS), ethambutol (ETB),
and rifampicine (RFP) as well as the 192 strain, fully susceptible to the drugs administered.
The investigations were performed by a classical test-tube method of successive dilution
with Youman‘s liquid medium containing 10% of bovine serum.3 The determined mini-
mum concentrations inhibiting the growth of tuberculous strains (MIC) for all the tested
compounds were within the limits 50–100 µg/mL, which indicates low tuberculostatic
activity. These results show that CH3 group in position 1 of the imidazopyridine ring does
not increase the tuberculostatic activity of the obtained compounds.
EXPERIMENTAL
Melting points were determinated with a Reichert apparatus and are uncorrected.
IR spectra: Termo Nicolet Satelite FT IR spectrophotometer (pellets in KBr). 1H and 13
C
NMR: Varian Gemini 200 spectrometer (200 MHz for 1H, 50 MHz for 13C) with TMS as
an internal standard; chemical shifts δ in ppm. MS spectra: Varian Mat 711 apparatus with
direct inlet; ionization energy 70 eV. The results of elemental analyses (C, H, N) for all
new compounds obtained were in agreement with the calculated values 0.4%. Physical
and spectral data of the synthesized compounds are given in Tables 1 and 2.
2-[(N-Substituted thiocarbamoyl)
cyanomethyl]-1-methyl-1H-imidazo[4,5-b]pyridines (4–9): General Procedure
◦
To a suspension of finely powdered KOH (5 mmol) in dry DMF (15 mL) at 0 C,
the nitrile 16 (5 mmol) and then the appropriate isothiocyanate (5 mmol) were added in

884

885

886
L. BUKOWSKI ET AL.
portions with stirring. The reaction mixture was stirred at room temperature for 3 h, then
poured into ice/water (150 mL) and acidified with 0.1 N HCl to pH 3–4. The resulting
precipitate was filtered off, dried, and recrystallized from the proper solvent (Table 2).
1-Methyl-1H-imidazo[4,5-b]pyridines (10–13): General Procedure
◦
To a cooled (0 C) suspension of finely powdered KOH (5 mmol) in dry DMF (15
mL), the nitrile 16 (5 mmol) and then methyl- or phenylisothiocyanate (5 mmol) were added
in portions with stirring. The reaction mixture was stirred at room temperature for 3 h, then
cooled again to 0 ◦C, treated with the appropriate dibromoalkane (5 mmol), and stirred at
room temperature for additional 3–5 h. After that time, the reaction mixture was poured
into ice/water (150 mL), the resulting product was filtered off, dried, and recrystallized
from the proper solvent (Table 2).
1-Methyl-1H-imidazo[4,5-b]pyridines (14,15): General Procedure
A mixture of nitrile 16 (5 mmol), finely powdered sulfur (5 mmol), and triethylamine
(5 mmol) in abs. EtOH (15 mL) was stirred at room temperature for 30 min. The proper
isothiocyanate (5 mmol) was then added gradually and stirring was continued for 20 min.
Next, the reaction mixture was refluxed with constant stirring for 2 h. After cooling, the
resulting precipitate was filtered off, washed with ether (2 × 3 mL), dried, and recrystallized
(Table 2).
2-(1-Methyl-1H-imidazo[4,5-b]pyridine-2-yl) Acetonitriles (16,17):
General Procedure
A mixture of nitrile 16 (2 mmol), nitrosobenzene or 4-nitroso-N,N-dimethylaniline (3
mmol), and piperidine (0,3 mL) in absolute ethanol (10 mL) was stirred at room temperature
for 4–5 h. The resulting solid was filtered off and recrystallized (Table 2).
Synthesis of Compounds 18–21: General Procedure
A cooled (0 ◦C–2 ◦C) suspension of finely powdered KOH (2 mmol) in dry DMF (10
mL) and nitrile 16 (2 mmol) was stirred for 30 min. Then a cooled solution of the appropriate
acid chloride (2 mmol) in DMF (1 mL) was added dropwise and stirring was continued for
1 h. After that time, the reaction mixture was further stirred at room temperature for 2 h,
and then, poured into ice/water (100 mL). The resulting precipitate was filtered off, dried,
and recrystallized (Table 2).
2-[(1-Methyl-1H-imidazo[4,5-b]pyridin-2-yl)methyl]-1,3-thiazol-4(5H)-one
(22)
Nitrile 16 (0.52 g, 3 mmol), thioglycolic acid (0.21 mL, 3 mmol), and phenyl ether
◦
◦
(0.5 g) were heated with stirring at 175 C–180 C for 8 min. The solid obtained after
cooling was washed with ether (2 × 5 mL) and recrystallized (Table 2).

SYNTHESIS OF SOME NEW IMIDAZO[4,5-B]PYRIDINE DERIVATIVES
887
Synthesis of 1,3-Thiazol-4(5H)-ones (23–25): General Procedure
To a suspension of compound 22 (2 mmol) and the appropriate aldehyde (2.5 mmol)
in anhydrous ethanol (10 mL), 0.3 mL of piperidine was added and the mixture was refluxed
with stirring for 3 h. The solid precipitated after cooling was filtered off and recrystallized
(Table 2).
5-Methyl-7-oxo-7,8-dihydro-5H-pyrrolo[2’,1’:2,3]imidazo[4,5-b]pyridine-
6-carbonitrile (26)
◦
Powdered compound 18 (0.5 g) was heated with stirring at 250 C for about 5 min
(until HCl evolution was complete). The solid obtained after cooling was washed with ether
(2 × 3 mL) and recrystallized (Table 2).
1-(1-Methyl-1H-imidazo[4,5-b]pyridin-2-yl-acetyl)-4-substituted
Thiosemicarbazides (27–29): General Procedure
To a solution of compound 36 (1.5 mmol) in methanol or anhydrous benzene
(10 mL), the appropriate isothiocyanate (1,6 mmol) was added and the reaction mix-
ture was refluxed with stirring for 3 h. The solid precipitated after cooling was filtered off
and dried (Table 2).
2,4-Dihydro-3H-1,2,4-triazol-3-thiones (30–32): General Procedure
A solution of the appropriate thiosemicarbazide (27–29) (2 mmol) in 4% aqueous
NaOH (6 mL) was refluxed for 1–2 h. Then the reaction mixture was cooled and acidified
with 15% aqueous HCl to a pH of 3–4. The resulting precipitate was filtered off, dried, and
recrystallized (Table 2).
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