Synthesis of a new imidazo[4,5-b]pyridin-5-one via a vicarious nucleophilic substitution of hydrogen

Article abstract of DOI:10.3987/com-04-10069

A new imidazo [4,5-b]pyridin-5-one was prepared in five steps from 4(5)-nitro-1H-imidazole via a vicarious nucleophilic substitution of hydrogen of 1-benzyl-4-nitro-1H-imidazole with the carbanion generated from chloroform and potassium tert-butoxide. Hydrolysis of 1-benzyl-5-dichloromethyl-4-nitro-1H- imidazole and Knoevenagel condensation between the resulting aldehyde and diethyl malonate catalyzed by titanium(IV) chloride gave the corresponding 4-nitroimidazole bearing at 4 position the diethyl methylenemalonate group. Reduction and cyclization afforded the required ethyl 1-benzyl-5-oxo-4,5- dihydro-1H-imidazo[4,5-b]pyridine-6-carboxylate.

Full text of DOI:10.3987/com-04-10069

HETEROCYCLES, Vol. 63, No. 7, 2004, pp. 1629 - 1635
Received, 10th March, 2004, Accepted, 21st May, 2004, Published online, 21st May, 2004
SYNTHESIS OF A NEW IMIDAZO[4,5-b]PYRIDIN-5-ONE VIA A
VICARIOUS NUCLEOPHILIC SUBSTITUTION OF HYDROGEN
Maxime D. Crozet, Clément Suspène, Mustapha Kaafarani, Michel P. Crozet,
and Patrice Vanelle*
Laboratory of Pharmaceutical Organic Chemistry, CNRS UMR 6517, University
of the Méditerranée (Aix–Marseille 2), Faculty of Pharmacy, 27 Bd Jean Moulin,
13385 Marseille cedex 5, France. FAX +33 (0) 4 91 79 46 77. E-mail:
patrice.vanelle@pharmacie.univ-mrs.fr
Abstract – A new imidazo[4,5-b]pyridin-5-one was prepared in five steps from
4(5)-nitro-1H-imidazole via a vicarious nucleophilic substitution of hydrogen of
1-benzyl-4-nitro-1H-imidazole with the carbanion generated from chloroform and
potassium tert-butoxide. Hydrolysis of 1-benzyl-5-dichloromethyl-4-nitro-1H-
imidazole and Knoevenagel condensation between the resulting aldehyde and
diethyl malonate catalyzed by titanium(IV) chloride gave the corresponding
4-nitroimidazole bearing at 4 position the diethyl methylenemalonate group.
Reduction and cyclization afforded the required ethyl 1-benzyl-5-oxo-4,5-dihydro-
1H-imidazo[4,5-b]pyridine-6-carboxylate.
INTRODUCTION
1,2
In continuation of our studies of the reactivity of sulfonyl carbanions in electron transfer reactions and as
part of a program directed to the synthesis of new pyridinones of pharmaceutical interest for the treatment
of insomnia, anxiety, schizophrenia and Alzheimer's disease, we have recently disclosed, from
nitroheterocyclic sulfones prepared by vicarious nucleophilic substitution of hydrogen, a new synthetic
approach involving a direct Julia olefination between the anions of 1,2-dialkyl-4-phenylsulfonylmethyl-
5-nitro-1H-imidazoles and diethyl ketomalonate, which affords, in a one-pot reaction, original
5-nitroimidazoles bearing the diethyl methylenemalonate group at 4 position.3 (Figure 1)

CH3CH2O2C
H
CO2CH2CH3
O2S
CO2CH2CH3
CO2CH2CH3
N
N
Direct Julia olefination
+
O C
R2
R2
O2N
O2N
N
N
R1
R1
Figure 1. Synthesis of diethyl 2-(1,2-dialkyl-5-nitro-1H-imidazol-4-ylmethylene)malonates by direct Julia
olefination.
Unfortunately, in 4-nitroimidazole series, 5-benzenesulfonylmethyl-1-methyl-4-nitro-1H-imidazole4 (R1 =
CH3, R2 = H) and 5-benzenesulfonylmethyl-1,2-dimethyl-4-nitro-1H-imidazole4 (R1 = CH3, R2 = CH3)
prepared by vicarious nucleophilic substitution of hydrogen were found to be unreactive in this direct
olefination with diethyl ketomalonate, probably for steric hindrance of nitro and methyl groups (Figure 2).
O2N
SO2
Direct Julia
olefination
X
O2N
N
CO2CH2CH3
CO2CH2CH3
N
H
+
O C
R2
R2
N
N
R1
R1
CO2CH2CH3
CH3CH2O2C
Figure 2. Failure of the direct Julia olefination in 4-nitroimidazole series.
Thanks again to vicarious nucleophilic substitution of hydrogen, the preparation of a 4-nitroimidazole
bearing the diethyl methylenemalonate group at 5 position seemed possible via a vicarious nucleophilic
substitution of hydrogen with chloroform from 2, hydrolysis of the dichloromethyl derivative (3) in
aldehyde (4) and Knoevenagel condensation with diethyl malonate affords the desired compound (5) as
described in the Scheme.
RESULTS AND DISCUSSION
Herein, we describe the synthesis of 5 (Scheme) starting from the commercially available
4(5)-nitro-1H-imidazole (1) and the preparation of the firstly required ethyl 1-benzyl-5-oxo-4,5-dihydro-
1H-imidazo[4,5-b]pyridine-6-carboxylate (6) (Scheme). Condensation of 1 with benzyl chloride in a
mixture of acetic acid and DMF at 140 °C gave the expected 1-benzyl-4-nitro-1H-imidazole (2)5 in 27%
yield. Treatment of 1 with benzyl chloride in DMF in presence of K2CO3 at 75 °C during 4 h was also tried.
Contrary to Chen and coworkers,6 in our hands, under the same experimental conditions, we got a

compound in 67% yield, which is the 1-benzyl-4-nitro-1H-imidazole (2) and not the
1
1-benzyl-5-nitro-1H-imidazole obtained by Chen and coworkers. The H NMR spectral data and the
melting point of 2 are in agreement with the literature.7-9
O2N
O2N
N
N
N
O2N
i
ii
Cl
Cl
H
H
H
N
N
N
H
1
2
3
H
N
O
O2N
O2N
N
N
N
H
iii
iv
v
CH3CH2O2C
H
H
H
N
N
N
CH3CH2O2C
CH3CH2O2C
O
6
4
5
Scheme. Reagents and conditions: (i) C6H5CH2Cl, K2CO3, DMF, 75 °C, 4 h (67%). (ii) t-BuOK,
THF-DMF, -78 °C, CHCl3, N2, 10 min, CH3COOH-CH3OH (72%). (iii) HCOOH-H2O, 115 °C, 18 h (90%).
(iv) THF, TiCl4/ CH2Cl2, addition of 4, CH2(CO2CH2CH3)2, Pyridine, rt, 12 h, N2 (59%). (v) Iron powder
(14 eq.), CH3CO2H, reflux, 20 min (36%).
This result was expected because it is well established that 1-alkyl-4-nitro-1H-imidazoles are obtained from
4(5)-nitro-1H-imidazoles and alkyl halides in basic media.10,11 Vicarious nucleophilic substitution of
hydrogen of 2 with the anion generated from chloroform and potassium tert-butoxide at -78 °C afforded
1-benzyl-5-dichloromethyl-4-nitro-1H-imidazole (3)11 in 72% yield. The structure of 3 was confirmed by
X-Ray analysis (Figure 3).
Figure 3. ORTEP plot of the 1-benzyl-5-dichloromethyl-4-nitro-1H-imidazole (3).

Hydrolysis of 3 with formic acid gave the aldehyde (4)12 in 90% yield. The condensation of 4 with diethyl
malonate anion formed from diethyl malonate by NaH in DMSO failed as the reaction of 4 with diethyl
malonate in presence of piperidine in ethanol at reflux. The low reactivity of such an aldehyde in
Knoevenagel condensation has been reported by Perandones.13 Indeed, 5-amino-2,3-dimethyl-3H-
imidazole-4-carbaldehyde after 10 h at reflux of methanol with diethyl malonate and sodium methoxide
was found to be unreactive and the formation of the expected ethyl 1,2-dimethyl-5-oxo-4,5-dihydro-
1H-imidazo[4,5-b]pyridine-6-carboxylate was not observed. In contrast, the Knoevenagel reaction of 4
with diethyl malonate catalyzed by TiCl4/pyridine14,15 gave the desired diethyl 2-(3-benzyl-5-nitro-
3H-imidazol-4-ylmethylene)malonate (5) in 59% yield.
Finally, treatment of 5 with an excess of iron powder in glacial acetic acid at reflux afforded the target
molecule of this work, the ethyl 1-benzyl-5-oxo-4,5-dihydro-1H-imidazo[4,5-b]pyridine-6-carboxylate (6),
in 36% yield (Scheme).
Further functional group transformations of 6 could give new imidazo[4,5-b]pyridin-5-one derivatives of
13,16,17
pharmaceutical interest.
In conclusion, the previously unknown diethyl 2-(3-benzyl-5-nitro-3H-imidazol-4-ylmethylene)malonate
(5) can be prepared from 4(5)-nitro-1H-imidazole via a vicarious nucleophilic substitution of hydrogen.
Reduction and cyclization afforded the required ethyl 1-benzyl-5-oxo-4,5-dihydro-1H-
imidazo[4,5-b]pyridine-6-carboxylate (6). The imidazopyridinone is formed in only five steps from
commercially available 4(5)-nitro-1H-imidazole, thus providing a new synthetic approach to this
heterocyclic series with potential applications in medicinal chemistry.
EXPERIMENTAL
General Methods. Melting points were determined with a B-540 Büchi melting point apparatus. 300 MHz
1
13
H NMR and 75.4 MHz C NMR spectra were recorded on a Bruker Avance DPX 300 in CDCl or
3
DMSO-d solution at the Centre Régional de RMN de la Faculté des Sciences et Techniques de
6
1
13
Saint-Jérôme. H and C NMR chemical shifts (δ) are reported in ppm with respect to CHCl3 7.26 ppm
1
13
( H) and 77.16 ppm ( C). Elemental analyses were carried out at the Centre de Microanalyses de la
Faculté des Sciences et Techniques de Saint-Jérôme. X-Ray analysis was carried out at the Laboratoire de
Cristallochimie, UMR CNRS 6517, Faculté des Sciences et Techniques de Saint-Jérôme.
1-Benzyl-4-nitro-1H-imidazole (2). Following the procedure described in the reference 5, 2 was obtained
in 27% yield. Following the procedure described in the reference 6, 2 was obtained in 67% yield. The
analytical sample of 2 was obtained as a white solid by crystallization (diethyl ether/chloroform 3:1), mp
1
1
74 °C. H NMR (CDCl3) δ 5.10 (s, 2H, CH ); 7.10-7.35 (m, 5H); 7.48 (s, 1H), 7.68 (s, 1H). H NMR
2

(DMSO-d6) δ 5.32 (s, 2H, CH ); 7.39 (s, 5H); 8.01 (s, 1H); 8.50 (s, 1H). 13C NMR(DMSO-d6) δ 52.4 (CH2);
2
123.2 (CH); 129.6 (2xCH); 130.0 (CH); 130.6 (2xCH); 137.9 (C); 139.1 (CH); 148.9 (C).
1-Benzyl-5-dichloromethyl-4-nitro-1H-imidazole (3). Following the procedure described in the
reference 6, 3 was obtained after flash column chromatography of the crude product on silica gel
(AcOEt/Hexane 1:3) in 72% yield. The analytical sample of 3 was obtained as a white solid by
1
crystallization (hexane/chloroform), mp 82 °C. H NMR (CDCl3) δ 5.62 (s, 2H, CH2); 7.27-7.48 (m, 5H);
7.78 (s, 1H); 8.03 (s, 1H). 13C NMR (CDCl3) δ 51.7 (CH2); 58.7 (CHCl2); 127.6 (CH); 128.8 (2xCH); 129.7
(C); 129.8 (2xCH); 133.2 (C); 137.9 (CH). The C-NO was not observed under these experimental
2
conditions. Anal. Calcd for C11H9N3O2Cl2: C. 46.18; H. 3.17; N. 14.69. Found: C. 46.05; H. 3.16; N. 14.67.
Data of X-Ray analysis.
Suitable crystals for X-Ray analysis were obtained by slow evaporation from a solution of chloroform at
room temperature. Crystal size: 0.6x 0.5x 0.4 mm. Crystal color: colorless. Crystal description: prism.
Crystal data for C11H9N3O2Cl2: Mr = 286.11, orthorhombic, space group P n a 21, a = 9.3810 (2) Å, b =
-3
22.6750 (5) Å, c = 5.9420 (10) Å, V = 1263.9(2) Å3, Z = 4, Dc = 1.504 Mg m , θ range for measured
-1
reflections θ = 2.35-26.33°, µ = 0.510 cm , F(000) = 584, T = 293(2) K. Bruker-Nonius KappaCCD
diffractometer,18 data collected using Mo-Κα radiation (λ = 0.71073 Å). The structure was solved by direct
methods (SHELX97)19 followed by full-matrix least-squares refinement (SHELXL97) on F2 to final
2
2
2
2
indices R1 = 0.035 [F0 > 4σ (F0 )] and wR2 = 0.091 [w = 1/[σ2(F0 ) + (0.0446P)2 + 0.3989P] where P = (F0
-
+ 2Fc2)/3. Final Fourrier peaks: ρ+ = 0.226, ρ = -0.169.
CCDC 236135 contains the supplementary crystallographic data for this paper. These data can be obtained
free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge Crystallographic Data
Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: (internat.) +44-1223/336-033; E-mail:
deposit@ccdc.cam.ac.uk].
3-Benzyl-5-nitro-3H-imidazole-4-carbaldehyde (4). A solution of 1 g (3.5 mmol) of 3 in formic acid (15
mL) and water (5 mL) was stirred at 115 °C for 18 h. After cooling, the solution was extracted with
dichloromethane and dried (MgSO4), filtered and concentrated in vacuo to give 4 (0.727 g) in 90% yield.
1
The analytical sample of 4 was obtained as a orange solid by crystallization (chloroform), mp 85 °C. H
NMR (CDCl3), δ 5.50 (s, 2H, CH2); 7.15-7.19 (m, 2H); 7.31-7.40 (m, 3H); 7.50 (s, 1H); 10.42 (s, 1H). 13C
NMR (CDCl3) δ 52.3 (CH2); 127.4 (C); 128.4 (2xCH); 129.5 (CH); 129.7 (2xCH); 134.0 (CH); 139.3 (C);
145.8 (C); 181.9 (C=O). Anal. Calcd for C11H9N3O3: C. 57.14; H. 3.92; N. 18.17. Found: C. 57.30; H. 4.06;
N. 18.29.
Diethyl 2-(3-benzyl-5-nitro-3H-imidazol-4-ylmethylene)malonate (5). Titanium(IV) chloride in
dichloromethane (0.63 mL) was added dropwise to anhydrous THF (25 mL) under N2 and the stirred

mixture was cooled in ice-bath. After 15 min, 0.380 g (2.26 mmol) of 4 in anhydrous THF (4 mL) and
diethyl malonate (0.362 g; 2.26 mmol) in anhydrous THF (4 mL) were added. After 5 min, pyridine (0.8
mL, 10 mmol) in anhydrous THF (3 mL) was added dropwise and the reaction mixture was allowed to
warm to ambient temperature and was stirred 12 h. The reaction was quenched with H2O (6 mL) and Et2O
(6 mL), the organic layer was separated and the aqueous layer extracted with Et2O (2x25 mL). The
combined organic layer was washed with a saturated NaHCO3 solution (2x25 mL), dried (MgSO4), and
evaporated. The crude product was purified by column chromatography eluting with chloroform/acetone
(95:5) to give 5 as solid (0.470 g) in 59% yield. The analytical sample of 5 was obtained as a brown solid by
1
crystallization (isopropanol), mp 116.4 °C. H NMR (CDCl3) δ 1.11 (t, J = 7.2 Hz, 3H, CH3); 1.27 (t, J =
7.2 Hz, 3H, CH3); 4.08 (q, J = 7.2 Hz, 2H, CH2); 4.24 (q, J = 7.2 Hz, 2H, CH2); 5.04 (s, 2H); 7.07-7.10 (m,
5H); 7.45 (s, 1H); 7.46 (s, 1H). 13C NMR (CDCl3) δ 14.1 (CH3); 14.3 (CH3); 51.0 (CH2); 62.4 (CH2); 62.6
(CH2); 125.3 (C); 128.1 (2xCH); 129.5 (CH); 129.6 (CH); 129.7 (2xCH); 133.6 (C); 135.3 (C); 136.7 (CH);
162.9 (C=O); 163.7 (C=O). The C-NO2 was not observed under these experimental conditions. Anal. Calcd
for C18H19N3O6: C, 57.90; H, 5.13; N, 11.25. Found: C, 58.07; H, 5.19; N, 10.77.
Ethyl 1-benzyl-5-oxo-4,5-dihydro-1H-imidazo[4,5-b]pyridine-6-carboxylate (6). A solution of 5, 0.15
g (0.4 mmol) in glacial acetic acid (6 mL) was stirred and refluxed. To this refluxing solution 0.31 g (5.62
atom/g) of iron powder was added portionwise and the mixture was refluxed for 20 min. After cooling the
solution was filtered through celite and celite was washed with glacial acetic acid. The acetic acid solution
was then evaporated on a rotary evaporator and the residue basified with a saturated Na2CO3 solution. The
aqueous layer was extracted with chloroform. The combined organic layer was dried (MgSO4), and
evaporated to give 6 (0.042 g) in 36% yield. The analytical sample of 6 was obtained as a white solid by
1
crystallization (isopropanol), mp 205-206 °C. H NMR (CDCl3) δ 1.40 (t, J = 7.3 Hz, 3H, CH3); 4.42 (q, J
= 7.3 Hz, 2H, CH2); 5.35 (s, 2H); 7,35-7.40 (m, 5H); 8.12 (s, 1H), 8.14 (s, 1H), 11.34 (s, 1H). 13C NMR
(CDCl3) δ 14.5 (CH3); 50.1 (CH2); 62.4 (CH2); 104.9 (C); 121.2 (CH); 123.39 (CH); 127.6 (2xCH); 129.2
(CH); 129.6 (2x CH); 134.5 (C); 148.6 (C); 158.2 (C); 162.7 (C=O); 169.3 (C=O). Anal. Calcd for
C16H15N3O3: C, 64.64; H, 5.09; N, 14.13. Found: C, 64.67; H, 5.28; N, 14.08.
ACKNOWLEDGEMENTS
This paper is dedicated to Prof. Mieczyslaw Makosza on the occasion of his 70th anniversary.
This work was supported by the CNRS and the University of the Méditerranée. M. D. Crozet thanks the
Ministery of National Education for a student research fellowship and the Paul Cézanne University
(Aix-Marseille 3) for an ATER appointment. The authors thank Dr M. Giorgi, Laboratoire de
Cristallochimie, UMR CNRS 6517, for X-Ray diffraction data and structure analysis.

REFERENCES AND NOTES
1. M. D. Crozet, P. Perfetti, M. Kaafarani, P. Vanelle, and M. P. Crozet, Tetrahedron Lett., 2002, 43,
4127.
2. M. D. Crozet, P. Vanelle, M. Giorgi, and A. Gellis, Acta Cryst., 2002, C58, 496.
3. M. D. Crozet, P. Perfetti, M. Kaafarani, M. P. Crozet, and P. Vanelle, Lett. Org. Chem., 2004, in press.
4. M. Makosza and E. Kwast, Bull. Acad. Pol. Sci., Ser. Sci Chem., 1987, 35, 287.
5. A. K. S. B. Rao, C. G. Rao, and B. B. Singh, J. Chem. Soc., Perkin Trans. 1, 1994, 2399.
6. B.-C. Chen, S. T. Chao, J. E. Sundeen, J. Tellew, and S. Ahmad, Tetrahedron Lett., 2002, 43, 1595.
7. A. Tallec, R. Hazard, J. Suwinski, and P. Wagner, Pol. J. Chem., 2000, 74, 1177.
8. M. Searcey, P. L. Pye, and J. B. Lee, Synth. Commun., 1989, 19, 1309.
9. C. Cosar, C. Crisan, R. Horclois, R. M. Jacob, J. Robert, S. Tchelitcheff, and R. Vaupré,
Arzneim.-Forsch./Drug Res., 1966, 16, 23.
10. A. K. S. B. Rao, C. G. Rao, and B. B. Singh, Synth. Commun. 1991, 21, 427 and references therein.
11. M. Makosza and Z. Owczarczyk, J. Org. Chem., 1989, 54, 5094.
12. S. Ostrowski, Pol. J. Chem. 1994, 68, 2237.
13. F. Perandones and J. L. Soto, J. Heterocycl. Chem., 1997, 34, 107.
14. W. Lehnert, Tetrahedron, 1973, 29, 635.
15. S. F. Wnuk, E. Lewandowska, C. A. Valdez, and S. Kinastowski, Tetrahedron, 2000, 56, 7667.
16. G. Tennant, C. J. Wallis, and G. W. Weaver, J. Chem. Soc., Perkin Trans. 1, 1999, 827.
17. A. H. M. Al-Shaar, R. K. Chambers, D. W. Gilmour, D. J. Lythgoe, I. McClenaghan, and C. A.
Ramsden, J. Chem. Soc., Perkin Trans. 1, 1992, 2789.
18. Nonius (1998). KappaCCD Reference Manual. Nonius B. V., P.O. Box 811, 2600 Av, Delft, The
Netherlands.
19. G. M. Sheldrick, (1997). SHELXL97. Program for the refinement of crystal structures. University of
Göttingen, Germany.