Rapid synthesis of imidazo[4,5-b]pyridine containing polycyclics by means of palladium-catalyzed amidation of 2-chloro-3-nitropyridine

Article abstract of DOI:10.1016/j.tetlet.2009.04.031

Regioselective nucleophilic substitution of 2-chloro 3-nitropyridine with heterocyclic amides under Pd-catalyzed reaction conditions as described by Buchwald yielded imidazo [4,5-b] pyridine-containing polycyclics as novel scaffolds.

Full text of DOI:10.1016/j.tetlet.2009.04.031

Tetrahedron Letters 50 (2009) 3798–3800
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Rapid synthesis of imidazo[4,5-b]pyridine containing polycyclics by means
of palladium-catalyzed amidation of 2-chloro-3-nitropyridine
*
Christophe Salomé, Martine Schmitt , Jean-Jacques Bourguignon
Laboratoire d’Innovation thérapeutique, UMR 7200, Faculté de Pharmacie, 74 route du Rhin, BP 60024, 67401 Illkirch, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 February 2009
Revised 1 April 2009
Accepted 3 April 2009
Available online 14 April 2009
Regioselective nucleophilic substitution of 2-chloro 3-nitropyridine with heterocyclic amides under Pd-
catalyzed reaction conditions as described by Buchwald yielded imidazo [4,5-b] pyridine-containing
polycyclics as novel scaffolds.
Ó 2009 Elsevier Ltd. All rights reserved.
Substituted benzimidazoles and structurally related com-
pounds are of pharmacological and therapeutical interest.1 In some
cases, bioisosteric replacement within the benzimidazole scaffold
leading to imidazo[4,5-b]pyridines resulted in improved properties
as compared to the corresponding parent compound.2 Their prep-
aration resulted from reaction of a primary amine with 2-chloro-3-
nitropyridine 1. The resulting 2-aminopyridine intermediate was
N-acylated (method a). Finally, the N-acyl 2-amino pyridine 2
was reduced and submitted to cyclization after an activation step
involving a Brönsted1,3, or Lewis acid4 catalyst (Scheme 1).
This Letter presents a very straightforward method for prepar-
ing differently substituted imidazo [4,5-b] pyridines 4. The target
compounds mainly result from direct amidation (method b) of
the highly electrophilic 2-chloro-3-nitropyridine 1 with various
amides including primary, secondary, and cyclic amides using
Pd-coupling reactions, as described recently by Buchwald.5
More recently, Buchwald6,7 and co-workers reinvestigated the
N-arylation of heterocyclic compounds containing a NHCO-moiety
by using catalytic amounts of a commercially available copper
catalyst.8
by Buchwald within the aryl series, and were explained by steric
hindrance deriving from the cis–trans geometry of the deproto-
nated amide, and its capacity to complex the palladium.10 In con-
trary, cyclic amides, as secondary amides constrained in cis
amide geometry, were found to be highly reactive (entries 4–9).
However, the presence of a benzo ring in the dihydroquinolone
led to a dramatic decrease in reactivity (compare entries 5 and
10), as a result of electronic or steric effects of the N-phenylamide
system. A similar lack of activity was observed in the attempted N-
arylation of various NH amide heterocycles by copper-catalyzed
Ullmann condensation.8
The data listed in Table 1 highlighted specific electronic features
combined with steric effects, which may lead to some interesting
regio- or chemoselective N-arylation reactions. Various cyclic
amides including five (compounds 2d, 2f, 2g), six (compounds
2e, 2h, 2j), or seven (compound 2i) membered-ring systems were
NO2
method a
NO2
or
R1
Despite the poor nucleophilic character of amides, when re-
acted with aryl halides, the reaction could be extended to sulfona-
mides, carbamates, and ureas by means of Xantphos as ligand and
Cs2CO3 as the base in dioxane in the presence of Pd(OAc)2 or
N
N
method b
N
Cl
O
R2
1
2
5
Pd2(dba)3.
method a: i) amination; ii) N-acylation
method b: Buchwald reaction with amide
A first set of model reactions was performed with 1 in refluxing
dioxane under similar experimental conditions9 as described by
Buchwald5 (Table 1).
The yields were satisfactory with primary amides (R1 = H). Sur-
prisingly a dramatic drop in reactivity was found with N-methylac-
etamide (entry 3), as no reaction could be also observed with the
more electrophilic 2,6-dichloropyridine. Similar results were found
NH2
R1
N
Activation step
Cyclisation
R2
N
N
N
R1
N
O
R2
3
4
* Corresponding author.
E-mail address: schmitt@pharma.u-strasbg.fr (M. Schmitt).
Scheme 1. Preparation of imidazo [4,5-b] pyridines 4.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.031

C. Salomé et al. / Tetrahedron Letters 50 (2009) 3798–3800
3799
Table 1
NO2
O
N
N
i), ii)
NO2
NO2
Cl
i)a
N
N
N
R1
R2
N
N
N
2d-j
4d-j
O
N
N
1
2
N
N
O
Entry
R2CONHR1
R2
Compd
Yieldb (%)
N
N
N
R1
O
1
2
3
H
H
Me
Me
Ph
Me
2a
2b
2c
82
4i, 85%a
4h, 65%a
65
n.r.c
a) i)+ii)cumulative yield after purification
A
Scheme 3. Easy access to novel polyheterocyclic compounds. (i) Fe/NH4Cl, EtOH,
H2O, (ii) SiCl4, CH2Cl2 -waves, 10 min, 180 °C.
O
l
N
H
4
5
6
7
A = CH2
2d
2e
2f
80d
72
90
60
Lewis catalyst.4 However, the reaction needed long reaction times
(1–4 days) to complete the cyclization. This reaction could be also
performed in 10 min after exposure to microwave irradiation at
180 °C. The overall yields (reduction and cyclization) was satisfac-
tory to good (55–90%).12
A = (CH2)2
A = O
A = NMe
2g
O
O
N
8
2h
2i
60
Finally, depending on the amide-containing heterocycle (mono-
or bicyclic compound), various imidazo pyridine-fused polycyclic
compounds could be easily obtained in good yield. As typical
examples given in Scheme 3, the preparation of the tricyclic imi-
dazo pyridine 4h constituted an interesting ‘umpolung approach’
of the recently described13 Buchwald reaction of 2-chloro-3-iodo-
pyridine (instead of 1 in our method) and 2-aminopyridine (in-
stead of 3-methoxypyridin-2(1H)-one (entry 8) in our example)
leading to a common dipyrido imidazole system (compound 4h).
Also, in another example involving an NH-amide bicycle (entry
9), the resulting tetracyclic compound 4i could be prepared in good
overall yield. A similar strategy may be extended to larger polycy-
clic compounds possessing a common fused imidazole ring at the
junction of both reagents.
In conclusion, the search of novel polyheterocyclic scaffolds
useful in medicinal chemistry led us to develop a methodology
involving a highly electrophilic heteroarylchloride (i.e., 2-chloro-
3-nitropyridine 1) and various free NH-amide heterocycles includ-
ing mono- and bicyclic systems. The reaction only needed two sep-
arate reaction steps, and generally the expected compound was
obtained in satisfactory overall yield and possessed some addi-
tional functionalities for further substitutions.
N
H
O
9
85
NH
O
10
2j
n.r.c
N
H
O
a
Pd(OAc)2/Xantphos, Cs2CO3, dioxane (100 °C, 16 h).9
Non-optimized yields.
b
c
n.r. no reaction.
d
The reaction performed in similar experimental conditions (a), but without Pd/L
catalysts gave less than 10% of 2d.
efficiently N-substituted under these conditions, even if they were
presenting strong aromatic character (compound 2h). In particular
the very low reactivity of N-arylamide-containing heterocycles
toward N-aryl substitution was observed in general (see entry
10). Surprisingly, the Buchwald reaction described here showed
interesting regioselectivity, as illustrated by reaction of 1 with free
NH-diamide heterocycles (see Scheme 2). When reacted with 1,
1,4-benzodiazepin-2,5-dione 5 yielded a single regioisomer (com-
pound 6) in the reaction mixture. This result is in good agreement
with the lack of reactivity observed with another cyclic N-phenyla-
mide (see entry 10 in Table 1)
Acknowledgment
Financial support from Neuro3D is gratefully acknowledged.
Supplementary data
The nitro intermediates 2 were quantitatively reduced by
means of iron in presence of ammonium chloride in a mixture of
ethanol and water. The resulting crude amino intermediate was
further submitted to cyclization using SiCl4 as an efficient, low-cost
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.04.031.
References and notes
1. Arvanitis, A.; Rescinito, J. T.; Arnold, C. R.; Wilde, R. G.; Cain, G. A.; Sun, J. H.;
Yan, J.-S.; Teleha, C. A.; Fitzgerald, L. W.; McElroy, J.; Zaczek, R.; Hartig, P. R.;
Grossman, S.; Arneric, S. P.; Gilligan, P. J.; Olson, R. E.; Robertson, D. W. Bioorg.
Med. Chem. Lett. 2003, 13, 125–128.
2. Janssens, F.; Torremans, J.; Janssen, M.; Stokbroekx, R.; Luyckx, M.; Janssen, P. J.
Med. Chem. 1985, 28, 1943–1947.
3. Chang, L. C. W.; von Frijtag Drabbe Kunzel, J. K.; Mulder-Krieger, T.;
Westerhout, J.; Spangenberg, T.; Brussee, J.; IJzerman, A. P. J. Med. Chem.
2007, 50, 828–834.
N
H
O
O
N
1
N
NO2
NH
i)
N
O
H
O
5
6, 52%
4. Désaubry, L.; Wermuth, C.; Bourguignon, J.-J. Tetrahedron Lett. 1995, 36, 4249–
4252.
5. Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043–6048.
Scheme 2. Regio- and chemoselectivity of the reaction. (i) Pd(OAc)2/Xantphos,
Cs2CO3, dioxane (100 °C), 16 h.11

3800
C. Salomé et al. / Tetrahedron Letters 50 (2009) 3798–3800
6. Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 7421–7428.
7. Zheng, N.; Buchwald, S. L. Org. Lett. 2007, 9, 4749–4751.
8. Sugahara, M.; Ukita, T. Chem. Pharm. Bull. 1997, 45, 719.
J = 8.0 Hz, J = 4.7 Hz, ArH), 7.56 (td, 1H, J = 8.1 Hz, J = 1.4 Hz, PhH), 7.98 (dd, 1H,
J = 7.8 Hz, J = 1.4 Hz, PhH), 8.33 (dd, 1H, J = 8.0 Hz, J = 1.5 Hz, ArH), 8.51 (br, 1H,
NH), 8.75 (dd, 1H, J = 4.7 Hz, J = 1.5 Hz, ArH); 13C NMR (75 MHz, CDCl3): d
(ppm) 49.7 (CH2CO), 120.6, 122.1, 124.6, 124.8, 131.9, 133.0, 133.1, 135.9,
141.7 (CNO2), 145.3, 151.8, 166.7 (CO), 169.1 (CO); HRMS: m/z (APCI) 299.0780
(MH+ C14H10N4O4H+ requires 299.0780).
9. Supplementary data available: Experimental procedures and spectral data. This
material is available free of charge.General procedure for the Buchwald reaction
with the 2-chloro-3-nitropyridine: In a flame-dried Schlenk tube, palladium
acetate (0.016 mmol, 0.05 equiv), Xantphos (0.032 mmol, 0.1 equiv), and
Cs2CO3 (0.480 mmol, 1.5 equiv) were introduced under Argon. The Schlenk
tube was purged few minutes with Ar. A solution of 2-chloro-3-nitropyridine
(1) (0.320 mmol, 1 equiv) and amide (0.384 mmol, 1.2 equiv) in dioxane (1 mL)
was added. The Schlenk tube was purged 3 times with Ar. The mixture was
stirred at 100 °C (16 h). The solution was filtered through a pad of Celite. The
pad was washed with CH2Cl2. Water (5 mL) was added and the layers were
separated. The aqueous layer was washed with EtOAc (3 ꢀ 50 mL). The organic
layers were combined, dried (MgSO4), filtered, and concentrated under
vacuum. The residue was purified by silica gel column chromatography
(Heptane/EtOAc) to obtain the desired compounds. 1-Methyl-3-(3-nitro-
12. General procedure for the formation of imidazo[4,5-b]pyridine derivatives (4a–j):
NH4Cl (1.27 mmol, 0.6 equiv) and iron (6.36 mmol, 3 equiv) were added to a
stirring solution of the 3-nitropyridine derivatives (2a–i and 6) (2.12 mmol,
1 equiv) in EtOH/H2O (2 mL/2 mL). The mixture was stirred at 80 °C (2 h). The
mixture was filtered through a pad of Celite. The pad was washed with CH2Cl2.
The organic layers were combined, dried (MgSO4), and the solvents were
evaporated under vacuum. The residue was solubilized in CH2Cl2 (5 mL) and
the solution was introduced into a
l-wave tube and then triethylamine was
added (8.48 mmol, 4 equiv) followed by SiCl4 (5.30 mmol, 2.5 equiv). The
solution was microwave heated at 110 °C (15 min) with stirring. The reaction
was quenched by addition of an aqueous saturated solution of NaHCO3. The
aqueous layer was extracted three times with CH2Cl2 (3 ꢀ 50 mL). The organic
layers were combined, dried (MgSO4), filtered, and concentrated under
vacuum. The residue was purified by silica gel column chromatography
(cyclohexane/EtOAc) to obtain the imidazo[4,5-b]pyridine derivatives. 6-
Methoxy-dipyrido[1,2-a;30,20-d]imidazole (4h); white solid; TLC/Rf = 0.47
(EtOAc); Yield: 65%; 1H NMR (300 MHz, CDCl3): d (ppm) 4.11 (s, 3H, OCH3),
6.78 (d, 1H, J = 6.9 Hz, PhH), 7.49 (t, 1H, J = 6.9 Hz, PhH), 7.51 (dd, 1H, J = 8.3 Hz,
J = 4.5 Hz, ArH), 8.25 (dd, 1H, J = 8.3 Hz, J = 1.3 Hz, ArH), 8.46 (d, 1H, J = 6.9 Hz,
PhH), 8.51 (d, 1H, J = 4.5 Hz, ArH); Dept-135 13C NMR (75 MHz, CDCl3): d (ppm)
56.0 (CH3), 105.9, 111.0, 116.8, 121.5, 127.7, 142.6; LRMS: m/z (APCI) 200.0
pyridin-2-yl)-imidazolidin-2-one
(2g);
yellow
solid;
TLC/Rf = 0.37
(cyclohexane/EtOAc 7/3); Yield : 60%; 1H NMR (300 MHz, CDCl3): d (ppm)
2.93 (s, 3H, NCH3), 3.61 (t, 2H, J = 7.4 Hz, CH2NMe), 4.15 (t, 2H, J = 7.4 Hz, CH2N),
7.16 (dd, 1H, J = 8.0 Hz, J = 4.7 Hz, ArH), 8.18 (dd, 1H, J = 8.0 Hz, J = 1.6 Hz, ArH),
8.50 (dd, 1H, J = 4.7 Hz, J = 1.6 Hz, ArH); 13C NMR (75 MHz, CDCl3): d (ppm) 30.8
(CH3), 42.1 (CH2N), 43.7 (CH2NMe), 118.3, 133.5, 138.5, 144.4, 150.6, 156.2
(CO); LRMS: m/z (APCI) 223.0 (MH+. C9H10N4O3H+ requires 223.0).
10. Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2(8), 1101–1104.
11. Preparation of 4-(3-nitropyridin-2-yl) -3,4-dihydro-1H-benzo[e] [1,4]diazepine-
2,5-dione (6): In a flame-dried Schlenk tube, palladium acetate (0.016 mmol,
0.05 equiv), Xantphos (0.032 mmol, 0.1 equiv), and Cs2CO3 (0.480 mmol,
1.5 equiv) were introduced under Ar. The Schlenk tube was purged few
(MH+.
dibenzo[a,e]azulen-6-one (4i); brown solid; TLC/Rf = 0.17 (EtOAc); Yield:
85%; 1H NMR (300 MHz, CDCl3):
(ppm) 3.41–3.46 (m, 4H, NMe and
C11H10N3O
requires
200.0).
5-Methyl-5H-5,7a,8,12-tetraaza-
minutes with Ar.
A
solution of 2-chloro-3-nitropyridine (1) (0.320 mmol,
d
1 equiv) and 5 (0.384 mmol, 1.2 equiv) in dioxane (1 mL) was added. The
mixture was stirred at 100 °C (16 h). The solution was filtered through a pad of
Celite. The pad was washed with CH2Cl2. The organic layers were combined
and the solvents were evaporated. The residue was purified by silica gel
column chromatography (cyclohexane/EtOAc 4/6 to EtOAc) to obtain the
coupled compound as a yellowish solid; TLC/Rf = 0.16 (Cyclohexane/EtOAc 4/
6); mp 231–232 °C; Yield: 52%; 1H NMR (300 MHz, CDCl3): d (ppm) 4.77 (s, 2H,
NCH2CO), 7.08 (d, 1H, J = 8.1 Hz, PhH), 7.31 (t, 1H, J = 7.8 Hz, PhH), 7.46 (dd, 1H,
CHH0N), 3.49 (d, 1H, J = 6.7 Hz, CHH0N), 7.33 (dd, 1H, J = 8.2 Hz, J = 4.8 Hz,
ArH), 7.47 (m, 2H, PhH), 7.66 (td, 1H, J = 7.8 Hz, J = 1.6 Hz, PhH), 8.16 (m, 2H,
ArH and PhH), 8,45 (dd, 1H, J = 4.8 Hz, J = 1.4 Hz, ArH); 13C NMR (75 MHz,
CDCl3): d (ppm) 37.1 (CH3), 44.1 (CH2), 118.9, 122.9, 126.2, 127.4, 130.3, 131.7,
134.9, 140.1, 144.2, 159.8 (C imid), 165.9 (CO); LRMS: m/z (APCI) 265.0 (MH+.
C15H12N4OH+ requires 265.29).
13. Loones, K. T. J.; Maes, B. U. W.; Dommisse, R. A.; Lemière, G. Chem. Commun.
2004, 2466–2467.