A simple two-step access to diversely substituted imidazo[4,5-b]pyridines and benzimidazoles from readily available 2-imidazolines

Article abstract of DOI:10.1016/j.tetlet.2013.04.036

We discovered a facile rearrangement of N-(hetero)aryl 2-imidazolines into diversely substituted imidazo[4,5-b]pyridines and benzimidazoles, under Bechamp reduction conditions. Combined with the earlier reported protocol for Pd-catalyzed (hetero)arylation of 2-imidazolines, it provides a simple two-step access to a range of compounds based on these medicinally important heterocyclic cores.

Full text of DOI:10.1016/j.tetlet.2013.04.036

Tetrahedron Letters 54 (2013) 3336–3340
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A simple two-step access to diversely substituted imidazo[4,5-b]pyridines
and benzimidazoles from readily available 2-imidazolines
⇑
Prashant Mujumdar, Tanja Grkovic, Mikhail Krasavin
Eskitis Institute, Griffith University, Nathan, Queensland 4111, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
We discovered a facile rearrangement of N-(hetero)aryl 2-imidazolines into diversely substituted
imidazo[4,5-b]pyridines and benzimidazoles, under Bechamp reduction conditions. Combined with the
earlier reported protocol for Pd-catalyzed (hetero)arylation of 2-imidazolines, it provides a simple
two-step access to a range of compounds based on these medicinally important heterocyclic cores.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 4 March 2013
Revised 9 April 2013
Accepted 10 April 2013
Available online 23 April 2013
Keywords:
Pd-catalyzed arylation
N-(Hetero)aryl 2-imidazolines
Bechamp reduction
Rearrangement
Imidazo[4,5-b]pyridines
Benzimidazoles
Discovery of new, non-conventional methods to prepare classi-
cal heterocycles broadens the arsenal of synthetic methods and of-
ten allows accessing densely functionalized heterocyclic templates
more flexibly and in fewer synthetic operations compared to the
routes based on the existing methodologies. In this Letter we re-
port on a serendipitous discovery of a straightforward method to
prepare two important heterocyclic cores—imidazo[4,5-b]pyri-
dines and benzimidazoles—with full control over three elements
of diversity.
Recently, we developed an efficient methodology for Pd-cata-
lyzed (hetero)arylation of 2-imidazolines1 that has allowed us to
access a wide range of drug-like compounds belonging to the rela-
tively unexplored2 N-(hetero)aryl-2-imidazoline chemotype (1). As
the medicinal chemistry potential of the latter began to unravel,
we were facing a need to introduce various functionalities in the
Br
N
N
Br
N
[H]
NO2
Cl
NH2
N
Br
2a
X
N
N
N
NH2
N
[H]
Pd(OAc)2/BINAP
Cs2CO3
HN
4a
NO2
Br
N
3
N
N
toluene, 100 o
12-16 h
C
5a
[H]: Fe, NH4Cl, EtOH/H2O, 70 oC, 16-24 h
Scheme 1. Practical outcome of the Fe/NH4Cl reduction of 3a in aqueous ethanol.
N
R
nitro
group
N
N
N
R
imidazoline
R
HN
+
R
N-arylation
reduction
H2N
O2N
O2N
N
Cl
N
N
N
N
(Het)Ar
N
3
1
2
Figure 1. Strategy to access N-(3-aminopyrid-2-yl)-2-imidazolines.
⇑
Corresponding author. Tel.: +61 7 3735 6041; fax: +61 7 3735 6001.
E-mail address: m.krasavin@griffith.edu.au (M. Krasavin).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.036

P. Mujumdar et al. / Tetrahedron Letters 54 (2013) 3336–3340
3337
Figure 2. HMBC correlations confirming the imidazo[4,5-b]pyridine structure of 5a.
4
basic core 1. In particular, we were interested in incorporating an
amino group into the N-aryl (specifically, 2-pyridyl) substituent
(as in 2), via the use of 2-chloro-3-nitropyridine in the imidazoline
arylation step with subsequent reduction of the nitro group in 3
(Fig. 1). We expected 2-chloro-3-nitropyridine to be a reactive
partner in imidazoline N-arylation and, indeed, the respective
model compound 3a (R = 2-bromophenyl) was prepared from 2-
(2-bromophenyl)imidazoline (4a) in 80% yield using the aforemen-
tioned protocol. When we subjected 3a to the modified Bechamp
NO2
Hal
5
NH2
N
3
R
Y
6
Fe, NH4Cl
2
N
N
X
R
X
X
N
N
EtOH/H2O, 70 o
16-24 h
C
Pd(OAc)2/BINAP
Cs2CO3
HN
Y
R
NO2
Y
toluene, 100 o
12-16 h
C
4
3
5
Scheme 2. General two-step access to imidazo[4,5-b]pyridines and
benzimidazoles.
Table 1
Imidazo[4,5-b]pyridines and benzimidazoles prepared in this work
Compound
R
X
Y in 3 (in 5)
Hal
Cl
Yield imidazoline arylation step (%)
Yield reduction–rearrangement step (%)
Br
Cl
5a
5b
5c
N
N
N
H
H
H
80
81
84
71
79
77
*
Cl
*
Cl
Cl
MeO
MeO
*
5d
5e
5f
N
N
N
H
H
H
Cl
Cl
Cl
92
68
97
62
81
81
F
*
O
O
*
Cl
*
N
N
*
5g
N
H
Cl
96
63
*
5h
5i
N
N
H
H
Cl
Cl
90
76
28
*
60
(continued on next page)

3338
P. Mujumdar et al. / Tetrahedron Letters 54 (2013) 3336–3340
Table 1 (continued)
Compound
R
X
Y in 3 (in 5)
Hal
Cl
Yield imidazoline arylation step (%)
90
Yield reduction–rearrangement step (%)
83
5j
F
*
N
4-Me
5k
N
5-Br
Cl
98
73
*
*
5l
N
N
N
N
5-Br
Cl
Cl
Cl
Cl
50
87
56
81
74
74
56
75
*
5m
5n
5o
4-Me
5-Br
*
*
4-Me
5p
5q
CH
CH
5-Br
5-Br
Br
Br
41
35
52
55
*
*
Cl
5r
CH
CH
5-CN
5-CN
Br
Br
93
84
91
65
MeO
Br
*
5s
5t
*
*
CH
CH
5-CN
Br
Cl
80
76
69
92
5ua
5-NO2 (5-NH2)
Cl
*
a
6 equiv of Fe and 1.2 equiv of NH4Cl were used, the 5-aminobenzimidazole product was obtained.
reduction conditions (Fe/NH4Cl in aqueous EtOH),3 an efficient
conversion to a more polar compound took place. The product
was isolated chromatographically and characterized. Although its
molecular weight corresponded to the desired amine 2, close
examination of its 1H NMR spectra revealed the absence of the
tightly grouped multiplets around dH 4.0 ppm characteristic of
the imidazoline bis-methylene bridge. Instead, two triplets at dH
4.25 and 3.10 ppm, more characteristic of a 2-aminoethyl side
chain were observed. After substantial brainstorming, isomeric
imidazo[4,5-b]pyridine structure 5a was proposed for the product
obtained (Scheme 1). It was, to our delight, later confirmed by 2D
HMBC NMR spectral data (Fig. 2).
in 3 may first be reduced to the amino group which would then
trigger a 5-exo-trig attack on the imidazoline’s amidine carbon
(route a) that would ultimately lead to the formation of the imi-
dazo-fused aromatic core. Alternatively (route b), the imidazoline
core could be hydrolyzed, under the mildly acidic reaction condi-
tions, to give amide 6. The latter would then undergo reduction
and dehydrative cyclization (of the amine 7) to form the observed
aromatic nucleus. Based on the abundance of examples of imidaz-
oline hydrolysis in the literature9 one could a priori conclude that
route b would be the preferred reaction course. We further con-
firmed it by heating a representative compound (3p) in aqueous
Imidazo[4,5-b]pyridines containing 2-aminoethyl side chain are
somewhat underexplored bioisosteres of the privileged4 benzimi-
dazoles. To-date, imidazo[4,5-b]pyridines have been documented
as histamine H3 receptor inverse agonists,5 histone deacetylase
inhibitors6, and cannabinoid CB2 receptor modulators.7 We ap-
peared to have identified a conceptually novel and practically sim-
ple protocol to prepare these medicinally important compounds
from the readily available 2-imidazolines 4. Therefore we pro-
ceeded to investigate the scope of this two-step transformation
(Scheme 2) and found it applicable to the preparation of a range
of diversely substituted imidazo[4,5-b]pyridines 5a–o as well as
benzimidazoles 5p–u (Table 1). The methodology8 is equally work-
able for 2-alkyl, 2-aryl, and 2-heteroaryl imidazolines and conve-
H+
N
H+
HN
Route a
R
N
R
N
[H]
H
N
X
H2N
X
NH2
N
B
N
Y
Y
R
NO2
X
N
N
X
H+
O
NH2
Y
R
NH2
3
H2O
Y
[H]
O
5
N
R
H2N
N
R
NO2
Route b
X
X
6
7
Y
Y
niently allows incorporating
a range of substituents in the
Observed:
imidazo-fused aromatic nucleus via the use of appropriately
substituted (hetero)aryl halides. Particularly noteworthy is the
preparation of 5-aminobenzimidazole 5u via the double reduction
of 3,5-dinitrophenyl moiety in the N-arylimidazoline precursor.
From the mechanistic standpoint, the formation of imidazo[4,5-
b]pyridines and benzimidazoles in the reduction–rearrangement
step could be rationalized as depicted in Scheme 3. The nitro group
NH4Cl
N
O
N
NH2
N
EtOH/H2O, 70 o
5 h
C
N
N
NO2
NO2
(confirmed by LC MS)
Br
Br
Scheme 3. Mechanistic rationale for the formation of imidazo-fused compounds 5.

P. Mujumdar et al. / Tetrahedron Letters 54 (2013) 3336–3340
3339
X
NH2
NO2
Cl
NH2
N
H2N
N
O
X
X
Fe, NH4Cl
X
N
N
N
N
N
H
N
NBS, DCM
oC --> r. t.
ref. 10
EtOH/H2O, 70 o
16-24 h
C
Pd(OAc)2/BINAP
Cs2CO3
0
NO2
X
8a
8b
toluene, 100 o
12-16 h
C
, 78%
10a
, 76%
9a, 52%
, 63%
10b
9b
, 91%
, 82%
a.
b.
c.
X = 3-Br; X = 4-Cl; X= 4-F
8c, 83%
10c, 74%
9c
, 89%
Scheme 4. Side-chain substitutions in the imidazo-fused aromatic products.
NH2
NH2
NO2
Cl
H2N
N
N
N
O
Fe, NH4Cl
N
N
N
N
HN
NBS, DCM
0 oC --> r. t.
EtOH/H2O, 70 o
16-24 h
C
Pd(OAc)2/BINAP
Cs2CO3
N
NO2
toluene, 100 o
12-16 h
C
10, 45%
12
, 69%
11, 12%
Scheme 5. Synthesis of 3-aminopropyl-substituted imidazo[4,5-b]pyridine 12.
ethanolic solution of NH4Cl at 70 °C. After 5 h, the starting material
underwent a complete conversion into amide 6p (as confirmed by
LC MS analysis). This observation further argues for the formation
of imidazo[4,5-b]pyridines and benzimidazoles predominantly
proceeding via route b.
mass spectrometry measurements. Mr. Pakornwit Sarnpitak is
acknowledged for the preparation of the starting material
imidazolines.
Supplementary data
According to this rationale, the use of additionally substituted
imidazolines in the two-step sequence would result in regiospeci-
fic incorporation of substituents in the 2-aminoethyl side chain of
the resulting imidazo-fused aromatic products. Pd-catalyzed N-
arylation of imidazolines 8a–c (prepared from the respective benz-
aldehydes and propane-1,2-diamine according to the literature
procedure10) with 2-chloro-3-nitropyridine proceeded with >90%
regiospecificity, as reported by us earlier,11 to give compounds
9a–c in good to excellent yields. Treatment of 9a–c under the Be-
champ reduction conditions resulted in excellent yields of com-
pounds 10a–c (Scheme 4). Regiochemistry of the side chain
substitution was unequivocally confirmed by 2D HMBC NMR
experiments (see Supplementary data).
Finally, we were curious to see if the present methodology
could be extended to the preparation of imidazo[4,5-b]pyridines
containing 3-aminopropyl side chains, via Pd-catalyzed N-aryla-
tion of 1,4,5,6-tetrahydropyrimidines and subsequent reduction-
rearrangement. N-Arylation of a model 1,4,5,6-tetrahydropyrimi-
dine 10 provided the desired compound 11 (albeit in disappoint-
ingly low yield). The latter, under Bechamp reduction conditions,
underwent a smooth and high-yielding transformation into the ex-
pected 3-aminopropyl-substituted imidazo[4,5-b]pyridine 12
(Scheme 5). Thus, should the yield of N-(hetero)arylation of
1,4,5,6-tetrahydropyrimidines be improved,12 our two-step proto-
col would be of practical value to access 3-aminopropyl-substi-
tuted imidazo-fused aromatic templates as well.
Supplementary data (copies of 1H and 13C NMR spectra for the
newly synthesized compounds 5a-u, 10a-c, 12; copies of 2D HMBC
NMR spectra for selected compounds) associated with this article
can be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2013.04.036.
References and notes
1. Krasavin, M. Tetrahedron Lett. 2012, 53, 2876–2880.
2. According to our literature survey, N-(heteroaryl)imidazolines were seldom
implicated as central scaffolds in biologically active chemical series. However,
they were often reported as essential elements of compound’s periphery, e.g.,
in inhibitors of polo-like kinase (Neitz, R. J.; Troung, A. P.; Galemmo, R. A.; Ye, X.
M.; Sealy, J.; Adler, M.; Bowers, S.; Beroza, P.; Anderson, J. P.; Aubele, D. L.; Artis,
D. R.; Hom, R. K.; Zhu, Y.-L. PCT Int. Appl. WO 2012048129A2, 408 pp; Chem.
Abstr. 2012, 156, 534299) or MDM2/4 modulators (Bold, G.; Furet, P.; Gessier,
F.; Kallen, J.; Hergovich Lisztwan, J.; Masuya, K.; Vaupel, A. PCT Int. Appl.
WO2011023677A1, 274 pp Chem. Abstr. 2011, 154, 310643).
3. Ramadas, K.; Srinivasan, N. Synth. Commun. 1992, 22, 3189–3195.
4. Han, C.; Zhang, J.; Zheng, M.; Xiao, Y.; Li, Y.; Liu, G. Mol. Diversity 2011, 15, 857–
876.
5. Chytil, M.; Engel, S. R.; Fang, Q. K.; Spear, K. L. PCT Int. Appl.
WO20100204214A1, 138 pp; Chem. Abstr. 2010, 153, 311281.
6. Deng, W.; Chen, D.; Zhou, Y. PCT Int. Appl. WO2006101456A1, 93 pp; Chem.
Abstr. 2006, 145, 1009636.
7. Kon-I, K.; Matsumizu, M.; Shima, A. US Patent Appl. US20060094750A1, 63 pp;
Chem. Abstr. 2006, 144, 409719.
8. Typical procedure for the synthesis of 5: N-(hetero)aryl 2-imidazoline
3
(0.3 mmol), prepared as described earlier, 1 was dissolved in a mixture of EtOH
(2.25 mL) and H2O (0.45 mL). Fe dust (3 equiv, 0.9 mmol, 50 mg) and NH4Cl
(0.6 equiv, 0.18 mmol, 10 mg) were added and the mixture was heated, under
vigorous stirring, at 70 °C for 16–24 h. It was then cooled down to rt, filtered
through a plug of Celite and the filtrate was evaporated. The residue was
absorbed on silica gel, transferred onto a silica gel column and the column was
eluted with 8% MeOH in DCM. Fractions containing the product were combined
and evaporated to provide the desired imidazo[4,5-b]pyridines or
benzimidazoles.
In summary, we discovered a facile rearrangement of N-(het-
ero)aryl 2-imidazolines into diversely substituted imidazo[4,5-
b]pyridines and benzimidazoles,13 under Bechamp reduction con-
ditions. Combined with the earlier reported protocol for Pd-cata-
lyzed (hetero)arylation of 2-imidazolines, it provides a simple
two-step access to a range of compounds based on these medici-
nally important heterocyclic cores14. Further applications of this
methodology to the synthesis of novel, more complex heterocyclic
templates are being investigated in our laboratories and the results
will be reported in due course.
9. (a) Loeppky, R. N.; Cui, W. Tetrahedron Lett. 1998, 39, 1845–1848; (b) Loeppky,
R. N.; Yu, L. Tetrahedron Lett. 1990, 31, 3263–3266; (c) Bondareva, S. O.; Lisitskii,
V. V.; Yakovtseva, N. I.; Murinov, Yu. I. Russ. Chem. Bull. 2004, 53, 803–807; (d)
Anderson, M. W.; Jones, R. C. F.; Saunders, J. Hydrolysis of 1,2-disubstituted
imidazolines in aqueous media J. Chem. Soc., Perkin Trans. 1 1986, 205–209; (e)
Focati, M. P.; Brescello, R.; Powles, K. A.; Cotarca, L.; Soriato, G.; Giovanetti, R.;
Foletto, J.; Massaccesi, F. PCT Int. Appl. WO 2008010796A1, 27 pp; Chem. Abstr.
2008, 148, 168591.; (f) Aspinall, S. R. J. Org. Chem. 1941, 6, 895–901; (g) Ye, G.;
Chen, C.; Chatterjee, S.; Collier, W. E.; Zhou, A.; Song, Y.; Beard, D. J.; Pittman, C.
U., Jr Synthesis 2010, 141–152; (h) Korshin, E. E.; Sabirova, L. I.; Akhmadullin, A.
G.; Levin, Ya. A. Izv. Akad. Nauk, Ser. Khim 1994, 472–479.
Acknowledgements
Mikhail Krasavin acknowledges support from Griffith Univer-
sity. Dr. Hoan Vu of Eskitis Institute is thanked for high-resolution
10. Fujioka, H.; Murai, K.; Ohba, Y.; Hiramatsu, A.; Kita, Y. Tetrahedron Lett. 2005,
46, 2197–2199.

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P. Mujumdar et al. / Tetrahedron Letters 54 (2013) 3336–3340
J = 14.6, 5.6 Hz, 1H), 3.62–3.72 (m, 1H), 1.10 (d, J = 6.5 Hz, 3H), NH2 protons in
11. Krasavin, M. Lett. Org. Chem. in press.
12. N-Arylation of 1,4,5,6-tetrahydropyrimidines is
a
surprising void in the
exchange; 13C NMR (125 MHz, CD3OD): dC 155.6, 150.4, 146.6, 136.6, 135.8,
134.4, 133.7, 132.9, 130.2, 129.5, 124.9, 121.5, 50.7, 48.9, 19.3; HRMS m/z
[M+H]+ calcd for C15H16BrN4 331.0552, found 331.0551. Compound 10b:
Grayish brown solid; mp = 105–107 °C; 1H NMR (500 MHz, CD3OD): dH 8.42 (d,
J = 4.5 Hz, 1H), 8.07–8.09 (m, 1H), 7.77 (d, J = 8.4, 2H), 7.62 (t, J = 8.4 Hz, 2H),
7.37 (dd, J = 4.9, 8.0 Hz, 1H), 4.90 (s, 2H), 4.58 (dd, J = 14.8, 7.2 Hz, 1H), 4.48 (dd,
J = 14.8, 5.5 Hz, 1H), 3.67–3.72 (m, 1H), 1.08 (d, J = 6.6 Hz, 3H); 13C NMR (125
MHz, CD3OD): dC 156.1, 150.5, 146.4, 139.0, 136.6, 133.1, 131.4, 130.1, 129.3,
121.5, 50.3, 49.0, 18.9; HRMS m/z [M+H]+ calcd for C15H16ClN4 287.1058, found
287.1049. Compound 10c: Brown oil; 1H NMR (500 MHz, CD3OD): dH 8.45 (d,
J = 7.7 Hz, 1H), 8.10 (d, J = 7.9, 1H), 7.86 (dd, J = 8.7, 5.3, 2H), 7.39 (d, J = 8.7 Hz,
2H), 7.36–7.38 (m, 1H), 4.88 (s, 2H), 4.55 (dd, J = 14.8, 7.1 Hz, 1H), 4.47 (dd,
J = 14.9, 5.6 Hz, 1H), 3.60-3.67 (m, 1H), 1.06 (d, J = 6.5 Hz, 3H); 13C NMR
(125 MHz, CD3OD): dC 166.4 (d, JC-F = 248.8 Hz), 156.4, 150.5, 146.3, 136.6,
133.9 (d, JC-F = 8.8 Hz), 129.2, 127.9 (d, JC-F = 3.7 Hz), 121.4, 118.1 (d, JC-
F = 22.3 Hz), 50.9, 48.8, 19.6; HRMS m/z [M+H]+ calcd for C15H16FN4 271.1353,
found 271.1346.
currently available synthetic methods. Efforts are currently underway in our
laboratories to identify optimized conditions to achieve
arylation of this special case of cyclic amidines.
a high-yielding
13. Characterization data for selected compounds: 5f: Brown oil; 1H NMR
(500 MHz, CD3OD): dH 8.45 (d, J = 4.5 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.85 (d,
J = 1.0 Hz, 1H), 7.73–7.76 (m, 1H), 7.60–7.65 (m, 2H), 7.40 (dd, J = 7.8, 4.7 Hz,
1H), 4.57 (t, J = 6.4 Hz, 2H), 3.25 (s, 2H), NH2 protons in exchange; 13C NMR
(125 MHz, CD3OD): dC 155.6, 150.4, 146.4, 136.9, 136.6, 133.4, 132.7, 132.6,
131.4, 129.7, 129.3, 121.4, 46.3, 42.0; HRMS m/z [M+H]+ calcd for C14H14ClN4
273.0901, found 273.0890. 5g: 63% yield (10% MeOH in DCM), brown solid,
mp = 222–224 °C. 1H NMR (500 MHz, CD3OD): dH 9.07 (d, J = 4.4 Hz, 1H), 8.51
(d, J = 4.6 Hz, 1H), 8.18 (t, J = 8.7 Hz, 2H), 7.85 (d, J = 7.8 Hz, 1H), 7.82 (d,
J = 4.3 Hz, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.65 (t, J = 6.8 Hz, 1H), 7.46 (dd, J = 8.0,
5.2 Hz, 1H), 4.42 (t, J = 5.7 Hz, 2H), 3.22 (t, J = 5.6 Hz, 2H), NH2 protons in
exchange; 13C NMR (125 MHz, CD3OD): dC 153.1, 151.9, 150.1, 150.0, 147.0,
137.9, 136.9, 132.8, 131.1, 130.5, 129.9, 128.6, 127.2, 125.2, 121.7, 45.2, 41.6;
HRMS m/z [M+H]+ calcd for C17H16N5 290.1400, found 290.1390. Compound
10a: Brown oil; 1H NMR (500 MHz, CD3OD): dH 8.50 (d, J = 4.6 Hz, 1H), 8.16 (d,
J = 8.0 Hz, 1H), 8.04 (d, J = 1.4 Hz, 1H), 7.83 (t, J = 9.3 Hz, 2H), 7.60 (t, J = 7.9 Hz,
1H), 7.45 (dd, J = 8.1, 4.9 Hz, 1H), 4.60 (dd, J = 14.7, 7.2 Hz, 1H), 4.52 (dd,
14. All of the compounds synthesized in this work have been deposited with the
Queensland Compound Library (Griffith University) and are available for
collaborative discovery projects.