Exploration of versatile reactions on 2-chloro-3-nitroimidazo[1,2-a] pyridine: Expanding structural diversity of C2- and C3-functionalized imidazo[1,2-a]pyridines

Article abstract of DOI:10.1016/j.tetlet.2013.07.113

Alternative strategies for functionalizing 2-chloro-3-nitroimidazo[1,2-a] pyridine have been developed. Suzuki-Miyaura cross-coupling reaction provided easily the corresponding 2-arylated compounds, and herefrom the nitro group was reduced into amine which afforded amides, anilines, and ureas in the 3-position. The amination of the key compound using a metal-catalyzed reaction was reported. This study highlighted the importance of the nitro group to facilitate the chlorine displacement. Other nucleophilic aromatic substitutions open a route to various products derived from imidazo[1,2-a]pyridine.

Full text of DOI:10.1016/j.tetlet.2013.07.113

Accepted Manuscript
Exploration of versatile reactions on 2-chloro-3-nitroimidazo[1,2-a]pyridine:
expanding structural diversity of C2- and C3-functionalized imidazo[1,2-a]pyr‐
idines
Marc-Antoine Bazin, Sophie Marhadour, Alain Tonnerre, Pascal Marchand
PII:
S0040-4039(13)01272-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.07.113
TETL 43311
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
12 June 2013
17 July 2013
22 July 2013
Please cite this article as: Bazin, M-A., Marhadour, S., Tonnerre, A., Marchand, P., Exploration of versatile reactions
on 2-chloro-3-nitroimidazo[1,2-a]pyridine: expanding structural diversity of C2- and C3-functionalized
imidazo[1,2-a]pyridines, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.07.113
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Graphical Abstract
Exploration of versatile reactions on 2-
chloro-3-nitroimidazo[1,2-a]pyridine:
expanding structural diversity of C2- and
C3-functionalized imidazo[1,2-a]pyridines
Leave this area blank for abstract info.
Marc-Antoine Bazin, Sophie Marhadour, Alain Tonnerre and Pascal Marchand
N
R5
N
Buchwald and
Ullmann-type
aminations
SNAr
N
N
NO2
NR3R4
Cl
N
N
Suzuki
NO2
NO2
N
R1
N
R1
N
N
NO2
NHR2

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Exploration of versatile reactions on 2-chloro-3-nitroimidazo[1,2-a]pyridine:
expanding structural diversity of C2- and C3-functionalized imidazo[1,2-a]pyridines
Marc-Antoine Bazin , Sophie Marhadour, Alain Tonnerre and Pascal Marchand
Université de Nantes, Nantes Atlantique Universités, Laboratoire de Chimie Thérapeutique, Cibles et Médicaments des Infections et du Cancer, IICiMed EA
1155, UFR des Sciences Pharmaceutiques et Biologiques, 1 rue Gaston Veil, 44035 Nantes, France
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Alternative strategies for functionalizing 2-chloro-3-nitroimidazo[1,2-a]pyridine have been
developed. Suzuki-Miyaura cross-coupling reaction provided easily the corresponding 2-
arylated compounds, and herefrom the nitro group was reduced into amine which afforded
amides, anilines and ureas in the 3-position. The amination of the key compound using metal-
catalyzed reaction was reported. This study highlighted the importance of nitro group to
facilitate the chlorine displacement. Other nucleophilic aromatic substitutions open a route to
various products derived from imidazo[1,2-a]pyridine.
Available online
Keywords:
Imidazo[1,2-a]pyridines
2-Chloro-3-nitroimidazo[1,2-a]pyridine
Suzuki-Miyaura reaction
Buchwald-Hartwig amination
Ullmann amination
2013 Elsevier Ltd. All rights reserved.
———
Corresponding author. Tel.: +33 240 411 114; fax: +33 240 412 876; e-mail: marc-antoine.bazin@univ-nantes.fr
Corresponding author. Tel.: +33 240 412 874; fax: +33 240 412 876; e-mail: pascal.marchand@univ-nantes.fr

2
Tetrahedron Letters
N
N
2,3-Disubstituted imidazo[1,2-a]pyridines represent the
structural motif of various substances possessing relevant
i
X
X
N
N
X = Cl, 81%
biological
and
pharmacological
properties1
including
antinfective,2 anti-inflammatory,3 hypnotic,4 antipsychotic,5 and
gastric antisecretory properties.6 Besides, imidazo[1,2-
a]pyridines display photophysical properties of great interest.7
Br, 64%
OTf, 63%
NO2
X = Cl, Br, OTf
ii
ii
N
N
As part of our studies towards the synthesis of biologically
active compounds,8 we were interested in functionalizing 2-
chloro-3-nitroimidazo[1,2-a]pyridine 1, a key compound leading
to a great diversity of 2,3-disubstituted imidazo[1,2-a]pyridines
(Scheme 1). In particular, we set out to develop a convenient
synthesis of 3-amino-2-arylimidazo[1,2-a]pyridines derivatives
and useful reactions such as nucleophilic aromatic substitutions
(SNAr) and metal-catalyzed cross-coupling reactions starting
from 1. A few examples of functionalizations of 2-chloro-3-
nitroimidazo[1,2-a]pyridine 1 are reported in the literature,
including only SNAr in the 2-position with amines,9
heterocycles,10 phenols11 and alcohols.12 Azaheterocycles bearing
such ortho-nitro chloro system are efficient scaffolds to introduce
amines or amides.13 Thus we envisaged an extended
methodology based on metal-catalyzed reactions exploiting nitro
group in the 3-position to provide a wide range of novel 2,3-
disubstituted imidazo[1,2-a]pyridines.
R1
R1
N
N
NO2
3a-d
2
Scheme 2. Reagents and conditions: (i) HNO3, H2SO4, -5 °C→r.t., 3
h, 63–81%; (ii) ArB(OH)2 1.2 equiv., Pd(PPh3)4 5% mol, Na2CO3
2.5 equiv., DME/H2O (2:1), reflux, 3 h–20 h.
Table 1. Attempts for Suzuki cross-coupling in the 2-position.
Entry
Substrate
X = Cl
X = Br
X = OTf
X = Cl
X = Br
X = OTf
X = Cl
X = Cl
X = Cl
Product
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
R1 = H
R1 = H
R1 = H
R1 = H
R1 = H
R1 = H
2
6
6
7
6
6
6
3
3
4
25
51
2
2
43
3a
3a
3a
3b
3c
3d
68 (90b)
72
We first explored the preparation of 3-aminoimidazo[1,2-
a]pyridines. Such compounds are usually synthesized using
multi-component reaction (MCR) Groebke-Blackburn-Bienaymé
reaction.14 Moreover we thought that compound 1 could be an
alternative and that a sequence including a Suzuki cross-coupling
reaction and a reduction of the nitro group could easily provide
the target compounds.
traces
96
R1 = OMe
R1 = F
97
NH2
N
N
9
R1 = NO2
72
R1
3 steps
3 steps
Cl
a Isolated yield.
N
N
N
b Reaction carried out with C6H5B(OH)2: 2.0 equiv, Na2CO3: 4.0 equiv.
NO2
NHR2
1
Moreover, nitration of 2-phenylimidazo[1,2-a]pyridine 2 was
envisaged to obtain 3a but a nitration of the phenyl ring was
observed as a side reaction, as Hand and Paudler had previously
mentioned.18 To examine briefly the scope of Suzuki-Miyaura
reaction with 1,19 we carried out other couplings starting from
boron reagents bearing either an electron donating group (i.e.
methoxy) or an electron withdrawing group (i.e. fluor or nitro)
(Table 1, entries 7–9). Products 3b–3d were obtained in good to
excellent yields in a short reaction time. These results suggest
that Suzuki coupling on 2-chloro-3-nitroimidazo[1,2-a]pyridine 1
in the position 2 could be extended to a greater variety of boron
reagents.
Subsequent reduction of the nitro group with H-Cube® afforded
easily amine 4 (96% yield) (Scheme 3). This amine was obtained
in an excellent 44% overall yield from 2-aminopyridine over 5
steps. Thus we synthesized amides, anilines and ureas to scope
the reactivity of the amine in the 3-position. First, acetylation of
4 with acetic anhydride provided acetamide 5a in a good yield
(Table 2, entry 1). Thus this amine 4 was enough reactive
towards other electrophilic reagents such as benzoyl chloride
(entry 2). Given the success of these reactions we expanded the
scope of electrophiles to obtain ureas 6a-f from amine 4 and
various isocyanates. Classical conditions20,21 were used to afford
firstly product 6a in 55% yield (Table 2, entry 3). This method
was subsequently applied to a wide range of isocyanates
furnishing corresponding ureas. To our delight, ureas were
formed in yields ranging from 41–70% (Table 2, entries 4, 6–8)
while compound 6c was surprisingly obtained in a lower yield
(16%) due to purification problems (entry 5).
N
N
NR3R4
N
R5
N
NO2
NH2
(R5 = Cl, CN)
Scheme 1. Reactivity of 2-chloro-3-nitroimidazo[1,2-a]pyridine 1 in
this study.
Initial trials were carried out on 2-halogenoimidazo[1,2-
a]pyridines and imidazo[1,2-a]pyridin-2-yl triflate15 which were
subjected to
a nitration to afford corresponding 3-nitro
derivatives (Scheme 2).16 Suzuki-Miyaura couplings furnished
the required 3-nitro-2-phenylimidazo[1,2-a]pyridine17 3a from 2-
chloro- and 2-bromo- derivatives in good yields, respectively
68% and 72% (Table 1, entries 4 and 5). The reaction with 2-
chloro-3-nitroimidazo[1,2-a]pyridine 1 was complete when 2
equivalents of phenyl boronic acid were used (entry 4).
Surprisingly, only traces were detected for this reaction with
triflate derivative (entry 6). The yield of the reaction was clearly
improved due to electron withdrawing effect of the nitro group in
the 3-position (entries 1–2 vs 4–5), except for triflate derivative.
Further, we focused on the use of 2-chloro-3-nitroimidazo[1,2-
a]pyridine
1
because 2-bromoimidazo[1,2-a]pyridine was
obtained in poor yield (i.e. 9%) from commercially available 2-
aminopyridine.15
We next envisaged to arylate amine 4 with halogenoarenes in a
Pd-catalyzed Buchwald-Hartwig reaction.22 Indeed, N,2-
diarylimidazo[1,2-a]pyridin-3-amines have attracted growing
interest due to their biological applications.2d,23 The reaction was

3
performed as described in the general procedure.24 Conditions
used in the first attempt with bromobenzene were found to be
acceptable and provided 7a in 70% yield (Table 2, entry 9). The
reaction took place with various haloarenes to provide the
corresponding products in low to moderate yields (Table 2,
entries 10–12) whereas the reaction with 4-bromoanisole failed,
likely due to electron-donor effect of methoxy group (entry 13).
yield but the use of microwave heating for 1 hour enhanced the
yield to 83%. It is noteworthy that Pd-catalyzed amination of 2-
chloroimidazo[1,2-a]pyridine with benzylamine and aniline in
the same conditions did not afford the corresponding amine in the
2-position. These results confirmed once again the influence of
nitro group to carry out the chlorine displacement with an amine.
Microwave heating allowed convenient yields in Buchwald
coupling with primary amines in a short heating time (1 h). In
contrast, reaction of 1 with a less nucleophilic reagent such as
benzophenone imine led to 8d in a very low yield (5%).
In another set of experiments, a copper-catalyzed amination
with CuI, DMEDA and K3PO4 in toluene afforded 8a and 8b in
lower yields than Pd-catalyzed aminations and no reaction
occurred with benzophenone imine. Thus the use of palladium in
Buchwald-Hartwig conditions seemed to improve the yield of
such substitution in the 2-position rather than copper-catalyzed
reaction. Finally, the reduction of nitro group of compounds 8a
and 8b was envisaged. The conversion occurred with H-Cube®
(about 50% conversion from LC–MS) but the purification failed
on neither alumina nor silica gel (data not reported).
Other functionalizations of 2-chloro-3-nitroimidazo[1,2-
a]pyridine 1 were explored and are reported in Scheme 5.
Compound 9 was synthesized via cyanation using copper(I)
cyanide in NMP at 170 °C for 4 days. Subsequent reduction of
nitro group with Sn/HBr afforded easily 3-amino-2-
cyanoimidazo[1,2-a]pyridine 10 which would be subjected to
further cyclization.29 In addition, chemical reduction of nitro
group of 1 provided amine 11 in 87% yield, and such compound
seemed to show a significant interest in heteroannulation of
imidazo[1,2-a]pyridines.30
To investigate the behavior of 2-chloro-3-nitroimidazo[1,2-
a]pyridine 1, we reasoned that amines would favour SNAr
displacement of the chlorine as previously described.9-10,25 Such
substitution was recently achieved by Salgado-Zamora and co-
workers on 2-cyano-3-nitroimidazo[1,2-a]pyridine.26 We carried
out a reaction between 1 and benzylamine, aniline and n-
propylamine in the presence of t-BuOK in tetrahydrofurane
(Scheme 4, Table 3). As expected, the substitution occurred in a
good yield for benzylamine (56%) and in a lower yield for aniline
(35%) even heating at 50 °C and adding double quantity of
reagents. Surprisingly, the conversion was decreased when n-
propylamine was used even in harsher conditions (15%). With
these initial trials in hand, we were keen to enhance the
performance of the substitution implementing metal-catalyzed
reactions. It is well-known that Buchwald-Hartwig27 and
Ullmann-type28 aminations can improve such coupling through
transition-metal-mediated processes. Standard conditions of Pd-
catalyzed amination were used with benzylamine, Pd2dba3,
BINAP and t-BuONa in toluene to provide 8a in a higher yield
(76%). Microwave-promoted reaction (monomode CEM
Discover® SP) allowed a similar yield (84%). Microwave-
promoted Buchwald amination with n-propylamine afforded the
desired product in an acceptable yield (56%). Performing same
reaction with the less nucleophilic aniline provided 8b in 37%
.
N
N
N
i
ii, iii or iv
Amides 5a-b,
Ureas 6a-f,
N
N
N
Anilines 7a-e
NHR2
NO2
NH2
3a
4
Scheme 3. Synthesis of 3-aminoimidazo[1,2-a]pyridines derivatives 5a-b, 6a-f and 7a-e. Reagents and conditions: (i) H-Cube®, Raney Ni
cartridge, Full H2, flow rate 1 mL/min, EtOH/THF (9:1), 40 °C, overnight, 96%; (ii) Cpd 5a: Ac2O, toluene, reflux, 16 h, 65%; Cpd 5b:
benzoyl chloride, THF, Et3N, r.t., 48 h, 43%; (iii) Cpds 6a-f: isocyanate, DMF, 80 °C, 16 h–24 h, 16–70%.; (iv) Cpds 7a-e: (het)ArBr or ArI,
Pd2(dba)3, BINAP, t-BuONa, toluene, sealed tube, 110 °C, 4 h–16 h, 29–70%.
Table 2. Synthesis of 5a-b, 6a-f and 7a-e from 3-amino-2-phenylimidazo[1,2-a]pyridine 4.
Entry
Reagent
Compd
R2
Time
Yielda (%)
65
CH3
1
Ac2O
5a
16 h
O
2
PhCOCl
5b
48 h
43
O
O
O
H
N
3
4b
5
6a
6b
6c
16 h
24 h
16 h
55
41
16
NCO
NCO
H
N
H
N
NCO
O
H
N
6
6d
16 h
45
O
NCO

4
Tetrahedron
H
N
7
8
6e
6f
24 h
70
54
O
NCO
H
NCO
N
16 h
O
Br
9
7a
7b
7c
7d
7e
4 h
16 h
1.5 h
16 h
24 h
70
66
40
29
0d
NO2
NO2
Cl
Br
10
11c
12
13
Cl
I
N
N
Br
OMe
OMe
Br
a Isolated yield.
b 3 Equiv. of isopropylisocyanate.
c Conditions: 1-chloro-4-iodobenzene, sealed tube, MW, 125 °C, 1.5 h.
d No product was detected on UPLC/MS chromatogram.
N
N
N
N
N
conditions a, b or c
ii
i
amine
+
Cl
NR3R4
Cl
CN
CN
N
N
N
N
N
NO2
NO2
NO2
iii
NO2
NH2
1
8a-d
1
9
10
N
Scheme 4. Synthesis of compounds 8a-d. Reagents and conditions:
(a) SNAr: amine (1.2 equiv.), t-BuOK (1.3 equiv.), THF, r.t., 18 h;
(b) Buchwald amination: amine (2.0 equiv.), Pd2dba3 (0.1 equiv.),
BINAP (0.3 equiv.), t-BuONa (1.0 equiv.), toluene, sealed tube, 110
°C, 20 h under classical heating; 120 °C, 1 h, microwave heating (P
= 75 W); (c) Ullmann-type amination: amine (2.0 equiv.), CuI (0.1
equiv.), DMEDA, (0.3 equiv.), K3PO4 (2.0 equiv.), toluene, sealed
tube, 110 °C, 20 h.
Cl
N
NH2
11
Scheme 5. Synthesis of compounds 9–11. Reagents and conditions:
(i) CuCN, NMP, sealed tube, 170 °C, 96 h, 39%; (ii) Sn/HBr,
0°C→r.t., 1 h, 81%; (iii) Sn/HCl, 0°C→r.t., 2 h, 87%.
In summary, we have reported new synthetic methods from
2-chloro-3-nitroimidazo[1,2-a]pyridine 1 as a valuable scaffold
to perform metal-catalyzed reactions. The presence of the nitro
group in the 3-position was essential to develop functionalization
in the 2-position with aryles and amines. In particular, the
obtention of 2-arylimidazo[1,2-a]pyridin-3-amine derivatives is
an alternative to the multi-component reaction (MCR) Groebke-
Blackburn-Bienaymé reaction. Moreover, a broad range of
Table 3. Amination of 1 via SNAr, Buchwald or Ullmann-type
reactions in the 2-position.
Buchwald (yield %)
SNAr
(yield %)
Ullmann
(yield %)
Amine
Product
Classical
heating
MW
heating
Ph
NH2
8a
56
76
84
62
transformations of 2-chloro-3-nitroimidazo[1,2-a]pyridine
could offer highly diverse products derived from imidazo[1,2-
a]pyridine scaffold for medicinal chemistry.
1
35a
15b
37
–
83
56
10
–
Ph NH2
8b
8c
n-Pr
NH2
Acknowledgments
Ph
8d
–
5
–
0
The financial support from the Région des Pays de la Loire is
gratefully acknowledged.
Ph
NH
–: not implemented.
a Aniline: 2.4 equiv, t-BuOK: 2.6 equiv, 50 °C.
b n-Propylamine: 2.0 equiv, t-BuOK: 2.0 equiv, sealed tube, 80 °C.
References and notes
1.
Enguehard-Gueiffier, C.; Gueiffier, A. Mini-Rev. Med. Chem.
2007, 7, 888–899 and references cited herein.

5
2.
Shotwell, J. B.; Baskaran, S.; Chong, P.; Creech, K. L.; Crosby, R.
M.; Dickson, H.; Fang, J.; Garrido, D.; Mathis, A.; Maung, J.;
Parks, D. J.; Pouliot, J. J.; Price, D. J.; Rai, R.; Seal, J. W. III,
Schmitz, U.; Tai, V. W. F.; Thomson, M.; Xie, M.; Xiong, Z. Z.;
Peat, A. J. ACS Med. Chem. Lett. 2013, 3, 565–569; (b) Bode, M.
L.; Gravestock, D.; Moleele, S. S.; van der Westhuyzen, C. W.;
Pelly, S. C.; Steenkamp, P. A.; Hoppe, H. C.; Khan, T.; Nkabinde,
L. A. Bioorg. Med. Chem. 2011, 19, 4227–4237; (c) Hamdouchi,
C.; de Blas, J.; del Prado, M.; Gruber, J.; Heinz, B. A.; Vance, L.
J. Med. Chem. 1999, 42, 50–59; (d) Shukla, N. M.; Salunke, D.
B.; Yoo, E.; Mutz, C. A.; Balakrishna, R.; David, S. A. Bioorg.
Med. Chem. 2012, 20, 5850–5863.
(a) Hieke, M.; Rödl, C. B.; Wisniewska, J. M.; Buscató, E. l.;
Stark, H.; Schubert-Zsilavecz, M.; Steinhilber, D.; Hofmann, B.;
Proschak, E. Bioorg. Med. Chem. Lett. 2012, 22, 1969–1975; (b)
Abe, Y.; Kayakiri, H.; Satoh, S.; Inoue, T.; Sawada, Y.; Imai, K.;
Inamura, N.; Asano, M.; Hatori, C.; Katayama, A.; Oku, T.;
Tanaka, H. J. Med. Chem. 1998, 41, 564–578.
dissolved in dichloromethane and dried over sodium sulfate. The
aqueous filtrate was extracted with dichloromethane. The
combined organic layers were washed with brine, dried over
sodium sulfate, filtered and concentrated under vacuum. The crude
product was purified by silica gel chromatography using ethyl
acetate/petroleum ether (4/6) as eluent to afford 2-
chloroimidazo[1,2-a]pyridine as a white powder (20.0 g, 88%
yield). mp 76–77 °C; 1H NMR (400MHz, DMSO-d6) 8.53 (d, 3J
= 6.8 Hz, 1 H), 8.08 (s, 1 H), 7.56 (d, 3J = 9.0 Hz, 1 H), 7.35 (ddd,
3J = 9.0 Hz, 3J = 6.8 Hz, 4J = 1.2 Hz, 1 H), 7.02 (dd, 3J = 3J’ = 6.8
Hz, 1 H); 13C NMR (100 MHz, DMSO-d6) 143.22, 133.94,
126.78, 125.86, 116.20, 113.08, 109.12; IR (KBr) 3106, 1509,
1484, 744 cm-1; MS (ESI) m/z (%): 152.9 (100) [M+H]+, 155.0
(40) [M+H+2]+. 2-Chloroimidazo[1,2-a]pyridine (18.0 g, 118
mmol) was slowly added to concentrated sulfuric acid (178 mL)
cooled to – 5 °C keeping the temperature above 5 °C. To the
solution was added nitric acid (18 mL), keeping the temperature
above 5 °C too. At the end of the addition, the mixture was
allowed to reach room temperature and then stirred for 3.5 h. The
mixture was poured onto ice and the formed precipitate was
collected by filtration and dissolved in dichloromethane. The
organic layer was dried over sodium sulfate, filtered and
concentrated under vacuum to give 2-chloro-3-nitroimidazo[1,2-
a]pyridine 1 as a yellow powder (18.9 g, 81% yield). mp 175–176
°C; 1H NMR (400MHz, DMSO-d6) 9.39 (d, 3J = 7.2 Hz, 1 H),
7.97–7.90 (m, H7, 2 H), 7.57 (ddd, 3J = 8.4 Hz, 3J = 7.2 Hz, 4J =
1.6 Hz, 1 H); 13C NMR (100 MHz, DMSO-d6) 143.15, 138.67,
3.
4.
5.
Hanson, S. M.; Morlock, E. V.; Satyshur, K. A.; Czajkowski, C. J.
Med. Chem. 2008, 51, 7243–7252.
Trabanco, A. A.; Tresadern, G.; Macdonald, G. J.; Vega, J. A.; de
Lucas, A. I.; Matesanz, E.; Garcia, A.; Linares, M. L.; Alonso de
Diego, S. A.; Alonso, J. M.; Oehlrich, D.; Ahnaou, A.;
Drinkenburg, W.; Mackie, C.; Andrés, J. I.; Lavreysen, H.; Cid, J.
M. J. Med. Chem. 2012, 55, 2688–2701.
Kaminski, J. J.; Doweyko, A. M. J. Med. Chem. 1997, 40, 427–
436.
(a) Burchak, O. N.; Mugherli, L.; Ostuni, M.; Lacapère, J. J.;
Balakirev, M. Y. J. Am. Chem. Soc. 2011, 133, 10058–10061; (b)
Stasyuk, A. J.; Banasiewicz, M.; Cyrański, M. K.; Gryko, D. T. J.
Org. Chem. 2012, 77, 5552–5558.
6.
7.
132.84, 128.66, 127.50, 117.75, 117.38; IR (KBr) 3114, 1507,
1450, 1477, 1347, 768, 749 cm-1; MS (ESI) m/z (%): 197.9 (100)
[M+H]+, 199.9 (35) [M+H+2]+.
17. Recently, 3-nitro-2-phenylimidazo[1,2-a]pyridine was obtained
from 2-aminopyridine and (E)-(2-nitrovinyl)benzene: Yan, R.-L.;
Yan, H.; Ma, C.; Ren, Z.-Y.; Gao, X.-A.; Huang, G.-S.; Liang, Y.-
M. J. Org. Chem. 2012, 77, 2024–2028.
18. Hand, E. S.; Paudler, W. W. J. Org. Chem. 1978, 43, 658–663.
19. General procedure for Suzuki coupling: 2-(4-fluorophenyl)-3-
nitroimidazo[1,2-a]pyridine (3c). To a solution of 2-chloro-3-
nitroimidazo[1,2-a]pyridine (100 mg, 0.5 mmol) in a mixture
dimethoxyethane–water (12 mL, 2:1) was added 4-
8.
9.
Marhadour, S.; Marchand, P.; Pagniez, F.; Bazin, M.-A.; Picot, C.;
Lozach, O.; Ruchaud, S.; Antoine, M.; Meijer, L.; Rachidi, N.; Le
Pape, P. Eur. J. Med. Chem. 2012, 58, 543–556.
(a) Hand, E. S.; Paudler, W. W. J. Org. Chem. 1976, 41, 3549–
3556; (b) Leonardi, A.; Motta, G.; Riva, C.; Poggesi, E.; Graziani,
D. PCT Int. Appl. 2010089119, 2010; Chem. Abstr. 2010, 153,
311117; (c) Leonardi, A.; Motta, G.; Riva, C.; Poggesi, E.;
Graziani, D.; Longhi, M. M. PCT Int. Appl. 2009015897, 2009;
Chem. Abstr. 2009, 150, 168179.
fluorophenylboronic acid (85 mg, 0.6 mmol), sodium carbonate
(134 m g, 1.3 mmol) and Pd(PPh3)4 (5% mol, 30 mg). The
suspension was then purged with argon through the septum inlet
for 5 min and heated at reflux for 3 h. After cooling, the resulting
mixture was diluted with dichloromethane. Water was added and
the organic layer was extracted with dichloromethane. The
combined organic layers were washed with water, dried over
sodium sulfate, filtered and concentrated under vacuum. The crude
product was purified by silica gel chromatography using
dichloromethane/ethanol (99:1) as eluent to afford 2-(4-
fluorophenyl)-3-nitroimidazo[1,2-a]pyridine 3c as a yellow
powder (126 mg, 97% yield). mp 227–228 °C; 1H NMR
(400MHz, DMSO-d6) 7.40 (dd, 3J = 8.8 Hz, 3J = 8.8 Hz, 2 H),
7.53 (ddd, 3J = 7.0 Hz, 3J = 7.0 Hz, 4J = 1.2 Hz, 1 H), 7.87–7.91
(m, 1 H), 7.94–8.02 (m, 3 H), 9.47 (dd, 3J = 7.0 Hz, 4J = 1.2 Hz, 1
H); 13C NMR (100 MHz, DMSO-d6) 114.96 (d, 2JC-F = 21 Hz, 2
C), 117.17, 117.78, 128.44, 128.67 (d, 4JC-F = 3 Hz), 128.86,
131.96, 132.34 (d, 3JC-F = 9 Hz, 2 C), 144.63, 148.10, 162.95 (d,
1JC-F = 246 Hz); IR (KBr) 3032, 1605, 1481, 1366, 1327, 1211,
833, 756 cm-1; MS (ESI) m/z (%): 258.1 (100) [M+H]+; Anal.
Calcd for C13H8FN3O2: C 60.70; H 3.13; N 16.34. Found: C 61.03;
H 3.05; N 16.68%.
10. Tran, V. C.; Dao, D. T.; Tran, V. L.; Van Sung, T. Tap Chi Hoa
Hoc 2007, 45, 781–784.
11. Ohta, K.; Minami, K.; Yoshikawa, H.; Ishida, Y. Biosci.
Biotechnol. Biochem. 1993, 57, 1844–1848.
12. Newton, C. G.; Ollis, W. D.; Wright, D. E. J. Chem. Soc., Perkin
Trans. 1 1984, 1, 69–73.
13. (a) Désaubry, L.; Wermuth, C. G.; Bourguignon, J.-J. Tetrahedron
Lett. 1995, 36, 4249–4252; (b) Salomé, C.; Schmitt, M.;
Bourguignon, J.-J. Tetrahedron Lett. 2009, 50, 3798–3800.
14. (a) Groebke, K.; Weber, L.; Mehlin, F. Synlett 1998, 661–663; (b)
Blackburn, C.; Guan, B.; Fleming, P.; Shiosaki, K.; Tsai, S.
Tetrahedron Lett. 1998, 39, 3635–3638; (c) Bienaymé, H.;
Bouzid, K. Angew. Chem. Int. Ed. 1998, 37, 2234–2237.
15. Marhadour, S.; Bazin, M.-A.; Marchand, P. Tetrahedron Lett.
2012, 53, 297–300.
16. Three-step synthesis of 2-chloro-3-nitroimidazo[1,2-a]pyridine 1.
To chloroacetic acid (19.0 g, 201 mmol) in water (31 mL) was
added triethylamine (32 mL, 232 mmol) dropwise at room
temperature. After stirring for 10 min, 2-aminopyridine (23.0 g,
244 mmol) was added and the resulting brown solution was
warmed to 90 °C for 5 h. After cooling to room temperature,
ethanol (21 mL) was added and the suspension was stirred at 5 °C
for 2 h. The precipitate was collected by filtration and washed
with cold ethanol to afford (2-iminopyridin-1(2H)-yl)acetic acid
as a white powder (26.4 g, 71% yield). mp 257–258 °C; 1H NMR
(400MHz, DMSO-d6) 7.35 (d, 3J = 6.4 Hz, 1 H), 6.90 (ddd, 3J =
8.6 Hz, 3J = 6.4 Hz, 4J = 2.0 Hz, 1 H), 6.42 (d, 3J = 8.6 Hz, 1 H),
5.78 (dd, 3J = 3J’ = 6.4 Hz, 1 H), 3.32 (s, 2 H); 13C NMR (100
MHz, DMSO-d6) 158.34, 139.38, 135.32, 119.07, 103.36, 38.76;
20. Blackburn, C.; Guan, B. Tetrahedron Lett. 2000, 41, 1495–1500.
21. General procedure for the synthesis of ureas 6a-f: 1-ethyl-3-(2-
phenylimidazo[1,2-a]pyridin-3-yl)urea (6a). To a solution of 2-
phenylimidazo[1,2-a]pyridin-3-amine 4 (100 mg, 0.48 mmol, 1
equiv.) in dimethylformamide (2 mL) was added ethyl isocyanate
(75 L, 0.96 mmol, 2 equiv.). The suspension was heated at 80 °C
for 16 h. After cooling, the solvent was removed under reduced
pressure. The crude product was purified by silica gel
IR (KBr) 3246, 3041, 1701, 1627, 1586 cm-1; MS (ESI) m/z (%):
153.0 (100) [M+H]+. To (2-iminopyridin-1(2H)-yl)acetic acid
(23.0 g, 151 mmol) in toluene (200 mL) was added dropwise
phosphorus oxychloride (42.0 mL, 453 mmol) at room
temperature. The reaction mixture was refluxed for 16 h and
cooled to room temperature. Cold water (500 mL) was added and
the solution was stirred for 15 min. The layers were separated. In
an ice bath, the aqueous layer was neutralized with 10% sodium
hydroxide aqueous solution. The precipitate was filtered,
chromatography using EtOAc/petroleum ether/ (2:3) as eluent to
afford 1-ethyl-3-(2-phenylimidazo[1,2-a]pyridin-3-yl)urea 6a as a
beige powder (74 mg, 55% yield). mp 190–191 °C; 1H NMR
(400MHz, DMSO-d6) 3.18–2.99 (m, 5 H), 6.99 (dd, 3J = 3J’ = 6.8
Hz, 1 H), 7.41–7.36 (m, 2 H), 7.49 (dd, 3J = 3J’ = 7.4 Hz, 2 H),
7.70 (d, 3J = 9.2 Hz, 1 H), 7.85 (d, 3J = 7.4 Hz, 2 H), 8.05 (d, 3J =
6.8 Hz, 1 H), 8.32–8.29 (m, 2 H); 13C NMR (100 MHz, DMSO-d6)
14.96, 35.03, 112.85, 114.65, 117.31, 123.30, 125.80, 126.26 (2

6
Tetrahedron
C), 128.13, 128.82 (2 C), 133.33, 139.37, 143.10, 154.30 (C=O);
Anal. Calcd for C18H14N4: C 75.51; H 4.93; N 19.57. Found: C
75.41; H 5.00; N 19.59%.
IR (KBr) 3254, 2970, 1722, 1634, 1501, 1485 cm-1; MS (ESI)
m/z (%): 281.1 (100) [M+H]+; Anal. Calcd for C16H16N4O: C
68.55; H 5.75; N 19.99. Found: C 68.88; H 5.96; N 19.78%.
22. Sandulenko, Y.; Komarov, A.; Rufanov, K.; Krasavin, M.
25. Paolini, J. P.; Robins, R. K. J. Org. Chem. 1965, 30, 4085–4090.
26. (a) Arias, L.; Salgado-Zamora, H.; Cervantes, H.; Campos, E.;
Reyes, A.; Taylor, E. C. J. Heterocyclic Chem. 2006, 43, 565–
569; (b) Marquez-Flores, Y. K.; Campos-Aldrete, M. E.; Salgado-
Zamora, H.; Correa-Basurto, J.; Melendez-Camargo, M. E. Med.
Tetrahedron Lett. 2008, 49, 5990–5993.
23. (a) Dahan-Farkas, N.; Langley, C.; Rousseau, A. L.; Yadav, D.
B.; Davids, H.; de Koning, C. B. Eur. J. Med. Chem. 2011, 46,
4573–4583; (b) Al-Tel, T. H.; Al-Qawasmeh, R. A. Eur. J. Med.
Chem. 2010, 45, 5848–5855.
Chem. Res. 2012, 21, 775–782.
27. For a recent review on Pd-catalyzed aminations of aryl halides,
see Surry, D. S.; Buchwald, S. L. Chem. Sci. 2011, 2, 27–50 and
references cited therein.
24. General procedure for Buchwald-Hartwig amination (Cpds 7a-e):
2-Phenyl-N-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-amine (7d). To
a 10 mL vial with a magnetic stir bar were added 2-
28. For a recent review on Cu-catalyzed aminations, see Monnier, F.;
Taillefer, M. Angew. Chem. Int. Ed. 2009, 48, 6954–6971 and
references cited therein.
phenylimidazo[1,2-a]pyridin-3-amine 4 (100 mg, 0.48 mmol, 1
equiv.), 3-bromopyridine (46 L, 0.48 mmol, 1 equiv.), Pd2(dba)3
(22 mg, 0.02 mmol, 0.04 equiv.), BINAP (45 mg, 0.07 mmol, 0.15
equiv.) and sodium tert-butoxide (46 mg, 0.48 mmol, 1 equiv.) in
toluene (3.0 mL). The vial was sealed and purged with argon
through the septum inlet for 5 min. The suspension was then
heated at 110 °C for 16 h. After cooling, the resulting mixture was
diluted with ethyl acetate. Water was added and the organic layer
was extracted, washed with brine, dried over sodium sulfate,
filtered and concentrated under vacuum. The crude product was
purified by silica gel chromatography using EtOAc/petroleum
ether/ (3:2) as eluent to afford 2-phenyl-N-(pyridin-3-
29. (a) Loidreau, Y.; Marchand, P.; Dubouilh-Benard, C.; Nourrisson,
M.-R.; Duflos, M.; Loaëc, N.; Meijer, L.; Besson, T. Eur. J. Med.
Chem. 2013, 59, 283-295; (b) Loidreau, Y.; Marchand, P.;
Dubouilh-Benard, C.; Nourrisson, M.-R.; Duflos, M.; Besson, T.
Tetrahedron Lett. 2012, 53, 944–947; (c) Loidreau, Y.; Marchand,
P.; Dubouilh-Benard, C.; Nourrisson, M.-R.; Duflos, M.; Lozach,
O.; Loaëc, N.; Meijer, L.; Besson, T. Eur. J. Med. Chem., 2012,
58, 171-183; (d) Loidreau, Y.; Besson, T. Tetrahedron 2011, 67,
4852–4857; (e) Foucourt, A.; Dubouilh-Benard, C.; Chosson, E.;
Corbière, C.; Buquet, C.; Iannelli, M.; Leblond, B.; Marsais, F.;
yl)imidazo[1,2-a]pyridin-3-amine 7d as a beige powder (40 mg,
29% yield). mp 234–235 °C ; 1H NMR (400MHz, DMSO-d6)
6.74 (dd, 3J = 8.2 Hz, 4J = 1.2 Hz, 1 H), 6.97 (dd, 3J = 3J’ = 6.8
Hz, 1 H), 7.15 (dd, 3J = 8.2 Hz, 3J = 4.8 Hz, 1 H), 7.31–7.39 (m, 2
H), 7.44 (dd, 3J = 3J’ = 7.2 Hz, 2 H), 7.68 (d, 3J = 9.2 Hz, 1 H),
7.99 (d, 3J = 4.8 Hz, 1 H), 8.04–8.07 (m, 4 H), 8.54 (s, 1 H, NH);
13C NMR (100 MHz, DMSO-d6) 112.64, 117.40, 117.97, 119.21,
123.24, 124.35, 125.48, 126.58 (2 C), 127.81, 128.70 (2 C),
133.67, 136.15, 137.69, 139.99, 142.02, 142.13; IR (KBr) 3156,
2920, 1564, 1470 cm-1; MS (ESI) m/z (%): 287.2 (100) [M+H]+;
Besson, T. Tetrahedron 2010, 66, 4495–4502; (f) Baell, J. B.;
Street, I. P.; Sleebs, B. E. PCT Int. Appl. 2012131297, 2012;
Chem. Abstr. 2012, 157, 548660.
30. Dechambre, C.; Chezal, J. M.; Moreau, E.; Estour, F.;
Combourieu, B.; Grassy, G.; Gueiffier, A.; Enguehard, C.;
Gaumet, V.; Chavignon, O.; Teulade, J. C. Tetrahedron 2002, 43,
9119–9123.
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7
Graphical Abstract
Exploration of versatile reactions on 2-
chloro-3-nitroimidazo[1,2-a]pyridine:
expanding structural diversity of C2- and
C3-functionalized imidazo[1,2-a]pyridines
Leave this area blank for abstract info.
Marc-Antoine Bazin, Sophie Marhadour, Alain Tonnerre and Pascal Marchand
N
R5
N
Buchwald and
Ullmann-type
aminations
SNAr
N
N
NO2
NR3R4
Cl
N
N
Suzuki
NO2
NO2
N
R1
N
R1
N
N
NO2
NHR2