Short and efficient access to imidazo[1,2-a]pyrrolo[3,2-c]pyridine derivatives

Article abstract of DOI:10.1016/j.tetlet.2010.09.056

Access to N-protected or N-free imidazo[1,2-a]pyrrolo[3,2-c]pyridine derivatives as potential antiviral compounds was achieved in good yields from N-protected 7-amino-8-halo-2-methylimidazo[1,2-a]pyridines by catalytic coupling of terminal acetylenes under mild conditions using [PdCl₂(PPh ₃)₂] or [Cu(Phen)(PPh₃)₂]NO ₃.

Full text of DOI:10.1016/j.tetlet.2010.09.056

Tetrahedron Letters 51 (2010) 6082–6085
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Short and efficient access to imidazo[1,2-a]pyrrolo[3,2-c]pyridine derivatives
Vincent Gaumet a,b,c, , Emmanuel Moreau a,b,c, Abbass Taleb a, Fernand Leal a,b,c, Johan Neyts d,
⇑
Jan Paeshuyse d, Claire Lartigue a,b,c, Olivier Chavignon a,b,c, Alain Gueiffier e, Jean-Claude Teulade a,b,c
,
Jacques Métin a, Jean-Michel Chezal a,b,c
a UFR Pharmacie, Université Clermont 1, Université d’Auvergne, F-63001 Clermont-Ferrand, France
b Inserm, UMR 990, F-63005 Clermont-Ferrand, France
c Centre Jean Perrin, F-63011 Clermont-Ferrand, France
d Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
e UFR Sciences et Techniques, Université François Rabelais, F-37200 Tours, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 July 2010
Revised 6 September 2010
Accepted 10 September 2010
Available online 17 September 2010
Access to N-protected or N-free imidazo[1,2-a]pyrrolo[3,2-c]pyridine derivatives as potential antiviral
compounds was achieved in good yields from N-protected 7-amino-8-halo-2-methylimidazo[1,2-a]pyr-
idines by catalytic coupling of terminal acetylenes under mild conditions using [PdCl2(PPh3)2] or
[Cu(Phen)(PPh3)2]NO3.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Imidazo[1,2-a]pyridine
Imidazo[1,2-a]pyrrolo[3,2-c]pyridine
Heterocyclization
Palladium catalyst
Copper catalyst
1. Introduction
boxylate (1), obtained by condensation of chloroacetone with ethyl
2-aminopyridine-3-carboxylate, was converted to ethyl azidoprop-
Numerous imidazo[1,2-a]pyridine compounds are described in
the literature, especially for their therapeutic qualities, for example,
antifungal,1–3 antibacterial,4–8 analgesic, anti-inflammatory,9,10
enoate (2) in three steps followed by thermal annulations to give the
desired tricyclic ester in 7% overall yield.27,29
We extended our structure–activity relationship study to 7- and
8-substituted imidazo[1,2-a]pyrrolo[2,3-c]pyridine derivatives. To
this end, we explored the short, efficient synthetic methods devel-
oped by Larock and Sonogashira for the synthesis of indole ring
systems.30,31 We assessed the heteroannulation, catalyzed by cop-
per and palladium complexes, of N-protected 7-amino-8-haloimi-
dazo[1,2-a]pyridines with either terminal or internal alkynes, and
we explored the cyclization of 7-amino-8-alkyn-yl-imidazo[1,2-
a]pyridines mediated by strong bases or catalyzed by palladium
or copper complexes.
antiparasitic,11,12 antitumoral13–16 and antiviral activities.17–22
,
These compounds also include pharmaceutical agents such as the
cardiotonic olprinone23,24 and the hypnotic zolpidem.25,26 The reac-
tivity of various nitrogen bridgehead systems and especially the
imidazo[1,2-a]pyridine ring structure has been a subject of study
for several years in our laboratory. Recently we focused on the syn-
thesis of novel imidazo[1,2-a]pyrrolo[3,2-c]pyridine derivatives
(IPPs).27 The activities and mechanisms of action of these IPPs as
inhibitors of the replication of pestiviruses have been evaluated.
One, ethyl 2-methylimidazo[1,2-a]pyrrolo[2,3-c]pyridine-8-car-
boxylate (AG110), displayed a strong antiviral activity against the
bovine viral diarrhea virus.28
A broad range of 2- or 3-substituted alkyl imidazo[1,2-a]pyrrol-
o[2,3-c]pyridine-8-carboxylates, including the lead compound
AG110, have been prepared using the three-step procedure depicted
in Scheme 1. Briefly, ethyl 2-methylimidazo[1,2-a]pyridine-8-car-
⇑
Corresponding author. Tel.: +33 (0)473178004.
E-mail address: vincent.gaumet@u-clermont1.fr (V. Gaumet).
Scheme 1. AG110 synthesis.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.056

V. Gaumet et al. / Tetrahedron Letters 51 (2010) 6082–6085
6083
Table 1
2. Results and discussion
Selected results of screening for optimal conditionsa
Our building blocks, 7-amino-8-bromo(or iodo)-2-methylimi-
dazo[1,2-a]pyridines (5a, b), were prepared in two steps using reg-
iospecific halogenation of 2,4-diaminopyridine followed by
condensation with chloroacetone (Scheme 2). A methyl group
was chosen to occupy the 2-position as it was found to give the
best biological activity in our previous study.27
Our attempts to obtain 8- and/or 9-substituted IPPs via a one-
pot heteroannulation32–36 from 5a, b, compounds containing a free
amino group in position 7, failed with internal or terminal alkynes
(for conditions see Ref. 37). As the failure of the annulation process
could be attributed to the high nucleophilicity of the amino group,
we turned our attention to N-protected 7-amino-8-halo-2-methy-
limidazo[1,2-a]pyridine derivatives. The electron-withdrawing ef-
fect of the N-protecting groups is crucial to promote the
cyclization reaction. It has been demonstrated that the strong elec-
tron-withdrawing groups must be avoided because they lead to
highly acidic-substituted NH groups, which can be deprotonated
under the reaction conditions. The best results reported in the lit-
erature have been obtained by employing alkoxycarbonyl or triflu-
oroacetyl substituents.38–42 The primary amines 5a, b were thus
first substituted with an ethoxycarbonyl group, and the resulting
carbamates 6a, b then reacted with phenylacetylene under Sono-
gashira conditions to give the alkynyl 7a and/or the cyclized 8a
derivatives (Table 1). The cross-coupling reaction proved to be very
sensitive to the halogen on the substrate, the iodine derivative giv-
ing the best result (Table 1, entry 1 vs entry 2). We expected sim-
ilar yields with Pd(0) or Pd(II) catalysts, as Pd(0) species could be
generated in situ by reduction of [PdCl2(PPh3)2].33 The observed
difference (Table 1, entry 2 vs entry 3) was probably because
[PdCl2(PPh3)2] was more stable than [Pd(PPh3)4] toward air and
moisture. ortho-Iodo carbamate 6a was thus totally converted into
the alkenyl compound 7a in 91% yield when [PdCl2(PPh3)2] was
used as catalyst at room temperature (Table 1, entry 3). To promote
the heteroannulation reaction, temperature was increased, but
unfortunately attempts made under the same conditions at
100 °C resulted in the decomposition of starting materials (Table
1, entry 5). Heteroannulation was demonstrated to be effective
only when operating at 60 °C, causing the concomitant formation
of alkenyl 7a and N-protected tricyclic 8a compounds, respectively,
in 50% and 24% yields (Table 1, entry 4).
Entry
X
Pd-cat.
Temp (°C)
Recoveryb (%)
Yieldb (%)
6a, b
7a
8a
1
2
3
4
5
Br
I
I
I
I
[Pd(PPh3)4]
[Pd(PPh3)4]
[PdCl2(PPh3)2]
[PdCl2(PPh3)2]
[PdCl2(PPh3)2]
25
25
25
60
100
55
—
3
—
—
1
1
68
91
50
—
—
—
24
—
a
Reaction conditions: 6a, b (1.0 mmol), phenylacetylene (1.2 mmol), Pd catalyst
(2 mol %), CuI (20 mol %), Et3N (3 mmol), DMF (20 mL) under argon (1 atm) for 2 d.
b
Isolated yield.
53% and 8% yields, respectively. As before, decomposition was ob-
served above 100 °C.
Based on these disappointing results and in accordance with the
literature,44 we examined the Lewis acid-catalyzed cyclization in
1,2-dichloroethane at 65 °C of N-7-ethoxycarbonylamino-8-alky-
nyl derivatives. This reaction gave the corresponding N-protected
tricycle compounds 8a–d in moderate yields (Table 2, entry 4).
Alternatively, compounds 8a–d could be easily converted to the
free NH derivatives 10a–d by the use of tetrabutylammonium fluo-
ride with similar yields (Table 2, entry 5).
We next set out to prepare products 10a–d in a one-step proce-
dure from 6a via a copper-catalyzed coupling-cyclization-depro-
tection process already described for indole synthesis.45
Unfortunately, compound 6a was rapidly decomposed to resinous
products in the course of the reaction. By contrast, replacement of
the ethoxycarbonyl moiety by trifluoroacetyl group, giving 11 (Ta-
ble 2, entry 2), provided the expected compounds 10a–d (Table 2,
entry 6) in acceptable yields under the same conditions used for
6a. Using this last method, compounds 10a–d were obtained from
5a with a substantial improvement in the overall yields compared
with the three-step procedures involving alkynyl intermediates
7a–d (16–36% vs 4–15%).
As these uncyclized and cyclized isomers were difficult to sep-
arate by column chromatography, and in order to improve yields of
tricyclic compounds, we prepared IPPs in an integrated process
comprising two basic steps: (i) preparation of the alkynyl deriva-
tive by the palladium-catalyzed cross-coupling reaction with ter-
minal alkynes via a Sonogashira reaction43 using the conditions
reported in Table 1, entry 3, followed by (ii) intramolecular cycliza-
tion of NH to the triple bond.
First, 7a was heated with sodium ethoxide in ethanol at 60 °C
(Scheme 3). 8-Phenyl-2-methylimidazo[1,2-a]pyrrolo[3,2-c]pyri-
dine 10a was obtained in 22% yield with a concomitant formation
of the deprotected alkynyl compound 9 and starting material 7a in
In conclusion, the foregoing results suggest that these strategies
offer considerable advantages and inherent potential for the
Scheme 2. Preparation of 7-amino-8-halo-2-methylimidazo[1,2-a]pyridines.
Reagents and conditions: (i) for 4a: HIO4, I2, AcOH, H2O, H2SO4, 55 °C; (ii) for 4b:
Br2, AcOH, rt; (iii) chloracetone, EtOH, 65 °C.
Scheme 3. Heteroannulation of 7a with a strong base.

6084
V. Gaumet et al. / Tetrahedron Letters 51 (2010) 6082–6085
Table 2
Efficient routes for the synthesis of novel IPP derivatives
Entry
Conditions
Substrate
R
Product
Yielda (%)
1
2
3
(i) Ethyl chloroformate, NaHCO3, DMAP,CH2Cl2, rt, 20 h
(ii) TFAA, pyridine, CH2Cl2, rt, 15 h
(iii) Terminal alkyne, [PdCl2(PPh3)2], CuI, Et3N, DMF, rt, 2 d
5a
5a
6a
—
—
C6H5
p-CH3OC6H4
p-FC6H4
n-Bu
6a
11
7a
7b
7c
7d
8a
8b
44
64
91
25
70
61
56
17
44
40
36
35
43
55
56
37
25
40
4
5
6
(iv) Cu(OAc)2, 1,2-dichloroethane, 65 °C
7a
7b
7c
7d
7a
7b
7c
7d
11
C6H5
p-CH3OC6H4
p-FC6H4
n-Bu
8c
8d
(v) (n-Bu)4NF, THF, reflux, 1 d
C6H5
10a
10b
10c
10d
10a
10b
10c
10d
p-CH3OC6H4
p-FC6H4
n-Bu
(vi) Terminal alkyne, [Cu(phen)(PPh3)2]NO3, K3PO4, DMF, 115 °C, 2 d
C6H5
p-CH3OC6H4
p-FC6H4
n-Bu
a
Isolated yield.
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Supplementary data
Supplementary data (a complete description of experimental
details and product characterizations) associated with this article
can be found, in the online version, at doi:10.1016/j.tetlet.2010.
09.056.
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