New and efficient palladium(0)-mediated microwave-assisted direct C3 alkenylation of imidazo[1,2-a]pyridines

Article abstract of DOI:10.1055/s-2008-1067181

In this paper, we present the synthesis of 3-alkenylimidazo[1,2-a]pyridines in high to moderate yields by microwave direct palladium-catalyzed C-H alkenylation between bromoalkenes and imidazo[1,2-a]pyridines. The scope and limitation of the palladium(0)-catalyzed alkenylation method were investigated. Optimized conditions were successfully applied to a wide variety of imidazo[1,2-a]pyridine derivatives and bromoalkenes. The compatibility of the synthesis with the presence of a chlore substituent in the 6-position was investigated. The 6-chloroimidazo[1,2-a]pyridines were functionalized using Suzuki cross-coupling conditions to give polyfunctional compounds. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067181

PAPER
2537
New and Efficient Palladium(0)-Mediated Microwave-Assisted Direct C3
Alkenylation of Imidazo[1,2-a]pyridines
D
irec
t
C3
a
A
lkenylatio
m
n of Imidazo[1, 2-
aa
]pyridines l Koubachi,a,b Saïd El Kazzouli,a,b Sabine Berteina-Raboin,*a Abderrahim Mouaddib,b Gérald Guillaumeta
a
Institut de Chimie Organique et Analytique, UMR CNRS 6005, Université d’Orléans, BP 6759, 45067 Orléans Cedex 2, France
E-mail: sabine.berteina-raboin@univ-orleans.fr
b
Faculté des Sciences et Techniques de Beni-Mellal, Université Soultan Moulay Sliman, BP 523, 23000 Beni-Mellal, Morocco
Received 31 March 2008; revised 2 April 2008
(pathway D).20 Although these sequences were success-
ful, an additional step for the activation of the 3-position
is required and expensive reagents are utilized (alkenylbo-
ronic acids for the Suzuki reaction and alkenylstannanes
Abstract: In this paper, we present the synthesis of 3-alkenylimida-
zo[1,2-a]pyridines in high to moderate yields by microwave direct
palladium-catalyzed C–H alkenylation between bromoalkenes and
imidazo[1,2-a]pyridines. The scope and limitation of the palladi-
um(0)-catalyzed alkenylation method were investigated. Optimized for the Stille reaction).
conditions were successfully applied to a wide variety of imida-
The direct C–H arylation coupling of various heterocycles
zo[1,2-a]pyridine derivatives and bromoalkenes. The compatibility
of the synthesis with the presence of a chloro substituent in the 6-
position was investigated. The 6-chloroimidazo[1,2-a]pyridines
were functionalized using Suzuki cross-coupling conditions to give
polyfunctional compounds.
has received considerable attention.21 As far as we know,
only two methods for this C–C bond-forming reaction us-
ing either palladium or ruthenium-catalyzed direct alke-
nylation of heteroaromatic systems have been
reported.22,23
Key words: palladium-catalyzed coupling, alkenylation, imida-
zo[1,2-a]pyridines, microwave irradiation
Our group has a long-standing interest in imidazo[1,2-
a]pyridine derivatives.1,24 We previously developed a re-
gioselective palladium-catalyzed (hetero)arylation at the
3-position of imidazo[1,2-a]pyridines for both traditional
heating and microwave irradiation.25 Based on our experi-
ence we decided to investigate a similar method for C–H
alkenylation of imidazo[1,2-a]pyridines. The use of bro-
moalkenes as reactants in direct palladium-catalyzed C–H
alkenylation has not been performed with imidazo[1,2-
a]pyridines as substrates.
Nitrogen-bridgehead-fused heterocycles containing an
imidazole ring are a common structural motif in pharma-
cologically important molecules. These heterocycles dis-
play a wide range of biological activity, i.e., as melatonin
receptor ligands,1 antiviral,2 antiulcer,3 antibacterial,4 and
antifungal compounds,5 agonist of benzodiazepine recep-
tor,6 calcium channel blocker,7 b-amyloid formation in-
hibitor,8 ligand for detecting b-amyloid,9 herbicidal,10 and
cyclin-dependent kinases (CDK) inhibitors,11 and
GABAA receptor modulator,12 they also constitute a
novel class of orally active nonpeptide bradykinin B2 re-
ceptor antagonists.13 Moreover, the imidazo[1,2-a]pyri-
dine derivative Zolpidem is commercialized as a
hypnotic14 and Olprinone is available as an inhibitor of
PDE 3,15 as well as other experimental molecules.16
8
(A) bromination
or iodination
N 1
N
7
R2
2
R2
N
N
6
R1
R1
4
3
5
X
II
I
(B) Heck, (C) Stille or
(D) Suzuki coupling
X = Br or I
N
Herein, we report a new microwave synthesis of imida-
zo[1,2-a]pyridines with substituted alkenyl groups in the
3-position. In order to achieve high flexibility in the bro-
moalkenes, we chose a route to introduce them by direct
palladium-catalyzed C–H alkenylation. The key feature of
this method is the combination of C–H functionalization
and C–C bond-forming processes. To the best of our
knowledge, few approaches including palladium cross-
coupling are known for the preparation of 3-alkenylimida-
zo[1,2-a]pyridines III (Scheme 1) from imidazo[1,2-
a]pyridines I: pathway A, involving iodination or bromi-
nation of the 3-position2f,17 followed by Heck (pathway
B),1,2g,18 Stille (pathway C),19 or Suzuki cross-coupling
R2
N
R1
R3
III
Scheme 1
For these studies, the required imidazo[1,2-a]pyridine in-
termediates 1, 3, and 4 were prepared by condensation of
suitable 2-amino-5-substituted pyridines with a-halocar-
bonyl derivatives in refluxing ethanol according to the lit-
erature procedure.26
To optimize the reaction conditions, we initially chose to
investigate the direct cross-coupling alkenylation between
2-bromopropene and 6-chloroimidazo[1,2-a]pyridine (1)
as a model reaction. We first tested conditions already de-
scribed in our laboratories for the (hetero)arylation
reaction25 [2-bromopropene (2 equiv), Pd(OAc)2 (10
SYNTHESIS 2008, No. 16, pp 2537–2542
x
x.
x
x
.
2
0
0
8
Advanced online publication: 17.07.2008
DOI: 10.1055/s-2008-1067181; Art ID: Z07508SS
© Georg Thieme Verlag Stuttgart · New York

2538
J. Koubachi et al.
PAPER
mol%), PPh3 (20 mol%), K2CO3 (2 equiv), DMF, micro- Table 2 Alkenylation of Various Imidazo[1,2-a]pyridines under
Microwave Irradiation
wave irradiation, 130 °C] (Scheme 2). Thus, treatment of
6-chloroimidazo[1,2-a]pyridine (1) under these condi-
tions for one or two hours gave 2 in 58% and 59% yields,
respectively (Table 1, entries 1 and 2). Using 20 mol% of
palladium(II) acetate and 40 mol% of triphenylphosphine
for two hours under the same reaction conditions gave
compound 2 in 66% yield (Table 1, entry 3). Replacement
of potassium carbonate with cesium carbonate afforded a
similar yield (Table 1, entry 4). The use of sodium carbon-
ate as the base led to a decrease in the yield to 26%
(Table 1, entry 5). Stimulated by these observations, we
decided to optimize other parameters. The use of palladi-
um(II) acetate/triphenylphosphine system and silver car-
bonate/triethylamine as base resulted in the formation of
2 in 63% yield (Table 1, entry 6). No significant effect on
the yield was observed by using palladium(II) acetate/
triphenylarsine as catalyst and cesium carbonate as base
(Table 1, entry 7). Increasing the amounts of palladi-
um(II) acetate (0.2 equiv), triphenylarsine (0.4 equiv), and
silver carbonate (2 equiv) in a mixture of N,N-dimethyl-
formamide and triethylamine (2:1) under microwave irra-
diation at 130 °C for two hours afforded 2 with total
conversion and in 71% yield (Table 1, entry 8).
Entry
X
R1
Product Yield (%)
R3
R4
R2
1
2
Cl
Cl
H
H
2
5
71
56
Me
Ph
O
Me
Me
3
4
Cl
Cl
H
H
6
7
60
54
Ph
Ph
Ph
5
Cl
H
8
0
H
O
N
N
H
6
Cl
H
9
61
O
Me
O
N
Pd(0), base, DMF
N
N
N
130 °C, MW
Br
Me
+
N
N
7
8
9
H
H
H
H
H
H
10
11
12
69
55
52
Me
Cl
Me
Cl
Me
1
2
Ph
Scheme 2
O
Table 1 Optimization of the Alkenylation Reaction on 6-Chloro-
imidazo[1,2-a]pyridine under Microwave Irradiation
Me
O
N
N
Entry Pd (equiv), ligand (equiv)
Base
Time Yield
(h)
(%)
58
59
66
68
26
63
61
71
Me
10
H
H
H
H
Ph
Ph
Ph
Ph
13
13
13
14
26
42
43
48
Me
1
2
3
4
5
6
7
8
Pd(OAc)2 (0.1), PPh3 (0.2)
Pd(OAc)2 (0.1), PPh3 (0.2)
Pd(OAc)2 (0.2), PPh3 (0.4)
Pd(OAc) (0.2), PPh3 (0.4)
Pd(OAc)2 (0.2), PPh3 (0.4)
Pd(OAc)2 (0.2), PPh3 (0.4)
K2CO3
1
K2CO3
2
11a
12b
13a
Me
Me
Ph
K2CO3
2
Cs2CO3
Na2CO3
Ag2CO3, Et3N
2
2
2
Pd(OAc)2 (0.2), AsPh3 (0.4) Cs2CO3
2
a Reaction conditions : Pd(OAc)2 (0.2 equiv), AsPh3 (0.4 equiv);
130 °C for 4 h.
Pd(OAc)2 (0.2), AsPh3 (0.4) Ag2CO3, Et3N
2
b Reaction conditions : Pd(OAc)2 (0.2 equiv), AsPh3 (0.4 equiv),
150 °C for 4 h.
Pd(OAc)2 (0.2 equiv)
AsPh3 (0.4 equiv), Ag2CO3/Et3N
N
N
DMF, 130 °C, MW, 2 h
R1
R1
With these reaction conditions [Pd(OAc)2, AsPh3,
Ag2CO3, Et3N, DMF] in hand, we evaluated the scope and
limitation of our method using various imidazo[1,2-a]py-
ridines and bromoalkenes (Scheme 3, Table 2). Thus,
under microwave irradiation, the alkenylation of imida-
zo[1,2-a]pyridines 1, 3, and 4 with two equivalents of dif-
N
N
R4
R3
Br
R2
X
R4
X
1, X = Cl, R1 = H
3, X = H, R1 = H
4, X = H, R1 = Ph
R2
R3
2 and 5–14
Scheme 3
Synthesis 2008, No. 16, 2537–2542 © Thieme Stuttgart · New York

PAPER
Direct C3 Alkenylation of Imidazo[1,2-a]pyridines
2539
Pd(PPh3)4 (0.1 equiv), NaOH (2 equiv)
ferent alkenyl bromides proceeded to give the desired
products 2, 5–12, and 13, 14, respectively, in high to mod-
erate yields (Table 2). In contrast, the reaction between 4
and 2-bromopropene at 130 °C for either two or four
hours, afforded compound 13 in low yields of 26% and
42%, respectively; irradiation at 150 °C also failed to im-
prove the yield (43%, Table 2, entry 12).
RB(OH)2 (1.2 equiv), DME–H2O
N
N
150 °C, MW
N
N
Cl
R
Me
Me
1
18–20
Scheme 5
Indeed, the reaction was not complete and starting materi-
al was recovered (Table 2, entries 10–12). This result is
probably due to the presence of the phenyl group in the 2-
position. A similar yield was obtained for reactions be-
tween 2-bromostyrene and 4 (Table 2, entry 13). The pro-
posed mechanism for direct alkenylation reaction of 6-
chloroimidazo[1,2-a]pyridine with 2-bromopropene can
be subdivided into five parts: (A) insertion of the alkene
into the Pd–C bond; (B) nucleophilic attack by the 3-posi-
tion of the 6-chloroimidazo[1,2-a]pyridine 1 on to the iso-
propenylpalladium halide species 15 to form 16; (C)
deprotonation to give the isopropenyl(6-chloroimida-
zo[1,2-a]pyridin-3-yl)palladium(II) intermediate 17; (D)
reductive elimination to give product 2; and (E) regenera-
tion of the palladium(0) catalyst (Scheme 4).
Table 3 Suzuki Cross Coupling of 3-Alkenyl-6-chloroimidazo[1,2-
a]pyridine under Microwave Irradiation
Entry
R
Compound
Yield (%)
1
2
3
4-MeOC4H4
3-AcC6H4
Ph
18
19
20
64
68
60
In conclusion, the study reported provides a new method
for the direct alkenylation of the 3-position of imida-
zo[1,2-a]pyridines with bromoalkenes. We found condi-
tions to generate selectively 3-alkenylimidazo[1,2-
a]pyridines by investigating palladium-catalyzed regiose-
lective alkenylation. We also report the tolerance of the
alkenylation reaction conditions with the presence of a
chloro group that was later used for the synthesis of poly-
functional compounds. Further investigations to extend
the scope of this method to other classes of heterocycles
are currently being investigated.
N
Br
N
Pd(0)
Cl
Me
2
A
Me
E
D
N
Me
Br
All reagents were purchased from Sigma-Aldrich, Acros Organics,
and Alfa Aesar and used without further purification. Microwave-
assisted reactions were carried out in a Biotage Initiator microwave
synthesis instrument and temperatures were measured by an IR sen-
sor. Melting points were determined with a Büchi SMP-20 melting
N
Pd
Cl
Me
Cl
15
17
Pd
N
B
C
N
N
Cl
1
point apparatus and were uncorrected. H and 13C NMR were re-
N
1
corded on a Bruker Avance DPX250 spectrometer (250.19 MHz 1H,
62.89 MHz 13C) using TMS as the internal standard, multiplicities
were determined by the DEPT 135 sequence. HRMS were recorded
with a TOF spectrometer (ESI mode) or with a Finnigan MAT 95
XL (CI mode) at the Regional Center of Physical Measurement
University Blaise Pascal. All commercial solvents were used with-
out further purification. Column chromatography was carried out
using Silica gel 60N (spherical, neutral, 40–63 mm, Merck); PE =
petroleum ether. TLC was carried out on Merck silica gel 60F254
precoated plates and visualized with UV light.
Me
16
H
Pd
base:
Scheme 4
In this work, we have demonstrated the compatibility of
the alkenylation reactions conditions with the presence of
a chloro substituent in the 6-position, which could be im-
portant for the introduction of various substitutions using
a palladium cross-coupling reaction thus giving highly di-
verse structures. To explore the potential of this approach,
after initial optimization studies, we found the best reac-
tion conditions. Thus, 6-chloro-3-isopropenylimidazopy-
ridine 1 was treated with different arylboronic acids (1.2
equiv), tetrakis(triphenylphosphine)palladium(0) (0.1
equiv), and sodium hydroxide (2 equiv) in a mixture of
1,2-dimethoxyethane–water (3:1) under microwave irra-
diation at 150 °C for 75 minutes. These conditions afford-
ed 3,6-disubstituted imidazo[1,2-a]pyridines 18–20 in
good yields (Scheme 5, Table 3).
3-Alkenylimidazo[1,2-a]pyridines 2, 5–14 by Microwave Irradi-
ation; General Procedure
To a soln of imidazo[1,2-a]pyridine (0.1 g) dissolved in DMF–Et3N
(2:1, 2 mL) in a vial microwave tube was added, under argon, a stir-
rer bar, bromoalkene (2 equiv), Ag2CO3 (2 equiv), AsPh3 (0.4
equiv), and Pd(OAc)2 (0.2 equiv). The vial was sealed with a silicon
septum and subjected to microwave irradiation (1–12: at 130 °C for
2 h; 13, 14: at 150 °C, for 4 h) with stirring. The reaction vessel was
allowed to cool to r.t., diluted with CH2Cl2 (15 mL) and extracted (3
×). The combined organic layers were dried (MgSO4) and concen-
trated under vacuum. The residue was purified by column chroma-
tography (silica gel, EtOAc–PE) to give the desired product.
6-Chloro-3-isopropenylimidazo[1,2-a]pyridine (2)
Yellow oil; yield: 71%.
Synthesis 2008, No. 16, 2537–2542 © Thieme Stuttgart · New York

2540
J. Koubachi et al.
PAPER
1H NMR (250 Hz, CDCl3): d = 2.23 (s, 3 H), 5.33 (s, 1 H), 5.36 (s,
1 H), 7.13 (dd, J = 1 Hz, J = 9.5 Hz, 1 H), 7.56 (d, J = 9.5 Hz, 1 H),
7.65 (s, 1 H), 8.43 (d, J = 1 Hz, 1 H).
1H NMR (250 Hz, CDCl3): d = 5.60 (d, J = 1.2 Hz, 1 H), 5.74 (d,
J = 1.2 Hz, 1 H), 6.61 (m, 1 H), 7.13 (m, 1 H), 7.27–7.57 (m, 5 H),
7.61 (m, 2 H), 7.70 (s, 1 H).
13C NMR (62.5 Hz, CDCl3): d = 23.5, 113.1, 118.6, 121.1, 123.1,
125.5, 126.6, 132.6, 133.8, 144.9.
13C NMR (62.5 Hz, CDCl3): d = 112.1, 117.1, 118.1, 124.2, 125.1,
127.1, 128.7, 128.9, 134.5, 137.6, 138.5, 146.5.
HRMS: m/z [M + H]+ calcd for C10H9ClN2: 193.0533; found:
HRMS: m/z [M + H]+ calcd for C15H12N2: 221.1079; found:
193.0533.
221.1078.
6-Chloro-3-(2-methylpropenyl)imidazo[1,2-a]pyridine (5)
Beige solid; yield: 56%; mp 100–101 °C.
5-(Imidazo[1,2-a]pyridin-3-yl)-1,3-dimethylpyrimidine-
2,4(1H,3H)-dione (12)
Yellow solid; yield: 52%; mp 197–198 °C.
1H NMR (250 Hz, CDCl3): d = 1.94 (s, 3 H), 2.03 (s, 3 H), 6.11 (s,
1 H), 7.13 (dd, J = 1.5 Hz, J = 9.5 Hz, 1 H), 7.55 (dd, J = 1.5 Hz,
J = 9.5 Hz, 1 H), 7.59 (s, 1 H), 8.02 (d, J = 1.5 Hz, 1 H).
13C NMR (62.5 Hz, CDCl3): d = 20.6, 26.7, 109.8, 118.3, 120.7,
121.3, 123.4, 125.1, 133.6, 140.4, 143.2.
HRMS: m/z [M + H]+ calcd for C11H11ClN2: 207.0689; found:
207.0699.
1H NMR (250 Hz, CDCl3): d = 3.44 (s, 3 H), 3.5 (s, 3 H), 6.81 (t,
J = 6.7 Hz, 1 H), 7.22 (t, J = 7.6 Hz, 1 H), 7.44 (s, 1 H), 7.59 (m, 2
H), 7.91 (d, J = 6.7 Hz, 1 H).
13C NMR (62.5 Hz, CDCl3): d = 28.4, 37.4, 103.4, 112.2, 117.8,
118.2, 124.9, 125.8, 133.4, 143.3, 146.9, 151.4, 161.4.
HRMS: m/z [M + H]+ calcd for C13H12N4O2: 257.1039; found:
257.1026.
6-Chloro-3-(1-phenylvinyl)imidazo[1,2-a]pyridine (6)
Brown oil; yield: 60%.
3-Isopropenyl-2-phenylimidazo[1,2-a]pyridine (13)
Yellow oil; yield: 43%.
1H NMR (250 Hz, CDCl3): d = 5.61 (d, J = 0.75 Hz, 1 H), 5.81 (d,
J = 0.75 Hz, 1 H), 7.13 (dd, J = 1.8 Hz, J = 9.5 Hz, 1 H), 7.27–7.38
(m, 5 H), 7.6 (d, J = 9.5 Hz, 1 H), 7.68 (m, 2 H).
13C NMR (62.5 Hz, CDCl3): d = 117.8, 118.5, 120.7, 123.0, 125.8,
127.1, 129.1, 129.2, 135.2, 137.2, 138.1.
HRMS: m/z [M + H]+ calcd for C15H11ClN2: 255.0689; found:
255.0692.
1H NMR (250 Hz, CDCl3): d = 2.06 (s, 3 H), 5.39 (s, 1 H), 5.71 (s,
1 H), 6.77 (t, J = 7.2 Hz, 1 H), 7.16 (t, J = 9.1 Hz, 1 H), 7.31 (t,
J = 7.2 Hz, 1 H), 7.42 (m, 2 H), 7.63 (d, J = 9.1 Hz, 1 H), 7.93 (m,
2 H), 8.11 (d, J = 7.2 Hz, 1 H).
13C NMR (62.5 Hz, CDCl3): d = 22.6, 112.2, 117.6, 121.4, 122.1,
123.7, 124.3, 127.8, 127.9, 128.5, 134.6, 134.9, 141.4, 144.7.
HRMS: m/z [M + H]+ calcd for C16H14N2: 235.1235; found:
6-Chloro-3-(triphenylvinyl)imidazo[1,2-a]pyridine (7)
235.1242.
Yellow solid; yield: 54%; mp 177–178 °C.
2-Phenyl-3-(1-phenylvinyl)imidazo[1,2-a]pyridine (14)
Yellow oil; yield: 48%.
1H NMR (250 Hz, CDCl3): d = 6.94–7.17 (m, 16 H), 7.28 (s, 1 H),
7.47 (d, J = 9.4 Hz, 1 H), 7.52 (d, J = 1.2 Hz, 1 H).
13C NMR (62.5 Hz, CDCl3): d = 117.9, 120.2, 122.3, 125.2, 125.9,
127.0, 127.4, 127.6, 127.8, 128.0, 128.2, 128.3, 129.5, 130.8, 131.5,
137.2, 140.1, 142.2, 143.2, 144.7.
HRMS: m/z [M + H]+ calcd for C27H19ClN2: 407.1315; found:
407.1312.
1H NMR (250 Hz, CDCl3): d = 5.56 (s, 1 H), 6.15 (s, 1 H), 6.61 (t,
J = 6.7 Hz, 1 H), 7.14 (t, J = 7.7 Hz, 1 H), 7.24–7.35 (m, 8 H), 7.63
(m, 2 H), 7.93 (m, 2 H).
13C NMR (62.5 Hz, CDCl3): d = 112.2, 117.5, 120.2, 121.4, 124.3,
124.7, 126.3, 127.7, 128.0, 128.4, 128.8, 129.1, 134.2, 137.7, 137.7,
143.6, 144.9.
5-(6-Chloroimidazo[1,2-a]pyridin-3-yl)-1,3-dimethylpyrimi-
dine-2,4(1H,3H)-dione (9)
HRMS: m/z [M + H]+ calcd for C21H16N2: 297.1392; found:
297.1398.
Yellow solid; yield: 61%; mp 205–206 °C.
6-Aryl-3-isopropenylimidazopyridines; General Procedure
To a soln of 6-chloro-3-isopropenylimidazo[1,2-a]pyridine (0.1 g,
0.52 mmol) dissolved in DME–H2O (2:1, 2 mL) in a vial microwave
tube were added under argon a stirrer bar, arylboronic acid (1.2
equiv), NaOH (2 equiv), and Pd(PPh3)4 (0.1 equiv). The reaction
vessel was sealed with a silicon septum and subjected to microwave
irradiation at 150 °C for 75 min with stirring. The mixture was then
allowed to cool to r.t., diluted with CH2Cl2 (15 mL) and extracted (3
×). The combined organic layers were dried (MgSO4) and concen-
trated under vacuum. The crude material obtained was purified by
column chromatography (silica gel, EtOAc–PE) to give the desired
product.
1H NMR (250 Hz, CDCl3): d = 3.47 (s, 3 H), 3.52 (s, 3 H), 7.2 (dd,
J = 1.4 Hz, J = 9.4 Hz, 1 H), 7.44 (s, 1 H), 7.59 (m, 2 H), 7.96 (d,
J = 1.4 Hz, 1 H).
13C NMR (62.5 Hz, CDCl3): d = 28.6, 37.6, 103.0, 118.3, 118.8,
120.7, 123.9, 126.4, 134.4, 143.5, 145.4, 151.4, 161.4.
HRMS: m/z [M + H]+ calcd for C13H11ClN4O2: 291.0649; found:
291.0650.
3-Isopropenylimidazo[1,2-a]pyridine (10)
Yellow oil; yield: 69%.
1H NMR (250 Hz, CDCl3): d = 2.22 (s, 3 H), 5.31 (s, 1 H), 5.34 (s,
1 H), 6.81 (t, J = 6.6 Hz, 1 H), 7.15 (t, J = 7.7 Hz, 1 H), 7.62 (m, 2
H), 8.40 (d, J = 6.6 Hz, 1 H).
13C NMR (62.5 Hz, CDCl3): d = 23.3, 111.9, 112.5, 118.2, 124.0,
125.0, 125.9, 132.7, 132.9, 146.5.
3-Isopropenyl-6-(4-methoxyphenyl)imidazo[1,2-a]pyridine (18)
Brown oil; yield: 64%.
1H NMR (250 Hz, CDCl3): d = 2.25 (s, 3 H), 3.86 (s, 3 H), 5.35 (s,
1 H), 5.40 (s, 1 H), 7.01 (d, J = 8.7 Hz, 2 H), 7.41 (dd, J = 1.4 Hz,
J = 9.2 Hz, 1 H), 7.49 (d, J = 8.7 Hz, 2 H), 7.63 (s, 1 H), 7.68 (dd,
J = 1.4 Hz, J = 8.7 Hz, 1 H), 8.52 (s, 1 H).
3-(1-Phenylvinyl)imidazo[1,2-a]pyridine (11)
Brown oil; yield: 55%.
13C NMR (62.5 Hz, CDCl3): d = 23.5, 55.5, 112.3, 114.7, 117.9,
121.9, 125.1, 126.3, 126.9, 128.3, 130.2, 133.0, 133.4, 145.8, 159.8.
Synthesis 2008, No. 16, 2537–2542 © Thieme Stuttgart · New York

PAPER
Direct C3 Alkenylation of Imidazo[1,2-a]pyridines
2541
HRMS: m/z [M + H]+ calcd for C17H16N2O: 265.1341; found:
265.1341.
M.; Sanna, E.; Biggio, G.; Liso, G. J. Med. Chem. 1999, 42,
3934. (c) Trapani, G.; Franco, M.; Ricciardi, L.; Latrofa, A.;
Genchi, G.; Sanna, E.; Tuveri, F.; Gagetti, E.; Biggio, G.;
Liso, G. J. Med. Chem. 1997, 40, 3109.
1-[3-(3-Isopropenylimidazo[1,2-a]pyridin-6-yl)phenyl]etha-
none (19)
Yellow solid; yield: 68%; mp 126–127 °C.
(7) Sanfilippo, P. J.; Urbanski, M.; Press, J. B.; Dubinsky, B.;
Moore, J. B. Jr. J. Med. Chem. 1988, 31, 2221.
(8) Fuchs, K.; Romig, M.; Mendla, K.; Briem, H.; Fechteler, K.
WO 0,214,131, 2002; Chem. Abstr. 2002, 136, 183824r.
(9) Zhuang, Z. P.; Kung, M. P.; Wilson, A.; Lee, C. W.; Plössl,
K.; Hou, C.; Holtzman, D. M.; Kung, H. F. J. Med. Chem.
2003, 46, 237.
(10) Franke, H.; Geisler, J.; Hartfiel, U.; Franke, W.;
Dorfmeister, G.; Ganzer, M.; Johahann, G.; Rees, R. DE
4,120,108, 1991; Chem. Abstr. 1992, 18, 213075v.
(11) Byth, K. F.; Culshaw, J. D.; Green, S.; Oakes, S.; Thomas,
A. P. Bioorg. Med. Chem. Lett. 2004, 14, 2245.
1H NMR (250 Hz, CDCl3): d = 2.26 (s, 3 H), 2.67 (s, 3 H), 5.39 (s,
1 H), 5.42 (s, 1 H), 7.45 (dd, J = 1.8 Hz, J = 9.4 Hz, 1 H), 7.59 (t,
J = 7.7 Hz, 1 H), 7.66–7.79 (m, 3 H), 7.97 (m, 1 H), 8.16 (m, 1 H),
8.61 (s, 1 H).
13C NMR (62.5 Hz, CDCl3): d = 23.5, 26.9, 112.8, 118.4, 122.8,
124.6, 126.3, 126.6, 126.7, 127.9, 129.5, 131.6, 132.9, 133.7, 138.0,
138.4, 145.9, 197.8.
HRMS: m/z [M + H]+ calcd for C18H16N2O: 277.1341; found:
277.1346.
(12) Humphries, A. C.; Gancia, E.; Gilligan, M. T.; Goodacre, S.;
Hallett, D.; Merchant, K. J.; Thomas, S. R. Bioorg. Med.
Chem. Lett. 2006, 16, 1518.
3-Isopropenyl-6-phenylimidazo[1,2-a]pyridine (20)
Yellow oil; yield: 60%.
(13) 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.
(14) Holm, K. J.; Goa, K. L. Drugs 2000, 59, 865.
(15) Ueda, T.; Mizusgige, K.; Yukiiri, K.; Takahashi, T.; Kohno,
M. CerebroVasc. Dis. 2003, 16, 396.
(16) Colletti, S. L.; Frie, J. L.; Dixon, E. C.; Singh, S. B.; Choi,
B. K.; Scapin, G.; Fitzgerald, C. E.; Kumar, S.; Nichols, E.
A.; O’Keefe, S. J.; O’Neill, E. A.; Porter, G.; Samual, K.;
Schmatz, D. M.; Schwartz, C. D.; Shoop, W. L.; Thompson,
C. M.; Thompson, J. E.; Wang, R.; Woods, A.; Zaller, D. M.;
Doherty, J. B. J. Med. Chem. 2003, 46, 349.
(17) (a) Paolini, J. P.; Robins, R. K. J. Org. Chem. 1965, 30,
4085. (b) Fischer, M. H.; Lusi, A. J. Med. Chem. 1972, 15,
982. (c) Hand, E. S.; Paudler, W. W. J. Org. Chem. 1978, 43,
2900.
(18) Gudmundsson, K. S.; Drach, J. C.; Townsend, L. B.
Tetrahedron Lett. 1996, 37, 6275.
(19) (a) Kawai, Y.; Satoh, S.; Yamasaki, H.; Kayakiri, N.;
Yoshihara, K.; Oku, T. WO 96, 34866; 1996; Chem. Abstr.
1996, 126, 74840. (b) Badger, A.; Bender, P.; Esser, K.;
Griswold, D.; Nabil, H.; Lee, J.; Votta, B.; Simon, P. WO
9,100,092, 1991; Chem. Abstr. 1991, 115, 64756.
(20) Enguehard, C.; Renou, J. L.; Collot, V.; Hervet, M.; Rault,
S.; Gueiffier, A. J. Org. Chem. 2000, 65, 6572.
(21) (a) Bellina, F.; Cauteruccio, S.; Mannina, L.; Rossi, R.; Viel,
S. J. Org. Chem. 2005, 70, 3997. (b) Li, W.; Nelson, D. P.;
Jenson, M. S.; Hoerrner, R. S.; Javadi, G. J.; Cai, D.; Larsen,
R. D. Org. Lett. 2003, 5, 4835. (c) Park, C.-H.; Ryabova,
V.; Seregin, I. V.; Sromek, A. W.; Gevorgyan, V. Org. Lett.
2004, 6, 1159. (d) Zhuravlev, F. A. Tetrahedron Lett. 2006,
47, 2929.
1H NMR (250 Hz, CDCl3): d = 2.25 (s, 3 H), 5.36 (s, 1 H), 5.41 (s,
1 H), 7.39–7.58 (m, 6 H), 7.64–7.72 (m, 2 H), 8.58 (s, 1 H).
13C NMR (62.5 Hz, CDCl3): d = 23.6, 112.6, 118.2, 122.7, 125.1,
127.2, 127.3, 128.1, 128.3, 129.3, 133.1, 133.6, 137.9, 146.1.
HRMS: m/z [M + H]+ calcd for C16H14N2: 235.1235; found:
235.1234.
References
(1) Guillaumet, G.; Berteina-Raboin, S.; El Kazzouli, S.;
Delagrange, P.; Caignard, D.-H. WO 2006,027,474, 2006;
Chem. Abstr. 2006, 144, 254132.
(2) (a) Elhakmaoui, A.; Gueiffier, A.; Milhavet, J. C.; Blache,
Y.; Chapat, J. P.; Chavignon, O.; Teulade, J. C.; Snoeck, R.;
Andrei, G.; De Clercq, E. Bioorg. Med. Chem. Lett. 1994, 4,
1937. (b) Gueiffier, A.; Lhassani, M.; Elhakmoui, A.;
Snoeck, R.; Andrei, G.; Chavignion, O.; Teulade, J. C.;
Kerbal, A.; Essassi, M.; Debouzy, J. C.; Witurowo, J. P.;
Blache, Y.; Balzarini, J.; De Clercq, E.; Chapat, J. P. J. Med.
Chem. 1996, 39, 2856. (c) Lhassani, M.; Chavignon, O.;
Chezal, J. M.; Teulade, J. C.; Chapat, J. P.; Snoeck, R.;
Andrei, G.; Balzarini, J.; De Clercq, E.; Gueiffier, A. Eur. J.
Med. Chem. 1999, 34, 2856. (d) Gudmundsson, K. S.;
Drach, J. C.; Townsend, L. B. J. Org. Chem. 1997, 62, 3453.
(e) Pan, S.; Wang, G.; Shinazi, R. F.; Zhao, K. Tetrahedron
Lett. 1998, 39, 8191. (f) Hamdouchi, C.; de Blas, J.;
del Prado, M.; Gruber, J.; Heinz, B. A.; Vance, L. J. Med.
Chem. 1999, 42, 50. (g) Gudmundsson, K. S.; Williams, J.
D.; Drach, J. C.; Townsend, L. B. J. Med. Chem. 2003, 46,
1449.
(3) (a) Kaminsky, J. J.; Doweyko, A. M. J. Med. Chem. 1997,
40, 427. (b) Kaminsky, J. J.; Puchalski, C.; Solomon, D. M.;
Rizvi, R. K.; Conn, D. J.; Elliot, A. J.; Lovey, R. G.; Guzik,
H.; Chui, P. J. S.; Long, J. F.; McPhail, A. T. J. Med. Chem.
1989, 32, 1686.
(4) (a) Rival, Y.; Grassy, G.; Michael, G. Chem. Pharm. Bull.
1992, 40, 1170. (b) Rewankar, G. R.; Matthews, J. R.;
Robins, R. K. J. Med. Chem. 1975, 18, 1253.
(22) (a) Zaitsev, V. G.; Daugulis, O. J. Am. Chem. Soc. 2005,
127, 4156. (b) Zaitsev, V. G.; Daugulis, O.; Shabahov, D.;
Pham, Q.-N.; Lazareva, A. Synlett 2006, 3382.
(23) (a) Oi, S.; Aizawa, E.; Ogino, Y.; Inoue, Y. J. Org. Chem.
2005, 70, 3113. (b) Oi, S.; Ogino, Y.; Fukita, S.; Inoue, Y.
Org. Lett. 2002, 4, 1783. (c) Oi, S.; Fukita, S.; Hirata, N.;
Watanuki, N.; Miyano, S.; Inoue, Y. Org. Lett. 2001, 3,
2579.
(24) (a) El Kazzouli, S.; Berteina-Raboin, S.; Mouaddib, A.;
Guillaumet, G. Tetrahedron Lett. 2003, 44, 6265.
(b) El Kazzouli, S.; Berthault, A.; Berteina-Raboin, S.;
Mouaddib, A.; Guillaumet, G. Lett. Org. Chem. 2005, 2,
184.
(5) (a) Beswick, P. J.; Campbell, I. B.; Naylor, A. WO
9,631,509, 1996; Chem. Abstr. 1997, 126, 8117j.
(b) Abiegnente, E. Actual. Chim. Ther. 1991, 18, 1253.
(6) (a) Tully, W. R.; Guardner, C. R.; Gillespie, R. J.;
Westwood, R. J. Med. Chem. 1991, 34, 2060. (b) Trapani,
G.; Franco, M.; Latrofa, A.; Ricciardi, L.; Carotti, A.; Serra,
Synthesis 2008, No. 16, 2537–2542 © Thieme Stuttgart · New York

2542
J. Koubachi et al.
PAPER
(26) Gueiffier, A.; Mavel, S.; Lhassani, M.; Elhakmaoui, A.;
(25) (a) Koubachi, J.; El Kazzouli, S.; Berteina-Raboin, S.;
Mouaddib, A.; Guillaumet, G. Synlett 2006, 3237.
Snoeck, R.; Andrei, G.; Chavignon, O.; Teulade, J.-C.;
Witvrouw, M.; Balzarini, J.; De Clercq, E.; Chapat, J. P.
J. Med. Chem. 1998, 41, 5108.
(b) Koubachi, J.; El Kazzouli, S.; Berteina-Raboin, S.;
Mouaddib, A.; Guillaumet, G. J. Org. Chem. 2007, 72, 7650.
Synthesis 2008, No. 16, 2537–2542 © Thieme Stuttgart · New York