Pd/Cu-catalyzed oxidative C-H alkenylation of imidazo[1,2-α]pyridines

Article abstract of DOI:10.1055/s-0028-1083252

A novel direct and regioselective Pd/Cu-catalyzed intermolecular oxidative coupling of imidazo[1,2-α]pyridines with alkenes was successfully developed. The scope and limitations of the reaction were further studied by using various alkenes. This method pr

Full text of DOI:10.1055/s-0028-1083252

PAPER
271
Pd/Cu-Catalyzed Oxidative C–H Alkenylation of Imidazo[1,2-a]pyridines
C
-3 Alken
a
ylation of
I
m
midazo[1,2-
a
]pyrid
a
ines l Koubachi,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
Fax +33(2)38417281; E-mail: sabine.berteina-raboin@univ-orleans.fr
Faculté des Sciences et Techniques de Beni-Mellal, Université Sultan Moulay Slimane, BP 523, 23000 Beni-Mellal, Morocco
b
Received 4 September 2008; revised 8 September 2008
X
Abstract: A novel direct and regioselective Pd/Cu-catalyzed inter-
molecular oxidative coupling of imidazo[1,2-a]pyridines with alk-
enes was successfully developed. The scope and limitations of the
reaction were further studied by using various alkenes. This method
provides a ‘green’ route to 3-alkenylimidazo[1,2-a]pyridine deriva-
tives in high yields.
R1
N
R2
Y
R3
N
2
Y = H, B(OH)2, SnR3
bromination or
iodination
pathway A
H
R3
Key words: palladium/copper-catalyzed oxidative coupling, alke-
nylation, imidazo[1,2-a]pyridines
R1
N
R2
R1
oxidative coupling
Pd/Cu
N
N
R2
1
N
+
The ability to form C–C bonds is an indispensable tool in
synthetic organic chemistry, and the development of pow-
erful catalytic methods has opened new routes to complex
molecule synthesis. Usually, heteroaryl–aryl bonds are
formed by the coupling of two functionalized heteroaro-
matic carbons, but that is not always necessary. It is some-
times possible to directly arylate an aromatic ring by
replacing a C–H bond with a C–C bond. In the past three
decades, the development of transition-metal-catalyzed
C–H activation reactions has received considerable atten-
tion.1 A wide range of metal catalysts, including Ru, Rh,
Pt, and Pd catalysts, have been exploited with varying lev-
els of success.
3
H
R3
pathway B
bromination
compound 1
Br
R3
Scheme 1
ample of intermolecular oxidative C-3 alkenylation of
bicyclic heterocycles with a bridgehead nitrogen atom.
To the best of our knowledge, few approaches, including
palladium cross-coupling, are known for preparing 3-alk-
enylimidazo[1,2-a]pyridines 3 from imidazo[1,2-a]py-
ridines 1 (Scheme 1): pathway A, involving halogenation
of imidazo[1,2-a]pyridines 15a,8–10 followed by Heck,5a,8,11
Stille,12 or Suzuki13 cross-coupling; pathway B, involving
bromination of alkene followed by the ‘inverse’ Heck re-
action.14 Although these sequences were successful, an
additional step for the activation of imidazo[1,2-a]py-
ridines and alkenes is required and expensive reagents are
used (alkenylboronic acids for Suzuki and alkenylstan-
nanes for Stille couplings). Compared to these methods,
Considering the remarkable progress made in the devel-
opment of palladium-catalyzed C–C bond-forming reac-
tions of various heterocycles,2,3 we turned our attention to
intermolecular C–H alkenylation via oxidative Pd/Cu-cat-
alyzed reactions. In the recent years a limited number of
methods for regioselective couplings of heteroaromatic
systems using oxidative palladium-catalyzed reactions of
arenes and olefins have been described;4 however, in
some cases, these procedures have shown moderate regio-
selectivity.4
Our group has a long-standing interest in imidazo[1,2- the oxidative alkenylation reaction is obviously advanta-
a]pyridine derivatives.5 We have reported a regioselective geous in terms of starting material price and byproduct
palladium-catalyzed (hetero)arylation6 at C-3 of imida- (i.e., brominated alkene) formation.
zo[1,2-a]pyridines and the first examples of one-pot, two-
step Suzuki cross-coupling/direct arylation and one-pot,
The alkenylation reaction was examined using 2-phe-
nylimidazo[1,2-a]pyridine (4)15 and methyl acrylate
three-step cyclization/Suzuki cross-coupling/regioselec-
(Scheme 2, Table 1). The key to success was the optimum
combined choice of the catalyst, solvent, and oxidant. Ini-
tive arylation.7 Herein, we describe recent advances in the
direct and regioselective alkenylation of imidazo[1,2-
tial investigations consisted of testing the reaction condi-
a]pyridines by oxidative Pd/Cu-catalyzed C–H bond acti-
tions reported for the oxidative dimerization of an
vation (Scheme 1). As far as we know, this is the first ex-
imidazotriazine16 [Pd(OAc)2 (10 mol%), KOAc (2
equiv)]. Under these conditions, the coupling between 2-
phenylimidazo[1,2-a]pyridine (4) and methyl acrylate (4
equiv) in N,N-dimethylformamide at 120 °C for 60 hours
using either O2 or air as oxidant led to the formation of the
SYNTHESIS 2009, No. 2, pp 0271–0276
Advanced online publication: 12.12.2008
DOI: 10.1055/s-0028-1083252; Art ID: Z20608SS
x
x
.
x
x
.2
0
0
8
© Georg Thieme Verlag Stuttgart · New York

272
J. Koubachi et al.
PAPER
Table 1 Effect of the Oxidant and the Solvent
Entry
Additivea
Solvent
DMF
Time (h)
Recovered 4 (%)
Yieldb (%) of 5
Yieldb (%) of 6
1
2
KOAc, O2
60
60
60
3
0
0
51
50
54
44
62
63
52
25
41
85
0
0
KOAc, air
DMF
3
no base, air
DMF
0
0
4
Cu(OAc)2, air
Cu(OAc)2, air
Cu(OAc)2, air
Ag2O, argon
1,4-benzoquinone, argon
CuO, argon
DMF
0
11
0
5
toluene
xylene
xylene
xylene
xylene
xylene
3
0
6
3
0
0
7
30
30
30
3
23
33
32
0
0
8
0
9
0
10
Cu(OAc)2, argon
0
a 2 Equivalents of oxidant or base were used.
b Yields given are for isolated products.
CO2Me
CO2Me
Ph
H
Pd(OAc)2,
H
O
H
additive, solvent,
120 °C
Pd(II), Cu(OAc)2
xylene, 120 °C
N
N
N
N
N
Ph
+
Ph
Ph
Ph
N
CO2Me
N
N
CO2Me
N
N
4
5
6
4
5
Scheme 2
Scheme 3
desired compound 5 in 51% and 50% yield, respectively
(Table 1, entries 1 and 2). When the same reaction was ex-
posed to atmospheric oxygen in the absence of potassium
acetate for 60 hours, product 5 was isolated in 54% yield
(entry 3). We found that when copper(II) acetate was used
as co-oxidant under air in N,N-dimethylformamide at
120 °C, the reaction gave the alkenylated product 5 and
the formylated byproduct 617 in 44% and 11% yield, re-
spectively (entry 4). The use of toluene or xylene as sol-
vent avoided the formation of this byproduct and
furnished the desired compound 5 in 62% and 63% yield,
respectively (entries 5 and 6). Then, the effect of the oxi-
dant on the coupling efficacy was investigated. Thus, four
oxidants [Ag2O, 1,4-benzoquinone, CuO, Cu(OAc)2]
were tested (Table 1, entries 7–10). First, the use of sil-
ver(I) oxide (2 equiv) in the presence of palladium(II) ac-
etate (10 mol%) in xylene at 120 °C resulted in 52% of the
desired compound 5 (entry 7). 1,4-Benzoquinone or cop-
per(II) oxide, under similar reaction conditions, gave
compound 5 in only 25% and 41% yield, respectively (en-
tries 8 and 9). It is noteworthy that a significant amount of
starting material was recovered (entries 7–9). Interesting-
ly, when copper(II) acetate was used as oxidant, the
desired methyl 3-(2-phenylimidazo[1,2-a]pyridin-3-
yl)acrylate (5) was isolated in excellent yield (entry 10).
Table 2 Effect of the Palladium Catalyst
Entry
Catalyst
Time (h)
Recovered 4 Yielda (%)
(%)
of 5
85
78
83
80
77
35
87
1
2
3
4
5
6
7
Pd(OAc)2
Pd(PPh3)4
PdCl2(PPh3)2
PdCl2(PhCN)2
Pd2(dba)3
3
0
3
0
3
0
4
0
3
0
PdCl2
30
2
28
0
PdCl2(dppf)2
a Yields given are for isolated products.
Pd(OAc)2 (entry 1) by Pd(PPh3)4 afforded compound 5 in
78% yield (entry 2). Similar results were observed using
PdCl2(PPh3)2, PdCl2(PhCN)2, or Pd2(dba)3 (entries 3–5).
In contrast, PdCl2 afforded compound 5 in poor yield and
starting material was recovered (entry 6). Results compa-
rable to those for Pd(OAc)2 were obtained using
PdCl2(dppf)2 (10 mol%). Under these conditions, the ex-
pected compound 5 was obtained in 87% yield (entry 7).
Then, we focused our attention on the study of the influ-
ence of the palladium catalyst on the cross-coupling alke-
nylation (Scheme 3, Table 2). The replacement of
In order to explore the scope and limitations of the oxida-
tive Pd/Cu-catalyzed alkenylation method (Scheme 4),
Synthesis 2009, No. 2, 271–276 © Thieme Stuttgart · New York

PAPER
C-3 Alkenylation of Imidazo[1,2-a]pyridines
273
R3
R2
Table 3 Alkenylation of Various Imidazo[1,2-a]pyridines
Pd(OAc)2 (0.1 equiv)
Cu(OAc)2 (2 equiv)
xylene, 120 °C
H
Entry
R1
H
H
H
H
H
R2
Ph
Ph
Ph
Ph
Ph
R3
Product
Yielda (%)
R1
R1
N
N
R2
1
2
3
4
5
CO2Me
CO2Et
CO2Bn
COEt
Ph
5
87
85
81
76
R3
N
N
10
11
12
4, R1 = H, R2 = Ph
7, R1 = Cl, R2 = Ph
8, R1 = Cl, R2 = H
9, R1= H, R2 = H
5, 10–13, 15–25
Scheme 4
13
39
28
14b
we applied the optimized reaction conditions to imida-
zo[1,2-a]pyridines 4, 7,14 8,14 and 9,14 and various alkenes
(Table 3). The results showed that compounds 4, 7, 8, and
9 could be efficiently functionalized at the 3-position.
Thus, vinyl ketones and alkyl acrylates were successfully
used leading to the desired compounds in excellent yields,
ranging between 69% and 87%. It is noteworthy that most
of the assays gave only regioselective reactions (Table 3)
and no starting material was detected in the crude reaction
mixtures. In contrast, the reaction between 4 and acryloni-
trile, using the same reaction conditions, afforded com-
pound 15 in low yield (45%) after 24 hours (entry 6). In
this case, the reaction was not complete and starting ma-
terial was partially recovered. The coupling reaction be-
tween 4 and styrene led to two different compounds 13
and 14 in 39% and 28% yield, respectively (entry 5).
6
7
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
CN
15
16
17
18
19
20
21
22
23
24
25
45c
74
81
83
85
73
78
74
70
71
69
H
CO2t-Bu
CO2Me
CO2Et
8
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
9
10
11
12
13
14
15
16
CO2Bn
COEt
CO2t-Bu
CO2Me
CO2t-Bu
CO2Me
CO2Bn
H
H
H
H
In conclusion, we have developed a new and robust meth-
odology for the direct alkenylation of imidazo[1,2-a]py-
ridines at the 3-position, via a Pd/Cu-catalyzed oxidative
process. We found the optimum conditions are the use of
palladium(II) acetate [or PdCl2(dppf)2] as catalyst, cop-
per(II) acetate as oxidant, and xylene (or toluene) as sol-
vent. This method offers several advantages: high yields,
a single step (compared to Heck, Stille, or Suzuki cross-
coupling), and shorter reaction times. Further work is un-
derway in our laboratory to evaluate the synthetic poten-
a Yields given are for isolated products.
b 14:
Ph
N
Ph
N
c 22% of compound 4 was recovered.
tial of these products and to develop Pd/Cu-catalyzed layer chromatography was carried out on Merck silica gel 60F254
precoated plates. Visualization was made with UV light.
oxidative alkenylation reactions involving other classes of
heterocycles.
Direct C-3 Alkenylation of Imidazo[1,2-a]pyridines with Alk-
enes; General Procedure
All reagents were purchased from Sigma–Aldrich, Acros Organics,
and Alfa Aesar and were used without further purification. Melting
points were determined with a Büchi SMP-20 melting point appara-
Pd(OAc)2 (0.1 equiv) was added to a mixture of an alkene (2 equiv),
Cu(OAc)2 (2 equiv), and an imidazo[1,2-a]pyridine (0.1 g, 1 equiv)
in xylene (3 mL), and the reaction mixture was stirred at 120 °C for
2 to 6 h. The reaction mixture was allowed to cool to r.t., concen-
trated under reduced pressure, and diluted with CH2Cl2 (15 mL),
then extracted with CH2Cl2 (3 × 15 mL). The combined organic lay-
er was dried (MgSO4) and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel
(EtOAc–hexanes) to give the C-3 alkenylated imidazo[1,2-a]pyri-
dine derivatives 5, 6, and 10–25.
1
tus and are uncorrected. H NMR and 13C NMR spectra were re-
corded on a Bruker Avance DPX250 spectrometer (1H, 250.19
MHz; 13C, 62.89 MHz) or a Bruker Avance II 400 spectrometer (1H,
400 MHz; 13C, 100 MHz) using tetramethylsilane as the internal
standard; multiplicities were determined using the DEPT 135 se-
quence. Chemical shifts are reported in parts per million (ppm, d
units). Coupling constants are reported in units of hertz (Hz). Split-
ting patterns are designated as s: singlet, d: doublet, t: triplet, and m:
multiplet. High-resolution mass spectra (HRMS) were recorded
with a TOF spectrometer in the electrospray ionization (ESI) mode
or with a Finnigan MAT 95 XL spectrometer in the chemical ion-
ization (CI) mode at the Regional Center of Physical Measurement,
Blaise Pascal University. All commercial solvents were used with-
out further purification. Column chromatography was carried out
using silica gel 60N (spherical, neutral, 40–63 mm, Merck). Thin-
Methyl (E)-3-(2-Phenylimidazo[1,2-a]pyridin-3-yl)acrylate (5)
Yield: 87%; yellow solid; mp 150–151 °C.
1H NMR (250 MHz, CDCl3): d = 3.80 (s, 3 H), 6.35 (d, J = 16.3 Hz,
1 H), 7.00 (dt, J = 3.4, 9.3 Hz, 1 H), 7.28–7.37 (m, 1 H), 7.43–7.54
(m, 3 H), 7.71–7.76 (m, 3 H), 8.04 (d, J = 16.3 Hz, 1 H), 8.45 (d,
J = 7.0 Hz, 1 H).
Synthesis 2009, No. 2, 271–276 © Thieme Stuttgart · New York

274
J. Koubachi et al.
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13C NMR (62.5 MHz, CDCl3): d = 51.8, 113.2, 114.1, 117.2, 118.3,
125.4, 126.8, 128.8, 128.9, 129.5, 130.8, 133.7, 147.3, 151.3, 167.9.
2-Phenyl-3-(1-phenylvinyl)imidazo[1,2-a]pyridine (14)
Yield: 28%; yellow oil.
HRMS: m/z [M + H+] calcd for C17H15N2O2: 279.1134; found:
279.1145.
1H NMR (250 MHz, 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),
7.60–7.68 (m, 2 H), 7.92–7.95 (m, 2 H).
2-Phenylimidazo[1,2-a]pyridine-3-carbaldehyde (6)
Yield: 11%; yellow solid; mp 134–135 °C.
1H NMR (400 MHz, CDCl3): d = 7.13 (t, J = 7 Hz, 1 H), 7.51–7.61
(m, 4 H), 7.80–7.85 (m, 3 H), 9.66 (d, J = 7 Hz, 1 H), 10.1 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 115.5, 117.6, 120.9, 128.9, 129.1,
130.0, 130.6, 132.5, 147.9, 158.5, 179.7.
13C NMR (62.5 MHz, CDCl3): d = 112.2, 117.5, 120.2, 121.4,
124.3, 126.3, 127.7, 128.4, 128.8, 129.1, 134.2, 137.7, 137.7, 143.6,
144.9.
HRMS: m/z [M + H+] calcd for C21H17N2: 297.1392; found:
297.1398.
(E)-3-(2-Phenylimidazo[1,2-a]pyridin-3-yl)acrylonitrile (15)
Yield: 45%; yellow solid; mp 163–164 °C.
1H NMR (400 MHz, CDCl3): d = 5.75 (d, J = 16.8 Hz, 1 H), 7.06 (t,
J = 6.8 Hz, 1 H), 7.41 (t, J = 7.8 Hz, 1 H), 7.48–7.54 (m, 3 H), 7.64
(d, J = 16.8 Hz, 1 H), 7.67–7.70 (m, 2 H), 7.76 (d, J = 9.2 Hz, 1 H),
8.31 (d, J = 6.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 91.1, 114.6, 116.9, 118.6, 119.1,
124.9, 127.4, 129.1, 129.4, 129.5, 133.3, 135.7, 147.6, 151.7.
HRMS: m/z [M + H+] calcd for C16H12N3: 246.1031; found:
246.1033.
HRMS: m/z [M + H+] calcd for C14H11N2O: 223.0871; found:
223.0877.
Ethyl (E)-3-(2-Phenylimidazo[1,2-a]pyridin-3-yl)acrylate (10)
Yield: 85%; colorless solid; mp 107–108 °C.
1H NMR (400 MHz, CDCl3): d = 1.33 (t, J = 7.2 Hz, 3 H), 4.27 (q,
J = 7.2 Hz, 2 H), 6.36 (d, J = 16.4 Hz, 1 H), 7.00 (t, J = 6.8 Hz, 1
H), 7.35 (t, J = 7.8 Hz, 1 H), 7.42–7.46 (m, 1 H), 7.49–7.52 (m, 2
H), 7.72–7.77 (m, 3 H), 8.05 (d, J = 16.4 Hz, 1 H), 8.47 (d, J = 6.8
Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.6, 60.8, 113.8, 114.1, 117.4,
118.4, 125.6, 126.8, 128.9, 129.1, 129.7, 130.8, 133.8, 147.4, 151.3,
167.6.
tert-Butyl (E)-3-(2-Phenylimidazo[1,2-a]pyridin-3-yl)acrylate
(16)
Yield: 74%; red oil.
HRMS: m/z [M + H+] calcd for C18H17N2O2: 293.1290; found:
293.1300.
1H NMR (250 MHz, CDCl3): d = 1.44 (s, 9 H), 6.20 (d, J = 16.5 Hz,
1 H), 6.85–6.91 (m, 1 H), 7.18–7.26 (m, 1 H), 7.33–7.44 (m, 3 H),
7.61–7.69 (m, 3 H), 7.90 (d, J = 16.5 Hz, 1 H), 8.37 (d, J = 7 Hz, 1
H).
Benzyl (E)-3-(2-Phenylimidazo[1,2-a]pyridin-3-yl)acrylate (11)
Yield: 81%; yellow solid; mp 145–146 °C.
1H NMR (400 MHz, CDCl3): d = 5.26 (s, 2 H), 6.41 (d, J = 16.4 Hz,
1 H), 7.00 (t, J = 6.8 Hz, 1 H), 7.34–7.52 (m, 9 H), 7.73–7.76 (m, 3
H), 8.12 (d, J = 16.4 Hz, 1 H), 8.46 (d, J = 6.8 Hz, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 38.3, 80.6, 113.9, 115.5, 117.3,
118.2, 125.6, 126.5, 128.7, 128.8, 129.5, 129.8, 133.7, 147.2, 150.9,
166.7.
13C NMR (100 MHz, CDCl3): d = 66.5, 112.9, 114.1, 117.3, 118.4,
125.6, 126.9, 128.4, 128.4, 128.7, 128.9, 129.0, 129.6, 131.3, 133.7,
136.2, 147.5, 151.7, 167.4.
HRMS: m/z [M + H+] calcd for C20H21N2O2: 321.1603; found:
321.1597.
Methyl (E)-3-(6-Chloro-2-phenylimidazo[1,2-a]pyridin-3-
yl)acrylate (17)
Yield: 81%; yellow oil.
HRMS: m/z [M + H+] calcd for C23H19N2O2: 355.1447; found:
355.1441.
(E)-1-(2-Phenylimidazo[1,2-a]pyridin-3-yl)pent-1-en-3-one (12)
Yield: 76%; yellow solid; mp 115–116 °C.
1H NMR (250 MHz, CDCl3): d = 3.82 (s, 3 H), 6.37 (d, J = 16.3 Hz,
1 H), 7.27–7.34 (m, 1 H), 7.45–7.53 (m, 3 H), 7.66–7.74 (m, 3 H),
8.00 (d, J = 16.3 Hz, 1 H), 8.47 (s, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 52.0, 114.7, 117.6, 118.6, 122.4,
123.2, 127.9, 128.9, 129.2, 129.5, 130.3, 133.3, 145.5, 151.5, 167.6.
HRMS: m/z [M + H+] calcd for C17H14N2O235Cl: 313.0744; found:
313.0732.
1H NMR (250 MHz, CDCl3): d = 1.16 (t, J = 7.3 Hz, 3 H), 2.62 (q,
J = 7.3 Hz, 2 H), 6.72 (d, J = 16.5 Hz, 1 H), 7.00 (t, J = 7 Hz, 1 H),
7.32–7.42 (m, 1 H), 7.44–7.54 (m, 3 H), 7.70–7.76 (m, 3 H), 7.94
(d, J = 16.5 Hz, 1 H), 8.47 (d, J = 7 Hz, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 8.4, 34.5, 114.0, 117.3, 118.2,
121.2, 125.5, 126.8, 128.2, 128.7, 128.9, 129.4, 133.7, 147.4, 151.6,
200.3.
Ethyl (E)-3-(6-Chloro-2-phenylimidazo[1,2-a]pyridin-3-
yl)acrylate (18)
Yield: 83%; yellow solid; mp 144–145 °C.
1H NMR (400 MHz, CDCl3): d = 1.35 (t, J = 8.0 Hz, 3 H), 4.29 (q,
J = 8.0 Hz, 2 H), 6.37 (d, J = 16.0 Hz, 1 H), 7.32 (m, 1 H), 7.43–
7.53 (m, 3 H), 7.66–7.69 (m, 1 H), 7.73–7.75 (m, 2 H), 8.00 (d,
J = 16.0 Hz, 1 H), 8.49 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.5, 60.9, 115.1, 118.6, 122.3,
123.3, 127.9, 128.9, 129.2, 129.5, 130.2, 133.4, 145.5, 151.3, 167.2.
HRMS: m/z [M + H+] calcd for C18H16N2O235Cl: 327.0900; found:
327.0885.
HRMS: m/z [M + H+] calcd for C18H17N2O: 277.1341; found:
277.1343.
(E)-2-Phenyl-3-styrylimidazo[1,2-a]pyridine (13)
Yield: 39%; yellow oil.
1H NMR (250 MHz, CDCl3): d = 6.51 (t, J = 6.2 Hz, 1 H), 6.76 (d,
J = 12.5 Hz, 1 H), 6.95 (d, J = 12.5 Hz, 1 H), 6.99–7.03 (m, 2 H),
7.10–7.14 (m, 4 H), 7.31–7.48 (m, 4 H), 7.67 (d, J = 9.1 Hz, 1 H),
8.04–8.07 (m, J = 7.2 Hz, 2 H).
13C NMR (62.5 MHz, CDCl3): d = 111.7, 116.6, 117.3, 124.6,
124.9, 127.9, 127.9, 128.1, 128.2, 128.5, 128.7, 133.9, 134.6, 136.6,
143.8, 145.4.
Benzyl (E)-3-(6-Chloro-2-phenylimidazo[1,2-a]pyridin-3-
yl)acrylate (19)
Yield: 85%; yellow solid; mp 166–167 °C.
HRMS: m/z [M + H+] calcd for C21H17N2: 297.1392; found:
297.1398.
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275
1H NMR (250 MHz, CDCl3): d = 5.27 (s, 2 H), 6.41 (d, J = 16.3 Hz,
1 H), 7.29–7.52 (m, 9 H), 7.65–7.74 (m, 3 H), 8.06 (d, J = 16.3 Hz,
1 H), 8.47–8.49 (m, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 66.7, 114.2, 117.7, 118.6, 122.4,
123.4, 128.0, 128.5, 128.7, 128.9, 129.2, 129.5, 130.7, 133.3, 136.0,
145.7, 151.9, 167.1.
Hz, 1 H), 7.89 (d, J = 16.0 Hz, 1 H), 8.05 (s, 1 H), 8.31 (d, J = 6.8
Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 51.9, 113.8, 114.1, 118.7, 121.7,
124.2, 126.2, 128.8, 137.3, 148.1, 167.7.
HRMS: m/z [M + H+] calcd for C11H11N2O2: 203.0821; found:
203.0820.
HRMS: m/z [M + H+] calcd for C23H18N2O235Cl: 389.1057; found:
389.1046.
Benzyl (E)-3-(Imidazo[1,2-a]pyridin-3-yl)acrylate (25)
Yield: 69%; yellow solid; mp 129–130 °C.
(E)-1-(6-Chloro-2-phenylimidazo[1,2-a]pyridin-3-yl)pent-1-en-
3-one (20)
Yield: 73%; yellow oil.
1H NMR (400 MHz, CDCl3): d = 5.28 (s, 2 H), 6.46 (d, J = 16.0 Hz,
1 H), 6.99 (t, J = 6.8 Hz, 1 H), 7.31–7.45 (m, 6 H), 7.71 (d, J = 8.8
Hz, 1 H), 7.93 (d, J = 16.0 Hz, 1 H), 8.06 (s, 1 H), 8.31 (d, J = 6.8
Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 66.6, 113.7, 114.1, 118.7, 124.3,
126.3, 128.5, 128.8, 129.1, 136.2, 137.5, 167.1.
1H NMR (250 MHz, CDCl3): d = 1.17 (t, J = 7.2 Hz, 3 H), 2.65 (q,
J = 7.2 Hz, 2 H), 6.31 (d, J = 16.5 Hz, 1 H), 7.31 (m, 1 H), 7.44–
7.54 (m, 3 H), 7.65–7.73 (m, 3 H), 7.95 (d, J = 16.5 Hz, 1 H), 8.49
(m, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 8.4, 34.7, 117.8, 118.5, 122.3,
122.4, 123.4, 127.7, 128.0, 128.9, 129.2, 129.4, 133.4, 145.6, 151.9,
200.2.
HRMS: m/z [M + H+] calcd for C17H15N2O2: 279.1134; found:
279.1150.
HRMS: m/z [M + H+] calcd for C18H16N2O35Cl: 311.0951; found:
311.0939.
References
(1) For reviews on directed C–H activation reactions, see:
(a) Dyker, G. Angew. Chem. Int. Ed. 1999, 38, 1698.
(b) See also: Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. Rev.
2002, 102, 1731; and references cited therein. (c) Murai, S.;
Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda,
M.; Chatani, N. Nature (London) 1993, 366, 529.
(d) Thalji, R. K.; Ahrendt, K. A.; Bergman, R. G.; Ellman, J.
A. J. Am. Chem. Soc. 2001, 123, 9692. (e) Godula, K.;
Sames, D. Science (Washington, D.C.) 2006, 312, 67.
(f) Bergman, R. G. Nature (London) 2007, 446, 391.
(2) For recent reviews on heteroarene direct arylation, see:
(a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007,
107, 174. (b) Satoh, T.; Miura, M. Chem. Lett. 2007, 36,
200. (c) Fairlamb, I. J. S. Chem. Soc. Rev. 2007, 36, 1036.
(d) Campeau, L.-C.; Fagnou, K. Chem. Commun. 2006,
1253.
tert-Butyl (E)-3-(6-Chloro-2-phenylimidazo[1,2-a]pyridin-3-
yl)acrylate (21)
Yield: 78%; yellow oil.
1H NMR (250 MHz, CDCl3): d = 1.56 (s, 9 H), 6.31 (d, J = 16.5 Hz,
1 H), 7.31 (m, 1 H), 7.44–7.54 (m, 3 H), 7.69–7.75 (m, 3 H), 7.95
(d, J = 16.5 Hz, 1 H), 8.49 (s, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 28.5, 81.2, 117.1, 118.7, 122.3,
123.6, 127.9, 129.1, 129.2, 129.5, 129.6, 133.5, 145.6, 151.4, 166.6.
HRMS: m/z [M + H+] calcd for C20H20N2O235Cl: 355.1213; found:
355.1218.
Methyl (E)-3-(6-Chloroimidazo[1,2-a]pyridin-3-yl)acrylate (22)
Yield: 74%; yellow solid; mp 215–216 °C.
1H NMR (250 MHz, CDCl3): d = 3.84 (s, 3 H), 6.42 (d, J = 16.0 Hz,
1 H), 7.26–7.30 (m, 1 H), 7.64 (d, J = 9.5 Hz, 1 H), 7.82 (d, J = 16.0
Hz, 1 H), 8.04 (s, 1 H), 8.33 (s, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 52.0, 115.1, 118.8, 122.2, 122.5,
127.4, 128.1, 137.7, 146.2, 167.3.
HRMS: m/z [M + H+] calcd for C11H10N2O235Cl: 237.0431; found:
237.0428.
(3) For recent examples of heteroarene direct arylation, see:
(a) Chiong, H. A.; Daugulis, O. Org. Lett. 2007, 9, 1449.
(b) Wang, X.; Gribkov, D. V.; Sames, D. J. Org. Chem.
2007, 72, 1476. (c) Yanagisawa, S.; Sudo, T.; Noyori, R.;
Itami, K. J. Am. Chem. Soc. 2006, 128, 11748. (d) Rech, J.
C.; Yato, M.; Duckett, D.; Ember, B.; Lo Grasso, P. V.;
Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2007, 129,
490. (e) Mitsudo, K.; Thansandote, P.; Wilhelm, T.;
Mariampillai, B.; Lautens, M. Org. Lett. 2006, 8, 3939.
(f) Čerňa, I.; Pohl, R.; Hocek, M. Chem. Commun. 2007,
4729. (g) Leclerc, J.-P.; Fagnou, K. Angew. Chem. Int. Ed.
2006, 45, 7781; Angew. Chem. 2006, 118, 7945. (h) Lewis,
J. C.; Wu, J. Y.; Bergman, R. G.; Ellman, J. A. Angew.
Chem. Int. Ed. 2006, 45, 1589; Angew. Chem. 2006, 118,
1619. (i) Deprez, N. R.; Kalyani, D.; Krause, A.; Sanford,
M. S. J. Am. Chem. Soc. 2006, 128, 4972. (j) Campeau,
L.-C.; Fagnou, K. Chem. Commun. 2006, 1253.
(4) (a) Beck, E. M.; Grimster, N. P.; Hatley, R.; Gaunt, M. J.
J. Am. Chem. Soc. 2006, 128, 2528. (b) Stahl, S. S. Angew.
Chem. Int. Ed. 2004, 43, 3400. (c) Capito, E.; Brown, J. M.;
Ricci, A. Chem. Commun. 2005, 1854. (d) Tani, M.;
Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2004, 69, 1221.
(e) Yamada, T.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2005,
70, 5471. (f) Kong, A.; Han, X.; Lu, X. Org. Lett. 2006, 8,
1339. (g) Beccalli, E. M.; Broggini, G.; Martinelli, M.;
Sottocornola, S. Chem. Rev. 2007, 107, 5318.
tert-Butyl (E)-3-(6-Chloroimidazo[1,2-a]pyridin-3-yl)acrylate
(23)
Yield: 70%; yellow solid; mp 119–120 °C.
1H NMR (250 MHz, CDCl3): d = 1.56 (s, 9 H), 6.36 (d, J = 16.0 Hz,
1 H), 7.24–7.29 (m, 1 H), 7.63 (d, J = 9.5 Hz, 1 H), 7.67 (d, J = 16.0
Hz, 1 H), 7.99 (s, 1 H), 8.31 (s, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 28.3, 81.0, 117.7, 118.8, 122.2,
122.3, 126.9, 127.1, 137.1, 146.0, 166.2.
HRMS: m/z [M + H+] calcd for C14H16N2O235Cl: 279.0900; found:
279.0918.
Methyl (E)-3-(Imidazo[1,2-a]pyridin-3-yl)acrylate (24)
Yield: 71%; yellow solid; mp 142–143 °C.
1H NMR (400 MHz, CDCl3): d = 3.83 (s, 3 H), 6.41 (d, J = 16.0 Hz,
1 H), 7.28 (t, J = 6.8 Hz, 1 H), 7.30–7.34 (m, 1 H), 7.70 (d, J = 9.2
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J. Koubachi et al.
PAPER
(11) Gudmundsson, K. S.; Drach, J. C.; Townsend, L. B.
(5) (a) Guillaumet, G.; Berteina-Raboin, S.; El Kazzouli, S.;
Delagrange, P.; Caignard, D.-H. PCT Int. Appl. WO
2006027474, 2006; Chem. Abstr. 2006, 144, 254132.
(b) El Kazzouli, S.; Berteina-Raboin, S.; Mouaddib, A.;
Guillaumet, G. Tetrahedron Lett. 2003, 44, 6265.
(c) El Kazzouli, S.; Berthault, A.; Berteina-Raboin, S.;
Mouaddib, A.; Guillaumet, G. Lett. Org. Chem. 2005, 2,
184.
Tetrahedron Lett. 1996, 37, 6275.
(12) (a) Kawai, Y.; Satoh, S.; Yamasaki, H.; Kayakiri, N.;
Yoshihara, K.; Oku, T. PCT WO 96/34866, 1996.
(b) Badger, A.; Bender, P.; Esser, K.; Griswold, D.; Nabil,
H.; Lee, J.; Votta, B.; Simon, P. PCT WO 91/00092, 1990.
(13) Enguehard, C.; Renou, J. L.; Collot, V.; Hervet, M.; Rault,
S.; Gueiffier, A. J. Org. Chem. 2000, 65, 6572.
(6) Koubachi, J.; El Kazzouli, S.; Berteina-Raboin, S.;
Mouaddib, A.; Guillaumet, G. Synlett 2006, 3237.
(7) Koubachi, J.; El Kazzouli, S.; Berteina-Raboin, S.;
Mouaddib, A.; Guillaumet, G. J. Org. Chem. 2007, 72, 7650.
(8) Gudmundsson, K. S.; Williams, J. D.; Drach, J. C.;
Townsend, L. B. J. Med. Chem. 2003, 46, 1449.
(9) (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,
658.
(14) Koubachi, J.; El Kazzouli, S.; Berteina-Raboin, S.;
Mouaddib, A.; Guillaumet, G. Synthesis 2008, 2537.
(15) Gueiffier, A.; Mavel, S.; Lhassani, M.; Elhakmaoui, A.;
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.
(16) Gauthier, D. R. Jr.; Limanto, J.; Devine, P. N.; Desmond, R.
A.; Szumigala, R. H. Jr.; Foster, B. S.; Volante, R. P. J. Org.
Chem. 2005, 70, 5938.
(17) Anaflous, A.; Benchat, N.; Mimouni, M.; Abouricha, S.;
Ben-Hadda, T.; El-Bali, B.; Hakkou, A.; Hacht, B. Lett.
Drug Des. Discovery 2004, 1, 224.
(10) Hamdouchi, C.; de Blas, J.; del Prado, M.; G ruber, J.;
Heinz, B. A.; Vance, L. J. Med. Chem. 1999, 42, 50.
Synthesis 2009, No. 2, 271–276 © Thieme Stuttgart · New York