The synthesis of 3-pyrazinyl-imidazo[1,2-a]pyridines from a vinyl ether

Article abstract of DOI:10.1016/j.tetlet.2010.04.117

A new method has been developed for the synthesis of 3-pyrazinyl-imidazo[1, 2-a]pyridines. 2-Chloro-6-[(Z)-2-ethoxyethenyl]pyrazine was treated with N-bromosuccinimide in dioxane-water to generate the 2-bromo-2-(6-chloropyrazin- 2-yl)-1-ethoxyethanol intermediate. In a subsequent one-pot step, optional treatment with various 2-aminopyridines provided the cyclized 3-pyrazinyl-imidazo[1,2-a]pyridines in 31-76% yields.

Full text of DOI:10.1016/j.tetlet.2010.04.117

Tetrahedron Letters 51 (2010) 3528–3530
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
The synthesis of 3-pyrazinyl-imidazo[1,2-a]pyridines from a vinyl ether
*
Michael Raymond Collins , Qinhua Huang, Martha A. Ornelas, Stephanie A. Scales
Pfizer Pharmaceuticals, 10770 Science Center Drive, La Jolla, CA 92121, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A new method has been developed for the synthesis of 3-pyrazinyl-imidazo[1,2-a]pyridines. 2-Chloro-6-
[(Z)-2-ethoxyethenyl]pyrazine was treated with N-bromosuccinimide in dioxane–water to generate the
2-bromo-2-(6-chloropyrazin-2-yl)-1-ethoxyethanol intermediate. In a subsequent one-pot step, optional
treatment with various 2-aminopyridines provided the cyclized 3-pyrazinyl-imidazo[1,2-a]pyridines in
31–76% yields.
Received 12 April 2010
Revised 27 April 2010
Accepted 27 April 2010
Available online 4 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Many biologically active compounds contain bicyclic heterocycles
with a bridgehead nitrogen atom. Medicinal chemistry optimization
requireda methodtopreparevarious3-pyrazinyl-imidazo[1,2-a]pyr-
idines as intermediates for synthesizing pharmaceutically active
compounds.1 The initial approach employed palladium-catalyzed di-
rect arylation of imidazo[1,2-a]pyridines with 2,6-dichloropyrazine
which gave 3-pyrazinyl-imidazo[1,2-a]pyridines (Scheme 1).2
Although this reaction was successful with imidazo[1,2-a]pyri-
dine (entry 1), the direct arylation reaction gave low yields in the
case of imidazo[1,2-a]pyridine-7-carbonitrile and 5-methylimi-
dazo[1,2-a]pyridine (entries 2 and 3). Moreover, a diverse set of
commercially available imidazo[1,2-a]pyridines is unavailable.
Thus, a new method was required that would allow rapid and ro-
bust preparation of diverse 3-pyrazinyl-imidazo[1,2-a]pyridines.
Ethyl b-ethoxyacrylate 3 will react with N-bromosuccinimide
of compound 9, which showed two singlets in the aromatic region
and no coupling between the aromatic protons. A plausible mech-
anistic explanation for the nucleophilic tele-substitution is de-
scribed by Edward McDonald.4
The synthesis of 3-pyrazinyl-imidazo[1,2-a]pyridines is shown in
Scheme 4. The vinyl ether 9 was dissolved in a mixture of dioxane and
water (3:1, respectively) and treated with NBS. The reaction mixture
was stirred at room temperature for 10 min. Next, 2-aminopyridine
11 was added to the in situ-generated hemiacetal 10 and the reaction
mixture was heated in a microwave for 10 min at 100 °C.6 We believe
that the endocyclic nitrogen of 2-aminopyridine 11 displaces the bro-
mide of the hemiacetal 10 which generates a pyridinium ion and
1 equiv of HBr. The acid catalyzes the hydrolysis of the hemiacetal
to the aldehyde and subsequent nucleophilic attack by the exocyclic
nitrogen on the aldehydic carbon, followed by aromatization, to pro-
vide 3-pyrazinyl-imidazo[1,2-a]pyridines 12.
(NBS) and water to form
a-bromo-a-formylacetate hemiacetal 4,
which can then cyclize with thiourea to give ethyl 2-amino-1,3-
The presence of 10 in the crude reaction mixture was not
detected by LCMS. To confirm the formation of 10, a separate
thiazole-5-carboxylate 5 (Scheme 2).3
An analogous approach from the appropriately substituted vinyl
ether was investigated to produce diverse imidazo[1,2-a]pyridines
with the 3-position pyrazine installed. This Letter describes the syn-
thesis of 2-chloro-6-[(Z)-2-ethoxyethenyl]pyrazine, the in situ gen-
eration of the hemiacetal, and subsequent cyclization with various
2-aminopyridines to give 3-pyrazinyl-imidazo[1,2-a]pyridines.
2-Chloro-6-[(Z)-2-ethoxyethenyl]pyrazine 9 was prepared from
the nucleophilic tele-substitution on 2,3-dichlorpyrazine by the vi-
nyl anion 7 (Scheme 3).4 To prepare 7, the cis-vinyl bromide 6 was
dissolved in THF, cooled to À78 °C, and treated with n-BuLi. The vi-
nyl anion was treated with 2,3-dichloropyrazine which gave only
the cis-2,6-disubstituted pyrazine 9.5 The trans-2,6-disubstituted
compound or the corresponding 2,3-disubstituted compounds
were not observed in the crude reaction mixture. The regiochem-
istry of the reaction was confirmed by the proton NMR spectrum5
8
5
1
N
Pd(OAc)2, PPh3
K2CO3, dioxane
7
N
N
1
+
2
R
6
N
4
Cl
Cl
3
18 h, 100 o
C
2
Table 1.
N
N
Entry
R
H
% Yield
40
1
2
Cl
N
N
7-CN
28
23
3
3
5-CH3
R
* Corresponding author. Tel.: +1 858 622 3294.
E-mail address: michael.collins@pfizer.com (M. R. Collins).
Scheme 1. Palladium-catalyzed direct arylation.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.117

M. R. Collins et al. / Tetrahedron Letters 51 (2010) 3528–3530
3529
Table 2
Cyclization of hemiacetal 10 with 2-aminopyridines 11
OH
CO2Et
NBS
CO2Et
Entry
2-Aminopyridine
Product
% Yield
EtO
EtO
H2N
H2O-dioxane
Br
H2N
H2N
H2N
H2N
N
N
N
N
Ar
30 min, -10 oC to rt
N
N
62 (40)a
46 (3)a
31
3
4
1
S
CH3
Ar
N
N
NH2
N
2
3
CO2Et
CH3
Ar
1 h, 80 o
90% yield
C
H2N
S
OCH3
5
N
N
Scheme 2. Synthesis of aminothiazole.
OCH3
Ar
N
N
n-BuLi
EtO
EtO
CN
4
5
6
62
44
63
Br
THF
Li
0.5 h, -78 o
C
CN
Ar
6
7
H2N
H2N
H2N
N
N
N
N
N
N
Cl
Cl
NO2
N
N
8
NO2
Ar
N
Cl
N
N
OEt
0.5 h, -78 o
50% yield
C
OCH3
9
OCH3
Ar
Scheme 3. Tele substitution.
N
N
experiment was conducted where the vinyl ether 9 was dissolved
in D2O and 1,4-dioxane-d8 and treated with NBS. The 1H NMR spec-
trum of the crude reaction mixture confirmed the clean conversion
of the vinyl ether 9 to the hemiacetal 10.7
The scope of the reaction was investigated and the results are
summarized in Table 2.
The cyclization of the hemiacetal 10 with 2-aminopyridine gave
a 62% yield of the 3-(6-chloropyrazin-2-yl)imidazo[1,2-a]pyridine
(entry 1 of Table 2). The 1H NMR spectrum was identical to that
of the product obtained in the direct arylation reaction (entry 1
of Table 1). The scope of this method is broad, with only moderate
variation in yields observed. The presence of a methyl or methoxy
group at the 6-position of the 2-aminopyridine reactant provided
slightly lower yields than that of the unsubstituted 2-aminopyri-
7
8
60 (23)a
CN
N
NC
N
H2N
Ar
N
49
OCH3
N
H3CO
H2N
H3C
Ar
N
N
9
10
11
12
46
56
48
61
H3C
H2N
N
Ar
N
N
N
H3CO
H3CO
N
N
N
N
NBS
OH
H2N
F
N
N
Ar
N
Cl
H2O-dioxane
10 min, rt
EtO
Cl
Br
OEt
F
9
10
H2N
Cl
Ar
N
N
R
Cl
N
N
N
H2N
N
Ar
N
11
NH2
Cl
N
N
N
13
76
Br
Microwave
10 min, 100 o
C
12
R
Br
a
Yield for the direct arylation method.
Scheme 4. Synthesis of imidazo[1,2-a]pyridines.

3530
M. R. Collins et al. / Tetrahedron Letters 51 (2010) 3528–3530
2. Koubachi, J.; El Kazzouli, S.; Berteina-Raboin, S.; Mouaddib, A.; Guillaumet, G.
Synlett 2006, 3237–3242.
3. Zhao, R.; Gove, S.; Sundeen, J. E.; Chen, B. C. Tetrahedron Lett. 2001, 42, 2101–
2102.
dine (entries 2 and 3, 46% and 31%, respectively), suggesting that
steric congestion of the endocyclic nitrogen has a moderate nega-
tive impact on a key step in this cyclization reaction.
4. Torr, J. E.; Large, J. M.; Horton, P. N.; Hursthouse, M. B.; McDonald, E. Tetrahedron
Lett. 2006, 47, 31–34.
The yields for the cyclization were unaffected by the electronics
of the pyridine ring as demonstrated by the similar results for elec-
tron-withdrawing or electron-donating groups at the 5 or 4 posi-
tions of the 2-aminopyridine reactant (entries 4–8 in Table 2).
The entries 9–12 in Table 2 demonstrate that substitution of 2-
aminopyridine at the 3-position with a chloro, fluoro, methyl, or
methoxy group gave the desired products in 46–61% yields. The
synthesis of the brominated compound shown in entry 13 of Table
2 may be difficult using the palladium-catalyzed direct arylation
conditions shown in Scheme 1, however, 7-bromo-3-(6-chloropyr-
azin-2-yl)imidazo[1,2-a]pyridine was readily prepared using the
vinyl ether chemistry (76% yield).
Compared with the direct arylation method, the vinyl ether
chemistry provided higher yields across three direct pairs as
shown in entries 1, 2, and 7 of Table 2.
In conclusion, a new and robust synthesis of 3-pyrazinyl-imi-
dazo[1,2-a]pyridines has been developed. This procedure provides
higher yields than the palladium-catalyzed direct arylation proce-
dure and provides access to a diverse set of 3-pyrazinyl-imi-
dazo[1,2-a]pyridines from readily available 2-aminopyridines.
5. 2-Chloro-6-[(Z)-2-ethoxyethenyl]pyrazine 9: To a solution of (Z)-1-bromo-2-
ethoxyethene (11.6 mL, 92.6 mmol, 1.1 equiv) in THF (150 mL) at À78 °C was
added n-BuLi (37 mL, 2.5 M in hexane, 92.6 mmol, 1.1 equiv). The mixture was
stirred at À78 °C for 30 min yielding a colorless solution. A solution of 2,3-
dichloropyrazine (12.8 g, 84 mmol, 1.0 equiv) in THF (50 mL) was added slowly
to the vinyl anion. The resulting brown solution was stirred at À78 °C for
30 min. The reaction was quenched with water and the reaction mixture was
warmed to room temperature. The mixture was diluted with EtOAc and the
organic layer was washed with water and brine, dried over Na2SO4, filtered, and
the filtrate was concentrated under reduced pressure. The residue was purified
over silica gel (flash chromatography, 15–30% ethyl acetate–heptane) affording
8.0 g of the desired product as a brown oil (50% yield). 1H NMR (400 MHz,
DMSO-d6) d ppm 9.01 (s, 1H), 8.44 (s, 1H), 6.91 (d, J = 7.1 Hz, 1H), 5.36 (d,
J = 7.1 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz,
DMSO-d6) d ppm 154.6, 151.7, 147.6, 142.6, 139.8, 101.9, 70.5, 15.8. LCMS (APCI)
m/z 185 (M+H)+.
6. (3-(6-Chloropyrazin-2-yl)imidazo[1,2-a]pyridine): To a solution of 2-chloro-6-
[(Z)-2-ethoxyethenyl]pyrazine 9 (200 mg, 1.08 mmol, 1.05 equiv) in a mixture
of water (2.5 mL) and dioxane (7 mL) was added NBS (183 mg, 1.05 mmol,
1.0 equiv). The heterogeneous mixture became homogeneous after several
minutes. The homogeneous solution was stirred at room temperature for
10 min. 2-Aminopyridine (102 mg, 1.08 mmol, 1.05 equiv) was added and the
reaction mixture was heated in a microwave for 10 min at 100 °C. The crude
product was poured into 50% saturated NaHCO3 (70 mL) and the aqueous layer
was extracted with EtOAc (2 Â 50 mL). The organic layer was washed with
brine, dried over MgSO4, filtered, and the filtrate was concentrated under
reduced pressure. The residue was purified over silica gel (Biotage 25S cartridge,
0–10% methanol–ethyl acetate) furnishing 154 mg of the desired product as a
beige solid (62% yield). 1H NMR (400 MHz, DMSO-d6) d ppm 9.57 (d, J = 6.8 Hz,
1H), 9.32 (s, 1H), 8.69 (s, 1H), 8.57 (s, 1H), 7.80 (d, J = 9.1 Hz, 1H), 7.52 (t,
J = 7.8 Hz, 1H), 7.24 (t, J = 6.8 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) d ppm
147.7, 146.5, 145.7, 140.3, 139.2, 137.8, 127.2, 127.1, 119.1, 117.5, 114.3. LCMS
(APCI) m/z 231 (M+H)+.
Acknowledgment
We thank Robert Kania, Steven Tanis, and Professor Andrew
Myers for extremely helpful advice.
References and notes
7. 2-Bromo-2-(6-chloropyrazin-2-yl)-1-ethoxyethanol 10: 1H NMR (400 MHz,
dioxane-d8—D2O) d ppm 8.52 (s, 1H), 8.44 (s, 1H), 5.03 (d, J = 6.6 Hz, 1H), 4.84
(d, J = 6.6 Hz, 1H), 3.54–3.59 (m, 1H), 3.27–3.33 (m, 1H), 0.85 (t, J = 7.1 Hz, 3H).
1. Ninkovic, S.; Braganza, J. F.; Collins, M. R.; Kath, J. C.; Li, H.; Richter, D. T. World
Intellectual Property Organization, WO 2010/016005 A1.