Evaluation of the 2-substituent effect on the reactivity of the 8-haloimidazo[1,2-α]pyridine series towards Suzuki-type cross-coupling reaction

Article abstract of DOI:10.1246/bcsj.78.154

The purpose of this work was to complete a general study that we initiated on the influence of a 2-substitution on the reactivity of 8-haloimidazo[1 ,2-α]pyridines towards a Suzuki cross-coupling reaction, using conventional reactants in order to obtain e

Full text of DOI:10.1246/bcsj.78.154

154 Bull. Chem. Soc. Jpn., 78, 154–159 (2005)
Ó 2005 The Chemical Society of Japan
Evaluation of the 2-Substituent Effect on the Reactivity
of the 8-Haloimidazo[1,2-a]pyridine Series towards
Suzuki-Type Cross-Coupling Reaction
ꢀ
´
Jean-Yves Kazock, Cecile Enguehard-Gueiffier, Isabelle Thery, and Alain Gueiffier
´
´
Laboratoire de Chimie Therapeutique, EA 3247, Faculte de Pharmacie, 31 avenue Monge, F-37200 Tours, France
´
Received July 12, 2004; E-mail: alain.gueiffier@univ-tours.fr
The purpose of this work was to complete a general study that we initiated on the influence of a 2-substitution on
the reactivity of 8-haloimidazo[1,2-a]pyridines towards a Suzuki cross-coupling reaction, using conventional reactants in
order to obtain easily performed (hetero)arylation methods with a high degree of flexibility with regard to functional
groups.
Imidazo[1,2-a]pyridines are currently the object of a re-
X
newed interest in the pharmaceutical field. Lately, many pub-
lications have reported on their pharmacological properties
in various biological areas [e.g., p38 MAP kinase inhibitors,1
ligands for detecting ꢀ-amyloid plaques in the brain,2 cyclin-
dependent kinase inhibitors,3 antiviral molecules4]. New
approaches for the synthesis of functionalized imidazo[1,2-
a]pyridines have also been described.5–7 Nevertheless, meth-
ods for functionalization that allow the rapid preparation of a
number of structural variants in these series, and notably on
the pyridine moiety, are still needed.
N
R
N
H3C
1a-c, 2a-c
X
Br
I
R = CH3 R = 4-FC6H4 R = CO2C2H5
1a
2a
1b
2b
1c
2c
During the course of our work to evaluate the applicability
of metallo-catalyzed cross-coupling reactions in the imi-
dazo[1,2-a]pyridine series,8,9 we previously reported that the
reactivity towards the Suzuki cross-coupling reaction10–12 of
3-iodoimidazo[1,2-a]pyridine diversely substituted at C(2) is
largely influenced by the nature of the 2-substituent.13 More
surprisingly, the reactivity of the 6-position in these series
was also shown to be highly dependent on the 2-substitution.14
With the aim to complete this study concerning the effect of
the 2-substituent on the reactivity of the imidazo[1,2-a]pyri-
dine core, we tried to evaluate the applicability of the Suzuki
cross-coupling reaction to the 8-haloimidazo[1,2-a]pyridine.
In this work, our purpose was to determine the best Suzuki re-
action conditions applicable to the 8 position of the imi-
dazo[1,2-a]pyridine, depending on the nature of the 2-substitu-
tion, using conventional reactants in order to obtain easily per-
formed (hetero)arylation methods with a high degree of flexi-
bility with regard to functional groups.
Scheme 1.
the 2-position: methyl, phenyl, and ester groups.
In the first approach, the coupling reaction was applied
to the 8-bromo-2,6-dimethylimidazo[1,2-a]pyridine 1a under
the traditional reaction conditions: 1.1 molar amount of (het-
ero)arylboronic acid, 5 mol% of Pd(PPh3)4, 2 molar amounts
of NaOH in a refluxing mixture of 1,2-dimethoxyethane (8
mL/mmol) and water (4 mL/mmol) (Method A). As previous-
ly observed, the diversely substituted phenylboronic acids pre-
sented higher reactivities than the studied heteroarylboronic
acids. The benzene coupling occurred within 3 h in more than
90% yields, with apparently no influence of the electronic ef-
fects of the benzene substituent (e.g., 4-F, 4-OCH3, 2,4,6-tri-
CH3 and 3-CF3). Only the 3-nitrophenylboronic acid was cou-
pled in poor yield (40%). An attempt to use the 8-iodinated
starting material 2a even decreased the yield from 40 to
20%. The lowest efficiency of the nitrophenyl coupling was
already noticed in the literature.16
Using the same conditions (Method A), the coupling of
thien-2-ylboronic acid to 1a proceeded very slowly, and only
34% of the desired compound 10a was obtained after 3 h of
heating. An attempt to switch to the iodinated derivative 2a
slightly improved the coupling efficacy (42% yield), but pro-
longing the reaction time to 8 h had no effect on the coupling
yield. From these observations, we then decided to modify the
Results and Discussion
The reason for choosing 8-halo-6-methyl-2-substituted imi-
dazo[1,2-a]pyridines 1–2 (Scheme 1) as the starting materials,
instead of non-methyl substituted analogues, was that they are
synthesized in better yield on a large scale. They were easily
obtained by the condensation of 3-halo-5-methylpyridin-2-
amine with a convenient ꢁ-halo ketone in refluxing ethanol,
according to Tschitschibabin,15 in moderate-to-good yields
(45–84%). Three representative groupings were introduced at
Published on the web January 13, 2005; DOI 10.1246/bcsj.78.154

J.-Y. Kazock et al.
Bull. Chem. Soc. Jpn., 78, No. 1 (2005)
155
reaction conditions in terms of the catalyst and the base, and to
adopt the method that we previously determined in the 6-posi-
tion of the imidazo[1,2-a]pyridine: 1.1 molar amount of (het-
ero)arylboronic acid, 5 mol% of PdCl2dppf, 2 molar amounts
of Ba(OH)2 in a refluxing mixture of 1,2-dimethoxyethane (8
mL/mmol) and water (4 mL/mmol) (Method B). Under these
modified conditions, the thien-2-yl coupling proceeded more
efficiently from 2a, leading to 10 in 67% yield after 8 h of
heating. Traces of the starting material still remained at the
end of the reaction, but no improvement of the yield was
achieved from a prolonged reaction time. Furthermore, an at-
tempt to associate Ba(OH)2 to Pd(PPh3)4 as catalyst (Method
C) was deleterious for the coupling efficacy (37% yield in 8
h). We noticed that the coupling yield of thien-2-ylboronic
acid with 2a, was inversely proportional to the strength of
the base associated to Pd(PPh3)4, because the best result was
obtained using Na2CO3 (68% yield). This correlation was
not observed with PdCl2dppf, which could be efficiently asso-
ciated to Ba(OH)2.
From the heteroarylboronic acids studied, the thien-3-ylbo-
ronic acid appeared to be the most reactive substrate. Using
method A, 72% of compound 11a was obtained from 2a after
8 h of heating. The less-reactive substrate was the fur-2-ylbo-
ronic acid with only 19% of compound 12a obtained using
method A after 24 h. Method B led to a significantly increased
yield (55% after 8 h). Again, prolonging the reaction time was
not beneficial for the Suzuki coupling. These results may have
been due to competitive protodeboronation, which is a known
issue for heteroarylboronic acids, specifically when the boron
is on a carbon adjacent to a heteroatom. This could explain
the order of reactivity of the different boronic acids tested
(thien-3-yl > thien-2-yl > fur-2-yl) and the presence of the
remaining starting material at the end of the reaction, even
with a prolonged reaction time.17,18
The 8-halo-2-(4-fluorophenyl)imidazo[1,2-a]pyridine deriv-
atives 1b–2b were then submitted to the same Suzuki reaction
conditions as previously, to compare the reactivity of the 2-
methyl and 2-phenyl series. Substituted phenylboronic acids
were coupled in 82 to 95% yields from 1b (Method A).
Thien-2-yl coupling to 2b using method B, led to 69% of com-
pound 10b after 8 h of heating (67% in the 2-methyl series),
whereas 85% of thien-3-yl derivative 11b were obtained using
Method A (72% in the 2-methyl series). Thus, no dramatic dif-
ferences were noticed concerning the reactivity of these two
series of compounds towards the Suzuki coupling.
Concerning the 8-haloimidazo[1,2-a]pyridine-2-carboxylic
ester derivatives 1c–2c, the base sensitivity of the ester func-
tion prevented us from using bases stronger than Na2CO3 or
K3PO4, or a too long reaction time. The reactions were carried
out in the presence of Pd(PPh3)4 and Na2CO3 for 3 h. Phenyl,
thien-2-yl, and thien-3-yl couplings were performed from 1c in
69, 47, and 37% yields, respectively. Prolonged reaction times
led to dramatically decreased yields. Only 19% of 8-furyl de-
rivative 12c were obtained after 8 h of heating. Using K3PO4
as a base improved the coupling efficacy, leading to 76% of
8-phenyl compound 3c and 88% of 8-thienyl derivative 11c.
In conclusion, the 2-methyl and 2-phenyl series exhibited
very similar reactivity towards the Suzuki coupling reaction.
Using Pd(PPh3)4 and NaOH, phenylboronic acids were cou-
pled in more than 80% yields, while heteroarylboronic acids
presented lower reactivities. For the couplings of these hetero-
arylboronic acids, two different catalytic systems could be
used: Pd(PPh3)4/Na2CO3 or PdCl2dppf/Ba(OH)2. It appeared
that the efficacy of Pd(PPh3)4 is inversely proportional to the
strength of the base, while PdCl2dppf doesn’t seem to be sen-
sitive to the nature of the base. As far as the 2-ester series is
concerned, no effect of the 2-substitution was observed on
the reactivity of the 8 position as it was noticed on the 3 posi-
tion.13 Indeed, the 3-position was highly activated by the pres-
ence of the ester group in the 2-position compared with the 2-
phenyl series. We were then confronted with the base sensitiv-
ity of the ester function. The use of K3PO4 appeared to be a
good alternative to utilising Na2CO3.
Experimental
General. The melting points were determined in a capillary
apparatus, and are uncorrected. NMR experiments were per-
formed at 200 MHz (1H) and 50 MHz (13C) in CDCl3 on Bruker
DPX 200 instruments. Possible inversion of two values in the
NMR spectra is expressed by an asterisk.
Materials:
Tetrakis(triphenylphosphine)palladium(0),19 3-
bromo-5-methylpyridin-2-amine,20 and 3-iodo-5-methylpyridin-
2-amine21 were prepared as described in the literature.
8-Bromo-2,6-dimethylimidazo[1,2-a]pyridine (1a). A mix-
ture of 8 g (42.8 mmol) of 3-bromo-5-methylpyridin-2-amine
and 5.26 mL (73 mmol) of 1,3-dichloroacetone in dry EtOH (50
mL) was refluxed for 24 h. After concentration to dryness of the
reaction mixture, the residue was suspended in H2O, made basic
with Na2CO3, and the precipitate was filtered off. After dissolu-
tion of the solid in CH2Cl2 and drying with CaCl2, the organic lay-
er was evaporated under reduced pressure. Column chromatogra-
phy on neutral alumina, eluting with CH2Cl2, led to 1a (55%). mp
83–84 ꢁC. 1H NMR ꢂ 7.77 (m, 1H, H-5), 7.31 (d, 1H, J ¼ 0:8 Hz,
H-3), 7.22 (d, 1H, J ¼ 1:4 Hz, H-7), 2.46 (s, 3H, CH3), 2.26 (s,
3H, CH3). 13C NMR ꢂ 144.2 (C-2), 142.4 (C-8a), 129.7 (C-7),
122.8 (C-5), 122.0 (C-6), 111.5 (C-3), 110.4 (C-8), 18.2 (CH3),
14.9 (CH3). Anal. Calcd for C9H9N2Br: C, 48.02; H, 4.03; N,
12.45%. Found: C, 47.86; H, 4.36; N, 12.57%.
8-Iodo-2,6-dimethylimidazo[1,2-a]pyridine (2a). The same
conditions were applied starting from 8 g (34.2 mmol) of 3-
iodo-5-methylpyridin-2-amine and 4.65 mL (58.2 mmol) of 1,3-
dichloroacetone. Purification by column chromatography on neu-
tral alumina, and eluting with CH2Cl2 gave 2a (51%). mp 119–
ꢁ
1
120 C. H NMR ꢂ 7.82 (m, 1H, H-5), 7.49 (d, 1H, J ¼ 1:5 Hz,
H-7), 7.39 (d, 1H, J ¼ 0:7 Hz, H-3), 2.49 (s, 3H, CH3), 2.28 (s,
ꢀ
ꢀ
3H, CH3). 13C NMR ꢂ 144.1 (C-2 ), 143.9 (C-8a ), 136.7 (C-
7), 123.7 (C-5), 122.7 (C-6), 111.8 (C-3), 83.0 (C-8), 18.0
(CH3), 14.9 (CH3). Anal. Calcd for C9H9N2I: C, 39.73; H, 3.33;
N, 10.30%. Found: C, 39.84; H, 3.27; N, 10.48%.
8-Bromo-6-methyl-2-(4-fluorophenyl)imidazo[1,2-a]pyridine
(1b). The same conditions were applied starting from 10 g (53
mmol) of 3-bromo-5-methylpyridin-2-amine and 12.76 g (58.9
mmol) of 20-bromo-4-fluoroacetophenone in dry EtOH (150 mL)
for 16 h. Purification by column chromatography on neutral alu-
mina, and eluting with CH2Cl2, gave 1b (45%). mp 192–193
ꢁC. 1H NMR ꢂ 7.95 (dd, 2H, J ¼ 8:8, 5.4 Hz, F–Ph-2,6), 7.85
(m, 1H, H-5), 7.78 (s, 1H, H-3), 7.31 (d, 1H, J ¼ 1:4 Hz, H-7),
7.13 (t, 2H, J ¼ 8:8 Hz, F–Ph-3,5), 2.29 (s, 3H, CH3). 13C NMR
ꢀ
ꢀ
ꢂ 163.2 (J ¼ 245:5 Hz, F–Ph-4), 145.6 (C-2 ), 143.1 (C-8a ),
130.6 (C-7), 130.1 (J ¼ 3:5 Hz, F–Ph-1), 128.3 (J ¼ 8 Hz,

156 Bull. Chem. Soc. Jpn., 78, No. 1 (2005)
Reactivity of 8-Haloimidazo[1,2-a]pyridines
F–Ph-2,6), 123.2 (C-5), 122.8 (C-6), 115.9 (J ¼ 21:5 Hz, F–Ph-
3,5), 111.2 (C-8), 109.6 (C-3), 18.3 (CH3). Anal. Calcd for
C14H10N2BrF: C, 55.10; H, 3.30; N, 9.18%. Found: C, 55.24;
H, 3.49; N, 8.99%.
2H, Ph-2,6), 7.84 (m, 1H, H-5), 7.50 (m, 3H, Ph-3,4,5), 7.35 (s,
1H, H-3), 7.11 (d, 1H, J ¼ 1:6 Hz, H-7), 2.50 (s, 3H, CH3),
ꢀ
ꢀ
2.37 (s, 3H, CH3). 13C NMR ꢂ 143.6 (C-2 ), 143.4 (C-8a ),
137.2 (Ph-1), 129.3 (C-8), 129.2 (Ph-2,6), 128.9 (Ph-3,5), 128.5
(Ph-4), 126.1 (C-7), 122.5 (C-5), 121.6 (C-6), 110.2 (C-3), 18.5
(CH3), 15.1 (CH3). Anal. Calcd for C15H14N2: C, 81.05; H,
6.35; N, 12.60%. Found: C, 81.15; H, 6.33; N, 12.57%.
8-Iodo-6-methyl-2-(4-fluorophenyl)imidazo[1,2-a]pyridine
(2b). The same conditions were applied starting from 8 g (34.2
mmol) of 3-iodo-5-methylpyridin-2-amine and 8.16 g (37.6
mmol) of 20-bromo-4-fluoroacetophenone in dry EtOH (150 mL)
for 24 h. Purification by column chromatography on neutral alu-
mina, and eluting with CH2Cl2, gave 2b (61%). mp 173–174
ꢁC. 1H NMR ꢂ 7.98 (dd, 2H, J ¼ 8:7, 5.4 Hz, F–Ph-2,6), 7.90
(m, 1H, H-5), 7.86 (s, 1H, H-3), 7.51 (d, 1H, J ¼ 1:5 Hz, H-7),
7.15 (t, 2H, J ¼ 8:7 Hz, F–Ph-3,5), 2.35 (s, 3H, CH3). 13C NMR
2,6-Dimethyl-8-(4-fluorophenyl)imidazo[1,2-a]pyridine (4a).
ꢁ
1
Neutral alumina, eluting with CH2Cl2. mp 107–108 C. H NMR
ꢂ 8.02 (dd, 2H, J ¼ 8:6, 5.6 Hz, F–Ph-2,6), 7.82 (s, 1H, H-5), 7.33
(s, 1H, H-3), 7.19 (t, 2H, J ¼ 8:6 Hz, F–Ph-3,5), 7.05 (s, 1H, H-7),
2.49 (s, 3H, CH3), 2.35 (s, 3H, CH3). 13C NMR ꢂ 163.1
ꢀ
ꢀ
(J ¼ 245:5 Hz, F–Ph-4), 143.6 (C-2 ), 143.1 (C-8a ), 133.2
(J ¼ 3:5 Hz, F–Ph-1), 130.5 (J ¼ 8 Hz, F–Ph-2,6), 128.2 (C-8),
125.8 (C-7), 122.6 (C-5), 121.6 (C-6), 115.8 (J ¼ 21:5 Hz, F–
Ph-3,5), 110.3 (C-3), 18.4 (CH3), 14.9 (CH3). Anal. Calcd for
C15H13N2F: C, 74.98; H, 5.45; N, 11.66%. Found: C, 75.12; H,
5.54; N, 11.52%.
ꢀ
ꢀ
ꢂ 163.2 (J ¼ 245:5 Hz, F–Ph-4), 145.6 (C-2 ), 144.5 (C-8a ),
137.5 (C-7), 130.2 (J ¼ 3 Hz, F–Ph-1), 128.3 (J ¼ 7 Hz, F–Ph-
2,6), 124.0 (C-5), 123.4 (C-6), 115.9 (J ¼ 21:5 Hz, F–Ph-3,5),
109.8 (C-3), 83.8 (C-8), 18.1 (CH3). Anal. Calcd for C14H10N2FI:
C, 47.75; H, 2.86; N, 7.96%. Found: C, 47.85; H, 2.77; N, 8.03%.
Ethyl 8-Bromo-6-methylimidazo[1,2-a]pyridine-2-carboxyl-
ate (1c). A mixture of 8 g (47.8 mmol) of 3-bromo-5-methylpyri-
din-2-amine and 9.12 mL (73 mmol) of aq. sol. of ethyl bromo-
pyruvate (90%) in DME (50 mL) was stirred at room temperature
for 24 h. The resulting solid was filtered off, suspended in dry
EtOH (150 mL), and the reaction mixture was refluxed for 24 h.
After concentration to dryness, the residue was suspended in
H2O, made alkaline with Na2CO3 and the precipitate was filtered
off. After dissolution of the solid in CH2Cl2 and drying with
CaCl2, the organic layer was evaporated under reduced pressure.
Column chromatography on neutral alumina, and eluting with
CH2Cl2, led to 1c (84%). mp 149–150 ꢁC. 1H NMR ꢂ 8.17 (s,
1H, H-3), 7.92 (m, 1H, H-5), 7.38 (d, 1H, J ¼ 1:4 Hz, H-7),
4.44 (q, 2H, J ¼ 7:1 Hz, CH2), 2.36 (s, 3H, CH3), 1.42 (t, 3H, J ¼
2,6-Dimethyl-8-(4-methoxyphenyl)imidazo[1,2-a]pyridine
(5a).
Neutral alumina, eluting with CH2Cl2. mp 72–73 ꢁC.
1H NMR ꢂ 7.99 (d, 2H, J ¼ 8:8 Hz, CH3O–Ph-2,6), 7.81 (m,
1H, H-5), 7.34 (s, 1H, H-3), 7.07 (m, 1H, H-7), 7.05 (d, 2H, J ¼
8:8 Hz, CH3O–Ph-3,5), 2.50 (s, 3H, CH3), 2.36 (s, 3H, CH3).
13C NMR ꢂ 160.0 (CH3O–Ph-4), 143.4 (C-2, C-8a), 130.4
(CH3O–Ph-2,6), 129.7 (CH3O–Ph-1), 128.9 (C-8), 125.3 (C-7),
122.0 (C-5), 121.6 (C-6), 114.4 (CH3O–Ph-3,5), 110.1 (C-3),
55.8 (CH3O), 18.6 (CH3), 15.1 (CH3). Anal. Calcd for
C16H16N2O: C, 76.16; H, 6.39; N, 11.10%. Found: C, 76.28; H,
6.41; N, 11.25%.
2,6-Dimethyl-8-(2,4,6-trimethylphenyl)imidazo[1,2-a]pyri-
dine (7a). Neutral alumina, eluting with CH2Cl2. mp 219–220
ꢁC. 1H NMR ꢂ 7.87 (m, 1H, H-5), 7.33 (s, 1H, H-3), 6.99 (s,
2H, Ph-3,5), 6.77 (m, 1H, H-7), 2.44 (s, 3H, CH3), 2.43 (s, 3H,
CH3), 2.42 (s, 3H, CH3), 2.01 (s, 6H, 2CH3). 13C NMR ꢂ 143.7
ꢀ
7:1 Hz, CH3). 13C NMR ꢂ 163.4 (CO), 142.9 (C-8a ), 137.4 (C-
ꢀ
2 ), 132.2 (C-7), 124.4 (C-6), 123.5 (C-5), 118.7 (C-3), 112.5
ꢀ
ꢀ
(C-8), 61.6 (CH2), 18.3 (CH3), 14.8 (CH3). Anal. Calcd for
C11H11N2O2Br: C, 46.66; H, 3.92; N, 9.89%. Found: C, 46.52;
H, 3.81; N, 10.02%.
(C-2 ), 143.6 (C-8a ), 137.6 (Ph-1), 136.8 (Ph-2,6), 133.9 (Ph-
4), 129.4 (C-8), 128.7 (Ph-3,5), 127.7 (C-7), 122.4 (C-5), 121.3
(C-6), 109.9 (C-3), 21.6 (CH3), 20.8 (CH3), 18.5 (CH3), 15.2
(CH3). Anal. Calcd for C18H20N2: C, 81.78; H, 7.63; N,
10.60%. Found: C, 81.83; H, 7.74; N, 10.59%.
Ethyl 8-Iodo-6-methylimidazo[1,2-a]pyridine-2-carboxylate
(2c). The same conditions were applied using 8 g (34.2 mmol)
of 3-iodo-5-methylpyridin-2-amine and 6.44 mL (51.3 mmol) of
aq. sol. of ethyl bromopyruvate. Purification by column chroma-
tography on neutral alumina gel using CH2Cl2 as an eluant gave
2c (49%). mp 128–129 ꢁC. 1H NMR ꢂ 8.23 (s, 1H, H-3), 7.94
(m, 1H, H-5), 7.65 (m, 1H, H-7), 4.45 (q, 2H, J ¼ 7:1 Hz,
CH2), 2.32 (s, 3H, CH3), 1.44 (t, 3H, J ¼ 7:1 Hz, CH3). 13C NMR
ꢂ 163.4 (CO), 144.3 (C-8a), 139.3 (C-7), 137.2 (C-2), 124.9 (C-6),
124.4 (C-5), 119.0 (C-3), 84.8 (C-8), 61.5 (CH2), 18.1 (CH3), 14.8
(CH3). Anal. Calcd for C11H11N2O2I: C, 40.02; H, 3.36; N,
8.49%. Found: C, 40.31; H, 3.61; N, 8.46%.
2,6-Dimethyl-8-(3-trifluoromethylphenyl)imidazo[1,2-a]pyri-
dine (8a). Neutral alumina, eluting with CH2Cl2. mp 105–106
1
ꢁC. H NMR ꢂ 8.33 (m, 1H, Ph-6), 8.20 (m, 1H, Ph-2), 7.90 (m,
1H, H-5), 7.64 (m, 2H, Ph-4,5), 7.38 (d, 1H, J ¼ 0:8 Hz, H-3),
7.13 (d, 1H, J ¼ 1:6 Hz, H-7), 2.51 (s, 3H, CH3), 2.40 (s, 3H,
ꢀ
ꢀ
CH3). 13C NMR ꢂ 143.91 (C-2 ), 142.94 (C-8a ), 137.95 (Ph-
1), 132.83 (Ph-6), 131.23 (J ¼ 31:5 Hz, Ph-3), 129.33 (Ph-5),
127.75 (C-8), 126.30 (C-7), 125.87 (J ¼ 4 Hz, Ph-2), 125.00
(J ¼ 3:5 Hz, Ph-4), 124.70 (J ¼ 270:5 Hz, CF3), 123.20 (C-5),
121.60 (C-6), 110.37 (C-3), 18.47 (CH3), 14.96 (CH3). Anal.
Calcd for C16H13N2F3: C, 66.20; H, 4.51; N, 9.65%. Found: C,
66.37; H, 4.44; N, 9.78%.
Suzuki Cross-Coupling Reaction: General Procedure. Into
a three-necked round bottom flask was introduced the 8-halo-
6-methyl-2-substituted imidazo[1,2-a]pyridine derivative 1–2 (1
mmol) in 1,2-dimethoxyethane (8 mL) under N2. The catalyst (5
mol%), the boronic acid (1.1 molar amount) and the base (2 molar
amounts) in H2O (4 mL) were then added under vigorous stirring.
2,6-Dimethyl-8-(3-nitrophenyl)imidazo[1,2-a]pyꢁridine (9a).
1
Neutral alumina, eluting with CH2Cl2. mp 114–115 C. H NMR
ꢂ 8.87 (m, 1H, Ph-2), 8.51 (dt, 1H, J ¼ 7:8, 1.1 Hz, Ph-6), 8.27
(ddd, 1H, J ¼ 8:2, 2.3, 1.1 Hz, Ph-4), 7.93 (m, 1H, H-5), 7.69
(dd, 1H, J ¼ 8:2, 7.8 Hz, Ph-5), 7.39 (d, 1H, J ¼ 0:7 Hz, H-3),
7.20 (d, 1H, J ¼ 1:6 Hz, H-7), 2.51 (s, 3H, CH3), 2.43 (s, 3H,
ꢁ
The reaction mixture was warmed at 75 C (Table 1). After cool-
ing, the resulting mixture was diluted in H2O and the aqueous
layer extracted with CH2Cl2. The organic layers were dried on
CaCl2, filtered, and evaporated to dryness. Column chromatogra-
phy afforded the pure product.
2,6-Dimethyl-8-phenylimidazo[1,2-a]pyridine (3a). Neutral
alumina, eluting with CH2Cl2. mp 93–94 ꢁC. 1H NMR ꢂ 8.02 (m,
ꢀ
ꢀ
CH3). 13C NMR ꢂ 148.9 (Ph-3), 144.1 (C-2 ), 142.7 (C-8a ),
138.8 (Ph-1), 135.5 (Ph-4), 129.9 (Ph-5), 126.6 (C-8), 126.5 (C-
7), 124.0 (Ph-2), 123.6 (C-5), 123.2 (Ph-6), 121.6 (C-6), 110.5
(C-3), 18.5 (CH3), 15.0 (CH3). Anal. Calcd for C15H13N3O2: C,
67.40; H, 4.90; N, 15.72%. Found: C, 67.55; H, 4.87; N, 15.63%.

J.-Y. Kazock et al.
Table 1. Synthesis of 8-(Hetero)arylimidazo[1,2-a]pyridines 3–12aÞ
Bull. Chem. Soc. Jpn., 78, No. 1 (2005)
157
X
R'
N
N
R'-B(OH)2, Pd(0), Base
DME, H2O, Reflux
R
R
N
N
H3C
H3C
1a-c, 2a-c
3-12
a: R = CH3
b: R = 4-FC6H4
c: R = CO2C2H5
R ¼ CH3
Yield/%bÞ
(Time/h)
R ¼ 4-FC6H4
Yield/%bÞ
(Time/h)
R ¼ CO2C2H5
Yield/%bÞ
(Time/h)
Compd
R0
X
Catalyst
Base
3
C6H5
Br
Br
I
Br
Br
I
Br
Br
Br
Br
Br
I
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
NaOH
Na2CO3
Na2CO3
K3PO4
NaOH
Na2CO3
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
94 (3)
95 (3)
69 (3), 25 (8)
46 (3)
49 (3), 76 (8)
4
4-FC6H4
95 (3)
94 (3)
96 (3)
50 (3)
5
6
7
8
9
4-CH3OC6H4
3-CH3OC6H4
2,4,6-(CH3)3C6H2
3-CF3C6H4
82 (3)
88 (3)
94 (3)
91 (3)
40 (3)
20 (3)
3-NO2C6H4
10
Thien-2-yl
Br
Br
I
I
I
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
PdCl2dppf
NaOH
Na2CO3
NaOH
Na2CO3
Ba(OH)2
Ba(OH)2
34 (3)
55 (3)
62 (8)
54 (24)
47 (3), 28 (8)
42 (3), 42 (8)
68 (8)
37 (8)
I
67 (8), 62 (24)
69 (8)
11
12
Thien-3-yl
Fur-2-yl
Br
I
Br
Br
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
NaOH
NaOH
Na2CO3
K3PO4
55 (8)
72 (8)
58 (8)
85 (8)
70 (8)
37 (3), 42 (8)
88 (8)
Br
I
Br
Br
Pd(PPh3)4
PdCl2dppf
Pd(PPh3)4
Pd(PPh3)4
NaOH
Ba(OH)2
Na2CO3
K3PO4
19 (24)
55 (8), 50 (24)
19 (8)
traces (8)
ꢁ
a) Couplings were carried out in a mixture of DME (8 mL) and water (4 mL) at 75 C. b) Isolated yields.
2,6-Dimethyl-8-(thien-2-yl)imidazo[1,2-a]pyridine (10a).
H, 5.30; N, 12.27%. Found: C, 68.37; H, 5.31; N, 12.22%.
2,6-Dimethyl-8-(fur-2-yl)imidazo[1,2-a]pyridine
ꢁ
1
Neutral alumina, eluting with CH2Cl2. mp 73–74 C. H NMR ꢂ
8.19 (dd, 1H, J ¼ 3:7, 1.2 Hz, Th-3), 7.79 (m, 1H, H-5), 7.41
(dd, 1H, J ¼ 5:1, 1.2 Hz, Th-5), 7.32 (s, 1H, H-3), 7.30 (m, 1H,
H-7), 7.19 (dd, 1H, J ¼ 5:1, 3.7 Hz, Th-4), 2.53 (s, 3H, CH3),
(12a).
ꢁ
1
Neutral alumina, eluting with CH2Cl2. mp 107–108 C. H NMR
ꢂ 7.78 (m, 1H, H-5), 7.77 (d, 1H, J ¼ 3:4 Hz, Fu-3), 7.57 (d, 1H,
J ¼ 1:8 Hz, Fu-5), 7.48 (d, 1H, J ¼ 1:5 Hz, H-7), 7.31 (d, 1H, J ¼
1:5 Hz, H-3), 6.62 (dd, 1H, J ¼ 3:4, 1.8 Hz, Fu-4), 2.53 (s, 3H,
CH3), 2.37 (s, 3H, CH3). 13C NMR ꢂ 149.8 (Fur-2), 143.4 (C-
ꢀ
ꢀ
2.36 (s, 3H, CH3). 13C NMR ꢂ 143.5 (C-2 ), 142.0 (C-8a ),
138.9 (Th-2), 128.2 (Th-3), 127.8 (Th-4), 126.3 (Th-5), 123.7
(C-7), 122.6 (C-8), 122.2 (C-5), 121.4 (C-6), 110.4 (C-3), 18.5
(CH3), 15.1 (CH3). Anal. Calcd for C13H12N2S: C, 68.39; H,
5.30; N, 12.27%. Found: C, 68.27; H, 5.41; N, 12.59%.
ꢀ
ꢀ
2 ), 142.8 (Fur-5), 140.8 (C-8a ), 122.0 (C-5), 121.5 (C-7),
121.4 (C-6), 118.8 (C-8), 112.6 (Fur-3), 112.3 (Fur-4), 110.2
(C-3), 18.6 (CH3), 15.0 (CH3). Anal. Calcd for C13H12N2O: C,
73.56; H, 5.70; N, 13.20%. Found: C, 73.94; H, 5.57; N, 13.24%.
6-Methyl-2-(4-fluorophenyl)-8-phenylimidazo[1,2-a]pyri-
dine (3b). Neutral alumina, eluting with CH2Cl2. mp 116–117
2,6-Dimethyl-8-(thien-3-yl)imidazo[1,2-a]pyridine (11a).
Silica gel, eluting with ether. mp 108–109 ꢁC. 1H NMR ꢂ 8.63
(dd, 1H, J ¼ 3:1, 1.3 Hz, Th-2), 7.81 (m, 1H, H-5), 7.76 (dd,
1H, J ¼ 5:1, 1.3 Hz, Th-4), 7.44 (dd, 1H, J ¼ 5:1, 3.1 Hz, Th-
5), 7.33 (s, 1H, H-3), 7.27 (d, 1H, J ¼ 1:5 Hz, H-7), 2.52 (s,
ꢁC. H NMR ꢂ 8.23 (m, 2H, Ph-2,6), 7.98 (dd, 2H, J ¼ 8:7, 5.5
1
Hz, F–Ph-2,6), 7.75 (m, 1H, H-5), 7.68 (s, 1H, H-3), 7.56 (m,
3H, Ph-3,4,5), 7.19 (d, 1H, J ¼ 1:6 Hz, H-7), 7.15 (t, 2H, J ¼
8:7 Hz, F–Ph-3,5), 2.34 (s, 3H, CH3). 13C NMR ꢂ 163.0
ꢀ
3H, CH3), 2.37 (s, 3H, CH3). 13C NMR ꢂ 143.4 (C-2 ), 142.8
ꢀ
(C-8a ), 137.1 (Th-3), 127.1 (Th-4), 125.8 (Th-2), 125.7 (Th-5),
ꢀ
ꢀ
124.4 (C-7), 123.7 (C-8), 122.0 (C-5), 121.4 (C-6), 110.1 (C-3),
18.6 (CH3), 15.0 (CH3). Anal. Calcd for C13H12N2S: C, 68.39;
(J ¼ 244:5 Hz, F–Ph-4), 144.9 (C-2 ), 143.8 (C-8a ), 136.8
(Ph-1), 130.9 (J ¼ 3 Hz, F–Ph-1), 129.5 (Ph-4), 129.4 (Ph-2,6),

158 Bull. Chem. Soc. Jpn., 78, No. 1 (2005)
Reactivity of 8-Haloimidazo[1,2-a]pyridines
128.9 (Ph-3,5), 128.8 (C-8), 128.1 (J ¼ 8 Hz, F–Ph-2,6), 126.5
(C-7), 122.9 (C-5), 122.4 (C-6), 116.1 (J ¼ 21 Hz, F–Ph-3,5),
108.4 (C-3), 18.6 (CH3). Anal. Calcd for C20H16N2F: C, 79.45;
H, 5.00; N, 9.27%. Found: C, 79.51; H, 5.03; N, 9.38%.
8:8, 5.5 Hz, F–Ph-2,6), 7.84 (dd, 1H, J ¼ 5:1, 1.2 Hz, Th-4), 7.77
(s, 1H, H-5), 7.70 (s, 1H, H-3), 7.46 (dd, 1H, J ¼ 5:1, 3 Hz, Th-5),
7.31 (d, 1H, J ¼ 1:3 Hz, H-7), 7.16 (t, 2H, J ¼ 8:8 Hz, F–Ph-3,5),
2.35 (s, 3H, CH3). 13C NMR ꢂ 162.9 (J ¼ 244:5 Hz, F–Ph-4),
ꢀ
ꢀ
6-Methyl-2,8-bis(4-fluorophenyl)imidazo[1,2-a]pyridine (4b).
Silica gel, eluting with ether. mp 110–111 ꢁC. 1H NMR ꢂ 8.19 (dd,
2H, J ¼ 9, 5.5 Hz, F–Ph0-2,6), 7.99 (dd, 2H, J ¼ 9, 5.5 Hz, F–Ph-
2,6), 7.95 (m, 1H, H-5), 7.83 (s, 1H, H-3), 7.24 (t, 3H, J ¼ 9 Hz,
F–Ph0-3,5), 7.18 (d, 1H, J ¼ 1:4 Hz, H-7), 7.15 (t, 2H, J ¼ 9 Hz,
F–Ph-3,5), 2.41 (s, 3H, CH3). 13C NMR ꢂ 163.3 (J ¼ 246:5 Hz,
144.6 (C-2 ), 143.3 (C-8a ), 136.8 (Th-3), 130.8 (J ¼ 3 Hz, F–
Ph-1), 128.0 (J ¼ 8 Hz, F–Ph-2,6), 126.9 (Th-4), 126.3 (Th-2),
125.6 (Th-5), 124.7 (C-7), 123.8 (C-8), 122.3 (C-5, C-6), 115.9
(J ¼ 21:5 Hz, F–Ph-3,5), 108.2 (C-3), 18.6 (CH3). Anal. Calcd
for C18H13N2SF: C, 70.11; H, 4.25; N, 9.08%. Found: C, 70.35;
H, 4.36; N, 9.14%.
ꢀ
F–Ph0-4), 163.0 (J ¼ 244:6 Hz, F–Ph-4), 145.0 (C-2 ), 143.7
Ethyl 6-Methyl-8-phenylimidazo[1,2-a]pyridine-2-carboxyl-
ate (3c). Neutral alumina, eluting with CH2Cl2. mp 107–108 ꢁC.
1H NMR ꢂ 8.17 (s, 1H, H-3), 8.06 (m, 2H, Ph-2,6), 7.93 (m, 1H,
H-5), 7.49 (m, 3H, Ph-3,4,5), 7.25 (d, 1H, J ¼ 1:6 Hz, H-7), 4.46
(q, 2H, J ¼ 7:1 Hz, CH2), 2.40 (s, 3H, CH3), 1.45 (t, 3H, J ¼ 7:1
ꢀ
(C-8a ), 132.8 (J ¼ 3 Hz, F–Ph0-1), 131.1 (J ¼ 8 Hz, F–Ph0-
2,6), 130.7 (J ¼ 3 Hz, F–Ph-1), 128.5 (C-8), 128.1 (J ¼ 7:5 Hz,
F–Ph-2,6), 126.3 (C-7), 122.9 (C-5), 122.4 (C-6), 115.9 (J ¼
21:5 Hz, F–Ph0-3,5), 115.7 (J ¼ 21:5 Hz, F–Ph-3,5 ), 108.4 (C-
ꢀ
ꢀ
3), 18.6 (CH3). Anal. Calcd for C16H16N2O: C, 74.99; H, 4.41;
N, 8.75%. Found: C, 75.05; H, 4.38; N, 8.75%.
Hz, CH3). 13C NMR ꢂ 163.9 (CO), 143.8 (C-2 ), 137.0 (Ph-1),
ꢀ
136.2 (C-8a ), 131.3 (C-8), 129.3 (Ph-2,6), 128.9 (Ph-3,4,5),
6-Methyl-2-(4-fluorophenyl)-8-(3-methoxyphenyl)imidazo-
[1,2-a]pyridine (6b). Neutral alumina, eluting with a mixture
ether/petroleum ether (2/1). mp 114–115 ꢁC. 1H NMR ꢂ 7.99
(dd, 2H, J ¼ 8:6, 5.5 Hz, F–Ph-2,6), 7.93 (m, 1H, H-5), 7.89
(m, 1H, CH3O–Ph-2), 7.83 (s, 1H, H-3), 7.71 (bd, 1H, J ¼ 7:9
Hz, CH3O–Ph-6), 7.45 (t, 1H, J ¼ 7:9 Hz, CH3O–Ph-5), 7.24
(d, 1H, J ¼ 1:5 Hz, H-7), 7.14 (t, 2H, J ¼ 8:6 Hz, F–Ph-3,5),
7.02 (dd, 1H, J ¼ 7:9, 2.3 Hz, CH3O–Ph-4), 3.95 (s, 3H, CH3O),
2.41 (s, 3H, CH3). 13C NMR ꢂ 163.0 (J ¼ 245 Hz, F–Ph-4), 160.0
128.0 (C-7), 124.1 (C-6), 123.0 (C-5), 117.6 (C-3), 61.4 (CH2),
18.7 (CH3), 14.8 (CH3). Anal. Calcd for C17H16N2O2: C, 72.84;
H, 5.75; N, 9.99%. Found: C, 73.08; H, 5.61; N, 10.03%.
Ethyl 6-Methyl-8-(4-fluorophenyl)imidazo[1,2-a]pyridine-2-
carboxylate (4c). Neutral alumina, eluting with CH2Cl2. mp
121–122 ꢁC. 1H NMR ꢂ 8.16 (s, 1H, H-3), 8.07 (dd, 2H, J ¼
8:7, 5.5 Hz, F–Ph-2,6), 7.94 (m, 1H, H-5), 7.23 (m, 1H, H-7),
7.21 (t, 2H, J ¼ 8:7 Hz, F–Ph-3,5), 4.57 (q, 2H, J ¼ 7:1 Hz,
CH2), 2.42 (s, 3H, CH3), 1.46 (t, 3H, J ¼ 7:1 Hz, CH3). 13C NMR
ꢀ
ꢀ
ꢀ
(Ph-3), 145.0 (C-2 ), 143.8 (C-8a ), 138.1 (Ph-1), 130.8 (J ¼ 3
Hz, F–Ph-1), 129.8 (Ph-5), 129.4 (C-8), 128.1 (J ¼ 8 Hz, F–Ph-
2,6), 126.5 (C-7), 122.9 (C-5), 122.4 (C-6), 121.7 (Ph-6), 115.9
(J ¼ 21:5 Hz, F–Ph-3,5), 115.0 (Ph-2), 114.6 (Ph-4), 108.3 (C-
3), 55.8 (CH3O), 18.6 (CH3). Anal. Calcd for C21H17N2OF: C,
75.89; H, 5.16; N, 8.43%. Found: C, 75.84; H, 5.12; N, 8.57%.
6-Methyl-2-(4-fluorophenyl)-8-(3-trifluoromethylphenyl)imi-
dazo[1,2-a]pyridine (8b). Silica gel, eluting with ether. mp 104–
ꢂ 163.5 (J ¼ 246 Hz, F–Ph-4), 163.8 (CO), 143.7 (C-2 ), 137.1
ꢀ
(C-8a ), 132.2 (J ¼ 3 Hz, F–Ph-1), 131.1 (J ¼ 8 Hz, F–Ph-2,6),
130.2 (C-8), 127.8 (C-7), 124.1 (C-6), 123.0 (C-5), 117.7 (C-3),
115.9 (J ¼ 21:5 Hz, F–Ph-3,5), 61.47 (CH2), 18.70 (CH3),
14.83 (CH3). Anal. Calcd for C17H15N2O2F: C, 68.45; H, 5.07;
N, 9.39%. Found: C, 68.54; H, 5.11; N, 9.48%.
Ethyl 6-Methyl-8-(thien-2-yl)imidazo[1,2-a]pyridine-2-car-
boxylate (10c).
Neutral alumina, eluting with CH2Cl2. mp
ꢁ
1
105 C. H NMR ꢂ 8.50 (s, 1H, Ph-2), 8.43 (d, 1H, J ¼ 7:1 Hz,
Ph-6), 7.97 (dd, 2H, J ¼ 8:9, 5.4 Hz, F–Ph-2,6), 7.91 (s, 1H, H-
5), 7.79 (s, 1H, H-3), 7.68 (m, 2H, Ph-4,5), 7.23 (s, 1H, H-7),
7.15 (t, 2H, J ¼ 8:9 Hz, F–Ph-3,5), 2.40 (s, 3H, CH3). 13C NMR
149–150 ꢁC. 1H NMR ꢂ 8.35 (dd, 1H, J ¼ 3:7, 1.2 Hz, Th-3),
8.11 (s, 1H, H-3), 7.82 (m, 1H, H-5), 7.42 (dd, 1H, J ¼ 5:1, 1.2
Hz, Th-5), 7.36 (d, 1H, J ¼ 1:4 Hz, H-7), 7.18 (dd, 1H, J ¼
5:1, 3.7 Hz, Th-4), 4.47 (q, 2H, J ¼ 7:1 Hz, CH2), 2.35 (s, 3H,
CH3), 1.46 (t, 3H, J ¼ 7:1 Hz, CH3). 13C NMR ꢂ 163.8 (CO),
ꢀ
ꢀ
ꢂ 163.9 (J ¼ 244:5 Hz, F–Ph-4), 145.2 (C-2 ), 143.5 (C-8a ),
132.6 (Ph-6), 131.2 (J ¼ 39 Hz, Ph-3), 130.6 (J ¼ 3 Hz, F–Ph-
1), 129.2 (Ph-5), 128.0 (J ¼ 8 Hz, F–Ph-2,6), 127.9 (C-8), 126.6
(C-7), 126.2 (J ¼ 4 Hz, Ph-2), 125.2 (J ¼ 3:5 Hz, Ph-4), 124.7
(J ¼ 270:5 Hz, CF3), 123.5 (C-5), 122.4 (C-6), 115.9 (J ¼ 21:5
Hz, F–Ph-3,5), 108.4 (C-3), 18.5 (CH3). Anal. Calcd for
C21H14N2F4: C, 68.11; H, 3.81; N, 7.57%. Found: C, 68.54; H,
3.78; N, 7.75%.
ꢀ
ꢀ
142.4 (C-2 ), 137.8 (C-8a ), 136.8 (Th-2), 129.1 (Th-3), 128.5
ꢀ
ꢀ
(Th-4), 126.9 (Th-5), 125.4 (C-7), 124.5 (C-8 ), 123.9 (C-6 ),
122.5 (C-5), 117.7 (C-3), 61.4 (CH2), 18.6 (CH3), 14.8 (CH3).
Anal. Calcd for C15H14N2O2S: C, 62.92; H, 4.93; N, 9.78%.
Found: C, 63.05; H, 4.89; N, 9.75%.
Ethyl 6-Methyl-8-(thien-3-yl)imidazo[1,2-a]pyridine-2-cꢁar-
boxylate (11c). Silica gel, eluting with ether. mp 150–151 C.
1H NMR ꢂ 8.79 (dd, 1H, J ¼ 3:1, 1.3 Hz, Th-2), 8.15 (s, 1H, H-
3), 7.87 (m, 1H, H-5), 7.76 (dd, 1H, J ¼ 5:1, 1.3 Hz, Th-4),
7.44 (dd, 1H, J ¼ 5:1, 3.1 Hz, Th-5), 7.39 (d, 1H, J ¼ 1:5 Hz,
H-7), 4.48 (q, 2H, J ¼ 7:1 Hz, CH2), 2.39 (s, 3H, CH3), 1.48 (t,
6-Methyl-2-(4-fluorophenyl)-8-(thien-2-yl)imidazo[1,2-a]pyri-
dine (10b). Neutral alumina, eluting with CH2Cl2. mp 149–150
ꢁC. 1H NMR ꢂ 8.38 (dd, 1H, J ¼ 3:7, 1.2 Hz, Th-3), 8.04 (dd, 2H,
J ¼ 8:9, 5.5 Hz, F–Ph-2,6), 7.82 (m, 1H, H-5), 7.75 (s, 1H, H-3),
7.47 (dd, 1H, J ¼ 5:1, 1.2 Hz, Th-5), 7.36 (d, 1H, J ¼ 1:4 Hz, H-
7), 7.24 (dd, 1H, J ¼ 5:1, 3.7 Hz, Th-4), 7.17 (t, 2H, J ¼ 8:9 Hz,
F–Ph-3,5), 2.37 (s, 3H, CH3). 13C NMR ꢂ 163.0 (J ¼ 244:5 Hz,
ꢀ
3H, J ¼ 7:1 Hz, CH3). 13C NMR ꢂ 163.9 (CO), 143.3 (C-2 ),
ꢀ
136.8 (C-8a ), 135.95 (Th-3), 127.0 (Th-2), 126.7 (Th-4), 126.0
(C-7), 125.9 (Th-5), 125.5 (C-8), 124.0 (C-6), 122.4 (C-5),
117.6 (C-3), 61.4 (CH2), 18.7 (CH3), 14.8 (CH3). Anal. Calcd
for C15H14N2O2S: C, 62.92; H, 4.93; N, 9.78%. Found: C,
62.97; H, 4.96; N, 9.84%.
ꢀ
ꢀ
F–Ph-4), 144.8 (C-2 ), 142.4 (C-8a ), 138.7 (Th-2), 130.7 (J ¼
3 Hz, F–Ph-1), 128.1 (Th-3,4), 128.0 (J ¼ 8 Hz, F–Ph-2,6),
126.8 (Th-5), 123.9 (C-7), 123.1 (C-8), 122.3 (C-5), 122.2 (C-
6), 115.9 (J ¼ 21:5 Hz, F–Ph-3,5), 108.3 (C-3), 18.6 (CH3). Anal.
Calcd for C18H13N2SF: C, 70.11; H, 4.25; N, 9.08%. Found: C,
70.26; H, 4.22; N, 9.09%.
Ethyl
6-Methyl-8-(fur-2-yl)imidazo[1,2-a]pyridine-2-cꢁar-
boxylate (12c). Silica gel, eluting with ether. mp 126–127 C.
1H NMR ꢂ 8.14 (s, 1H, H-3), 7.91 (d, 1H, J ¼ 3:2 Hz, Fu-3),
7.85 (s, 1H, H-5), 7.58 (m, 2H, H-7, Fu-5), 6.64 (m, 1H, Fu-4),
4.48 (q, 2H, J ¼ 7:1 Hz, CH2), 2.40 (s, 3H, CH3), 1.48 (t, 3H, J ¼
7:1 Hz, CH3). 13C NMR ꢂ 163.8 (CO), 148.7 (Fu-2), 143.3 (Fu-5),
6-Methyl-2-(4-fluorophenyl)-8-(thien-3-yl)imidazo[1,2-a]pyri-
Silica gel, eluting with ether. mp 149–150 ꢁC.
dine (11b).
1H NMR ꢂ 8.92 (dd, 1H, J ¼ 3, 1.2 Hz, Th-2), 8.01 (dd, 2H, J ¼

J.-Y. Kazock et al.
Bull. Chem. Soc. Jpn., 78, No. 1 (2005)
159
ꢀ
141.3 (C-2), 136.8 (C-8a ), 124.0 (C-8), 123.1 (C-7), 122.2 (C-5),
120.7 (C-6), 117.6 (C-3), 113.8 (Fu-3), 112.8 (Fu-4), 61.4 (CH2),
18.8 (CH3), 14.8 (CH3). Anal. Calcd for C15H14N2O3: C, 66.66;
H, 5.22; N, 10.36%. Found: C, 66.58; H, 5.43; N, 10.32%.
Tetrahedron, 58, 9965 (2002).
C. Enguehard, H. Allouchi, A. Gueiffier, and S. L.
Buchwald, J. Org. Chem., 68, 4367 (2003).
C. Enguehard, H. Allouchi, A. Gueiffier, and S. L.
8
9
Buchwald, J. Org. Chem., 68, 5614 (2003).
10 N. Miyaura and A. Suzuki, Chem. Rev., 95, 2457 (1995).
11 N. Miyaura, Top. Curr. Chem., 219, 11 (2002).
12 A. Suzuki and H. C. Brown, ‘‘Organic Synthesis Via
Boranes,’’ Aldrich Chemical Company, Inc., Milwaukee (2003),
Vol. 3.
We express our grateful acknowledgement to Frederic
Montigny (SAVIT) for NMR data.
References
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S. L. Colletti, J. L. Frie, E. C. Dixon, S. B. Singh, B. K.
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