Comparartive Study on the Reactivity of 6-Haloimidazo[1,2-a]pyridine Derivatives towards Negishi- and Stille-Coupling Reactions

Article abstract of DOI:10.1002/hlca.200390290

The scope of the Suzuki-cross-coupling reaction of 6-haloimidazo[1,2-a]pyridines is dependent on the availability of the (hetero)arylboronic acids. Thus, with the aim to develop expanded applications of (hetero)arylations of imidazo[1,2-a]pyridines, we investigated the Negishi- and Stille-cross-coupling reactions at the 6-position. Remarkably, attempts to aply the Negishi-cross-coupling conditions to the organozinc derivative prepared from 6-haloimidazo[1,2-a]pyridine via a lithium-zinc exchange led to the 5-phenyl compound 3 in 54 percent yield instead of the desired 6-phenyl-isomer (Scheme 1). In contrast, various commercially available halogenated five- or six-membered-ring heterocycles were efficiently coupled to the 6-(trialkylstannyl)imidazo[1,2-a]pyridine under Stille conditions (Table 2).

Full text of DOI:10.1002/hlca.200390290

Helvetica Chimica Acta Vol. 86 (2003)
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Comparative Study on the Reactivity of 6-Haloimidazo[1,2-a]pyridine
Derivatives towards Negishi- and Stille-Coupling Reactions
by Maud Hervet, Isabelle The¬ry, Alain Gueiffier*, and Ce¬cile Enguehard-Gueiffier
¬
¬
Laboratoire de Chimie Therapeutique EA 3247, Faculte de Pharmacie, 31 avenue Monge, F-37200 Tours
The scope of the Suzuki-cross-coupling reaction of 6-haloimidazo[1,2-a]pyridines is dependent on the
availability of the (hetero)arylboronic acids. Thus, with the aim to develop expanded applications of
(hetero)arylations of imidazo[1,2-a]pyridines, we investigated the Negishi- and Stille-cross-coupling reactions at
the 6-position. Remarkably, attempts to apply the Negishi-cross-coupling conditions to the organozinc
derivative prepared from 6-haloimidazo[1,2-a]pyridine via a lithiumÀzinc exchange led to the 5-phenyl
compound 3 in 54% yield instead of the desired 6-phenyl isomer (Scheme 1). In contrast, various commercially
available halogenated five- or six-membered-ring heterocycles were efficiently coupled to the 6-(trialkyl-
stannyl)imidazo[1,2-a]pyridine under Stille conditions (Table 2).
Introduction. The imidazo[1,2-a]pyridine scaffold has demonstrated significant
and potential biological activities in medicinal chemistry (e.g., as benzodiazepine-
receptor ligands (Ambien) [1a], antiviral molecules [1b d], inhibitors of p38 MAP
kinase [1e], and ligands for detecting b-amyloid plaques in the brain [1f]). However,
despite the intensive research in the imidazo[1,2-a]pyridine series, efficient routes that
allow rapid access to a variety of analogues with different substituents at the pyridine
moiety are still needed to conduct detailed structureÀactivity-relationship studies. In
this area, we have developed new rapid pharmacomodulation methods for these series
[2]. Among them, we previously reported Suzuki-cross-coupling processes with 6-
haloimidazo[1,2-a]pyridines and demonstrated the influence of the substituent present
at C(2) on the reactivity of the 6-position. The best coupling results were obtained with
the 2-aryl derivative [3]. Both aryl- or heteroarylboronic acids were efficiently coupled
to 6-haloimidazo[1,2-a]pyridines, but this protocol still presents limitations depending
on the commercially available boronic acids.
With the aim to develop expanded applications of (hetero)arylations of imida-
zo[1,2-a]pyridines, we now developed new functionalization methods and investigated
and compared Negishi- and Stille-cross-coupling reactions.
Results and Discussion.
The first part of this study was devoted to the
investigation of the applicability of the Negishi reaction to the 2-(4-fluorophenyl)-6-
haloimidazo[1,2-a]pyridines 1a,b [2a][3]. Indeed, consistent with our previous studies
in these series, compounds 1a,b are convenient starting materials as they are easily
obtained and more stable and reactive than the corresponding 2-alkyl derivatives under
Suzuki conditions. To the best of our knowledge, no Negishi coupling in the
imidazo[1,2-a]pyridine series has been described in the literature. In a first approach,
compound 1b was reacted with phenylzinc chloride (1.1 equiv.) in the presence of

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Helvetica Chimica Acta Vol. 86 (2003)
[Pd(PPh3)4] (10 mol-%) as catalyst according to the procedure of Gmeiner and co-
workers [4]. After refluxing for 16 h in THF, only 10% of 2, i.e., reduced 1b, was
obtained, besides starting material. Thus, we decided to prepare the organozinc
derivative of imidazo[1,2-a]pyridine. We attempted its formation by MgÀZn exchange;
unfortunately, only 13% of 2 was recovered from the product mixture (data not
shown). Finally, we tried to synthesize the organozinc derivative by LiÀZn exchange.
For this purpose, compound 1a was treated with BuLi (1.6 equiv.) and then with ZnCl2
(1.15 equiv.) in THF atÀ788, and finally overnight with iodobenzene (1.1 equiv.) in the
presence of [Pd(PPh3)4] (10 mol-%) in refluxing THF. Besides compound 2 obtained in
27% yield, the 5-phenyl derivative 3 was obtained in 54% yield (Scheme 1), and not the
desired 6-phenyl compound 4. The structure of 3 as 2-(4-fluorophenyl)-5-phenyl-
1
imidazo[1,2-a]pyridine was established by H- and 13C-NMR spectroscopy. We have
already reported cine-substitutions with compound 1a [2b] and the interest they present
in the direct preparation of 5-functionalized 2-arylimidazo[1,2-a]pyridine derivatives.
As we have already pointed out, our attempts to form 5-halo-2-phenylimidazo[1,2-
a]pyridine failed to give the convenient starting material for Suzuki-coupling reactions.
Scheme 1
In a second approach, we investigated the Stille-cross-coupling reaction. Only two
examples of Stille reaction have been described in these series [5]. Following the same
strategy, we first studied the reaction of 1b with tributylphenylstannane (1.1 equiv.) in
the presence of [Pd(PPh3)4] (5 mol-%) as catalyst in refluxing toluene. Under these
conditions, the 6-phenyl derivative 4 was obtained in 30% yield besides 2 (29% yield)
(Scheme 2). As an example of a heteroaryl coupling reaction that can not be performed
via the Suzuki method, we then tried to introduce the 1-trityl-1H-imidazol-4-yl moiety.
Thus, 4-(tributylstannyl)-1-trityl-1H-imidazole [6] (1.1 equiv.) was allowed to react
with 1b according to the same procedure to give the target compound 5 in 65% yield,
together with only 5% of 2.

Helvetica Chimica Acta Vol. 86 (2003)
3463
Scheme 2
Since only few aryl- or heteroarylstannyl derivatives are commercially available, we
turned our attention to the preparation of 6-(trialkylstannyl)imidazo[1,2-a]pyridines.
In a first attempt, we tried to prepare the 2-(4-fluorophenyl)-6-(tributylstannyl)imi-
dazo[1,2-a]pyridine from 1a via a LiÀSn exchange. After treatment with BuLi
(2 equiv.) in THF at À788, reaction with tributyl chlorostannane (1.2 equiv.) afforded
compound 2 in 20% yield, admixed with 19% of the 5-tributylstannyl compound 6
1
(Scheme 3). The structure of 6 was established by H- and 13C-NMR, and by mass
spectroscopy. Further confirmation was obtained from the coupling of iodobenzene
with 6, leading to the previously described 5-phenyl derivative 3 in 20% yield (not
optimized).
Scheme 3
Then we tried to obtain the 6-(tributylstannyl) derivative using a MgÀSn exchange.
Compound 1a was treated with ethylmagnesium bromide (3 equiv.) in refluxing THF
according to the procedure of Yamanaka et al. [7], and the obtained magnesium
derivative was exposed to tributylchlorostannane (1.25 equiv.) at room temperature for
18 h; however, after treatment with NH4Cl, only 49% of 2 were isolated.

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Based on previously reported methods [1f][5a][5b], we then attempted to prepare
the organotin compound using a Pd-catalyzed process. Compound 1a was allowed to
react with hexabutyldistannane (2 equiv.) in the presence of [Pd(PPh3)4] (8 mol-%) in
refluxing toluene according to the procedure of Katsifis et al. (Table 1) [8]. Under these
conditions, the 6-(tributylstannyl) compound 7 was obtained in only 28% yield due to
difficulties encountered during its isolation, besides 2 (5%) and the 6-phenyl derivative
4 (5%). Formation of 4 has already been reported in the literature; its phenyl group is
provided by an exchange with the triphenylphosphine ligand before the transmetalla-
tion step [9]. To optimize the reaction conditions, we decided to use compound 1b as
starting material and to modify the catalyst loading. The best result was obtained with 5
mol-% of [Pd(PPh3)4], starting from compound 1b, leading to 7 in 56% yield (Table 1).
To overcome the purification problems, we changed to hexamethyldistannane as reactant.
Thus, the 6-(trimethylstannyl) compound 8 was obtained from 1a in 68% yield after an
easier purification step than that for compound 7 (Scheme 4).
Table 1. Palladium-Catalyzed Synthesis of 2-(4-Fluorophenyl)-6-(tributylstannyl)imidazo[1,2-a]pyridine 7
X
Catalyst loading
Time [h]
Yield [%] of
2
4
7
1a
1b
Br
I
I
8 mol-%
8 mol-%
5 mol-%
5.5
3
2.25
5
8
5
5
8
5
28
43
56
Scheme 4
The Stille coupling was then applied to the (trialkylstannyl)imidazo[1,2-a]pyridines
7 and 8 and different aryl and heteroarylhalides in the presence of [Pd(PPh3)4] as
catalyst (Table 2). After refluxing overnight in toluene, the desired compounds 9 12
were obtained from differently substituted phenyl halides in moderate to good yields
(32 77%), the 2- or 4-nitrophenyl compounds 9 and 10, respectively, being isolated in
ca. 76% yield. The steric hindrance of the halogenated benzene did not perturb the
reactivity. Moreover, the nature of the trialkylstannyl substituent in the starting
material did not influence the coupling efficiency of the 4-nitrophenyl bromide (76%
yield starting from 7; 77% yield from 8). In the cases of compounds 11 and 12, obtained
in ca. 40% yield, the 6-phenylimidazo[1,2-a]pyridine 4 (ca. 30%) was also observed as
by-product, but difficult to separate from the target products. Thus, the electron-
withdrawing NO2 group seemed to largely improve the benzene-coupling efficiency
compared to electron-donating groups such as MeO or Me. Similarly, different

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Table 2. Stille Cross-Coupling Reaction of (Hetero)arylhalides ((Het)ArX) with 7 and 8
(Het)ArX
Catalyst
Yield [%]
R ˆ Me
75
R ˆ Bu
9
[Pd(PPh3)4]
10
[Pd(PPh3)4]
77
76
11
12
[Pd(PPh3)4]
[Pd(PPh3)4]
46
40
43
32
5
[Pd(PPh3)4]
[Pd(PPh3)4]
traces
13
14
82
36
[Pd(PPh3)4]
[PdCl2(MeCN)2]
47
12
15
16
[Pd(PPh3)4]
65
[Pd(PPh3)4]
[Pd(PPh3)4]
61
45
17
18
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(Cl2(dppf)]
[PdCl2(MeCN)2]
11
6a)
12
22
a) Reaction was run for 48 h.

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commercially available five- or six-membered-ring heterocycles were introduced at the
6-position of the imidazo[1,2-a]pyridine; e.g., the 2-iodothiophene was combined very
efficiently with 7 to give 13 in 82% yield. In contrast, only moderate yields were
obtained with 3-bromofuran and 5-bromo-1H-indole as substrates (47% of 14 and 11%
of 18, resp.). Again, a significant amount of compound 4 was formed during the
coupling reactions, making the purification step of the targets 14 and 18 more difficult.
To improve the process and to overcome the formation of compound 4, we decided to
switch to bis(acetonitrile)dichloropalladium(II) as catalyst. Unfortunately, in both
cases, the coupling rate was slower, and remaining starting material was present in
larger amount at the end of the reaction. Also observed were 22% of compound 2 in the
furan-coupling reaction. However, as far as compound 18 is concerned, the absence of
4 led to a slight increase of the yield (22%) and largely facilitated the purification.
Finally, the reaction with 5-bromopyrimidine, 3-bromopyridine, and 2-bromopyridine
provided the desired products 15 17 in good yields (45 65%) considering the very
easy applicability of this procedure.
Conclusions.
The Stille procedure can serve as a valuable tool for the
functionalization of C(6) in the imidazo[1,2-a]pyridine series. 4-(Tributylstannyl)-1-
trityl-1H-imidazole could be introduced into 6-iodoimidazo[1,2-a]pyridine (1b) in 65%
yield. To the best of our knowledge, no imidazolylboronic acid synthesis was reported
in the literature. The Stille-cross-coupling reaction is, thus, a new convenient synthetic
approach that allows the introduction of the imidazolyl moiety at C(6). In contrast, the
6-(trimethylstannyl)imidazo[1,2-a]pyridine was not reactive in the presence of 4-iodo-
1-trityl-1H-imidazole. Nevertheless, different halogenated five- or six-membered-ring
heterocycles (thiophene, furan, pyrimidine, and pyridine) could be efficiently coupled
to 6-(trialkylstannyl)imidazo[1,2-a]pyridines. The two steps of this synthetic approach,
obtention of the trialkylstannyl derivative and Stille-cross-coupling reaction, required a
very simple reaction procedure.
Experimental Part
General. Commercial reagents were used as received without additional purification. The compounds
tetrakis(triphenylphosphine)palladium(0) [10], 6-bromo-2-(4-fluorophenyl)imidazo[1,2-a]pyridine (1a) [3],
and 6-iodo-2-(4-fluorophenyl)imidazo[1,2-a]pyridine (1b) [2a] were prepared according to literature proce-
dures. All metallation reactions were carried out in a flame-dried glass apparatus under N2, and reagents were
handled with syringes through septa. CC ˆ Column chromatography. M.p.: Kofler bench; uncorrected. IR
Spectra: in cmÀ1. NMR Spectra: Bruker-DPX-200 or AM-400-WB instruments; chemical shifts d in ppm from
residual CHCl3 (d 7.3 (1H)) and the central resonance of CDCl3 (d 77.1 (13C)); * means that assigments may be
interchanged. EI- and CI-MS: HP-5989A-GC-MS spectrometer. Elemental analyses were performed at the
University of Rouen (Institut de recherche en Chimie Organique Fine), France.
2-(4-Fluorophenyl)-5-phenylimidazo[1,2-a]pyridine (3): Negishi Procedure. At À788, 2.6m BuLi in hexane
(0.6 ml, 1.56 mmol) was added to a soln. of 1a (300 mg, 1.03 mmol) in THF (4.6 ml). After stirring for 1 h, a soln.
of freshly fused ZnCl2 (165 mg, 1.21 mmol) in THF (4.6 ml) was added dropwise. After stirring for 1 h at À788,
[Pd(PPh3)4] (119 mg, 10 mol-%) and iodobenzene (231 mg, 1.13 mmol) were added, and the mixture was
refluxed for 16 h. After cooling and dilution with sat. aq. NH4Cl soln., the aq. phase was extracted with CH2Cl2,
the combined org. layer dried (CaCl2) and evaporated, and the residue purified by CC (silica gel, Et2O; then
neutral alumina, Et2O/petroleum ether 1:1): 3 (54%). White solid. M.p. 1308. 1H-NMR (CDCl3): 7.92 (dd, J ˆ
8.7, 5.4, HÀC(2), HÀC(6) of C6H4); 7.89 (s, HÀC(3)); 7.58 7.72 (m, HÀC(8), 5 H of Ph); 7.30 (dd, J ˆ 9, 6.9,
HÀC(7)); 7.12 (t, J ˆ 8.7, HÀC(3), HÀC(5) of C6H4); 6.77 (dd, J ˆ 6.9, 1.1, HÀC(6)). 13C-NMR (CDCl3): 163.1

Helvetica Chimica Acta Vol. 86 (2003)
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(J ˆ 245, C(4) of C6H4); 146.9 (C(8a)*); 145.1 (C(2)*); 138.6 (C(5)); 134.9 (C(1) of Ph); 130.5 (J ˆ 3.5, C(1) of
C6H4); 130.2 (C(4) of Ph); 129.7 (C(3), C(5) of Ph); 128.7 (C(2), C(6) of Ph); 128.1 (J ˆ 8.5, C(2), C(6) of
C6H4); 125.6 (C(7)); 116.6 (C(8)); 116.0 (J ˆ 21.5, C(3), C(5) of C6H4); 113.2 (C(6)); 106.8 (C(3)).
2-(4-Fluorophenyl)-6-phenylimidazo[1,2-a]pyridine (4). Stille Procedure. A mixture of 1b (300 mg,
0.89 mmol), tributylphenylstannane (359 mg, 0.98 mmol), and [Pd(PPh3)4] (51.4 mg, 5 mol-%) in toluene
(15 ml) was refluxed for 16 h. After cooling, the mixture was diluted with 10% aq. KF soln. and extracted with
CH2Cl2. The extract was dried (CaCl2) and evaporated, and the residue was purified by CC (silica gel, Et2O): 4
(30%). White solid. M.p. 1918 ([3]: 1918).
2-(4-Fluorophenyl)-6-[1-(triphenylmethyl)-1H-imidazol-4-y]imidazo[1,2-a]pyridine (5): Stille Procedure.
As described for 4, with 1b (300 mg, 0.89 mmol), 4-(tributylstannyl)-1-(triphenylmethyl)-1H-imidazole
(533 mg, 0.89 mmol), [Pd(PPh3)4] (51.4 mg, 5 mol-%), and toluene (15 ml): 5 (65%). White solid. M.p. 2528.
1H-NMR (CDCl3): 8.71 (s, HÀC(5)); 7.95 (dd, J ˆ 8.9, 5.4, HÀC(2), HÀC(6) of C6H4); 7.83 (s, HÀC(3)); 7.58
(d, J ˆ 9.7, HÀC(8)); 7.56 (d, J ˆ 1.2, HÀC(5) of Im); 7.43 7.37 (m, HÀC(7), 9 H of Tr); 7.26 7.10
(m, HÀC(3), HÀC(5) of C6H4, HÀC(2) of Im, 6 H of Tr). 13C-NMR (CDCl3): 163.1 (J ˆ 245, C(4) of C6H4);
145.4 (C(2)*); 142.6 (C(1) of Tr); 140.0 (C(2) of Im); 137.9 (C(8a)*); 130.5 (J ˆ 3, C(1) of C6H4); 130.2 (C(3), C(6)
of Tr); 128.7 (C(4) of Tr); 128.6 (C(3), C(5) of Tr); 128.5 (C(4) of Im); 128.0 (J ˆ 8, C(2), C(6) of C6H4); 124.0
(C(7)); 121.7 (C(5)); 120.7 (C(6)); 118.0 (C(5) of Im); 117.3 (C(8)); 116.0 (J ˆ 21.5, C(3), C(5), of C6H4); 108.7
(C(3)); 76.1 (C of Tr). Anal. calc. for C35H25FN4: C 80.75, H 4.84, N 10.76; found: C 80.84, H 4.86, N 10.73.
2-(4-Fluorophenyl)-5-(tributylstannyl)imidazo[1,2-a]pyridine (6). To 1a (300 mg, 1.03 mmol) and THF
(5 ml) at À788, 2.6m BuLi in hexane (1.25 ml, 2.06 mmol) was added. The mixture was stirred at À788 for 1 h,
then tributylchlorostannane (402 mg, 1.24 mmol) was added. The soln. was stirred at À788 for 1 h and then at
208 for 2 h. The mixture was diluted with 10% aq. KF soln. and extracted with AcOEt, the combined org. layer
was dried (MgSO4) and evaporated, and the residue was purified by CC (silica gel, Et2O/petroleum ether 3 :7): 6
1
(19%). Colorless oil. H-NMR (CDCl3): 7.94 (dd, J ˆ 8.9, 5.4, HÀC(2), HÀC(6) of C6H4); 7.71 (s, HÀC(3));
7.58 (d, J ˆ 9, HÀC(8)); 7.15 (m, HÀC(7), HÀC(3), HÀC(5) of C6H4); 6.82 (dd, J ˆ 6.4, 1.2, HÀC(6)); 1.67
1.56 (m, 3 CH2); 1.48 1.31 (m, 6 CH2); 1.28 0.89 (m, 3 Me). 13C-NMR (CDCl3): 163.0 (J ˆ 245, C(4) of C6H4);
146.1 (C(8a)*); 144.7 (C(2)*); 143.8 (C(5)); 130.7 (J ˆ 3, C(1) of C6H4); 128.0 (J ˆ 8, C(2), C(6) of C6H4); 124.7
(C(7)); 122.6 (C(6)); 117.2 (C(8)); 116.1 (J ˆ 21.5, C(3), C(5) of C6H4); 110.1 (C(3)); 29.4 (3 CH2ÀSn); 27.7
‡
(3 CH2); 14.1 (3 Me); 10.6 (3 CH2). EI-MS: 502 (M ). Anal. calc. for C25H35FN2Sn: C 59.90, H 7.04, N 5.59;
found: C 59.85, H 6.92, N 5.49.
2-(4-Fluorophenyl)-6-(tributylstannyl)imidazo[1,2-a]pyridine (7). A mixture of 1b (300 mg, 0.89 mmol),
hexabutyldistannane (678 mg, 1.16 mmol), and [Pd(PPh3)4] (51 mg, 5 mol-%) in toluene (15 ml) was refluxed
for 2.25 h. After cooling, the mixture was diluted with 10% aq. KF soln. and then extracted with AcOEt. The
combined org. layer was dried (MgSO4) and evaporated, and the residue was purified by CC (alumina, petroleum
1
ether/Et3N 99 :1, then CH2Cl2/petroleum ether/Et3N 50 :49 :1): 7 (56%). Colorless oil. H-NMR (CDCl3): 8.01
(s, HÀC(5)); 7.95 (dd, J ˆ 8.6, 5.4, HÀC(2), HÀC(6) of C6H4); 7.80 (s, HÀC(3)); 7.62 (d, J ˆ 8.8, HÀC(8)); 7.19
(d, J ˆ 8.8, HÀC(7)); 7.13 (t, J ˆ 8.6, HÀC(3), HÀC(5) of C6H4); 1.68 1.53 (m, 3 CH2ÀSn); 1.44 1.15
(m, 6 CH2); 1.11 0.90 (m, 3 Me). 13C-NMR (CDCl3): 163.0 (J ˆ 245, C(4) of C6H4); 146.1 (C(8a)*); 144.7
(C(2)*); 131.8 (C(7)); 130.7 (J ˆ 3, C(1) of C6H4); 130.5 (C(5)); 128.1 (J ˆ 8, C(2), C(6) of C6H4); 122.6 (C(6));
117.4 (C(8)); 116.0 (J ˆ 21.5, C(3), C(5) of C6H4); 107.3 (C(3)); 29.2 (3 CH2ÀSn); 27.7 (3 CH2); 14.1 (3 Me); 10.2
‡
(3 CH2). EI-MS: 502 (M ). Anal. calc. for C25H35FN2Sn: C 59.90, H 7.04, N 5.59; found: C 59.96, H 7.01, N 5.46.
2-(4-Fluorophenyl)-6-(trimethylstannyl)-1H-imidazo[1,2-a]pyridine (8). As described for 7, with 1a
(807 mg, 2.77 mmol), hexamethyldistannane (1 g, 3.05 mmol), [Pd(PPh3)4] (160 mg, 5 mol-%), and toluene
(25 ml) for 45 min: 8 (68%). White solid. M.p. 1378. 1H-NMR (CDCl3): 8.03 (d, J ˆ 0.9, HÀC(5)); 7.94 (dd, J ˆ 8.7,
5.4, HÀC(2), HÀC(6) of C6H4); 7.78 (s, HÀC(3)); 7.62 (d, J ˆ 8.9, HÀC(8)); 7.21 (dd, J ˆ 8.9, 0.9, HÀC(7)); 7.14
(t, J ˆ 8.7, HÀC(3), HÀC(5) of C6H4); 0.40 (s, 3 Me). 13C-NMR (CDCl3): 163.0 (J ˆ 245, C(4) of C6H4); 146.1
(C(8a)*); 144.7 (C(2)*); 131.4 (C(7)); 130.1 (J ˆ 3, C(1) of C6H4); 129.8 (C(5)); 128.0 (J ˆ 8, C(2), C(6) of C6H4);
122.8 (C(6)); 117.1 (C(8)); 115.9 (J ˆ 21.5, C(3), C(5) of C6H4); 107.3 (C(3)); À8.95 (3 Me). EI-MS: 361 ([M À
‡
‡
15] ), 331. CI-MS: 376 (M ). Anal. calc. for C16H17FN2Sn: C 51.25, H 4.57, N 7.47; found: C 51.18, H 4.50, N 7.42.
Stille-Cross-Coupling Reaction: General Procedure. To a soln. of 2-(4-fluorophenyl)-(6-trialkylstannyl)-
1H-imidazo[1,2-a]pyridine (0.80 mmol) in toluene (15 ml) were added the aryl or heteroaryl halide (1 equiv.)
and [Pd(PPh3)4] (46 mg, 5 mol-%). The mixture was refluxed for 16 h. After cooling, the mixture was diluted
with a 10% aq. KF soln. The aq. layer was extracted with CH2Cl2, the combined org. phase was dried (CaCl2)
and evaporated, and the residue was purified by CC.
2-(4-Fluorophenyl)-6-(2-nitrophenyl)imidazo[1,2-a]pyridine (9): CC (alumina, CH2Cl2). M.p. 1818.
1H-NMR (CDCl3): 8.15 (m, HÀC(5)); 8.01 (dd, J ˆ 7.7, 1.5, HÀC(3) of NO2ÀC6H4); 7.97 (dd, J ˆ 8.8, 5.3,

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HÀC(2), HÀC(6) of FÀC6H4); 7.87 (s, HÀC(3)); 7.73 (td, J ˆ 7.7, 1.5, HÀC(5) of NO2ÀC6H4); 7.68 (d, J ˆ 9.3,
HÀC(8)); 7.64 (dd, J ˆ 7.7, 1.8, HÀC(6) of NO2ÀC6H4); 7.55 (td, J ˆ 7.7, 1.8, HÀC(4) of NO2ÀC6H4); 7.17 (t, J ˆ
8.8, HÀC(3), HÀC(5) of FÀC6H4); 7.14 (dd, J ˆ 9.3, 1.8, HÀC(7)). 13C-NMR (CDCl3): 162.9 (J ˆ 246, C(4) of
FÀC6H4); 149.6 (C(2) of NO2ÀC6H4); 146.2 (C(2)*); 145.2 (C(8a)*); 133.3 (C(5) of NO2ÀC6H4); 132.6 (C(4) of
NO2ÀC6H4); 130.2 (J ˆ 3.5, C(1) of FÀC6H4); 129.6 (C(6) of NO2ÀC6H4); 128.2 (J ˆ 8, C(2), C(6) of FÀC6H4);
126.2 (C(7)); 125.0 (C(3) of NO2ÀC6H4); 124.2 (C(5)); 123.8 (C(1) of NO2ÀC6H4); 117.6 (C(8)); 116.1 (J ˆ
21.5, C(3), C(5) of FÀC6H4); 108.8 (C(3)); C(6) not found. Anal. calc. for C19H12FN3O2: C 68.47, H 3.63,
N 12.61; found: C 68.54, H 3.92, N 12.86.
2-(4-Fluorophenyl)-6-(4-nitrophenyl)imidazo[1,2-a]pyridine (10): CC (alumina, CH2Cl2). M.p. 2388.
1H-NMR ((D6)DMSO): 8.44 (m, HÀC(5)); 8.39 (d, J ˆ 8.5, HÀC(3), HÀC(5) of NO2ÀC6H4); 7.99 (dd, J ˆ
8.4, 5.4, HÀC(2), HÀC(6) of FÀC6H4); 7.95 (s, HÀC(3)); 7.79 (m, HÀC(2), HÀC(6) of NO2ÀC6H4, HÀC(8));
7.50 (dd, J ˆ 9.4, 1.9, HÀC(7)); 7.19 (t, J ˆ 8.4, HÀC(3), HÀC(5) of FÀC6H4). 13C-NMR (CDCl3): 162.0 (J ˆ
248, C(4) of FÀC6H4); 146.6 (C(8a)*); 144.5 (C(2)*); 144.2 (C(4)* of NO2ÀC6H4); 143.2 (C(1)* of NO2ÀC6H4);
260.2 (J ˆ 2.8, C(1) of FÀC6H4); 127.6 (J ˆ 9, C(2), C(6) of FÀC6H4); 127.4 (C(3), C(5) of NO2ÀC6H4); 125.6
(C(5)); 124.4 (C(7)); 124.1 (C(2), C(6) of NO2ÀC6H4); 122.9 (C(6)); 116.8 (C(8)); 115.6 (J ˆ 21.5, C(3), C(5) of
FÀC6H4); 109.6 (C(3)). Anal. calc. for C19H12FN3O2: C 68.47, H 3.63, N 12.61; found: C 68.77, H 3.46, N 12.65.
2-(4-Fluorophenyl)-6-(4-methoxyphenyl)imidazo[1,2-a]pyridine (11): CC (silica gel, petroleum ether, then
petroleum ether/Et2O 1:1). M.p. 1718. 1H-NMR (CDCl3): 8.27 (m, HÀC(5)); 7.97 (dd, J ˆ 8.7, 5.5, HÀC(2),
HÀC(6) of FÀC6H4); 7.88 (s, HÀC(3)); 7.69 (d, J ˆ 9.3, HÀC(8)); 7.53 (d, J ˆ 8.6, HÀC(2), HÀC(6) of
MeOÀC6H4); 7.45 (dd, J ˆ 9.3, 1.8, HÀC(7)); 7.17 (t, J ˆ 8.7, HÀC(3), HÀC(5) of FÀC6H4); 7.05 (d, J ˆ 8.6,
HÀC(3), HÀC(5) of MeOÀC6H4); 3.91 (s, MeO). 13C-NMR (CDCl3): 163.1 (J ˆ 245, C(4) of FÀC6H4); 160.0
(C(4) of MeOÀC6H4); 145.7 (C(2)*); 145.3 (C(8a)*); 130.4 (J ˆ 3, C(1) of FÀC6H4); 130.0 (C(1) of
MeOÀC6H4); 128.4 (C(2), C(6) of MeOÀC6H4); 128.1 (J ˆ 8, C(2), C(6) of FÀC6H4); 127.1 (C(6)); 126.0
(C(7)); 122.6 (C(5)); 117.6 (C(8)); 116.1 (J ˆ 21.5, C(3), C(5) of FÀC6H4); 115.0 (C(3), C(5) of MeOÀC6H4);
108.5 (C(3)); 55.8 (MeO). Anal. calc. for C20H15FN2O: C 75.46, H 4.75, N 8.80; found: C 75.68, H 4.49, N 8.77.
6-(3,5-Dimethylphenyl)-2-(4-fluorophenyl)imidazo[1,2-a]pyridine (12): CC (silica gel, AcOEt/petroleum
1
ether 1:1; then neutral alumina, CH2Cl2). M.p. 1348. H-NMR (CDCl3): 8.31 (dd, J ˆ 1.6, 0.8, HÀC(5)); 7.98
(dd, J ˆ 9, 5.4, HÀC(2), HÀC(6) of C6H4); 7.88 (s, HÀC(3)); 7.72 (dd, J ˆ 9.2, 0.8, HÀC(8)); 7.47 (dd, J ˆ 9.2,
1.6, HÀC(7)); 7.22 (m, HÀC(2), HÀC(6) of C6H3); 7.17 (t, J ˆ 9, HÀC(3), HÀC(5) of C6H4); 7.09 (m, HÀC(4)
of C6H3); 2.44 (s, 2 Me). 13C-NMR (CDCl3): 164.1 (J ˆ 245.3, C(4) of C6H4); 145.7 (C(8a)*); 145.5 (C(2)*);
139.1 (C(3), C(5) of C6H3); 137.5 (C(1) of C6H3); 130.4 (J ˆ 3, C(1) of C6H4); 130.0 (C(4) of C6H3); 128.0 (J ˆ 8,
C(2), C(6) of C6H4); 127.6 (C(6)); 126.1 (C(7)); 125.1 (C(2), C(6) of C6H3); 123.1 (C(5)); 117.5 (C(8)); 116.0
(J ˆ 21.5, C(3), C(5) of C6H4); 108.5 (C(3)); 21.8 (2 Me). Anal. calc. for C21H17FN2: C 79.72, H 5.42, N 8.85;
found: C 79.74, H 5.36, N 8.91.
2-(4-Fluorophenyl)-6-(2-thienyl)imidazo[1,2-a]pyridine (13): CC (silica gel, CH2Cl2; then silica gel, Et2O).
M.p. 1748. 1H-NMR (CDCl3): 8.33 (dd, J ˆ 1.8, 0.9, HÀC(5)); 7.94 (dd, J ˆ 8.9, 5.4, HÀC(2), HÀC(6) of C6H4);
7.81 (s, HÀC(3)); 7.64 (dd, J ˆ 9.4, 0.9, HÀC(8)); 7.44 (dd, J ˆ 9.4, 1.8, HÀC(7)); 7.34 (dd, J ˆ 5.1, 1.2, HÀC(5)
of Th); 7.29 (dd, J ˆ 3.6, 1.2, HÀC(3) of Th); 7.15 (t, J ˆ 8.9, HÀC(3), HÀC(5) of C6H4); 7.13 (dd, J ˆ 5.1, 3.6,
HÀC(4) of Th). 13C-NMR (CDCl3): 163.2 (J ˆ 245.5, C(4) of C6H4); 145.9 (C(8a)*); 145.2 (C(2)*); 140.2 (C(2)
of Th); 130.2 (J ˆ 3.5, C(1) of C6H4); 128.6 (C(4) of Th); 128.1 (J ˆ 8, C(2), C(6) of C6H4); 125.6 (C(5) of Th);
125.2 (C(7)); 124.3 (C(3) of Th); 122.0 (C(5)); 121.3 (C(6)); 117.7 (C(8)); 116.1 (J ˆ 21.5, C(3), C(5) of C6H4);
108.6 (C(3)). Anal. calc. for C17H11FN2S: C 69.37, H 3.77, N 9.52; found: C 69.39, H 3.70, N 9.48.
2-(4-Fluorophenyl)-6-(furan-3-yl)imidazo[1,2-a]pyridine (14): CC (silica gel, Et2O/petroleum ether 1 :1).
1
M.p. 1938. H-NMR (CDCl3): 8.22 (dd, J ˆ 1.7, 1, HÀC(5)); 7.95 (dd, J ˆ 8.9, 5.4, HÀC(2), HÀC(6) of C6H4);
7.82 (s, HÀC(3)); 7.76 (dd, J ˆ 1.6, 0.9, HÀC(2) of Fur); 7.65 (d, J ˆ 9.3, HÀC(8)); 7.56 (dd, J ˆ 1.9, 1.6, HÀC(5)
of Fur); 7.34 (dd, J ˆ 9.3, 1.7, HÀC(7)); 7.15 (t, J ˆ 8.9, HÀC(3), HÀC(5) of C6H4); 6.69 (dd, J ˆ 1.9, 0.9,
HÀC(4) of Fur). 13C-NMR (CDCl3): 163.2 (J ˆ 245, C(4) of C6H4); 145.6 (C(8a)*); 145.3 (C(2)*); 144.6 (C(5)
of Fur); 139.1 (C(2) of Fur); 130.3 (J ˆ 3, C(1) of C6H4); 128.1 (J ˆ 8, C(2), C(6) of C6H4); 125.0 (C(7)); 123.1
(C(3) of Fur); 121.8 (C(5)); 118.9 (C(6)); 117.9 (C(8)); 116.1 (J ˆ 21.5, C(3), C(5) of C6H4); 108.7 (C(4) of Fur);
108.5 (C(3)). Anal. calc. for C17H11FN2O: C 73.37, H 3.98, N 10.07; found: C 73.15, H 3.76, N 9.96.
2-(4-Fluorophenyl)-6-(pyrimidin-5-yl)imidazo[1,2-a]pyridine (15): Upon cooling, the coupling product
precipitated and was filtered off and washed with Et2O. M.p. >2608. 1H-NMR ((D6)DMSO): 9.24 (s, HÀC(4),
HÀC(6) of Py); 9.23 (s, HÀC(2) of Py); 9.11 (m, HÀC(5)); 8.45 (s, HÀC(3)); 8.08 (dd, J ˆ 8.6, 5.6, HÀC(2),
HÀC(6) of C6H4); 7.76 (m, HÀC(7), HÀC(8)); 7.31 (t, J ˆ 8.6, HÀC(3), HÀC(5) of C6H4). 13C-NMR
((D6)DMSO): 162.9 (J ˆ 243, C(4) of C6H4); 158.3 (C(2) of Py); 155.5 (C(4), C(6) of Py); 145.3 (C(8a)*); 145.1
(C(2)*); 131.3 (C(5) of Py); 131.0 (J ˆ 3, C(1) of C6H4); 128.6 (J ˆ 8, C(2), C(6) of C6H4); 126.0 (C(5)); 125.1

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(C(7)); 120.1 (C(6)); 117.9 (C(8)); 116.5 (J ˆ 21, C(3), C(5) of C6H4); 110.5 (C(3)). Anal. calc. for C17H11FN4:
C 70.34, H 3.82, N 19.30; found: C 70.32, H 3.31, N 19.22.
2-(4-Fluorophenyl)-6-(pyridin-3-yl)imidazo[1,2-a]pyridine (16): CC (silica gel, AcOEt/petroleum ether
1:1; then silica gel, AcOEt). M.p. 173 1748. 1H-NMR (CDCl3): 8.88 (d, J ˆ 2.3, HÀC(2) of Py); 8.69 (dd, J ˆ
4.8, 1.6, HÀC(6) of Py); 8.34 (dd, J ˆ 1.7, 0.9, HÀC(5)); 7.97 (dd, J ˆ 8.8, 5.4, HÀC(2), HÀC(6) of C6H4); 7.91
(s, HÀC(3)); 7.88 (dd, J ˆ 8, 2.3, HÀC(4) of Py); 7.75 (dd, J ˆ 9.3, 0.9, HÀC(8)); 7.46 (dd, J ˆ 8, 4.8, HÀC(5) of
Py); 7.43 (dd, J ˆ 9.3, 1.7, HÀC(7)); 7.17 (t, J ˆ 8.8, HÀC(3), HÀC(5) of C6H4). 13C-NMR (CDCl3): 163.2 (J ˆ
245.5, C(4) of C6H4); 149.6 (C(6) of Py); 148.3 (C(2) of Py); 146.3 (C(8a)*); 145.4 (C(2)*); 134.6 (C(4) of Py);
133.4 (C(3) of Py); 130.2 (J ˆ 3, C(1) of C6H4); 128.2 (J ˆ 8, C(2), C(6) of C6H4); 125.2 (C(7)); 124.2 (C(5) of
Py); 124.1 (C(6)); 123.5 (C(5)); 118.2 (C(8)); 115.9 (J ˆ 21.5, C(3), C(5) of C6H4); 108.7 (C(3)). Anal. calc. for
C18H12FN3: C 74.73, H 4.18, N 14.52; found: C 74.20, H 4.12, N 14.49.
2-(4-Fluorophenyl)-6-(pyridin-2-yl)imidazo[1,2-a]pyridine (17): CC (silica gel, AcOEt/petroleum ether
1:1; then neutral alumina, CH2Cl2). M.p. 183 1848. 1H-NMR (CDCl3): 8.89 (dd, J ˆ 1.6, 1, HÀC(5)); 8.69
(dd, J ˆ 4.8, 0.8, HÀC(6) of Py); 7.95 (dd, J ˆ 8.6, 5.4, HÀC(2), HÀC(6) of C6H4); 7.84 (s, HÀC(3)); 7.83 7.70
(m, HÀC(8), HÀC(3), HÀC(4) of Py); 7.67 (dd, J ˆ 9.1, 1.6, HÀC(7)); 7.27 (dd, J ˆ 7.3, 4.8, HÀC(5) of Py);
7.14 (t, J ˆ 8.6, HÀC(3), HÀC(5) of C6H4). 13C-NMR (CDCl3): 163.2 (J ˆ 245.5, C(4) of C6H4); 154.3 (C(2) of
Py); 150.3 (C(6) of Py); 146.1 (C(2)*); 145.9 (C(8a)*); 137.5 (C(3) of Py); 130.2 (J ˆ 3, C(1) of C6H4); 128.1 (J ˆ
8, C(2), C(6) of C6H4); 125.4 (C(6)); 124.9 (C(5)); 124.2 (C(4) of Py); 123.0 (C(5) of Py); 120.2 (C(7)); 117.4
(C(8)); 116.1 (J ˆ 21.5, C(3), C(5) of C6H4); 108.9 (C(3)). Anal. calc. for C18H12FN3: C 74.73, H 4.18, N 14.52;
found: C 74.36, H 4.09, N 14.45.
6-(1H-Indol-5-yl)-2-(4-fluorophenyl)imidazo[1,2-a]pyridine (18): CC (silica gel, Et2O), then recristalliza-
tion from MeOH. M.p. 246 2478. IR (neat): 3132. 1H-NMR ((D6)DMSO): 11.26 (br. s, NH); 8.83 (s, HÀC(5));
8.39 (s, HÀC(3)); 8.04 (dd, J ˆ 8.4, 5.4, HÀC(2), HÀC(6) of C6H4); 7.90 (s, HÀC(4) of Ind); 7.66 (m, HÀC(7),
HÀC(8)); 7.56 7.43 (m, HÀC(2), HÀC(6), HÀC(7) of Ind); 7.30 (t, J ˆ 8.4, HÀC(3), HÀC(5) of C6H4); 6.53
(br. s, HÀC(3) of Ind). 13C-NMR ((D6)DMSO): 162.7 (J ˆ 243, C(4) of C6H4); 144.9 (C(8a)*); 144.6 (C(2)*);
136.4 (C(7a) of Ind); 131.4 (J ˆ 3, C(1) of C6H4); 129.2 (C(3a) of Ind); 128.4 (C(5)* of Ind); 128.3 (J ˆ 8, C(2),
C(6) of C6H4); 127.9 (C(2) of Ind); 127.2 (C(7)); 126.7 (C(6)*); 124.0 (C(5)); 120.9 (C(6) of Ind); 119.0 (C(4) of
Ind); 117.3 (C(8)); 116.5 (J ˆ 21.5, C(3), C(5) of C6H4); 112.9 (C(7) of Ind); 110.1 (C(3)); 102.4 (C(3) of Ind).
Anal. calc. for C21H14FN3: C 77.05, H 4.31, N 12.84; found: C 77.10, H 4.25, N 12.78.
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Received May 30, 2003