Reactions with N-chlorosuccinimide of various 5-methylimidazo[1,2-a]pyridine derivatives with an electron-withdrawing group substituted at the 3-position

Article abstract of DOI:10.3987/COM-00-9063

Chlorination reactions using N-chlorosuccinimide (NCS) was investigated for various 5-methylimidazo[1,2-a]pyridine derivatives with an electron-withdrawing group substituted at the 3-position. These reactions showed different results, and by examining these, we proposed a reaction mechanism via the appropriate 3-halogenoimidazo[1,2-a]pyridium compounds as the reaction intermediates.

Full text of DOI:10.3987/COM-00-9063

HETEROCYCLES, Vol.55, No.9, pp. 99 - 108, received, 18th September, 2000
REACTIONS WITH N-CHLOROSUCCINIMIDE OF VARIOUS 5-
METHYLIMIDAZO[1,2-a]PYRIDINE
DERIVATIVES
WITH
AN
ELECTRON-WITHDRAWING GROUP SUBSTITUTED AT THE 3-
POSITION
Tomomi Ikemoto* and Mitsuhiro Wakimasu
Chemical Development Laboratory, Takeda Chemical Industries, Ltd., 17-85
Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan: e-mail:
Ikemoto_Tomomi@takeda.co.jp
Abstracts-Chlorination reactions using N-chlorosuccinimide (NCS) was
investigated for various 5-methylimidazo[1,2-a]pyridine derivatives with an
electron-withdrawing group substituted at the 3-position. These reactions showed
different results, and by examining these, we proposed a reaction mechanism via
the appropriate 3-halogenoimidazo[1,2-a]pyridium compounds as the reaction
intermediates.
INTRODUCTION
Imidazo[1,2-a]pyridine moieties have attracted much recent interest because of their broad range of
pharmacological activities,1 and products incorporating imidazo[1,2-a]pyridine are already on the market,
e.g. zolimidine,2a an anti-ulcer drug, and zolpidem,2b which is used as a hypnotic drug. Electrophilic
reagents react preferentially at the 3-position of imidazo[1,2-a]pyridine, such as halogenation, nitration,3,4
acylation,3 and the Mannich reaction.3a,4 By contrast, there were few reports of any electrophilic reactions
for substrates blocked at this position.5 The only reports are by Hand and Paudler for the case of
halogenation, where they have reported that the treatment of 3-methylimidazo[1,2-a]pyridine5b or 3-
bromo-7-methylimidazo[1,2-a]pyridine5a with N-bromosuccinimide (NBS) in chloroform gave rise to
compounds by apparent nucleophilic substitution at the 2-position. However, we have found that ethyl 5-
methylimidazo[1,2-a]pyridine-3-carboxylate (3e) reacted with N-chlorosuccinimide (NCS) in ethyl acetate
or tetrahydrofuran to give regioselectively ethyl 5-(chloromethyl)imidazo[1,2-a]pyridine-3-carboxylate
(6e) in 83% and 76% yields respectively, while the reaction of 3e with NCS in acetic acid gave ethyl 5-
methyl-2-oxo-2,3-dihydroimidazo[1,2-a]pyridine-3-carboxylate (8e) in 83% yield.6 These results are
similar to those for the reaction of 2-methylimidazo[1,2-a]pyridine4 with NBS in chloroform, which gave
3-halogeno-halomethylimidazo[1,2-a]pyridines via 1-halogenoimidazo[1,2-a]pyridiums (11) as the
reaction intermediates. Thus, the chlorination of 3-substituted imidazo[1,2-a]pyridines show different
products depending on whether the imidazo[1,2-a]pyridines have a methyl group or not. In this paper, we
will discuss our investigation of the reactions of NCS with various 3-substituted 5- methylimidazo[1,2-
a]pyridine derivatives substituted with an electron-withdrawing group. Moreover, the reactions of 2,3-
disubstituted 5-methylimidazo[1,2-a]pyridines with NCS were also studied, because the unsubstituted

compound (3e) at the 2-position reacted with NCS in acetic acid to give the 2-oxo-imidazo[1,2-a]pyridine
(8e).
RESULTS AND DISCUSSION
Synthesis of 3-substituted 5-methylimidazo[1,2-a]pyridines(3a-g)
N
NCS
N
CHCl3
Cl
Me
48%
N
3a
ClCH2CHO
N
N
EtOH
65%
NBS
CHCl3
57%
Me
N
2
Br
Me
3b
N
HCOCHClCO2Et
N
N
c. HNO3
N
EtOH
62%
CO2Et
Me
c. H2SO4
62%
NO2
Me
NH2
3e
3c
N
N
Me
MeCOCHClCO2Et
N
Me
HMTA
N
1
N
EtOH
45%
CO2Et
Me
AcOH
29%
CHO
Me
3f
3d
NHCOCF3
NCOCF3
CO2Et
(CF3CO)2O,
pyridine
NaH, BrCH2CO2Et
N
N
23%
Me
Me
94%
4
5
DBU
CF3
N
98%
N
CO2Et
3g
Me
Scheme 1
Imidazo[1,2-a]pyridines (3a-g) were synthesized as shown in Scheme 1. Condensation of 2-amino-6-
methylpyridine (1) with 2-chloroacetaldehyde, ethyl 2-chloro-3-oxopropanoate, or ethyl 2-
chloroacetoacetate according to the procedure of Tchitchibain7 gave the products (2, 3e, and 3f)in 65%, 62%,
and 45% yields, respectively. Subsequently, treatment of 2 with the appropriate respective electrophilic
reagents gave 3a-d. The reaction of 2 with NCS or NBS gave 3a and 3b in 48% and 57% yields,

respectively. Compound (2) was readily nitrated with concentrated nitric acid in the presence of
concentrated sulfuric acid to give 3c in 62% yield. The Vilsmeier-Haack reaction1a of 2 afforded 3d in less
than 2% yield (analyzed by HPLC) under the reported conditions. However, the reaction of 2 with
hexamethylenetetramine in acetic acid at 90°C gave 3d in 29% yield. Our results are of interest in the
context of the previously reported literature, while Hand and Paudler have reported that the condensation of
2 with acetaldehyde does not proceed by the peri-effect.8 Compound (3g) was synthesized by the reaction of
2,2,2-trifluoro-N-(6-methyl-2-pyridinyl)acetamide (4) with ethyl 2-bromoacetate, followed by treatment
with 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU).
Reactions of 3 with NCS
The reactions of 3 with NCS (1.2 eq.) in tetrahydrofuran was carried out at room temperature (Table 1). The
chlorination of 3a showed similar reactivity in 3e to yield the chloromethyl derivatives (6a and 7a), which
1
lost their methyl protons to become the methylene or methyne proton (s), as analyzed by their H-NMR
spectra. On the other hand, the treatment of 3b with NCS provided unexpected results, because it give a
mixture (8b-1 and 8b-2) that could not be separated. The FAB-MS (Na) spectrum of the mixture of 8b-1
and 8b-2 showed peaks at m/z 398 and 354. The 1H-NMR spectra of a mixture of 8b-1 and 8b-2 revealed a
pair of two methyl protons, with each singlet proton corresponding to the H-2 (8.99 and 8.96 ppm). From
these results and the related reports,5 these structures of 8b-1 and 8b-2 were confirmed to be mixed
compounds in which the imidazo[1,2-a]pyridine (3a) is replaced by the chloride at the 3-position of 3b,
bonds the N-1 of the parent (3b) or itself (3a) at the 2-position, respectively. These compounds would not
occur if the reaction of 3b with NCS proceeded via 1-chloroimidazo[1,2-a]pyridium (11a)5 as the
intermediate. Therefore, from these results, a possible reaction mechanism might be that 3-
halogenoimidazo[1,2-a]pyridium (12a) as an intermediate reacted with 3b, or that compound (3a) was
replaced by the chloride to yield the appropriate mixtures, as shown in Scheme 2. In our previous report,6
the mechanism of formation of 6e and 8e from 3e was thought from the AM1 calculations of 3e to be that
the carbon at the 3-position attacked NCS (or AcOCl) to give the 3-chloroimidazo[1,2-a]pyridium (12b).
The successive 1,4-chlorine shift produced the chloromethyl derivative (6e), while acetic acid (quenching
water) nucleophilically substituted the intermediate (12b) at the 2-position to lead to 3e in the case where
acetic acid was the solvent. The reaction mechanism for 3b is similar to that for 3e. The treatment of 3c with
NCS produced the ipso-replacement reaction to obtain 3a and 6a in 6% and 41% yields respectively, and to
recover 3c in 36% yield. This result showed that the chlorination of the methyl group in 3a took place
preferentially when compared with the ipso-replacement reaction in 3c, by considering the relative
quantities of 3c, 3a, 6a and NCS. Similarly, replacement at the 3-position occurred by the treatment of 3d
with NCS (30% yield recovery).
The treatment of 3f with NCS gave the chloromethyl derivatives (9f and 10f), substituted at the 2-methyl
group. The structures of 9f and 10f were confirmed by long-range proton-carbon decoupling experiments,
1
and H-NMR spectral data indicated the loss of methyl protons at the 2-position rather than the 5-position.
The reaction of 3g with NCS at 50°C yielded 6g and 7g, in which the chlorination occurred at the 5-methyl
group, while the reaction at room temperature did not go to completion due to the effect of an electron-
withdrawing group (trifluoromethyl group) at the 2-position.

Furthermore, the reactions of 5-methylimidazo[1,2-a]pyridines (3a, 3c and 3g) with NCS in acetic acid as a
solvent showed similar results to those obtained when tetrahydrofuran was used as the solvent.
Table 1. Reaction of 3 with NCS (1.2 eq.) in THF
Entry
Conditions
Products
Substrate
N
N
N
N
14%
(11%b)
32%
(35%b)
3a
1
rt, 2 h
Cl
CH2Cl
Cl
CHCl2
6a
7a
N
N
X
18%
2a
rt, 1 h
Y
3b
3c
N
N
8b-1 ; X = Br
8b-2 ; X = Cl
Y = Br or Cl or mixture
Cl
8b
Me
Me
3a ; 6% (12%b), 6a ; 41% (29%b), 3c ; 36% (40%b)
rt, overnight
3
6a ; 7%b, 3d ; 30%b
rt, overnight
3d
3e
4
N
N
N
76%b
(1%b)
4%b
(NDb,d
O
6%b
(83%b)
N
N
N
56
)
rt, 4 h
CO2Et
CO2Et
CO2Et
8e
Me
CH2Cl
CHCl2
6e
7e
N
N
CHCl2
CH2Cl
7%
N
N
rt, 2 h
3f•HCl ; 21%
6
7
3f
26%
CO2Et
CO2Et
Me
Me
10 f
9f
N
N
CF3
5%b
CF3
N
N
90%b
(87%b)
50°C, 2 h
3g
CO2Et
CHCl2
CO2Et
CH2Cl
(3%b)
7g
6g
a. Yield as chloride anion, and the ratio of the mixture was analyzed by 1H-NMR in DMSO-d6 (8b-1 : 8b-2 = 20 : 13).
b. Analyzed by HPLC.
c. The yields in parentheses using acetic acid as a solvent.
d. ND = Not detected.

Cl
N
3b
N
Br
N
N
N
N
Me
Br
Me
Br
11a
Me
8b- 3
Cl
N
N
Cl
N
N
N
Cl
Cl
CHCl2
N
CH2Cl
NCS
NCS
NCS
7a
6a
Cl
Me
N
N
Br
Cl
Me
3a
N
N
N
N
3b
N
Br
NCS
N
N
N
Br
Me
Cl
Me
Br
Cl
Me
Me
8b-1
Br
3b
12a
N
3a
N
Cl
N
N
Cl
Me
Me
8b-2
Br
Scheme 2
CONCLUSION
The reactions of various 5-methylimidazo[1,2-a]pyridine derivatives substituted by an electron-
withdrawing group at the 3-position with NCS provided a variety of products. Treatment of the
imidazo[1,2-a]pyridines with a formyl, nitro, or bromide group at the 3-position using NCS produced the
ipso-reaction products. The reactions with NCS of the imidazo[1,2-a]pyridines with an ester or chlorine
group effected chlorination at the methyl group. From these results, we proposed that these reactions gave
their various products via 3-halogenoimidazo[1,2-a]pyridium (12), as shown in Scheme 3. NCS might
electrophilically react with the imidazo[1,2-a]pyridines at the 3-position to lead to the subsequent reactions,
such as the ipso-replacement reaction, the nucleophilic reaction of the other imidazo[1,2-a]pyridines(or
water or AcOH) or chlorination at the methyl group.
nucleophilic reaction
N
N
ipso-reaction
NCS
R
R
N
N
products
EWG
chlorination at the methyl group
EWG
Cl
Me
Me
12
Scheme 3

EXPERIMENTAL
Melting points were recorded on a Yanagimoto micro-melting apparatus, and were uncorrected. IR spectra
1
were recorded on a Horiba FT-210 spectrophotometer. H-NMR spectra were recorded on a Bruker DPX-
300 spectrometer using tetramethylsilane as an internal standard. Column chromatography was performed
with a Wakogel C-200 (75-150µm) system. HPLC was performed on a YMC-Pack ODS-A302 column
(6i.d. x 150 mm) with 0.05M KH2PO4 aqueous solution-MeCN (55:45) at 25℃. Detection was effected with
a Shimadzu SPD-10A spectrophotometric detector at 254 nm. Elemental analyses and MS spectra were
carried out by Takeda Analytical Research Laboratories, Ltd.
5-Methylimidazo[1,2-a]pyridine (2)
40% 2-Chloroacetaldehyde solution (588.5 g, 2.2 mol) was added to a mixture of 2-amino-6-
methylpyridine (108.1 g, 1.0 mol) and EtOH (1 L). The whole was stirred under reflux for 2 h. After cooling,
the reaction mixture was concentrated in vacuo. The residue was diluted with water, neutralized with 30%
NaOH solution and extracted with AcOEt. The AcOEt extract was washed with water, dried over Na2SO4
and concentrated in vacuo. The residue was chromatographed on SiO2 with n-hexane-AcOEt (4 : 1, v/v) to
1
give 2 (77.1 g, 65 %) as a light brown oil. EI-MS : 132 (M+). H-NMR (CDCl3) : δ 2.57 (s, 3H), 6.63 (d,
J=6.8, 1H), 7.13 (dd, J=6.8, 9.1, 1H), 7.47 (s, 1H), 7.55 (d, J=9.1, 1H), 7.79 (s, 1H). IR (Neat, cm-1) : 1639,
1540, 1509, 1299, 1149, 781, 700.
3-Chloro-5-methylimidazo[1,2-a]pyridine (3a)
NCS (5.2 g, 37.8 mmol) was added to a mixture of 2 (5.0 g, 37.8 mmol) and CHCl3 (50 mL). After the
whole was stirred at RT for 2 h, the reaction mixture was extracted with 1 N-HCl solution. The aqueous
layer was neutralized with 1 N-NaOH solution and extracted with AcOEt. The AcOEt extract was washed
with water, dried over Na2SO4 and concentrated in vacuo. The residue was triturated with n-hexane,
collected by filtration to give 3a (3.1 g, 48 %) as a colorless solid. mp 82-84°C (AcOEt / n-hexane). Anal.
Calcd for C8H7N2Cl : C, 57.67 ; H, 4.23 ; N, 16.81 ; Cl, 21.28. Found : C, 57.54 ; H, 4.22 ; N, 16.63 ; Cl,
21.08. 1H –NMR (CDCl3) : δ 2.97 (s, 3H), 6.50 (d, J=6.8, 1H), 7.01 (dd, J=6.8, 9.1, 1H), 7.45 (d, J=9.1, 1H),
7.48 (s, 1H). IR (Nujol, cm-1) :2923, 2854, 1286, 1238, 1149, 1081, 840.
3-Bromo-5-methylimidazo[1,2-a]pyridine (3b)
NBS (18.0 g, 100 mmol) was added to a mixture of 2 (12.0 g, 90.8 mmol) and CHCl3 (120 mL). After the
whole was stirred at rt for 2 h, the reaction mixture was extracted with 1 N-HCl solution. The aqueous layer
was neutralized with 1 N-NaOH solution and extracted with AcOEt. The AcOEt extract was washed with
water, dried over Na2SO4 and concentrated in vacuo. The residue was triturated with n-hexane, collected by
filtration to give 3b (11.0 g, 57 %) as a colorless solid. mp 81-83°C (AcOEt / n-hexane). Anal. Calcd for
C8H7N2Br : C, 45.53 ; H, 3.34 ; N, 13.27 ; Br, 37.86. Found : C, 45.50 ; H, 3.32 ; N, 13.22 ; Br, 37.53. 1H-
NMR (CDCl3) : δ 3.04 (s, 3H), 6.50 (d, J=6.8, 1H), 7.05 (dd, J=6.8, 9.1, 1H), 7.48 (d, J=9.1, 1H), 7.53 (s,
1H). IR (Nujol, cm-1) :2923, 2854, 1459, 1376, 1228, 1147, 838.
5-Methyl-3-nitroimidazo[1,2-a]pyridine (3c)

Concentrated nitric acid (61 %, 32 mL) was slowly added to a mixture of 2 (24.0 g, 181.6 mmol) and conc.
sulfuric acid (40 mL) at 0°C. The whole was stirred at rt for 5 h. The reaction mixture was added to water,
adjusted to pH 2.0 with 30% NaOH solution. The resulting precipitate was collected by filtration and
washed successively with water to give 3c (19.7 g, 62 %) as a light yellow solid. mp 116-117°C (EtOH).
Anal. Calcd for C8H7N3O2･0.1H2O : C, 53.69 ; H, 4.06 ; N, 23.48. Found : C, 53.70 ; H, 3.94 ; N, 23.79.
1H-NMR (CDCl3) : δ 2.68 (s, 3H), 7.31 (d, J=6.9, 1H), 7.73-78.4 (m, 2H), 8.73 (s, 1H). IR (Nujol, cm-1) :
2923, 2854, 1633, 1434, 1276, 889.
3-Formyl-5-methylimidazo[1,2-a]pyridine (3d)
Hexamethylenetetramine (56.1 g, 400 mmol) was added to a mixture of 2 (24.0 g, 181.6 mmol) in AcOH
(240 mL). The whole was stirred at 90°C for 3 h. After cooling, the reaction mixture was poured into water
and extracted with AcOEt. The AcOEt extract was neutralized with 30% NaOH solution, washed with
water, dried over Na2SO4 and concentrated in vacuo. The residue was triturated with diisopropyl ether,
collected by filtration to give 3d (8.4 g, 29 %) as a colorless solid. mp 131-132°C (AcOEt / n-hexane). Anal.
1
Calcd for C9H8N2O : C, 67.49 ; H, 5.03 ; N, 17.49. Found : C, 67.45 ; H, 5.06 ; N, 17.45. H –NMR
(CDCl3) : δ 2.97 (s, 3H), 6.90 (d, J=7.0, 1H), 7.46 (dd, J=6.8, 9.1, 1H), 7.65 (d, J=9.1, 1H), 8.40 (s, 1H),
9.90 (s, 1H). IR (Nujol, cm-1) : 2921, 2854, 1635, 1440, 1157, 890.
Ethyl 2,5-dimethylimidazo[1,2-a]pyridine-3-carboxylate (3f)
Ethyl 2-chloroacetoacetate (54.0 g, 329 mmol) was added to a mixture of 2-amino-6-methylpyridine (17.8 g,
164 mmol) and EtOH (89 mL), and the whole was refluxed for 2 h. After cooling, the reaction mixture was
concentrated in vacuo. The residue was added to AcOEt, extracted with 1 N-HCl solution. The aqueous
layer was neutralized with 30% NaOH solution and extracted with AcOEt. The AcOEt extract was washed
with water, dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on SiO2 with
1
n-hexane-AcOEt (4 : 1, v/v) to give 3f (16.0 g, 45 %) as a light brown oil. EI-MS : 218 (M+). H-NMR
(CDCl3) : δ 1.44 (t, J=7.1, 3H), 2.65 (s, 6H), 4.42 (q, J=7.1, 2H), 6.74 (d, J=7.0, 1H), 7.31 (dd, J=7.0, 8.8,
1H), 7.50 (d, J=8.8, 1H). IR (Nujol, cm-1) : 2829, 1702, 1542, 1509, 1407, 572.
2,2,2-Trifluoro-N-(6-methyl-2-pyridinyl)acetamide (4)
Trifluoroacetic anhydride (48.0 g, 220 mmol) was dropped into a mixture of 2-amino-6-methylpyridine
(21.6 g, 200 mmol), pyridine (31.6 g, 400 mmol) and THF (200 mL) at 0°C. The whole was stirred at rt
overnight. The reaction mixture was concentrated in vacuo. The residue was added to water, extracted with
AcOEt. The AcOEt extract was washed with water, dried over Na2SO4 and concentrated in vacuo to give 4
(41.6 g, 94 %) as a colorless oil. EI-MS : 204 (M+). 1H-NMR (CDCl3) : δ 2.94 (s, 3H), 7.03 (d, J=7.6, 1H),
7.68 (dd, J=7.6, 8.3, 1H), 7.96 (d, J=8.3, 1H), 8.05 (br s, 1H). IR (Neat, cm-1) : 2933, 2859, 1737, 1606,
1577, 1294, 1168, 1157, 792.
Ethyl {2-[(trifluoroacetyl)imino]pyridin-1-(2H)-yl}acetate (5)
60% Sodium hydride (6.8 g, 170 mmol) was added to a suspension of 4 (34.7 g, 170 mmol) in DMF (170
mL) in an ice-bath. After this the solution was stirred at the same temperature for 30 min, ethyl 2-

bromoacetate (28.4 g, 170 mmol) was added and then the whole was stirred at rt for 4 h. The reaction
mixture was poured into water and extracted with AcOEt. The AcOEt extract was washed with water, dried
over Na2SO4 and concentrated in vacuo. The residue was triturated with diisopropyl ether, collected by
filtration to give 5 (11.3 g, 23 %) as a colorless solid. mp 119-120°C (AcOEt / n-hexane). Anal. Calcd for
1
C12H13N2O3F3 : C, 49.66 ; H, 4.51 ; N, 9.65 ; F, 19.64. Found : C, 49.34 ; H, 4.48 ; N, 9.58 ; F, 19.62. H-
NMR (CDCl3) : δ 1.30 (t, J=7.2, 3H), 2.55 (s, 3H), 4.25 (q, J=7.2, 2H), 5.12 (s, 2H), 6.75 (d, J=7.2, 1H),
7.70 (dd, J=7.2, 8.9, 1H), 8.40 (d, J=8.9, 1H). IR (Nujol, cm-1) :2919, 2854, 1739, 1619, 1558, 1168, 1124,
792.
Ethyl 2-trifluoromethyl-5-methylimidazo[1,2-a]pyridine-3-carboxylate (3g)
DBU (0.1 mL, 0.7 mmol) was added to a mixture of 5 (1.0 g, 3.5 mmol) and THF (10 mL). The whole was
stirred at 50°C for 16 h. After cooling, AcOH (0.1mL) was added to the reaction mixture and concentrated
in vacuo. The residue was poured into water and extracted with AcOEt. The AcOEt extract was washed
with water, dried over Na2SO4 and concentrated in vacuo. The residue was triturated with diisopropyl ether,
collected by filtration to give 3g (0.92 g, 98 %) as a colorless solid. mp 44-45°C (AcOEt / n-hexane). Anal.
Calcd for C12H11N2O2F3 : C, 52.95 ; H, 4.07 ; N, 10.29 ; F, 20.94. Found : C, 52.84 ; H, 4.00 ; N, 10.30 ; F,
1
20.98. H-NMR (CDCl3) : δ 1.44 (t, J=7.1, 3H), 2.65 (s, 3H), 4.47 (q, J=7.1, 2H), 6.85 (d, J=7.0, 1H), 7.40
(dd, J=7.0, 9.0, 1H), 7.68 (d, J=9.0, 1H). IR (Nujol, cm-1) : 2848, 1725, 1519, 1461, 1176, 1145.
Reaction of 3a and NCS
NCS (0.96 g, 7.2 mmol) was added to a mixture of 3a (1.0 g, 6.0 mmol) and THF (12 mL). The whole was
stirred at rt for 2 h. The reaction mixture was poured into AcOEt. The AcOEt extract was washed with water,
dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on SiO2 with n-hexane-
AcOEt (1 : 1, v/v) to give 6a (385 mg, 32 %) and 7a (200 mg, 14 %) as a colorless solid. 6a : mp 98-99°C
(AcOEt / n-hexane). Anal. Calcd for C8H6N2Cl2 : C, 47.79 ; H, 3.01 ; N, 13.93. Found : C, 47.59 ; H, 3.14 ;
N, 13.85. 1H-NMR (CDCl3) : δ 5.21 (s, 2H), 6.88 (d, J=6.9, 1H), 7.15 (dd, J=6.9, 9.1, 1H), 7.62 (d, J=9.1,
1H), 7.59 (s, 1H). IR (Nujol, cm-1) : 2944, 2881, 1509, 1290, 846. 7a : mp 74-75°C (AcOEt / n-hexane).
Anal. Calcd for C8H5N2Cl3•0.1H2O : C, 40.49 ; H, 2.17 ; N, 11.81 ; Cl, 44.89. Found : C, 40.97 ; H, 2.24 ; N,
1
11.85 ; Cl, 44.76. H-NMR (CDCl3) : δ 7.27 (dd, J=7.4, 9.0, 1H), 7.61 (s, 1H), 7.64-7.69 (m, 2H), 8.08 (s,
1H). IR (Nujol, cm-1) : 2967, 2850, 1290, 1205, 1149, 848.
Reaction of 3b and NCS
NCS (1.52 g, 9.5 mmol) was added to a mixture of 3b (2.0 g, 11.4 mmol) and THF(24 mL). The whole was
stirred at rt for 1 h. The resulting crystals were collected by filtration, washed with AcOEt, and
recrystallized from MeOH to give a mixture (0.69 g, 18 % as chloride salt) of 8b-1 and 8b-2 as a colorless
solid. FAB-MS : 398 (M+Na)+, 354 (M+Na)+. 1H-NMR (DMSO-d6) : δ; 8b-1 : 8b-2=20 : 13; 8b-1; 3.03 (s,
3H), 3.25 (s, 3H), 7.03 (d, J=7.0, 1H), 7.47 (dd, J=7.0, 9.0, 1H), 7.57-7.59 (m, 2H), 7.65 (d, J=9.0, 1H),
8.03-8.15(m, 1H), 8.99 (s, 1H); 8b-2; 3.03 (s, 3H), 3.19 (s, 3H), 7.03 (d, J=7.0, 1H), 7.47 (dd, J=7.0, 9.0,
1H), 7.57-7.59 (m, 2H), 7.65 (d, J=9.0, 1H), 8.03-8.15(m, 1H), 8.96 (s, 1H).

Reaction of 3c and NCS
NCS (0.50 g, 3.8 mmol) was added to a mixture of 3c (0.50 g, 3.1 mmol) and THF (7 mL). The whole was
stirred at rt overnight. The reaction mixture was poured into AcOEt and extracted with 1 N-HCl solution.
The aqueous layer was neutralized with 30% NaOH solution and extracted with AcOEt. The AcOEt extract
was washed with water, dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed
on SiO2 with n-hexane-AcOEt (2 : 1, v/v) to give 3c (0.18 g, 36 %) as a colorless solid and the mixed oil of
3a and 6a (0.29 g, 6 % (3a) and 41% (6a) analyzed by 1H-NMR).
Reaction of 3d and NCS
NCS (0.45 g, 3.4 mmol) was added to a mixture of 3d (0.50 g, 2.8 mmol) and THF (6 mL). The whole was
stirred at rt overnight. Yields (6a; 7 %, 3d; 30 %) were determined by HPLC.
Reaction of 3f and NCS
NCS (0.73 g, 5.5 mmol) was added to a mixture of 3f (1.0 g, 4.6 mmol) and THF (12 mL). The whole was
stirred at rt for 2 h. The resulting crystals were collected by filtration, washed with AcOEt to give 3f•HCl
(0.21 g, 21 %) as a colorless solid. The filtrate was washed with water, dried over Na2SO4 and concentrated
in vacuo. The residue was chromatographed on SiO2 with n-hexane-AcOEt (4 : 1, v/v) to give 9f (80 mg,
7%) and 10f (0.3 g, 26 %) as colorless solids. 9f : mp 67-68°C (AcOEt / n-hexane). Anal. Calcd for
1
C12H13N2O2Cl•1/4H2O : C, 56.03 ; H, 5.29 ; N, 10.89. Found : C, 56.07 ; H, 5.07 ; N, 10.89. H-
NMR(CDCl3) : δ 1.47 (t, J=7.1, 3H), 2.66 (s, 3H), 4.76 (q, J=7.1, 2H), 4.96 (s, 2H), 6.79 (d, J=7.0, 1H), 7.35
(dd, J=7.2, 8.8, 1H), 7.58 (d, J=8.8, 1H). IR (Nujol, cm-1) : 2913, 2856, 1712, 1509, 1207, 1097. 10f : mp
68-69°C (AcOEt / n-hexane). Anal. Calcd for C12H12N2O2Cl2 : C, 50.19 ; H, 4.21 ; N, 9.76. Found : C,
49.99 ; H, 4.16 ; N, 9.53. 1H-NMR (CDCl3) : δ 1.49 (t, J=7.1, 3H), 2.66 (s, 3H), 4.49 (q, J=7.1, 2H), 6.84 (d,
J=7.0, 1H), 7.40 (s, 1H), 7.41 (dd, J=7.0, 8.9, 1H), 7.69 (d, J=8.9, 1H). IR (Nujol, cm-1) : 2921, 2852, 1710,
1508, 1159, 796.
Ethyl 5-chloromethyl-2-trifluoromethylimidazo[1,2-a]pyridine-3-carboxylate (6g)
NCS (0.59 g, 4.4 mmol) was added to a mixture of 3g (1.0 g, 3.7 mmol) and THF (12 mL). The whole was
stirred under reflux for 2 h. The reaction mixture was poured into AcOEt. The AcOEt extract was washed
with water, dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on SiO2 with
n-hexane-AcOEt (4 : 1, v/v) to give 6g (0.56 g, 50 %) as a colorless solid. mp 114-116°C (AcOEt / n-
hexane). Anal. Calcd for C12H10N2O2ClF3: C, 47.00 ; H, 3.29 ; N, 9.13 ; Cl, 11.56 ; F, 18.59. Found : C,
46.91 ; H, 3.15 ; N, 9.11 ; Cl, 11.55 ; F, 18.42. 1H-NMR (CDCl3) : δ 1.47 (t, J=7.2, 3H), 4.50 (q, J=7.2, 2H),
5.18 (s, 2H), 7.13 (d, J=7.0, 1H), 7.47 (dd, J=7.0, 9.0, 1H), 7.86 (d, J=9.0, 1H). IR (Nujol, cm-1) : 2923, 2854,
1722, 1539, 1211, 802.
Ethyl 5-dichloromethyl-2-trifluoromethylimidazo[1,2-a]pyridine-3-carboxylate (7g)
NCS (0.54 g, 4.1 mmol) was added to a mixture of 3g (0.5 g, 1.8 mmol) and THF (6 mL). The whole was
stirred under reflux for 2 h. The reaction mixture was poured into AcOEt. The AcOEt extract was washed
with water, dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on SiO2 with

n-hexane-AcOEt (4 : 1, v/v) to give 7g (0.32 g, 51 %) as a colorless solid. mp 122-123°C (AcOEt / n-
hexane). Anal. Calcd for C12H9N2O2Cl2F3･0.5H2O: C, 41.17 ; H, 2.88 ; N, 8.00 ; Cl, 20.25 ; F, 16.28.
Found : C, 40.97 ; H, 2.53 ; N, 8.11 ; Cl, 20.285 ; F, 16.37. 1H-NMR (CDCl3) : δ 1.46 (t, J=7.2, 3H), 4.52 (q,
J=7.2, 2H), 7.62 (dd, J=7.8, 8.6, 1H), 7.86 (s, 1H), 7.91-7.95 (m, 2H) . IR (Nujol, cm-1) : 2921, 2854, 1712,
1513, 1201, 808.
Reaction of 3g and NCS
NCS (0.29 g, 2.2 mmol) was added to a mixture of 3g (0.50 g, 1.8 mmol) and THF (6 mL). The whole was
stirred at 50°C for 2 h. Yields (6g; 90 %, 7g; 5 %) were determined by HPLC.
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