Efficient synthesis of novel dipyridoimidazoles and pyrido[1′,2′;1,2]imidazo[4,5-d]pyridazine derivatives

Article abstract of DOI:10.1016/S0040-4020(03)00938-4

Novel dipyrido[1,2-a;3′,4′-d]imidazoles 7a-d, dipyrido[1,2-a;4′,3′-d]imidazoles 8a,c and pyrido[1′,2′;1,2]imidazo[4,5-d]pyridazine derivatives 9a-d were synthesized by two pathways: thermal electrocyclic reaction of 3-alkenylimidazopyridine-2-oximes 10 and direct condensation of ethyl glycinate (or hydrazine) with 2,3-dicarbonylimidazo[1,2-a]pyridines 11.

Full text of DOI:10.1016/S0040-4020(03)00938-4

Tetrahedron 59 (2003) 5869–5878
Efficient synthesis of novel dipyridoimidazoles and
pyrido[10,20;1,2]imidazo[4,5-d]pyridazine derivatives
Jean M. Chezal,a Emmanuel Moreau,a Olivier Chavignon,a Claire Lartigue,a Yves Blacheb
and Jean C. Teuladea
,
*
a
´
Faculte de Pharmacie, Chimie Organique, UMR-INSERM 484, 28 place Henri-Dunant, B.P. 38,
63001 Clermont-Ferrand CEDEX 1, France
b
´
Laboratoire de Chimie Organique Pharmaceutique, Faculte de Pharmacie, 15 avenue Ch.-Flahault, 34060 Montpellier, France
Received 2 April 2003; revised 13 May 2003; accepted 12 June 2003
Abstract—Novel dipyrido[1,2-a;30,40-d]imidazoles 7a–d, dipyrido[1,2-a;40,30-d]imidazoles 8a,c and pyrido[10,20;1,2]imidazo[4,5-d]-
pyridazine derivatives 9a–d were synthesized by two pathways: thermal electrocyclic reaction of 3-alkenylimidazopyridine-2-oximes 10
and direct condensation of ethyl glycinate (or hydrazine) with 2,3-dicarbonylimidazo[1,2-a]pyridines 11.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
7(8H)-one (5) have interesting cytotoxic activities.5,6
Recently, pyridopurine (6a), an analog of the genotoxic
Glu-P-1 (6b) and Glu-P-2 (6c),7 showed intercalant
properties8 (Fig. 1).
The skeleton of carbolines or pyridazino[4,5-b]indole are of
great interest owing to their varied and important biological
properties. For example lavendamycin (1),1 a potent
antitumor antibiotic,2 and ethyl 4-methyl-5-isopropyloxy-
b-carboline-3-carboxylate (2), a synthetic compound, show
significant memory enhancing effects in humans via
interaction with the benzodiazepine receptor of the central
nervous system.3 Intoplicin (3) has been shown to
display inhibitory activity against topoisomerase I and II
enzymes.4 The heterocyclic amines Trp-P-1 (4a) and Trp-P-
2 (4b)5 and 11-methylbenzo[g]pyridazin[4,5-b]indol-
Pursuing our interest in the development of new nitrogen
bridgehead azaindolizines9 and in view of the pharmaco-
logical interest of these structures exemplified above, we
focused on the synthesis of dipyrido[1,2-a;30,40-d], [1,2-
a;40,30-d]imidazole 7, 8 and pyrido[10,20;1,2]imidazo[4,5-d]-
pyridazine derivatives 9. To our knowledge, these fused
conjugate ring systems have rarely been reported10 and only
with complicated synthetic approaches.
Figure 1.
Keywords: imidazo[1,2-a]pyridine; dipyridoimidazole; azacarboline; pyridoimidazopyridazine.
*
Corresponding author. Tel.: þ33-4-73-17-80-00; fax: þ33-4-73-17-80-12; e-mail: j-claude.teulade@u-clermont1.fr
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00938-4

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Scheme 1.
We report the heteroannulation via two pathways from the
same bromoketal compounds 12: thermal cyclization of
vinyloxime 10 (method A)11 and direct condensation of
ethyl glycinate with dicarbonyl compounds 11 (method B)12
as shown in Scheme 1.
The halogen–metal exchange performed with 12a,b using
n-butyllithium at 2608C followed by quenching with DMF
gave a mixture of aldehydes 16a,b and 17a,b (Scheme 3).
The main products were the expected 3-formyl derivatives
16a,b (68–41%) while the minor isomers proved to be the
5-formyl compounds 17a,b (18–14%). These unexpected
compounds were probably obtained via lithiation at position
5 of 12a,b followed by bromine–lithium isomerisation at
positions 3, 5. This halogen-dance reaction has been
observed in a pyridine series15 and with some imi-
dazo[1,2-a]pyrazine.16 Wittig reactions using aldehydes
16a,b and (carbethoxymethylene) triphenylphosphorane in
THF under reflux gave the corresponding (E)-acrylates
18a,b. Compounds 18a,b were easily deprotected to provide
the carbonyl group. The resulting 19a,b treated with
hydroxylamine hydrochloride and AcONa gave the desired
2. Results and discussion
The first step in our synthesis required 2-ketal-3-bromo-
imidazo[1,2-a]pyridine compounds 12a,b. Ketal protection
of 3-bromo-2-formylimidazo[1,2-a]pyridine (13)13 by
ethanol in the presence of catalytic p-toluenesulfonic acid
in benzene gave the desired acetal 12a9d in 51% yield.
Tchitchibabin cyclization14 with 2-aminopyridine and
bromobutanedione (prepared in situ from commercial
butanedione) in ethanol gave 2-acetylimidazo[1,2-a]pyri-
dine (14) in 24% yield (Scheme 2). Finally, compound 12b
was easily prepared by protection of the carbonyl group of
14 to yield 15 followed by bromination with NBS in
acetonitrile.
The synthetic route A involves preparation of vinyloximes
10 from 12a,b. We investigated the formation of the
3-acrylate moiety by lithiation of 12, electrophilic
substitution with DMF or N-methyl-N-methoxyacetamide,
followed by Wittig condensation.
Scheme 2. Reagents and conditions. (i) Ethanol, benzene, PTSA, D;
(ii) EtOH, bromobutanedione, D; (iii) ethyleneglycol, benzene, PTSA, D;
(iv) NBS, CH3CN, D.
Scheme 3. Reagents and conditions. (i) 1/n-BuLi, THF, 2608C, 2/DMF,
room temperature; (ii) Ph3PCHCO2Et, THF, reflux; (iii) CH3CN/H2O (3/1,
v/v), HCl cat.; (iv) NH2OH/HCl, AcONa, EtOH, 608C.

J. M. Chezal et al. / Tetrahedron 59 (2003) 5869–5878
5871
oximes 10a,b, which were fully characterized by NMR and
mass spectra. The stereochemistry of the a,b-unsaturated
esters 18a,b, 19a,b and 10a,b were found by 1H NMR data
to possess the E-configuration (J<16 Hz).
We sought to extend this method to 3-acetyl derivatives.
Bromide 12a was lithiated using n-butyllithium at 2608C,
and the resulting solution was treated with an excess of
N-methyl-N-methoxyacetamide according to Wai’s pro-
cedure17 to give the desired acetyl 20 (58%)
and 2-diethoxymethylimidazo[1,2-a]pyridine13 (30%).
Attempts to extend the method to 12b were unsuccessful
and produced the 5-bromo derivative 22 (35%) and
dehalogenated acetal 15 (24%) (Scheme 4).
Scheme 5. Reagents and conditions. (i) Nitrobenzene, CH3COCI
(12 equiv.), 2108C; (ii) PH3PCHCO2Et, toluene, reflux; (iii) AgNO3,
EtOH, reflux; (iv) CH3CN/H2O (3/1, v/v), HCl cat.; (v) NH2OH, HCl,
AcONa, EtOH, 608C.
Scheme 4. Reagents and conditions. (i) 1/n-BuLi, THF, 2608C, 2/N-
methyl-N-methoxyacetamide, room temperature; (ii) Ph3PCHCO2Et, THF,
reflux.
Condensation of 20 with (carbethoxymethylene)triphenyl-
phosphorane by a Wittig reaction in THF failed to give 21
and left only recovered starting material. Several solvents,
temperature and reaction times were unsuccessful evalu-
ated. We therefore, developed an alternative strategy, based
on direct acylation18 of dichloromethyl compound 23.13
Treatment of 23 with excess acetyl chloride in nitrobenzene
at 2108C gave acetyl 24 in 33% yield (Scheme 5).
Scheme 6.
Condensation of 24 with (carbethoxymethylene)triphenyl-
phosphorane gave the expected acrylate 25 in low yield
(13%) and starting material (15%). Compound 25 was
converted by Arbarca’s method19 (silver nitrate in ethanol)
to give the minor acetal 21 (13%) and the major aldehyde 26
(50%). Compound 21 was easily transformed to 26 by acid
hydrolysis in acetonitrile. Finally, treatment of 26 with
hydroxylamine gave the desired oxime 10c.
of acetals 16a,b gave the corresponding carbonyls 11a,b in
good yields (73–97%) (Scheme 7).
Treatment of dichloromethyl 24 with silver nitrate, under
the previous conditions, afforded the 2-formyl product 11c
as well as the acetal 20 in a ca. 2:1 ratio with a total yield of
76%. Deprotection of 20 yielded the required 11c in high
yield (90%). When acetyl compound 14 was treated under
the same conditions used for 23, it reacted to form the 2,3-
diacetylimidazo[1,2-a]pyridine (11d).
The electrocyclization reactions11 of 10a–c were carried
out by heating in 1,2-dichlorobenzene. Conversion of 10a–
c to the cyclization products 7a–c occurred in 16–54%
yield. In the case of 10a,c, nitrile derivatives 27a,b were
readily observed and easily separated by chromatography
on alumina gel (Scheme 6).
Accordingly, we investigated the reactivity of 2,3-dicarbo-
nyl compounds 11a–d with ethyl glycinate using modified
Meziane’s method.12d A solution of dialdehyde 11a
(4.95 mmol) in ethanol was treated with excess ethyl
glycinate (11.5 mmol) at room temperature for 20 h to
give a mixture of isomeric dipyridoimidazoles 7a and 8a
(Scheme 8). These compounds were readily separated by
The fact that thermolysis of oximes 10a,c gave a mixture of
expected dipyridoimidazoles 7a,c and unexpected cyano
derivatives 27a,b prompted us to explore a new method of
cyclization from dicarbonyl compounds 11a–d. Hydrolysis

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J. M. Chezal et al. / Tetrahedron 59 (2003) 5869–5878
group. Presumably, the intramolecular cyclization reaction
of the imine formed on the second carbonyl group is, the
determining stage of the reaction. This step preferably takes
place on the aldehydic rather than on the ketonic function. In
this way, by displacement of the equilibre aldehyde-imine,
the initial ethyl glycinate condensation reaction preferably
takes place on the acetyl group, leading to the corresponding
dipyridoimidazoles 7b and 8c.
Scheme 7. Reagents and conditions. (i) CH3CN/H2O (3/1, v/v), HCl cat.;
(ii) AgNO3, EtOH, D; (iii) CH3COCl, nitrobenzene, 2108C.
In the same way, we studied the heterocyclization of the 2,3-
diacetyl compound. Reaction of 11d with ethyl glycinate
over 8 days led to dimethyldipyridoimidazole 7d as the only
product in 61% yield (Table 1, entry 7). Structural
determination of 7d was achieved on the basis of NOESY
experiments. The presence of strong NOESY effects
between Me(C-4) and CH2CH3, and Me(C-4) and H-6,
unequivocally pointed to the dipyrido[1,2-a;30,40-d]imida-
zolic structure.
In a similar way, we tested the reaction conditions of the
above procedure with 11a–d and hydrazine monohydrate.
Substituted or unsubstituted pyridoimidazopyridazines
9a–d were produced in 30–89% yields (Table 1, entries
2, 4, 6, 8).
Scheme 8. Reagents and conditions. (i) NH2CH2CO2Et, EtOH, room
temperature; (ii) NH2NH2, EtOH, room temperature.
column chromatography, and the isolated yields are shown
in Table 1, entry 1.
3. Conclusion
In summary, we describe two synthetic routes for the
synthesis of new dipyridoimidazoles 7a–d, 8a,c and
pyridoimidazopyridazines 9a–d. These tricyclic systems
were synthesized by electrocyclization of vinyloxime or by
direct condensation of dicarbonyl compounds with ethyl
glycinate or hydrazine monohydrate. In the case of ethyl
glycinate, regioselectivity was observed. Work is now in
progress to study the intercalating abilities and antitumor
activities of all these chemical entities.
Structural assignment of 8a was secured by INEPT
experiments. According to these results, we consider that
compounds 7a and 8a initially resulted from condensation
of the amino group of ethyl glycinate with the 2 or 3-formyl
groups, respectively. The imino intermediates (not isolated)
yielded the pyridine moiety after cyclization (Scheme 9).
Next, we examined the effects of the aldehyde and keto
groups of 2-(or 3-)acetyls 11b (or 11c) in the presence of
ethyl glycinate they gave essentially the annulated com-
pounds 7b and 8c, respectively (Table 1, entries 3, 5). We
thought that the initial reaction was done between the amine
and the aldehydic function, more reactive than ketone
4. Experimental
4.1. General procedures
Table 1. Condensation of 11a–d with ethyl glycinate and hydrazine
All column chromatography was performed with Merck
neutral aluminium oxide 90 standardized (63–200 mm). All
thin-layer chromatography was performed on Merck neutral
aluminium oxide 60F254 plates. The plates were visualized
with UV light (254 nm). Melting points were determined on
an Electrothermal IA9300 (capillary) and are not corrected.
NMR (400 MHz for 1H or 100 MHz for 13C) were recorded
on a Bruker Avance 400 spectrophotometer using CDCl3 as
solvent unless otherwise specified. Chemical shifts are
expressed in parts per million (ppm) relative to tetra-
methylsilane (TMS). Infrared spectra were recorded on a
FTIR Nicolet Impact 410. Mass spectral analyses were
Entry Dicarbonyl
Reagent
Product (yield (%))
7
8
9
1
2
3
4
5
6
7
8
11a
11a
11b
11b
11c
11c
11d
11d
Ethyl glycinate
Hydrazine monohydrate
Ethyl glycinate
Hydrazine monohydrate
Ethyl glycinate
Hydrazine monohydrate
Ethyl glycinate
Hydrazine monohydrate
7a (12) 8a (39)
7b (28)
9a (89)
9b (30)
9c (63)
9d (75)
8c (61)
7d (61)
Scheme 9.

J. M. Chezal et al. / Tetrahedron 59 (2003) 5869–5878
5873
performed on a Hewlett–Packard 5985B or 5989A instru-
ment. All air-sensitive reactions were run under argon
atmosphere. All solvents were dried using common
techniques.
organic layers were dried (Na2SO4) and evaporated.
Purification of the crude product by chromatography on
alumina gel with CH2Cl2 as eluent afforded the desired
product 12b in 91% yield (6.29 g); Rf¼0.51 (CH2Cl2); mp
58–608C; IR (KBr) 1682, 1239, 1168 cm21; MS m/z 284
(Mþþ2, 31), 282 (Mþ, 31), 269 (96), 267 (100), 241 (91),
239 (95), 225 (76), 223 (81), 197 (20), 87 (32), 78 (47), 51
(33); 1H NMR d 1.87 (s, 3H), 3.99 (t, 2H, J¼5 Hz), 4.13 (t,
2H, J¼5 Hz), 6.95 (t, 1H, J¼7 Hz), 7.26 (m, 1H), 7.64 (d,
1H, J¼9 Hz), 8.16 (d, 1H, J¼7 Hz); 13C NMR d 25.4, 64.9,
91.4, 106.3, 113.2, 117.9, 123.8, 125.1, 144.6, 144.7. Anal.
calcd for C11H11N2O2Br: C: 46.66; H: 3.92; N: 9.89. Found:
C: 46.54; H: 3.92; N: 9.92.
4.1.1. 2-Acetylimidazo[1,2-a]pyridine (14). To a cooled
solution (08C) of butanedione (15.2 g, 177 mmol) was
added dropwise bromine (6.1 mL, 119 mmol). The solution
was stirred at room temperature for 4 h. A solution of
2-aminopyridine (6.90 g, 73.4 mmol) in EtOH (150 mL)
was then added slowly. The mixture was refluxed for 6 h.
After cooling, the solution was evaporated under vacuum.
Water (100 mL) was poured into the crude product and the
solution was basified with Na2CO3 (15.0 g, 142 mmol) and
extracted with CH2Cl2 (3£40 mL). The organic layer was
dried over Na2SO4 and the solvent of the filtrate was
evaporated. The crude residue was purified by column
chromatography on alumina gel with CH2Cl2 as eluent to
give 14 (2.80 g, 24%); Rf¼0.25 (CH2Cl2); mp 127–1298C;
IR (KBr) 1670 cm21; MS m/z 160 (Mþ, 79), 145 (100), 132
(14), 117 (41), 90 (21), 78 (17); 1H NMR d 2.65 (s, 3H), 6.82
(t, 1H, J¼7 Hz), 7.20 (m, 1H), 7.60 (d, 1H, J¼9 Hz), 8.09 (s,
1H), 8.12 (d, 1H, J¼7 Hz); 13C NMR d 27.1, 114.0, 114.8,
118.9, 126.1, 126.5, 144.1, 144.9, 195.7. Anal. calcd for
C9H8N2O: C: 67.49; H: 5.03; N: 17.49. Found: C: 67.55; H:
5.02; N: 17.52.
4.1.4. General procedure for metalation of 12a,b. To a
cold solution (2608C) of the appropriate bromo compound
(25.9 mmol) in anhydrous THF (65 mL) was added
dropwise n-BuLi (20 mL, 1.6 M in hexanes) when the
mixture immediately became dark. To this solution was
added dropwise the appropriate amides (34.1 mmol for
DMF and 102.3 mmol for N-methyl-N-methoxyacetamide)
in THF (15 mL). The mixture was returned back room
temperature, stirred for 30 mn and poured into aqueous
saturated ammonium chloride solution (100 mL). The
aqueous layer was extracted with CH2Cl2 (3£40 mL)
dried (Na2SO4) and removed in vacuo. The crude product
was chromatographed using CH2Cl2 as eluent.
4.1.2. General procedure for the preparation of acetals
12 and 15. A solution of anhydrous ethanol or ethylene-
glycol (466 mmol) in dry benzene (150 mL), the appropriate
carbonyl (66.6 mmol) and a small quantity of p-toluene-
sulfonic acid (10%) was refluxed using a Dean–Stark
separator. After cooling the solvent was removed to dryness
and the residue was taken up with water (150 mL) and
basified with Na2CO3 (7.50 g, 71 mmol). The resulting
solution was extracted with CH2Cl2 (3£60 mL). After
drying (Na2SO4) the organic solution was evaporated and
the remaining viscous oil was chromatographed using
CH2Cl2 as eluent.
From 12a and DMF: to give in order of elution:
2-diethoxymethyl-3-formylimidazo[1,2-a]pyridine (16a)
yield: 68% as an oil; Rf¼0.57 (CH2Cl2); IR (CCl4) 1650,
1497, 1327, 1259, 1139, 1067 cm21; MS m/z 248 (Mþ, 2),
204 (24), 175 (73), 147 (23), 118 (24), 90 (10), 78 (100), 51
(20); 1H NMR d 1.19 (t, 6H, J¼7 Hz), 3.62 (q, 2H, J¼7 Hz),
3.70 (q, 2H, J¼7 Hz), 5.81 (s, 1H), 7.02 (t, 1H, J¼7 Hz),
7.50 (m, 1H), 7.73 (d, 1H, J¼9 Hz), 9.58 (d, 1H, J¼7 Hz),
10.38 (s, 1H); 13C NMR d 15.1, 62.4, 99, 115.5, 117.6,
121.4, 128.9, 130.4, 146.9, 155.5, 181.0. Anal. calcd for
C13H16N2O3: C: 62.89; H: 6.50; N: 11.28. Found: C: 63.10;
H: 6.48; N: 11.26. 2-Diethoxymethyl-5-formylimidazo[1,2-
a]pyridine (17a) yield: 18%; Rf¼0.30 (CH2Cl2); mp 81–
838C; IR (KBr) 1672, 1310, 1050 cm21; MS m/z 248 (Mþ,
1), 204 (18), 175 (100), 147 (15), 90 (10), 78 (32); 1H NMR
d 1.19 (t, 6H, J¼7 Hz), 3.65 (m, 4H), 5.74 (s, 1H), 7.31 (m,
1H), 7.46 (d, 1H, J¼7 Hz), 7.87 (d, 1H, J¼9 Hz), 8.99 (s,
1H), 9.83 (s, 1H); 13C NMR d 15.2, 61.5, 98.4, 112.7, 122.5,
124.2, 125.9, 132.1, 145.1, 147.8, 184.4. Anal. calcd for
C13H16N2O3: C: 62.89; H: 6.50; N: 11.28. Found: C: 62.75;
H: 6.49; N: 11.31.
From 13: 3-bromo-2-diethoxymethylimidazo[1,2-a]pyri-
dine (12a)9b reaction time 48 h, yield: 51% as an yellow
oil; Rf¼0.36 (CH2Cl2).
From 14: 2-(2-methyl[1,3]dioxolan-2-yl)imidazo[1,2-
a]pyridine (15) reaction time 40 h, yield: 87%; Rf¼0.20
(CH2Cl2); mp 72–748C; IR (KBr) 1189, 1041 cm21; MS
m/z 204 (Mþ, 10), 189 (44), 161 (100), 145 (89), 117 (23),
78 (48), 51 (31); 1H NMR d 1.82 (s, 3H), 4.01 (m, 4H), 6.73
(t, 1H, J¼7 Hz), 7.12 (m, 1H), 7.56 (d, 1H, J¼9 Hz), 7.57 (s,
1H), 8.07 (d, 1H, J¼7 Hz); 13C NMR d 25.4, 64.9, 106.2,
109.2, 112.3, 117.7, 124.6, 125.7, 145.1, 147.9. Anal. calcd
for C11H12N2O2: C: 64.69; H: 5.92; N: 13.72. Found: C:
64.49; H: 5.93; N: 13.69.
From 12a and N-methyl-N-methoxyacetamide: to give in
order of elution: 3-acetyl-2-diethoxymethylimidazo[1,2-
a]pyridine (20) yield: 58% as an oil; Rf¼0.56 (CH2Cl2);
IR (CCl4) 1641, 1499, 1332 cm21; MS m/z 262 (Mþ, 1), 218
1
(20), 189 (100), 161 (15), 145 (18), 119 (18), 78 (51); H
4.1.3. 3-Bromo-2-(2-methyl[1,3]dioxolan-2-yl)imi-
dazo[1,2-a]pyridine (12b). To a solution of 15 (5.0 g,
24.5 mmol) in acetonitrile (100 mL), was added N-bromo-
succinimide (4.80 g, 26.95 mmol). The solution was stirred
at reflux for 3 h. After cooling, the solution was concen-
trated in vacuo to dryness. Water (80 mL) was added and the
aqueous solution was basified with Na2CO3 (4.00 g,
37.7 mmol) and extracted with CH2Cl2 (3£30 mL). The
NMR d 1.26 (t, 6H, J¼7 Hz), 2.83 (s, 3H), 3.71 (m, 4H),
5.96 (s, 1H), 7.06 (t, 1H, J¼7 Hz), 7.47 (m, 1H), 7.76 (d, 1H,
J¼9 Hz), 9.78 (d, 1H, J¼7 Hz); 13C NMR d 15.2, 30.6,
62.8, 99.7, 115.3, 117.6, 120.9, 129.0, 129.2, 146.0, 151.7,
189.8. Anal. calcd for C14H18N2O3: C: 64.10; H: 6.92; N:
10.68. Found: C: 63.99; H: 6.90; N: 10.69. 2-Diethoxy-
methylimidazo[1,2-a]pyridine13 yield: 30%; Rf¼0.25
(CH2Cl2).

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J. M. Chezal et al. / Tetrahedron 59 (2003) 5869–5878
From 12b and DMF: to give in order of elution (eluate with
AcOEt/hexanes, 8/2, v/v): 3-formyl-2-(2-methyl[1,3]dioxo-
lan-2-yl)imidazo[1,2-a]pyridine (16b) yield: 41%; Rf¼0.64
(AcOEt/hexanes, 8:2); mp 123–1258C; IR (KBr) 1638,
1324, 1255, 1180 cm21; MS m/z 232 (Mþ, 19), 217 (21),
189 (50), 187 (51), 173 (49), 161 (59), 145 (25), 87 (34), 78
dazo[1,2-a]pyridin-3-yl)propenoate (18b); (reaction time
9 h, using 3 equiv. of (carbethoxymethylene)triphenylphos-
phorane) yield: 52% as an oil; Rf¼0.27 (CH2Cl2); IR (CCl4)
1716, 1625, 1176 cm21; MS m/z 302 (Mþ, 51), 287 (84),
259 (100), 213 (49), 171 (92), 143 (30), 87 (42), 78 (51); 1H
NMR d 1.28 (t, 3H, J¼7 Hz), 1.75 (s, 3H), 3.85 (t, 2H,
J¼6.5 Hz), 4.05 (t, 2H, J¼6.5 Hz), 4.22 (q, 2H, J¼7 Hz),
6.39 (d, 1H, J¼16.5 Hz), 6.91 (t, 1H, J¼7 Hz), 7.24 (m,
1H), 7.63 (d, 1H, J¼9 Hz), 8.24 (d, 1H, J¼16.5 Hz), 8.35 (d,
1H, J¼6.5 Hz); 13C NMR d 14.4, 26.0, 60.6, 64.8, 107.1,
114.1, 114.5, 117.1, 118.6, 125.4, 126.3, 130.3, 146.4,
151.5, 167.5. Anal. calcd for C16H18N2O4: C: 63.56; H:
6.00; N: 9.27. Found: C: 63.55; H: 6.02; N: 9.29.
1
(100), 51 (36); H NMR d 1.80, 4.04 (m, 4H), 7.02 (t, 1H,
J¼7 Hz), 7.45 (m, 1H), 7.69 (d, 1H, J¼9 Hz), 9.54 (d, 1H,
J¼7 Hz), 10.30 (s, 1H); 13C NMR d 27.1, 65.0, 106.4,
115.4, 117.7, 120.6, 128.9, 129.9, 146.1, 158.9, 181.1. Anal.
calcd for C12H12N2O3: C: 62.06; H: 5.21; N: 12.06. Found:
C: 61.95; H: 5.22; N: 12.10. 5-Formyl-2-(2-methyl[1,3]-
dioxolan-2-yl)imidazo[1,2-a]pyridine (17b) yield: 14%;
Rf¼0.46 (AcOEt/hexanes, 8:2); mp 114–1168C; IR (KBr)
1677, 1189, 1041 cm21; MS m/z 232 (Mþ, 11), 217 (87),
189 (93), 173 (100), 90 (30); 1H NMR d 1.83 (s, 3H), 4.06
(m, 4H), 7.38 (m, 1H), 7.52 (d, 1H, J¼7 Hz), 7.95 (d, 1H,
J¼9 Hz), 9.00 (s, 1H), 9.89 (s, 1H); 13C NMR d 25.6, 65.1,
106.4, 111.5, 122.6, 124.5, 125.9, 132.1, 145.5, 151.2,
184.5. Anal. calcd for C12H12N2O3: C: 62.06; H: 5.21; N:
12.06. Found: C: 62.04; H: 5.21; N: 12.05.
From 24: ethyl 3-(2-dichloromethylimidazo[1,2-a]pyridin-
3-yl)butenoate (25); (using toluene as solvent) to give in
order of elution starting material yield: 15% and 25 yield:
13%; Rf¼0.74 (CH2Cl2); mp 118–1208C; IR (KBr) 1709,
1634, 1223 cm21; MS m/z 316 (Mþþ4, 11), 314 (Mþþ2,
65), 312 (Mþ, 94), 279 (31), 277 (94), 241 (64), 229 (51),
1
213 (23), 203 (32), 169 (100), 78 (50), 51 (36); H NMR d
1.34 (t, 3H, J¼7 Hz), 2.55 (d, 3H, J¼1.5 Hz), 4.25 (q, 2H,
J¼7 Hz), 6.10 (q, 1H, J¼1.5 Hz), 6.89 (m, 2H), 7.29 (dd,
1H, J¼7, 9 Hz), 7.68 (d, 1H, J¼9 Hz), 7.95 (d, 1H,
J¼7 Hz); 13C NMR d 14.2, 18.6, 60.5, 64.2, 113.9, 118.7,
122.2, 124.4, 124.5, 126.3, 141.1, 141.7, 145.2, 165.5. Anal.
calcd for C14H14N2O2Cl2: C: 53.69; H: 4.51; N: 8.94.
Found: C: 53.58; H: 4.50; N: 8.92.
From 12b and N-methyl-N-methoxyacetamide: to give in
order of elution (eluate with AcOEt/hexanes, 6/4, v/v):
5-bromo-2-(2-methyl[1,3]dioxolan-2-yl)imidazo[1,2-a]-
pyridine (22) yield: 35%; Rf¼0.84 (AcOEt/hexanes,
6:4); mp 47–498C; MS m/z 284 (Mþþ2, 10), 282 (Mþ,
10), 269 (49), 267 (52), 241 (94), 239 (100), 225 (65), 223
65), 223 (74), 197 (22), 116 (52), 87 (52), 51 (32); 1H NMR
d 1.73 (s, 3H), 3.98 (m, 4H), 6.95 (m, 2H), 7.54 (d, 1H,
J¼9 Hz), 7.68 (s, 1H); 13C NMR d 25.6, 65.2, 106.2, 110.5,
114.3, 116.4, 125.4, 145.6, 147.8. Anal. calcd for
C11H11N2O2Br: C: 46.67; H: 3.92; N: 9.89. Found: C:
46.77; H: 3.93; N: 9.91. 2-(2-Methyl[1,3]dioxolan-2-
yl)imidazo[1,2-a]pyridine (15) yield: 24%; Rf¼0.43
(AcOEt/hexanes, 6:4).
4.1.6. General procedure for hydrolysis of acetals. To a
solution of the appropriate acetal (8.06 mmol) in 40 mL of
CH3CN/H2O (3/1, v/v) was added a catalytic quantity of
concentrated HCl (3 drops). The solution was heated. After
cooling, the solution was basified with Na2CO3 (1.00 g,
9.43 mmol) and extracted with CH2Cl2 (3£20 mL). The
extract was dried (Na2SO4) and evaporated to dryness to
yield acetals.
4.1.5. General procedure for the preparation of vinyl
compounds 18a,b and 25. A solution of the appropriate
carbonyl (3.42 mmol) and (carbethoxymethylene)triphenyl-
phosphorane (1.79 g, 5.14 mmol) in THF (40 mL) was
heated under reflux for 72 h. After cooling, water was added
(50 mL) and the solution was extracted with CH2Cl2
(3£20 mL). The extract was dried (Na2SO4) and the solvent
was removed under vacuo. The residue was chromato-
graphed using CH2Cl2 as eluent.
From 16a: 2,3-diformylimidazo[1,2-a]pyridine (11a);
(reaction time 6 h at 708C) yield: 97%; mp 179–1818C;
IR (KBr) 1762, 1698, 1645, 1500, 1320, 1255 cm21; MS m/
z 174 (Mþ, 13), 146 (49), 118 (27), 90 (14), 78 (100), 63
(16), 51 (31); 1H NMR d 7.29 (t, 1H, J¼7 Hz), 7.68 (m, 1H),
7.94 (d, 1H, J¼9 Hz), 9.62 (d, 1H, J¼7 Hz), 10.35 (s, 1H),
10.60 (s, 1H); 13C NMR d 117.6, 119.2, 123.4, 129.2, 130.8,
147.4, 148.5, 181.0, 189.2. Anal. calcd for C9H6N2O2: C:
62.07; H: 3.47; N: 16.09. Found: C: 61.92; H: 3.47; N:
16.12.
From 16a: (E) ethyl 3-(2-diethoxymethylimidazo[1,2-
a]pyridin-3-yl)propenoate (18a); yield: 85%; Rf¼0.42
(CH2Cl2); mp 63–658C; IR (KBr) 1701, 1623, 1519,
1497, 1342, 1273 cm21; MS m/z 318 (Mþ, 10), 273
(16), 245 (100), 217 (10), 199 (52), 171 (61), 143 (32),
116 (14), 78 (73), 51 (17); 1H NMR d 1.29 (m, 6H, 3CH3),
1.37 (t, 3H, J¼7 Hz), 3.31 (m, 4H), 4.25 (q, 2H, J¼7 Hz),
5.86 (s, 1H), 6.55 (d, 1H, J¼16 Hz), 7.00 (t, 1H, J¼7 Hz),
7.33 (m, 1H), 7.73 (d, 1H, J¼9 Hz), 8.18 (d, 1H, J¼16 Hz),
8.38 (d, 1H, J¼7 Hz); 13C NMR d 14.4, 15.2, 60.5,
61.9, 98.5, 114.1, 116.1, 118.3, 118.6, 124.8, 126.3,
128.9, 146.1, 147.4, 167.4. Anal. calcd for C17H22N2O4:
C: 64.13; H: 6.97; N: 8.80. Found: C: 64.09; H: 6.98; N:
8.79.
From 16b: 3-acetyl-2-formylimidazo[1,2-a]pyridine (11b);
(reaction time 3 h at 1008C) yield: 73%; mp 171–1738C; IR
(KBr) cm21; MS m/z 188 (Mþ, 25), 160 (53), 145 (40), 132
(57), 118 (57), 90 (34), 78 (100), 51 (36); 1H NMR d 2.80 (s,
3H), 7.19 (t, 1H, J¼7 Hz), 7.59 (m, 1H), 7.83 (d, 1H,
J¼9 Hz), 9.59 (d, 1H, J¼7 Hz), 10.57 (s, 1H); 13C NMR d
27.9, 117.0, 118.8, 123.2, 129.0, 130.4, 146.2, 149.2, 182.6,
197.0. Anal. calcd for C10H8N2O2: C: 63.83; H: 4.28; N:
14.89. Found: C: 63.78; H: 4.29; N: 14.88.
From 18a: (E) ethyl 3-(2-formylimidazo[1,2-a]pyridin-3-
yl)propenoate (19a); (reaction time 1 h at 1008C) yield:
94%; mp 130–1328C; IR (KBr) 1710, 1689, 1629, 1516,
1305, 1171 cm21; MS m/z 244 (Mþ, 6), 171 (100), 143 (18),
From 16b: (E) ethyl 3-(2-methyl[1,3]dioxolan-2-yl)imi-

J. M. Chezal et al. / Tetrahedron 59 (2003) 5869–5878
5875
116 (15), 89 (11), 78 (71), 64 (12), 51 (34); 1H NMR d 1.38
(t, 3H, J¼7 Hz), 4.32 (q, 2H, J¼7 Hz), 7.10 (t, 1H, J¼7 Hz),
7.16 (d, 1H, J¼16 Hz), 7.44 (dd, 1H, J¼7, 9 Hz), 7.77 (d,
1H, J¼9 Hz), 8.15 (d, 1H, J¼16 Hz), 8.42 (d, 1H, J¼7 Hz),
10.30 (s, 1H); 13C NMR d 14.3, 61.0, 115.7, 119.7, 121.3,
123.0, 125.1, 126.9, 127.8, 142.7, 146.4, 167.0, 188.6. Anal.
calcd for C13H12N2O3: C: 63.93; H: 4.95; N: 11.47. Found:
C: 63.98; H: 4.96; N: 11.48.
128.9, 129.3, 145.6, 148.4, 191.0, 197.8. Anal. calcd for
C11H10N2O2: C: 65.34; H: 4.98; N: 13.85. Found: C: 65.29;
H: 4.99; N: 13.85.
From 2313: 3-acetyl-2-dichloromethylimidazo[1,2-a]pyri-
dine (24); (reaction time 9 h at 2108C) yield: 33%;
Rf¼0.88 (CH2Cl2); mp 140–1428C; IR (KBr) 1638, 1500,
1381, 1351 cm21; MS m/z 246 (Mþþ4, 6), 244 (Mþþ2,
34), 242 (Mþ, 55), 231 (2), 229 (12), 227 (18), 207 (68), 209
(30), 201 (9), 199 (22), 197 (7), 193 (24), 172 (32), 165 (29),
129 (48), 78 (100), 51 (78); 1H NMR d 2.77 (s, 3H), 7.10 (t,
1H, J¼7 Hz), 7.36 (s, 1H), 7.52 (m, 1H), 7.80 (d, 1H,
J¼9 Hz), 9.61 (d, 1H, J¼7 Hz); 13C NMR d 30.4, 64.5,
116.1, 118.0, 119.0, 129.1, 130.0, 146.5, 149.7, 186.8. Anal.
calcd for C10H8N2OCl2: C: 49.41; H: 3.32; N: 11.52. Found:
C: 49.55; H: 3.33; N: 11.56.
From 18b: (E) ethyl 3-(2-acetylimidazo[1,2-a]pyridin-3-
yl)propenoate (19b); (reaction time 3 h at 1008C) yield:
45%; mp 132–1348C; IR (KBr) 1710, 1677, 1506, 1308,
1177 cm21; MS m/z 258 (Mþ, 9), 185 (100), 78 (40), 51
(12); 1H NMR d 1.35 (t, 3H, J¼7 Hz), 2.77 (s, 3H), 4.29 (q,
2H, J¼7 Hz), 6.86 (d, 1H, J¼16.5 Hz), 7.04 (t, 1H,
J¼7 Hz), 7.39 (m, 1H), 7.73 (d, 1H, J¼9 Hz), 8.33 (d,
1H, J¼16.5 Hz), 8.43 (d, 1H, J¼7 Hz); 13C NMR d 14.3,
28.4, 60.8, 115.2, 119.5, 119.9, 122.0, 125.3, 127.3, 129.2,
143.3, 145.6, 167.0, 197.1. Anal. calcd for C14H14N2O3: C:
65.11; H: 5.46; N: 10.85. Found: C: 64.89; H: 5.47; N:
10.81.
4.1.8. General procedures for preparation of oximes
10a–c. To a stirred mixture of the appropriate carbonyl
(0.94 mmol) in EtOH (10 mL) was added NH2OH, HCl
(70 mg, 0.98 mmol) in water (3 mL) and NaOAc (82 mg,
1 mmol) in water (3 mL). The solution was stirred at room
temperature for 20 mn and at 608C for 1 h. After cooling the
solvent was removed under reduced pressure and water was
added (5 mL). The mixture was cooled to 08C. The resulting
precipitate was filtered off, and washed with cold ethanol
(2 mL) to give the title compounds.
From 21: ethyl 3-(2-formylimidazo[1,2-a]pyridin-3-yl)-
butenoate (26); (reaction time 3 h at 708C) yield: 90%; mp
152–1548C; IR (KBr) 1711, 1688, 1213, 1176 cm21; MS
1
m/z 258 (Mþ, 4), 185 (100), 78 (51), 51 (16); H NMR d
1.27 (t, 3H, J¼7 Hz), 2.55 (s, 3H), 4.20 (q, 2H, J¼7 Hz),
6.07 (s, 1H), 6.89 (t, 1H, J¼7 Hz), 7.27 (m, 1H), 7.63 (d, 1H,
J¼9 Hz), 8.07 (d, 1H, J¼7 Hz), 10.11 (s, 1H); 13C NMR d
14.1, 19.1, 60.5, 114.7, 119.4, 124.5, 124.6, 126.9, 130.3,
139.3, 142.2, 145.2, 165.3, 187.1. Anal. calcd for
C14H14N2O3: C: 65.11; H: 5.46; N: 10.85. Found: C:
65.01; H: 5.48; N: 10.86.
From 19a: (E) ethyl 3-(2-hydroxyiminomethylimidazo[1,2-
a]pyridin-3-yl)propenoate (10a); yield: 62%; mp 227–
2298C; IR (KBr) 2753, 1694, 1626, 1489, 1389, 1368,
1274 cm21; MS m/z 259 (Mþ, 1), 241 (17), 196 (32), 186
(54), 170 (100), 141 (13), 78 (60), 51 (29); 1H NMR
(DMSO-d6) d 1.30 (t, 3H, J¼7 Hz), 4.23 (q, 2H, J¼7 Hz),
6.75 (d, 1H, J¼16.5 Hz), 7.15 (t, 1H, J¼7 Hz), 7.51 (m,
1H), 7.72 (d, 1H, J¼9 Hz), 8.33 (d, 1H, J¼16.5 Hz), 8.32 (s,
1H), 8.65 (d, 1H, J¼7 Hz); 13C NMR (DMSO-d6) d 14.3,
60.0, 114.3, 114.8, 117.4, 118.1, 127.2, 127.7, 129.6, 142.3,
144.5, 146.7, 166.9. Anal. calcd for C13H13N3O3: C: 60.23;
H: 5.05; N: 16.21. Found: C: 60.37; H: 5.07; N: 16.18.
From 20: 3-acetyl-2-formylimidazo[1,2-a]pyridine (11c);
(reaction time 3 h at 708C) yield: 90%; mp 125–1278C; IR
(KBr) 1711, 1640, 1495, 1203 cm21; MS m/z 188 (Mþ, 6),
160 (60), 145 (81), 117 (18), 90 (28), 78 (100), 63 (20), 51
1
(50); H NMR d 2.87 (s, 3H), 7.17 (t, 1H, J¼7 Hz), 7.56
(m, 1H), 7.84 (d, 1H, J¼9 Hz), 9.68 (d, 1H, J¼7 Hz), 10.40
(s, 1H); 13C NMR d 31.5, 117.0, 118.9, 122.5, 129.2,
129.8, 146.0, 146.6, 188.5, 190.3. Anal. calcd for C10H8N2O2:
C: 63.83; H: 4.28; N: 14.89. Found: C: 63.97; H: 4.30; N:
14.92.
From 19b: (E) ethyl 3-(2-(1-hydroxyiminoethyl)imi-
dazo[1,2-a]pyridin-3-yl)propenoate (10b); (reaction time
18 h at 608C) yield: 84%; mp 219–2218C; IR (KBr) 3150–
2830, 1708, 1629, 1285, 1189 cm21; MS m/z 273 (Mþ, 1),
200 (72), 184 (100), 183 (79), 78 (36); 1H NMR (DMSO-d6)
d 1.31 (t, 3H, J¼7 Hz), 2.33 (s, 3H), 4.24 (q, 2H, J¼7 Hz),
6.69 (d, 1H, J¼16.5 Hz), 7.19 (t, 1H, J¼7 Hz), 7.54 (m,
1H), 7.79 (d, 1H, J¼9 Hz), 8.38 (d, 1H, J¼16.5 Hz), 8.89 (d,
1H, J¼7 Hz), 11.79 (s, 1H); 13C NMR (DMSO-d6) d 12.6,
14.3, 59.9, 113.1, 114.9, 117.1, 117.4, 127.3, 127.5, 131.3,
146.0, 146.1, 151.4, 167.1. Anal. calcd for C14H15N3O3: C:
61.53; H: 5.53; N: 15.38. Found: C: 61.49; H: 5.52; N:
15.41.
4.1.7. Standard procedure for acetylation of 14 and 23.
To a solution of the appropriate compound (17.5 mmol) in
nitrobenzene (150 mL) was added acetyl chloride
(18.13 mL, 210 mmol). The mixture was heated at 1308C
for 1 h and at 2108C (external temperature) for 6 h. After
cooling, the solvent was removed to dryness and then water
was added (200 mL). The aqueous layer was basified with
Na2CO3 (20.0 g, 189 mmol), extracted with CH2Cl2
(3£80 mL) and dried (Na2SO4). The extract was concen-
trated under vacuo. The crude product was purified by
chromatography on alumina gel using CH2Cl2 as eluent.
From 26: ethyl 3-(2-hydroxyiminomethylimidazo[1,2-
a]pyridin-3-yl)butenoate (10c); yield: 94%; mp 172–
1748C; IR (KBr) 3200–2700, 1705, 1619, 1503, 1213,
1179 cm21; 1H NMR d 1.33 (t, 3H, J¼7 Hz), 2.58 (s, 3H),
4.25 (q, 2H, J¼7 Hz), 6.09 (s, 1H), 6.87 (t, 1H, J¼7 Hz),
7.27 (m, 1H), 7.71 (d, 1H, J¼9 Hz), 8.05 (d, 1H, J¼7 Hz),
8.36 (s, 1H); 13C NMR d 14.3, 19.1, 60.5, 113.5, 118.4,
123.6, 124.3, 126.1, 126.4, 136.2, 142.8, 142.9, 145.7,
From 14: 2,3-diacetylimidazo[1,2-a]pyridine (11d); yield:
48%; Rf¼0.75 (CH2Cl2); mp 102–1048C; IR (KBr) 1700,
1640 cm21; MS m/z 202 (Mþ, 85), 187 (100), 145 (57), 117
(19), 78 (33); 1H NMR d 2.67 (s, 3H), 2.79 (s, 3H), 7.07 (t,
1H, J¼7 Hz), 7.48 (m, 1H), 7.73 (d, 1H, J¼9 Hz), 9.53 (d,
1H, J¼7 Hz). 13C NMR d 29.4, 30.8, 116.1, 118.3, 121.9,

5876
J. M. Chezal et al. / Tetrahedron 59 (2003) 5869–5878
165.9. Anal. calcd for C14H15N3O3: C: 61.53; H: 5.53; N:
15.38. Found: C: 61.70; H: 5.53; N: 15.42.
132.9, 138.9, 140.8, 141.8, 150.6, 166.9. Anal. calcd for
C14H13N3O2: C: 65.87; H: 5.13; N: 16.46. Found: C: 65.95;
H: 5.13; N: 16.47.
4.1.9. General procedures for thermolysis of oximes
10a–c. A stirred mixture of the appropriate oxime
(9.46 mmol) in 1,2-dichlorobenzene (80 mL) was refluxed
for 21 h. After removal of solvent, the residue was purified
by column chromatography on alumina gel with CH2Cl2/
EtOH, (99/1, v/v) as eluent.
4.1.10. Procedure for hydrolysis of compounds 24 and
25. A solution of the appropriate dichloride derivative
(2.59 mmol) in EtOH (40 mL) was mixed with silver nitrate
(2.64 g, 15.5 mmol) in hot water (5 mL). The mixture was
refluxed for 3 h then cooled at room temperature. Con-
centrated hydrochloric acid was added until pH¼1 (pH test
paper). The silver salts were removed by filtration under
reduced pressure, and the filtrate was basified with Na2CO3
(0.50 g, 4.72 mmol). The mixture was extracted with
CH2Cl2 (3£20 mL) and the dried organic layers were
evaporated to dryness. The product was purified by column
chromatography on alumina gel using CH2Cl2/EtOH, (99/1,
v/v) as eluent.
From 10a to give in order of elution (E) ethyl 3-(2-
cyanoimidazo[1,2-a]pyridin-3-yl)propenoate (27a); yield:
15%; Rf¼0.77 (CH2Cl2/EtOH, 99:1); mp 141–1438C; IR
(KBr) 2234, 1703, 1667, 1630, 1489, 1382, 1278,
1237 cm21; MS m/z 241 (Mþ, 57), 213 (13), 196 (98),
169 (100), 141 (30), 78 (53), 51 (44); 1H NMR d 1.42 (t, 3H,
J¼7 Hz), 4.37 (q, 2H, J¼7 Hz), 6.75 (d, 1H, J¼16 Hz), 7.18
(t, 1H, J¼7 Hz), 7.52 (m, 1H), 7.77 (d, 1H, J¼9 Hz), 7.91
(d, 1H, J¼16 Hz), 8.34 (d, 1H, J¼7 Hz); 13C NMR d 14.3,
61.3, 114.8, 115.7, 118.6, 119.3, 120.9, 124.0, 124.9, 126.8,
128.4, 146.6, 166.4. Anal. calcd for C13H11N3O2: C: 64.72;
H: 4.60; N: 17.42. Found: C: 64.52;0 H: 4.59; N: 17.44.
3-Ethoxycarbonyldipyrido[1,2-a;30,4 -d]imidazole (7a);
yield: 50%; Rf¼0.29 (CH2Cl2/EtOH, 99:1); mp 172–
1748C; IR (KBr) 1703, 1282, 1243 cm21; MS m/z 241
(Mþ, 13), 183 (15), 169 (100), 141 (8), 78 (35), 51 (16); 1H
NMR d 1.50 (t, 3H, J¼7 Hz), 4.55 (q, 2H, J¼7 Hz), 7.04 (t,
1H, J¼7 Hz), 7.64 (m, 1H), 7.81 (d, 1H, J¼9 Hz), 8.58 (d,
1H, J¼7 Hz), 8.79 (s, 1H), 9.40 (s, 1H); 13C NMR d 14.6,
62.1, 108.8, 112.6, 119.2, 126.1, 132.3, 133.4, 138.8, 143.1,
143.4, 151.0, 165.8. Anal. calcd for C13H11N3O2: C: 64.72;
H: 4.60; N: 17.42. Found: C: 64.77; H: 4.60; N: 17.41.
From 24: to give in order of elution 3-acetyl-2-diethoxy-
methylimidazo[1,2-a]pyridine (20); yield: 23%; Rf¼0.70
(CH2Cl2/EtOH, 99:1);. 3-Acetyl-2-formylimidazo[1,2-
a]pyridine (11c); yield: 53%; Rf¼0.26 (CH2Cl2/EtOH,
99:1).
From 25: (reaction time 1 h, eluate with CH2Cl2 to give in
order of elution ethyl 3-(2-diethoxymethylimidazo[1,2-
a]pyridin-3-yl)butenoate (21); yield: 13% as an oil;
Rf¼0.48 (CH2Cl2); IR (CCl4) 1717, 1172 cm21; MS m/z
332 (Mþ, 5), 288 (15), 259 (100), 241 (17), 213 (31), 185
(35), 78 (28); 1H NMR d 1.23 (t, 6H, J¼7 Hz), 1.32 (t, 3H,
J¼7 Hz), 2.57 (d, 3H, J¼1.5 Hz), 3.69 (m, 4H), 4.23 (q, 2H,
J¼7 Hz), 5.72 (s, 1H), 6.08 (q, 1H, J¼1.5 Hz), 6.82 (t, 1H,
J¼7 Hz), 7.20 (m, 1H), 7.65 (d, 1H, J¼9 Hz), 8.04 (d, 1H,
J¼7 Hz); 13C NMR d 14.3, 15.2, 19.5, 60.2, 61.8, 97.7,
113.0, 118.5, 122.6, 123.9, 124.3, 125.0, 141.8, 144.0,
144.8, 166.2. Anal. calcd for C18H24N2O4: C: 65.04; H:
7.28; N: 8.43. Found: C: 65.25; H: 7.31; N: 8.42. Ethyl 3-(2-
formylimidazo[1,2-a]pyridin-3-yl)butenoate (26); yield:
50%; Rf¼0.29 (CH2Cl2).
From 10b: 2-ethoxycarbonyl-2-methyldipyrido[1,2-a;30,40-
d]imidazole (7b); yield: 54%; Rf¼0.38 (CH2Cl2/EtOH,
99:1); mp 139–1418C; IR (KBr) 1697, 1246 cm21; MS m/z
255 (Mþ, 12), 183 (100), 155 (12), 78 (42). 1H NMR d 1.42
(t, 3H, J¼7 Hz), 3.02 (s, 3H), 4.47 (q, 2H, J¼7 Hz), 6.96 (t,
1H, J¼7 Hz), 7.53 (m, 1H), 7.76 (d, 1H, J¼9 Hz), 8.47 (d,
1H, J¼7 Hz), 8.57 (s, 1H); 13C NMR d 14.4, 20.8, 62.0,
107.1, 112.3, 119.1, 126.0, 131.7, 132.3, 138.1, 141.9,
150.0, 152.9, 165.9. Anal. calcd for C14H13N3O2: C: 65.87;
H: 5.13; N: 16.46. Found: C: 66.02; H: 5.11; N: 16.44.
4.1.11. General procedure for the preparation of
pyridazines 9a–d. To a solution of the appropriate
carbonyl derivative (4.02 mmol) in EtOH (30 mL) was
added hydrazine monohydrate (0.25 g, 5.00 mmol). The
solution was stirred at room temperature for 2 h and
concentrated under vacuo. The yellow precipated was
filtered and washed with ether (5 mL).
From 10c to give in order of elution ethyl 3-(2-cyanoimi-
dazo[1,2-a]pyridin-3-yl)butenoate (27b); yield: 2%;
Rf¼0.68 (CH2Cl2/EtOH, 99:1); mp 171–1738C; IR (KBr)
2238, 1712, 1219, 1181 cm21; MS m/z 255 (Mþ, 71), 226
(15), 209 (87), 181 (100), 168 (24), 143 (36), 78 (92); H
From 11a: pyrido[10,20;1,2]imidazo[4,5-d]pyridazine (9a);
yield: 89%; mp 253–2558C; IR (KBr) 1641, 1583, 1564,
1481, 1355, 1259, 1149 cm21; MS m/z 170 (Mþ, 100), 142
(12), 115 (20), 78 (97), 64 (31), 51 (51); 1H NMR (DMSO-
d6) d 7.34 (t, 1H, J¼7 Hz), 7.88 (m, 1H), 7.95 (d, 1H,
J¼9 Hz), 9.34 (d, 1H, J¼7 Hz), 9.81 (s, 1H), 10.23 (s, 1H);
13C NMR (DMSO-d6) d 113.2, 117.7, 126.9, 128.6, 133.9,
138.3, 140.4, 145.2, 149.8. Anal. calcd for C9H6N4: C:
63.52; H: 3.55; N: 32.92. Found: C: 63.48; H: 3.54; N:
32.86.
1
NMR d 1.28 (t, 3H, J¼7 Hz), 2.62 (s, 3H), 4.20 (q, 2H,
J¼7 Hz), 6.19 (s, 1H), 6.94 (t, 1H, J¼7 Hz), 7.31 (m, 1H),
7.61 (d, 1H, J¼9 Hz), 8.11 (d, 1H, J¼7 Hz); 13C NMR d
14.2, 18.5, 60.7, 114.5, 115.0, 119.1, 123.2, 124.7, 127.5,
140.0, 145.2, 165.4, one carbon not observed. Anal. calcd
for C14H13N3O2: C: 65.87; H: 5.13; N: 16.46. Found: C:
65.78; H: 5.15; 0 N: 16.52. 3-Ethoxycarbonyl-4-methyldi-
pyrido[1,2-a;30,4 -d]imidazole (7c); yield: 16%; Rf¼0.33
(CH2Cl2/EtOH, 99:1); mp 92–948C; IR (KBr) 1704, 1254,
122, 1081 cm21; MS m/z 255 (Mþ, 20), 183 (100), 155 (24),
78 (37); 1H NMR d 1.42 (t, 3H, J¼7 Hz), 3.07 (s, 3H), 4.44
(q, 2H, J¼7 Hz), 6.91 (t, 1H, J¼7 Hz), 7.49 (m, 1H), 7.71
(d, 1H, J¼9 Hz), 8.80 (d, 1H, J¼7 Hz), 9.14 (s, 1H); 13C
NMR d 14.4, 15.1, 61.8, 112.2, 119.2, 121.9, 128.1, 131.1,
From 11b: 1-methylpyrido[10,20;1,2]imidazo[4,5-d]pyrida-
zine (9b); yield: 30%; mp 186–1888C; IR (KBr) 1637,
1577, 1355, 1267 cm21; MS m/z 184 (Mþ, 100), 155 (46),
1
78 (72), 63 (18), 51 (43); H NMR d 3.13 (s, 3H), 7.15 (t,

J. M. Chezal et al. / Tetrahedron 59 (2003) 5869–5878
5877
1H, J¼7 Hz), 7.69 (m, 1H), 7.91 (d, 1H, J¼9 Hz), 8.64 (d,
1H, J¼7 Hz), 9.73 (s, 1H); 13C NMR d 18.4, 113.5, 119.1,
125.9, 126.3, 132.5, 135.6, 140.7, 149.7, 155.2. Anal. calcd
for C10H8N4: C: 65.21; H: 4.38; N: 30.42. Found: C: 65.12;
H: 4.40; N: 30.31.
J¼7 Hz), 7.09 (t, 1H, J¼7 Hz), 7.65 (m, 1H), 7.86 (d, 1H,
J¼9 Hz), 8.57 (s, 1H), 8.83 (d, 1H, J¼7 Hz); 13C NMR d
14.5, 23.3, 62.0, 112.7, 115.7, 118.6, 127.6, 128.1, 131.6,
142.7, 144.9, 149.6, 151.2, 165.8. Anal. calcd for
C14H13N3O2: C: 65.87; H: 5.13; N: 12.53. Found: C:
66.01; H: 5.14; N: 12.54.
From 11c: 4-methylpyrido[10,20;1,2]imidazo[4,5-d]pyrida-
zine (9c); yield: 63%; mp 264–2668C; IR (KBr) 1635, 1475,
1309 cm21; MS m/z 184 (Mþ,100), 155 (52), 78 (90), 51
(51); 1H NMR d 3.25 (s, 3H), 7.15 (t, 1H, J¼7 Hz), 7.69 (m,
1H), 7.89 (d, 1H, J¼9 Hz), 8.77 (d, 1H, J¼7 Hz), 9.69 (s,
1H); 13C NMR d 20.7, 113.6, 119.0, 126.3, 127.8, 132.1,
140.9, 145.2, 146.6, 150.2. Anal. calcd for C10H8N4: C:
65.21; H: 4.38; N: 30.42. Found: C: 65.19; H: 4.37; N:
30.51.
From0 11d: 3-ethoxycarbonyl-1,4-dimethyldipyrido[1,2-
a;30,4 -d]imidazole (7d); reaction time 8 days, eluate with
CH2Cl2; yield: 61%; Rf¼0.19 (CH2Cl2); mp 143–1458C; IR
(KBr) 1700, 1230 cm21; MS m/z 269 (Mþ, 24), 197 (100),
169 (17), 78 (23), 51 (10); 1H NMR d 1.41 (t, 3H, J¼7 Hz),
2.93 (s, 3H), 2.97 (s, 3H), 4.44 (q, 2H, J¼7 Hz), 6.85 (t, 1H,
J¼7 Hz), 7.44 (m, 1H), 7.70 (d, 1H, J¼9 Hz), 8.73 (d, 1H,
J¼7 Hz); 13C NMR d 14.3, 14.8, 20.2, 61.7, 112.0, 118.8,
119.0, 127.8, 130.5, 131.8, 138.8, 140.5, 149.5, 149.8,
167.2. Anal. calcd for C15H15N3O2: C: 66.90; H: 5.61; N:
15.60. Found: C: 66.83; H: 5.62; N: 15.59.
From 11d: 1,4-dimethylpyrido[10,20;1,2]imidazo[4,5-
d]pyridazine (9d); reaction time 1 h 30 min; yield: 75%;
mp 211–2138C; IR (KBr) 1640, 770 cm21; MS m/z 198
1
(Mþ, 100), 169 (45), 84 (22), 78 (27); H NMR d 3.06 (s,
3H), 3.19 (s, 3H), 7.14 (t, 1H, J¼7 Hz), 7.67 (m, 1H), 7.91
(d, 1H, J¼9 Hz), 8.76 (d, 1H, J¼7 Hz); 13C NMR d 18.1,
20.6, 113.6, 119.2, 125.5, 127.7, 131.7, 140.7, 145.3, 149.7,
153.9. Anal. calcd for C11H10N4: C: 66.65; H: 5.08; N:
28.26. Found: C: 66.52; H: 5.10; N: 28.21.
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From 11a: (reaction time 20 h (the solution became red after
20 mn), eluate with CH2Cl2/EtOH, (99/1, v/v)) to give in
order of elution: 3-ethoxycarbonyldipyrido[1,2-a;40,30-
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99:1); mp 200–2028C; IR (KBr) 1721, 1298, 1231 cm21
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MS m/z 241 (Mþ, 9), 169 (100), 142 (10), 78 (21); 1H NMR
d 1.55 (t, 3H, J¼7 Hz), 4.61 (q, 2H, J¼7 Hz), 7.17 (t, 1H,
J¼7 Hz), 7.75 (m, 1H), 7.92 (d, 1H, J¼9 Hz), 8.76 (s, 1H),
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5878
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