Copper(i)-mediated preparation of new pyrano[3′,4′:4,5] imidazo[1,2-a]pyridin-1-one compounds under mild palladium-free conditions

Article abstract of DOI:10.1039/c0ob00622j

A general and efficient Cu(i)-mediated cross-coupling and heterocyclization reaction of 3-iodoimidazo[1,2-a]pyridine-2-carboxylic acid, and terminal alkynes was developed under very mild conditions. This method allows the introduction in one pot of a thir

Full text of DOI:10.1039/c0ob00622j

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PAPER
Copper(I)-mediated preparation of new pyrano[3¢,4¢:4,5]imidazo[1,2-a]-
pyridin-1-one compounds under mild palladium-free conditions†
Zineb Bahlaouan,a Mohamed Abarbri,*a Alain Ducheˆne,a Je´roˆme Thibonnet,a Nicolas Henry,b
Ce´cile Enguehard-Gueiffierb and Alain Gueiffierb
Received 24th August 2010, Accepted 3rd November 2010
DOI: 10.1039/c0ob00622j
A general and efficient Cu(I)-mediated cross-coupling and heterocyclization reaction of
3-iodoimidazo[1,2-a]pyridine-2-carboxylic acid, and terminal alkynes was developed under very mild
conditions. This method allows the introduction in one pot of a third ring fused in positions 2 and 3 of
the imidazo[1,2-a]pyridine core with reasonable yields and total regioselectivity. This procedure does
not require the use of any expensive supplementary additives, and is palladium-free.
membered lactones have been obtained in some cases, resulting
1. Introduction
from the 6-endo-dig mode. However such synthesis suffered from
The significant and potential biological activities of the
lack of selectivity. In all cases described in the literature, the
imidazo[1,2-a]pyridine series have been widely studied in various
pharmacological areas of medicinal chemistry: e.g. (i) in virology,
synthesis of oxygenated heterocycles such as butenolides, pyran-2-
ones, phthalides, etc., starting from 2-halobenzoic acid derivatives
in the treatment of hepatitis C virus infection,1 herpes virus
and alkynes using copper as catalyst has been performed in two
infection2 and HIV infection;3 (ii) in cancerology, as antagonists
separate steps: (1) coupling of 2-halobenzoic acid derivatives
of the gonadotropin releasing hormone receptor,4 PI3 kinase
p110a inhibitors,5 histone deacetylase inhibitors,6 receptor tyro-
sine kinase inhibitors7 and ligands for peripheral benzodiazepine
receptors;8 and (iii) in neurology, as C3a receptor antagonists,9
partial D4 agonist10 and derivatives for imaging amyloid deposits
in the brain to allow diagnosis of Alzheimer’s disease.11
In the course of our studies evaluating the chemical and
pharmacological properties of the imidazo[1,2-a]pyridine core,
we have extensively investigated the metal-catalyzed methods of
functionalization which allow the rapid preparation of a number
of structural variants.12 In particular we studied the Sonogashira
cross-coupling reaction leading to alkyne derivatives.13 Transition
metal-catalyzed cyclization of alkynes possessing a nucleophile in
close proximity to the triple bond is one of the most important
processes in organic synthesis, which can construct various
heterocycles in an efficient and atom economic way.14 Over the
past ten years, a wide range of transition metal-based catalysts (Ag,
Hg, Rh, Pd, Zn, Au . . . ) have been reported as effective catalysts to
promote intramolecular addition of carboxylic acid to alkynes.15,16
In addition to the formation of five membered lactones, six-
with terminal alkynes, typically by the Sonogashira reaction,17
and (2) cyclization mediated by metal complexes,18 bases,19 and
halogen.20 The past few years have seen a resurgence of interest
in copper(I)-catalyzed cross-coupling reactions.21 Many synthesis
protocols basedoncopper(I) catalysts for the formation of carbon–
carbon and carbon–heteroatom bonds have been reported and
they have been the subject of increasing attention.22,23 In addition
to being simple and mild, the newer copper-based methods have
been shown to accommodate substrates that are difficult to
couple by palladium reactions.24 Copper catalysts still have the
advantage of being of low cost for use in large-scale industrial
applications.
In connection with our project to develop synthesis of new
heterocycles via copper(I) mediated coupling heterocyclization
reaction, we decided to develop a method to introduce a third
ring fused in positions 2 and 3 of the imidazo[1,2-a]pyridine core,
using copper(I) catalyzed-cross-coupling and a heterocyclization
reaction sequence. This kind of tricyclic heterocycle has been
little studied in the literature and could provide interesting
pharmacological activities particularly as antitumoral agents.25
To the best of our knowledge, one pot non-palladium cat-
alyzed synthesis of pyrano[3¢,4¢:4,5]imidazo[1,2-a]pyridin-1-one
from alkynes and 3-iodoimidazo[1,2-a]pyridin-2-carboxylic acid
has never previously been reported. Only one synthesis of an
unsubstituted compound of this type has been reported to date,26
and synthesis of this tricyclic compound from 3-iodoimidazo[1,2-
a]pyridine-2-carboxylate required a three step sequence: Sono-
gashira coupling reaction, saponification of the ester group and
copper catalyzed cyclization.
aFaculte´ des Sciences, Laboratoire de PhysicoChimie des Mate´riaux et
Biomole´cules EA 4244, Universite´ Franc¸ois Rabelais, Parc de Grand-
mont, 37200 Tours, France. E-mail: mohamed.abarbri@univ-tours.fr;
Fax: +33(0) 2 47.36.70.73
bFaculte´ de Pharmacie, Laboratoire de PhysicoChimie des Mate´riaux et
Biomole´cules EA 4244, Universite´ Franc¸ois Rabelais, 31 Avenue Monge,
37200 Tours, France
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c0ob00622j
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Table 1 Optimization studies for the Cu-catalyzed coupling–
heterocyclization sequence
site. The same report is observed in the case of other nitrogenized
cycles undergoing the same type of reaction. This work is under
development in our laboratory.
Several solvents were tested to evaluate their effects. As shown
in Table 1, the use of DMF or DMSO as the solvent led to the
formation of reasonable yields of heterocyclization product 2a
(entries 4 and 13, Table 1) whereas poor yields of the desired
adducts were obtained in toluene, THF and CH3CN (<10%)
(entries 14–16, Table 1). After screening of different bases, the
use of K2CO3, an inexpensive base, provided the best results
(entries 4 and 13, Table 1), while lower yields were observed
with NaOH, Cs2CO3 and K3PO4 (entries 10–12, Table 1). In
addition, no coupling–heterocyclization reaction was observed in
the absence of base (entry 1, Table 1). Temperature was also a
crucial parameter. The coupling reactions did not proceed at room
temperature (the starting material was completely recovered) but
required heating at 100 ◦C (entries 2 and 4, Table 1). After a careful
analysis of our results, the optimum conditions used 1 equivalent
of copper iodide, 1.5 equivalents of alkyne, and 2.0 equivalents of
potassium carbonate in DMF at 100 ◦C for 12 h.
Entry
CuX (100%)
Base
Solvent
Yield (%)a
1
CuI
CuI
CuI (20%)
none
K2CO3
DMF
0
0
9
2b
3c
4
¢¢
¢¢
¢¢
CuI
CuCl
CuBr
CuCN
Cu2O
CuBr2
CuI
¢¢
K2CO3
DMF
40
33
35
29
30
8
10
12
9
5
6
7
8
¢¢
¢¢
¢¢
¢¢
¢¢
¢¢
¢¢
¢¢
9
¢¢
¢¢
10
11
12
13
14
15
16
NaOH
Cs2CO3
K3PO4
K2CO3
¢¢
¢¢
¢¢
¢¢
¢¢
¢¢
DMSO
Toluene
THF
MeCN
39
4
6
¢¢
¢¢
¢¢
¢¢
¢¢
7
The reaction scope and limitations were then examined under
the optimized conditions, and the results are summarized in
Table 2.
a Isolated yields. b Reaction performed at rt. c 20% CuI was used in this
case.
3. Scope of the method: preparation of 2
We recently reported the first one pot general and efficient
regioselective palladium-free synthesis of 5-ylidene-5H-furan-2-
ones and isocoumarins via the tandem cross-coupling heterocy-
clization reaction of terminal alkynes and (Z)-3-iodopropenoic
acid derivatives under copper catalysis.27 On the basis of the above,
we now report the first efficient and regioselective one pot synthe-
sis of pyrano[3¢,4¢:4,5]imidazo[1,2-a]pyridin-1-one via the cross-
coupling-heterocyclization reaction sequence of terminal alkynes
and 3-iodoimidazo[1,2-a]pyridin-2-carboxylic acid mediated by a
simple salt.
To investigate the scope of the copper-mediated tandem coupling-
heterocyclization reaction, a variety of available terminal alkynes
were used to react with 1a. This reaction showed very high
regioselectivity. In each case, only the six-membered ring from 6-
endo-dig cyclization was obtained, and no five-membered exocyclic
products were detected by TLC monitoring. The six membered
rings obtained could be differentiated from the corresponding
five-membered rings on the basis of several spectroscopic find-
ings, especially from IR spectra. Using a previously reported28
comparison between the five- and six-membered lactone rings of
butenolides [umax (C O) 1770–1800 cm-1] and pyranones [umax
(C O) 1710–1740 cm-1], we found that our results were in
full agreement with the spectral data reported for pyranones.
The yields of isolated products 2 after purifying by column
chromatography are presented in Table 2.
2. Results and discussion
To optimize the reaction conditions of this coupling–
heterocyclization reaction, we examined a range of copper(I) salts,
solvents and bases for the tandem C–C coupling–heterocyclization
reaction using the coupling of 1a with phenylacetylene as a test
reaction (Table 1).
The reaction described is extremely versatile and pro-
vides
a convenient method for the synthesis of various
As shown in Table 1, all the copper(I) salts (CuBr, CuCl, CuBr2,
Cu2O, CuCN . . . ) tested provided moderate to poor yields of
the tricyclic compound 2a. Upon optimization, we found that
CuI was the most effective catalyst for the coupling of 1a with
phenylacetylene (entries 4 and 13, Table 1). It should be noted that
copper(II) salts were ineffective as catalysts for this reaction, and
very low conversions were observed (<10%) (entry 9, Table 1).
The effects of the amount of copper were investigated in the
optimization process, and further experiments showed that the
reaction was completed within 12 h at 100 ◦C with 40% yield using
a stoichiometric amount of CuI (entry 4, Table 1). Lowering the
amount of catalyst to 20 mol% of CuI provided very unsatisfactory
yields of the desired product (<10%) (entry 3, Table 1). This result
could be explained by the presence of nitrogen atoms in the starting
material, such as the imidazo pyridine core 1a, which is able to
complex the copper(I) catalyst and prevent it reaching the reaction
pyrano[3¢,4¢:4,5]imidazo[1,2-a]pyridin-1-ones with total regiose-
lectivity, demonstrating that our strategy avoided the presence of
any 1,3-diH-furano[3¢,4¢:4,5] imidazo[1,2-a]pyridin-1-one deriva-
tives.
Using this copper-mediated tandem coupling–cyclization pro-
cess, a variety of functional groups (including alkyl, alkenyl,
alkoxy, amino, phenyl, etc.) present in the acetylenic compounds
employed so far were tolerated during the course of the reaction
(Table 2). As shown in Table 2, phenylacetylene substituted
with the methyl group on the aromatic ring give the coupling–
heterocyclization product with reasonable yield (entry 2, Table 2).
No significant electronic effects were observed for the electron-
donating substituent methyl group at the meta-position of the
terminal aromatic ring. Unfortunately, when the aromatic ring was
substituted by an electron-withdrawing group such as NO2, only
trace amounts of the coupling–heterocyclization product could be
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Table 2 Copper-mediated coupling–heterocyclization of 3-iodoimidazo-
[1,2-a]pyridin-2-carboxylic acid with terminal alkynes
Table 2 (Contd.)
Entry
10
R
Product
No. Yield (%)
Entry
1
R
Product
No. Yield (%)
2j
60
65
40
Ph
2a
2b
2c
40
2
3
m-CH3C6H4
41
11
12
13
2k
m-NO2C6H4
<2%
BnN(CH3)CH2
2l
4
5
6
n-CH3(CH2)8
n-CH3(CH2)5
Cyclopropyl
2d
2e
2f
66
50
62
CH3OCH2
2m 55
obtained (entry 3, Table 2). This result indicates that the electron-
withdrawing groups on the aromatic ring must have an important
role in the reaction, and the protocol did not tolerate electron-
poor aryl acetylene, presumably due to the reduced electron
density of the triple bond. Attempts to improve the yield by
increasing the amount of copper catalyst (2.0 equiv) and alkyne
(2.0 equiv) met with no success. We were pleased to find that
the alkyne bearing a propargylic or a homopropargylic acetal
reacted well with 1a, affording reasonable isolated yields of the
corresponding tricyclic compounds 2g–h as sole products (entries
7–8, Table 2). Gratifyingly, the presence of a long-chain alkyl
group in the terminal alkyne did not affect the regioselectivity of
the coupling–cyclization process, and six-membered heterocycles
2d–f were isolated exclusively with moderate yields (entries 4–
6, Table 2), demonstrating again that the successful coupling–
heterocyclization protocol is not specific to aryl acetylenes. The
reason for the regioselectivity observed associated with the use
of CuI (100 mol%) as catalyst system is not clear at this stage.
Cu(I) salts are known to catalyze the intramolecular cyclization
of 2-(alkynyl)benzoic acid or its derivative to the six-membered
lactone ring.21b,d,e,24
7
8
CH(OEt)2
2g
2h
43
45
CH2CH(OEt)2
9
CH2CH(Ph)OTHP
2i
60
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In another case, the coupling–heterocyclization reaction
of 1a with (E)-6-(but-1-en-3-ynyl)-1,5,5-trimethylcyclohex-1-ene
(a)29 (entry 10, Table 1) or (E)-2-(but-1-en-3-ynyl)-1,3,3-
trimethylcyclohex-1-ene (b)29 (entry 11, Table 1) under the same
conditions as described above provided reasonable yields of the
desired dienylpyranones 2j–k. A NOESY NMR experiment on
2j–k confirmed the retention of the double bond configuration of
the starting materials. The structures of all products 2a–m were
5.2 General procedure for synthesis of compounds 2a–m
A dry Schlenk tube equipped with a Teflon-coated magnetic stirrer
was charged with K2CO3 (478 mg, 3.46 mmol, 2 equiv) and 3-
iodoimidazo[1,2-a]pyridine-2-carboxylic acid (500 mg, 1.73 mmol,
1 equiv). The mixture was evacuated and backfilled with argon.
Anhydrous DMF (10 mL) was added and the suspension was
stirred for 15 min. Then, the mixture was degassed at -80 ◦C for
10 min and backfilled with argon. After reaching room temper-
ature, the alkyne (2.59 mmol, 1.5 equiv) was added and finally
CuI (330 mg, 1.73 mmol, 1 equiv). The Schlenk tube was sealed,
placed in a preheated oil bath at 100 ◦C and was stirred overnight.
The reaction mixture was allowed to reach room temperature,
was taken again with 50 mL of ethyl acetate and filtered over
a Celite pad. The filtrate was partitioned between ethyl acetate
(40 mL ¥ 2) and saturated aqueous NH4Cl (30 mL). The organic
portions were dried over Na2SO4, filtered and concentrated by
rotary evaporation. The material thus obtained was purified by
flash chromatography on silica gel or by crystallization to give the
desired pyrano[3¢,4¢:4,5]imidazo[1,2-a]pyridin-1-one.
1
confirmed by satisfactory spectroscopic data (MS, IR, H and
13C NMR). Extension of this tandem coupling–heterocyclization
reaction using a copper-catalyst to other classes of functionalized
imidazo[1,2-a]pyridine derivatives is currently being studied in our
laboratory.
4. Conclusion
The aim of this research was to develop an efficient and cheap
method for the synthesis of a new imidazo[1,2-a]pyridine library
under mild and more environmentally friendly conditions. These
issues were addressed by replacing the expensive palladium
catalysts with less expensive 100 mol% CuI.
The numbering system of pyrano[3¢,4¢:4,5]imidazo[1,2-
a]pyridinone shown below is used in the assignment of the
chemical shifts.
In summary, we have developed a practical and general copper
mediated system [Cu(I) salts in DMF] for the efficient tan-
dem coupling–heterocyclization reaction of 3-iodoimidazo[1,2-
a]pyridin-2-carboxylic acid with terminal alkynes, leading to
straightforward and easy access to an important range of
pyrano[3¢,4¢:4,5]imidazo[1,2-a]pyridin-1-ones. The overall yields
are reasonably good. The present methodology does not involve
the use of an expensive, air-sensitive palladium(0) catalyst or any
additive ligand. The process holds promise as a useful tool for the
construction of complex heterocycles containing the imidazo[1,2-
a]pyridine unit. Further applications of this catalytic system to
generate new heterocycle-based chemical libraries of potential
pharmacological interest are under investigation in our laboratory.
3-Phenylpyrano[3¢,4¢:4,5]imidazo[1,2-a]pyridinone (2a)
Yellow solid, 40% yield. Mp: 148–150 ◦C; umax (KBr)/cm-1 3108,
1716, 1637, 1607 and 1120; dH (200 MHz; DMSO) 7.22 (1 H, t, J
6.6, H3), 7.51–7.58 (4 H, m, 3HPh + H2), 7.75 (1 H, d, J 9.4, H1),
7.92 (2 H, d, J 7.4, HPh), 8.26 (1 H, s, H5) and 8.87 (1 H, d, J 6.6,
H4); dC (50 MHz; DMSO) 92, 114, 118.5, 124.8 (2C), 126.8, 127.2,
129.2 (2C), 129.6, 129.9, 131.8, 133.1, 147.0, 153.0 and 157.8; m/z
(EI) 262 (M+, 100), 234 (23), 205 (62), 157 (10), 129 (14), 78 (42)
and 51 (25); HRMS for C16H10N2O2 (M+): calcd. 262.0742, found
262.0750
5. Experimental section
5.1 Materials
3-(3-Methylphenyl)pyrano[3¢,4¢:4,5]imidazo[1,2-a]pyridin-1-one
(2b)
Et2O was dried and freshly distilled from sodium/benzophenone.
CH2Cl2 and DMF were dried by distillation over CaH2 and stored
under argon. Petroleum ether (PE) used was the fraction boiling
in the range 40–60 ◦C. Flash chromatography was carried out with
Merck silica gel (silica gel, 230–400 mesh). 1H NMR spectra were
recorded at 200 or 300 MHz using CDCl3 as solvent. The findings,
reported using the residual solvent proton resonance of CDCl3
(dH = 7.25 ppm) as internal reference, were as follows (in order):
chemical shift (d in ppm in relation to Me4Si), multiplicity (s, d,
t, q, m, b for singlet, doublet, triplet, quartet, multiplet, broad)
and coupling constants (J in Hz). 13C NMR were recorded at
50.3 or 75 MHz using the CDCl3 solvent peak at dC = 77.0 ppm
as reference. Mass spectra were obtained in the GC-MS (70 eV)
mode. IR spectra were recorded on a Perkin–Elmer 781 FT-IR
spectrophotometer and are reported in cm-1. Melting points were
uncorrected.
Yellow solid, 41% yield. Mp: 180–182 ◦C; umax (KBr)/cm-1 3095,
1720, 1633, 1605 and 1125; dH (200 MHz; CDCl3) 2.45 (3 H, s,
CH3-Ph), 7.12 (1 H, t, J 6.0, H3), 7.24–7.32 (2HPh, m), 7.35–7.45
(2H, m, HPh + H2), 7.75 (1H, d, J 9.2, H1), 7.79 (1H, s, H5), 7.81
(1H, d, J 7.0, HPh) and 8.27 (1H, d, J 6.0, H4); dC (50 MHz; CDCl3)
26.6, 97.0, 118.7, 123.5, 127.2, 130.4, 131.7, 132.6, 133.8, 134.1,
135.1, 135.4, 136.9, 142.1, 143.3, 158.7 and 163; MS (EI): 276 (M,
100), 248 (32), 205 (14), 91 (14), 78 (29); MS (EI) 276 (M, 100), 248
(32), 205 (14), 91 (14) and 78 (29); HRMS for C17H12N2O2 (M+):
calcd. 276.0899, found 276.0903.
3-Nonylpyrano[3¢,4¢:4,5]imidazo[1,2-a]pyridin-1-one (2d)
Yellow solid, 66% yield. Mp: 136–138 ◦C; umax (KBr)/cm-1
3106, 2917, 1714, 1627, 1469, 1146 and 1035; dH (200 MHz;
CDCl3) 0.82 (3H, t, J 7, CH3CH2), 1.20–1.24 (12H, m,
CH2CH2CH2CH2CH2CH2CH2CH2CH3), 1.65 (2H, qt, J 7 0,
3-Iodoimidazo[1,2-a]pyridine-2-carboxylic acid 1a was pre-
pared from ethyl-3-iodoimidazo[1,2-a]pyridine-2-carboxylate ac-
cording to a known procedure.30
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CH2CH2CH3), 2.61 (2H, t, J 7.2, CH2CH2), 7.10 (1H, t, J 6.6,
H3), 7.33 (1H, s, H5), 7.48 (1H, dd, J 9.2, 6.6, H2), 7.69 (1H, d,
J 9.2, H1), 8.78 (1H, d, J 6.6, H4); dC (50 MHz; CDCl3) 14.5,
23.0, 27.7, 29.4, 29.7 (2C), 29.8, 32.3, 34.5, 92.1, 114.1, 120.0,
125.0, 127.7, 128.2, 132.6, 147.5, 159.5 and 160.7; MS (EI) 312
(M, 100), 213 (39), 199 (51), 171 (33), 130 (27), 78 (40); HRMS for
C19H24N2O2 (M+): calcd. 312.1838, found 312.1845.
229 (16), 228 (23), 200 (17), 103 (100), 78 (45), 75 (89) and 47 (64);
HRMS for C16H18N2O4 (M+): calcd. 302.1267, found 302.1260.
3-[2-(Phenyltetrahydro-2H-pyran-2-yloxy)ethyl]pyrano-
[3¢,4¢:4,5]imidazo[1,2-a]pyridin-1-one (2i)
Yellow solid: 60% yield. Mp: 201–203 ◦C; umax (KBr)/cm-1 3070,
2923, 1732, 1625, 1348 and 1124; dH (200 MHz; CDCl3) 1.41–1.68
(6H, m, 3 ¥ CH2CH2), 2.95 (1H, dd, J 14.5 and J 6.0, CH2CHO),
3.19 (1H, dd, J 14.5 and J 8.5, CH2CHO), 3.40–3.45 (1H, m,
OCH2CH2), 3.68–3.63 (1H, m, OCH2CH2), 4.45 (1H, t, J 6.0,
CH2CHO), 5.27 (1H, dd, J 8.6 and J 5.0, OCHCH2), 6.76 (1H, s,
H5), 6.97 (1H, t, J 6.8, H3), 7.28–7.37 (6H, m, 5HPh + H2), 7. 72
(1H, d, J 9.2, H1) and 8.07 (1H, d, J 6.8, H4); dC (50 MHz; CDCl3)
20.0, 25.7, 31.0, 43.2, 62.8, 74.6, 94.1, 96.0, 114.2, 120.1, 124.8,
126.7, 127.2 (2C), 128.4, 128.5, 129.1 (2C), 132.4, 141.1, 147.4,
156.8 and 159.3; MS (EI) 390 (M, 1), 200 (100), 182 (6), 154 (5),
129 (6), 85 (29), 78 (20), 57 (9) and 41 (9); HRMS for C23H22N2O4
(M+): calcd. 390.1580, found 390.1588.
3-Hexylpyrano[3¢,4¢:4,5]imidazo[1,2-a]pyridin-1-one (2e)
Yellow solid, 50% yield. Mp: 141–143 ◦C; umax (KBr)/cm-1 3109,
2954, 1722, 1624, 1269 and 1140; dH (200 MHz; CDCl3) 0.90 (3H,
t, J 7.0, CH3CH2), 1.30–1.36 (6H, m, CH2CH2CH2CH2CH3),
1.73 (2H, qt, J 7.0, CH2CH2CH3), 2.66 (2H, t, J 7.6, CH2CH2),
6.61 (1H, s, H5), 6.96 (1H, t, J 6.8, H3), 7.36 (1H, dd, J 9.0,
6.8, H2), 7.72 (1H, d, J 9.0, H1), and 8.11 (1H, d, J 6.8, H4);
dC (50 MHz; CDCl3) 14.5, 23.0, 27.6, 29.0, 31.8, 34.4, 92.1,
114.1, 120.0, 125.0, 127.7, 128.3, 132.6, 147.5, 159.5 and 160.7;
MS (EI) 270 (M, 100),199 (65), 171 (50), 130 (40), 79 (26), and
78 (68); HRMS for C16H18N2O2 (M+): calcd. 270.1368, found
270.1376.
(E)-3-[2-(2,6,6-Trimethylcyclohex-2-enyl)vinyl]pyrano-
[3¢,4¢:4,5]imidazo[1,2-a]pyridin-1-one (2j)
3-[Cyclopropyl]pyrano[3¢,4¢:4,5]imidazo[1,2-a]pyridin-1-one (2f)
Yellow solid: 60% yield. Mp: 125–127 ◦C; umax (KBr)/cm-1 3065,
2926, 1732, 1637, 1508, 1262 and 1035; dH (200 MHz; DMSO)
0.85 (3H, s, CH3), 0.91 (3H, s, CH3), 1.50–1.53 (2H, m, CH2CH2),
1.58 (3H, s, CH3), 1.99–2.02 (2H, m, CH2CH2), 2.36–2.40 (1H,
m, CHCH CH), 5.48 (1H, bs, CH2CH C), 6.20–6.24 (2H, m,
CH CH), 7.33 (1H, t, J 6.4, H3), 7.46 (1H, s, H5), 7.53 (1H, dd,
J 9.0, 6.4, H2), 7.72 (1H, d, J 9.0, H1) and 8.74 (1H, d, J 6.4, H4);
dC (50 MHz; DMSO) 22.7, 26.6, 27.7, 30.8, 32.8, 53.5, 94.0, 113.8,
118.4, 121.6, 123.4, 126.7, 127.3, 129.3, 132.7, 132.8, 135.5, 135.7,
146.8, 152.2 and 157.6; MS (EI) 334 (M+, 99), 278 (100), 249 (54),
213 (96), 149 (49) and 39 (34); HRMS for C21H22N2O2 (M+): calcd.
334.1681, found 334.1687.
Yellow solid: 62% yield. Mp: 150–152 ◦C; umax (KBr)/cm-1 3091,
2918, 1739, 1621, 1516 and 1037; dH (200 MHz; CDCl3) 0.99–1.03
(2H, m, CHCH2CH2), 1.14–1,18 (2H, m, CHCH2CH2), 1.91–1,97
(1H, m, CH2CHCH2), 6.68 (1H, s, H5), 6.96 (1H, t, J 6.6, H3),
7.35 (1H, dd, J 9.4, 6.6, H2), 7.71 (1H, d, J 9,4, H1) and 8.12 (1H,
d, J 6.6, H4); dC (50 MHz; CDCl3) 7.5, 14.2, 89.5, 113.2, 119.1,
124, 126.4, 127.4, 132.2, 146.4, 158.2 and 160; MS (EI) 226 (100),
197 (30), 184 (26), 169 (93), 155 (16), 129 (26), 78 (93), 51 (34)
and 39 (14); HRMS for C13H10N2O2 (M+): calcd. 226.0742, found
226.0747.
3-(Diethoxymethyl)pyrano[3¢,4¢:4,5]imidazo[1,2-a]pyridin-1-one
(2g)
(E)-3-[2-(2,6,6-Trimethylcyclohex-1-enyl)vinyl]pyrano-
[3¢,4¢:4,5]imidazo[1,2-a]pyridin-1-one (2k)
Yellow solid: 43% yield. Mp: 168–170 ◦C; umax (KBr)/cm-1 3059,
2974, 1734, 1685, 1636 and 1506; dH (200 MHz; CDCl3) 1.30 (6H,
t, J 7.0, 2 ¥ CH3CH2O), 3.66–3.79 (4H, m, 2 ¥ OCH2CH3), 5.36
(1H, s, CH(OEt)2), 7.01 (1H, t, J 6.6, H3), 7.16 (1H, s, H5), 7.40–
7.43 (1H, m, H2), 7.74–7.76 (1H, m, H1) and 8.18–8.21 (1H, m,
H4); dC (50 MHz; CDCl3) 15.6 (2C), 63.0 (2C), 91.7, 98.0, 114.7,
120.3, 125.4, 128.8, 155.1 and 158.7; MS (EI) 288 (M, 70), 260 (54),
243 (62), 231 (39), 215 (100), 185 (46), 78 (72), 75 (49) and 47 (68);
HRMS for C15H16N2O4 (M+): calcd. 288.1110, found 288.1119.
Yellow solid: 65% yield. Mp: 119–121 ◦C. umax (KBr)/cm-1 3071,
2926, 1327, 1637, 1508, 1262 and 1035; dH (200 MHz; DMSO)
1.08 (6H, s, 2 ¥ CH3), 1.49–1.58 (4H, m, 2 ¥ CH2CH2CH2), 1.78
(3H, s, CH3), 2.07 (2H, t, J 6.0, CH2CH2), 6.28 (1H, d, J 15.4,
CH CH), 6. 88 (1H, d, J 15.0, CH CH), 7.14 (1H, t, J 6.6,
H3), 7.48 (1H, s, H5), 7.49 (1H, dd, J 8.6, 6.6, H2), 7.70 (1H, d, J
8.6, H1) and 8.72 (1H, d, J 6.6, H4); dC (50 MHz; DMSO) 19.1,
21.8, 28.9 (2C), 33.3, 34.3, 39.6, 92.3, 113.9, 119.7, 123.4, 124.1,
124.8, 128.1, 131.9, 132.8, 133.4, 136.9, 152.9, 154.2 and 158.5;
MS (EI) 334 (M+, 50), 278 (58), 249 (39), 213 (40), 199 (39), 185
(37), 129 (25), 122 (32), 107 (24), 91 (17), 78 (72), 69 (23), 44 (86)
and 36 (100); HRMS for C21H22N2O2 (M+): calcd. 334.1681, found
334.1689.
3-(2,2-Diethoxyethyl)pyrano[3¢,4¢:4,5]imidazo[1,2-a]pyridin-1-one
(2h)
Yellow solid: 45% yield. Mp: 164–166 ◦C. umax (KBr)/cm-1 3070,
2964, 1735, 1685, 1636 and 1507; dH (200 MHz; CDCl3) 1.17 (6H,
t, J 7.0, 2 ¥ CH3CH2O), 2.96 (2H, d, J 5.6, CH2CH), 3.51–3.77
(4H, m, 2 ¥ OCH2CH3), 4.96 (1H, t, J = 5.8 Hz, CH2CH(OEt)2),
6.75 (1H, s, H5), 6.99 (1H, t, J 6.7, H3), 7.38 (1H, dd, J 9.4, 6.7, H2),
7.73 (1H, d, J 9.4, H1) and 8.12 (1H, d, J 6.7, H4); dC (50 MHz;
CDCl3) 14.8 (2C), 39.0, 62.2 (2C), 93.5, 100.0, 113.9, 118.7, 118.8,
124.4, 127.5, 128.5, 145.2, 155.4 and 158.2; MS (EI) 302 (M, 3),
3-[(N-Benzyl-N-methylamino)methyl]pyrano[3¢,4¢:4,5]-
imidazo[1,2-a]pyridin-1-one (2l)
◦
Yellow solid: 40% yield. Mp: 175-176 C. umax (KBr)/cm-1 3094,
2925, 2852, 1731, 1616; dH (200 MHz; CDCl3) 2.39 (3H, s, CH3N),
3.58 (2H, s, CH2N), 3.71 (2H, s, NCH2Ph), 6.96 (1H, s, H5), 6.99
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(1H, t, J 6.8, H3), 7.28–7.38 (6H, m, (5HPh+H2), 7.74 (1H, d, J
9.2, H1) and 8.17 (1H, d, J 6.8, H4); dC (50 MHz; CDCl3) 42.7,
58.0, 61.9, 92.6, 113.9, 119.7, 124.5, 127.3, 127.4, 128.0, 128.1,
128.2 (2C), 128.8, 131.4, 138.3, 147.0, 157.5 and 158.7; MS (EI).
319 (21), 275 (8), 228 (7), 199 (15), 184 (14), 134 (28), 120 (14), 91
(100) and 78 (20); HRMS for C19H17N3O2 (M+): calcd. 319.1321,
found 319.1329.
4, 749; K. R. Roesch and R. C. Larock, J. Org. Chem., 2002, 67, 86
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15 For recent synthesis using Pd or Ag catalysts, see: V. Subramanian,
V. R. Batchu, D. Barrange and M. Pal, J. Org. Chem., 2005, 70, 4778;
C. Xu and E.-I. Negishi, Tetrahedron Lett., 1999, 40, 431; S. Ma and Z.
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Yellow solid: 55% yield. Mp: 155–157 ◦C. umax (KBr)/cm-1 3091,
2918, 1739, 1621, 1516 and 1037; dH (200 MHz; CDCl3) 3.56 (3H, s,
OCH3), 4.45 (2H, s, CH2OCH3), 6.94 (1H, s, H5), 7.02 (1H, t, J
7.2, H3), 7.42 (1H, dd, J 10.2, 7.2, H2), 7.78 (1H, d, J 10.2, H1)
and 8.18 (1H, d, J 7.2, H4); dC (50 MHz; CDCl3) 59.2, 70.4, 91.9,
114.0, 119.6, 124.5, 128.5, 132.1, 147.2, 155.6 and 158.3; MS (EI)
230 (M, 100), 199 (29), 185 (40), 171 (50), 157 (19), 143 (18), 129
(39), 79 (15), 78 (91) and 51 (28); HRMS for C12H10N2O3 (M+):
calcd. 230.0691, found 230.0686.
16 Catalyzed by other metal complexes, see: T. Yao and R. C. Larock,
J. Org. Chem., 2003, 68, 5936; M. Biagetti, F. Bellina, A. Carpita, P.
Stabile and R. Rossi, Tetrahedron, 2002, 58, 5023; R. Mukhopadhyay
and N. G. Kundu, Tetrahedron, 2001, 57, 9475.
17 K. Sonogashira, in Comprehensive Organic SynthesisB. M. Trost,
Ed.; Pergamon press, Oxford, UK, 1999; Vol. 3,
p 521; K.
Acknowledgements
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We thank MESR for providing financial support and the “SAVIT,
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18 S. Caachi, G. Fabrizi and P. Pace, J. Org. Chem., 1998, 63, 1001; S.
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