Efficient synthesis of new 8-aryl tricyclic pyridinones

Article abstract of DOI:10.1055/s-2006-942505

New tricyclic pyridinones were synthesized from 6-bromo-2-chloromethyl-3- nitroimidazo[1,2-a]pyridine in four steps involving a Suzuki-Miyaura cross-coupling reaction and a direct olefination with diethyl ketomalonate as key steps. Subsequent one-pot redu

Full text of DOI:10.1055/s-2006-942505

PAPER
2777
Efficient Synthesis of New 8-Aryl Tricyclic Pyridinones
S
ynthesis of 8-A
r
a
yl Tricyclic
r
Pyridin
o
one
s
line Castera-Ducros, Maxime D. Crozet, Patrice Vanelle*
Laboratoire de Chimie Organique Pharmaceutique, LCOP-UMR CNRS 6517, Faculté de Pharmacie, Université de La Méditerranée,
27 Boulevard Jean Moulin, 13385 Marseille Cedex 5, France
Fax +33(4)91794677; E-mail: patrice.vanelle@pharmacie.univ-mrs.fr
Received 31 March 2006; revised 26 April 2006
lonate involving an original direct olefination,9 we report
herein an original and efficient four-step synthesis of new
8-aryl tricyclic pyridinones. These potentially bioactive
pyridinones for the treatment of central nervous system
Abstract: New tricyclic pyridinones were synthesized from 6-bro-
mo-2-chloromethyl-3-nitroimidazo[1,2-a]pyridine in four steps in-
volving a Suzuki–Miyaura cross-coupling reaction and a direct
olefination with diethyl ketomalonate as key steps. Subsequent one-
pot reduction–cyclization provided new ethyl 8-aryl-2-oxo-1,2-di- disorders10,11 were synthesized from 6-bromo-3-nitroimi-
hydrodipyrido[1,2-a;3¢,2¢-d]imidazole-3-carboxylates.
dazo[1,2-a]pyridine bearing the 4-chlorophenylsulfonyl-
methyl group in an ortho-like position to the nitro group.
Key words: Suzuki–Miyaura cross-coupling, sulfones, diethyl
methylenemalonate, nitro reduction, pyridin-2-ones
The first step is the synthesis of 6-bromo-2-(4-chloro-
phenylsulfonyl)methyl-3-nitroimidazo[1,2-a]pyridine (2),
which was performed by reaction of sodium 4-chloroben-
zenesulfinate and 6-bromo-2-chloromethyl-3-nitroimid-
azo[1,2-a]pyridine (1) in DMSO. In the presence of two
equivalents of sodium 4-chlorobenzenesulfinate and un-
der photostimulation in DMSO, 1 reacts only at the chlo-
romethyl position with good yield probably following a
SN2 mechanism12,13 (Scheme 1).
Pyridin-2(1H)-ones are attractive and important reagents
in organic synthesis.1 Among fused pyridin-2(1H)-one
derivatives with pharmacological activities, tricyclic pyri-
dinones have been the subject of several recent reports. In-
deed, they are interesting intermediates in the synthesis of
important drugs or drug candidates [e.g. the antitumor
agent (+)-camptothecin,2 benzodiazepine receptor
ligands,3–5 or subtype-selective GABAA receptor
antagonists6]. Various syntheses of tricyclic pyridinones
have been developed to find new compounds with en-
hanced biological activities.7
Several new sulfonyl derivatives 3a–g were obtained
from 2 by cross-coupling reactions with some arylboronic
acids in aqueous medium (Scheme 2). The 4-chlorosulfo-
nyl compound 2 with bromine atom in 6-position was re-
acted with arylboronic acids according to Suzuki–
Miyaura reaction in water using Pd(PPh3)4 as catalyst.
This method required 10 mol% of Pd(PPh3)4 as catalyst, 5
equivalents of Na2CO3 as base and 1.3 equivalents of aryl-
In continuation of our program directed towards the study
of Suzuki–Miyaura reaction8 in 2-arylsulfonylmethyl-6-
halo-3-nitroimidazo[1,2-a]pyridine series and the reactiv-
ity of sulfonyl carbanion derivatives with diethyl ketoma-
Cl
N
4-ClC6H4SO2–Na+
O2S
Cl
N
N
DMSO, r.t., hν
N
Br
Br
NO2
NO2
1
2
Scheme 1
RB(OH)2
Na2CO3
O2S
Cl
O2S
Cl
N
N
N
N
10% Pd(PPh3)4
Br
R
H2O, ∆
NO2
NO2
3e R = 3-CF3-C6H4
2
3a
3b R = 2-Me-C6H4
R = C6H5
R = 2-naphthyl
R = 1-naphthyl
3f
3g
3c
3d
R = 4-MeO-C6H4
R = 4-F-C6H4
Scheme 2
SYNTHESIS 2006, No. 16, pp 2777–2783
x
x.
x
x
.
2
0
0
6
Advanced online publication: 19.07.2006
DOI: 10.1055/s-2006-942505; Art ID: Z06806SS
© Georg Thieme Verlag Stuttgart · New York

2778
C. Castera-Ducros et al.
PAPER
boronic acid.13 A large amount of base was employed be- argon at room temperature by reaction with 60% NaH for
cause of the easy formation of the sulfonyl anion of 2. The 1 hour and reacted with diethyl ketomalonate at room
formation of the sulfonyl anion in basic medium allows a temperature for 12 to 24 hours. After work-up and purifi-
better solubility of the reagent in water, which allows the cation, this reaction led directly to diethyl methylenema-
cross-coupling reaction to proceed in aqueous medium.
lonate derivatives 4a–g in moderate yields as expected
and not to the b-alkoxysulfones (Scheme 3, Table 2).
The reaction was carried out by refluxing a mixture of 6-
bromo-2-(4-chlorophenyl)sulfonylmethyl-3-nitroimida-
zo[1,2-a]pyridine (2), arylboronic acid, Pd(PPh3)4, and
Na2CO3 in water, from 2–3.5 hours, until the disappear-
ance of starting materials as monitored by TLC. No organ-
ic solvent or co-solvent was used or investigated.
Although the reaction mixtures were non-homogeneous
and aggregated, the overall yields were good. Some yields
appeared to suffer from difficulties in the extractive work-
up. Moreover, the aggregation coupled with the high sur-
face tension of water, diminishes the surface contact be-
tween hydrophobic species and water molecules.14 Under
these conditions 3a–g were obtained in moderate to good
yields (Scheme 2, Table 1) and the structure of the boron-
ic acid had little influence on the yield, even if the best
yields were obtained with boronic acids bearing an elec-
tron-withdrawing group (Table 1, entries 4 and 5). Fur-
thermore, no by-product was observed from a possible
cross-coupling reaction with the chlorine atom on the p-
sulfonyl group.
Table 2 Reactions of Sulfonyl Carbanions with Diethyl Ketoma-
lonatea
Entry
R
Product
4a
Time (h) Yield (%)
1
2
3
4
5
7
8
C6H5
24
24
24
24
12
24
24
35
35
50
31
31
32
35
2-CH3C6H4
4-CH3OC6H4
4-FC6H4
3-CF3C6H4
2-naphthyl
1-naphthyl
4b
4c
4d
4e
4f
4g
a Conditions: 6-aryl-2-(4-chlorophenyl)sulfonylmethyl-3-nitroimida-
zo[1,2-a]pyridine (1 equiv), diethyl ketomalonate (1.5 equiv), NaH
(1.1 equiv), and DMSO. All reactions are performed at r.t. under N2
and irradiated with a fluorescent lamp (60 W).
The arylsulfonyl derivatives 3a–g prepared by the Suzu-
ki–Miyaura cross-coupling reaction were studied for the
reactivity of the sulfonyl carbanion with diethyl ketoma-
lonate. Compounds 3a–g were metalated in DMSO under
The analogous sulfonyl carbanions of 6-aryl-3-nitro-2-
phenylsulfonylmethylimidazo[1,2-a]pyridine13 and 6-
aryl-3-nitro-2-(tosylmethyl)imidazo[1,2-a]pyridine13
were found as reactive as the sulfone derivatives 3a–g un-
der these experimental conditions. The chlorine or hydro-
gen atom or the methyl group as substituent in the para
position to the sulfonyl group does not seem to have a
strong effect on the reactivity.
Table 1 Cross-Coupling Reactions of 2 with Arylboronic Acidsa
Entry
R
Product
3a
Time (h) Yield (%)
1
2
3
4
5
6
7
C6H5
3
60
70
56
73
70
67
67
This study also shows an enhanced reactivity of 6-arylsul-
fonyl carbanion derivatives with diethyl ketomalonate, as
disclosed recently9 in the direct Julia olefination used for
the preparation of the 3-nitroimidazo[1,2-a]pyridines
bearing the diethyl methylenemalonate group in the 2-po-
sition. This enabled the preparation of the precursors 4 of
the desired functionalized tricyclic pyridinones 5.
2-CH3C6H4
4-CH3OC6H4
4-FC6H4
3-CF3C6H4
2-naphthyl
1-naphthyl
3b
2
3c
2
3d
3.5
3
3e
3f
3
Finally, taking into account the high degree of functional-
ization of the pyridinone precursors (malonic acid diethyl
ester, conjugated double bond, nitro group, heterocyclic
ring with nucleophilic heteroatom) we chose a mixture of
iron powder in glacial acetic acid as the reducing agent.15
3g
3
a Conditions: catalyst Pd(PPh3)4 (10 mol%), 6-bromo-2-(4-chlo-
rophenyl)sulfonylmethyl-3-nitroimidazo[1,2-a]pyridine (1 equiv),
arylboronic acid (1.3 equiv), Na2CO3 (5 equiv), H2O, 100 °C.
EtO2C
1) NaH, DMSO, r.t., N2
2) 0=C(CO2CH2CH3)2
O2S
Cl
CO2Et
N
N
N
N
R
R
NO2
NO2
4a
4b
R = C6H5
R = 2-Me-C6H4
4e R = 3-CF3-C6H4
3a–g
R = 2-naphthyl
R = 1-naphthyl
4f
4g
4c R = 4-MeO-C6H4
R = 4-F-C6H4
4d
Scheme 3
Synthesis 2006, No. 16, 2777–2783 © Thieme Stuttgart · New York

PAPER
Synthesis of 8-Aryl Tricyclic Pyridinones
2779
were performed on 5 cm × 10 cm aluminum plates coated with silica
gel 60F-254 (Merck) in an appropriate solvent. 6-Bromo-2-(chloro-
methyl)-3-nitroimidazo [1,2-a]pyridine (1) was prepared as previ-
ously described.13
After refluxing diester derivatives 4a–g in glacial acetic
acid with an excess of iron powder (28 equiv) for 2–24
hours, and work-up, the target lactams 5a–g were ob-
tained in moderate to good yields in a one-pot reduction-
cyclization reaction (Scheme 4, Table 3).
6-Bromo-2-(4-chlorophenyl)sulfonylmethyl-3-nitroimida-
zo[1,2-a]pyridine (2)
EtO2C
To a solution of sodium 4-chlorobenzenesulfinate (4.09 g, 20.6
mmol) in DMSO (45 mL) under N2, was added 1 (3.0 g, 10.3 mmol)
and the mixture was irradiated with a tungsten lamp (60 W) . The
mixture was stirred at r.t. for 3 h. After the disappearance of 1 (mon-
itored by TLC), the mixture was poured into an ice-water mixture.
The precipitated solid was collected by filtration and dried in the air
to give after purification by recrystallization from toluene 2.66 g
(60%) of 2 as white solid; mp 220 °C.
1H NMR (200 MHz, CDCl3): d = 5.12 (s, 2 H), 7.48–7.55 (m, 2 H),
7.69–7.94 (m, 4 H), 9.54 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 56.7, 112.6, 119.1, 127.7, 129.6,
129.8, 134.7, 137.5, 139.2, 141.1, 143.3.
CO2Et
Fe, AcOH
N
N
N
R
N
reflux
R
NO2
CO2Et
HN
O
4a–g
5a
R = C6H5
5e R = 3-CF3-C6H4
5b R = 2-Me-C6H4
5c R = 4-MeO-C6H4
5d
R = 2-naphthyl
R = 1-naphthyl
5f
5g
R = 4-F-C6H4
Scheme 4
Anal. Calcd for C14H9BrClN3O4S: C, 39.04; N, 9.76; H, 2.11.
Found: C, 39.37; N, 10.00; H, 2.24.
Table 3 Reduction Reactions of the Nitro Group and Cyclization of
the Resulting Amino Derivativesa
Cross-Coupling Reaction of Heteroaryl Bromides with Aryl-
boronic Acids; 2-(4-Chlorophenyl)sulfonylmethyl-3-nitro-6-
phenylimidazo[1,2-a]pyridine (3a); Typical Procedure
A mixture of phenylboronic acid (180 mg, 1.48 mmol) with 2 (500
mg, 1.16 mmol), Na2CO3·10H2O (1.66 g, 5.80 mmol) and Pd(PPh3)4
(0.14 g, 0.12 mmol) in demineralized H2O (20 mL) was refluxed for
2–3.5 h (Table 1). After disappearance of 2 (monitored by TLC),
the mixture was cooled and the solid was collected by filtration and
dried in the air. The crude product was purified by column chroma-
tography (silica gel, eluent: CHCl3–EtOAc, 9:1) and recrystallized
from i-PrOH, to give 298 mg (60%) of 3a as yellow solid; mp
192 °C.
Entry
R
Product
5a
Time (h)
Yield (%)
1
2
3
4
5
7
8
C6H5
24
24
2
68
31
46
42
30
30
44
2-CH3C6H4
4-CH3OC6H4
4-FC6H4
3-CF3C6H4
2-naphthyl
1-naphthyl
5b
5c
5d
24
24
24
4
5e
5f
1H NMR (200 MHz, CDCl3): d = 5.17 (s, 2 H), 7.44–7.96 (m, 11 H),
9.56 (m, 1 H).
5g
13C NMR (50 MHz, CDCl3): d = 56.9, 118.4, 125.0, 127.4, 129.2,
a Conditions: diethyl 2-(6-aryl-3-nitroimidazo[1,2-a]pyridin-2-yl-
methylene)malonate (1 equiv), iron powder (28 equiv), glacial
AcOH, 115 °C.
129.5, 129.6, 130.0, 131.7, 132.1, 135.6, 137.8, 139.5, 141.0, 144.2.
Anal. Calcd for C20H14ClN3O4S: C, 56.14; H, 3.30; N, 9.82. Found:
C, 56.46; H, 3.35; N, 9.74.
In conclusion, an efficient method for the preparation of
new ethyl 8-aryl-2-oxo-1,2-dihydrodipyrido[1,2-a;3¢,2¢-
d]imidazole-3-carboxylates has been developed on the
2-(4-Chlorophenyl)sulfonylmethyl-6-(2-methylphenyl)-3-nitro-
imidazo[1,2-a]pyridine (3b)
Cross-coupling reaction of 2-methylphenylboronic acid (160 mg,
basis of palladium-mediated coupling of arylboronic acid 1.18 mmol) with 2 (400 mg, 0.93 mmol), Na2CO3·10H2O (1.33 g,
4.64 mmol) and Pd(PPh3)4 (0.10 g, 0.09 mmol) gave, after purifica-
and reaction of sulfonyl carbanions with diethyl ketoma-
tion by column chromatography (silica gel, eluent: CHCl3–EtOAc,
lonate. Moreover, we have shown the functional compat-
9:1) and recrystallization from i-PrOH, 288 mg (70%) of 3b as
black solid; mp 193 °C.
1H NMR (200 MHz, CDCl3): d = 2.32 (s, 3 H), 5.19 (s, 2 H), 7.28–
ibility of the 4-chlorophenylsulfonylmethyl group in
ortho-like position of the nitro group in the Suzuki reac-
tion with 6-bromo-2-(4-chlorophenylsulfonyl)methyl-3-
7.40 (m, 4 H), 7.54 (d, J = 8.3 Hz, 2 H), 7.68 (dd, J = 1.6, 9.1 Hz, 1
nitroimidazo[1,2-a]pyridine (2).
H), 7.84–7.90 (m, 3 H), 9.36 (dd, J = 1.0, 1.6 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 20.4, 56.9, 117.7, 126.5, 126.6,
Melting points were determined with a B-540 Büchi melting point
apparatus. 200 MHz 1H NMR and 50 MHz 13C NMR spectra were
recorded on a Bruker ARX 200 spectrometer in CDCl3 solution at
the Faculté de Pharmacie de Marseille. 1H and 13C NMR chemical
shifts (d) are reported in ppm with respect to CHCl3 7.26 ppm (1H)
and 76.9 ppm (13C). Elemental analyses were carried out at the Cen-
tre de Microanalyses de la Faculté des Sciences et Techniques de
Saint-Jérôme and at the Service Central d’Analyse du Centre Na-
tional de la Recherche Scientifique de Vernaison. The following ad-
sorbent was used for column chromatography: silica gel 60 (Merck,
particle size 0.063–0.200 mm, 70–230 mesh ASTM). TLC analyses
129.2, 129.6, 129.9, 130.0, 131.0, 132.3, 133.6, 135.7, 135.8, 137.9,
139.4, 141.0, 144.0.
Anal. Calcd for C21H16ClN3O4S: C, 57.08; H, 3.65; N, 9.51. Found:
C, 57.00; H, 3.73; N, 9.26.
2-(4-Chlorophenyl)sulfonylmethyl-6-(4-methoxyphenyl)-3-
nitroimidazo[1,2-a]pyridine (3c)
Cross-coupling reaction of 4-methoxyphenylboronic acid (230 mg,
1.51 mmol) with 2 (500 mg, 1.16 mmol), Na2CO3·10H2O (1.66 g,
5.80 mmol) and Pd(PPh3)4 (0.14 g, 0.12 mmol), gave after purifica-
tion by column chromatography (silica gel, eluent: CHCl3–EtOAc,
Synthesis 2006, No. 16, 2777–2783 © Thieme Stuttgart · New York

2780
C. Castera-Ducros et al.
PAPER
9:1) and recrystallization from i-PrOH, 300 mg (56%) of 3c as yel-
low solid; mp 160 °C.
5.80 mmol), Pd(PPh3)4 (0.14 g, 0.12 mmol), gave after purification
by column chromatography (silica gel, eluent: CHCl3–EtOAc, 9:1)
and recrystallization from EtOAc, 370 mg (67%) of 3g as yellow
solid; mp 246 °C.
1H NMR (200 MHz, CDCl3): d = 5.21 (s, 2 H), 7.49–8.02 (m, 13 H),
9.52 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 57.0, 117.7, 124.6, 125.4, 126.5,
127.1, 127.2, 128.0, 128.8, 129.6, 129.7, 130.0, 131.4, 133.8, 133.9,
134.3, 137.9, 139.5, 141.1, 142.2.
1H NMR (200 MHz, CDCl3): d = 3.88 (s, 3 H), 5.16 (s, 2 H), 7.04
(d, J = 8.8 Hz, 2 H), 7.55 (d, J = 8.8 Hz, 2 H), 7.55 (d, J = 8.9 Hz, 2
H), 7.81 (d, J = 8.8 Hz, 2 H), 7.85–7.92 (m, 2 H), 9.51 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 55.5, 56.9, 115.0, 118.3, 124.3,
127.8, 128.5, 129.5, 129.9, 131.5, 131.8, 137.7, 139.4, 141.0, 144.0,
160.5.
Anal. Calcd for C21H16ClN3O5S: C, 55.08; H, 3.52; N, 9.18. Found:
C, 55.28; H, 3.63; N, 9.32.
Anal. Calcd for C24H16ClN3O4S: C, 60.31; H, 3.37; N, 8.79. Found:
C, 60.13; H, 3.39; N, 8.85.
2-(4-Chlorophenyl)sulfonylmethyl-6-(4-fluorophenyl)-3-nitro-
imidazo[1,2-a]pyridine (3d)
Reactions of Sulfonyl Carbanions with Diethyl Ketomalonate;
Diethyl 2-(3-Nitro-6-phenylimidazo[1,2-a]pyridin-2-ylmethyl-
ene)malonate (4a); Typical Procedure
Cross-coupling reaction of 4-fluorophenylboronic acid (210 mg,
1.50 mmol) with 2 (500 mg, 1.16 mmol), Na2CO3·10H2O (1.66 g,
5.80 mmol), Pd(PPh3)4 (0.14 g, 0.12 mmol), gave after purification
by column chromatography (silica gel, eluent: CHCl3–EtOAc, 9:1)
and recrystallization from i-PrOH, 380 mg (73%) of 3d as yellow
solid; mp 265 °C.
1H NMR (200 MHz, CDCl3): d = 5.18 (s, 2 H), 7.20–7.29 (m, 2 H),
7.50–7.89 (m, 8 H), 9.55 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 56.9, 116.4, 116.8, 118.5, 124.9,
128.4, 129.1, 129.3, 129.6, 129.9, 131.1, 131.5, 131.7, 131.8, 137.7,
139.6, 141.0, 144.1, 163.4.
To a solution of 3a (0.54 g, 1.27 mmol) in DMSO (10 mL) was add-
ed NaH (60% dispersion in mineral oil, 0.06 g, 1.40 mmol) under
N2 and the mixture was irradiated with a tungsten lamp (60 W). The
mixture was stirred 1 h at r.t. and diethyl ketomalonate (0.33 g, 1.90
mmol) was added dropwise over a period of about 10 min. The mix-
ture was stirred at r.t. for 24 h and then poured into ice-water mix-
ture (200 mL). The aqueous solution was extracted with Et2O
(5 × 100 mL) and the combined organic extracts were washed with
H2O (2 × 20 mL) and dried (MgSO4). Filtration and removal of the
solvent on a rotary evaporator followed by a flash chromatography
on silica gel (eluent: cyclohexane–EtOAc, 1:1) and recrystallization
from i-PrOH gave 182 mg (35%) of 4a as yellow solid; mp 205 °C.
Anal. Calcd for C20H13ClFN3O4S: C, 53.88; H, 2.94; N, 9.42.
Found: C, 54.05; H, 3.17; N, 9.35.
1H NMR (200 MHz, CDCl3): d = 1.37 (t, J = 7.1 Hz, 3 H), 1.38 (t,
J = 7.2 Hz, 3 H), 4.36 (q, J = 7.1 Hz, 2 H), 4.46 (q, J = 7.1 Hz, 2 H),
7.48–7.66 (m, 5 H), 7.78 (dd, J = 0.9, 9.3 Hz, 1 H), 7.88 (dd,
J = 1.7, 9.3 Hz, 1 H), 8.48 (s, 1 H), 9.60 (dd, J = 0.9, 1.7 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 14.0, 14.1, 61.7, 62.1, 118.5,
124.8, 127.3, 129.1, 129.2, 129.4, 131.6, 131.8, 133.6, 135.7, 142.3,
144.1, 163.3, 165.6.
2-(4-Chlorophenyl)sulfonylmethyl-3-nitro-6-[3-(trifluorometh-
yl)phenyl]imidazo[1,2-a]pyridine (3e)
Cross-coupling reaction of 3-(trifluoromethyl)phenylboronic acid
(290 mg, 1.52 mmol) with 2 (500 mg, 1.16 mmol), Na2CO3·10H2O
(1.66 g, 5.80 mmol) and Pd(PPh3)4 (0.14 g, 0.12 mmol), gave after
purification by column chromatography (silica gel, eluent: CHCl3)
and recrystallization from i-PrOH, 400 mg (70%) of 3e as beige sol-
id; mp 224 °C.
1H NMR (200 MHz, CDCl3): d = 5.18 (s, 2 H), 7.51–7.94 (m, 10 H),
9.61 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 56.9, 118.8, 124.9, 125.0, 125.4,
126.4, 129.6, 129.9, 130.2, 130.6, 130.7, 130.8, 131.2, 132.1, 136.6,
137.7, 139.8, 141.1, 144.2.
Anal. Calcd for C21H19N3O6: C, 61.61; H, 4.68; N, 10.26. Found: C,
61.98; H, 4.77; N, 10.38.
Diethyl 2-[6-(2-Methylphenyl)-3-nitroimidazo[1,2-a]pyridin-2-
ylmethylene]malonate (4b)
The reaction of sulfonyl derivative 3b (90 mg, 0.2 mmol) with NaH
(60%, 8.8 mg, 0.22 mmol) and diethyl ketomalonate (52 mg, 0.3
mmol) gave after purification by column chromatography (silica
gel, eluent: cyclohexane–EtOAc, 1:1) and recrystallization from
i-PrOH, 30 mg (35%) of 4b as yellow solid; mp 153 °C.
Anal. Calcd for C21H13ClF3N3O4S: C, 50.87; H, 2.64; N, 8.47.
Found: C, 51.17; H, 2.88; N, 8.38.
1H NMR (200 MHz, CDCl3): d = 1.38 (t, J = 7.1 Hz, 3 H), 1.41 (t,
J = 7.2 Hz, 3 H), 2.31 (s, 3 H), 4.37 (q, J = 7.1 Hz, 2 H), 7.29–7.39
(m, 4 H), 7.47 (q, J = 7.2 Hz, 2 H), 7.63 (dd, J = 1.7, 9.2 Hz, 1 H),
7.76 (dd. J = 0.9, 9.2 Hz, 1 H), 8.49 (s, 1 H), 9.37 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 14.0, 14.1, 20.4, 61.8, 62.2, 117.8,
126.5, 129.1, 129.3, 130.0, 130.9, 132.1, 133.5, 133.7, 135.7, 135.8,
142.3, 144.0, 163.3, 165.7.
2-(4-Chlorophenyl)sulfonylmethyl-6-(naphthalen-2-yl)-3-
nitroimidazo[1,2-a]pyridine (3f)
Cross-coupling reaction of naphthalen-2-ylboronic acid (260 mg,
1.51 mmol) with 2 (500 mg, 1.16 mmol), Na2CO3·10H2O (1.66 g,
5.80 mmol) and Pd(PPh3)4 (0.14 g, 0.12 mmol), gave after purifica-
tion by column chromatography (silica gel, eluent: CHCl3–EtOAc,
9:1) and recrystallization from i-PrOH, 370 mg (67%) of 3f as yel-
low solid; mp 262 °C.
Anal. Calcd for C22H21N3O6: C, 62.41; H, 5.00; N, 9.92. Found: C,
62.00; H, 5.05; N, 9.83.
1H NMR (200 MHz, CDCl3): d = 5.20 (s, 2 H), 7.51–8.10 (m, 13 H),
9.71 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 57.0, 117.7, 124.6, 125.4, 126.5,
127.1, 127.2, 128.0, 128.8, 129.6, 129.7, 130.0, 131.4, 133.8, 133.9,
134.3, 137.9, 139.5, 141.1, 144.2.
Diethyl 2-[6-(4-Methoxyphenyl)-3-nitroimidazo[1,2-a]pyridin-
2-ylmethylene]malonate (4c)
The reaction of sulfonyl derivative 3c (330 mg, 0.72 mmol) with
NaH (60%, 30 mg, 0.79 mmol) and diethyl ketomalonate (188 mg,
1.08 mmol) gave after purification by column chromatography (sil-
ica gel, eluent: cyclohexane–EtOAc, 1:1) and recrystallization from
i-PrOH, 160 mg (50%) of 4c as orange solid; mp 166 °C.
Anal. Calcd for C24H16ClN3O4S: C, 60.31; H, 3.37; N, 8.79. Found:
C, 60.56; H, 3.48; N, 8.61.
2-(4-Chlorophenyl)sulfonylmethyl-6-(naphthalen-1-yl)-3-nitro-
imidazo[1,2-a]pyridine (3g)
Cross-coupling reaction of naphthalen-1-ylboronic acid (260 mg,
1.51 mmol) with 2 (500 mg, 1.16 mmol), Na2CO3·10H2O (1.66 g,
1H NMR (200 MHz, CDCl3): d = 1.38 (t, J = 7.1 Hz, 3 H), 1.39 (t,
J = 7.0 Hz, 3 H), 3.89 (s, 3 H), 4.36 (q, J = 7.1 Hz, 2 H), 4.46 (q,
Synthesis 2006, No. 16, 2777–2783 © Thieme Stuttgart · New York

PAPER
Synthesis of 8-Aryl Tricyclic Pyridinones
2781
J = 7.1 Hz, 2 H), 7.05 (d, J = 8.9 Hz, 2 H), 7.56 (d, J = 8.8 Hz, 2 H),
7.75 (dd, J = 1, 9.3 Hz, 1 H), 7.86 (dd, J = 1.8, 9.3 Hz, 1 H), 8.48 (s,
1 H), 9.55 (dd, J = 0.9, 1.8 Hz, 1 H).
0.23 mmol) gave after purification by column chromatography (sil-
ica gel, eluent: cyclohexane–EtOAc, 1:1) and recrystallization from
i-PrOH, 24 mg (35%) of 4g as yellow solid; mp 186 °C.
13C NMR (50 MHz, CDCl3): d = 14.0, 14.1, 55.5, 61.7, 62.1, 114.9,
118.4, 124.2, 128.0, 128.5, 129.3, 131.5, 133.4, 142.2, 144.0, 160.5,
163.3, 165.7, 171.1.
1H NMR (200 MHz, CDCl3): d = 1.39 (t, J = 7.2 Hz, 3 H), 1.43 (t,
J = 7.2 Hz, 3 H), 4.38 (q, J = 7.2 Hz, 2 H), 4.49 (q, J = 7.2 Hz, 2 H),
7.46–8.01 (m, 9 H), 8.50 (s, 1 H), 9.52 (m, 1 H).
Anal. Calcd for C22H21N3O7: C, 60.13; H, 4.82; N, 9.56. Found: C,
59.87; H, 4.86; N, 9.93.
13C NMR (50 MHz, CDCl3): d = 14.0, 14.1, 61.8, 62.2, 117.8,
124.6, 125.4, 126.5, 127.0, 127.1, 127.9, 128.8, 129.2, 129.6, 131.1,
131.3, 133.7, 133.8, 134.2, 142.3, 144.1, 163.3, 165.7.
Diethyl 2-[6-(4-Fluorophenyl)-3-nitroimidazo[1,2-a]pyridin-2-
ylmethylene]malonate (4d)
The reaction of sulfonyl derivative 3d (300 mg, 0.67 mmol) with
NaH (60%, 30 mg, 0.74 mmol) and diethyl ketomalonate (174 mg,
1.0 mmol) gave, after purification by column chromatography (sil-
ica gel, eluent: cyclohexane–EtOAc, 1:1) and recrystallization from
i-PrOH, 89 mg (31%) of 4d as yellow solid; mp 190 °C.
1H NMR (200 MHz, CDCl3): d = 1.38 (t, J = 7.1 Hz, 3 H), 1.39 (t,
J = 7.1 Hz, 3 H), 4.36 (q, J = 7.1 Hz, 2 H), 4.47 (q, J = 7.1 Hz, 2 H),
7.19–7.28 (m, 2 H), 7.57–7.61 (m, 2 H), 7.71 (dd, J = 1.1, 9.3 Hz, 1
H), 7.85 (dd, J = 1.7, 9.3 Hz, 1 H), 8.48 (s, 1 H), 9.56 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 14.0, 14.1, 61.8, 62.2, 116.4,
116.8, 118.6, 124.7, 129.1, 129.2, 130.9, 131.4, 131.9, 132.0, 133.7,
138.6, 142.4, 144.1, 164.5.
Anal. Calcd for C25H21N3O6: C, 65.35; H, 4.61; N, 9.15. Found: C,
65.37; H, 4.72; N, 9.05.
Reduction of the Nitro group and Cyclization of the Resulting
Amino Derivatives; Ethyl 2-Oxo-8-phenyl-1,2-dihydrodipyri-
do[1,2-a;3¢,2¢-d]imidazole-3-carboxylate (5a)
In a two-necked flask equipped with a reflux condenser, 4a (200
mg, 0.49 mmol) and glacial AcOH (10 mL) were stirred and heated
at reflux. To this solution was added iron powder (766 mg, 13.72
mmol). The reflux was maintained for 24 h. After cooling, the solu-
tion was filtered through Celite and washed with glacial AcOH. The
AcOH solution was evaporated on a rotary evaporator and the resi-
due basified with aq sat. solution of Na2CO3. The aqueous layer was
extracted with CHCl3 (3 × 50 mL). The combined organic layers
were dried (MgSO4), and evaporated on a rotary evaporator to give,
after purification by column chromatography (silica gel, eluent:
CHCl3–EtOAc, 4:1) and recrystallization from i-PrOH, 111 mg
(68%) of 5a as yellow solid; mp 218 °C.
Anal. Calcd for C21H18FN3O6: C, 59.02; H, 4.25; N, 9.83. Found: C,
59.28; H, 4.39; N, 9.88.
Diethyl 2-[6-(3-Trifluoromethylphenyl)-3-nitroimidazo[1,2-
a]pyridin-2-ylmethylene]malonate (4e)
1H NMR (200 MHz, CDCl3): d = 1.50 (t, J = 7.1 Hz, 3 H), 4.53 (q,
J = 7.1 Hz, 2 H), 7.41–7.78 (m, 7 H), 8.85 (s, 1 H), 11.88 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 14.2, 62.5, 107.2, 118.3, 121.4,
125.8, 126.7, 128.3, 129.3, 131.6, 132.3, 136.3, 161.3, 169.8.
The reaction of sulfonyl derivative 3e (350 mg, 0.7 mmol) with
NaH (60%, 30 mg, 0.77 mmol) and diethyl ketomalonate (183 mg,
1.05 mmol) (reaction time 12 h) gave after purification by column
chromatography (silica gel, eluent: cyclohexane–EtOAc, 1:1) and
recrystallization from i-PrOH, 104 mg (31%) of 4e as yellow solid;
mp 150 °C.
Anal. Calcd for C19H15N3O3: C, 68.46; H, 4.54; N, 12.61. Found: C,
68.29; H, 4.61; N, 12.54.
1H NMR (200 MHz, CDCl3): d = 1.38 (t, J = 7.2 Hz, 3 H), 1.40 (t,
J = 7.1 Hz, 3 H), 4.35 (q, J = 7.1 Hz, 2 H), 4.48 (q, J = 7.2 Hz, 2 H),
7.67–7.90 (m, 6 H), 8.47 (s, 1 H), 9.62 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 14.0, 14.1, 61.8, 62.3, 118.9,
123.3, 124.1, 125.2, 129.0, 130.1, 130.4, 130.7, 131.2, 132.1, 134.0,
136.7, 142.6, 144.1, 163.2, 165.6.
Ethyl 8-(2-Methylphenyl)-2-oxo-1,2-dihydrodipyrido[1,2-
a;3¢,2¢-d]imidazole-3-carboxylate (5b)
The reduction and cyclization of 4b (600 mg, 1.42 mmol) in glacial
AcOH (10 mL) with iron powder (2.22 g, 39.76 mmol) gave, after
purification by column chromatography (silica gel, eluent: CHCl3–
EtOAc, 8:2) and recrystallization from i-PrOH, 150 mg (31%) of 5b
as yellow solid; mp 169 °C.
1H NMR (200 MHz, CDCl3): d = 1.49 (t, J = 7.1 Hz, 3 H), 2.35 (s,
3 H), 4.53 (q, J = 7.1 Hz, 2 H), 7.27–7.34 (m, 4 H), 7.46 (dd,
J = 0.8, 9.6 Hz, 1 H), 7.65 (dd, J = 0.7, 9.6 Hz, 1 H), 8.59 (s, 2 H),
8.81 (s, 2 H), 11.86 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 20.4, 62.5, 107.1, 117.4, 123.1,
126.1, 126.3, 128.5, 129.8, 130.8, 132.2, 133.7, 135.9, 136.5, 143.3,
148.3, 161.2, 169.8.
Anal. Calcd for C22H18F3N3O6: C, 55.35; H, 3.80; N, 8.66. Found:
C, 55.48; H, 3.81; N, 8.90.
Diethyl 2-[6-(Naphthalen-2-yl)-3-nitroimidazo[1,2-a]pyridin-2-
ylmethylene]malonate (4f)
The reaction of sulfonyl derivative 3f (190 mg, 0.40 mmol) with
NaH (60%, 17 mg, 0.44 mmol) and diethyl ketomalonate (104 mg,
0.60 mmol) gave after purification by column chromatography (sil-
ica gel, eluent: cyclohexane–EtOAc, 1:1) and recrystallization from
i-PrOH, 59 mg (32%) of 4f as yellow solid; mp 153 °C.
1H NMR (200 MHz, CDCl3): d = 1.38 (t, J = 7.1 Hz, 3 H), 1.41 (t,
J = 7.1 Hz, 3 H), 4.37 (q, J = 7.2 Hz, 2 H), 4.48 (q, J = 7.1 Hz, 2 H),
7.54–8.08 (m, 9 H), 8.49 (s, 1 H), 9.70 (m, 1 H).
Anal. Calcd for C20H17N3O3: C, 69.15; H, 4.93; N, 12.10. Found: C,
69.16; H, 5.03; N, 12.14.
Ethyl 8-(4-Methoxyphenyl)-2-oxo-1,2-dihydrodipyrido[1,2-
a;3¢,2¢-d]imidazole-3-carboxylate (5c)
The reduction and cyclization of 4c (250 mg, 0.57 mmol) in glacial
AcOH (10 mL) with iron powder (891 mg, 15.96 mmol) (reaction
time, 2 h) gave, after purification by column chromatography (silica
gel, eluent: CHCl3–EtOAc, 8:2) and recrystallization from i-PrOH,
95 mg (46%) of 5c as green solid; mp 246 °C.
1H NMR (200 MHz, CDCl3): d = 1.49 (t, J = 6.8 Hz, 3 H), 3.87 (s,
3 H), 4.53 (q, J = 6.8 Hz, 2 H), 7.02 (d, J = 7.9 Hz, 2 H), 7.54 (d,
J = 7.9 Hz, 2 H), 7.67 (m, 2 H), 8.78 (m, 2 H), 11.87 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 14.0, 14.1, 61.8, 62.1, 118.5,
124.5, 125.0, 126.6, 127.0, 127.7, 128.3, 129.2, 129.4, 131.7, 132.8,
133.2, 133.4, 133.6, 142.3, 144.1, 163.3, 165.7.
Anal. Calcd for C25H21N3O6: C, 65.35; H, 4.61; N, 9.15. Found: C,
65.40; H, 4.65; N, 9.40.
Diethyl 2-[6-(Naphthalen-1-yl)-3-nitroimidazo[1,2-a]pyridin-2-
ylmethylene]malonate (4g)
The reaction of sulfonyl derivative 3g (70 mg, 0.15 mmol) with
NaH (60%, 6.4 mg, 0.16 mmol) and diethyl ketomalonate (40 mg,
Synthesis 2006, No. 16, 2777–2783 © Thieme Stuttgart · New York

2782
C. Castera-Ducros et al.
PAPER
13C NMR (50 MHz, CDCl3): d = 14.2, 55.4, 62.5, 107.1, 114.7,
118.2, 120.5, 125.4, 127.8, 128.7, 131.6, 132.2, 143.4, 148.4, 159.8,
161.1, 169.8.
1H NMR (CDCl3): d = 1.50 (t, J = 7.1 Hz, 3 H), 4.54 (q, J = 7.1 Hz,
2 H), 7.48–7.96 (m, 9 H), 8.78 (s, 1 H), 8.84 (s, 1 H), 11.88 (s, 1 H).
13C NMR (CDCl3): d = 14.2, 62.5, 107.2, 117.5, 123.7, 125.0,
125.1, 125.4, 126.2, 126.7, 127.5, 128.7, 129.0, 131.5, 132.3, 133.9,
134.3, 134.6, 161.2, 169.8.
Anal. Calcd for C20H17N3O4: C, 66.11; H, 4.72; N, 11.56. Found: C,
65.77; H, 4.78; N, 11.47.
Anal. Calcd for C23H17N3O3: C, 72.05; H, 4.47; N, 10.96. Found: C,
71.93; H, 4.65; N, 10.96.
Ethyl 8-(4-Fluorophenyl)-2-oxo-1,2-dihydrodipyrido[1,2-
a;3¢,2¢-d]imidazole-3-carboxylate (5d)
The reduction and cyclization of 4d (320 mg, 0.75 mmol) in glacial
AcOH (10 mL) with iron powder (1.17 g, 21.00 mmol) gave, after
purification by column chromatography (silica gel, eluent: CHCl3–
EtOAc, 8:2) and recrystallization from i-PrOH, 110 mg (42%) of 5d
as yellow solid; mp 246 °C.
1H NMR (200 MHz, CDCl3): d = 1.49 (t, J = 7.1 Hz, 3 H), 4.52 (q,
J = 7.1 Hz, 2 H), 7.14–7.65 (m, 7 H), 8.78 (s, 1 H), 11.87 (s, 1 H).
Acknowledgment
This work was supported by the CNRS and the Universities of Aix-
Marseille. C. Castera-Ducros thanks the Assistance Publique-Hôpi-
taux de Marseille for hospital appointment. The authors thank V.
Rémusat for recording the 1H and 13C NMR spectra.
13C NMR (50 MHz, CDCl3): d = 14.1, 62.5, 107.2, 116.3, 118.4,
121.2, 124.7, 128.4, 131.3, 131.6, 132.3, 132.4, 132.5, 143.4, 161.2,
169.7, 162.9.
References
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Anal. Calcd for C19H14FN3O3: C, 64.95; H, 4.02; N, 11.96. Found:
C, 64.74; H, 4.08; N, 11.78.
Ethyl 8-(3-Trifluoromethylphenyl)-2-oxo-1,2-dihydrodipyri-
do[1,2-a;3¢,2¢-d]imidazole-3-carboxylate (5e)
The reduction and cyclization of 4e (250 mg, 0.52 mmol) in glacial
AcOH (10 mL) with iron powder (813 mg, 14.56 mmol) gave, after
purification by column chromatography (silica gel, eluent: CHCl3–
EtOAc, 9:1) and recrystallization from i-PrOH, 63 mg (30%) of 5e
as yellow solid; mp 239 °C.
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1H NMR (200 MHz, CDCl3): d = 1.49 (t, J = 7.1 Hz, 3 H), 4.53 (q,
J = 7.1 Hz, 2 H), 7.58–7.88 (m, 6 H), 8.82 (s, 1 H), 8.89 (s, 1 H),
11.90 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 14.2, 62.6, 107.5, 118.8, 122.0,
123.1, 123.5, 124.3, 125.0, 129.8, 130.8, 131.7, 131.9, 132.5, 137.2,
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Ethyl 8-Naphthalen-2-yl-2-oxo-1,2-dihydrodipyrido[1,2-a;3¢,2¢-
d]imidazole-3-carboxylate (5f)
The reduction and cyclization of 4f (440 mg, 0.96 mmol) in glacial
AcOH (10 mL) with iron powder (1.50 g, 26.88 mmol) gave, after
purification by column chromatography (silica gel, eluent: CHCl3–
EtOAc, 8:2) and recrystallization from i-PrOH, 110 mg (30%) of 5f
as yellow solid; mp 253 °C.
1H NMR (200 MHz, CDCl3): d = 1.50 (t, J = 7.1 Hz, 3 H), 4.54 (q,
J = 7.1 Hz, 2 H), 7.52–8.10 (m, 9 H), 8.82 (s, 1 H), 8.98 (s, 1 H),
11.89 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 14.2, 62.5, 107.3, 118.4, 121.6,
124.3, 125.6, 126.6, 126.8, 127.7, 128.2, 129.2, 131.5, 131.7, 132.4,
133.0, 133.5, 133.7, 153.6, 156.4, 161.3, 169.8.
MS (ESI-MS): m/z = 384 ([M + H]+)
Ethyl 8-Naphthalen-1-yl-2-oxo-1,2-dihydrodipyrido[1,2-a;3¢,2¢-
d]imidazole-3-carboxylate (5g)
The reduction and cyclization of 4g (260 mg, 0.56 mmol) in glacial
AcOH (10 mL) with iron powder (891 mg, 15.96 mmol) (reaction
time, 4 h) gave, after purification by column chromatography (silica
gel, eluent: CHCl3–EtOAc, 8:2) and recrystallization from i-PrOH,
96 mg (44%) of 5g as yellow solid; mp 199 °C.
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Synthesis 2006, No. 16, 2777–2783 © Thieme Stuttgart · New York