Synthesis of tricyclic quinolones and naphthyridones by intramolecular heck cyclization of functionalized electron-rich heterocycles

Article abstract of DOI:10.1002/ejoc.200400817

Starting from commercially available pyrrole- and thiophene-2-carboxylic acids 1 or thiophene- and furan-3-carboxylic acids 6, we report the synthesis of tricyclic fused quinolone and naphthyridone derivatives, in only three steps, by an intramolecular He

Full text of DOI:10.1002/ejoc.200400817

FULL PAPER
Synthesis of Tricyclic Quinolones and Naphthyridones by Intramolecular Heck
Cyclization of Functionalized Electron-Rich Heterocycles
Egle M. Beccalli,*[a] Gianluigi Broggini,[b] Michela Martinelli,[a] Giuseppe Paladino,[a] and
Caterina Zoni[a]
Keywords: Heck reaction / Palladium / Cyclization / Lactam / Microwaves
Starting from commercially available pyrrole- and thio-
of microwave irradiation to obtain, in some cases, better
phene-2-carboxylic acids 1 or thiophene- and furan-3-car- yields of cyclized products.
boxylic acids 6, we report the synthesis of tricyclic fused qui-
nolone and naphthyridone derivatives, in only three steps,
by an intramolecular Heck cyclization. We also report the use
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
tivity[11] and hypocholesteremic activity.[11] Aza-analogues
of furonaphthyridones and thienonaphthyridones show ef-
fects against hyperproliferative skin disease,[12] and antial-
lergy,[13] immunomodulator,[14] and inflammation inhibitor
activity.[14]
Introduction
Among basic types of palladium-catalyzed transforma-
tions, the Heck reaction and related chemistry occupy a
special place. During the last thirty years this reaction has
emerged as a highly efficient and well-documented mild
procedure for forming carbon–carbon bonds.[1] The wide
variety of functional groups tolerated makes the Heck reac-
tion particularly versatile for organic synthesis. The starting
materials may be readily available from simple precursors,
and thus this strategy has been used for the construction of
carbocyclic and heterocyclic systems.[2]
Following our research on the reactivity of indole deriva-
tives, we first studied Pd-catalyzed reactions of these sub-
strates.[3] We then extended this analysis to other electron-
rich heterocyclic systems such as pyrroles, furans, and thio-
phenes. Moreover, we noticed from literature data the
promising biological properties of quinolones and naph-
thyridones fused with pyrrole, furan, or thiophene rings.
Among them, members of the furo[3,2-c]quinoline alka-
loids group show activities as tyrosine kinase inhibitors,[4]
as cytotoxic agents,[5] antimalarials,[6] antiosteoporosis
agents,[7] and anticonvulsants.[8] Pyrrolo[2,3-c]quinolines
have been reported to show activities as antitumor agents.[9]
Thieno[2,3-c]quinolines have been found to exert cytostatic
or cytotoxic activities against malignant cell lines,[10] and
some derivatives show platelet aggregation inhibitory ac-
A few general, although not simple, approaches to tricy-
clic pyrrolo-, furo-, and thienoquinolines have been de-
scribed in the literature. Photochemical[10a,10b,15] and radi-
cal[16] cyclizations of amide systems have been reported to
give poor yields of thieno- and pyrrolo[2,3-c]quinolines,
while the cycloaddition of 4-hydroxy-2-quinolones[17] and
diazoquinolinediones[18] gives furoquinolines. Pyrolysis of
azidoquinoline derivatives[19] and the traditional Paal–
Knorr reaction[20] give pyrroloquinolines, while pyrolysis of
azidobenzylthiophene derivatives gives thienoquinolines.[21]
Such considerations prompted us to search for a new
synthetic path to these heteropolycyclic systems by ex-
ploiting a Pd-catalyzed intramolecular reaction as the key
step.
Results and Discussion
We report here a very efficient and concise method for
the construction of tricyclic fused quinolone and naphthyr-
idone derivatives, which we planned to build starting from
pyrrole- and thiophene-2-carboxylic acids 1 or thiophene-
and furan-3-carboxylic acids 6. The corresponding un-
known N-(hetero)arylcarboxamides 4 and 8 were prepared
in high yields by treatment of the acyl chlorides, generated
in situ, with the appropriate 2-halo(hetero)arylamines 2, as
depicted in Schemes 1 and 2. The anilines 2 were preferably
ortho-substituted with an iodine atom, which is better
suited to give the best results in the Heck reaction. How-
ever, the reaction also proceeded with the bromo-substi-
tuted pyridine 2c, since the pyridine is a π-electron-deficient
[a] Istituto di Chimica Organica “A. Marchesini”, Facoltà di Farm-
acia, Università di Milano,
via Venezian 21, 20133 Milano, Italy
Fax: +39-02-5031-4476
E-mail: egle.beccalli@unimi.it
[b] Dipartimento di Scienze Chimiche e Ambientali, Università
dell’Insubria,
via Valleggio 11, 22100 Como, Italy,
Fax: +39-031-238-6449
E-mail: gianluigi.broggini@uninsubria.it
Eur. J. Org. Chem. 2005, 2091–2096
DOI: 10.1002/ejoc.200400817
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2091

E. M. Beccalli, G. Broggini, M. Martinelli, G. Paladino, C. Zoni
FULL PAPER
heterocycle. In fact the halopyridines are more susceptible
to the oxidative addition to Pd0 than simple carbocyclic
aryl halides. In the case of 2b, the presence of the Cl atom
didn’t interfere in the cyclization reaction, thus confirming
the poor reactivity of chlorine-substituted substrates in the
Pd-catalyzed coupling process. The subsequent N-methyla-
tion step, carried out with NaH and methyl iodide in THF
solution, was necessary to avoid N–Pd complexation. Then,
the intramolecular Heck cyclization at the positions 2 or 3
of the heterocyclic nucleus was the key step to obtain the
desired tricyclic fused systems in excellent yields. This reac-
tion was performed in DMA as solvent, with AcOK as base
and [Pd(PPh3)4] as catalyst at 120 °C for 24 h.
Scheme 2. Synthesis of compounds 7–9.
heat. Local overheating at the walls leads to decomposition
of the catalyst. Deployment of heat directly to the reacting
molecules by means of absorption of microwave energy by
a polar solvent effectively affords high temperatures in a
short time and in a uniform way. DMA has a dielectric
constant of 37.8 D and would be expected to heat rapidly
during the irradiation process. Taking the amide 4ac as a
probe, the reaction mixture was irradiated, in a multimode
oven equipped with temperature control, at 450 W for
12 min, and in this period the solution temperature reached
140 °C. The irradiation time for each experiment was deter-
mined by TLC control and the results are reported in
Table 1. This procedure gave quantitative yield of cyclized
product 5ac. Similar satisfactory results were also obtained
for compounds 4bc, 8ac, and 8bc. In the light of these re-
sults, the microwave technique represents the best reaction
conditions. The main advantages of this procedure are short
reaction times and very good yields (Scheme 2).
Scheme 1. Synthesis of compounds 3–5.
In the case of heteroarylamides 4ac, 4bc, 8ac, and 8bc,
bearing a bromine atom, a large amount of unreacted start-
ing material was recovered after 72 h heating. Since metal-
catalyzed processes are often ideal candidates for accelera-
tion by microwaves, non-conventional heating was tested. A
wide range of organic reactions have recently been pro-
moted by microwave irradiation,[22] but in the field of Heck
chemistry only a limited number of papers have appeared
(Scheme 1).[23]
Table 1. Heck reaction of bromo-substituted substrates.[a]
Microwave heating can be very rapid, producing a heat
profile that is not easily accessible by other heating tech-
niques. Experiments performed using this methodology
may therefore result in a different outcome when compared
to conventional heating, even if the final temperature is the
same. In conventional heating the energy is transferred by
heat transfer through the walls of the reaction vessel and
Substrate Product
Heat[b]
Yield [%]
Microwave[c]
Yield [%] t [min]
t [h]
4ac
4bc
8ac
8bc
5ac
5bc
9ac
9bc
52
49
49
36
24
24
24
24
90
92
96
91
30
12
12
30
[a] All reactions were performed with AcOK (1.5 equiv.), [Pd-
then by convection, causing a nonuniform distribution of (PPh3)4] (10 mol-%) in DMA (4 mL). [b] At 120 °C. [c] At 450 W.
2092 © 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
Eur. J. Org. Chem. 2005, 2091–2096

Synthesis of Tricyclic Quinolones and Naphthyridones
FULL PAPER
1.2 Hz, 1 H), 8.25–8.31 (overlapping, 2 H; after deuteration: d, J
= 1.2 Hz, 1 H) ppm; minor invertomer: 2.32 (s, 3 H), 3.90 (s, 3 H),
6.03 (dd, J = 3.9 3.9 Hz, 1 H), 6.72–6.76 (overlapping, 2 H), 7.77
(s, 1 H), 8.21 (s, 1 H), 8.29 (br. s, 1 H, absent after deuteration)
ppm. 13C NMR: major invertomer: δ = 17.9 (q), 37.5 (q), 108.1
(d), 111.8 (s), 113.7 (d), 130.0 (d), 131.3 (s), 134.4 (s), 142.2 (d),
146.8 (s), 147.6 (d), 159.0 (s) ppm; minor invertomer: 17.8 (q), 36.7
(q), 108.6 (d), 118.7 (d), 127.4 (s), 130.0 (d), 130.5 (s), 134.4 (s),
Conclusions
The applied reaction path provides an effective short syn-
thesis of the target molecules − tricyclic fused quinolone
and naphthyridone derivatives − starting from commer-
cially available starting materials. This strategy should lead
also to a variety of new analogues possessing modifications
around the heterocyclic nucleus. In addition, conventional
heating in the Pd-catalyzed coupling reaction has been
compared with microwave irradiation and the benefits of
the latter technique are shown. The speed and efficiency of
the microwaves in accelerating coupling reactions suggest
additional applications in heterocycle analogues.
143.0 (d), 148.8 (d), 151.1 (s), 164.8 (s) ppm. IR: ν = 1643,
˜
3264 cm–1. C12H12BrN3O (294.15): calcd. C 49.00, H 4.11, N 14.29;
found C 49.19, H 4.12, N 14.32.
N-(2-Iodophenyl)thiophene-2-carboxamide (3ba): Yield: 89%. M.p.
1
102–104 °C (diisopropyl ether). H NMR: δ = 6.84 (ddd, J = 1.4,
7.2, 8.0 Hz, 1 H), 7.15 (dd, J = 3.6, 5.2 Hz, 1 H), 7.38 (ddd, J =
1.4, 7.2, 8.4 Hz, 1 H), 7.59 (dd, J = 1.0, 5.2 Hz, 1 H), 7.72 (dd, J
= 1.0, 3.6 Hz, 1 H), 7.80 (dd, J = 1.4, 8.0 Hz, 1 H), 8.16 (br. s, 1
H, absent after deuteration), 8.38 (dd, J = 1.4, 8.4 Hz, 1 H) ppm.
13C NMR: δ = 90.3 (s), 113.1 (d), 116.1 (d), 122.1 (d), 126.4 (d),
129.7 (d), 138.3 (s), 139.3 (d), 145.2 (d), 147.8 (s), 160.9 (s) ppm.
Experimental Section
General Remarks: Melting points were measured with a Büchi B-
540 heating unit and are not corrected. NMR spectra were re-
corded with an AVANCE 400 Bruker spectrometer at 400 MHz for
1H NMR and 100 MHz for 13C NMR in CDCl3. Chemical shifts,
relative to TMS as internal standard, are given in δ values. IR spec-
tra were recorded with a Perkin–Elmer 1725X FT-IR spectropho-
tometer. The microwave reactions were performed with a Micro-
synth microwave system (Milestone) in a quartz reactor vessel.
IR: ν = 1641, 3265 cm–1. C H INOS (329.16): calcd. C 40.14, H
˜
11
8
2.45, N 4.26; found C 40.21, H 2.56, N 4.39.
N-(4-Chloro-2-iodophenyl)thiophene-2-carboxamide (3bb): Yield:
1
86%. M.p. 98–100 °C (diisopropyl ether). H NMR: δ = 7.13 (dd,
J = 3.5, 4.2 Hz, 1 H), 7.30 (dd, J = 1.9, 8.8 Hz, 1 H), 7.55 (d, J =
4.2 Hz, 1 H), 7.70 (d, J = 3.5 Hz, 1 H), 7.72 (d, J = 1.9 Hz, 1 H),
8.13 (br. s, 1 H, absent after deuteration), 8.21 (d, J = 8.8 Hz, 1 H)
ppm. 13C NMR: δ = 90.8 (s), 115.5 (d), 122.7 (d), 128.5 (d), 129.7
(d), 130.4 (s), 132.1 (d), 137.2 (s), 139.0 (d), 146.1 (s), 160.1 (s)
General Procedure for the Preparation of Heteroamides 3 and 7: A
solution of 1 or 6 (10 mmol) and SOCl2 (3.2 mL, 44.5 mmol) in
toluene (10 mL) was stirred at 70 °C for 2.5 h. After evaporation
of the solvent, the residue was taken up with CH2Cl2 (20 mL). A
solution of 2 (13.3 mmol) and TEA (1.9 mL, 13.6 mmol) in CH2Cl2
(5 mL) was then added dropwise at 0 °C. After stirring for 5 h at
room temperature, the solution was washed with 5% HCl
(2×20 mL) and then with 5% aqueous NaOH (2×20 mL). The
organic layer was dried (Na2SO4) and the solvent evaporated under
reduced pressure. The residue was chromatographed on a silica gel
column with light petroleum ether/Et2O (4:1) as eluent to give com-
pounds 3 and 7.
ppm. IR: ν = 1642, 3262 cm–1. C H ClINOS (363.61): calcd. C
˜
11
7
36.34, H 1.94, N 3.85; found C 36.21, H 2.05, N 3.78.
N-(3-Bromo-5-methylpyridin-2-yl)thiophene-2-carboxamide (3bc):
Yield: 69%. M.p. 112–114 °C (diisopropyl ether). 1H NMR: δ =
2.30 (s, 3 H), 7.10 (dd, J = 3.6, 4.4 Hz, 1 H), 7.55 (d, J = 4.4 Hz,
1 H), 7.70 (d, J = 3.6 Hz, 1 H), 7.73 (s, 1 H), 8.22 (s, 1 H), 8.63
(br. s, 1 H, absent after deuteration) ppm. 13C NMR: δ = 18.0 (q),
113.9 (s), 128.2 (d), 129.9 (d), 131.8 (d), 132.6 (s), 133.9 (d), 138.9
(s), 142.4 (d), 143.2 (s), 159.9 (s) ppm. IR: ν = 1644, 3263 cm–1.
˜
C11H9BrN2OS (297.18): calcd. C 44.46, H 3.05, N 9.43; found C
44.57, H 3.17, N 9.51.
N-(2-Iodophenyl)-1-methyl-1H-pyrrole-2-carboxamide (3aa): Yield:
83%. M.p. 66–67 °C (diisopropyl ether). H NMR: δ = 4.01 (s, 3
1
N-(2-Iodophenyl)thiophene-3-carboxamide (7aa): Yield: 92%. M.p.
120–122 °C (diisopropyl ether). H NMR: δ = 6.86 (ddd, J = 1.4,
H), 6.20 (dd, J = 2.6, 3.8 Hz, 1 H), 6.83–6.87 (overlapping, 2 H),
6.90 (dd, J = 1.5, 3.8 Hz, 1 H), 7.37 (ddd, J = 1.1, 7.3, 8.8 Hz, 1
H), 7.80 (d, J = 1.1, 7.9 Hz, 1 H), 8.07 (br. s, 1 H, absent after
deuteration), 8.36 (dd, J = 1.2, 8.8 Hz, 1 H) ppm. 13C NMR: δ =
37.3 (q), 90.4 (s), 108.2 (d), 113.4 (d), 121.7 (d), 125.8 (d), 129.6
1
7.7, 7.7 Hz, 1 H), 7.34 (ddd, J = 1.2, 7.7, 8.4 Hz, 1 H), 7.40 (dd, J
= 2.8, 5.0 Hz, 1 H), 7.56 (dd, J = 1.1, 5.0 Hz, 1 H), 7.78 (dd, J =
1.2, 7.7 Hz, 1 H), 8.07 (dd, J = 1.1, 2.8 Hz, 1 H), 8.19 (br. s, 1 H,
absent after deuteration), 8.35 (dd, J = 1.4, 8.4 Hz, 1 H) ppm. 13C
NMR: δ = 90.9 (s), 122.4 (d), 126.5 (d), 127.0 (d), 127.5 (d), 128.5
(d), 129.7 (d), 139.0 (s), 139.1 (s), 139.2 (d), 159.9 (s) ppm. IR: ν =
˜
1649, 3266 cm–1. C12H11IN2O (326.14): calcd. C 44.19, H 3.40, N
8.59; found C 44.02, H 3.47, N 8.68.
(d), 129.8 (d), 138.5 (s), 139.1 (s), 139.2 (d), 161.2 (s) ppm. IR: ν =
˜
1641, 3264 cm–1. C11H8INOS (329.16): calcd. C 40.14, H 2.45, N
4.26; found C 40.21, H 2.32, N 4.17.
N-(4-Chloro-2-iodophenyl)-1-methyl-1H-pyrrole-2-carboxamide (3ab):
Yield: 81%. M.p. 116–117 °C (diisopropyl ether). 1H NMR: δ =
4.00 (s, 3 H), 6.19 (dd, J = 2.5, 4.0 Hz, 1 H), 6.84 (dd, J = 1.5,
2.5 Hz, 1 H), 6.87 (dd, J = 1.5, 4.0 Hz, 1 H), 7.34 (dd, J = 2.3,
8.8 Hz, 1 H), 7.77 (d, J = 2.3 Hz, 1 H), 8.02 (br. s, 1 H, absent
after deuteration), 8.30 (d, J = 8.8 Hz, 1 H) ppm. 13C NMR: δ =
37.3 (q), 89.9 (s), 108.3 (d), 113.5 (d), 121.9 (d), 125.5 (s), 129.9
N-(4-Chloro-2-iodophenyl)thiophene-3-carboxamide (7ab): Yield:
1
89%. M.p. 86–88 °C (diisopropyl ether). H NMR: δ = 7.31 (dd, J
= 2.0, 8.8 Hz, 1 H), 7.40 (dd, J = 1.8, 4.8 Hz, 1 H), 7.54 (d, J =
4.8 Hz, 1 H), 7.74 (d, J = 2.0 Hz, 1 H), 8.06 (d, J = 1.8 Hz, 1 H),
8.12 (br. s, 1 H, absent after deuteration), 8.27 (d, J = 8.8 Hz, 1 H)
ppm. 13C NMR: δ = 90.7 (s), 122.7 (d), 126.4 (d), 127.6 (d), 129.2
(d), 129.7 (d), 130.3 (s), 137.2 (s), 137.4 (s), 138.2 (d), 161.1 (s)
(d), 131.0 (d), 137.8 (s), 138.2 (d), 139.1 (s), 159.8 (s) ppm. IR: ν =
˜
1641, 3266 cm–1. C12H10ClIN2O (360.58): calcd. C 39.97, H 2.80,
N 7.77; found C 39.80, H 2.97, N 7.90.
ppm. IR: ν = 1645, 3250 cm–1. C H ClINOS (363.61): calcd. C
˜
11
7
36.34, H 1.94, N 3.85; found C 36.47, H 2.05, N 4.01.
N-(3-Bromo-5-methylpyridin-2-yl)-1-methyl-1H-pyrrole-2-carbox-
1
amide (3ac): Yield: 61%. M.p. 100–102 °C (diisopropyl ether). H N-(3-Bromo-5-methylpyridin-2-yl)thiophene-3-carboxamide (7ac):
NMR: major invertomer: δ = 2.33 (s, 3 H), 4.01 (s, 3 H), 6.18 (dd,
J = 3.2, 3.2 Hz, 1 H), 6.80–6.84 (overlapping, 2 H), 7.75 (d, J =
Yield: 71%. M.p. 98–100 °C (diisopropyl ether). 1H NMR: δ = 2.28
(s, 3 H), 7.36 (d, J = 4.0 Hz, 1 H), 7.52 (d, J = 4.0 Hz, 1 H), 7.73
Eur. J. Org. Chem. 2005, 2091–2096
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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E. M. Beccalli, G. Broggini, M. Martinelli, G. Paladino, C. Zoni
C13H12ClIN2O (374.61): calcd. C 41.68, H 3.23, N 7.48; found C
FULL PAPER
(s, 1 H), 7.87 (br. s, 1 H, absent after deuteration), 8.02 (s, 1 H),
8.21 (s, 1 H) ppm. 13C NMR: δ = 17.8 (q), 117.8 (s), 125.7 (d), 41.80, H 3.37, N 7.60.
127.9 (d), 130.4 (d), 133.1 (s), 137.5 (s), 142.6 (d), 147.5 (s), 148.0
N-[(3-Bromo-5-methylpyridin-2-yl)methyl]-1-methyl-1H-pyrrole-2-carb-
(d), 161.8 (s) ppm. IR: ν = 1642, 3265 cm–1. C H BrN OS
˜
11
9
2
oxamide (4ac): Yield: 78%. M.p. 127–128 °C (diisopropyl ether).
1H NMR: δ = 2.33 (s, 3 H), 3.38 (s, 3 H), 3.92 (s, 3 H), 5.61 (br. s,
1 H), 5.77 (dd, J = 2.7, 3.6 Hz, 1 H), 6.59 (br. s, 1 H), 7.65 (d, J =
1.1 Hz, 1 H), 8.29 (d, J = 1.1 Hz, 1 H) ppm. 13C NMR: δ = 17.9
(q), 35.4 (q), 36.5 (q), 107.2 (d), 115.6 (d), 119.3 (s), 126.3 (s), 127.3
(297.18): calcd. C 44.46, H 3.05, N 9.43; found C 44.37, H 3.17, N
9.31.
N-(2-Iodophenyl)furan-3-carboxamide (7ba): Yield: 89%. M.p. 93–
1
94 °C (diisopropyl ether). H NMR: δ = 6.78 (d, J = 1.3 Hz, 1 H),
6.86 (ddd, J = 1.4, 8.0, 8.2 Hz, 1 H), 7.33 (ddd, J = 1.0, 7.8, 8.2 Hz,
1 H), 7.48 (dd, J = 1.3, 1.6 Hz, 1 H), 7.76 (dd, J = 1.0, 8.0 Hz, 1
H), 7.96 (br. s, 1 H, absent after deuteration), 8.09 (d, J = 1.6 Hz,
1 H), 8.27 (dd, J = 1.4, 7.8 Hz, 1 H) ppm. 13C NMR: δ = 91.1 (s),
108.7 (d), 122.6 (d), 123.3 (s), 126.6 (d), 129.7 (d), 138.3 (s), 139.1
(d), 134.5 (s), 143.1 (d), 148.6 (d), 153.6 (s), 163.7 (s) ppm. IR: ν =
˜
1631 cm–1. C13H14BrN3O (308.18): calcd. C 50.67, H 4.58, N 13.63;
found C 50.79, H 4.52, N 13.52.
N-[(2-Iodophenyl)methyl]thiophene-2-carboxamide (4ba): Yield:
1
88%. M.p. 94–96 °C (diisopropyl ether). H NMR: δ = 3.28 (s, 3
(d), 144.6 (d), 145.9 (d), 160.9 (s) ppm. IR: ν = 1642, 3265 cm–1.
˜
H), 6.68–6.77 (overlapping, 2 H), 7.06 (dd, J = 7.6, 7.6 Hz, 1 H),
7.21 (d, J = 4.7 Hz, 1 H), 7.27 (d, J = 7.6 Hz, 1 H), 7.36 (dd, J =
7.6, 7.9 Hz, 1 H), 7.86 (d, J = 7.9 Hz, 1 H) ppm. 13C NMR: δ =
38.2 (q), 100.7 (s), 127.2 (d), 130.4 (d), 130.5 (d), 130.7 (d), 131.3
C11H8INO2 (313.10): calcd. C 42.20, H 2.58, N 4.47; found C
42.39, H 2.68, N 4.48.
N-(4-Chloro-2-iodophenyl)furan-3-carboxamide (7bb): Yield: 81%.
1
M.p. 97–99 °C (diisopropyl ether). H NMR: δ = 7.26 (dd, J, 1.8,
(d), 132.4 (d), 138.0 (s), 140.7 (d), 146.4 (s), 162.5 (s) ppm. IR: ν =
˜
1626 cm–1. C12H10INOS (343.19): calcd. C 42.00, H 2.94, N 4.08;
found C 42.11, H 2.86, N 4.19.
8.6 Hz, 1 H), 7.36 (d, J = 4.7 Hz, 1 H), 7.50 (d, J = 4.7 Hz, 1 H),
7.70 (d, J = 1.8 Hz, 1 H), 8.0 (s, 1 H), 8.14 (br. s, 1 H, absent after
deuteration), 8.17 (d, J = 8.6 Hz, 1 H) ppm. 13C NMR: δ = 100.0
(s), 124.1 (d), 127.3 (d), 129.4 (d), 131.3 (s), 132.1 (d), 135.1 (s),
N-[(4-Chloro-2-iodophenyl)methyl]-thiophene-2-carboxamide (4bb):
Yield: 86%. M.p. 97–98 °C (diisopropyl ether). 1H NMR: δ = 3.28
(s, 3 H), 6.79 (br. s, 1 H), 6.89 (br. s, 1 H), 7.22 (d, J = 7.9 Hz, 1
H), 7.29 (br. s, 1 H), 7.36 (d, J = 7.9 Hz, 1 H), 7.86 (s, 1 H) ppm.
13C NMR: δ = 38.2 (q), 101.1 (s), 127.3 (d), 129.7 (d), 130.9 (d),
131.4 (d), 132.7 (d), 135.4 (s), 137.5 (s), 140.0 (d), 145.3 (s), 162.5
137.4 (s), 137.5 (d), 138.7 (d), 161.1 (s) ppm. IR: ν = 1642,
˜
3263 cm–1. C11H7ClINO2 (347.54): calcd. C 38.02, H 2.03, N 4.03;
found C 38.19, H 2.11, N 4.15.
N-(3-Bromo-5-methylpyridin-2-yl)furan-3-carboxamide (7bc): Yield:
1
(s) ppm. IR: ν = 1635 cm–1. C H ClINOS (377.63): calcd. C 38.17,
68%. M.p. 104–106 °C (diisopropyl ether). H NMR: δ = 2.38 (s,
˜
12
9
3 H), 6.54 (s, 1 H), 7.36 (d, J = 1.4 Hz, 1 H), 7.80 (br. s, 1 H, absent
after deuteration), 7.82–7.87 (overlapping, 2 H), 8.27 (s, 1 H) ppm.
13C NMR: δ = 18.1 (q), 110.4 (d), 119.7 (s), 123.1 (s), 136.0 (s),
142.9 (d), 144.1 (d), 147.8 (d), 148.6 (d), 149.3 (s), 165.7 (s) ppm.
H 2.40, N 3.71; found C 38.01, H 2.25, N 3.78.
N-[(3-Bromo-5-methylpyridin-2-yl)methyl]thiophene-2-carboxamide
(4bc): Yield: 84%. M.p. 121–123 °C (diisopropyl ether). H NMR:
1
IR: ν = 1644, 3263 cm–1. C H BrN O (281.11): calcd. C 47.00, H
δ = 2.28 (s, 3 H), 3.29 (s, 3 H), 6.67–7.01 (overlapping, 2 H), 7.22
(dd, J = 2.6, 3.3 Hz, 1 H), 7.68 (s, 1 H), 8.23 (s, 1 H) ppm. 13C
NMR: δ = 18.0 (q), 36.1 (q), 120.0 (s), 127.0 (d), 130.6 (d), 131.3
(d), 133.8 (s), 136.0 (s), 143.4 (d), 149.1 (d), 152.3 (s), 163.2 (s)
˜
11
9
2
2
3.23, N 9.97; found C 46.90, H 3.16, N 9.79.
General Procedure for the Preparation of Heteroamides 4 and 8:
NaH (324 mg, 13.5 mmol) was added portionwise to a solution of
3 or 7 (9 mmol) in THF (25 mL) under nitrogen. After 10 min MeI
(0.67 mL, 10.8 mmol) was added dropwise and the mixture was
stirred at room temperature for 6 h. The solvent was then evapo-
rated to dryness. The residue was taken up in water (20 mL) and
adjusted to pH 7 with HCl. The mixture was extracted with Et2O,
the organic layer was dried with Na2SO4, and the solvent was evap-
orated under reduced pressure. The residue was chromatographed
on a silica gel column with light petroleum ether/Et2O (4:1) as elu-
ent to give compounds 4 and 8.
ppm. IR: ν = 1638 cm–1. C H BrN OS (311.20): calcd. C 46.32,
˜
12 11
2
H 3.56, N 9.00; found C 46.47, H 3.47, N 9.11.
N-[(2-Iodophenyl)methyl]thiophene-3-carboxamide (8aa): Yield:
1
84%. M.p. 134–135 °C (diisopropyl ether). H NMR: δ = 3.32 (s,
3 H), 6.97–7.04 (overlapping, 3 H), 7.10 (s, 1 H), 7.19 (d, J =
7.5 Hz, 1 H), 7.30 (dd, J = 7.5, 7.5 Hz, 1 H), 7.84 (d, J = 7.9 Hz,
1 H) ppm. 13C NMR: δ = 37.9 (q), 99.9 (s), 115.1 (d), 120.1 (d),
124.9 (d), 128.9 (d), 130.0 (d), 136.8 (s), 139.2 (d), 140.6 (d), 147.2
(s), 165.0 (s) ppm. IR: ν = 1639 cm–1. C H INOS (343.19): calcd.
˜
12 10
C 42.00, H 2.49, N 4.08; found C 42.12, H 2.52, N 4.17.
N-[(2-Iodophenyl)methyl]-1-methyl-1H-pyrrole-2-carboxamide (4aa):
Yield: 77%. M.p. 110–112 °C (diisopropyl ether). 1H NMR: δ =
3.35 (s, 3 H), 3.95 (s, 3 H), 5.53 (br. s, 1 H), 5.79 (dd, J = 2.6,
4.0 Hz, 1 H), 6.60 (dd, J = 2.2, 2.6 Hz, 1 H), 7.03 (ddd, J = 1.8,
7.0, 7.0 Hz, 1 H), 7.15–7.23 (overlapping, 2 H), 7.85 (dd, J = 1.4,
7.0 Hz, 1 H) ppm. 13C NMR: δ = 36.7 (q), 37.5 (q), 108.0 (d), 108.6
(d), 111.7 (s), 113.6 (d), 118.7 (d), 129.9 (d), 130.5 (d), 131.2 (s),
N-[(4-Chloro-2-iodophenyl)methyl]thiophene-3-carboxamide (8ab):
Yield: 85%. M.p. 96–98 °C (diisopropyl ether). 1H NMR: δ = 3.11
(s, 3 H), 6.80–6.87 (overlapping, 2 H), 6.97–7.01 (overlapping, 2
H), 7.11 (d, J = 7.4 Hz, 1 H), 7.63 (s, 1 H) ppm. 13C NMR: δ =
37.8 (q), 100.3 (s), 125.3 (d), 128.7 (d), 129.8 (d), 130.3 (d), 130.6
(d), 134.4 (s), 136.6 (s), 139.6 (d), 145.9 (s), 164.6 (s) ppm. IR: ν =
˜
1638 cm–1. C12H9ClINOS (377.63): calcd. C 38.17, H 2.40, N 3.71;
found C 38.27, H 2.55, N 3.63.
142.0 (d), 146.8 (s), 159.1 (s) ppm. IR: ν = 1633 cm–1. C H IN O
˜
13 13
2
(340.17): calcd. C 45.90, H 3.85, N 8.24; found C 45.84, H 3.71, N
8.30.
N-[(3-Bromo-5-methylpyridin-2-yl)methyl]thiophene-3-carboxamide
1
N-[(4-Chloro-2-iodophenyl)methyl]-1-methyl-1H-pyrrole-2-carboxami- (8ac): Yield: 78%. M.p. 118–120 °C (diisopropyl ether). H NMR:
de (4ab): Yield: 84%. M.p. 113–115 °C (diisopropyl ether). 1H NMR:
δ = 3.26 (s, 3 H), 3.87 (s, 3 H), 5.55 (br. s, 1 H), 5.77 (br. s, 1 H),
6.56 (br. s, 1 H), 7.19 (d, J = 8.4 Hz, 1 H), 7.30 (dd, J = 2.1, 8.4 Hz,
1 H), 7.76 (d, J = 2.1 Hz, 1 H) ppm. 13C NMR: δ = 37.3 (q), 37.7
(q), 100.3 (s), 107.4 (d), 116.3 (d), 125.3 (s), 127.6 (d), 130.2 (d), 130.3
δ = 2.24 (s, 3 H), 3.29 (s, 3 H), 6.93–6.99 (overlapping, 2 H), 7.12
(s, 1 H), 7.61 (s, 1 H), 8.18 (s, 1 H) ppm. 13C NMR: δ = 17.9 (q),
35.7 (q), 119.4 (s), 125.1 (d), 128.2 (d), 129.2 (d), 135.3 (s), 137.2
(s), 143.2 (d), 148.9 (d), 152.8 (s), 165.6 (s) ppm. IR: ν = 1637 cm–1.
˜
C12H11BrN2OS (311.20): calcd. C 46.32, H 3.56, N 9.00; found C
46.37, H 3.41, N 9.11.
(d), 134.0 (s), 139.7 (d), 146.8 (s), 163.0 (s) ppm. IR: ν = 1637 cm–1.
˜
2094
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 2091–2096

Synthesis of Tricyclic Quinolones and Naphthyridones
FULL PAPER
N-[(2-Iodophenyl)methyl]furan-3-carboxamide (8ba): Yield: 89%.
M.p. 81–83 °C (diisopropyl ether). 1H NMR: δ = 3.34 (s, 3 H), 6.21
(s, 1 H), 6.81 (s, 1 H), 7.11 (ddd, J = 1.4, 7.7, 8.8 Hz, 1 H), 7.18 (s,
1 H), 7.32 (dd, J = 1.4, 7.7 Hz, 1 H), 7.44 (ddd, J = 1.2, 7.7, 8.8 Hz,
1 H), 7.96 (dd, J = 1.2, 7.7 Hz, 1 H) ppm. 13C NMR: δ = 37.4 (q),
100.3 (s), 111.3 (d), 120.2 (d), 122.2 (s), 130.3 (d), 139.3 (d), 140.6
5-Methyl-5H-thieno[2,3-c]quinolin-4-one (5ba): Yield: 57%. M.p.
177–179 °C (CH2Cl2/diisopropyl ether). 1H NMR: δ = 3.82 (s, 3
H), 7.33 (ddd, J = 1.6, 6.6, 7.0 Hz, 1 H), 7.44–7.60 (overlapping, 2
H), 7.60–7.78 (overlapping, 2 H), 8.00 (dd, J = 1.6, 8.0 Hz, 1 H)
ppm. 13C NMR: δ = 29.9 (q), 115.6 (d), 118.9 (s), 122.6 (d), 122.8
(d), 124.8 (d), 129.4 (d), 131.1 (s), 133.6 (d), 139.0 (s), 142.2 (s),
(d), 142.6 (d), 145.6 (d), 146.5 (s), 163.3 (s) ppm. IR: ν = 1638 cm–1.
160.1 (s) ppm. IR: ν = 1658 cm–1. C H NOS (215.28): calcd. C
˜
12 9
˜
C12H10INO2 (327.12): calcd. C 44.06, H 3.08, N 4.28; found C
43.99, H 2.98, N 4.38.
66.95, H 4.21, N 6.51; found C 66.86, H 4.11, N 6.39.
8-Chloro-5-methyl-5H-thieno[2,3-c]quinolin-4-one (5bb): Yield:
1
N-[(4-Chloro-2-iodophenyl)methyl]furan-3-carboxamide
(8bb):
56%. M.p. 208–210 °C (CH2Cl2/diisopropyl ether). H NMR: δ =
Yield: 82%. M.p. 79–81 °C (diisopropyl ether). 1H NMR: δ = 3.23
(s, 3 H), 6.14 (s, 1 H), 6.88 (s, 1 H), 7.11–7.21 (overlapping, 2 H),
7.34 (s, 1 H), 7.86 (s, 1 H) ppm. 13C NMR: δ = 37.4 (q), 100.6 (s),
111.2 (d), 115.4 (d), 122.0 (s), 130.5 (d), 135.2 (s), 139.9 (d), 142.8
3.82 (s, 3 H), 7.40 (d, J = 8.8 Hz, 1 H), 7.51 (dd, J = 2.2, 8.8 Hz,
1 H), 7.68 (d, J = 5.2 Hz, 1 H), 7.81 (d, J = 5.2 Hz, 1 H), 7.96 (d,
J = 2.2 Hz, 1 H) ppm. 13C NMR: δ = 29.9 (q), 116.8 (d), 119.7 (s),
122.3 (d), 124.1 (d), 128.2 (s), 129.1 (d), 131.3 (s), 133.8 (d), 137.3
(d), 145.3 (s), 145.6 (d), 163.2 (s) ppm. IR: ν = 1641 cm–1.
(s), 140.8 (s), 158.4 (s) ppm. IR: ν = 1659 cm–1. C H ClNOS
˜
˜
12
8
C12H9ClINO2 (361.57): calcd. C 39.86, H 2.51, N 3.87; found C
39.97, H 2.41, N 3.90.
(249.72): calcd. C 57.72, H 3.23, N 5.61; found C 57.61, H 3.09, N
5.78.
N-[(3-Bromo-5-methylpyridin-2-yl)methyl]furan-3-carboxamide (8bc):
Yield: 83%. M.p. 92–94 °C (diisopropyl ether). 1H NMR: δ = 2.40
(s, 3 H), 3.36 (s, 3 H), 6.19 (s, 1 H), 7.06 (s, 1 H), 7.19 (s, 1 H),
7.78 (d, J = 1.4 Hz, 1 H), 8.33 (d, J = 1.4 Hz, 1 H) ppm. 13C NMR:
δ = 18.0 (q), 35.4 (q), 110.6 (d), 120.0 (s), 122.4 (s), 135.8 (s), 142.7
5,8-Dimethyl-5H-thieno[2,3-c][1,8]naphthyridin-4-one (5bc): Yield:
49%. M.p. 185–187 °C (CH2Cl2/diisopropyl ether). H NMR: δ =
1
2.45 (s, 3 H), 3.82 (s, 3 H), 7.66 (d, J = 5.1 Hz, 1 H), 7.77 (d, J =
5.1 Hz, 1 H), 8.00 (s, 1 H), 8.40 (s, 1 H) ppm. 13C NMR: δ = 18.2
(q), 36.1 (q), 113.6 (s), 122.3 (d), 127.8 (s), 131.4 (s), 132.6 (d) 133.7
(d), 140.0 (s), 143.4 (d), 149.1 (s), 159.0 (s) ppm. IR: ν = 1660 cm–1.
(d), 143.4 (d), 145.2 (d), 149.0 (d), 152.5 (s), 163.9 (s) ppm. IR: ν
˜
˜
= 1638 cm–1. C12H11BrN2O2 (295.14): calcd. C 48.84, H 3.76, N
9.49; found C 48.70, H 3.66, N 9.59.
C12H10N2OS (230.29): calcd. C 62.59, H 4.38, N 12.16; found C
62.57, H 4.37, N 12.31.
General Procedure for the Preparation of Fused Quinolones and
Naphthyridones 5 and 9: A solution of 4 or 8 (0.5 mmol), [Pd-
(PPh3)4] (59 mg, 0.05 mmol), and AcOK (75 mg, 0.77 mmol) in
DMA (4 mL) was stirred at 120 °C for 24 h. The residue was di-
luted with H2O/NaCl (15 mL) and extracted with Et2O. The or-
ganic layer was dried with Na2SO4 and evaporated under reduced
pressure. The residue was chromatographed on a silica gel column
with light petroleum ether/Et2O (5:1) as eluent to give compounds
5 and 9.
5-Methyl-5H-thieno[3,2-c]quinolin-4-one (9aa): Yield: 68%. M.p.
141–143 °C (diisopropyl ether). 1H NMR: δ = 3.83 (s, 3 H), 7.34
(ddd, J = 1.6, 7.7, 8.0 Hz, 1 H) 7.40 (d, J = 5.2 Hz, 1 H), 7.44 (dd,
J = 1.6, 8.0 Hz, 1 H), 7.53 (ddd, J = 1.0, 7.7, 7.8 Hz, 1 H), 7.75 (d,
J = 5.2 Hz, 1 H), 7.86 (dd, J = 1.6, 7.8 Hz, 1 H) ppm. 13C NMR:
δ = 29.8 (q), 115.5 (d), 118.4 (s), 122.8 (d), 124.6 (d), 125.1 (d),
126.9 (d), 129.7 (d), 131.2 (s), 137.9 (s), 145.7 (s), 159.1 (s) ppm.
IR: ν = 1659 cm–1. C H NOS (215.28): calcd. C 66.95, H 4.21, N
˜
12
9
6.51; found C 66.83, H 4.27, N 6.72.
3,5-Dimethyl-3,5-dihydropyrrolo[2,3-c]quinolin-4-one (5aa): Yield:
89%. M.p. 191–193 °C (CH2Cl2/diisopropyl ether). H NMR: δ =
8-Chloro-5-methyl-5H-thieno[3,2-c]quinolin-4-one (9ab): Yield:
60%. M.p. 210–212 °C (CH2Cl2/diisopropyl ether). H NMR: δ =
1
1
3.79 (s, 3 H), 4.22 (s, 3 H), 6.70 (d, J = 2.7 Hz, 1 H), 7.04 (d, J =
2.7 Hz, 1 H), 7.27 (ddd, J = 1.3, 6.4, 8.0 Hz, 1 H), 7.40 (dd, J =
1.3, 8.3 Hz, 1 H), 7.43 (ddd, J = 1.3, 6.4, 8.3 Hz, 1 H), 7.91 (dd, J
= 1.3, 8.0 Hz, 1 H) ppm. 13C NMR: δ = 29.1 (q), 36.6 (q), 100.8
(d), 115.2 (d), 119.1 (s), 120.3 (s), 122.4 (d), 123.6 (d), 127.0 (d),
3.51 (s, 3 H), 7.05–7.24 (overlapping, 3 H), 7.32–7.53 (overlapping,
2 H) ppm. 13C NMR: δ = 29.8 (q), 117.0 (d), 119.1 (s), 123.5 (d),
126.1 (d), 126.6 (d), 128.5 (s), 129.4 (d), 131.5 (s), 136.2 (s), 143.9
(s), 158.4 (s), ppm. IR: ν = 1660 cm–1. C H ClNOS (249.72):
˜
12
8
calcd. C 57.72, H 3.23, N 5.61; found C 57.67, H 3.35, N 5.53.
128.2 (s), 131.4 (d), 137.1 (s), 156.7 (s) ppm. IR: ν = 1655 cm–1.
˜
5,8-Dimethyl-5H-thieno[3,2-c][1,8]naphthyridin-4-one (9ac): Yield:
C13H12N2O (212.25): calcd. C 73.57, H 5.70, N 13.20; found C
73.62, H 5.51, N 13.11.
1
49%. M.p. 189–190 °C (CH2Cl2/diisopropyl ether). H NMR: δ =
2.38 (s, 3 H), 3.81 (s, 3 H), 7.36 (d, J = 5.2 Hz, 1 H), 7.68 (d, J =
5.2 Hz, 1 H), 7.74 (d, J = 1.4 Hz, 1 H), 8.32 (d, J = 1.4 Hz, 1 H)
ppm. 13C NMR: δ = 18.1 (q), 28.8 (q), 113.3 (s), 126.0 (d), 126.7
(d), 128.3 (s), 131.9 (d), 135.2 (s), 143.1 (s), 146.3 (s), 149.3 (d),
8-Chloro-3,5-dimethyl-3,5-dihydropyrrolo[2,3-c]quinolin-4-one (5ab):
Yield: 74%. M.p. 205–207 °C (CH2Cl2/diisopropyl ether). 1H
NMR: δ = 3.71 (s, 3 H), 4.18 (s, 3 H), 6.61 (br. s, 1 H), 7.02 (br. s,
1 H), 7.25 (d, J = 8.8 Hz, 1 H), 7.32 (d, J = 8.8 Hz, 1 H), 7.78 (s,
1 H) ppm. 13C NMR: δ = 29.3 (q), 36.6 (q), 101.0 (d), 116.5 (d),
120.3 (s), 122.5 (s), 123.0 (d), 126.8 (d), 126.9 (s), 127.8 (s), 131.5
159.7 (s) ppm. IR: ν = 1659 cm–1. C H N OS (230,29): calcd. C
˜
12 10
2
62.59, H 4.38, N 12.16; found C 62.47, H 4.37, N 12.11.
5-Methyl-5H-furo[3,2-c]quinolin-4-one (9ba):[24] Yield: 85%. M.p.
132–134 °C (diisopropyl ether). 1H NMR: δ = 3.82 (s, 3 H), 7.09
(d, J = 2.0 Hz, 1 H), 7.34 (dd, J = 7.5, 7.6 Hz, 1 H), 7.41–7.63
(overlapping, 2 H), 7.66 (d, J = 2.0 Hz, 1 H), 8.04 (dd, J = 1.4,
7.5 Hz, 1 H) ppm. 13C NMR: δ = 28.8 (q), 107.7 (d), 112.5 (s),
114.4 (s), 114.7 (d), 120.5 (d), 121.6 (s), 128.8 (s), 137.4 (d), 143.3
(d), 135.6 (s), 156.3 (s) ppm. IR: ν = 1657 cm–1. C H ClN O
˜
13 11
2
(246.70): calcd. C 63.29, H 4.49, N 11.36; found C 63.20, H 4.57,
N 11.50.
3,5,8-Trimethyl-3,5-dihydropyrrolo[2,3-c][1,8]naphthyridin-4-one (5ac):
Yield: 52%. M.p. 136–138 °C (diisopropyl ether). 1H NMR: δ =
2.44 (s, 3 H), 3.88 (s, 3 H), 4.22 (s, 3 H), 6.67 (d, J = 2.7 Hz, 1 H),
7.05 (d, J = 2.7 Hz, 1 H), 7.95 (d, J = 1.9 Hz, 1 H), 8.31 (d, J =
1.9 Hz, 1 H) ppm. 13C NMR: δ = 18.2 (q), 28.4 (q), 36.6 (q), 101.3
(d), 114.2 (s), 118.8 (s), 122.3 (s), 125.9 (s), 127.6 (s), 129.0 (d),
(d), 154.4 (d), 158.8 (s) ppm. IR: ν = 1660 cm–1. C H NO
˜
12
9
2
(199.21): calcd. C 72.35, H 4.55, N 7.03; found C 72.29, H 4.68, N
7.18.
131.3 (d), 146.2 (d), 157.2 (s) ppm. IR: ν = 1660 cm–1. C H N O
8-Chloro-5-methyl-5H-furo[3,2-c]quinolin-4-one (9bb): Yield: 63%.
M.p. 186–188 °C (CH2Cl2/diisopropyl ether). 1H NMR: δ = 3.71
(s, 3 H), 7.02 (d, J = 1.6 Hz, 1 H), 7.31 (d, J = 9.0 Hz, 1 H), 7.42
˜
13 13
3
(227.27): calcd. C 68.71, H 5.77, N 18.49; found C 68.76, H 5.83,
N 18.56.
Eur. J. Org. Chem. 2005, 2091–2096
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2095

E. M. Beccalli, G. Broggini, M. Martinelli, G. Paladino, C. Zoni
FULL PAPER
[5] Y.-L. Chen, C.-H. Chung, I.-L. Chen, P.-H. Chen, H.-Y. Jeng,
Bioorg. Med. Chem. 2002, 10, 2705–2712.
[6] Z. Xiao, N. C. Waters, C. L. Woodard, Z. Li, P.-K. Li, Bioorg.
Med. Chem. Lett. 2001, 11, 2875–2878.
(dd, J = 2.2, 9.0 Hz, 1 H), 7.60 (d, J = 1.6 Hz, 1 H), 7.83 (d, J =
2.2 Hz, 1 H) ppm. 13C NMR: δ = 29.9 (q), 108.8 (d), 114.3 (s),
116.5 (s), 116.8 (d), 120.8 (d), 128.3 (s), 129.7 (d), 136.8 (s), 144.9
(d), 154.0 (s), 159.3 (s) ppm. IR: ν = 1659 cm–1. C H ClNO
˜
12
8
2
[7] a) T. Yamada, N. Saito, A. Noriyasu, M. Anraku, T. Imai,
M. Otagiri, Pharm. Develop. Techn. 2000, 5, 443–454; b) K.
Kawashima, T. Inoue, N. Tsutsumi, H. Endo, Biochem. Pharm-
acol. 1996, 51, 133–139; c) M. Kojima, N. Tsutsumi, H. Na-
gata, F. Itoh, A. Ujiie, K. Kawashima, H. Endo, M. Okazaki,
Biol. Pharm. Bull. 1994, 17, 504–508.
[8] M. Rowley, J. J. Kulagowski, A. P. Watt, D. Rathbone, G. I.
Stevenson, R. W. Carling, R. Baker, G. R. Marshall, J. A.
Kemp, A. C. Foster, S. Grimwood, R. Hargreaves, C. Hurley,
K. L. Saywell, M. D. Tricklebank, P. D. Leeson, J. Med. Chem.
1997, 40, 4053–4068.
[9] a) J.-P. Alazard, C. Millet-Paillusson, D. Guènard, C. Thal,
Bull. Soc. Chim. Fr. 1996, 133, 251–266; b) C. Thal, O. Boye,
D. Guenard, P. Potier (Centre National de la Recherche Sci-
entifique, Fr.), Patent No. WO 9002733, 1990; Chem. Abstr.
1990, 113, 115077; c) I. R. Fryer, R. Y.-F. Ning, L. H.
Sternbach, A. Walser (Hoffmann-La Roche, Inc., USA), Patent
No. US 4014883, 1977; Chem. Abstr. 1977, 87, 39450.
[10] a) J. D. Koruznjak, M. Grdisa, N. Slade, B. Zamola, K. Pavelic,
G. Karminski-Zamola, J. Med. Chem. 2003, 46, 4516–4524; b)
J. D. Koruznjak, N. Slade, B. Zamola, K. Pavelic, G. Karmin-
ski-Zamola, Chem. Pharm. Bull. 2002, 50, 656–660; c) X. Bu,
L. W. Deady, W. A. Denny, Aust. J. Chem. 2000, 53, 143–147.
[11] J. E. Ombetta, S. Lyet, A. Xicluna, J. F. Robert, J. J. Panouse,
Ann. Pharm. Fr. 1989, 46, 377–389.
(233.66): calcd. C 61.69, H 3.45, N 5.99; found C 61.66, H 3.41, N
5.90.
5,8-Dimethyl-5H-furo[3,2-c][1,8]naphthyridin-4-one (9bc): Yield:
1
36%. M.p. 184–186 °C (CH2Cl2/diisopropyl ether). H NMR: δ =
2.44 (s, 3 H), 3.85 (s, 3 H), 7.07 (s, 1 H), 7.64 (s, 1 H), 8.00 (s, 1
H), 8.40 (s, 1 H) ppm. 13C NMR: δ = 18.2 (q), 28.9 (q), 108.5 (s),
108.7 (d), 116.8 (s), 127.7 (s), 129.3 (d), 145.1 (d), 147.1 (s), 149.0
(d), 153.7 (s), 159.9 (s) ppm. IR: ν = 1660 cm–1. C H N O
˜
12 10
2
2
(214.23): calcd. C 67.28, H 4.71, N 13.08; found C 67.40, H 4.66,
N 13.19.
General Procedure for the Preparation of Fused Quinolones and
Naphthyridones 5 and 9 under Microwave Irradiation: A suspension
of the appropriate heteroamide (0.5 mmol), [Pd(PPh3)4] (59 mg,
0.05 mmol), and AcOK (75 mg, 0.77 mmol) in DMA (4 mL) was
heated in a microwave oven (450 W) at 120 °C for 12 min for 4bc
and 8ac and at 140 °C for 30 min for 4ac and 8bc. After cooling,
the residue was diluted H2O/NaCl (15 mL) and extracted with
Et2O. The organic layer was dried with Na2SO4 and evaporated
under reduced pressure. The residue was chromatographed on a
silica gel column with light petroleum ether/Et2O (5:1) as eluent to
give compounds 5 or 9.
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3,5,8-Trimethyl-3,5-dihydropyrrolo[2,3-c][1,8]naphthyridin-4-one
(5ac): Yield: 90%.
5,8-Dimethyl-5H-thieno[2,3-c][1,8]naphthyridin-4-one (5bc): Yield:
92%
5,8-Dimethyl-5H-thieno[3,2-c][1,8]naphthyridin-4-one (9ac): Yield:
96%.
5,8-Dimethyl-5H-furo[3,2-c][1,8]naphthyridin-4-one (9bc): Yield:
91%.
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Acknowledgments
The authors gratefully acknowledge the MIUR for financial sup-
port.
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Received: November 16, 2004
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