Synthesis of 5-methylfuro[3,2-c]quinolin-4(5H)-one via palladium-catalysed cyclisation of N-(2-iodophenyl)-N-methyl-3-furamide

Article abstract of DOI:10.1016/j.tetlet.2006.08.032

A new synthesis of the furo[3,2-c]quinolin-4(5H)-one heterocycle has been developed using a palladium-catalysed cyclisation of N-(2-iodophenyl)-N-methyl-3-furamide. By varying the catalyst, base and solvent, the yield of the cyclisation was optimised. It

Full text of DOI:10.1016/j.tetlet.2006.08.032

Tetrahedron Letters 47 (2006) 7493–7495
Synthesis of 5-methylfuro[3,2-c]quinolin-4(5H)-one via palladium-
catalysed cyclisation of N-(2-iodophenyl)-N-methyl-3-furamide
Karl-Fredrik Lindahl, Anthony Carroll, Ronald J. Quinn and Justin A. Ripper*
Eskitis Institute, Griffith University, Brisbane, Queensland 4111, Australia
Received 16 May 2006; revised 4 August 2006; accepted 10 August 2006
Abstract—A new synthesis of the furo[3,2-c]quinolin-4(5H)-one heterocycle has been developed using a palladium-catalysed
cyclisation of N-(2-iodophenyl)-N-methyl-3-furamide. By varying the catalyst, base and solvent, the yield of the cyclisation was
optimised. It was found that the use of palladium oxide with potassium acetate in N,N-dimethylacetamide (DMA) with a small
amount of tetrabutylammonium chloride gave the highest yield of 5-methylfuro[3,2-c]quinolin-4(5H)-one (9).
Ó 2006 Elsevier Ltd. All rights reserved.
Alkaloids containing the furoquinolinone core consti-
tute a significant group of the quinoline alkaloids and
this class of compounds have been shown to exhibit a
range of biological activities including, antifungal, anti-
bacterial, antiviral, antimicrobial, antimalarial, insecti-
cidal, antineoplastic, antidiuretic, antiarrhythmic and
sedative properties.1–4 Some examples of natural prod-
ucts containing the furoquinolinone core structure
include (+)-araliopsine, isolated from Ariliopsis soy-
auxii,5 and almeine (the absolute configuration of which
remains unknown), isolated from Almeida guyanensis6
(Fig. 1). Both of these plants belong to the family
Rutaceae.
(Fig. 2) have been published.2–4,7,8 However, the major-
ity of these syntheses use commercially available
4-hydroxy-1-methyl-2(1H)quinolone (2) or derivatives
thereof, as the starting material. When 2 is used as the
starting material an alkylation/cyclisation step using
various methods is required to build on the furan
ring.2–4 Alternatively, syntheses have been developed
using a palladium-catalysed arylation, to link the benz-
ene and the furan rings. Functional group manipula-
tion to allow the amide bond to form between the
benzene and furan rings generates the complete tri-
cycle.7,8 We wished to investigate an alternative strategy,
which has been used previously in the synthesis of other
similar tricyclic compounds.9,10 An example of this is the
synthesis of 1H-imidazo[4,5-c]quinolin-4(5H)-one (3),
an analogous structure to that of the furoquinolinone
core (1), developed by Kuroda and Suzuki.10
Several syntheses of natural and synthetic compounds
containing the furoquinolinone core structural unit 1
The alternative strategy, which was used in the synthesis
of 3,10 when applied to the synthesis of the furoquinol-
inone core 1, involves first forming an amide bond
between the benzene and furan rings followed by an
OH
O
O
N
O
N
O
Me
Me
OH
N
O
N
O
(+)-araliopsine
almeine
Figure 1.
N
H
O
N
N
O
H
2
Keywords: Furoquinolinones; Palladium catalyst; Palladium oxide.
1
3
*
Corresponding author. Tel.: +61 7 37356018; fax: +61 7 37356001;
e-mail: j.ripper@griffith.edu.au
Figure 2.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.032

7494
K.-F. Lindahl et al. / Tetrahedron Letters 47 (2006) 7493–7495
with an N-methyl group to aid the cyclisation reaction.
O
X
O
Indeed, it was found that all attempts to perform the
palladium-catalysed cyclisation reaction using 7 as the
starting material gave no indication of the cyclised
product.
N
R
O
N
O
R
A
B
The optimum conditions for the palladium-catalysed
cyclisation were found through a series of experiments
where sequential changes were made to the catalyst,
base and the solvent used (Table 1). Kuroda and Suzu-
ki10 had found that the use of palladium acetate and
sodium hydrogen carbonate, with the addition of
tetrabutylammonium chloride as additive, gave the best
result for cyclisation to give stricycle 3. The use of these
conditions in our system gave the cyclised product 9,13
in 83% yield (entry 1), however, if the catalyst was ex-
changed for palladium tetrakis or palladium oxide, the
yield was dramatically reduced. It was also noted that
there was a poor recovery of starting material in these
cases (entries 2 and 3). Performing the same reactions
in a non-polar solvent such as toluene gave only trace
amounts of the cyclisation product and an almost com-
plete recovery of the starting material when all three
types of catalysts were used (entries 4–6). Changing
the base to potassium acetate gave good yields for the
cyclisation product 9, and complete consumption of
the starting material, with all of the catalysts when the
Scheme 1.
intramolecular palladium-catalysed cyclisation. This can
be illustrated retrosynthetically where disconnection of a
C–C bond in A gives an N-phenyl-3-furamide derivative
B, as the precursor (Scheme 1). The key step in this ap-
proach would then be an intramolecular phenyl-furan
coupling reaction.
The synthesis of the amide precursor B, to be used in the
investigation of the palladium-catalysed cyclisation, is
shown in Scheme 2. The reaction of acid chloride 5 (gen-
erated from furoic acid 4 and thionyl chloride) with
2-iodoaniline 6 gave N-(2-iodophenyl)-3-furamide 7,11
which upon methylation, using methyl iodide and
sodium hydride in THF, gave tertiary amide 8.12 It had
been reported previously,9,10 that the palladium cyclisa-
tion had failed where a secondary amide was used as the
starting material. Therefore, the amide was protected
O
O
SOCl2, DCM
Cl
O
HO
O
95%
5
4
I
O
I
MeI, NaH,
Toluene
O
I
NH2
O
THF
Δ
N
O
Cl
N
H
O
95%
93%
O
Me
5
6
7
8
Scheme 2.
Table 1. Palladium-catalysed cyclisation of 8
Palladium
Catalyst, Base,
Solvent, Additive
O
I
O
N
O
N
O
Me
Me
8
9
Entrya
Solvent
Catalyst (0.1 equiv)
Base (1.4 equiv)
Temp (°C)
Yield 9 (%)
Recovered 8 (%)
1
2
3
4
5
6
7
8
9
DMA
DMA
DMA
Toluene
Toluene
Toluene
DMA
DMA
DMA
Pd(OAc)2
Pd(PPh)4
PdO
Pd(OAc)2
Pd(PPh)4
PdO
Pd(OAc)2
Pd(PPh)4
PdO
Pd(OAc)2
Pd(PPh)4
PdO
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
KOAc
KOAc
KOAc
KOAc
KOAc
150
150
150
100
100
100
150
150
150
100
100
100
83
9
0
0
0
90
90
90
0
0
0
30
55
27
10
<5
<5
<5
76
64
89
14
12
26
10
11
12
Toluene
Toluene
Toluene
KOAc
a All reactions were performed in the presence of tetrabutylammonium chloride (0.25 equiv) as additive and heated for 18 h under nitrogen.

K.-F. Lindahl et al. / Tetrahedron Letters 47 (2006) 7493–7495
7495
6. Moulis, C.; Wirasutisna, K. R.; Gleye, J.; Loiseau, P.;
Stanislas, E.; Moretti, C. Phytochemistry 1983, 22, 2095–
2096.
7. Gronowitz, S.; Timari, G. J. Heterocycl. Chem. 1990, 27,
1159–1160.
8. Glover, B.; Harvey, K. A.; Liu, B.; Sharp, M. J.;
Tymoschenko, M. F. Org. Lett. 2003, 5, 301–304.
9. Ames, D. E.; Opalko, A. Tetrahedron 1984, 40, 1919–1925.
10. Kuroda, T.; Suzuki, F. Tetrahedron Lett. 1991, 32, 6915–
6918.
reaction was run in DMA (entries 7–9). The best catalyst
was interestingly found to be palladium oxide under
these conditions, giving the cyclised product 9 in 89%
yield (entry 9). Repeating the reactions using potassium
acetate in toluene gave only slightly better yields of 9
(entries 10–12) compared with the reactions using
sodium hydrogen carbonate (entries 4–6), while the
amount of starting material recovered was significantly
lower.
11. Data for 7: mp 95–97 °C. IR (KBr) mmax: 3369, 3264, 3124,
3054, 2337, 1654, 1561, 1502, 1426, 1310, 1158, 1065, 1018,
866, 744 cmÀ1. UV kmax (MeOH): 205.8 nm (21460),
225.0 nm (19732). 1H NMR (CDCl3, 500 MHz): d 6.82
(s, 1H), 6.90 (dd, J = 8, 8 Hz, 1H), 7.41 (dd, J = 8, 8 Hz,
1H), 7.54 (s, 1H), 7.83 (d, J = 8 Hz, 1H), 7.90 (s, 1H, NH),
8.12 (s, 1H), 8.41 (d, J = 8 Hz, 1H). 13C NMR (CDCl3,
125 MHz): d 90.2, 108.5, 121.9, 123.5, 126.2, 129.7, 138.1,
139.0, 144.5, 145.6, 160.6. MS (ESI): m/z 314 [M+H]+,
187 [M+HÀIÅ]+. Anal. Calcd for C11H8INO2: C, 42.20; H,
2.58; N, 4.47. Found: C, 42.03; H, 2.51; N, 4.35.
12. Data for 8: mp 80–82 °C. IR (KBr) mmax: 3440, 3135, 2917,
1631 cmÀ1. UV kmax (MeOH) 204.6 nm (13460), 226.2 nm
(10716). 1H NMR (CDCl3, 500 MHz): d 3.35 (s, 3H), 6.22
(s, 1H), 6.82 (s, 1H), 7.14 (ddd, J = 7.5, 7.5, 1.5 Hz, 1H),
7.19 (s, 1H), 7.32 (dd, J = 7.5, 1.5 Hz, 1H), 7.44 (ddd,
J = 7.5, 7.5, 1.5 Hz, 1H), 7.95 (dd, J = 7.5, 1.5 Hz, 1H).
13C NMR (CDCl3, 125 MHz): d 37.23, 100.2, 111.2, 122.1,
130.0, 130.1, 130.4, 140.6, 142.4, 145.5, 146.5, 163.2. MS
(ESI): m/z 328 [M+H]+, 350 [M+Na]+. Anal. Calcd for
C12H10INO2: C, 44.06; H, 3.08; N, 4.28. Found: C, 43.88;
H, 3.04; N, 4.14.
In conclusion, a convenient and high yielding route to
5-methylfuro[3,2-c]quinolin-4(5H)-one has been devel-
oped using palladium-catalysed cyclisation as a key step.
It has been found that one of the simplest palladium cat-
alysts available, palladium oxide, in combination with
potassium acetate as base and tetrabutylammonium
chloride in DMA, gave the best yield for the intramole-
cular cyclisation.
Acknowledgements
One of us (K.-F.L.) acknowledges the Griffith Univer-
sity for financial support through a Griffith Postgradu-
ate Research Scholarship.
References and notes
1. Boyd, D. R.; Sharma, N. D.; Barr, S. A.; Carroll, J. G.;
Mackerracher, D.; Malone, J. F. J. Chem. Soc., Perkin
Trans. 1 2000, 3397–3405.
2. Bar, G.; Parsons, A. F.; Thomas, C. B. Tetrahedron 2001,
57, 4719–4728.
3. Lee, Y. R.; Kim, B. S.; Kweon, H. I. Tetrahedron 2000, 56,
3867, and references therein.
4. Pirrung, M. C.; Blume, F. J. Org. Chem. 1999, 64, 3642–
3649.
13. Data for 9: mp 126–128 °C. IR (KBr) mmax: 3579, 1660,
1257, 738 cmÀ1. UV kmax (MeOH): 228.8 nm (82846),
285.2 nm (15376), 319.2 nm (19621), 332.2 nm (18589). 1H
NMR (CDCl3, 500 MHz): d 3.81 (s, 3H), 7.10 (d, J =
2 Hz, 1H), 7.33 (dd, J = 7.5, 7.5 Hz, 1H), 7.48 (d,
J = 7.5 Hz, 1H), 7.58 (dd, J = 7.5, 7.5 Hz, 1H), 7.64 (d,
J = 2 Hz, 1H), 8.04 (d, J = 7.5 Hz, 1H). 13C NMR
(CDCl3, 125 MHz): d 29.7, 108.6, 113.5, 115.3, 115.6,
121.5, 122.5, 129.8, 138.4, 144.2, 155.4, 159.7. MS (ESI):
m/z 200 [M+H]+. Anal. Calcd for C12H9NO2: C, 72.35; H,
4.55; N, 7.03. Found: C, 72.14; H, 4.53; N, 6.86.
5. Vaquette, J.; Hifnawy, M. S.; Pousset, J. L.; Fournet, A.;
Bouquet, A.; Cave, A. Phytochemistry 1976, 15, 743–745.