One-pot synthesis of 2-substituted furo[3,2-c]quinolines via tandem coupling-cyclization under Pd/C-copper catalysis

Article abstract of DOI:10.1016/j.tetlet.2006.08.025

Pd/C-Cu catalyzed coupling reactions of 3-iodo-1H-quinolin-4-ones with a variety of terminal alkynes afforded furo[3,2-c]quinolines regioselectively in good to excellent yields. 3-Alkynyl quinolones were isolated under the same reaction conditions when th

Full text of DOI:10.1016/j.tetlet.2006.08.025

Tetrahedron Letters 47 (2006) 7317–7322
One-pot synthesis of 2-substituted furo[3,2-c]quinolines
via tandem coupling–cyclization under Pd/C-copper catalysisI
Subramanian Venkataraman, Deepak Kumar Barange and Manojit Pal*
Chemistry-Discovery Research, Dr. Reddy’s Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500 049, India
Received 25 May 2006; revised 31 July 2006; accepted 10 August 2006
Available online 1 September 2006
Abstract—Pd/C–Cu catalyzed coupling reactions of 3-iodo-1H-quinolin-4-ones with a variety of terminal alkynes afforded
furo[3,2-c]quinolines regioselectively in good to excellent yields. 3-Alkynyl quinolones were isolated under the same reaction
conditions when the nitrogen of 3-iodo-1H-quinolin-4-one was substituted with an alkyl group.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Furoquinoline derivatives are of particular interest
because they are isomers of the known family of
furo[2,3-b]quinoline alkaloids, which possess a broad
range of biological properties such as antiviral, antimi-
crobial, and antiplatelet aggregation activity.1 Recently,
linear and angular furoquinolinones (A and B, Fig. 1)
have shown promising blocking activities of the volt-
age-gated potassium channel Kv1.3.2 This channel is
considered to be a novel pharmacological target for
immunosuppressive therapy3 and therefore potent, spe-
cific Kv1.3 inhibitors have the potential to be of utility
in transplantation, autoimmune disease, and inflamma-
tion therapy.3a
an appropriate carbon chain at the C-3 position, which
is then modified into the furan ring depending on the
presence of an oxygen substituent at the C-2 or C-4 posi-
tions. A major drawback of this protocol is that once the
quinoline ring has been constructed, incorporation of a
carbon chain at C-3 through electrophilic aromatic sub-
stitution is difficult. While improved12c and alternative
methodologies15–17 have been reported to overcome this
problem, a general methodology for the synthesis of
angular furoquinolines has not been reported so far.
Recently, the construction of furan rings18 fused with
benzene or other six-membered heterocycles via palla-
dium-catalyzed annulation of alkynes19 has attracted
considerable interest. For example, furopyrimidine
derivatives have been synthesized via palladium- or cop-
per-catalyzed 5-endo-dig cyclization of 5-alkynyluridines
involving the C-4 pyrimidine oxygen and the acetylenic
bond.20,21 The use of a similar strategy has been revealed
in the synthesis of linear furoquinolines.22 However,
most of these processes require isolation of the Sono-
gashira product followed by cyclization in the next step.
While the use of copper acetylide under Castro reaction
conditions afforded linear and angular quinolines in low
yields (26–35%),23 this methodology also suffered from
a cumbersome, preparative procedure as well as the
stoichiometric use of an organometallic reagent, the
use of pyridine as a base and harsh reaction conditions.
In connection with our studies on the use of halogenated
enones of type –C@C(X)CO– (where X = I or Br,
Fig. 2) under modified Sonogashira conditions, we have
recently reported a new and one-pot synthesis of
3-enynyl(thio)flavones along with their 3-alkynyl
Among the many methods reported2,4–14 for the synthe-
sis of furoquinoline derivatives, a common strategy
involves the construction of a quinoline ring possessing
O
O
R2
R1
R1
O
N
O
N
CH3
CH3
B
A
Figure 1.
Keywords: Furo[3,2-c]quinolines; Palladium catalyst; Terminal alkynes;
3-Iodo-1H-quinolin-4-ones.
q DRL Publication No. 593.
*
Corresponding author. Tel.: +91 40 23045439; fax: +91 40 23045438/
23045007; e-mail: manojitpal@drreddys.com
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.025

7318
S. Venkataraman et al. / Tetrahedron Letters 47 (2006) 7317–7322
Table 1. The effect of palladium catalysts on the coupling reaction of
O
Z
3-iodo-2-phenyl quinolin-4-one with 2-methyl-3-butyn-2-ol in DMFa
X
R
R
O
O
O
Pd-catalyst, CuI
I
Z= O, S
Et3N, DMF
+
C6H5
N
H
2a
C6H5
Figure 2.
R
N
H
1a
C6H5
N
R = C(OH)Me2
3a
analogues.24 In continuation of this work, we now
report the use of 2-substituted 3-iodo-1H-quinolin-4-
one (Fig. 2, Z = NR0, R0 = H or CH3) as a starting
point to synthesize a variety of angular furoquinolines.
Palladium-catalyzed alkynylation of aryl or heteroaryl
rings (the Sonogashira coupling)25a has proved to be a
powerful tool for the C–C bond formation;25b however,
an one-pot process involving Sonogashira type coupling
followed by the electrophilic or transition-metal-medi-
ated cyclization of the resulting alkynes possessing a
suitable nucleophilic group in proximity to the triple
bond has now emerged as a versatile and efficient route
to various substituted heterocyclic systems.26 Typically
these coupling–cyclization reactions are carried out
using a palladium catalyst [e.g., Pd(PPh3)4, (PPh3)2-
PdCl2, etc.] and a copper salt as co-catalyst in the
presence of an amine base. While the use of Pd/C–
CuI–PPh3 as a less expensive catalytic system has been
studied extensively27 its application in coupling–cycliza-
tion is not common.28 Due to our interest in Pd/C-based
methodologies,27a,28 we now report the first palladium
(on charcoal)-copper mediated synthesis of diverse
2-substituted furo[3,2-c]quinolines.
Entry
Pd-catalyst
Temp (ꢁC); time (h)
Yield (%)c
3ab
1ab
1d
2
10% Pd/C–PPh3
Pd(PPh3)4
Pd(PPh3)2Cl2
10% Pd/C–PPh3
10% Pd/C–PPh3
10% Pd/C
75–80; 3
75–80; 2
75–80; 2
75–80; 3
75–80; 3
80; 3
70
11
85
80
34
n.d.
22
n.d.
n.d.
n.d.
17
3
4e
5f
6
n.d.
n.d. = not detected.
a Reaction conditions: 2a (1.0 equiv), terminal alkyne (2.0 equiv), Pd-
catalyst (0.03 equiv), CuI (0.06 equiv), Et3N (5 equiv) in DMF under
N2 atmosphere.
b Identified by 1H NMR, 13C NMR, IR, and mass spectroscopy.
c Isolated yields.
d The reaction was carried out using a 1:4:2 ratio of Pd/C–PPh3–CuI.
e THF was used in the place of DMF.
f CuI was not used.
a cheaper source of palladium catalyst, we continued
our studies using only this catalyst system. The results
of our studies are summarized in Table 1. DMF was
used as a solvent, other solvents such as THF (Table
1, entry 4) and acetonitrile were found to be less effec-
tive, perhaps due to the poor solubility of 2a in these sol-
vents. The formation of only de-iodinated product
(Table 1, entry 5) in the absence of copper salt high-
lighted the crucial role of CuI in this coupling–cycliza-
tion process. The absence of PPh3 resulted in a poor
yield of 3a (Table 1, entry 6).
To initiate our studies, we first prepared a series of
3-iodoquinolin-4-ones 2a–d in good yields through
iodination of the corresponding quinolin-4-ones29 using
iodine and ceric ammonium nitrate (CAN) in aceto-
nitrile at 70–80 ꢁC (Scheme 1).30a
Firstly, 3-iodo-2-phenyl-1H-quinolin-4-one 2a was trea-
ted with 2.0 equiv of 2-methyl-3-butyn-2-ol in dimethyl-
formamide (DMF) in the presence of 10% Pd/C
(0.03 equiv), PPh3 (0.12 equiv), CuI (0.06 equiv), and tri-
ethylamine (5 equiv) under a nitrogen atmosphere to
give 2-(4-phenylfuro[3,2-c]quinolin-2-yl)-2-ol 3a in 70%
yield along with a minor quantity of de-iodinated prod-
uct (Table 1, entry 1). The use of Pd(PPh3)4 or
Pd(PPh3)2Cl2 in the place of Pd/C–PPh3 improved the
yield of 3a to 80–85% and no de-iodinated product
was detected (Table 1, entries 2 and 3). Notably, the
use of 2b in the presence of 10%Pd/C–PPh3–CuI as a
catalyst afforded the desired product in 83% yield (Table
2, entry 1).30b Encouraged by this result and Pd/C being
In view of the encouraging results obtained using 2b, we
decided to explore the generality and scope of this cou-
pling–cyclization process. Thus 2b was treated with a
variety of terminal alkynes under the conditions
described earlier (Table 1, entry 1) and the results are
summarized in Table 2. Good yields of the desired
furo[3,2-c]quinolines 4 were obtained irrespective of
the nature of terminal alkynes used (Table 2, entries
1–5). Aryl, alkyl, and hydroxy groups present in the
terminal alkynes were well tolerated. Similarly, 2a was
treated with a number of terminal alkynes to afford
the corresponding furo[3,2-c]quinolines 3 in 67–72%
yields (Table 2, entries 6–9). The use of 3-iodo-2-thien-
2-yl-1H-quinolin-4-one 2c also afforded the desired
product albeit in moderate yield (Table 2, entry 10).
Notably, in contrast to the earlier observations22a,b
no 3-alkynyl quinolone was isolated in our examples.
However, de-iodinated product (1a or 1c) was isolated,
at least in 10–12% yields, when 2a or 2c was used. This
was not observed when Pd(PPh3)4 was employed in
place of Pd/C–PPh3 and better yields (>80%) of 3 were
obtained.
O
O
R2
R2
I2 / (NH4)2Ce(NO3)6
MeCN, 70-80 o
I
R3
C
R3
N
N
R1
R1
1a R1 = H; R2 = H; R3 = C6H5
2a (80%)
2b (78%)
2c (64%)
2d (75%)
1b R1 = H; R2 = F; R3 = CO2CH3
1c R1 = H; R2 = H; R3 = thien-2-yl
1d R1 = CH3; R2 = H; R3 = CO2CH3
The key features of the present tandem coupling–cycli-
zation process are the transition-metal-mediated activa-
Scheme 1. Preparation of 3-iodoquinolin-4-one derivatives.

S. Venkataraman et al. / Tetrahedron Letters 47 (2006) 7317–7322
Table 2. Pd/C mediated synthesis of 2-substituted furo[3,2-c]quinolinesa
7319
R
O
O
Pd/C, PPh3, CuI
Et3N, DMF
R2
R2
I
R3
R
N
N
R3
R1 = H
R1
3 or 4
2
Entry
1
3-Iodoquinoline-4-one (2)
Alkyne
Time (h)
2
Productb (3/4)
Yield (%)c
O
HO
O
F
I
„—C(OH)Me2
83
F
N
CO2CH3
H
2b
N
COOMe
4a
HO
O
2
3
2b
„—CH(OH)Me
2
2
F
85
75
N
COOMe
4b
HO
O
F
2b
„—
CH(OH)CH2CH3
N
COOMe
4c
OH
O
F
F
4
5
2b
2b
„—CH2OH
2
75
76
N
COOMe
4d
C6H5
O
„—Ph
1.5
N
COOMe
4e
HO
O
O
I
6
„—C(OH)Me2
3
70
N
N
H
C6H5
2a
3a
HO
O
7
2a
„—
3
68
CH(OH)CH2CH3
N
3b
OH
O
8
2a
„—CH2CH2OH
3
72
N
3c
(continued on next page)

7320
S. Venkataraman et al. / Tetrahedron Letters 47 (2006) 7317–7322
Table 2 (continued)
Entry
3-Iodoquinoline-4-one (2)
Alkyne
Time (h)
Productb (3/4)
C6H5
Yield (%)c
O
9
2a
„—Ph
3
67
N
3d
3e
C6H5
O
10
2c
„—Ph
3
60
S
N
a All reactions were carried out by using 2 (1.0 equiv), terminal alkyne (2.0 equiv), 10% Pd/C (0.03 equiv), PPh3 (0.12 equiv), CuI (0.06 equiv), Et3N
(5 equiv) in DMF at 75–80 ꢁC.
b Identified by 1H NMR, 13C NMR, IR, and mass spectroscopy.
c Isolated yields.
O
O
O
R
O
O
Pd/C-PPh3-CuI
Et3N, DMF
I
I
Pd
R3
I
Pd
R3
R
R
Pd(0)
N
H
R3
CuI
N
CO2CH3
R
N
CO2CH3
N
H
N
H
CH3
CH3
2d
2
5a; R = CMe2OH (60%)
5b; R = C6H5 (70%)
X
Pd(0)
5c; R = C6H3(OMe)-m,p (65%)
R
O
R
O
Scheme 2. Preparation of 2-substituted 9-methyl-9H-furo[2,3-b]-
quinolin-4-ones 5.
-Cu(I)
Cu
N
H
R3
N
R3
3 or 4
tion of the triple bond of the 3-alkynyl quinoline gener-
ated in situ followed by an intramolecular attack of the
oxygen on the activated triple bond with subsequent
proton transfer and release of the metal ion to give the
desired furoquinoline (see later for mechanistic discus-
sion). The NH of the quinolone ring has a critical role
in the cyclization step and perhaps facilitated the prefer-
ential participation of the C-4 quinoline oxygen over the
ester when 2b was used as the halide component. This is
particularly interesting as a Lewis acid mediated cycliza-
tion of 2-ethynylbenzoic acid ester leading to a 3-substi-
tuted isocoumarin has been reported.31 However, to
assess the role of the N-hydrogen, we treated 3-iodo-1-
Scheme 3. Proposed mechanism for the tandem coupling–cyclization
process.
in the case of 2b perhaps resulted from an intramolecu-
lar coordination of the neighboring carbonyl oxygen to
the palladium during the iodide displacement step
(Scheme 4).
O
O
I
Pd
Pd
R
R
O
CuI
Et3N
N
H
N
H
CO2CH3
methyl-4-oxo-1,4-dihydroquinoline-2-carboxylic
acid
OMe
methyl ester 2d with terminal alkynes under the same
conditions. Only 3-alkynyl quinolones 5 were isolated
in these cases as a result of normal Sonogashira coupling
and no formation of furoquinoline was observed, even
in trace amounts (Scheme 2).
X
Scheme 4. Effect of neighboring group on the coupling of X with a
terminal alkyne.
In conclusion, we have shown that 2-substituted
3-iodoquinolones can react with a variety of terminal
alkynes under the palladium/copper catalysis. These
reactions proceed under mild conditions and afford
furo[3,2-c]quinolines with remarkable regioselectivity
irrespective of the nature of the substituent present at
C-2 of the starting quinolone. The presence of an ester
moiety at this position leads to the best yields of prod-
ucts. The present one-pot and regioselective synthesis
of 2-substituted furo[3,2-c]quinolines via Pd/C based
methodology does not involve the use of expensive
A plausible reaction mechanism is depicted in Scheme 3.
The Pd(0) species generated in situ from Pd/C and PPh3
catalyzes the coupling of 3-iodoquinolin-4-one 2 with
copper(I) acetylide (generated in situ from the terminal
alkyne) via intermediate X leading to the 3-alkynyl quin-
olin-4-one. This subsequently affords the corresponding
furoquinoline (3 or 4) via activation of the triple bond
through its complexation with the copper(I) salt fol-
lowed by intramolecular cyclization20,32 with regenera-
tion of the Cu(I) catalyst.33 The better yields observed

S. Venkataraman et al. / Tetrahedron Letters 47 (2006) 7317–7322
7321
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reagents or catalysts and therefore permits a new and
practical access to angular furoquinolines. The ongoing
work seeks to expand the scope of this process to the
synthesis of compounds of pharmacological interest.
Acknowledgements
The authors thank Dr. A. Venkateswarlu, Dr. R. Raja-
gopalan, and Professor J. Iqbal of Dr. Reddy’s Labora-
tories Ltd., Hyderabad, India for their constant
encouragement. The authors also thank Dr. K. Vyas
and his group for the spectral support.
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T.; Horwitz, C. P.; Fessak, A.; Keshavarz-K, M.; Nash,
K. E.; Toscano, P. J. J. Am. Chem. Soc. 1993, 115, 10444–
10445; (j) De la Rosa, M. A.; Velarde, E.; Guzman, A.
Synth. Commun. 1990, 20, 2059–2064.

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28. For Pd/C mediated synthesis of 2-substituted benzo[b]fur-
ans, see: (a) Pal, M.; Subramanian, V.; Yeleswarapu, K.
R. Tetrahedron Lett. 2003, 44, 8221–8225; For indoles, see:
(b) Pal, M.; Subramanian, V.; Batchu, V. R.; Dager, I.
Synlett 2004, 1965–1969; For isocoumarins, see: (c)
Subramanian, V.; Batchu, V. R.; Barange, D.; Pal, M. J.
Org. Chem. 2005, 70, 4778–4783.
29. 2-Phenyl-1H-quinolin-4-one 1a was prepared according
to a known procedure, see: (a) Kuo, S.-C.; Lee, H.-Z.;
Juang, J.-P.; Lin, Y.-T.; Wu, T.-S.; Chang, J.-J.; Lednicer,
D.; Paull, K. D.; Lin, C. M.; Hamel, E.; Lee, K.-H.
J. Med. Chem. 1993, 36, 1146–1156; For the preparation
of 6-fluoro-4-oxo-1,4-dihydroquinoline-2-carboxylic acid
methyl ester 1b, see: (b) Edmont, D.; Rocher, R.; Plisson,
C.; Chenault, J. Bioorg. Med. Chem. Lett. 2000, 10,
1831–1834; For the preparation of 1-methyl-4-oxo-1,4-
dihydroquinoline-2-carboxylic acid methyl ester 1d, see:
(c) Cairns, H.; Payne, A. R. J. Heterocycl. Chem. 1978,
15, 551–553.
30. (a) To a solution of appropriately substituted quinolin-4-
one (1, 4.52 mmol) in acetonitrile (25 mL) was added ceric
ammonium nitrate (0.248 g, 0.45 mmol) followed by
iodine (0.631 g, 4.97 mmol). The mixture was stirred at
70–80 ꢁC under nitrogen for 3–8 h. After completion of
the reaction, the mixture was cooled to room temperature
and treated with an ice-cold aqueous solution of sodium
thiosulfate with stirring. The resulting precipitated solid
was filtered to afford the desired product.; (b) Typical
procedure: preparation of 8-fluoro-2-(1-hydroxy-1-meth-
ylethyl)furo[3,2-c]quinoline-4-carboxylic acid methyl ester
(4a, entry 1, Table 2): A mixture of 2b (0.86 mmol), 10%
Pd/C (0.026 mmol), PPh3 (0.10 mmol), CuI (0.05 mmol),
and triethylamine (4.3 mmol) in dry DMF (5 mL) was
stirred for 1.5 h under a nitrogen atmosphere. To this was
added 2-methylbut-3-yn-2-ol (1.72 mmol) slowly and the
mixture was stirred at 75–80 ꢁC for 2 h. The mixture was
then cooled to room temperature and filtered through
Celite. The filtrate was diluted with water (20 mL) and
extracted with EtOAc (3 · 10 mL). The organic layers
were collected, combined, washed with water (2 · 10 mL),
dried over anhydrous Na2SO4, and concentrated. The
residue thus obtained was purified by column chromato-
graphy using EtOAc–petroleum ether (1:2) to afford the
1
title compound as a pale brown solid; mp 194–196 ꢁC; H
NMR (CDCl3, 400 MHz) d 8.40–8.36 (m, 1H), 7.92–7.89
(m, 1H), 7.53–7.48 (m, 1H), 7.37 (s, 1H), 4.13 (s, 3H,
COOCH3), 2.22 (br s, D2O exchangeable, –OH), 1.78 (s,
6H); m/z (CI) 304 (M+1, 100%); IR (cmꢀ1, neat) 3408,
2985, 1737, 1457, 1304, 1199, 819; UV (nm, MeOH)
254.50, 229.00; HPLC 98.5%, Column: INERTSIL ODS
3V (250 · 4.6) mm, mobile Phase: A: 0.01 M KH2PO4, B:
CH3CN, gradient (T/%B) 0/40, 5/40, 20/80, 25/80, 30/40,
35/40, flow rate: 1.0 mL/min, UV 254 nm, retention time
12.4 min.
31. See for example: Sakamoto, T.; Annaka, M.; Kondo, Y.;
Yamanaka, H. Chem. Pharm. Bull. 1986, 34, 2754–2759.
32. Cu(I) in DMF has been reported as an efficient catalytic
system for a similar cyclization process; see for example:
Patil, N. T.; Wu, H.; Yamamoto, Y. J. Org. Chem. 2005,
70, 4531–4534.
33. An alternative pathway involving activation of the carbonyl
group through the coordination of Cu(I) to the carbonyl
oxygen and the p-bond of the alkyne may also facilitate the
intramolecular cyclization process, see Ref. 32.