Copper-free palladium-catalyzed sonogashira coupling-annulation: Efficient one-pot synthesis of functionalized pyrano[4,3-b]quinolines from 2-chloro-3-formylquinolines

Article abstract of DOI:10.1021/jo900606j

(Equation Presented) A convenient, one-pot, copper-free, Pd-catalyzed methodology has been described for the synthesis of 1,3-disubstituted pyrano[4,3-b]quinolines from 2-chloro-3-formylquinolines. Formation of annulated products 3 is attributed to the pr

Full text of DOI:10.1021/jo900606j

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processes, initially involving the formation of Sonogashira
Copper-Free Palladium-Catalyzed Sonogashira
Coupling-Annulation: Efficient One-Pot Synthesis
of Functionalized Pyrano[4,3-b]quinolines from
2-Chloro-3-formylquinolines
coupling products followed by transition-metal-catalyzed7
or electrophile-catalyzed8 cyclization of the resulting alkynes
with their preexisting nucleophile in the subsequent step.
Recently, a one-pot synthesis9 involving Sonogashira cou-
pling followed by cyclization of the resulting alkynes with
suitable nucleophiles in proximity to the triple bond has
emerged as an efficient route to the synthesis of variety of
heterocycles. Generally, in these coupling-cyclization reac-
tions, copper salts were used as cocatalysts along with
palladium catalyst [e.g., Pd(PPh3)4, PdCl2(PPh3)2, Pd/C-
PPh3] in the presence of amine base. However, one-pot
Sonogashira coupling and cyclization reactions of o-chlor-
obenzaldehyde have not been explored. However, Yamamo-
to et al. have reported the Pd(OAc)2-catalyzed cyclization of
o-alkynylbenzaldehydes using methanol as nucleophile to
the synthesis of the 1,3-disubstituted cyclic alkenyl ether
moiety of isochromenes.10
Atish Chandra, Bhawana Singh, Ranjana S. Khanna, and
Radhey M. Singh*
Department of Chemistry, Banaras Hindu University,
Varanasi - 221 005, U.P., India
rmohan@bhu.ac.in
Received March 27, 2009
In continuation of our interest in the synthesis of carbo-/
heteroannulated quinolines,11 we have recently reported the
copper-free Sonogashira coupling of 2-chloroquinoline-3-
carboxaldehydes with phenylacetylene followed by N-nu-
cleophile cyclization of the resulting alkyne in the subsequent
step to benzo[b][1,6]naphthyridines.12 We realized from
these observations that copper-free palladium-catalyzed re-
action of o-haloaryl/heteroaryl aldehydes with terminal
alkynes and methanol as nucleophile could lead to the
synthesis of isochromenes/heteroanalogues in one pot via
Sonogashira coupling and annulation. Because of our recent
interest in palladium-catalyzed coupling-annulation, we
report here the one-pot synthesis of 1,3-disubstituted 1H-
pyrano[4,3-b]quinolines from 2-chloroquinoline-3-carbox-
aldehydes (1)13 with phenylacetylene using Pd(OAc)2 as a
catalyst, PPh3 as ligand, Et3N as base, and methanol as
nucleophile.
A convenient, one-pot, copper-free, Pd-catalyzed meth-
odology has been described for the synthesis of 1,3-
disubstituted pyrano[4,3-b]quinolines from 2-chloro-3-
formylquinolines. Formation of annulated products 3 is
attributed to the presence of Pd(OAc)2 and PPh3.
Further, PPh3 in the reaction mixture promotes the
cyclization by reducing the reaction time and increasing
the yield of cyclized product.
Over the past few years, palladium-catalyzed coupling/
annulation reactions of alkynes mostly with vinyl/aryl ha-
lides containing preexisting nucleophiles have been studied
for the synthesis of a variety of heterocycles/annulated
heterocycles,1 for example, R-pyrones,2 pyridines,3 indoles,4
benzofurans,5 benzopyrans,6 isocoumarins,2 and isoquino-
lines.3 In contrast to internal alkynes, terminal alkynes
require two-step reactions in most of these annulation
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Published on Web 06/04/2009
DOI: 10.1021/jo900606j
r
2009 American Chemical Society

JOCNote
SCHEME 1. One-Pot Synthesis of Pyrano[4,3-b]quinoline via Palladium Catalyst
TABLE 1. Optimization of the Reaction Conditions for Cyclization of 1a to 3a and 2a to 3a
entry
reaction conditions
substrate
total time (h)
3a, yield (%)
1
5% Pd(OAc)2, 10% PPh3, 2 equiv TEA, MeOH (4 mL), 80 °C
5% Pd(OAc)2, 10% PPh3, 2 equiv TEA, 80 °C
10% Pd(OAc)2, 20% PPh3, 2 equiv TEA, 80 °C
10% Pd(OAc)2, 20% PPh3, 3 equiv TEA, 80 °C
10% PdCl2, 20% PPh3, 2 equiv TEA, 80 °C
10% Pd(OAc)2, 20% PPh3, 80 °C
1a
1a
1a
1a
1a
2a
2a
overnight
overnight
6
6
7
SM
28
76
76
68
80
70
2a
3a
4a
5a
6b
7b
2.5
16
10% Pd(OAc)2, 80 °C
a Each reaction contained 2-chloro-3-formylquinoline 1a (0.25 mmol), and excess methanol (4 mL) was added after consumption of substrate 1a.
b Each reaction contained 2a (0.25 mmol) and excess methanol (4 mL), which is used as nucleophile and solvent.
TABLE 2. One-Pot Synthesis of Pyrano[4,3-b]quinolines
entry substrate product total time (h) 3, yield (%)
The pyranoquinoline derivatives have wide applications,
for example, as drugs, pharmaceuticals, and agrochemicals,
and possess a significant range of biological activities, such
as anti-inflammatory, antiallergic, psychotropic, and estro-
genic.14
R
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
H
3a
3b
3c
3d
3e
3f
6
5
4.5
5
5.5
6
76
74
71
73
69
78
71
6-Me
7-Me
7-OMe
8-Me
8-Et
Initially, the reaction of 2-chloro-3-formylquinolines (1)
with phenylacetylene under our optimized copper-free
Sonogashira coupling conditions and using methanol as
a nucleophile was examined for the desired cyclized
products, 1-methoxy-3-phenyl-1H-pyrano[4,3-b]quinolines
(3) (Scheme 1). Thus, the reaction of 1a with phenylacetylene
using 5 mol % of Pd(OAc)2, 10 mol % of PPh3, 2 equiv
of Et3N in acetonitrile, and methanol (4.0 mL) as a nucleo-
phile at 80 °C for overnight did not give the desired cyclized
product 3a15 at all, and the starting material 1a was recov-
ered (Table 1, entry 1). On the other hand, methanol
was added to the reaction mixture after the formation of
the Sonogashira product 2a, using optimized copper-free
Songashira coupling conditions, to provide the cyclized
product 3a in 28% yield along with uncyclized 2a (Table 1,
entry 2). Encouraged by this result, we next attempted
the reaction to explore the optimum reaction conditions by
using various combinations of palladium source, ligand, and
base for the best yield of 3a. The combination of 10 mol % of
Pd(OAc)2, 20 mol % of PPh3, and 2 equiv of Et3N in
acetonitrile at 80 °C for 3.5 h followed by addition of
methanol (4.0 mL) at 80 °C and continued heating for a
further 2.5 h not only gave the best yield of the cyclized
product 3a (76%) but also reduced the reaction time (Table 1,
entry 3). An increase in the number of equivalents of Et3N
did not improve the yield of the cyclized product 3a (Table 1,
entry 4).16 Thus, the increase in the yield of the cyclized
product 3a could be attributed to an increase in the mol % of
Pd(OAc)2 and PPh3. However, the use of PdCl2 under similar
condition for 7 h did not improve the yield of cyclized
1g
6-OMe
3g
5
product 3a (Table 1, entry 5), although the use of PdCl2 in
place of Pd(OAc)2 afforded a better yield of the Sonogashira
products 2.12
Encouraged by the establishment of the optimum reaction
conditions (Table 1, entry 3), we tested the series of sub-
stituted 2-chloroquinoline-3-carboxaldehydes 1b-g under
our standard Sonogashira coupling-annulation conditions
using 10 mol % of Pd(OAc)2, 20 mol % of PPh3, and 2 equiv
of Et3N in acetonitrile at 80 °C followed by addition
of methanol (4.0 mL) at 80 °C and continued heating to
afford the corresponding 1-methoxy-1H-pyrano[4,3-b]qui-
nolines 3b-g in good yields. The results are summarized
in Table 2.
To explore the mechanism of the cyclization, we fur-
ther examined the reaction of 2a with various reagents such
as Pd(OAc)2/PPh3, Pd(OAc)2, PPh3, and Et3N. Thus, the
reaction of 2a with 10 mol % of Pd(OAc)2 and 20 mol % of
PPh3 in methanol (4.0 mL) at 80 °C for 2.5 h afforded the
cyclized product 3a in 80% yield (Table 1, entry 6). However,
when Yamamoto conditions were applied,10 using only 10
mol % of Pd(OAc)2 in methanol (4.0 mL) at 80 °C for 16 h
afforded the cyclized product 3a in 70% yield (Table 1, entry
7). In contrast, using PPh3 (20 mol %) in the absence of Pd
(OAc)2 in methanol with 2a at 80 °C for 4 h afforded the
mixture of unidentified products. Further, Et3N and Et3N-
HCl were also examined for cyclization and proved to be
totally ineffective; none of the desired product was detected
at all.16 These observations clearly indicated that the PPh3
ligand with the Pd(OAc)2 facilitated the cyclization reaction
and increased the yield of the product 3a.
(14) (a) Yamada, N.; Kadowaki, S.; Takahashi, K.; Umezu, K. Biochem.
Pharmacol. 1992, 44, 1211–1213. (b) Faber, K.; Stueckler, H.; Kappe, T. J.
Heterocycl. Chem. 1984, 21, 1177–1181. (c) Johnson, J. V.; Rauckmann, B.
S.; Baccanari, D. P.; Roth, B. J. Med. Chem. 1989, 32, 1942–1949.
(d) Mohmed, E. A. Chem. Pap. 1994, 48, 261-267; Chem. Abstr. 1995,
123, 9315x
(15) Godet, T.; Bosson, J.; Belmont, P. Synlett 2005, 2786–2790.
(16) Yue, D.; Ca, N. D.; Larock, R. C. J. Org. Chem. 2006, 71,
3381–3388.
In conclusion, we have developed a new, one-pot
palladium-catalyzed methodology for the synthesis of
J. Org. Chem. Vol. 74, No. 15, 2009 5665

JOCNote
1,3-disubstituted pyrano[4,3-b]quinolines without copper as
a cocatalyst and avoiding column purification steps.
Further, the presence of the PPh3 ligand with Pd(OAc)2
facilitates the cyclization reaction by reducing the reaction
time and increasing the yield of cyclized product.
MS m/z = 290 [M + H]+; HRMS calcd for C19H16NO2 [M + H]+
290.1181, found 290.1175.
1-Methoxy-8-methyl-3-phenyl-1H-pyrano[4,3-b]quinoline
(3b):. light yellow solid; yield 74%; mp 115 °C; 1H NMR
(300 MHz, CDCl3) δ 2.53 (s, 3H), 3.69 (s, 3H), 6.35 (s, 1H),
6.97 (s, 1H), 7.43-7.56 (m, 5H), 7.88-7.96 (m, 4H); 13C NMR
(75 MHz, CDCl3) δ 21.5, 55.8, 100.2, 102.0, 113.9, 122.5, 125.3,
126.8, 128.2, 128.6, 129.7, 132.1, 132.6, 133.8, 135.5, 147.2,
148.6, 155.4; IR (KBr) 1021, 1465, 1621 cm-1; HRMS calcd
for C20H18NO2 [M+H]+ 304.1338, found 304.1335.
Experimental Section
General Procedure for the Pd-Catalyzed One-Pot Synthesis of
Pyrano[4,3-b]quinolines 3. A mixture of 2-chloro-3-formylqui-
nolines (1) (0.25 mmol), phenylacetylene (0.26 mmol), Pd(OAc)2
(10 mol %), and PPh3 (20 mol %) in CH3CN (4.0 mL) and TEA
(2 equiv) was stirred under N2 at 80 °C for 3.5 h (as monitored by
TLC) followed by addition of methanol (4.0 mL) at the same
temperature for 2.5 h. After completion of the reaction, mixture
was concentrated in vacuo and residue was purified by column
chromatography on silica gel (silica gel was neutralized by TEA)
using 10:90 EtOAc/hexane as eluent.
Acknowledgment. We acknowledge the Council of Scien-
tific and Industrial Research (CSIR), New Delhi, India, and
the University Grant Comission (UGC), New Delhi, India,
for financial support. A.C. and B.S. are thankful to CSIR,
New Delhi, for the award of Senior Research Fellowship. We
also thank Prof. S. Baskaran, Department of Chemistry,
IIT Madras, Chennai, India, Director and SAIF, CDRI,
Lucknow, India, for HRMS data.
1-Methoxy-3-phenyl-1H-pyrano[4,3-b]quinoline (3a):. yellow
solid; yield 76%; mp 125 °C; 1H NMR (300 MHz, CDCl3) δ 3.70
(s, 3H), 6.36 (s, 1H), 6.98 (s, 1H), 7.44-7.49 (m, 4H), 7.70 (t, J =
7.2 Hz, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.89 (m, 2H), 8.03-8.10
(m, 2H); 13C NMR (75 MHz, CDCl3) δ 56.1, 98.9, 99.6, 122.5,
125.9, 126.4, 126.7, 128.0, 128.3, 128.7, 130.0, 130.8, 131.7,
Supporting Information Available: Experimental details,
spectroscopic and analytical data, and 1H and 13C NMR spectra
of the products 3a-g. This material is available free of charge
via the Internet at http://pubs.acs.org.
133.3, 135.7, 148.7, 158.7; IR (KBr) 1022, 1376, 1445, 1615 cm-1
;
5666 J. Org. Chem. Vol. 74, No. 15, 2009