Base-free NIS promoted electrophilic cyclization of alkynes: An efficient synthesis of iodo substituted pyrano[4,3-b]quinolines

Article abstract of DOI:10.1016/j.tet.2010.10.081

A simple and mild procedure for the synthesis of iodo substituted 1H-pyrano[4,3-b]quinolines has been achieved using NIS reagent in the absence of base from 2-alkynylquinoline-3-carboxaldehydes via intramolecular electrophilic cyclization onto alkynes in good to excellent yields in a short duration of time. The reactions proceeded smoothly in a normal solvent in aerobic atmosphere at room temperature. The presence of substituent at either quinoline or alkyne moieties did not show effect on reaction rate of cyclization. The palladium-catalyzed transformations of iodo group to C-C bond are also discussed. Copyright

Full text of DOI:10.1016/j.tet.2010.10.081

Tetrahedron 67 (2011) 505e511
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Tetrahedron
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Base-free NIS promoted electrophilic cyclization of alkynes: an efficient synthesis
of iodo substituted pyrano[4,3-b]quinolines
*
Bhawana Singh, Atish Chandra, Seema Singh, Radhey M. Singh
Department of Chemistry, Banaras Hindu University, Varanasi 221 005, U.P., India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 July 2010
Received in revised form 19 October 2010
Accepted 27 October 2010
Available online 12 November 2010
A simple and mild procedure for the synthesis of iodo substituted 1H-pyrano[4,3-b]quinolines has been
achieved using NIS reagent in the absence of base from 2-alkynylquinoline-3-carboxaldehydes via in-
tramolecular electrophilic cyclization onto alkynes in good to excellent yields in a short duration of time.
The reactions proceeded smoothly in a normal solvent in aerobic atmosphere at room temperature. The
presence of substituent at either quinoline or alkyne moieties did not show effect on reaction rate of
cyclization. The palladium-catalyzed transformations of iodo group to CeC bond are also discussed.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Base-free
NIS
Electrophilic
Pyrano[4,3-b]quinolines
1. Introduction
In contrast, o-alkynyl heterocyclic carboxaldehydes have been
less studied, although it could be a facile route to pyrano/benzo
Iodocyclization of functionally substituted alkynes has emerged
as an important and efficient route for the preparation of a wide
variety of carbocyclic and heterocyclic structures.1 Recently, iodo-
cyclization of alkyne with an aldehyde in o-alkynylbenzaldehydes
has been explored providing either oxygen heterocycles in the form
of the 1,3-disubstituted cyclic alkenyl ether moiety of isochromene2
or carbocycles, such as the benzene moiety of naphthalene3 (Fig. 1).
The aromatic structure studied in these reactions was typically
a benzene ring.
annulated heterocycles. Recently, Barluenga et al. have reported
iodocyclization of 3-alkynyl-2-carboxaldehyde derivatives of pyr-
role, furan, and thiophene using IPy2BF4 and HBF4 reagents and
alkene nucleophiles in the synthesis of indole, benzofuran, benzo-
thiophene, and alcohol nucleophiles in the synthesis of 7H-thieno
[2,3-c]pyran.4 Larock et al. have reported iodocyclization of
2-phenylethynylpyridine-3-carboxaldehydes to the synthesis of 5H-
pyrano[4,3-b]pyridine using I2/K2CO3 and methanol nucleophile.2b
However, iodocyclization of 2-alkynylquinoline-3-carboxaldehydes
2 using alcohol nucleophiles has not been explored. Although silver
and palladium-catalyzed cyclization of alkynylquinoline-3-car-
boxaldehydes have been reported to the synthesis of furo/pyrano
annulated quinolines recently.5,6 These chemical methods have
certain limitations, such as availability of expensive metal cata-
lysts, inert atmosphere, high temperature, and longer reaction
time conditions. Hence, it is desirable to search an inexpensive
reagent for the cyclization of 2-alkynylquinoline-3-carbox-
aldehydes to the synthesis of pyranoquinolines that can over-
come some of the limitations associated with the existing
methodologies. Recently, we have reported an intramolecular
iodocyclization of alkene to the synthesis of pyranoquinolines.7
This observation inspired us to investigate the scope of iodo-
nium reagents for the intramolecular iodocyclization of alkynes
of 2-alkynylquinoline-3-carboxaldehydes (2). We delighted to
observe that NIS is found an effective iodonium reagent for an
OMe
MeOH
O
CHO
R'
I+
DCM
I
R2
R1
R'
R2
R1
I
Fig. 1. Iodocyclization of o-alkynebenzaldehyde.
* Corresponding author. Tel.: þ91 542 6702482; fax: þ91 542 2368127; e-mail
address: rmohan@bhu.ac.in (R.M. Singh).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.10.081

506
B. Singh et al. / Tetrahedron 67 (2011) 505e511
Table 1
intramolecular cyclization of alkyne providing an alternative
route to the synthesis of pyrano annulated quinolines. Herein, we
report NIS as an effective reagent for the iodocyclization, pro-
Optimization of the reaction conditions for cyclization of 2b
Entry Solvent Electrophile Base
Product
Time
Yield
(equiv)
(equiv)
(min) of 3b (%)
viding synthesis of 1-alkoxy-4-iodopyrano[4,3-b]quinolines
3
1
2
3
4
5
6
MeOH
MeOH
MeOH
MeOH
MeOH
DCM
NIS (1.5)
NIS (1.2)
NIS (2.0)
NIS (2.5)
NIS (1.5)
NIS (1.5)
e
3b
3b
3b
3b
4
5
180
5
5
5
93
81
92
92
e
without using base (Scheme 2). Reactions proceeded in mild
conditions and very short time providing pyranoquinolines in
good to excellent yields. The iodo group at position 4 could be
further extended to CeC bond formation by Pd-catalyzed cou-
pling reactions.
The pyranoquinoline moiety constitutes the basic skeleton of
a number of alkaloids, such as flindersine, oricine, and verprisine.
Derivatives of these alkaloids are widely used as pharmaceuticals
and agrochemicals and possess a significant range of biological
activity including anti-inflammatory, anti-allergic, psychotropic,
and estrogenic effects.8
e
e
e
K2CO3(1.5)
K2CO3(1.5) 3bþ4 (3:1)
5
55a
a
MeOH (1.2 equiv) was used.
To further examine the generality of this cyclization, other
commercially available electrophiles, such as I2, Br2, NBS, and ICl
have also been examined in this process under similar reaction
conditions. The results are summarized in Table 2. It is noteworthy
that the use of I2 electrophile with 2b in methanol required
overnight reaction time, a 3:2 mixture of acetal 5 and cyclized
product 3b was observed, respectively, from 1H NMR spectro-
scopic analysis (Table 2, entry 3). While, NBS electrophile with 2b
for 1 h provided a 2.5:1 mixture of cyclized products 3s (4-bromo-
1-methoxy-8-methyl-3-phenyl-1H-pyrano[4,3-b]quinoline) and 6
(1-(4-bromo-8-methyl-3-phenyl-1H-pyrano[4,3-b]quinolin-1-yl)-
pyrrolidine-2,5-dione) (entry 5), in which succinimidyl ring acts
as a nucleophile, was observed by 1H NMR and IR spectroscopic
analysis. Undesired mixture was observed when bromine was
employed for cyclization. However, ICl electrophile was as effi-
cient as NIS (88%, entry 6).
To examine the generality of this strategy, carbonecarbon triple
bond bearing different substituent, such as phenyl, substituted
phenyl rings, and alkyl substituent of 2-alkynylquinoline-3-car-
boxaldehydes were allowed to react under our standard iodocyc-
lization conditions using NIS and methanol to afford the
corresponding pyranoquinolines in excellent yields (Table 2, entries
7e12). The presence of a phenyl group and electron donating group
on the phenyl ring of the carbonecarbon triple bond enhances the
rate of iodocyclization and the yield of the cyclized products (en-
tries 7e9). However, the corresponding alkyl substituted alkynes
also cyclized smoothly with slightly lower yield in longer time
(entries 10e12).
Further, different substituents on quinoline moiety of 2-phe-
nylethynylquinolinyl-3-carboxaldehydes (2iem) were allowed
to react under our standard reaction conditions for iodocyclization.
Reactions proceeded smoothly and provided corresponding pyr-
anoquinolines (3iem) in good to excellent yields (Table 2, entries
13e17). Electron donating substituent at position 6 in 2b and 2i
slightly enhanced the yield of cyclized products corresponding to
position 7 in 2j and 2k, respectively. Substituents at position 8 in 2l
and 2m also lowered the yield of the products 3l and 3m. Pyridine
carboxaldehyde 2n has also been allowed to react under our
standard cyclization condition using NIS and methanol. Cyclization
reaction proceeded with the same rate and afforded the product 3n
in excellent yield (entry 18).
2. Results and discussion
The required 2-alkynylquinoline-3-carboxaldehydes (2) were
prepared from 2-chloroquinoline-3-carboxaldehydes (1) and ter-
minal alkynes under copper-free Sonogashira coupling conditions
using our previously reported procedure9 (Scheme 1).
R1
CHO
CHO
Cl
PdCl2/PPh3/TEA
CH CN,
80 C
°
3
N
N
R
R
R1
2
1
R1 = Ph, p-tolyl, p-anisolyl, o-anilinyl, CH2OH
R = H, Me, Et, OMe
CH2O-cyclohexyl, (CH2)5CH3
Scheme 1. Synthesis of 2-alkynylquinoline-3-carboxaldehydes.
The iodocyclization of 6-methyl-2-phenylethynylquinoline-3-
carboxaldehyde (2b) was examined in methanol using NIS reagent
to optimize the reaction conditions for cyclization. We were de-
lighted to observe that the reaction of 0.25 mmol of 2b with
1.5 equiv of NIS in 4.0 mL methanol was completed at room tem-
perature in 5 min, furnishing the desired cyclized product 3b in
excellent yield (93%, Scheme 2, Table 1, entry 1). Using 1.2 equiv of
NIS required much longer reaction time and yield of the product 3b
was substantially dropped (entry 2). Further, increasing the amount
of NIS did not improve the yield of 3b (entries 3 and 4). It is note-
worthy that no cyclized product was obtained when K2CO3 was
added as base in reaction mixture (entry 5). Using Larock’s condi-
tions (2b, methanol as nucleophile, K2CO3 as base in DCM solvent)
at room temperature in 5 min furnished the mixture of desired
cyclized product 3b and an ester (6-methyl-2-phenylethynyl-
quinoline-3-carboxylic acid methyl ester)10 4 in 3:1 ratio (entry 6).
Thus, based on above investigations 1.5 equiv of NIS in 4 mL
methanol at room temperature in 5 min gave the best yield of the
product.
The structures of the products were confirmed from the single
crystal X-ray data of 3j (Fig. 2).11
It is noteworthy that methanol functioned both as a solvent and
as an oxygenated nucleophile in the iodocyclization. This obser-
vation prompted us to explore the scope of this chemistry with
other alcohols. Various alcohols, such as EtOH, i-PrOH, and n-BuOH
have been tested for cyclization using 2b and NIS. All alcohols
reacted well and provided good to excellent yields of the desired
iodocyclized products (Table 2, entries 19e22). Increasing the
length or the branching of the alcohol chain had a slight effect on
both reaction rate and yield of the products.
OMe
CHO
O
NIS/MeOH
r.t., 5 min
N
2
N
3
R1
R
R
R1
I
The iodopyranoannulated quinolines synthesized using this ap-
proach are very useful intermediates in many palladium-catalyzed
Scheme 2. Synthesis of functionalized pyrano[4,3-b]quinolines.

B. Singh et al. / Tetrahedron 67 (2011) 505e511
507
Table 2
Synthesis of functionalized pyrano[4,3-b]quinolines
Entry
Substrate
Electrophile
NuH
Product
Time (min)
Yield of 3 (%)
OMe
O
CHO
CHO
CHO
1
NIS
NIS
I2
MeOH
5
88
93
27
00
N
2a
N
Ph
Ph
Ph
I
3a
OMe
O
2
3
4
MeOH
MeOH
MeOH
5
N
N
Ph
2b
I
3b
OMe
OMe
Overnight
N
N
Ph
2b
Ph
5
+
Br2
e
e
5
NBS
MeOH
60
35a
6
7
ICl
MeOH
MeOH
5
5
88
95
NIS
8
9
NIS
NIS
MeOH
MeOH
5
5
96
94
10
NIS
MeOH
45
83
11
12
NIS
NIS
MeOH
MeOH
30
20
85
89
13
NIS
MeOH
5
91
(continued on next page)

508
B. Singh et al. / Tetrahedron 67 (2011) 505e511
Table 2 (continued )
Entry
Substrate
Electrophile
NuH
Product
Time (min)
Yield of 3 (%)
14
15
NIS
NIS
MeOH
5
88
MeOH
5
85
16
17
18
19
NIS
NIS
NIS
NIS
MeOH
MeOH
MeOH
EtOH
5
82
82
87
89
5
5
10
20
21
NIS
NIS
EtOH
10
20
82
80
i-PrOH
22
NIS
n-BuOH
20
75
a
By NMR ratio.
reactions. Thus, when compound 3b was treated under standard
Heck and Sonogashira conditions, the corresponding coupling
products 7 and 8 were isolated in 95% and 89% yields, respectively
(Scheme 3).
a. Heck Reaction
OMe
OMe
COOCMe3
O
O
N
Ph
PdCl2, PPh3, Et3N,
80 C, 2h
N
Ph
°
CH3CN,
I
7 (95%)
3b
COOCMe3
b. Sonogashira Coupling
OMe
OMe
O
PdCl2, PPh3, CuI, Et3N,
Ph,
O
CH3CN,
°C, 2h
N
Ph
N
Ph
8 (89%)
80
I
3b
Ph
Scheme 3. Palladium-catalyzed substitution of iodo group on 3b.
Fig. 2. ORTEP view of 3j.

B. Singh et al. / Tetrahedron 67 (2011) 505e511
509
3. Conclusions
HRMS (EI): m/z [MþH]þ found: 430.0306. C20H17NO2I requires
430.0304.
In summary, we have developed a simple and mild procedure
for the synthesis of iodo substituted 1H-pyrano[4,3-b]quinolines
using NIS reagent in the absence of base at room temperature. The
reactions are completed in a very short duration of time to afford
the products in good to excellent yields. Further, the iodo de-
rivatives provide a route to CeC bond formations.
4.2.3. 4-Iodo-1-methoxy-8-methyl-3-p-tolyl-1H-pyrano[4,3-b]quin-
oline (3c). Light yellow solid; yield: 95%; mp 102 ꢁC; Rf (5% EtOAc/
hexane) 0.45; IR (KBr): 1045, 1610, 2918 cmꢂ1
; dH (300 MHz, CDCl3)
2.43 (3H, s), 2.54 (3H, s), 3.71 (3H, s), 6.21 (1H, s), 7.26 (1H, s),
7.54e7.64 (5H, m), 7.87 (1H, s), 8.08 (1H, d, J 8.4 Hz); dC (75 MHz,
CDCl3) 21.5, 21.6, 56.3, 77.7, 100.4, 121.8, 126.3, 127.5, 128.6, 129.2,
129.8, 132.3, 132.5, 134.1, 136.2, 139.9, 147.2, 147.4, 157.2; HRMS (EI):
m/z [MþH]þ found: 444.0322. C21H19NO2I requires 444.0460.
4. Experimental section
4.1. General
4.2.4. 4-Iodo-1-methoxy-3-(4-methoxy-phenyl)-8-methyl-1H-pyr-
ano[4,3-b]quinoline (3d). Light yellow solid; yield: 96%; mp 125 ꢁC;
Melting points are measured using Buchi Melting-point appa-
ratus in an open capillary tube and are uncorrected. IR spectra were
recorded on VARIAN 3300 FTIR spectrophotometers. 1H (300 MHz)
and 13C (75 MHz) NMR spectra were recorded on JEOL AL 300 MHz
Rf (5% EtOAc/hexane) 0.35; IR (KBr): 1049, 1606, 2934 cmꢂ1
; dH
(300 MHz, CDCl3) 2.54 (3H, s), 3.72 (3H, s), 3.88 (3H, s), 6.21 (1H, s),
6.97 (2H, d, J 8.4 Hz), 7.54e7.58 (2H, m), 7.72 (2H, d, J 8.4 Hz), 7.87
(1H, s), 8.08 (1H, d, J 8.4 Hz); dC (75 MHz, CDCl3) 21.5, 55.3, 56.3,
100.4,113.2,121.9,126.3,127.3,127.4,129.1,129.2,131.6,132.2, 132.4,
136.1, 141.9, 147.4, 156.8, 160.6; HRMS (EI): m/z [MþH]þ found:
460.0002. C21H19NO3I requires 460.0409.
spectrometer. The chemical shifts (d ppm) and coupling constants
(Hz) are reported in the standard fashion with reference to either
internal tetramethylsilane (for 1H) or the central line (77.0 ppm) of
CDCl3 (for 13C). Elemental analyses were performed on Exter Ana-
lytical Inc. ‘Model CE-400 CHN Analyzer’ from Department of
chemistry, BHU, Varanasi. Mass spectra were recorded from SAIF,
CDRI, Lucknow, and IIT Kanpur. High resolution mass spectra
(HRMS) were recorded using Micromass Q-TOF micro mass spec-
trometer apparatus using electron spray ionization mode from SAIF,
IIT Madras, Chennai, IIT Kanpur and SAIF, CDRI Lucknow. Thin-layer
chromatographies (TLC) were performed on glass plates (7.5ꢀ2.5
and 7.5ꢀ5.0 cm) coated with Loba Chemie’s silica gel GF 254 and
various combinations of ethyl acetate and hexane were used as
eluent. Visualization of spots was accomplished by exposure to UV
light. Qualigen’s silica gel (60e120 mesh) was used for column
chromatography (approximately 15e20 g per 1 g of the crude
product).
4.2.5. 2-(4-Iodo-1-methoxy-8-methyl-1H-pyrano[4,3-b]quinolin-3-
yl)-phenylamine (3e). Light yellow solid; yield: 94%; mp 110 ꢁC; Rf
(5% EtOAc/hexane) 0.30; IR (KBr): 1045, 1610, 3341 cmꢂ1
; dH
(300 MHz, CDCl3) 2.54 (3H, s), 3.64 (3H, s), 4.54 (2H, s), 6.15 (1H, s),
7.48 (1H, s), 7.58e7.61 (3H, m), 7.87 (2H, m), 7.99 (1H, s), 8.10 (1H, d,
J 8.1 Hz); dC (75 MHz, CDCl3) 21.6, 29.6, 56.6, 82.4, 85.5, 100.8, 121.4,
124.1,126.4,127.6,129.3,132.7,132.8,136.8,138.5,144.1,145.5,147.2,
147.4, 154.2. Anal. Calcd for C20H17N2O2I: C, 54.07; H, 3.86; N, 6.31.
Found: C, 54.16; H, 3.81; N, 6.29.
4.2.6. (4-Iodo-1-methoxy-8-methyl-1H-pyrano[4,3-b]quinolin-3-yl)-
methanol (3f). Light brown solid; yield: 83%; mp 85 ꢁC; Rf (10%
EtOAc/hexane) 0.30; IR (KBr): 1086, 1624, 2924, 3412 cmꢂ1
; dH
(300 MHz, CDCl3) 2.53 (3H, s), 3.39 (3H, s), 3.64 (2H, s), 4.04 (1H, s,
D2O exchangeable), 6.18 (1H, s), 7.55e7.67 (2H, m), 7.85 (1H, s), 8.07
(1H, d, J 9.0 Hz); dC (75 MHz, CDCl3) 25.7, 51.3, 70.2, 80.3, 99.7, 121.8,
126.2,126.5,127.3,129.1,129.4,136.3,145.6,147.1,156.1. Anal. Calcdfor
C15H14NO3I:C, 47.02; H, 3.68; N, 3.66. Found:C, 46.87; H, 3.74; N, 3.73.
4.2. General procedure for the NIS promoted synthesis of
pyrano[4,3-b]quinolines 3
A
mixture of 2-alkynylquinoline-3-carboxaldehyde (2)
(0.25 mmol) and nucleophile (4e5 mL) was added to NIS (1.5 equiv)
stirred at room temperature for 5e45 min. After completion of
reaction, the reaction mixture was quenched with saturated solu-
tion of aqueous Na2S2O3. The resulting solution was extracted using
ethyl acetate. The combined organic extracts were dried over an-
hydrous sodium sulfate (Na2SO4) and concentrated under vacuum.
The crude product was purified by flash column chromatography
on silica gel (silica gel was neutralized by TEA) using various ratio of
EtOAc/hexane as eluent.
4.2.7. 3-Cyclohexyloxymethyl-4-iodo-1-methoxy-8-methyl-1H-pyr-
ano[4,3-b]quinoline (3g). Light yellow oil; yield: 85%; Rf (5% EtOAc/
hexane) 0.60; IR (KBr): 1084, 1190, 1610, 2930 cmꢂ1
; dH (300 MHz,
CDCl3) 1.26e1.41 (4H, m),1.58 (2H, m),1.76 (2H, m), 2.03 (2H, m), 2.53
(3H, s), 3.50 (1H, m), 3.65 (3H, s), 4.60 and 4.76 (2H, ABq, J 12.6 Hz),
6.14 (1H, s), 7.54 (2H, m), 7.83 (1H, s), 8.06 (1H, d, J 8.7 Hz); dC (75 MHz,
CDCl3) 21.4, 24.0, 25.6, 29.5, 51.2, 56.0, 70.1, 80.2, 99.6, 121.9, 126.3,
127.4, 129.0, 132.5, 136.3, 145.7, 147.1, 156.2, 177.9. Anal. Calcd for
C21H24NO3I:C, 54.20;H, 5.20; N, 3.01. Found: C, 54.03;H, 5.26; N, 3.03.
4.2.1. 4-Iodo-1-methoxy-3-phenyl-1H-pyrano[4,3-b]quinoline
(3a). Light yellow solid; yield 88%; mp 114 ꢁC; Rf (5% EtOAc/hexane)
4.2.8. 3-Hexyl-4-iodo-1-methoxy-8-methyl-1H-pyrano[4,3-b]quino-
0.45; IR (KBr): 1052, 1610, 2923 cmꢂ1
;
dH (300 MHz, CDCl3) 3.73
line (3h). Light yellow oil; yield: 89%; Rf (4% EtOAc/hexane) 0.80; IR
(3H, s), 6.24 (1H, s), 7.47e7.54 (4H, m), 7.71e7.76 (3H, m), 7.84 (1H,
d, J 8.1 Hz), 7.99 (1H, s), 8.20 (1H, d, J 8.4 Hz); dC (75 MHz, CDCl3)
56.4, 77.9, 100.4, 121.8, 126.3, 127.4, 127.5, 127.9, 129.5, 129.8, 129.9,
130.2, 133.1, 136.9, 147.8, 148.8, 157.7; HRMS (EI): m/z [MþH]þ
found: 416.0123. C19H15NO2I requires 416.0147.
(KBr): 1079,1190,1604, 2929 cmꢂ1
; dH (300 MHz, CDCl3) 0.90 (3H, t, J
6.6 Hz),1.25e1.71 (8H, m), 2.51 (3H, s), 2.83 (2H, m), 3.61 (3H, s), 6.07
(1H, s), 7.54 (2H, m), 7.79 (1H, s), 8.03 (1H, d, J 8.7 Hz); dC (75 MHz,
CDCl3)14.1, 21.5, 22.6, 27.2, 28.8, 31.7, 38.0, 55.9, 77.7, 99.8,121.5,126.3,
127.2, 129.0, 132.3, 132.4, 135.9, 146.5, 147.3, 161.2. Anal. Calcd for
C20H24NO2I:C,54.93;H, 5.53;N,3.20. Found:C,55.07;H,5.45;N,3.22.
4.2.2. 4-Iodo-1-methoxy-8-methyl-3-phenyl-1H-pyrano[4,3-b]quin-
oline (3b). Light yellow solid; yield: 93%; mp 94 ꢁC; Rf (5% EtOAc/
4.2.9. 4-Iodo-1,8-dimethoxy-3-phenyl-1H-pyrano[4,3-b]quinoline
hexane) 0.45; IR (KBr): 1052, 1609, 2922 cmꢂ1
;
dH (300 MHz, CDCl3)
(3i). Light yellow solid; yield: 91%; mp 142 ꢁC; Rf (5% EtOAc/hexane)
2.54 (3H, s), 3.72 (3H, s), 6.22 (1H, s), 7.45e7.47 (3H, m), 7.55e7.59
(2H, m), 7.70e7.73 (2H, m), 7.88 (1H, s), 8.09 (1H, d, J 8.4 Hz); dC
(75 MHz, CDCl3) 21.5, 56.4, 78.1, 100.4, 121.7, 126.3, 127.5, 127.9,
129.1, 129.7, 129.9, 132.4, 132.5, 136.3, 136.9, 146.9, 147.4, 157.1;
0.27; IR (KBr): 1054,1613, 2925 cmꢂ1
; dH (300 MHz, CDCl3) 3.71 (3H,
s), 3.94 (3H, s), 6.21(1H, s), 7.10 (1H, d, J 2.7 Hz), 7.37e7.47 (4H, m),
7.71e7.73 (2H, m), 7.87 (1H, s), 8.10 (1H, d, J 9.0 Hz); dC (75 MHz,
CDCl3) 55.5, 56.4, 78.0, 100.4, 105.1, 122.1, 122.9, 127.9, 128.5, 129.7,

510
B. Singh et al. / Tetrahedron 67 (2011) 505e511
129.9, 130.9, 131.8, 137.0, 144.9, 145.6, 156.5, 157.7; HRMS (EI): m/z
[MþH]þ found: 446.0255. C20H17NO3I requires 446.0253.
55.6, 64.6, 77.9, 99.3, 107.5, 119.7, 119.9, 122.7, 127.9, 128.4, 129.7,
129.9, 132.7, 137.2, 148.1, 150.6, 157.6, 161.3; HRMS (EI): m/z [MþH]þ
found: 460.0384. C21H19NO3I requires 460.0409.
4.2.10. 4-Iodo-1-methoxy-7-methyl-3-phenyl-1H-pyrano[4,3-b]
quinoline (3j). Light yellow solid; yield: 88%; mp 94 ꢁC; Rf (5%
4.2.17. 4-Iodo-1-isopropoxy-8-methyl-3-phenyl-1H-pyrano[4,3-b]
EtOAc/hexane) 0.45; IR (KBr): 1052, 1609, 2922 cmꢂ1
;
dH (300 MHz,
quinoline (3q). Light brown solid; yield: 80%; mp 81 ꢁC; Rf (5%
CDCl3) 2.57 (3H, s), 3.72 (3H, s), 6.22 (1H, s), 7.35 (1H, d, J 8.1 Hz),
7.45e7.47 (3H, m), 7.70e7.74 (3H, m), 7.93 (1H, s), 8.00 (1H, s); dC
(75 MHz, CDCl3) 21.8, 56.4, 78.2, 100.5, 120.9, 125.5, 127.1, 127.9,
128.6, 128.7, 129.7, 129.9, 132.8, 137.0, 140.7, 147.7, 149.0, 157.4;
HRMS (EI): m/z [MþH]þ found: 430.0287. C20H17NO2I requires
430.0304.
EtOAc/hexane) 0.30; IR (KBr): 1081, 1619, 2927 cmꢂ1
; dH (300 MHz,
CDCl3) 1.30 (3H, d, J 6.6 Hz), 1.35 (3H, d, J 6.0 Hz), 2.53 (3H, s), 4.35
(1H, m), 6.38 (1H, s), 7.44e7.46 (3H, m), 7.53e7.59 (2H, m),
7.68e7.70 (2H, m), 7.82 (1H, s), 8.07 (1H, d, J 8.4 Hz); dC (75 MHz,
CDCl3) 21.8, 29.5, 57.9, 77.9, 99.2, 107.4, 119.6, 122.5, 127.8, 128.1,
128.8, 129.7, 129.9, 130.3, 134.5, 138.3, 148.0, 150.5, 161.3; HRMS
(EI): m/z [MþH]þ found: 458.0564. C22H21NO2I requires 458.0617.
4.2.11. 4-Iodo-1,7-dimethoxy-3-phenyl-1H-pyrano[4,3-b]quinoline
(3k). Light yellow solid; yield: 85%; mp 154 ꢁC; Rf (5% EtOAc/hex-
4.2.18. 1-Butoxy-4-iodo-8-methyl-3-phenyl-1H-pyrano[4,3-b]quino-
ane) 0.40; IR (KBr): 1048, 1612, 2923 cmꢂ1
;
dH (300 MHz, CDCl3)
line (3r). Colorless oil; yield: 75%; Rf (5% EtOAc/hexane) 0.35; IR
3.71 (3H, s), 3.99 (3H, s), 6.22 (1H, s), 7.17 (1H, dd, J 2.4, 9.0 Hz),
7.46e7.52 (4H, m), 7.69e7.72 (3H, m), 7.89 (1H, s); dC (75 MHz,
CDCl3) 55.7, 56.3, 78.0, 100.5, 107.5, 119.6, 119.8, 122.6, 127.9, 128.4,
129.8, 129.9, 132.9, 137.1, 147.9, 150.7, 157.5, 161.4; HRMS (EI): m/z
[MþH]þ found: 446.0243. C20H17NO3I requires 446.0253.
(KBr): 1022, 1615, 2926 cmꢂ1
; dH (300 MHz, CDCl3) 0.92 (3H, t, J
7.5 Hz), 1.39e1.70 (4H, m), 2.54 (3H, s), 3.80 (1H, m), 4.07 (1H, m),
6.29 (1H, s), 7.45 (3H, m), 7.54e7.60 (2H, m), 7.69e7.71 (2H, m), 7.85
(1H, s), 8.08 (1H, d, J 8.4 Hz); dC (75 MHz, CDCl3) 19.3, 21.6, 29.7, 31.6,
69.1, 77.7, 99.5, 122.2, 126.4, 127.6, 127.9, 129.0, 129.7, 129.9, 132.3,
132.5, 136.3, 137.1, 147.1, 147.2, 157.5; HRMS (EI): m/z [MþH]þ found:
472.0413. C23H23NO2I requires 472.0773.
4.2.12. 4-Iodo-1-methoxy-6-methyl-3-phenyl-1H-pyrano[4,3-b]
quinoline (3l). Yellow solid; yield: 82%; mp 125 ꢁC; Rf (5% EtOAc/
hexane) 0.47; IR (KBr): 1053, 1608, 2924, 1615 cmꢂ1
;
dH (300 MHz,
4.3. General procedure for the Heck reaction on 3b
CDCl3) 2.90 (3H, s), 3.72 (3H, s), 6.26 (1H, s), 7.39e7.48 (4H, m),
7.59e7.75 (4H, m), 7.96 (1H, s); dC (75 MHz, CDCl3) 17.9, 56.3, 79.1,
100.4, 121.3, 125.3, 126.1, 127.4, 127.9, 129.7, 129.9, 130.2, 133.2,
136.9, 137.6, 146.4, 147.7, 157.1; HRMS (EI): m/z [MþH]þ found:
430.0285. C20H17NO2I requires 430.0304.
A mixture of 3b (0.25 mmol), tert-butyl acrylate (0.26 mmol),
PdCl2 (5 mol %), PPh3 (10 mol %), and TEA (0.5 mmol) in CH3CN
(4 mL) was stirred under N2 at 80 ꢁC for 2 h (as monitored by TLC).
The reaction mixture was concentrated in vacuo and residue was
purified by column chromatography on silica gel using EtOAc/
hexane as eluent.
4.2.13. 6-Ethyl-4-iodo-1-methoxy-3-phenyl-1H-pyrano[4,3-b]quino-
line (3m). Light brown solid; yield: 82%; mp 135 ꢁC; Rf (5% EtOAc/
hexane) 0.57; IR (KBr): 1048, 1606, 2925 cmꢂ1
;
dH (300 MHz, CDCl3)
4.3.1. 3-(1-Methoxy-8-methyl-3-phenyl-1H-pyrano[4,3-b]quinolin-
1.44 (3H, t, J 7.5 Hz), 3.29e3.47 (2H, m), 3.71 (3H, s), 6.25 (1H, s),
7.43e7.48 (4H, m), 7.59 (1H, d, J 6.3 Hz), 7.67e7.74 (3H, m), 7.95 (1H,
s); dC (75 MHz, CDCl3) 15.1, 25.1, 56.3, 79.4, 100.4, 121.2, 125.3, 126.3,
127.5, 127.9, 128.8, 129.7, 129.9, 133.2, 136.9, 143.4, 146.2, 147.2,
156.9; HRMS (EI): m/z [MþH]þ found 444.0429. C21H19NO2I re-
quires 444.0460.
4-yl)-acrylic acid tert-butyl ester (7). Yellow solid; yield: 95%; mp
130 ꢁC; Rf (5% EtOAc/hexane) 0.40; IR (KBr): 1068, 1609, 2922 cmꢂ1
;
dH (300 MHz, CDCl3) 1.48 (9H, s), 2.55 (3H, s), 3.78 (3H, s), 6.21 (1H,
s), 7.49e7.71 (9H, m), 7.99 (1H, s), 8.10 (1H, d, J 9.0 Hz); dC (75 MHz,
CDCl3) 21.6, 28.2, 29.7, 56.6, 79.5, 100.7, 111.7, 121.7, 122.8, 126.5,
126.6, 128.3, 129.3, 130.4, 132.1, 132.4, 133.9, 136.2, 137.9, 146.9,
148.1, 161.3, 167.9; HRMS (EI): m/z [MþH]þ found: 430.2011.
C27H28NO4 requires 430.2018.
4.2.14. 8-Iodo-5-methoxy-3,7-diphenyl-5H-pyrano[4,3-b]pyridine
(3n). Light yellow solid; yield: 87%; mp 107 ꢁC; Rf (5% EtOAc/hex-
ane) 0.50; IR (KBr): 1052, 1623, 2924 cmꢂ1
;
dH (300 MHz, CDCl3)
4.4. General procedure for the Sonogashira coupling on 3b
3.71 (3H, s), 6.18 (1H, s), 7.41e7.52 (6H, m), 7.60e7.63 (2H, m),
7.70e7.72 (3H, m), 8.95 (1H, s); dC (75 MHz, CDCl3) 29.7, 56.3, 100.2,
122.2, 126.9, 127.9, 128.3, 129.2, 129.8, 129.9, 131.7, 135.5, 136.6,
137.0, 146.9, 149.1, 155.9; HRMS (EI): m/z [MþH]þ found: 442.0309.
C21H17NO2I requires 442.0304.
A mixture of 3b (0.25 mmol), phenyl acetylene (0.26 mmol),
PdCl2 (4 mol %), PPh3 (8 mol %), CuI (8 mol %), and TEA (0.5 mmol) in
CH3CN (4 mL) was stirred under N2 at 80 ꢁC for 2 h (as monitored by
TLC). The reaction mixture was concentrated in vacuo and residue
was purified by column chromatography on silica gel using EtOAc/
hexane as eluent.
4.2.15. 1-Ethoxy-4-iodo-8-methyl-3-phenyl-1H-pyrano[4,3-b]quino-
line (3o). Light brown solid; yield: 89%; mp 106 ꢁC; Rf (10% EtOAc/
hexane) 0.50; IR (KBr): 1031, 1612, 2923 cmꢂ1
;
dH (300 MHz, CDCl3)
4.4.1. 1-Methoxy-8-methyl-3-phenyl-4-phenylethynyl-1H-pyrano
1.32 (3H, t, J 6.9 Hz), 2.54 (3H, s), 3.90 (1H, m), 4.12 (1H, m), 6.31
(1H, s), 7.44e7.46 (3H, m), 7.53e7.59 (2H, m), 7.68e7.70 (2H, m),
7.82 (1H, s), 8.08 (1H, d, J 8.4 Hz); dC (75 MHz, CDCl3) 21.6, 29.7, 64.7,
77.9, 99.2, 122.1, 126.4, 127.6, 127.9, 128.0, 129.1, 129.7, 129.9, 132.3,
132.5, 136.3, 137.1, 147.3, 157.3; HRMS (EI): m/z [MþH]þ found:
444.0465. C21H19NO2I requires 444.0460.
[4,3-b]quinoline (8). Light brown solid; yield: 89%; mp 98 ꢁC; Rf (5%
EtOAc/hexane) 0.30; IR (KBr): 1062, 1611, 2923 cmꢂ1
; dH (300 MHz,
CDCl3) 2.55 (3H, s), 3.77 (3H, s), 6.34 (1H, s), 7.32e7.36 (1H, m),
7.47e7.48 (8H, m), 7.99 (2H, m), 8.11 (1H, d, J 8.4 Hz), 8.27 (m, 2H);
dC (75 MHz, CDCl3) 21.6, 56.4, 77.6, 88.3, 92.0, 100.5, 121.9, 124.2,
126.9, 127.7, 127.9, 128.2, 128.3, 128.6, 129.5, 129.9, 132.3, 132.4,
132.8, 136.1, 136.6, 147.7, 148.1, 160.0; HRMS (EI): m/z [MþH]þ
found: 404.1656. C28H22NO2 requires 404.1650.
4.2.16. 1-Ethoxy-4-iodo-7-methoxy-3-phenyl-1H-pyrano[4,3-b]
quinoline (3p). Light brown solid; yield: 82%; mp 116 ꢁC; Rf (15%
EtOAc/hexane) 0.30; IR (KBr): 1051, 1610, 2925 cmꢂ1
;
dH (300 MHz,
Acknowledgements
CDCl3) 1.32 (3H, t, J 6.9 Hz), 3.86e3.94 (1H, m), 3.98 (3H, s),
4.07e4.15 (1H, m), 6.32 (1H, s), 7.15 (1H, dd, J 2.4, 9.0 Hz), 7.46e7.52
(4H, m), 7.68e7.72 (3H, m), 7.88 (1H, s); dC (75 MHz, CDCl3) 15.1,
We thank CSIR (New Delhi) and UGC (New Delhi) for funding.
A.C. is thankful to UGC for awarding DSK Postdoc. fellowship, B.S. is

B. Singh et al. / Tetrahedron 67 (2011) 505e511
511
Larock, R. C. J. Org. Chem. 2008, 73, 6666; (t) Mancuso, R.; Mehta, S.; Gabriele, B.;
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Gridnev, I. D.; Yamamoto, Y. J. Org. Chem. 2010, 75, 1266; (v) Mehta, S.; Larock,
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Org. Chem. 2006, 71, 1626; (x) Aillaud, I.; Bossharth, E.; Conreaux, D.; Desbordes,
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thankful to CSIR, New Delhi, for the award of Senior Research Fel-
lowship, and S.S. is thankful to UGC for project fellowship. We
thank Prof. Qiang Xu, AIST, Ikeda, Osaka, Japan for providing single
crystal X-ray data. We are also thankful to Prof. S. Bhaskaran, Deptt.
Of Chemistry, IIT Madras, Prof. Sandeep Verma, Deptt. of Chemistry,
IIT Kanpur, Dr. J.K. Saxena, Medicinal and Biochemistry Division,
CDRI, Lucknow for use of the HRMS facility.
Supplementary data
2. (a) Barluenga, J.; Vanquez-Villa, H.; Ballesteros, A.; Gonzalez, J. M. J. Am. Chem.
ꢀ
Soc. 2003, 125, 9028; (b) Yue, D.; Ca, N. D.; Larock, R. C. Org. Lett. 2004, 6, 1581;
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.10.081.
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