Single-Step Synthesis of 3-Iodoquinolines from 2-Aminophenyl Ketones through a Regioselective (6-endo-dig) Electrophilic Cyclization

Article abstract of DOI:10.1002/ejoc.201700668

A highly facile single-step synthetic approach to 3-iodoquinolines has been developed for the first time from readily available 2-aminobenzophenones and terminal alkynes. The reaction involves the nucleophilic addition of terminal alkynes to 2-aminobenzophenones followed by a regioselective iodocyclization (6-endo-dig) to furnish 2,4-disubstituted 3-iodoquinolines in high yields. In general, 2,4-diaryl-substituted products were isolated without the need for column chromatography.

Full text of DOI:10.1002/ejoc.201700668

A Journal of
Accepted Article
Title: Single-Step-Synthesis of 3-Iodoquinolines from 1-(2-
aminophenyl)ketones through a Regioselective (6-endo dig)
Electrophilic-cyclization
Authors: SRINIVASARAO YARAGORLA, Abhishek Pareek,
Ravikrishna Dada, and Pyare Lal Saini
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700668
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700668
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201700668
FULL PAPER
Single-Step-Synthesis of 3-Iodoquinolines from 1-(2-
aminophenyl)ketones through a Regioselective (6-endo dig)
Electrophilic-cyclization
[
a,b]
[a,b]
[a,b]
[b]
Srinivasarao Yaragorla,* Abhishek Pareek, Ravikrishna Dada
and Pyare Lal Saini
th
Dedication (We dedicate this work to Prof. Goverdhan Mehta on the occasion of his 74 Birth Day)
[
12]
Abstract: Highly facile, single-step synthetic approach of 3-
iodoquinolines is developed for the first time from readily available 2-
aminobenzophenones and terminal alkynes. The reaction involves a
nucleophilic addition of terminal alkynes to 2-aminobenzophenones
followed by intramolecular regioselective iodocyclization (6-endo dig)
to furnish 2,4-disubstituted, 3-iodoquinolines in high yields. In case
of 2,4-diaryl substitution, the products were isolated without a
column chromatography.
al extended the scope of this method with (unprotected) 1-(2-
aminoaryl)-2-yn-ols (Figure 1, eq 3). Though the efficient
methods are available, the following limitations such as a multi-
step synthesis, usage of alkynylmagnesium bromide, alkynyl
lithium reagents, halogenated solvents and non-readily available
starting materials indicates the need to develop an efficient and
eco-friendly single step synthesis. In continuation of our
research aimed towards alkyne tethered inter and intramolecular
[
14]
annulations and sustainable chemical synthesis,
herein we
designed a single step, green synthesis of 3-iodoquinolines from
readily available 2-aminobenzophenones and terminal alkynes.
Introduction
R2
Quinolines are important heterocyclic molecules present in a
large number of natural products (alkaloids), pharmaceutical and
OH
O
F
1.NMe2
O
MeMgCl
R2
Me
2.
Li
[
1]
agrochemicals. Quinoline moiety also serves as a key building
block for the synthesis of many synthetic molecules with diverse
R2
NMe2
3. MnO2
NMe2
--(1)
[
2]
Me
pharmacological properties. Further functionalized quinolines
Me
I
[
3]
[4]
I
Ph P, Sulfolane,
are widely used as organic materials and catalysts. Owing to
their diverse applications the synthesis of quinoline and their
I2, CH3CN or
CH2Cl2, heat
3
heat
R2
R2
N
N
[
5]
derivatives become an active research area starting from well-
known classic reactions such as Combes synthesis, Conrad–
Limpach–Knorr synthesis, Friedlander reaction, and Skraup–
Me
O
O
R2
Pyridine,
TsCl
OH
[
6]
[7]
Doebner–Von Miller reaction to metal catalyzed approaches .
R1
R1
NHTs
R2
MgBr
R1
Among the quinoline derivatives, in particularly halogenated
quinolones are of special interest due to the reason that they
NH2
NHTs
--(2)
R1
[
8]
provide a viable platform for further functionalization .
I2, MeOH,
0 oC, 6-12 h
I
6
In recent years, iodine mediated electrophilic cyclization of
heteroatom nucleophiles with tethered alkynes has proven to be
an effective method for the synthesis of a large number of
R2
N
R2
O
OH
R1
1 1. R2
[
9]
MgBr
1
heterocyclic molecules.
While searching for the reported
R
R I , CH Cl , rt
I
2
2
2
--(3)
[
10-13]
2. H+
methods for the synthesis of 3-iodoquinolines,
we found that
NH2
NH2
R2
N
few reports are available through an iodocyclization of tethered
alkynes with the amino nucleophile (Figure 1). For example,
[
10]
O
R1
Flynn et al.
reported an electrophilic iodocyclization of 1-(2-
R2
R1
I
N,N-dimethylaminoaryl)-2-yn-ols (Figure 1, eq 1), Liang and his
[
11]
KOtBu, neat, rt, 2 h
add H2O+EtOAC, I2
This Work
co-workers
reported another iodocyclization of 1-(2- N-
NH2
N
R2
tosylaminoaryl)-2-yn-ols (Figure 1, eq 2). Later M. S. Reddy et
Figure 1. Comparison of iodocyclization strategies for 3-iodoquinolines
[
[
a]
b]
Srinivasarao Yaragorla, Abhishek Pareek, Ravikrishna Dada
School of Chemistry, Gurbaksh Building, W-16, 17, University of
Hyderabad, P.O. Central University, Gachibowli, Hyderabad,
Results and Discussion
5000046, Telangana State, India
E-mail: Srinivas.yaragorla@uohyd.ac.in;
https://sites.google.com/site/syorgchem/home
Department of Chemistry, Central University of Rajasthan,
Bandersindri, 305817, Rajasthan, India
To implement our idea of single step synthesis, the in-situ
generation of propargylic alcohol is a key task because all the
previous approaches were involved in a multi-step synthesis and
isolation of the propargylic alcohol. A thorough literature survey
suggested that Chen et al reported a solvent-free synthesis of
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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European Journal of Organic Chemistry
10.1002/ejoc.201700668
FULL PAPER
[
15]
propargylic alcohols from arylacetylenes and ketones.
Recently our group reported the synthesis of 3-oxindolyl
propargylic alcohols from readily available isatins and terminal
alkynes using potassium tert-butoxide under neat conditions at
Ph
Ph
I
t
KO Bu, I
2
R
O
+
[
14a]
2
room temperature
and unlike Chen’s report, our method
H O/EtOAc (1/1)
2
NH2
N
R
works with aryl and aliphatic alkynes. With this background, we
1a
3
treated 2-aminobenzophenone (1a) and phenylacetylene (2a)
t
with KO Bu under neat conditions at room temperature and after
Ph
Ph
N
Ph
N
2
2
h we were glad to isolate 1-(2-aminophenyl)-1,3-diphenylprop-
I
I
I
-yn-1-ol 1a2a (Scheme 1) in quantitative yield.
N
O
3a11
3b11
Me
3c11
OMe
Me
OH
t
KO Bu, neat,
+
9
0%, 2.5 h
94%, 3 h
95%, 2.5 h
NH2
r.t.; 2 h, quantitaive
NH2
Ph
Ph
Ph
1
a
2a
1a2a
I
I
Me
I
Me
Scheme 1. Direct synthesis of 1a2a without using organometallic reagents
N
N
N
Encouraged by this result, we planned to investigate a one-pot
3
d11
3e13a
3f12
iodocyclization of 1a2a to achieve the synthesis of 2,4-diphenyl-
7
9%, 4 h
84%, 3 h
85%, 3 h
3
-iodoquinoline (3a). Hence a mixture of 1a (110 mg, 0.5 mmol),
t
2
a (77 mg, 076 mmol) and KO Bu (85 mg, 0.76 mmol) were
slowly stirred in a round bottom flask under nitrogen atmosphere
at room temperature for 2 h and then iodine was (256 mg, 1
mmol) added and the stirring continued for 6 h. However, the
proposed iodocyclization could not occur and only the propargyl
alcohol 1a2a was isolated again. Agreeing that solvent is
required for iodocyclization, the reaction was repeated again and
water (1 mL) was added along with iodine to the reaction after 2
h, but cyclization of 1a2a did not happen. In the next time
Ph
Ph
Ph
N
I
Ph
I
I
N
N
3
g
3h
3i
8
0%, 2.5 h
79%, 2.5 h
82%, 2.5 h
Scheme 3. Scope of various alkynes in the single step synthesis of 2,4-
disubstituted, 3-iodoquinolines. Reaction conditions: a mixture of 1a (1 equiv),
H
2
O/DCM (1:1) 2 mL was added and delightfully the reaction
yielded 76% of desired product 3a after 1 h. When the solvent
combination is changed to H O/DCE, a slight increase in the
t
2
(1.5 equiv.), KO Bu (1.5 equiv) were stirred at rt for 2 h and then added aq-
2
ethyl acetate (2 mL, 1:1) and I (2 equiv.)
2
yield was observed (82%). Encouraged by the success of a
single step synthesis of 3-iodo-2,4-diphenylquinoline 3a in 82%
yield at room temperature, we further thought of making this
method more environmental friendly reaction by avoiding the
halogenated solvents. Hence other combinations of solvents
After developing a suitable experimental condition for a single
step synthesis of 3-iodo-2,4-diphenylquinoline (3a) from 2-
aminobenzophenone (1a) and phenylacetylene (2a), we were
interested in studying the scope of different terminal alkynes in
the iodocyclization reaction as depicted in the Scheme 3. Hence
t
2 2
such as MeOH/H O and Toluene/H O were tried but none of
1
a was treated with p-tolylacetylene (2b) in presence of KO Bu/I
2
them were found effective. Nevertheless, aqueous-ethyl acetate
in aqueous ethyl acetate (1:1) for 3 h to obtain the iodoquinoline
b in 94% yield. Similarly, another aryl alkyne, 4-methoxy
(H
2
O/EtOAc, 1:1) gave an excellent yield of 3a (90%) in 2.5 h
3
(
Scheme 2) [refer to supporting information for the optimization
phenylacetylene (2c) also gave the desired product 3c in 95%
yield after 2.5 h. Encouraged by the reactivity of aryl alkynes; we
further investigated the reactivity of aliphatic alkynes.
Interestingly, 1-pentyne (2d), 1-hexyne (2e), 1-heptyne (2f) and
pent-4-yn-1-ylbenzene (2g) reacted with 2-aminobenzophenone
Table] without a column chromatography and this made our
synthetic protocol certainly a better and economic synthesis
when compared to the existing methods.
(
1a) and yielded the respective iodoquinolines 3d, 3e, 3f and 3g
in high yields after the purification by column chromatography
(Scheme 3). Latter cyclic alkynes such as cyclopropyl acetylene
(
2h) and ethynylcyclohexane (2i) also reacted with 1a under
standard optimized conditions and furnished the desired
products 3h and 3i in 79 and 82% respective yields.
Scheme 2. Single-Step-Synthesis of 3a (A Green Synthesis)
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European Journal of Organic Chemistry
10.1002/ejoc.201700668
FULL PAPER
R2
R2
t
KO Bu (1.2 eq.),
I
neat, rt, 2 h
R1
O
R3
R1
+
R3
H2O/EtOAc (1/1)
I2 ( 2 eq), rt
N
NH2
2
1
3
Ph
N
Ph
N
Ph
I
Ph
Ph
I
Cl
I
Cl
I
Cl
Cl
I
Cl
Me
Me
N
N
N
ae
2%, 3.5 h
3
aa11
Me
OMe
3ad
79%, 3 h
3
3ab
82%, 3 h
3ac
2%, 3 h
8
9
9
3%, 2.5 h
Ph
Ph
N
Ph
Ph
Cl
Cl
I
Cl
I
Cl
I
Cl
I
Cl
I
Ph
N
Me
N
N
N
3
af
3ag
83%, 2.5 h
3ah
92%, 2.5 h
3ai
83%, 2.5 h
3aj
89%, 2.5 h
8
7%, 3 h
Cl
Cl
Cl
Cl
Cl
Cl
I
Cl
I
Cl
I
Cl
I
Cl
I
Me
N
N
N
Me
N
N
Me
Me
OMe
3
am
3an
88%, 2.5 h
3ao
83%, 2.5 h
3ak
3al
87%, 3 h
8
0%, 2.5 h
84%, 2.5 h
Cl
F
F
F
F
Cl
I
Cl
I
Cl
I
Cl
I
Cl
I
Ph
N
N
N
N
N
Me
Me
OMe
3ap
3aq
3ar
3as
3at
88%, 3.5 h
88%, 3 h
F
90%, 2.5 h
88%, 3.5 h
81%, 3 h
F
Br
I
Br
I
Br
I
Cl
I
I
N
N
Me
N
3ba
N
N
Br
Me
3
au
2%, 2.5 h
3av
92%, 3h
3bb
88%, 2.5 h
3bc
86%, 3 h
8
86%, 2.5 h
Br
I
Cl
I
Cl
I
N
N
N
Br
Br
Br
Me
Me
3
bd
3be
88%, 3.5 h
3bf
77%, 2.5 h
8
3%, 3.5 h
t
Scheme 4. Substrate scope in the single step synthesis of 2,4-disubstituted, 3-iodoquinolines. Reaction conditions: a mixture of 1 (1 equiv.), 2 (1.5 equiv.), KO Bu
1.5 equiv.) was stirred at rt for 2 h and then added aq-ethyl acetate (2 mL, 1:1) and I (2 equiv.) at rt.
(
2
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European Journal of Organic Chemistry
10.1002/ejoc.201700668
FULL PAPER
[
19]
Encouraged by the participation of diverse alkynes such as aryl,
acyclic and cyclic alkynes with 2-aminobenzophenone in the one
pot synthesis of 3-iodo quinolines, further the generality of the
synthetic protocol is expanded and described in the Scheme 4.
furnished 4b in excellent yield (93%). Sonogashira coupling
with phenylacetylene furnished 4c in 96% yield and this reaction
was also repeated with TMS-acetylene followed by silyl
deprotection (K
2 3
CO , MeOH, rt) furnished 4d in 68% yield as
[
20]
2
-amino-5-chloro-benzophenone (1b) was treated with aryl
alkynes such as 2a, 2b and 2c, acyclic alkynes: 2d, 2e, 2f and
g and cyclic alkynes: 2h and 2i under standard conditions and
schemed in Scheme 5.
2
the respective 3-iodoquinolines 3aa-3ai were obtained in
excellent yields at room temperature. Another 2-aminophenone
namely
(2-amino-5-chlorophenyl)(2-chlorophenyl)methanone
(
1c) was also equally reactive towards the alkynes 2a-2g and
furnished the 2,4-disubstituted, 3-iodoquinolines 3aj-3ap in high
yields. Alkynes 2a, 2b, 2c, 2d and 2f reacted with (2-amino-5-
fluorophenyl)(2-chlorophenyl)methanone (1d) under the same
reaction conditions to provide the respective products 3aq-3au
in good yields. Another 2-aminobenzophenone derivative 1e
yielded 3ba and 3bb in 86% and 88% yields. 2-amino-3,5-
[
16]
dibromobenzophenone (1f) reacted with phenyl acetylene and
p-tolyl acetylenes to furnish the respective 3-iodoquinolines 3bc
and 3bd in excellent yields. Finally, 2-amino-3-bromo-5-
Scheme 6. Proposed mechanism for the synthesis of 3-iodoquinolines
[
16]
chlorobenzophenone (1g)
towards the synthesis of 3be and 3bf with high yields (Scheme
).
also showed good reactivity
The plausible mechanism for the single step synthesis of 3-
iodoquinoline (3) from a simple 2-aminobenzophenone (1) and
terminal alkyne (2) is described in the Scheme 6. The reaction
4
initiated by the nucleophilic addition of acetylenic anion
t
(
generated with KO Bu) on carbonyl carbon to furnish the
corresponding akynol I (alkynol derivative 1a2a was isolated and
confirmed by spectral data). In the next step, cyclic iodonium ion
formation (II) followed by
intramolecular nucleophilic attack by –NH
furnish intermediate III. Dehydration (-H O) of Quinoline III gives
a
regioselective (6-endo dig),
2
N
(S 2) takes place to
2
a stable 2,4-disubstituted, 3-iodoquinoline 3.
Conclusions
In conclusion, we developed a first, single step synthesis of 2,4-
disubstituted, 3-iodoquinolines from readily available 1-(2-
aminophenyl)ketones and terminal alkynes in aqueous ethyl
t
acetate using KO Bu/I
2
at room temperature. This one pot
regioselective
economic synthesis proceeds through
a
iodocyclization and provides the large substrate scope of 3-
iodoquinolines. Further 2,4-diaryl, 3-iodoquinolines were isolated
without column chromatography. The synthetic utility of these
compounds was demonstrated through cross-coupling reactions
(Suzuki, Heck and Sonogoshira).
Scheme 5. Gram scale synthesis and synthetic utility of 3-iodoquinoline (3aa).
a
Conditions: Heck = ethyl acrylate (3 eq), Pd(OAc)
2
(5 mol%), Bu
(1 eq), DMF, 80 C, 21 h.; Suzuki = PhB(OH) (1.3 eq), Pd(OAc)
Na CO (1 eq), DMF/H (2:1),
Sonogashira =Phenylacetylene (2 eq), Pd(OAc)
MeCN, rt.; 12 h
4
NBr (1 eq),
o
b
Na
mol%),
2
CO
3
2
2
(5
h.;
o
2
3
2
O
100
C,
4
c
2
(2 mol%), DABCO (3 eq),
.
After the successful demonstration of the substrate scope, a Experimental Section
gram scale synthesis of 3aa (1.73 g, 91%, 3 h) is performed
from 1a (1 g, 4.32 mmol) and 2a (0.63 g, 6.48 mmol) using
General information: Unless otherwise noted, all reagents were used as
t
received from commercial suppliers. Reactions were monitored using
thin-layer chromatography (TLC) with aluminium sheets silica gel 60 F254
from Merck. TLC plates were visualized with UV light (254 nm), iodine
2
KO Bu (0.72 g, 6.48 mmol) and I (1.09 g, 8.65 mmol) in aq-ethyl
acetate (5 mL/5mL) at rt (Scheme 5). Then we moved to show
the synthetic utility of 3-iodoquinolines and hence performed the
following cross-coupling reactions (Scheme 5). 6-chloro-3-iodo-
treatment or using p-anisaldehyde or KMNO
4
stain. Column
chromatography was carried out using silica gel 60-120 mesh as the
stationary phase. NMR spectra were recorded at 400 & 500 MHz
2
,4-diphenylquinoline 3aa was treated with ethyl acrylate under
[
17]
Heck reaction conditions
to yield 4a in 91%. A Suzuki
(Proton) and at 100 & 125 MHz (Carbon), respectively on Avance Bruker
[
18]
coupling
reaction with phenylboronic acid and iodide 3aa
spectrometer. Chemical shifts (δ) are reported in ppm, using the residual
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European Journal of Organic Chemistry
10.1002/ejoc.201700668
FULL PAPER
solvent peak in CDCl
3
(H: δ = 7.26 and C: δ = 77.0 ppm) as an internal
reduced pressure to give product dissolved in 5 mL of MeOH then added
standard, and coupling constants (J) are given in Hz. HRMS were
recorded using ESI-TOF techniques. Melting points were measured with
Lab India (MEPA) melting point apparatus.
was K
evaporated under reduced pressure. The Crude product extracted with
EtOAc. Combined organics dried over anhydrous Na SO . The solvent
2 3
CO (62.7 mg, 2 equiv) stirred at rt for 3 h. The resulting mixture
2
4
was evaporated under reduced pressure and the residue was purified by
column chromatography with silica gel to give product 4d (68%, 52 mg)
General procedure for the synthesis of 3-iodo-2,4-diphenylquinoline
(
3): A mixture of terminal alkyne 2a (77.6 mg, 0.76 mmol.), t-BuOK (85.2
mg, 0.76 mmol) and 2-aminobenzophenone 1a (100 mg, 0.50 mmol) was
placed into reaction flask at room temperature under nitrogen
atmosphere and the mixture was stirred for 2 h then 2 mL of water/EtOAc
1:1) were added to the reaction mixture along with Iodine (256 mg, 1
3-iodo-4-phenyl-2-(3-phenylpropyl)quinoline (3g): White solid; mp:
o
1
a
129-131 C; yield: 80%; H NMR (500 MHz, CDCl3): δ 8.12 (d, J = 8.5 Hz,
1H), 7.74-7.71 (m, 1H), 7.60-7.57 (m, 3H), 7.34-7.32 (m, 5H), 7.27-7.23
(m, 4H), 3.38 (t, J = 7.5 Hz, 2H), 2.90-2.86 (m, 2H), 2.30-2.25 (m, 2H)
(
1
3
mmol) and further stir till completion of the reaction. The progress of
reaction was monitored by TLC. After completion of the reaction, the
3
ppm; C NMR (100 MHz, CDCl ): δ 162.2, 153.9, 146.9, 142.3, 142.2,
129.7, 128.7, 128.6, 128.5, 128.4, 128.3, 127, 126.8, 127, 126.8, 126.5,
125.8, 100.3, 42.8, 35.8, 30.7 ppm; IR (KBr): 2939, 1649, 1443, 1375,
resulting mixture was quenched with saturated solution of Na
mL) and extracted with ethyl acetate (15 mL, thrice). Combined organic
layers were dried over anhydrous Na SO and the solvent was
2 2 3
S O (20
-1
+
1122, 1090, 777 cm ; HRMS (ESI) m/z calcd. for C24H20IN [M +H]
2
4
450.0718; found 450.0722.
evaporated under reduced pressure and the residue was purified by
washing with diethyl ether (3a-3c, 3aa-3ac, 3aj-3al and 3aq-3as) or
column chromatography (3d-3i, 3ae-3ai, 3am-3ap and 3at-3au) to give of
product 3a (90%, 185 mg).
2
1
7
2
1
-cyclopropyl-3-iodo-4-phenylquinoline (3h): White solid; mp: 127-
o
1
28 C; yield: 79%; H NMR (500 MHz, CDCl
3
): δ 7.98 (d, J = 7.5 Hz, 1H),
.67-7.57 (m, 4H), 7.31-7.25 (m, 4H), 2.84-2.80 (m, 1H), 1.32-1.30 (m,
Synthesis of ethyl (E)-3-(6-chloro-2,4-diphenylquinolin-3-yl)acrylate
13
3
H), 1.15-1.13 (m, 2H) ppm; C NMR (100 MHz, CDCl ): δ 162.1, 153.2,
[
11]
(
4a)
chloro-3-iodo-2,4-diphenylquinoline 3aa (92 mg, 0.23 mmol) in DMF (1.8
mL) containing K CO (53 mg, 2.5 eq) and Bu NBr (50 mg, 1 equiv) and
stirred at room temperature for 5 min. Pd(OAc) (5 mol %) was then
added and the flask was flushed with N , sealed and allowed to stir at
0 °C for 22 h. The resulting mixture was filtered off, washed and
extracted with diethyl ether. The combined organics were washed with
water and then with brine and dried over anhydrous Na SO . The solvent
Ethyl acrylate (47 mg, 0.47 mmol), was added to a solution of 6-
46.9, 142.4, 129.6, 129.1, 128.7, 128.6, 128.3, 127.2, 126.7, 126.0,
-
1
01.8, 22.1, 11.0 ppm; IR (KBr): 1561, 1478, 1396, 1215, 1091, 982 cm
1
+
2
3
4
;
HRMS (ESI) m/z calcd. for C18
H
14IN [M+H] 372.0248; found 372.0248.
2
2
2
-cyclohexyl-3-iodo-4-phenylquinoline (3i): Yellow solid; mp: 103-105
8
o
1
C; yield: 82%; H NMR (400 MHz, CDCl
3
): δ 8.12-8.05 (m, 1H), 7.95-
7
3
.69 (m, 1H), 7.60-7.54 (m, 1H), 7.39-7.33 (m, 3H), 7.29-7.24 (m, 3H),
2
4
13
.56-3.53 (m, 1H), 2.17- 1.90 (m, 8H), 1.59-1.48 (m, 2H) ppm; C NMR
): δ 165.3, 153.6, 149.3, 147.1, 142.7, 138.3, 135.4,
29.5, 128.8, 128.6, 127.4, 126.8, 101.6, 49.3, 32.3, 26.6, 26.2 ppm; ESI
was evaporated under reduced pressure and the residue was purified by
column chromatography with silica gel to give of product 4a (95%, 91
mg).
(125 MHz, CDCl
3
1
+
m/z [M+H] 414.2
[
11]
Synthesis of 6-chloro-2,3,4-triphenylquinoline (4b) PhB(OH)
mg, 0.33 mmol) was added to solution of 6-chloro-3-iodo-2,4-
diphenylquinoline 3aa (115.5 mg, 0.27 mmol) in 3.0 mL of DMF/H O (2:1)
containing Na CO (27.4 mg, 1 equiv) and stirred at room temperature for
min. Pd(OAc) (5 mol %) was then added and the flask was flushed
, sealed and allowed to stir at 100 °C for 4 h. The resulting mixture
2
(41.1
a
6
1
1
7
1
1
-chloro-3-iodo-4-phenyl-2-(p-tolyl)quinolone (3ab): Yellow solid; mp:
2
o
1
12-116 C; yield: 82%; H NMR (500 MHz, CDCl
3
): δ 8.09 (d, J = 9 Hz,
2
3
H), 7.67-7.64 (m, 1H), 7.61-7.56 (m, 5H), 7.37 (d, J = 2.5 Hz, 1H), 7.31-
5
2
13
3
.28 (m, 4H), 2.46 (s, 3H) ppm; C NMR (125 MHz, CDCl ): δ 162.3,
with N
2
53.9, 145.4, 141.6, 140.6, 138.7, 133, 131.1, 131, 129.2, 129.1, 128.9,
was filtered off, washed and extracted with diethyl ether. The combined
organics were washed with water and then with brine and dried over
28.8, 128.7, 127.8, 125.6, 100.5, 21.5 ppm; HRMS (ESI) m/z calcd. for
+
C
22
H
15ClIN [M +H] 456.0015; found 456.0032
2 4
anhydrous Na SO . The solvent was evaporated under reduced pressure
and the residue was purified by column chromatography with silica gel to
6
-chloro-3-iodo-2-(4-methoxyphenyl)-4-phenylquinoline (3ac): Pale
give of product 4b (91%, 92 mg).
o
1
Yellow solid; mp: 118-122 C; yield: 92%; H NMR (500 MHz, CDCl
3
): δ
.09 (d, J = 9 Hz, 1H), 7.68-7.64 (m, 3H), 7.61-7.57 (m, 3H), 7.37 (d, J =
Hz, 1H), 7.30-7.28 (m, 2H), 7.03 (d, J = 9 Hz, 2H), 3.90 (s, 3H) ppm;
8
2
Synthesis
of
4c) First Pd(OAc)
indicated amount of Pd(OAc)
6-chloro-2,4-diphenyl-3-(phenylethynyl)quinolone
(2 mol%) was dissolved in MeCN (1mL). Then, the
acetonitrile solution was added to a mixure
[
18]
(
2
1
3
C NMR (125 MHz, CDCl
3
): δ 161.8, 160.6, 153.9, 145.4, 141.7, 135.9,
2
1
32.9, 131, 130.9, 129, 128.8, 128.7, 127.7, 125.5, 113.4, 100.2, 55.4
of alkyne (44.5 mg, 0.45 mmol), aryl halide 3aa (100 mg, 0.22 mmol),
-1
ppm; IR (KBr): 2946, 1642, 1439, 1126, 790 cm ; HRMS (ESI) m/z calcd.
DABCO (76 mg, 3 equiv), and MeCN (4 mL). Then mixure was stirred
+
for C22
H
15ClINO [M +H] 471.9965; found 471.9948
2
under N at room temperature for 12 h. The resulting mixture was filtered
off, washed and extracted with diethyl ether. The combined organics
were washed with water and then with brine and dried over anhydrous
6-chloro-3-iodo-4-phenyl-2-propylquinoline (3ad): Yellow solid; mp:
o
1
Na
2
SO
4
. The solvent was evaporated under reduced pressure and the
3
88-90 C; yield: 79%; H NMR (500 MHz, CDCl ): δ 7.95-7.93 (m, 1H),
residue was purified by column chromatography with silica gel to give of
7.79 (d, J = 4 Hz, 1H), 7.68 (d, J = 2 Hz, 1H), 7.59-7.56 (m, 3H), 7.22-
7.20 (m, 2H), 3.26-3.23 (m, 2H), 1.93-1.89 (m, 2H), 1.12 (t, J = 7 Hz, 3H)
product 4c (96%, 90 mg).
13
ppm; C NMR (125 MHz, CDCl
3
): δ 163, 153.1, 145.3, 141.6, 132.2,
[
18]
130.6, 130.4, 129, 128.8, 128.7, 127.5, 125.5, 101.7, 45.1, 22.4, 14.1
6
-chloro-3-ethynyl-2,4-diphenylquinoline (4d)
mol %) was dissolved in MeCN (1 mL). Then, the indicated amount of
Pd(OAc) acetonitrile solution was added to a mixture of tri methyl silyl
2
First Pd(OAc) (2
-1
ppm; IR (KBr): 2941, 1645, 1449, 1378, 1126, 1020, 758 cm ; HRMS
+
(ESI) m/z calcd. for C18
H15ClIN [M +H] 408.0015; found 408.0028
2
acetylene (44.5 mg, 0.45 mmol), aryl halide 3aa (100 mg, 0.26 mmol),
DABCO (76 mg, 3 equiv), and MeCN (4 mL). Then mixture was stirred
2-butyl-6-chloro-3-iodo-4-phenylquinoline (3ae): Pale White solid; mp:
o
1
under N
off, washed and extracted with diethyl ether. The combined organics
dried over anhydrous Na SO The solvent was evaporated under
2
at room temperature for 12 h. The resulting mixture was filtered
3
128-130 C; yield: 82%; H NMR (500 MHz, CDCl ): δ 7.99 (d, J = 8.5 Hz,
1H), 7.62-7.54 (m, 4H), 7.28 (d, J = 2.5 Hz, 1H), 7.22-7.20 (m, 2H), 3.27
(t, J = 8 Hz, 2H), 1.88-1.84 (m, 2H), 1.57-1.52 (m, 2H), 1.02 (t, J = 7.5 Hz,
2
4
.
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201700668
FULL PAPER
1
3
13
3
1
4
4
H) ppm; C NMR (125 MHz, CDCl
3
): δ 162.8, 153.9, 149.9, 142.3,
3
7.04 (d, J = 9 Hz, 2H), 3.90 (s, 3H) ppm; C NMR (125 MHz, CDCl ): δ
29.7, 129.1, 129, 128.8, 128.7, 128.6, 128.4, 127, 126.8, 126.4, 100.3,
161.7, 160.1,159.9, 157.9, 148.6, 145.4, 135.6, 133.3, 131.2, 131.1,
130.8, 129.1, 127.6, 124.8, 124.7, 116.5, 116.3, 113.3 100.8, 55.3 ppm;
+
3, 31.4, 22.8, 14.1 ppm; HRMS (ESI) m/z calcd. for C19H17ClIN [M +H]
-
1
22.0172; found 422.0162
IR (KBr): 3123, 2966, 1542, 1364, 1286 cm ; HRMS (ESI) m/z calcd. for
+
22 2
C H14Cl INO [M+H] 505.9575; found 505.9573
6
8
1
7
4
1
1
-chloro-3-iodo-2-pentyl-4-phenylquinoline (3af): Yellow solid; mp:
o
1
8-90 C; yield: 87%; H NMR (500 MHz, CDCl3): δ 8.01 (d, J = 9 Hz,
H), 7.63 (d, J = 2.5 Hz, 1H), 7.60-7.55 (m, 3H), 7.29 (d, J = 2.5 Hz, 1H),
.23-7.21 (m, 2H), 3.29-3.26 (m, 2H), 1.90-1.87 (m, 2H), 1.53-1.42 (m,
6-chloro-4-(2-chlorophenyl)-3-iodo-2-propylquinoline (3am): Pale
o
1
3
Yellow solid; mp: 92-94 C; yield: 80 %; H NMR (500 MHz, CDCl ): δ
8.02 (d, J = 9 Hz, 1H), 7.64-7.60 (m, 2H), 7.53-7.46 (m, 2H), 7.27-7.17
(m, 2H), 3.26-3.23 (m, 2H), 1.94-1.88 (m, 2H), 1.11 (t, J = 7 Hz, 3H)
13
3
H), 0.96 (t, J = 7 Hz, 3H) ppm; C NMR (125 MHz, CDCl ): δ 163.2,
13
53.1, 145.4, 141.6, 132.2, 130.6, 130.4, 129, 128.8, 128.7, 127.4, 125.5,
3
ppm; C NMR (125 MHz, CDCl ): δ 163.1, 150.6, 145.4, 140.1, 133,
01.7, 43.2, 31.9, 28.8, 22.6, 14.2 ppm; HRMS (ESI) m/z calcd. for
132.6, 130.8, 130.7, 130.6, 130.4, 130.1, 127.4, 127, 124.7, 101.8, 44.8,
+
-1
C
20
H
19ClIN [M +H] 436.0328; found 436.0318
22.4, 14.1 ppm; IR (KBr): 2935, 1692, 1402, 1313, 1090, 786 cm ;
+
HRMS (ESI) m/z calcd. for
41.9622
C
18
H14Cl
2
IN [M +H] 441.9626; found
4
6-chloro-3-iodo-4-phenyl-2-(3-phenylpropyl)quinoline (3ag): Yellow
o
1
solid; mp: 104-106 C; yield: 83%; H NMR (400 MHz, CDCl
3
): δ 8.03 (d,
J = 9.2 Hz, 1H), 7.62-7.57 (m, 4H), 7.31-7.21 (m, 8H), 3.30 (s, 2H), 2.87-
2-butyl-6-chloro-4-(2-chlorophenyl)-3-iodoquinoline
(3an):
Pale
): δ
13
o
1
2
1
1
2
.86 (m, 2H), 2.46-2.42 (m, 2H) ppm; C NMR (100 MHz, CDCl
3
): δ
yellow solid; mp:169-170 C; yield: 88%; H NMR (500 MHz, CDCl
3
62.6, 153.1, 145.3, 142.2, 141.5, 132.3, 130.7, 130.6, 130.4, 129, 128.7,
28.3, 127.5, 125.8, 125.6, 125.5, 101.7, 42.7, 35.8, 30.6 ppm; IR (KBr):
8.03 (d, J = 9 Hz, 1H), 7.65-7.61 (m, 2H), 7.52-7.48 (m, 2H), 7.18 (d, J =
2.5 Hz, 2H), 3.30-3.27 (m, 2H), 1.89-1.86 (m, 2H), 1.58-1.53 (m, 2H),
-1
+
13
895, 1648, 1463, 1303, 1150, 758 cm ; ESI m/z [M+H] 484.02
3
1.03 (t, J = 7.5 Hz, 3H) ppm; C NMR (125 MHz, CDCl ): δ 163.2, 150.6,
1
1
1
45.4, 140.1, 132.9, 132.5, 130.7, 130.6, 130.6, 130.3, 130.1, 127.3,
26.9, 124.0, 101.7, 42.7, 31.1, 22.7, 14.0 ppm; IR (KBr): 2923, 1529,
6
-chloro-2-cyclopropyl-3-iodo-4-phenylquinoline (3ah): Pale yellow
-1
o
1
2
486, 1344, 1289, 1026 cm ; HRMS (ESI) m/z calcd. for C19H16Cl IN
solid; mp: 202-203 C; yield: 92%; H NMR (500 MHz, CDCl
J = 9.5 Hz, 1H), 7.59-7.56 (m, 4H), 7.27 (s, 1H), 7.24-7.22 (m, 2H), 2.83-
3
): δ 7.90 (d,
+
[
M+H] 455.9782; found 455.9785
13
2
.80 (m, 1H), 1.30-1.29 (m, 2H), 1.15-1.13 (m, 2H) ppm; C NMR (125
MHz, CDCl ): δ 162.7, 152.4, 145.4, 141.7, 131.7, 130.4, 130.3, 129.0,
28.8, 128.6, 127.6, 125.4, 102.9, 22.0, 11.2 ppm; IR (KBr): 1535, 1442,
3
6-chloro-4-(2-chlorophenyl)-3-iodo-2-pentylquinoline (3ao): Pale
o
1
1
1
4
White solid; mp: 87-89 C; yield: 83%; H NMR (500 MHz, CDCl
3
): δ 7.94
-1
+
282, 1127, 1029 cm ; HRMS (ESI) m/z calcd. for C18H13ClIN [M+H]
(d, J = 9 Hz, 1H), 7.57-7.54 (m, 2H), 7.39-7.33 (m, 2H), 7.29-7.24 (m, 2H),
13
05.9859; found 405.9857.
3.56-3.53 (m, 1H), 2.17-1.89 (m, 8H), 1.59-1.48 (m, 3H) ppm; C NMR
125 MHz, CDCl ): δ 163.3, 150.6, 145.4, 140.1, 133, 132.6, 130.8, 130.7,
30.4, 130.1, 127.4, 127, 124.7, 101.8, 42.9, 31.8, 28.7, 22.6, 14.1 ppm;
(
3
1
6-chloro-2-cyclohexyl-3-iodo-4-phenylquinoline (3ai): Pale white
-1
o
1
IR (KBr): 2902, 1702, 1586, 1324, 1140, 998, 703 cm ; HRMS (ESI) m/z
solid; mp: 211-212 C; yield: 83% H NMR (500 MHz, CDCl
3
): δ 8.01 (d,
+
2
calcd. for C20H18Cl IN [M +H] 469.9939; found 469.9942
J = 9.5 Hz, 1H), 7.62-7.55 (m, 4H), 7.29 (s, 1H), 7.23-7.21 (m, 2H), 3.49-
3
1
1
1
1
4
.44 (m, 1H), 2.07-2.05 (m, 2H), 1.95-1.93 (m, 2H), 1.81-1.76 (m, 3H),
13
.52-1.14 (m, 3H) ppm; C NMR (125 MHz, CDCl
3
): δ 165.8, 152.8,
6-chloro-4-(2-chlorophenyl)-3-iodo-2-(3-phenylpropyl)quinoline
o
1
45.5, 142.0, 132.0, 130.7, 130.3, 129.0, 128.7, 128.6, 127.7, 125.4,
02.7, 49.2, 32.1, 26.5, 26.1 ppm; IR (KBr): 2925, 2847, 1602, 1473,
(3ap): Pale Yellow solid; yield: 88%; mp: 106-108 C; H NMR (400 MHz,
CDCl ): δ 8.11-8.09 (d, J = 8.8 Hz, 1H) 7.74-7.70 (m, 1H), 7.60-7.55 (m,
3H), 7.37-7.32 (m, 1H), 7.28-7.22 (m, 6H), 3.38 (t, J = 8 Hz, 2H), 2.90-
3
-1
+
442, 1029 cm ; HRMS (ESI) m/z calcd. for
21
C H19ClIN [M+H]
13
48.0328; found 448.0328.
2.84 (m, 2H), 2.30-2.23 (m, 2H) ppm; C NMR (100 MHz, CDCl
3
): δ
62.1, 153.9, 146.9, 142.2, 142.1, 138.5, 135.3, 130.5, 129.7, 129, 128.8,
28.7, 128.6, 128.5, 128.3, 127, 126.8, 126.4, 125.7, 100.3, 42.8, 35.8,
1
1
3
6-chloro-4-(2-chlorophenyl)-3-iodo-2-phenylquinoline (3aj): White
+
o
1
2
0.7 ppm; HRMS (ESI) m/z calcd. for C24H18Cl IN [M +H] 517.9939;
solid; mp:156-157 C; yield: 89%; H NMR (500 MHz, CDCl
3
): δ 8.15 (d, J
found 517.9945
=
2
1
1
1
4
9 Hz, 1H), 7.71-7.64 (m, 4H), 7.55-7.49 (m, 5H), 7.27 (d, J = 8.5 Hz,
13
3
H) ppm; C NMR (125 MHz, CDCl ): δ 162.2, 151.4, 145.4, 143.0,
40.1, 133.5, 132.9, 131.3, 131.2, 130.7, 130.5, 130.2, 129.3, 128.8,
28.0, 127.5, 127.4, 124.7, 99.9 ppm; IR (KBr): 3211, 3106, 1569, 1423,
6-chloro-4-(2-fluorophenyl)-3-iodo-2-phenylquinoline (3aq): Pale
o
1
white solid; mp:124-125 C; yield: 88%; H NMR (500 MHz, CDCl
8.01 (d, J = 8.5 Hz, 1H), 7.59-7.42 (m, 3H), 7.40 (t, J = 7.5 Hz, 1H), 7.39-
3
): δ
-1
+
2
418, 1289, 1063 cm ; HRMS (ESI) m/z calcd. for C21H12Cl IN [M+H]
13
75.9469; found 475.9473.
7.21 (m, 3H), 7.19 (d, J = 8 Hz, 2H), 7.17-7.14 (m, 2H) ppm; C NMR
125 MHz, CDCl ): δ 162.2, 159.9, 157.9, 148.7, 145.3, 143.1, 133.5,
31.3, 131.3, 131.2, 131.1, 131.0, 129.0, 128.8, 127.7, 124.8, 124.7(2C),
116.5, 116.4, 100.4 ppm; IR (KBr): 3123, 2819, 1643, 1516, 1433, 1227
(
3
1
6-chloro-4-(2-chlorophenyl)-3-iodo-2-(p-tolyl)quinoline (3ak): White
o
1
solid; mp: 167-168 C; yield: 84%; H NMR (500 MHz, CDCl
3
): δ 8.14 (d,
-1
+
cm ; HRMS (ESI) m/z calcd. for C21
59.9767.
H12ClFIN [M+H] 459.9765; found
J = 9 Hz, 1H), 7.70-7.64 (m, 2H), 7.61 (d, J = 8 Hz, 2H), 7.56-7.50 (m,
13
4
2H), 7.34 (d, J = 8 Hz, 2H), 7.28-7.26 (m, 2H), 2.47 (s, 3H) ppm;
C
3
NMR (125 MHz, CDCl ): δ 162.2, 151.4, 145.4, 140.2, 140.1, 138.8,
1
1
1
33.4, 132.9, 131.3, 131.2, 130.7, 130.4, 130.1, 129.2, 128.7, 127.4,
6-chloro-4-(2-fluorophenyl)-3-iodo-2-(p-tolyl)quinoline (3ar): Pale
o
1
27.3, 124.7, 100.2, 21.4 ppm; IR (KBr): 3156, 2913, 1598, 1423, 1403,
yellow solid; mp: 137-138 C; yield: 90%; H NMR (500 MHz, CDCl
7.97 (d, J = 9 Hz, 1H), 7.51 (d, J = 8 Hz, 1H), 7.45-7.38 (m, 3H), 7.23-
3
): δ
-1
+
2
289 cm ; HRMS (ESI) m/z calcd. for C22H14Cl IN [M+H] 489.9654;
1
3
found 489.9656.
7.10 (m, 6H), 2.30 (s, 3H) ppm; C NMR (125 MHz, CDCl
3
): δ 162.2,
59.9, 158.0, 148.6, 145.4, 140.3, 138.8, 133.4, 131.2, 131.1, 131.0,
29.3, 129.1, 129.0, 127.7, 124.8, 124.8, 124.7, 116.5, 116.4, 100.7,
1
1
6-chloro-4-(2-chlorophenyl)-3-iodo-2-(4-methoxyphenyl)quinolone
-1
o
1
21.5 ppm; IR (KBr): 3312, 3225, 1607, 1584, 1421, 1193 cm ; HRMS
(3al): Yellow solid; mp: 143-144 C; yield: 87%; H NMR (500 MHz,
+
(
ESI) m/z calcd. for C22H14ClFIN [M+H] 473.9921; found 473.9921
CDCl ): δ 8.12 (d, J = 9 Hz, 1H), 7.69-7.57 (m, 4H), 7.41-7.26 (m, 4H),
3
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201700668
FULL PAPER
6
-chloro-4-(2-fluorophenyl)-3-iodo-2-(4-methoxyphenyl)quinoline
139.1, 136.3, 129.9, 129.0, 128.9, 128.9, 128.7, 128.5, 128.5, 126.3,
o
1
+
(3as): Pale yellow solid; mp: 130-132 C; yield: 88%; H NMR (400 MHz,
2
120.3, 100.9, 21.5 ppm; HRMS (ESI) m/z calcd. for C22H14Br IN [M+H]
CDCl ): δ 8.21 (d, J = 8.4 Hz, 1H), 7.70-7.56 (m, 4H), 7.42-7.25 (m, 4H),
3
577.8616; found 577.8634
13
7
1
1
3
.04 (d, J = 8.8 Hz, 2H), 3.91 (s, 3H) ppm; C NMR (100 MHz, CDCl ): δ
60.4, 158.8, 156.4, 147.3, 144.1, 134.3, 131.9, 129.9, 129.8, 129.7,
29.6, 127.8, 127.7, 126.3, 123.5, 123.4, 115.2, 115.0, 112.0, 99.5, 54.1
8-bromo-6-chloro-3-iodo-2,4-diphenylquinoline (3be): White solid;
o
1
mp: 185-186 C; yield: 88%; H NMR (400 MHz, CDCl
7.78 (d, J = 9.6 Hz, 2H), 7.61-7.58 (m, 3H), 7.52 (d, J = 6.8 Hz, 3H), 7.35
3
): δ 8.04 (s, 1H),
-1
ppm; IR (KBr): 3116, 2947, 1623, 1459, 1328, 1126 cm ; HRMS (ESI)
+
13
m/z calcd. for C22
H
14ClFINO [M+H] 489.9870; found 489.9867
(s, 1H), 7.28-2.66 (m, 2H) ppm; C NMR (100 MHz, CDCl
3
): δ 162.3,
54.5, 142.8, 142.7, 141.5, 134.0, 132.5, 129.9, 129.8, 128.9, 128.8,
28.3, 127.8, 127.6, 126.2, 125.4, 100.7 ppm; IR (KBr): 2923, 1663,
1
1
6
-chloro-4-(2-fluorophenyl)-3-iodo-2-propylquinoline (3at): Yellow
-1
o
1
1548, 1356, 1284, 841 cm ; HRMS (ESI) m/z calcd. for C21H12BrClIN [M
solid; mp: 86-88 C; yield: 81%; H NMR (500 MHz, CDCl
3
): δ 7.92 (d, J
9 Hz, 1H), 7.55-7.53 (m, 1H), 7.50-7.45 (m, 1H), 7.26 (d, J = 7 Hz, 1H),
.19-7.18 (m, 2H), 7.10-7.08 (m, 1H), 3.15 (t, J = 7.5 Hz, 2H), 1.86-1.80
+
+
H] 519.8964; found 519.8959
=
7
13
8-bromo-6-chloro-3-iodo-4-phenyl-2-(p-tolyl)quinoline (3bf): White
(
m, 2H), 1.03 (t, J = 7 Hz, 3H) ppm; C NMR (125 MHz, CDCl
3
): δ 163,
59.9, 157.9, 147.8, 145.4, 132.6, 131.2, 131, 130.8, 130.7, 129, 127.4,
24.8, 116.5, 102.3, 45, 22.4, 14.1 ppm; HRMS (ESI) m/z calcd. for
o
1
solid; mp: 205-206 C; yield: 77%; H NMR (500 MHz, CDCl
J = 2.5 Hz, 1H), 7.71 (d, J = 8 Hz, 2H), 7.60-7.58 (m, 3H), 7.34-7.26 (m,
3
): δ 8.03 (d,
1
1
13
+
3
5H), 2.47 (s, 3H) ppm; C NMR (125 MHz, CDCl ): δ 162.3, 154.4, 142.8,
C
18
H
14ClFIN [M +H] 425.9921; found 425.9924
1
41.6, 139.9, 139.0, 133.9, 132.4,130.9, 129.8, 129.0, 128.9, 128.5,
28.2, 126.2, 125.4, 100.8, 21.4 ppm; IR (KBr): 2984, 1775, 1546, 1274,
1
6
-chloro-4-(2-fluorophenyl)-3-iodo-2-pentylquinoline (3au): Yellow
-1
+
o
1
1004, 780 cm ; HRMS (ESI) m/z calcd. for C22
33.9120; found 533.9124
H14BrClIN [M +H]
solid; mp: 91-93 C; yield: 82%; H NMR (400 MHz, CDCl
3
): δ 7.09 (d, J
12 Hz, 1H), 7.7 (s, 1H), 7.56 (d, J = 6 Hz, 3H), 7.25 (d, J = 5.6 Hz, 2H),
.30 (t, J = 8 Hz, 2H), 1.90 (s, 2H), 1.53-1.45 (m, 4H), 0.97 (t, J = 6.8 Hz,
5
=
3
3
1
2
8
13
Ethyl (E)-3-(6-chloro-2,4-diphenylquinolin-3-yl)acrylate (4a): Yellow
3
H) ppm; C NMR (100 MHz, CDCl ): δ 162.8, 153.9, 146.9, 142.3,
o
1
solid; mp: 153-154 C; yield: 91%; H NMR (400 MHz, CDCl
J = 8.8 Hz, 1H), 7.66-7.60 (m, 3H), 7.54-7.45 (m, 8H), 7.28 (t, J = 4.8 Hz,
H), 5.40 (d, J = 8.8 Hz, 1H), 4.06-4.01 (m, 2H), 1.14 (t, J = 6.8 Hz, 3H)
3
): δ 8.11 (d,
29.8, 129.1, 129, 128.7, 128.4, 127, 126.8, 126.4, 100.3, 43.3, 31.9, 29,
2.6, 14.1 ppm; IR (KBr): 2899, 1603, 1446, 1422, 1398, 1117, 1027,
-1
+
2
02 cm ; HRMS (ESI) m/z calcd. for C20H18ClFIN [M +H] 454.0234;
13
ppm; C NMR (100 MHz, CDCl
3
): δ 165.9, 159.2, 147.8, 145.6, 141.2,
40.1, 135.5, 132.8, 131.3, 131.1, 129.7, 129.6, 128.9, 128.8, 128.7,
28.4, 127.3, 126.3, 126.0, 125.5, 60.4, 14.1 ppm; IR (KBr): 3064, 2976,
found 454.0222
1
1
4
-(4-fluorophenyl)-3-iodo-2-phenylquinoline (3av): Pale white solid;
-1
o
1
1715, 1634, 1546, 1368 cm ; HRMS (ESI) m/z calcd. for C26
H20ClNO
2
mp: 182-183 C; yield: 92%; H NMR (500 MHz, CDCl
Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.76 (s, 1H), 7.65-7.63 (m, 2H), 7.51-
3
): δ 8.00 (d, J = 2
+
[
M+H] 414.1260; found 414.1262.
13
7
1
1
1
3
.49 (m, 3H), 7.30-7.27 (m, 5H)--- ppm; C NMR (125 MHz, CDCl ): δ
o
6
-chloro-2,3,4-triphenylquinoline (4b): White solid; mp: 195-196 C;
62.5, 152.6, 145.8, 143.3, 139.0, 135.2, 131.1, 131.0, 130.9, 129.1,
28.8, 128.7, 128.0, 127.9, 116.1, 116.0, 93.4 ppm; IR (KBr): 2895,
1
yield: 93%; H NMR (400 MHz, CDCl
dd, J = 2.4, J = 8.8 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.23-7.25 (m, 5H),
.21-7.19 (m, 3H), 7.12-7.09 (m, 2H), 7.01-6.99 (m, 3H), 6.87-6.85 (m,
3
): δ 8.17 (d, J = 8.8 Hz, 1H), 7.66
-1
(
1
2
648, 1463, 1303, 1150, 758 cm ; HRMS (ESI) m/z calcd. for C21H13FIN
+
7
2
[
M +H] 426.0154 found 424.0151
13
3
H) ppm; C NMR (100 MHz, CDCl ): δ 159.3, 146.9, 145.7, 140.8,
6
1
1
-bromo-3-iodo-2,4-diphenylquinoline (3ba): Pale yellow solid; mp:
137.9, 136.2, 133.8, 132.4, 131.4, 131.2, 130.3, 130.2, 129.8, 128.1,
128.0, 127.8, 127.7, 127.6, 127.4, 126.5, 125.3 ppm; IR (KBr): 3471,
o
1
3
42-145 C; yield: 86%; H NMR (400 MHz, CDCl ): δ 8.02 (d, J = 9.2 Hz,
H), 7.82 (d, J = 8.8 Hz, 1H), 7.68-7.49 (m, 9H), 7.30 (t, J = 8.5 Hz, 2H)
-1
3014, 1654, 1501, 1319 cm ; HRMS (ESI) m/z calcd. for C27
H18ClN
13
+
ppm; C NMR (100 MHz, CDCl
3
): δ 162.4, 153.9, 145.5, 143.4, 141.5,
33.7, 131.2, 129.2, 129.0, 128.9, 128.8, 128.3, 128.1, 121.5, 99.8 ppm;
[M+H] 392.1206; found 392.1206.
1
+
HRMS (ESI) m/z calcd. for C21
H13BrIN [M+H] 485.9354; found 485.9353
6-chloro-2,4-diphenyl-3-(phenylethynyl)quinolone (4c): White solid;
o
1
mp: 166-167 C; yield: 96%; H NMR (400 MHz, CDCl
3
): δ 8.15 (d, J =
6
1
1
-bromo-3-iodo-4-phenyl-2-(p-tolyl)quinoline (3bb): White solid; mp:
8
.8 Hz, 1H), 8.08 (dd, J
1
= 1.2, J
2
= 9.6 Hz, 2H), 7.65-7.53 (m, 10H),
o
1
13
56-158 C; yield: 88%; H NMR (400 MHz, CDCl
H), 7.82-7.79 (m, 1H), 7.61-7.56 (m, 6H), 7.34-7.28 (m, 4H), 2.49 (s, 3H)
3
): δ 8.03 (d, J = 9.2 Hz,
7.24-7.22 (m, 3H), 6.97 (dd, J
1
2
= 1.6, J = 4 Hz, 2H) ppm; C NMR (100
MHz, CDCl
3
): δ 159.7, 151.0, 145.2, 139.8, 136.4, 132.8, 131.4, 131.1,
30.8, 129.9, 129.7, 129.1, 128.6, 128.5, 128.4, 128.2, 127.9, 126.5,
24.9, 122.8, 116.4, 99.1, 87.4 ppm; IR (KBr): 3459, 3024, 2983, 1542,
13
ppm; C NMR (100 MHz, CDCl
3
): δ 162.4, 153.8, 145.6, 141.5, 140.6,
1
1
1
4
1
1
4
38.8, 133.6, 131.2, 129.2, 129.1, 128.9, 128.8, 128.8, 128.7, 128.2,
+
-1
+
31.3, 100.1, 21.5 ppm; HRMS (ESI) m/z calcd. for C22H15BrIN [M+H]
403 cm ; HRMS (ESI) m/z calcd. for C29H18ClN [M+H] 416.1205; found
99.9511; found 499.9512
16.1206.
6
1
7
2
1
1
5
,8-dibromo-3-iodo-2,4-diphenylquinoline (3bc): Pale yellow solid; mp:
6
-chloro-3-ethynyl-2,4-diphenylquinoline (4d): Yellow sticky liquid;
o
1
95-197 C; yield: 86%; H NMR (500 MHz, CDCl
.79-7.77 (m, 2H), 7.61-7.58 (m, 3H), 7.52-7.51 (m, 4H), 7.28-7.26 (m,
3
): 8.17 (d, J = 2 Hz, 1H),
1
yield: 68%; H NMR (400 MHz, CDCl
dd, J = 1.6, J = 4 Hz, 2H), 7.69-7.45 (m, 10H), 3.10 (s, 1H) ppm;
NMR (100 MHz, CDCl ): δ 160.2, 152.6, 145.3, 139.6, 136.0, 132.9,
3
): δ 8.14 (d, J = 8.8 Hz, 1H), 8.08
13
(
1
2
C
13
H) ppm; C NMR (100 MHz, CDCl
3
): δ 162.5, 154.4, 143.1, 142.7, 141.5,
3
36.4, 129.8, 129.1, 129.0, 128.9, 128.9, 128.8, 128.7, 127.8, 126.3,
1
31.4, 131.1, 129.6, 129.1, 128.7, 128.4, 128.0, 127.9, 126.4, 125.0,
+
20.5, 100.7 ppm; HRMS (ESI) m/z calcd. for
C
21
H12Br
2
IN [M+H]
-
1
15.1, 87.2, 80.5 ppm; IR (KBr): 3398, 3136, 3083, 1642, 1592, 1403 cm
63.8459; found 563.8462
1
+
;
HRMS (ESI) m/z calcd. for
C
23
H
14ClN [M+H] 440.0892; found
4
40.0889.
6
,8-dibromo-3-iodo-4-phenyl-2-(p-tolyl)quinoline (3bd): White solid;
o
1
mp: 211-212 C; yield: 83%; H NMR (400 MHz, CDCl
Hz, 1H), 7.72-7.70 (m, 2H), 7.61-7.59 (m, 4H), 7.51-7.27 (m, 4H), 2.48 (s,
3
): 8.17 (d, J = 2
13
3H) ppm; C NMR (100 MHz, CDCl
3
): δ 162.5, 154.4, 143.1, 141.6, 140,
Acknowledgements
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European Journal of Organic Chemistry
10.1002/ejoc.201700668
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CSIR-India is acknowledged for the financial support
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Keywords: 3-iodoquinolines •Iodocyclization •Green Synthesis •
Regioselective • Cross-Coupling
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European Journal of Organic Chemistry
10.1002/ejoc.201700668
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Entry for the Table of Contents (Please choose one layout)
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Iodocyclization*
[
a,b]
Srinivasarao Yaragorla,*
Abhishek
[
a,b]
[a,b]
Pareek,
Ravikrishna Dada
and
[
b]
Pyare Lal Saini
Page No. – Page No.
Text for Table of Contents
Single-Step-Synthesis
of
3-Iodo
quinolines from 1-(2-aminophenyl)
ketones through a Regioselective (6-
endo dig) Electrophilic-cyclization
*
A single-step-synthesis of 3-iodoquinolines is achieved through a regioselective iodocyclization. The synthesis commenced
t
from readily available materials in aqueous-ethylacetate medium, promoted by KO Bu and I
synthetic utility of the products in cross-coupling reactions was demonstrated.
2
at room temperature. The
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