Microwave-Assisted Metal- and Ligand-Free O-Arylation of Quinolones Using Diaryliodonium Salts: An Easy and Rapid Synthesis of Aryloxyquinolines

Article abstract of DOI:10.1055/s-0035-1560367

A microwave-assisted metal- and ligand-free direct O-arylation of quinolones has been achieved by employing easily accessible diaryliodonium salts in the presence of a base to afford various aryloxyquinolines in good yields. The operationally simple and r

Full text of DOI:10.1055/s-0035-1560367

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, 604–610
letter
604
M. K. Mehra et al.
Letter
Synlett
Microwave-Assisted Metal- and Ligand-Free O-Arylation of Quino-
lones Using Diaryliodonium Salts: An Easy and Rapid Synthesis of
Aryloxyquinolines
Manish Kumar Mehra
Mukund P. Tantak
Indresh Kumar
O
X
R
I
R
Ar
Ar
O
toluene/DMF
K2CO3 MW
N
H
Dalip Kumar*
O
100 °C, 5 min
N
Department of Chemistry, Birla Institute of Technology and
Science, Pilani 333 031, India
dalipk@pilani.bits-pilani.ac.in
N
16 examples
55–90% yield
N
H
O
benzofuroquinolines
80–83% yield
operationally simple
metal- & ligand-free
mild reaction conditions
short reaction time
good to high yield
amenable to benzofuroquinolines
Received: 19.08.2015
Accepted after revision: 05.10.2015
Published online: 16.11.2015
furnish ‘drug-like’ small molecules for biological screening.
For example, the C-2 and C-4 positions have been modified
by introducing a number of carbon-, oxygen-, nitrogen-,
and sulfur-based nucleophiles to achieve substituted quin-
olines. For example, aryloxyquinolines 1–3 were identified
as potent inhibitors of HMG CoA reductase, tyrosin kinase,
and thrombin, respectively (Figure 1).7–9 For the prepara-
tion of 2- and 4-quinolinyl aryl ethers, quinolin-2(1H)-ones
and quinolin-4(1H)-ones are the key precursors.
DOI: 10.1055/s-0035-1560367; Art ID: st-2015-d0650-l
Abstract A microwave-assisted metal- and ligand-free direct O-aryla-
tion of quinolones has been achieved by employing easily accessible di-
aryliodonium salts in the presence of a base to afford various aryloxy-
quinolines in good yields. The operationally simple and rapid protocol
has also been utilized for the construction of biologically important
benzofuro[3,2-c]quinolines.
Generally, quinolinyl aryl ethers are prepared by the ac-
tivation of the 2/4-positions of quinolones using POCl3 fol-
lowed by nucleophilic substitution with an appropriate
phenol. Recently, 4-aryloxyquinolines have been synthe-
sized by a Cu-catalyzed reaction of 4-haloquinolines with
phenols in the presence of picolinic acid as a ligand.10 Ana-
loguous 2-aryloxy-3-substituted quinolines were synthe-
sized through 1,4-diazabicyclo[2.2.2]octane (DABCO) medi-
ated reactions of O-alkynyl arylisocyanides and phenols.11
However, some of the existing synthetic protocols involve
Key words quinolones, aryloxyquinolines, microwave-assisted reac-
tions, diaryliodonium salts, metal-free reactions
The quinoline motif is present widely in natural prod-
ucts as well as in synthetic organic molecules of biological
interest.1,2 In particular, many compounds with this struc-
tural motif have been found to display antimalarial, anti-
asthmatic, antimicrobial, antituberculosis, antileishmanial,
anti-HIV, and anticancer activity.3–6 There is continuing in-
terest in making modifications to the quinoline scaffold to
F
Me
R
HO
F
N
NH
O
O
O
O
N
O
NH
O
R
R
MeO
MeO
NH2
N
Br
N
O
R
cabozantinib
tyrosine kinase inhibitor (2)
thrombin inhibitor (3)
HMG CoA reductase inhibitor (1)
Figure 1 Representative examples of biologically important aryloxyquinolines
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 604–610

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M. K. Mehra et al.
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Synlett
O
R1
R2
Ar
O
X–
N
H
N
O
R1
R2
4
H
7
+I
Ar
Ar
Ar
K2CO3, toluene
MW, 100 °C, 5 min
K2CO3, DMF
MW, 100 °C, 5 min
N
O
N
5
6
8
Scheme 1 O-Arylation of quinolones 4 and 7
multistep sequences, use metal catalysts and ligands or
harsh reaction conditions, and can give low product yields.
In recent years, diaryliodonium salts have received sub-
stantial attention as powerful electrophilic arylating agents
due to their high reactivity, stability, and low toxicity.12,13
They have been employed in metal-free as well as in metal-
catalyzed arylation reactions leading to the formation of bi-
ologically important heterocycles.14,15 Many transition-
metal catalysts and associated ligands are normally very ex-
pensive and some of them are air- and moisture-sensitive.
Most of the transition metals are toxic to different degrees,
and their removal from the final products is an expensive
challenge in medicinal chemistry.16 The limitations associ-
ated with metal-based reagents, together with the biologi-
cal significance of heteroaryl ethers and analogues, have
stimulated us to develop an operationally simple and met-
al-free protocol for the O-arylation of quinolones to prepare
an array of aryloxyquinolines.
using Cs2CO3 as base without any metal catalyst; albeit in
low yield (entry 1). To improve the yield, we screened dif-
ferent bases and solvents at different temperatures using
conventional heating as well as MW irradiation. A slight im-
provement in yield was observed when K2CO3 was used as
base (entry 2). By increasing the reaction temperature from
100 to 130 °C, the product yield improved significantly (up
to 65%). Under similar conditions, the reaction of 4 with 5a
in DMSO resulted in a poor yield of 6a (entries 4 and 5).
Product 6a was only obtained in moderate yield when the
same reaction in DCE was performed using K2CO3 or t-BuOK
Table 1 Optimization of Reaction Conditions for O-Arylation of Quino-
lone 4
OTf–
+I
Very recently, significant progress has been made by
several researchers who have explored the metal-free aryl-
ation of various nucleophiles using diaryliodonium
salts.17,18 Recently, Olofsson et al. reported the metal-free
arylation of phenols, alcohols, N-hydroxyphthalimides, and
N-hydroxysuccinimides by employing diaryliodonium
salts.19–21 Subsequently, Karade et al. utilized diaryliodoni-
um salts in the metal-free O-arylation of pyrimidine-2(1H)-
one to prepare aryloxypyrimidines.22
5a
conditions
N
O
N
H
O
6a
4
Entry Base
Solvent
Conventional heating
MW irradiation
Temp
(°C)a
Time
(h)
Yield Time Yield
(%)b
(min) (%)b
By employing diaryliodonium salts, we have recently
developed high-yielding syntheses of diaryl sulfones and
arylated azaheterocycles.23,24 Herein, we wish to report a
novel and metal-free direct O-arylation of quinolones uti-
lizing readily available and stable diaryliodonium salts to
access aryloxyquinolines (Scheme 1).
The requisite diaryliodonium salts were prepared by
following the reported protocols.25–27 The 4-methylquino-
lin-2(1H)-one and quinolin-4(1H)-one precursors 4 and 7,
respectively, were synthesized from the reaction of aniline
with ethyl acetoacetate or diethyl (ethoxymethy-
lene)malonate.28,29 To optimize reaction conditions, aryla-
tion of 4-methyl-quinolin-2(1H)-one (4) with di-
phenyliodonium triflate (5a) under conventional and mi-
crowave (MW) irradiation conditions was selected as a
model reaction; the results are summarized in Table 1. To
our satisfaction, the reaction of 4 with 5a proceeded in DMF
1
2
Cs2CO3
K2CO3
K2CO3
Cs2CO3
K2CO3
K2CO3
t-BuOK
K2CO3
K2CO3
K3PO4
K3PO4
–
DMF
100
100
130
70
5.0
4.5
3.5
8.0
6.0
4.0
3.5
5.0
–
30
40
60
25
30
45
50
65
–
10
10
10
10
10
10
10
5.0
10
10
10
40
45
65
30
30
50
50
85
85
35
70
trace
DMF
3
DMF
4
DMSO
DMSO
DCE
5
100
80
6
7
DCE
80
8
toluene
toluene
THF
100
100
80
9
10
11
12
6.0
3.5
5.0
35
55
toluene
toluene
130
130
Trace 10
a We note that the stated temperatures under MW conditions are probably
not the genuine reaction temperatures.
b Isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 604–610

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M. K. Mehra et al.
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as bases (entries 6 and 7). The reaction of 4 and 5a in tolu-
ene using K2CO3 at 100 °C also gave 6a in moderate yield.
However, when the same reaction mixture was subjected to
MW irradiation for 5 minutes, 6a was obtained in 85% yield.
The yield of the reaction was unaffected when the time
of MW exposure was extended (Table 1, entries 8 and 9).
Changing the base from K2CO3 to K3PO4 led to the formation
of 6a in lower yields (entries 10 and 11). To ascertain the
role of the base, reaction of 4 and 5a was performed in tolu-
ene without any base, which afforded only a trace amount
of the product even after heating to reflux for 24 hours or
exposure to MW irradiation for 10 minutes (entry 12). With
the use of 1.0, 2.0, and 2.5 equivalents of K2CO3 in the reac-
tion of 4 and 5a, some unchanged starting material was re-
covered, however, the use of 3.0 equivalents of K2CO3 was
found to be optimum to produce 6a in good yield. We also
performed the arylation of 4 with diphenyliodonium to-
sylate (5g) using K2CO3 as base in toluene at 100 °C to pro-
Table 2 Synthesis of Aryloxyquinolines 6a–f
X–
X = OTf, OTs
+I
Ar
Ar
5
Ar
N
O
N
O
K2CO3, 100 °C, toluene
5 min, MW
H
4
6
Entry
1
Diaryliodonium salt
Product
Yield (%)
81
OTf–
+I
N
N
N
N
N
O
O
O
O
O
5a
6a
6b
6c
6d
OTf–
+I
Br
Cl
2
3
4
73
75
62
Br
Cl
Br
5b
OTf–
+I
Cl
5c
OTs–
+I
5d
5e
OTf–
+I
5
67
6e
OTs–
+I
OMe
6
7
65
65
OMe
MeO
5f
N
O
6f
OTs–
+I
6a
5g
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 604–610

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M. K. Mehra et al.
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Synlett
duce 6a in 65% yield (Table 2, entry 7). With the optimized
reaction conditions in hand, the scope of the O-arylation
was undertaken by employing various diaryliodonium salts
5 (Table 2).30
Table 3 Optimization of Reaction Conditions for O-Arylation of Quino-
lone 7a
OTf–
+I
The synthesized 4-methyl-2-aryloxyquinolines 6a–f
were fully characterized based on their IR, NMR (1H and
13C) spectroscopic and mass spectrometric data. The
1H NMR spectra of 6a–f displayed a characteristic singlet at
δ = 6.9 to 7.0 ppm, corresponding to the C-3 proton. Simi-
larly, in the 13C NMR spectra, the C-2 carbon of the quino-
line ring resonated at δ = 161 to 162 ppm.
O
O
5a
Conditions
N
H
N
8a
7a
Entry Base
Solvent
Temp
Conventional
heating
MW irradiation
We then explored the arylation of quinolone 7a. Reac-
tion conditions for the O-arylation of 7a using 5a were opti-
mized under conventional heating conditions as well as un-
der MW irradiation; the results are summarized in Table 3.
Initial reaction of 7a and 5a was performed in THF, DMF,
and toluene, using Cs2CO3 as base, but we could isolate 8a
only in a low to moderate yield (entries 1–3). Given the
good solubility of 7a in DMF, we performed the model reac-
tion in this solvent using various bases. No product was
formed when the reaction was carried out in DMF without
any base at 100 °C, even after heating to reflux for 24 h un-
der conventional heating or heating under MW irradiation
for 10 min (entry 13). Use of the bulkier base t-BuOK was
also not satisfactory in DMF (entry 4). At low temperature,
the use of K2CO3 in dioxane, DCE, or DMF gave 8a in moder-
ate yield (entries 5–7). Interestingly, when the reaction
temperature was raised from 70 to 100 °C in DMF, 8a was
obtained in 75% yield. The product yield increased to 80%
when the same reaction mixture was heated under MW ir-
radiation (entry 8). Further increase in temperature (up to
120 °C) and use of DMSO and toluene as reaction solvents
at 100 °C did not improve the product yield (entries 9–11).
Under these optimized conditions, the influence of differ-
ent diaryliodonium salts was investigated to prepare a
range of aryloxyquinoline derivatives 8a–j in good yields
(Table 4).26 Again, the synthesized products were fully char-
acterized based on their NMR, IR spectroscopic and mass
spectrometric data. In the 13C NMR spectra, a characteristic
peak was observed between δ values of 159 to 162 ppm,
corresponding to the C-4 carbon of the quinoline ring.
Interestingly, solvents and bases were found to play an
important role in the O-arylation of quinolones. Diaryliodo-
nium salts with a triflate counter anion gave better yields of
aryloxyquinolines when compared with their tosylate
counterparts (Table 2, entries 1 and 7). A number of dia-
ryliodonium salts possessing electron-withdrawing or elec-
tron-donating groups smoothly transferred their aryl rings
to afford the corresponding aryloxyquinolines in good
yields.
(°C)a
Time
(h)
Yield Time
Yield
(%)b
(min) (%)b
1
2
CsCO3
THF
70
100
100
100
90
6.0
30
55
45
25
40
50
50
75
75
50
55
NR
10
10
10
10
10
10
10
42
63
65
25
54
55
60
80
80
52
60
NR
Cs2CO3
Cs2CO3
t-BuOK
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
–
DMF
4.0
3.5
5.0
6.0
3.5
5.0
2.0
2.0
3.5
4.0
24
3
toluene
DMF
4
5
dioxane
DCE
6
80
7
DMF
70
8
DMF
100
120
100
100
100
5.0
5.0
10
9
DMF
10
11
13
DMSO
toluene
DMF
10
10
a We note that the stated temperatures under MW conditions are probably
not the genuine reaction temperatures.
b Isolated yield.
such as methyl and methoxyl. Furthermore, diaryliodonium
salts possessing sterically hindered substituents such as
tert-butyl (5h) and mesityl (5e) arylated the quinolones ef-
ficiently. Notably, the synthesized halo-substituted aryl-
oxyquinolinesthis could be useful for the synthesis of fur-
ther functionalized bioactive heterocycles.
A control experiment to detect the involvement of radi-
cal species in the reactions of 4/7a with 5a was carried out
in the presence of 2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO). The outcome of this experiment showed that the
radical inhibitor TEMPO did not have any influence on the
reaction rate, suggesting the formation of aryloxyquino-
lines through an ionic pathway. A plausible mechanism for
the O-arylations of quinolones 4/7 is depicted in Scheme 2.
Initially, the tautomeric form of quinolones 4/7 in the pres-
ence of K2CO3 is proposed to generate species A that, in
turn, undergoes a displacement reaction with diaryliodoni-
um salt 5 to form intermediate B. Finally, ligand coupling in
B generates aryloxyquinolines 6/8.
The salts 5b–c, with electron-withdrawing groups, pro-
duced the O-arylated products in better yields compared
with salts 5d–f and 5h–i, with electron-donating groups
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Table 4 Synthesis of Aryloxyquinolines 8a–j
X = OTf, OTs
Ar
X–
Ar
O
O
N
+I
R1
R2
R1
R2
Ar
5
N
H
K2CO3, 100 °C, DMF
5 min, MW
7
8
R1 = H, Br
2 = H, Ph
R
Entry
Diaryliodonium salts
Products
Yield (%)
OTf–
O
N
+I
1
80
5a
8a
Cl
OTf–
+I
O
N
2
3
4
70
55
58
Cl
Cl
5c
8b
OTs–
+I
O
N
5h
8c
OTs–
O
N
+I
5l
8d
OTf–
+I
O
N
5
6
74
55
5e
8e
OTs–
OMe
+I
O
N
OMe
MeO
5f
8f
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Table 4 (continued)
Entry
Diaryliodonium salts
Products
Yield (%)
OMe
O
N
Br
Br
Br
7
5f
60
8g
8h
8i
Cl
O
N
8
5c
5a
5a
70
80
76
O
N
9
O
N
10
Ph
8j
We then utilized the synthesized 4-aryloxyquinolines
8g–i for the construction of benzofuro[3,2-c]quinolines
9a–c. Fused quinoline derivatives of this nature are import-
ant because of their anticancer, antimicrobial, antiplasmo-
dial, antiviral, and antituberculosis properties.31,32
Fused quinolines 9a–c were smoothly achieved in good
yields (80–83%) through the Pd-catalyzed intramolecular
Heck coupling of 3-bromo-4-aryloxyquinolines 8g–i in the
presence of triethylamine, as depicted in Scheme 3. Howev-
er, our attempts to convert 2-aryloxyquinolines 6 into the
corresponding benzofuro[2,3-b]quinolines through double
C–H activation were unsuccessful.
In summary, a novel and efficient MW-enhanced metal-
and ligand-free synthetic protocol for the direct O-arylation
of quinolones using diaryliodonium salts has been devel-
oped. Important features of this experimentally simple syn-
thetic protocol are the use of readily available and stable di-
aryliodonium salts, metal- and ligand-free conditions, use
of MW energy, short reaction times, and good product
yields. Furthermore, the synthetic potential of the aryloxy-
quinolines thus synthesized was demonstrated by prepar-
ing benzofuro[3,2-c]quinolines in good yields.
N
H
O
O
N
Ar2IOTf
5
4
K2CO3
– ArI
OAr
OK
O
I
ligand
coupling
Ar
N
N
6/8
Ar
N
H
A
B
7
Scheme 2 Plausible mechanism for the O-arylation of quinolones
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 604–610

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M. K. Mehra et al.
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(12) Merritt, E. A.; Olofsson, B. Angew. Chem. Int. Ed. 2009, 48, 9052.
(13) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299.
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(i), 370.
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(17) Ackermann, L.; Dell’Acqua, M.; Fenner, S.; Vicente, R.;
Sandmann, R. Org. Lett. 2011, 13, 2358.
R2
R2
O
O
N
Br
PdCl2
Et3N, 90 °C, 4 h
N
8g–i
9
(18) Umierski, N.; Manolikakes, G. Org. Lett. 2013, 15, 188.
(19) Jalalian, N.; Ishikawa, E. E.; Silva, L. F.; Olofsson, B. Org. Lett.
2011, 13, 1552.
Cl
OMe
(20) Lindstedt, E.; Ghosh, R.; Olofsson, B. Org. Lett. 2013, 15, 6070.
(21) Ghosh, R.; Olofsson, B. Org. Lett. 2014, 16, 1830.
(22) Thorat, P. B.; Waghmode, N. A.; Karade, N. N. Tetrahedron Lett.
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(24) Kumar, D.; Pilania, M.; Arun, V.; Pooniya, S. Org. Biomol. Chem.
2014, 12, 6340.
O
N
O
O
N
N
9a, 83%
9b, 80%
9c, 82%
(25) Bielawski, M.; Aili, D.; Olofsson, B. J. Org. Chem. 2008, 73, 4602.
(26) Bielawski, M.; Olofsson, B. Chem. Commun. 2007, 2521.
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193.
Scheme 3 Synthesis of benzofuro[3,2-c]quinolines 9
Acknowledgment
(29) Huang, L.-J.; Hsieh, M.-C.; Teng, C.-M.; Lee, K.-H.; Kuo, S.-C.
Bioorg. Med. Chem. 1998, 6, 1657.
Financial support from the DBT, New Delhi is gratefully acknowl-
edged. M.K.M. thanks the CSIR, New Delhi for the award of Junior Re-
search Fellowship.
(30) Synthesis of Aryloxyquinolines; General Procedure:
A
mixture of quinolone (0.62 mmol), diaryliodonium salt (0.62
mmol) and potassium carbonate (260 mg, 1.88 mmol) in
toluene (1 mL) or DMF (2–3 drops) was irradiated in a CEM Dis-
cover MW reactor (100 W power) at 100 °C for 5 min. Upon
completion of the reaction, as indicated by TLC, solvent was
removed and the residue was dissolved in dichloromethane (20
mL). To this solution, water (20 mL) was added and the mixture
stirred at room temperature for 10 min. The organic phase was
separated, washed with brine (2 × 15 mL), dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo. The crude product
thus obtained was purified by silica gel (100–200) column chro-
matography to afford the pure aryloxyquinoline.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560367.
S
u
p
p
ortiInfogrmoaitn
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p
p
ortioInfgrmoaitn
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4-Methyl-2-phenoxyquinoline (6a): Yield: 119 mg (81%); off-
white solid; mp 76–77 °C. 1H NMR (400 MHz, CDCl3): δ = 7.94
(dd, J = 8.3, 1.2 Hz, 1 H), 7.80 (dd, J = 8.4, 0.7 Hz, 1 H), 7.66–7.62
(m, 1 H), 7.56–7.53 (m, 2 H), 7.50–7.46 (m, 1 H), 7.28 (s, 1 H),
7.18–7.15 (m, 2 H), 6.96 (d, J = 0.9 Hz, 1 H), 2.71 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 161.0, 153.0, 148.5, 146.2, 132.5,
129.7, 128.4, 126.0, 124.9, 123.7, 123.3, 117.3, 112.7, 18.9. IR
(KBr): 1612, 1574, 1512, 1481, 1381, 1342, 1219, 825, 756 cm–1
.
MS (ESI): m/z [M + H]+ calcd for C16H17NO: 236.1; found: 236.2.
4-Phenoxyquinoline(8a): Yield: 122 mg (80%); yellow liquid.
1H NMR (400 MHz, CDCl3): δ = 8.68 (d, J = 5.2 Hz, 1 H), 8.44–
8.33 (m, 1 H), 8.12 (d, J = 8.5 Hz, 1 H), 7.78–7.73 (m, 1 H), 7.59–
7.55 (m, 1 H), 7.49–7.44 (m, 2 H), 7.33–7.27 (m, 1 H), 7.22–7.16
(m, 2 H), 6.55 (d, J = 5.2 Hz, 1 H). 13C NMR (101 MHz, CDCl3): δ =
161.9, 154.4, 151.1, 149.7, 130.3, 130.1, 129.0, 126.1, 125.6,
121.8, 121.5, 121.1, 104.3. IR (KBr): 1566, 1489, 1420, 1389,
. MS (ESI): m/z [M +
1304, 1211, 771 cm–1 H]+ calcd for
C
15H12NO: 222.0; found: 222.1.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 604–610