Metal-free regioselective formation of C-N and C-O bonds with the utilization of diaryliodonium salts in water: Facile synthesis of: N-Arylquinolones and aryloxyquinolines

Article abstract of DOI:10.1039/c7ob00940b

Regioselective construction of crucial C-N and C-O bonds leading to N-Arylquinolones and aryloxyquinolines has been accomplished by employing easily accessible diaryliodonium salts and quinolones in water under metal-and ligand-free conditions. This opera

Full text of DOI:10.1039/c7ob00940b

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Metal-free Regioselective Formation of C-N and C-O Bonds with
the Utilization of Diaryliodonium Salts in Water: Facile Synthesis
of N-Arylquinolones and Aryloxyquinolines
Received 00th January 20xx,
Accepted 00th January 20xx
Manish Kumar Mehra, Mukund P. Tantak, V. Arun, Indresh Kumar and Dalip Kumar*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Regioselective construction of crucial C-N and C-O bonds leading to
In recent past, diaryliodonium salts have been successfully used
N-arylquinolones and aryloxyquinolines have been accomplished by by synthetic chemists as mild and environmentally benign arylating
employing easily accessible diaryliodonium salts and quinolones in water agents due to their high reactivity, stability and low toxicity.7 They
under metal- and ligand-free conditions. This operationally simple are often employed in the organic synthesis mainly for the arylation
strategy is significant due to mild reaction conditions, high product yields, of azaheterocycles.8 For example, very recently, a domino approach
recyclability of released iodoarenes and scalable to gram level. The for N-/C-arylation via in situ generation of a directing group in the
practical utility of the developed protocol was proved by arylation of presence of [RuCl2(p-cymene)]2 has been developed by Greaney
medicinally
important
heterocycles
like
acridin-9(10H)-one, and co-workers.9 Likewise, N-arylation of 2-pyridones with
3-methylquinoxalin-2(1H)-one and 1H-benzo[d]imidazol-2(3H)-one.
diaryliodonium salts occurred at room temperature in the presence
of CuCl.10 Kang et al. described the N-arylation of azoles, lactams
and primary amides with catalytic CuI or Cu(acac)2 in the presence
of Na2CO3 or K2CO3 base.11 Independently, Chen and Greaney co-
workers achieved N-arylindoles by a copper-catalyzed reaction of
indoles with diaryliodonium salts.12 Similarly, β-aryloxy carbonyl
C–N and C–O bonds forming reactions have received wider
attention in organic synthesis due to their utilities in preparation
of diverse bioactive heterocycles.1 Recognized and predominant
classical name reactions in organic chemistry for the formation of
C-N and C-O bonds are Ullmann reaction, Chan-Lam coupling, and
Buchwald–Hartwig coupling.2 Very recently, Miura et al. have
developed a transition-metal catalyzed elegant method to prepare
compounds were prepared by Liu group involving
a copper
iodide-catalyzed arylation of enolates with diaryliodonium salts.13
Selective monoarylation of vicinal diols was achieved by using
diaryliodonium salts in the presence of a copper(II) catalyst.14
However, metal (Pd, Ru, Ir, Cu etc.) catalyzed reactions require the
removal of remaining metal traces from the final products which
possess an exorbitant challenge in medicinal chemistry.15
various carbazoles.3 Fu group disclosed
a copper-catalyzed
synthesis of tetrahydroisoquinolino[2,1-a]quinazolinones via C-N
bond formation.4 Similarly, Lautens and co-workers reported
Rh/Pd-catalyzed preparation of chiral dihydrobenzofuran
frameworks through the formation of C-O bond.5 Especially,
N -/O-arylquinolone and quinoline derivatives are endowed with
antibacterial, antiulcer, antitumor (1 and 2), inhibition of selective
Recently, arylation under greener reaction conditions has
become an emerging area of broad research by avoiding unsuitable
metal catalysts, ligands, and environmentally unfavorable organic
solvents. Many metal-free methods have been disclosed for the
preparation of tertiary amides,16 N-aryloxyimides and
aryloxyamines,17 aryl ethers18 and alkylaryl ethers19 by employing
diaryliodonium salts. Similarly, amination,20 N-arylation of
pyrazoles21 and indolines22 with diaryliodonium salts have been
serotonin-norepinephrine reuptake
activities (Fig.1).6
3 and PDGFR kinase 4
developed
under
metal-free
conditions.
Additionally,
N-arylanilines have also been achieved by the use of diaryliodonium
salts at higher temperature (130 °C) under metal-free conditions.23
Nevertheless, the N-/O-arylation of quinolones are still unexplored
in water under metal-free conditions. Aiming to develop efficient
and eco-friendly protocols for the arylation of bioactive
heterocycles, in this paper we wish to report a metal-free N-/O-
arylation of quinolones using diaryliodonium salts in an aqueous
medium.
Temafloxacin
(antibacterial
potency)
Defloxacin
(antibacterial
potency)
Selective serotonin
norepinephrine
reuptake inhibitor
PDGFR
Kinase inhibitor
Fig.1 Examples of bioactive arylquinolones and aryloxyquinolines
Department of Chemistry, Birla Institute of Technology and Science, Pilani 333 031,
Rajasthan, India
E-mail: dalipk@pilani.bits-pilani.ac.in
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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Water has dielectric constant 78 at 25 °C, which reduces with N-phenylquinolin-4(1H)-one (6aa) under conventional heating as
the increment in temperature. Hence, water at an elevated well as MW irradiation. Results of this investigation are presented
temperature can behave as a pseudo-organic solvent and it can be a in Table 1. Treatment of 4a with 5a in the presence of NaOH (3.0
benign replacement for an organic solvent. Water as a solvent has equiv) in DMSO at 80 °C produced the 4-phenoxyquinoline 7aa
attracted much interest due to readily availablity appealing (Table 1, entry 1). Changing the base from NaOH to cesium
properties such as inexpensive, nontoxicity, nonflammability. The carbonate, potassium carbonate and potassium t-butoxide led to a
use of neat water helps to reduce the production of organic solvent mixture of regioisomers 6aa and 7aa (Table 1, entries 2-4).
waste during the organic synthesis and also simplify the workup Screening of various solvents such as DMSO, PEG-400, and toluene
procedures.24 Additionally to improve the significance of synthetic revealed that the reaction in PEG-400 in the presence of NaOH or
protocol in terms of short reaction time and high product yield is t-BuOK, produced 6aa in 45% and 40% yields (Table 1, entries 5 and
extremely desirable. Ascribed to the selective mode of heating, 6). Only trace amount of 7aa could be produced, when the reaction
Microwave (MW) radiations widely interacts with polar molecules was performed in toluene using NaOH or NaH as a base (Table 1,
due to differences in the dielectric properties.25 Thus, MW heating entries 7 and 8). Consequently, use of polar protic solvent, water
has become a co-operative process because it allows quick and and potassium hydroxide as a base indeed improved the efficiency
convenient superheating which dramatically diminishes reaction of reaction to afford 6aa in 87% yield (Table 1, entry 9). Later, the
time under sealed vessel conditions with low-energy consumption. reaction of 4a and 5a using sodium hydroxide as a base in water
MW heating increases product yield and purity by avoiding produced highest 91% yield of 6aa under MW irradiation (30 min)
unwanted side reactions.
whereas conventional heating provided 6aa in 85% yield after 3h
Encouraged from our successful exploration of diaryliodonium (Table 1, entry 10). Varying the base from NaOH to K2CO3 and K3PO4
salts in the synthesis of 2-arylindoles,26 diarylsulfones,27 delivered 6aa in reduced yields (Table 1, entries 11 and 12).
arylazaheterocycles,28 diverse biaryls29 and aryloxyquinolines30 Increasing reaction temperature from 80 to 100 °C didn’t affect the
herein, we report a rapid and metal-free regioselective arylation of outcome of the reaction, but the yield of 6aa was significantly
quinolones 4 using diaryliodonium salts 5 in water.
dropped at reduced temperature (60 °C) (Table 1, entries
At the outset of the study, we selected 4-quinolone (4a) and 13 and 14). Finally, we found that 80 °C was the
diphenyliodonium triflate (5a) as test substrates to prepare optimum temperature for the satisfactory yield of 6aa.
Table 1 Optimization of reaction conditions for N-arylation of quinolin-4(1H)-onea
Conventional heating
Yield (%)b
MW Irradiation
Time (min)
Yield (%)b
6aa 7aa
Entry
Base
NaOH
Solvent
Temp. (°C) Time (h)
6aa
7aa
1
DMSO
DMSO
DMSO
DMSO
PEG-400
PEG-400
Toluene
Toluene
Water
Water
Water
Water
Water
Water
Water
80
80
80
80
80
80
80
80
80
80
80
80
100
60
100
10
10
10
10
10
10
10
10
04
03
10
10
10
10
10
-
20
60
60
60
60
60
60
60
60
35
30
60
60
30
60
60
-
25
2
3
4
5
6
7
8
9
Cs2CO3
K2CO3
t-BuOK
NaOH
t-BuOK
NaOH
NaH
10
10
15
40
30
-
40
15
10
15
45
40
50
40
45
30
40
-
-
-
-
Trace
-
-
Trace
-
Trace
Trace
KOH
80
85
25
30
85
60
NR
-
-
-
-
-
-
-
87
91
35
35
91
67
NR
-
-
-
-
-
-
-
10
11
12
13
14
15
NaOH
K2CO3
K3PO4
NaOH
NaOH
-
aReaction conditions: 4a (0.68 mmol), 5a (0.68 mmol), NaOH (2.04 mmol, 3.0 equiv) in water (1 mL) at 80 °C ( 30 min). bIsolated
yield of product. NR = no reaction
2 | J. Name., 2012, 00, 1-3
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Table 2 Effect of counter anion in N-arylation of 4aa
tosylate ion when compared to counter ions OTf, PF6 and BF4 in
diaryliodonium salts are probably responsible for the reduced
reactivity of diaryliodonium tosylate. Similar observation has also
been disclosed by Nagorny group.31 Generality of the optimized
protocol was investigated by arylation of quinolone 4a with a variety
of electron-rich and electron-deficient diaryl-iodonium salts 5.
Reaction with electron-neutral and halogens (Cl and Br) bearing
diaryliodonium salts (5a-c, 5f) either at meta- or para-positions
afforded the corresponding N-arylquinolones (6aa-ac, 6af) in
excellent 75-91% yields. Halo-substituted derivatives could be
potential precursors for further synthetic manipulations to access
useful compounds. Notably, heating the reaction mixture of 4a and
5c for 5h at 80 °C produced 6ac in 72% yield. Diaryliodonium salts
(5d, 5e, 5g-j) with electron-donating substituents had little influence
on product yield, whereas, diaryliodonium salt 5k with an electron-
deficient group easily delivered 6ak in 79% yield. Unfortunately,
sterically hindered bis(mesityl)iodonium triflate (5e) failed to afford
the corresponding N-arylquinolone. Particularly, unsymmetrical
mesityl(aryl)iodonium salts (5e-k) are frequently used due to their
easy preparation, high yields, use of cheap iodomesitylene, wide
substrate scope and selective transfer of an aryl ring.32 Accordingly,
Entry
X
Time (min.)
Yield (%)b
1
2
3
4
OTf
BF4
PF6
Br
30
35
40
40
91
90
89
80
5
OTs
60
35
aReaction conditions: 4a (0.68 mmol),
5
(0.68 mmol), NaOH
(2.04 mmol) in water (1 mL) at 80 °C (30 min). bIsolated yields of 6aa
.
A control experiment confirmed that no 6aa was furnished in the
absence of a base (Table 1, entry 15). Next, we examined the
influence of counterion in diphenyliodonium salt. Utilizing
diphenyliodonium salts 5 bearing OTf, BF4 and PF6 counteranions
rapidly afforded the desired product 6aa in excellent yields (Table 2,
entries 1-3). Marginally low yield (80%) was observed in case of
diphenyliodonium bromide (Table 2, entry 4). Use of
diphenyliodonium tosylate produced 6aa in poor yield (Table 2,
entry 5). Relatively better coordinating and nucleophilic nature of
we utilized unsymmetrical diaryliodonium salts
5
for
N-arylation of 4a. Delightfully, the electron-deficient or sterically less
hindered aryl moiety was selectively transferred to generate 6af-ak
(Table 3) with the concomitant release of iodomesitylene. This
unusual selectivity could be due to an unfavorable steric hinderance
between bulkier incoming mesityl moiety and C8-hydrogen of
quinolone, which is in agreement with the recent reports on
iodonium salts-promoted arylation.33
Table 3 N-Arylation of quinolin-4(1H)-onea
To test the versatility of this protocol, we further explored the
optimized reaction conditions for the N-arylation of analogue
4-methylquinolin-2(1H)-one (4b) utilizing diaryliodonium salts 5 in
Table 4 N-Arylation of 4-methylquinolin-2(1H)-onea
aReaction conditions: 4a (0.68 mmol), 5 (0.68 mmol), NaOH (2.04 mmol) in
water (1 mL ) at 80 °C (30 min). bReaction was performed under conventional
heating mode. cIsolated product yield.
aReaction conditions: 4b (0.62 mmol), 5 (0.62 mmol), NaOH (1.86 mmol) in
water (1 mL) at 80 °C (30 min). bReaction was performed under conventional
heating mode.cIsolated product yield.
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the presence of sodium hydroxide in water. Reaction of 4b with 5a
resulted 6ba (85%) under the optimized MW irradiation. But, under
heating at 80 °C same reaction afforded 6ba in 45% yield after 12h.
Further, we successfully achieved the desired N-aryl-4-
methylquinolin-2(1H)-ones (6ba-bi) in moderate to good yields (42-
85%) under MW irradiation at 80 °C for 30 min as illustrated in Table
4. Diaryliodonium salts 5 possessing electronically neutral and halo
substituents, produced the corresponding products 6ba-bc in better
yields than with the electronically-rich substituents (6bd, 6be and
6bg-bi).
Table 6 Regioselective O-arylation of quinolin-4(1H)-onea,c
Cl
O
N
O
N
O
N
CH3
O
N
O
N
Next, we focused our attention to arylate pharmaceutically
relevant heterocycles, for examples, acridin-9(10H)-one (7a),
quinoxalin-2(1H)-one (7b) and 1H-benzo[d]imidazol-2(3H)-one (7c)
which are well-known for their antiviral, antitumor, anti-HIV,
anticancer, antimalarial, antibiotic and antifungal activities.34 Usually
arylations of these heterocycles 7a-c are achieved in the presence of
copper catalysts (CuI, Cu(OAc)2).35 Reaction of 7a with 5a in water
exclusively produced N-phenylacridone (8a) probably due to the
existence of 9-acridone 7a in –NH form in an aqueous medium.36
Furthermore, reactions of 5a with 7b and 7c afforded 8b and 8c in
72% and 70% yields, respectively.
Ph
CH3
CH3
Ph
CH3
9a, (91%)a
(50%, 14h)b
9e, (72%)c
9d, (60%)c
9b, (90%)a
9c, (80%)c
aReaction conditions: 4aa (0.45 mmol), 5 (0.45 mmol), NaOH (1.35 mmol) in
water (1.0) mL at 80 °C, 30 min. bReaction was performed under
conventional heating mode. c4ab (0.62 mmol), 5 (0.62 mmol), NaOH (1.86
mmol) water (1.0 mL) at 80 °C (30 min). dIsolated product yield.
produced a mixture of 4-phenoxy-2-phenylquinoline (9a, 40%) and
4-(mesityloxy)-2-phenyl-quinoline (9b, 60%).
It is noteworthy to mention that the reaction of 4a with
iodobenzene under the optimized conditions could not afford 6aa,
which indicates the greater reactivity of diphenyliodonium triflate.
To illustrate the usefulness of this strategy, gram-scale synthesis of
6aa was accomplished from the reaction of 4a (1.0 g, 6.9 mmol) and
5a (2.98 g, 6.9 mmol). N-Phenylquinolin-4(1H)-one 6aa was obtained
in 86% yield as depicted in Scheme 1. Released iodobenzene was
recovered in 90% yield and reused to achieve diaryliodonium salt 5a.
Table 5 N-Arylation of medicinally significant heterocycles
aReaction conditions: 7 (0.51 mmol), 5a (0.51 mmol), NaOH (1.53 mmol) in
water (1.0 mL) at 80 °C (30 min.) bIsolated product yield
.
1 g, 6.9 mmol
1.31 g, 86%
Next, the reaction of 2-phenylquinolin-4(1H)-one 4aa with 5a
furnished unexpected 4-phenoxyquinoline 9a instead of N-arylated
quinolone (Table 6). Structure of 9a was unambiguously confirmed
Scheme 1 Gram scale synthesis of 6aa
Based on the formation of N-arylquinolones 6 and 4-aryloxy-
quinolines 9 and literature precedence,38 a plausible pathway for
the formation of 6 and 9 is illustrated in Scheme 2. In basic solution,
quinolones may exist in keto-enol tautomeric forms A and B which
may be influenced by two crucial parameters including, solvent and
steric factor. Tautomerization of quinolone may exhibit ambident
nucleophilicity and facilitates attack through oxygen or nitrogen
atom. It is believed that in aqueous medium, keto form of quinolone
may get stabilized by water molecules through hydrogen-bonding
and hinders the reactivity of oxygen atom. Consequently, available -
NH in 4a exclusively reacts with the diaryliodonium salts to generate
by comparing its melting point and NMR (1H and 13C) and IR spectral
37
data as reported in the literature.30,
Under the identified
conditions, reaction of 4aa with 5a under conventional heating (14h)
produced 9a only in 50% yield. Moreover, bis(mesityl)iodonium salt
was also smoothly transferred the mesityl group to afford
4-mesityloxyquinoline 9b in excellent yield (90%). To further
investigate the role of C2-substituent in quinolin-4(1H)-one, reaction
of 2-methylquinolin-4(1H)-one 4ab with diaryiodonium salts 5 was
performed. Under the optimized reaction conditions, corresponding
O-arylated products 9c-e were successfully achieved in good yields
(60-80%). Interestingly, C2-substituent in quinolin-4(1H)-ones 4aa-
ab were found to play an important role in controlling the selectivity
to exclusively generate the aryloxyquinolines 9a-e. Increase in steric
demand at C2-position of quinolone is believed to hinder the N-
arylation to afford 4-aryloxyquinolines 9a-e.10 In case of
unsymmetrical iodonium salts, for example, reaction of 4aa with
mesityl(phenyl)iodonium triflate
6
as the sole product.39 With the presence of 2-methyl or
2-phenyl in 4, steric factor likely to dominate over solvent effect and
might be responsible for the exclusive formation of 9.10, Initial
40
deprotonation of quinolone may generate reactive species A or B
which reacts with diaryliodonium salt (Ar2IOTf) to form a T-shape
intermediate C or D. 1,2-Phenyl migration in C or D believed to
facilitate the formation of arylquinolones 6 or aryloxyquinolines 9.
4 | J. Name., 2012, 00, 1-3
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O-Arylation
N-Arylation
Scheme 2 Putative mechanism for arylation of quinolones
To conclude, we have disclosed a novel straightforward metal-
and ligand-free regioselective synthesis of N-arylquinolones and
4-aryloxyquinolines in aqueous medium. This protocol utilized easily
accessible, environmentally safe and stable solids diaryliodonium
salts as versatile arylating agents. Diaryliodonium salts with
electron-donating as well as electron-withdrawing groups delivered
the desired products in good to excellent yields (42-91%). Highlights
of the present strategy include operationally simple, short reaction
times, compatible to arylate other heterocycles such as acridin-
9(10H)-one, 3-methylquinoxalin-2(1H)-one and 1H benzo[d]imid-
azol-2(3H)-one, recyclability of the released iodoarenes and gram
scale synthesis of N-phenylquinolin-4(1H)-one. Detailed mechanistic
studies and extensions of this protocol to other relevant heterocyclic
systems are currently in progress.
9. C. J. Teskey, S. M. A. Sohel, D. L. Bunting, S. G. Modha and M. F.
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Acknowledgements
M.K.M. thanks the CSIR, New Delhi for the award of Senior Research
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