An efficient synthesis of 4-phenoxy-quinazoline, 2-phenoxy-quinoxaline, and 2-phenoxy-pyridine derivatives using aryne chemistry

Article abstract of DOI:10.1039/d0ra09994e

Herein we report the mild and efficient synthesis of 4-phenoxyquinazoline, 2-phenoxyquinoxaline, and 2-phenoxypyridine derivatives from the starting materials viz. quinazolin-4(3H)-one, quinoxalin-2(1H)-one, and pyridin-2(1H)-one and aryne generated in si

Full text of DOI:10.1039/d0ra09994e

RSC Advances
View Article Online
View Journal | View Issue
PAPER
An efficient synthesis of 4-phenoxy-quinazoline, 2-
phenoxy-quinoxaline, and 2-phenoxy-pyridine
derivatives using aryne chemistry†
Cite this: RSC Adv., 2021, 11, 3477
Mahesh K. Zilla,‡ab Sheena Mahajan,‡b Rajni Khajuria,c Vivek K. Gupta,d
e
bf
*
Kamal K. Kapoor and Asif Ali
Herein we report the mild and efficient synthesis of 4-phenoxyquinazoline, 2-phenoxyquinoxaline, and 2-
phenoxypyridine derivatives from the starting materials viz. quinazolin-4(3H)-one, quinoxalin-2(1H)-one,
Received 25th November 2020
and
pyridin-2(1H)-one
and
aryne
generated
in
situ
from
2-(trimethylsilyl)phenyl
Accepted 4th January 2021
DOI: 10.1039/d0ra09994e
rsc.li/rsc-advances
trifluoromethanesulfonate and cesium fluoride. This synthetic methodology gives a new environmentally
benign way for the preparation of several unnatural series of 4-phenoxyquinazoline, 2-
phenoxyquinoxaline and 2-phenoxypyridine compounds with high yields and broad substrate scope.
on aryne chemistry,9 the main focus of the present work is the
development of a mild, simple, eco-benign methodology using
Introduction
aryne chemistry with heterocyclic compounds.
Aryne intermediates are one of the most important classes of
organic species and are useful as substrates in various reactions
for developing new synthetic methodologies,1 preparing
heterocyclic molecules2 and in the total synthesis of natural
products.3 Although aryne was generated from different starting
materials, among all the reported methods, generation of aryne
developed using the Kobayashi et al.4 method from trime-
thylsilyl phenyl triate and cesium uoride has been widely
used for the last two decades because of its easy formation in
situ and generation under normal conditions. Due to the highly
electrophilic nature of arynes,5 these readily participated in
reactions with the reactants and gave addition,6 insertion type
products with good yields and atom economy.7 Because of their
high reactivity in the reactions, arynes readily participate in
reactions with substrates like styrenes without the use of any
catalyst.8 Aer reading several reviews published by top authors
Literature reports reveals very few reactions of arynes with
amides. Pintori et al.10 reported the insertion of benzene ring
into the amide bond by using aryne chemistry. Later on, facile
N-arylation of acetanilides with arynes was reported by Haber
et al.11 Herein our method, we have got the result of aryl
substituted iminoxy derivatives on amide group containing
heterocyclic compounds (Scheme 1).
Heterocyclic compounds have unique importance in organic
synthesis and in biological activity. Among these quinazolines,
quinoxalines are the important class of building blocks found
in
a variety of pharmaceuticals. Quinazolines are the
aDepartment of Chemical Sciences, Indian Institute of Science Education and Research
(IISER), Berhampur, Odisha 760010, India. E-mail: mzilla@iiserbpr.ac.in
bCSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu-180001, India.
E-mail: sheena01mahajan@gmail.com
cDepartment of Chemistry, GDC for Women Kathua, Kathua-184101, India. E-mail:
khajuriarajni36@gmail.com
dPost-Graduate Department of Physics & Electronics, University of Jammu, Jammu
Tawi- 180006, India. E-mail: vivek.gupta2k9@gmail.com
eDepartment of Chemistry, University of Jammu, Jammu Tawi-180006, India. E-mail:
kamalkka@gmail.com
fCSIR-Traditional Knowledge Digital Library (TKDL), 14-Satsang Vihar, Vigyan Suchna
Bhawan, New Delhi-110067, India. E-mail: asifali@csir.res.in
† Electronic supplementary information (ESI) available: 1H, 13C NMR, other
spectra of all the compounds and crystal data of 8c & 8e. CCDC 1451640 and
1451639. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/d0ra09994e
Scheme 1 Reactions of arynes with amides.
‡ Mahesh K. Zilla and Sheena Mahajan have equally contributed as a rst author.
© 2021 The Author(s). Published by the Royal Society of Chemistry
RSC Adv., 2021, 11, 3477–3483 | 3477

View Article Online
RSC Advances
Paper
Table 1 Optimization reaction for the preparation of 4-phenoxy-2-
phenylquinazoline 3a from 2-phenylquinazolin-4(3H)-one 1a with
arynea
compounds showing different medicinal properties such as
anti-convulsant,12 anti-bacterial,13 anti-diabetic,14 anti-carcin-
ogen15 etc., whereas quinoxalines are having anti-biotic,16 anti-
mycobacterial,17 anti-viral,18 anti-osteoclast,19 anti-convulsant20
properties. Some of the important biologically active quinazo-
line and quinoxaline derivatives are shown in Fig. 1.
When we processed the work on developing mild and simple
synthetic methodologies with aryne, we got an unfortunate
result of aryl substituted iminoxy quinazoline of unnatural
compound with an appropriate yield which would be useful for
the preparation of a series of compounds in efficient manner.
So the main objective of the present methodology was the
diversication in preparation of unnatural heterocyclic
compounds.
Entry
Fꢀ source
Equiv.
Solvent
Yieldb (%)
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
KF/18-crown-6
KF/18-crown-6
KF/18-crown-6
TBAFc
2.0
3.0
3.0
2.0
2.0
2.0
3.0
3.0
3.0
3.0
CH3CN
CH3CN
DME
CH3CN
CH3CN
CH3CN
CH3CN
DCM
45
48
22
55
48
72
89
5
TBATd
CsF
CsF
CsF
CsF
CsF
Results and discussion
Toluene
DME
5
48
We commenced our investigation using 2-phenylquinazolin-
4(3H)-one 1a and readily available 2-(trimethylsilyl)phenyl tri-
uoromethanesulfonate 2 (Table 1). When the reaction was
performed with KF/18-crown-6 as the uoride source for the
generation of benzyne from 2-(trimethylsilyl)phenyltriuoro
methane sulfonate 2 at room temperature in acetonitrile,
desired product 3a was obtained in a moderate yield of 45%
(Table 1, entry 1). However by performing the same reaction
with the increased amount of KF/18-crown-6 and KF/18-crown-
6, minor effect in the product 3a yield i.e. 48% (Table 1, entry 2)
was observed. Also by changing the solvent of the reaction as
DME, poor yield of the desired product 3a (Table 1, entry 3) was
obtained. Further, with different uoride sources such as TBAF,
TBAT the product 3a in moderate yields of 55% and 48% was
obtained. Further, by employing CsF as a uoride source,
product 3a was obtained in high yield (72%). Later, by
increasing the amount of CsF, to our delight, yield of the
product 3a increased to 89%. Also by carrying out the reaction
in different solvents such as DCM, toluene, DME less yields of
product was obtained (Table 1, entry 8, 9, 10). Thus, 1 mmol of
2-phenyl quinazolin-4(3H)-one 1a, 1.2 mmol of 2-(trimethylsilyl)
phenyl triuoromethanesulfonate 2 in acetonitrile in presence
a
Reaction conditions (unless otherwise stated): 1a (0.45 mmol, 1.0
equiv.), 2 (0.54 mmol, 1.2 equiv.), Fꢀ source, solvent (8 mL), at room
b
c
temperature for 4 h. Isolated yield. Tetrabutylammonium uoride.
d
Tetrabutylammonium diuorotriphenylsilicate.
of 3 mmol of CsF at room temperature were the optimized
reaction conditions.
With the optimized reaction conditions in hand, we exam-
ined the substrate scope with different substituted 2-phenyl-
quinazolin-4(3H)-one derivatives, and the results are depicted in
Scheme 2. With electron donating groups (OCH3, SCH3)
Scheme
2 Substrate scope of different substituted 2-phenyl-
quinazolin-4(3H)-one derivatives with benzynea. aReaction conditions
(unless otherwise stated): 1a–e (0.45 mmol, 1.0 equiv.), 2 (0.54 mmol,
Fig.
1 Representative biologically active quinazolines and 1.2 equiv.), CsF (1.35 mmol, 3 equiv.), acetonitrile solvent (8 mL), at
quinoxalines.
room temperature for 4–6 h.
3478 | RSC Adv., 2021, 11, 3477–3483
© 2021 The Author(s). Published by the Royal Society of Chemistry

View Article Online
Paper
RSC Advances
substituted on 2-phenylquinazolin-4(3H)-one, high yield of the
desired product was obtained (Scheme 2: ex. OCH3, SCH3).
Whereas with electron withdrawing groups, less yield of the
desired product was obtained (Scheme 2: ex. CF3, OCF3).
Next, we extended to apply the same optimized reaction
condition on quinoxalin-2(1H)-one derivatives which resulted in
two different compounds viz. 2-phenoxyquinoxaline and 1-
phenylquinoxalin-2(1H)-one in the ratio of 7 : 3. 2-Phenox-
yquinoxaline was obtained as major product which was
conrmed by the absence of carbonyl stretching peak in the IR
spectrum indicated that it was arylated to iminoxy compound.
Whereas the minor quantity compound, 1-phenylquinoxalin-
2(1H)-one structure was conrmed by the IR spectrum having
specic peak at 1663 cmꢀ1 for the carbonyl group of amide
indicating that no change in the carbonyl of the amide group
conrming the N-arylated product. Further, we have enlarged
the work for different substituted quinoxalin-2(1H)-one deriva-
tives and the results are shown in Scheme 3.
Further, we have applied the optimized reaction on the
pyridin-2(1H)-ones, predominantly resulting 2-phenoxy pyri-
dine derivatives in high yield. Although the reaction of pyr-
idones with aryne was reported by Masayuki Kuzuva et al. in
1984, the authors have generated aryne from the anthranilic
acid with the use of hazardious chemical isopentyl nitrile in
a mixture of solvents acetone and chloroform at a temperature
of 70 ꢁC with moderate yield. Where as in our method, we have
Scheme
4
Application of the optimized reaction condition on
different substituted pyridine-2(1H)-one derivatives with benzynea.
aReaction conditions (unless otherwise stated): 7a–f (0.24 mmol, 1.0
equiv.), 2 (0.29 mmol, 1.2 equiv.), CsF (0.72 mmol, 3 equiv.), acetonitrile
solvent (8 mL), at room temperature for 4–6 h. bIsolated yield.
4.21 The geometry of the molecule was calculated using the
WinGX,22 PARST23 and PLATON24 sowares. The crystallo-
graphic data is summarized in ESI.†
generated
aryne
from
2-(trimethylsilyl)phenyl
tri-
uoromethanesulfonate with CsF at room temperature result-
ing in a high yield of product in an efficient manner. Further, we
have applied this reaction to enlarge the substrate scope, and
the results are mentioned in Scheme 4. Structure of product 8e
was conrmed by X-ray crystallographic studies. An ORTEP view
of the compound 8e with atomic labeling is shown in Scheme
Experimental
Materials and methods
All the experiments were performed in an oven dried glass
apparatus. All the commercially available reagents were
purchased from Aldrich and were used without further puri-
cation. Melting points (ꢁC) were measured in open glass capil-
laries using Pert melting point apparatus and are uncorrected.
The progress of reaction was monitored by thin layer chroma-
tography (TLC) using silica gel pre-coated aluminium sheets (60
F254, Merck). Visualization of spots was effected by exposure to
ultraviolet light (UV) at 365 nm and 254 nm, iodine vapours and
2% 2,4-dinitrophenylhydrazine in methanol containing few
drops of H2SO4, dragendroff reagent and anisaldehyde reagent.
Solvents used in purication were distilled before use. Recrys-
tallization was achieved with ethanol. IR spectra (n, cmꢀ1) were
recorded on Perkin-Elmer FTIR spectrophotometer using KBr
1
discs. H and 13C NMR were recorded on Bruker AC-400 spec-
trometer operating at 400 MHz for 1H and 100 MHz for 13C with
tetramethylsilane (TMS) as an internal standard. The chemical
shis are expressed in d (ppm) downeld from TMS. All the 13
C
NMR spectra are proton decoupled. J values are given in Hertz
(Hz). The abbreviations s, d, dd, t, q and m in 1H NMR spectra
refer to singlet, doublet, doublet of doublet, triplet, quartet and
multiplet respectively. Solvents were removed using Heidolph
rotary evaporator. Electrospray ionization mass spectra MS (ESI)
were recorded on Micro Mass VG-7070 H mass spectrometer at
Scheme
3 Application of the optimized reaction condition on
different substituted (E)-3-styrylquinoxalin-2(1H)-one derivatives with
benzynea. aReaction conditions (unless otherwise stated): 4a–e
(0.28 mmol, 1.0 equiv.), 2 (0.33 mmol, 1.2 equiv.), CsF (0.84 mmol, 3
equiv.), acetonitrile solvent (8 mL), at room temperature for 4–6 h.
b
Isolated yield.
© 2021 The Author(s). Published by the Royal Society of Chemistry
RSC Adv., 2021, 11, 3477–3483 | 3479

View Article Online
RSC Advances
Paper
70 eV. Elemental analysis was performed on Leco CHNS-932 combined organic phase was dried over sodium sulphate, and
analyzer.
concentrated in vacuo. The crude product was puried by
column chromatography (EtOAc in hexane) resulting the
product.
Crystal structure determination and renement for 4-(3-
nitrophe-nyl)-2-phenoxy-6-phenylpyridine (8c)
4-Phenoxy-2-phenylquinazoline (3a). 1H NMR (400 MHz,
CDCl3): d 8.25 (d, J ¼ 7.7 Hz, 3H), 7.94 (d, J ¼ 8.4 Hz, 1H), 7.75
(dd, J ¼ 11.3, 4.0 Hz, 1H), 7.47 (t, J ¼ 7.6 Hz, 1H), 7.39 (t, J ¼
7.8 Hz, 2H), 7.26 (ddd, J ¼ 19.9, 10.0, 4.5 Hz, 6H); 13C NMR (101
MHz, CDCl3) d 167.51, 160.71, 153.53, 153.49, 138.51, 134.77,
131.38, 130.25, 129.28, 129.19, 128.97, 127.64, 126.35, 124.39,
122.85, 115.94; HRMS-ESI [M + H]+ m/z calcd for C20H15N2O:
299.1179, found 299.1176.
X-ray intensity data of 7234 reections (of which 3530 unique)
were collected on X'calibur CCD area-detector diffractometer
equipped with graphite monochromated MoKa radiation (l ¼
˚
0.71073 A). The crystal used for data collection was of dimen-
sions 0.30 ꢂ 0.20 ꢂ 0.20 mm. The cell dimensions were deter-
mined by least-squares t of angular settings of 1788 reections
in the q range 3.93 to 27.57ꢁ. The intensities were measured by u
scan mode for q ranges 3.53 to 26.00ꢁ. 2176 reections were
treated as observed (I > 2s (I)). Data were corrected for Lorentz,
polarisation and absorption factors. The structure was solved by
direct methods using SHELXS97.25 Full-matrix least-squares
renement was carried out using SHELXL97.25 The nal
renement cycles converged to an R ¼ 0.0445 and wR (F2) ¼
0.0911 for the observed data. Residual electron densities ranged
4-Phenoxy-2-(3,4,5-trimethoxyphenyl)quinazoline (3b). 1H
NMR (400 MHz, CDCl3): d 8.25 (d, J ¼ 7.9 Hz, 1H), 7.95 (d, J ¼
8.4 Hz, 1H), 7.79 (dd, J ¼ 11.2, 4.1 Hz, 1H), 7.55 (s, 2H), 7.49 (t, J
¼ 7.5 Hz, 1H), 7.39 (t, J ¼ 7.8 Hz, 2H), 7.28 (d, J ¼ 7.7 Hz, 2H),
7.22 (t, J ¼ 7.3 Hz, 1H), 3.79 (s, 3H), 3.76 (s, 6H); 13C NMR (101
MHz, CDCl3): d 166.61, 159.11, 153.07, 152.84, 152.74, 140.40,
133.97, 132.90, 129.21, 128.05, 126.74, 125.50, 123.53, 122.40,
114.81, 105.49, 60.88, 55.91; HRMS-ESI [M + H]+ m/z calcd for
from ꢀ0.126 < Dr < 0.158 eAꢀ3. Atomic scattering factors were
˚
C
23H21N2O4: 389.1496, found 389.1506.
taken from International Tables for X-ray Crystallography (1992,
vol. C, Tables 4.2.6.8 and 6.1.1.4). The crystallographic data are
summarized in ESI.†
2-(4-(Methylthio)phenyl)-4-phenoxyquinazoline (3c). 1H
NMR (400 MHz, CDCl3): d 8.41 (d, J ¼ 8.4 Hz, 2H), 8.03 (d, J ¼
8.1 Hz, 1H), 7.86 (d, J ¼ 8.4 Hz, 1H), 7.70 (t, J ¼ 7.4 Hz, 1H), 7.43–
7.29 (m, 5H), 7.28–7.17 (m, 3H), 4.15 (s, 3H); 13C NMR (101 MHz,
CDCl3): d 167.05, 159.44, 151.81, 139.46, 136.62, 134.81, 133.50,
132.00, 129.84, 129.34, 129.16, 127.92, 127.58, 126.43, 123.46,
115.29, 54.05; HRMS-ESI [M + H]+ m/z calcd for C21H17N2OS:
355.1624, found 355.1628.
Crystal structure determination and renement for 6-
phenoxy-4-phenyl-2,20-bipyridine (8e)
X-ray intensity data of 5807 reections (of which 3223 unique)
were collected on X'calibur CCD area-detector diffractometer
equipped with graphite monochromated MoKa radiation (l ¼
4-Phenoxy-2-(4-(triuoromethoxy)phenyl)quinazoline (3d).
1H NMR (400 MHz, CDCl3): d 8.24 (t, J ¼ 7.5 Hz, 3H), 7.91 (d, J ¼
8.4 Hz, 1H), 7.76 (dd, J ¼ 11.2, 4.0 Hz, 1H), 7.47 (t, J ¼ 7.5 Hz,
1H), 7.42–7.36 (m, 2H), 7.28–7.19 (m, 3H), 7.11 (d, J ¼ 8.5 Hz,
2H): 13C NMR (101 MHz, CDCl3): d 166.83, 158.56, 152.66,
152.57, 151.07, 136.26, 134.10, 130.10, 129.51, 128.17, 127.09,
125.70, 123.62, 122.03, 120.47, 115.10; HRMS-ESI [M + H]+ m/z
calcd for C21H14F3N2O2: 383.1002, found 383.1004.
˚
0.71073 A). The crystal used for data collection was of dimen-
sions 0.30 ꢂ 0.20 ꢂ 0.20 mm. The cell dimensions were deter-
mined by least-squares t of angular settings of 1471 reections
in the q range 4.12 to 26.09ꢁ. The intensities were measured by
u scan mode for q ranges 3.52 to 26.00ꢁ. 1919 reections were
treated as observed (I > 2s(I)). Data were corrected for Lorentz,
polarisation and absorption factors. The structure was solved by
direct methods using SHELXS97.25 All non-hydrogen atoms of
the molecule were located in the best E-map. Full-matrix least-
squares renement was carried out using SHELXL97.25 The
nal renement cycles converged to an R ¼ 0.0533 and wR (F2) ¼
0.1235 for the observed data. Residual electron densities ranged
1
4-Phenoxy-2-(4-(triuoromethyl)phenyl)quinazoline (3e). H
NMR (400 MHz, CDCl3): d 8.34 (d, J ¼ 8.1 Hz, 2H), 8.28 (d, J ¼
8.1 Hz, 1H), 7.96 (d, J ¼ 8.4 Hz, 1H), 7.81 (t, J ¼ 7.7 Hz, 1H), 7.54
(t, J ¼ 7.8 Hz, 3H), 7.42 (t, J ¼ 7.8 Hz, 2H), 7.30–7.24 (m, 3H); 13
C
NMR (101 MHz, CDCl3): d 167.76, 159.26, 153.46, 153.36,
141.82, 135.04, 130.35, 129.52, 129.15, 128.26, 126.58, 126.13,
126.10, 124.49, 122.83, 116.16; HRMS-ESI [M + H]+ m/z calcd for
from ꢀ0.162 < Dr < 0.172 eAꢀ3. Atomic scattering factors were
˚
taken from International Tables for X-ray Crystallography (1992,
vol. C, Tables 4.2.6.8 and 6.1.1.4). The crystallographic data are
summarized in ESI.†
C
21H14F3N2O: 367.1053, found 367.1055.
General procedure for the preparation of 4-phenoxy-2-
arylquinazoline (3a–e) with aryne
General procedure for the preparation of (E)-2-phenoxy-3-
styrylquinoxaline (5a–e) with aryne
To a stirred solution of 2-phenylquinazolin-4(3H)-one (1a–e) To a stirred solution of (E)-3-styrylquinoxalin-2(1H)-one (4a–e)
(0.45 mmol, 1.0 equiv.) and trimethylsilyl phenyl triate (2) (0.28 mmol, 1.0 equiv.) and trimethylsilyl phenyl triate (2)
(0.54 mmol, 1.2 equiv.) in acetonitrile as solvent, was added (0.33 mmol, 1.2 equiv.) in acetonitrile as solvent, was added
cesium uoride (1.35 mmol, 3.0 equiv.) at room temperature. cesium uoride (1.35 mmol, 3.0 equiv.) at room temperature.
The mixture was stirred at room temperature for 4 h, aer The mixture was stirred at room temperature for 4 h, aer
completing the reaction, reaction mixture was concentrated in completing the reaction, reaction mixture was concentrated in
vacuo. To the resulting residue, water was added, and the vacuo. To the resulting residue, water was added, and the
mixture was extracted with ethyl acetate three times. The mixture was extracted with ethyl acetate three times. The
3480 | RSC Adv., 2021, 11, 3477–3483
© 2021 The Author(s). Published by the Royal Society of Chemistry

View Article Online
Paper
RSC Advances
combined organic phase was dried over sodium sulphate, and 130.34, 129.46, 129.36, 129.20, 128.27, 124.07, 124.05, 120.70,
concentrated in vacuo. The crude product was puried by 115.42, 108.56, 106.44, 101.40; HRMS-ESI [M + H]+ m/z calcd for
column chromatography (EtoAc in hexane), resulting the
product.
C
23H17N2O3: 369.1234, found 369.1237.
(E)-2-Phenoxy-3-(4-(triuoromethyl)styryl)quinoxaline (5d).
(E)-2-(4-Methoxystyryl)-3-phenoxyquinoxaline (5a). 1H NMR 1H NMR (400 MHz, CDCl3): d 8.10 (d, J ¼ 16.1 Hz, 1H), 8.01–7.96
(400 MHz, CDCl3): d 8.04 (d, J ¼ 16.0 Hz, 1H), 7.96–7.91 (m, 1H), (m, 1H), 7.77 (dd, J ¼ 21.8, 12.1 Hz, 3H), 7.63 (ddd, J ¼ 15.1, 8.5,
7.62–7.54 (m, 4H), 7.52–7.44 (m, 2H), 7.40 (t, J ¼ 7.8 Hz, 2H), 5.1 Hz, 3H), 7.56–7.50 (m, 2H), 7.46–7.40 (m, 2H), 7.29–7.18 (m,
7.21 (dd, J ¼ 13.1, 11.1 Hz, 3H), 6.86 (d, J ¼ 8.6 Hz, 2H), 3.77 (s, 3H). 13C NMR (126 MHz, CDCl3): d 155.26, 152.88, 143.17,
3H). 13C NMR (101 MHz, CDCl3): d 160.58, 155.15, 153.11, 139.88, 139.83, 139.74, 135.70, 129.84, 129.68, 128.66, 127.83,
144.33, 139.95, 139.30, 137.27, 129.59, 129.37, 129.29, 129.04, 127.79, 127.37, 125.80, 125.77, 125.49, 123.38, 121.87; HRMS-
128.38, 127.52, 127.28, 125.28, 121.86, 118.65, 114.30, 55.38; ESI [M + H]+ m/z calcd for C23H16F3N2O: 393.1209, found
HRMS-ESI [M + H]+ m/z calcd for C23H19N2O2: 355.1441, found 393.1225.
355.1447.
(E)-1-Phenyl-3-(4-(triuoromethyl)styryl)quinoxalin-2(1H)-
(E)-3-(4-Methoxystyryl)-1-phenylquinoxalin-2(1H)-one (6a). one (6d). 1H NMR (500 MHz, CDCl3): d 8.17 (d, J ¼ 16.2 Hz, 1H),
1H NMR (400 MHz, CDCl3): d 8.13 (d, J ¼ 16.2 Hz, 1H), 7.84–7.78 7.87–7.82 (m, 1H), 7.68 (dd, J ¼ 14.2, 12.3 Hz, 3H), 7.56 (dd, J ¼
(m, 1H), 7.59–7.45 (m, 6H), 7.28–7.16 (m, 4H), 6.84 (d, J ¼ 10.1, 4.7 Hz, 4H), 7.51 (d, J ¼ 7.5 Hz, 1H), 7.28–7.21 (m, 4H),
8.6 Hz, 2H), 6.57 (d, J ¼ 8.1 Hz, 1H), 3.76 (s, 3H). 13C NMR (101 6.62–6.57 (m, 1H). 13C NMR (126 MHz, CDCl3): d 154.82, 152.55,
MHz, CDCl3): d 160.73, 154.93, 153.36, 138.57, 136.13, 133.64, 139.91, 136.95, 135.87, 133.88, 133.25, 130.42, 130.00, 129.74,
133.43, 130.31, 129.50, 129.41, 129.40, 129.32, 129.07, 128.30, 129.60, 128.21, 127.94, 125.79, 125.76, 124.99, 124.23, 115.55;
124.00, 120.27, 115.40, 114.31, 55.37; HRMS-ESI [M + H]+ m/z HRMS-ESI [M + H]+ m/z calcd for C23H16F3N2O: 393.1209, found
calcd for C23H19N2O2: 355.1441, found 355.1435.
393.1218.
(E)-2-(2-Chlorostyryl)-3-phenoxyquinoxaline (5e). 1HNMR
(E)-2-Phenoxy-3-(3,4,5-trimethoxystyryl)quinoxaline (5b). 1H
NMR (400 MHz, CDCl3): d 8.11 (d, J ¼ 16.0 Hz, 1H), 8.02 (dd, J ¼ (500 MHz, CDCl3): d 8.02 (d, J ¼ 16.0 Hz, 1H), 7.94 (dd, J ¼ 8.0,
7.8, 1.7 Hz, 1H), 7.70–7.62 (m, 2H), 7.57 (ddd, J ¼ 7.6, 5.2, 1.8 Hz, 1H), 7.67 (d, J ¼ 16.0 Hz, 1H), 7.62–7.58 (m, 1H), 7.56 (d,
1.8 Hz, 2H), 7.52–7.47 (m, 2H), 7.35–7.29 (m, 3H), 6.94 (s, 2H), J ¼ 8.6 Hz, 2H), 7.51–7.48 (m, 2H), 7.40 (t, J ¼ 7.9 Hz, 2H), 7.30
3.94 (s, 6H), 3.91 (s, 3H). 13C NMR (126 MHz, CDCl3): d 155.25, (d, J ¼ 8.5 Hz, 2H), 7.22 (dd, J ¼ 5.9, 4.9 Hz, 2H), 7.18–7.16 (m,
153.46, 152.99, 143.81, 139.87, 139.40, 139.22, 137.73, 132.13, 1H). 13C NMR (126 MHz, CDCl3): d 154.15, 151.90, 142.55,
129.68, 129.37, 128.41, 127.65, 127.30, 125.45, 122.01, 120.37, 138.82, 138.53, 135.08, 133.96, 133.83, 128.59, 128.50, 128.03,
104.83, 61.04, 56.23; HRMS-ESI [M + H]+ m/z calcd for 127.88, 127.51, 126.64, 126.30, 124.36, 120.80, 120.44, 28.68;
C
25H23N2O4: 415.1652, found 415.1653.
(E)-1-Phenyl-3-(3,4,5-trimethoxystyryl)quinoxalin-2(1H)-one
HRMS-ESI [M + H]+ m/z calcd for C22H16ClN2O: 359.0946, found
359.0951.
(6b). 1H NMR (400 MHz, CDCl3): d 8.21 (d, J ¼ 16.1 Hz, 1H),
(E)-3-(2-Chlorostyryl)-1-phenylquinoxalin-2(1H)-one (6e). 1H
7.92–7.87 (m, 1H), 7.67–7.54 (m, 4H), 7.36–7.27 (m, 4H), 6.90 (s, NMR (400 MHz, CDCl3): d 8.12 (d, J ¼ 16.2 Hz, 1H), 7.87–7.81
2H), 6.67 (dd, J ¼ 7.8, 1.8 Hz, 1H), 3.90 (s, 6H), 3.89 (s, 3H). 13
C
(m, 1H), 7.65–7.49 (m, 5H), 7.27 (ddd, J ¼ 8.9, 7.2, 5.3 Hz, 6H),
NMR (126 MHz, CDCl3): d 154.92, 153.38, 152.89, 139.28, 7.19 (s, 1H), 6.60 (dd, J ¼ 7.6, 2.0 Hz, 1H). 13C NMR (126 MHz,
139.01, 135.98, 133.62, 133.37, 132.14, 130.34, 129.49, 129.46, MeOD): d 154.95, 152.42, 136.68, 136.01, 135.07, 134.79, 133.74,
129.40, 128.23, 124.16, 122.00, 115.49, 104.88, 61.01, 56.11; 133.23, 130.08, 129.70, 129.35, 129.07, 128.85, 128.76, 128.12,
HRMS-ESI [M + H]+ m/z calcd for C25H23N2O4: 415.1652, found 124.12, 122.03, 115.36; HRMS-ESI [M + H]+ m/z calcd for
415.1606.
2-((E)-2-(Benzo[d][1,3]dioxol-5-yl)vinyl)-3-
C22H16ClN2O: 359.0946, found 359.0952.
phenoxyquinoxaline (5c). 1H NMR (400 MHz, CDCl3): d 8.11 (d, J
¼ 15.9 Hz, 1H), 8.05 (dd, J ¼ 7.8, 1.4 Hz, 1H), 7.70 (dd, J ¼ 7.8,
1.5 Hz, 1H), 7.64 (d, J ¼ 16.0 Hz, 1H), 7.59 (td, J ¼ 7.3, 1.6 Hz,
General procedure for the preparation of 2-phenoxypyridine
derivatives (8a–f) with aryne
2H), 7.52 (t, J ¼ 7.9 Hz, 2H), 7.36–7.31 (m, 3H), 7.29 (s, 1H), 7.20 To a stirred solution of 4, 6-diphenylpyridin-2(1H)-one (7a–f)
(d, J ¼ 8.0 Hz, 1H), 6.88 (d, J ¼ 8.0 Hz, 1H), 6.03 (s, 2H). 13C NMR (0.24 mmol, 1.0 equiv.) and trimethylsilyl phenyl triate (2)
(101 MHz, CDCl3): d 155.14, 153.04, 148.72, 148.33, 144.09, (0.29 mmol, 1.2 equiv.) in acetonitrile as solvent, was added
139.91, 139.35, 137.29, 131.08, 129.62, 129.16, 128.41, 127.58, cesium uoride (0.72 mmol, 3.0 equiv.) at room temperature.
127.29, 125.33, 123.73, 121.87, 119.02, 108.58, 106.40, 101.42; The mixture was stirred at room temperature for 4 h, aer
HRMS-ESI [M + H]+ m/z calcd for C23H17N2O3: 369.1234, found completing the reaction, reaction mixture was concentrated in
369.1243.
(E)-3-(2-(Benzo[d][1,3]dioxol-5-yl)vinyl)-1-phenylquinoxalin-
vacuo. To the resulting residue, water was added, and the
mixture was extracted with ethyl acetate three times. The
2(1H)-one (6c). 1H NMR (400 MHz, CDCl3): d 8.19 (d, J ¼ 16.1 Hz, combined organic phase was dried over sodium sulphate, and
1H), 7.94–7.88 (m, 1H), 7.66 (t, J ¼ 7.4 Hz, 2H), 7.59 (t, J ¼ concentrated in vacuo. The crude product was puried by
12.0 Hz, 2H), 7.33 (t, J ¼ 7.1 Hz, 3H), 7.26 (d, J ¼ 20.9 Hz, 2H), column chromatography (EtoAc in hexane), resulting the
7.15 (d, J ¼ 8.1 Hz, 1H), 6.85 (d, J ¼ 8.0 Hz, 1H), 6.68 (d, J ¼ product.
7.7 Hz, 1H), 6.03 (s, 2H). 13C NMR (101 MHz, CDCl3): d 154.91,
2-Phenoxy-6-phenyl-4-(3,4,5-trimethoxyphenyl)pyridine (8a).
153.17, 148.87, 148.29, 138.61, 136.07, 133.65, 133.39, 131.14, 1H NMR (400 MHz, CDCl3): d 7.87 (dd, J ¼ 8.0, 1.4 Hz, 2H), 7.54
© 2021 The Author(s). Published by the Royal Society of Chemistry
RSC Adv., 2021, 11, 3477–3483 | 3481

View Article Online
RSC Advances
Paper
(d, J¼ 1.1 Hz, 1H), 7.36–7.27 (m, 5H), 7.17 (dd, J ¼ 8.6, 0.9 Hz, aryne intermediate. The present method enables very easy
2H), 7.12 (dd, J ¼ 11.5, 4.2 Hz, 1H), 6.89 (d, J ¼ 1.0 Hz, 1H), 6.75 preparation of phenoxylated quinazoline, quinaxazoline and
(s, 2H), 3.84 (s, 6H), 3.82 (s, 3H). 13C NMR (126 MHz, CDCl3): pyridine derivatives that will be useful for a feasible access to
d 163.92, 156.01, 154.38, 153.73, 153.26, 139.05, 138.49, 134.35, the unnatural product molecules and their biological screening.
129.54, 129.26, 128.70, 126.92, 124.45, 121.12, 113.54, 107.61,
104.44, 61.04, 56.36; HRMS-ESI [M + H]+ m/z calcd for
Conflicts of interest
C
26H24NO4: 414.17, found 414.1687.
2-(4-Methoxyphenyl)-6-phenoxy-4-(3,4,5-trimethoxyphenyl)
There are no conicts to declare.
1
pyridine (8b). H NMR (400 MHz, CDCl3): d 7.95 (d, J ¼ 8.9 Hz,
2H), 7.59 (d, J ¼ 1.2 Hz, 1H), 7.45 (dd, J ¼ 8.5, 7.4 Hz, 2H), 7.28
(dd, J ¼ 8.6, 1.0 Hz, 2H), 7.24 (dd, J ¼ 11.5, 4.2 Hz, 1H), 6.95 (dd,
Acknowledgements
J ¼ 9.0, 5.0 Hz, 3H), 6.87 (s, 2H), 3.97 (s, 6H), 3.94 (s, 3H), 3.86 (s, MKZ thankful to the Council of Scientic and Industrial
3H). 13C NMR (101 MHz, CDCl3): d 163.83, 160.68, 155.73, Research (CSIR) for the nancial assistance. We are thankful to
154.50, 153.72, 153.15, 139.14, 134.48, 131.13, 129.47, 128.23, Deepika Singh for NMR spectral data analysis. One of the
124.32, 121.09, 114.04, 112.63, 106.76, 104.57, 60.98, 56.37, authors (Vivek) acknowledges the Department of Science &
55.34; HRMS-ESI [M + H]+ m/z calcd for C27H26NO5: 444.1805, Technology for single crystal X-ray diffractometer as a National
found 444.1799.
Facility under Project No. SR/S2/CMP-47/2003.
1
4-(3-Nitrophenyl)-2-phenoxy-6-phenylpyridine (8c). H NMR
(400 MHz, CDCl3): d 8.40 (t, J ¼ 1.9 Hz, 1H), 8.19 (ddd, J ¼ 8.2,
2.2, 1.0 Hz, 1H), 7.86 (ddd, J ¼ 4.6, 2.4, 1.4 Hz, 3H), 7.56 (dd, J ¼
11.3, 4.6 Hz, 2H), 7.32 (ddd, J ¼ 8.1, 6.2, 4.6 Hz, 5H), 7.19–7.11
(m, 3H), 6.91 (d, J ¼ 1.2 Hz, 1H). 13C NMR (126 MHz, CDCl3):
d 164.20, 156.60, 154.08, 150.45, 148.79, 140.18, 137.99, 133.09,
130.21, 129.63, 129.56, 128.77, 126.93, 124.74, 123.82, 122.09,
121.27, 113.10, 107.50; HRMS-ESI [M + H]+ m/z calcd for
Notes and references
1 (a) T. Kaicharla, M. Thangaraj and A. T. Biju, Org. Lett., 2014,
16, 1728; (b) C. Xie and Y. Zhang, Org. Lett., 2007, 9, 781; (c)
H. Y. Li, L. J. Xing, M. M. Lou, H. Wang, R. H. Liu and
B. Wang, Org. Lett., 2015, 17, 1098; (d) T. Truong,
M. Mesgar, K. K. A. Le and O. Daugulis, J. Am. Chem. Soc.,
2014, 136, 8568; (e) K. Neog, D. Dutta, B. Das and P. Gogoi,
Org. Lett., 2017, 19, 730.
C
23H17N2O3: 369.1234, found 369.1232.
4-(4-Bromophenyl)-2-(4-chlorophenyl)-6-phenoxypyridine
(8d). 1H NMR (400 MHz, CDCl3): d 7.80 (d, J ¼ 8.7 Hz, 2H), 7.51
(dd, J¼ 12.8, 4.9 Hz, 3H), 7.44–7.39 (m, 2H), 7.37–7.31 (m, 2H),
7.29 (d, J ¼ 8.7 Hz, 2H), 7.18–7.12 (m, 3H), 6.87 (d, J ¼ 1.2 Hz,
1H). 13C NMR (126 MHz, CDCl3): d 164.18, 154.98, 154.12,
151.97, 137.17, 136.73, 135.40, 132.32, 129.64, 128.89, 128.68,
128.16, 124.71, 123.74, 121.24, 112.87, 107.39; HRMS-ESI [M +
H]+ m/z calcd for C23H16BrClNO: 436.0098, found 436.0095.
2 (a) E. Yoshikawa and Y. Yamamoto, Angew. Chem., Int. Ed.,
2000, 39, 173; (b) H. Yoshida, H. Fukushima, J. Ohshita
and A. Kunai, J. Am. Chem. Soc., 2006, 128, 11040; (c)
C. D. Gilmore, K. M. Allan and B. M. Stoltz, J. Am. Chem.
Soc., 2008, 130, 1558.
3 (a) K. M. Allan and B. M. Stoltz, J. Am. Chem. Soc., 2008, 130,
17270; (b) P. M. Tadross, S. C. Virgil and B. M. Stoltz, Org.
Lett., 2010, 12, 1612; (c) U. K. Tambar, D. C. Ebner and
B. M. Stoltz, J. Am. Chem. Soc., 2006, 128, 11752; (d)
P. M. Tadross and B. M. Stoltz, Chem. Rev., 2012, 112, 3550.
4 Y. Himeshima, T. Sonoda and H. Kobayashi, Chem. Lett.,
1983, 12, 1211.
5 A. Bhunia, S. R. Yetra and A. T. Biju, Chem. Soc. Rev., 2012,
41, 3140.
6 H. Yoshida, E. Shirakawa, Y. Honda and T. Hiyama, Angew.
Chem., Int. Ed., 2002, 41, 3247.
7 (a) Y. L. Liu, Y. Liang, S. F. Pi and J. H. Li, J. Org. Chem., 2009,
74, 5691; (b) H. Yoshida, M. Watanabe, J. Ohshita and
A. Kunai, Tetrahedron Lett., 2005, 46, 6729.
8 S. S. Bhojgude, A. Bhunia, R. G. Gonnade and A. T. Biju, Org.
Lett., 2014, 16, 676.
9 (a) T. Roy and A. T. Biju, Chem. Commun., 2018, 54, 2580; (b)
T. Matsuzawa, S. Yoshida and T. Hosoya, Tetrahedron Lett.,
2018, 59, 4197; (c) M. Asamdi and K. H. Chikhalia, Asian J.
Org. Chem., 2017, 6, 1331; (d) K. Okuma, Heterocycles, 2012,
85, 515; (e) C. Wu and F. Shi, Asian J. Org. Chem., 2013, 2,
116; (f) A. G. Flores and R. Martin, Synthesis, 2013, 45, 563;
(g) P. M. Tadross and B. M. Stoltz, Chem. Rev., 2012, 112,
3550; (h) S. S. Bhojgude and A. T. Biju, Angew. Chem., Int.
Ed., 2012, 51, 1520; (i) A. Bhunia, S. R. Yetra and A. T. Biju,
1
6-Phenoxy-4-phenyl-2,20-bipyridine (8e). H NMR (500 MHz,
CDCl3): d 8.73–8.70 (m, 1H), 8.51 (d, J ¼ 1.3 Hz, 1H), 8.25 (d, J ¼
8.0 Hz, 1H), 7.81–7.75 (m, 3H), 7.55–7.46 (m, 5H), 7.31 (dt, J ¼
15.8, 4.2 Hz, 4H), 7.16 (d, J ¼ 1.3 Hz, 1H). 13C NMR (126 MHz,
CDCl3): d 163.89, 155.46, 154.69, 154.42, 153.27, 149.04, 138.14,
136.96, 129.62, 129.24, 129.02, 127.23, 124.53, 123.89, 121.45,
121.21, 114.18, 108.91; HRMS-ESI [M + H]+ m/z calcd for
C22H17N2O: 325.1335, found 325.1337.
4-(Furan-2-yl)-2-phenoxy-6-phenylpyridine (8f). 1H NMR (400
MHz, CDCl3): d 7.89 (dd, J ¼ 8.1, 1.5 Hz, 2H), 7.66 (d, J ¼ 1.1 Hz,
1H), 7.48–7.45 (m, 1H), 7.38–7.28 (m, 5H), 7.19–7.11 (m, 3H),
6.94 (d, J ¼ 1.1 Hz, 1H), 6.81 (dd, J ¼ 3.4, 0.5 Hz, 1H), 6.46 (dd, J
¼ 3.4, 1.8 Hz, 1H). 13C NMR (101 MHz, CDCl3): d 164.13, 156.25,
154.40, 151.49, 143.77, 141.75, 138.36, 129.56, 129.24, 128.64,
126.87, 124.46, 121.12, 112.10, 109.73, 108.95, 103.37; HRMS-
ESI [M + H]+ m/z calcd for C21H16NO2: 314.1176, found 314.118.
Conclusions
In conclusion, we have developed a simple, mild, metal free,
efficient, room temperature method for the preparation of 4-
phenoxy-2-phenylquinazoline,
(E)-2-phenoxy-3-
styrylquinoxaline and 2-phenoxypyridine derivatives via an
3482 | RSC Adv., 2021, 11, 3477–3483
© 2021 The Author(s). Published by the Royal Society of Chemistry

View Article Online
Paper
RSC Advances
Chem. Soc. Rev., 2012, 41, 3140; (j) C. M. Gampe and 16 (a) Y. B. Kim, Y. H. Kim, J. Y. Park and S. K. Kim, Bioorg. Med.
E. M. Carreira, Angew. Chem., Int. Ed., 2012, 51, 3766; (k)
I. S. Kovalev, D. S. Kopchuk, G. V. Zyryanov,
Chem. Lett., 2004, 14, 541; (b) J. Peng, D. Kong, L. Liu,
S. Song, H. Kuang and C. Xu, Anal. Methods, 2015, 7, 5204.
P. A. Slepukhin, V. L. Rusinov and N. O. Chupakhin, Chem. 17 (a) E. Moreno, S. Ancizu, S. P. Silanes, E. Torres, I. Aldana
Heterocycl. Compd., 2012, 48, 536; (l) D. Perez, D. Pena and
E. Guitian, Eur. J. Org. Chem., 2013, 5981; (m) D. Wu,
H. Ge, S. H. Liu and J. Yin, RSC Adv., 2013, 3, 22727; (n)
J. Shi and Y. Li, Chem. Soc. Rev., 2017, 46, 1707.
and A. Monge, Eur. J. Med. Chem., 2010, 45, 4418; (b)
L. E. Seitz, W. J. Suling and R. C. Reynolds, J. Med. Chem.,
2002, 45, 5604.
18 (a) E. Tombary and E. Hawash, Med. Chem., 2014, 10, 521; (b)
M. A. Henen, S. E. Bialy, F. E. Goda, M. N. A. Nasr and
H. M. Eisa, Med. Chem. Res., 2012, 21, 2368; (c)
L. M. Wilhelmsson, N. Kingi and J. Bergman, J. Med.
Chem., 2008, 51, 7744.
10 D. G. Pintori and M. F. Greaney, Org. Lett., 2009, 12, 168.
11 J. C. Haber, M. A. Lynch, S. L. Spring, A. D. Pechulis, J. Raker
and Y. Wang, Tetrahedron Lett., 2011, 52, 5847.
12 J. F. Wolfe, T. L. Rathman, M. C. Sleevi, J. A. Campbell and
T. D. Greenwood, J. Med. Chem., 1990, 33, 161.
19 Y.-C. Zhang, Q. Shen, M.-W. Zhu, J. Wang, Y. Du, J. Wu and
J.-X. Li, ChemistrySelect, 2020, 5(4), 1526.
13 (a) P. P. Kung, M. D. Casper, K. L. Cook, L. Wilson-Lingardo,
L. M. Risen, T. A. Vickers, R. Ranken, L. B. Blyn, J. R. Wyatt 20 (a) A. A. Elhelby, R. R. Ayyad and M. F. Zayed, Arzneim.
and P. D. Cook, J. Med. Chem., 1999, 42, 4705; (b) L. S. Reddy
and B. E. Naik, Heterocycl. Lett., 2019, 9(4), 487.
14 M. Saeedi, M. Mohammadi-Khanaposhtani, P. Pourrabia,
Forsch., 2011, 61, 379; (b) E. Elkaeed, A. Ghiaty,
A. E. Morsy, K. E. Gamal and H. Sakr, Chem. Sci. Rev. Lett.,
2014, 3, 1375.
N. Razzaghi, R. Ghadimi, S. Imanparast, M. A. Faramarzi, 21 L. J. Farrugia, J. Appl. Crystallogr., 1997, 30, 565.
F. Bandarian, E. N. Esfahani, M. Safavi, M. Safavi, 22 L. J. Farrugia, J. Appl. Crystallogr., 1999, 32, 837.
H. Rastegar, B. Larijani, M. Mahdavi and T. Akbarzadeh, 23 M. Nardelli, J. Appl. Crystallogr., 1995, 28, 659.
Bioorg. Chem., 2019, 83, 161.
15 X.-W. Wei, J.-M. Yuan, W.-Y. Huang, N.-Y. Chen, X.-J. Li,
24 A. L. Spek, Acta Crystallogr., Sect. D: Biol. Crystallogr., 2009,
65, 148–155.
C.-X. Pan, D.-L. Mo and G.-F. Su, Eur. J. Med. Chem., 2020, 25 G. M. Sheldrick, Acta Crystallogr., Sect. A: Found. Crystallogr.,
186, 111851.
2008, 64, 112.
© 2021 The Author(s). Published by the Royal Society of Chemistry
RSC Adv., 2021, 11, 3477–3483 | 3483