“On water” ultrasound-assisted one pot efficient synthesis of functionalized 2-oxo-benzo[1,4]oxazines: First application to the synthesis of anticancer indole alkaloid, Cephalandole A

Article abstract of DOI:10.1016/j.tetlet.2017.03.048

For the first time, an efficient, simple, synthetic green protocol for the one-pot synthesis of functionalized 2-oxo-benzo[1,4]oxazines 24–29 in water under ultrasound irradiation is presented. As compared to conventional methods, the present protocol avo

Full text of DOI:10.1016/j.tetlet.2017.03.048

Accepted Manuscript
“On water” ultrasound-assisted one pot efficient synthesis of functionalized 2-
oxo-benzo [1, 4] oxazines: First application to the synthesis of anticancer indole
alkaloid, Cephalandole A
Pradeep K. Jaiswal, Vashundhra Sharma, Jaroslav Prikhodko, Irina V.
Mashevskaya, Sandeep Chaudhary
PII:
S0040-4039(17)30352-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.03.048
TETL 48749
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
2 February 2017
15 March 2017
16 March 2017
Please cite this article as: Jaiswal, P.K., Sharma, V., Prikhodko, J., Mashevskaya, I.V., Chaudhary, S., “On
water” ultrasound-assisted one pot efficient synthesis of functionalized 2-oxo-benzo [1, 4] oxazines: First application
to the synthesis of anticancer indole alkaloid, Cephalandole A, Tetrahedron Letters (2017), doi: http://dx.doi.org/
10.1016/j.tetlet.2017.03.048
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“On water” ultrasound-assisted, one-pot
efficient synthesis of functionalized 2-oxo-
benzo [1, 4] oxazines: First Application to
the synthesis of anticancer indole alkaloid,
Cephalandole A
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Pradeep K. Jaiswal, a,‡ Vashundhra Sharma,a,‡ Jaroslav Prikhodko,b Irina V. Mashevskaya,b and Sandeep Chaudhary a, c*

1
Tetrahedron Letters
“On water” ultrasound-assisted one pot efficient synthesis of functionalized 2-oxo-
benzo [1, 4] oxazines: First application to the synthesis of anticancer indole alkaloid,
Cephalandole A
Pradeep K. Jaiswal, a,‡ Vashundhra Sharma,a,‡ Jaroslav Prikhodko,b Irina V. Mashevskaya,b and Sandeep
Chaudhary a, c*
aDepartment of Chemistry, Malaviya National Institute of Technology, Jawaharlal Nehru Marg, Jaipur-302017, India.
bDepartment of Organic Chemistry, Faculty of Chemistry, Perm State University, 15 Bukireva, Perm 614990, Russian Federation
cMaterials Research Centre, Malaviya National Institute of Technology, Jawaharlal Nehru Marg, Jaipur-302017, India.
E-mail: schaudhary.chy@mnit.ac.in
‡Both authors have equal contribution.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
For the first time, an efficient, simple, synthetic green protocol for the one-pot synthesis of
functionalized 2-oxo-benzo [1, 4] oxazines 24-29 in water under ultrasound irradiation is
presented. As compared to conventional methods, the present protocol avoids traditional
chromatography and purification steps and furnished the target molecules in excellent yields
(upto 98%) with no side products. The methodology was also demonstrated on gram scale
synthesis. Moreover, functionalized 2-oxo-quinoxaline analogues 31-33, another class of bio-
active heterocyclic scaffolds, were also prepared using this method. For the first time, this
protocol was successfully applied in the synthesis of the anticancer indole alkaloid,
Cephalandole A 35.
Available online
Keywords:
Sonochemistry, green protocol
water as solvent, 2-oxo-benzo [1, 4] oxazines
2-oxo-quinoxaline, Cephalandole A
2009 Elsevier Ltd. All rights reserved.
important molecules.6 Natural products such as blepharin 3,7
Cephalandole A 4,8a-d C-1027-chr 5,9 and other pharmaceuticals
Introduction
Water is a versatile solvent for many chemical reactions and
becomes very valuable for organic chemists, because it is safe,
cheap, environmentally benign, readily available, non-flammable,
non-toxic and also in respect of isolation procedure of desired
products (because most of the organic compounds are insoluble
in water and they may be isolated in pure form only by filtration
and/or recrystallization for avoiding column chromatography
with hazardous solvents).1 “On water” synthesis, firstly given by
Barry K. Sharpless (2005),2 is a unique concept of showing
higher reactivity by the organic compounds in aqueous medium.
Generally, reactions in water require vigorous stirring of water-
insoluble reagents as they are not miscible in water due to the
absence of organic co-solvents. This concept introduces the fact
that reaction those occur in high yields in water, is due to the dual
role played by water as a solvent and as a catalyst, in catalyzing
the reaction.1b-c, 3
incorporating 2H-1,4-benzoxazine-3(4H)one key scaffolds 6-9,
exhibit a wide range of biological activities such as potential
activity against several diseases including heart disease,10 an
inhibitor of bacterial histidine protein kinase,11 serotonin-3(5-
HT3) receptor antagonists,12 neurodegenerative agents,13
antihypertensive agents,14 inflammatory agents,15 analgesic,16 D2
receptor antagonists,17 antimycobacterial,18 and antifungal
agents.19 (Figure 1)
Ultrasound irradiation has been recognized as a clean and
advantageous greener approach to accelerate organic reactions.4
The salient features of the ultrasound-assisted reactions are
higher reaction rates, formation of products in higher yield and
selectivity, milder reaction conditions and shorter reaction time.
Moreover, this technique is capable to activate many organic
synthetic transformations due to acoustic cavitational collapse. In
comparison to conventional heating, which provides thermal
energy into the macro system; ultrasound irradiation reduces
reaction time, increases yield, minimize waste and involve
energy conservation by providing the activation energy to micro
environment which emphasizes its greener significance.5
Figure 1. Structures of some natural products 3-5 and pharmaceutically
active compounds 6-9 possessing 1, 4-benzoxazine scaffolds.
A
number of synthetic approaches for the synthesis of
benzo[1,4]oxazines, 2-oxo-benzo[1,4]oxazines and similar
moieties have been reported over the past few decades.20-24 In
general, 2-oxo-benzo[1,4]oxazines and similar derivatives are
Benzo[1, 4]oxazines 1 and 2-oxo-benzo[1, 4]oxazines 2 are an
important class of heterocycles which are found in many natural
products as well as in several biologically active and medicinally

2
Tetrahedron Letter
synthesized by the treatment of o-aminophenols with either α-
‘’on water’’ ultrasound-assisted, catalyst free, diverse one-pot
synthesis of highly functionalized 2-oxo-benzo[1,4]oxazines 24-
29 (Scheme 1, reaction–iv). This protocol involve one-pot
reaction of substituted 2-aminophenol 20a-f and substituted 2, 4-
dioxo-4-phenylbutanoic acid 21-23 on water under ultrasound
irradiation at 80 °C for 75-120 min, which furnished substituted
2-oxo-benzo[1,4]oxazines 24-29, respectively upto 98% yields.
Compounds 24a-g, 24i-j, 31a-b had been prepared earlier by
known procedures.21 To the best of our knowledge, this is the
first report of “on water” ultrasonic-assisted green synthesis of
functionalized 2-oxo-benzo[1, 4]oxazines and its derivatives in
excellent yields.
ketoesters,24a-c or with domino reaction of substituted β-
nitroacrylates24h or with alkyl propiolates.24f Another method
involves synthesis of the 2-oxo-3-aryl-benzo[1,4]oxazines by
condensation
of
arylacetates
with
methyl-o-
quinonemonoximes.24d-e Furthermore, 4-alkyl- and 4-benzyl-3,4-
dihydro-1,4-benzoxazin-2-one derivatives were also synthesized
from reaction between an aldehydes and ethyl 2-(2-
hydroxyphenylamino)acetate.24g In addition, a special type of
MnO2 catalysed tandem oxidation-inverse electron demand Diels
Alder (IEDDA) reaction of o-aminophenol derivatives 10 with
enamines 11 had also been reported to synthesize substituted 3,3-
dialkyl-1,4-benzoxazines 12 with complete regiochemical control
(Scheme 1, reaction–i).25a All these methodologies were
associated with several drawbacks such as the use of toxic
catalysts23e and starting materials, hazardous organic solvents,
somewhat multistep and requirement of complicated reaction
assembly, limited number of appropriate substrates for diverse
synthesis,25 tedious workup and low yields etc. Hence, green
protocols having large substrate scope and wide diversification
along with functional group compatibility as well as versatile
nature for the synthesis of such bioactive moieties are in great
demand.
Results and discussion
Initially, we performed the model reactions between 2-
aminophenol 20a (0.1 mmol) and 2,4-dioxo-4-phenylbutanoic
acid 21a (0.1 mmol) in several polar solvents (2.0 mL) at room
temperature for 120 min. The condensation product 24a in
isopropanol was isolated in only 16% yield; but when the same
reaction was performed under ultrasound irradiation for 45 min at
room temperature then, to our surprise, we obtained 24a in 46 %
yield (entry 1, Table 1). Further for getting the better yield, we
subjected the same reaction at 90°C under conventional as well
as in ultrasound irradiation for 120 min and 45 min respectively,
which afforded 24a in 39 % and 62 % yield, respectively (entry
1, Table 1). After obtaining the improved yield under ultrasound
irradiation, we anticipated that ultrasound irradiation could
potentially accelerate the reaction and increase yields. Thus,
these results prompted us to investigate in detail the effect of
sonication, temp, time and solvent on the rate and yield of the
reaction. The obtained condensed product 24a was fully
characterized by their spectroscopic data (1H and 13C NMR,
HRMS and IR).
Table 1. Optimization study a: Synthesis of 2-oxo-benzo[1,4]oxazines 24a by
the reaction of 2-aminophenol 20a and 2, 4-dioxo-4-phenylbutanoic acid 21a
Entry
Solvent
Temp
(°C)
Method Ab
Time
Yieldd
Method Bc
Time
Yieldd
(%)
(min)
(%)
(min)
Scheme 1. Previous and present approaches for the synthesis of substituted 1,
4-benzoxazines.
1
2
3
4
5
6
7
Isopropanol
Isopropanol
EtOH
EtOH
DMF
DMSO
Diethylene
glycol
H2O
rt
90
rt
80
80
80
80
120
120
120
120
120
120
120
16
39
22
52
61
64
60
45
45
45
45
45
45
45
46
62
44
70
78
73
81
So far, there is no green protocol available in the literature using
ultrasonic-assisted “on water” synthesis of these 2-oxo-
benzo[1,4]oxazines. Earlier, Albanese et. al. reported a sequential
two-step reaction involving R4N+F− directed ring opening of
epoxides 14 with aryl sulfonamides 13 followed by in situ
cyclization of 15 to synthesize 2-alkyl/aryl substituted 3,4-
dihydro-2H-1,4-benzoxazines 16 in simple mild conditions
(Scheme 1, reaction–ii).24i&j Further, recently, a green protocol
for the synthesis of 3-oxo-1,4-benzoxazine derivatives 19 have
also been developed via the reaction of o-substituted anilines 17
with dimethyl but-2-ynedioate 18.25b However, this methodology
is associated with limited diversification (Scheme-1, reaction–
iii).
8
9
10
11
12
13
rt
80
100
80
80
80
120
120
120
240
300
360
12
69
73
78
82
80
45
45
45
60
75
90
62
86
89
94
98
97
H2O
H2O
H2O
H2O
H2O
a Reaction condition: 20a (0.1 mmol), 21a (0.1 mmol) in solvent (2.0 mL), at given time
b
c
and temp under method A or B; Method A: Conventional heating; Method B:
Ultrasound Irradiation; dIsolated yield after recrystalization/column chromatography.
It is noteworthy that most of the earlier methods report the
synthesis of 3-oxo-1,4-benzoxazines or 3-substituted 1,4-
benzoxazines using greener approach whereas no green synthesis
using water as a solvent under ultrasonic irradiation is reported
for 2-oxo-1,4-benzoxazines. Herein, we report a simple, efficient,
In order to increase the yield of the desired 2-oxo-
benzo[1,4]oxazine 24a, we did this reaction in EtOH, DMF,
DMSO, Diethylene glycol, water etc. at different temperature
using method A as well as method B. As can be seen from the

3
table 1; yield was significantly improved under ultrasonic
conditions (method B) as compared to conventional method
(method A) conditions (entries 3-8; Table 1). So, we performed
our model reaction in water as solvent only (entries 8-13). When
we performed our model reaction on water at room temp for 120
min and under ultrasound irradiation for 45 min, we obtained 24a
in 12 % and 62 % yield, respectively (entry 8, Table 1). Then, we
carried out the model reaction under heating at 80 °C under
conventional as well as under ultrasound irradiation conditions;
24a was obtained in 69 % and 86 % yield respectively (entry 9,
Table 1). Either on further increasing the reaction temperature
from 80°C to 100 °C or increasing /decreasing the reaction time,
under conventional heating, there was slight improvement in
yields ranging from 73-80 % (entries 10-13, Table 1). But, to our
delight, the yield of desired product 24a was increased up to 98
% when time was extended from 45 to 75 min. under ultrasonic
irradiation conditions (entries 10-12, Table 1). On further
extending the time from 75 min to 90 min at the same reaction
conditions, i.e. at 80 °C temp under ultrasound irradiation
condition, yield of 24a dropdown slightly to 97 % (entries 13,
Table 1). Thus, based on above screening studies, water as
solvent, 80°C temperature for 75 min was found to be the best
optimized reaction condition under ultrasound irradiation for the
synthesis of desired 2-oxo-benzo[1,4]oxazines 24a (entry 12,
Table 1).
intramolecular condensation via either path A or path B. This
can be explained by taking 24a as reference example, which is
formed by the reaction between 20a and 21a, (Figure 2). The H-
bonding between the oxygen atom of water and the phenolic
hydrogen of 2-aminophenol increased the nucleophilicity of the
oxygen atom of the 2-aminophenol (20aa’). On the other hand,
the hydrogen bond between hydrogen atom of water and
carboxylic oxygen increased the electrophilic character of carbon
adjacent to the carbonyl group (21aa’).Therefore, according to
path A; in the probable intermediate (I), the nucleophilic attack
at the carboxylic carbon atom by the phenolic oxygen (II)
followed by removal of water led to conjugated acyclic adduct
(III). Then, the second nucleophilic attack of nitrogen atom to
the carbonyl carbon adjacent to newly formed ester linkage of
this acyclic adduct took place (IV) and the corresponding 2-oxo-
benzo[1,4]oxazine 24a was obtained followed by the removal of
second water molecule. Whereas, contrary to this, as depicted in
path B; firstly the nucleophilic attack by nitrogen of
aminophenol 20aa’ at the carbonyl carbon (adjacent to the
carboxylic group) of 21aa’ led to the intermediate (V), which on
removal of the water molecule gets converted to the conjugated
acyclic adduct (VIII). Finally, the desired product 2-oxo-
benzo[1,4]oxazine 24a was obtained after the second
nucleophilic attack by phenolic oxygen at carboxylic carbon
followed by removal of second water molecule from intermediate
(IX).
The proposed mechanism of this optimized reaction might
involves intermolecular condensation followed by an
Figure 2. Probable mechanism for the synthesis of 2-oxo-benzo[1,4]oxazine 24a.
Substrate scope and versatility
with electron donating (21a-h) and electron withdrawing
substituents (21i), which was present on 2,4 -dioxo-4-
phenylbutanoic acid 21a-i. In the case of polycyclic (aromatic as
well as aliphatic) diketo acids i.e., 22 and 23a and aliphatic
diketo acid 23b; 25a-d, 26 and 27 were obtained in excellent
yields (86-93%) whereas 28 and 29 was obtained in 79% and
76% yields, respectively. Thus, these result shows that the
aromatic diketo acids, 21a-i and 22, afforded the target 2-oxo-
benzo[1,4]oxazines in high yields (upto 98%) as compared with
that obtained from alicyclic diketo acids 23a and alkyl diketo
acids 23b.
The generality and versatile nature of our optimized reaction
conditions was then investigated. Several alkyl/halide/nitro-
substituted 2-aminophenol 20a-f was reacted with alkoxy/
alkyl/halide/nitro-substituted 2, 4-dioxo-4-phenylbutanoic acid
21a-i and 22-23 in water in excellent yields (upto 98%) under our
optimized
conditions
furnished
the
desired
2-oxo-
benzo[1,4]oxazines 24a-q, 25a-d and 26-29, respectively
(Scheme 2, figure 3).26 All the compounds were purified either
by flash column chromatography method or by recrystallization
method (see experimental section).
It has been also observed that the several functional groups, like
F, Cl, Br, OMe and NO2 are well tolerable under our reaction
conditions as the desired products were obtained in high isolated
yields indicating the versatility of the methodology.
The electron donating substituents present (20b or 20e) on 2-
aminophenol increases the yields, while the electron withdrawing
substituents (as in 20c, 20d and 20f) slightly decreases the yields
of products. The same trend of isolated yield was also obtained
Scheme 2. Ultrasound-assisted one-pot green synthesis of 2-oxo-
benzo[1,4]oxazines 24a-q, 25a-d and 26-29.a

4
Tetrahedron Letter
Figure 3. Structures of all synthesized 2-oxo-benzo[1,4]oxazines.
aUnless otherwise mentioned, all the reactions were carried out with substrates aminophenols 20a-f (0.2 mmol) and 21- 23 (0.2 mmol) in water (2.0 mL) at 80 °C
temperature at given time under ultrasound irradiation. bIsolated yield.
Furthermore, we demonstrated its practicality by performing the
model reaction in gram scale. The gram scale synthesis was
performed taking 24a as representative example (Scheme 3). The
heterogeneous reaction mixture of 2-amino phenol (20a, 1.12 g,
10.26 mmol) and 2,4-dioxo-4-phenylbutanoic acid (21a, 1.97 g,
10.26 mmol) in water was stirred and heated at 80 °C for 90 min
under ultrasonic irradiations (monitored by TLC). The solid 2-
oxo-benzo[1,4]oxazines 24a was precipitated out, which was
After successful application of developed methodology for 2-
oxo-benzo[1,4]oxazines class of molecules, the study was further
extended to 2-oxo-quinoxaline class of molecules, an important
easily isolated in 92 % yield by simple filtration followed by
class of heterocyclic bioactive compound present in various
washing and recrystallization with EtOH.
natural products. 30a-b on reaction with several 2,4-dioxo-4-
aryl/alicyclic acid 21a, 22 and 23a furnished the corresponding
substituted 2-oxo-quinoxaline analogues (31a-b, 32a-b & 33a-b)
Scheme 3. Ultrasound-assisted gram scale synthesis of 2-oxo-
benzo[1,4]oxazines 24a.
in excellent 80-95% yields under our optimized reaction
conditions (Scheme 4).27
Scheme 4. Ultrasound-assisted one-pot green synthesis of 2-oxo- to 2-oxo-
quinoxaline 31-33.a

5
Grant [02 (0189)/14/EMR-II], DST, New Delhi for DST-RFBR
Indo-Russian Joint Research Project (INT/RUS/RFBR/P-169)
and SERB, New Delhi for SERB Fast track young scientist
award (CS-037/2013). P. K. J. And V. S. thanks CSIR, New
Delhi and MNIT, Jaipur respectively for providing financial
assistance in the form of Research Associateship and institute
fellowship, respectively. Materials Research Centre, MNIT,
Jaipur is gratefully acknowledged for providing analytical
facilities.
References and notes
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aUnless otherwise mentioned, all the reactions were carried out with
substrates 30a-b (0.2 mmol) and 21a, 22 and 23a (0.2 mmol) in water (2.0
mL) at 80 °C temperature at given time under ultrasound irradiation. bIsolated
yield.
Finally, we extended the application of our developed
methodology in the synthesis of 2H-benzo[b][1,4]oxazin-2-one-
based anticancer indole alkaloid, Cephalandole A. It was isolated
from the Taiwanese orchid Cephalanceropsis gracilis
(Orchidaceae) in 2006.8a-d The crude extract of this plant
exhibited activity against lung (NCI-H460; IC50 = 7.8 µM), breast
(MCF-7; IC50 = 7.57 µM) and CNS (SF-268; IC50 = 12.2 µM)
carcinoma cell lines. Aminophenol 20a on reaction with 3-
indoleglyoxylic acid 34 in water under our optimized conditions
furnished Cephalandole A 35 in 81 % yield.28 (Scheme-5). The
spectral data of 35 was found identical with the literature data.
Scheme 5. Synthesis of Cephalandole A 35.
Conclusions
In summary, we have developed a simple, highly efficient
green protocol for the synthesis of functionalized 2-oxo-
benzo[1,4]oxazines 24a-q, 25a-d, and 26-29 in excellent yields
°
upto 98% under ultrasound irradiation conditions at 80 C in 75-
120 min. Moreover, this methodology tolerates a broad range of
functional groups and their positions under simple reaction
conditions, and provides a straightforward access to a library of
functionalized 2-oxo-benzo[1, 4]oxazines analogues from readily
available starting substrates. To the best of our knowledge, this is
the first report of ultrasound assisted synthesis of functionalized
2-oxo-benzo[1,4]oxazines in water. In addition, functionalized 2-
oxo-quinoxaline analogues 31a-b, 32a-b and 33a-b were also
synthesized utilizing this methodology in excellent yields (upto
95%). Gram scale synthesis and synthesis of Cephalandole A 35,
highlights the practicality of this methodology.
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Acknowledgements
S. C. acknowledges MNIT Jaipur for providing necessary
facilities. S.C also acknowledges CSIR, New Delhi for CSIR

6
Tetrahedron Letter
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26. General procedure for the Synthesis of 2-oxo-benzo[1, 4] oxazines
(24a-q, 25a-d and 26-29): To a solution of the compound 20a-f
(substituted 2-amino phenol; 0.2 mmol) in water was added 0.2 mmol
of compound 21a-i (substituted 2,4-dioxo-4-phynyl butanoic acid), or
22 or 23; and the reaction mixture was irradiated under ultrasonic
sonicator at 80 ˚C temperature for about 75-120 min. (depending upon
the substrate employed). The progress of reaction was monitored by
TLC. After completion of reaction, the reaction mixture was filtered
off, washed with distilled water (3 × 50 ml) and dried it, which
furnished the crude product. The crude product were purified either by
recrystallization using EtOAc/Hexane or EtOH; or by flash column
chromatography method over silica gel using 9:1 Hexane/ethyl acetate
as an eluent which afforded the pure desired 2-oxo-benzo[1,4]oxazines
24a-q, 25a-d and 26-29, respectively in excellent yield (76-98 %).
Characterization data of representative (Z)-7-nitro-3-(2-oxo-2-
phenylethylidene)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (24n):
Yellowish solid; yield: 57.5 mg (89 %), m.p. 240-242 °C; FT-IR (KBr,
νmax/cm-1) 3436, 1763, 1622, 1596, 1268; 1H NMR (400 MHz) δ
8.06 - 8.00 (m, 4H), 7.83 – 7.81 (m, 1H), 7.62 (t, J = 7.3 Hz, 1H), 7.54
(t, J = 7.5 Hz, 2H), 6.99 (s, 1H); 13C NMR (100 MHz) 190.7, 156.1,
142.2, 141.1, 139.2, 138.3, 133.6, 131.3, 129.6, 128.0, 121.4, 117.4,
112.6, 96.0; HRMS (ESI) calcd. for C16H10N2O5 [M+H]+: 311.0590;
found 311.0595.
27. General procedure for the Synthesis of 2-oxo-quinoxaline
analogues (31a-b, 32a-b and 33a-b):To a solution of 0.2 mmol of
benzene-1,2-diamine 30a-b in water was added 0.2 mmol of
compound 21a or 22 or 23; and the reaction mixture was irradiated
under ultrasonic sonicator at 80 ˚C temperature for about 75-120 min.
(depending upon the substrate employed). Progress of reaction was
monitored by TLC. After completion of reaction, the reaction mixture
was filtered off, washed with distilled water (3 × 50 ml) and dried it,
which furnished the crude product. The crude product were purified
either by recrystallization using EtOAc/Hexane or EtOH; which
afforded the pure desired 2-oxo-quinoxaline analogues (31a-b, 32a-b
and 33a-b) having excellent yield (80-95 %).
20. (a) Stepanova, E. E.; Babenysheva, A. V.; Maslivets, A. N. Russ. J.
Org. Chem. 2011, 47, 937-940; (b) Stepanova, E. E.; Aliev, Z. G.;
Maslivets, A. N. Russ. J. Org. Chem. 2013, 49, 1762-1767; (c) Aliev,
Z. G.; Krasnykh, O. P.; Maslivets, A. N.; Atovmyan, L. O. Russ.
Chem. Bull. 2000, 49, 2045-2047;(d) Koini, E. N.; Papazafiri, P.;
Vassilopoulos, A.; Koufaki, M.; Horváth, Z.; Koncz, I.; Virág, L.;
Papp, G. J.; Varró, A.; Calogeropoulou, T. J. Med. Chem. 2009, 52,
2328-2340; (e) Ramesh, C.; Raju, B. R.; Kavala, V.; Kuo, C.-W.; Ya,
C.-Fa. Tetrahedron, 2011, 67, 1187-1192; (f) Jangili, P.; Kashanna, J.;
Das, B. Tetrahedron Letters, 2013, 54, 3453–3456; (g) Huo, C.; Dong,
J.; Su, Y.; Tang, J.; Chen, F. Chem. Commun. 2016, 52, 13341—
13344;(h) Feng, E.; Huang, H.; Zhou, Y.; Ye, D.; Jiang, H.; Liu, H. J.
Org. Chem. 2009, 74, 2846; (i) Feng, G.; Wu, J.; Dai, W.-M.
Tetrahedron Lett. 2007, 48, 401; (j) Yuan, Y.; Liu, G.; Li, L.;Wang,
Z.;Wang, L. J. Comb. Chem. 2007, 9, 158; (k) Xing, X.; Wu, J.; Feng,
G.; Dai, W.-M. Tetrahedron 2006, 62, 6774; (l) Kundu, N. G.;
Chaudhuri, G.; Upadhyay, A. J. Org. Chem. 2001, 66, 20; (m) Henry,
N.; Guillaumet, G.; Pujol, M. D. Tetrahedron Lett. 2004, 45, 1465.
21. For known compounds, see: (a) Xia, M. Faming Zhuanli Shenqing
Gongkai Shuomingshu, 2008, CN 101108860 A; (b) Mashevskaya, I.
V.; Tolmacheva, I. A.; Voronova, E. V.; Odegova, T. F.;
Aleksandrova, G. A.; Goleneva, A. F.; Kol'tsova, S. V.; Maslivets, A.
N. Pharm. Chem. J. (Translation of Khimiko-Farmatsevticheskii
Zhurnal), 2002, 36 (2), 33-35; (c) Iwanami, Y.; Seki, T.; Inagaki, T.
Bull. Chem. Soc. Jpn. 1971, 44 (5), 1316-1321; (d) Kozminykh, E. N.;
Igidov, N. M.; Shavkunova, G. A.; Kozminykh, V. O. Russ. Chem.
Bull. (Translation of Izvestiya Akademii Nauk, Seriya Khimicheskaya),
1997, 46 (7), 1285-1290; (e) Gein, V. L.; Rassudikhina, N. A.;
Shepelina, N. V.; Vakhrin, M. I.; Babushkina, E. B.; Voronina, E. V.
Pharm. Chem. J. 2008, 42 (9), 529-532; (f) Xia, M.; Wu, B.; Xiang, G.
J. Fluor. Chem. 2008, 129 (5), 402-408; (g) Habash, M.; Taha, M. O.
Bioorg. Med. Chem. 2011, 19 (16), 4746-4771; (h) Reynisson, J.;
Court, W.; Neill, C. O.; Day, J.; Patterson, L.; McDonald, E.;
Workman, P.; Katan, M.; Eccles, S. A. Bioorg. Med. Chem. 2009, 17
(8), 3169-3176; (i) Maslivets, V. A.; Maslivets, A. N. Russ. J. Org.
Chem. 2012, 48 (9), 1233-1237 and references cited therein; (j) Lia,
X.; Liua, N.; Zhanga, H.; Knudsonb, S. E.; Slaydenb, R. A.; Tongea, P.
J. Bioorg. Med. Chem. Lett. 2010, 20 (21), 6306-6309; (k) Khalturina,
V. V.; Shklyaev, Yu. V.; Aliev, Z. G.; Maslivets, A. N. Russ. J. Org.
Chem. 2009, 45g(10), 1519-1522.
Characterization data of representative (Z)-3-(2-(anthracen-9-yl)-2-
oxoethylidene)-3,4-dihydroquinoxalin-2(1H)-one (32a):
Yellowish solid; yield: 64.6 mg (90 %), m.p. > 250 °C; FT-IR (Neat,
νmax/cm-1) 2920, 1671, 1596, 1455, 1131; 1H NMR (400 MHz) δ
11.86 (s, 1H), 8.66 (d, J = 6.0 Hz, 1H), 8.13 – 8.09 (m, 4H), 7.59 –
7.47 (m, 5H), 7.20 – 7.19 (m, 3H), 6.37 (d, J = 7.2 Hz, 1H); 13C NMR
(100 MHz) δ 193.7, 155.1, 144.5, 136.2, 130.5, 128.2, 127.9, 127.3,
126.8, 126.7, 125.9, 125.8, 125.0, 124.9, 124.7, 123.8, 116.3, 96.2;
HRMS (ESI) calcd. for C24H16N2O2 [M+H]+: 365.1212; found
365.1218.
22. For selected examples see: (a) Nicolaou, K. C.; Sugita, K.; Baran, P.
S.; Zhong, Y. L. Angew. Chem., Int. Ed. 2001, 40, 207; (b) Nicolaou,
K. C.; Baran, P. S.; Zhong, Y. L.; Sugita, J. Am. Chem. Soc. 2002,
124, 2212; (c) Largeron, M.; Neudörff er, A.; Vuilhorgne, M.; Blattes,
E.; Fleury, M.-B. Angew. Chem. Int. Ed. 2002, 41, 824; (d) Choudhary,
G.; Naganaboina, R. T.; Peddinti, R. K. RSC Adv. 2014, 4, 17969; (e)
Achari, B.; Mandal, S. B.; Dutta, P. K.; Chowdhury, C. Synlett 2004,
2449 and references therein; (f) Macias, F. A.; Marin, D.; Oliveros
Bastidas, A.; Molinillo, J. M. G. Nat. Prod. Rep. 2009, 26, 478; (g)
Ilas, J.; Stefanic Anderluh, P.; Sollner Dolenc, M.; Kikelj, D.
Tetrahedron 2005, 61, 7325 and references therein.
28. Synthesis of 3-(1H-indol-3-yl)-2H-benzo[b][1,4]oxazin-2-one (35):
To a solution of the compound 20a (130.8 mg, 1.20 mmol) in water
was added 3-Indoleglyoxylic acid 34 (226.9 mg, 1.20 mmol); and the
reaction mixture was irradiated under ultrasonic sonicator at 80 ˚C
temperature for about 180 min. The progress of reaction was monitored
by TLC. After completion of reaction, the reaction mixture was filtered
off, washed with distilled water (3 × 50 ml) and dried it, which
furnished the crude product. The crude product was further purified by
recrystalization using EtOAc/Hexane and EtOH; which afforded the
pure desired Cephalandole A 35 having good yield (255.4 mg, 81 %).
Yellowish solid; yield: 255 mg (81) %, m.p. 230-232 °C; FT-IR (KBr,
νmax/cm-1) 3292, 3053, 2921, 2852, 1713, 1604, 1428, 1151; 1H
NMR (400 MHz) δ 11.99 (s, 1H), 8.77 – 8.75 (m, 1H), 8.70 (s, 1H),
23. For selected recent examples, see: (a) Gabriele, B.; Salerno, G.; Veltri,
L.; Mancuso, R.; Li, Z.; Crispini, A.; Bellusci, A. J. Org. Chem. 2006,
71, 7895; (b) Bhadra, S.; Adak, L.; Samanta, S.; Maidul Islam, A. K.
M.; Mukherjee, M.; Ranu, B. C. J. Org. Chem. 2010, 75, 8533; (c)

7
7.84 (d, J = 6.4 Hz, 1H), 7.55 – 7.53 (m, 1H), 7.48 – 7.38 (m, 3H), 7.29
– 7.24 (m, 2H); 13C NMR (100 MHz) δ 152.1, 147.9, 144.9, 136.6,
133.8, 131.9, 128.7, 127.7, 126.0, 125.3, 123.1, 122.9, 121.6, 115.9,
112.2, 110.6; HRMS (ESI) calcd. for C16H10N2O2 [M+H]+: 263.0742;
found 263.0749.
Supplementary Material
The supporting information related to this article includes
1
general experimental procedure, copies of H and 13C spectral
data of all the compounds 24a-q, 25a-d, 26-29, 31a-b, 32a-b,
33a-b and Cephalandole A 35 can be found at electronic
supplementary material section.