Lewis acid-promoted synthesis of highly substituted pyrrole-fused benzoxazinones and quinoxalinones

Article abstract of DOI:10.1080/00397911.2020.1832528

A synthesis of a series of novel fused tricyclic heterocyclic compounds has been achieved in one-pot reaction set up starting from (E)-3-(2-oxo-2-phenylethylidene)indolin-2-one and 1,4-benzoxazinone/quinoxalinone derivatives promoted by tin(IV) chloride.

Full text of DOI:10.1080/00397911.2020.1832528

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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Lewis acid-promoted synthesis of highly
substituted pyrrole-fused benzoxazinones and
quinoxalinones
Suresh Selvendran & Saravanakumar Rajendran
To cite this article: Suresh Selvendran & Saravanakumar Rajendran (2020): Lewis acid-promoted
synthesis of highly substituted pyrrole-fused benzoxazinones and quinoxalinones, Synthetic
Communications, DOI: 10.1080/00397911.2020.1832528
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https://doi.org/10.1080/00397911.2020.1832528
Lewis acid-promoted synthesis of highly substituted
pyrrole-fused benzoxazinones and quinoxalinones
Suresh Selvendran and Saravanakumar Rajendran
Chemistry Division, School of Advanced Sciences, Vellore Institute of Technology Chennai Campus,
Chennai, India
ABSTRACT
ARTICLE HISTORY
Received 8 April 2020
A synthesis of a series of novel fused tricyclic heterocyclic com-
pounds has been achieved in one-pot reaction set up starting from
(E)-3-(2-oxo-2-phenylethylidene)indolin-2-one and 1,4-benzoxazinone/
quinoxalinone derivatives promoted by tin(IV) chloride. The reaction
is supposed to occur via a sequential intermolecular Michael addition
of the 1,4-benzoxazinone derivatives to the oxindoles, intramolecular
cyclization, and aromatization with the elimination of water. Apart
from spectroscopic characterization, the structure of one of the pyr-
rolo[1,4]benzoxazinone derivative is confirmed by single-crystal X-ray
diffraction. Thus, the developed domino protocol provides easy
access to multifunctional pyrrolo[1,4]benzoxazines in one-pot with
high efficiency.
KEYWORDS
Benzoxazinone; oxindole;
pyrrole; quinoxalinones;
tin(IV) chloride
GRAPHICAL ABSTRACT
Introduction
Pyrrole-fused heterocyclic compounds are prevalent in bioactive compounds and natural
products. These compounds possess a broad spectrum of biological activities including,
anticancer,[1] antimicrobial,[2] antiviral,[3] and antioxidant.[4] The fused heterocyclic
compounds are widely investigated in pharmacology as often specific drug-receptor
interactions are attained via pre-disposing such heterocycles in the molecular architec-
ture.[5] Moreover, integrating two or more heterocyclic moieties in a single molecule
may enhance the biological activity significantly. Pyrrole-fused benzoxazinones and ben-
zoxazepines attracted wide attention owing to diverse pharmacological activities.[4,6–9]
For example, a benzopyrimido-pyrrolo-1,4-benzoxazine (A) was proved to be a potent
CFTR inhibitor (Scheme 1).[10] Patrice Demonchaux et al. reported a series of pyrrolo-
CONTACT Saravanakumar Rajendran
saravanakumar.r@vit.ac.in, sar.org@gmail.com
Chemistry Division, School of
Advanced Sciences, Vellore Institute of Technology Chennai Campus, Chennai, Tamil Nadu, India.
Supplemental data for this article can be accessed on the publisher’s website
ß 2020 Taylor & Francis Group, LLC

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S. SELVENDRAN AND S. RAJENDRAN
Scheme 1. Some of the biologically important pyrrole-fused compounds.
1,4-benzoxazine derivatives (B) as potent antiasthmatic compound.[11] A series of
pyrrolo[1,2-a]quinoxalinones and Imidazo[1,2-a]quinoxalinones (C) shown to possess
potent antiallergic activity.[12] Fedora Grande et al developed novel G-protein coupled
estrogen receptor (GPER) antagonists based on pyrrole-fused 1,4-benzoxazinones
(D).[13] Lamellarin-D (E), a pyrrole fused marine natural product has been identified as
an anticancer agent and as a potent inhibitor of human topoisomerase.[1] Nevertheless,
pyrrolo-1,4-benzoxazines is an important scaffold in pharmacology and drug discovery
process, the available synthetic methods are limited.[4,9,14–17] Thus, developing facile and
efficient procedures for the synthesis of these biologically important scaffolds remains
highly desirable to augment synthetic organic tools to generate a repository of complex
fused heterocyclic compounds. In the present work, we report a SnCl4-promoted highly
facile tandem reaction of benzoxazinone/quinoxalinones and (E)-3-(2-oxo-2-phenylethy-
lidene)indolin-2-one to furnish multifunctional pyrrole-fused benzoxazinones and qui-
noxalinones. To the best of our knowledge, synthesis of highly functionalized
pyrrolobenzoxazinones and quinoxalinones compounds are scarce in the literature.
Results and discussion
Oxindole (11) and simple 1,4-benzoxazinone derivative (12a) were taken as a model
substrate and the reaction condition was optimized with various solvent and reagents as
outlined in Table 1. Initially, the tandem reaction was attempted with FeCl3 and toluene
as solvent at room temperature (Table 1, entry 1). The reaction did not progress at
room temperature. Hence, the reaction mass was gradually heated to 110 ꢀC and main-
tained at this temperature for 16 h nonetheless, the reaction did not progress only the
starting materials were recovered. When the reaction was attempted with other Lewis
acids, AgOTf, InCl3, BF3.OEt2, and Cu(OTf)2 and Bronsted acids, TFA, and AcOH
(Table 1, entry 2–7) the formation of the product was not observed. Similarly, the

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Table 1. Optimization of reaction conditionsa.
Entry
Solvent
Toluene
Toluene
DCE
CH2Cl2
THF
AcOH
DCE
ACN
Toluene
DCE
Reagent (equiv.)
FeCl3 (1.0)
AgOTf (1.0)
TFA (7.0)
InCl3 (1.0)
BF3 OEt2 (2.0)
AcOH (excess)
Cu(OTf)2 (1.0)
I2 (1.0)
PTSA (3.0)
BF3OEt2 (3.0)
SnCl4 (3.0)
T (ꢀC)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
110
80
85
40
70
110
70
70
75
70
70
16
12
24
24
24
18
17
15
20
12
10
nr
nr
nr
nd
nr
nr
nr
nr
Trace
10
70
9
10
11
DCE
aOxindole (1 mmol), benzoxazinone (1 mmol), in 5 mL of solvent; bisolated yield.
reaction did not work with I2 (Table 1, entry 8). Although some of the above reaction
condition works with less hindered 1,4-benzoxazinones,[9,14,17] it did not work in our
hands for sterically bulk 1,4-benzoxazainones. When the reaction was conducted in the
presence of PTSA, the expected product formed in trace amount (<10%) and with
BF3.OEt2 10% product formation was observed (Table 1, entries 9 and 10). To our
delight, the tandem reaction progressed smoothly with SnCl4 and the expected product
formed in 70% yield. Attempt to reduce the SnCl4 equivalence (1–2 equiv.), drastically
reduced the yield (30%).
To study the substrate scope of the reaction, variously substituted 1,4-benzoxazinones
(12a–h) were reacted with oxindole (11). As shown in Table 2, a variety of 1,4-benzoxa-
zinones bearing electron-donating and withdrawing substituents at the para position of
benzoyl were tolerated under the reaction conditions and yielded the corresponding
pyrrolobenzoxazinones (1–8, Table 2) in 63–74% yields. Electron withdrawing and
donating substituent on the 1,4-benzoxazinones have minimum impact on prod-
uct yield.
We then explored the applicability of the above reaction conditions for 1,4-quinoxali-
nones (13a–b, Table 2) instead of 1,4-benzoxazinone. The reaction progressed smoothly.
The tandem reaction of 1,4-quinoxalinones and oxindole yielded the corresponding pyr-
rolo[1,4]quinoxalinones (9 and 10, Table 2) in moderate yields 63–65%.
1
The synthesized compounds (1–10), were characterized by H NMR, 13C NMR, FT-
IR, and HR-MS. The characterization data matched with the structural attributes of pyr-
rolobenzoxazinones and pyrroloquinoxalinones (refer to ESI). The structural elucidation
is exemplified by taking compound 1 as an example. Oxindole –N–Hi (Table 1, com-
pound 1) proton appeared as a broad singlet at 10.36 ppm. The oxindole –C–Hii

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S. SELVENDRAN AND S. RAJENDRAN
Table 2. Pyrrole-fused benzoxazinone and quinoxalinone derivatives synthesizeda.
aReaction conditions: oxindole (1 mmol), benzoxazinone (1 mmol), in 5 mL of DCE.
1
(Table 1, compound 1) proton appeared as a broad singlet at 4.24 ppm (refer H-NMR
spectrum, ESI). The aromatic protons appeared as broad featureless multiplet around
7.66–6.41 ppm integrated to 18 protons. The broad featureless pattern might due to
phenyl-pyrrole biaryl conformers which results from high rotational barrier around phe-
nyl-pyrrole pivotal bond and/or due to amide resonance of oxindole moiety. Hence, we
1
recorded H NMR spectrum (of compound 1) at variable temperature (Fig. 1; 25, 40,
ꢀ
60, and 80 C). The broad featureless peaks were much resolved at higher temperature
(Fig. 1). This indicates that at a higher temperature biaryl rotational barrier was over-
come and conformers were averaged. FT-IR spectrum, showed a broad peak at
1663 cmꢁ1 which was assigned to indole carbonyl and peaks at 1600 and 1587 cmꢁ1
were assigned to benzoxazolinone and benzoyl carbonyls, respectively. High-resolution
mass spectra showed molecular mass correspond to [M þ H] ion. Further, the structure
of compound 1 was confirmed by single-crystal X-ray diffraction.
Single crystal X-ray structure
Compound 1 was dissolved in CHCl3:CH3OH (9:1) and allowed to evaporate slowly at
room temperature. After a week colorless crystals suitable for X-ray analysis were
obtained. In the crystal structure, CHCl3 trapped as solvent of crystallization (it is

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1
Figure 1. H NMR spectrum compound 1 at variable temperature, 25, 40, 60, and 80 ꢀC.
omitted in the ORTEP diagram for clarity (Fig. 2a). The compound crystallized in the
triclinic system with the P-1 space group (Fig. 2). Oxindole’s –N–H and –C¼O involved
in intermolecular hydrogen bonding. They hydrogen bonded with adjacent oxindole’s
–C¼O and –N–H, respectively. In addition to hydrogen bonding, the crystal structure
is stabilized by a series of weak interactions, such as p–p, –C–H–p, and C–H … O.
Plausible mechanism for formation of pyrrolo[1,4]benzoxazinone from oxoindole
and 1,4-benzoxazinones
On the basis of the obtained product and previously reported literature,[9,17] a possible
mechanism for the tandem reaction is depicted in Scheme 2. It is presumed that tin(IV)
chloride activates both the substrate and promotes Michael addition of 1,4-benzoxazinone
(12) on the a-position of oxindole (11) to furnishes the intermediate F. Intramolecular pro-
ton transfer and imine-enamine tautomerization of F lead to the intermediate G.

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S. SELVENDRAN AND S. RAJENDRAN
Figure 2. (a) ORTEP diagram of pyrrolo[1,4]benzoxazinone (1), solvent (CHCl3) of crystallization is
omitted for clarity; (b) Chemdraw structure of pyrrolo[1,4]benzoxazinone (1).
Scheme 2. A plausible reaction mechanism for the formation of pyrrolo-1,4-benzoxazinones.
Subsequent intramolecular cyclization of G involves enamine nitrogen and carbonyl group
to afford the dihydropyrrole intermediate H. Aromatization of intermediate H with the
elimination of water yields the final product, pyrrolo-1,4-benzoxazinones I.
Conclusions
A simple and efficient protocol has been developed for the synthesis of pharmacologic-
ally important scaffolds, pyrrolobenzoxazinone/quinoxalinones. Tin(IV) chloride
mediated the tandem reaction of 3-(2-oxo-2-arylethylidene)-oxindoles and 1,4-

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benzoxazinones/quinoxalinones to form highly substituted pyrrolobenzoxazinones/qui-
noxalinones in one-pot with moderate to good yield. The structure of one of the pyrro-
lobenzoxazinones is confirmed by single-crystal X-ray diffraction. The reaction has a
wide substrate scope and functional group tolerance. The methodology is applicable for
the synthesis of highly substituted pyrrolobenzoxazinones/quinoxalinones. Thus, the
developed protocol would expand the synthetic organic tool to generate multi-function-
alized fused heterocyclic system for biological applications.
Experimental section
General procedure for synthesis of pyrrolobenzoxazinone and quinoxalinone
derivatives
A solution of (E)-3-(2-oxo-2-phenylethylidene)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-
one/(E)-3-(2-oxo-2-phenylethylidene)-3,4-dihydroquinoxalin-2(1H)-one (1 mmol), and
anhy.SnCl4 (3 mmol) in 1,2-dichloroethane (5.0 mL) was heated at reflux for 10 h under
N2 atm. Progress of the reaction was monitored by TLC (Hexane:EtOAc, 70:30). The
reaction mixture was cooled to room temperature and quenched by the addition of
aqueous sat. NaHCO3 solution. The reaction mixture was extracted using chloroform
(3 ꢂ 50 mL), dried with anhyd. Na2SO4 and concentrated under reduced pressure. The
residue was purified by a silica gel (100 ꢁ 200 mesh) column chromatography using
chloroform:methanol (99:1) mixture to get pure product.
3-Benzoyl-2-(2-oxoindolin-3-yl)-1-phenyl-4-Hbenzo (b) pyrrol [1, 2-d][1,4]oxazine-4-
one (1)
Yield: 347.5 mg, 70%. m.p.: 308–309 ꢀC. Spectral data: FT-IR (KBr,vmax cmꢁ1): 1663
1
(C¼O str), 1600 (C¼O str), 1587 (C¼O str), and 1501 (C¼C aromatic). H NMR
(400 MHz, DMSO d6), d: 10.36 (1H, s, NH), 7.79 (18H, m, ArH), 4.24 (1H, s,
ꢁCHindole) ppm. 13C NMR (100 MHz, DMSO d6), d: 43.5, 79.6, 109.3, 116.8, 118.7,
199.4, 121.1, 121.2, 121.3, 123.3, 123.4, 124.7, 124.8, 124.9, 127.1, 128.4, 129.3, 129.5,
129.6, 129.7, 129.8, 130.1, 130.1, 130.2, 130.3, 130.4, 130.6, 130.7, 131.2, 143.5, 152.8,
176.6 ppm. HR-MS: (ESIþ): m/z calculated for C32H21N2O4 [M þ H] 497.1501
found 497.1556.
Full experiment details, characterization data (1H NMR, 13C NMR spectra, HR-MS
1
and FT-IR) and copies of H NMR and 13C NMR spectra of pyrrolobenzoxazinone/qui-
noxalinones are included in the Supplementary material. CIF data of compound (1) is
deposited in Cambridge Crystallographic Data CentreCenter (CCDC) and its CCDC
number: 1994955. The data is available free of charge at http://www.ccdc.cam.ac.uk
Acknowledgments
S.S and R.S.K gratefully acknowledge Chemistry Division and VIT Chennai, for financial support
to S.S, infrastructure facilities, and instrumentation facilities (FT-IR and GC-MS) to complete
this work. Thanks extended to SAIF, VIT Vellore for recording 1H, NMR, and 13C NMR for
our samples.

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S. SELVENDRAN AND S. RAJENDRAN
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