The Rearrangement of Peroxides for the Construction of Fluorophoric 1,4-Benzoxazin-3-one Derivatives

Article abstract of DOI:10.1021/acs.orglett.9b00155

An unprecedented skeletal rearrangement of 3-(tert-butylperoxy)indolin-2-one using a tin catalyst has been developed. This rearrangement is highly selective to afford a series of fluorophoric (Z)-2-arylidene and alkylidene-2H-benzo[b][1,4]oxazin-3(4H)-one derivatives in good to excellent yield. In contrast with Sn(OTf)₂, the reaction of 3-(tert-butylperoxy)indolin-2-one derivatives with FeCl₃ afforded the Hock fragmentation product via C-C bond cleavage.

Full text of DOI:10.1021/acs.orglett.9b00155

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
The Rearrangement of Peroxides for the Construction of
Fluorophoric 1,4-Benzoxazin-3-one Derivatives
Moreshwar B. Chaudhari, Atul Chaudhary, Vishnupriya Kumar, and Boopathy Gnanaprakasam*
Department of Chemistry, Indian Institute of Science Education and Research, Pune-411008, Maharashtra, India
S
* Supporting Information
ABSTRACT: An unprecedented skeletal rearrangement of 3-
(tert-butylperoxy)indolin-2-one using a tin catalyst has been
developed. This rearrangement is highly selective to afford a
series of fluorophoric (Z)-2-arylidene and alkylidene-2H-
benzo[b][1,4]oxazin-3(4H)-one derivatives in good to
excellent yield. In contrast with Sn(OTf)2, the reaction of 3-
(tert-butylperoxy)indolin-2-one derivatives with FeCl3 afforded the Hock fragmentation product via C−C bond cleavage.
he peroxidation and related reactions have pivotal
Timportance in the oxidation processes of bioconjugates
and drug discovery. The organic peroxide serves as an
important intermediate in several oxidative transformation-
s.1a−e The synthesis, isolation, and storage of peroxides suffer
minor difficulties, because of weak oxygen−oxygen bonds
(ΔH°298 = 158−194 kJ mol−1).2 The low bond energy of a
peroxide make them intriguing scaffolds for several trans-
formations. The rearrangement of organic peroxide constitutes
a modification in the starting molecule to produce an isomeric
or nonisomeric compound with or without peroxy groups.
Synthetically, the cumene process or Hock process is the basis
of synthesizing phenol from cumene hydroperoxide and is one
of the remarkable examples for rearrangement of organic
peroxide, which can be attributed to the acidic source (Figure
1).3 In biochemistry, lipid peroxidation is an important
research area; as a result, attracting scientific community
from across many disciplines. The naturally occurring oxylipins
constitute a family of oxygenated natural products that are
ubiquitous in plants, animals, and fungi. Enzymatically, in
oxylipin metabolism, hydroperoxide lyase (HPL) converts fatty
acid hydroperoxides to hemiacetal derivatives via Hock-type
rearrangement that spontaneously decomposes to the
aldehydes (Figure 1).4a−e In past decades, varieties of
named5 and unnamed6 rearrangement of organic peroxides
are documented in the literature. However, the migration of
aryl or alkyl group toward electron-deficient oxygen atom has
been widely studied for the Baeyer−Villiger oxidation7a−d,e,f
and Criegee solvolysis of peresters.8a−d
The syntheses of nitrogen-containing heterocyclic com-
pounds are important in all facets of chemistry. In particular,
the chemistry of 2-oxindole derivatives is well-studied, because
of their omnipresence in pharmaceuticals and natural products.
However, maneuvering for the ring-expansion of 2-oxindole
derivatives is an enticing paradigm in organic synthesis.
Interestingly, the base-mediated skeletal rearrangement of
peroxyoxindole was reported by Stoltz and co-workers.9 The
1,4-benzoxazin-3-one derivatives exemplify a class of important
compounds, which exhibits the biological properties such as
CNS depressant,10 antiproliferative,11 neuroprotective
agents.12 Recently, Sharma and co-workers reported the Pd-
catalyzed synthesis of 1,4-benzoxazin-3-one derivatives by
employing an Ugi adduct as a precursor.13 The unique
structure and properties of 1,4-benzoxazin-3-ones gave us an
inducement to develop an operationally simple and novel
pathway for their synthesis.
Herein, we report a Lewis acid, Sn(OTf)2 or Brønsted acid-
mediated activation of 3-peroxy-2-oxindoles and its rearrange-
ment to 1,4-benzoxazin-3-one with the liberation of
isobutylene. The expansion of the ring was triggered by the
C3−C4 carbon shift of 2-oxindole bond toward the electro-
Received: January 14, 2019
Figure 1. State of the art on the rearrangement of peroxides
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00155
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Organic Letters
Letter
philic oxygen on the peroxide functionality. Moreover, we have
demonstrated that the 3-peroxy-2-oxindoles could be cleaved
via Hock rearrangement in the presence of FeCl3 to yield isatin
and aldehyde (Figure 1). Such types of cleavage reactions can
be employed as a probe to determine homolytic versus
heterolytic cleavage.14
which results in the formation of isatin 5 and aldehyde 6
(Scheme 1). We proposed that the peroxide 1a will react via
Scheme 1. FeCl3-Catalyzed Hock Rearrangement of
a
Peroxides
A series of Lewis acids were tested for the rearrangement of
1a to get the best-optimized condition (Table 1). We
a
Table 1. Optimization for the Rearrangement of Peroxide
b
entry
catalyst
none
none
Sc(OTf)3
Sc(OTf)3
Ag(OTf)
temp [°C]
yield 2a:3a [%]
1
2
3
4
5
6
7
8
9
rt
100
rt
100
100
rt
no reaction
no reaction
00:52
40:49
no reaction
00:57
00:60
90:00
30:63
28:51
a
Reaction conditions: 0.25 mmol (1a), FeCl3·6H2O (10 mol %) in 2
mL acetonitrile was heated at 100 °C for 16 h in a sealed tube. The
mentioned yields are isolated yields.
Sn(OTf)2‑
Sn(OTf)2
Sn(OTf)2
BF3.OEt2
Cu(OTf)2
Amberlyst-15
Amberlyst-15
Amberlyst-15
60
100
100
100
100
100
100
Hock rearrangement. The two possible pathways A and B are
depicted in Scheme 1. In pathway A, the migration of phenyl
group on the oxygen will generate isatin 5 and (tert-
butoxymethyl)benzene 7. The isobutylene will serve as a
leaving group to afford benzaldehyde 6a as a cleaved product.15
However, the existence of pathway B is unlikely, because of the
absence of benzyl alcohol in the reaction mixture. Further-
more, to rule out the possibility of pathway B, the reaction of
3a was performed with FeCl3, which afforded the traces of
rearranged product 2a and not even traces of benzaldehyde 6a
or benzyl alcohol (most of the 3a was recovered).
10
11
12
13
c
31:39
87:00
81:10
d
e
a
Reaction conditions: 0.25 mmol (1a), catalyst (10 mol %) in a 2 mL
acetonitrile was heated at a specified temperature for 16 h in a sealed
tube. 0.25 mmol or 78 mg of substrate (1a). Catalyst amount = 10
mol %. 26 mg. 156 mg. 78 mg of Amberlyst-15 was used (w/w
substrate to Amberlyst-15 ratio is taken). Amberlyst-15 (Dry) form is
used. The mentioned yields are isolated yields.
b
c
d
e
With optimized conditions in hand, the scope of Sn-
catalyzed and Amberlyst-15 mediated rearrangement was
investigated (Scheme 2). The variety of alkyl or benzyl-
substituted peroxyoxindoles were subjected for rearrangement
reaction. Benzyl groups bearing electron-donating groups
afforded the rearranged product (2a−2d) with good to
excellent yield (Scheme 2). Gratifyingly, the reaction of 3-
(tert-butylperoxy)-3-cyclohexylindolin-2-one and 3-(tert-butyl-
peroxy)-3-hexylindolin-2-one afforded 2e and 2f in yields of
78% and 75%, respectively, using Sn(OTf)2. However, the use
of Amberlyst-15 provided 2e and 2f in isolated yields of 82%
and 87%, respectively.
In the case of ethyl 2-(3-(tert-butylperoxy)-2-oxoindolin-3-
yl)acetate instead of rearrangement, only isobutylene removal
was observed (Scheme 2, 2g). In addition, the rearrangement
reaction tolerated a wide variety of electron-withdrawing
substituents as well to give products (2h−2k) in very good
yield (Scheme 2). The reaction of C3-substituted-6-chloro-2-
oxindole derivatives gives a moderate yield of the product 2l
and 2m (starting material recovered). The low yield of the
product is may be due to electronic destabilization by negative
inductive effect of the chlorine. Moreover, N-protected peroxy
compound reacted smoothly to afford rearranged product 2n
in very good yield (Scheme 2).
commenced our investigation with the 3-benzyl-3-(tert-
butylperoxy)indolin-2-one 1a as a model molecule for the
rearrangement. In control experiments, 1a in acetonitrile
(MeCN) was stirred at room temperature and 100 °C in the
absence of an acid source, which did not provide any product
(Table 1, entries 1 and 2). Next, in the presence of 10 mol %
Sc(OTf)3, we observed only the removal of the tert-butyl group
from 1a to afford hydroperoxy compound 3a (52%) and no
rearranged product 2a at room temperature (Table 1, entry 3).
However, when increasing the temperature to 100 °C, we
observed two products, rearranged 2a and deprotected 3a in a
40% and 49% isolated yield, respectively, with the liberation of
isobutylene in 16 h (Table 1, entry 4). The structure of the
compound was unambiguously characterized by single-crystal
X-ray diffraction. Next, the use of Ag(OTf) did not afford any
product or byproduct formation (Table 1, entry 5). The
copper triflate provided 28% yield of the rearranged product 2a
and 51% yield of the deprotected compound 3a. Among the
different Lewis acids used, Sn(OTf)2 was noticeably better, in
terms of selectivity and yield (Table 1, entry 8). To our delight,
the rearranged product 2a was achieved using Brønsted acid,
Amberlyst-15 with a comparable yield to that of Lewis acid
(Table 1, entry 12). The selection of Amberlyst-15 for the
rearrangement is rational, because it is mild, easy to measure,
safe to handle, and easily separable at the end of the reaction.
Interestingly, in contrast to Sn(OTf)2 when FeCl3 was used as
Lewis acid source with 1a, we observed Hock rearrangement,
Furthermore, 3-aryl-3-((2-phenylpropan-2-yl)peroxy)-
indolin-2-one derivatives 4 afforded (Z)-2-arylidine-2H-benzo-
[b][1,4]oxazin-3(4H)-one compound in moderate to good
yield with the removal of α-methylstyrene (Scheme 3)
B
DOI: 10.1021/acs.orglett.9b00155
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Letter
a
Scheme 2. Substrate Scope for Rearrangement of Peroxide
Figure 2. Emission spectra for the selected compounds in DMSO.
compared to 2k. The prepared compounds could be employed
as a fluorescent motif to understand the complex mode of
action in the biological processes.10−12
To shed light on the reaction parameters, a model reaction
was performed with 3-(tert-butylperoxy)-3-methylindolin-2-
one and 3-hydroperoxy-3-methylindolin-2-one, which does not
afford any rearranged product. Next, the reaction of 0.25 mmol
of 3-benzhydryl-3-(tert-butylperoxy)indolin-2-one with Sn-
(OTf)2 (10 mol %) provided a complicated reaction mixture
(Scheme 4). Above studies indicate the need of the −(CH2)−
Scheme 4. Experiments for Mechanistic Studies
a
Reaction conditions: 0.25 mmol (1a), Sn(OTf)2 (10 mol %) or
Amberlyst-15 (w/w ratio to the substrate) in a 2 mL acetonitrile was
b
heated at 100 °C for 16 h in a sealed tube. 20 mol % of Sn(OTf)2
was used and heated for 36 h. The mentioned yields are isolated
yields.
Scheme 3. Substrate Scope for the Rearrangement of
a
Peroxide 4 with the Removal of α-Methyl Styrene
group at the C3-position of peroxyoxindole (except entry 2e).
Next, 3-benzyl-3-(tert-butylperoxy)indolin-2-one was subjected
to established reaction conditions and a gaseous component of
the reaction mixture was analyzed using GC-MS. The GC-MS
spectra indicated m/e = 56, which corresponds to the
isobutylene gas (see Figure S1 in the Supporting Information
(SI)). A parallel reaction was performed with labeled (1a′),
and unlabeled peroxy (1a) compound and a normal primary
kinetic isotope effect (KIE) of 1.75 was detected, representing
that a H atom transfer is involved in the rate-determining step
(Figures S5 and S6 in the SI).18
a
Reaction conditions: 0.25 mmol (4), Amberlyst-15 (w/w ratio to the
substrate) in a 2 mL acetonitrile was heated at 100 °C for 16 h in a
sealed tube.
(starting material recovered). To show the utility of the
synthesized compounds, we have recorded emission spectra for
the selected compounds (Figure 2). The compound displayed
a fluorescent emission band at ∼430−450 nm (2k, 454 nm; 2a,
452 nm; 2f, 428 nm) in dimethylsulfoxide (DMSO) solvent.
The fluorescent emission band for 2f, 2a showed a bath-
ochromic shift (of ∼26 nm). This shift is attributed to the
presence of extended conjugation in the aromatic rings,
To gain insight into the reaction mechanism, the hydro-
peroxy compound 3a was prepared separately and subjected to
standard reaction conditions. The expected product 2a was
isolated with a 86% yield which suggests that the reaction
C
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Letter
Accession Codes
proceeded via 3a as an intermediate. Furthermore, the reaction
of Sn(OTf)2 and 3-benzyl-3-(tert-butylperoxy)indolin-2-one in
acetonitrile-d3 was performed in an NMR tube. The notable
peaks was observed at 6.82, singlet which belongs to alkene C−
H of arylidine product 2a. Moreover, at 4.66 ppm (septet) and
1.71 (triplet) was also observed, which arises due to the
presence of isobutylene (see Figure S2 in the SI).
Based on the experimental results and previous literature
reports,16a,b,17 a plausible reaction mechanism for Sn-catalyzed
rearrangement is illustrated in Figure 3. Mechanistically, the
CCDC 1889817 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: gnanaprakasam@iiserpune.ac.in.
ORCID
Boopathy Gnanaprakasam: 0000-0002-3047-9636
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the DST-SERB, (No. EMR/
2014/000700) and Council of Scientific and Industrial
Research [No. 02(0296/17/EMR-II)], India. M.B.C. thanks
IISER-Pune for a research fellowship. B.G. thanks SERB and
CSIR-India for the financial support.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00155.
Experimental procedures and spectroscopic data for the
compounds (PDF)
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