Sn-Catalyzed Criegee-Type Rearrangement of Peroxyoxindoles Enabled by Catalytic Dual Activation of Esters and Peroxides

Article abstract of DOI:10.1021/acs.joc.9b03160

We report here the Sn-catalyzed mild protocol for ring expansion of peroxyoxindoles to afford the series of substituted-2H-benzo[b][1,4]oxazin-3(4H)-one derivatives. In this protocol, we showed the in situ conversion of tert-butyl peroxy compounds into peresters with the aid of external esters, which then underwent the ring-expansion process, and the incipient carbocation was trapped with the alcohol residue generated from the esters. The reaction is also demonstrated in a continuous flow process to afford the rearranged product in 22 min of residence time.

Full text of DOI:10.1021/acs.joc.9b03160

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Sn-Catalyzed Criegee-Type Rearrangement of Peroxyoxindoles
Enabled by Catalytic Dual Activation of Esters and Peroxides
Moreshwar B. Chaudhari, Krishna Jayan, and Boopathy Gnanaprakasam*
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ABSTRACT: We report here the Sn-catalyzed mild protocol for
ring expansion of peroxyoxindoles to afford the series of
substituted-2H-benzo[b][1,4]oxazin-3(4H)-one derivatives. In
this protocol, we showed the in situ conversion of tert-butyl
peroxy compounds into peresters with the aid of external esters,
which then underwent the ring-expansion process, and the
incipient carbocation was trapped with the alcohol residue
generated from the esters. The reaction is also demonstrated in a
continuous flow process to afford the rearranged product in 22 min
of residence time.
scope, and lack of mechanistic aspects preclude these reports
from blossoming. Notably, the reported protocols9d−g does not
comment on mechanistic insights. In our case, the ring
expansion of 3-(tert-butylperoxy)-3-methylindolin-2-one or 3-
hydroperoxy-3-methylindolin-2-one was not selective or was
not successful in the presence of Brønsted acid or catalyst. For
that reason, we envisioned that the readily available esters can
be employed as a source of an acyl group for the in situ
generations of peresters and will facilitate the rearrangement
reaction. The use of peresters has been successfully employed
for the Criegee rearrangement, which proceeds via the ion-pair
mechanism.10
To this context, we report here, the Sn-catalyzed in situ
conversion of tert-butyl peroxy compounds into peresters with
the aid of inexpensive and readily available external esters,
which then underwent ring-expansion process, and incipient
carbocation was trapped with the alcohol residue, which was
generated from the esters. The key step involves dual activation
of ester as well as of peroxide using Sn-catalyst. The formation
of a stable C−O bond is attributed to the stereoelectronic
effect, which involves a favorable overlap of donor C-3−C-3a σ
bond of substituted-2-oxindole with acceptor O−O σ* orbital.
In the course of our studies, we discovered dichotomy with
Criegee rearrangement, viz. absence of assistance by the lone
pair of the oxygen atom.
INTRODUCTION
■
Rearrangement reactions contribute to the construction of
complex organic skeletons and convenient retrosynthetic
strategies by exploiting challenging bond-breaking or new
bond-forming abilities.1 Accordingly, the rearrangement of
organic peroxides plays a pivotal role in the chemical,
industrial, and biological processes.2 In particular, the
rearrangement of electron-deficient oxygen has been exten-
sively studied for the Baeyer−Villiger (BV),3 Criegee,4 and
other rearrangements.5 The application of the rearrangement
of peroxides is profoundly ranging from the conversion of a
ketone to ester or in the ring expansion.3
The family of 2-oxindole derivatives can be used for
inhibiting the PDK1/Akt signaling pathway.6 In the Poaceae,
the 2-oxindole serves as a precursor in the biosynthesis of
cyclic hydroxamic acids. The 1,4-benzoxazin-3-one scaffolds
epitomize the secondary metabolites and play a decisive role in
the biosynthetic pathway of plant defense mechanism in
grasses.7 Apart from this, the 1,4-benzoxazin-3-ones show a
structural resemblance with many natural products and
bioactive molecules (Figure 1).8
The incorporation of peroxide moiety or other functionality
on the substituted-2-oxindole or indole derivatives makes them
an intriguing precursor for rearrangement reactions.9 In the
literature, the reaction of C2 and C3 substituted indole with
singlet oxygen generated the 3-hydroperoxy-1,3-dimethyl-2-
phenylindoline, which on treatment with HCl and methanol
provides 2-methoxy-2,4-dimethyl-3-phenyl-3,4-dihydro-2H-
benzo[b][1,4]oxazine. Very recently, Zhong and co-workers
reported the TsOH·H2O mediated alkoxylation of 3a-(tert-
butylperoxy)-1-tosyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]-
indole to afford tricyclic core (Scheme 1). The use of a
stoichiometric amount of corrosive acid, restriction in substrate
Received: November 25, 2019
Published: January 30, 2020
https://dx.doi.org/10.1021/acs.joc.9b03160
© 2020 American Chemical Society
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Figure 1. Substituted-2H-benzo[b][1,4]oxazin-3(4H)-one derivatives possessing biological activity.
Scheme 1. Criegee-Type Rearrangement of Peroxides: Prior Arts and This Work
of acetate ester is necessary for a reaction to undergo in the
forward direction. The structure of the rearranged product was
unambiguously characterized by single-crystal XRD technique.
The use of Sc(OTf)3 only produced 24% of rearranged
product 3a (Table 1, entry 8). However, use of AgOTf and
Pd(TFA)2 was ineffective to produce the rearranged product
3a (Table 1, entry 9, 10). In the presence of FeCl3, the
rearranged product 3a was observed in 45% yield in 53 h
(Table 1, entry 11). In the case of 5 mol % of Sn(OTf)2, poor
yield and selectivity was observed (Table 1, entry 12). To our
delight, use of 10 mol % Sn(OTf)2 and 1 mL of ethyl acetate
was found to be the best catalyst in terms of yield and
selectivity to produce the rearranged product 3a in 89%
isolated yield (Table 1, entry 13). Moreover, the use of
Amberlyst-15 was rational since it is mild, non corrosive, easy
to handle, and can be easily separable at the end of the
reaction. Thus, the reaction of 1 with Amberlyst-15 in the
presence of 1 mL ethyl acetate afforded rearranged product 3a
in 85% yield (Table 1, entry 14).
With these optimized conditions in hand, we next
concentrated on the generality of this rearrangement (Scheme
2). A variety of esters that are used in fragrances, flavoring
agents, and common solvent were smoothly reacted with 3-
(tert-butylperoxy)-3-methylindolin-2-one (1a) to produce
rearranged products 3a−3h in good to excellent yield (Scheme
2). Notably, the reaction underwent smoothly by installing the
Phenyl group on the 2-oxindole part. In particular, the reaction
RESULTS AND DISCUSSION
■
In the previous literature, peresters have been successfully
employed as a precursor for Criegee rearrangement.10 Hence,
we envisioned the in situ generations of 3-methyl-2-
oxoindolin-3-yl ethaneperoxoate (perester). For this purpose,
a readily available, eco-friendly, naturally abundant feedstock
chemical, ethyl acetate was chosen as a model substrate. In
literature, the reactions of ethyl acetate/ester were commenced
by an corrosive acid catalyst such as H2SO4, and TsOH for
transesterification;11 however, the use of strong acids may
affect other sensitive functionalities in the substrate. Therefore,
we were interested in finding the catalyst which should
perform the multiple roles: (i) assist for removal of
isobutylene, (ii) activation of ester, and (iii) weakens the
peroxide O−O bond. In the control experiment, the reaction
of 3-(tert-butylperoxy)-3-methylindolin-2-one and 1 mL of
ethyl acetate in the absence of any catalyst at room
temperature or 60 °C did not afford even traces of product
3a (Table 1, entries 1, 2). Other acids such as hydrochloric
acid, triflic acid and p-toluenesulfonic acid was not efficient or
selective (Table 1, entries 3−5). These experiments suggest
the non pH dependence of rearrangement reaction.
Next, to use the minimal amount of ethyl acetate, the
reaction of 1 with 10 mol % of Sn(OTf)2 with two equivalents
and ten equivalents of ethyl acetate in THF solvent afforded
15% and 24% yield of the product 3a, respectively (Table 1,
entries 6−7). These results indicated that the use of an excess
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a
acetate and butyl acetate afforded rearranged products 3j and
3k in 90% and 81% yield, respectively (Scheme 2).
Table 1. Optimization for the Rearrangement of Peroxide
Gratifyingly, the reaction of cyclohexyl acetate and menthyl
acetate with peroxide (1a), provided 37% and 19% yield of
(3l) and (3m) respectively and the major amount of
hydroperoxy (4a) was recovered back (Scheme 2). The
decrease in the yield of product in the case of secondary esters
might be due to steric factors. Apart from the steric factor, it
might be also due to the leaving group effect of the alkoxy
group of ester. Primary alkoxy is better leaving group than
secondary and tertiary alkoxy which is due to the electronic
factor. The electronegativity of the oxygen decreases while
increasing the alkyl substitution. Thus results in lowering the
yield of the reaction. The reaction of aromatic acetates with
peroxide (1a) delivered decent yields to afford rearranged
products (3n) and (3o), respectively. Surprisingly, in the NMR
spectrum, two types of signals were observed for (3n). These
signals may arise due to the presence of equilibrium form
between 3n and benzyl alcohol. To get clarity, we have grown
the crystal for 3n and evidenced the structure by single-crystal
XRD, NMR, and HRMS. In the case of 3o, the presence of 3-
phenylpropan-1-ol was detected by NMR and GC-MS (see
Supporting Information, (SI), Figure S1).
entry
catalyst
temp (°C)
yield [%] 1:3a:4a
1
2
3
4
5
none
none
rt
no reaction
no reaction
no reaction
00:15:20
00:00:79
00:15:70
60
60
60
60
60
60
60
60
60
60
60
60
60
TsOH
triflic acid
hydrochloric acid
Sn(OTf)2
Sn(OTf)2
Sc(OTf)3
AgOTf
Pd(TFA)2
FeCl3
Sn(OTf)2
Sn(OTf)2
Amberlyst-15
b
6
7
c
00:24:62
8
9
55:24:traces
no reaction
no reaction
00:45:38
10:25:45
00:89:09
10
11
12
d
e
13
14
f
00:85:10
a
Reaction conditions: All reactions were carried out at 50 mg of 1a in
ethyl acetate (1 mL) using 10 mol % of catalyst at a specified
The use of other green solvents such as dimethyl carbonate
and diethyl carbonate also afforded rearrangement reaction
with moderate yield (Scheme 3). Next, the outcome of a
reaction was investigated by replacing one of the methyl
substituents on peroxide with a −Ph group. Remarkably, the
reaction of 3-methyl-3-((2-phenylpropan-2-yl)peroxy)indolin-
2-one with ethyl acetate preceded efficiently to offer the
rearranged product (3a) in 94% yield (Scheme 3). The
reaction of butyl butyrate with 1a afforded product 3d in 72%
isolated yield. Unfortunately, the reaction of 1a with tert-butyl
acetate and benzyl benzoate does not afford the desired
temperature for 14 h in a resealable tube. In the case of triflic acid and
b
hydrochloric acid, 1−2 drops of acid was used. 2 equiv of ethyl
c
acetate in THF solvent. 10 equiv of ethyl acetate in THF solvent.
d
e
f
Heated for 53 h. 5 mol % of (SnOTf)2, (w/w ratio × 2) of
substrate/Amberlyst-15 was taken. The mentioned yields are isolated
yields.
of 3-(tert-butylperoxy)-3-phenylindolin-2-one with ethyl ac-
etate afforded 2-ethoxy-2-phenyl-2H-benzo[b][1,4]oxazin-
3(4H)-one (3i) in 73% isolated yield. Similarly, the reaction
of 3-(tert-butylperoxy)-3-phenylindolin-2-one with methyl
a
Scheme 2. Substrate Scope for the Rearrangement of Peroxides Using Various Acetates
a
Reaction condition: 0.2 mmol of starting material peroxide 1, 10 mol % of Sn(OTf)2, in 1 mL ester (2) was heated at 60 °C for 14 h in a
b
resealable tube. Heated at 80 °C. The mentioned yields are isolated yields.
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intermediate for a rearrangement to occur. Furthermore, to
gain insights into the mechanistic aspects, the gaseous
component of a reaction mixture was subjected to GC-MS
analysis, and we observed m/e = 56 owing to the formation of
isobutylene gas (Scheme 4, eq 3) (see SI, Figure S2).
Scheme 3. Substrate Scope for the Rearrangement by
Varying the Peroxide and Ester Part
a
Furthermore, the reaction of 1a with butyl butyrate under
standard conditions afforded product 3d and butanoic acid
(detected by GC-MS, m/e = 88) (Scheme 4, eq 4) (see SI,
Figure S3). Moreover, the reaction of 4a with ethyl acetate in
the presence of Sn(OTf)2 afforded the desired product in 89%
yield (Scheme 4, eq 5). Furthermore, 3-methyl-2-oxoindolin-3-
yl ethaneperoxoate (3a′) was synthesized separately and
reacted with ethanol and isotope-labeled methanol (CD3-
OD) under standard conditions, which provided rearranged
product 3a and 3b′ in 80% and 75% yield (Scheme 4, eq 6 and
7). The reaction of 1a with isotopically labeled acetate (octyl-
1,1-d2 acetate) proceeded smoothly to afford 2-methyl-2-
((octyl-1,1-d2)oxy)-2H-benzo[b][1,4]oxazin-3(4H)-one (3g′)
in 72% yield with 64.5% deuterium incorporation (Scheme 4,
eq 8). The above experiments prove that the 3a′ is a key
intermediate in this transformation.
a
Reaction condition: 0.2 mmol of starting material peroxide 1, 10 mol
% of Sn(OTf)2, in 1 mL ester (2) was heated at 60 °C for 14 h in a
resealable tube.
On the basis of experimental evidence and literature reports,
we posit the mechanism for a novel rearrangement reaction
(Scheme 5).12,13 Initially, the coordination of Sn(OTf)2 with
ester may lead to form the Sn-chelated ester (B). On the other
hand, the coordination of another molecule of Sn(OTf)2 with
peroxide (D) assists in the removal of olefin (liberation of
isobutylene detected by GC-MS) leads to offer hydroperoxide
(F). The intermediate (F) is originated after removal of
isobutylene followed by reaction of TfOH with the O-chelated
Sn-complex (E) to afford the Sn(OTf)2. The perester (G) is
formed by the attack of peroxide (F) on chelated ester (B).
Interestingly, the ring expansion (H) is attributed to the
formation of stable C−O bond through favorable overlap of
donor C(3)−C(3a) σ bond with acceptor O−O σ* orbital.
After bond migration, carboxylic acid leaves, and the catalyst is
regenerated for the next cycle. During this process, the
carbocation (H) is generated, which is trapped by an in situ
formed alcohol group to afford the rearranged product (I).
Overall, this concerted reaction involves ester activation-
deprotection-acylation-bond migration-trapping of a carboca-
tion in a cascade fashion.
product. On the other hand, in case of phenyl benzoate there
was no reaction under the standard reaction conditions
(Scheme 3). In the case of C3-benzyl substituted 2-oxindole
under the standard reaction condition result in aryl migration
followed by deprotonation to form the previously reported
rearranged product.9c
The rearrangement reaction proceeded smoothly with
heterogeneous Brønsted acid, Amberlyst-15 (Table 1, entry
14). Accordingly, to establish the heterogeneous version, we
have chosen Amberlyst-15, since it is selective, mild, safe,
reusable and easy to pack and remove from a packed bed
reactor. The parameters from batch reaction were transformed
for this rearrangement reaction to continuous flow. The
Vapourtec R-series reactor was used, and a continuous flow
setup was fixed according to reaction parameters.
To get the better yield and selectivity, two glass columns
(Omnifit, 6.6 × 150 mm) were packed with Amberlyst-15 (1
g) and telescoped. Later, the solution of 1a (0.1 M) in 5 mL
ethyl acetate flowed through the packed bed reactors with the
flow rate of 0.2 mL/min to afford rearranged product 3a in
84% yield with residence time (tR) = 22 min (Figure 2).
To shed light on the mechanism, the reaction of 1a and 4a
with ethanol instead of ethyl acetate was performed in the
presence of Amberlyst-15 or Sn(OTf)2, in which the desired
product 3a is not observed (Scheme 4, eq 1 and 2). This
experiment clearly puts emphasis on the need of the perester
CONCLUSIONS
■
In conclusion, we have discovered a novel rearrangement of
peroxides for the construction of valuable substituted-2H-
benzo[b][1,4]oxazin-3(4H)-one. The in situ formation of key
intermediate viz. perester has been accomplished by using
readily available esters as a source of an acetyl group.
Moreover, the carbocation is trapped by an in situ generated
alcohol group. The heterogeneous version of the current
reaction is established by integrating the supported catalyst in a
continuous flow to obtain the expedient synthesis of
rearranged products in 22 min of residence time. Future
efforts will be made to understand the more detailed
theoretical and mechanistic aspects of this rearrangement.
EXPERIMENTAL SECTION
■
General Information and Data Collection. All the solvents
used were dry grade and stored over 4 Å molecular sieves. The
acetates were brought from Sigma-Aldrich, Rankem, and AVRA
chemicals. Deuterated solvents were used as received. Column
chromatographic separations performed over 100−200 Silica-gel.
Figure 2. Continuous flow setup for rearrangement reaction.
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Scheme 4. Experiments for Mechanistic Studies
Visualization was accomplished with UV light and PMA, CAM stain
followed by heating. The Amberlyst-15 (Dry form), Sn(OTf)2 and
other metal triflates were purchased from Sigma-Aldrich. The flow
bath for 14 h. After 14 h, volatile component was evaporated using a
vacuum, and the residue was directly purified by silica gel
chromatography (EtOAc:hexane = 15:85).
1
chemistry experiments were carried on Vapourtec R-series. H and
B. Experimental Procedure for the Rearrangement Reac-
tion Using Amberlyst-15. In a 20 mL resealable vial (equipped
with a stir bar, rubber septum and N2 balloon) was added Amberlyst-
15 (Dry) (100 mg) (substrate to Amberlyst-15 weight ratio of 1:2),
ethyl acetate (1 mL), and finally, 3-(tert-butylperoxy)-3-methylindo-
lin-2-one (50 mg, 0.21 mmol). The tube was purged with N2 and
sealed with a cap using crimper. The reaction mixture was heated at
60 °C in an oil bath for 14 h. After 14 h, reaction mixture filtered to
remove solid Amberlyst-15. The volatile component was evaporated
using a vacuum and the residue was directly purified by silica gel
chromatography (EtOAc:hexane = 15:85) to afford 3a (37.5 mg,
85%) as a white solid.
13C NMR spectra were recorded on 400 and 100 MHz respectively,
using a Bruker 400 MHz or JEOL 400 MHz spectrometers.
Abbreviations used in the NMR follow-up experiments: b, broad; s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet. High-resolution
mass spectra were recorded with Waters- synapt G2 using
electrospray ionization (ESI). Fourier-transform infrared (FT-IR)
spectra were obtained with a Bruker Alpha-E Fourier transform
infrared spectrometer.
A. General Experimental Procedure for the Rearrangement
Reaction Using Sn(OTf)2. In a 20 mL resealable vial (equipped with
a stir bar, rubber septum and N2 balloon) was added Sn(OTf)2 (0.1
equiv, 10 mol %), ester (1 mL), and finally, peroxy compound (50
mg, 1 equiv). The tube was purged with N2 and sealed with a cap
using crimper. The reaction mixture was heated at 60 °C in an oil
C. Experimental Procedure for 1 mmol Scale. In a 20 mL
resealable vial (equipped with a stir bar, rubber septum and N2
balloon) was added Sn(OTf)2 (0.1 mmol, 41.7 mg, 10 mol %), ethyl
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Scheme 5. Plausible Mechanism for the Rearrangement Reaction
acetate (4 mL), and finally, 3-(tert-butylperoxy)-3-methylindolin-2-
one (1 mmol, 235 mg, 1 equiv). The tube was purged with N2 and
sealed with a cap using a crimper. The reaction mixture was heated at
60 °C in an oil bath for 14 h. After 14 h, a volatile component was
evaporated using a vacuum and the residue was directly purified by
silica gel chromatography (EtOAc:hexane = 15:85) to afford 3a (170
mg, 82%) as a white solid.
D. Experimental Procedure for Detection of Isobutylene
Gas Using GC-MS. In a 20 mL resealable vial (equipped with stir
bar, rubber septum and N2 balloon) was added Sn(OTf)2 (8.9 mg,
0.021 mmol, 10 mol %), ethyl acetate (1 mL), and finally, 3-(tert-
butylperoxy)-3-methylindolin-2-one (50 mg, 0.21 mmol, 1 equiv).
The tube was purged with N2 and sealed with a cap using a crimper.
The reaction mixture was heated at 60 °C in an oil bath for 14 h. After
reaction completion, the gaseous component was taken using the
Gastight syringe and injected into a GC-MS instrument. The presence
of a peak at retention time = 1.55 and m/z = 56 corresponds to
isobutylene gas (Figure S2).
E. Experimental Procedure for the Detection of Butanoic
Acid. In a 20 mL resealable vial (equipped with stir bar, rubber
septum and N2 balloon) was added Sn(OTf)2 (8.9 mg, 0.021 mmol,
10 mol %), butyl acetate (1 mL), and finally, 3-(tert-butylperoxy)-3-
methylindolin-2-one (50 mg, 0.21 mmol, 1 equiv). The tube was
purged with N2 and sealed with a cap using a crimper. The reaction
mixture was heated at 60 °C in an oil bath for 14 h. After reaction
completion, the reaction mixture was injected into a GC-MS
instrument. The presence of a peak at retention time = 8.47 and
m/z = 88 corresponds to butanoic acid (Figure S3).
F. Experimental Procedure for the Synthesis of Octanol-d3
and Octyl-1,1-d2 Acetate. The deuterated benzyl alcohol was
prepared by using the reported procedure with few modifications by
Gunanathan et al.14 In a typical procedure, octanol (7.69 mmol, 1000
mg), Ru-MACHO (0.005 mmol, 3.1 mg), KO-tBu (0.005 mmol, 0.56
mg) were charged in a 20 mL resealable vial, which was equipped with
rubber septum and N2 balloon. The D2O (3 mL) was added using a
syringe and reaction mixture purged with N2, and the tube is sealed
with a cap using a crimper and heated at 80 °C in an oil bath. The
reaction was stopped after 6 h, and the reaction mixture is extracted
with dichloromethane, and the combined organic layers was dried
with Na2SO4. The removal of the solvent under reduced pressure
provided pure products for further reaction. The 1H NMR data
showed 68% deuterium incorporation for octanol-d3. Subsequently, in
a typical procedure, octanol-d3 (7.51 mmol, 1000 mg), acetyl chloride
(9.01 mmol, 707 mg), CoCl2 (0.75 mmol, 97 mg) were added in a
round-bottom flask containing 50 mL of DCM; the reaction mixture
was stirred at room temperature until completion. After reaction
completion, the reaction mixture was quenched by the addition of
water. The organic layer was collected and washed with a solution of
Na2CO3. The volatile component was evaporated using a vacuum,
and the crude reaction mixture was passed through a silica gel column
1
to afford octyl-1,1-d2 acetate 930 mg, 71% yield. The H NMR data
showed 66% deuterium incorporation for octyl-1,1-d2 acetate.
G. Procedure for the Synthesis of 2-Methyl-2-((octyl-1,1-
d2)oxy)-2H-benzo[b][1,4]oxazin-3(4H)-one Using Isotope-La-
beled Ester. In a 20 mL resealable vial (equipped with stir bar,
rubber septum and N2 balloon) was added Sn(OTf)2 (0.021 mmol,
8.75 mg, 10 mol %), octyl-1,1-d2 acetate (1 mL), and finally, 3-(tert-
butylperoxy)-3-methylindolin-2-one (0.21 mmol, 50 mg, 1 equiv).
The tube was purged with N2 and sealed with a cap using a crimper.
The reaction mixture was heated at 60 °C in an oil bath for 14 h. The
residue was directly purified by silica gel chromatography
(EtOAc:hexane = 15:85) to afford 3g′ 42 mg, 72% yield as a white
1
solid. The H NMR data showed 64.5% deuterium incorporation.
Melting Point: 85−86 °C. HRMS (ESI-TOF) m/z (M + Na)+ Calcd
for C17H23D2NO3Na 316.1857, found 316.1856.
H. Procedure for the Synthesis of 2-(Methoxy-d3)-2-methyl-
2H-benzo[b][1,4]oxazin-3(4H)-one Using Deuterated Metha-
nol. In a 20 mL resealable vial (equipped with stir bar, rubber septum
and N2 balloon) was added Sn(OTf)2 (0.018 mmol, 7.5 mg, 10 mol
%), Methanol-d4 (0.75 mL), and finally, 3-methyl-2-oxoindolin-3-yl
ethaneperoxoate (0.18 mmol, 40 mg, 1 equiv). The tube was purged
with N2 and sealed with a cap using a crimper. The reaction mixture
was heated at 60 °C in an oil bath for 14 h. After 14 h, a volatile
component was evaporated using a vacuum, and the residue was
directly purified by silica gel chromatography to afford 2-(methoxy-
d3)-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one 3b′ in 75% isolated
yield. Melting Point: 114−116 °C. HRMS (ESI-TOF) m/z [M + H]+
Calcd for C10H8D3NO3 197.1005, found 197.1001.
I. Analytical Data for the Product. 2-Ethoxy-2-methyl-2H-
benzo[b][1,4]oxazin-3(4H)-one (3a). Prepared according to general
procedure (A), using 3-(tert-butylperoxy)-3-methylindolin-2-one (50
mg, 0.21 mmol) to afford 2-ethoxy-2-methyl-2H-benzo[b][1,4]-
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oxazin-3(4H)-one 3a (39 mg, 89%) as a white solid. Melting Point:
126−128 °C. H NMR (400 MHz, CDCl3) δ 8.84 (bs, 1H), 7.03−
23.61*, 23.06, 23.05*, 19.15, 19.14*, 14.2, 11.2, 11.0*. (The starred
peaks in 13C NMR shows the presence of diastereoisomer). FTIR
(KBr) 3486, 2929, 1693, 1503, 1399, 1242, 1099 cm−1. HRMS (ESI-
TOF) m/z (M + Na)+ Calcd for C17H25NO3Na 314.1732, found
314.1733.
1
6.96 (m, 3H), 6.90−6.85 (m, 1H), 3.74−3.62 (m, 2H), 1.78 (s, 3H),
1.06 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 164.7,
141.7, 126.6, 124.1, 122.9, 117.4, 115.7, 99.3, 58.3, 19.6, 15.3. FTIR
(KBr) 3452, 1712, 1506, 1398, 1246, 1172, 1108, 1046 cm−1. HRMS
(ESI-TOF) m/z [M + Na]+ Calcd for C11H13NO3Na 230.0793, found
230.0795.
2-Methyl-2-(octyloxy)-2H-benzo[b][1,4]oxazin-3(4H)-one (3g).
Prepared according to general procedure (A), using 3-(tert-
butylperoxy)-3-methylindolin-2-one (50 mg, 0.21 mmol) to afford
2-methyl-2-(octyloxy)-2H-benzo[b][1,4]oxazin-3(4H)-one 3g (40
mg, 65%) as a white solid. Melting Point: 88−90 °C. 1H NMR
(400 MHz, CDCl3) δ 9.35 (bs, 1H), 7.02−6.95 (m, 3H), 6.93−6.88
(m, 1H), 3.64−3.54 (m, 2H), 1.78 (s, 3H), 1.45−1.36 (m, 2H),
1.29−1.01 (m, 10H), 0.85 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100
MHz, CDCl3) δ 165.0, 141.7, 126.7, 124.0, 122.8, 117.4, 115.8, 99.1,
62.4, 31.9, 29.6, 29.3, 29.3, 26.0, 22.8, 19.4, 14.2. FTIR (KBr) 3400,
3168, 2326, 1717, 1620, 1502, 1409, 1102 cm−1. HRMS (ESI-TOF)
m/z (M + Na)+ Calcd for C17H25NO3Na 314.1732, found 314.1735.
2-(2-Ethoxyethoxy)-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one
(3h). Prepared according to general procedure (A), using 3-(tert-
butylperoxy)-3-methylindolin-2-one (50 mg, 0.21 mmol) to afford 2-
(2-ethoxyethoxy)-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one 3h
(37.5 mg, 70%) as a light yellow semisolid. Melting Point: 65−67
2-Methoxy-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (3b).
Prepared according to general procedure (A), using 3-(tert-
butylperoxy)-3-methylindolin-2-one (50 mg, 0.21 mmol) to afford
2-methoxy-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one 3b (33.5
1
mg, 82%) as a white solid. Melting Point: 110−112 °C. H NMR
(400 MHz, CDCl3) δ 9.28 (bs, 1H), 7.06−6.97 (m, 3H), 6.93−6.89
(m, 1H), 3.35 (s, 3H), 1.78 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 164.7, 141.5, 126.5, 124.2, 123.0, 117.4, 115.9, 99.3, 49.9,
18.9. FTIR (KBr) 3533, 1699, 1506, 1245, 1171, 1109 cm−1. HRMS
(ESI-TOF) m/z (M + Na)+ Calcd for C10H11NO3Na 216.0637,
found 216.0640.
2-Methyl-2-propoxy-2H-benzo[b][1,4]oxazin-3(4H)-one (3c).
Prepared according to general procedure (A), using 3-(tert-
butylperoxy)-3-methylindolin-2-one (50 mg, 0.21 mmol) to afford
2-methyl-2-propoxy-2H-benzo[b][1,4]oxazin-3(4H)-one 3c (33 mg,
1
°C. H NMR (400 MHz, CDCl3) δ 9.42 (bs, 1H), 7.03−6.95 (m,
1
3H), 6.93−6.87 (m, 1H), 3.81−3.71 (m, 2H), 3.43 (t, J = 5.3 Hz,
2H), 3.39−3.28 (m, 2H), 1.79 (s, 3H), 1.04 (t, J = 7.0 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 164.6, 141.5, 126.6, 124.1,
122.9, 117.4, 115.9, 99.1, 69.1, 66.7, 62.0, 19.5, 15.2. FTIR (KBr)
3427, 1713, 1609, 1504, 1399, 1259, 1124, 1063 cm−1. HRMS (ESI-
TOF) m/z (M + Na)+ Calcd for C13H17NO4Na 274.1055, found
274.1058.
70%) as a white solid. Melting Point: 115−117 °C. H NMR (400
MHz, CDCl3) δ 9.12 (s, 1H), 7.03−6.96 (m, 3H), 6.92−6.87 (m,
1H), 3.56 (qt, J = 8.8, 6.5 Hz, 2H), 1.78 (s, 3H), 1.48−1.39 (m, 2H),
0.69 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 164.8,
141.7, 126.7 124.0, 122.8, 117.4, 115.7, 99.1, 64.0, 22.9, 19.4, 10.5.
FTIR (KBr) 3078, 2925, 1714, 1614, 1505, 1398, 1107 cm−1. HRMS
(ESI-TOF) m/z (M + H)+ Calcd for C12H15NO3 222.1130, found
222.1121.
2-Ethoxy-2-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one (3i). Pre-
pared according to general procedure (A), using 3-(tert-butylperoxy)-
3-phenylindolin-2-one (50 mg, 0.17 mmol) to afford 2-ethoxy-2-
phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one 3i (33 mg, 73%) as a
white solid. Melting Point: 187−188 °C. 1H NMR (400 MHz,
CDCl3) δ 9.00 (bs, 1H), 7.75−7.68 (m, 2H), 7.47−7.39 (m, 3H),
7.16−7.12 (m, 1H), 7.08−6.99 (m, 2H), 6.87−6.84 (m, 1H), 3.61−
3.47 (m, 2H), 1.08 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 163.7, 141.5, 135.1, 129.4, 128.2, 127.9, 126.6, 124.2, 123.1,
117.5, 115.8, 100.6, 59.8, 15.2. FTIR (KBr) 3369, 2847, 1723, 1630,
1502, 1267 cm−1. HRMS (ESI-TOF) m/z (M + Na)+ Calcd for
C16H15NO3Na 292.0950, found 292.0950.
2-Butoxy-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (3d). Pre-
pared according to general procedure (A), using 3-(tert-butylperoxy)-
3-methylindolin-2-one (50 mg, 0.21 mmol) to afford 2-butoxy-2-
methyl-2H-benzo[b][1,4]oxazin-3(4H)-one 3d (36.5 mg, 73%) as a
white solid. Melting Point: 98−100 °C. 1H NMR (400 MHz, CDCl3)
δ 8.98 (bs, 1H), 7.03−6.96 (m, 3H), 6.91−6.85 (m, 1H), 3.65−3.54
(m, 2H), 1.78 (s, 3H), 1.44−1.35 (m, 2H), 1.18−1.07 (m, 2H), 0.76
(t, J = 7.4 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 164.7,
141.7, 126.7, 124.0, 122.8, 117.5, 115.6, 99.1, 62.2, 31.6, 19.4, 19.1,
13.8. FTIR (KBr) 3407, 3224, 2917, 1714, 1619, 1505, 1398, 1105
cm−1. HRMS (ESI-TOF) m/z (M + Na)+ Calcd for C13H17NO3Na
258.1106, found 258.1110.
2-Methyl-2-(pentyloxy)-2H-benzo[b][1,4]oxazin-3(4H)-one (3e).
Prepared according to general procedure (A), using 3-(tert-
butylperoxy)-3-methylindolin-2-one (50 mg, 0.21 mmol) to afford
2-methyl-2-(pentyloxy)-2H-benzo[b][1,4]oxazin-3(4H)-one 3e (38
mg, 72%) as a white solid. Melting Point: 91−92 °C. 1H NMR
(400 MHz, CDCl3) δ 9.50 (bs, 1H), 7.02−6.95 (m, 3H), 6.94−6.89
(m, 1H), 3.64−3.54 (m, 2H), 1.78 (s, 3H), 1.45−1.37 (m, 2H), 1.16
(qd, J = 7.6, 1.4 Hz, 2H), 1.10−1.01 (m, 2H), 0.76 (t, J = 7.2 Hz,
3H). 13C{1H} NMR (100 MHz, CDCl3) δ 165.1, 141.7, 126.7, 124.0,
122.8, 117.4, 115.8, 99.0, 62.4, 29.3, 28.1, 22.4, 19.5, 14.0. FTIR
(KBr) 3452, 2938, 2583, 2363, 1714, 1614, 1504, 1396, 1246, 1102,
cm−1. HRMS (ESI-TOF) m/z (M + Na)+ Calcd for C14H19NO3Na
272.1263, found 272.1268.
2-Methoxy-2-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one (3j).
Prepared according to general procedure (A), using 3-(tert-
butylperoxy)-3-phenylindolin-2-one (50 mg, 0.17 mmol) to afford
2-methoxy-2-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one 3j (38.5 mg,
1
90%) as a white solid. Melting Point: 178−180 °C. H NMR (400
MHz, CDCl3) δ 8.6 (bs, 1H), 7.73−7.68 (m, 2H), 7.48−7.40 (m,
3H), 7.17 (d, J = 7.3 Hz, 1H), 7.12−7.00 (m, 2H), 6.88−6.83 (m,
1H), 3.25 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 163.3, 141.3,
134.2, 129.5, 128.3, 128.0, 126.6, 124.3, 123.3, 117.7, 115.7, 100.6,
51.1. FTIR (KBr) 3420, 3216, 2990, 2856, 1666, 1623, 1506, 1267,
1030 cm−1. HRMS (ESI-TOF) m/z (M + Na)+ Calcd for
C15H13NO3Na 278.0793, found 278.0794.
2-Butoxy-2-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one (3k). Pre-
pared according to general procedure (A), using 3-(tert-butylperoxy)-
3-phenylindolin-2-one (50 mg, 0.17 mmol) to afford 2-butoxy-2-
phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one 3k (40.5 mg, 81%) as a
white solid. Melting Point: 133−135 °C. 1H NMR (400 MHz,
CDCl3) δ 8.43 (bs, 1H), 7.73−7.69 (m, 2H), 7.47−7.41 (m, 3H),
7.15 (dd, J = 7.2, 2.1 Hz, 1H), 7.08−6.99 (m, 2H), 6.86−6.83 (m,
1H), 3.51−3.38 (m, 2H), 1.46−1.38 (m, 2H), 1.22−1.11 (m, 2H),
0.76 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 163.4,
141.5, 134.9, 129.4, 128.2, 128.0, 126.6, 124.1, 123.1, 117.7, 115.5,
100.4, 63.5, 31.6, 19.2, 13.8. FTIR (KBr) 3425, 3301, 3152, 2959,
2930, 1705, 1622, 1506, 1384, 1252 cm−1. HRMS (ESI-TOF) m/z
(M + Na)+ Calcd for C18H19NO3Na 320.1263, found 320.1262.
2-(Cyclohexyloxy)-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one
(3l). Prepared according to general procedure (A), using 3-(tert-
butylperoxy)-3-methylindolin-2-one (50 mg, 0.21 mmol) to afford 2-
2-((2-Ethylhexyl)oxy)-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-
one (3f). Prepared according to general procedure (A), using 3-(tert-
butylperoxy)-3-methylindolin-2-one (50 mg, 0.21 mmol) to afford 2-
((2-ethylhexyl)oxy)-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one 3f
(28 mg, 45%) as a white solid. The obtained compound is
diastereoisomer and distinguished by 13C NMR. Melting Point:
67−69 °C. 1H NMR (400 MHz, CDCl3) δ 8.30 (bs, 1H), 7.03−6.96
(m, 3H), 6.88−6.81 (m, 1H), 3.51−3.42 (m, 2H), 1.78 (s, 3H),
1.34−1.28 (m, 1H), 1.17−1.00 (m, 8H), 0.83−0.76 (m, 3H), 0.73−
0.67 (m, 3H). (The merging of two triplets in between the range of
1
0.83−0.76 and 0.73−0.67 ppm in H NMR shows the presence of
diastereoisomer. By NMR the dr ratio is ∼50:50%). 13C{1H} NMR
(100 MHz, CDCl3) δ 164.3, 141.7, 126.8, 124.0, 122.8, 117.6, 115.4,
99.0, 64.6, 64.3*, 39.50, 39.48*, 30.40, 30.36*, 29.1, 28.9*, 23.65,
3380
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J. Org. Chem. 2020, 85, 3374−3382

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(cyclohexyloxy)-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one 3l
(20.5 mg, 37%) as a white solid. Melting Point: 148−150 °C. H
1707, 1616, 1504, 1404, 1244, 1107 cm−1. HRMS (ESI-TOF) m/z
(M + H)+ Calcd for C18H19NO3 298.1443, found 298.1442.
1
NMR (400 MHz, CDCl3) δ 8.51 (bs, 1H), 7.03−6.95 (m, 3H), 6.87−
6.83 (m, 1H), 3.94−3.84 (m, 1H), 1.80 (s, 3H), 1.73−1.54 (m, 4H),
1.37−1.27 (m, 2H), 1.22−1.01 (m, 4H). 13C{1H} NMR (100 MHz,
CDCl3) δ 164.4, 141.9, 126.6, 124.0, 122.7, 117.6, 115.6, 99.6, 72.2,
34.3, 33.8, 29.85, 25.5, 24.5, 20.2. FTIR (KBr) 3411, 2319, 1714,
1623, 1498, 1402, 1263, 1174 cm−1. HRMS (ESI-TOF) m/z (M +
Na)+ Calcd for C15H19NO3Na 284.1263, found 284.1258.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.9b03160.
■
sı
Copies of 1H and 13C NMR spectra for compounds and
mechanistic studies and crystallographic data (PDF)
Crystallographic data for compound 3a (CIF)
Crystallographic data for compound 3n (CIF)
2-(((1S,2R,5S)-2-Isopropyl-5-methylcyclohexyl)oxy)-2-methyl-
2H-benzo[b][1,4]oxazin-3(4H)-one (3m). Prepared according to
general procedure (A), using 3-(tert-butylperoxy)-3-methylindolin-2-
one (50 mg, 0.21 mmol) to afford 2-(((1S,2R,5S)-2-isopropyl-5-
methylcyclohexyl)oxy)-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one
AUTHOR INFORMATION
Corresponding Author
1
3m (13 mg, 19%) as a white solid. Melting Point: 109−111 °C. H
■
NMR (400 MHz, CDCl3): The compound exist in diastereomeric
1
form. The H NMR values are given for major isomer and marked
Boopathy Gnanaprakasam − Department of Chemistry, Indian
Institute of Science Education and Research, Pune 411008,
India; orcid.org/0000-0002-3047-9636;
Email: gnanaprakasam@iiserpune.ac.in
with X in NMR spectra δ 8.84 (s, 1H), 7.02−6.93 (m, 3H), 6.87−
6.85 (m, 1H), 3.73−3.63 (m, 1H), 2.08−1.99 (m, 2H), 1.84 (s, 3H),
1.62−1.54 (m, 3H), 1.15−0.96 (m, 4H), 0.86 (d, J = 6.5 Hz, 6H),
0.72 (d, J = 6.9 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) Values
are for 2 diastereomers δ 164.2, 163.9, 141.8, 126.6, 125.9, 123.91,
123.88, 122.53, 122.47, 117.8, 117.5, 115.53, 115.46, 99.8, 99.6, 74.55,
74.50, 48.5, 47.8, 43.7, 43.0, 34.3, 34.2, 31.8, 31.7, 29.85, 29.81, 25.3,
24.5, 23.3, 23.2, 22.8, 22.4, 21.7, 21.4, 21.2, 20.0, 16.3, 16.2. FTIR
(KBr) 3361, 2851, 1701, 1506, 1381, 1167 cm−1. HRMS (ESI-TOF)
m/z (M + Na)+ Calcd for C19H27NO3Na 340.1889, found 340.1892.
2-(Benzyloxy)-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (3n).
Prepared according to general procedure (A), using 3-(tert-
butylperoxy)-3-methylindolin-2-one (50 mg, 0.21 mmol) to afford
2-(benzyloxy)-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one 3n (50
mg, 88%) as a white solid. The presence of benzyl alcohol was
detected by using GC-MS and NMR. Interestingly, on TLC
compound shows single spot but when submitted for NMR, then
compound shows two type of protons in NMR. We have assigned one
type of protons for rearranged product 3n and other type of proton
belongs to benzyl alcohol. The structure of the product 3n supported
Authors
Moreshwar B. Chaudhari − Department of Chemistry, Indian
Institute of Science Education and Research, Pune 411008,
India
Krishna Jayan − Department of Chemistry, Indian Institute of
Science Education and Research, Pune 411008, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.9b03160
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the SERB (CRG/2018/
003935), India. M.B.C. thanks CSIR, India and IISER-Pune for
a research fellowship. B.G. thanks IISER-Pune for the research
support.
1
by single crystal XRD and HRMS. Melting Point: 163−165 °C. H
NMR (400 MHz, CDCl3) Values assigned for compound 3n and
benzyl alcohol δ 8.83 (bs, 1H), 7.39−7.35 (m, 4H), 7.33−7.27 (m,
1H), 7.23−7.19 (m, 3H), 7.10−6.98 (m, 5H), 6.89−6.84 (m, 1H),
4.70 (s, 2H belongs to benzyl alcohol), 4.67 (s, 1H, merged with
adjacent peak), 4.65 (d, J = 11.1 Hz, 1H), 1.87 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3) Values assigned for compound 3n and
benzyl alcohol δ 164.2, 141.5, 141.0, 137.1, 128.7, 128.4, 127.8, 127.8,
127.1, 126.7, 124.2, 123.1, 117.5, 115.8, 99.4, 65.5, 64.6, 19.7. FTIR
(KBr) 3415, 2922, 1697, 1612, 1502, 1393, 1168, 1105 cm−1. HRMS
(ESI-TOF) m/z (M + Na)+ Calcd for C16H15NO3Na 292.0950,
found 292.0953.
REFERENCES
■
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2-Methyl-2-(3-phenylpropoxy)-2H-benzo[b][1,4]oxazin-3(4H)-
one (3o). Prepared according to general procedure (A), using 3-(tert-
butylperoxy)-3-methylindolin-2-one (50 mg, 0.21 mmol) to afford 2-
methyl-2-(3-phenylpropoxy)-2H-benzo[b][1,4]oxazin-3(4H)-one 3o
(53 mg, 84%) as a white solid. Interestingly, on TLC compound
shows single spot but when submitted for NMR, then compound
shows two type of protons in NMR. The presence of 3-phenylpropan-
1-ol was detected using GC-MS and NMR. We have assigned one
type of protons for rearranged product 3o and other type of proton
belongs to 3-phenylpropan-1-ol. The structure of the product 3o
1
supported by HRMS data. Melting Point: 121−123 °C. H NMR
(400 MHz, CDCl3) Values assigned for compound 3o and 3-
phenylpropan-1-ol δ 8.67 (bs, 1H), 7.32−7.27 (m, 2H), 7.24−7.24
(m, 6H), 7.18−7.12 (m, 1H), 7.04−6.98 (m, 5H), 6.89−6.86 (m,
1H), 3.69 (t, J = 6.4 Hz, 2H), 3.65−3.57 (m, 2H), 2.72 (t, J = 7.6 Hz,
2H), 2.42 (t, J = 7.6 Hz, 2H), 1.94−1.87 (m, 2H), 1.78 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) Values assigned for compound 3o
and 3-phenylpropan-1-ol δ 164.3, 141.9, 141.8, 141.6, 128.6, 128.5,
128.5, 128.4, 126.6, 126.0, 125.9, 124.2, 123.0, 117.6, 115.6, 99.1,
62.4, 61.5, 34.4, 32.2, 32.1, 31.1, 19.3. FTIR (KBr) 3492, 2925, 2571,
3381
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Oxidation of Phenols with Alkyl Hydroperoxides. A Novel, Facile
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G. I. Oxidation of Cycloalkanones with Hydrogen Peroxide: An
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Dicarboxylic Acid Esters. Tetrahedron 2008, 64, 7944−7948.
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