DBU/O2-Mediated Oxidation of Dienones

Article abstract of DOI:10.1021/acs.joc.1c00529

Herein, we describe a DBU/O₂-promoted novel method for oxidation of dienones to 2,6-dione derivatives. The reaction involves treatment of a dienone with DBU in acetonitrile employing molecular oxygen as the oxidant. Metal free conditions and an eco-friendly reagent are the striking features of this protocol. This transformation proceeds through a peroxide intermediate that upon Kornblum-DeLaMare rearrangement produces 2,6-diones. The method was successfully utilized for the synthesis of (±)-pleodendione with improved yields versus those of the traditional PDC-TBHP method.

Full text of DOI:10.1021/acs.joc.1c00529

pubs.acs.org/joc
Note
DBU/O2‑Mediated Oxidation of Dienones
Paresh R. Athawale,∥ Hanuman P. Kalmode,∥ and D. Srinivasa Reddy*
Cite This: J. Org. Chem. 2021, 86, 9200−9205
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Herein, we describe a DBU/O2-promoted novel
method for oxidation of dienones to 2,6-dione derivatives. The
reaction involves treatment of a dienone with DBU in acetonitrile
employing molecular oxygen as the oxidant. Metal free conditions
and an eco-friendly reagent are the striking features of this protocol.
This transformation proceeds through a peroxide intermediate that
upon Kornblum−DeLaMare rearrangement produces 2,6-diones.
The method was successfully utilized for the synthesis of ( )-pleodendione with improved yields versus those of the traditional
PDC-TBHP method.
we wanted to perform a double bond migration reaction in
compound 1 to obtain compound 1a.
n organic synthesis, the discovery of new methods for allylic
Ioxidation is an ever developing active area. Generally, a
double bond present in the system activates the allylic carbon
hydrogen bond that aids in the selective installation of the
oxygen functionality.1 These types of reactions are fundamen-
tal methods for allylic functionalization and have a great impact
on the synthetic chemistry of molecules having commercial
value.2,3 In natural product synthesis, allylic oxidation is greatly
important, and to date, a variety of reagents and conditions
have been reported. However, there are certain limitations in
terms of productivity and chemo- and regioselectivity because
of the structural diversity of natural products.
When the reaction was conducted under the standard
protocol using DBU as a base in CH3CN, we observed
compound 2a in ∼5% yield in addition to expected product 1a
(Scheme 1A). This was quite surprising because no oxidant or
metal catalyst was utilized in this reaction. Thus, the only
possible oxygen source could be dissolved oxygen from the
solvent. To confirm this, we conducted two control experi-
ments, one reaction under a completely inert atmosphere of
Scheme 1. Background
Conventionally, reagents based on chromium(VI) such as
pyridinium chlorochromate (PCC), pyridinium dichromate
(PDC), PDC-tert-butyl hydroperoxide, the CrO3-pyridine
complex, CrO3 and 3,5-dimethylpyrazole, sodium chromate,
sodium dichromate in acetic acid, pyridinium fluorochromate,
3,5-dimethylpyrazolium fluorochromate, and a combination of
an N-hydroxydicarboxylic acid imide with a chromium-
containing oxidant have been used to perform allylic
oxidations.4 Manganese dioxide, potassium permanganate,
and selenium dioxide are the other classical methods that
use a stoichiometric amount of the reagent.5 However, these
reagents have become less preferred for industrial scale
production based on the quantities of reagents required, the
volume of solvent used, and tedious workup procedures of the
environmentally hazardous metal residues and/or byproducts.
Other catalytic methods involve rhodium, iron, copper, cobalt,
and palladium as catalysts, most of which are costly, toxic, and
avoided in the final stages of API synthesis.2
Received: March 4, 2021
Published: June 18, 2021
Although various allylic oxidations have been reported in the
literature,6 the development of metal free, eco-friendly
synthetic transformations is highly desirable.7 In this context,
while we were working on the synthesis of the peribysin family
of natural products,8 we made an interesting observation when
https://doi.org/10.1021/acs.joc.1c00529
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 9200−9205
9200

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
nitrogen and another reaction in the presence of oxygen. To
our delight, the reaction under a nitrogen atmosphere
exclusively gave double bond migrated compound 1a while
the reaction under an oxygen atmosphere exclusively furnished
oxygenated compound 2a (Scheme 1B). This experiment
confirmed that oxygen acted as an oxidant in this reaction. A
similar kind of observation was made by P. L. Fuchs et al. using
DBU and oxygen in CH3CN (Scheme 1C).9 However, the
corresponding conjugated compound (B) did not give an
oxidized product even after heating at 60 °C. Thus, to confirm
this, we applied this method on our substrate 1a having a
conjugated system. At 60 °C, only a trace amount of product
was observed, but when the temperature was increased to 80
°C, a 94% yield of the diketo product 2a was isolated. This
unoptimized condition was previously employed by our group
for the synthesis of ( )-periconianone A.10
enones to 1,4-enediones, and very recently, the Wang group
reported a highly step and atom economic Pd/Cu combination
for accessing 1,4-enediones under aerobic conditions.12
Therefore, the optimal reaction condition for the preparation
of 2,6-dione derivatives (2a) was found to be DBU as a base
and molecular O2 as the oxidant in acetonitrile at the reflux
temperature.
Considering the importance of this method in total
synthesis12 and to explore the generality of this protocol for
the synthesis of 2,6-dione derivatives (2a), various dienones
(1) synthesized using known procedures13 were examined
under the optimized reaction conditions (Table 2). Trienone
(1b) via the allylic oxidation reaction under optimized
conditions gave compound 2b in a good yield (78%). The
oxidation reaction of epimerized trienone and epoxy dienones
(1c and 1d) went smoothly to afford the corresponding
products (2c and 2d, respectively) in 75% and 44% yields,
respectively. The regioselective allylic oxidation of dienones
(1e−h) having alkenyl, ester, hydroxy alkenyl, and benzyl
substituents on a decalin skeleton resulted in good to moderate
yields (48−79%) of diketones (2e−h). Although the structure
of diketone 2h was proposed on the basis of NMR analysis, it
was further confirmed by X-ray analysis (see Table 2 for the
ORTEP diagram).
Inspired with this result in hand and considering the
presence of a naphthalene-2,6-dione skeleton in natural
products,11 we decided to optimize this method and test it
with various substrates (selected natural products are captured
in Figure 1). For this purpose, compound 1a was chosen as a
Encouraged by these results in hand, we extended the scope
of the reaction to the extended trienone of hexahydroan-
thracene (1i) and found that along with allylic oxidation
hydroxylation was observed (2i, 52%), which was confirmed by
1H and 13C NMR in which one of the quaternary carbons at δ
66.5 was observed (no further studies were performed to
determine the stereochemistry of the new quaternary center).
Additionally, the substrate scope was extended to an alicyclic
system such as α-ionone and β-ionone. In both cases, we
observed the formation of dione (2j) in 76% and 68% yields,
respectively. It means α-ionone was converted to β-ionone first
and then allylic oxidation occurred.
Figure 1. Natural products having 2,6-dione functionality.
Similarly, in the case of aliphatic dienone 1k, the reaction
proceeded smoothly to give 2k in 48% yield. In addition, the
reaction of ethyl sorbate and deconjugated ethyl sorbate under
optimized conditions gave a moderate yield of the product
(2l). Here, it is interesting to note that natural product
( )-pleodendione (2m) was obtained in 67% isolated yield
compared to our previous report using the conventional PDC-
TBHP method (46%) (Scheme 2).13 An ionic mechanism was
proposed on the basis of the literature reports and control
experiments (see the Supporting Information).14
In summary, we have developed a mild and efficient method
for the oxidation of dienones to form 2,6-diones, which might
find application in the synthesis of natural products and
bioactive molecules. Additionally, employing inexpensive DBU
as the base and O2 (balloon) as the oxidant makes this reaction
more practical and sustainable. The method was successfully
applied for the synthesis of ( )-pleodendione with an
improved yield. Further synthetic exploration of this method
is underway in our laboratory.
model substrate. In our preliminary observations, we obtained
desired product 2a in 46% yield along with <10% formation of
8-hydroxy dienone (2a′) and the starting material (1a, 45%)
was recovered (Table 1, entry 2). To further optimize the
reaction condition, we increased the amount of DBU (1.5−2.5
equiv) and observed the formation of 2a in 94% yield (Table 1,
entries 3 and 4). To check the possibility of a further increase
in the yield of 2a, various solvents such as 1,4-dioxane, THF,
EtOAc, and DMSO were screened (Table 1, entries 5−8,
respectively). The use of 1,4-dioxane and EtOAc as the solvent
resulted in a moderate to low yield of 2a, 49% and 18%,
respectively, along with recovery of the starting material
(entries 5 and 7, respectively). A trace amount of 2a was
formed in THF, whereas in the case of DMSO, decomposition
of the starting material was observed (entries 6 and 8). 1,2-
Dichloroethane and toluene gave a low yield of 2a, while in
DMF, the product was not formed (entries 9−11).
Various bases such as NMM, DIPEA, and DABCO were also
used for the allylic oxidation reaction (Table 1, entries 12−14,
respectively). However, using these bases, no product
formation was observed, and only the starting material was
recovered. We also tried the reaction of dienone (1a) without
the use of base, but in that case, only the starting material was
recovered (entry 15). Only a trace amount of tetrahydronaph-
thalene-2,6-dione (2a) was observed by oxidation of dienone
(1a) using Pearlman’s catalyst (entry 16). Corey’s group has
explored this highly selective method for the oxidation of α,β-
EXPERIMENTAL SECTION
■
General Information. All reactions were carried out in oven-
dried glassware under a positive pressure of argon or nitrogen unless
otherwise mentioned with magnetic stirring. Air sensitive reagents and
solutions were transferred via syringe or cannula and introduced into
the apparatus via rubber septa. All reagents, starting materials, and
solvents were obtained from commercial suppliers and used as such
9201
https://doi.org/10.1021/acs.joc.1c00529
J. Org. Chem. 2021, 86, 9200−9205

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
a
Table 1. Optimization of Reaction Conditions
c
yield (%)
entry
catalyst/base (equiv)
promoter/oxidant (equiv)
solvent
temp (°C)
time (h)
2a
28
36
46
94
49
1a
2a′
1
2
3
4
5
6
7
8
−
PDC (5)/TBHP (5)
−
−
−
−
−
−
−
−
−
−
−
−
−
−
benzene
CH3CN
CH3CN
CH3CN
1,4-dioxane
THF
rt
16
12
6
−
<10
<5
ND
<5
DBU (1.5)
DBU (2.5)
DBU (2.5)
DBU (2.5)
DBU (2.5)
DBU (2.5)
DBU (2.5)
DBU (2.5)
DBU (2.5)
DBU (2.5)
NMM (2.5)
DIPEA (2.5)
DABCO (2.5)
−
reflux
reflux
reflux
80
reflux
reflux
80
80
80
80
reflux
reflux
reflux
reflux
rt
45
32
ND
46
12
12
12
12
12
12
12
12
12
12
12
12
12
trace
18
∼92
77
decomposed
ND
trace
EtOAc
DMSO
1,2-DCE
toluene
DMF
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
9
4
9
90
86
ND
trace
10
11
12
13
14
decomposed
trace
ND
ND
ND
trace
90
98
95
98
91
ND
ND
ND
ND
ND
b
15
16
Pd(OH)2/C (0.05), K2CO3 (0.5)
TBHP (5)
a
Reaction conditions: dienone (1a, 1.0 mmol), catalyst (0.05 mmol) or base (0.5−2.5 mmol) or oxidant (5 mmol) and promoter (5 mmol),
solvent (10 mL) stirred at rt to reflux for 6−12 h under an oxygen atmosphere. Abbreviations: PDC, pyridinium dichromate; TBHP, tert-butyl
hydroperoxide; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; NMM, N-methylmorpholine; DIPEA, N,N-diisopropylethylamine; DABCO, 1,4-
diazabicyclo[2.2.2]octane; ND, not detected. In the absence of a catalyst or base. Isolated yields.
b
c
Table 2. Scope of the Method
a
The carbonyl group/OH group is from the reaction with DBU, and O2 is colored blue.
without further purification. Reactions were monitored by thin layer
chromatography (TLC) with 0.25 mm precoated silica gel plates (60
F254). Visualization was accomplished either with UV light or by
immersion in an ethanolic solution of phosphomolybdic acid (PMA),
p-anisaldehyde, 2,4-DNP, a KMnO4 solution, or iodine adsorbed on
silica gel followed by heating with a heat gun for ∼15 s. Column
chromatography was performed on silica gel (100−200 or 230−400
mesh). Melting points were determined using a Bruker capillary
melting point apparatus and are uncorrected. S*/R* nomenclature is
used to show the relative stereochemistry of the product. Deuterated
solvents for NMR spectroscopic analyses were used as received. All
1H and 13C NMR spectra were recorded using a Jeol/Bruker 400
MHz or Bruker 500 MHz spectrometer. Coupling constants are
reported in hertz. Chemical shifts are quoted in parts per million,
relative to TMS, using the residual solvent peak as a reference
standard. The following abbreviations were used to explain the
9202
https://doi.org/10.1021/acs.joc.1c00529
J. Org. Chem. 2021, 86, 9200−9205

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
(1aR*,7R*,7aR*,7bR*)-7,7a-Dimethyl-1a,7,7a,7b-
tetrahydronaphtho[1,2-b]oxirene-2,6-dione (2d). Purified by silica
gel column chromatography (77:23 petroleum ether/ethyl acetate):
isolated yield of 0.045 g, 44%; yellowish oily liquid; IR υmax (film)
2919, 1710, 1676, 1463, 1215, 1094 cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.13 (d, J = 8.0 Hz, 1 H), 6.21 (d, J = 12.0 Hz, 1 H), 6.02
(s, 1 H), 3.68 (d, J = 3.6 Hz, 1 H), 3.48 (dd, J = 3.2, 2.0 Hz, 1 H),
2.74 (q, J = 7.2 Hz, 1 H), 1.36 (s, 3 H), 1.35 (d, J = 7.2 Hz, 3 H);
13C{1H} NMR (100 MHz, CDCl3) δ 197.9, 191.4, 157.1, 142.6,
Scheme 2. Synthesis of ( )-Pleodendione
131.8, 124.4, 60.76, 54.2, 49.3, 40.8, 19.0, 7.6; HRMS (ESI) m/z [M
+ H]+ calcd for C12H13O3 205.0859, found 205.0858.
multiplicities: br s, broad singlet; s, singlet; d, doublet; dd, doublet of
doublets; t, triplet; td, triplet of doublets; q, quartet; m, multiplet.
HRMS (ESI) spectra were recorded on an ORBITRAP mass analyzer
(Thermo Scientific, QExactive). Infrared (IR) spectra were recorded
on an FT-IR spectrometer as a thin film. The chemical nomenclature
was generated using Chem Bio Draw Ultra 14.0.
(1R*,7R*,8aR*)-7-Allyl-1,8a-dimethyl-1,7,8,8a-tetrahydronaph-
thalene-2,6-dione (2e). Purified by silica gel column chromatography
(75:25 petroleum ether/ethyl acetate): isolated yield of 0.094 g, 61%;
light yellow solid; IR υmax (film) 2922, 1718, 1665, 1612, 1580, 1388,
1161 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.01 (d, J = 9.6 Hz, 1 H),
6.22 (d, J = 10.0 Hz, 1 H), 6.05 (s, 1 H), 5.83−5.73 (m, 1 H), 5.12−
5.07 (m, 2 H), 2.77−2.72 (m, 1 H), 2.64−2.47 (m, 2 H), 2.21 (dd, J
= 14.6, 8.4 Hz, 1 H), 2.14 (dd, J = 13.0, 5.2 Hz, 1 H), 1.70 (t, J = 13.6
Hz, 1 H), 1.17 (s, 3 H), 1.14 (d, J = 6.4 Hz, 3 H); 13C{1H} NMR
(100 MHz, CDCl3) δ 199.8, 199.6, 158.7, 142.1, 135.5, 132.0, 128.8,
117.3, 52.2, 41.4, 40.4, 39.9, 33.5, 18.6, 6.9; HRMS (ESI) m/z [M +
H]+ calcd for C15H19O2 231.1380, found 231.1378.
General Procedure for the Oxidation of Dienones. Into a
stirred solution of 1a−m (1 mmol, 1 equiv) in dry acetonitrile (10
mL) was bubbled oxygen gas for 10 min at room temperature. DBU
(2.5 mmol, 2.5 equiv) was added dropwise, and the reaction mixture
was refluxed for a period of 6−24 h (using an oil bath as the heating
source) under an O2 atmosphere. The reaction mixture was diluted
with ice-cold water (20 mL) and extracted with EtOAc (3 × 30 mL).
The combined organic layers were washed with water, dried over
Na2SO4, filtered, and concentrated to give the crude product that was
purified by column chromatography (ethyl acetate/petroleum ether)
to afford 2a−m in 30−94% yield.
Ethyl 2-[(8aR*)-8,8a-Dimethyl-3,7-dioxo-3,7,8,8a-tetrahydro-
naphthalen-2-yl]acetate (2f) (dr 7:3). Purified by silica gel column
chromatography (70:30 petroleum ether/ethyl acetate): isolated yield
of 0.086 g, 63%; yellowish oily liquid; IR υmax (film) 2976, 1730, 1662,
1
1632, 1452, 1256, 1163, 1027 cm−1; H NMR (400 MHz, CDCl3) δ
(1R*,8aR*)-1,8a-Dimethyl-1,7,8,8a-tetrahydronaphthalene-2,6-
dione (2a). Purified by silica gel column chromatography (80:20
petroleum ether/ethyl acetate): isolated yield of 0.122 g, 94%; off-
7.28−7.20 (m, 1 H), 7.03 (s, 0.3 H), 6.73 (s, 0.7 H), 6.55 (s, 0.7 H),
6.45 (s, 0.3 H), 6.28 (d, J = 9.8 Hz, 0.3 H), 6.16 (d, J = 9.8 Hz, 0.7
H), 4.19−4.13 (m, 2 H), 3.48−3.29 (m, 2 H), 2.64 (q, J = 6.7 Hz, 1
H), 1.38 (s, 2 H), 1.33 (d, J = 6.7 Hz, 1 H), 1.29−1.23 (m, 4 H), 0.96
(d, J = 7.3 Hz, 2 H); 13C{1H} NMR (100 MHz, CDCl3) δ 201.2,
198.3, 184.8, 184.2, 170.7, 170.6, 157.5, 154.8, 152.5, 151.2, 142.3,
142.1, 133.8, 132.7, 131.2, 130.3, 129.1, 128.3, 60.9, 52.4, 49.5, 45.1,
44.3, 34.9, 34.6, 29.6, 27.9, 22.3, 15.5, 14.1, 7.8; HRMS (ESI) m/z [M
+ H]+ calcd for C16H19O4 275.1283, found 275.1292.
1
white solid; IR υmax (film) 1655, 1607, 1574, 755 cm−1; H NMR
(400 MHz, CDCl3) δ 7.05 (dd, J = 0.6, 9.9 Hz, 1 H), 6.20 (d, J = 9.9
Hz, 1 H), 6.08 (s, 1 H), 2.68 (d, J = 15.6 Hz, 1 H), 2.46−2.32 (m, 3
H), 2.26 (dd, J = 4.0, 6.4 Hz, 1 H), 1.17−1.14 (m, 3 H), 1.01 (d, J =
6.5 Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.6, 197.8,
158.7, 143.6, 131.6, 129.6, 48.9, 41.7, 39.7, 39.0, 18.4, 14.6; HRMS
(ESI) m/z [M + H]+ calcd for C12H15O2191.1067, found 191.1064.
(4R,4aS)-6-Hydroxy-4,4a-dimethyl-4,4a,5,6-tetrahydronaphtha-
len-2(3H)-one (2a′). Purified by silica gel column chromatography
(72:28 petroleum ether/ethyl acetate): isolated yield of 0.148 g; pale
(1R*,7R*,8aR*)-7-[(R*)-But-3-en-2-yl]-7-hydroxy-1,8a-dimethyl-
1,7,8,8a-tetrahydronaphthalene-2,6-dione (2g). Purified by silica
gel column chromatography (80:20 petroleum ether/ethyl acetate):
isolated yield of 0.089 g, 48%; off-white solid; IR υmax (film) 3412,
1
yellow liquid; IR υmax (film) 3378, 2958, 1651, 1287, 1041 cm−1; H
1
1720, 1666 cm−1; H NMR (400 MHz, CDCl3) δ 7.04 (d, J = 10.0
NMR (400 MHz, CDCl3) δ 6.29−6.11 (m, 2 H), 5.79 (s, 1 H), 4.54
(br s, 1 H), 2.39−2.30 (m, 3 H), 2.16−2.04 (m, 1 H), 1.69−1.60 (m,
1 H), 1.07 (s, 3 H), 1.01 (d, J = 6.9 Hz, 3 H); 13C{1H} NMR (100
MHz, CDCl3) δ 199.5, 161.5, 140.1, 128.5, 125.2, 66.1, 43.1, 41.6,
38.6, 37.9, 16.5, 14.8; HRMS (ESI) m/z [M + H]+ calcd for
C12H17O2 193.1228, found 193.1228.
(8aR*)-1,8a-Dimethyl-1,8a-dihydronaphthalene-2,6-dione (2b)
(dr 7:3). Purified by silica gel column chromatography (75:25
petroleum ether/ethyl acetate): isolated yield of 0.114 g, 78%;
colorless solid; IR υmax (film) 2973, 1653, 1625, 1452, 1215 cm−1; 1H
NMR (400 MHz, CDCl3) δ 7.28−7.11 (m, 1.2 H), 6.82 (d, J = 9.8
Hz, 1 H), 6.53 (s, 0.7 H), 6.45−6.38 (m, 1.2 H), 6.28 (d, J = 9.8 Hz,
0.3 H), 6.17 (d, J = 9.8 Hz, 1 H), 2.67−2.60 (m, 1 H), 1.37 (s, 2 H),
1.35−1.31 (m, 1 H), 1.24 (s, 1 H), 0.94 (d, J = 7.3 Hz, 2 H); 13C{1H}
NMR (100 MHz, CDCl3) δ 201.2, 198.3, 185.8, 185.2, 157.5, 154.8,
154.5, 153.3, 142.5, 142.4, 131.2, 131.0, 129.5, 129.1, 128.9, 128.5,
52.2, 49.5, 45.0, 44.3, 29.6, 28.0, 15.6, 7.8; HRMS (ESI) m/z [M +
H]+ calcd for C12H13O2 189.0910, found 189.0907.
(1S*,8aR*)-1,8a-Dimethyl-1,8a-dihydronaphthalene-2,6-dione
(2c). Purified by silica gel column chromatography (75:25 petroleum
ether/ethyl acetate): isolated yield of 0.093 g, 75%; white solid; IR
υmax (film) 2974, 1667, 1649, 1618, 1597, 1452, 1307, 1187 cm−1; 1H
NMR (400 MHz, CDCl3) δ 7.21 (d, J = 12.0 Hz, 1 H), 6.81 (d, J =
12.0 Hz, 1 H), 6.53 (s, 1 H), 6.42 (d, J = 12.0 Hz, 1 H), 6.16 (d, J =
12.0 Hz, 1 H), 2.63 (q, J = 8.0 Hz, 1 H), 1.37 (s, 3 H), 0.94 (d, J = 8.0
Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ 201.2, 185.9, 154.8,
154.5, 142.5, 131.1, 129.6, 129.1, 52.3, 45.0, 28.1, 15.6; HRMS (ESI)
m/z [M + H]+ calcd for C12H13O2 [M + H]+ 189.0916, found
189.0925.
Hz, 1 H), 6.25 (d, J = 10.0 Hz, 1 H), 6.18 (s, 1 H), 5.98−5.89 (m, 1
H), 5.22 (d, J = 10.8 Hz, 1 H), 5.16 (d, J = 16.8 Hz, 1 H), 3.49 (q, J =
7.6 Hz, 1 H), 2.79−2.73 (m, 1 H), 2.61 (q, J = 6.8 Hz, 1 H), 2.33 (s, 1
H), 2.06−1.95 (m, 1 H), 1.26 (s, 3 H), 1.18 (d, J = 6.8 Hz, 3 H), 0.95
(d, J = 6.0 Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ 200.1,
199.7, 160.5, 141.7, 137.6, 132.4, 127.9, 117.5, 75.5, 52.1, 45.9, 40.3,
39.5, 22.8, 14.6, 7.3; HRMS (ESI) m/z [M + Na]+ calcd for
C16H20O3Na 283.1305, found 283.1298.
(1R*,8aR*)-5-Benzyl-1,8a-dimethyl-1,7,8,8a-tetrahydronaphtha-
lene-2,6-dione (2h). Purified by silica gel column chromatography
(70:30 petroleum ether/ethyl acetate): isolated yield of 0.075 g, 79%;
colorless solid; IR υmax (film) 2971, 1716, 1663, 1599, 1492, 1453,
1
1317, 1183 cm−1; H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 10.4
Hz, 1 H), 7.29−7.27 (m, 2 H), 7.21 (d, J = 6.8 Hz, 1 H), 7.14 (d, J =
7.2 Hz, 2 H), 6.23 (d, J = 9.6 Hz, 1 H), 3.89 (s, 2 H), 2.66−2.64 (m, 3
H), 2.13 (d, J = 12.8 Hz, 1 H), 2.04 (dd, J = 12.0, 7.2 Hz, 1 H), 1.23
(s, 3 H), 1.18 (d, J = 6.4 Hz, 3 H); 13C{1H} NMR (100 MHz,
CDCl3) δ 199.9, 197.5, 153.7, 139.4, 139.3, 137.4, 131.5, 128.6 (2C),
127.9 (2C), 126.2, 52.4, 40.9, 33.6, 33.4, 30.3, 17.8, 6.9; HRMS (ESI)
m/z [M + H]+ calcd for C19H21O2 281.1542, found 281.1544.
(1R*,9aR*)-8a-Hydroxy-1,9a-dimethyl-1,7,8,8a,9,9a-hexahy-
droanthracene-2,6-dione (2i). Purified by silica gel column
chromatography (65:35 petroleum ether/ethyl acetate): isolated
yield of 0.069 g, 52%; pale yellow solid; IR υmax (film) 3409, 2923,
1647, 1596, 1452, 1323, 1260, 1218 cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.03 (d, J = 9.2 Hz, 1 H), 6.41 (s, 1 H), 6.14 (d, J = 9.6 Hz,
1 H), 5.91 (s, 1 H), 2.89 (td, J = 15.6, 5.2 Hz, 1 H), 2.52 (s, 1 H),
2.48−2.43 (m, 1 H), 2.19 (d, J = 14.8 Hz, 2 H), 2.06 (dd, J = 13.4, 4.4
9203
https://doi.org/10.1021/acs.joc.1c00529
J. Org. Chem. 2021, 86, 9200−9205

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
Hz, 2 H), 1.71 (d, J = 14.0 Hz, 1 H), 1.34 (s, 3 H), 1.15 (d, J = 6.8
Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ 200.4, 199.4, 153.1,
149.8, 142.8, 129.5, 129.0, 126.5, 66.5, 53.3, 47.2, 40.6, 37.5, 33.1,
20.9, 7.1; HRMS (ESI) m/z [M + H]+ calcd for C16H19O3 259.1329,
found 259.1327.
Integrated Medicine, Jammu 180001, India; orcid.org/
0000-0003-3270-315X; Phone: 0191-2584999, 2585222;
Email: reddy.ds@iiim.res.in, ds.reddy@ncl.res.in;
Fax: 0191-2586333
(E)-2,4,4-Trimethyl-3-(3-oxobut-1-en-1-yl)cyclohex-2-en-1-one
(2j). Purified by silica gel column chromatography (80:20 petroleum
ether/ethyl acetate): isolated yield of 0.146 g, 68%; yellowish oily
liquid; IR υmax (film) 2962, 1694, 1666, 1613, 1353, 1312, 1249, 1174
cm−1; 1H NMR (400 MHz, CDCl3) δ 7.17 (d, J = 16.4 Hz, 1 H), 6.11
(d, J = 16.4 Hz, 1 H), 2.45 (t, J = 7.2 Hz, 2 H), 2.28 (s, 3 H), 1.82 (t, J
= 6.8 Hz, 2 H), 1.72 (s, 3 H), 1.12 (s, 6 H); 13C{1H} NMR (100
MHz, CDCl3) δ 198.3, 197.2, 157.6, 140.1, 133.4, 131.1, 37.1, 35.3,
33.9, 27.7, 27.1 (2C), 13.2; HRMS (ESI) m/z [M + H]+ calcd for
C13H19O2 207.1380, found 207.1378.
Authors
Paresh R. Athawale − Organic Chemistry Division, CSIR-
National Chemical Laboratory, Pune 411008, India;
Academy of Scientific and Innovative Research (AcSIR),
Ghaziabad 201002, India; orcid.org/0000-0001-6157-
9704
Hanuman P. Kalmode − Organic Chemistry Division, CSIR-
National Chemical Laboratory, Pune 411008, India;
orcid.org/0000-0002-1577-5103
Ethyl (2E,4E)-6-Oxohexa-2,4-dienoate (2k) (see ref 15 for
literature data). Purified by silica gel column chromatography
(70:30 petroleum ether/ethyl acetate): isolated yield of 0.080 g, 48%;
yellowish oily liquid; IR υmax (film) 2957, 2853, 1716, 1690, 1642,
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00529
1
1603, 1461, 1367, 1272, 1178, 1095, 1030, 969, 764 cm−1; H NMR
Author Contributions
(400 MHz, CDCl3) δ 9.68 (d, J = 8.0 Hz, 1 H), 7.42 (dd, J = 15.6,
11.2 Hz, 1 H), 7.17 (dd, J = 15.2, 11.2 Hz, 1 H), 6.43 (dd, J = 15.2,
8.0 Hz, 1 H), 6.31 (d, J = 15.2 Hz, 1 H), 4.27 (q, J = 7.2 Hz, 2 H),
1.33 (t, J = 7.6 Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ 192.9,
165.4, 147.2, 140.3, 136.9, 129.9, 61.1, 14.2; HRMS (ESI) m/z [M +
Na]+ calcd for C8H10O3Na 177.0522, found 177.0516.
(3E,5E)-Nona-3,5-diene-2,7-dione (2l) (see ref 16 for literature
data). Purified by silica gel column chromatography (85:15
petroleum ether/ethyl acetate): isolated yield of 0.165 g, 30% (90%
brsm); pale yellow liquid; IR υmax (film) 2927, 1678, 1590, 1251
cm−1; 1H NMR (400 MHz, CDCl3) δ 7.24−7.08 (m, 2 H), 6.57−6.39
(m, 2 H), 2.64 (q, J = 7.3 Hz, 2 H), 2.33 (s, 3 H), 1.14 (t, J = 7.3 Hz,
3 H); 13C{1H} NMR (100 MHz, CDCl3) δ 200.2, 197.7, 139.8,
138.6, 136.6, 135.9, 34.5, 29.7, 27.8; HRMS (ESI) m/z [M + Na]+
calcd for C8H10O3Na 177.0522, found 177.0516.
∥P.R.A. and H.P.K. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge the Council of Scientific and
Industrial Research (CSIR), New Delhi, for its financial
support through the Mission Mode Project (HCP0008) and
Dr. Rajesh Gonnade, Mr. Samir Shaikh, and Dr. Rama Krishna
Rao Gamidi of the Center for Materials Characterization
(CSIR-NCL, Pune) for single-crystal X-ray analysis. H.P.K.
thanks SERB for the award of National Postdoctoral
Fellowship PDF/2016/001638. P.R.A. thanks CSIR, New
Delhi, for the award of a Senior Research Fellowship.
(1R*,7S*,8aR*)-7-Isopropyl-1,8a-dimethyl-1,7,8,8a-tetrahydro-
naphthalene-2,6-dione (2m). Purified by silica gel column
chromatography (78:22 petroleum ether/ethyl acetate): isolated
yield of 0.107 g, 67%; colorless oil; IR υmax (film) 2925, 1721,
REFERENCES
■
1
1665, 1580, 1461, 1386, 1208 cm−1; H NMR (400 MHz, CDCl3) δ
(1) (a) White, M. C. C-H Bond Functionalization & Synthesis in the
21st Century: A Brief History and Prospectus. Synlett 2012, 23,
2746−2748. (b) Wencel-Delord, J.; Dröge, T.; Liu, F.; Glorius, F.
Towards mild metal-catalyzed C-H bond activation. Chem. Soc. Rev.
2011, 40, 4740−4761. (c) Bergman, R. G. C-H activation. Nature
2007, 446, 391−393. (d) Shilov, A. E.; Shul’pin, G. B. Activation of
C-H Bonds by Metal Complexes. Chem. Rev. 1997, 97, 2879−2932.
(2) Weidmann, V.; Maison, W. Allylic Oxidations of Olefins to
Enones. Synthesis 2013, 45, 2201−2221.
7.0 (d, J = 9.6 Hz, 1 H), 6.22 (d, J = 9.6 Hz, 1 H), 6.03 (s, 1 H),
2.65−2.57 (m, 2 H), 2.40−2.34 (m, 1 H), 2.01 (dd, J = 13.0, 4.8 Hz,
1 H), 1.77 (t, J = 13.6 Hz, 1 H), 1.26 (s, 3 H), 1.16 (d, J = 2.4 Hz, 3
H), 1.00 (d, J = 7.2 Hz, 3 H), 0.86−0.84 (m, 3 H); 13C{1H} NMR
(100 MHz, CDCl3) δ 200.1, 199.9, 158.2, 142.2, 131.9, 129.5, 52.3,
47.2, 40.1, 34.2, 25.8, 20.1, 18.4, 17.6, 7.0; HRMS (ESI) m/z [M +
H]+ calcd for C15H21O2 233.1536, found 233.1533.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00529.
(3) Nakamura, A.; Nakada, M. Allylic Oxidations in Natural Product
Synthesis. Synthesis 2013, 45, 1421−1451.
■
sı
(4) (a) Dauben, W. G.; Lorber, M.; Fullerton, D. S. Allylic Oxidation
of Olefins with Chromium Trioxide-Pyridine Complex. J. Org. Chem.
1969, 34, 3587−3592. (b) Salmond, W. G.; Barta, M. A.; Havens, J. L.
Allylic Oxidation with 3,5-Dimethylpyrazole. Chromium Trioxide
Complex. Steroidal Δ5-7-Ketones. J. Org. Chem. 1978, 43, 2057−
2059. (c) Parish, E. J.; Wei, T. Y. Allylic Oxidation of Δ5-Steroids with
Pyridinium Chlorochromate (PCC) and Pyridinium Dichromate
(PDC). Synth. Commun. 1987, 17, 1227−1233. (d) Chidambaram,
N.; Chandrasekaran, S. tert-Butyl Hydroperoxide-Pyridinium Dichro-
mate: A Convenient Reagent System for Allylic and Benzylic
Oxidations. J. Org. Chem. 1987, 52, 5048−5051. (e) Marshall, C.
W.; Ray, R. E.; Laos, I.; Riegel, B. 7-Keto Steroids. II. Steroidal 3β-
Hydroxy-Δ5-7-ones and Δ3,5-7-Ones. J. Am. Chem. Soc. 1957, 79,
6308−6313. (f) Amann, A.; Ourisson, G.; Luu, B. Stereospecific
Syntheses of the Four Epimers of 7,22-dihydroxycholesterol. Synthesis
1987, 1987, 1002−1005. (g) Bora, U.; Chaudhuri, M. K.; Dey, D.;
Kalita, D.; Kharmawphlang, W.; Mandal, G. C. 3,5-Dimethylpyr-
azolium fluorochromate(VI), C5H8N2H[CrO3F], (DmpzHFC): a
convenient new reagent for oxidation of organic substrates.
Tetrahedron 2001, 57, 2445−2448.
1H and 13C NMR spectra of all compounds (PDF)
Accession Codes
CCDC 1988574 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
■
D. Srinivasa Reddy − Organic Chemistry Division, CSIR-
National Chemical Laboratory, Pune 411008, India;
Academy of Scientific and Innovative Research (AcSIR),
Ghaziabad 201002, India; CSIR-Indian Institute of
9204
https://doi.org/10.1021/acs.joc.1c00529
J. Org. Chem. 2021, 86, 9200−9205

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
(5) Hudlicky, M. Oxidations in Organic Chemistry; ACS Monograph
Series 186; American Chemical Society: Washington, DC, 1990; p
174 and references cited therein.
(16) Raap, J.; Nieuwenhuis, S.; Creemers, A.; Hexspoor, S.; Kragl,
U.; Lugtenburg, J. Synthesis of Isotopically Labelled L-Phenylalanine
and L-Tyrosine. Eur. J. Org. Chem. 1999, 1999, 2609−2621.
(6) Bulman, P. C.; McCarthy, T. J. In Comprehensive Organic
Synthesis, Vol. 7; Trost, B. M., Fleming, I., Paquette, L. A., Eds.;
Pergamon Press: Oxford, U.K., 1991; pp 83−117.
(7) Adam, W.; Saha-Möller, C. R.; Ganeshpure, P. A. Synthetic
Applications of Nonmetal Catalysts for Homogeneous Oxidations.
Chem. Rev. 2001, 101, 3499−3548.
(8) Athawale, P. R.; Kalmode, H. P.; Motiwala, Z.; Kulkarni, K. A.;
Reddy, D. S. Overturning the Peribysin Family Natural Products
Isolated from Periconia byssoides OUPS-N133: Synthesis and
Stereochemical Revision of Peribysins A, B, C, F, and G. Org. Lett.
2020, 22, 3104−3109.
(9) Jin, Z.; Fuchs, P. L. A Highly Efficient Synthesis of β-Substituted
Six- and Seven-Membered-Ring Enones via Carbon Alkylation of γ-
Methoxy Allylsulfonyl Anions. J. Am. Chem. Soc. 1994, 116, 5995−
5996.
(10) (a) Kalmode, H. P.; Patil, S. S.; Handore, K. L.; Athawale, P. R.;
Dandela, R.; Verma, A. K.; Basu, A.; Reddy, D. S. Neural Anti-
Inflammatory Natural Product Periconianone A: Total Synthesis and
Biological Evaluation. Eur. J. Org. Chem. 2019, 2019, 2376−2381.
(b) Liffert, R.; Linden, A.; Gademann, K. Total Synthesis of the
Sesquiterpenoid Periconianone A Based on a Postulated Biogenesis. J.
Am. Chem. Soc. 2017, 139, 16096−16099.
(11) (a) Yuyama, K. T.; Fortkamp, D.; Abraham, W.-R.
Eremophilane-type sesquiterpenes from fungi and their medicinal
potential. Biol. Chem. 2017, 399, 13−28. (b) Liu, J.; Zhang, D.;
Zhang, M.; Zhao, J.; Chen, R.; Wang, N.; Zhang, D.; Dai, J.
Eremophilane Sesquiterpenes from an Endophytic Fungus Periconia
Species. J. Nat. Prod. 2016, 79, 2229−2235. (c) Peixoto, P. A.;
Cormier, M.; Ekosso Epane, J.; Jean, A.; Maddaluno, J.; De Paolis, M.
Metal-free aerobic C-H oxidation of cyclic enones. Org. Chem. Front.
2014, 1, 748−754. (d) Peixoto, P. A.; Jean, A.; Maddaluno, J.; De
Paolis, M. Formal Enantioselective Synthesis of Aplykurodinone-1.
Angew. Chem., Int. Ed. 2013, 52, 6971−6973. (e) Xu, J.; Ji, C.; Zhang,
Y.; Su, J.; Li, Y.; Tan, N. Inhibitory activity of eudesmane
sesquiterpenes from Alpinia oxyphylla on production of nitric oxide.
Bioorg. Med. Chem. Lett. 2012, 22, 1660−1663.
(12) (a) Yu, J.-Q.; Corey, E. J. A Mild, Catalytic, and Highly
Selective Method for the Oxidation of α,β-Enones to 1,4-Enediones. J.
Am. Chem. Soc. 2003, 125, 3232−3233. (b) Zhao, B.; Zhang, X.; Guo,
R.; Wang, M.; Gao, Y.; Wang, Y. Aerobic Oxidative Dehydrogenation
of Ketones to 1,4-Enediones. Org. Lett. 2021, 23, 1216−1221.
(13) (a) Handore, K. L.; Jadhav, P. D.; Hazra, B.; Basu, A.; Reddy,
D. S. Total Syntheses and Biological Evaluation of ( )-Botryosphaer-
idione, ( )-Pleodendione, 4-epi-Periconianone B, and Analogues.
ACS Med. Chem. Lett. 2015, 6, 1117−1121. For synthesis of
compound 1k, see: (b) Zou, Y.; Garayalde, D.; Wang, Q.; Nevado, C.;
Goeke, A. Gold-Catalyzed Cycloisomerization of Cyclopropyl Alkynyl
Acetates: A Versatile Approach to 5-, 6-, and 7-Membered
Carbocycles. Angew. Chem., Int. Ed. 2008, 47, 10110−10113.
(14) (a) Kornblum, N.; DeLaMare, H. E. The base catalyzed
decomposition of a dialkyl Peroxide. J. Am. Chem. Soc. 1951, 73, 880−
881. (b) Staben, S. T.; Linghu, X.; Toste, F. D. Enantioselective
Synthesis of γ-Hydroxyenones by Chiral Base-Catalyzed Kornblum
DeLaMare Rearrangement. J. Am. Chem. Soc. 2006, 128, 12658−
12659. (c) Novkovic, L.; Trmcic, M.; Rodic, M.; Bihelovic, F.; Zlatar,
M.; Matovic, R.; Saicic, R. N. Synthesis of endoperoxides by domino
reactions of ketones and molecular oxygen. RSC Adv. 2015, 5, 99577.
(d) Chen, B. C.; Zhou, P.; Davis, F. A.; Ciganek, E. Org. React. 2003,
62, 1. (e) Li, M.; Chen, B.; Monteiro, S.; Rustum, A. M. Mechanism
of base-catalyzed autooxidation of corticosteroids containing 20-keto-
21-hydroxyl side chain. Tetrahedron Lett. 2009, 50, 4575.
(15) Han, X.; Zhou, Z.; Wan, C.; Xiao, Y.; Qin, Z. Co(acac)2-
catalyzed allylic and benzylic oxidation by tert-butyl hydroperoxide.
Synthesis 2013, 45, 615−620.
9205
https://doi.org/10.1021/acs.joc.1c00529
J. Org. Chem. 2021, 86, 9200−9205