Stereoselective synthesis of para-quinone monoketals through tri-bromide (TBr) mediated oxidative dearomatization of phenols

Article abstract of DOI:10.1016/j.tetlet.2020.151646

A metal free one-pot stereoselective synthesis of para-quinone monoketals and their derivatives has been reported in this present work. Tri-bromides (TBrs) have been employed as an effective reagent for intramolecular spirocyclizations leading to excellen

Full text of DOI:10.1016/j.tetlet.2020.151646

Tetrahedron Letters xxx (xxxx) xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective synthesis of para-quinone monoketals through
tri-bromide (TBr) mediated oxidative dearomatization of phenols
⇑
Sushree Ranjan Sahoo, Debayan Sarkar
Organic Synthesis and Molecular Engineering Laboratory, Department of Chemistry, National Institute of Technology, Rourkela, Odisha 769008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A metal free one-pot stereoselective synthesis of para-quinone monoketals and their derivatives has been
reported in this present work. Tri-bromides (TBrs) have been employed as an effective reagent for
intramolecular spirocyclizations leading to excellent yields of the monoketals. The TBrs are slowly turn-
ing out to be an important reagent for oxidative dearomatization which is further attested in the pre-
sented work. In addition, the obtained substituted para-quinone monoketals and their derivatives were
readily transformed into more complex products by reaction with Pd/C under hydrogen atmosphere lead-
ing to saturated para-monoacetal, which are important building blocks in organic synthesis.
Ó 2020 Published by Elsevier Ltd.
Received 11 December 2019
Revised 14 January 2020
Accepted 16 January 2020
Available online xxxx
Keywords:
Stereoselective
Spiroquinone monoketal
Oxidative dearomatization
Tribromides
Introduction
spirooxacyclisation of phenols and naphthols towards generation
of the spirocycles [6]. The problem retains with the development
Monoacetal i.e. masked para benzoquinones (MPBs) are effi-
cient building blocks of various biologically and pharmaceutically
active natural products. Some of these natural products are shown
Fig. 1, which were synthesized from masked para benzoquinones
as starting materials [1–3].
of a generalized arene-iodine catalyst which can be applied to a
wide variety of substrate was mentioned by Harned [7]. Some
marked reports in this direction comes from the groups of Ciufolini
[8], Kita [9], Ishihara [10], Ibrahim [11] where hypervalent iodine
reagents have been suitably employed to achieve varied spirooxa-
cycles [10]. Preparation of hypervalent iodine reagents require
presence of oxidative additives and are synthesized in multiple
steps. There have been less successful attempts to develop metal
free protocols towards such transformations. Previously, our group
first recognized PTAB as an effective reagent for dearomatization of
phenols [12]. (Scheme 1b) Based on our previous findings, we
Recentll, Pansare and co-workers reported the total synthesis of
(+)-fistulopsine
B
from 1,4-dioxaspiro[4.5]decan-8-one [1].
Previously, the same group also reported the formal synthesis of
(+)-lasubine II and (À)-subcosine II via organocatalytic Michael
addition of a ketone to
a-nitrostyrene from 1,4-dioxaspiro[4.5]
decan-8-one [2]. Danishefsky accomplished total synthesis of
Jiadifenin molecule from 7-methyl-1,4-dioxaspiro[4.5]decan-8-
one [3].
Masked benzoquinones (MBs), cyclohexa-2,4- and 2,5-dienones
are thus attractive synthons. Transformations such as 1,2- and 1,4-
additions, Diels–Alder reactions, sigmatropic rearrangement etc [4]
are carried out on this benzoquinones. By far, oxidative dearomati-
zation with ortho- and para-alkoxyphenols employing hypervalent
iodine reagents have been the best possible strategies towards
development of these MBs [4]. (Scheme 1a) Recently, Ishihara
reported a chiral hypervalent iodine (III) catalyst in the presence
of co-catalyst meta-chloroperbenzoic acid (m-CPBA) to generate
Masked benzoquinones (MBs) [5]. The last decade has noted a rig-
orous application of hypervalent iodine reagents into dearomative
⇑
Corresponding author.
E-mail address: sarkard@nitrkl.ac.in (D. Sarkar).
Fig. 1. Biologically important natural product synthesized from para-monoketals.
https://doi.org/10.1016/j.tetlet.2020.151646
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Please cite this article as: S. R. Sahoo and D. Sarkar, Stereoselective synthesis of para-quinone monoketals through tri-bromide (TBr) mediated oxidative
dearomatization of phenols, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151646

2
S.R. Sahoo, D. Sarkar / Tetrahedron Letters xxx (xxxx) xxx
Table 1
Optimization of reaction conditionsa for the formation of 4d.
Entry
No.
Solvent
TBr
Base
Yield (%)b
Scheme 1. Reaction design for the synthesis of MBs.
1
2
3
CH3CN
DCM
DCE
I
I
I
K2CO3
66
envisioned that our tri-bromide salts could be applied to the oxida-
tive dearomatization of 4-alkoxy phenols at para-position for the
generation of masked para-benzoquinones (MPBs). (Scheme 1c)
K2CO3 / MeONa
K2CO3 / MeONa
< 55
> 55
Entry No.
Solvent
TBr
Base
Yield (%)b
Results and discussion
1
2
3
4
5
6
7
8
CH3CN
DCM
DCE
Dioxane
MeOH
Et2O
THF
THF
THF
THF
THF
I
I
I
I
I
I
I
I
K2CO3
66
K2CO3/MeONa
K2CO3/MeONa
K2CO3/Cs2CO3
K2CO3
K2CO3/Na2CO3
MeONa/EtONa
Cs2CO3
Pyridine
K2CO3
K2CO3
<55
>55
<72
65
>60
<70
65
<55
70
62
To start with, 4-(2-ethyl-2-hydroxybutoxy)-2-methylphenol 1d
was chosen as a model substrate for the planned reaction. On expo-
sure, the reaction mixture in the presence of PTATB (1 equiv),
K2CO3 (1 equiv) as a base and CH3CN as a solvent, delivered the
desired 2,2-diethyl-7-methyl-1,4-dioxaspiro[4.5]deca-6,9-dien-8-
one 4d at 25 °C with 66% yield (Table 1, entry 1). On screening of
different solvents, bases and TBrs towards the standardization of
the experiments, it was observed that a combination of the TBATB,
K2CO3 and THF as the solvent conveyed the best combination
(Table 1, entry 12).
With the optimized reaction conditions in hand, a variety of
substituted phenols underwent the same transformation which
illustrated a wider substrate scope for the formation of para-1,4-
quinone monoketals. The reaction has been quite general and
delivered for a wide substrate scope of 2-hydroxyphenol. Different
alkyl substituents on branch chain as well as substituents with
electron-donating and withdrawing groups in different sub-
stituents of the aromatic ring smoothly afforded the desired prod-
ucts in high to excellent yields. Substituent like phenyl and benzyl
on branch chain (R1) did not deliver the desired compound due to
enhanced steric hindrance. For para-1,4-quinone monoketals, the
substrate scopes are illustrated in Table 2.
In order to further increase the substrate scope, the synthesis
was further extended to para-1,5-quinone monoketals with opti-
mized reaction conditions and in all cases we were able to found
good yields. Different alkyl substituents on branch chain as well
as alkyl substituents on aromatic ring were afforded good yields.
For para-1,5-quinone monoketals, the substrate scope are illus-
trated in Table 3.
In order to investigate the stereoselectivity synthesis of para-
1,4-quinone monoketals, we were explored racemic 4-((3-ethyl-
3-hydroxypentan-2-yl)oxy)-2-methylphenol 3c, was use as a pri-
mary substrate to check the diastereoselectivity. On exploring
the substrate 3c with PTATB, we were able to found that the
diastereoselectivity of the product para-1,4-quinone monoketals
9
I
I
10
11
12
13
14
15
II
III
IV
V
VI
THF
THF
THF
THF
K2CO3
K2CO3
K2CO3
K2CO3
80
64
68
62
a
Reaction conditions: 1d (0.2 mmol), Base (0.2 mmol), TBr (0.2 mmol), dry sol-
vent (5 mL), for 12 h under a nitrogen atmosphere at 25 °C.
b
Isolated yield after column chromatography.
(6c:6c’), with a ratio of 5:1 and overall yield of 70% (Table 4,
entry-1). On screening of different tri-bromides, delivered TBATB
(III) as the best choice and the overall yield of the product para-
1,4-quinone monoketals (6c:6c’) enhanced to 82% with good
diastereoselectivity of ratio 8:1 (Table 4, entry 3).
With the optimized reaction conditions in hand, different alkyl
substituents on branch chain as well as substituents on aromatic
ring were afforded good yields and good diastereoselectivity. Sub-
stituent like phenyl and benzyl on branch chain (R2) did not deliver
the desired compound due to enhanced steric hindrance but sub-
stituent like homo benzyl on branch chain (R2), was delivered good
diasterioselectivity 6e of ratio 20:1. If there is no substitution on
branch chain (R2), then there was a slight decrease in diasteriose-
lectivity 6a of ratio 6:1. Interestingly, the seemingly stereoselective
para-1,4-quinone monoketals could be easily separated in silica-
gel chromatography. Here we report the major diastereomer as
(3R,5R)/(3S,5S)-spiropara-quinone monoketal. The substrate scope
for the stereoselective synthesis of para-1,4-quinone monoketals
were illustrated in Table 5.
Please cite this article as: S. R. Sahoo and D. Sarkar, Stereoselective synthesis of para-quinone monoketals through tri-bromide (TBr) mediated oxidative
dearomatization of phenols, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151646

S.R. Sahoo, D. Sarkar / Tetrahedron Letters xxx (xxxx) xxx
3
Table 2
Table 4
Substrate scope for synthesis of para-1,4-quinone monoketals.
Optimization of reaction conditionsa for 6c and 6c’.
Entry No.
QATB
dr (6c:6c’)b
Yield (%)c
1
2
3
4
5
6
I
5:1
1:1
8:1
1:1
3:1
1:1
70
62
82
65
68
60
II
III
IV
V
VI
Entry No.
QATB
dr (6c:6c’)b
Yield (%)c
1
2
3
4
5
6
I
II
III
IV
V
5:1
1:1
8:1
1:1
3:1
1:1
70
62
82
65
68
60
VI
a
Reaction conditions: 3c (0.2 mmol), K2CO3 (0.2 mmol), TBr (0.2 mmol), dry THF
(5 mL), for 12 h under a nitrogen atmosphere at 25 °C.
b
dr is determined by 1H NMR.
Isolated yields after column chromatography for both diastereomers.
c
Table 5
Substrate scope for synthesis of stereoselective para-1,4-quinone monoketals.
Table 3
Substrate scope for synthesis of para-1,5-quinone monoketals.
Please cite this article as: S. R. Sahoo and D. Sarkar, Stereoselective synthesis of para-quinone monoketals through tri-bromide (TBr) mediated oxidative
dearomatization of phenols, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151646

4
S.R. Sahoo, D. Sarkar / Tetrahedron Letters xxx (xxxx) xxx
Conclusion
In a nutshell, we feel enthusiastic to report the way out of tri-
bromide (TBr) mediated dearomative intramolecular stereoselec-
tive spiropara-quinone monoketals of 2-alkoxy phenols and 3-
alkoxy phenols, with overall fantastic yields and good diastereose-
lectivity under mild conditions along with the economy involved
make this sustainable methodology. Additionally, this work has
no side reactions like polymerization and bromination at ortho-
position of phenol which is commonly observed in dearomatisa-
tion reactions, thus makes it an effective reaction. The study of
asymmetric version is currently in progress in our laboratory.
Fig. 2. NOE studies attesting the relative stereochemistry for compound 6b and 6c.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgments
We sincerely acknowledge the Department of Science and Tech-
nology (DST), Government of India (Grant No. EEQ/2016/000518),
INSPIRE-DST, Government of India (Grant 04/2013/000751) and
NIT Rourkela.
Scheme 2. Product diversification of the para-1,4-quinone monoketals product.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.151646.
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Please cite this article as: S. R. Sahoo and D. Sarkar, Stereoselective synthesis of para-quinone monoketals through tri-bromide (TBr) mediated oxidative
dearomatization of phenols, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151646