Oxidative de-aromatization of para-alkyl phenols into para-peroxyquinols and para-quinols mediated by oxone as a source of singlet oxygen

Article abstract of DOI:10.1002/anie.200504605

(Chemical Equation Presented) Easy does it: Easily handled and environmentally safe oxone generates singlet oxygen which effects the simple and selective oxidative de-aromatization of para-alkyl phenols 1 into para-peroxyquinols 2 under very mild conditions with good to excellent yields. A one-pot access to para-quinols 3 from 1 is also possible after treatment of the crude reaction mixture with sodium thiosulfate.

Full text of DOI:10.1002/anie.200504605

Angewandte
Chemie
Oxidation
DOI: 10.1002/anie.200504605
Oxidative De-aromatization of para-Alkyl
Phenols into para-Peroxyquinols and
para-Quinols Mediated by Oxone as a
Source of Singlet Oxygen**
M. Carmen Carreæo,* Marcos Gonzµlez-López, and
Antonio Urbano*
The controlled oxidation of organic compounds is particularly
important for aromatic derivatives bearing alkyl substituents
that are prone to suffer over-oxidation. The search for
selective methods to effect the oxidative de-aromatization
of para-alkyl phenols into 4-alkyl-4-hydroperoxy-2,5-cyclo-
hexadienones (para-peroxyquinols) and 4-alkyl-4-hydroxy-
2,5-cyclohexadienones (para-quinols) is of huge interest
G
because of the essential role played by such derivatives in
the skeletons of many natural products,[1] as well as being
valuable building blocks in organic synthesis[2] and novel
therapeutic agents.[3] Although natural products with peroxy
functional groups are relatively abundant,[4] there are only a
few examples of natural derivatives possessing the para-
hydroperoxy-2,5-cyclohexadienone structure.[5] In contrast,
the para-quinol moiety is found in a great number of natural
products (Scheme 1).[6]
Scheme 1. Examples of natural para-peroxyquinol and para-quinol
structures.
The synthesis of para-peroxyquinols[7] is usually achieved
by the reaction of para-substituted phenols with singlet
oxygen (1O2)[8] formed by irradiation of gaseous oxygen
with ultraviolet light in the presence of sensitizers.[9] However,
[*] Prof. Dr. M. C. Carreæo, M. Gonzµlez-López, Dr. A. Urbano
Departamento de Química Orgµnica (C-I)
Universidad Autónoma de Madrid
Cantoblanco, 28049 Madrid (Spain)
Fax: (+34)91-497-3966
E-mail: carmen.carrenno@uam.es
antonio.urbano@uam.es
[**] We thank the Ministerio de Ciencia y Tecnología (Grants BQU2002-
03371 and CTQ2005-02095/BQU) and the Comunidad Autónoma
de Madrid (Grant GR/MAT/0152/2004) for financial support.
M.G.-L. thanks the Comunidad Autónoma de Madrid for a fellow-
ship.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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despite its efficiency, this method has not been applied
reducing agents were used, to simplify such a transformation.
Thus, by adding Na2S2O3 (10.0 equiv) to the reaction medium
after completion of the oxidative de-aromatization step, we
were pleased to observe the formation of para-quinol 3a
(Scheme 2), which was isolated in 83% yield, without further
purification.
extensively. Chemical sources of 1O2 involve the use of
transition-metal ions such as CrVI, TiIV, MoVI, or CeIV in the
presence of H2O2, or RuIII or IIII using tBuOOH as a
cooxidant. Among the numerous methods described for the
preparation of para-quinols,[7] hypervalent iodine
ACHTREUNG
We later extended the scope of the method to the
preparation of the para-peroxyquinols and para-quinols
shown in Table 1, where we have also included, for compar-
ison, the maximum yields reported for previous transforma-
tions of para-alkyl phenols 1 into para-peroxyquinols 2 or
para-quinols 3. The oxidative de-aromatization of para-alkyl
phenols 1b–k with oxone was performed as indicated before
for 1a (see also the Supporting Information). The reaction
was very fast (15–140 min) and para-peroxyquinols 2b–k
were obtained in good to excellent yields (53–100%) when
the crude mixture was quenched with water (Method A),
without further purification in most cases. Direct access to
para-quinols 3b–k was also possible by adding solid Na2S2O3
(10.0 equiv) to the crude reaction mixture after completion of
the oxidative de-aromatization step (disappearance of phe-
nols 1 as judged by thin-layer chromatography), and stirring
for 30 min at room temperature (Method B). This route
enabled the expected para-quinols 3 to be isolated in
moderate to excellent yields (33–98%), without further
purification in most cases.
The results compiled in Table 1 deserve some comment.
As can be seen, phenols 1a–e bearing methyl groups at
different positions (entries 1–5) furnished, in very short times
(25–50 min), exclusively para-peroxyquinols 2a–e (Meth-
od A) in excellent yields (91–99%), which are higher than
those reported for different sources of singlet oxygen. The
para-quinols 3a–e were obtained from phenols 1a–e (Meth-
od B) in good to excellent yields (72–95%), which again
improve upon those described using other oxidants, mainly IIII
reagents. It is worth mentioning the excellent result achieved
in the reaction of 1d (entry 4), which gave rise to 4-hydroxy-
2,4,6-trimethyl-2,5-cyclohexadienone (3d), a known drug and
vitamin E precursor, in 95% yield.[15]
ACHTREUNG
of choice for the oxidation of para-alkyl phenols.[10] Very
recently, Jacobs and co-workers reported the oxidation of
para-substituted phenols to form para-quinol ethers in which
H2O2 was used in the presence of a tungstate-exchanged
layered double hydroxide catalyst.[11]
Oxone is an inexpensive and easily handled solid consist-
ing of a 2:1:1 mixture of KOSO2OOH, KHSO4, and K2SO4.
As a result of its nontoxic “green” nature, affordability, and
safety profile, oxone is nowadays a popular reagent for
different chemical oxidations,[12] and very commonly for the
generation of dimethyldioxirane for selective epoxidations.[13]
During the course of our recent work on asymmetric
synthesis based on para-(tolylsulfinyl)methyl-para-quinols,[14]
we found that oxone is an efficient reagent for the practical
and selective oxidative de-aromatization of several para-alkyl
phenols. Herein, we describe that it is possible to gain direct
access to para-peroxyquinols or the corresponding para-
quinols, depending on the experimental conditions, in excel-
lent yields under very mild conditions. The effectiveness of
the method is illustrated with the synthesis of two natural
products, hallerone and rengyolone which contain the para-
quinol moiety.
The reaction of 3,4,5-trimethylphenol (1a) with oxone
(8.0 equiv) in the presence of NaHCO3 (24.8 equiv), in a
mixture of CH3CN/H2O at room temperature, afforded para-
peroxyquinol 2a which was isolated pure in 93% yield
(Scheme 2). The hydroperoxy structure of 2a was initially
established by spectroscopic methods and later confirmed by
its reduction to para-quinol 3a by treatment with an excess of
PPh3 (Scheme 2). Although the hydroperoxy function was
cleanly reduced, separation of para-quinol 3a from the
generated triphenylphosphine oxide was troublesome. We
then designed a one-pot procedure, in which water-soluble
The reaction of 1 f (entry 6), bearing an ortho-OMe group,
gave rise to para-peroxyquinol 2 f (53%) or para-quinol 3 f
(33%). Although these yields are only moderate, our syn-
thesis improved upon the yields previously obtained under
different conditions (see Table 1). It is noteworthy that the
reaction of 1 f with iodine(iii) reagents exclusively furnished
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the corresponding ortho-quinone monoacetal.[16]
This oxone-mediated process was also extended to
polycyclic phenols. Thus, the reaction of tetrahydronaphthol
1g with oxone (entry 7) gave para-peroxyquinol 2g (65%) or
para-quinol 3g (56%), whereas derivatives 2h (100%) or 3h
(98%) were obtained in excellent yields from the oxidative
de-aromatization of naphthol 1h (entry 8).
With these results in hand, we decided to apply the
methodology to the synthesis of some simple natural products
based on a para-quinol structure such as hallerone (3i) or
halleridone (rengyolone) (3j). These cyclohexylethanoids
have been isolated from the plant Halleria Lucida,[6a] and
were found to have interesting biological and therapeutic
properties.[17] Both derivatives have been synthesized previ-
Scheme 2. Formation of para-peroxyquinols and para-quinols from
para-alkyl phenols in the presence of oxone.
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Table 1: Oxidative de-aromatization of para-alkyl phenols 1 into para-peroxyquinols 2 or para-quinols 3 with oxone.[a]
Entry
Substrate
R1
R2
R3
R4
Product method A[b]
t [min][c]
Yield [%][d]
Product method B[e]
Yield [%][f]
1
2
3
4
5
6
1a
1b
1c
1d
1e
1 f
H
Me
H
Me
H
OMe
Me
H
Me
H
H
H
H
H
H
Me
H
Me
H
H
H
H
2a
2b
2c
2d
2e
2 f
35
25
35
50
35
20
93
3a
3b
3c
3d
3e
3 f
83 (63)[29]
75 (60)[29]
72 (67)[29]
95 (91)[11]
81 (61)[19]
33 (25)[30]
92 (75)[24]
91 (68)[24]
99 (70)[25]
93 (87)[26]
53 (14)[27]
H
H
7
40
65 (65)[28]
56 (55)[31]
8
20
100
98
9
140
62
80
74
48 (38)[18a]
50 (37)[18b]
50
10[g]
25
11[g]
15
[a] All reactions were typically performed on a 1 mmol scale by adding 8.0 equiv of oxone and 24.8 equiv of sodium bicarbonate to a solution of the
para-alkyl phenol 1 in a mixture of CH3CN/H2O at 258C (see the Supporting Information). [b] The reaction was quenched with water. [c] Time required
for disappearance of para-alkyl phenols 1 as judged by thin-layer chromatography. [d] The maximum reported yields for the transformation of para-alkyl
phenols 1 into para-peroxyquinols 2, with the corresponding reference yield given in parentheses. [e] The reaction was diluted with H2O, then
10.0 mmol of solid sodium thiosulfate (Na2S2O3) was added, and the resulting mixture was stirred at 25–288C until the corresponding hydroperoxide
had been consumed (ca. 30 min). [f] The maximum reported yields for the transformation of para-alkyl phenols 1 into para-quinols 3, with the
corresponding reference are given in parentheses. [g] The reaction was carried out in H2O as the sole solvent.
ously in yields of 38 and 37%, respectively, by sensitized
photooxygenation of the corresponding phenols.[18] Thus, the
oxidative de-aromatization of phenol 1i under our typical
reaction conditions (entry 9) afforded, para-peroxyquinol 2i
in 62% yield (Method A) or para-quinol 3i in 48% yield
(Method B). The physical and spectroscopic data of the latter
compound were identical to those described for the natural
product hallerone. The reaction of phenol 1j with oxone
(entry 10) took place in H2O as the sole solvent and gave
para-peroxyquinol 2j (Method A) in 80% yield. The bicyclic
para-quinol 3j, identified as the natural product rengyolone,
was obtained in 50% yield from phenol 1j (Method B) in a
one-pot three-reaction sequence comprising oxidative de-
aromatization, reduction of the peroxy functionality, and
intramolecular conjugate addition to the cyclohexadienone
moiety which gave rise to the cis-fused tetrahydrofurane ring.
Finally, the reaction of phenol 1k, bearing a C3 chain at
the para position, with oxone in H2O (entry 11) gave rise to
para-peroxyquinol 2k (Method A) in 74% yield, or para-
quinol 3k (Method B) in 50% yield. It is also noteworthy that
the reaction of phenol 1k with hypervalent iodine reagents
did not yield para-quinol 3k but exclusively afforded, through
intramolecular attack of the aliphatic OH on the para position
of the phenolic OH, the corresponding oxa-spiro cyclohex-
adienone,[19] which was not detected in our case.
Angew. Chem. Int. Ed. 2006, 45, 2737 –2741
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Communications
Although it is known that the active ingredient of oxone,
times, and generally improves upon the yields obtained with
other oxidants.
potassium peroxymonosulphate, decomposes in aqueous
basic medium to generate singlet oxygen (Scheme 3),[20] to
the best of our knowledge this process has not been exploited
Received: December 28, 2005
Published online: March 20, 2006
Keywords: natural products · oxidation · oxone · singlet oxygen ·
.
syntheticmethods
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from a synthetic point of view. In our case, it could be assumed
that the reactive 1O2 species, which is generated from an
excess of oxone in the presence of NaHCO3, would be the
species responsible for the oxidative de-aromatization of
para-alkyl phenols to para-peroxyquinols (Scheme 3). The
process involves a [4+2] cycloaddition[21] between 1O2 and
electron-rich para-alkyl phenols and gives rise initially to the
formation of a 1,4-endoperoxide, which immediately evolves
to the 4-hydroperoxy-2,5-cyclohexadienone as a result of its
unstable peroxyhemiacetal structure. The presence of water
seems to be essential for the success of this process, which is
consistent with the well-documented enhanced rate of
1
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peroxide–acetal intermediate to yield the required substrates.
This mechanistic pathway also accounts for the exclusive
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alkyl phenols to para-peroxy quinols and para-quinols in good
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