Phase-Transfer-Catalyzed Oxaziridine-Mediated Hydroxylative Phenol and Naphthol Dearomatization

Article abstract of DOI:10.1002/ejoc.201501340

A new methodology for the dearomative ortho-hydroxylation of substituted phenolic substrates is reported. In the presence of a phase-transfer catalyst and a base, N-sulfonyloxaziridines react with phenols to give the corresponding 6-alkyl-6-hydroxycyclohe

Full text of DOI:10.1002/ejoc.201501340

DOI: 10.1002/ejoc.201501340
Communication
Dearomatization
Phase-Transfer-Catalyzed Oxaziridine-Mediated Hydroxylative
Phenol and Naphthol Dearomatization
[a]
[a,b]
Charlotte Grandclaudon and Patrick Y. Toullec*
Abstract: A new methodology for the dearomative ortho- alkyl-6-hydroxycyclohexadienone products in moderate to
hydroxylation of substituted phenolic substrates is reported. In good yields. The reaction proceeds in fair to good yields and
the presence of a phase-transfer catalyst and a base, N-sulfonyl- excellent chemoselectivity for 2,6-disubstituted phenols, 1-
oxaziridines react with phenols to give the corresponding 6- naphthols, and 2-naphthols.
Introduction
Catalytic dearomatization reactions represent an ideal method
to introduce molecular complexity by starting from cheap, read-
ily accessible starting materials in a straightforward and highly
[
1]
efficient manner. During the last decade, these dearomatiza-
tion reactions have also been successfully used in the key step
of the synthesis of highly functionalized polycyclic natural pro-
[
2]
ducts. Among these, hydroxylative phenol and naphthol de-
aromative strategies play a pivotal role in metabolite degrada-
tion[ through the formation of the 6-hydroxy-2,4-cyclohexadi-
3]
[
4]
enone moiety 1, which thus represents a key structural inter-
mediate in the biomimetic total synthesis of natural products,
[
5]
[6]
including bacchopetiolone (2), bisorbicillinol (3), sclero-
[
7]
[8]
tiorin (4), and arianciamycinone (5) (Figure 1).
The transformation of phenols and naphthols into the corre-
sponding ortho-quinol products was investigated by using a
[
9]
[10]
Figure 1. Selection of natural products resulting from the ortho-quinol inter-
mediate 1.
variety of reagents including peracids, (PhSeO) O, hyperva-
2
[
11]
lent iodine compounds,
as well as (oxo)- or (peroxo)metal
[
12]
[13]
species either in a stoichiometric or catalytic amount. Un-
fortunately, these methodologies often exhibit low chemo- and
regioselectivities due to side-reactions including competitive
[
11f,13b]
[11d]
para oxidation,
ketol rearrangement[12,13a] or phenol homocoupling
Scheme 1).
New strategies for the synthesis of the 6-alkyl-6-hydroxy-2,4-
overoxidation of alkene functions,
α-
[11f,12]
(
cyclohexadienone moiety 1 from phenols or naphthols still rep-
resents a synthetic challenge. Since the first report of their
[
14]
preparation by Emmons in 1957, oxaziridine heterocycles es-
[
[
a] Institut de Recherche de Chimie Paris
PSL Research University, Chimie ParisTech-CNRS
1
1 rue P. et M. Curie, 75005 Paris, France
E-mail: patrick.toullec@chimie-paristech.fr
b] Univ. Bordeaux, ISM, UMR 5255,
3
3400 Talence, France
E-mail: patrick.toullec@u-bordeaux.fr
http://www.ism.u-bordeaux1.fr/
Scheme 1. Chemo- and regioselectivity of the hydroxylative dearomatization
reactions of phenols.
Supporting information and ORCID(s) from the author(s) for this article
are available on the WWW under http://dx.doi.org/10.1002/
ejoc.201501340.
tablished itself as a class of organic aprotic oxidizing reagents
mainly known for their ability to act as oxene transfer agents.
[
15]
Eur. J. Org. Chem. 2016, 260–264
260
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Scheme 2. Phase-transfer-catalyzed phenol dearomatization reactions.
They noticeably found applications in organomagnesium com-
[
16]
[17]
pound hydroxylation,
alkene epoxidation,
sulfide to sulf-
[
18]
[19]
oxide oxidation, amine to hydroxylamine oxidation,
remain mostly known for enolate or enol surrogates, such as
but
[
20]
[
21]
silyl enol ethers,
to α-hydroxy ketone oxidations. Further-
[
22]
more, recent reports
highlighted the possibility to obtain
dearomatized 2,2-disubstituted cyclohexanone products from
phenols under either cationic (CPTC) or anionic (APTC) phase-
transfer catalysis in the presence of an adequate electrophile
(
Scheme 2). Taking these literature precedents into account, we
decided to engage in a study dealing with the hydroxylative
dearomatization of phenolic substrates under phase-transfer
conditions in the presence of oxaziridines as electrophilic rea-
gents.
Results and Discussion
As a test experiment, the hydroxylation of 2,6-dimethylphenol
With the optimized conditions in hand, we examined the
(
11a) was investigated in the presence of an oxaziridine 12 and scope of the transformation (Scheme 3). The reaction pro-
a base by using a variety of conditions. Results are reported in ceeded in good yield for the ortho-dimethyl-substituted phenol
Table 1. Treatment of the sodium phenolate of 11a with oxazir- substrates 11a,b. A lower yield was observed for the very chal-
idine 12a in THF at room temperature provided the [4+2] cy- lenging derivative 11c, which contains a bulky, electron-with-
cloadduct of the α-hydroxycyclohexadienone 13a in 8 % yield drawing chlorine atom in the para position. The molecular
(
Entry 1). The use of Na CO alone as a base failed to provide structure of this representative product 13c was confirmed by
2 3
any conversion, whereas its combination with an ammonium X-ray crystallography and shows the endo selectivity previously
[
3a,23]
salt such as BnEt NCl, acting as a phase-transfer agent, gave demonstrated for 13a
2
(Figure 2). In the presence of bulkier
0 % yield (Entries 2 and 3). The use of an aqueous solution of substituents on the ortho positions, lower yields of the [4+2]
NaOH resulted in only trace amounts of the oxidized product tricycles 13d–f were also observed. In the case of phenol 11f,
Entry 5), but shifting to solid NaOH proved beneficial (Entry 4). the product was obtained as a mixture of two different cycload-
3
(
The screening of different ammonium salts showed that benzyl- ducts 13f and 13f′ (16 % and 6 % yield, respectively). Whereas
cinchonidinium chloride (14) exhibits the best catalytic activity the formation of 13f resulted from the endo [4+2] cyclodimeri-
(
Entry 8 vs. Entries 4, 6, 7), whereas toluene turned out to be zation of 1f, the formation of 13f′ was the consequence of a
the best solvent for this transformation (Entries 12–14). The best Diels–Alder reaction between one molecule of 1f, playing the
yield was obtained at an optimal concentration in substrate of role of the dienophile, and one molecule of 1f′, playing the role
1
M (see Entries 9, 10 for comparison). An increase of the oxazir- of the diene. This observation seems to indicate that, with this
idine/substrate ratio (Entry 11) or the use of other hydroxide system, phenol hydroxylation is controlled by the steric hin-
salts (Entries 15, 16) had no beneficial effect on the yield. The drance of the ortho positions. Finally, it should also be men-
screening of various oxidants showed that the 4-chlorophenyl- tioned that no conversion was obtained for substrates with an
substituted N-sulfonyloxaziridine 12b gave the best yield (En- unsubstituted ortho position such as 11g or with 2,6-diphenyl-
try 17), whereas the use of the N-benzyloxaziridine 12d, known phenol (11h). Remarkably, for sterically congested substrates,
to exhibit a weaker electrophilic character, did not lead to any the [4+2] cycloaddition reaction was not straightforward, and
conversion (Entry 19).
the intermediate 6-alkyl-6-hydroxy-2,4-cyclohexadienone 1 may
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Table 1. Optimization of the reaction conditions.[a]
be monitored by H NMR spectroscopy or even isolated upon
filtration.
1
[
24]
Entry Oxaziridine
Base
NaH
Cat.
Solvent Yield of 13a[b]
1
2
3
4
12a
12a
12a
12a
12a
12a
12a
12a
12a
12a
12a
12a
12a
12a
12a
12a
12b
12c
12d
–
–
THF
toluene
8 %
0 %
Na
Na
2
CO
CO
3
2
3
BnEt
BnEt
BnEt
3
3
3
NCl
NCl
NCl
toluene
20 %
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
KOH
toluene
22 %
5[
c]
toluene
4 %
6
7
8
Bu
Me(C10
4
NCl
toluene
19 %
H
21
)
3
NCl toluene
toluene
36 %
56 % (54 %)
45 %
14
14
14
14
14
14
14
14
14
14
14
14
[
d]
9
toluene
1
1
0[
1
e]
toluene
47 %
[
f]
toluene
46 %
1
2
3
4
5
6
7
8
9
CH
iPr
2
Cl
2
44 %
19 %
1
1
1
1
1
1
1
2
O
C
6
H
12
7 %
Figure 2. Structure of cyclodimer 13c determined by X-ray crystallography.
toluene
toluene
toluene
toluene
toluene
46 %
44 %
64 % (60 %)
59 %
Only one enantiomer is represented.[
25]
CsOH
NaOH
NaOH
NaOH
This strategy of oxidation was also successfully employed for
the hydroxylative dearomatization of naphthols. In the case of
0 %
1
-naphthols 15a–c, the reaction proceeded with moderate
[
(
a] Conditions unless otherwise stated: substrate 11a (0.2 mmol), base
0.2 mmol), oxaziridine 12a–d (0.2 mmol) and catalyst (0.02 mmol) were
yields to give – depending on the nature of the substituent in
ortho position – either the expected 2-alkyl-2-hydroxynaphth-
alen-1-one 16 or the 1-alkyl-1-hydroxynaphthalen-2-one 17 re-
sulting from the α-ketol rearrangement (Table 2). In the case of
15a (R = Me), the hydroxylative dearomatization furnished
added to toluene (2 mL), and the mixture was stirred at room temperature
for 16 h. [b] Yields were determined by H NMR spectroscopy by using fluor-
1
ene as a standard. Isolated yields are given in parerntheses. [c] 1 mL of a 1
solution of NaOH in water was used. [d] [11a] = 2 . [e] [11a] = 0.4
f] Ratio substrate 11a/oxaziridine 12a = 1:2.
M
M
M.
[
Scheme 3. Scope of the phase-transfer-catalyzed phenol hydroxylative dearomatization reaction.
Eur. J. Org. Chem. 2016, 260–264 www.eurjoc.org
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
exclusively the 1-naphthalenone 16a in 55 % yield (Entry 1), ated (products 17f–j). The hydroxylation also took place cleanly
whereas for 15b (R = Et), a mixture of 16b/17b in a 83:17 ratio with a naphthol bearing a silyl substituent in position 3 to de-
was formed (Entry 2). In the case of the substrate 15c bearing liver the hydroxylated product 17k in excellent yield and select-
a prenyl substituent, a reversal of selectivity was observed. The ivity. Finally, in the case of 2-naphthols, we have also shown
hydroxylation reaction delivered a mixture of 16c/17c in a 24:76 that it was possible to observe the hydroxylation at a position
ratio with a modest 11 % yield (Entry 3).
bearing a phenyl substituent in position 1; the 1-hydroxy-1-
phenylnaphthalen-2-one 17l was isolated in 56 % yield.
Table 2. 1-Naphthol phase-transfer-catalyzed hydroxylative dearomatization
The postulated mechanism involves the initial formation of
the phenolate anion 19 upon phase transfer of the hydroxide
anion in the presence of the ammonium salt, followed by a
reaction with the oxaziridine to give transiently the intermedi-
ate 20, in analogy with what has been proposed for the α-
[
a]
reaction.
[
26]
hydroxylation of ketones (Scheme 5). Liberation of the imine
furnishes the anion of 1 that is released after protonation.
Entry
R
Yield[b]
16/17 ratio
1
2
3
Me, a
Et, b
55 %
61 %
11 %
100:0
83:17
24:76
,
c
[
(
a] Conditions unless otherwise stated: substrate 15a–c (0.2 mmol), NaOH
0.2 mmol), oxaziridine 12a (0.2 mmol) and catalyst 14 (0.02 mmol) were
added to toluene (2 mL), and the mixture was stirred at room temperature
for 16 h. [b] Isolated yields.
We also investigated the hydroxylative dearomatization of 2-
naphthol substrates (Scheme 4). The reaction was compatible
with a large range of substituents, affording the products in
good yields (ranging from 56 to 87 %). Substrates bearing a
single substituent in position 1 (18a,d,e) gave clean conversion,
and no product resulting from the hydroxylation in position 3
could be detected. The reaction was also amenable to sub-
strates possessing a disubstitution in positions 1 and 3. Alkyl,
aryl and allyl groups as well as a bromine atom were all toler-
Scheme 5. Postulated mechanism of the hydroxylative dearomatization of
phenols.
Conclusions
We have developed a new methodology for the hydroxylative
dearomatization of phenols and naphthols furnishing the corre-
sponding ortho-quinol building blocks in moderate to good
yields. This method exhibits a large substrate scope in the case
of the 2-naphthols. Phenolate and naphtholate anions, gener-
ated under phase-transfer conditions, react with N-sulfonyloxaz-
iridines to give the hydroxylated products at room temperature
in toluene. This methodology holds promise for the develop-
ment of an enantioselective version of the hydroxylative dearo-
matization of phenols and naphthols in the presence of a chiral
[
27]
phase-transfer catalyst. Studies toward this goal are currently
underway in our laboratory and will be reported in due course.
Acknowledgments
This work was supported by the Centre National de la Recher-
che Scientifique (CNRS) and the Ministère de l'Education et de
la Recherche for financial support. C. G. is grateful to the
Agence Nationale de la Recherche (ANR-13-JS07-0010) for a
PhD grant. Dr. M.-N. Rager (Chimie ParisTech) is acknowledged
for 2D NMR experiments. L.-M. Chamoreau (IPCM, UPMC) is
ackowledged for the structural characterization of compound
13c.
Scheme 4. Hydroxylative dearomatization of 2-naphthols 18 mediated by N-
sulfonyloxaziridines.
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Communication
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14] W. D. Emmons, J. Am. Chem. Soc. 1957, 79, 5739.
Keywords: Phenols · Naphthols · Dearomatization · Phase-
transfer catalysis · Oxidation
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Received: October 19, 2015
Published Online: December 3, 2015
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim