Novel dienone-phenol type rearrangement of 4,4-disubstituted cyclohexadienone system using thiosilane

Article abstract of DOI:10.1039/b915294f

Thiosilane and a catalytic amount of a Bronsted acid mediate the novel domino-type rearrangement reaction of the 4,4-disubstituted cyclohexadienones to produce the 3,4-disubstituted benzenethioethers; the key step is 1,2-addition of thiosilane to dienone.

Full text of DOI:10.1039/b915294f

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Novel dienone-phenol type rearrangement of 4,4-disubstituted
cyclohexadienone system using thiosilanew
Yasufumi Wada,z Kouji Otani, Noriko Endo, Yasuyuki Kitay and Hiromichi Fujioka*
Received (in Cambridge, UK) 28th July 2009, Accepted 17th November 2009
First published as an Advance Article on the web 9th December 2009
DOI: 10.1039/b915294f
Thiosilane and
a catalytic amount of a Brønsted acid
mediate the novel domino-type rearrangement reaction of the
4,4-disubstituted cyclohexadienones to produce the 3,4-disubsti-
tuted benzenethioethers; the key step is 1,2-addition of thiosilane
to dienone.
The dienone-phenol rearrangement is one of the oldest
transformations of the carbon skeletons.1 The reaction is
found in the biosynthesis of many natural products,2 and also
affords a useful tool in organic synthesis. Therefore, detailed
studies of it have already been conducted.3 There are many
reports for the synthesis of highly substituted phenol
compounds.4 The mechanism of the acid-catalyzed dienone-
phenol rearrangement has been well established. The only
drawback of the reaction is that the resulting functional group
in this transformation is limited to only the phenolic hydroxyl
group. It is difficult to convert the phenolic hydroxyl group
into other functional groups. For example, the synthesis of
benzenethioether compounds from the parent phenols requires
a four-step procedure of thiocarbamoylation, Newman-Kwart
rearrangement and cleavage under hydrolytic or reductive
conditions followed by alkylation.5
Scheme 2 The reactions of 1a and p-MeOBnSH using various acids.
CH2Cl2 (Scheme 2). Compound 1a was prepared from the
commercially available 4,4-dimethyl cyclohexenone by DDQ
oxidation in one step. The reaction with the Brønsted acid,
trifluoroacetic acid (TFA) or trifluoromethanesulfonic acid,
resulted in no reaction. We next tried to use some Lewis acids.
The reactions using BF3ꢀEt2O or AlCl3 gave poor results
(trace, 12%). The reaction with ZnCl2 gave a slightly better
result (22%). The reaction with TMSOTf gave the desired
compound 2a in 43% yield. The use of additional
p-MeOBnSH and TMSOTf did not significantly improve the
yields. The reaction using TMSOTf was then studied in detail
concerning the reaction solvents. Reactions in various
solvents, such as acetonitrile (CH3CN), tetrahydrofuran
(THF) and benzene, gave poor results (trace, 23%, 26%).
Therefore, CH2Cl2 was proven to be the solvent of choice.
However, the yield was not satisfactory.
If the other functional groups such as a thioether, amine,
and ether could be directly obtained by the dienone-phenol
type rearrangement, the reaction would become more useful
(Scheme 1). However, to the best of our knowledge, such
studies have not yet been reported. We now present a novel
dienone-phenol type rearrangement yielding thioether products.z
We first examined the reaction of 4,4-dimethyl cyclohexa-
dienone 1a and p-MeOBnSH to give 2a using various acids in
Evans et al. reported that the thermal and catalyzed
addition reactions of alkyl- or arylthiol and trimethylsilyl
chrolide to carbonyl functions occurred under basic
conditions.6 They mentioned that thiosilanes, which are made
from thiols and trimethylsilyl chloride, were the actual active
species, which reacted with aldehydes and ketones to
O-silylhemithioketals. For improvement of the above reaction
yields, the reaction of the dienone 1a with various thiosilanes
and acids was next studied (Table 1). The reaction with
p-MeOBnSTMS and TfOH at rt gave a better result than that
of using p-MeOBnSH and TMSOTf (entry 1). The reaction at
reflux gave a moderate result (entry 2). The longer time was
needed for completing the reaction (entry 3). Reactions with
various acids (HCl, TFA, Montmorillonite K10 (MK10)) gave
poor results (entries 4–6). We then examined other thiosilanes.
The reactions with PhSTMS and MeSTMS also proceeded
successfully (entries 7, 8).
Scheme 1 Plan of dienone-phenol type new reaction.
Graduate School of Pharmaceutical Sciences, Osaka University,
1-6 Yamada-oka, Suita, Osaka, 565-0871, Japan.
E-mail: fujioka@phs.osaka-u.ac.jp; Fax: +81 6 6879 8229;
Tel: +81 6 6879 8225
w Electronic supplementary information (ESI) available: Typical
experimental procedures, and analytical data for products. See DOI:
10.1039/b915294f
The reactions of various 4,4-disubstituted cyclohexa-
dienones were examined next (Table 2). In the case of 1b
(R0 = Me), the reactivity was low due to a steric effect, and the
usual dienone-phenol rearrangement product was obtained in
39% and 35% yield (entries 1, 2). The reaction yields from
6,6-spiro and 6,5-spiro compounds (1c and 1d) were good
(entries 3–6).
z JSPS Research Fellow.
y Present address: Faculty of Pharmaceutical Sciences, Ritsumeikan
University, 1-1-1 Nojihigashi, Kusatsu, Shiga, 525-8577.
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Table 1 The reactions of 1a and thiosilanes with various acids
Entry
R
Acid
Temp.
Time
Product (yield %)
SM (1a) (yield %)
1a
2a
3
p-MeOBn
p-MeOBn
p-MeOBn
p-MeOBn
p-MeOBn
p-MeOBn
Ph
TfOH
TfOH
TfOH
HCl
rt
6 h
6 h
5 days
6 h
6 h
6 h
7 days
12 h
2a (66%)
2a (73%)
2a (81%)
2a (23%)
2a (18%)
2a (8%)
13%
9%
0%
40%
47%
74%
0%
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
4a
5a
6a
7b
8
TFA
MK10
TfOH
TfOH
2b (86%)
2c (84%)
Me
0%
a
b
Use of additional thiosilanes and acids did not significantly improve yields. 1a (1.0 equiv.), TMSSPh (1.1 equiv.) and TfOH (0.3 equiv.) under
CH2Cl2 (0.02 M) reflux for 7 days.
Table 2 Dienone-phenol type rearrangement of various 4,4-disubstituted
cyclohexadienone
the intermediate I would then give the intermediate II.
The thionium cation intermediate III would be formed by
the elimination of Me3SiOH of the intermediate II. The
generation of Me3SiOH was confirmed by TLC, GC-MS and
1H-NMR. The thionium cation would be an activator of the
1,2-migration of the alkyl group. The rearrangement of the
alkyl group would then proceed to give the intermediate IV,
followed by aromatization to produce the thioether 2.
Entry R1
R2
R3
Substrate
R
Product Yield
1b
2b
3c
4c
5
Me Me
Me Me
Me
Me
1b
1b
1c
1c
1d
1d
Me 3a
Ph 3b
Me 4a
Ph 4b
Me 5a
Ph 5b
42%
32%
74%
89%
62%
51%
Table 3 Dienone-phenol type rearrangement of various complex
substrates
H
H
H
H
CH2(CH2)3CH2
CH2(CH2)3CH2
CH2(CH2)2CH2
CH2(CH2)2CH2
Entry Substrate
Product
Time Yield
5 days 40%a
6
a
All reactions in CH2Cl2 (0.1 M) were caused by a side reaction
b
1
dienone-phenol rearrangement.
A
2,4,5-trimethylphenol was
c
obtained (39% in entry 1, 35% in entry 2). 1b–d (1.0 equiv.), TMSSR
(1.1 equiv.) and TfOH (0.3 equiv.) under CH2Cl2 (0.02 M) reflux for
7 days.
2
6 days 51%
A plausible reaction mechanism of the novel dienone-
phenol type rearrangement reaction is illustrated in
Scheme 3 using 1a as a substrate. Thus, the intermediate I
would first be formed by the unusual 1,2-addition of the
thiosilane to the carbonyl group of 1a due to the prevention
of the 1,4-addition by the steric effect of the 4-alkyl substitute.
The protonation of the oxygen atom of the silyl ether in
21%
3
5 days 86%
4
12 h
72%
a
The dienone phenol rearrangement compound was obtained at 49%.
Scheme 3 Plausible reaction mechanism.
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Reproduction of the acid during the reaction would make use
of a catalytic amount of TfOH possible.
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The reaction was applicable to more complex substrates
having various substitutions (Table 3). It should be noted that
the substrates having a ketone or ester were useable. Santonin
(6a) and 1,4-androstadiene-3,17-dione (6b) were representative
substrates for the dienone-phenol rearrangement. Treatment
of them under our reaction conditions gave the corresponding
thioether derivatives (7a) and (7b, 7b0) in moderate yields
(entries 1, 2). The structure of 7b was deduced from the
consideration of the result of the typical dienone-phenol
rearrangement of 6b.7–9 Furthermore, in the cases of the
spirodienones 6c and 6d, single isomers 7c and 7d were
obtained, respectively. The structures of 7c and 7d were
determined by nOe studies. This selectivity might depend on
the presence of the enamino structure of 6c and 6d.10,11
In conclusion, we have developed an effective and novel
thiosilane-induced dienone-phenol type domino reaction of
4,4-disubstituted cyclohexadienones using a catalytic amount
of TfOH as the appropriate Brønsted acid. This is the first
method to synthesize a variety of benzenethioethers by the
dienone-phenol type reaction. Organic sulfides are useful
chemical intermediates in organic synthesis. For example,
the sulfur functional groups in the products permitted the
installation of a second carbon functional group at the
ipso-position.12 This method provides a new aspect for
the dienone-phenol rearrangement. More applications of this
useful reaction are now underway in our laboratory.
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IV0(6d) from 6d. This is the reason for this regioselectivity. For the
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Notes and references
z Typical Experimental Procedure: A solution of dienone (1.0 equiv.)
in CH2Cl2 (0.1 M) was heated in a reflux. After being stirred for
15 min, TMSSR (1.1 equiv.) and acid (0.1 equiv.) was added to the
resulting solution. The mixture was stirred at the same temperature for
12 h–7 days. The reaction was quenched with H2O and extracted with
AcOEt. The organic layer was washed with brine, dried over Na2SO4,
and evaporated in vacuo. The residue was purified by SiO2 column
chromatography using hexane–AcOEt as the eluent to give the
thioether.
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Chem. Commun., 2010, 46, 797–799 | 799