Novel access to cyclohexane-1,4-diones and 1,4-hydroquinones via radical 1,2-acyl rearrangement on 2-(halomethyl)cyclopentane-1,3-diones using cobaloxime-mediated electroreduction or tributyltin hydride

Article abstract of DOI:10.1016/S0040-4039(02)00163-6

A new preparative access to synthetically useful cyclohexane-1,4-diones 2 and their oxidized analogues, hydroquinones 3, with the option of introducing alkyl and aryl substituents, was developed by radical 1,2-acyl rearrangement on 2-(halomethyl)cyclopentane-1,3-diones 1, accessible from 1,2-bis(trimethylsiloxy)cyclobutene and α-bromo ketone dimethyl acetals. The electroreduction of monoacetals of 1 in the presence of cobaloxime as a catalyst afforded the cyclohexane-1,4-dione monoacetals in good yields. The Bu₃SnH-reduction of 2-aryl 1 under refluxing in benzene effected the rearrangement, affording 2, and when the reaction was prolonged, aromatization to 3 proceeded in moderate yields.

Full text of DOI:10.1016/S0040-4039(02)00163-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2051–2054
Novel access to cyclohexane-1,4-diones and 1,4-hydroquinones
via radical 1,2-acyl rearrangement on
2-(halomethyl)cyclopentane-1,3-diones using cobaloxime-mediated
electroreduction or tributyltin hydride
Hiroyuki Kawafuchia and Tsutomu Inokuchib,*
aDepartment of Chemical and Biochemical Engineerings, Toyama National College of Technology, Hongo-machi,
Toyama 939-8630, Japan
bDepartment of Bioscience and Biotechnology, Faculty of Engineering, Okayama University, Okayama 700-8530, Japan
Received 9 October 2001; accepted 18 January 2002
Abstract—A new preparative access to synthetically useful cyclohexane-1,4-diones 2 and their oxidized analogues, hydroquinones
3, with the option of introducing alkyl and aryl substituents, was developed by radical 1,2-acyl rearrangement on 2-
(halomethyl)cyclopentane-1,3-diones 1, accessible from 1,2-bis(trimethylsiloxy)cyclobutene and a-bromo ketone dimethyl acetals.
The electroreduction of monoacetals of 1 in the presence of cobaloxime as a catalyst afforded the cyclohexane-1,4-dione
monoacetals in good yields. The Bu3SnH-reduction of 2-aryl 1 under refluxing in benzene effected the rearrangement, affording
2, and when the reaction was prolonged, aromatization to 3 proceeded in moderate yields. © 2002 Elsevier Science Ltd. All rights
reserved.
Cyclohexane-1,4-diones 2 are fundamental compounds
in organic synthesis especially as intermediates for
bioactive compounds1 as well as speciality chemicals
such as TCNQ.2 In contrast to the easy availability of
their congeners, cyclohexane-1,2-diones and 1,3-diones,
by the intermolecular and intramolecular Claisen con-
densations, cyclohexane-1,4-diones are not obtained by
this condensation.3 On the other hand, catalytic hydro-
genation or dissolving metal reduction of catechols,
resorcinols, and hydroquinones can promise a large-
scale preparation of the corresponding cyclohexane-
diones, which is, however, less selective due to
overreduction.4 Furthermore, hydroquinone synthesis is
also currently an important issue because of its signifi-
cant role in bioactive compounds.5 Here we report a
novel synthetic access to cyclohexane-1,4-diones 2 as
well as their oxidized analogues, 1,4-hydroquinones 3,
from 2-(bromomethyl)cyclopentane-1,3-diones 1 by a
radical 1,2-acyl rearrangement tactics which has
recently attracted intensive interest from the synthetic6,7
and biological8 points of view (Scheme 1).
As shown in the general strategy in Scheme 2, the
starting 2-alkyl- or 2-aryl 1 for the radical rearrange-
ments were easily prepared by employing Nakamura’s
protocol9 for cyclopentane-1,3-dione synthesis, slightly
modified by using a lanthanide catalyst such as
Yb(OTf)3.10 Thus, the aldol reaction of 1,2-
Scheme 1.
Keywords: biaryls; catalysts; cobalt and compounds; cyclohexanones; electrochemical reactions; phenols; radicals and radical reactions; rearrange-
ment.
* Corresponding author. Fax: +81-86-251-8021; e-mail: inokuchi@biotech.okayama-u.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00163-6

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H. Kawafuchi, T. Inokuchi / Tetrahedron Letters 43 (2002) 2051–2054
bis(trimethylsiloxy)cyclobutene (4) and a-bromoketone
dimethyl acetal 5 by use of BF3·Et2O, giving the
adducts 6, was followed by treatment with Yb(OTf)3 at
room temperature to afford 1 as a result of the pinacol-
type rearrangement of 6. Typically, the compound 1c
(R=C6H4OMe-4) was obtained in 71% overall yield
from 5c (Scheme 2).
In a previous paper, we reported the cobalt-mediated
electroreduction of 2-alkyl-2-bromomethylcycloalka-
nones, giving the corresponding one carbon-enlarged
2-cycloalkenenones. This can be best explained by the
1,2-acyl rearrangement of the 3-oxomethyl radical,
which is followed by the concomitant recombination of
the homologated cycloalkyl radical with the cobalt(II)
species and the subsequent b-elimination of the thus-
formed alkyl-cobalt complex.6d However, this enone
synthesis was not viable with the substrates examined in
this study. Since the amount of 2-methylcyclopentane-
1,3-diones 11, possibly produced from either the radical
i or the anionic species v, was very small, the radical
process was considered to be dominant for the present
1,2-acyl rearrangement reaction (Scheme 3).13 We antic-
ipated that the 2-oxoalkyl radical intermediate iii
formed by the 1,2-acyl rearrangement of 1 via i and ii
was less reactive towards the cobalt(II) reagent to form
the alkyl-cobalt complex because this species was stabi-
lized by delocalization with the adjacent carbonyl
group,14 and then converted to the anionic species iv by
electrochemical one-electron reduction, producing the
saturated 2 after protonation. Similarly, the formation
of 10 from the b-keto ester derivative 9 was also
explained along this line (Table 1, entry 5). In the case
of the acetal 7 (entries 3 and 4), on the other hand, the
radical intermediate after the rearrangement is likely to
be hindered by the neighboring acetal group to form
the alkyl-cobalt intermediate, and then converted to the
saturated 8 by the subsequent one-electron reduction
and protonation.
The electrochemical reactions were carried out in the
same manner as reported without adding 40% NaOH
and the electricities were passed until most of the
substrates were consumed.11 As shown in Table 1, the
electrolysis of the 2-methylcyclopentane-1,3-dione 1a
produced the desired cyclohexane-1,4-dione 2a in 61%
yield. However, in this case, formation of a small
amount of methyl 4-oxo-5-methyl-5-hexenoate (3%)
was found as a result of retro-Claisen condensation and
elimination of the bromide ion presumably due to an
electrogenerated base such as Zn(OMe)2. To our disap-
pointment, the 2-aryl derivative 2c was more suscepti-
ble to ring cleavage with electrogenerated bases,
forming not the desired 1,4-cyclohexanedione but the
ring-opened 4-oxo-5-hexenoate. Subsequently, in order
to avoid the retro-Claisen condensation, the cyclopen-
tane-1,3-diones 1 with alkyl and aryl substituents were
protected as monoacetals 7 and then submitted to the
electrolysis. In the event, the desired cyclohexane-1,4-
dione monoacetals 8 were obtained cleanly in 69–74%
yields by the electroreduction of 7 with cobaloxime.12
However, in these cases, the desired 2-cyclohexenones
were not found.6c,d
OCH3
(CH3)3SiO
OSi(CH3)3
OSi(CH3)3
OCH3
Br
CH3O
R
Yb(OTf)3
or
BF3•Et2O
CH2Cl2
- 70 oC
1
Br
+
R
CF3CO2H
O
4
5
6
Scheme 2.
Table 1. Electrochemical cobaloxime-mediated radical 1,2-acyl rearrangementsa

H. Kawafuchi, T. Inokuchi / Tetrahedron Letters 43 (2002) 2051–2054
2053
Scheme 3.
Table 2. Reductions of 2-aryl 1 with Bu3SnH in benzenea
Products, Yield, %b
Hydroquinones 3
Substrates 1
Reflux
h
Entry
Cyclohexane-1,4-diones 2
R
--
46
75
--
1
2
12
44
Ph
b
c
--
42
70
--
3
4
18
40
OMe
Me
--
43
75
--
5
6
4
42
d
e
48
--
7
29
aCarried out by using 1 (0.13~0.19 mmol), n-Bu3SnH (1.2 eq.) and AIBN (0.1 eq.) in benzene (3 mL)
at reflux. bIsolated yields by column chromatography (SiO2).
We next examined the Bu3SnH-induced radical rear-
Acknowledgements
rangement of aryl-substituted 1. When carried out in
benzene for about 12–18 h, 2-arylcyclohexane-1,4-
diones 2 were, as expected, produced as a result of the
usual radical 1,2-acyl rearrangement. However, when
the reactions were prolonged for about 40 h,
hydroquinones 3 were obtained as a major product.
This aromatization of 2 to 3 was only found with the
aryl derivatives; no aromatization was detected with
alkyl derivative 2a (R=Me). As shown in Table 2,
biaryls substituted with a hydroquinone ring are gener-
ally formed, though in moderate yields (42–48%).12 At
present, we are unable to explain the aromatization of
the aryl substituted cyclohexane-1,4-diones under the
conditions using a reducing reagent. However, we have
found that this kind of aromatization occurred by
heating 2 with tributylditin ((Bu3Sn)2) which was pro-
duced in the radical rearrangement of 1 with Bu3SnH.
For example, treatment of 2b with 1.2 equiv. of
(Bu3Sn)2 in refluxing benzene for 43 h produced 3b
(36% yield) and the recovery of 2b (12%).15 Further
experiments to gain mechanistic insight into this phe-
nomenon are under investigation.
This work was supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Culture,
Sports, Science and Technology, Japan (T.I. and H.K.).
We are grateful to SC NMR Laboratory of Okayama
University for high-field NMR experiments and Shiono
Koryo Kaisha, Ltd for GC–MS analyses.
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2054
H. Kawafuchi, T. Inokuchi / Tetrahedron Letters 43 (2002) 2051–2054
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