Reductive radical cyclization of cyclic γ-cyanoketones promoted by samarium(II) iodide without photoirradiation

Article abstract of DOI:10.1016/S0040-4039(01)01579-9

Reaction of cyclic γ-cyanoketones with 3 equiv. of SmI₂ in the presence of t-BuOH as a proton source in HMPA-THF without photoirradiation gave the desired α-hydroxycycloalkanones along with overreduced ketones after hydrolysis. In the absence of t-BuOH, the formation of the overreduced ketones was depressed and the yields of the α-hydroxyketones increased, while the reaction proceeded slowly.

Full text of DOI:10.1016/S0040-4039(01)01579-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7595–7598
Reductive radical cyclization of cyclic g-cyanoketones promoted
by samarium(II) iodide without photoirradiation
a,
b
a
a
a
Kiyomi Kakiuchi, * Yasunari Fujioka, Hirohisa Yamamura, Ken Tsutsumi, Tsumoru Morimoto
b
and Hideo Kurosawa
a
Graduate School of Materials Science, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama, Ikoma,
Nara 630-0101, Japan
b
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
Received 23 July 2001; accepted 24 August 2001
Abstract—Reaction of cyclic g-cyanoketones with 3 equiv. of SmI in the presence of t-BuOH as a proton source in HMPA–THF
2
without photoirradiation gave the desired a-hydroxycycloalkanones along with overreduced ketones after hydrolysis. In the
absence of t-BuOH, the formation of the overreduced ketones was depressed and the yields of the a-hydroxyketones increased,
while the reaction proceeded slowly. © 2001 Elsevier Science Ltd. All rights reserved.
In extension of our study on the development of new
skeletal transformations and their application, we have
recently found a radical ring-opening reaction of 6-
cyanobicyclo[4.2.0]octan-2-one (1) promoted by SmI2
gives 1-hydroxybicyclo[3.3.1]nonan-9-one (3) in high
yield along with a small amount of 5-cyanocyclo-
reduction of the ketone by SmI forms the ketyl radical
2
A, which goes 5-exo-dig cyclization to produce the
iminyl radical B. Further reduction by SmI followed
2
by acidic hydrolysis of the samarium species C gives the
hydroxycyclopentanone. Since a cyanoethyl group can
be easily introduced at the a-position of a carbonyl
group via the well-documented cyanoethylation, the
establishment of this reaction can offer a method for
the construction of the five-membered ring utilizing the
carbonyl group. There are several examples for ketyl-
1
octanone (2). Similar treatment of the cyanoketone 2
furnished the hydroxyketone 3 quantitatively. These
results suggested that the ketone 3 is produced by
intramolecular ketyl-nitrile cyclization of the primary
product, the cyanoketone 2, which is formed through
radical-fission of the central cyclobutane bond (C1ꢀC6)
of the ketone 1. The finding prompted us to investigate
the intramolecular ketyl-nitrile cyclization of cyclic g-
2
nitrile cyclization promoted by Zn/TMSCl, by
3
4
Cp TiPh, and by electrochemical reduction. Although
2
a few reports of SmI -mediated reaction have also
2
5,6
appeared, the yields were not satisfactory and the
substrates were limited. During this study, Molander
and Wolfe reported an efficient method of the ketyl-
cyanoketones
4
to a-hydroxycyclopentanones
5
prompted by SmI (Scheme 1). Namely, one-electron
2
CN
CN
CN
6
H+
SmI , t-BuOH
2
+
HMPA, THF, rt
1
OH
O
OSmI2
O
2
2%
3 88%
1
N
N
NSmI2
C
SmI , t-BuOH
SmI2
H+
2
2
3
HMPA, THF, rt
9
9%
OSmI2
OSmI2
OSmI2
Keywords: samarium(II) iodide; g-cyanoketone; reductive radical cyclization; a-hydroxycycloalkanone.
*
Corresponding author. Tel.: +81-743-72-6080; fax: +81-743-72-6089; e-mail: kakiuchi@ms.aist-nara.ac.jp
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
0
PII: S0040-4039(01)01579-9

7
596
K. Kakiuchi et al. / Tetrahedron Letters 42 (2001) 7595–7598
O
OH
O
SmI2 (3eq), HMPA, THF, rt
n
n
then H3O+
CN
H
4
5
SmI2
H+
NSmI2
SmI2O
n
N•
SmI2O
n
SmI2O
N
5-exo-dig
SmI2
•
C
n
H
H
A
B
C
Scheme 1.
1
1
nitrile cyclization using SmI activated by irradiation of
visible light. We wish to report here a systematic study
7). However, the higher homologue 4f did not give the
2
7
desired product on using 4 equiv. of SmI and 4 equiv.
of t-BuOH (entry 8).
2
of ketyl-nitrile cyclization of cyclic g-cyanoketones pro-
8
moted by SmI without photoirradiation.
2
4
Like electrochemical reactions, the diquinane cyano-
Reactions of various g-cyanoketones 4 with 3 equiv. of
ketones 4g and 4h, prepared by cyanoethylation of 6a,
also gave the linearly fused triquinane ketones 5g and the
angularly fused triquinane ketone 5h in moderate yields,
respectively (entries 9 and 10).
SmI were carried out in the presence or absence of 3
2
9
equiv. of t-BuOH in HMPA (20 equiv.) and THF at
room temperature, and the results are summarized in
1
0
Table 1. Reaction of g-cyanoethylcyclopentanone 4a in
the presence of t-BuOH gave hydroxybicy-
clo[3.3.0]octan-2-one (5a) in 41% yield along with the
overreduced ketone 6a in 11% yield (Table 1, entry 1).
Since the deoxygenated ketone 6a is considered to be
formed from the iminyl species C by protonation and
subsequent dehydration followed by 1,4-reduction of the
resulting a,b-unsaturated imine D (Scheme 2), we carried
out the reaction of 4a in the absence of t-BuOH as a
proton source. Consequently, the yield of 5a increased to
The g-cyanoketones 4i and 4j, which did not produce the
hydroxyketones by electrochemical ketyl-nitrile cycliza-
4
tion, gave the 5-5-6 and 5-6-6 fused ketones 5i and 5j
in good yields, respectively (entries 11 and 12). In the case
of the more hindered substrate, a,a-dimethylcyclopen-
tanone derivative 4k, the cyclized product 5k was
obtained in 94% yield based on the consumed starting
material, though the conversion was 51% (entry 13).
Reactions of the bridged bicyclic ketones 4l and 4m did
not afford the cyclopentane ring-fused products proba-
bly due to the severe steric hindrance, but gave the
corresponding alcohols by reduction of the carbonyl
group.
77% and the formation of 6a was depressed, although the
reaction time was prolonged (entry 2). A similar tendency
was also observed in the case of cyanoethylcyclohex-
anone 4b (entries 3 and 4). Without t-BuOH, the 5-6
fused hydroxyketone 5b was obtained in 82% yield.
Reactions of the higher homologues 4c and 4d furnished
the 5-7 fused compounds 5b and 6b, and the 5-8 fused
ketones 5c and 6c in good yields as a mixture of cis- and
trans-fused diastereomers along with overreduced
ketones, respectively (entries 5 and 6). The yields of
a-hydroxyketones are higher than those obtained by
NC
NC
O
O
OTBS
4l
4m
2
3
4
Zn/TMSCl, Cp TiPh, and electrochemical reductions,
2
and are also comparable to those prepared by SmI -
2
7
photoactivation.
Thus, the ketyl-nitrile cyclization using SmI proceeds
efficiently without photoirradiation to give the corre-
2
In the case of ketone 4e having an ester group at the
a-carbon, the desired a-hydroxyl ketone 5e was obtained
as the sole product even in the presence of t-BuOH (entry
sponding hydroxycylopentanones in high yields, unlike
the report of Molander et al. It may be reasonably
7
presumed that use of 3 equiv. of SmI and enhancement
2
SmI2
HN
NH
O
H
t-BuOH
H2O
SmI2
SmI2
C
n
n
n
then H+
-
•
H
D
6
Scheme 2.

K. Kakiuchi et al. / Tetrahedron Letters 42 (2001) 7595–7598
Table 1. Reductive radical cyclization of g-cyanoketones promoted by SmI2
7597
entry
cyanoketone
t-BuOH
time (h)
product and % isolated yield
O
O
HO
H
O
n
n
n
CN
1
2
3
4
5
6
4a n = 1
4b n = 2
3 eq
–
2
16
0.5
17
24
22
5a 41a
5a 77
5b 73
5b 82
5c 80c
5d 74e
6a 11
6a
6b 17b
6b 4b
6c 14d
6d 18f
4
3 eq
–
4c n = 3
4d n = 4
–
–
O
HO
O
n
n
CN
CO Et
2
CO Et
2
7
8
4e n = 1
4f n = 4g
3 eq
4 eq
3
5e 73
5f
4.5
–
O
O
H
O
HO
CN
H
5g 43a
6g 12i
9
4gh
CN
–
90
O
O
O
O
OH
H
10
4h
3 eq
3
5h 58
6h 29
O
O
H
HO
CN
n
n
n
5i 58a
5j 71
6j 13
1
1
2
4i n = 1
4j n = 2
–
–
17
22
1
6j
5
O
HO
O
CN
5k 48 (94 based on conversion)a
13
4k
–
20
a
b
The starting material was recovered, for 4a: 21%, for 4g: 17%, for 4i: 16%, for 4k: 49%.
A 16 : 84 mixture
c
d
of diastereomers.
The cis- and trans-fused products were obtained in 68% and 12% yields. A 1 : 1 mixture
e
f
of diastereomers. The cis- and trans-fused products were obtained in 49% and 25% yields. A 62 : 38
mixture of diastereomers. 4 equiv. of SmI was used. A 7 : 3 mixture of the cis and trans diastereomers,
and 6 equiv. of SmI was used. A 9 : 1 mixture of anti and syn diastereomers.
g
h
2
i
2
9
of the reactivity of SmI by addition of HMPA raise
Acknowledgements
2
the concentration of the ketyl A and, therefore, that of
the iminyl radical B. Using more than 3 equiv. of SmI2
This research was supported in part by a Grant-in-Aid
for Scientific Research from the Ministry of Education,
Sports, Culture, and Technology, Japan, and Nagase
Science and Technology Foundation.
increases the formation of an overreduced product such
as 6, and using a lesser amount of SmI decreases the
2
conversion of the reaction.

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K. Kakiuchi et al. / Tetrahedron Letters 42 (2001) 7595–7598
99.9%, 496 mg, 3.3 mmol), purchased from High Purity
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1
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