Synthesis of medium-sized cyclic γ-haloketones by radical mediated ring-opening reaction of Lewis acid catalyzed (2+2)-cycloaddition products

Article abstract of DOI:10.1016/j.tetlet.2004.12.024

Novel entry to synthesize medium-sized cycloalkanones is described. Thus, employment of catalytic (2+2)-cycloaddition for cyclic silyl enol ether followed by radical mediated ring-opening reaction provided medium-sized γ-halocycloalkanones.

Full text of DOI:10.1016/j.tetlet.2004.12.024

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Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1005–1008
Synthesis of medium-sized cyclic c-haloketones by radical
mediated ring-opening reaction of Lewis acid catalyzed
(2+2)-cycloaddition products
Kiyosei Takasu,* Satoshi Nagao and Masataka Ihara*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University,
Aobayama, Sendai 980-8578, Japan
Received 1 October 2004;revised 7 December 2004;accepted 8 December 2004
Abstract—Novel entry to synthesize medium-sized cycloalkanones is described. Thus, employment of catalytic (2+2)-cycloaddition
for cyclic silyl enol ether followed by radical mediated ring-opening reaction provided medium-sized c-halocycloalkanones.
Ó 2004 Elsevier Ltd. All rights reserved.
Synthesis of medium-sized ring system is one of the chal-
(2+2)-
[Si]O
lenging and intriguing issues in synthetic chemistry,1
since there exist many natural products showing attrac-
tive biological activities. Among several approaches re-
ported, ring cleavage reaction of bicyclic framework is
one of the promising entries for the construction of med-
ium-sized cyclic compounds. In this communication, we
describe ring transformation reaction of cyclic silyl enol
ethers into c-halocycloalkanones by means of catalytic
(2+2)-cycloaddition followed by radical cleavage
reaction.
EWG
R
O[Si]
cycloaddition
ref. 2
EWG
+
O
X
radical ring-
opening reaction
OH
R
Scheme 1. Our strategy for formation of medium-sized cyclic ketones.
We recently reported Lewis acid catalyzed (2+2)-cyclo-
addition of silyl enol ethers and a,b–unsaturated esters
to give substituted cyclobutanols in high yields.2 As
the extension of our findings, we envisaged the (2+2)-
cycloadducts would be a potential precursor for med-
ium-sized cycloalkanones by the cleavage of a ring fu-
sion C–C bond (Scheme 1). There have been reported
several methods for ring opening of cyclobutanols,3 such
as ionic C–C cleavage reaction,4 radical mediated b-scis-
sion5 and transition metal catalyzed reaction.6 As the re-
sults of our preliminary examinations, radical mediated
reaction has been selected for this project on account of
good productivity in the desired reaction.
Bicyclic cyclobutanols 1a–f as substrates for the ring
cleavage reaction were prepared by our reported method
with some modification. Namely, reaction of cyclic silyl
enol ether 2a with hexafluoroisopropyl acrylate in the
presence of a catalytic amount of EtAlCl2 gave bicy-
clo[4.2.0]octane 3a. After reduction of ester trans-3a,
4a was converted into 1a by desilylation of tertiary
alcohol, followed by TBDPS-protection of the resulted
diol 5a (Scheme 2). Substrate 1f, which is a diastereomer
of 1b having opposite stereochemistry of siloxymethyl
substituent, was prepared from cis-3b by the same
sequence.
Next, radical reaction of 1a was examined under several
conditions to generate an alkoxyl radical (Table 1).
The reaction would promote through radical fragmenta-
tion (atom transfer reaction) of alkoxyl radical, which
would be generated from the corresponding hypoiodite.
Keywords: Medium-sized cycloalkanones;Ring-opening reaction;
Cyclobutanols;Alkoxyl radicals;(2 + 2)-Cycloaddition.
*
Corresponding authors. Tel.: +81 22 217 6887;fax: +81 22 217
6878;e-mail addresses: kay-t@mail.pharm.tohoku.ac.jp;mihara@
mail.pharm.tohoku.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.024

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1006
K. Takasu et al. / Tetrahedron Letters 46 (2005) 1005–1008
promoted the desired ring-opening reaction to furnish
c-iodocyclooctanone 6a as a 1:1 mixture of two diaste-
reomers in 24% yield (Table 1, entry 1).7,8 Stereochemis-
try of both diastereomers were determined by NOE
measurements. When using 3 equiv of HgO, chemical
yield of 6a was improved to 64% (Table 1, entry 2).
When the radical reaction was carried out using
PhI(OAc)2, the desired ketone 6a was obtained in high
yields under whether photoirradiation or thermal condi-
tions (Table 1, entries 3 and 4).9 Irradiation of ultrasonic
accelerated the radical reaction under the thermal condi-
tions. The thermal reaction required less amount of re-
agents (iodine and hypervalent reagent) than
photoreaction.
TBSO
CO2CH(CF3)2
CO2CH(CF3)2
OTBS
EtAlCl2 (0.2 eq.)
CH2Cl2, —78 °C
n H
n
trans : cisa
3a: 93% (93 : 7)b
3b: 74% (60 : 40)b
3c: 82% (100 : 0)b
3d: 48% (100 : 0)
2a (n = 2)
2b (n = 1)
2c (n = 3)
2d (n = 4)
TBSO
OH
TBAF
THF, reflux
LiAlH4
OH
OH
THF, 0 °C
n H
n H
for trans-3
5a: 100%
5b: 90%
5c: 96%
5d: 96%
4a: 80%
4b: 92%
4c: 93%
4d: 93%
N-Iodo succinimide (NIS) as a source of iodonium cation
instead of molecular iodine promoted the desired radical
reaction to give 6a in medium to good yield (Table 1, en-
tries 5 and 6), although substrate 1a was not completely
consumed. Further exploration found addition of a cata-
lytic amount of cuprous(I) iodide enhanced the reac-
tion rate and improved chemical yields of 6a without
irradiation of ultrasonic (Table 1, entry 7)10 Although
the action mechanism of CuI in the radical ring-opening
reaction is still unclear, we guess CuI accelerates the
transformation of alcohol 1 into the corresponding
hypoiodite. The reaction using NIS–CuI proceeded
smoothly in toluene or cyclohexane (Table 1, entries 8
and 9). The optimized conditions (NIS–CuI) would be
estimated as a rather convenient alternative for the rad-
ical b-scission reaction compared by the other condi-
tions. On the other hand, only trace amount of the
desired product was obtained under NBS–CuBr
conditions.
TBDPSCl,
imidazole
OH
OH
OTBDPS
OTBDPS
DMF, rt
n H
H
1f
1a: 81%
1b: 84%
1c: 76%
1d: 76%
90% from cis-3b
in 3 steps
i) methyl acrylate,
EtAlCl2 (0.2 eq)
ii) DIBAL
OH
OTBS
OTBDPS
iii) TBAF
iv) TBDPSCl,
imidazole
2e
1e
40% from 2e in 4 steps
Scheme 2. atrans-isomer: a-ester, cis-isomer: b-ester. See Ref. 2a.
b
Next, radical ring-opening reactions of alcohol 1b–1f to
synthesize medium-sized c-iodocycloalkanones were
examined under two conditions, such as NIS–CuI (con-
dition A) and PhI(OAc)2–I2 (condition B). Reaction of
Photoinduced reaction of 1a in the presence of HgO
(1 equiv) and I2 (3 equiv) using high pressure Hg lump
Table 1. Radical mediated ring-opening reaction of 1a under various conditions
O
I
O
O
O
R
R
conditions
R
OTBDPS
1
n H
n H
n
n
I
6
Entry
Conditions
Solvent
Temp (°C)
Time (h)
% Yield of 6ad
1
2
3
4
5
6
7
8
9
HgO (1 equiv), I2 (3 equiv), hm
HgO (3 equiv), I2 (3 equiv), hm
PhI(OAc)2 (2 equiv), I2 (3 equiv), hm
PhI(OAc)2 (1.4 equiv), I2 (1.4 equiv), ultrasonic
NIS (1.2 equiv)
Benzene
Benzene
Benzene
rt
6.0b
2.0c
2.0c
0.5c
8.5b
5.0b
2.0c
1.0c
3.5c
24
64
81
74
50
70
80
60
84
rt
rt
45
Cyclohexane/benzenea
CH2Cl2
Reflux
Reflux
Reflux
95
NIS (1.2 equiv)
Cyclohexane/benzenea
Cyclohexane/benzenea
Toluene
NIS (1.2 equiv), CuI (0.1 equiv)
NIS (1.2 equiv), CuI (0.1 equiv)
NIS (1.2 equiv), CuI (0.1 equiv)
Cyclohexane
Reflux
a Cyclohexane–benzene = 10:1.
b Starting material was still remained at the time.
c Reaction was stopped after 1 was completely consumed.
d Compound 6a was obtained as a ca. 1:1 diastereomeric mixtures in all entries.

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K. Takasu et al. / Tetrahedron Letters 46 (2005) 1005–1008
1007
addition product 82a was further investigated. As ex-
pected, the desired b-scission reaction promoted under
the condition B to furnish iodobicyclo[5.3.0]decanones
10 and bicyclo[5.3.0]decenones 11 as inseparable mix-
tures in 8% and 65% yields, respectively. 11 could be ob-
tained by the elimination reaction of 10 (Scheme 3).
Table 2. Synthesis of 7 to 10-membered c-iodocycloalkanones by
radical mediated ring-opening reaction
Entry
Substrate
Conditionsa
Product
% Yield
1
2
3
4
5
6
7
8
1b
1b
1c
1c
1d
1d
1e
1f
A
B
A
B
A
B
A
B
6b
6b
6c
6c
6d
6d
6e
6b
88b
92b
30c
76d
3d
In summary, we have demonstrated the synthesis of
medium ring-sized c-iodocycloalkanones from bicy-
clo[n.2.0] compounds, which were readily prepared by
Lewis acid catalyzed (2 + 2)-cycloaddition from cyclic
silyl enol ethers and a,b–unsaturated esters. From the
outset of this paper and our preceding results, combina-
tion of the (2 + 2)-cycloaddition and radical mediated
ring-opening reaction would be a new method for two-
carbon ring-enlargement of cycloalkanones.
62d
Tracee
79b
a (Condition A) NIS (1.2 equiv), CuI (0.1 equiv), toluene, 95 °C,
(condition B) PhI(OAc)2 (1.4 equiv), I2 (1.4 equiv), cyclohexane/
benzene (10:1), 45 °C, sonication.
b Products were obtained as ꢀ1:1 diastereomeric mixtures.
c As ꢀ9:1 diastereomeric mixtures.
d As ꢀ4:1 diastereomeric mixtures.
e Compound 7e was obtained as a mixture of isomers.
O
Acknowledgements
OTBDPS
This work was financially supported by a Grant-in-Aid
from the Ministry of Education, Culture, Sports, Sci-
ence and Technology, Japan.
7e
bicyclo[3.2.0]heptanol 1b under the condition A in tolu-
ene provided c-iodocycloheptanone 6b in 88% yield as a
1:1 mixture of diastereomers (Table 2, entry 1). How-
ever, reaction of alcohol 1c and 1d under condition A re-
sulted in poor productions of 6 and a lot of unknown
by-products formed (Table 2, entries 3 and 5). On the
other hand, reaction of 1b–d under condition B afforded
the corresponding 6b–d in 62–92% yield (Table 2, entries
2, 4 and 6). In the reaction of 1e, which possesses methyl
substituent at the position of ring juncture, trace
amount of desired product 6e but dehydrohalogenated
product 7e was obtained as a mixture of regioisomeric
olefins under condition A. No significant effect of the
stereochemistry of a-substituent of 1 was observed in
the radical ring-opening reaction. Thus, the reaction of
1f afforded 6b, which is the same product from diaste-
reomer 1b, in 79 % yield as a 1:1 diastereomeric mixture
(Table 2, entry 8 vs Table 1, entry 4).
References and notes
1. (a) Hesse, M. Ring Enlargement in Organic Chemistry;
VCH: Weinheim, 1991;(b) Yet, L. Tetrahedron 1999, 55,
9349–9403.
2. (a) Takasu, K.;Ueno, M.;Inanaga, K.;Ihara, M. J. Org.
Chem. 2004, 69, 517–521;(b) Takasu, K.;Nagao, S.;
Ueno, M.;Ihara, M. Tetrahedron 2004, 60, 2071–2078;
(c) Inanaga, K.;Takasu, K.;Ihara, M.
J. Am. Chem.
Soc. 2004, 126, 1352–1353;(d) Ihara, M.;Ohnishi, M.;
Takano, M.;Makita, K.;Taniguchi, N.;Fukumoto, K. J.
Am. Chem. Soc. 1992, 114, 4408–4410;(e) Takasu, K.;
Misawa, K.;Yamada, M.;Furuta, Y.;Taniguchi, T.;
Ihara, M. Chem. Commun. 2000, 1739–1740;(f) Takasu,
K.;Ueno, M.;Ihara, M. J. Org. Chem. 2001, 66, 4667–
4672.
3. Namyslo, J. C.;Kaufmann, D. E. Chem. Rev. 2003, 103,
1485–1537.
4. (a) Thies, R. W.;Shih, H.-H. J. J. Org. Chem. 1977, 42,
280–281;(b) Winkler, J. D.;Doherty, E. M. J. Am. Chem.
Soc. 1999, 121, 7425–7426;(c) Mislin, G. L.;Miesch, M. J.
Org. Chem. 2003, 68, 433–441.
5. (a) Zhang, W.;Dowd, P. Tetrahedron 1993, 49, 1965–
1978;(b) Kobayashi, K.;Konishi, A.;Itoh, M.;Suginome,
H. J. Chem. Soc., Perkin Trans. 1 1993, 825–829;(c)
Tsunoi, S.;Ryu, I.;Tamura, S.;Yamasaki, N.;Sonoda, N.
Synlett 1994, 1009–1011.
Radical ring-opening reaction of tricyclic compound 9
which was prepared from intramolecular (2+2)-cyclo-
TESO
OH
CO2Me
OTBDPS
i) DIBAL-H
ii) TBAF
6. Nishimura, T.;Ohe, K.;Uemura, S. J. Am. Chem. Soc.
1999, 121, 2645–2646.
iii) TBDPSCl,
imidazole
7. Procedure for photoinduced ring-opening reaction using
HgO-I2: A mixture of 1a (23 mmol, 58 lmol), HgO
(37 mg, 0.17 mmol) and I2 (47 mg, 0.18 mmol) in
degassed benzene (3.8 mL) was irradiated for 2 h, with
Pyrex-filtered light (400 W Hg lump) under Ar atmo-
sphere. After the resulting mixture was filtered through
Celite, the filtrate was diluted with Et2O. The organic
layer was successively washed with 5% aq sodium
thiosulfate and water, dried over Na2SO4 and concen-
trated. The residue was purified by silica gel PTLC
(AcOEt/hexane = 1:9) to give trans-6a (10 mg, 32%) and
cis-6a (10 mg, 32%).
8
9 (82% for 3 steps)
TBDPSO
TBDPSO
O
O
H
H
PhI(OAc)2, I2
+
ultrasonic, 45 °C
I
10 (8%)
11 (65%)
Scheme 3.

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1008
K. Takasu et al. / Tetrahedron Letters 46 (2005) 1005–1008
8. Spectral data for c-iodocyclooctanone 6a. trans-6a: col-
ourless oil, IR (neat) m 2930, 2856, 1697, 1427, 1113, 739,
802 cmÀ1 1H NMR (400 MHz, CDCl3) d 7.66–7.58 (m,
NOE
TBDPSO
O
OTBDPS
H
O
H
NOE
;
4H), 7.47–7.35 (m, 6H), 4.60–4.51 (m, 1H), 3.86 (dd, 1H,
J = 5.8, 10.2 Hz), 3.73 (dd, 1H, J = 6.6, 10.2 Hz), 2.89–
2.79 (m, 1H), 2.70–2.60 (m, 1H), 2.60–2.51 (m, 1H), 2.51–
2.38 (m, 2H), 2.00–1.42 (m, 6H), 1.05 (s, 9H); 13C NMR
(100 MHz, CDCl3) d 216.8, 135.5, 135.4, 133.0, 132.9,
129.7, 127.7, 127.6, 64.2, 53.2, 41.1, 37.2, 37.0, 33.0, 28.4,
27.3, 26.9, 19.3;LRMS m/z 463 (M+À57);HRMS calcd
for C21H24IO2 Si (M+–C4H9): 463.0590;found: 463.0574.
cis-6a: colourless oil, IR (neat) m 2932, 2858, 1703, 1427,
1111, 739, 702 cmÀ1; 1H NMR (400 MHz, CDCl3) d 7.64–
7.57 (m, 4H), 7.48–7.34 (m, 6H), 4.44–4.34 (m, 1H), 3.69
(dd, 2H, J = 2.8, 6.0 Hz), 2.78–2.51 (m, 3H), 2.43–2.33 (m,
1H), 2.30–2.15 (m, 2H), 1.99–1.48 (m, 5H), 1.03 (s, 9H);
13C NMR (100 MHz, CDCl3) d 216.9, 135.5, 135.4, 132.8,
132.7, 129.8, 129.7, 127.7, 65.6, 56.5, 40.6, 40.5, 36.9, 31.6,
27.1, 26.8, 25.1, 19.3;LRMS m/z 463 (M+À57);HRMS
calcd for C21H24IO2Si (M+ÀC4H9): 463.0590;found:
463.0584;Selected NOEs of trans-6a and cis-6a were
shown in the following chart.
H
I
H
I
trans-6a
cis-6a
9. Procedure for ring-opening reaction under PhI(OAc)2–I2
conditions: A mixture of 1a (20 mg, 51 lmol), PhI(OAc)2
(23 mg, 71 lmol) and I2 (18 mg, 69 lmol) in cyclohexane/
benzene (3 mL/0.3 mL) was maintained at 45 °C for
30 min with ultrasonic irradiation. Work-up and purifica-
tion were carried out as the similar manner as above to
give 6a (20 mg, 74%) as a mixture of diastereomers.
10. Procedure for ring-opening reaction under NIS–CuI
conditions: A mixture of 1a (17 mg, 44 lmol), NIS
(12 mg, 52 lmol) and CuI (0.9 mg, 4.7 lmol) in cyclohex-
ane (2.9 mL) was refluxed for 3.5 h. Work-up and puri-
fication were carried out as the similar manner as above to
give 6a (19 mg, 84%) as a mixture of diastereomers.