Abnormal Ito-Saegusa oxidation of TIPS enol ether assisted by a hydroxy group on a side chain

Article abstract of DOI:10.1016/j.tetlet.2011.03.119

Although Ito-Saegusa oxidation gives defined α,β-unsaturated ketones from silyl enol ether of ketones controlled by the position of the sp² carbon of the silyl enol ether, the formation of a regioisomeric product that was oxidized abnormally wa

Full text of DOI:10.1016/j.tetlet.2011.03.119

Tetrahedron Letters 52 (2011) 3079–3082
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Abnormal Ito–Saegusa oxidation of TIPS enol ether assisted by a hydroxy
group on a side chain
⇑
Shiharu Hiraoka, Shinji Harada, Atsushi Nishida
Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263 8522, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Although Ito–Saegusa oxidation gives defined
a,b-unsaturated ketones from silyl enol ether of ketones
controlled by the position of the sp2 carbon of the silyl enol ether, the formation of a regioisomeric prod-
uct that was oxidized abnormally was observed. The structural requirements for the substrates, the con-
ditions, and a plausible mechanism are presented.
Received 5 February 2011
Revised 22 March 2011
Accepted 24 March 2011
Available online 7 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Ito-Saegusa oxidation
Palladium
a,b-Unsaturated ketone
Silys enol ether
1. Introduction
applied to the asymmetric total synthesis of (+)-ent- and (À)-platy-
phyllide (natural).5 During these synthetic studies, we found that
Ito–Saegusa oxidation1 is a well-known reaction for obtaining
the catalytic Ito-Saegusa oxidation of the silyl enol ether of
a
,b-unsaturated carbonyl compounds from silyl enol ether, and is
cyclohexanone derivative 3 gave compound 4, which is the
widely used in organic syntheses.2,3 A catalytic version of this reac-
tion has been developed by Larock, which uses molecular oxygen
as a reoxidant to regenerate Pd(II) species.4 Recently, we reported
a new application of this reaction to the synthesis of b-methoxy-
cyclohexenone, which is a selectively protected cyclohexane-1,3-
dione equivalent, in chiral form. This method was successfully
Table 1
Search for essential functional groups
Entry
6
Time (h)
Products (%)
7
8%
1
2
3
4
6
18
18
26
7a:73%
7a:25%
7a:10%
7b:19%
8a:2%
8a:45%
8b:48%
8c:0%
Scheme 1. Abnormal Ito–Saegusa oxidation in the total synthesis of (+)-ent-
platyphyllide.
⇑
Corresponding author. Tel.: +81 43 290 2907, fax: +81 43 290 2909.
E-mail address: nishida@p.chiba-u.ac.jp (A. Nishida).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.119

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S. Hiraoka et al. / Tetrahedron Letters 52 (2011) 3079–3082
Table 2
Screening of reaction conditions
Entry
Pd(OAc)2 (eq)
Conc (M)
Temp. (°C)
Time (h)
10 (%)
11 (%)
Recovery (%)
1
2
3
4
5
1.1
1.1
1.1
1.1
2
0.4
1
0.1
0.1
0.1
rt
rt
rt
60
rt
36
22
7 days
36
48
12
13
11
Trace
Trace
41
36
42
19
23
—
—
—
21
—
Table 3
Substrate scope and limitations
Si
O
O
O
+
HO
Pd(OAc)2 (1.1 eq)
+
MeCN (0.4 M), rt
R
R
R
R
12
13
14
15
Entry
12
Time (h)
Products
13
14
15
HO
TIPSO
14a:11 = 5:1
23%
OH
1
2
23
22
10:25%
CHO
15a: 17%
12a
TIPSO
OH
13a:13%
14b:39%
15b:0%
12b
TIPSO
TIPSO
14c:14b = 1:0.7
4%
OH
3
4
23
24
13a:26%
13b:8%
15b:7%
15c:0%
12c
14d:0%
OH
12d
Scheme 4. Examination of isomerization under acidic conditions.
Scheme 2. Abnormal Ito–Saegusa oxidation of 16.
Reactions were performed with stoichiometric palladium acetate
in acetonitrile, which are the standard conditions for Ito–Saegusa
oxidation.1 The bulkiness of a silyl group had a significant effect
on the formation of isomer 8a (entries 1–2). The relative stereo-
chemistry of the substituents changed the ratio between the nor-
mal enone product and its regioisomer (entry 3). When the free
hydroxy group was protected, the isomer was not observed at all
(entry 4). This result showed that the free hydroxy group is essen-
tial for abnormal oxidation. As a result, a free hydroxy group and
bulky silyl group were necessary for obtaining the isomer.
Scheme 3. Isomerization of olefin under acidic conditions by Danishefsky et al.
mechanistically expected oxidized product, along with isomer 5 as
a minor product (Scheme 1). In this Letter, we report the structural
requirements for the substrates, the reaction conditions, and
mechanistic aspects of this abnormal oxidation.
We also observed that there was no difference between a meth-
oxy group and methyl group at the b position7 (Table 2, entry 1).
We then screened the reaction conditions using 9 as a substrate.
A higher concentration affected the ratio of the isomer to the
We initially studied the effect of functional groups of compound
3, such as TES–enol ether6 and a hydroxy group (Table 1).

S. Hiraoka et al. / Tetrahedron Letters 52 (2011) 3079–3082
3081
Figure 1. Plausible mechanism of olefin isomerization.
normal oxidation product, while a lower concentration had no ef-
fect and only increased the reaction time (entries 2–3). At 60 °C,
the reaction was not completed, probably due to decomposition
of the active palladium species (entry 4). Although excess palla-
dium accelerated the reaction, the total yield was reduced (entry
5). The best conditions were those in entry 1, which are the same
as those originally reported by Ito and Saegusa.1,8
We then examined the substrate generality (Table 3). The reac-
tivity of trans substrate 12a was different from that of cis 9, and
gave a 1:1 mixture of normal and abnormal products, along with
overoxidized phenol 15a (entry 1). The abnormal isomers were ob-
tained as a 5:1 mixture of diastereomers. With a trans substrate,
tertiary alcohol 12b, the ratio of isomer to normal oxidation prod-
uct was increased (entry 2). However, with cis substrate 12c, the
abnormal isomers were obtained in very low yield and partially
epimerized (entry 3). When the secondary alcohol 12d was used
as a substrate, decomposition of the substrate mainly occurred (en-
try 4).
(Table 3, entries 1 and 3), since the product 29 was not epimerized
under the reaction conditions.10 Further studies on the roles of
each functional group are in progress.
In conclusion, we observed abnormal Ito–Saegusa oxidation by
using substrates with a TIPS enol ether and a free hydroxy group on
the side chain. A mechanistic study indicated that palladium(II)
species were necessary for production of the abnormal isomer.
Oxidation of 16, which is not suitable for normal Ito-Saegusa oxi-
dation gave the enone compound, and represents a new synthetic
tool in organic synthesis.11 This work demonstrated a new applica-
tion of Ito-Saegusa oxidation and a new palladium chemistry.
2. Experimental
2.1. General procedure for the Ito–Saegusa oxidation (6c to 7a
and 8b)
A solution of 6c (94 mg, 0.3 mmol) in MeCN (750 lL) was added
Surprisingly, dimethyl derivative 16, which is not a substrate of
Pd(OAc)2 (72 mg, 0.33 mmol) and stirred for 18 h at rt. The mixture
was diluted with CH2Cl2 (3 mL) and filtered through a CeliteÒ pad.
After volatile material was removed under reduced pressure, the
resulting residue was purified by column chromatography (SiO2,
hexane/AcOEt = 1/1) to give 7a (4.5 mg, yield 10%) as a colorless so-
lid and 8b (22.5 mg, yield 48%) as a colorless solid.
normal Ito-Saegusa oxidation, gave 17 as
a single product
(Scheme 2).
Finally, we designed a mechanistic experiment to prove that
palladium participates in isomerization, since olefin isomerization
under acidic conditions has already been reported by Danishefsky
(Scheme 3).6b
2.1.1. 4-(Hydroxymethyl)-3-methoxycyclohex-2-enone (7a)
1H NMR (CDCl3, 400 MHz) d 1.84 (1H, br s), 1.95–2.12 (2H, m),
2.34 (1H, ddd, J = 5.2, 9.6, 14.8 Hz), 2.51 (1H, ddd, J = 5.2, 5.8,
12.0 Hz), 2.67–2.73 (1H, m), 3.73 (3H, s), 3.84 (2H, br s), 5.43
(1H, s); 13C NMR (CDCl3, 100 MHz) d 23.8, 34.6, 41.1, 55.8, 62.8,
103.1, 178.4, 199.7; IR(neat) 3384, 1631, 1583 cmÀ1; HRMS(ESI)
Calcd for C16H24O6Na 335.1471. Found 335.1477.
However, in the presence of one equivalent of acetic acid in-
stead of palladium acetate, no isomerization occurred (Scheme 4).
Furthermore, no conversion of normal oxidation product 10 into
abnormal product 11 was observed under the reaction conditions.9
Based on these experiments, we propose that production of the
isomer from silyl enol ether should be triggered by palladium(II)
species and offers the reaction mechanism as shown in Figure 1.
When the silyl group is TMS or TES, the silyl ether is cleaved to
generate intermediate 22, which leads to enone 23 via b-hydride
elimination. A stable TIPS group may help to stabilize the oxonium
cation intermediate 24. The hydroxy group may coordinate to pal-
ladium atom intramolecularly and stabilize the intermediates 24–
26. The length of the side chain is important for ligation of a hydro-
xy group to palladium (Table 3, entry 4). The oxonium cation inter-
mediate 28 may be epimerized to give a mixture of diastereomers
2.1.2. cis-4-(Hydroxymethyl)-5-methoxycyclohex-2-enone (8b)
1H NMR (CDCl3, 400 MHz) d 2.62 (1H, dd, J = 3.6, 16.8 Hz), 2.86
(1H, br s), 2.88 (1H, dd, J = 6.4, 16.8 Hz), 2.88–2.93 (1H, m), 3.42
(3H, s), 3.88 (1H, dd, J = 3.6, 11.2 Hz), 3.94 (1H, dd, J = 6.8,
11.2 Hz), 4.09 (1H, ddd, J = 3.6, 3.6, 6.4 Hz), 6.13 (1H, dd, J = 2.4,
10.4 Hz), 6.85 (1H, dd, J = 3.6, 10.4 Hz); 13C NMR (CDCl3,
100 MHz) d 40.4, 42.3, 56.6, 62.8, 79.1, 130.5, 147.6, 197.0; IR(neat)

3082
S. Hiraoka et al. / Tetrahedron Letters 52 (2011) 3079–3082
3420, 1663 cmÀ1; HRMS(FAB) Calcd for C16H24O6Na 335.1471.
Found 335.1483.
2. For recent examples in 2010–2011, see: (a) Yoshimura, F.; Takahashi, Y.;
Tanino, K.; Miyashita, M. Chem. Asian J. 2011, 6, 922; (b) Han, Y.; Zhu, L.; Gao, Y.;
Lee, C.-S. Org. Lett. 2011, 13, 588; (c) Liu, J.; Lotesta, S. D.; Sorensen, E. J. Chem.
Commun. 2011, 47, 1500; (d) Xue, Y.-P.; Li, W.-D. Z. J. Org. Chem. 2011, 76, 57;
(e) Kim, N.-J.; Moon, H.; Park, T.; Yun, H.; Jung, J.-W.; Chang, D.-J.; Kim, D.-D.;
Suh, Y.-G. J. Org. Chem. 2010, 75, 7458; (f) Shimizu, Y.; Shi, S.-L.; Usuda, H.;
Kanai, M.; Shibasaki, M. Tetrahedron 2010, 66, 6569; (g) Burns, A. R.; McAllister,
G. D.; Shanahan, S. E.; Taylor, R. J. K. Angew. Chem., Int. Ed. 2010, 49, 5574; (h)
Zhang, Y.; Danishefsky, S. J. J. Am. Chem. Soc. 2010, 132, 9567; (i) Furuta, H.;
Hasegawa, Y.; Hase, M.; Mori, Y. Chem. Eur. J. 2010, 16, 7586; (j) McLachlan, M.
M. W.; O’Connor, P. D.; Fairweather, K. A.; Willis, A. C.; Mander, L. N. Aust. J.
Chem. 2010, 63, 742; (k) Chen, G.-H.; Chen, Y.-K.; Sha, C.-K. Org. Lett. 2010, 12,
1377; (l) Flick, A. C.; José, M.; Caballero, A.; Lee, H. I.; Padwa, A. J. Org. Chem.
2010, 75, 1992; (m) Berhal, F.; Pérard-Viret, J.; Royer, J. Tetrahedron Asymmetry
2010, 21, 325; (n) Shimizu, Y.; Shi, S.-L.; Usuda, H.; Kanai, M.; Shibasaki, M.
Angew. Chem., Int. Ed. 2010, 49, 1083.
2.2. Procedure for abnormal Ito–Saegusa oxidation of 16
A solution of 16 (18.8 mg, 0.06 mmol) in MeCN (150 lL) was
added Pd(OAc)2 (14.4 mg, 0.066 mmol) and stirred for 23 h at rt.
The mixture was diluted with CH2Cl2 (1 mL) and filtered through
a CeliteÒ pad. After volatile material was removed under reduced
pressure, resulting residue was purified by column chromatogra-
phy (SiO2, hexane/AcOEt = 1/1) to give 17 (4.3 mg, yield 51%) as a
colorless solid.
3. For a recent review of Pd(II)-mediated oxidation to obtain
a,b-unsaturated
carbonyl compounds, see: Muzart, J. Eur. J. Org. Chem. 2010, 3779.
4. Larock, R. C.; Hightower, T.; Kraus, G. A.; Hahn, P.; Zheng, D. Tetrahedron Lett.
1995, 36, 2423.
5. Hiraoka, S.; Harada, S.; Nishida, A. J. Org. Chem. 2010, 75, 3871.
6. For examples of the use of TES enol ether in Ito-Saegusa oxidation, see: (a)
Danishefsky, S. J.; Uang, B. J.; Quallich, G. J. J. Am. Chem. Soc. 1985, 107, 1285;
(b) Angeles, A. R.; Waters, S. P.; Danishefsky, S. J. J. Am. Chem. Soc. 2008, 130,
13765.
2.2.1. 4-(Hydroxymethyl)-5,5-dimethylcyclohex-2-enone (17)
1H NMR (CDCl3, 400 MHz) d 0.95 (3H, s), 1.14 (3H, s), 1.51 (1H,
brs), 2.33 (2H, d, J = 3.6 Hz), 2.40–2.45 (1H, m), 3.64–3.70 (1H, m),
3.94–3.97(1H, m), 6.11 (1H, dd, J = 2.0, 10.0 Hz), 6.96 (1H, dd,
J = 2.8, 10.0 Hz); 13C NMR (CDCl3, 100 MHz) d 22.6, 29.1, 35.8,
48.9, 52.2, 61.6, 129.2, 149.9, 199.7; IR(neat) 3412, 1666 cmÀ1
HRMS(ESI) Calcd for C18H28O4Na 331.1885. Found 331.1876.
;
7. Successful examples of Ito–Saegusa or other oxidations with a b-ethereal group
have been limited to hydropyran- or hydrofuran-type compounds. See Ref. 5
and references therein.
Acknowledgments
8. Other palladium sources (PdCl2, PdS, and Pd(CN)2) and solvents (THF, DMF,
DMSO, and CH2Cl2) were also examined. However, they were not suitable for
this reaction.
9. 10 was subjected to the reaction conditions (1 equiv of Pd(OAc)2, MeCN, rt,
24 h) and no reaction occurred.
This work was supported by a Grant-in-Aid for Scientific Re-
search (B) and a Grant-in-Aid for Young Scientists (B) from JSPS
and MEXT.
10. 11 was subjected to the reaction conditions (1 equiv of Pd(OAc)2, MeCN, rt,
24 h) and no epimerization occurred.
11. The abnormal oxidation of
9
was observed under catalytic conditions4
References and notes
(20 mol % of Pd(OAc)2 under oxygen atmosphere at 80 °C) to give 10 (yield
37%) and 11 (yield 34%). Furthermore, the catalytic abnormal oxidation of 16
was also observed under the same conditions to give 17 (yield 39%).
1. Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011.