Oxidative rearrangement of cyclic tertiary allylic alcohols with IBX in DMSO

Article abstract of DOI:10.1021/ol048210u

(Chemical Equation Presented) A practical and environmentally friendly method for oxidative rearrangement of five- and six-membered cyclic tertiary allylic alcohols to β-disubstituted α,β-unsaturated ketones by the IBX/DMSO reagent system is described. Several conventional protecting groups (e.g., Ac, MOM, and TBDPS) are compatible under the reaction conditions prescribed.

Full text of DOI:10.1021/ol048210u

ORGANIC
LETTERS
2004
Vol. 6, No. 23
4303-4306
Oxidative Rearrangement of Cyclic
Tertiary Allylic Alcohols with IBX in
DMSO
Masatoshi Shibuya, Shinichiro Ito, Michiyasu Takahashi, and
Yoshiharu Iwabuchi*
Graduate School of Pharmaceutical Sciences, Tohoku UniVersity, Aobayama,
Sendai 980-8578, Japan
iwabuchi@mail.pharm.tohoku.ac.jp
Received September 4, 2004
ABSTRACT
A practical and environmentally friendly method for oxidative rearrangement of five- and six-membered cyclic tertiary allylic alcohols to
-disubstituted -unsaturated ketones by the IBX/DMSO reagent system is described. Several conventional protecting groups (e.g., Ac,
â
r,â
MOM, and TBDPS) are compatible under the reaction conditions prescribed.
Methods enabling the transposition of a functional group
from one carbon to another offer a wide range of latitude in
synthesis of architecturally complex molecules.1 The alky-
lative carbonyl transposition of R,â-unsaturated ketones,2
which entails the 1,2-addition of organometallic reagents to
R,â-unsaturated ketones and the oxidative rearrangement of
the resulting tertiary allylic alcohols to yield â-disubstituted
R,â-unsaturated ketones, is representative of such methods,
and several synthesis achievements relying on this sequence
have been reported in the literature (Scheme 1).3 To our
key oxidation step. We herein report an eco-friendly method
for the oxidative rearrangement of cyclic tertiary allylic
alcohols to â-substituted cyclic ketones.
Regarding the ecological profiles on available oxidizing
agents and the mechanism of the oxochromium(VI)-mediated
oxidative rearrangement where the CrdO substructure plays
crucial roles2,6 (Scheme 2), we presumed that less toxic,
hypervalent iodine-based reagents7 capable of serving an
(1) Schlecht, M. F. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Ley, S. V., Eds.; Pergamon: Oxford, 1991; Vol. 7, pp 815-
837.
(2) (a) Babler, J. H.; Coghlan, M. J. Synth. Commun. 1976, 6, 469. (b)
Dauben, W. G.; Michno, D. M. J. Org. Chem. 1977, 42, 682. (c)
Sundararabhan, P.: Herz, W. J. Org. Chem. 1977, 42, 813.
(3) (a) Mohr, P. J.; Halcomb, R. L. J. Am. Chem. Soc. 2003, 125, 1712.
(b) Hanada, K.; Miyazawa, N.; Ogasawara, K. Org. Lett. 2002, 4, 4515.
(c) Nagata, H.; Miyazawa, N.; Ogasawara, K. Chem. Commun. 2001, 1094.
(d) Trost, B. M.; Pinkerton, A. B. Org. Lett. 2000, 2, 1601. (e) Majetich,
G.; Song, J.-S.; Leigh, A. J.; Condon, S. M. J. Org. Chem. 1993, 58, 1030.
(f) Luzzio, F. A.; Moor, W. J. J. Org. Chem. 1993, 58, 2966 and references
therein. (g) Takano, S.; Inomata, K.; Ogasawara, K. J. Chem. Soc., Chem.
Commun. 1989, 271
Scheme 1. Alkylative Carbonyl Transposition Sequence
(4) For a recent review on an oxochromium(VI)-based oxidant, see:
Luzzio, F. A. Org. React. 1998, 53, 1.
(5) For an eminent review on chromium-catalyzed oxidations, see:
Muzart, J. Chem. ReV. 1992, 92, 113. See also: Riahi, A.; He´nin, F.; Muzart,
J. Tetrahedron Lett. 1999, 40, 2303.
knowledge, however, there is only one method using more
than a stoichiometric amount of hazardous oxochromium-
(VI)-based oxidants4,5 such as PCC and PDC that effects the
10.1021/ol048210u CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/19/2004

Scheme 2. Cr(VI)-Mediated Oxidative Rearrangement of
Table 1. Reaction Properties of Hypervalent Iodine Reagents
Tertiary Allylic Alcohols
IdO structural motif would complementarily surrogate the
function of Cr(VI)-based reagents.
Using 1-phenyl-2-cyclohexen-1-ol (1a), we probed the
ability of a panel of hypervalent iodine compounds to
promote the desired oxidative rearrangement (Table 1).
It was revealed that 1.5 equiv of an iodine(V)-based
reagent, 1-hydroxy 1,2-benziodoxal-3(1H)-one-1-oxide (IBX),
in DMSO7 gradually promoted the oxidative rearrangement
of 1a at room temperature to yield 78% 3-phenyl-2-
cyclohexenone (1b) as the sole product with 17% recovered
1a after 24 h (entry 1). The gentle warming of the reaction
using 1.5 equiv of IBX at 55 °C caused a marked acceleration
to afford 85% 1b within 1 h, along with 13% 1-phenyl-1,3-
cyclohexadiene as the only detectable byproduct (entry 2).
The use of 3 equiv of IBX reasonably enhanced the efficacy
of the reaction to yield 93% 1b (entry 3). It was noted that
IBX in DMSO immediately oxidized 3-phenyl-2-cyclohexen-
1-ol to 1b at room temperature, indicating that heat is
effectual for allylic transposition.
PhIO29 in DMSO also effected the oxidative rearrangement
with almost the same efficacy as IBX at the high temperature
of 90 °C, suggesting the important role of the carboxy group
in IBX in enhancing the reaction10 (entry 4). The Dess-
Martin periodinane11 suffered from a significant side reaction
to yield 46% 3-acetoxy-1-phenyl 2-cyclohexene (entry 5).
HIO3 and I2O5,12 which seem to be more atom-efficient, gave
1b in a moderate yield of 40%, due to the decomposition
a 1a (17%) was recovered. b 1-Phenyl-1,3-cyclohexadiene (13%) was also
obtained. c 1-Acetoxy-1-phenyl-2-cyclohexen-1-ol (46%) was obtained.d 3-
Phenyl-2-cyclohenen-1-ol (35%) was obtained with 65% recovery of 1a.
caused by the considerably acidic properties of the reagents
used (entries 6 and 7). The iodine(III)-based oxidant PhIO
did not exhibit an oxidizing ability in DMSO. The recently
developed oxidation reagents PhIO/KBr/H2O13 also failed to
afford 1b (entries 8 and 9). At this point, it is interesting to
point out that the heating of a 1:1.1 mixture of 1a and PhIO
in DMSO at 55 °C caused allylic transposition to yield 35%
3-phenyl-2-cyclohexen-1-ol and 65% starting 1a. This result
indicates that PhIO does not exhibit an oxidizing ability under
these conditions.14 After some experiments, it was also noted
that the addition of a substoichiometric amount of CSA
induces the oxidation of 1a by PhIO to yield 38% 1b,
although the reaction involved considerable decomposition
(entry 10).
(6) Oxidative rearrangement can also go through an allylic cation
generated by solvolysis of the chromate ester, as similarly described in
Scheme 4 (vide infra). See also ref 4.
(7) (a) Varvoglis, A. HyperValent Iodine in Organic Synthesis; Academic
Press: London, 1997. (b) Wtrth, T.; Hirt, U. H. Synthesis 1999, 1271. (c)
Zhdankin, V.; Stang, P. J. Chem. ReV. 2002, 102, 2523. (d) Wirth, T.
HyperValent Iodine Chemistry; Springer-Verlag: Berlin Hiderberg, 2003.
(e) Wirth, T. In Organic Synthesis Highlights V; Schmalz, H.-G., Wirth,
T., Eds.; Wiely-VCH: Weiheim, 2003; pp 144-150.
(8) (a) Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 43, 8019.
(b) Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano, G. J. Org. Chem.
1995, 60, 7272. (c) Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem.
1999, 64, 4537.
Having established the novel use of IBX in the DMSO
system in oxidative allylic transposition, we next investigated
the scope and limitations of the present method using various
(12) Nicolaou, K. C.; Montagnon, T.; Baran, P. S. Angew. Chem., Int.
Ed. 2002, 41, 1386.
(9) Kazmeirczak, P.; Skulski, L.; Kraszkiewicz, L. Molecules 2001, 6,
881.
(10) We reasoned that the carboxy group imparts considerable solubility
in DMSO and suitable acidity to IBX.
(11) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b)
Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(13) (a) Tohma, H.; Takizawa, S.; Maegawa, T.; Kita, Y. Angew. Chem.,
Int. Ed. 2000, 39, 1306. (b) Tohma, H.; Maegawa, T.; Takizawa, S.; Kita,
Y. AdV. Synth. Catal. 2002, 344, 328.
(14) PhIO has been found to oxidize various alcohols to carbonyl
compounds in refluxing dioxane; see: Takaya, T.; Enyo, H.; Imoto, E. Bull.
Chem. Soc., Jpn. 1968, 41, 1032.
4304
Org. Lett., Vol. 6, No. 23, 2004

tertiary allylic alcohols (Table 2). Compared with the phenyl-
substituted substrate 1a, the alkyl-substituted substrate 2a
was prone to dehydration under standard conditions15 (entries
1 and 2). We eventually found that the addition of 2 equiv
of pyridine is effective in suppressing undesired side reac-
tions in this particular case to yield 81% 2b (entry 3).16
Conventional protecting groups such as Ac, MOM, and
TBDPS were tolerated under the standard reaction conditions
(entries 4-6). However, the TBS group attached to the
primary alcohol was partially deprotected17 and oxidized to
yield 29% 3-(4-formylphenyl)-2-cyclohenenone as the byprod-
uct, together with 49% 5b. Notably, TBS on phenol was
intact (entry 8). The five-membered substrate 8a also yielded
a transposed product with approximately the same efficacy
as the six-membered substrate (entry 9). Both the confor-
mationally constrained bicyclic and tricyclic compounds 9a
and 10a, respectively, required slightly harsh conditions, but
they gave the expected products of 9b and 10b in 79% yields
(entries 10 and 11). The seven-membered substrate 11a
suffered from dehydration to yield 53% 1-phenyl-1,3-
heptadiene, and the desired enone 11b was obtained in a
moderate yield of 38% (entry 11). However, the potency of
IBX on oxidative rearrangement crucially decreased in the
case of acyclic substrates (entries 13-15). From these results,
we confirmed the general applicability of the IBX-mediated
oxidative rearrangement to five- and six-membered cyclic
tertiary allylic alcohols.
Table 2. Scope of IBX-Enhanced Oxidative Rearrangementa
To gain insight into the chemoselectivity of the multital-
ented oxidizing agent IBX,18 an intermolecular competition
experiment was undertaken in which 1a was preferentially
converted into 1b in the presence of 1 equiv of 4-tert-
butylcyclohexanone (15) in DMSO at 55 °C (Scheme 3).
Scheme 3. Intermolecular Competitive Reaction
This result, presumably, reflects a lower activation energy
for the allylic transposition when compared to that of single
electron-transfer process mediated by IBX.
We speculate that there are two pathways that operate in
the IBX-mediated oxidative rearrangement.19 Considering the
(15) Representative Procedure for IBX-Mediated Oxidative Rear-
rangement of tert-Allylic Alcohols. IBX (1.2 mmol) was added to a solution
of 1a (0.57 mmol) in DMSO (3 mL), and the mixture was heated at 55 °C
for 1 h. After cooling, the pale-yellow colored mixture was diluted with
Et2O and washed with H2O and brine. The organic layer was dried over
MgSO4 and concentrated in vacuo. The remaining residue was purified by
column chromatography on silica gel to give 85% of 1b.
(16) Addition of pyridine had unpredictable results. For example, it
suppressed the dehydration of 1a and decreased the yield of 1b to 70%
due to the contamination of dark-brown byproducts derived from pyridine.
(17) Wu, Y.; Huang, J.-H.; Shen, X.; Hu, Q.; Tang, C.-J.; Li, L. Org.
Lett. 2002, 4, 2141.
a Standard reaction conditions employed 2 equiv of IBX in DMSO at
55 °C. b Numbers in parentheses are reported yields using PCC. c 1-Butyl-
1-cycohexene (33%) was obtained. d Pyridine (2 equiv) was added. e 3-(4-
Formylphenyl)-2-cyclihexenone (29%) was also obtained. f IBX (5 equiv)
was used. g 1-Phenyl-1,3-cycloheptadiene (53%) was obtained. h E:Z ) 98:
1
2. Diastereomeric ratio was determined by H NMR analysis.
Org. Lett., Vol. 6, No. 23, 2004
4305

of the tertiary alcohol to an allylic cation that subsequently
collapses with an IBX at less substituted termini to generate
an isomeric iodic ester that undergoes oxidation, as in
pathway A (Scheme 4). Alternatively, tertiary iodic ester
formation20 and the following rearrangement may precede
the oxidation, as in pathway B.
Scheme 4. Plausible Reaction Mechanisms
In summary, we disclosed the additional use of IBX in
the DMSO system, which allows us to perform the oxidative
transposition of five- and six-membered cyclic tertiary allylic
alcohols in an ecologically and user-friendly manner.
Supporting Information Available: Experimental de-
1
tails, copies of H and 13C NMR spectra, and complete
characterization of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL048210U
(18) (a) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Barluenga, S.; Hunt,
K. W.; Kranich, R.; Vega, J. A. J. Am. Chem. Soc. 2002, 124, 2233. (b)
Nicolaou, K. C.; Montagnon, T.; Baran, P. S.; Zhong, Y.-L. J. Am. Chem.
Soc. 2002, 124, 2245. (c) Nicolaou, K. C.; Montagnon, T.; Baran, P. S.
Angew. Chem., Int. Ed. 2002, 41, 993. (d) Nicolaou, K. C.; Gray, D. L. F.;
Montagnon, T.; Harrison, S. T. Angew. Chem., Int. Ed. 2002, 41, 996. (e)
Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T. Angew. Chem., Int.
Ed. 2003, 42, 4077.
(19) Addition of a radical inhibitor, galvinoxyl, did not affect the IBX-
mediated oxidative rearrangement of 1a, suggesting that the reaction does
not involve discrete radical intermediates. Cf.: Nicolaou, K. C.; Baran, P.
S.; Zhong, Y.-L.; Sugita, K. J. Am. Chem. Soc. 2002, 124, 2212.
(20) Munari, S. D.; Frigerio, M.; Santagostino, M. J. Org. Chem. 1996,
61, 9272.
mild acidity of IBX,18b it is possible to induce the solvolysis
4306
Org. Lett., Vol. 6, No. 23, 2004