Deuterium-Labeling Studies Establishing Stereochemistry at the Oxypalladation Step in Wacker-Type Oxidative Cyclization of an o-Allylphenol

Article abstract of DOI:10.1021/ja031946m

The stereochemical pathway (syn or anti) of the oxypalladation step was studied in the palladium(II)-catalyzed Wacker-type cyclization of stereospecifically deuterated 6-(2-hydroxyphenyl)-3-deuteriocyclohexenes, cis-3-d-1 and trans-3-d-1, giving dihydrobe

Full text of DOI:10.1021/ja031946m

Published on Web 02/18/2004
Deuterium-Labeling Studies Establishing Stereochemistry at the
Oxypalladation Step in Wacker-Type Oxidative Cyclization of an o-Allylphenol
Tamio Hayashi,* Kaori Yamasaki, Michihiro Mimura, and Yasuhiro Uozumi
Department of Chemistry, Graduate School of Science, Kyoto UniVersity, Sakyo, Kyoto 606-8502, Japan
Received December 25, 2003; E-mail: thayashi@kuchem.kyoto-u.ac.jp
Scheme 1
The Wacker-type oxidation is one of the most important
processes catalyzed by palladium complexes.1 The oxidation
proceeds through oxypalladation in the catalytic cycle, and there
has been controversy concerning the stereochemistry of the oxy-
palladation step. In early studies, the oxypalladation was reported
by Ba¨ckvall, Stille, and Kurosawa to proceed with anti stereo-
chemistry.2 Recently, it has been proposed by Henry and others
that the stereochemistry is dependent on the reaction conditions,
syn stereochemistry being predominant at low chloride ion con-
centration.3 Although several reaction systems have been used for
determination of the stereochemical pathway, they have not always
brought about definite stereochemical results due to the ambiguity
inherent in the systems.
On the basis of the report by Hosokawa and Murahashi that 6-(2-
hydroxyphenyl)cyclohexene undergoes the palladium-catalyzed
oxidative cyclization giving tetrahydrodibenzofurans,4 we designed
and prepared stereospecifically deuterated racemic 6-(2-hydroxy-
phenyl)-3-deuteriocyclohexenes, cis-3-d-1 and trans-3-d-1, by a
sequence of reactions whose stereochemistry is unambiguous (see
Supporting Information for their preparation), and we used them
for the determination of the stereochemistry at the oxypalladation
step under some reaction conditions including our chiral dicationic
catalyst system5 consisting of Pd(MeCN)4(BF4)2 and (S,S)-2,2′-bis-
(4-isopropyloxazolyl)-1,1′-binaphthyl ((S,S)-ip-boxax). Here, we
report our deuterium-labeling studies which unambiguously deter-
mine the stereochemistry.6
Scheme 2
Oxidative cyclization of cis-3-d-1 proceeded in high yield by
treatment with 5 mol % of dicationic palladium catalyst, generated
from Pd(MeCN)4(BF4)2, and (S,S)-ip-boxax, and benzoquinone (4
equiv) in methanol at 40 °C5 to give 78% yield of a mixture of
four regioisomeric tetrahydrodibenzofuran derivatives 2, 3, 4, and
5 in a ratio of 16/46/29/9 (Scheme 1).7 They were separated by
silica gel chromatography and fully characterized by comparison
of their 1H and 2H NMR spectra with those of the isomers obtained
from nondeuterated 6-(2-hydroxyphenyl)cyclohexene. Remarkable
points are as follows: (1) All of the isomers 2, 3, and 4, whose
basic structure is dihydrobenzofuran, have a cis-fused five- and
six-membered ring system. (2) Isomer 2 does not contain deuterium
on any of the carbon atoms. (3) Deuterium is incorporated over
95% at the 2-position cis to the oxygen in the isomers 3 and 4. (4)
Benzofuran 5 contains >90% deuterium at the 2-position and
5-10% deuterium at the 3- and 4-positions. The lack of deuterium
on the 3-position of 2, 3, and 4 and the shift of deuterium from the
3-position to the 2-position in 3 and 4 demonstrate that the
stereochemistry of the oxypalladation step under these conditions
is syn. Thus, addition of phenol oxygen and palladium to the double
bond in a syn fashion from the same face of 2-hydroxyphenyl group
forms alkylpalladium intermediate A where palladium is located
on the same face as deuterium on the cyclohexane ring (Scheme
2). The deuterium is abstracted by â-hydrogen elimination, which
proceeds in a syn fashion, to give intermediate B where the
palladium is bonded with the π-olefin and deuterium. Dissociation
of palladium from the double bond produces dihydrobenzofuran
2, which does not contain a deuterium atom on the 3-position.
Addition of palladium-deuteride to the double bond on B in the
other way forming the alkylpalladium intermediate C followed by
â-hydrogen elimination from 4-position produces regioisomer cis-
2-d-3 by way of π-olefin-hydride complex D. The hydropalladation
on D and â-hydrogen elimination in a similar manner leads to the
isomer cis-2-d-4. By the â-deuterium elimination from A and
deuteriopalladation forming C, the deuterium moved from the
3-position to the 2-position. The formation of benzofuran 2-d-5 in
a small amount is rationalized by the isomerization of 2, 3, and/or
4, which is caused by the coordination of a hydrido-palladium
species to the other face of the cyclohexene ring. The hydropalla-
dation and â-hydrogen elimination sequences lead to the thermo-
dynamically more stable benzofuran 5 (an example starting from
9
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J. AM. CHEM. SOC. 2004, 126, 3036-3037
10.1021/ja031946m CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3
Scheme 5
Scheme 4
stereochemistry observed here with the dicationic palladium catalyst
in the absence of chloride ion may suggest that the present reaction
involves a phenoxy(π-olefin)palladium(II) species which undergoes
migratory insertion, giving a â-phenoxyalkylpalladium intermediate.
Acknowledgment. This work was supported by a Grant-in-Aid
for Scientific Research, the Ministry of Education, Japan.
Supporting Information Available: Preparation of stereospecifi-
cally deuterated 6-(2-hydroxyphenyl)-3-deuteriocyclohexenes, cis-3-
d-1 and trans-3-d-1, experimental procedures for the oxidative cycliza-
tion, and spectroscopic and analytical data for the substrates and
products (PDF). This material is available free of charge via the Internet
at http://pubs.acs.org.
cis-2-d-4 is shown in Scheme 3). The anti stereochemistry at the
oxypalladation step is excluded because the deuterium in 5 is located
mainly at the 2-position. The anti-oxypalladation would lead to
the incorporation of deuterium at the 3-position in 5.
The syn stereochemistry of the oxypalladation step was con-
firmed in the reaction of the trans isomer, trans-3-d-1, which gave
3-d-2, 3-d-3, trans-3-d-4, and 3-d-5 in a ratio of 33/33/23/11
(Scheme 4). The deuterium remained at the 3-position in all of the
isomeric products because the deuterium is located at the face
opposite to that of palladium in the alkylpalladium intermediate J
which was generated by syn-oxypalladation.
Hosokawa and Murahashi’s catalyst system, which consists of
bis[acetoxy(3,2,10-η3-pinene)palladium(II)8 (10 mol %) and Cu-
(OAc)2 (10 mol %) in the presence of oxygen in refluxing
methanol,8 also proceeded with syn stereochemistry, cis-3-d-1
giving 2, cis-2-d-3, and cis-2-d-4 (82% total yield) in a ratio of
83/14/3. The formation of benzofuran 5 was not observed. Under
these conditions, the dissociation of a palladium-hydride species
from olefin is fast and the lifetime of the palladium-hydride is short
as compared to the palladium/boxax and benzoquinone system,
resulting in the formation of 2 as a major product.
References
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On the other hand, anti stereochemistry was observed in the
presence of a chloride ion. Thus, the oxidative cyclization of cis-
3-d-1 with PdCl2(MeCN)2 (10 mol %), benzoquinone (1 equiv),
Na2CO3 (2 equiv), and LiCl (2 equiv) in THF under reflux9 for 24
h gave 2, cis-2-d-3, cis-2-d-4, and 3-d-5 in a ratio of 6/5/7/82.
Although the deuterium location in 2, cis-2-d-3, and cis-2-d-4 shows
that they were formed through syn-oxypalladation, the formation
of 3-d-5 as a major product which contains the deuterium at the
3-position is rationalized only by the anti-oxypalladation (Scheme
5).
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(7) At 42% conversion, recovered cis-1 was 10% ee, indicating that a low
level of kinetic resolution (S ) 1.4) took place. In the absence of the
boxax ligand, the reaction gave a considerable amount of 1-(2-hydroxy-
phenyl)-1-methoxycyclohexane together with a low yield (total 33%) of
a mixture of the tetrahydrobenzofurans.
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In conclusion, the oxypalladation step in the Wacker-type
cyclization takes place with high syn stereochemistry with regard
to palladium and oxygen in the absence of chloride, and the
stereochemistry is mainly anti in the presence of chloride. The syn
(9) Hegedus, L. S.; McKearin, J. M. J. Am. Chem. Soc. 1982, 104, 2444.
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