C O M M U N I C A T I O N S
Scheme 1. Proposed Mechanism for the Pd-Catalyzed
Dialkoxylation of Olefins
If the reaction is proceeding through a quinone methide, this
intermediate can only be accessed by addition of MeOH to the
â-carbon. Both Hosokawa’s results of addition to the â-carbon of
styrenes5 and the formation of product 13 support this proposal.
Further evidence for MeOH attack at the â-carbon is derived from
the experiment in eq 5 where the trisubstituted olefin 14 is converted
to a mixture of dialkoxylation product 15 and allylic ether 16. The
formation of 15 would result from the mechanism proposed in
Scheme 1, while the allylic ether 16 would result from competitive
attack of MeOH at the less hindered R-position followed by
â-hydride elimination. Alternative processes to form these products
are difficult to envision.
is the role of the o-phenol, and (2) if the first C-O bond is formed
by nucleopalladation, how does the second C-O bond form?
To help address these questions, isotopic labeling experiments
were performed to determine whether palladium-hydride chemistry
is involved. Substrate 2 was submitted to the dialkoxylation reaction
in CD3OD. No deuterium was incorporated into the propane chain
of the product. Additionally, exposure of the isotopically labeled
substrate 11 to the reaction conditions resulted in no deuterium
transfer within the product (eq 3). Together, these data rule out
â-hydride elimination of solvent or substrate during the dialkoxyl-
ation reaction.
On the basis of these results, a mechanism is proposed that
includes two intimately coupled steps: (a) regioselective nucleopal-
ladation of A via MeOH addition to the â-carbon of the styrene
yielding B and (b) subsequent formation of a quinone methide8
species C with concomitant reduction of palladium (Scheme 1).
Dialkoxylation is achieved by addition of a second equivalent of
MeOH to C, leading to rearomatization.9 Previously, a propenyl
phenol derivative, upon treatment with stoichiometric Pd(II) and a
base, is proposed to undergo a similar conversion into a quinone
methide by Chapman in his classic synthesis of Carpanone.10
Although alternative mechanistic proposals cannot be discounted,
possibilities such as direct nucleophilic substitution or oxidatively
induced reductive elimination11 of a Pd-alkoxide to form the second
C-O bond do not account for the requirement of the phenol or the
mild reaction conditions.
In conclusion, we have discovered a new Pd(II)-catalyzed
dialkoxylation of styrene derivatives containing an o-phenol. These
products are attributed to nucleopalladation at the â-carbon of the
styrene followed by attack of a second equivalent of MeOH to a
quinone methide species. A key finding is that â-hydride elimination
is avoided in the dialkoxylation process, revealing the potential for
integration with cross-coupling chemistry. This possibility and
evaluation of other nucleophiles in enantioselective variants will
be the subject of future research.
Acknowledgment. This work was supported by the National
Institutes of Health (NIGMS RO1 GM3540). M.S.S. thanks the
Dreyfus foundation (Teacher-Scholar) and Pfizer for their support.
M.J.S. thanks the University of Utah for a graduate research
fellowship. We thank Professor Jim Mayer for insightful discus-
sions. We are grateful to Johnson Matthey for the gift of various
Pd-salts.
Supporting Information Available: Experimental procedures and
characterization data for substrates and products. This material is
References
(1) For a review, see: Netherton, M. R.; Fu, G. C. In Topics in Organometallic
Chemistry: Palladium in Organic Synthesis; Tsuji, J., Ed.; Springer-
Verlag: Germany: 2005; pp 85-108.
(2) For recent reviews of Pd-catalyzed oxidations, see: (a) Stahl, S. S. Angew.
Chem., Int. Ed. 2004, 43, 3400-3420. (b) Sigman, M. S.; Schultz, M. J.
Org. Biomol. Chem. 2004, 2, 2551-2554.
(3) It has been reported that allyl phenol isomerizes under similar conditions,
see: Gross, J. L. Tetrahedron Lett. 2003, 44, 8563-8565.
(4) Byproducts of this reaction resulted from Wacker-type cyclizations.
(5) Recently, two reports have appeared on Pd-catalyzed diamination of
olefins: (a) Streuff, J.; Ho¨velmann, C. H.; Nieger, M.; Mun˜iz, K. J. Am.
Chem. Soc. 2005, 127, 14586-14587. (b) Bar, G. L. J.; Lloyd-Jones, G.
C.; Booker-Milburn, K. I. J. Am. Chem. Soc. 2005, 127, 7308-7309.
(6) The relative stereochemistry was assigned by comparison to an indepen-
dently prepared syn product. The diastereomeric ratio was measured via
1H NMR. See Supporting Information for details.
(7) Hosokawa, T.; Ohta, T.; Kanayama, S.; Murahashi, S.-I. J. Org. Chem.
1987, 52, 1758-1764.
(8) For a review on quinone methides, see: Van de Water, R. W.; Pettus, T.
R. R. Tetrahedron 2002, 58, 5367-5405.
The sensitivity of the reaction12 to substrate electronic character
supports a quinone methide intermediate. This is highlighted by
the formation of cyclic acetal 13 when evaluating the electron-
poor substrate 12 (eq 4). The cyclic acetal is a common byproduct
for electron-poor substrates and is presumably formed by a
combination of â-hydride elimination and insertion steps rather than
a quinone methide intermediate.13 This competing pathway presum-
ably arises from the slow formation of the electron-poor quinone
methides. Additionally, since the propenyl phenol derivatives
isomerize rapidly to the E-isomer, we attribute the modest diaster-
eoselection to the influence of the chiral center on C during MeOH
attack.14
(9) Chapman has reported methanol attacking a similar quinone methide,
see: Chapman, O. L.; McIntosh, C. L. Chem. Commun. 1971, 383-384.
(10) Chapman, O. L.; Engel, M. R.; Springer, J. P.; Clardy, J. C. J. Am. Chem.
Soc. 1971, 93, 6696-6698.
(11) For a recent example, see: Dick, A. R.; Kampf, J. W.; Sanford, M. S. J.
Am. Chem. Soc. 2005, 127, 12790-12791 and references therein.
(12) Evaluation of a p-phenol did not lead to product but instead to significant
substrate and catalyst decomposition.
(13) For examples of a similar cyclic acetal formation, see: (a) Hosokawa,
T.; Nakajima, F.; Iwasa, S.; Murahashi, S.-I. Chem. Lett. 1990, 1387-
1390. (b) Igarashi, S.; Haruta, Y.; Ozawa, M.; Nishide, Y.; Kinoshita,
H.; Inomata, K. Chem. Lett. 1989, 737-740.
(14) For similar observed diastereomeric ratios in Michael-type reactions,
see: Yamamoto, Y.; Chounan, Y.; Nishii, S.; Ibuka, T.; Kitahara, H. J.
Am. Chem. Soc. 1992, 114, 7652-7660.
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