A mild and efficient method for the stereoselective formation of C-O bonds: Palladium-catalyzed allylic etherification using zinc(II) alkoxides

Article abstract of DOI:10.1021/ol027104u

(equation presented) A highly chemo-and stereoselective palladium-catalyzed allylic etherification reaction is described. The use of zinc(II) alkoxides proved effective in promoting the addition of the oxygen nucleophile derived from aliphatic alcohols to η³-allylpalladium complexes. Using diethylzinc (0.5 equiv), 5 mol % of Pd(OAc)₂, and 7.5 mol % of 2-di(tert-butyl)phosphinobiphenyl in THF, the cross-coupling reaction between various aliphatic alcohols and allylic acetates proceeded at ambient temperature to furnish allylic ethers with high stereoselectivity.

Full text of DOI:10.1021/ol027104u

ORGANIC
LETTERS
2002
Vol. 4, No. 24
4369-4371
A Mild and Efficient Method for the
Stereoselective Formation of C−O
Bonds: Palladium-Catalyzed Allylic
Etherification Using Zinc(II) Alkoxides
Hahn Kim and Chulbom Lee*
Department of Chemistry, Princeton UniVersity, Princeton, New Jersey 08544
cblee@princeton.edu
Received October 15, 2002
ABSTRACT
A highly chemo- and stereoselective palladium-catalyzed allylic etherification reaction is described. The use of zinc(II) alkoxides proved effective
in promoting the addition of the oxygen nucleophile derived from aliphatic alcohols to η3-allylpalladium complexes. Using diethylzinc (0.5
equiv), 5 mol % of Pd(OAc)2, and 7.5 mol % of 2-di(tert-butyl)phosphinobiphenyl in THF, the cross-coupling reaction between various aliphatic
alcohols and allylic acetates proceeded at ambient temperature to furnish allylic ethers with high stereoselectivity.
Ether linkages conjoining stereogenic carbon(s) are structural
motifs in many natural products of biological importance,1
and access to them has been a topic of considerable synthetic
interest.2 However, construction of C-O bonds via a direct
SN2 type O-alkylation as exemplified by the Williamson ether
synthesis is impractical due to complications associated with
the strong basicity of an alkoxide anion. With the exception
of a few facile cyclization reactions, displacements with
alkoxide nucleophiles at stereogenic carbon centers are prone
to elimination and loss of stereochemical integrity.3 The
addition of an oxygen nucleophile to an η3-allylmetal
intermediate represents an attractive alternative approach
because the C-O bond forming event may occur under mild
conditions with stereocontrol.4 However, in contrast to the
widespread use of carbon and nitrogen nucleophiles, transi-
tion metal-catalyzed O-allylation remains largely limited to
carboxylate and phenolic nucleophiles. Far less success has
been achieved using aliphatic alcohols as nucleophiles due
to their poor nucleophilicity.5 Scattered literature precedents
rely on an intramolecular setting or a large excess of alcohol
(4) (a) Tsuji, J. Palladium Reagents and Catalysis; Wiley: New York,
1996; Chapter 4, pp 290-404. (b) Pfaltz, A.; Lautens, M. ComprehensiVe
Asymmetric Catalysis; Springer: New York, 1999; Vol. 2, pp 833-884.
(c) Trost, B. M.; Lee, C. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima,
I., Ed.; Wiley-VCH: New York, 2000; Chapter 8, pp 593-649.
(5) (a) Takacs, J. M. In ComprehensiVe Organometallic Chemistry II;
Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Elsevier Science: New
York, 1995; Vol. 12 (Hegedus, L. S., Ed.), pp 814-817. For early examples,
see: (b) Takahashi, K.; Miyake, A.; Hata, G. Bull. Chem. Soc. Jpn. 1972,
45, 230. (c) Stork, G.; Poirier, J. M. J. Am. Chem. Soc. 1983, 105, 1073.
(d) Stanton, S. A.; Felman, S. W.; Parkhurst, C. S.; Godleski, S. A. J. Am.
Chem. Soc. 1983, 105, 1964. (e) Keinan, E.; Roth, Z. J. Org. Chem. 1983,
48, 1172. (f) Keinan, E.; Sahai, M.; Roth, Z.; Nudelman, A.; Herzig, J. J.
Org. Chem. 1985, 50, 3558.
(1) Buckingham, J. Dictionary of Natural Products; University Press:
Cambridge, MA, 1994.
(2) Elliott, M. C.; Willams, E. J. Chem. Soc., Perkin Trans. 1 2001, 2303
and references therein.
(3) (a) Feuer, H.; Hooz, J. In The Chemistry of Ether Linkage; Patai, S.,
Ed.; Interscience Publishers: London, UK, 1967; pp 445-449 and 460-
468. (b) Baggett, N. In ComprehensiVe Organic Chemistry; Stoddart, J. F.,
Ed.; Pergamon Press: New York, 1979; Vol. 1, pp 799-850. (c) Mitsunobu,
O. In ComprehensiVe Organic Chemistry; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: New York, 1991; Vol. 6 (Winterfeldt, E., Ed.), pp 1-31.
10.1021/ol027104u CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/06/2002

to effect catalysis.6,7 In particular, these examples have
mainly employed primary alcohols because of the difficulties
associated with the reactions of structurally complex alco-
hols.8 Therefore, a general and reliable protocol for this cross-
coupling reaction would be of significant synthetic utility.
We hoped to address the reactivity mismatch between the
hard alkoxide anions and soft η3-allylmetal cations by
modulating the apparent “hardness” of an alkoxide nucleo-
phile. In this regard, we noted the “zinc effect” in metal-
loenzymes which leads to a dramatic increase in the acidity
of the hydroxylic proton of a coordinated alcohol.9 We
contemplated that this might reflect a “softening” of the
alkoxide anion by the Zn(II) center. Thus, it was intriguing
to test whether zinc-bound alkoxides possess attenuated
basicity while retaining sufficient nucleophilicity toward a
metal-bound allylic cation.10 Herein we report our investiga-
tions of Pd-catalyzed allylic etherification using zinc alkox-
ides as nucleophiles. Our results provide a solution to one
of the long-standing problems in η3-allylmetal chemistry.
Initial studies centered on a model system in which
cinnamyl acetate 1 was used as substrate and Et2Zn served
as the source of base and counterion (Scheme 1). Exposing
a comparable result. Decreasing the loading of Et2Zn to 0.25
equiv gave 3a in 48% yield with a 50% recovery of unreacted
1 and 2a, indicating that a 1:2 ratio of Et2Zn to alcohol is
required for the completion of the reaction. Ethers 3b and
3c were obtained from the reactions of methanol and
2-propanol in 83% and 56% yield, respectively. In these
cases, cinnamyl alcohol (3d, R ) H) and bis(cinnamyl) ether
(3e, R ) trans-cinnamyl) were also isolated in low yields
(<5%), presumably via an acetyl transfer reaction. In
contrast, transacylation predominates in the reaction of tert-
butyl alcohol, where only cinnamyl alcohol and bis(cin-
namyl) ether were obtained.
The stereochemical course of the reaction was next
examined in the context of a disubstituted allylic system
(Table 1).11 It was anticipated that due to the propensity of
Table 1. Stereoselectivity of Pd-Catalyzed O-Allylation of
Zinc(II) Benzyloxide with Allylic Acetate 4a
entry
Pd/ligand
Pd(PPh3)4
yield 5,b % yield 6,b % 5a :5bc
Scheme 1
1
20
48
28
22
52
70
65
35
1:2
2:1
2
Pd(PPh3)4/dppb
Pd(PPh3)4/dppf
Pd(PPh3)4/BINAP
Pd(OAc)2/7
3
58
4.5:1
10:1
4
60
5
6d
20
>40:1
>40:1
Pd(OAc)2/7
<10
a All reactions were carried out in THF (1.0 M) with 1.1 equiv of benzyl
alcohol at 25 °C in the presence of 5 mol % of Pd and 7.5 mol % of ligand
except for entry 1 where 5 mol % of Pd(Ph3P)4 was used as catalyst.
b Isolated yields. c Diastereomeric ratio of the crude product mixture
1 to a preformed solution of benzyl alcohol (2a, 1 equiv)
and Et2Zn (0.5 equiv) in THF at 25 °C for 2 h in the presence
of 5 mol % of Pd(PPh3)4 led to the smooth formation of
allylic ether 3a in nearly quantitative yield. Control experi-
ments established that both the Pd and Zn were required for
this reaction and that alkali metal benzyloxides induced an
instantaneous transacylation. The use of Me2Zn also provided
1
determined by H NMR. d NH4OAc (10 mol %) was added.
the cyclic substrate 4 to epimerization and â-H elimination,
the alkylation of 4 would present a more challenging testing
ground for the reaction.5f Indeed, under the same conditions
as initial studies the reaction gave a mixture of 5a and 5b in
low yields, along with a large amount of diene 6 (entry 1).
Despite the low yields, the strong dependence of the
diastereomeric ratio of 5 on the catalyst and ligand was
noteworthy. Whereas using Pd(PPh3)4 as catalyst gave the
anti isomer 5b as the major product, the addition of a
bidentate ligand favored the formation of the syn isomer 5a
(entries 1 vs 2-4). Significant improvements came from the
use of biphenyl-derived ligand 7,12 which produced only 5a
with a decreased yield of diene 6 (entry 5). Interestingly,
the formation of diene 6 could be further diminished by
running the reaction in the presence of 10% NH4OAc (entry
(6) (a) Trost, B. M.; Tenaglia, A. Tetrahedron Lett. 1988, 29, 2931. (b)
Suzuki, T.; Sato, O.; Hirama, M. Tetrahedron Lett. 1990, 31, 4747. (c)
Suzuki, T.; Sato, O.; Hirama, M.; Yamamoto, Y.; Murata, M.; Yasumoto,
T.; Harada, N. Tetrahedron Lett. 1991, 32, 4505. (d) Thorey, C.; Wilken,
J.; He´nin, F.; Martens, J.; Mehler, T.; Muzart, J. Tetrahedron Lett. 1995,
36, 5527. (e) Fournier-Nguefack, C.; Lhoste, P.; Sinou, D. Tetrahedron
1997, 53, 4353. (f) Jiang, L.; Burke, S. D. Org. Lett., 2002, 4, 3411. For
internal delivery, see: (g) Trost, B. M.; McEachern, E. J.; Toste, F. D. J.
Am. Chem. Soc. 1998, 120, 12702.
(7) (a) Lakhmiri, R.; Lhoste, P.; Sinou, D. Tetrahedron Lett. 1989, 30,
4669. (b) van der Deen, H.; van Oeveren, A.; Kellogg, R. M.; Feringa, B.
L. Tetrahedron Lett. 1999, 40, 1733. (c) Hamada, Y.; Seto, N.; Takayanagi,
Y.; Nakano, T.; Hara, O. Tetrahedron Lett. 1999, 40, 7791. (d) Lautens,
M.; Fagnou, K.; Rovis, T. J. Am. Chem. Soc. 2000, 122, 5650.
(8) During the preparation of this manuscript, another group reported
Rh(I)-catalyzed allylic etherification using copper(I) alkoxide based nu-
cleophiles, see: Evans, P. A.; Leahy, D. K. J. Am. Chem. Soc. 2002, 124,
7882.
(9) (a) Pocker, Y.; Page, J. D. J. Biol. Chem. 1990, 265, 22101. (b) Parkin,
G. Chem. Commun. 2000, 1971 and references therein.
(10) For the only reported use of a zinc alkoxide in polyether synthesis,
see: Suzuki, M.; Haruyama, T.; Ii, A.; Saegusa, T. Polym. Bull. 1996, 36,
265.
(11) Trost, B. M.; Verhoeven, T. R. J. Am. Chem. Soc. 1980, 102, 4730.
(12) Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, J.
P.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 4369.
4370
Org. Lett., Vol. 4, No. 24, 2002

condition B in Table 2). While the origin of 5b and the role
of NH4OAc are unclear at the moment, the results indicate
that the Pd-catalyzed allylic etherification can be performed
with high stereoselectivity.
Table 2. Pd-Catalyzed Etherification of Aliphatic Alcohols
with Allylic Acetates
As summarized in Table 2, a variety of acyclic and cyclic
substrates participate in inter- and intramolecular allylic
etherification. In general, primary alcohols gave higher yields
than more sterically hindered secondary alcohols. The
remarkably mild nature of the present method is manifest in
the facile and selective O-alkylation of 2-bromo- and 2-silyl-
ethanols in preference to oxirane formation or Peterson-type
elimination (entries 1 and 2). Also of interest is entry 3 in
which a substrate susceptible to metal-halogen exchange
or oxidative addition undergoes uneventful allylic alkylation.
When the alcohol and allylic acetate both are used in
enantiomerically enriched forms, an ether linkage flanked
by R,R′-stereogenic centers could be established with
complete stereochemical fidelity (entries 9 and 10). In these
cases, higher yields could be easily attained by using 2 equiv
of nucleophile while a 1-1.5:1 ratio of the two reaction
partners is generally sufficient to obtain serviceable yields.
Finally, using an internal hydroxyl group as a nucleophile,
five- and six-membered oxacycles are formed in excellent
yields (entries 11 and 12). It is noteworthy that unlike
previous reports which required a 2,6-dichlorobenzoate5c or
a tin alkoxide for cyclization,6a preactivation of the leaving
group or the nucleophile was unnecessary.
In summary, we have described a mild and efficient
method for stereoselective allylic etherification. The use of
a zinc alkoxide based nucleophile is critical for promoting
the Pd-catalyzed O-allylation of aliphatic alcohols. The high
level of functional group tolerance, high generality, and
operational simplicity are important features of the present
method. Our protocol greatly expands the current scope of
this important cross-coupling process and will undoubtedly
form the basis for further development. Extensions of these
findings including the development of a bimetallic catalytic
system are currently in progress and will be reported in due
course.
Acknowledgment. We thank Princeton University for
startup research funding and the Hugh Stott Taylor Fellow-
ship for a fellowship to H.K. We also thank Christina M.
Kraml at Wyeth Research for chiral HPLC analysis.
a Condition A: 1 equiv of alcohol, 1 equiv of allylic acetate, 0.5 equiv
of Et2Zn, 5 mol % of Pd(PPh3)4, THF (1.0 M), rt, 2 h. b Condition B: 1
equiv of alcohol, 1.5 equiv of allylic acetate, 0.5 equiv of Et2Zn, 5 mol %
of Pd(OAc)2, 7.5 mol % of 7, 10 mol % of NH4OAc, THF (0.5 M), rt,
6-12 h. c The product was obtained as a 1:1 mixture of diastereomers.d Only
1
a single isomer was detected by GC and H NMR. e Isolated yield. f The
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
reaction was carried out with 2.2 equiv of alcohol and 1.1 equiv of Et2Zn
under condition B.
6). Thus, these conditions were subsequently employed for
the reactions of 1,3-disubstituted allylic acetates (vide infra,
OL027104U
Org. Lett., Vol. 4, No. 24, 2002
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