5012
J. Am. Chem. Soc. 2000, 122, 5012-5013
Table 1. Counterion and Temperature Effect on Regioselectivity in
the Rhodium-Catalyzed Allylic Etherification Reaction
Regioselective and Enantiospecific
Rhodium-Catalyzed Intermolecular Allylic
Etherification with Ortho-Substituted Phenols
P. Andrew Evans* and David K. Leahy
Brown Laboratory
Department of Chemistry and Biochemistry
UniVersity of Delaware, Newark, Delaware 19716
entry counterion Ma
temp
30 °C
30 °C
30 °C
RT
ratio 2m/3mb yield (%)c
1
2
3
4
5
Li
Na
K
Na
Na
38:1
20:1
12:1
30:1
70:1
11
97
97
87
96
ReceiVed February 1, 2000
Aryl ethers are ubiquitous to a variety of biologically important
molecules, thus the development of new methods for their
construction has become a topic of considerable synthetic interest.1
The transition metal-catalyzed cross-coupling of aryl halides with
alcohols provides an excellent method for the preparation of this
important structural motif.2 However, we anticipated that ortho-
disubstituted aryl halides would provide poor substrates for this
transformation, due to the difficulties associated with the oxidative
addition of a metal into a sterically encumbered environment of
this type. The metal-catalyzed allylic etherification provides a
complementary approach to this problem, in which the cross-
coupling reaction generally occurs at ambient temperature and
facilitates the introduction of a new stereogenic center.3-5 Despite
some excellent preliminary work the etherification of unsym-
metrical allylic alcohol derivatives, particularly sterically demand-
ing ortho-disubstituted phenols, remains problematic in terms of
both the regio- and enantioselective outcome.4,5 In a program
directed toward controlling regioselectivity in metal-catalyzed
allylic substitution reactions, we have recently demonstrated that
the rhodium-catalyzed reactions proceed with excellent selectiv-
ity.6,7 Herein, we describe the first rhodium-catalyzed allylic
etherification reaction using the sodium salt of ortho-substituted
phenols to afford the aryl allyl ethers 2/3a-l in excellent yield,
favoring the secondary derivative 2 (eq 1). The ability to utilize
highly substituted phenols in this manner is expected to provide
a useful cross-coupling reaction for organic synthesis.
0 °C to RT
a All reactions were carried out on a 0.5 mmol reaction scale at the
designated temperature for ca. 4 hours. b Ratios determined by capillary
GLC on crude reaction mixtures. c Isolated yields.
Table 2. Regioselective Rhodium-Catalyzed Allylic Etherification
with Ortho-Substituted Phenols
ArONaa
entry
R1
R2
ratio of 2/3b,c
yield (%)d
1
2
3
Me
iPr
Ph
H
H
H
H
H
H
Br
Br
Br
Me
iPr
Ph
a
b
c
d
e
f
g
h
i
39:1
56:1
44:1
g99:1
11:1
25:1
36:1
57:1
36:1
36:1
14:1
25:1
94
95
90
95
82
88
94
90
90
94
80
92
4
5
6
NHAc
OMe
Br
7
8
Me
iPr
9
Ph
Me
iPr
10
11
12
j
k
l
Ph
a All reactions were carried out on a 0.5 mmol reaction scale.9
b Ratios of regioisomers were determined by HPLC or Capillary GC
on crude reaction mixtures. c The primary products 3 were prepared
independently Via Pd(0) catalysis.3 d Isolated yields.
Li)8 that had proven crucial in the development of the corre-
sponding rhodium-catalyzed allylic amination.6c,d Treatment of
the allylic carbonate 1 with the alkali metal-salt (Li, Na, and K)
of phenol and Wilkinson’s catalyst modified with trimethyl
phosphite at 30 °C furnished the corresponding alkylation products
2m/3m with the yields and selectivities outlined in Table 1 (entries
1-3). Hence, although the lithium and potassium counterions
favored the formation of 2m, poor turnover and selectivity
prompted the optimization of the alkylation using the sodium salt
of the phenol. To improve the selectivity further, we decided to
examine the effect of temperature on regioselectivity. Contrary
to earlier studies with carbon and nitrogen nucleophiles that
demonstrated 30 °C was crucial for obtaining good selectiVity
and turnoVer rates, the rhodium-catalyzed allylic etherification
proceeds smoothly at lower temperature affording the aryl allyl
ether 2m with significantly improVed regioselectiVity (entry 5).
Table 2 summarizes the results for the application of the
optimized reaction conditions to a series of ortho-substituted
phenols, as outlined in eq 1. The etherification appears to tolerate
Preliminary studies demonstrated that the etherification using
phenol was subject to a similar counterion effect (K, Na, and
(1) For a recent review on transition metal-catalyzed aryl ether formation,
see: Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046 and pertinent
references therein.
(2) For leading references on intra- and intermolecular metal-catalyzed aryl
ether formation from aryl halides and alcohols, see: (a) Palucki, M.; Wolfe,
J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 10333. (b) Mann, G.;
Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 13109. (c) Palucki, M.; Wolfe,
J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 3395. (d) Mann, G.;
Hartwig, J. F. J. Org. Chem. 1997, 62, 5413. (e) Widenhoefer, R. A.; Zhong,
H. A.; Buchwald, S. L J. Am. Chem. Soc. 1997, 119, 6787. (f) Mann, G.;
Incarvito, C.; Rheingold, A. L.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121,
3224 and pertinent references therein.
(3) For recent reviews on the metal-catalyzed allylic substitution reaction,
see: (a) Frost, C. G.; Howarth, J.; Williams, J. M. J. Tetrahedron: Asymmetry
1992, 3, 1089. (b) Trost, B. M.; Van Vranken, D. L. Chem. ReV. 1996, 96,
395. (c) Tsuji, J. In Palladium Reagents and Catalysts; John Wiley and Sons:
New York, 1996; p 290. For an example of a highly regio- and enantioselective
palladium-catalyzed allylic etherification, see: Trost, B. M.; Toste, F. D. J.
Am. Chem. Soc. 1998, 120, 9074.
(6) (a) Evans, P. A.; Nelson, J. D. Tetrahedron Lett. 1998, 38, 1725. (b)
Evans, P. A.; Nelson, J. D. J. Am. Chem. Soc. 1998, 120, 5581. (c) Evans, P.
A.; Robinson, J. E.; Nelson, J. D. J. Am. Chem. Soc. 1999, 121, 6761. (d)
Evans, P. A.; Robinson, J. E. Org. Lett. 1999, 1, 1929.
(7) (a) Tsuji, J.; Minami, I.; Shimizu, I. Tetrahedron Lett. 1984, 25, 5157.
(b) Minami, I.; Shimizu, I.; Tsuji, J. J. Organomet. Chem. 1985, 296, 269.
(c) Takeuchi, R.; Kitamura, N. New J. Chem. 1998, 695.
(4) For a working model that highlights the challenges of the regio- and
enantioselective metal-catalyzed allylic etherification reactions with unsym-
metrical substrates, see: Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999,
121, 4545 and pertinent references therein.
(5) For an example of the problems associated with obtaining selectivity
in the metal-catalyzed allylic etherification reaction, see: Goux, C.; Massacret,
M.; Lhoste, P.; Sinou, D. Organometallics 1995, 14, 4585 and pertinent
references therein.
(8) The rhodium-catalyzed allylic alkylation of 1 with phenol at 30 °C
furnished the aryl allyl ethers 2/3m in only 9% yield, as a 33:1 mixture of
regioisomers favoring 2m. Hence, the deprotonated nucleophile appears to
be crucial for smooth turnover.
10.1021/ja0003831 CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/04/2000