Regioselective and enantiospecific rhodium-catalyzed intermolecular allylic etherification with ortho-substituted phenols [17]

Full text of DOI:10.1021/ja0003831

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

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 20, 2000 5013
alkyl, including branched alkanes (entries 1-2), aryl substituents
(entry 3), heteroatoms (entries 4 and 5), and halogens (entry 6).
These results prompted the examination of ortho-disubstituted
phenols, which were expected to be more challenging substrates
for this type of reaction. Remarkably, the ortho-disubstituted
phenols furnished the secondary aryl allyl ethers 2g-l with similar
selectivity (entries 7-12). The excellent regioselectiVities obtained
with the rhodium-catalyzed reaction, and tolerance of heteroatoms
and halogens, proVides a unique solution to the metal-catalyzed
allylic etherification reaction. Furthermore, the ability to employ
halogen-bearing ortho-disubstituted phenols will facilitate sub-
stitutions that would have proven extremely challenging for
conventional cross-coupling protocols.
Scheme 1
undertaking.13 Herein, we describe a two-step sequence for the
preparation of enantiomerically enriched oxygen containing
heterocycles (Scheme 1). The rhodium-catalyzed allylic etheri-
fication of (S)-7 (g99% ee), with the sodium anion of 2-iodo-
6-methylphenol, furnished the corresponding aryl allyl ether (S)-
8/9 in 87% yield, as a 28:1 mixture of regioisomers favoring (S)-8
(92% cee). Treatment of the aryl iodide (S)-8 with tris(trimeth-
ylsilyl)silane14 and triethylborane at room temperature, in the
presence of air, furnished the dihydrobenzo[b]furan derivatives
10a/b in 76% yield, as a 29:1 mixture of diastereoisomers in favor
of 10a.
In conclusion, we have developed the first regioselective and
enantiospecific rhodium-catalyzed allylic etherification reaction.
In the course of this study we also demonstrated that the alkylation
is tolerant to alkyl, aryl, and heteroatom substituents. Furthermore,
the ability to utilize ortho-halogenated phenols provides a direct
route to substituted aryl ethers that would prove difficult to
construct using conventional cross-coupling protocols. Hence, the
ability to prepare substituted aryl allyl ethers in this manner is
likely to gain prominence as a useful synthetic method for target
directed synthesis.
The enantiospecific rhodium-catalyzed etherification was also
examined, in which the reaction proceeds with net overall
retention of absolute configuration, as outlined in the alkylation
of the chiral nonracemic allylic carbonate (R)-4. Treatment of
(R)-4 (95% ee) with the trimethyl phosphite modified Wilkinson’s
catalyst and the sodium salt of o-phenyl phenol furnished the aryl
allyl ether (R)-5 in 96% yield (2°:1° ) g99:1), and with 98%
cee (eq 2).10,11 This reaction is consistent with a double inversion
process proceeding through an enyl (σ + π)12 organorhodium
intermediate analogous to that of stabilized carbon and nitrogen
nucleophiles.6b-d
The preparation of highly substituted enantiomerically enriched
dihydrobenzo[b]furan derivatives remains an important synthetic
(9) Representative experimental procedure: Trimethyl phosphite (24 µL,
0.20 mmol) was added directly to a red solution of Wilkinson’s catalyst (43.7
mg, 0.047 mmol) in anhydrous THF (2.0 mL) at 30 °C, under an atmosphere
of argon. The catalyst was allowed to form over ca. 15 min resulting in a
light yellow homogeneous solution. Sodium hexamethyldisilyl azide (475 µL,
0.95 mmol, 2.0 M solution in THF) was added to o-phenyl phenol (0.184 g,
1.1 mmol) in anhydrous THF (3.0 mL) and the anion allowed to form over
ca. 10 min. The catalyst and the sodium phenoxide solutions were then cooled
with stirring to 0 °C. The optically active allylic carbonate (R)-4 (65.7 mg,
0.5 mmol; 95% ee by capillary GLC analysis) was then added Via a tared
100 µL syringe to the preformed rhodium catalyst. The sodium phenoxide
solution was then added Via Teflon cannula to the catalyst/carbonate mixture,
and the resulting reaction mixture allowed to slowly warm to room temperature
over ca. 4 h (tlc control). The reaction mixture was then quenched with 30%
H2O2 solution (1 mL) and partitioned between diethyl ether and saturated
aqueous NH4Cl solution. The organic layers were combined, washed with
saturated aqueous NaCl solution, dried (Na2SO4), filtered, and concentrated
in Vacuo to afford a crude oil. Purification by flash chromatography (eluting
with a 3% ethyl acetate/hexane) furnished the allyl aryl ether (R)-5 (0.108 g,
96%) as a colorless oil, with 93% enantiomeric excess by chiral GLC analysis.
(10) The term conservation of enantiomeric excess {cee ) (product ee/
starting material ee) × 100} provides a convenient method of describing the
enantiopecificity of the reaction.6c
Acknowledgment. We sincerely thank the National Institutes of
Health (GM58877) for generous financial support. We also thank Zeneca
Pharmaceuticals for an Excellence in Chemistry Award, Eli Lilly for a
Young Faculty Grantee Award, Glaxo Wellcome for a Chemistry Scholar
Award, and the Camille and Henry Dreyfus Foundation for a Camille
Dreyfus Teacher-Scholar Award (PAE).
Supporting Information Available: Spectral data for 2a-m, (R)-5,
(S)-8, and 10a (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
JA0003831
(12) Enyl complexes can be defined as those having a discrete σ- and
π-metal carbon component within a single ligand. For definitions and
examples, see: (a) Sharp P. R. In ComprehensiVe Organometallic Chemistry
II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon Press: New
York, 1995; Chapter 2, p 272. (b) Lawson, D. N.; Osborn, J. A.; Wilkinson,
G. J. Chem. Soc. (A) 1966, 1733. (c) Tanaka, I.; Jin-no, N.; Kushida, T.;
Tsutsui, N.; Ashida, T.; Suzuki, H.; Sakurai, H.; Moro-oka, Y.; Ikawa, T.
Bull. Chem. Soc. Jpn. 1983, 56, 657 and pertinent references therein.
(13) For recent examples of approaches to dihydrobenzo[b]furans, see: (a)
Bernard, A. M.; Cocco, M. T.; Onnis, V.; Piras, P. P. Synthesis 1997, 41. (b)
Snider, B. B.; Han, L.; Xie, C. J. Org. Chem. 1997, 62, 6978. (c) Larock, R.
C.; Yang, H.; Pace, P.; Cacchi, S.; Fabrizi, G. Tetrahedron Lett. 1998, 39,
237. (d) Olivero, S.; Rolland, J.-P.; Dun˜ach, E. Organometallics 1998, 17,
3747. (e) Engler, T. A.; Letavic, M. A.; Iyengar, R.; LaTessa, K. O.; Reddy,
J. P. J. Org. Chem. 1999, 64, 2391 and pertinent references therein.
(14) For a recent review on this reagent, see: Chatgilialoglu, C. Chem.
ReV. 1995, 60, 3826.
(11) The retention of absolute configuration in the rhodium-catalyzed
etherification was assigned by the comparison of (R)-5 prepared from (R)-4
(eq 2) with (S)-5 prepared Via Mitsunobu inversion of the allylic alcohol (R)-i
with 2-phenylphenol.