Regio- and enantiospecific rhodium-catalyzed allylic etherification reactions using copper(I) alkoxides: Influence of the copper halide salt on selectivity

Article abstract of DOI:10.1021/ja026337d

The transition metal-catalyzed allylic etherification represents a fundamentally important cross-coupling reaction for the construction of allylic ethers. We have developed a new regio- and enantiospecific rhodium-catalyzed allylic etherification of acycl

Full text of DOI:10.1021/ja026337d

Published on Web 06/12/2002
Regio- and Enantiospecific Rhodium-Catalyzed Allylic Etherification
Reactions Using Copper(I) Alkoxides: Influence of the Copper Halide Salt on
Selectivity
P. Andrew Evans* and David K. Leahy
Department of Chemistry, Indiana UniVersity, Bloomington, Indiana 47405
Received March 27, 2002
The transition metal-catalyzed allylic substitution with alcohols
represents a fundamentally important cross-coupling reaction for
the construction of allylic ethers. Despite the enormous synthetic
Table 1. Effect of Copper(I) Salts and Leaving Groups on the
Regioselective Rhodium-Catalyzed Allylic Etherification
1
potential for the construction of allylic ethers, many of the current
approaches utilize intramolecular or proximal effects to circumvent
poor regioselectivity with unsymmetrical allylic alcohol deriva-
tives.2,3 Furthermore, the intermolecular metal-catalyzed allylic
leaving group
Lg
2°:1° b
yield
(%)
a
c
entry
CuX
2a′:3a′
etherification has, for the most part, been limited to reactions with
primary alcohols due to the challenges associated with the corre-
sponding secondary and tertiary alcohols. This may be attributed
to poor regioselectivity, and the propensity for metal alkoxides to
promote elimination of the metal-allyl intermediate or hydrolysis
of the leaving group in the allylic alcohol precursor. Hence, the
ability to facilitate a regioselective metal-catalyzed allylic etheri-
fication, using substituted alcohols, would provide an important
cross-coupling reaction for target directed synthesis.
1
2
3
4
5
6
CO
2
Me
”
”
CuCN
CuCl
CuBr
CuI
CuI
CuI
1:1
44:1
72:1
g99:1
g99:1
g99:1
73
58
66
73
42
96
”
t
CO Bu
t
CO
2
Bu
a
All reactions were carried out on a 0.5 mmol reaction scale using 10
mol % of RhCl(PPh3)3 modified with 40 mol % P(OMe)3, 1.9 equiv of the
lithium alkoxide, and 2.0 equiv of CuX. b Ratios of regioisomers were deter-
c
mined by capillary GLC on aliquots of the crude reaction mixture. GLC
yields.
Table 2. Scope of the Regioselective Rhodium-Catalyzed Allylic
Etherification Reaction (eq 1)a
allylic carbonate 1
2°:1°
2: 3
yield
(%)
t
b,c
d
entry
(Lg ) CO
2
Bu) R)
R′)
1
2
3
4
5
6
7
8
9
Ph(CH
Me
2
)
2
iPr
2
CH-
a
b
c
d
e
f
g
h
i
g99:1
g99:1
g99:1
g99:1
g99:1
18:1
13:1
22:1
28:1
73
65
67
70
71
50
46
70
73
”
”
”
”
”
”
”
”
n
We envisioned that the rhodium-catalyzed allylic substitution
would facilitate the regioselective etherification as a result of its
propensity to undergo selective alkylation through a configuration-
Pr
CH
(CH
BnOCH
CH dCH
Ph
Npth
2
dCH(CH
2 3
)
3
)
2
CH(CH
2
)
2
2
ally stable distorted π-allyl or enyl (σ + π) organorhodium inter-
2
mediate.4,5 The main problem anticipated with this approach was
the necessity to employ a hard alkali metal salt of the alcohol to
promote alkylation. Hence, we decided to examine the transmeta-
lation of the alkali metal alkoxide with a copper(I) salt,6,7 with the
expectation this would soften the basic character of the metal
alkoxide. Herein, we now describe the rhodium-catalyzed inter-
molecular allylic etherification of acyclic unsymmetrical secondary
alcohol derivatives 1 using copper(I) alkoxides of primary, second-
ary, and tertiary alcohols to afford the secondary allylic ethers 2
with excellent regioselectivity (eq 1).
Preliminary studies confirmed that alkali metal alkoxides would
not be suitable nucleophiles for the rhodium-catalyzed allylic
etherification owing to extensive side-reactions. Table 1 summarizes
the optimization of this reaction using various copper(I) salts and
a
All reactions were carried out on a 0.5 mmol reaction scale. b Ratios
of regioisomers were determined by capillary GLC on the crude reaction
mixture. c The primary products 3 were prepared for comparison using
d
the copper(I) cyanide additive (Table 1, entry 1). Isolated yields.
there was a pronounced halide effect (I > Br > Cl) on the selectivity
entries 2-4). Additional improvements were obtained by changing
the leaving group to suppress competitive transacylation, in which
the tert-butyloxycarbonate proved optimum (entry 6).
Although our initial studies utilized a copper(I) alkoxide derived
from a primary alcohol, we anticipated a secondary alcohol would
provide a more challenging and useful nucleophile to determine
the scope and limitations of this transformation. Table 2 summarizes
the application of the optimized reaction conditions (Table 1, entry
8
(
2
leaving groups. Treatment of the allylic carbonate 1a (Lg ) CO -
Me) with the trimethyl phosphite modified Wilkinson’s catalyst,
followed by the copper(I) alkoxide derived using copper cyanide,
furnished the allylic ethers 2a′/3a′ in good yield, albeit with no
selectivity (entry 1). Gratifyingly, the addition of a copper(I) halide
salt led to significant improvement in the regioselectivity, in which
6
) to a variety of racemic secondary allylic carbonates, using the
copper(I) alkoxide derived from 2,4-dimethyl-3-pentanol (Vide
supra). The allylic etherification is clearly tolerant of linear alkyl
substituents (Table 2, entries 1-4), while branched derivatives
9
proved challenging in terms of selectivity and turnover. Indeed,
the γ-position appears to be the first point at which branching does
not interfere with the substitution (entry 5). The allylic etherification
* To whom correspondence should be addressed. E-mail: paevans@indiana.
edu.
7882
9
J. AM. CHEM. SOC. 2002, 124, 7882-7883
10.1021/ja026337d CCC: $22.00 © 2002 American Chemical Society

C O MMU N I C A T I O N S
also proved feasible for hydroxymethyl, alkene, and aryl substit-
uents, albeit with lower selectivity (entries 6-9). This transforma-
tion is remarkably tolerant, given that the classical alkylation of a
hindered metal alkoxide with a secondary alkyl halide would
undoubtedly lead to elimination. Hence, the regioselectiVe rhodium-
catalyzed allylic etherification with a secondary copper(I) alkoxide
proVides an important new method for the synthesis of allylic ethers.
most likely the result of the equilibration of the rhodium-allyl
intermediate prior to etherification through a dissociative-type
mechanism. The trend in regiospecificity is tentatively attributed
to the in situ exchange (I for Cl) of the counterion on the metal,
which results in a more selective catalyst.10
In conclusion, we have developed a new regio- and enantiospe-
cific rhodium-catalyzed allylic etherification of acyclic unsym-
metrical allylic alcohol derivatives using copper(I) alkoxides derived
from primary, secondary, and tertiary alcohols. This study dem-
onstrates that the choice of copper(I) salt is crucial for obtaining
high stereospecificity, providing another example of the effect of
halide ions in asymmetric transition metal-catalyzed reactions.
Finally, the ability to modify alkali metal alkoxides in this manner
may provide a useful method for related cross-coupling reactions.
Encouraged by the results in Table 2, we anticipated that the
rhodium-catalyzed allylic etherification could be extended to tertiary
alcohols (eq 2). Preliminary attempts revealed that, although the
alkylation was indeed feasible, the reaction required increased cata-
lyst loading. Treatment of the allylic carbonate 1a with the copper-
Acknowledgment. We sincerely thank the National Institutes
of Health (GM58877) and the donors of the Petroleum Research
Fund, administered by the American Chemical Society for generous
financial support. We also thank Johnson and Johnson for a Focused
GiVing Award, Pfizer Pharmaceuticals for the CreatiVity in Organic
Chemistry Award and Novartis Pharmaceuticals for an Academic
AchieVement Award. The Camille and Henry Dreyfus Foundation
is thanked for a Camille Dreyfus Teacher-Scholar Award (P.A.E.),
and the Department of Education for a GAANN Fellowship
(
I) alkoxide derived from lithium anion of 3-methyl butene-3-ol
and the trimethyl phosphite modified Wilkinson’s catalyst (20 mol
), furnished the allylic ether 4 in 67% yield (2°:1° ) 47:1 by
%
GLC).
(D.K.L.).
Table 3. Exploring the Influence of the Copper(I) Halide Salt on
Enantiospecificity
Supporting Information Available: Representative experimental
procedure and spectral data for 2a-i and 4 (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
References
copper
2°:1°
cee
yield
(%)
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-10 °C
g99:1
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41
85
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a
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(
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catalyzed allylic substitution reactions prompted the examination
of the enantiomerically enriched allylic carbonate (R)-1b with a
copper(I) alkoxide (Table 3). Treatment of (R)-1b (94% ee) under
the optimized reaction conditions, furnished the allyl ether 2b′ in
4% yield (2°:1° g 99:1), albeit with poor enantiospecificity (41%
cee) which was a significant departure from our earlier studies (entry
). The low specificity prompted the reexamination of the effect
of the copper halide salt. Treatment of the allylic carbonate (R)-1a
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adducts (R)-2b′ with significantly improved chirality transfer
1
21, 6761, 12214. (c) Evans, P. A.; Leahy, D. K. J. Am. Chem. Soc. 2000,
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1
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4
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(
5
8
2
(
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4
1
(
7) Although the exact composition of a copper(I) alkoxide prepared through
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6
to consist of an associated lithium halide salt.
(
8) For a recent review on halide effects in transition-metal catalysis, see:
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(
entries 2 and 3). Interestingly, the trend for enantiospecificity is
(
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the reverse of that for the regiospecificity, illustrating that they are
independent (cf. Table 1, entries 2-4). Although the origin of the
erosion of enantiospecificity with copper(I) iodide is unclear, it is
JA026337D
J. AM. CHEM. SOC.
9
VOL. 124, NO. 27, 2002 7883