Direct, iridium-catalyzed enantioselective and regioselective allylic etherification with aliphatic alcohols

Article abstract of DOI:10.1002/anie.200705267

(Chemical Equation Presented) From alcohol to ether: Iridium-catalyzed allylations yield α chiral ether derivatives directly from aliphatic alcohols with a simple alkali metal base (see equation). These reactions form ethers from primary, secondary, and tertiary alkoxides with high enantioselectivity. By-products from isomerization were suppressed by the use of an alkyne additive.

Full text of DOI:10.1002/anie.200705267

Communications
DOI: 10.1002/anie.200705267
Allylic Etherification
Direct, Iridium-Catalyzed Enantioselective and Regioselective Allylic
Etherification with Aliphatic Alcohols**
Satoshi Ueno and John F. Hartwig*
Intermolecular, enantioselective allylic substitution with
alcohols[1,2] remains an undeveloped catalytic process. Few
reports have been published that describe the intermolecular
allylation of aliphatic alcohols with high yield and enantio-
selectivity,[3] and the most selective of these systems has
required copper additives.[4] The large number of a chiral
ethers and oxygen heterocycles in natural products and
pharmaceutical candidates makes enantioselective routes to
these materials important.
cyclooctadiene) and phosporamidite L1 as precursors to the
metallacyclic iridium catalyst [Ir(cod)(k2L1)(L1)] in Equa-
tion (1). These reactions were conducted with potassium
This transformation has been difficult because alcohols
are poor nucleophiles for allylic substitution, and the high
basicity of alkoxides can induce elimination processes and
catalyst deactivation. Thus, phenoxides,[5–12] siloxides,[13] and
hydroxylamines[14,15] serve as nucleophiles for allylic substi-
tution, but intermolecular additions of common alcohols have
been limited.[10,16] Tin,[17] boron,[18,19] zinc,[20] and copper[4,21–23]
alkoxides have been used with the idea of softening an oxygen
nucleophile, but these additives complicate reaction proce-
dures and have only led to high yields and high enantiose-
lectivities for reactions of allylic esters with an iridium–
phosphoramidite catalyst.[4]
Herein we report that primary, secondary, and tertiary
alcohols, as well as silanols, can participate directly in catalytic
asymmetric allylic substitution in the presence of an alkali
metal base. Reactions conducted with a metallacyclic iridium
catalyst[24–33] form chiral, branched allylic ethers and silyl
ethers in high yield and high enantioselectivity.[3] These results
reveal convenient procedures for the use of alcohol nucleo-
philes, improve the scope and yield of the allylation of
primary, secondary, and tertiary alcohols, and include the use
of a catalytic amount of an alkyne additive to suppress olefin
isomerization that forms vinyl ether side products. More
generally, these results show that alkali metal alkoxides in low
concentrations can be competent nucleophiles for allylic
substitution.
À
phosphate as base in toluene at 408C. Although C O bond
formation occurred, some of the desired allylic ether product
3 converted into the isomeric enol ether 4,[19,34,35] and low
isolated yields of 3 were obtained [Eq. (1)]. After some
experimentation, we found that the simple addition of a
catalytic amount of an alkyne, such as 1-phenyl propyne, to
the reaction medium suppressed this isomerization and led to
high yields of the allylic ether product. For example, the
reaction of cyclopentanol under these conditions afforded
allylic ether 5 in 73% yield and 95% ee and 91:9 branched to
linear ratio [Eq. (2), and entry 1 in Table 1]. Other internal
Our efforts to develop a direct allylation of alcohols began
with studies of the reaction of cinnamyl acetate (1) with
benzyl alcohol (2) in the presence of [{Ir(cod)Cl}2] (cod = 1,5-
alkynes, such as 1,2-diphenyl acetylene and 4-octyne, also
suppressed the isomerization, but terminal alkynes did not.
Although we have not yet studied the origin of this alkyne
effect, we presume the alkyne poisons a separate isomer-
ization catalyst present in small amounts.[36]
Studies on the effect of solvent, base, and leaving group
were also conducted. Reactions in toluene occurred in the
highest yields. Reactions in the more polar solvents THF and
1,4-dioxane, as well as halogenated solvents, such as CH2Cl2,
afforded the substitution product in low yields. Additionally,
the use of Cs2CO3 as base resulted in the formation of
significant amounts of a by-product resulting from transes-
terification of cinnamyl acetate with cyclopentanol and
[*] S. Ueno, Prof. Dr. J. F. Hartwig
Department of Chemistry
University of Illinois Urbana-Champaign
Urbana, IL 61801 (USA)
Fax: (+1)217-244-8024
E-mail: jhartwig@uiuc.edu
[**] We are grateful to the NIH (NIGMS GM-55382) for support of this
work and Johnson-Matthey for iridium. S.U. acknowledges the
J.S.P.S. fellowships for youngscientists.
Supportinginformation for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Effect of ligands on the allylic etherification.[a]
Table 2: Scope of the allylic etherification with various alcohols.[a]
L
Ligand
5:6[b]
Yeld [%]
ee [%][c]
L1
L2
L3
L4
L5
L6
R1 =Ph
91:9
95:5
87:13
90:10
82:8
73
62
64
64
59
60
95
99
91
91
89
71
R1 =2-anisyl
R1 =1-Np
R2 =Ph
Entry
R
t [h]
b:l[b]
Yield [%], ee[c] or de
R2 =2-anisyl
R2 =1-Np
1
2
Bn
n-hexyl
n-hexyl
cyclo-hexyl
22
40
20
40
50
80
40
40
99:1
99:1
84:16
99:1
99:1
99:1
99:1
98:2
68, 93% ee
71, 91% ee
77, 94% ee
68, 93% ee
66, 90% ee
67, 88% de[f]
63, 90% de
85, 98% ee
88:12
3[d]
4[d]
5
[a] All ratios of 5:6, isolated yields and ee or de values are averages from
two independent runs. [b] Ratio of 5:6 determined by 1H NMR analysis of
the crude reaction mixture. [c] Determined by HPLC.
N-Boc-4-piperidinyl[e]
(S)-1-phenylethanol
(S)-1-phenylethanol
TBDMS[h]
6
7[g]
8
[a] All times, ratios of b:l, isolated yields and ee or de values are averages
from two independent runs. [b] Ratio of b:l determined by 1H NMR
analysis of the crude reaction mixture. [c] Determined by HPLC.
[d] Alcohols (2.5 mmol) and K3PO4 (2.5 mmol) were used. [e] Boc=
tert-butoxycarbonyl. [f] d.r. 94:6. [g] (S,S,S)-L1 was used; d.r.=95:5.
[h] TBDMS=tert-butyldimethylsilyl.
allylation of the resulting cinnamyl alcohol. Reactions con-
ducted with NEt3 as base formed racemic products in 49%
yield, presumably because NEt3 and the iridium precursor
generate an active achiral catalyst. For high conversions, the
use of highly powdered K3PO4 was important. Finally, the use
of allylic carbonates as electrophile led to low yields of the
desired ether, owing to cleavage of the carbonates to form the
corresponding allylic alcohols and the alkyl carbonates
derived from the alcohol nucleophile.
Table 1 summarizes results on the allylation of alcohols
catalyzed by iridium complexes generated from several C2-
symmetric and C1-symmetric phosphoramidites. The direct
allylation of alcohols occurred with the highest regioselectiv-
ity and enantioselectivity in the presence of the catalyst
generated from L2. However, ligand L1 is more accessible,
and reactions catalyzed by the complex generated from L1
occurred in higher yield, and with acceptable regioselectivity
and enantioselectivity. Reactions conducted with catalysts
generated from L3–L5 occurred in only 59–64 yields with 89-
91% enantioselectivity, and reactions conducted with L6
occurred with low enantioselectivity. With none of the
catalysts was the enol ether detected in significant amounts
when the reaction was conducted with added alkyne. Thus,
further studies were conducted with the catalyst generated
from L1 with added 1-phenyl-1-propyne.
the allylation product in diasereomeric ratios d.r. 94:6
(88% de) and 95:5 (90% de) with the two enantiomers of
the catalyst, although partial racemization of the alcohol
(90 and 88% ee) was observed after the reaction. The high
selectivities for both pairs of the alcohol and catalyst
enantiomers allow this simple reaction to form bis a-chiral
ethers with diasatereocontrol. tert-Butyldimethylsilanol also
underwent the allylation chemistry in high yield and enantio-
selectivity. Enantioselective allylation of potassium triethyl-
siloxide with the cyclometalated iridium catalyst developed in
our laboratory was reported by Carreira et al.,[13] but the
current process bypasses the need to prepare the potassium
siloxides. In all of these reactions with added 1-phenyl-1-
propyne, enol ether sideproducts were not observed in
significant amounts.
The scope of the reactions of a variety of allylic acetates
with different alcohols is summarized in Scheme 1 and
Equation (3). For all but one these reactions, the branched-
The scope of the alcohols that undergo allylation using
cinnamyl acetate 1 as electrophile under optimized conditions
is summarized in Table 2. The reaction of 1 with benzyl
alcohol 2 gave the branched allylation product 3 without
formation of enol ether 4 in 68% yield and 93% ee after 22 h
(Table 2, entry 1). The representative primary aliphatic
alcohol, n-hexanol formed the allyation product in 71%
yield and 91% ee (Table 2, entry 2). The use of 5 equiv of n-
hexanol slightly increased the yield and enantioselectivity
(entry 3). Secondary alcohols besides cyclopentanol used for
the studies in Table 1 also reacted. For example, cyclohexanol
and N-Boc-protected piperadin-4-ol reacted in acceptable
yield and high regioselectivity and enantioselectivity. a Chiral
secondary alcohols, such as (S)-1-phenylethanol, also formed
Scheme 1. Reactions of various combinations of allyl acetates and
alcohols. Boc=tert-butoxycarbonyl. [a] All ratios of b:l, isolated yields
and ee or de values are averages from two independent runs and ee
values are determined by HPLC. [b] Ratio of b:l determined by
1H NMR analysis of the crude reaction mixture. [c] Alcohols
(2.5 mmol) and K3PO4 (2.5 mmol). [d] Isolated yield of the combined
regioisomers of b:l. [e] d.r.=98:2; (S,S,S)-L1 was used.
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addition of 1-phenyl-1-propyne (0.100 mmol, 12.5 mL) and allyl
acetate (0.5 mmol) by syringe. When the reaction was complete
(determined by GC analysis), the crude mixture was passed through a
pad of silica gel, and eluted with 100 mL of ether. The resulting
solutions were evaporated. The ratio of regioisomers was determined
by 1H NMR spectroscopy (usually based on integration of the olefinic
protons). The mixture was then purified by flash column chromatog-
raphy on silica gel to give the desired product.
Received: November 16, 2007
Published online: January 31, 2008
to-linear ratios were higher than 96:4 and, with one exception,
enantioselectivities were at least 92% ee. Aromatic allylic
acetates containing anisyl and furyl groups on the aryl ring
gave the corresponding branched allylic ethers in high yields.
Not only aromatic but also purely aliphatic allylic carbonates
reacted to give the substitution products in acceptable yields
with good to excellent ee values and branched site selectivity.
The reactions of aliphatic allylic acetates with the secondary
alcohol N-(Boc)piperidinol occurred with high enantioselec-
tivity and site selectivity, but the yield was modest.
In addition to simplifying reactions of primary and
secondary alcohols, these conditions led to the first allylation
of a tertiary alcohol to form substitution products with high
enantioselectivity. The iridium-catalyzed reaction of 4-
methoxycinnamyl acetate with 2-phenyl-2-propanol gave the
substitution product in 56% yield with excellent enantiose-
lectivity at 408C. Previous reactions of tertiary alkoxides with
copper additives formed the substitution product in only
63% ee.[4]
Keywords: alkoxides· allylic substitution · asymmetricsynthesis ·
.
iridium · metallacycle
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