Iridium-catalyzed kinetic asymmetric transformations of racemic allylic benzoates

Article abstract of DOI:10.1021/ja103779e

Versatile methods for iridium-catalyzed, kinetic asymmetric substitution of racemic, branched allylic esters are reported. These reactions occur with a variety of aliphatic, aryl, and heteroaryl allylic benzoates to form the corresponding allylic substitution products in high yields (74-96%) with good to excellent enantioselectivity (84-98% ee) with a scope that encompasses a range of anionic carbon and heteroatom nucleophiles. These kinetic asymmetric processes occur with distinct stereochemical courses for racemic aliphatic and aromatic allylic benzoates, and the high reactivity of branched allylic benzoates enables enantioselective allylic substitutions that are slow or poorly selective with linear allylic electrophiles.

Full text of DOI:10.1021/ja103779e

Published on Web 06/16/2010
Iridium-Catalyzed Kinetic Asymmetric Transformations of Racemic Allylic
Benzoates
Levi M. Stanley, Chen Bai, Mitsuhiro Ueda, and John F. Hartwig*
Department of Chemistry, UniVersity of Illinois, 600 South Mathews AVenue, Urbana, Illinois 61801
Received May 3, 2010; E-mail: jhartwig@illinois.edu
Allylic substitution catalyzed by metallacyclic iridium complexes
derived from phosphoramidites1 has become a valuable method to
prepare enantioenriched small molecules with broad scope by the
addition of carbon2 and heteroatom3 nucleophiles to allylic esters.
Although many linear allylic carbonates react to form products with
high enantiomeric excess (eq 1), iridium-catalyzed allylic substitu-
tion of racemic, branched allylic esters typically occurs with much
lower enantioselectivity (eq 2).4 Such allylic esters are attractive
substrates for metal-catalyzed allylic substitution because they are
readily prepared from a wide range of aldehydes and a vinyl
Grignard reagent. Moreover, these allylic esters are less substituted
at the alkene unit and typically react with rates that are faster than
those of the corresponding linear isomers.4b,c
metallacyclic iridium catalyst with much different binding con-
stants.11 These data implied that the metallacyclic iridium catalyst
should select for reaction of one enantiomer of a racemic, branched
allylic ester and form a substitution product with high enantiomeric
excess, as long as the allylic substitution occurs with a high degree
of retention of configuration. Prior reactions of enantioenriched
allylic esters with iridium catalysts formed the substitution product
with a modest enantiomeric excess,4a,b but reactions of enantioen-
riched allylic esters catalyzed by metallacyclic iridium complexes
could occur with a higher degree of retention of configuration. Such
substitutions of racemic, branched allylic esters would contrast with
typical kinetic resolutions that leave behind an enantioenriched
reactant but form products possessing modest enantiopurity.
To date, enantioselective substitution of racemic, branched allylic
electrophiles has been limited primarily to reactions of stabilized
carbon nucleophiles catalyzed by complexes of Mo,5 Pd,6 or Rh7
and a few examples of allylic amination catalyzed by complexes
of Rh8 and Pd.9 Examples of iridium-catalyzed allylic substitution
of racemic, branched allylic electrophiles that occur with high
enantioselectivity are rare. Helmchen reported allylic alkylation of
racemic allylic acetates catalyzed by an iridium-phosphoramidite
complex, but only one substrate reacted in greater than 80% ee.4a,b
In addition, Carreira4c and Alexakis4d reported kinetic resolutions
by etherification and alkylation of racemic, branched allylic
carbonates or esters with catalysts generated in situ from
[Ir(COE)2Cl]2 and a chiral diene ligand or [Ir(COD)Cl]2 and a chiral
phosphoramidite ligand. However, these allylic etherifications
occurred with widely varying levels of enantioselectivity, and the
one example of allylic alkylation occurred in 84% ee. Palladium-
catalyzed isomerization of branched allylic esters to linear allylic
esters, followed by iridium-catalyzed enantioselective, allylic
substitution of the linear isomer, has been reported,10 but this
strategy requires removal of the palladium catalyst prior to the
allylic substitution step and is limited to reactions of aromatic allylic
esters that fully rearrange to the linear isomer.
Here, we report enantioselective allylic substitution of racemic,
branched allylic benzoates with a variety of anionic carbon and
heteroatom nucleophiles in the presence of a single-component,
metallacyclic iridium complex to form substitution products with high
enantioselectivity. These kinetic asymmetric processes occur with
distinct stereochemical courses for racemic aliphatic and aromatic
allylic benzoates, and the higher reactivity of the branched allylic esters
enables transformations of sterically demanding electrophiles.
Recently published mechanistic studies on allylic amination
showed that enantiomeric, branched allylic amines coordinate to a
Figure 1. Metallacyclic iridium-phosphoramidite complexes 1a and 1b.
Table 1. Ir-Catalyzed Allylic Substitution of Racemic Aliphatic
Allylic Benzoatesa
yield
(%)b
ee
(%)c
entry
R (2)
nucleophile
product
1
2
3
BnCH2 (2a)
n-Pr (2b)
i-Pr (2c)
Cy (2d)
t-Bu (2e)
BnCH2 (2a)
BnCH2 (2a)
BnCH2 (2a)
BnCH2 (2a)
BnCH2 (2a)
BnCH2 (2a)
NaOPh
NaOPh
NaOPh
NaOPh
3a
3b
3c
3d
3e
4a
5a
6a
7a
8a
9a
83
86
76
86
88
96
74
84
80
82
77
95
92
98
96
96
93
98
97
94
94
88
4
5d
6
NaOPh
LiN(Boc)2
KNHC(O)CF3
NaBzIm
NaTs
NaCH(CO2Me)2
NaCH(CN)2
7
8
9
10
11
a See Supporting Information for experimental details. b Isolated yield
of products 3-9. Branched-to-linear selectivities were >95:5. c The
enantiomeric excess of 3-9 was determined by chiral HPLC methods.
d Reaction was run in the presence of 4 mol % 1b at 50 °C for 24 h.
To test if we could obtain substitution products having high
enantiomeric excess from the selective reaction of one enantiomer of
a racemic mixture of allylic esters, we conducted reactions of the
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C O M M U N I C A T I O N S
racemic, branched allylic esters derived from 5-phenylpent-1-en-3-ol
with sodium phenoxide (NaOPh) in the presence of our single-
component, metallacyclic Ir-phosphoramidite complexes 1a11 and
1b3d (Figure 1). After testing several allylic carbonates and esters, we
found that the reaction of NaOPh with 2.2 equiv of allylic benzoate
2a in the presence of 2 mol % 1b formed allyl phenyl ether 3a in
83% yield and 95% ee at 0 °C (Table 1, entry 1).12
benzoate from (S)-2 (K1k3 . K2k4);14 the rate for nucleophilic attack
(k6) on allyliridium complex B is greater than the rate constant for
collapse (k4) to form the linear allylic benzoate from B. We sought
to exploit these relative rates to convert the more reactive
(R)-enantiomer of the branched allylic benzoate 2 to the linear
isomer, followed by allylic substitution of the remaining (S)-
enantiomer of 2 with retention of configuration. This process would
lead to the product of allylic substitution with high enantiomeric
excess.
To establish the foundation for this strategy, we evaluated the
selectivity factors (s) for kinetic resolution of racemic aromatic
allylic benzoates in the absence of a nucleophile and the stereo-
chemical outcome from allylic substitutions of the less reactive
enantiomer of the branched allylic benzoates. As anticipated from
the preliminary experiment, reaction of the racemic allylic ester
from 1-phenylprop-2-en-1-ol formed a mixture of the (S)-enantiomer
of the starting material and the achiral linear allylic benzoate with
a high s-value. The kinetic resolution of (()-2f in the presence of
0.5 mol % of 1b occurred with a selectivity factor of 50. The linear
allylic benzoate 10a formed in 49% yield, and the remaining
branched allylic benzoate (S)-2f was isolated in 45% yield with
98% ee (eq 3).15 In addition, allylic substitution of the (S)-
enantiomer of a representative branched allylic benzoate in the
presence of 2b occurred with essentially complete retention of
configuration. The reaction of (S)-2f (98% ee) with NaOPh and 2
mol % of 2b formed allyl aryl ether (S)-3f in 91% yield and 98%
ee (eq 4).
Reactions of a series of anionic nucleophiles with aliphatic allylic
benzoates are summarized in Table 1. As shown in entries 2-4,
NaOPh reacted with branched allylic benzoates 2b-2d (R ) n-Pr,
i-Pr, or c-hexyl) to form allyl aryl ethers 3b-3d in 76-86% yield
and 92-98% ee. The reactions of the branched allylic esters occur
faster than the analogous reactions of the linear isomers. This higher
reactivity allowed for an unusual asymmetric allylic substitution
process. The reaction of NaOPh with allylic benzoate 2e in which
the allyl unit is substituted with a t-Bu group occurred at 50 °C to
set a neopentyl stereocenter in the allyl aryl ether product 3e in
96% ee (entry 5). The reaction of NaOPh with the linear isomer of
2e did not occur under identical or more forcing conditions.
Nucleophilic substitutions at neopentyl centers are challenging, and
enantioselective substitutions at such a site are particularly rare.13
The enantioselective allylic substitution also occurred with
anionic nitrogen, sulfur, and carbon nucleophiles in the presence
of catalyst 1b, as summarized in entries 6-11. The reactions of 2a
with the ammonia equivalents LiN(Boc)2 and KNHC(O)CF3, the
heteroaromatic derivative sodium benzimidazolate (NaBzIm), the
sulfur nucleophile sodium p-toluenesulfinate (NaTs), and the sodium
salts of the carbon nucleophiles dimethyl malonate and malononitrile
occurred with high enantioselectivity (88-98% ee). The resulting
products 4a-9a were isolated in good yields (74-96%).
Scheme 1. Strategy for Kinetic Asymmetric Allylic Substitution of
Racemic, Branched Aromatic Allylic Benzoatesa
Having established that kinetic resolution of racemic aromatic
allylic benzoates by metallacycle 1b is highly selective and that
the allylic substitution of the less reactive enantiomer occurs with
complete retention of configuration, we developed a protocol to
convert these racemic electrophiles to enantioenriched substitution
products by sequential kinetic resolution and allylic substitution.
The kinetic resolution of (()-2f in the presence of 2 mol % of 1b
at 0 °C in THF occurred in approximately 2 h. Addition of NaOPh
to the resulting solution containing the less reactive enantiomer of
the branched allylic benzoate (S)-2f and the linear cinnamyl
benzoate 10a formed allyl aryl ether (S)-3f in 81% yield and 96%
ee (Table 2, entry 1). The absolute stereochemistry of the product
shows that the allyl aryl ether (S)-3f was formed by reaction of the
phenoxide with the less reactive S-enantiomer of the allylic benzoate
2f, not by reaction with the linear allylic benzoate. The absolute
stereochemistry of the product was the opposite of that resulting
from etherification of linear aromatic allylic electrophiles.3g
The scope of this combined enantioselective isomerization and
allylic substitution is shown in Table 2. This process encompasses
reactions of branched allylic benzoates containing a variety of aryl
groups. The reactions of NaOPh with electron-rich, electron-neutral,
and electron-deficient aromatic allylic benzoates containing para, meta,
and ortho substitution as well as reactions of heteroaromatic allylic
benzoates occurred in 83-90% yield and in 84-98% ee (entries 1-8).
Reactions of nitrogen, sulfur, and carbon nucleophiles with
branched aromatic allylic benzoates also occurred in high yields
and enantioselectivities. The reactions of LiN(Boc)2 and KNH-
a [Ir] ) [Ir(COD)(κ2-L2)(ethylene)] (1b), K1 ) k1/k-1, and K2 ) k2/k-2
.
The reactivity of branched aromatic allylic benzoates was distinct
from that of branched aliphatic allylic benzoates. Allylic substitution
of branched aromatic allylic benzoates in the presence of catalyst
1b occurred in competition with isomerization to the linear isomer.
The isomerization of one enantiomer of the allylic benzoate was
faster than isomerization of the other, but the competitive processes
resulted in reaction mixtures. These mixtures consisted of (1) the
(R)-allylic substitution product with modest enantiopurity, (2) the
achiral linear aromatic allylic benzoate, and (3) the (S)-enantiomer
of the branched allylic benzoate possessing high enantiopurity.
These data are consistent with a system that reacts with the
relative rates and equilibria in Scheme 1. The rate constant for
nucleophilic attack (k5) on allyliridium complex A is competitive
with the rate constant for collapse (k3) to form the linear allylic
benzoate from A (k5 ≈ k3); the rate (controlled by K1k3) for the
formation of the linear allylic benzoate from (R)-2 is greater than
the rate for the formation (controlled by K2k4) of the linear allylic
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C O M M U N I C A T I O N S
Table 2. Ir-Catalyzed Allylic Substitution of Racemic Aromatic
sponding allylic substitution products with good to excellent
enantioselectivity. The high reactivity of branched allylic benzoates
enables enantioselective allylic substitutions that are slow or poorly
selective with linear allylic electrophiles. Moreover, the high-yield,
one-pot synthesis of the branched allylic esters makes these
reactions practical with 2.2 equiv of this reagent, particularly for
processes in which the nucleophile is a valuable component. Efforts
to extend the current methods to neutral nucleophiles and to
reactions of additional allylic electrophiles are ongoing.
Allylic Benozatesa
yield
(%)b c
entry
R (2)
nucleophile
product
ee (%)d
,
1
2
3
4
Ph (2f)
NaOPh
3f
81
90
86
84
95
87
83
86
92
76
75
93
87
83
96
95
95
98
98
4-MeO-C6H4 (2g) NaOPh
3g
3h
3i
3j
3k
3l
3m
4b
5b
7b
7c
8b
9b
Acknowledgment. We thank the NIH for financial support of
this work (GM55382 and GM58108 to J.F.H. and GM84584 to
L.M.S.), Johnson-Matthey for gifts of IrCl3 and [Ir(COD)Cl]2, and
Dr. Klaus Ditrich and BASF for gifts of chiral amines. M.U. thanks
the JSPS for a fellowship.
4-F3C-C6H4 (2h)
4-Br-C6H4 (2i)
3-Br-C6H4 (2j)
2-F-C6H4 (2k)
2-Me-C6H4 (2l)
3-pyridyl (2m)
Ph (2f)
Ph (2f)
Ph (2f)
2-Me-C6H4 (2l)
Ph (2f)
Ph (2f)
NaOPh
NaOPh
NaOPh
NaOPh
NaOPh
NaOPh
LiN(Boc)2
KNHC(O)CF3
NaTs
5
6
94
7e
8
-84
92
93
92
96
9
Supporting Information Available: Experimental procedures and
characterization data. This material is available free of charge via the
Internet at http://pubs.acs.org.
10f
11
12e
13
14
NaTs
NaCH(CO2Me)2
NaCH(CN)2
-94
98
91
References
a See Supporting Information for experimental details. b Isolated yield
of products 3-9. Branched-to-linear selectivities were >95:5. c The
yields of 10 (based on 2) ranged from 48-52% (entries 1-6, 8-11, and
13-14). The yield of 10 was 5-8% for reactions of 2l (entries 7 and
12). See Table S2 in the Supporting Information. d Enantiomeric excess
of 3-9 determined by chiral HPLC methods. e Nucleophile was added
prior to isomerization. f Allylic substitution was run at 0 °C to rt in the
presence of 4 mol % 1b.
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C(O)CF3 with 2f formed protected allylamines 4b and 5b in 93%
and 92% ee (entries 9 and 10). The reactions of NaTs with allylic
benzoates 2f and 2l generated (S)-7b (R ) Ph) and (R)-7c (R )
2-Me-C6H4) in good yields with excellent enantioselectivities
(entries 11 and 12). Furthermore, the sodium salts of dimethyl
malonate and malononitrile reacted with 2f to form allylic alkylation
products 8b and 9b in 98% and 91% ee (entries 13 and 14).
In principle, enantioselective allylic substitution without isomer-
ization is possible if the rate of nucleophilic attack on complex A
(k5) greatly exceeds that for collapse to the linear allylic benzoate
(k3) (Scheme 1). The identity of the nucleophile does not substan-
tially alter the ratio of rate constants k5/k3. However, ortho
substitution on the aromatic group (R) of 2 did substantially change
the ratio of rate constants k5/k3. The branched aromatic allylic
benzoate 2k containing a small ortho-fluoro group (entry 6) reacted
like para- and meta-substituted branched allylic benzoates to form
(S)-3k with high enantioselectivity. In contrast, branched aromatic
allylic benzoates containing larger ortho substituents rearranged to
the linear isomer much more slowly than did the ortho-fluoro-,
meta-, and para-substituted substrates. Thus, ortho-methyl derivative
2l underwent substitution in a manner that was similar to that of
the aliphatic electrophiles; the reactions of NaOPh and NaTs with
aromatic allylic benzoate 2l (R ) o-Me-C6H4) formed allyl aryl
ether (R)-3l in 83% yield and 84% ee and allylic sulfone (R)-7c in
93% yield and 94% ee by addition of the nucleophile at the same
time as the catalyst (entry 7). The enantioselectivities of the
reactions of the branched cinnamyl carbonates containing ortho
substituents were substantially higher than those of the linear isomer,
further underscoring the improved transformations that can be
realized in some cases by use of the branched isomers.
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(12) The remaining branched allylic benzoate 2a was isolated in 52% yield
(based on 2.2 equiv of 2a) and 78% ee. The ee of the remaining 2a-e is
necessarily modest in reactions conducted with 2.2 equiv of 2a-e that occur
to form products 3-9 with high ee. However, the ee of remaining 2a was
94-97% with concomitant decreasing ee of 3a (75-93%) when performing
the reactions of NaOPh with less than 2.2 equiv of 2a (1.8-2.0 equiv).
See Table S1 in the Supporting Information for these data.
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(14) The rates of formation of allyliridium complexes A and B from the linear
allylic benzoate are considered to be negligible in this analysis because
the linear allylic benzoate does not undergo conversion under these reaction
conditions.
(15) The selectivity factor (s) ) ln{(1- c)(1-ee)}/ln{(1- c)(1 + ee)} where c
is the conversion of (()-2f and ee is the enantiomeric excess of the
remaining branched allylic benzoate 2f. Kagan, H. G.; Fiaud, J. C. Topics
in Stereochemistry; John Wiley & Sons; New York, 1988; Vol. 18, p 249.
In summary, we have developed versatile methods for iridium-
catalyzed, kinetic asymmetric substitution of racemic allylic elec-
trophiles. These reactions occur between a variety of aliphatic,
aromatic, and heteroaromatic allylic benzoates and a range of
anionic heteroatom and carbon nucleophiles to form the corre-
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