Kinetic resolution and unusual regioselectivity in palladium-catalyzed allylic alkylations with a chiral P,S ligand

Article abstract of DOI:10.1021/ol0497382

Effective kinetic resolutions of acyclic allylic acetates and benzoates have been obtained using a palladium/(S)-BINAP(S) catalyst system. Unusually large preferences for the formation of branched alkylation products from 3-but-2-enyl and crotyl substrate

Full text of DOI:10.1021/ol0497382

ORGANIC
LETTERS
2004
Vol. 6, No. 8
1301-1304
Kinetic Resolution and Unusual
Regioselectivity in Palladium-Catalyzed
Allylic Alkylations with a Chiral P,S
Ligand
J. W. Faller,* Jeremy C. Wilt, and Jonathan Parr
Department of Chemistry, Yale UniVersity, New HaVen, Connecticut 06520
jack.faller@yale.edu
Received February 14, 2004
ABSTRACT
Effective kinetic resolutions of acyclic allylic acetates and benzoates have been obtained using a palladium/(S)-BINAP(S) catalyst system.
Unusually large preferences for the formation of branched alkylation products from 3-but-2-enyl and crotyl substrates have been observed.
The palladium-catalyzed asymmetric allylic alkylation reac-
tion has emerged as an extremely versatile C-C bond
forming tool.1,2 Numerous efficient ligand systems have been
developed for this transformation, including many chiral
bisphosphines, chiral P,N ligands,3,4 and, less commonly,
chiral P,O and P,S ligands.5-9
This report describes the kinetic resolution of some allylic
substrates (see Scheme 1) with the readily prepared axially
Scheme 1
Although the usual synthetic target has been the product
from a nucleophilic addition, several reports have recently
appeared documenting the kinetic resolution of allylic
acetates and carbonates in the course of these reactions.9-14
(1) Trost, B. M.; VanVranken, D. L. Chem. ReV. 1996, 96, 395.
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2419.
chiral (S)-BINAP(S) ligand 1.15-17 The regiochemistry of
reactions using ligand 1 are unusual, as it promotes the
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M. R. J. Org. Chem. 1999, 64, 2994.
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10.1021/ol0497382 CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/13/2004

Table 1. Kinetic Resolution of Symmetrically Substituted Allylic Substrates
entry
substrate
2 (mol %)a
T
% convb
eec of unreacted substrate (R)d
eec of alkylated product (X)d
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3a
3a
4a
4a
5
5
5
5
5
1
5
5
25
25
25
25
-30
25
23
55
69
100
62
51
27
>98
>98
68 (S)
74 (S)
72 (S)
72 (S)
80 (S)
19 (S)
56 (R)
67 (R)
>98
46
52
25
-30
44
40
54
a With respect to substrate. b Determined by 1H NMR (CDCl3) of the quenched reaction mixture. c Determined by 1H NMR chiral shift experiments with
(+)-Eu(hfc)3. d Assigned by comparison of optical rotation values with published values.
formation of branched isomers in reactions that would
otherwise be expected to yield linear products. Although
catalysis with other metals can yield branched products with
3-buten-2-ol and crotyl alcohol derivatives, palladium-
catalyzed reactions usually yield a preponderance of linear
products.1,2
standpoint, benzoate esters were preferred over acetate esters
owing to their lower volatility and ease of chromatographic
separation. For example, entry 3 was performed on a 300-
mg scale with comparable optical purity for the materials
produced at that conversion. This was an important finding
since the most recent advances in kinetic resolutions of this
type have achieved excellent selectivity results with cyclic
carbonates but acyclic carbonates have yielded products with
lower selectivity.
Ligand 1 and its corresponding palladium complex 2 are
prepared as shown in Scheme 2. Significant kinetic resolution
The selectivity factor (the ratio of relative rate constants
for the reaction of the two enantiomers) determines the %
conversion required to achieve an acceptably high ee.
Generally a value >10 gives a synthetically useful system.
Prior to 2001 the best published systems gave values for
rac-3 of krel ≈ 5. Gais18 has recently developed one of the
best systems based on palladium, which uses tert-butylsul-
finate as the nucleophile. For rac-3 this system gave 51%
ee at 36% conversion (these values imply a krel ≈ 30 if one
assumes pseudo-first-order kinetics), and ∼99% ee was
observed at 73% conversion. Our results show a >98% ee
at 55% conversion at 25 °C and 27% ee at 23% conversion,
suggesting a value for krel ≈ 26 at 25 °C.
Scheme 2
The selectivity of this BINAP(S)/Pd system suggested its
potential use with unsymmetrically substituted allylic alco-
hols. Low molecular weight secondary allylic alcohols, such
as 3-buten-2-ol, are particularly difficult substrates for
effective use of the Sharpless kinetic resolution procedure.
Although the procedure yields the allylic alcohol in high
enantiomeric purity in the case of the higher molecular
weight 3-octen-2-ol, the reaction takes 6-12 days.18 Fur-
thermore, low molecular weight alcohols are difficult to
separate from the reaction mixture. The Sharpless protocol
has been successfully used for the preparation of the epoxy
alcohol derived from 3-buten-2-ol; however, the allylic
of racemic 1,3-diphenylallyl acetate, rac-3, was initially
observed when using sodium dimethylmalonate as nucleo-
phile. Alkylation of this substrate proceeded rapidly at room
temperature (<5 min), and it proved to be easier to control
the progress of the reaction by adjusting the loading of the
nucleophile than by quenching the reaction after a certain
period of time (Table 1). Upon reaching a conversion of 55%,
the (S)-alkylation product was obtained in modest enantio-
meric purity (60% ee), but more importantly unreacted (R)-
allylic acetate was recovered in >98% ee.
Encouraged by these results, we began to examine the
scope of the kinetic resolution (Table 2). From a practical
(18) Gais, H. J.; Jagusch, T.; Spalthoff, N.; Gerhards, F.; Frank, M.;
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1302
Org. Lett., Vol. 6, No. 8, 2004

Table 2. Reaction of Unsymmetrically Substituted Allylic Substratesa
entry
substrate
T
% convb
eec of unreacted substrate (R)d
eec of alkylated product (R)d
branched:linear product ratiob
1
2
3
4
5
5a
5a
5a
5a
6a
25
53
47
63
100
100
59
58
81
10
12
14
16
20
60:40
71:29
76:24
79:21
64:36
-30
-30
-30
-30
1
1
a All reactions performed with 5 mol % catalyst to substrate. b Determined by H NMR (CDCl3) of the quenched reaction mixture. c Determined by H
NMR chiral shift experiments with (+)-Eu(hfc)3. d Configuration assigned by comparison of sign of optical rotation with published values.
alcohol was not isolated in this case.19 Generally, successful
kinetic resolution of low molecular weight allylic alcohols
are conspicuous by their absence in reviews of the Sharpless
epoxidation.20 Hence, synthetic procedures for natural prod-
ucts often use alternatives, such as preparations from lactic
acid.21
This suggests that a viable alternative kinetic resolution
route to 3-buten-2-ol derivatives may be especially useful.22
Our results show that 3-buten-2-yl benzoate may be kineti-
cally resolved conveniently using the BINAP(S)/Pd system
(see Table 2).
Interestingly, the unsymmetrically substituted substrate
rac-5 exhibited an unusually high ratio of branched to linear
alkylation product. There are examples of other metal allyl
species (Mo, Rh, Ir) and achiral palladium catalysts providing
a high branched to linear product ratio; however, in most
palladium-catalyzed allylic alkylation reactions, the linear
alkylation product is observed predominantly.23-27
Alkylation of linear substrate 6 also proceeded with a
regiochemical preference for the branched alkylation product
but in a smaller ratio than when starting from substrate rac-
5. This phenomenon is termed a regiochemical memory
effect, whereby the position of the leaving group determines
the regiochemistry of the alkylated product to some extent.28-34
The observation of a regiochemical preference for the
branched product has generally been attributed to steric
effects in some cases and electronic effects in others. Larger
bite angles and steric crowding can produce a lower energy
transition state in the incipient formation of the less
encumbered terminal olefin bound to the metal when a
branched isomer is formed. Thus on rare occasions when
higher branched to linear ratios have been observed, they
are often with higher coordination number metals, such as
molybdenum35 or ruthenium.36,37 High branched to linear
ratios have also been observed with iridium38,39 and rho-
dium40,41 catalysis wherein Ir(III) and Rh(III) complexes are
produced upon oxidative addition and tend to be six-
coordinate; hence, steric factors can also be more important
in these systems than with Pd(II) complexes that tend to be
four-coordinate. Thus, when high branched to linear ratios
have been observed for palladium catalysis, they have often
been promoted by larger bite angle ligands.42-45 With
unsymmetrical ligands, in particular, electronic effects can
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of Allylic Alcohols. In Catalytic Asymmetric Synthesis; Ojima, I, Ed.; VCH
Publishers: New York, 1993.
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D. T. J. Am. Chem. Soc. 1997, 119, 9641. (b) Klingler, F. D.; Psiorz, M.
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Org. Lett., Vol. 6, No. 8, 2004
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also direct regiochemistry by varying the charge distribution
at allylic termini trans to particular donors.46-48 We believe
that the electronic asymmetry of the BINAP(S) ligand plays
a more important role in the regiocontrol in the system
discussed here, since we would anticipate a normal bite angle
of ∼88°, assuming P,S binding is involved. The steric effects
in BINAP(S) would tend to place the more sterically
congested terminus of the η3-allyl cis to sulfur and trans to
phosphorus. Attack trans to phosphorus is preferred electron-
ically,49-51 which would favor branched products. One should
also note that anion effects that change rates of intercon-
version or enhance the production of η1-allyls could be
important.52 In this context one expects that the leaving group
departs trans to palladium and the benzoate does not
necessarily immediately bind to the metal. Hence, an anion
bound in an intermediate might well be one from the pool
of anions in solution. Although we intend to investigate the
mechanism in greater detail, a subtle interplay of the possible
interactions53 may be responsible for the regiocontrol ob-
served in this system.
In summary, we have shown that ligand 1 is effective for
the kinetic resolution of allylic acetates and benzoates for
palladium-catalyzed allylic alkylation. Unsymmetrically sub-
stituted allylic substrates show a high degree of selectivity
for the branched regioisomer with this catalytic system.
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Acknowledgment. This research was supported by a
grant from the National Science Foundation.
Supporting Information Available: Preparation of cata-
lyst and general procedure for catalytic reactions. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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