Mechanism of the cobalt oxazoline palladacycle (COP)-catalyzed asymmetric synthesis of allylic esters

Article abstract of DOI:10.1021/ja106688j

The catalytic enantioselective S_N2′ displacement of (Z)-allylic trichloroacetimidates catalyzed by the palladium(II) complex [COP-OAc]₂ is a broadly useful method for the asymmetric synthesis of chiral branched allylic esters. A vari

Full text of DOI:10.1021/ja106688j

Published on Web 10/13/2010
Mechanism of the Cobalt Oxazoline Palladacycle
(COP)-Catalyzed Asymmetric Synthesis of Allylic Esters
Jeffrey S. Cannon, Stefan F. Kirsch,† Larry E. Overman,* and Helen F. Sneddon‡
Department of Chemistry, 1102 Natural Sciences II, UniVersity of California, IrVine,
California 92697-2025
Received July 27, 2010; E-mail: leoverma@uci.edu
Abstract: The catalytic enantioselective SN2′ displacement of (Z)-allylic trichloroacetimidates catalyzed by
the palladium(II) complex [COP-OAc]2 is a broadly useful method for the asymmetric synthesis of chiral
branched allylic esters. A variety of experiments aimed at elucidating the nature of the catalytic mechanism
and its rate- and enantiodetermining steps are reported. Key findings include the following: (a) the
demonstration that a variety of bridged-dipalladium complexes are present and constitute resting states of
the COP catalyst (however, monomeric palladium(II) complexes are likely involved in the catalytic cycle);
(b) labeling experiments establishing that the reaction proceeds in an overall antarafacial fashion; (c)
secondary deuterium kinetic isotope effects that suggest substantial rehybridization at both C1 and C3 in
the rate-limiting step; and (d) DFT computational studies (B3-LYP/def2-TZVP) that provide evidence for
bidentate substrate-bound intermediates and an anti-oxypalladation/syn-deoxypalladation pathway. These
results are consistent with a novel mechanism in which chelation of the imidate nitrogen to form a cationic
palladium(II) intermediate activates the alkene for attack by external carboxylate in the enantiodetermining
step. Computational modeling of the transition-state structure for the acyloxy palladation step provides a
model for enantioinduction.
Introduction
Enantioenriched allylic alcohols and their derivatives are
widely employed intermediates in the enantioselective syn-
thesis of a variety of chiral organic molecules.1,2 Recently,
we reported the use of the enantiopure palladium(II) complex
[(Rp,S)-COP-OAc]2 (4)3 and its enantiomer to catalyze the
transformation of prochiral (Z)-allylic trichloroacetimidates
1 to enantioenriched branched allylic esters 2 of high
enantiomeric purity (86-99% ee) (eq 1).4 Using the same
palladium(II) catalyst, enantioenriched branched allylic aryl
ethers 3 can be synthesized in an analogous manner in high
enantiomeric purity (90-98%) and yield (61-97%, eq 2).5
† Current address: Department Chemie, Technische Universita¨t Mu¨nchen,
Lichtenbergstrasse 4, 85747 Garching, Germany.
‡ Current address: GlaxoSmithKline Pharmaceuticals, Medicines Re-
search Centre, Gunnels Wood Road, Stevenage, Herts SG1 2NY, United
Kingdom.
(1) Selected recent examples include the following: (a) Shimizu, Y.; Shi,
S.-L.; Usuda, H.; Kanai, M.; Shibasaki, M. Angew. Chem., Int. Ed.
2010, 49, 1103–1106. (b) Crimmins, M. T.; Jacobs, D. L. Org. Lett.
2009, 11, 2695–2698. (c) Stivala, C. E.; Zakarian, A. J. Am. Chem.
Soc. 2008, 130, 3774–3776.
(2) Hodgson, D. M.; Humphreys, P. G. In Science of Synthesis; Clayden,
J. P., Ed.; Thieme: Stuttgart: 2007; Vol. 36, pp 583-665.
(3) (a) Anderson, C. E.; Kirsch, S. F.; Overman, L. E.; Richards, C. J.;
Watson, M. P. Org. Synth. 2007, 84, 148–155. (b) Anderson, C. E.;
Overman, L. E.; Richards, C. J.; Watson, M. P.; White, N. S. Org.
Synth. 2007, 84, 139–147. (c) Stevens, A. M.; Richards, C. J.
Organometallics 1999, 18, 1346–1348.
The COP-catalyzed SN2′-displacement of prochiral (Z)-allylic
trichloroacetimidates to form allylic esters and allylic aryl ethers
is characterized by exceptionally high branched-to-linear ratios.
The linear product is typically not seen by 1H NMR analysis of
crude reaction products, with branched-to-linear ratios greater
(4) (a) Cannon, J. S.; Kirsch, S. F.; Overman, L. E. J. Am. Chem. Soc.
2010, 132, http://dx.doi.org/10.1021/ja106685w, previous paper in this
issue. (b) Kirsch, S. F.; Overman, L. E. J. Am. Chem. Soc. 2005, 127,
2866-2867.
(5) Kirsch, S. F.; Overman, L. E.; White, N. S. Org. Lett. 2007, 9, 911–
913.
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15192 J. AM. CHEM. SOC. 2010, 132, 15192–15203
10.1021/ja106688j  2010 American Chemical Society

COP-Catalyzed Asymmetric Synthesis of Allylic Esters
A R T I C L E S
than 800:1 being established in several cases.4,5 Carboxylic acids
with low pKa values (<3.5) can generate allylic cations by
protonolysis of the imidate leaving group; as a result of this
background reaction, lower branched-to-linear selectivities are
observed in the synthesis of chiral allylic esters with these
stronger acids.4a
Scheme 1. Originally Proposed Mechanism for
[COP-OAc]2-Catalyzed Synthesis of Allylic Esters
The [COP-OAc]2-catalyzed enantioselective allylic displace-
ment reactions of carboxylic acids and phenols are limited to
(Z)-allylic trichloroacetimidate precursors, because the corre-
sponding E stereoisomers 7 preferentially undergo [COP-OAc]2-
catalyzed [3,3]-sigmatropic rearrangement (eq 3). This enanti-
oselective rearrangement to form chiral allylic amides, which
is optimally catalyzed by [COP-Cl]2 (5),6 has been established
to take place by a two-step, cyclization-induced rearrangement
mechanism.7
the exceptionally high branched-to-linear ratios strongly suggest
that the reaction does not proceed via η3-allylpalladium inter-
mediates.10
Our studies to further understand the nature of these
mechanistically novel palladium(II)-catalyzed SN2′ reactions are
the subject of this account. The scope and limitations of the
[COP-OAc]2-catalyzed enantioselective synthesis of allylic esters
are addressed in the preceding article.4a
In some cases, the nature of the bridging ligand of the COP
complex can influence the partitioning between the SN2′ and
[3,3]-sigmatropic rearrangement pathways. In the synthesis of
allylic phenyl ethers, but not allylic esters, changing the COP
catalyst to the di-µ-amidate dipalladium complex 6 allows
prochiral (E)-allylic trichloroacetimidates 7 to be employed (eq
4).8 Success in this case derives from [COP-NHCOCCl3]2 (6)
being a poor catalyst for allylic trichloroacetimidate rearrange-
ments.
Results
Catalytic Species in Solution. NMR observation of the
reaction of imidate 1 (R ) Et) with varying amounts of added
acetic acid in the presence of 1 equiv of [COP-OAc]2 (4)
revealed the presence of two new palladium(II) complexes: one
is the well-characterized di-µ-trichloroacetamidate dipalladium
complex 6,11 and the second is a structurally uncharacterized
mixed dimer 12 having acetate and trichloroacetamidate as the
two bridging ligands. To explore the composition of COP
complexes, which changes during the course of the [COP-
OAc]2-catalyzed reaction of (Z)-allylic trichloroacetimidates and
carboxylic acids as trichloroacetamide is produced, COP
catalysts 4 and/or 6 were mixed with acetic acid or trichloro-
acetamide in CD2Cl2 and the resulting solution was monitored
In our original report,4b a catalytic cycle for the [COP-OAc]2-
catalyzed allylic ester synthesis that involves chelation of the
allylic imidate substrate to the palladium(II) catalyst was
proposed (Scheme 1). In this mechanism, reversible coordination
of the imidate nitrogen to palladium gives complex 8. Displace-
ment of acetate by the tethered C-C π-bond generates cationic
palladium(II) complex 9, which is activated for attack by an
external carboxylic acid to produce complex 10.9 Deoxypalla-
dation of this palladacyclic intermediate delivers alkene complex
11, and after ligand exchange the allylic ester product 2.
The initial mechanistic proposal depicted in Scheme 1 was
founded on three observations. First, allylic N-arylimidates are
unsuitable leaving groups even though they are effective
substrates for COP-catalyzed [3,3]-sigmatropic rearrangements.4a
This difference in reactivity is attributed to reduced binding to
the palladium center by the imidate nitrogen in the less-basic
and more-sterically hindered arylimidate precursors. Second,
substrates such as allylic esters having leaving groups that lack
the strongly coordinating nitrogen atom are unreactive.4a Third,
1
by H NMR until equilibrium was reached (Table 1). Starting
solutions of [COP-OAc]2 (4) and trichloroacetamide, or of
[COP-NHCOCCl3]2 (6) and acetic acid, converged to the same
equilibrium mixture (Table 1, entries 1-2). In addition, mixtures
of [COP-OAc]2 and [COP-NHCOCCl3]2 also converged to
similar equilibrium mixtures (Table 1, entries 3-4). Equilibrium
was reached within 4 h, which is faster than the time frame of
the SN2′ reaction (typically 17 h). The equilibrium mixture of
catalyst species agrees with a simple statistical distribution,
indicating no significant thermodynamic preference for forming
either of the three palladacyclic complexes.
The rapid equilibration of [COP-OAc]2 (4) with [COP-
NHCOCCl3]2 (6) in the presence of acetic acid provides a
rationale for the inability of complex 6 to be an effective catalyst
for enantioselective displacement of (E)-allylic trichloroace-
timidates with acetic acid. As a result of this catalyst equilibra-
tion, the [3,3]-rearrangement of the allylic trichloroacetimidate
(6) Anderson, C. E.; Overman, L. E. J. Am. Chem. Soc. 2003, 125, 12412–
12413.
(7) Watson, M. P.; Overman, L. E.; Bergman, R. G. J. Am. Chem. Soc.
2007, 129, 5031–5044.
(10) (a) Onitsuka, K. J. Synth. Org. Chem. Jpn. 2009, 67, 584–594. (b)
Trost, B. M. J. Org. Chem. 2004, 69, 5813–5837. (c) Trost, B. M.;
Crawley, M. L. Chem. ReV. 2003, 103, 2921–2943. (d) Szabo´, K. J.
J. Am. Chem. Soc. 1996, 118, 7818–7826.
(8) Olson, A. C.; Overman, L. E.; Sneddon, H. F.; Ziller, J. W. AdV. Synth.
Catal. 2009, 351, 3186–3192.
(9) Although anti oxypalladation was originally suggested and is depicted
in Scheme 1, no evidence concerning this stereochemical issue was
available at the time.
(11) The structure shown for complexes 4 and 6 is consistent with single-
crystal X-ray analyses; see ref 8 for a detailed discussion and leading
references.
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A R T I C L E S
Cannon et al.
Table 1. Equilibria of [COP-OAc]2 (4) and [COP-NHCOCCl3]2 (6)
initial concentration (mM)a
equilibrium concentration (mM)b
[COP]2-OAc/NHCOCCl3 (12) [COP-NHCOCCl3]2 (6)
entry
[COP-OAc]2 (4)
[COP-NHCOCCl3]2 (6)
HOAc
H2NCOCCl3
[COP-OAc]2 (4)
Kc
1
2
3
4
9.28
18.8
2.16
2.06
2.07
3.64
2.81
2.68
4.55
4.31
4.32
4.52
2.69
1.35
9.28
4.65
3.10
18.5
4.65
6.20
3.7
3.8
b
c
a Experiments conducted in CD2Cl2. Determined by H NMR spectroscopy. K ) [12]2/([4][6]).
1
Table 2. New Palladium Species Formed by Exposure of
[COP-OAc]2 (4) to Carboxylic Acidsa
Table 3. Product Enantiomeric Excess vs Conversion
time (h)
1
2
3
5
10
25
ee (%)a
conversion (%)b
96
18
95
26
95
35
94
50
93
71
91
81
4:new COP
speciesb
SN2′ reactivity of
a Determined by enantioselective HPLC analysis. b Determined by
HPLC analysis against an internal standard.
entry
R
RCO2Hc
pKa
1
2
3
4
5
6
7
8
adamantyl
t-Bu
p-MeC6H5
Ph
o-ClC6H4CH2
ClCH2CH2
MeOCH2
Cl2CH
1:3.6
1:7.8
1:4.6
1:10.8
1:3.1
1.2:1
1:5.0
0:>95
26
40
67
84
92
40
38
14
6.8
5.0
4.4
4.2
4.1
4.0
3.6
1.3
Table 4. Test for Nonlinear Effects in the [COP-OAc]2-Catalyzed
Allylic Esterificationa
entry
cat. ee (%)b
product ee (%)c
eecalc (%)d
1
2
3
4
5
6
0
20
40
60
80
-2
15
34
52
75
90
0
16
34
53
71
90
a [4] ) 9.3 mM, [RCO2H] ) 18.6 mM, CD2Cl2. b Measured as the
sum of all dimeric or heterodimeric species that are not homodimeric 4.
See Supporting Information for more details. c % conversion after 24 h:
[imidate 1 (R ) Bn)] ) 0.5 M, 3 equiv of RCO2H, 1 mol % 4, in
CD2Cl2, 23 °C.
>99
a 1 equiv of 1 (R ) Bn), 3 equiv of PhCO2H, 1 mol % 4, substrate
concentration ) 0.5 M. b Produced by mixing solutions of opposite
enantiomer catalyst of >99% ee. c Determined by enantioselective SFC.
d Calculated as a straight line between 0% ee catalyst and 100% ee
catalyst (eecalc ) ee0 ·eecat, where ee0 is product ee when eecat ) 100%,
i.e. 90%).
substrate remains a competitive reaction even when the di-µ-
amidate dipalladium complex 6 is employed.
The equilibration of [COP-OAc]2 with various carboxylic
acids is summarized in Table 2. Both sterically demanding acids
(Table 2, entries 1-2) and benzoic acids (Table 2, entries 3-4)
readily formed new palladacyclic species. Addition of allylic
imidate 1 (R ) Et) to these mixtures resulted in the formation
of the branched allylic ester products 2 (R ) Et) with high
enantiomeric excess, suggesting that any of the dimers could
be the active catalyst or could be easily converted to the active
catalyst, in the presence of the allylic imidate substrate. No
obvious correlation between the equilibrium of the various di-
µ-carboxylate dipalladium complexes and either the acidity of
the carboxylic acid or the rate of the [COP-OAc]2catalyzed
reaction of the acid with allylic imidate 1 (R ) Et) is apparent.4a
% ee as a Function of Time. The enantiomeric excess of the
allylic ester product 2 (R ) Bn) produced from the [COP-OAc]2-
catalyzed reaction of (Z)-allylic imidate 1 (R ) Bn) with acetic
acid was monitored during the course of the reaction (Table 3).
The enantiomeric excess of the product formed during the
reaction was found to decrease only slightly over 25 h
(96-91%). These results show that the distribution of [COP-
OAc]2 (4), [COP-HNCOCCl3]2 (6), and unsymmetrical dimers
has no, or only a minor, influence on stereoinduction. The
observed small decrease in enantiomeric excess of 2 (R ) Bn)
could well result from slight catalyst decomposition at extended
reaction times. In a control experiment, ester 2 (R ) Bn) was
found to be configurationally stable when exposed to 1 mol %
of catalyst 4, 1 equiv of trichloroacetamide, and 2 equiv of acetic
acid in dichloromethane at room temperature for 24 h.
Nonlinear Effects. Because nonracemic dimeric enantiose-
lective catalysts can exhibit nonlinear effects,12 we examined
the [COP-OAc]2-catalyzed reaction of (Z)-allylic imidate 1 (R
) Bn) with acetic acid by using catalysts of varying enantio-
meric purity. Nonlinear effects were not observed (Table 4).
This result is consistent with an active catalyst monomer where
neither the (R/S) nor (R/R) dimeric resting state is thermody-
namically favored.
(12) Guillaneux, D.; Zhao, S.-H.; Samuel, O.; Rainford, D.; Kagan, H. B.
J. Am. Chem. Soc. 1994, 116, 9430–9439.
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COP-Catalyzed Asymmetric Synthesis of Allylic Esters
A R T I C L E S
Scheme 2. Synthesis of Enantioenriched Chiral Primary Imidates
13 and 14
Figure 1. Mosher’s conformational model for MTPA esters derived from
chiral primary alcohols 21 and 22.
2
Table 5. 1H and H NMR Chemical Shifts of MTPA Adducts of 21
and 22
entry
compound
H δ (ppm)
D δ (ppm)
1
2
3
4
21-(R)-MTPA ester (A/B)
21-(S)-MTPA ester (A′/B′)
22-(R)-MTPA ester (A/B)
22-(S)-MTPA ester (A′/B′)
4.82
4.86
4.69
4.73
4.90
4.85
4.76
4.72
Therefore, alcohols 21 and 22 were converted into their
corresponding R and S Mosher esters, which were analyzed by
17,18
2
1H and H NMR spectroscopy.
Mosher has shown that
shielding by the phenyl group of an MTPA ester causes a
distinctive upfield shift of groups oriented in-plane with the
π-electrons of the phenyl ring (Figure 1a). However, because
of the similar size of 1H and 2H, no distinct preference for 60°
rotation about the allylic C-O bond (A or B, A′ or B′) would
be expected. A modification of the Mosher model was developed
in order to address this issue. For the purposes of this model,
discussion is centered on the S enantiomers of primary alcohols
21 and 22. In the R,S MTPA ester (A or B), the deuterium atom
would never experience the in-plane shielding effects of the
phenyl ring in either conformation A or B. Instead, it would
only be deshielded by interaction with the methoxy group in
conformation A. In contrast, the proton would be shielded by
interaction with the phenyl ring in conformation B (Figure 1b).
The opposite trends would be expected for the S,S diastereomer
(Figure 1c).19 Therefore, the R-hydrogen of the R,S diastereomer
should be shifted upfield relative to that of the S,S diastereo-
mer. Accordingly, the R-deuterium atom of the R,S diastereomer
should be shifted downfield relative to that of the S,S diaste-
Steric Course of the SN2′ Reaction. In order to determine
the geometry of the [COP-OAc]2-catalyzed allylic esterification
reaction, deuterium-labeled primary allylic imidates 13 and 14
were prepared (Scheme 2). Deuterium incorporation was
achieved by lithium aluminum deuteride reduction of ynoate
1513 to yield propargyl alcohol 16. Reduction of the triple bond
using Lindlar’s catalyst provided (Z)-allylic alcohol 17 (Z:E >
95:5). Alternatively, sodium bis(2-methoxyethoxy)aluminum-
hydride (Red-Al) reduction of alkynol 16 yielded (E)-allylic
alcohol 18 (E:Z > 95:5). Oxidation of these isomeric allylic
alcohols with TPAP/NMO14 provided the corresponding alde-
hydes 19 and 20. Enantioselective Keck reduction of these
aldehydes gave alcohols 21 and 22 in enantiomeric excesses of
85% and 91%, respectively.15 Standard base-promoted conden-
sation of these alcohols with trichloroacetonitrile delivered
allylic imidates 13 and 14.16 Quantitative NMR analyses of
imidates 13 and 14 found them to have E:Z ratios of 3:97 and
99:1, respectively.
1
reomer. The opposite effects (relative deshielding of H and
shielding of 2H) would be expected for an R configuration. As
1
2
summarized in Table 5, the observed H- and H-NMR shifts
of the methylene hydrogen and deuterium of the Mosher esters
As enantioselective reduction of only one R,ꢀ-unsaturated
aldehyde, (E)-cinnamaldehyde, was reported by Keck,15 we felt
it was essential to establish the absolute configuration of chiral
allylic alcohols 21 and 22 by an independent means (Figure 1).
(17) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512–519.
(18) (a) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092–4096. (b) Seco, J. M.; Quinoa, E.; Riguera, R.
Tetrahedron: Asymmetry 2000, 11, 2781–2791. (c) Kusumi, T.; Ooi,
T.; Ohkubo, Y.; Yabuuchi, T. Bull. Chem. Soc. Jpn. 2006, 79, 965–
980.
(13) Hall, D. G.; Deslongchamps, P. J. Org. Chem. 1995, 60, 7796–7814.
(14) TPAP ) tetrapropylammonium perruthenate (Pr4N+RuO4-): Ley, S. V.;
Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 639–666.
(15) Keck, G. E.; Krishnamurthy, D. J. Org. Chem. 1996, 61, 7638–7639.
(16) (a) Nishikawa, T.; Asai, M.; Ohyabu, N.; Yamamoto, N.; Fukuda,
Y.; Isobe, M. Tetrahedron 2001, 57, 3875–3883. (b) Numata, M.;
Sugimoto, M.; Koike, K.; Ogawa, T. Carbohydr. Res. 1987, 163, 209–
225.
(19) Because the C2 vinylic hydrogen would experience both the shielding
phenyl and the deshielding methoxy, a small difference in chemical
shift between the two diastereomers would be expected. In fact, the
chemical shift for the C2 proton was nearly identical in both
diastereomers.
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A R T I C L E S
Cannon et al.
Figure 3. Secondary kinetic isotope effect studies (R ) CH2CH2OTBDPS,
Ar ) p-MeOC6H4).
Secondary Kinetic Isotope Effects. To gain some insight into
the nature of the rate-limiting step of the catalytic cycle,
hydrogen secondary kinetic isotope effects were measured. The
straightforward synthesis and isotopic analysis of the deuterium-
labeled substrates 1 (R ) CH2CH2OTBDPS) having deuterium
at either carbons 1, 2, or 3 are documented in the Supporting
Information. Kinetic isotope effect studies were carried out as
competition experiments using mixtures of unlabeled and
deuterium-labeled 1, with the ratios of unlabeled and deuterium-
labeled starting allylic imidate 1 before addition of catalyst and
Figure 2. SN2′ substitution with enantioenriched allylic imidate precur-
sors.21
1
allylic ester products 27 being measured by H NMR. Kinetic
derived from allylic alcohols 21 and 22 are consistent with an
S configuration. These findings are in agreement with the
absolute configurations derived from the expected stereoselec-
tivity of the Keck reduction.15
isotope effects were calculated as the ratio of these two ratios
[(27-1H:27-2H)/(1-1H:1-2H)]. p-Methoxybenzoic acid was em-
1
ployed as the nucleophile, because the H NMR signals of 27
corresponding to Ha, Hb, and Hc were fully resolved. An inverse
hydrogen secondary kinetic isotope effect at C3 of 0.79, and a
normal secondary kinetic isotope effect at C1 of 1.16, were
observed (Figure 3). No kinetic isotope effect at the internal
allylic carbon was observed.
Enantioenriched (1S,2Z)-allylic trichloroacetimidate 13 was
allowed to react with benzoic acid and phenol in the presence
of 1 mol % [(Rp,S)-COP-OAc]2 under standard conditions
(Figure 2). Within experimental uncertainty, chirality transfer
was complete, with the Rp,S enantiomer of the catalyst giving
respectively (1E,3R)-allylic benzoate 23 and (1E,3R)-allylic
phenyl ether 24.20 In accord with these observations, reaction
of imidate 13 with benzoic acid in the presence of the Sp,R
catalyst enantiomer yielded (1Z,3S)-allylic benzoate 25. These
results establish that the SN2′ substitution reactions of (Z)-allylic
imidates with carboxylic acids and phenols cleanly occur with
antarafacial stereospecificity.
Chirality transfer in the reaction of (1S,2E)-allylic trichloro-
acetimidate 14 with phenol catalyzed by the Rp,S enantiomer
of di-µ-trichloroacetamidate dipalladium complex 6 also pro-
ceeded with complete transfer of chirality to produce (1E,3S)-
allylic phenyl ether ent-24 (eq 5). This result shows that the
[COP-NHCOCCl3]2-catalyzed asymmetric SN2′ etherification in
the E allylic imidate series also takes place by clean antarafacial
stereospecificity.
Computational Modeling of Potential Mechanisms. The
results of the chirality-transfer experiments indicate that the
[COP-OAc]2-catalyzed synthesis of allylic esters (eq 1) and
allylic aryl ethers (eq 2) occurs by an antarafacial process
wherein the imidate leaving group is eliminated from the
opposite face of the allyl system as carboxylate is added. In
the context of an oxypalladation/deoxypalladation mechanism,
this result requires that the oxypalladation and deoxypalladation
steps occur with opposite geometries. The two possibilities are
depicted in Scheme 3 for the [(Rp,S)-COP-OAc]2-catalyzed
reaction of a (1S,2Z)-allylic trichloroacetimidate with a car-
boxylate nucleophile. In pathway A, the palladium catalyst binds
to the Si face of the C-C π-bond, activating it for anti
oxypalladation to generate the observed 3R configuration of the
allylic ester product. This step is followed by syn deoxypalla-
dation to provide the 1E alkene. Alternatively, catalyst binding
to the Re face of the C-C π-bond followed by syn oxypalla-
dation and anti deoxypalladation would provide the same
(1E,3R)-allylic ester product.
Oxypalladation reactions are known that take place in both
anti and syn geometries.22 As the two reaction pathways
depicted in Scheme 3 cannot be unambiguously distinguished
by existing precedent, we turned to DFT calculations to examine
As expected, allylic rearrangement of trichloroacetimidate 14
with [(Rp,S)-COP-NHCOCCl3]2 yielded (1Z,3S)-allylic trichlo-
roacetamide 26 (eq 6). This result is consistent with the
established suprafacial nature of this transformation.7
(20) The E:Z ratio of purified products was determined by integration of
the terminal vinyl signal and is estimated to be accurate within 2%.
The E and Z protons were differentiated by analyzing the magnitude
of the vicinal vinyl H-H coupling constant JHH (E:JHH ) 17.2 Hz. Z:
JHH ) 10.6 Hz).
(21) Different batches of 21 provided different enantiomeric excesses. The
enhancement of all batches was sufficient to determine the stereospeci-
ficity of the reactions depicted in Figure 2. The same level of
stereospecificity was observed when different enantiomeric mixtures
were exposed to the reaction conditions.
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COP-Catalyzed Asymmetric Synthesis of Allylic Esters
A R T I C L E S
Scheme 3. Two Possible Stereochemical Courses of
Antarafacial-SN2′ Displacement
fragment (4). Furthermore, a geometric comparison of bond lengths
and angles confirmed 28 as a reasonable surrogate of crystallo-
graphically characterized COP complexes.8,29,30
Three possible reaction pathways were investigated (Figure
4). The first involved an anti-oxypalladation pathway, wherein
external acetate attacks a COP-alkene complex having an
acetate ligand (I, Figure 4). In this reaction pathway, the imidate
nitrogen is protonated. The second anti-oxypalladation mech-
anism investigated involved external acetate attack on a cationic
palladium complex in which the imidate nitrogen is bonded to
the palladium center (II). The third reaction simulation involved
syn oxypalladation of a palladium complex wherein the acetate
nucleophile is delivered internally (III). Although the possibility
of a concerted oxypalladation/deoxypalladation pathway was
initially pursued, transition states corresponding to this reaction
mode were not found.31 We reasoned that syn-oxypalladation
processes in which the nucleophile is not bound to palladium
would be sterically improbable because of the necessity of the
nucleophile to pass by either the tetraphenylcyclobutadiene or
oxazoline fragments of the COP framework to interact with the
activated π-bond.
which of the allowable reaction pathways is most plausible by
investigating computationally derived reaction coordinate
diagrams.
The TURBOMOLE V6.223 quantum chemistry program using
the B3-LYP24 hybrid functional was utilized throughout this
study. All atoms were represented by the triple-ꢁ def2-TZVP
basis set.25 A polarizable continuum solvation model (COSMO)
was implemented to model the bulk effects of the dichlo-
romethane solvent.26 Full geometry optimization and numerical
frequency calculations were performed on all structures. Transi-
tion-state structures were characterized by exactly one imaginary
vibrational mode along the elemental step studied; intermediates
were confirmed by the absence of imaginary vibrational
modes.27 All energies are reported as electronic energies plus
unscaled zero-point corrections.
Figure 4. Three reaction pathways investigated.
Coordination Geometry of Palladium in a COP Complex.
The coordination geometry at the palladium center was exam-
ined first (Figure 5). Each of the three pathways required slightly
different coordination geometries of the starting complex. For
the anti-oxypalladation pathway I, monodentate complexes, in
which the palladium was bound to the alkene Si-face, were
investigated (29-32). Monodentate complexes (33-36) with
For ease of calculation, palladacyclic fragment 28 was chosen
as a model for the COP ligand. Natural population analysis (NPA)28
indicated that 28 was a reasonable electronic substitute for the COP
(22) (a) Ba¨ckvall, J.-E. Acc. Chem. Res. 1983, 16, 335–342. (b) Francis,
J. W.; Henry, P. M. Organometallics 1991, 10, 3498–3503. (c) Francis,
J. W.; Henry, P. M. Organometallics 1992, 11, 2832–2836. (d) Zaw,
K.; Henry, P. M. Organometallics 1992, 11, 2008–2015. (e) Hamed,
O.; Henry, P. M. Organometallics 1997, 16, 4903–4909. (f) Hamed,
O.; Thompson, C.; Henry, P. M. J. Org. Chem. 1997, 62, 7082–7083.
(g) Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999, 64,
7745–7750. (h) ten Brink, G.-J.; Arends, I. W. C. W.; Papadogianakis,
G.; Sheldon, R. A. Appl. Catal., A 2000, 194-195, 435–442. (i) Trend,
R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127,
17778–17788.
(25) (a) Eichkorn, K.; Weigend, F.; Treutler, O.; Ahlrichs, R. Theor. Chem.
Acc. 1997, 97, 119–124. (b) Scha¨fer, A.; Huber, C.; Ahlrichs, R.
J. Chem. Phys. 1994, 100, 5829–5835. (c) Weigend, F.; Furche, F.;
Ahlrichs, R. J. Chem. Phys. 2003, 119, 12753–12762.
(26) Klamt, A.; Schu¨u¨rmann, G. J. Chem. Soc., Perkin Trans. 2 1993, 799–
805.
(27) Because the COSMO solvent model was used, analytical second
derivatives were unavailable; as a result, numerical differentiation was
performed (TURBOMOLE program NumForce) using a step size of
0.02 bohr on 3N coordinates.
(23) (a) TURBOMOLE V6.2, Turbomole GmbH: Karlsruhe, Germany, 2009;
http://www.turbomole.com. (b) Treutler, O.; Ahlrichs, R. J. Chem.
Phys. 1995, 102, 346–354.
(28) Reed, A. E.; Weinstock, R. B.; Weinhold, F. J. Chem. Phys. 1985,
83, 735–746.
(24) (a) Slater, J. C. Quantum Theory of Molecules and Solids, Vol. 4:
The Self-Consistent Field for Molecules and Solids; McGraw-Hill: New
York, 1974. (b) Vosko, S. H.; Wilk, L.; Nusair, M. Can. J. Phys.
1980, 58, 1200–1211. (c) Becke, A. D. Phys. ReV. A 1988, 38, 3098–
3100. (d) Lee, C. T.; Yang, W. T.; Parr, R. G. Phys. ReV. B 1988, 37,
785–789. (e) Miehlich, B.; Savin, A.; Stoll, H.; Preuss, H. Chem. Phys.
Lett. 1989, 157, 200–206. (f) Becke, A. D. J. Chem. Phys. 1993, 98,
5648–5652. (g) Stephens, P. J.; Devlin, F. J.; Chabalowski, C. F.;
Frisch, M. J. J. Phys. Chem. 1994, 98, 11623–11627.
(29) See the Supporting Information for details.
(30) (a) Kirsch, S. F.; Overman, L. E.; Watson, M. P. J. Org. Chem. 2004,
69, 8101–8104. (b) The four Pd-C distances in cyclooctadienylpal-
ladium(II) chloride were determined to be 2.200, 2.209, 2.211, and
2.259 Å by X-ray crystallography. These compare favorably to the
Pd-C distances found in our computational studies. See: Rettig, M. F.;
Wing, R. M.; Wiger, G. R. J. Am. Chem. Soc. 1981, 103, 2980–2986.
(31) All attempts to locate a concerted transition state converged on the
transition structure 49 (Figure 7).
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Cannon et al.
Figure 5. Relative energies of imidate binding geometries.
Figure 6. Relative energies of various imidate-bound palladium complexes.
palladium bound to the Re face of the C-C π-bond were
investigated as the starting complex for syn-oxypalladation
mechanism III. In these two model complexes, the allylic
imidate substrate could bind in one of four possible configura-
tions, either trans or cis to the oxazoline ligand, with the alkene
substituents either pointed toward or away from the acetate
ligand. Because of geometric constraints, only the cis and trans
isomers of the bidentate allylic imidate ligand were calculated
(37 and 38).
A universal preference for the alkene π-bond to bind trans
to the oxazoline ligand (29, 31, 33, 35, and 37) was found. This
coordination geometry was favored by 2-5 kcal/mol. This
observation agrees with earlier investigations of the palladium-
catalyzed [3,3]-sigmatropic rearrangement of allylic imidates7
and with the trans influence of ligands in palladium(II) square-
planar complexes.32 In these complexes, the preference for
orientation of the alkene substituents toward or away from the
acetate ligand was small. In the series of Si-bound complexes,
orientation toward the acetate was slightly favored, whereas
essentially no preference was found in the Re-bound complexes.
This trend held also for complexes in which the alkene binds
cis to the nitrogen ligand. These small energy differences in
the conformation of the alkene were well within the error of
the computational methods employed.33 Complexes 31, 33, and
37 were chosen as the starting geometries for the three reaction
pathways.
Energies of Imidate-Bound Palladium Complexes. In order
to gain a better understanding of various starting complexes
that could be present under catalysis conditions, several ad-
ditional complexes were evaluated computationally (Figure 6).
Bidentate complex 39 would originate from N-bound imidate
complex 40 or alkene-bound complex 41. These latter two
neutral complexes were calculated to be 16.1 and 9.0 kcal/mol,
respectively, lower in energy than cationic complex 39. The
Re-bound η2-alkenepalladium complex 33 was found to be 1.4
kcal/mol lower in energy than the Si-bound complex 41.
Protonation of 41 to generate complex 42 costs 23.9 kcal/mol.
Because of the expected low basicity of a trichloroacetimidate,34
protonation of neutral complex 41 by acetic acid would not be
expected to be favorable in CH2Cl2 but would be necessary in
order to achieve a sufficiently nucleophilic acetate species while
maintaining charge balance.
[COP-OAc]2-Catalyzed SN2′ Displacement Reaction. Reaction
coordinate diagrams were calculated for the three pathways
illustrated in Figure 4 based on these optimized starting
geometries (Figure 7).35 The monodentate anti-oxypalladation
pathway I begins at high-energy iminium complex 42, which
requires 8.7 kcal/mol to reach oxypalladation transition-state
structure 43. The resulting zwitterionic oxypalladate 44 is
calculated to possess similar energy to starting complex 42.
Deoxypalladation has a small activation barrier (<1 kcal/mol),
via transition-state structure 45, to generate neutral alkene
complex 46. Overall, pathway I is calculated to be exothermic
by 41.6 kcal/mol.
Pathway II begins with cationic bidentate palladium alkene
complex 39. The activation energy for C-O bond formation
via transition-state structure 47 is calculated to be 4.4 kcal/mol.
This oxypalladation step produces neutral alkylpalladium com-
plex 48, which is calculated to be 9.2 kcal/mol lower in energy
than starting complex 39. Deoxypalladation of this intermediate
via transition-state structure 49 is found to have an 11.0 kcal/
mol activation barrier, with 12.5 kcal/mol being released in the
formation of amidate-alkene complex 50. Pathway II to
generate complex 50 is calculated to be highly favorable: with
a 4.4 kcal/mol activation barrier and exothermic by 21.7 kcal/
mol.
The syn-oxypalladation process (pathway III) begins with
acetate-alkene complex 33, which lies 10.4 kcal/mol lower in
energy than cationic bidentate complex 39. Intramolecular
oxypalladation of 33 requires 21.0 kcal/mol to reach transition-
state structure 51. The product of this syn oxypalladation,
intermediate 52, is calculated to be 9.7 kcal/mol higher in energy
than the starting complex 33. An energy barrier of 9.9 kcal/
mol (via 53) separates this intermediate from the cationic ester
complex 54, which is 2.4 kcal/mol higher in energy than
intermediate complex 52. It is no surprise that this SN2′ pathway,
which transforms a cationic alkene complex having an acetate
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COP-Catalyzed Asymmetric Synthesis of Allylic Esters
A R T I C L E S
Figure 7. Calculated reaction coordinate diagrams for three palladium-catalyzed antarafacial SN2′ reactions.
counterion to one having a more basic trichloroacetamidate
counterion, is calculated to be endothermic (by 12.1 kcal/mol).
The results of this computational study indicate that pathway
II is the most likely mechanism. Although the chelated ion-
pair intermediate 39 is not the lowest energy imidate-bound
palladium complex, the transition-state structure for oxypalla-
dation of this intermediate, which in the three mechanisms
investigated is found to be the rate-limiting step, is the lowest
energy oxypalladation transition state by 6.2 kcal/mol.
and 58 having the coordinated nitrogen atoms trans are
calculated to be 3.5 and 4.9 kcal/mol higher in energy than the
corresponding cis complexes. Transition-state structure 56,
which leads to the minor enantiomer, is found to be 1.5 kcal/
mol higher in energy than the lowest-energy transition-state
structure 55.
To gain an appreciation of the nonbonded interactions that
are likely responsible for the differences in energy of the
isomeric transition-state structures 55-58, the closest contacts
between the imidate substrate and COP ligand were examined
(Table 6). In low energy transition-state complex 55, the
closest contact between the imidate and the cyclopentadiene
ligandisthecoordinatedalkenehydrogenH59-cyclopentadiene
hydrogen H75 distance of 2.37 Å (entry 1). This computed
structure also exhibits a 2.66 Å contact between the
coordinated-alkene hydrogen H62 and H92 of the tetraphe-
nylcyclobutadiene fragment. The closest imidate-to-cyclo-
pentadiene contact in transition-state complex 56 is 2.33 Å
(H56-H95), also between a coordinated-alkene hydrogen and
Transition-State Structures for [COP-OAc]2-Catalyzed
Oxypalladation. Based on the results from the model studies,
preferred antarafacial SN2′ pathway II was investigated com-
putationally using the entire COP catalyst structure (Figure 8).36
Enantiodetermining transition-state structure 47 was used as the
starting geometry for calculations of isomeric transition-state
structures 55-58. Transition structures 55-58 were confirmed
by the presence of a single imaginary vibrational mode along
the formation of the C-O bond. These complexes would be
derived from reaction of imidate 1 (R ) H) with acetic acid in
the presence of [(Rp,S)-COP-OAc]2 (4).37 Imidate bound starting
complexes based on structure 39 were also calculated as a
comparison. In transition-state structures 55 and 56, the reacting
C-C π-bond is positioned trans to the oxazoline ligand, whereas
the alkene is cis to the oxazoline in transition-state structures
57 and 58. Transition-state structures 55 and 57 would produce
the observed R enantiomer of the allylic ester product; the minor
S enantiomer would be generated from transition-state structures
56 and 58. Transition-state structure 55 was found to be the
lowest energy of the four complexes investigated when con-
sidering both the relative energies of the transition states (∆∆G‡)
and the activation energy from the corresponding precursor
imidate complex (∆G‡, e.g. 39 to 47, Figure 7). Complexes 57
(32) Hartley, F. R. Chem. Soc. ReV. 1973, 2, 163–179.
(33) It was anticipated that, for the purposes of these studies, this small
energy difference would not affect the qualitative conclusions drawn
from the computational results. Preliminary investigation of the small
conformational preference of the alkene ligand using the full COP
framework supported these findings.
(34) (a) To estimate the pKa of the conjugate acid of trichloroacetimidates
1, mixtures of methyl trichloroacetimidate and various acids were
analyzed by NMR. The pKa of 1 is estimated to be approximately 1.1
based on these studies. See the Supporting Information for further
details. (b) Comparison of trichloroacetimidates to other imidates for
which the pKa values of their conjugate acids are known suggests that
trichloroacetimidate salts should have a pKa in the range 0-2: Granik,
V. G.; Pyatin, B. M.; Persianova, J. V.; Peresleni, E. M.; Ko-
styuchenko, N. P.; Glushkov, R. G.; Sheinker, Y. N. Tetrahedron 1970,
26, 4367–4373.
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A R T I C L E S
Cannon et al.
Figure 8. Relative energies of four isomeric transition-state structures based on 47.38
Table 6. Key Interactions between the Allylic Imidate Fragment and the COP Liganda
imidate to Cp or imidate to tetraphenylcyclobutadiene oxazoline
entry
structure
∆∆G‡ (kcal/mol)
atoms
distance (Å)
atoms
distance (Å)
atoms
distance (Å)
1
2
3
4
55
56
57
58
0.0
+1.5
+3.5
+6.4
H59-H75
H95-H56
H91-H47
H95-H47
2.374
2.327
1.979
1.997
H62-H92
H95-H73
H95-H58
H91-H57
2.662
2.572
2.508
2.398
H61-C33
H93-C31
H94-C33
H89-C33
3.298
2.852
3.213
3.063
a Distances that are less than the sum of the Van Der Waals radii of the atoms involved are shown in bold font.
a hydrogen of the cyclopentadiene fragment (entry 2). Two
additional close contacts of the imidate fragment occur (1)
between coordinated alkene hydrogen H95 and H73 of the
tetraphenylcyclobutadiene fragment (2.57 Å) and (2) between
methyl hydrogen H93 and the carbon C31 tetraphenylcy-
clobutadiene unit (2.85 Å).
A similar analysis of transition-state complexes 57 and 58
identifies several close contacts (Table 6, entries 3 and 4).
Coordinated-alkene hydrogen H91 of transition-state structure
57 is positioned only 1.98 Å away from H47 of the isopropyl
group. Coordinated-alkene hydrogen H95 of transition-state
structure 57 and methyl hydrogen H94 have contacts with H58
and C33 of the nearest phenyl ring of the tetraphenylcyclo-
butadiene moeity of 2.51 Å and 3.21 Å, respectively. Transition-
state complex 58 also has a similar highly destabilizing
interaction between coordinated-alkene hydrogens H95 and H47
of the isopropyl group (2.00 Å), and it has 2.40 Å and 3.06 Å
contacts between H91 and H89 with a hydrogen (H57) and
carbon (C33) of the tetraphenylcyclobutadiene floor, respectively.
Discussion
Monomeric Palladium(II) Catalyst in Equilibrium with
Carboxylic Acids and Trichloroacetamide. The studies sum-
marized in Table 1 show that, in the presence of trichloroac-
etamide, [COP-OAc]2 (4) is in a statistical equilibrium with
[COP-NHCOCCl3]2 (6) and an unsymmetrical dimer 12. When
carboxylic acid nucleophiles other than acetic acid are present,
catalyst dimers incorporating these nucleophiles are formed
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COP-Catalyzed Asymmetric Synthesis of Allylic Esters
A R T I C L E S
Scheme 4. Proposed Catalytic Cycle and Off-Cycle Catalyst
Equilibria
trichloroacetimidates with carboxylic acids proceeds in an
overall antarafacial fashion (Figure 2), requiring that the steric
courses of the oxypalladation and deoxypalladation steps be
different. The inverse secondary kinetic isotope effect observed
for the C3 vinylic hydrogen of the allylic imidate substrate
indicates rehybridization from sp2 to sp3 occurs during the rate-
limiting step (Figure 3). Conversely, the smaller normal
secondary kinetic hydrogen isotope effect at C1 suggests that
some rehybridization from sp3 to sp2 also occurs during the rate-
limiting step. These kinetic isotope effect studies would be
consistentwitheitheraconcertedoxypalladation-deoxypalladation
process,39 a stepwise mechanism wherein deoxypalladation is
turnover-limiting,40-42 or a stepwise non-steady-state mecha-
nism wherein the transition states for oxypalladation and
deoxypalladation are similar in energy.
To pursue whether the antarafacial selectivity of this catalytic
enantioselective synthesis of allylic esters results from anti
acyloxypalladation followed by syn deoxypalladation or the
inverse (syn acyloxypalladation followed by anti deoxypalla-
dation), as well as which step in the catalytic cycle is rate-
limiting, three possible mechanisms were evaluated by DFT
calculations (Figure 7). This computational investigation sug-
gests that pathway II is the most likely mechanism. In this
mechanism, palladium-imidate coordination to form complex
59 is followed by alkene coordination to form chelated-cationic
palladium(II) intermediate 60 (Scheme 4). Anti acyloxypalla-
dation by external nucleophilic attack of a carboxylic acid at
C3 of the palladium-imidate complex 60 generates palladacy-
clic intermediate 61. Subsequent syn deoxypalladation forms
the alkene trichloroacetamidate complex 62. Finally, reaction
of this complex with allylic trichloroacetimidate 1 liberates
allylic ester product 2 and trichloroacetamide and regenerates
intermediate 59.
The DFT calculations support our original conjecture4b that
chelation of the allylic trichloroacetimidate substrate to generate
a cationic palladium(II)-alkene complex (60) significantly
lowers the activation energy for oxypalladation (see the relative
energies of 33, 39, and 42; Figure 7). Intramolecular syn
oxypalladation is further made unlikely because of the lack of
a correlation between reactivity and the ability of a carboxylic
acid to displace acetic acid from [COP-OAc]2 (mechanism III
of Figure 7). The expectation would be that a higher relative
concentration of reacting complex 33 would increase the overall
rate of reaction in this pathway.
Our kinetic isotope effect investigations are consistent with
the calculated results. The transition-state structures for both
the oxypalladation, 47, and deoxypalladation, 49, steps of
mechanism II are sufficiently similar in energy to be consistent
with a non-steady-state kinetics scenario: the activation barrier
for the reverse reaction from intermediate 48 to complex 39 is
rapidly. However, the propensity of a carboxylic acid to displace
acetic acid from [COP-OAc]2 (4) does not correlate with the
relative reactivity of the acid toward imidate electrophiles (Table
2). Furthermore, analysis of the % ee of allylic ester products
at different extents of conversion shows negligible change as
trichloroacetamide is produced and the relative abundance of
dimeric-amidate catalysts 6 and 12 increases (Table 3). In
addition, nonlinear effects are not observed (Table 4). Although
the resting state of the catalyst is a mixture of various COP
complexes, these combined observations suggest that in the
presence of an allylic trichloroacetimidate substrate these
dipalladium complexes generate a monomeric complex, most
likely imidate-nitrogen-coordinated complex 59 (Scheme 4).7
Allylic Imidate Chelation Followed by Anti Oxypalladation/
Syn Deoxypalladation. Deuterium labeling studies showed that
the [COP-OAc]2-catalyzed SN2′ reaction of (Z)- and (E)-allylic
(35) Although ∆G and ∆S can be calculated for complexes 33, 39, and
42-54,23 there are so many assumptions involved in calculating the
relative energies of structures of this complexity, that we prefer to
discuss ∆E. The analysis would be unchanged if entropy was included:
see the table of relative ∆S values in the Supporting Information.
Additionally, the COSMO solvent model accounts for the entropy of
solvation.
(36) Zero-point energy corrections to obtain ∆G and ∆H values (298.15
K, 1 atm) were calculated using the program FreeH included in the
TURBOMOLE V6.2 software package.
(37) For ease of calculation, the carbon and hydrogen atoms of the four
phenyl rings in complexes 55-58 were simplified using the single-ꢁ
SZ.benzene basis set optimized for aromatics included with the
TURBOMOLE V6.2 package. All other atoms were calculated with
the def2-TZVP basis set.
(39) The Bergman group has reported similar secondary kinetic isotope
effects for a zirconium-promoted concerted syn-SN2′ substitution
reaction of allylic chlorides, see: Fox, R. J.; Lalic, G.; Bergman, R. G.
J. Am. Chem. Soc. 2007, 129, 14144–14145.
(40) Small inverse deuterium equilibrium isotope effects would be expected
at C2 and C3 for alkene complexation,41 and at C2 and C3 for
reversible oxypalladation.42
(41) Schro¨der, D.; Wesendrup, R.; Hertwig, R. H.; Dargel, T. K.; Grauel,
H.; Koch, W.; Bender, B. R.; Schwarz, H. Organometallics 2000, 19,
2608–2615.
(42) To our knowledge, deuterium equilibrium isotope effects have not
been reported for oxymetallation of alkenes. We assume that they
would be similar, at least in direction, to those for addition of bromine
to an alkene: Koerner, T.; Brown, R. S.; Gainsforth, J. L.; Klo-
bukowski, M. J. Am. Chem. Soc. 1998, 120, 5628–5636.
(38) An alternate view of structures 55-58 can be found in the Supporting
Information.
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A R T I C L E S
Cannon et al.
clobutadiene fragment than the corresponding hydrogen H62
of complex 55 (Figure 8 and Table 6). This trend is more
significant when comparing the next-closest groups: the
methyl group of transition-state structure 56 is positioned
0.45 Å closer to the tetraphenylcyclobutadiene floor (Table
6, H93-C31) than the C1 methylene group of low energy
transition-state conformation 55 (Table 6, H61-C33). In
transition-state structure 55, the methyl group of the substrate
is positioned away from the tetraphenylcyclobutadiene floor
and is pointed away from the COP ligand entirely, whereas,
in transition-state structure 56, the methyl substituent projects
toward the large tetraphenylcyclobutadiene fragment.43
Conclusion
The experimental and computational data acquired during
this study are consistent with a novel mechanism for the
[COP-OAc]2-catalyzed SN2′ reaction of allylic trichloroace-
timidates with carboxylic acids to form 3-acyloxy-1-alkenes
of high enantiomeric purity.4 Experimental studies establish
that a variety of bridged-dipalladium complexes are present
and constitute resting states of the COP catalyst; however,
monomeric palladium(II) complexes are undoubtedly in-
volved in the catalytic cycle. Deuterium-labeling experiments
establish that that the [COP-OAc]2-catalyzed SN2′ reaction
of (Z)- and (E)-allylic trichloroacetimidates with carboxylic
acids proceeds in an overall antarafacial fashion. Computa-
tional studies indicate that this antarafacial selectivity results
from an anti acyloxypalladation/syn deoxypalladation reaction
sequence (Scheme 4). In this mechanism, chelation of the
allylic imidate substrate to the catalyst to form a cationic
Pd(II) intermediate (complex 60 of Scheme 4) activates the
alkene for external attack by a carboxylate nucleophile. This
step is enantiodetermining.
Computational studies also led to a model for enantiose-
lection. In this model, the tetraphenylcyclobutadiene floor
and not the isopropyl group of the oxazoline ligand is the
significant structural feature of the catalyst determining
enantioselection.43 Positioning of the terminal alkyl groups
of the allylic imidate substrate away from tetraphenylcy-
clobutadiene moeity of the Rp,S enantiomer of [COP-OAc]2
activates the Re-face of the olefin for nucleophilic attack.
Additionally, steric interactions between the imidate and the
isopropyl group and the trans effect of the ligands direct
coordination of the C-C π-bond of the substrate trans to
the oxazoline ligand. As the [COP-OAc]2-catalyzed SN2′
reaction of (Z)-allylic trichloroacetimidates with phenols takes
place in an identical antarafacial fashion, it is reasonable to
propose that a similar transition-state model rationalizes
stereoselection in this reaction also.
Figure 9. Model for enantioselection.
calculated to be only slightly higher (by 2.6 kcal/mol) than the
activation barrier for the forward reaction from 48 to 50. This
small energy difference would allow for secondary kinetic
isotope effects at the sites of both oxypalladation and deoxy-
palladation.
Model for Enantioselection. An important outcome of the
computational study was the development of a model for the
high degree of diastereoselection induced by the COP catalyst
framework (Figure 8). In this model, bidentate coordination
of the allylic imidate substrate is determined by a combination
of steric and stereoelectronic effects. The two nitrogen (L-
type) ligands prefer a cis orientation because of an electronic
preference for the strong σ-donating cyclopentadienide ligand
to be trans to the weak σ-donating nitrogen atom of the
imidate. This mode of chelation is also favored sterically, as
the more bulky alkene ligand is positioned away from the
isopropyl substituent of the oxazoline ligand. The DFT
calculations of the four potential transition-state structures
for anti acyloxypalladation suggest that these effects are also
manifest in this enantiodetermining step, as the calculated
energies of transition-state structures 55 and 56, in which
the nitrogen ligands are cis, are lower than those of structures
57 and 58, where these ligands are trans (Figure 8). The
destabilizing steric interactions between the isopropyl sub-
stituent of the oxazoline ligand and C3 of the imidate
substrate in transition-state complexes 57 and 58 are high-
lighted in red in Figure 9.
By applying the lessons learned from these mechanistic
findings, we hope to develop more effective and more practical
catalysts for SN2′ allylic substitution reactions.
Acknowledgment. We thank Professor Filipp Furche and Dr.
Nathan Crawford for assistance with the computational studies as
well as helpful discussion. This research was supported by NSF
(CHE-9726471) and postdoctoral fellowships for S.F.K. from the
However, it is the subtle difference in steric interactions
between the substrate and the tetraphenylcyclobutadiene floor
that likely is decisive in favoring transition-state structure
55, which leads to the observed R enantiomer of the allylic
ester product, over transition-state structure 56, leading to
the minor S enantiomer. In these two cis complexes, the
alkene hydrogen H95 of complex 56 is calculated to be 0.1
Å closer to the proximal phenyl rings of the tetraphenylcy-
(43) The importance of interactions with the planar chiral tetraphenylcy-
clobutadiene moiety of the COP catalyst structure in dictating
enantioselection is also found in allylic imidate rearrangements
catalyzed by [COP-X]2 catalysts: see ref 7 and: Prasad, R. S.;
Anderson, C. E.; Richards, C. J.; Overman, L. E. Organometallics
2005, 24, 77–81.
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15202 J. AM. CHEM. SOC. VOL. 132, NO. 43, 2010

COP-Catalyzed Asymmetric Synthesis of Allylic Esters
A R T I C L E S
Alexander von Humboldt Foundation (Feodor Lynen Fellowship)
and for H.F.S. from the Royal Commission for the Exhibition of
1851. Additional unrestricted support from Amgen, Merck and
Pfizer is also gratefully acknowledged. Computational studies were
performed on hardware purchased with funding from CRIF (CHE-
0840513), and NMR and mass spectra were performed with
instruments acquired with the assistance of NSF and NIH shared
instrumentation grants.
Supporting Information Available: General methods, ex-
perimental procedures, NMR and HPLC data of new com-
pounds, computational data, and XYZ coordinates. This
material is available free of charge via the Internet at http://
pubs.acs.org.
JA106688J
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