Spiroketal-based diphosphine ligands in Pd-catalyzed asymmetric allylic amination of Morita-Baylis-Hillman adducts: Exceptionally high efficiency and new mechanism

Article abstract of DOI:10.1021/ja410707q

Exceptionally high activity (with a TON up to 4750) of the palladium complexes of SKP ligand was discovered in the catalysis of asymmetric allylic amination of MBH adducts with aromatic amines. A comprehensive mechanistic study indicates that the unique structural features of the SKP ligand, with a long P···P distance in its solid-state structure, were favorable for allowing two P atoms to play a bifunctional role in the catalysis. Herein, one of the P atom forms a C-P σ-bond with the terminal carbon atom of allyl moiety as a Lewis base, and an alternative P atom coordinates to Pd atom. The cooperative action of organo- and organometallic catalysis discovered in the present catalytic system is most likely responsible for its high activity, as well as excellent regio- and enantioselectivities. The mechanism disclosed in the present catalytic system is distinct from most of the currently recognized mechanisms for Pd-catalyzed allylic substitutions.

Full text of DOI:10.1021/ja410707q

Subscriber access provided by DUESSELDORF LIBRARIES
Article
SKP ligands in Pd-catalyzed asymmetric allylic amination of
MBH adducts: Exceptionally high efficiency and new mechanism
Xiaoming Wang, Peihua Guo, Zhaobin Han, Xubin Wang, Zheng Wang, and Kuiling Ding
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 12 Dec 2013
Downloaded from http://pubs.acs.org on December 16, 2013
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 8
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
SKP ligands in Pd-catalyzed asymmetric allylic amination of
MBH adducts: Exceptionally high efficiency and new mecha-
nism
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Xiaoming Wang, Peihua Guo, Zhaobin Han, Xubin Wang, Zheng Wang, Kuiling Ding*
State Key Laboratory of Oganometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, P. R. China.
Supporting Information
ABSTRACT: Exceptionally high activity (with a TON up to 4750) of the palladium complexes of SKP ligand was
discovered in the catalysis of asymmetric allylic amination of MBH adducts with aromatic amines. A comprehensive
mechanistic study indicates that the unique structural features of the SKP ligand, with a long P…P distance in its solid
state structure, was favorable for allowing two P atoms to play a bifunctional role in the catalysis. Herein, one of the P
atom forms a CꢀP σ−bond with the terminal carbon atom of allyl moiety as a Lewis base and an alternative P atom
coordinates to Pd atom. The cooperative action of organoꢀ and organometallic catalysis discovered in the present
catalytic system is most likely responsible for its high activity, as well as excellent regio and enantioselectivities. The
mechanism disclosed in the present catalytic system is distinct from most of the currently recognized mechanisms for
Pdꢀcatalyzed allylic substitutions.
I. INTRODUCTION
port our new results on the discovery of exceptionally
high activity of the catalysis, a longꢀstanding challenge in
this type of reaction, and the disclosure of a new mechaꢀ
nism based on the bifunctional role of SKP ligand.
Palladiumꢀcatalyzed asymmetric allylic substitutions
have gained great successes in organic synthesis.1 Howꢀ
ever, it is still a great challenge in terms of the efficiency
and adaptability of catalysis for the application in indusꢀ
try.1,2 Moreover, the regioselective formation of a
branched product at the sterically more hindered posiꢀ
tion of allylic substrate is also particularly difficult in this
Pdꢀcatalyzed transformation.3
II. RESULTS AND DISCUSSION
1. The exceptionally high efficiency: The research
was initiated by following the reaction profile of 1a and
2a with a ReactIR in order to understand the kinetic beꢀ
haviors of the catalysis in the presence of 1 mol% of
Pd2(dba)3/SKP catalyst. It was surprising to find that the
complete conversion of MBH adduct has been observed
in a couple of minutes. This remarkably serendipitous
discovery allowed us to further reduce the catalyst loadꢀ
ing. As shown in Table 1, the complete conversion of subꢀ
strate can be realized in 1.5ꢀ2 h when the catalyst loading
of [Pd2(dba)3]/SKP was reduced to 0.1ꢀ0.05 mol%, afꢀ
fording the corresponding βꢀarylamino acid ester with
93ꢀ92% ee and 96/4 regioselectivity (entries 1ꢀ2). These
exciting results stimulated us to further diminish the catꢀ
alyst loading to 0.01%, 95% conversion of substrate has
been achieved in this case by extending the reaction time
to 12 h with comparable regioꢀ and enantioselectivities
with a TON of 4750 (entry 3). We believe this loading
should be among the lowest records in Pdꢀcatalyzed
asymmetric allylic substitutions.1 The remarkable activity,
excellent regio and enantioselectivity of this catalyst sysꢀ
tem coupled with the practical importance of this reacꢀ
tion prompted us to further undertake mechanistic stuty
to reveal the underlying reasons for its unique perforꢀ
mance.
Scheme 1. SKP/Pd catalyzed regio and enantioselective
allylic amination of MBH adducts.
Very recently, a type of chiral spiroketalꢀbased diꢀ
phosphine ligands (SKP)4 have been developed in our lab
and their palladium complexes have been discovered to
be effective to address the challenging issues of asymꢀ
metric allylic amination of racemic MoritaꢀBaylis–
Hillman (MBH) adducts with aromatic amines, affording
the βꢀaryl amino acid esters with excellent enantioꢀ and
regioselectivities (Scheme 1).4d This catalytic system has
also provided a facile approach for the synthesis of a chiꢀ
ral drug, Ezetimibe.4d In this work, we would like to reꢀ
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 8
1
2
3
4
5
6
7
8
Table 1. The exceptionally high efficiency of the SKP/Pd
conditions. This dramatic activity difference prompted us
catalyst for the allylic amination of MBH adduct 1a with
to probe into the structural features of the SKP ligand. As
shown in Figure 1a, Xꢀray structural analysis of (S,S,S)ꢀ
SKP revealed an intramolecular P,P distance of 6.293(8)
Å, much larger than those reported for analogous ligands
SPANphos (4.991 Å)11 or Xantphos (4.080 Å).12 Such an
extremely large inter P,P distance in SKP ligand is probꢀ
ably not favorable for adopting an intramolecular cisꢀ
chelating mode with metallic ions, but might provide the
opportunity to interact with metal ions in a transꢀ
coordination, or in a coordination with metals as a
monodentate ligand.13 Indeed, a PdCl2 complex of
(S,S,S)ꢀSKP, (S,S,S)ꢀ5, was prepared in 90% yield by reꢀ
action of (S,S,S)ꢀSKP with [Pd(CH3CN)2Cl2], and its Xꢀ
ray structural analysis showed the complex adopted a
distorted squareꢀplanar geometry, featuring a transꢀ
spanned chelating coordination with a PꢀPdꢀP angle of
160.08 (2)º (Figure 1b).13,14 The distance between two P
atoms 4.583(7) Å in the complex (S,S,S)ꢀ5 is much shortꢀ
er than that in free (S,S,S)ꢀSKP, indicating that a subꢀ
stantial conformational flexibility exists in the spiroketal
backbone of SKP ligand. Unfortunately, complex (S,S,S)ꢀ
5 only showed very poor activity and selectivities in the
reaction (Figure 2b vs 2a), implying that this complex is
not responsible for this highly selective and efficient caꢀ
talysis.
aniline 2a.a
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
entry
x(mol %)
0.1
t (h)
1.5
conv. (%)b yield (%)c 3aa/4aab
ee (%)d
93
1
>99
>99
95
90
89
91
96/4
96/4
97/3
2
0.05
2.0
92
3
0.01
12
92
a For details, see SI. b Determined by 1H NMR. c The yield of isolated (R)ꢀ3aa. d The
ee value of (R)ꢀ3aa is determined by HPLC on a chiral stationary phase.
2. The nature of the catalysis: Since it has been esꢀ
tablished that both Lewis bases (typically tertiary amines
or phosphines)5,6 and the transition metal complexes7 are
able to catalyze the allylic substitutions of MBH adducts
with various nucleophiles, control experiments were thus
carried out in the presence of either Pd precursor or
(S,S,S)ꢀSKP alone to clarify whether the reaction proceed
via organo or organometallic catalysis. The results
showed that no reaction occurs in either case (Figure S1),
clearly indicating both SKP ligand and Pd metal are esꢀ
sential for the catalysis. Furthermore, reaction profile
measurement in the presence of several different Pd preꢀ
cursors, including Pd(OAc)2, PdCl2(CH3CN)2, Pd2(dba)3
and [Pd(η3ꢀallyl)Cl]2, showed that Pd2(dba)3 is superior
to other Pd sources in terms of both activity and selectiviꢀ
ty, suggesting that the catalytic process might be trigꢀ
gered by a Pd(0) species (Figure S4). The exposure of the
reaction system to O2 results in an immediate inhibition
of the reaction, supporting that some lowꢀvalence Pd
species is involved in the catalytic cycle (Figure S5). Since
the in situ formation of Pd(0) nanoparticles have often
been found to be genuine active species in some Pdꢀ
catalyzed reactions,8 we also proceeded to clarify whether
the catalysis is homogeneous or heterogeneous in nature
by Hg(0)ꢀtest.9 As shown in Figure S5, reaction profile
accumulation indicated the progress is scarcely affected
by addition of an excessive amount of Hg(0) to the reacꢀ
tion mixture, consistent with the homogeneous nature of
the active species. Moreover, nonꢀlinear effect10 study
disclosed a linear relationship between the ee of 3aa and
the enaniopurity of SKP ligand, indicating only one SKP
ligand being most likely involved in the active Pd species
in the enantioꢀdetermining step (see Figure S9).
Figure 1. XꢀRay crystal structure of (S,S,S)ꢀSKP (a), and
its PdCl2 complex (S,S,S)ꢀ5 (b), hydrogen atoms are
omitted for clarity.
We next proceeded to investigate the solution behavior
by 31PꢀNMR (Figure S10) and the catalytic performance
(Figure S7) of (S,S,S)ꢀ5 and mixtures of Pd(CH3CN)2Cl2
with different ratio of (S,S,S)ꢀSKP. The results showed
that upon in situ mixing [Pd(CH3CN)2Cl2] with SKP ligꢀ
and, a dynamic mixture of (S,S,S)ꢀ5 and some Pd species
coordinated with a single P atom of SKP ligand coꢀ
existed in the solution, and the monodentate SKPꢀ
coordinated Pd species might be responsible for the forꢀ
mation of active species in the catalysis.13,15 Based on
these observations, a question about whether both P
moieties are necessary for the catalysis is raised. To adꢀ
dress this issue, monoxide of SKP ((S,S,S)ꢀSKPO'), a
monodentate SKP ligand analogue,16 was synthesized
and examined in the catalysis. The reaction catalyzed by
1 mol% of (S,S,S)ꢀSKPO'/Pd2(dba)3 at a ratio of 2/1 or
4/1 showed poor performance (Table S2), indicating that
SKP ligand does not simply act as a monophosphine ligꢀ
and, and both P atoms of the ligand should be involved
in the catalysis.
3. Structural features of the SKP ligand with a
long P…P distance: A quantitative comparison of imꢀ
pact of the ligand structure on the catalytic activity and
regio selectivity of the catalysis was also carried out with
several wellꢀestablished diphosphine ligands, including
(R)ꢀBINAP, DtBPF, Xantphos, and (S,S,S)ꢀSKP, respecꢀ
tively, in the reaction of 1a with 2a. The catalysis with
(S,S,S)ꢀSKP/Pd demonstrated a much faster rate than
other cases (Figure S6) under the otherwise identical
4. Bifunctional role of SKP ligand: To gain some
information of the possible intermediates in the catalysis,
we turned our attention to study πꢀally Pd complexes of
ACS Paragon Plus Environment

Page 3 of 8
Journal of the American Chemical Society
1
2
(S,S,S)ꢀSKP. Intriguingly, the reaction of [Pd(η3ꢀallyl)Cl]2
with analogous MBH adduct ((S,S,S)ꢀ10) (Scheme 3). It
precursor with (S,S,S)ꢀSKP ligand gave a crystalline
complex (S,S,S)ꢀ6 (85% yield), with a molecular compoꢀ
sition of (S,S,S)ꢀSKP/Pd(ally)Cl but not the expected πꢀ
allyl Pd(II) structure (Scheme 2a).17 To our surprise, Xꢀ
ray crystallographic analysis of this complex revealed
that two P atoms of (S,S,S)ꢀSKP do not coordinate to Pd
simultaneously (see Figure S29 in SI). Instead, a σ bond
is observed between the allyl moiety and one of the P
atoms of SKP ligand, to form an alkenylphosphonium
cation with its C=C double bond coordinating to a pallaꢀ
dium atom in an η2 fashion.18 The formation of the comꢀ
plex (S,S,S)ꢀ6 is probably caused by an intramolecular
nucleophilic attack of phosphorus atom at the terminal
carbon of a nascent η3ꢀallyl Pd intermediate, to lead to
the formation of the phosphorusꢀcarbon bond, followed
by C=C bond rearrangement via a hydrogen shift
(Scheme 2a).19 Inꢀsitu 31P NMR monitoring of the reacꢀ
tion of (S,S,S)ꢀSKP with [Pd(η3ꢀallyl)Cl]2 provided furꢀ
ther support of the proposed process (Figure S11), and an
analogous η2ꢀpropenyl Pd complex (S,S,S)ꢀ8 has been
isolated in 71% yield from the reaction of an allyphosꢀ
phonium salt of SKP (S,S,S)ꢀ7 with Pd2(dba)3 (Scheme
2b, for its crystal structure, see Figure S30 in SI)). Howꢀ
ever, tests of (S,S,S)ꢀ6 and (S,S,S)ꢀ8 in the catalysis indiꢀ
cated both complexes are less active than the catalyst
prepared inꢀsitu from (S,S,S)ꢀSKP with Pd2(dba)3 altꢀ
hough their regio and enantioselectivities were essentialꢀ
ly same (Figure 2c,d vs 2a). From the structural inforꢀ
mation and catalytic performance of (S,S,S)ꢀ6 and
(S,S,S)ꢀ8, it is clear that (S,S,S)ꢀSKP ligand likely beꢀ
haves as a “bifunctional ligand” in the catalysis. However,
these complexes are only catalyst precursors rather than
the direct active species involved in the catalytic cycle .
is assumed that (S,S,S)ꢀ10 might react with a Pd(0) preꢀ
sursor to form the active species ((S,S,S)ꢀ11), which may
immediately undergo the amination with aniline. Comꢀ
parison of the catalytic performance of (S,S,S)ꢀ
SKP/Pd2(dba)3 and (S,S,S)ꢀ10/Pd2(dba)3 indicated that
both catalyst systems resulted in the essentially same
activity, regioꢀ and enantioselectivities in the catalysis
(Figure 2e vs 2a). ESIꢀMS analysis of the catalyst system
generated from (S,S,S)ꢀ10 and Pd2(dba)3 indicated the
presence of species with the composition of [((S,S,S)ꢀ11)ꢀ
Br]+ (m/z 953.2291, see SI), supporting the formation of
an intermediate of (S,S,S)ꢀ11. A stoichiometric reaction
of phosphonium salt (S,S,S)ꢀ10 and Pd2(dba)3 with 2a in
the presence of AgOAc (1.2 equiv) indeed gave the exꢀ
pected amination product (R)ꢀ3aa in 80 % yield with
89/11 regioselectivity and 92% ee (see SI), directly reproꢀ
ducing the scenario of catalytic system. These results
strongly suggested that an intermediate (S,S,S)ꢀ11 should
most likely be involved in the catalysis, although we were
unable to get direct evidence of its exact molecular strucꢀ
ture.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. The proposed pathway for the formation of
active species (S,S,S)ꢀ11.
OAc
Pd2(dba)3
CO2Et
+
+
Ph
O
O
X = OAc
1a
Ph2P
PPh2
SKP
(S,S,S)-
O
O
X = Br
O
O
+
Pd2(dba)3
Br
Ph2P
PPh2
O
Ph2P
Ph
PPh2
Pd
X
CO2Et
Scheme 2. The reactions of (S,S,S)ꢀSKP with [Pd(η3ꢀ
allyl)Cl]2 (a), and an allyphosphonium salt of SKP
(S,S,S)ꢀ7 with Pd2(dba)3 to give unexpected complexes
(S,S,S)ꢀ6 and (S,S,S)ꢀ8.
Ph
OEt
(S,S,S)-10
(S,S,S)-11
(S,S,S)-SKP
in CH2Cl2
O
rt, 12 h
97%
K2CO3 PhNH2
2a
Ph
NH
O
OEt
OEt
9
Br
(a)
The difficulties associated with the isolation and charꢀ
acterization of intermediate (S,S,S)ꢀ11 are probably due
to its unstability and high reactivity. Fortunately, we obꢀ
tained an analogous complex (S,S,S)ꢀ13 by reacting a
triethoxylcarbonyl substituted allylic chloride (12) with
(S,S,S)ꢀSKP and Pd2(dba)3 (Scheme 4). Xꢀray single crysꢀ
tal structural analysis of (S,S,S)ꢀ13 clearly showed that
the complex adopts a structure analogous to that proꢀ
posed for intermediate (S,S,S)ꢀ11. A squareꢀplanar coorꢀ
dination geometry is found in this structure, wherein the
tetrasubstituted C=C bond coordinates in a η2ꢀfashion to
Pd atom which in turn bonded with one P atom of the
SKP ligand. The terminal carbon of allylic unit forms a Cꢀ
P σꢀbond with the alternative P atom of the ligand, to
generate an allyl phosphonium moiety (Scheme 4). Unꢀ
der such a circumstance, hydrogen shift as that in the
formation of complex (S,S,S)ꢀ6 or (S,S,S)ꢀ8 did not occur.
The C46ꢀC47 distance [1.532(6) Å] is very close to that of
a CꢀC single bond, and the bond lengths of Pd1ꢀC46
[2.056(8) Å] and Pd1ꢀC47 [2.059(5) Å] are also within
O
O
O O
+
[Pd( -allyl)Cl]2
Ph2P
PPh2
Ph2P
Cl
PPh2
Pd
(S,S,S)-SKP
(not isolated)
O
O
O
O
+
Cl
Pd
Ph2P
Cl
H3C
PPh2
Ph2P
PPh2
Pd
H
H
H
H
6
(S,S,S)- (85% yield)
(b)
O
O
CH2Cl2-hexane
+
O
O
Pd2(dba)3
-20oC
71%
Br-
PPh2
Ph2P
Br
PPh2
Pd
Ph2P
H3C
H
(S,S,S)-7
H
(S,S,S)-8
After some efforts to prepare a crystalline Pd complex
of (S,S,S)ꢀSKP with MBH adduct 1a failed, we were finalꢀ
ly successful to obtain a phosphonium salt of (S,S,S)ꢀSKP
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 8
1
2
3
4
5
6
7
8
the range of common PdꢀC(sp3) σꢀbond lengths (2.04ꢀ
caused by the stabilization of the transition state in the
2.08 Å),20 indicating that the palladium atom in the comꢀ
plex can be regarded as a Pd(II), likely as a result of the
very strong tendency of back electron transfer from elecꢀ
tron rich Pd atom to electronꢀdeficient olefinic moieꢀ
ty.18,21 The distance (3.174(5) Å) between carbonyl oxygen
(O7) and P1 atom of ligand is shorter than the sum of
their van der Waals radii (3.3 Å),22 indicating the presꢀ
ence of some weak intramolecular interaction of carbonꢀ
yl O7 atom with P atom of phosphonium salt. Such kind
of intramolecular interaction has been also proposed in
the phosphineꢀcatalyzed allylic substitution of MBH adꢀ
ducts.23
rateꢀlimiting step, gained from the formation of phosꢀ
phonium salt and the ensuing interaction of 2ꢀCO2Et
with phosphonium moiety,23 as well as the further stabiꢀ
lization by benzyl carbonꢀPd bond24 as that in the asꢀ
sumed active species (S,S,S)ꢀ11.
5. Kinetic studies and Hammett plots: Further kiꢀ
netic studies indicated the reaction follows a first order
dependence on the Pd catalyst and zeroꢀorder for 1a and
2a (see Figure S19ꢀ22 in SI). Although the kinetic studies
showed that the rate was independent of the concentraꢀ
tions of both substrates, the studies of the Hammett
plots25 showed that electronic features of the substituents
in substrates obviously impacts the reactivity (see Figure
S23ꢀS26 in SI). These results demonstrated that one catꢀ
alyst molecule has been involved in the rateꢀlimiting step,
and both MBH adduct (1a) and aniline (2a) substrates
probably have been readily embraced into the catalytic
center before the rateꢀdetermining step. Such kind of
kinetic behavior obviously favors a mechanism of dual
activation of both substrates and thereby allows a subseꢀ
quent intramolecular reaction of the activated species to
realize high catalytic activity and fine control of the selecꢀ
tivity.26,27 Moreover, the best correlation of log(kX/kH) of
arylamines with σ– (see Figure S24 in SI) reflected the
higher possibility of the involvement of aniline anion,
and the best correlation of log(kY/kH) of MBH adducts
with σ (see Figure S26 in SI) indicated no obvious posiꢀ
tive charge is developed at the benzyl carbon of allylic
component in the rateꢀlimiting transition state. Both of
them afforded a straight line with negative slope. Supꢀ
pose that the reductive elimination of amido and allyl
moieties from the Pd(II) key intermediate is involved in
the rateꢀlimiting step, the high electron distribution at
both amido and allyl moieties would be favorable for
their reductiveꢀelimination to form the new CꢀN
bond.28,29 Thus, all the kinetic data of catalysis and
Hammett plots of substituent effect support the hypotheꢀ
sis of reductive elimination mechanism for CꢀN bond
formation.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. Comparison of reaction profiles of model subꢀ
strates 1a and 2a using various catalyst precursors (at a
0.1 mol% [Pd]).
Scheme 4. The preparation and Xꢀray crystal structure
of (S,S,S)ꢀ13 (Hydrogen atoms are omitted for clarity).
6. The proposed mechanism: Based on these results,
a plausible reaction mechanism was proposed. As outꢀ
lined in Scheme 5, the catalysis is initiated by a Pd(0)
species (A), in which the SKP ligand either takes a
hemilabile transꢀchelating coordination or coordinates
to Pd(0) as a monodentate ligand. Complex A is assumed
to quickly undergoes oxidative addition with MBH adꢀ
duct, to form the corresponding πꢀallylic Pd intermediate
B coordinated by one P atom of SKP ligand owing to the
steric repulsion of allyl moiety and the long distance of P,
P atoms. This intermediate may exist an equilibrium with
complex C,30,31 formed by an intramolecular nucleophilic
attack of the noncoordinating P atom of SKP at the terꢀ
minal allyl carbon. The structure of C has been further
evidenced by Xꢀray diffraction analysis of an analogous
η2ꢀpropenyl Pd complex (S,S,S)ꢀ13 with comparable catꢀ
alytic activity (Figure 2f vs 2a). Alternatively, the πꢀallylic
Pd complex B may also accept the intermolecular nucleꢀ
ophilic attack of aniline on the less hindered end of the
allyl moiety to give the linear amination product 4aa
As shown in Figure 2, complex (S,S,S)ꢀ13 showed acꢀ
tivity, regio and enantioselectivities very similar to those
of (S,S,S)ꢀSKP/Pd2(dba)3, albeit a short incubation periꢀ
od (about 5 min.) was observed in the catalysis (Figure 2f
vs 2a). These results suggested that the complex (S,S,S)ꢀ
13 should be a competent active species for the allylic
amination. Accordingly, the preparation, characterizaꢀ
tion and catalytic activity studies of (S,S,S)ꢀ13 have proꢀ
vided strong albeit circumstantial evidences for the asꢀ
sumed active species (S,S,S)ꢀ11. Moreover, the evaluation
of the reactions of several allylic acetates with distinct
structural patterns(Figure S8), clearly demonstrated
that 1ꢀphenyl and 2ꢀCO2Et substituents in 1a were critiꢀ
cally important for its high reactivity. This was probably
ACS Paragon Plus Environment

Page 5 of 8
Journal of the American Chemical Society
1
2
directly by following the usual process of Pdꢀcatalyzed
sumably due to the weak nucleophilicity of arylamines.1i
In fact, the commonly used diphosphine ligands such as
BINAP, Xantphos, DtBPF only showed modest activity in
the reaction system (Figure S6), indicating the critical
importance of structural feature of SKP ligand. Accordꢀ
ingly, the origin of the acceleration of the catalysis using
SKP ligands should come from the changes of the reacꢀ
tion mechanism in comparison with that observed in
conventional nucleophilic allylic amination, thus avoidꢀ
ing the less efficient nucleophilic attack step. On the othꢀ
er hand, the novel multisite interaction pattern between
catalyst and substrates (D and E shown in Scheme 5) led
to the formation of a more tight reaction assembly
somewhat like enzyme, which thus facilitates the intraꢀ
molecular transformation and excludes the potential
product inhibition that observed in some metalꢀcatalyzed
reactions.32,34 Moreover, the formal charge separation
developed in intermediates D and E might be an inherent
driving force to facilitate the reductive elimination and
formation of C=C bond in the product with the regeneraꢀ
tion of the catalyst. To the best of our knowledge, such
kind of ligand/metal/substrate interaction pattern (Figꢀ
ure 3a) is unprecedented although various coordination
modes of diphosphine ligands with metal ions (Figure 3b)
have been extensively studied.13,35 The cooperative action
of both organo and organometallic catalysis discovered
in the present catalytic system is most likely responsible
for its exceptionally high efficiency and excellent regioseꢀ
lectivity.
allylic amination. Thanks to the weak nucleophilicity of
aromatic aniline and priority of intramolecular nucleoꢀ
philic attack of standby P atom, amination of complex B
only plays a minor role in the catalysis. Complex C is
expected to react readily with aniline to form key interꢀ
mediate D by elimination of HOAc under basic condiꢀ
tions. Although we are unable to isolate D, the formation
of analogous Pd(II) amido complexes have been reported
by Hartwig and Buchwald, respectively.29 On the basis of
Hammett plots of substituent effect in substrates 1 and 2,
a reductive elimination for the formation of C(sp3)ꢀN
bond seems to be more feasible. Considering the spatial
proximity of amido NꢀPd and benzyl CꢀPd bond in inꢀ
termediate D, the reductive elimination accordingly ocꢀ
curs at benzyl CꢀPd bond to yield the branched isomer
with simultaneous regeneration of C=C double bond in
the product and release of species A.32 The kinetic studꢀ
ies suggested the reductive elimination of D to be the
rateꢀdetermining step in the catalysis.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 5. The proposed mechanism for SKP/Pdꢀ
catalyzed asymmetric allylic amination of MBH adducts.
PhNH
Ph
(R)-3aa
OAc
CO2Et
CO2Et
Ph
O
O
1a
(0)
fast
Ph2P
PPh2
Pd
Ln
fast
A
CO2Et
NHPh
PhNH2 (2a)
Ph
O
O
O
O
Ph2
P
PPh2
O
(II)
4aa
Ph2P
AcO
PPh2
Pd
Pd
PhHN
H
Ph
Ph
OEt
CO2Et
E
B
rate-limiting step
O
O
fast
O
O
Ph2
P
PPh2
O
Ph2P
PPh2
O
Pd
Pd
PhNH2
K2CO3
KOAc + CO2 + H2
HOAc
Figure 3. Comparison of the present bifunctional catalꢀ
ysis involving cooperative actions of a metal and a Lewis
base (a), and conventional metal catalysis where both
phosphine moieties behaving as ‘spectator’ ligands (b).
PhHN
H
Ph
AcO
H
Ph
OEt
D
OEt
O
C
On the basis of the proposed mechanism mentioned
above, the unique performance of this catalytic system
can be rationalized. The appropriate distance of P, P coꢀ
ordinating atoms in SKP ligand is essentially important
for playing a bifunctional role in catalysis,33 in which one
P atom forms a CꢀP bond as a Lewis base with the termiꢀ
nal carbon atom of allyl moiety, and the other P atom
coordinates to Pd for organometallic catalysis. From the
view point of stereochemistry, 1ꢀphenyl and 2ꢀCO2Et
substituents at allyl moiety in intermediates C and D are
apt to take a cis arrangement and were extruded in the
opposite direction of central metal and SKP ligand, beꢀ
cause of the steric congestion between the 1ꢀPh group of
allyl moiety and aromatic sprioketal backbone of ligand
(see Scheme S2).7b,23 On the basis of the proposed conꢀ
figuration (R) at benzyl carbon bound to palladium atom
and the observed configuration of benzyl carbon in prodꢀ
uct 3aa (R), reductive elimination for the formation of Cꢀ
N bond would proceed via a concerted process, although
an ionic pathway would be also possible.29a It has been
known that the use of aromatic amines as nucleophiles in
Pdꢀcatalyzed allylic amination were rarely reported, preꢀ
III. SUMMARY AND CONCLUSIONS
In summary, the palladium complexes of spiroketalꢀ
based diphosphine ligand (SKP) have been disclosed to
show remarkably high activity (with a TON up to 4750)
in the catalysis of asymmetric allylic amination of raceꢀ
mic MBH adducts with aromatic amines, which is exꢀ
tremely important for the practical synthesis of βꢀaryl
amino acid derivatives, as well as a chiral drug,
Ezetimibe. The unique structures of the SKP ligand, the
related Pd complexes with allylic substrates and their
corresponding performance indicate that SKP ligand
plays a bifunctional role in the catalysis. The cooperative
action of both organo and organometallic catalysis disꢀ
covered in the present catalytic system is most likely reꢀ
sponsible for its exceptionally high efficiency and excelꢀ
lent regioselectivity. The reaction pathway revealed in
this study contrasts sharply with most of the currently
recognized mechanistic understandings on the scenarios
of allylic substitutions,1 and thus might stimulate future
work for the development of new catalytic reactions inꢀ
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 8
1
2
3
4
5
6
7
8
(3) For examples of branched regioselectivity control, see: (a)
volving the cooperative effect of organo and organomeꢀ
tallic catalysis with diphosphine ligands.
Hayashi, T.; Kishi, K.; Yamamoto, A.; Ito, Y. Tetrahedron
Lett. 1990, 31, 1743. (b) Hayashi, T.; Kawatsura, M.; Uoꢀ
zumi, Y. Chem. Comm. 1997, 561. (c) Prétôt, R.; Lloydꢀ
Jones, G. C.; Pfaltz, A. Pure. Appl. Chem. 1998, 70, 1035.
(d) You, S.ꢀL.; Zhu, X.ꢀZ.; Luo, Y.ꢀM.; Hou, X.ꢀL.; Dai, L.ꢀ
X. J. Am. Chem. Soc. 2001, 123, 7471. (e) Watson, I. D. G.;
Yudin, A. K. J. Am. Chem. Soc. 2005, 127, 17516. (f) Faller,
J. W.; Wilt, J. C. Org. Lett. 2005, 7, 633. (g) Johns, A. M.;
Liu, Z.; Hartwig, J. F. Angew. Chem., Int. Ed. 2007, 46,
7259. (h) Dubovyk, I.; Watson, I. D. G.; Yudin, A. K. J. Am.
Chem. Soc. 2007, 129, 14172.
ASSOCIATED CONTENT
Supporting Information
Experimental details for data acquisition and additional
discussion. This material is available free of charge via the
Internet at http://pubs.acs.org.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(4) (a) Wang, X.; Han, Z.; Wang, Z.; Ding, K. Angew. Chem.
Int. Ed. 2012, 51, 936. (b) Wang, X.; Guo, P.; Wang, X.;
Wang, Z. Ding, K. Adv. Synth. Cat. 2013, 355, 2900. (c)
Cao, Z.ꢀY.; Wang, X.; Tan C.; Zhao, X.ꢀL.; Zhou, J.; Ding,
K. J. Am. Chem. Soc. 2013, 135, 8197. (d) Wang, X.; Meng,
F.; Wang, Y.; Han, Z.; Chen, Y.ꢀJ.; Liu, L.; Wang, Z.; Ding,
K. Angew. Chem. Int. Ed. 2012, 51, 9276.
(5) For reviews, see: (a) Basavaiah, D.; Reddy, B. S.; Badsara, S.
S. Chem. Rev. 2010, 110, 5447. (b) Declerck, V.; Martinez,
J.; Lamaty, F. Chem. Rev. 2009, 109, 1; (c) Wei, Y.; Shi,
M. Chem. Rev. 2013, 113, 2059. (d) Rios, R. Catal. Sci.
Technol., 2012, 2, 267. (e) Liu, T.ꢀY.; Xie, M.; Chen, Y.ꢀC.
Chem. Soc. Rev. 2012, 41, 4101.
(6) (a) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535.
(b) Methot, J. L.; Roush, W. R. Adv. Synth. Catal. 2004,
346, 1035. (c) Ye, L.ꢀW.; Zhou, J.; Tang, Y. Chem. Soc. Rev.
2008, 37, 1140. (d) Nair, V.; Menon, R. S.; Sreekanth, A.
R.; Abhilash, N.; Biju, A. T. Acc. Chem. Res. 2006, 39,
520. (e) Marinetti, A.; Voituriez, A. Synlett 2010, 174.
(7) For Pdꢀcatalyzed reactions of MBH adducts, see: (a) Trost,
B. M.; Tsui, H.ꢀC.; Toste, F. D. J. Am. Chem. Soc. 2000,
122, 3534. (b) Trost, B. M.; Machacek, M. R.; Tsui, H. C. J.
Am. Chem. Soc. 2005, 127, 7014. (c) Trost, B. M.; Brenꢀ
nan, M. K. Org. Lett. 2007, 9, 3961. (d) Trost, B. M.; Thiel,
O. R.; Tsui, H.ꢀC. J. Am. Chem. Soc. 2002, 124, 11616. (e)
Trost, B. M.; Thiel, O. R.; Tsui, H.ꢀC. J. Am. Chem. Soc.
2003, 125, 13155. (f) Rajesh, S.; Banerji, B.; Iqbal, J. J.
Org. Chem. 2002, 67, 7852. (g) Nemoto, T.; Fukuyama,
T.; Yamamoto, E.; Tamura, S.; Fukuda, T.; Matsumoto, T.;
Akimoto, Y.; Hamada, Y. Org. Lett. 2007, 9, 927. (h) Cao,
H.; Vieira, T. O.; Alper, H. Org. Lett. 2011, 13, 11. (i) Wang,
Y.; Liu, L.; Wang, D.; Chen, Y.ꢀJ. Org. Biomol. Chem.
2012, 10, 6908. (j) Wang, Y.; Zhang, T.; Liu, L.; Wang, D.;
Chen, Y.ꢀJ. Chin. J. Chem. 2012, 30, 2641. (k) Li, Y.ꢀX.;
Xuan, Q.ꢀQ.; Liu, L.; Wang, D.; Chen, Y.ꢀJ.; Li, C.ꢀJ. J. Am.
Chem. Soc. 2013, 135, 12536. For other metals catalyzed
reactions, see: (l) Goldsmith, P. J.; Teat, S. J.; Woodward,
S. Angew. Chem. Int. Ed. 2005, 44, 2235. (m) Dabrowski,
J. A.; Haeffner, F.; Hoveyda, A. H. Angew. Chem. Int. Ed.
2013, 52, 7694.
AUTHOR INFORMATION
Corresponding Author
kding@mail.sioc.ac.cn
Funding Sources
We thank the Major Basic Research Development Program
of China (grant no. 2010CB833300), NSFC (grant nos.
21232009, 21172237, 21121062), and the Chinese Academy
of Sciences for financial support of this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This article is dedicated to Prof. LiꢀXin Dai on the occasion
of his 90th birthday. We appreciate the valuable discussion
of this work with Professor Shengming Ma, Professor Xueꢀ
Long Hou, Professor ShuꢀLi You and Professor Yuxue Li at
SIOC, and Professor Klaus Ruhland at Universität
Augsburg. We also thank Professor Jiabi Chen at SIOC for
his kind help in growing the single crystals.
Keywords
asymmetric catalysis, allylic amination, cooperative
catalysis, palladium, phosphine ligand, spiro
REFERENCES
(1) (a) Trost, B. M. Acc. Chem. Res. 1996, 29, 355. (b) Trost, B.
M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395. (c)
Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921.
(d) Dai, L.ꢀX.; Tu, T.; You, S.ꢀL.; Deng, W.ꢀP.; Hou, X.ꢀL.
Acc. Chem. Res. 2003, 36, 659. (e) Agrofoglio, L. A.; Gilꢀ
laizeau, I.; Saito, Y. Chem. Rev. 2003, 103, 1875. (f) Trost,
B. M.; Machacek, M. R.; Aponick, A. Acc. Chem. Res.
2006, 39, 747. (g) Helmchen, G.; Dahnz, A.; Dübon, P.;
Schelwies, M.; Weinhofen, R. Chem. Commun. 2007, 43,
675. (h) Lu, Z.; Ma, S. Angew. Chem., Int. Ed. 2008, 47,
258. (i) Trost, B. M.; Zhang, T.; Sieber, J. D. Chem. Sci.
2010, 1, 427. (j) Diéguez, M.; Pàmies, O. Acc. Chem. Res.
2010, 43, 312. For reviews of other metals as catalysts, see:
(k) Belda, O.; Moberg, C. Acc. Chem. Res. 2004, 37, 159.
(l) Hartwig, J. F.; Stanley, L. M. Acc. Chem. Res. 2010, 43,
1461. (m) Tosatti, P.; Nelson, A.; Marsden, S. Org. Biomol.
Chem. 2012, 10, 3147. (n) Liu, W.ꢀB.; Xia, J.ꢀB.; You, S.ꢀL.
Top Organomet Chem, 2012, 388, 155.
(8) For a critical review, see: Phan, N. T. S.; Sluys, M. V. D.;
Jones, C. W. Adv. Synth. Catal. 2006, 348, 609.
(9) For reviews describing experimental methods to distinguish
between homogeneous and heterogeneous catalytic reacꢀ
tions, see: (a) Widegren, J. A.; Finke, R.G. J. Mol. Catal. A:
Chem. 2003, 198, 317. (b) Phan, N. T. S.; Van Der Sluys,
M.; Jones, C. W. Adv. Synth. Catal. 2006, 348, 609. (c)
Crabtree, R. H. Chem. Rev. 2011, 112, 1536.
(10) (a) Satyanarayana, T.; Abraham, S.; Kagan, H. B. Angew.
Chem. Int. Ed. 2009, 48, 456. (b) Girard, C.; Kagan, H. B.
Angew. Chem. Int. Ed. 1998, 37, 2922.
(11) (a) Freixa, Z.; Beentjes, M. S.; Batema, G. D.; Dieleman, C.
B.; van Strijdonck, G. P. F.; Reek, J. N. H.; Kamer, P. C. J.;
Fraanje, J.; Goubitz, K.; van Leeuwen, P. W. N. M. Angew.
Chem. Int. Ed. 2003, 42, 1284. (b) Freixa, Z.; Kamer, P. C.
J.; Lutz, M.; Spek, A. L.; van Leeuwen, P. W. N. M. Angew.
Chem. Int. Ed. 2005, 44, 4385. (c) Jacquet, O.; Clément,
N. D.; Blanco, C.; Belmonte, M. M.; BenetꢀBuchholz, J.;
(2) (a) Large Scale Asymmetric Catalysis; Blaser, H. U.;
Schmidt, E., Eds.; WileyꢀVCH, Weinheim, 2003. (b) Blaser,
H.ꢀU.; Pugin, B.; Spindler, F. J. Mol. Catal. A: Chem.
2005, 231, 1.
ACS Paragon Plus Environment

Page 7 of 8
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
van Leeuwen, P. W. N. M. Eur. J. Org. Chem. 2012, 4844.
L.ꢀX.; Hou, X.ꢀL. Tetrahedron: Asymmetry 2007, 18,
1990. (e) Jiang, Y.ꢀQ.; Shi, Y.ꢀL.; Shi, M. J. Am. Chem. Soc.
2008, 130, 7202. (f) Ma, G.ꢀN.; Cao, S.ꢀH.; Shi, M. Tetraꢀ
hedron: Asymmetry 2009, 20, 1086.
(d) JiménezꢀRodríguez, C.; Roca, F. X.; Bo, C.; Benetꢀ
Buchholz, J.; EscuderoꢀAdán, E. C.; Freixa, Z.; van Leeuꢀ
wen, P. W. N. M. Dalton Trans., 2006, 268. (e) van Leeuꢀ
wen, P. W. N. M.; Zuideveld, M. A.; Swennenhuis, B. H. G.;
Freixa, Z.; Kamer, P. C. J.; Goubitz, K.; Fraanje, J.; Lutz,
M.; Spek, A. L. J. Am. Chem. Soc. 2003, 125, 5523. (f) Sala,
X.; Suárez, E. J. G.; Freixa, Z.; BenetꢀBuchholz, J.; van
Leeuwen, P. W. N. M. Eur. J. Org. Chem. 2008, 6197. (g)
Tschan, M. J.ꢀL.; LópezꢀValbuena, J.ꢀM.; Freixa, Z.;
Launay, H.; Hagen, H.; BenetꢀBuchholz, J.; van Leeuwen,
P. W. N. M. Organometallics, 2011, 30, 792. (h) Jacquet,
O.; Clément, N. D.; Freixa, Z.; Ruiz, A.; Claver, C.; van
Leeuwen, P. W. N. M. Tetrahedron: Asymmetry, 2011, 22,
1490.
(24) (a) Kuwano, R. Synthesis 2009, 7, 1049. (b) Johns, A. M.;
Tye, J. W.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128,
16010. (c) Trost, B. M.; Czabaniuk, L. C. J. Am. Chem. Soc.
2012, 134, 5778.
(25) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165.
(26) For reviews, see: (a) Du, Z.; Shao, Z. Chem. Soc. Rev.,
2013, 42, 1337. (b) Zhong, C.; Shi, X. Eur. J. Org. Chem.
2010, 2999. (c) Paull, D. H.; Abraham, C. J.; Scerba, M. T.;
AldenꢀDanforth, E.; Lectka, T. Acc. Chem. Res. 2008, 41,
655. (d) Ma, J.ꢀA.; Cahard, D. Angew. Chem. Int. Ed.
2004, 43, 4566. (e) Shibasaki, M.; Kanai, M.; Matsunaga,
S.; Kumagai, N. Acc. Chem. Res. 2009, 42, 1117. (f) Park,
J.; Hong, S. Chem. Soc. Rev., 2012, 41, 6931.
(27) For selected examples, see: (a) Jellerichs, B. G.; Kong, J.ꢀ
R.; Krische, M. J. J. Am. Chem. Soc. 2003, 125, 7758. (b)
Ibrahem, I. Cόrdova, A. Angew. Chem. Int. Ed. 2006, 45,
1952. (c) Jiang, G.; List, B. Angew. Chem. Int. Ed. 2011,
50, 9471..
(28) (a) Hartwig, J. F. Synlett 2006, 9, 1283. (b) Hartwig, J. F.
Acc. Chem. Res. 2008, 41, 1534. (c) Surry, D. S.; Buchꢀ
wald, S. L. Angew. Chem. Int. Ed. 2008, 47, 6338. (d)
Yamamoto, Y.; Takada, S.; Miyaura, N. Organometallics
2009, 28, 152.
(29) (a) Hanley, P. S.; Marquard, S. L.; Cundari, T. R.; Hartwig,
J. F. J. Am. Chem. Soc. 2012, 134, 15281. (b) Marquard, S.
L.; Rosenfeld, D. C.; Hartwig, J. F. Angew. Chem. Int. Ed.
2010, 49, 793. (c) Pan, J.; Su, M.; Buchwald, S. L. Angew.
Chem. Int. Ed. 2011, 50, 8647.
(30) (a) Macgregor, S. A. Chem. Soc. Rev., 2007, 36, 67. (b)
Basset, J.ꢀ M.; Bouchu, D.; Godard, G.; Karamé, I.; Kuntz,
E.; Lefebvre, F.; Legagneux, N.; Lucas, C.; Michelet, D.;
Tommasino, J. B. Organometallics 2008, 27, 4300.
(31) These solution behaviors of complex (S,S,S)ꢀ13 at different
temperatures indicated the possibility of CꢀP bond cleavꢀ
age by oxidative addition of Pd(0) to form an allylic Pd(II)
complex of SKP ligand with one P atom involved in the coꢀ
ordination with Pd, and to release a free P atom (see Figure
S15).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(12) (a) Kranenburg, M.; van der Burgt, Y. E. M.; Kamer, P. C.
J.; van Leeuwen, P. W. N. M. Organometallics 1995, 14,
3081. (b) Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Reek,
J. N. H. Acc. Chem. Res 2001, 34, 895.
(13) For excellent reviews, see: (a) Freixa, Z.; van Leeuwen, P.
W. N. M. Coord. Chem. Rev. 2008, 252, 1755. (b) Bessel,
C. A.; Aggarwal, P. Chem. Rev. 2001, 101, 1031.
(14) (a) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
6043. (b) Sawamura, M.; Hamashima, H.; Sugawara, M.;
Kuwano, R.; Ito, Y. Organometallics 1995, 14, 4549.
(15) Examples of diphosphine ligands acted as monodentate
ligands in catalysis, see: (a) Kawatsura, M.; Hartwig, J. F.
J. Am. Chem. Soc. 1999, 121, 1473. (b) Reetz, M. T.; Sostꢀ
mann, S. J. Organometall. Chem. 2000, 603, 105.
(16) Grushin, V. V. Chem. Rev. 2004, 104, 1629.
(17) (a) van Haaren, R. J.; Goubitz, K.; Fraanje, J.; van
Strijdonck, G. P. F.; Oevering, H.; Coussens, B.; Reek, J. N.
H.; Kamer, P. C. J.; van Leeuwen, P. W. N. M. Inorg.
Chem. 2001, 40, 3363. (b) Johns, A. M.; Utsunomiya, M.;
Incarvito, C. D.; Hartwig, J. F. J. Am. Chem. Soc. 2006,
128, 1828. (c) Butts, C. P.; Filali, E.; LloydꢀJones, G. C.;
Norrby, P.ꢀO.; Sale, D. A.; Schramm, Y. J. Am. Chem. Soc.
2009, 131, 9945. (d) Butts, C. P.; Crosby, J.; LloydꢀJones,
G. C.; Stephen, S. C. Chem. Commun., 1999, 35, 1707. (e)
Fairlamb, I. J. S.; LloydꢀJones, G. C. Chem. Commun.,
2000, 36, 2447.
(18) (a) Canovese, L.; Visentin, F. Inorg Chim Acta 2010, 363,
2375. (b) Duan, J.ꢀP.; Liao, F.ꢀL.; Wang, S.ꢀL.; Cheng, C.ꢀ
H. Organometallics 1997, 16, 3934. (c) Rybin, L. V.; Peꢀ
trovskaya, E. A.; Rubinskaya, M. I.; Kuz'mina, L. G.;
Struchkov, Y. T.; Kaverin, V. V.; Koneva, N. Y. J. Organoꢀ
metall. Chem. 1985, 288, 119. (d) Amatore, C.; Jutand, A.
Acc. Chem. Res. 2000, 33, 314. (e) Wakioka, M.; Nakajiꢀ
ma, Y.; Ozawa, F. Organometallics 2009, 28, 2527.
(19) (a) Ronde, N. J.; Totev, D.; Müller, C.; Lutz, M.; Spek, A.
L.; Vogt, D. ChemSusChem 2009, 2, 558. (b) Yamamoto,
T.; Saito, O.; Yamamoto, A. J. Am. Chem. Soc. 1981, 103,
5600. (c) Horner, L.; Ertel, I.; Ruprecht, H.ꢀD.; Bĕlovský,
O. Chem. Ber. 1970, 103, 1582. (d) Tamura, R.; Kato, M.;
Saegusa, K.; Kakihana, M.; Oda, D. J. Org. Chem. 1987,
52, 4121.
(32) The addition of product 3aa (0.5 equiv.) to the catalytic
system at the beginning of the reaction of 1a with 2a did
not result in observable negative effect on the outcome of
catalysis (see SI).
(33) For selected examples of bifunctional ligands with termiꢀ
nal functional group(s), see: (a) DiMauro, E. F.; Kozlowski,
M. C. J. Am. Chem. Soc. 2002, 124, 12668. (b) Handa, S.;
Gnanadesikan, V.; Matsunaga, S.; Shibasaki, M. J. Am.
Chem. Soc. 2010, 132, 4925. (c) Sladojevich, F.; Trabocchi,
A.; Guarna, A.; Dixon, D. J. J. Am. Chem. Soc. 2011, 133,
1710. (d) Lin, Y.ꢀM.; Boucau, J.; Li, Z.; Casarotto, V.; Lin,
J.; Nguyen, A. N.; Ehrmantraut, J. Org. Lett., 2007, 9, 567.
(e) Du, L.; Cao, P.; Liao, J. Acta Chim. Sinica 2013, 71,
1239.
(34) For reviews of catalysis involving product inhibition, see:
(a) van Leeuwen, P. W. N. M.; Chadwick, J. C., Homogeneꢀ
ous catalysts: activity, stability, deactivation; WileyꢀVCH:
Weinheim, 2011. (b) Blackmond, D. G. Angew. Chem. Int.
Ed. 2005, 44, 4302.
(20) (a) Braunstein, P.; Matt, D.; Dusausoy, Y.; Fischer, J.;
Mitschler, A.; Ricard, L. J. Am. Chem. Soc., 1981, 103,
5115. (b) Ferguson, G.; McAlees, A.; McCrindle, R.; Ruhl,
B. L. Acta Crystallogr. B, 1982, 38, 2553.
(21) Buchner, M. R.; Bechlars, B.; Wahl, B.; Ruhland, K. Orꢀ
ganometallics 2012, 31, 588.
(22) Pauling, L. The nature of the chemical bond. NY: Cornell
Univ. Press, 1939.
(23) (a) Cho, C.ꢀW.; Krische, M. J. Angew. Chem. Int. Ed.
2004, 43, 6689. (b) Cho, C.ꢀW.; Kong, J.ꢀR.; Krische, M. J.
Org. Lett. 2004, 6, 1337. (c) Park, H.; Cho, C.ꢀW.; Krische,
M. J. J. Org. Chem. 2006, 71, 7892. (d) Zhang, T.ꢀZ.; Dai,
(35) For reviews, see: (a) Phosphorus Ligands in Asymmetric
Catalysis; Borner, A., Ed.; WileyꢀVCH: Weinheim, 2008;
vol 1ꢀ3. (b) Chiral Ferrocenes in Asymmetric Catalysis;
Hou, X.ꢀL.; Dai, L.ꢀX., Eds.; WileyꢀVCH: Weinheim, 2010.
(c) Privileged Chiral Ligands and Catalysts; Zhou, Q.ꢀL.,
Ed.; WileyꢀVCH: Weinheim, 2011.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 8
1
2
3
4
5
6
7
8
NH2
Ph
NH
O
O
O
+
OEt
OAc
O
Ph2P
PhHN
H
PPh2
O
Pd
OEt
up to 4750 TON
97/3 B / L
92% ee
9
Ph
OEt
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment