Asymmetric Aminomethylative Etherification of Conjugated Dienes with Aliphatic Alcohols Facilitated by Hydrogen Bonding

Article abstract of DOI:10.1021/jacs.1c06144

The asymmetric construction of allylic C-O bonds with primary or secondary aliphatic alcohols remains a substantial challenge in Pd-catalyzed allylation chemistry. Here, we report the development of an additive-free, palladium-catalyzed asymmetric aminomethylative etherification of conjugated dienes that enables the efficient, asymmetric O-allylation of primary and secondary aliphatic alcohols as well as water. Mechanism studies revealed that the hydrogen-bonding interaction between the alcohol and the in situ introduced aminomethyl moiety is critical to facilitate the nucleophilic addition of the alcohol to the π-allylpalladium species, which opened up the possibility of using aliphatic alcohols and water as nucleophilic substrates. This reaction tolerates a broad range of functional groups and shows remarkable regioselectivities and uniformly high enantioselectivities, which provides a direct and rapid approach to optically pure allylic 1,3-amino ethers and 1,3-amino alcohols from simple starting materials.

Full text of DOI:10.1021/jacs.1c06144

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Asymmetric Aminomethylative Etherification of Conjugated Dienes
with Aliphatic Alcohols Facilitated by Hydrogen Bonding
Rui Chang,§ Shoule Cai,§ Guoqing Yang, Xuyang Yan, and Hanmin Huang*
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ABSTRACT: The asymmetric construction of allylic C−O bonds with primary or secondary aliphatic alcohols remains a substantial
challenge in Pd-catalyzed allylation chemistry. Here, we report the development of an additive-free, palladium-catalyzed asymmetric
aminomethylative etherification of conjugated dienes that enables the efficient, asymmetric O-allylation of primary and secondary
aliphatic alcohols as well as water. Mechanism studies revealed that the hydrogen-bonding interaction between the alcohol and the in
situ introduced aminomethyl moiety is critical to facilitate the nucleophilic addition of the alcohol to the π-allylpalladium species,
which opened up the possibility of using aliphatic alcohols and water as nucleophilic substrates. This reaction tolerates a broad range
of functional groups and shows remarkable regioselectivities and uniformly high enantioselectivities, which provides a direct and
rapid approach to optically pure allylic 1,3-amino ethers and 1,3-amino alcohols from simple starting materials.
alladium-catalyzed asymmetric allylic substitution reac-
tions provide efficient methods for the enantioselective
allylpalladium species, in which the hydrogen bond acceptor is
catalytically installed during the formation of the π-
allylpalladium species (Scheme 1A). Similar to the activation
of alcohols by the formation of a borate complex with
zwitterionic π-allylpalladium species,5 the hydrogen-bonding
interaction between the functionalized π-allylpalladium species
and alcohols not only can enhance the ability of the alcohols to
serve as good nucleophiles but also can improve the
regioselectivity by temporarily tethering the alcohols close to
the reaction site. It is conceivable that the successful
implementation of this strategy calls for the identification of
a suitable hydrogen bond acceptor and an efficient process to
install it to some readily available substrates.
The Pd-catalyzed asymmetric difunctionalization of con-
jugated 1,3-dienes has become an important transformation in
synthesis, which offers a convenient way to install a
synthetically versatile allylic unit onto the target molecules.8
If aliphatic alcohols or water could be engaged as nucleophiles
in this reaction (Scheme 1B), the resulting products can serve
as valuable intermediates to various classes of stereogenic
ethers or alcohols. On the basis of our continuous efforts to
develop efficient and new reactions by using the cyclo-
palladated complex A as a leading complex,9 we questioned
whether it would be possible to employ the cyclopalladated
complex A as the source of hydrogen bond acceptor and the
conjugated dienes as the precursors of the π-allylpalladium
species (Scheme 1C). If so, the hydrogen-bonding interaction
between the alcohol and the aminomethylated π-allylpalladium
P
construction of allylic C−X bonds.1 The extension of such
reactions to the formation of allylic C−O bonds is of
widespread interest due to a wide range of biological activities
associated with this motif.2 While substantial progress has been
reported for construction of aryloxy C−O bonds, the
construction of aliphatic dialkyl C−O bonds by these reactions
is often challenging to realize, partially because of the
inherently poor nucleophilicity of aliphatic alcohols.3 In this
context, the identification of effective strategies to activate
aliphatic alcohols for facilitating these reactions is a critical
task. Early studies on the alcohol activation largely relied on
the use of extra metals to soften the oxygen nucleophiles,
which not only suffered from the requirement of a
stoichiometric amount of metals but also resulted in intricately
poor regioselectivity.4 As a means of addressing these
problems, an elegant approach by the formation of borate
complex was developed by Trost and others, which allowed for
the efficient allylic etherification of isoprene oxides and
vinylethylene carbonates.5 Unfortunately, such a method was
restricted only to the substrates that could form zwitterionic π-
allylpalladium intermediates. Alternatively, the formation of a
hydrogen bond between the chiral ligand and alcohol had
shown great promise to facilitate the nucleophilic addition of
alcohols to the π-allylpalladium species.6 However, only
limited chiral ligands are capable of constructing such an
activation mode. Nevertheless, all of these methods can only be
utilized for O-allylation of primary aliphatic alcohols; the
catalytic asymmetric O-allylation of secondary aliphatic
alcohols with readily available starting materials that proceeds
under additive-free and mild conditions and displays broad
substrate scope remains rare.7
Received: June 16, 2021
To overcome these limitations, we envisioned a new strategy
to activate alcohols by formation of hydrogen bonds between
the alcohol and a hydrogen bond acceptor embellished π-
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© XXXX American Chemical Society
A

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complex A. Further catalytic reaction was conducted at 80 °C
in MeOH by using the N,O-acetal 2a as the aminomethyl
source, [Pd(allyl)Cl]2 as the palladium precursor, Xantphos as
the ligand, and AgClO4 as the counteranion source, giving the
desired allylic 1,3-amino ether 4 in 86% yield (Scheme 2b).
Stimulated by these results, the enantioselective variant was
realized in the presence of 2.5 mol % of [Pd(allyl)Cl]2, 5.5 mol
% of AgClO4, and 5.0 mol % H8-BINOL-derived phosphor-
amidite ligand L10, delivering the desired product 4 in 83%
yield with 90% ee (Scheme 2c). Several critical reaction
parameters are worth pointing out. In particular, no reaction
took place in the absence of chiral ligand, showing the reaction
is accelerated by the chiral ligand. The enantioselectivity of this
transformation decreased in pace with increasing the ratio of
L10 to [Pd] from 1:1 to 2:1, although the yield was not
affected. The AgClO4 was not essential, but both the reactivity
and enantioselectivity were decreased without AgClO4 (see
Supporting Information (SI)). It was important to mention
that no other regioisomer was detected in this catalytic
reaction, showing the efficiency of this strategy for controlling
the regioselectivity.
Scheme 1. New Strategy for Activation of Aliphatic Alcohols
and Pd-Catalyzed Aminomethylative Etherification of
Conjugated Dienes
Having established the optimized reaction conditions, we
investigated the scope of this transformation. As shown in
Table 1, an array of N,O-acetals prepared from different
a
Table 1. Substrate Scope for N,O-Acetals
entry
R1
R2
yield (%)
ee (%)
B formed via migratory insertion would promote the
subsequent C−O bond formation, thus furnishing the allylic
1,3-amino ether. Herein, we report our successful implementa-
tion of this strategy and the development of a Pd-catalyzed
asymmetric aminomethylative etherification of conjugated
dienes with N,O-acetals and aliphatic alcohols, which allows
for rapid access to valuable chiral allylic 1,3-amino ethers in
high yields with complete regioselectivities and uniformly high
enantioselectivities. The synthetic strategy is also suitable for
the asymmetric aminomethylative hydroxylation of dienes with
H2O to afford an allylic 1,3-amino alcohol with high
enantioselectivity.
We embarked on our investigations by treating 1,3-diene 1a
with a stoichiometric amount of cyclopalladated complex A
and 10 equiv of MeOH in CH2Cl2. The desired product 4 was
obtained in 24% yield in 2 h (Scheme 2a), which suggested
this transformation could be initiated by the cyclopalladated
1
2
3
4
5
6
7
8
Me
Et
n-Pr
i-Pr
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
4 (83)
5 (82)
6 (79)
7 (80)
8 (78)
9 (78)
10 (72)
11 (70)
12 (60)
13 (90)
14 (72)
15 (88)
16 (84)
17 (71)
90
90
93
84
88
87
88
90
90
92
92
90
84
93:7
n-Bu
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
4-CF3C6H5CH2
4-FC6H5CH2
4-CIC6H5CH2
9
4-BrC6H5CH2
10
11
12
13
4-MeC6H5CH2
4-MeOC6H5CH2
3-MeC6H5CH2
2-MeC6H5CH2
(S)-N-benzyl-N-1-phenyethyl
b
14
a
Reaction conditions: 1a (0.3 mmol), 2 (0.36 mmol), 3 (1.0 mL),
[Pd(allyl)Cl]2 (2.5 mol %), L10 (5 mol %), AgClO4 (5.5 mol %), 60
°C, 48 h, isolated yield, ee values were determined by chiral HPLC
analysis. ent-L10, 75% yield, >95:5 dr.
b
Scheme 2. Palladium-Catalyzed Aminomethylative
Etherification of Conjugated Dienes
alcohols and diversely substituted dibenzylamines were
investigated, generating the corresponding allylic 1,3-amino
ethers in 60−90% yields with 84−93% ee values (Table 1,
entries 1−13). To our interest, both steric and electronic
effects on the aryl rings showed subtle influences on the
catalytic system. Comparing with the N,O-acetals bearing
electron-withdrawing groups on the aryl ring (9−12), those
prepared from the benzylamines with electron-donating
substituents delivered better yields and higher enantioselectiv-
ities (13−15). However, with the increase of the steric
hindrance on the phenyl ring, the enantioselectivity decreased,
while the yield remained unaffected (16). Furthermore, (S)-N-
B
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a
benzyl-N-1-phenyethyl-derived N,O-acetal was also applicable
to this catalytic system, affording the corresponding product 17
with good yield and high diastereoselectivity.
Table 3. Substrate Scope of Alcohols
After investigating the generality of the N,O-acetals, a variety
of substituted 1,3-butadienes were incorporated into this
powerful enantioselective protocol as well (Table 2).
a
Table 2. Substrate Scope of Conjugate Dienes
entry
R
yield (%)
ee (%)
1
2
3
4
5
6
7
8
C6H5
4-FC6H4
4-CIC6H4
2-CIC6H4
3-CIC6H4
4-BrC6H4
4-CO2MeC6H4
4-CF3C6H4
2-CNC6H4
4-MeC6H4
3-MeC6H4
4-t-BuC6H4
2,3-(Me)2C6H3
2,5-(Me)2C6H3
2-thienyl
6 (79)
93
88
86
97
93
92
89
92
80
89
80
84
92
81
51
82
88
63
18 (72)
19 (70)
20 (85)
21 (69)
22 (66)
23 (87)
24 (73)
25 (82)
26 (72)
27 (80)
28 (75)
29 (79)
30 (78)
31 (85)
32 (68)
33 (73)
34 (40)
9
10
11
12
13
14
15
16
17
18
2-naphthyl
CO2Et
C6H5CH2CH2
a
Reaction conditions: 1a (0.3 mmol), 2c (0.36 mmol), 3c (1.0 mL),
[Pd(allyl)Cl]2(2.5 mol %), L10 (5 mol %), AgClO4 (5.5 mol %), 60
°C, 48 h, isolated yield, ee values were determined by chiral HPLC
analysis.
a
Reaction conditions: 1a (0.3 mmol), 2d (0.36 mmol), 3 (3.0 mmol),
[Pd(allyl)Cl]2 (2.5 mol %), L10 (5 mol %), AgClO4 (5.5 mol %),
DCM (1.0 mL), 60 °C, 48 h, isolated yield, ee values were determined
b
1
by HPLC analysis, dr was determined by H NMR analysis. MeOH
(2.4 mmol). MeOH (1.8 mmol). MeOH (1.2 mmol). MeOH (0.6
mmol). MeOH (0.3 mmol).
Impressively, arylbutadienes installed with all sorts of
substituents, including halogen, carboxylate, trifluoromethyl,
cyano, and alkyl, were all compatible with the reaction
conditions, giving the corresponding products with high
enantioselectivities ranging from 80% to 97% ee and up to
87% yield (18−30). The absolute configuration of 20 was
determined to be (S) by the ECD calculation (see SI). In
addition, 2-thienyl, 2-naphthyl, and ester-substituted 1,3-
butadienes all proved to be suitable substrates for this
transformation (31−33). More interestingly, the challenging
alkyl-substituted butadiene can also be transformed into the
desired product 34 in 40% yield with moderate enantiose-
lectivity (Table 2, entry 18). Noteworthily, the regio- and
enantioselectivity of this reaction were not affected by the E/Z
ratio of the corresponding dienes (see SI).
c
d
e
f
yields with uniformly high enantioselectivities (90−92% ee). It
is important to highlight that more challenging secondary
alcohols, which were rarely tolerated in the previously reports,
could smoothly deliver the desired products in our protocol (7,
50, and 53). In addition, chiral alcohols derived from natural
products as well as glycols were also suitable substrates,
affording target products in good stereoselectivities (51−56).
Most intriguingly, fluorinated alcohols possessing poor
nucleophilicity were all compatible with this catalytic
reaction,10 converting to corresponding products 57−59 in
high yields with excellent enantioselectivities.
Further investigation of this reaction disclosed that 5 equiv
of alcohol was enough to efficiently promote these trans-
formations when CH2Cl2 was utilized as solvent. Inspired by
this result, a series of simple alcohols including substituted
benzyl alcohols, furan-2-ylmethanol, 2-phenylethan-1-ol, and 3-
phenylpropan-1-ol were all tested in these modified reaction
conditions, providing the corresponding 1,3-amino ethers 35−
42 in 52−81% yields with 91−94% enantioselectivities (Table
3). Gratifyingly, functionalized alcohols with keto, cyano, ester,
N-tosyl, and alkenyl functionalities were all well-tolerated,
affording the desired 1,3-amino ethers 43−49 in 52−76%
To go a step further, we explored the feasibility by using
H2O as the nucleophile to prepare the corresponding allylic
1,3-amino alcohol, which might be employed for synthesizing
numerous pharmaceuticals and natural products.11 By using
Pd(acac)2 as the catalyst precursor, Cu(OTf)2 as cocatalyst,
and L10 as ligand, the desired product 60 was obtained in 54%
yield with 98% ee (Scheme 3). Hydrogenation of 60 with H2
followed by protection of the amino group with (Boc)2O could
smoothly furnish 61. In addition, product 37 cyclized to give
the chiral disubstituted isochroman 62 through Heck
coupling.12
C
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CF3CH2OH might have contributed to its enhanced reactivity,
since the CF3CH2OH is a better hydrogen bond donor than
EtOH.15 Collectively, these data are consistent with our new
aminomethylative etherification reaction being a hydrogen-
bonding direct process.16
Scheme 3. Synthesis of 1,3-Amino Alcohol and Its
Transformation
A new palladium-phosphinamide complex, [Pd(allyl)L10Cl]
(65), was prepared to obtain further information on the
reactive species (Scheme 4e), which was unambiguously
characterized by X-ray crystallographic analysis. The catalytic
activity of 65/AgClO4 was almost the same as that of the
palladium complex formed in situ from [Pd(allyl)Cl]2, L10,
and AgClO4 under the standard reaction conditions (see SI).
This result indicated that a palladium complex bearing 1 equiv
of L10 might work as a reactive species. Moreover, the good
linear relationship between the ee value of optically active
ligand L10 and the ee value of the product 4 (Scheme 4d)
provided strong evidence that only a single phosphoramidite
ligand and one palladium species were involved in the
enantioselectivity-determining step.
In summary, we have developed an efficient Pd-catalyzed
enantioselective aminomethylative etherification of conjugated
dienes facilitated by a hydrogen-bonding interaction. A broad
range of aliphatic primary and secondary alcohols with
different substituents as well as water were compatible with
this protocol, delivering the chiral allylic 1,3-amino ethers and
allylic 1,3-amino alcohol with complete regioselectivities and
uniformly high enantioselectivities. Not only does this
methodology address a long-standing challenge in chemistry,
but it may also inspire further exploration and application of
this novel strategy to broaden the scope of Pd-catalyzed
allylation reactions.
A series of experiments were conducted to shed light on the
mechanism of this transformation. First, a stoichiometric
reaction with Xantphos-ligated PhPdI,13 diene 1a, and MeOH
(10 equiv) was conducted, and no desired difunctionalization
product 63 was observed (Scheme 4a). Catalytic reactions by
Scheme 4. Mechanistic Studies
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c06144.
Detailed experimental procedures, characterization data
of all of the new compounds, copies of HPLC
chromatographies, 1H and 13C NMR spectra of the
products (PDF)
Accession Codes
CCDC 2089587 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
using PhI as the substrate in the presence of different bases
(K2CO3, KHCO3, KOAc, and Et3N) also failed to give the C−
O bond formation product (Scheme 4b). These results
indicated the key role of the aminomethyl moiety for
promoting the C−O bond formation. To further unravel
whether this key role was imparted primarily through the
chelation of the amino moiety to the palladium catalyst14 or
through the hydrogen-bonding interaction between the alcohol
and the amino moiety, we studied the kinetic behaviors of the
reactions with EtOH and CF3CH2OH, respectively. Given the
higher nucleophilicity, the reaction rate with EtOH should be
much faster than that with CF3CH2OH.10 However, the
reaction profiles shown in Scheme 4c clearly disclosed that
CF3CH2OH exhibited a much better reactivity than EtOH. We
reasoned that the stronger hydrogen-bonding interaction
between the aminomethylated π-allylpalladium species and
AUTHOR INFORMATION
■
Corresponding Author
Hanmin Huang − Hefei National Laboratory for Physical
Sciences at the Microscale and Department of Chemistry,
Center for Excellence in Molecular Synthesis of CAS,
University of Science and Technology of China, Hefei
230026, People’s Republic of China; State Key Laboratory
for Oxo Synthesis and Selective Oxidation, Lanzhou Institute
of Chemical Physics, Chinese Academy of Sciences, Lanzhou
730000, People’s Republic of China; orcid.org/0000-
0002-0108-6542; Email: hanmin@ustc.edu.cn
D
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Communication
Selectivity. J. Am. Chem. Soc. 2002, 124, 7882−7883. (d) Fisher, C.;
Defieber, C.; Suzuki, T.; Carreira, E. M. Readily Available [2.2.2]-
Bicyclooctadienes as New Chiral Ligands for Ir(I): Catalytic, Kinetic
Resolution of Allyl Carbonates. J. Am. Chem. Soc. 2004, 126, 1628−
1629. (e) Xie, J.; Guo, W.; Cai, A.; Escudero-Adán, E. C.; Kleij, A. W.
Pd-Catalyzed Enantio- and Regioselective Formation of Allylic Aryl
Ethers. Org. Lett. 2017, 19, 6388−6391.
(4) For selected examples, see: (a) Kienen, E.; Sahai, M.; Roth, Z.;
Nudelman, A.; Herzig, J. Organotin Nucleophiles. 6. Palladium-
Catalyzed Allylic Etherification with Tin Alkoxides. J. Org. Chem.
1985, 50, 3558−3566. (b) Evans, P. A.; Leahy, D. K. Regio- and
Enantiospecific Rhodium-Catalyzed Allylic Etherification Reactions
Using Copper(I) Alkoxides: Influence of the Copper Halide Salt on
Selectivity. J. Am. Chem. Soc. 2002, 124, 7882−7883. (c) Kim, H.;
Men, H.; Lee, C. Stereoselective Palladium-Catalyzed O-Glycosyla-
tion Using Glycals. J. Am. Chem. Soc. 2004, 126, 1336−1337.
(d) Evans, P. A.; Leahy, D. K.; Andrews, W. J.; Uraguchi, D.
Stereodivergent Construction of Cyclic Ethers by a Regioselective and
Enantiospecific Rhodium Catalyzed Allylic Etherification: Total
Synthesis of Gaur Acid. Angew. Chem., Int. Ed. 2004, 43, 4788−
4791. (e) Shu, C.; Hartwig, J. F. Iridium-Catalyzed Intermolecular
Allylic Etherification with Aliphatic Alkoxides: Asymmetric Synthesis
of Dihydropyrans and Dihydrofurans. Angew. Chem., Int. Ed. 2004, 43,
4794−4797.
(5) (a) Trost, B. M.; McEachern, E. J.; Toste, F. D. A Two-
Component Catalyst System for Asymmetric Allylic Alkylations with
Alcohol Pronucleophiles. J. Am. Chem. Soc. 1998, 120, 12702−12703.
(b) Trost, B. M.; Brown, B. S.; McEachern, E. J.; Kuhn, O.
Asymmetric Synthesis of Oxygen Heterocycles via Pd-Catalyzed
Dynamic Kinetic Asymmetric Transformations: Application to
Nucleosides. Chem. - Eur. J. 2003, 9, 4442−4451. (c) Khan, A.;
Khan, S.; Khan, I.; Zhao, C.; Mao, Y.; Chen, Y.; Zhang, Y. J.
Enantioselective Construction of Tertiary C-O Bond via Allylic
Substitution of Vinylethylene Carbonates with Water and Alcohols. J.
Am. Chem. Soc. 2017, 139, 10733−10741. (d) Khan, S.; Li, H.; Zhao,
C.; Wu, X.; Zhang, Y. J. Asymmetric Allylic Etherification of
Vinylethylene Carbonates with Diols via Pd/B Cooperative Catalysis:
A Route to Chiral Hemi-Crown Ethers. Org. Lett. 2019, 21, 9457−
9462.
Authors
Rui Chang − Hefei National Laboratory for Physical Sciences
at the Microscale and Department of Chemistry, Center for
Excellence in Molecular Synthesis of CAS, University of
Science and Technology of China, Hefei 230026, People’s
Republic of China
Shoule Cai − Hefei National Laboratory for Physical Sciences
at the Microscale and Department of Chemistry, Center for
Excellence in Molecular Synthesis of CAS, University of
Science and Technology of China, Hefei 230026, People’s
Republic of China
Guoqing Yang − Hefei National Laboratory for Physical
Sciences at the Microscale and Department of Chemistry,
Center for Excellence in Molecular Synthesis of CAS,
University of Science and Technology of China, Hefei
230026, People’s Republic of China
Xuyang Yan − Hefei National Laboratory for Physical Sciences
at the Microscale and Department of Chemistry, Center for
Excellence in Molecular Synthesis of CAS, University of
Science and Technology of China, Hefei 230026, People’s
Republic of China
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c06144
Author Contributions
§R.C. and S.C. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work is supported by funding from the National Natural
Science Foundation of China (21925111 and 21790333).
■
REFERENCES
■
(1) (a) Hartwig, J. F.; Pouy, M. J. Iridium-Catalyzed Allylic
Substitution. Iridium Catalysis; Springer-Verlag: Berlin, Germany,
2011; pp 169−208. (b) Lu, Z.; Ma, S. Metal-Catalyzed
Enantioselective Allylation in Asymmetric Synthesis. Angew. Chem.,
Int. Ed. 2008, 47, 258−297. (c) Trost, B. M.; Crawley, M. L.
Asymmetric Transition-Metal-Catalyzed Allylic Alkylations: Applica-
tions in Total Synthesis. Chem. Rev. 2003, 103, 2921−2944.
(d) Trost, B. M.; Zhang, T.; Sieber, J. D. Catalytic Asymmetric
Allylic Alkylation Employing Heteroatom Nucleophiles: a Powerful
Method for C-X Bond Formation. Chem. Sci. 2010, 1, 427−440.
(2) For selected examples, see: (a) Uozumi, Y.; Kimura, M.
Asymmetric π-Allylic Etherification of Cycloalkenyl Esters with
Phenols in Water Using a Resin-Supported Chiral Palladium
Complex. Tetrahedron: Asymmetry 2006, 17, 161−166. (b) Kim, D.;
Reddy, S.; Singh, O. V.; Lee, J. S.; Kong, S. B.; Han, H. Ir(I)-
Catalyzed Enantioselective Decarboxylative Allylic Etherification: A
General Method for the Asymmetric Synthesis of Aryl Allyl Ethers.
Org. Lett. 2013, 15, 512−515. (c) Li, C.; Breit, B. Rhodium-Catalyzed
Dynamic Kinetic Asymmetric Allylation of Phenols and 2-
Hydroxypyridines. Chem. - Eur. J. 2016, 22, 14655−14663.
(d) Patel, H. H.; Prater, M. B.; Squire, S. O.; Sigman, M. S.
Formation of Chiral Allylic Ethers via an Enantioselective Palladium
Catalyzed Alkenylation of Acyclic Enol Ethers. J. Am. Chem. Soc.
2018, 140, 5895−5898.
(6) Xu, J.-X.; Ye, F.; Bai, X.-F.; Cui, Y.-M.; Xu, Z.; Zheng, Z.-J.; Xu,
L.-W. A Mechanistic Study on Multifunctional Fei-Phos LigandCon-
trolled Asymmetric Palladium-Catalyzed Allylic Substitutions. RSC
Adv. 2016, 6, 70624−70631.
(7) Ueno, S.; Hartwig, J. F. Iridium-Catalyzed Enantioselective and
Regioselective Allylic Etherification with Aliphatic Alcohols. Angew.
Chem., Int. Ed. 2008, 47, 1928−1931.
(8) For selected reviews, see: (a) Wu, Z.; Zhang, W. Recent
Advances in Metal-Catalyzed 1,2-Difunctionalization of Conjugated
Dienes. Youji Huaxue 2017, 37, 2250−2262. (b) Xiong, Y.; Sun, Y.;
Zhang, G. Recent Advances on Catalytic Asymmetric Difunctionaliza-
tion of 1,3-Dienes. Tetrahedron Lett. 2018, 59, 347−355. (c) Wu, X.;
Gong, L.-Z. Palladium(0)-Catalyzed Difunctionalization of 1,3-
Dienes: From Racemic to Enantioselective. Synthesis 2019, 51,
122−134. (d) For selected examples, see: Du, H.; Yuan, W.; Zhao,
B.; Shi, Y. Catalytic Asymmetric Diamination of Conjugated Dienes
and Triene. J. Am. Chem. Soc. 2007, 129, 11688−11689. (e) Wu, X.;
Lin, H.-C.; Li, M.-L.; Li, L.-L.; Han, Z.-Y.; Gong, L.-Z.
Enantioselective 1,2-Difunctionalization of Dienes Enabled by Chiral
Palladium Complex-Catalyzed Cascade Arylation/Allylic Alkylation
Reaction. J. Am. Chem. Soc. 2015, 137, 13476−13479. (f) Adamson,
N. J.; Wilbur, K. C. E.; Malcolmson, S. J. Enantioselective
Intermolecular Pd-Catalyzed Hydroalkylation of Acyclic 1,3-Dienes
with Activated Pronucleophiles. J. Am. Chem. Soc. 2018, 140, 2761−
2764. (g) Shen, H.-C.; Wu, Y.-F.; Zhang, Y.; Fan, L.-F.; Han, Z.-Y.;
Gong, L.-Z. Palladium-Catalyzed Asymmetric Aminohydroxylation of
1,3- Dienes. Angew. Chem., Int. Ed. 2018, 57, 2372−2376. (h) Nie, S.-
Z.; Davison, R. T.; Dong, V. M. Enantioselective Coupling of Dienes
and Phosphine Oxides. J. Am. Chem. Soc. 2018, 140, 16450−16454.
(3) For selected examples, see: (a) Iourtchenko, A.; Sinou, D.
Asymmetric Palladium(0)-Catalyzed Synthesis of Allylic Ethers. J.
Mol. Catal. A: Chem. 1997, 122, 91−93. (b) Trost, B. M.; Toste, F. D.
Asymmetric O- and C-Alkylation of Phenols. J. Am. Chem. Soc. 1998,
120, 815−816. (c) Evans, P. A.; Leahy, D. K. Regio- and
Enantiospecific Rhodium-Catalyzed Allylic Etherification Reactions
Using Copper(I) Alkoxides: Influence of the Copper Halide Salt on
E
https://doi.org/10.1021/jacs.1c06144
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pubs.acs.org/JACS
Communication
(9) (a) Xie, Y.; Hu, J.; Wang, Y.; Xia, C.; Huang, H. Palladium-
Catalyzed Vinylation of Aminals with Simple Alkenes: A New Strategy
to Construct Allylamines. J. Am. Chem. Soc. 2012, 134, 20613−20616.
(b) Xie, Y.; Hu, J.; Xie, P.; Qian, B.; Huang, H. Palladium-Catalyzed
Difunctionalization of Enol Ethers to Amino Acetals with Aminals and
Alcohols. J. Am. Chem. Soc. 2013, 135, 18327−18330. (c) Qin, G.; Li,
L.; Li, J.; Huang, H. Palladium-Catalyzed Formal Insertion of
Carbenoids into Aminals via C-N Bond Activation. J. Am. Chem.
Soc. 2015, 137, 12490−12493. (d) Liu, Y.; Xie, Y.; Wang, H.; Huang,
H. Enantioselective Aminomethyl-amination of Conjugated Dienes
with Aminals Enabled by Chiral Palladium Complex-Catalyzed C-N
Bond Activation. J. Am. Chem. Soc. 2016, 138, 4314−4317. (e) Yu, B.;
Zou, S.; Liu, H.; Huang, H. Palladium-Catalyzed Ring-Closing
Reaction via C-N Bond Metathesis for Rapid Construction of
Saturated N-Heterocycles. J. Am. Chem. Soc. 2020, 142, 18341−
18345.
(10) (a) Minegishi, S.; Kobayashi, S.; Mayr, H. Solvent
Nucleophilicity. J. Am. Chem. Soc. 2004, 126, 5174−5181.
(b) Ammer, J.; Nolte, C.; Mayr, H. Free Energy Relationships for
Reactions of Substituted Benzhydrylium Ions: From Enthalpy over
Entropy to Diffusion Control. J. Am. Chem. Soc. 2012, 134, 13902−
13911.
(11) Lait, S.; Rankic, D.; Keay, B. A. 1,3-Aminoalcohols and Their
Derivatives in Asymmetric Organic Synthesis. Chem. Rev. 2007, 107,
767−796.
(12) Bankston, D.; Fang, F.; Huie, E.; Xie, S. Palladium(II) Acetate-
Tris(triphenylphosphine)rhodium(I) Chloride: A Novel Catalytic
Couple for the Intramolecular Heck Reactions. J. Org. Chem. 1999,
64, 3461−3466.
(13) Andersen, T. L.; Friis, S. D.; Audrain, H.; Nordeman, P.;
Antoni, G.; Skrydstrup, T. Efficient 11C-Carbonylation of Isolated
Aryl Palladium Complexes for PET: Application to Challenging
Radiopharmaceutical Synthesis. J. Am. Chem. Soc. 2015, 137, 1548−
1555.
(14) The chelation of a tertiary amine to the Pd catalyst could
enhance the regioselectivity of the Pd-catalyzed allylic substitution by
soft nucleophiles; see: (a) Krafft, M. E.; Wilson, A. M.; Fu, Z.;
Procter, M. J.; Dasse, O. A. Heteroatom-Directed, Palladium-
Catalyzed, Regioselective Allylation: Substitution with Inversion. J.
Org. Chem. 1998, 63, 1748−1949. (b) Krafft, M. E.; Lucas, M. C.
Palladium-Catalyzed, Heteroatom Assisted, Regioselective Cycliza-
tions. Chem. Commun. 2003, 1232−1233.
(15) Rao, B. D. N.; Venkateswarlu, P.; Murthy, A. S. N.; Rao, C. N.
R. Nuclear Magnetic Resonance Studies of Hydrogen Bonding in
Ethanol and 2,2,2-Trifluorothanol. Can. J. Chem. 1962, 40, 387−389.
(16) Kinetic studies revealed a first-order dependence of the rate on
the palladium catalyst concentration and alcohol concentration. These
results are consistent with the nucleophilic addition of alcohol to the
π-allylpalladium species being the rate-determination step. See SI for
details.
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