Synthesis of Allylamine Derivatives via Intermolecular Aza-Wacker-Type Reaction Promoted by Palladium-SPRIX Catalyst

Article abstract of DOI:10.1002/adsc.202000644

An intermolecular aza-Wacker-type reaction was developed. When a readily available olefin was treated with a nitrogen nucleophile in the presence of a Pd-SPRIX complex and potassium persulfate, allylamine derivatives were obtained with high yield and excellent regioselectivity. The mechanistic studies showed that the reaction followed first-order dependence on the olefin as well as palladium catalyst, but zero-order dependence on the nitrogen nucleophile. (Figure presented.).

Full text of DOI:10.1002/adsc.202000644

Title: Synthesis of Allylamine Derivatives via Intermolecular Aza-
Wacker-Type Reaction Promoted by Palladium–SPRIX Catalyst
Authors: Abhijit Sen, Linpeng Zhu, Shinobu Takizawa, Kazuhiro
Takenaka, and Hiroaki Sasai
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000644
Link to VoR: https://doi.org/10.1002/adsc.202000644

Advanced Synthesis & Catalysis
10.1002/adsc.202000644
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Synthesis of Allylamine Derivatives via Intermolecular Aza-
Wacker-Type Reaction Promoted by Palladium–SPRIX
Catalyst
Abhijit Sen, Linpeng Zhu, Shinobu Takizawa, Kazuhiro Takenaka,* Hiroaki Sasai*
The Institute of Scientific and Industrial Research, Osaka University, 8-1 Mihogaoka, Ibaraki, Osaka 567-0047, Japan
FAX: +81-6-6879-8469, Phone: +81-6-6879-8466, E-mail: sasai@sanken.osaka-u.ac.jp, takenaka-k@dg.kagawa-
nct.ac.jp
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. An intermolecular aza-Wacker-type reaction was
developed. When a readily available olefin was treated with Keywords: Aza-Wacker; Branched allylamines;
a nitrogen nucleophile in the presence of a Pd–SPRIX Intermolecular amination; Pd–SPRIX catalysis
complex and potassium persulfate, allylamine derivatives
were obtained with high yield and excellent
regioselectivity. The mechanistic studies showed that the
reaction followed first-order dependence on the olefin as
well as palladium catalyst, but zero-order dependence on
the nitrogen nucleophile.
enamine or amino-aldehyde, respectively. Although a
Introduction.
few examples of internal alkenes have been reported,
[19]
they are limited to cyclic systems. To the best of
our knowledge, intermolecular aza-Wacker-type
reaction of internal alkenes leading to allylamine
derivative has not been reported.
Allylamine derivatives have versatile applications
as synthetic building blocks in the construction of
various kinds of pharmaceuticals and biologically
active molecules.[ Especially branched allylamines
are present in several synthetic intermediates and
1,2]
[3]
natural products as a core structure.
Thus,
development of an efficient synthetic method for the
synthesis of branched allylamine derivatives has
attracted considerable attention. Although there are
several methods for the synthesis of branched
allylamines,[ palladium catalysis offers a powerful
way to synthesize such molecules via Overman
4-8]
[9]
rearrangement (Scheme 1a), Tsuji-Trost reaction
[
10]
(
1
Scheme 1b),
hydroamination reaction (Scheme
c),[ and allylic C–H amination (Scheme 1d).
11]
[12]
Unfortunately, Overman rearrangement and Tsuji-
Trost reactions are limited to pre-functionalized
olefins, and hydroamination suffers from diene
telomerization that demands excess diene. A cross-
dehydrogenative metal-free coupling were also
reported with[13]very limited scope and poor
regioselectvity.
The aza-Wacker reaction is
expected to be an ideal process for the generation of
such branched allylamines (Scheme 1e). Although the
aza-Wacker-type cyclization has been widely
investigated,[
14,15]
the successful intermolecular
reaction is scarce. In the reported intermolecular
reactions, the substrate is highly limited to a terminal
Scheme 1. Representative Examples of Branched Allyl-
amine Derivative Synthesis
olefin[16,17]
[18]
or alkenols,
which transformed to an
1
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Advanced Synthesis & Catalysis
10.1002/adsc.202000644
Recently, we constructed the branched allylamine
containing [ N-heterocycles via aza-Wacker-type
5
Pd(OAc)
Pd(F
toluene instead of DCE
60 °C instead of 90 °C
2,2'-bipyridine instead of
SPRIX
2
instead of
-acac)
36
86
6
2
14h]
cyclization
by using a chiral spiro bis(isoxazoline)
6
7
8
72
60
24
92
65
N.R.
ligand, SPRIX,[ which possesses an isoxazoline
coordination site on a rigid spiro backbone. The low
σ-donation ability of SPRIX, which preserved the
intrinsic Lewis acidity of palladium, is found to be
effective for the activation of the carbon–carbon
20]
[
c]
[
[
c]
c]
9
10
11
cod instead of SPRIX
White catalyst
24
24
24
N.R.
N.R.
N.R.
[21]
[c]
double bond. We, therefore, hypothesized that the
use of Pd–SPRIX catalysis could facilitate the
intermolecular aza-Wacker-type reaction. Herein, we
report the first example of the synthesis of allylamine
derivatives via the intermolecular aza-Wacker-type
reaction promoted by the Pd–SPRIX catalyst.
no ligand
[
a]
All reactions were performed with 1.2 equiv 1a, 1 equiv
2a, 10 mol% of Pd(F -acac) (F -acac)
hexafluoroacetylacetonate, 15 mol% of (rac)-i-Pr-SPRIX,
and 3 equiv of K in DCE (0.1 M) at 90 °C under
nitrogen atmosphere.
Isolated yield.
N.R.: No reaction.
6
2
,
6
2
:
2 2 8
S O
[
[
b]
c]
Results and Discussion
We investigated the reaction conditions from (E)-
1
,4-bis(2-methoxy-phenyl)but-2-ene
(1a)
and
After determining the optimized reaction
phthalimide (2a) as the starting materials. When the
conditions, we examined the substrate scopes for the
intermolecular aza-Wacker-type reaction. The
symmetric as well as non-symmetric olefin substrates
reaction was carried out in the presence of 3 equiv. of
K
2
S O
2 8
in dichloroethane (DCE) at 90 °C, the
allylamine derivative 3aa was obtained in 93% yield
within 20 h (entry 1, Table 1). p-Benzoquinone was
able to generate only a trace amount of the product,
whereas oxone afforded 89% yield with the
retardation of the reaction (entries 2 and 3).
Palladium bis(acetylacetonate) and palladium acetate
produced the allylamines with 91% and 86% yield,
respectively (entries 4 and 5). When DCE was
replaced by toluene, the desired product was obtained
with 92% yield; however, the reaction required 72 h
to complete (entry 6). When the reaction was
performed at 60 °C, only 65% yield was achieved
even after 60 h (entry 7). SPRIX plays a key role in
this transformation. Other ligands such as, 2,2'-
bipyridine, 1,5-cyclooctadiene (cod) and White
catalyst (for more ligand effect, see SI) were unable
to provide the allylamines (entries 8-10). No reaction
was observed in the absence of the ligand (entry 11).
These experiments clearly focused the importance of
SPRIX on this reaction.
provided
good
reactivity
with
excellent
regioselectivity (Table 2). Although we used E/Z
mixture (E:Z = 3:1) as a substrate, the product was
obtained as (E)-isomer with almost an exclusive
selectivity. Symmetric olefins such as, 2-methoxy
(
1a), 2,5-dimethoxy (1b), 4-methoxy (1c), and no
substituents (1d) furnished good to excellent
reactivity (entries 1–4). The electronic and steric
variation on the benzene ring had no significant effect
on the reactivity for non-symmetric substrates.
Irrespective of the substituent’s position on the
benzene ring, the reaction proceeded with excellent
regioselectivity. The reaction of (E)-but-2-en-1-
ylbenzene (1e) provided 58% of the allylamine
derivative 3ea (entry 5). Substrates having electron-
donating substituents such as MeO (1f, 1g, 1h), Me
(
1i and 1j), t-Bu (1k), electron-withdrawing
substituents like CF (1l), and halogens such as F
1m), Cl (1n), and Br (1o) all were well tolerated
under the catalytic reaction conditions. Tri-
substituted olefin, (E)-(2-methylbut-2-en-1-
yl)benzene (1p) afforded the desired product with
1% yield. The reaction of (3-methylbut-2-en-1-
3
(
Table 1. Intermolecular aza-Wacker-Type Reaction[a]
7
yl)benzene (1q) produced a regio-isomeric aza-
Wacker-type product (3qa) with 18% yield (entry 17).
The benzene ring can be easily replaced by
naphthalene (1r) or anthracene (1s). When the
benzene ring was replaced by thiophene (1t), only
2
6% of the allylamine derivative was obtained (entry
Entry
Deviation from
Optimal Conditions
none
Time
(h)
20
Yield
(%)
93
20). (E)-prop-1-ene-1,3-diyldibenzene (1u) and (E)-
(4-methoxybut-2-en-1-yl)benzene (1v) generated the
desired allylamines with good yields (entries 21 and
22). When the reaction was performed with (E)-but-
2-en-1-ylcyclohexane (1w), no desired allylamine
was observed (entry 23). (Z)-But-2-en-1-ylbenzene
provided comparable reactivity to that of its
corresponding (E)-isomer (entries 5 and 24).
1
2
[
b]
(
88 )
p-benzoquinone instead of
24
trace
2 2 8
K S O
3
4
oxone instead of K
Pd(acac) instead of
Pd(F -acac)
2
S
2
O
8
48
48
89
91
2
6
2
2
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Advanced Synthesis & Catalysis
10.1002/adsc.202000644
Table 2. Substrate Scope for Intermolecular Aza-Wacker-
oxidative amination products. Saccarine (2d)
provided 28% aza-Wacker-type product, whereas
nitro-saccarine (2e) failed to produce the desired
product. The strong-electron withdrawing ability of
the sulfonyl group reduced the nucleophilicity of the
nitrogen center, which results in lower reactivity. No
reaction was observed when tosylamine was used as
[
a]
Type Amination
[22]
nitrogen source.
Table 3. Substrate Scope for Nucleophile in
[
a]
Intermolecular Aza-Wacker-Type Reaction
[
a]
All reactions were performed in the presence of 1.2
equiv 1a, 1 equiv 2, 10 mol% of Pd(F -acac) , 15 mol% of
rac)-i-Pr-SPRIX, and 3 equiv of K in DCE (0.1 M)
at 90 °C under a nitrogen atmosphere. Isolated yield.
6
2
(
2 2 8
S O
[
b]
N.R.: No reaction.
The reaction was readily accessible in sub-gram
scale; starting materials (E)-1e (0.22 g) and 2a (0.2 g)
led to 0.24 g (63%) allylamine derivatives (Scheme
2
a). (E)-4-phenylbut-3-en-2-amine (4) was obtained
with high yield (86%) when 3ea was treated with
[17a]
hydrazine monohydrate (Scheme 2b).
amine 4 exhibits biological activity similar to the
dopamine
transporter.
The free
transporter
and
norepinephrine
[3e]
Scheme 2. Sub-Gram Scale Reaction and Synthesis of
Biologically Active Molecule
To elucidate the reaction mechanism, we carried
mechanistic studies. The presence of the
[
a]
All reactions were performed in the presence of 1.2
equiv 1, 1 equiv 2a, 10 mol% of Pd(F -acac) , 15 mol% of
rac)-i-Pr-SPRIX, and 3 equiv of K in DCE (0.1 M)
at 90 °C under a nitrogen atmosphere. Isolated yield.
stoichiometric
amount
of
(2,2,6,6)-
6
2
(
2
S
2
O
8
tetramethylpiperidine 1-oxyl (TEMPO) had no
significant effect on the reactivity, which clearly
prohibits any possibilities of radical intermediates
[
b]
N.R.: No reaction.
Several nitrogen nucleophiles were examined
(
Scheme 3a). The reaction with a stoichiometric
under the catalytic conditions (Table 3). Succinimide
(
amount of the palladium catalyst in the absence of the
oxidant furnished 71% allylamine derivatives,
2b) and maleimide (2c) efficiently furnished
3
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Advanced Synthesis & Catalysis
10.1002/adsc.202000644
confirming that the reaction is not a Pd(II)/Pd(IV)
catalysis (Scheme 3b).
K
2
S
2
O
8
regenerates the catalytically active Pd(II)–
SPRIX complex.
The enantioselective synthesis of 3aa was
examined by using several chiral ligands, and up to
3
9% enantioselectivity was obtained (Scheme 5) by
[23]
using the isoxazoline-isoxazole hybrid ligand (for
more details, see SI).
Scheme 3. Preliminary Mechanistic Studies
Scheme 5. Enantioselective Intermolecular Aza-Wacker-
Type Reaction
The kinetic isotope effect (KIE) for d
2
-1r was
observed at a value of 1.09 (Scheme 3c). White
reported KIE = 4.0 for allylic amination[
12m]
whereas
Conclusion
Hull reported KIE = 1.0 for the aza-Wacker-type
reaction.[17a]
In summary, we developed a new efficient and
straightforward method for the generation of versatile
branched allylamine derivatives from easily
accessible internal alkenes and nitrogen nucleophiles
via the intermolecular aza-Wacker-type reaction
promoted by the Pd–SPRIX catalyst. The mechanistic
study supports the aza-Wacker-type pathway.
Therefore, our reaction would follow the
aza-Wacker-type pathway. Chemical kinetics showed
that the reaction followed first-order dependence on
the olefin and palladium catalyst, whereas zero-order
dependence on the nitrogen nucleophile (for more
details, see SI).
Experimental Section
General procedure: A mixture of Pd(F
6
-acac)
2
(10 mol%,
6
1
.80 μmol, 3.54 mg) and (rac)-i-Pr-SPRIX (15 mol%,
0.20 μmol, 3.83 mg) was dissolved in dry
dichloromethane (1 mL). After stirring under nitrogen
atmosphere at 30 °C for 2 h, the solvent was removed and
the resulting yellow Pd complex was kept under vacuum
for 10 min. To the dried Pd complex, K
2
S
2
O
8
(3 equiv,
2
6
04.1 μmol, 55.1 mg), nitrogen nucleophile, 2 (1 equiv,
8.03 μmol) and olefinic substrate 1 (1.2 equiv, 81.63
μmol) were added. To the reaction mixture, 1,2-
dichloroethane (0.7 mL) was added, followed by stirring at
9
0 °C (chemiStation) under nitrogen until the full
consumption of 2, monitored by TLC (hexane/ethyl
acetate). After the reaction the solid inorganic compounds
was filtered off and the solvent was removed under
vacuum, and the remaining crude mass was purified by
short column chromatography to afford products 3.
Author Information (Present Address)
Kazuhiro Takenaka: National Institute of Technology,
Kagawa College, 551 Kohda, Takuma-cho, Mitoyo-shi,
Kagawa 769-1192, Japan
Scheme 4. Plausible Reaction Mechanism
Abhijit Sen: RIKEN, Center for Sustainable Resource
Science, Wako, Saitama 351-0198, Japan
Based on the chemical kinetics and Hammett plot
for more details, see SI), we concluded that the
(
olefin coordination is the rate-determining step
Scheme 4). Once the complex B is generated, the
(
nucleophilic attack by the nitrogen nucleophile Acknowledgements
provided the intermediate C. β-Hydride elimination
This work was supported by Advanced Catalytic Transformation
from intermediate C directly generated the desired
product 3 and palladium converted to the Pd(0)–
SPRIX complex after the reductive elimination of one
equivalent of hexafluoroacetylacetone. Finally,
program for Carbon utilization (ACT-C), Core Research for
Evolutionary Science and Technology (CREST), JP18KK0154 in
Fund for the Promotion of Joint International Research
(Fostering Joint International Research (B), Daiichi Sankyo
4
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Advanced Synthesis & Catalysis
10.1002/adsc.202000644
Foundation of Life Science, and Hoansha Foundation. A. S. is
grateful to JASSO and 99-Asia scholarship provider for their
generous financial support. We also thank the technical staff of
the Comprehensive Analysis Center of ISIR for their assistance.
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Advanced Synthesis & Catalysis
10.1002/adsc.202000644
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Advanced Synthesis & Catalysis
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FULL PAPER
Synthesis of Allylamine Derivatives via
Intermolecular Aza-Wacker-Type Reaction
Promoted by Palladium–SPRIX Catalyst
Adv. Synth. Catal. 2020, 362, Page – Page
Abhijit Sen, Linpeng Zhu, Shinobu Takizawa,
Kazuhiro Takenaka,* Hiroaki Sasai*
7
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