Advanced Synthesis & Catalysis

FULL PAPER 10.1002/adsc.202000644

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

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Abstract. An intermolecular aza-Wacker-type reaction was

A
developed. When a readily available olefin was treated with Keywords: Aza-Wacker; Branched
allylamines; a nitrogen nucleophile in the presence of a Pd–SPRIX
SPRIX catalysis complex and potassium persulfate, allylamine derivatives
were obtained with high yield and excellent
Intermolecular amination; Pd–
cc
ep
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.

te
d
Introduction. enamine or amino-aldehyde, respectively. Although a
few examples of internal alkenes have been reported,
Allylamine derivatives have versatile applications they are limited to cyclic systems. [19] To the best of
as synthetic building blocks in the construction of our knowledge, intermolecular aza-Wacker-type
various kinds of pharmaceuticals and biologically reaction of internal alkenes leading to allylamine
active molecules.[1,2] Especially branched allylamines
are present in several synthetic intermediates and
natural products as a core structure. [3] Thus,
development of an efficient synthetic method for the
derivative has not been reported.
M
an
synthesis of branched allylamine derivatives has
attracted considerable attention. Although there are
several methods for the synthesis of branched
allylamines,[4-8] palladium catalysis offers a powerful
way to synthesize such molecules via Overman
rearrangement (Scheme 1a),[9] Tsuji-Trost reaction
(Scheme 1b),[10] hydroamination reaction (Scheme
1c),[11] and allylic C–H amination (Scheme 1d). [12]
Unfortunately, Overman rearrangement and Tsuji-
us
cri
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 very limited scope and poor
regioselectvity.[13] 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-
olefin[16,17] or alkenols,[18] which transformed to an amine Derivative Synthesis

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 Recently, we constructed the branched allylamine
containing N-heterocycles via aza-Wacker-type
cyclization[14h] by using a chiral spiro bis(isoxazoline)
ligand, SPRIX,[20] 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 [c]
double bond.[c]
[21]
We, therefore, hypothesized that the use of Pd–SPRIX [c]
catalysis could facilitate the intermolecular aza-Wacker-
type reaction. Herein, we report the first example of the
synthesis of allylamine derivatives via the intermolecular (rac)-i-Pr-SPRIX, and 3 equiv of K2S2O8 in DCE (0.1 M) at 90 °C
aza-Wacker-type reaction promoted by the Pd–SPRIX
catalyst.
Results and Discussion
We investigated the reaction conditions from (E)-
1,4-bis(2-methoxy-phenyl)but-2-ene (1a) and
phthalimide (2a) as the starting materials. When the
reaction was carried out in the presence of 3 equiv. of
K2S2O8 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.
Table 1. Intermolecular aza-Wacker-Type Reaction
Entry Deviation from Time Yield
Optimal Conditions (h) (%)
1 none 20
93
(88[b])
2 p-benzoquinone instead of 24 trace
K2S2O8
3 oxone instead of K2S2O8 48 89
4 Pd(acac)2 instead of Pd(F6-
5 Pd(OAc)2 instead of 36 86
Pd(F6-acac)2
6 toluene instead of DCE 72 92
7 60 °C instead of 90 °C 60 65
8 2,2'-bipyridine instead of 24 N.R
SPRIX
9catalyst cod
24
N.R. instead of SPRIX 24 N.R.White
N.R.no ligand 24
[a]
[c]
[a]
All reactions were performed with 1.2 equiv 1a, 1 equiv 2a, 10 mol%
of Pd(F6-acac)2, (F6-acac)2: hexafluoroacetylacetonate, 15 mol% of
under nitrogen atmosphere.
[b]
Isolated yield.
A
[c]
N.R.: No reaction.
cc
After determining the optimized reaction
conditions, we examined the substrate scopes for the
ep
intermolecular aza-Wacker-type reaction. The
symmetric as well as non-symmetric olefin substrates
provided good reactivity with excellent
regioselectivity (Table 2). Although we used E/Z
mixture (E:Z = 3:1) as a substrate, the product was
te
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
d
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
M
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
an
(1i and 1j), t-Bu (1k), electron-withdrawing
substituents like CF3 (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 71% yield. The
reaction of (3-methylbut-2-en-1- yl)benzene (1q)
produced a regio-isomeric aza- Wacker-type product
(3qa) with 18% yield (entry 17). The benzene ring can
us
cri
be easily replaced by naphthalene (1r) or anthracene
(1s). When the benzene ring was replaced by
thiophene (1t), only
26% of the allylamine derivative was obtained (entry
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
acac)2
48 91 correspondin
g (E)-isomer
(entries 5 and
24).

2
 Table 2. Substrate Scope for Intermolecular Aza-Wacker-
Type Amination
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
nitrogen source.

Table 3. Substrate Scope for Nucleophile in

Intermolecular Aza-Wacker-Type Reaction[a]
[22]
[a]

A
cc
ep
[a]
te
All reactions were performed in the presence of 1.2 equiv 1a, 1 equiv
2, 10 mol% of Pd(F6-acac)2, 15 mol% of (rac)-i-Pr-SPRIX, and 3 equiv

d
of K2S2O8 in DCE (0.1 M) at 90 °C under a nitrogen atmosphere.
Isolated yield.
[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 2a). (E)-4-phenylbut-3-en-2-
amine (4) was obtained with high yield (86%) when 3ea was
M
treated with hydrazine monohydrate (Scheme 2b). [17a] The free
amine 4 exhibits biological activity similar to the dopamine

.
transporter and norepinephrine transporter
an
us
cri
Scheme 2. Sub-Gram Scale Reaction and Synthesis of
Biologically Active Molecule

(2b) and maleimide (2c) efficiently furnished

[3e]

All reactions were performed in the presence of 1.2 equiv 1, 1

[a]

equiv 2a, 10 mol% of Pd(F6-acac)2, 15 mol% of (rac)-i-Pr-

SPRIX, and 3 equiv of K2S2O8 in DCE (0.1 M) at 90 °C under a
nitrogen atmosphere. Isolated yield.
[b]
N.R.: No reaction.
Several nitrogen nucleophiles were examined
under the catalytic conditions (Table 3). Succinimide
 significant effect on the reactivity, which clearly
To elucidate the reaction mechanism, we prohibits any possibilities of radical intermediates
carried mechanistic studies. The presence of the (Scheme 3a). The reaction with a stoichiometric
stoichiometric amount of amount of the palladium catalyst in the absence of the
(2,2,6,6)- oxidant furnished 71% allylamine derivatives,
tetramethylpiperidine 1-oxyl (TEMPO) had no

3
confirming that the reaction is not a Pd(II)/Pd(IV)
catalysis (Scheme 3b).
Scheme 3. Preliminary Mechanistic Studies
The kinetic isotope effect (KIE) for d2-1r was
observed at a value of 1.09 (Scheme 3c). White
reported KIE = 4.0 for allylic amination[12m] whereas
Hull reported KIE = 1.0 for the aza-Wacker-type
reaction.[17a] 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).
Scheme 4. Plausible Reaction Mechanism
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
provided the intermediate C. β-Hydride elimination
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,
K2S2O8 regenerates the catalytically active Pd(II)–
SPRIX complex.
The enantioselective synthesis of 3aa was
examined by using several chiral ligands, and up to
39% enantioselectivity was obtained (Scheme 5) by
using the isoxazoline-isoxazole hybrid ligand [23] (for
more details, see SI).
A
Scheme 5. Enantioselective Intermolecular Aza-Wacker-
Type Reaction
Conclusion
cc
In summary, we developed a new efficient and
straightforward method for the generation of versatile
branched allylamine derivatives from easily
ep
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.
Experimental Section
General procedure: A mixture of Pd(F6-acac)2 (10 mol%,
6.80 μmol, 3.54 mg) and (rac)-i-Pr-SPRIX (15 mol%,
te
d
10.20 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, K2S2O8 (3 equiv,
M
204.1 μmol, 55.1 mg), nitrogen nucleophile, 2 (1 equiv,
68.03 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
90 °C (chemiStation) under nitrogen until the full
consumption of 2, monitored by TLC (hexane/ethyl
an
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,
us
cri
Kagawa 769-1192, Japan
Abhijit Sen: RIKEN, Center for Sustainable Resource
Science, Wako, Saitama 351-0198, Japan
Acknowledgements
This work was supported by Advanced Catalytic Transformation
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