Palladium-Catalyzed Aminomethylation of Nitrodienes and Dienones via Double C—N Bond Activation

Article abstract of DOI:10.1002/cjoc.202000184

A new strategy for the generation of the active Pd-alkyl species from aminal via C—N bond activation has been established, in which the formation of zwitterionic intermediate through aza-Michael addition of aminal to nitrodienes or dienones is identified as a key step for the activation of the C—N bond. The efficient strategy has enabled a new palladium-catalyzed α-aminomethylation of nitrodienes and dienones via double C—N bond activation. The scope and versatility of the reaction were demonstrated and a broad range of substrates bearing electron-donating and -withdrawing groups on the aromatic rings were all compatible with this reaction to furnish the desired α-aminomethylated products in moderate to good yields with excellent regioselectivities and E/Z selectivities.

Full text of DOI:10.1002/cjoc.202000184

Chinese Journal
of Chemistry
CJC
中 国 化 学 - An International Journal
Accepted Article
Title: Palladium-Catalyzed Aminomethylation of Nitrodienes and Dienones via
Double C-N Bond Activation
Authors: Bangkui Yu, Bao Gao, Xuexia Zhang, Haocheng Zhang, and Hanmin Huang*
This manuscript has been accepted and appears as an Accepted Article online.
This work may now be cited as: Chin. J. Chem. 2020, 38, 10.1002/cjoc.202000184.
The final Version of Record (VoR) of it with formal page numbers will soon be
published online in Early View: http://dx.doi.org/10.1002/cjoc.202000184.
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Chinese Journal
of Chemistry
Aminomethylation, nitrodienes, dienones, aminals, C-N bond activation
Report
CJC
中
国 化 学 - An International Journal
Palladium-Catalyzed Aminomethylation of Nitrodienes and Dienones via
Double C-N Bond Activation
Bangkui Yu,a Bao Gao,a Xuexia Zhang,a Haocheng Zhang,a and Hanmin Huang*,a,b
aHefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science and Technology of China, Hefei,
230026, P. R. China.
bCenter for Excellence in Molecular Synthesis of CAS, Hefei, 230026, P. R. China.
Cite this paper: Chin. J. Chem.2020, 38, XXX—XXX.DOI: 10.1002/cjoc.202000XXX
Summary of main observation and conclusion: A new strategy for the generation of the active Pd-alkyl species from aminal via C-N bond activation has
been established, in which the formation of zwitterionic intermediate through aza-Michael addition of aminal to nitrodienes and dienones is identified as
a key step for the activation of the C-N bond. The efficient strategy has enabled a new palladium-catalyzed α-aminomethylation of nitrodienes and
dienones via double C-N bond activation. The scope and versatility of the reaction were demonstrated and a broad range of substrates bearing
electron-donating and -withdrawing groups on the aromatic rings were all compatible with this reaction to furnish the desired α-aminomethylated
products in moderate to good yields with excellent regioselectivities and E/Z selectivities.
withdrawing substituent at the diene terminus like 1 are good
Michael acceptors, which are prone to be attacked by
Background and Originality Content
The dienyl allylic amines and their derivatives are not only
nucleophiles. Tertiary amines are good nucleophiles and have
important building blocks for the synthesis of various
been utilized as the catalyst for MBH reaction via aza-Michael
nitrogen-containing compounds, but also widely found in natural
products as well as biologically active molecules.1-6 It is a surprise
to find that the catalytic reactions for constructing such a kind of
scaffolds remain largely undeveloped, and only few Ir-catalyzed
allylic aminations of dienyl allylic carbonates or alcohols have
been reported.7-8 On the other hand, the reaction of activated
functionalized dienes with imines or iminium salts under the
Morita-Baylis-Hillman (MBH) conditions is another promising
approach to functionalized dienyl allylic amines.9-12 However, the
poor E/Z selectivity observed in most of these reactions restricted
the practicality of these reactions. Therefore, it is highly desirable
to explore a new and efficient catalytic reaction to prepare
functionalized dienyl allylic amines. Recently, we have reported an
efficient approach to dienyl allylic amines via palladium-catalyzed
aminomethylation of simple dienes with aminals via double C-N
bond activation.13 Inspired by this work and in connection with
addition15-16. Aminals contain two tertiary amine moieties, which
could be an excellent nucleophile to react with the
electron-deficient diene 1 to form the zwitterionic intermediate
through aza-Michael addition. In this context, we envisioned that
the in-situ formed zwitterionic intermediate would be capable of
undergoing oxidative addition with Pd(0) to generate the
cyclopalladated complex A together with the intermediate II. The
highly reactive amine-containing allyl anion would undergo
further transformations with the cyclopalladated complex A to
establish new reactions.
work:
ammonium
salt
(a)
Previous
via
Activation of C-N bond
formation of
Ln
quaternary
+
N
R2
NR2
Pd
N
R2
A
R2+N
NR2
Pd
Ln
NR2
R
R
our work on aminal chemistry, herein, we reported
a
R
Pd
Ln
palladium-catalyzed aminomethylation of activated
1,3-conjugated dienes with aminals to synthesize functionalized
dienyl allylic amine.
work:
This
Activation
of C-N
bond via aza-Michael addition
for formation of
zwitter-ion
(b)
N
R2
Pd
N
R2
(0)
R2+N
NR2
NR2
Recently, our research group has demonstrated that aminals
can serve as useful electrophiles undergoing oxidative addition
with Pd(0) to form the unique electrophilic cationic
cyclopalladated complex A (Huang-complex) in the presence of a
catalytic amount of acids.14 Further experiments disclosed that
the cyclopalladated complex A could be also generated via the
reaction of aminal with allylpalladium species, in which the allylic
quaternary ammonium salt was formed as the key intermediate
EWG
EWG
EWG
R
R
+
R
1
II
I
NR2
Pd
Ln
A
Scheme 1. The strategies for the formation of cyclopalladated complex
with aminal.
(Scheme 1a). The electron-deficient dienes containing
a
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through the copyediting, typesetting, pagination and proofreading process which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1002/cjoc.202000184
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First author et al.
Report
17d
18
Pd(COD)Cl2
-
P(4-CF3C6H4)3
P(4-CF3C6H4)3
-
1,4-dioxane
83
0
Results and Discussion
1,4-dioxane
1,4-dioxane
To verify the feasibility of the above strategy, we started our
research with the reaction of nitrodiene 1a and aminal 2a in DCM
at 120 oC by using Pd(CH3CN)2Cl2 as a catalyst precursor. When
Xantphos was used as the bidentate ligand, the
α-aminomethylated product 3aa was isolated in 13% yield (Table
1, entry 1). Furthermore, we investigated the effects of other
phosphine ligands, including typical bidentate phosphines and
mono-phosphines (Table 1, entries 2-5). It was a surprise to find
that the desired product 3aa was obtained in 72% yield when
P(4-CF3C6H4)3 was employed as the ligand (Table 1, entry 6). With
the best ligand in hand, we next hope to further improve the
efficiency of the reaction by examining the palladium precursors
in combination with P(4-CF3C6H4)3 and AgOTf. The results showed
that the reaction system was sensitive to the palladium precursor
(Table 1, entries 7-11). When Pd(COD)Cl2 was utilized as the
palladium source, the desired product 3aa was obtained in 81%
yield with complete regioselectivity. Screening of some
representative solvents disclosed that the reaction was most
efficient in 1,4-dioxane (Table 1, entry 15). Subsequently, we
examined the loading of catalyst and the amount of 2a, but the
yield of 3aa could not be further improved (Table 1, entries 16-17).
Notably, in the absence of palladium catalyst, no desired product
was obtained (Table 1, entry 18).
19
Pd(COD)Cl2
Trace
aReaction conditions: 1a (0.24 mmol), 2a (0.20 mmol), [Pd] (5 mol%),
Ligand (11 mol%), AgOTf (11 mol%), solvent (2.0 mL), 120 oC, 13 h,
isolated yield. bLigand (5.5 mol%). c[Pd] (2.5 mol%). d1a (0.20 mmol), 2a
(0.24 mmol).
With the optimized reaction conditions in hand, various
substituted nitrodienes 1 were tested to examine the generality
of our strategy. As shown in Table 2, the nitrodienes with
different substituents on the aromatic ring underwent
aminomethylation reaction smoothly, delivering corresponding
target products in good yields with excellent regioselectivities and
E/Z selectivities. Besides, this reaction was unbiased toward both
the electronic properties of the aromatic moiety and the
substitution pattern. Both electron-donating and -withdrawing
groups on the rings were smoothly converted to the desired
products in moderate to good yields (3aa-3ka). Notably, the
substituents at the meta-position or ortho-position of the
aromatic ring were also tolerated, albeit in slightly lower yields
(3ca and 3da). Typical functional groups such as fluoro, chloro,
trifluoromethyl were well tolerated under the optimized reaction
conditions
nitrodiene and thienyl-substituted nitrodiene were also
compatible with this new reaction, generating
(3ga-3ia).
Furthermore,
naphthyl-substituted
Table 1 Optimization of reaction conditions a
mol%)
mol%)
[Pd] (5
Ligand (11
AgOTf (11
α-aminomethylated nitrodienes in good yields with excellent
regioselectivities and E/Z selectivities (3ka-3la). Unfortunately,
the aliphatic nitrodiene failed to produce the desired product and
the starting material was intact, which might be ascribed to the
lower reactivity of the substrate to react with the aminal. In
addition, the scope of the aminal was also explored for this
aminomethylation. Aminals derived from benzylamines
containing different substituents afforded the desired products in
moderate to good yields (3ab-3ad). Either electron-donating or
electron-withdrawing groups on phenyl moiety were tolerated
well.
NBn2
NO2
Ph
NO2
+
Ph
mol%)
NBn2
2a
NBn2
solvent, 120 o 13 h
C,
3aa
1a
entry
[Pd]
Ligand
solvent
DCM
yield (%)
13
1b
2b
3
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
PdCl2
Xantphos
DPPE
DCM
DCM
14
PPh3
24
4
P(4-MeC6H4)3
P(C6F5)3
DCM
20
5
DCM
13
6
P(4-CF3C6H4)3
P(4-CF3C6H4)3
P(4-CF3C6H4)3
P(4-CF3C6H4)3
P(4-CF3C6H4)3
P(4-CF3C6H4)3
P(4-CF3C6H4)3
P(4-CF3C6H4)3
P(4-CF3C6H4)3
P(4-CF3C6H4)3
P(4-CF3C6H4)3
DCM
72
7
DCM
34
8
Pd(OAc)2
DCM
64
9
Pd(COD)Cl2
[Pd(ally)Cl]2
Pd(COD)Cl2
Pd(COD)Cl2
Pd(COD)Cl2
Pd(COD)Cl2
Pd(COD)Cl2
Pd(COD)Cl2
DCM
81
10
11
12
13
14
15
16c
DCM
75
DCE
58
THF
75
CH3CN
toluene
1,4-dioxane
1,4-dioxane
63
84
88
62
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© 2020 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2020,38, XXX－XXX
This article is protected by copyright. All rights reserved.

Running title
Chin. J. Chem.
Table 2 Scope of the substrates a
Table 3 Substrate scope of dienones a
mol%)
Pd(COD)Cl2 (5
C6H4
mol%)
)3 (11
O
O
NR2
NBn2
mol%)
mol%)
Pd(OAc)2 (5
DPPO
P(4-CF3
AgOTf (11
NO2
NR2
NO2
NBn2
NO2
+
+
Ar
(5.5
Ar
R1
R2
mol%)
R1
R2
NBn2
2a
CH3CN, 80 o 24 h
NR2
2
120 o 13 h
C,
Bn2N
1,4-dioxane,
C,
4
1
1
3
O
NO2
NO2
O
O
NBn2
NBn2
Me
Me
Bn2N
Me
Bn2N
Bn2N
4ba,
Me
Me
3aa
,
3ba
,
3ca
79%
,
88%
88%
4ca,
54%
O
4aa,
81%
78%
O
NO2
NO2
NO2
NBn2
NBn2
NBn2
Me
MeO
Bn2N
4da,
Bn2N
4ea,
OMe
F
Me
3fa 81%
3da
3ea
,
69%
92%
89%
90%
,
,
58%
76%
67%
O
O
O
O
NO2
NO2
NO2
NBn2
NBn2
NBn2
O
S
F
Cl
F3C
Bn2N
Bn2N
Bn2N
CF3
3ha
3ia
,
67%
92%
,
,
3ga
4fa, 54%
68%
4ha
,
,
4ga
O
O
NO2
NO2
NO2
Me
O
S
NBn2
NBn2
Ph
NBn2
Bn2N
4ia,
Bn2N
Bn2N
4ka,
64%
MeO
3ka 71%
3la
,
60%
,
,
3ja
63%
66%
84%
4ja,
O
O
NO2
NO2
NO2
S
Ar)2
Ar)2
Ar)2
N(CH2
Ar 4-FC6H4 3ab 82%
N(CH2
Ar 4-ClC6H4, 3ac 74%
N(CH2
t-Bu) C H 3ad 69%
Bn2N
Bn2N
4ma,
Bn2N
4na,
F
Cl
=
=
=
Ar
3,5-(
,
,
,
,
,
2
6
3
4la,
40%
66%
aReaction conditions: 1 (0.6 mmol), 2a (0.5 mmol), Pd(COD)Cl2 (5 mol%),
P(4-CF3C6H4)3 (11 mol%), AgOTf (11 mol%), 1,4-dioxane (2.0 mL), 120 oC,
13 h, isolated yield.
aReaction conditions: 1 (0.48 mmol), 2a (0.40 mmol), Pd(OAc)2 (5 mol%),
DPPO (5.5 mol%), CH3CN (1.5 mL), 80 oC, 24 h, isolated yield.
Having identified that the nitrodienes are adequately
substrates for the aminomethylated reaction, we aimed to
expand the substrate scope to other activated dienes bearing
different electron-withdrawing groups. Dienones are important
skeletons for the synthesis of biologically active molecules,
especially nitrogen-containing heterocyclic compounds.17-20
Studies have shown that some of them exhibit significant
anticancer activity and the selectivity index is superior to that of
Based on the optimal reaction conditions for the synthesis of
the α-aminomethylated dienones, we turned our attention to
examine the scope of dienones. As shown in Table 3, a variety of
dienones derived from aromatic acetophenone reacted smoothly
with aminal 2a, demonstrating that the reaction is unbiased
toward electronic properties of substituents (4aa-4fa). The
structure of product 4aa was determined by single-crystal X-ray
crystallographic analysis. Notably, the reaction efficiency of the
dienones bearing methyl-substituent at ortho-position was
significantly reduced, which may be due to the effect of steric
hindrance, and the corresponding products could only be
obtained in 54% yield. In addition, heterocycle-substituted
dienones were also compatible with this reaction and gave the
desired products in good yields (4ga-4ha). To our delight, the
dienone derived from acetone also provided the desired products
in good yield with excellent regioselectivity and E/Z selectivity
(4ia). Moreover, the α-mono-aminomethylated product 4ja could
be obtained in 84% yield when a symmetrical dienone derived
from acetone and cinnamaldehyde was used as the substrate.
Next, we evaluated the scope of dienones derived from
cinnamaldehydes containing different substituents. Typical
functional groups such as methoxy, fluoro-, chloro-, and thienyl
were also tolerated under the reaction conditions (4ka-4na).
However, the corresponding α-aminomethylation process could
doxorubicin.17
Therefore,
1m and
(2E,4E)-1,5-diphenylpenta-2,4-dien-1-one
N,N,N',N'-tetrabenzylmethanediamineaminal 2a were selected as
the benchmark substrates to optimize the reaction conditions.
After an extensive screening of the reaction conditions, the best
result was obtained when the combination of Pd(OAc)2/DPPO was
employed as the catalyst system. The desired product 4aa was
obtained in 81% isolated yield when the reaction was conducted
in CH3CN at 80 oC for 24 hours (see the Supporting Information).
only
be
achieved
in
40%
yield
when
using
4-chlorocinnamaldehyde-derived dienone to carry out this
reaction (4ma).
Chin. J. Chem. 2020,38, XXX－XXX
© 2020 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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This article is protected by copyright. All rights reserved.

First author et al.
Report
On the base of the previous studies13-14,21-29 and our
hours. The solvent was evaporated under reduced pressure and
the residue was purified by flash column chromatography (eluted
with petroleum ether/diethyl ether = 100/1 - 10/1) on a silica gel
to give the desired product 3.
experimental results,
a
plausible mechanism for this
α-aminomethylation is proposed (Figure 1). Firstly, the
aza-Michael addition reaction takes place between the aminal 1a
and the nitrodiene 2a to form the key intermediate I.
Subsequently, the SN2-type oxidative addition of allyl ammonium
salt I to Pd(0) delivers the allylic amine II together with generating
the active palladium-complex A. The intermediate II reacts with
the palladium-complex A through SN2-type reductive elimination
to give the complex B. Cleavage of the C-N bond of the allylic
amine B via oxidative addition to give the π-allylpalladium species
C, which isomerizes to intermediate D. Finally, β-H elimination of
intermediate D provides the α-aminomethylated nitrodienes 3aa
together with regenerating the Pd(0) to complete the catalytic
cycle. HRMS analysis of the reaction mixture showed a peak at
m/z 582.3135, which corresponded to the mass of [I+H]+ or
[B-Pd+H]+. This result supported that the intermediates I or B
might be involved in the catalytic cycle of this transformation.
For the aminomethylation of dienones: A mixture of dienone 1
(0.48 mmol), N,N,N’,N’-tetrabenzylmethanediamine 2a (162.4 mg,
0.4 mmol), Pd(OAc)2 (4.5 mg, 0.02 mmol), DPPO (10.6 mg, 0.022
mmol), CH3CN (1.5 mL) was added to a 25 mL flame-dried
Young-type tube under nitrogen atmosphere. The reaction
mixture was degassed via the freeze-thaw method and stirred at
80 oC for 24 hours. The solvent was evaporated under reduced
pressure and the residue was purified by flash column
chromatography (eluted with petroleum ether / ethyl acetate =
100/1 - 30/1) on a silica gel to give the desired product 4.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2020xxxxx.
N
N
Bn2
Bn2
N
Bn2
+
H2C
H2C
2a
H2C
N
Bn2
N
H
N
Bn2
Bn2
Ph
NO2
Pd
Ln
NO2
(0)
Ph
NO2
3aa
Ph
Acknowledgement
I
1a
β-H
elimination
oxidative
addition
This research was supported by the National Natural Science
Foundation of China (21672199, 21790333, 21925111 and
21702197) and the Fundamental Research Funds for the Central
Universities (No. WK2060190086).
N
Bn2
N
Bn2
H2C
Pd
Ln
H
CH2
Ph
NO2
A
Ph
Pd
Ln
D
(II)
O2N
N
Bn2
reductive
elimination
II
isomerisation
References
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N
Bn2
N
Bn2
H2C
H C
2
Pd
Ln
Ph
(0)
Ph
NO2
C
NO2
oxidative
addition
Pd
Ln
(II)
N
Bn2
B
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Conclusions
In summary, we have successfully developed an efficient
palladium-catalyzed α-aminomethylation of nitrodienes and
dienones with aminals to give the corresponding functional dienyl
allylic amines via double C-N bond activation. The reaction
proceeded well to give the desired products in moderate to good
yields with excellent regioselectivities and E/Z selectivities. The
formation of zwitterionic intermediate through aza-Michael
addition of aminal to nitrodienes and dienones is identified as a
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For the aminomethylation of nitrodienes ： A mixture of
nitrodiene 1 (0.6 mmol) and aminal 2 (0.5 mmol), Pd(COD)Cl2 (7.2
mg, 0.025 mmol), P(4-CF3C6H4)3 (25.6 mg, 0.055 mmol), AgOTf
(14.2 mg, 0.055 mmol) and 1,4-dioxane (2.0 mL) was added to a
Young-type tube in the glove box. The reaction mixture was
degassed via the freeze-thaw method and stirred at 120 oC for 13
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www.cjc.wiley-vch.de
© 2020 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2020,38, XXX－XXX
This article is protected by copyright. All rights reserved.

Running title
Chin. J. Chem.
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Crystallographic
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via
www.ccdc.cam.ac.uk/data_request/cif.
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Manuscript received: XXXX, 2020
Manuscript revised: XXXX, 2020
Manuscript accepted: XXXX, 2020
Accepted manuscript online: XXXX, 2020
Version of record online: XXXX, 2020
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Entry for the Table of Contents
Page No.
EWG
N
N
R2
Ar
Palladium-Catalyzed Aminomethylation of
Nitrodienes and Dienones via Double C-N Bond
Activation
[Pd]
EWG
-NO
+
Ar
R2
N
R2
=
-COR',
EWG
2
to
29
92%
examples, up
yield
and
excellent
E/Z selectivities
regioselectivities
A new strategy for the generation of the active Pd-alkyl species from aminal via C-N bond
activation has been established, in which the formation of zwitterionic intermediate through
aza-Michael addition of aminal to nitrodienes or dienones is identified as a key step for activation
of the C-N bond. The efficient strategy has enabled
a new palladium-catalyzed
α-aminomethylation of nitrodienes and dienones via double C-N bond activation.
Bangkui Yu, Bao Gao, Xuexia Zhang, Haocheng
Zhang, Hanmin Huang*
a
Department,
Institution,
Address
1
2
cDepartment,
E-mail:
Institution,
Address
3
E-mail:
bDepartment,
E-mail:
Institution,
Address
Chin. J. Chem. 2018,template
© 2018 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
This article is protected by copyright. All rights reserved.