Copper-Catalyzed Diamination of Alkenes of Unsaturated Ketohydrazones with Amines

Article abstract of DOI:10.1021/acs.orglett.7b03401

A convenient copper-catalyzed intra-/intermolecular diamination of β,γ-unsaturated hydrazones has been developed with simple amines as external amine sources. The protocol enables efficient access to various nitrogen-containing pyrazolines under mild reaction conditions.

Full text of DOI:10.1021/acs.orglett.7b03401

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Copper-Catalyzed Diamination of Alkenes of Unsaturated
Ketohydrazones with Amines
Manman Chen, Li-Jing Wang,* Pei-Xing Ren, Xiao-Ying Hou, Zhang Fang, Meng-Nan Han,
and Wei Li*
Key Laboratory of Medicinal Chemistry, and Molecular Diagnosis of the Ministry of Education, College of Chemistry &
Environmental Science, HeBei University, 180 Wusi Donglu, Baoding 071002, P. R. China
S
* Supporting Information
ABSTRACT: A convenient copper-catalyzed intra-/intermo-
lecular diamination of β,γ-unsaturated hydrazones has been
developed with simple amines as external amine sources. The
protocol enables efficient access to various nitrogen-containing
pyrazolines under mild reaction conditions.
been made, current diamination methods still have limitations,
icinal diamines are widely represented in biologically
Vactive compounds, synthetic building blocks, materials, particularly that most of them need to be carried out at high
catalysts, and ligands.1 The direct diamination of alkenes
temperature and required a stoichiometric amount of environ-
mentally unfriendly oxidants. Therefore, it is of great value to
develop more efficient and greener methodologies for the
alkene diaminations under mild conditions.
provides a straightforward route to the synthesis of such useful
compounds and is therefore of great interest.2 In particular, a
number of elegant transition metal catalyzed alkene diamina-
tion methods have been reported.3 [Pd]-, [Ni]-, [Au]-, or [Cu]-
catalyzed alkene diaminations with N,N′-disubstituted ureas
have been developed in the presence of an external oxidant.4 A
few reports also make use of diaziridines,5 N-fluorobenzene-
sulfonimide,6 or O-acylhydroxylamines7 as both nitrogen
sources and internal oxidants for framing these skeletons.
Recently, the Chemler group employed copper salts or MnO2
as an external oxidant, establishing the Cu-catalyzed and Cu-
promoted intra-/intermolecular alkene diamination reactions
with sulfonamides or anilines (Scheme 1a).8 In 2016, the Yu
group reported a copper-catalyzed intra-/intermolecular
diamination of γ,δ-unsaturated ketoximes and simple amines
by using di-tert-butyl peroxide (DTBP) or air as the external
oxidant (Scheme 1b).9 Although impressive achievements have
Pyrazoline derivatives are known to possess potent biological
activities, including antiproliferative, antimalarial, and anti-
bacterial activities and are also served as versatile intermediates
in organic synthesis.10 Consequently, these nitrogen hetero-
cycles have attracted much interest from synthetic and
pharmaceutical chemists. Traditionally, pyrazoline derivatives
are synthesized via the thermal cycloaddition reactions.11 In
recent years, the method of hydrazonyl radical-mediated
difunctionalization of β,γ-unsaturated hydrazones with a
functional group has emerged as a new powerful tool to
construct functionalized pyrazolines.12 Inspired by these works
and our continued interesting in constructing functionalized
heterocycles,13 we decided to test whether β,γ-unsaturated
hydrazones with simple amines could carry out a direct
diamination and afford the corresponding amine-substituted
pyrazolines (Scheme 1, c).
At the outset of our studies, we chose N-phenyl-β,γ-
unsaturated hydrazone 1a and aniline 2a as the substrates,
0.5 equiv Cu(OAc)2 as the catalyst, 0.5 equiv of K2CO3 as the
base, and DMF as solvent (Table 1, entry 1). The reaction was
stirred at room temperature for 40 h under an argon
atmosphere and gave the desired product 3a in 74% yield,
with 1a recovered in 5% yield. Increasing the temperature to 45
°C gave a decreased yield of 56% (Table 1, entry 2).
Subsequently, we investigated the influence of oxidants on
the reaction. When the reaction was carried out under air, it
produced the corresponding product 3a in a lower yield (50%),
while it failed to realize such a transformation when under an
oxygen atmosphere (Table 1, entries 3−4). Then, DTBP,
Scheme 1. Copper-Catalyzed and Copper-Promoted Intra-/
Intermolecular Alkene Diaminations
Received: November 1, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03401
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization of Reaction Conditions for
Diamination of 1a with Aniline
Scheme 2. Substrate Scope of β,γ-Unsaturated
Ketohydrazones
a
a
b
recovery of 1a (%)/
b
entry
1
[Cu]
solvent
base
t (h)
yield of 3a (%)
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuOAc
DMF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
−
40
15
40
40
40
25
40
40
35
40
40
25
5/74
−/56
9/50
c
2
DMF
d
3
DMF
e
4
f
DMF
9/trace
13/62
−/83
<2/32
53/7
5
DMF
6
DMSO
CH3CN
THF
7
8
9
DMSO
DMSO
DMSO
DMSO
−/83
7/46
10
11
12
Cu(OTf)2
Cu(OAc)2
−
15/56
92/N.R.
K2CO3
a
All reactions were carried out by using 1a (0.2 mmol), 2a (2.0 equiv),
copper salts (0.5 equiv), K2CO3 (0.5 equiv), oxidant (2.0 equiv), and
DMSO (3 mL) under argon and stirred at room temperature, unless
b
c
noted otherwise. Isolated yield. Reaction was carried out under 45
d
e
°C. Reaction was carried out under air. Reaction was carried out
under oxygen. 1.0 equiv of Cu(OAc)2 was used.
f
a
All reactions were carried out by using 1 (0.2 mmol), 2a (2.0 equiv),
Cu(OAc)2 (0.5 equiv), K2CO3 (0.5 equiv), and DMSO (3 mL) under
argon and stirred at room temperature for 25−40 h, unless noted
TBHP, TBPB, K2S2O8, and DDQ were tested under argon, but
no better results were observed (Supporting Information (SI)
Table S1). When 1.0 equiv of Cu(OAc)2 was used alone as the
oxidant, the yield was decreased to 62% (Table 1, entry 5).
Delightfully, when the solvent was changed to DMSO, the yield
was improved to 83%, with a shortened reaction time (entry 6),
while other solvents such as CH3CN and THF were not
suitable for this transformation (entries 7−8). These results
indicated that DMSO as a solvent was crucial for this reaction.
CuOAc produced the same yield after 35 h, while Cu(OTf)2
only gave a yield of 46% (entries 9−10). Employment of other
bases such as Na2CO3 and Et3N provided inferior results. The
loading of Cu(OAc)2 and K2CO3 were evaluated as well, but
there was no improvement in yield (Table S1). The subsequent
control experiments revealed that both Cu(OAc)2 and K2CO3
were crucial to this transformation (entries 11−12). (for details
see SI Table S1).
With the optimized conditions in hand (Table 1, entry 6), we
then examined the scope of this transformation. As shown in
Scheme 2, various β,γ-unsaturated ketohydrazones were
subjected to the standard conditions. First, a series of
hydrazone substrates with a para-substituent on the phenyl
ring including some with electronwithdrawing groups (Br, Cl)
and some with electron-donating groups (Me, OMe, and
isopropyl) underwent the diamination smoothly and provided
the desired products in excellent yields (3b−f). Then, as shown
in the synthesis of dihydropyrazoles 3g−j, substrates with a 3-
substituted phenyl ring were also proved to be suitable for the
transformation. We continued to investigate the hydrazone
substrates bearing aryls. 1k and 1m participated smoothly in the
tandem reaction and gave rise to the corresponding pyrazolines
in excellent yields, while 1l only gave the desired product in
42% yield. Moreover, aliphatic β,γ-unsaturated hydrazones 1n
and 1o could also give the desired products in 51% and 32%
yields, respectively. We next examined the possible structural
b
otherwise. Isolation yields. The reaction was carried out for 40 h, and
1l was recovered in 34% yield.
variation of the N-Phenyl moiety. And substituted β,γ-
unsaturated hydrazones with a range of electronic properties
all proceeded well in the reaction to yield the desired
pyrazolines in excellent yields (3p−u). However, N-tosyl and
N-acetyl substituted ketohydrazones were inert in the reaction
(3v−w).
To further demonstrate the synthetic potential of this
method, a vast variety of simple amines were employed in this
diamination reaction (Scheme 3). As expected, substituted
anilines with a broad range of electronic properties worked well
under the standard conditions and provided compounds 3ab−
ah in good to high yields. 2-Aminonaphthalene 2ai and
heterocyclic primary amine 2aj were also suitable for this
transformation. Use of primary aliphatic amine 2ak could give
the desired product 3ak in 44% yield, while benzamide 2al only
gave a trace amount of the corresponding products under the
stated conditions. Secondary aniline 2am could be transformed
into the desired product in 32% yield. Moreover, secondary
aliphatic amines, such as dimethylamine, piperidine, morpho-
line, and pyrrolidine, are good aminating reagents as well. We
can obtain the diamination products 3an−aq in good yields
with them.
To gain an insight into the mechanism of the chemical
reaction, two control experiments were carried out as shown in
Scheme 4. When the radical scavenger TEMPO (2, 2, 6, 6-
tetramethylpiperidine-1-oxyl, 2 equiv) was added in the
reaction under the standard reaction conditions, the desired
compound 3a could only be obtained in a trace amount and the
pyrazoline 4, which was obviously yielded from the trapping of
B
DOI: 10.1021/acs.orglett.7b03401
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Substrate Scope of Amines
Scheme 5. Proposed Mechanism
Finally, Cu(I) could be oxidized by DMSO to regenerate
Cu(II).14
In summary, a highly efficient and practical copper-catalyzed
intra-/intermolecular alkene diamination reaction between β,γ-
unsaturated hydrazones and simple amines with DMSO as the
oxidant has been developed. This transformation offers a useful
method to access a variety of aminomethyl-functionalized
pyrazolines, which are valuable building blocks in organic
synthesis and medicine. Further studies on the mechanisms
details of this reaction and more hydrazonyl radical promoted
reactions are underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
a
All reactions were carried out by using 1a (0.2 mmol), 2 (2.0 equiv),
Cu(OAc)2 (0.5 equiv), K2CO3 (0.5 equiv), and DMSO (3 mL) under
argon and stirred at room temperature for 25−40 h, unless noted
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03401.
b
otherwise. Isolation yields. Dimethylamine added as 2 M solution in
THF.
Detailed experimental procedures and spectral data for
all products (PDF)
Scheme 4. Control Experiment
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: wanglj0405@163.com.
*E-mail: liweihebeilab@163.com.
ORCID
Li-Jing Wang: 0000-0002-2411-2758
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
the C-centered radical derived from the 5-exo-trig cyclization of
1a by TEMPO, was formed in 85% yield (eq 1). Furthermore,
when BHT (butylated hydroxytoluene, 2 equiv) was added
under the standard reaction conditions, the yield of the desired
product 3a was also sharply decreased to 26% and the substrate
1a was recovered in 63% yield (eq 2). Together, these
observations clearly suggest that a radical pathway was involved.
Although the reaction mechanism is not completely clear yet,
on the basis of the above-mentioned results and literature
reports,5c,7,9 we propose a plausible mechanism for this
transformation (Scheme 5). Initially, the intramolecular
aminocupration of 1a occurs upon alkene activation by a
copper(II) catalyst via intermidate A to form alkyl-copper
complex B. Intermidate B may undergo homocleavage to form
the radical intermediate C. On the other hand, aniline 2a reacts
with the Cu(II) catalyst to form intermediate D. The obtained
C-centered radical intermediate C couples with intermediate D
to generate intermediate E, which was followed by a reductive
elimination process to form the desired product 3a and Cu(I).
We thank the National Natural Science Foundation of China
(No. 21702043), the Hebei Province Science Foundation for
Key Program (No. B2016201031), the Hebei Province Science
Foundation for Youths (No. B2017201041), and the Hebei
Province Higher School Science Foundation for High-level
Personnel (No. GCC2014014) for financial support.
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