Succinimide-Promoted Malonylamination of Alkenes with Amines and Iodonium Ylides via Trapping of Transient Aminium Radical Cations

Article abstract of DOI:10.1021/acs.orglett.9b00983

A conceptually distinct strategy enabling malonylamination of alkenes with abundant amines and iodonium ylides without assistance of any transition metal was developed. Succinimide was identified as a proton shuttle that can not only largely accelerate the process of trapping highly unstable radical ion pairs with alkenes but also significantly improve the chemical yields.

Full text of DOI:10.1021/acs.orglett.9b00983

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Succinimide-Promoted Malonylamination of Alkenes with Amines
and Iodonium Ylides via Trapping of Transient Aminium Radical
Cations
Liang Zhang, Xiangjin Kong, Shuya Liu, Zhiguo Zhao, Qun Yu, Wei Wang, and Yao Wang*
School of Chemistry and Chemical Engineering, Key Laboratory of the Colloid and Interface Chemistry, Shandong University, Jinan
250100, China
S
* Supporting Information
ABSTRACT: A conceptually distinct strategy enabling
malonylamination of alkenes with abundant amines and
iodonium ylides without assistance of any transition metal
was developed. Succinimide was identified as a proton shuttle
that can not only largely accelerate the process of trapping
highly unstable radical ion pairs with alkenes but also
significantly improve the chemical yields.
cations addition of double bonds under a ruthenium or an
arboamination of alkenes has emerged as a streamlined
Cstrategy for the synthesis of functionalized amines that iridium photoredox protocol (Figure 1a).10,11
Huang et al. discovered that an amine−I2 charge-transfer
are fundamentally important in many research areas such as
pharmaceuticals, agrochemicals, and materials science.1 As a
result, a diverse array of intramolecular,2 two-component,3 and
three-component4 carboamination of alkenes have been
established. For these carboamination transformations, tran-
sition metals generally play an essential role in the bond-
forming events while tailored amides, sulfamides, azides, or
nitriles were used as the most frequent nitrogen sources, as
these reagents are compatible with transition metals and
external oxidants. Despite these important advances, direct
carboamination of alkenes with simple amines in the absence
of transition metals remains an unresolved problem.
complex could facilitate the inert C−N bond activation.12
Recently, we found that the halogen-bonding complex between
iodonium ylides and tertiary arylamines could induce a single-
Instead of exploiting the classical nucleophilic property of
amines in the formation of carbon−nitrogen bonds, the
generation of transient aminium radical cations via one-
electron oxidation of amines would provide an alternative
approach. However, the application of amines to a
carboamination process via trapping of aminium radical cations
remains elusive. The lack of this type of reaction is presumably
attributed to the problem that the controllable one-electron
oxidation of amines and subsequent trapping of transient
aminium radical cations are generally not productive, as these
highly unstable species could undergo fast transformations to
give α-aminoalkyl radicals and iminium ions.5−9 As a
consequence, chemical bonds formed at carbon (adjacent to
nitrogen) rather than direct bond formation at nitrogen.
Though simple amine-mediated C−N bond formation through
aminium radical cation intermediates is challenging, the
research groups of Zheng and Knowles developed amination
of alkenes with secondary amines through aminium radical
Figure 1. Generation and trapping of transient aminium radical
cations.
Received: March 20, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00983
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
electron-transfer (SET) process, leading to the cyclization of
tertiary arylamines via C−C bond formation.13 Herein, we
established a distinct approach to achieving a three-component
malonylamination of alkenes with simple primary and
secondary amines and iodonium ylides. In this transformation,
C−N bond formation was realized via trapping of transient
aminium radical cations. Thus, the simple merging of alkenes,
carbon, and nitrogen sources together can directly lead to the
desirable products (Figure 1b).
Initially, we screened a broad range of different additives
including Brønsted bases and acids that can mediate the
proton transfer process. The experimental results reveal that
succinimide is an optimal choice. Using 20 mol % of
succinimide PS1 as a proton shuttle, the reaction of iodonium
ylide 1a, secondary arylamine 2a, and alkene 3a proceeded
smoothly at 70 °C in toluene to give 4a in 62% yield within
only 20 min (Table 1, entry 1). In contrast, the reaction was
product 4a was obtained using a Brønsted acid, such as
CH3COOH, CF3COOH et al., as a proton shuttle. The
variation of temperature (Table 1, entries 8−11) and amount
of succinimide (Table 1, entries 12−13) did not increase the
chemical yield of product 4a. Further screening of different
solvents reveals that toluene is an optimal choice.
Under the optimized reaction conditions, the substrate
scope was investigated. As shown in Scheme 1, different
amines, alkenes, and malonyl-type iodonium ylides were
studied. The results reveal that both primary and secondary
arylamines could be used as successful substrates. Regardless of
the substitution position (i.e., ortho, meta, para), the functional
a b
,
Scheme 1. Substrate Scope
a
Table 1. Optimization of Reaction Conditions
b
entry
variation from the “standard” conditions
time
yield (%)
1
2
3
4
5
6
7
8
none
without PS1
0.3 h
4.0 h
0.3 h
4.0 h
24 h
24 h
24 h
0.3 h
1.0 h
5.0 h
6.0 h
1.0 h
0.2 h
0.5 h
3.0 h
1.5 h
1.5 h
62
37
62
45
<5
<5
<5
60
59
52
40
56
60
53
50
34
44
PS2 instead of PS1
PS3 instead of PS1
PS4 instead of PS1
PS5 instead of PS1
PS6 instead of PS1
at 80 °C
at 60 °C
at 40 °C
at rt
10 mol % PS1
30 mol % PS1
DCE instead of toluene
hexane instead of toluene
dioxane instead of toluene
DME instead of toluene
9
10
11
12
13
14
15
16
17
a
Unless otherwise noted, all the reactions were carried out with 1a
(0.6 mmol), 2a (0.45 mmol), 3a (0.3 mmol), and PS1 (20 mol %) in
b
0.75 mL of solvent as indicated at 70 °C. Isolated yield.
much slower and the chemical yield of 4a dropped dramatically
without assistance of a proton shuttle (Table 1, entry 2).
Similarly, using phthalimide PS2 instead of PS1 as a proton
shuttle, nearly the same efficiency of this transformation was
observed (Table 1, entry 3). However, using a less acidic amide
PS3 instead of PS1, no substantial effect on the reaction
outcome was observed (Table 1, entry 4). The investigation of
the other potential proton shuttles PS4−5 reveals that this
transformation could not be compatible with these acids
(Table 1, entries 5−6). The pioneering work of Zhou and Zhu
revealed that Brønsted acids could serve as excellent proton
shuttles.14 For this malonylamination process, no desirable
a
Unless otherwise noted, all the reactions were carried out with 1 (0.6
mmol), 2 (0.45 mmol), 3 (0.3 mmol), and PS1 (20 mol %) in 0.75
b
mL of toluene at 70 °C. Isolated yield.
B
DOI: 10.1021/acs.orglett.9b00983
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Organic Letters
Letter
groups could be installed in different positions. Meanwhile,
substitution groups with different electronic properties, such as
electron-withdrawing, neutral, and electron-donating, were
tolerated in this transformation. Arylamines bearing multi-
substitutions were amendable to this malonylamination
reaction. Cyclic arylamines, 3,4-dihydro-2H-benzo[b][1,4]-
oxazine and indoline, were used as effective substrates to
generate the desirable products (4g and 4h). Significantly, the
formation of the C−N bond was achieved by using a pyridine-
base amine (4i) albeit with moderate chemical yields. 1,1′-
Binaphthyl-2,2′-diamine was employed as an effective substrate
to give product 4v, indicating that the final product bearing the
free amine group could be tolerated. An aliphatic amine such
as dibutylamine was reactive in this transformation while low
yield was obtained in this case (4w). Noteworthily, the
problematic primary amines could be used as effective
substrates in this carboamination process. This could be
attributed to the highly steric hindrance of the generated
secondary amines products, which prevents them from further
oxidation by iodonium ylides. Then different alkenes were
investigated. Aromatic rings of alkenes could be decorated with
a diversified array of substitution groups with different
electronic properties. Some of these alkenes allowed access
to hindered amines, such as 4ad and 4ae. A pyridine-
substituted alkene could be applicable to this transformation
to give product 4af. The structure of product 4al was
confirmed by single-crystal X-ray diffraction (CCDC
1881966). However, unactivated olefins, styrene, and stilbene
could not be tolerated under the optimized reaction
conditions. Further investigation of malonyl-type iodonium
ylides indicates that different esters (i.e., Me, Bn, iPr) were
amendable to this reaction. Remarkably, hydroxylamines could
also be used as effective reactants to give the desirable
carboamination products 4ao and 4ap within several minutes.
This carboamination transformation reaction was amendable
to gram-scale synthesis. Upon using 1.8 g of 3a (10 mmol) as
starting material, the desirable product 4a was obtained in 52%
(2.23 g) yield (Scheme 2).
Scheme 3. Mechanistic Investigation
diphenylamine 2b (0.6 mmol, 2.0 equiv) was carried out
(Scheme 3d). Consistent with the proposed reaction pathway,
despite the presence of excess N-ethylaniline, product 4b was
predominantly formed (4b:4a > 20:1), as diphenylamine 2b
could generate a much more stable aminium radical cation
intermediate albeit with weaker nucleophilicity in contrast to
N-ethylaniline 2a. This competitive experiment further
indicates that a radical pathway is in operation in the C−N
formation step rather than a nucleophilic trapping of a
carbocation with the amine.
The proposed reaction pathway was depicted in Figure 2.
Initially, the halogen-bonding complex between an iodonium
Scheme 2. Gram-Scale Synthesis
To provide some insight into this carboamination process,
several experiments were carried out to investigate the reaction
pathway (Scheme 3). Under standard reaction conditions,
there was no reaction between cyclopropane 3y and amine 2a;
thus, the approach to product 4a via a nucleophilic ring
opening of cyclopropane 3y was excluded (Scheme 3a). In
order to trap the radical intermediate, we performed the
reaction under oxygen. Lactone 5 was obtained in 37% yield
while the malonylamination product 4a was not observed
(Scheme 3b), suggesting the involvement of a possible radical
intermediate int-5. Then we further carried out a radical clock
experiment (Scheme 3c). Under the standard reaction
conditions, cyclopropane 3x could react with arylamine 2d
and iodonium ylide 1a to give the ring-opening product 4x.
Considering the possibility of further oxidation of intermediate
int-5 to a carbocation, a competitive reaction between N-
ethylaniline 2a (0.6 mmol, 2.0 equiv) and less nucleophilic
Figure 2. Proposed reaction pathway.
ylide and amine would induce an electron-transfer process to
generate an aminium radical cation and a malonyl radical
anion. Subsequently, the in situ generated malonyl radical
anion would abstract a proton from a proton shuttle (i.e.,
succinimide) to give the malonyl radical upon losing one
molecule of iodobenzene. Then malonyl radical addition of
double bonds would lead to the formation of carbon-centered
radicals that then engage in the C−N bond formation with
aminium radical cations. Finally, the anionic proton shuttle
C
DOI: 10.1021/acs.orglett.9b00983
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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forming events.
In conclusion, we developed a malonylamination of alkenes
using simple primary and secondary amines and iodonium
ylides as starting materials. This transformation did not require
any transition metals and external chemical oxidants, directly
generating γ-amino acid derivatives. The presence of
succinimide as a proton shuttle is essential for the high
efficiency of this transformation.
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00983.
Full experimental procedures and compound character-
ization (PDF)
Accession Codes
CCDC 1881966 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.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yaowang@sdu.edu.cn.
ORCID
Yao Wang: 0000-0002-8071-3267
Notes
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R.; Zottola, M. A.; Fraser-Reid, B. J. Am. Chem. Soc. 1993, 115, 6666−
6672.
The authors declare no competing financial interest.
(6) Mayer, P. M.; Glukhovtsev, M. N.; Gauld, J. W.; Radom, L. J.
Am. Chem. Soc. 1997, 119, 12889−12895.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Natural Science
Foundation of China (21772113, 21302075, 11501454), The
Key Research and Development Plan of Shandong Province
(2017GGX70109), and The Fundamental Research Funds of
Shandong University (2017JC004). We thank Prof. Di Sun
(Shandong University) for assistance with the X-ray crystal
structure analysis.
(7) Nakajima, K.; Miyake, Y.; Nishibayashi, Y. Acc. Chem. Res. 2016,
49, 1946−1956.
(8) Liu, S.; Zhao, Z.; Wang, Y. Chem.Eur. J. 2019, 25, 2423−2441.
(9) Hu, J.; Wang, J.; Nguyen, T. H.; Zheng, N. Beilstein J. Org. Chem.
2013, 9, 1977−2001.
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DOI: 10.1021/acs.orglett.9b00983
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