Visible-Light-Induced Copper-Catalyzed Intermolecular Markovnikov Hydroamination of Alkenes

Article abstract of DOI:10.1021/acs.orglett.9b02863

A visible-light-induced copper-catalyzed intermolecular hydroamination of alkenes using commercially accessible primary and secondary amines has been established. This effective method exhibits good tolerance of a broad range of functional groups and provides a facile access to an array of valuable amines with Markovnikov regioselectivity. The process can be positively expected to be used in bioactive amines, and it may provide new potential in the discovery of copper-catalyzed hydrofunctionalization reactions.

Full text of DOI:10.1021/acs.orglett.9b02863

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Visible-Light-Induced Copper-Catalyzed Intermolecular
Markovnikov Hydroamination of Alkenes
Yang Xiong and Guozhu Zhang*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Center for Excellence in Molecular
Synthesis, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, P. R.
China
S
* Supporting Information
ABSTRACT: A visible-light-induced copper-catalyzed intermolecular hydroamination of alkenes using commercially accessible
primary and secondary amines has been established. This effective method exhibits good tolerance of a broad range of
functional groups and provides a facile access to an array of valuable amines with Markovnikov regioselectivity. The process can
be positively expected to be used in bioactive amines, and it may provide new potential in the discovery of copper-catalyzed
hydrofunctionalization reactions.
Given many readily accessible copper salts serving as
photochemical catalysts,10 the development and expansion of
their applications in other attractive areas such as hydro-
amination are highly desired. Inspired by the impressive
pioneering work of Fu and Peters,10d−g also consistent with our
research interest in radical chemistry,11 we focused our
attention toward the addition of simple amines to readily
available alkenes catalyzed by copper salt in photochemistry.
Here, we describe a distinct pathway of a visible-light-induced
protocol for copper-catalyzed hydroamination of alkenes,
which could enable the rapid construction of valuable amines
in a Markovnikov regioselective manner with convenient and
environmentally benign reaction conditions. In this catalytic
strategy, the copper complex, which is generated in situ, is
supposed to function as the photocatalyst and coupling catalyst
without sacrificing reagents.
In our previous study, we found that the hydroamination
product 9-(1-phenylethyl)-9H-carbazole, c1, could be obtained
in 40% yield by using 9H-carbazole, 2-bromo-2-methylpro-
pane, and styrene under the reported reaction conditions.11b
The unpredicted discovery of the photoinduced protocol has
attracted our interest, due to the significance of the carbazole
motif which frequently occurs in natural products, drug
molecules, and chiral ligands.12 We started to optimize the
reaction conditions. The 9-(1-phenyl-ethyl)-9H-carbazole was
isolated in 60% yield using CuCl and LiOtBu in CH3CN (1.5
mL) (Table 1, entry 1). When other bases were tested (Table
1, entries 2−3), LiOtBu was found to be the most effective in
this reaction.13 The hydroamination also proceeded in other
solvents; however, the yields of c1 were considerably decreased
mines are fundamentally important frameworks in natural
Aproducts, synthetic drugs, agrochemicals, biological
probes, and functional materials.1 To date, considerable
endeavor has been devoted to the discovery and development
of new strategies for the formation of this critical organic
compound.2 Hydroamination of alkenes, combining two
commercially accessible and structurally diverse feedstocks in
a highly valuable and atom-economical way, is one particularly
significant method of such transformations. Marvelous
progress, especially metal-catalyzed alkene hydroamination,
has been achieved over the past decades.3 Among the various
metal-catalyzed hydroamination reactions, the direct copper-
catalyzed addition of amines to alkenes is considered to be an
intriguing and practical technique.4 For instance, recently, the
Miura5 and Buchwald6 groups have established the efficient
hydroamination of alkenes with electrophilic amines in the
presence of a copper catalyst. Meanwhile, in spite of the great
development and vibrant expansion of photochemistry during
the past decades,7 it seems only recently has success been
achieved in photodriven intermolecular hydroamination of
alkenes. In this regard, the Nicewicz group has realized the
novel and general approach to anti-Markovnikov olefin
hydroamination reactions by using a dual organic catalyst
system consisting of an acridinium photooxidant.8 The
Knowles group has developed an innovative and robust
method of visible-light photoredox protocols for the anti-
Markovnikov hydroamination of olefins through catalytically
generated aminium radical intermediates.9 However, the more
general and economic method for the direct coupling of
common and commercially available amines and olefins in a
green and easy-to-handle way remains a challenging synthetic
task.
Received: August 12, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02863
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
Table 1. Optimization of the Reaction Conditions
Scheme 1. Scope Studies with Alkenes
a
b
entry
catalyst
base
solvent
yield (%)
c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuBr
LiOtBu
NaOtBu
KOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
No
CH3CN
CH3CN
CH3CN
DMAC
MeOH
Toluene
THF
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
62 (60)
ND
ND
40
ND
ND
ND
60
70
83
82
20
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(OTf)2
d
d
No
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
ND
ND
e
LiOtBu
LiOtBu
f
c
15
76
a
b
0.2 mmol scale. Measured by 1H NMR analysis, using diethyl
c
d
phthalate as internal standard. Isolated yield. CH3CN (2.0 mL), 0.1
M. No light, 50 °C, 16 h. 0.4 mmol scale, 0.1 M. DMAC is
Dimethylacetamide
e
f
a
b
c
0.2 mmol scale. Isolated yield. Cu(OTf)2 was used as the copper
(Table 1, entries 4−7). In addition, testing of different copper
salts showed that a higher yield could be obtained by using
Cu(CH3CN)4PF6 or Cu(OTf)2 (Table 1, entries 8−11). The
control experiments demonstrated the essential roles of the
copper salt, LiOtBu, and light in the reaction13 (Table 1,
entries 12−14). Lastly, under the optimized reaction
conditions, c1 could be obtained in 76% isolated yield
(Table 1, entry 15).
salt.
a b
,
Scheme 2. Scope Studies with Amines
With the optimized reaction conditions established, we
evaluated the substrate scope of alkenes (Scheme 1). In the
reaction, electron-donating or -withdrawing substituents on the
aryl ring of styrenes could afford the products c2 to c8 in
satisfactory yields. The styrenes bearing functional groups of
halides and ether could be well tolerated. The di- or
trisubstituted styrenes proceeded efficiently to provide the
amines c9 and c10. Moreover, α- or β-substituted styrenes
could also afford the desired products c11 and c12. Even α,β-
disubstituted styrene underwent the photoinduced process to
provide c13 in a high yield, demonstrating the generality of the
procedure. Interestingly, the introduction of the ferrocene
motif in alkene could be allowed to yield the desired product
c14. Additionally, the 1,3-dienes both reacted well to give the
functionalized products (c15 and c16) in good 1,4-selectivity.
The strategy may pave a promising way toward transformation
of 1,3-dienes into allylic compounds. The reaction of aliphatic
alkenes with 9H-carbazole under the standard conditions did
not give the desired products probably because of the lower
reactivity of the nonactivated double bond.
Next, we investigated the generality of the amines (Scheme
2). The substituted 9H-carbazole and representative indole
derivatives, which are common elements in bioactive
compounds and natural products,14 could be converted to
c17 and c18 in good yields. However, the application of the
standard hydroamination process to the simple indoline, with a
further decreased π-system, was not successful. We reasoned
that the Cu−Nu complex may be less effective in the activation
a
b
c
0.2 mmol scale. Isolated yield. According to the reaction condition
d
A. According to the reaction condition B.
of the substrate or the stabilization of the intermediate in the
photoexcitation. Inspired by the elegant work of Fu and
Peters15 using BINOL as the cocatalyst and according to our
previous study,11b after extensive optimization of the reaction
conditions, to our delight, the desired product c19 was
obtained in 62% yield using rac-BINOL (20 mol %) and
CH3CN/DMAc (1.5 mL/0.4 mL) as the solvent. The
modified process has been proven to be general for an array
B
DOI: 10.1021/acs.orglett.9b02863
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
of aryl amines. The reaction of diphenylamine proceeded
efficiently to give the product c20. Anilines containing
electron-donating or -withdrawing groups could smoothly
react to afford the products c21 to c29. Meanwhile, functional
groups such as halides (F, Cl, Br), ether, and thioether were
tolerated to offer the desired products which bear a handle for
further C−C, C−O, and C−S cross-coupling reactions. The
1,1-disubstituted styrene also showed good reactivity to
provide the product c30 in 62% yield.
Finally, to acquire a good understanding of the possible
mechanistic pathway of this reaction, a series of control
experiments have been conducted. When the radical quencher,
TEMPO (1.5 equiv), was added in the reaction, the yield of
1
desired product c1 was less than 3% (measured by H NMR)
Figure 1. Simplified outline of the proposed reaction mechanism.
[Scheme 3, eq 1]. Then, by using CD3CN as solvent, the
Scheme 3. Preliminary Mechanistic Studies
Then the copper−nucleophile complex B was coordinated
with the alkene to generate the complex C.17 After irradiation
with light, the complex C could be transformed into the
excited complex D.17 The capability of initial photoexcitation
of copper complex C may depend on the strong π-system of
the nucleophilic site (carbazole and the indole).15 In the case
of a simple aryl amine with reduced photoactivity, the copper−
binaphtholate complex may act as the primary photo-
catalyst.15a Next, the intermediate E (the benzyl radical and
the organocoppern+1) could be generated via SET with the
excited complex D and the hydrogen atom abstraction of
CH3CN.10d−g,13,16 Lastly, the benzyl radical is captured by the
organocoppern+1 to afford the desired hydroamination product
and regenerate the copper catalyst A.10g Regarding the
copper−binaphtholate complex, the copper−amido complex
is forged with the ligand exchange to a simple amine15 before
capture.
In summary, we have established a green and expedient
method for Cu-catalyzed hydroamination reaction of an alkene
induced by visible light. This highly effective process was
compatible with a variety of functional groups and provides a
facile access to a range of aryl amines. Considering the
commercial availability of chemical substrates, highly opera-
tional flexibility, and comparatively simple and mild conditions,
this general platform described here not only could further be
applied to the hydrofunctionalization of complex amines but
also may pave a new pathway toward the discovery of
photoinduced copper-catalyzed hydro-amination reactions.
a
Measured by 1H NMR analysis, using diethyl phthalate as an internal
b
standard. Isolated yield.
1
deuterated product d-c1 (D/H > 99, measured by H NMR)
could be obtained in 60% yield [Scheme 3, eq 2]. Additionally,
the amine c31 was obtained in 40% yield by a ring-opening
route of the cyclopropane unit [Scheme 3, eq 3]. The above-
mentioned experimental results indicate that the radical
intermediates16a and the hydrogen atom abstraction of the
solvent8,16b may be involved in the present hydroamination
reaction pathway. When other nucleophiles (1.5 equiv), such
as naphthol, the isoquinoline, indazole, and benzene-
sulfonamide, were added in the reaction respectively, the
additives were almost recovered and no hydrofunctionalization
products could be found, except 4-methyl-benzenethiol10f
[Scheme 3, eq 4]. Those results suggest that the involvement
of cationic intermediates in the formation of the C−N bond is
less likely.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02863.
■
S
Research details, experimental procedures, full character-
ization of products, and NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: guozhuzhang@sioc.ac.cn.
ORCID
According to the literature8,10,13,16 and our preliminary
experiments, one of the plausible reaction pathways is outlined
in Figure 1. First, in the presence of the base, LnCunNu was
formed by the ligand exchange of LnCunX with the nucleophile.
Guozhu Zhang: 0000-0002-2222-6305
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.9b02863
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
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ACKNOWLEDGMENTS
■
Financial support by NSFC (21772218, 21821002),
XDB20000000, the “Thousand Plan” Youth program, State
Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, and the Chinese Academy of
Science is gratefully acknowledged.
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