Visible Light-Promoted Three-Component Carboazidation of Unactivated Alkenes with TMSN3 and Acrylonitrile

Article abstract of DOI:10.1002/cjoc.201800320

A novel difunctionalization of unactivated alkenes has been reported via visible light-promoted three-component carboazidation using TMSN₃ and acrylonitrile as partners without any stoichiometric oxidants. This protocol is operationally simple for straightforward access to azido derivatives with good functional group tolerance from readily available starting materials. A facile azido radical-catalyzed [3?+?2] cycloaddition reaction of vinylcyclopropane with acrylonitrile was also observed to deliver a multi-substituted cyclopentane.

Full text of DOI:10.1002/cjoc.201800320

Visible Light-Promoted Three-Component Carboazidation of Unactivated
Alkenes with TMSN3 and Acrylonitrile
Bo Yang,a Xiang Ren,a Xuzhong Shen,a Tongtong Li,a Zhan Lu*,a
ABSTRACT A novel difunctionalization of unactivated alkenes has been reported via visible light-promoted three-component carboazidation using TMSN3
and acrylonitrile as partners without any stoichiometric oxidants. This protocol is operationally simple for straightforward access to azido derivatives with
good functional group tolerance from readily available starting materials. A facile azido radical-catalyzed [3+2] cycloaddition reaction of vinylcyclopropane
with acrylonitrile was also observed to deliver a multi-substituted cyclopentane.
KEYWORDS alkene difunctionalization, visible light photocatalysis, three-component reaction, redox-neutral, organoazide
stoichiometric peroxides have to be used and aliphatic alkene is a
still challenging substrate. Here, we reported a three-component
Introduction
Alkene difunctionalizations have been continuously attractive
carboazidation of unactivated alkenes with TMSN3 and
for efficient construction of various useful synthetic intermediates
acrylonitrile via visible light photocatalysis without any
and targets.[1] Organoazides have been used as efficient synthetic
stoichiometric oxidants.
intermediates due to their diversity of further transformations.[2]
Our group is quite interested in visible light-promoted alkene
difunctionalizations.[9] In our previous studies, the azido radical[10]
The combination of the formations of carbon-azide bond and
could react with alkene to form carbon radical[11] which could be
carbon-X (halogen, P, O, N) bonds have been successfully
reported.[3] The carboazidation of alkenes used to form carbon-(sp
or sp2) carbon bonds or fluorinated carbon bonds.[4] However, to
the best of our knowledge, the three-component carboazidation
reaction with the formation of non-fluorinated carbon
(sp3)-carbon (sp3) is still limited (Scheme 1). Renaud and
co-workers reported two types of carboazidation of alkenes with
α-iodoacetate and phenylsulfonyl azide, or using alkylsulfonyl
azides as both alkyl and azido sources.[5] Recently, Zhu[6] group
and Yang[7] group, respectively, reported carboazidation of
terminal styrenes or cyclic styrene with acetonitrile or aldehydes
as carbon sources using peroxides as oxidants. Li and co-workers
reported an azidomethylation of active alkenes with dimethyl
sulfoxide as a methyl source using H2O2 as an oxidant.[8] So far,
over
trapped by dioxygen.[9e] Based on these result, we hypothesized
that the Michael acceptor, such as acrylonitrile, was an alternative
trapper which leads to the formation of carbon (sp3)-carbon (sp3)
bond to afford the carboazidation product (Scheme 1b).
The proposed mechanism was presented in Scheme 1c. The
azidotrimethylsilane could be oxidized by iridium photocatalyst
(EIr*/Ir-= +0.66 V)[12] to azido radical based on the oxidation
potential of the azidotrimethylsilane (measured 0.66 V vs SCE in
MeCN and 0.600 V vs SCE in acetone) or azido anion (0.655 V vs
SCE in MeCN) [13]
The azido radical could be trapped by alkene to generate
benzyl radical species I which could undergo radical Michael
addition to form carbon center radical II. This carbon radical II
could be reduced by low valent photocatalyst to regenerate the
ground state of photocatalyst, and afford the corresponding
product 3a in the presence of proton source.
Scheme 1 The Carboazidation of Alkenes
Results and Discussion
Based on the above hypothesis, we extensively investigated the
reaction conditions for the carboazidotion of α-methyl styrene
with various photocatalyst at room temperature under the
irradiation of 8 W blue LEDs for 9 h using water as proton donor
and acetonitrile as
a solvent. The various visible light
photocatalysts were screened using TMSN3 as an azido source
and acrylonitrile as a Michael acceptor, and Ir(ppy)2(dtbbpy)PF6
was found to catalyze the reaction to afford three-component
carboazidation product in 67% yield (entry 1, Table 1 and also in
Table S1). It should be noted that the generated azido radical
could react much rapider with α-methyl styrene than
electron-deficient acrylonitrile. Various solvents were tested and
no better results were observed (entries 2-7). The reaction with 2
equiv. of TMSN3 in a solvent of MeCN (0.2 M) afforded the
desired product in 80% yield (entry 8 as the standard conditions
A). No desired products were obtained in the absence of
photocatalyst or light (entries 10 and 11). Additionally, the
reaction took place by using MeOH (3 equiv.) instead of H2O (10
equiv.) to give 3a in 71% yield (entry 12 as the standard
conditions B).
a Department of Chemistry, Zhejiang University, Hangzhou, China, 310058
E-mail: luzhan@zju.edu.cn
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may lead to differences between this version and the Version of Record. Please cite this
article as doi: 10.1002/cjoc.201800320
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Table 1 Optimization of Conditions of Carboazidation of Alkenesa
Table 2 Substrate Scope
Entry
Changes to
Yieldb (%)
1
2
-
67
57
THF
3
MeOH
0
4
DCM
Acetone
21
5
61
6
MeNO2
17
7
dioxane
61
8
TMSN3 (2 equiv.), 0.2 M
TMSN3 (2 equiv.), 0.2 M without water
entry 8 without photocatalyst
80 (75)
67
9
10
0
11
entry 8 without light
0
TMSN3 (2 equiv.), acetone (0.2 M),
12
71 (70)
MeOH (3 equiv.) was used instead of H2O
a Conditions: α-methyl styrene (0.3 mmol), TMSN3 (3 equiv.), acrylonitrile
(6 equiv.), water (10 equiv.), Ir(ppy)2(dtbbpy)PF6 (2 mol%), solvent (0.1 M),
b
at room temperature under the irradiation of 8 W blue LEDs for 9 h.
Yields were determined by 1H NMR analysis using mesitylene as an
internal standard. Isolated yield in the parentheses.
With optimized conditions in hands, the scope of substrate
was explored (Table 2). The α-methyl styrenes with various
substituents, such as ether, halides, amine, amide, at para- or
meta- position on aryl ring were suitable for this transformation.
However,
the
sterically
hindered
substrates
with
ortho-substitution could not afford the desired product. The
α-1o-alkyl substituent could be tolerated (3k-l), however, the
α-2o-alkyl substituent was not suitable (3m). The simple styrenes
with electron-rich or electron-deficient substitutions could be
transferred to the corresponding carboazidation products in
58-79% yields. The aliphatic alkenes could participate in reactions
to afford 3u and 3v in 62% and 47% yield, respectively. The acyl
protected cinnamyl alcohol could be delivered to 3w in 37% yield
with poor diastereoselectivity. The trisubstituted alkene could
also involve in the reaction to give 3x in 45% yield with 3.9/1 dr.
The alkene containing estrone-derivative could be transformed
into the corresponding product. The intramolecular reaction of
1,6-diene 4 could undergo smoothly to afford cyclization product
5 in 62% yield with 3.2/1 dr (Table 2 eq. 1). The other Michael
acceptors have been tested. The reaction of styrene with diethyl
fumarate afforded 3aa in 21% yield with 2/1 dr. The reaction of
styrene with cyclohex-2-enone afforded 3ab in 34% yield with 1/1
dr. While the reaction of styrene with diethyl
2-methylenemalonate did not afford desired product 3ac.
a Conditions A: Ir(ppy)2(dtbbpy)PF6 (2 mol%), MeCN (0.2 M), alkene (0.3
mmol), Michael acceptor (6.0 equiv), TMSN3 (2 equiv), H2O (10 equiv), r.t.,
8 W blue LEDs. b Conditions B: Ir(ppy)2(dtbbpy)PF6 (2 mol%), acetone (0.2
M), alkene (0.3 mmol), Michael acceptor (6.0 equiv), TMSN3 (2 equiv),
MeOH (3 equiv), r.t., 8 W blue LEDs.
The reactions were inhibited in the presence of TEMPO or air
which demonstrated the possibility of radical process (eq. 2 and
3). The reaction of 1a using D2O afforded D-3a in 68% yield with
45% D-incooperation, which indicated that the H2O was the
hydrogen donor (eq. 4). We also carried out the fluorescence
quenching study, and found that the fluorescence of
photocatalyst could be quenched by TMSN3, which was consistent
with our hypothesis (See SI Figure S3.). The reaction of
radical-clock substrate 10 under the standard conditions did not
afford any carboazidation or ring-opening carboazidation
products (eq. 4). Unexpected, a facile azido radical initiated [3+2]
cycloaddition reaction of 10 with acrylonitrile was observed to
deliver a substituted cyclopentane 11 in 92% yield (major isomer/
other minor isomers 1.5/1). The reaction of 10 without TMSN3 did
not occur. To the best of our knowledge, it is a first case of
To demonstrate the synthetic utility, the further
derivatizations have been carried out (Scheme 2). The click
reaction of 3a afforded 6 in 67% yield. The reduction reaction of
3a could afford 7 in 97% yield. The nitrile group could be
hydrolyzed to give 8 in 66% yield, with the recovery of 3a for 25%.
The lactam 9 could be obtained via reduction and cyclization of 8
using 10 mol% Pd/C under one atmosphere of hydrogen in 56%
yield.
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nitrogen
radical-promoted
[3+2]
cycloaddition
of
Conclusions
vinylcyclopropane with alkene. These results also strongly
supported the radical pathway. We proposed that the generated
azido radical could attack carbon-carbon double bond on the VCP
to afford the benzyl radical species (B), which could lead to a
radical ring opening pathway and generate carbon center radical
(C). The radical C could be trapped by acrylonitrile to afford
radical species D which underwent the intramolecular cyclization
to afford E. The deazidination reaction of E could occur to afford
11 and regenerate the azido radical. The control experiments
have been added in SI.
In summary, we reported the first example of visible
light-promoted three-component carboazidation of unactivated
alkenes using TMSN3 and acrylonitrile as reaction partners
without any stoichiometric peroxides. The intramolecular reaction
of 1,6-diene could also undergo smoothly to afford the cyclization
product. The reaction afforded δ-azido alkylnitriles, which could
be readily converted into valuable building blocks for medicinal
chemistry and organic synthesis. A facile azido radical initiated
[3+2] cycloaddition reaction of vinylcyclopropane with
acrylonitrile was observed to deliver a substituted cyclopentane.
The asymmetric alkene difunctionalization is undergoing in our
laboratory.
Scheme 2 Further Derivatizations.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
Corresponding Author
* E-mail: luzhan@zju.edu.cn
Homepage: http://mypage.zju.edu.cn/lu
Author Contributions
† B. Yang and X. Ren are contributed equally to this work.
Acknowledgement
Financial support was provided by NSFC (21472162), the
National Basic Research Program of China (2015CB856600), the
Fundamental Research Funds for the Central Universities of China
(2018QNA3009), “Thousand Youth Talents Plan”, and Zhejiang
University. We were particularly grateful to Professor Bin Su and
Mr. Weiliang Guo in ZJU for their assistant in fluorescence
quenching studies. We were also grateful to Professor Chuande
Wu and Mr. Jijie Ye in ZJU for their assistant in CV studies for
TMSN3.
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Revised manuscript received: XXXX, 2017
Accepted manuscript online: XXXX, 2017
Version of record online: XXXX, 2017
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Entry for the Table of Contents
Page No.
Visible Light-Promoted Three-Component
Carboazidation of Unactivated Alkenes
with TMSN3 and Acrylonitrile
carboazidation; alkenes; visible light photocatalysis; stoichiometric oxidants free;
three-component reaction
Bo Yang, Xiang Ren, Xuzhong Shen,
Tongtong Li, Zhan Lu*,
a Department, Institution, Address 1
c Department, Institution, Address 3
E-mail:
E-mail:
b Department, Institution, Address 2
E-mail:
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