Transition-Metal-Free Three-Component Radical 1,2-Amidoalkynylation of Unactivated Alkenes

Article abstract of DOI:10.1002/chem.201805490

A transition-metal-free radical 1,2-amidoalkynylation of unactivated alkenes is presented. α-Amido-oxy acids were used as amidyl radical precursors, which were oxidized by an organic photoredox catalyst (4CzlPN). The electrophilic N-radicals chemoselectively reacted with various aliphatic alkenes and the adduct radicals were then trapped by ethynylbenziodoxolone (EBX) reagents to eventually provide the amidoalkynylation products. These transformations, which were conducted under practical and mild conditions, showed high functional group tolerance and broad substrate scope. Mechanistic studies supported the radical nature of these cascades.

Full text of DOI:10.1002/chem.201805490

A Journal of
Accepted Article
Title: Transition-Metal-Free Three-Component Radical 1,2-
Amidoalkynylation of Unactivated Alkenes
Authors: Heng Jiang and Armido Studer
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To be cited as: Chem. Eur. J. 10.1002/chem.201805490
Link to VoR: http://dx.doi.org/10.1002/chem.201805490
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Transition-Metal-Free Three-Component Radical 1,2-
Amidoalkynylation of Unactivated Alkenes
Heng Jiang and Armido Studer*
Abstract: A transition-metal-free radical 1,2-amidoalkynylation of
unactivated alkenes is presented. α-Amido-oxy acids are used as
amidyl radical precursors that are oxidized by an organic
photoredox catalyst (4CzlPN). The electrophilic N-radicals
chemoselectively react with various aliphatic alkenes and the
adduct radicals are then trapped by ethynylbenziodoxolones
(EBX) reagents to eventually provide the amidoalkynylation
products. These transformations, which are conducted under
practical and mild conditions, possess high functional group
tolerance and show broad substrate scope. Mechanistic studies
support the radical nature of these cascades.
materials science.[13] Hence, alkene aminoalkynylation by
sequentially introducing the highly valuable amino and alkynyl
groups across a carbon carbon double bond would be an
important
synthetic
transformation.
To date,
alkene
aminoalkynylation is mainly restricted to two-component reactions
comprising an intramolecular amidation with subsequent
intermolecular alkynylation using transition-metal catalysis
(Scheme 1b).[14] To our knowledge, transition-metal-free three-
component 1,2-amidoalkynylation of unactivated alkenes is
unprecedented.[15]
1,2-Difunctionalization of alkenes by sequentially forming two
novel vicinal σ-bonds increases complexity of a compound in a
single operation. Such transformations have gained great
interests in modern organic synthesis.[1] Along these lines, alkene
carboamination is a valuable approach for the preparation of
diverse amines. Transition-metal catalyzed or radical
carboamination of activated alkenes including styrenes,[2] vinyl
amides,[3] vinyl ethers[4] and acrylates[5] have been reported.
Considering unactivated terminal alkenes as substrates, 1,2-
carboamination generating a CC -bond at the terminal position
of the starting alkene has successfully been investigated in recent
years by several groups. Thus, aminocarbonylation,[6]
aminoalkylation,[7] azidofluoroalkylation[8] and aminoarylation[9]
were achieved by applying radical chemistry or by using
transition-metal catalysis. However, considering the reversed
regioselectivity, only a few examples were reported for 2,1-
carboamination of unactivated alkenes installing the CN-bond at
the terminal position of the alkene: In 2017, the Liu group
disclosed a three-component Minisci-type reaction leading to 1,2-
azidoheteroarylation of unactivated alkenes (Scheme 1a, right).[10]
Very recently, the Feng group published a two-component, visible
light initiated radical chain reaction for alkene 2,1-carboimidation
by using an iridium complex as a photosensitizer and O-
vinylhydroxylamine derivatives as both N-radical acceptors and
N-radical precursors (Scheme 1a, left).[11] Engle disclosed elegant
Pd-catalyzed 1,2-imidoarylation of specially designed terminal
alkenes bearing a directing 8-aminoquinoline group (Scheme 1a,
middle).[12]
Scheme 1. Different strategies for 2,1-carboamination of unactivated alkenes.
Herein, we introduce a method for three-component radical
alkene 1,2-difunctionalization by using α-amido-oxy acids as the
amidyl radical precursors[16] and ethynylbenziodoxolones (EBX)
as the alkynylating reagents (Scheme 1c).[17] We assumed that
due to polar effects, an electrophilic amidyl radical will
chemoselectively react with an unactivated alkene leaving the
EBX-reagent untouched, since such I(III)-reagents are known to
react efficiently with nucleophilic C-radicals.[18] Therefore, the
nucleophilic radical adducts thus formed should then
chemoselectively react with the EBX-reagent and telomerization
The carbon carbon triple bond is a highly versatile reactive
functionality in organic synthesis, which has found many
applications as conjugating moiety also in biochemistry and in
[*]
Dr. H. Jiang, Prof. Dr. A. Studer
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität
Corrensstraß 40, 48149 Münster (Germany)
E-mail: studer@uni-muenster.de
Supporting information for this article is given via a link at the end of
the document.
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COMMUNICATION
–
by renewed addition to the alkene acceptor should be
suppressed.[19]
as Eosin Y, Rhodamine B, Fluorescein and Mes-Acr+BF4
provided significantly lower yields (entries 9-12).[22] In control
experiments, product 4ac was not formed in the absence of either
photocatalyst or visible light irradiation (entries 13 and 14).
Table 2. 1,2-Amidoalkynylation of various alkenes.[a],[b]
Table 1. Reaction optimization.
Entry[a]
R1, R2
R3, R4
Photocatalyst
4CzlPN
Yield%[b] (4)
29 (4aa)
1
H, Cbz (1a)
H, Boc (1b)
H, Troc (1c)
H, PhOCO (1d)
H, Bz (1e)
Me, Me
Me, Me
Me, Me
Me, Me
Me, Me
Me, Me
H, Me
2
4CzlPN
35 (4ab)
77, 70[c] (4ac)
n.d. (4ad)
n.d. (4ae)
n.d. (4af)
40 (4ac)
3
4CzlPN
4
4CzlPN
5
4CzlPN
6
Phth (1f)
4CzlPN
7
H, Troc (1g)
H, Troc (1h)
H, Troc (1c)
H, Troc (1c)
H, Troc (1c)
H, Troc (1c)
H, Troc (1c)
H, Troc (1c)
4CzlPN
8
H, H
4CzlPN
11 (4ac)
9
Me, Me
Me, Me
Me, Me
Me, Me
Me, Me
Me, Me
Eosin Y
33 (4ac)
10
11
12
13
14[d]
Rhodamine B
Fluorescein
18 (4ac)
15 (4ac)
+
–
Mes-Acr BF4
7 (4ac)
–
n.d. (4ac)
n.d. (4ac)
4CzlPN
[a] Reaction conditions: A mixture of 1 (0.2 mmol, 1 equiv), 2a (0.6 mmol, 3
equiv), 3a (0.3 mmol, 1.5 equiv), photocatalyst (0.004 mmol, 2 mol%), NaHPO4
(0.2 mmol, 1 equiv) and H2O (20 mmol, 100 equiv) in DMSO (4 mL) was
irradiated by a 5 W blue LEDs at 25 ℃ for 12 h. [b] Isolated yields. [c] 1.0 mmol
reaction scale. [d] Conducted in the dark.
We chose 2-methylpent-1-ene (2a) as the amidyl radical
acceptor and ethynylbenziodoxolone (EBX) reagent 3a as the
alkyl radical acceptor to examine the targeted amidoalkynylation
cascade (Table 1). The organic photoredox catalyst 4CzlPN (see
Scheme 1) was first tested, since it features oxidative ability in its
excited state.[20],[21] We initially varied the N-protecting group of
the starting α-aminooxy-2-propanoic acids 1 in combination with
2a, 3a, 4-CzlPN and Na2HPO4 in the mixed solvent system
consisting of DMSO and H2O. Reagents 1 and 3a were readily
prepared according to literature procedures (see SI).[16a],[18a] Cbz-
protected amino-oxy-acid 1a gave the desired 1,2-
amidoalkynylated product 4aa in encouraging 29% yield after
irradiating the reaction mixture by 5W blue LEDs for 12 h (Table
1, entry 1). With the Boc-protected amino-oxy-acid 1b, the
targeted 4ab was obtained in a slightly improved yield (35%, entry
2). To our delight, Troc-protected amino-oxy-acid 2c provided 4ac
in 77% yield (entry 3, Troc = 2,2,2-trichloroethoxycarbonyl).
Reagents 1d-f bearing other common N-protecting groups such
as the phenyloxycarbonyl (PhOCO), benzoyl (Bz) or phthaloyl
(Phth) group turned out to be ineffective in this transformation
(entries 4-6). Worse results were also noted by successively
replacing the two methyl groups in reagent 1c by H atoms (entries
7 and 8). Other frequently used organic photoredox catalysts such
[a] Reaction conditions: A mixture of 1c (0.2 mmol, 1 equiv), 2 (0.6 mmol, 3
equiv), 3a (0.3 mmol, 1.5 equiv), 4CzlPN (0.004 mmol, 2 mol%), NaHPO4 (0.2
mmol, 1 equiv) and H2O (20 mmol, 100 equiv) in DMSO (4 mL) was irradiated
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by a 5 W blue LEDs at 25 ℃ for 12 h. [b] Isolated yields are provided base on
1c.
[a] Reaction conditions: A mixture of 1c (0.2 mmol, 1 equiv), 2 (0.6 mmol, 3
equiv), 3 (0.3 mmol, 1.5 equiv), 4CzlPN (0.004 mmol, 2 mol%), NaHPO4 (0.2
mmol, 1 equiv) and H2O (20 mmol, 100 equiv) in DMSO (4 mL) was irradiated
by a 5 W blue LEDs at 25 ℃ for 12 h. [b] Isolated yields are provided base on
1c.
To explore reaction scope, various unactivated mono-, di- and
tri-substituted alkenes were tested as substrates under optimized
conditions using reagents 1c and 3a (Table 2). Non-functionalized
1,1-disubstituted alkenes engage in this transformation to give the
desired Troc-protected amines bearing a newly formed all-carbon
quaternary carbon center in high yields (4b-d, 75-87%). The
amidoalkynylation features high functional group tolerance as
various functionalities, such as alcohol (4e), ester (4f,4g), dialkyl
ether (4h), silyl ether (4i), sulfonate (4j), ketone (4k) and imidyl
(4l) groups are compatible with the reaction conditions. The
corresponding products were isolated in good to excellent yields
(68-87%). The internal symmetrical double bond of cyclopentene
and cyclohexene could be amidoalkynylated to give the Troc-
amides 4m and 4n in moderate yields and excellent trans-
diastereoselectivity. We were pleased to find that sterically more
hindered trisubstituted alkenes are eligible substrates providing
the corresponding amides 4o-r in 43-62% yields with complete
regiocontrol. The slightly lower yields in these cases, as
compared to the transformations with terminal disubstituted
alkenes, can be understood considering steric effects, that lower
the rate constant for amidyl radical addition to the alkene.
Although monosubstituted alkenes are less nucleophilic than their
1,1-disubstituted congeners, reasonable yields were achieved for
such systems. Hence, terminal non-functionalized alkyl alkenes
(4s and 4t) and derivatives bearing silyl (4u), chloro (4v), ester
(4w and 4x), keto (4y), alcohol (4z), amino (4ba and 4bb),
diethoxyphosphanyl (4bc) and ether (4bd) groups provided the
corresponding Troc-amides in 43-72% yields. We also examined
the reactivity of electron-rich alkenes such as vinyl ethers and
enamides towards the radical 1,2-amidoalkynylation. As expected,
such nucleophilic alkenes react efficiently and the β-amino
alcohol derivatives 4be-4bg and 1,2-diamino compounds 4bh-4bj
were obtained in moderate to good yields, further enlarging the
scope of this method.
We next examined the scope with respect to the EBX trapping
reagent (Table 3). Arylalkynyl-I(III) compounds bearing both
electron-rich and electron-poor substituents at the aryl group such
as para-substituted Me, t-Bu, Ph, F, Cl, Br, CF3, CN and meta-
substituted OMe were found to be efficient C-radical trapping
reagents and the corresponding Troc-protected amines 5a-i were
isolated in good yields (57-80%). The use of -styryl-
benziodoxolone (3k) introduced by Olofsson and co-workers,[23]
allowed the amidostyrenylation of 1-hexene (5j, 33%). In addition,
amidocyanation of 1-hexene and vinyl butyl ether could also be
accomplished by using cyanobenziodoxolone (3l) to provide 5k
and 5l, albeit in lower yields.
Scheme 2. Mechanistic studies and synthetic applications.
Table 3. Variation of the EBX reagent.[a],[b]
Next, we conducted radical clock experiments to address the
mechanism of the alkene amidoalkynylation. Product 8, resulting
from a typical 5-exo cyclization was obtained from 1,6-diene 6 in
49% yield and high diastereoselectivity, strongly supporting that
radical intermediates are involved in this cascade. The radical
nature of the process was further documented by the
amidoalkynylation of vinylcyclopropane 7, which gave exclusively
the ring opening product 9 in 35% yield. Finally, to document the
potential of the amidoalkynylation, two follow-up transformations
were conducted. Hydrolysis of -alkynyl-amide 4ac gave the
ketone 10 in 90% yield[24] and cyclization of 4ac by using Au
catalysis provided the 2-pyrroline 11 (93%).[25]
The proposed mechanism of the radical alkene 1,2-
amidoalkynylation is presented in Scheme 3. The catalytic cycle
starts by photo-excitation of 4CzlPN upon visible light irradiation
to generate the excited 4CzlPN*, which oxidizes carboxylate A,
formed by deprotonation of substrate 1, to generate the carboxyl
radical B along with the radical anion (4CzlPN) . Sequential
fragmentation of CO2 and acetone from B generates the amidyl
radical C, which then adds to the carbon-carbon double bond in 2
to provide the adduct radical D. EBX reagent 3a traps the C-
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The authors declare no conflict of interest.
radical D to give product 4 with concomitant formation of iodanyl
radical E. Transient radical E is then reduced by the longer lived
[26]
radical anion (4CzlPN)
to give ortho-iodobenzoate F and
Keywords: alkene amidoalkynylation • radical cascades •
amidyl radical • photoredox catalysis • transition-metal-free
4CzlPN, thereby closing the catalytic cycle. Two additional
experiments were conducted to support the suggested
mechanism (for details, see SI). Stern-Volmer quenching
experiments of 4CzlPN with the sodium salt of 1c supported
formation of carboxyl radical B via SET oxidation of A with excited
4CzlPN. Moreover, cyclic voltammetry of A (tetrabutylammonium
salt) revealed an oxidation peak at +1.30 V vs. SCE in acetonitrile,
documenting the feasibility of the SET oxidation of A by photo-
excited 4-CzlPN (+1.35 V vs. SCE in MeCN).
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In summary, we have established a practical method for 1,2-
amidoalkynylation of various unactivated alkenes. By using a
readily available Troc-protected α-aminoxy acid as the amidyl
radical precursor and EBX-type reagents as the alkyl radical
acceptors, various unactivated alkenes including mono-, di- and
tri-substituted alkenes, vinyl ethers, vinyl esters and vinyl amides
are efficiently 1,2-difunctionalized providing diverse -alkynylated
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Acknowledgements
This work was supported by the Alexander von Humboldt
Foundation (postdoctoral fellowship to H. J.). We thank Dr. Ying
Cheng (WWU Münster) and Dr. Anup Bhunia (WWU Münster) for
providing some alkenes. We also thank Max Lübbesmeyer (WWU
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Conflict of Interest
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Layout 2:
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H. Jiang, A. Studer*
Page No. – Page No.
Transition-Metal-Free Three-
Component Radical 1,2-
Amidoalkynylation of Unactivated
Alkenes
Alkynylation and amidation shine up! Transition-metal-free 1,2-
amidoalkynylation of unactivated alkenes has been achieved using a Troc-
protected -aminoxy acid as the amidyl radical precursor and EBX reagents as
alkyl radical acceptors applying photoredox catalysis.
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