Selective 1,2-Aryl-Aminoalkylation of Alkenes Enabled by Metallaphotoredox Catalysis

Article abstract of DOI:10.1002/anie.202006439

A highly chemo- and regioselective intermolecular 1,2-aryl-aminoalkylation of alkenes by photoredox/nickel dual catalysis is described here. This three-component conjunctive cross-coupling is highlighted by its first application of primary alkyl radicals, which were not compatible in previous reports. The readily prepared α-silyl amines could be transferred to α-amino radicals by photo-induced single electron transfer step. The radical addition/cross-coupling cascade reaction proceeds under mild, base-free and redox-neutral conditions with good functional group tolerance, and importantly, provides an efficient and concise method for the synthesis of structurally valuable α-aryl substituted γ-amino acid derivatives motifs.

Full text of DOI:10.1002/anie.202006439

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Accepted Article
Title: Selective 1,2-Aryl-aminoalkylation of Alkenes Enabled by
Metallaphotoredox Catalysis
Authors: Weiming Yuan, Songlin Zheng, Zimin Chen, Yuanyuan Hu,
Xiaoxiang Xi, Zixuan Liao, and Weirong Li
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10.1002/anie.202006439
Angewandte Chemie International Edition
RESEARCH ARTICLE
Selective 1,2-Aryl-aminoalkylation of Alkenes Enabled by
Metallaphotoredox Catalysis
Songlin Zheng, Zimin Chen†, Yuanyuan Hu†, Xiaoxiang Xi, Zixuan Liao, Weirong Li and Weiming
Yuan*
[*]
S. Zheng, Z. Chen†, Y. Hu†, X. Xi, Z. Liao, W. Li and Prof. Dr. W. Yuan
Key Laboratory of Material Chemistry for Energy Conversion and Storage, Ministry of Education, Hubei Key Laboratory of Bioinorganic Chemistry and
Materia Medica, Hubei Key Laboratory of Materials Chemistry and Service Failure, School of Chemistry and Chemical Engineering, Huazhong University of
Science and Technology (HUST), 1037 Luoyu Road, Wuhan 430074, China
E-mail: yuanwm@hust.edu.cn
[†]
These authors contributed equally to this work.
Abstract: A highly chemo- and regioselective intermolecular 1,2-aryl-
aminoalkylation of alkenes by photoredox/nickel dual catalysis is
described here. This three-component conjunctive cross-coupling is
highlighted by its first application of primary alkyl radicals, which are
not compatible in previous reports. The readily prepared α-silyl
amines could be transferred to α-amino radicals by photo-induced
single electron transfer step. The radical addition/cross-coupling
cascade reaction proceeds under mild, base-free and redox-neutral
conditions with good functional group tolerance, and importantly,
provides an efficient and concise method for the synthesis of
structurally valuable α-aryl substituted γ-amino acid derivatives motifs.
Introduction
α-Aryl substituted γ-amino acid derivatives are unique
structural motifs with important biologically actives in antagonists
and pharmaceutical compounds, such as neurokinin 3 receptor
(NK3) antagonist I, HIV-1 therapeutic agent chemokine receptor
CCR5 antagonist II, antihyperalgesic agent mu receptor agonist
Loperamide III as well as antiarrhythmic agent Disobutamide IV,
and so on (Figure 1).[1] The traditional synthetic procedures [1c, 1d,
2] for α-aryl substituted γ-amino acid derivatives relied on multiple
synthetic steps and the usage of either strong oxidants or
reductants or highly reactive organometallic reagents, which
suffered from relatively narrow functional group compatibility and
low atom and step economy. Thus, developing more efficient and
concise protocols towards to them are of high interest.
Figure 1. Representative biologically active compounds containing α-aryl
substituted γ-amino acid derivative motifs.
functionalization of the substrates, thus, avoiding the use of
organometallic reagents. However, these catalytic processes
have to use stoichiometric amount of reductants such as Zn/Mn
powder or organic amines to sustain the catalytic cycles.
Therefore, further developing redox-neutral conjunctive cross-
coupling of alkenes dealing with more general and mild C-
nucleophilies, to broaden the substrate scope and enrich the
structural diversity of the synthetic target molecules are highly
valuable.
From readily simple feedstock chemicals to rapidly buildup
structurally complex and valuable molecules with high atom-,
step- and redox-economy is a longstanding topic in organic
synthesis. Among which, three-component conjunctive cross-
coupling of olefins provides a straightforward way to achieve this
The merger of nickel and visible light photoredox catalysis [7]
could enable common sp3-hybridized C-nucleophilies instead of
goal by simultaneous formation of two C–C bonds in a single step
[3]
highly reactive organometallic reagents to participate the
from easily accessible olefins.
Classically, transition metal
[8]
unprecedented C–C bond formations.
The excited state of
catalysis especially with palladium or nickel-catalyzed conjunctive
cross-coupling of alkenes with a C-nucleophilie and a C-
electrophilie via either two-electron [4] or single-electron [5] transfer
displays a powerful strategy in this context (Scheme 1-a).
Nevertheless, these protocols rely heavily on the use of
stoichiometric organometallic reagents, resulting sore for a variety
of functional groups. Recently, reductive conjunctive cross-
coupling [6] involving two C-electrophilies has been developed as
an alternative method, which did not require any additional pre-
visible light photocatalysts are potent single-electron oxidants,
which can readily undergo reductive quenching via single-
electron-transfer (SET) oxidation of various Csp3-nucleophilies to
the corresponding alkyl radicals. This novel synergistic catalytic
strategy provides a powerful potential to explore three-component
conjunctive cross-coupling of π-bond systems with sp3-hybridized
C-nucleophilies. In this aspect, Chu[9a], Nevado[9b], Molander[9c]
and Aggarwal group[9d] have recently reported elegant examples
of three-component conjunctive cross-coupling of alkenes with
1
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10.1002/anie.202006439
Angewandte Chemie International Edition
RESEARCH ARTICLE
aryl halides and alkyl radical precursors, namely alkyl oxalate
esters, silicates, trifluoroborates and carboxylic acids,
respectively (Scheme 1-b). One distinct feature of this dual
catalytic system is that the regioselectivity is completely reversed
due to the initial step arising from radical addition of C-
nucleophilie site, which is complementary to single metal
catalyzed processes.[4h,5e] Disappointingly, the aforementioned
catalytic systems are restricted to secondary and tertiary alkyl
radicals, while primary alkyl radicals are not compatible due to the
A proposed catalytic cycle is depicted in Scheme 2. Since α-
silyl amines have relatively low oxidative potentials (~0.4–0.8 V
vs SCE in MeCN),[12] which would be facile oxidized by the excited
state photocatalysts (PC*) to give primary α-amino radical A,
radical A rapidly undergo Giese-type addition to generate radical
B, which sequentially intercepted by Ni(0) to form alkyl-Ni(I) Int C,
then go through oxidative addition with Ar–X to produce the key
Ni(III) Int D (path a), followed by facile reductive elimination to get
the conjunctive cross-coupled product and Ni(I) int E, Final SET
overwhelmingly competitive two-component cross-coupling.[8a-b,10] between the reduced state of PC•¯ and Ni(I) int E regenerates the
So far, the sole example with applying primary alkyl radical in
ground-state PC as well as Ni(0) to complete both catalytic cycles.
Alternatively, the Ni(III) Int D could also be formed by the
recombination of radical B to Ni(II) Int F arising from the oxidative
addition of Ar–X with Ni(0) (path b).[13]
conjunctive cross-coupling was reported recently by Aggarwal et.
[9d]
al, however, the yield was pretty low (11%).
Thus, further
endeavors to develop conjunctive cross-coupling reactions with
new varieties of Csp3-nucleophilies as alkyl radical precursors,
especially primary alkyl radicals containing synthetic valuable
functionalities will be highly desired. Herein, we described a
practical three-component conjunctive cross-coupling of alkenes
with primary alkyl radicals derived from α-silyl amines (Scheme
1-c). Indeed, this highly valuable α-amino radical[11] triggered
This process has two major challenges: 1) compared with
secondary or tertiary alkyl radicals, primary alkyl radicals are
much less congested and thus, more reactive to participate the
competitive two-component cross-coupling to delivery undesired
byproduct 5;[14] 2) the thermodynamically favorable SET between
R•/R¯
alkyl radical B (E1/2
≈ –0.6 V vs SCE in CH3CN)[15] and the
cascade process paves
a
facile synthetic way for rapid
reduced state of PC•¯ (the oxidative potential for commonly used
PC•¯ ranges from –0.8 to –2.2 V vs SCE in CH3CN)[7a] facilitates
undesired Giese-type hydroalkylation byproduct 6.[16] Besides,
protodehalogenation of aryl halide under metallaphotoredox
conditions is another obstacle, [9d] which could not be neglected.
We envisioned that our proposed primary α-amino radical
triggered conjunctive cross-coupling of alkenes has a high
possibility to succeed based on the following hypotheses: 1) due
to the perfect polarity-matching-effect, the rate of addition of the
strong nucleophilic α-amino radical A to electron deficient alkene
could be faster than addition of A to Ni-center, this is the key to
avoid formation of the two-component cross-coupling byproduct
5; 2) due to the highly electron-deficient property of radical B, the
rate of addition of B to Ni-center could be faster than single
electron reduction of B by the reduced state photocatalyst (PC•¯)
to suppress the competitive Giese-type reaction.
constructing a fruitful library of α-aryl substituted γ-amino acid
derivatives, which are highly important skeletons in
pharmaceutically active molecules.
Scheme 2. Plausible mechanism.
Results and Discussion
Due to the advantages of low oxidative potentials, simple
synthetic procedure [14] (by a single SN2 reaction between amines
and (chloromethyl)trimethylsilane) as well as tolerating a base-
free condition with α-silyl amines, we chose 1-
((trimethylsilyl)methyl)piperidine 1a (E1/2(1a•+/1a) = +0.71 V vs
Scheme 1. State-of-the-art of redox-neutral difunctionalization of alkenes and
our proposal for primary alkyl radical triggered three-component conjunctive
cross-coupling with alkenes by metallaphotoredox catalysis.
2
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RESEARCH ARTICLE
Table 1. Selected optimization of the reaction conditions. [a]
SCE in CH3CN),[14] as the representative α-amino radical
precursor, and commenced our study with the reaction of benzyl
acrylate 2a and iodobenzene 3a (Table 1). After extensive
optimizations,[17] we were pleased to find that using Ir(ppy)2bpyPF6
Ir(III)/Ir(II)
[18]
(E1/2
*
= +0.91 V vs SCE in CH3CN)
as photocatalyst,
NiCl2•glyme combined with di(OMe)bpy as transition metal
catalyst, the three-component reaction was conducted smoothly
in DMF to get the desired product 4 with the best yield of 79%
(entry 1), the byproducts 5 and 6 were detected as result of the
competitive
two-component
cross-coupling
and
Giese
hydroalkylation, respectively. Ligand screening shown that dtbbpy
resulted in a comparable yield of 4, whereas electron-deficient
di(COOMe)bpy completely retarded the desired reaction (entries
2-3). To our delight, organo photocatalyst 4CzIPN could also be
employed in lieu of Ir-complex and give a wider choice of
photocatalysts selection (entry 4). The molar ratio between the
three reaction components has a big effect on the outcomes:
reducing the molar ratio of 1a and 2a to 1.5 equivalent lead a
significantly decreased yield of 4, and excess amount of 2a and
3a disfavored the conjunctive cross-coupling as well (entries 5-6).
Decreasing the catalyst loading to 0.5 mol% could also get an
acceptable yield (entry 7). Surprisingly, water was found to be well
tolerated in such catalytic process, even with 0.5 mL of H2O (v/v
= 1/1) could still get 20% yield (see SI), this result provides a
possibility to develop biomolecule-compatible neutral aqueous
conditions for future biological applications (entry 8). Finally, a
series of control experiments displayed that photocatalyst, nickel,
ligand and light are all indispensable (entries 9-11).
[a] All reactions were carried out on 0.1 mmol scale, and the optimal ratio of
1a:2a:3a = 2:2:1. [b] The yields were determined by crude 1H NMR spectrum
with 1,3,5-trimethylbenzene as an internal standard.
group (17-19) (e.g. methyl, ethyl, tert-butyl). Prolonged reaction
time did not promote the yield for sterically demanding substrate
(e.g. 19). There was no intramolecular cyclization product formed
when using allyl acrylate as substrate (20), indicating that the rate
of combination of electrophilic α-carbonyl radical with nickel
species is much faster than the intramolecular radical addition
cyclization. Acrylate with a distal N-hydroxyphthalimidyl group
also proceeded smoothly to give 22 with highly enriched
functionality. Those complex acrylates derived from natural
product such as estrone and cholesterol (23-24) were well
tolerated in the three-component conjunctive cross-coupling. It is
noteworthy to mention that among these three examples, alkene
was chosen as the limiting reagent (1.0 equiv.) to further
demonstrate the potential of this methodology in late-stage
modifications. Internal alkene reacted with significantly low yield,
probably due to the steric hindrance effect, but in excellent
diastereoselectivity (21). Besides of acrylates, acrylonitrile was an
alternative good Giese acceptor, some representative α-silyl
amines and aryl iodides were reacted with acrylonitrile smoothly,
delivering the corresponding products (25–30) in good yields. The
outcomes α-aryl-γ-amino substituted nitriles could be readily
transferred to the highly valuable 1,4-diamines, which are
ubiquitous moieties in important biologically active molecules. [20]
To our delight, we further found that the more challenging α, β-
unsaturated ketone and acrylamide substrate could also be
compatible with this dual catalytic conjunctive cross-coupling. For
instance, the reaction of pent-1-en-3-one was carried out
smoothly to obtain 31 in moderate yield. The less electron-
deficient acrylamide delivered the corresponding γ-amino amide
product 32 in 26% yield, and the competitive two-component
cross-coupling byproduct was obtained in 56% yield. However,
vinyl sulfone could not delivery any desired product, instead, a
huge amount of two-component cross-coupling byproduct
obtained (67% NMR yield) and a trace amount of desulfonation
With a set of optimized conditions in hand, we started to
evaluate the generality of this dual catalytic three-component
reaction (Table 2). Both cyclic and acyclic α-silyl amines worked
well to deliver the corresponding α-aryl substituted γ-amino acid
esters in moderate to excellent yields. Especially, the substrates
containing pharmaceutically relevant moieties such as piperidine,
pyrrolidine, morpholine and piperazine, which are among the
most frequent N-heterocyclic functions employed in drugs, were
incorporated smoothly with decent yields (4, 7-10). The reaction
was not only limited to aliphatic α-silyl amines, but also be suitable
for aromatic amines (13-14). α-Silyl secondary amine with a free
NH group was not compatible (15), which made the reaction quite
messy and only a little of radical precursor recovered (18% from
1
crude H NMR spectrum). Besides, less than 10% NMR yield of
Michael addition product detected. We suggested that secondary
amine might be able to form nitrogen radical intermediate via
deprotonation instead of desilylation. [19] We were curious about
the reactivity of α-amino radicals derived from amides as they are
less nucleophilic, for this purpose, Boc-protected amine substrate
was prepared and subjected to the reaction system, to our
surprise, no reaction occurred and almost quantitative starting
material recovered afterward (16). A rational explanation for this
could be that the oxidative potential of carbamate (≈ +1.69 V) was
outside of the reductive potential range of the excited-state of
Ir(ppy)2(bpy)PF6 (+ 0.91 V), leading a failure in SET process to
form α-amino radical properly. This might be the same reason why
the products (the average oxidation potential was ~0.3 V higher
than their α-silyl amine ancestors) were not further oxidized by the
photocatalyst.
Subsequently, we began to explore the applicability of
alkenes (Table 2, middle). Acrylates with different substituents
were investigated and the results shown that the yield linearly
decreased with the increasing of the steric hindrance of the ester
3
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RESEARCH ARTICLE
Table 2. Substrate scope of the dual photoredox/nickel-catalyzed three-component conjunctive cross-coupling reaction. [a]
[a] Unless otherwise stated, all reactions were performed on a 0.3 mmol scale and the yields are isolated yields by column chromatography on silica gel. [b] The
d.r. value was determined by the crude 1H NMR spectrum analysis. [c] The reaction was scaled up to 5.0 mmol scale. [d] The condition of acrylate (0.3 mmol, 1.0
equiv), PhI (0.6 mmol, 2.0 equiv) and 1-((trimethylsilyl)methyl)piperidine (0.6 mmol, 2.0 equiv) was used. [e] Aryl bromide (1.0 equiv) was used. [f] 1H NMR yield as
48 could not be isolated as its pure form. [g] 20 mol% of NiCl2·glyme/diOMebpy was added.
allylic amine observed (less than 5%) (33). Further Attempts to
utilize styrene, vinyl boronic ester as well as vinyl phosphate were
failed (for more details, see SI). To further demonstrate the
synthetic potential, the three-component reaction was scaled up
to a gram scale (5.0 mmol), affording products 17 and 25 without
diminished yield.
Finally, we turned our attentions to exploring the scope with
respect to aryl iodides (Table 2, below). A wide range of both
4
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10.1002/anie.202006439
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RESEARCH ARTICLE
electron-rich and electron-deficient substituted aryl iodides could
be efficiently coupled to deliver the desired products in moderate
to good yields. The reaction is sensitive to steric hindrance as
ortho-methyl substituted iodobenzene resulted in a consistent
decrease in yield (34-36). Aryl iodides incorporated with a variety
of functional groups, including ketone, ester, aldehyde, acetyl
protected hydroxyl and amino, nitrile, fluoride and chloride, were
viable coupling partners under the standard conditions (39-46). In
particular, heterocyclic iodides including unprotected indole and
pyridine did also participate successfully in the three-component
reaction (47-48). When using 4-iodopyridine as the substrate, 20
mol% of catalyst loading was necessary to ease the pyridine
coordination possibility to nickel center. Furthermore, apart from
aryl iodide, aryl bromide could also be suitable to perform the
reaction, albeit with a relatively lower efficiency (39-41, 44). It
should be noted that only a trace amount of protodehalogenation
byproduct was detected in some individual cases (< 5%).
To demonstrate the unique effect of α-silyl amines in this
three-component conjunctive cross-coupling, we further
examined the reactivity of α-amino acid, tertiary amine and α-
amino acid ester, which are commonly used as α-amino radical
precursors. To our surprise, the reaction involving the exact same
α-amino radical intermediate derived from 2-(piperidin-1-yl) acetic
acid hydrochloride could not work at all, and the amino acid
starting material was decomposed completely afterward.
Furthermore, N-(tert-butoxycarbonyl)-L-alanine under the
standard conditions could only afford a trace amount of the
desired product 49 (less than 5% 1H NMR yield), conversely, 40%
yield of two-component coupling product and 35% yield of Giese
hydroalkylation product were detected by the analysis of the crude
1H NMR spectrum. This result is consistent with the finding
reported by Aggarwal et al.[9d] On the other hand, N, N-
dimethylaniline and α-amino acid ester could not give any desired
product 50 or 51, in both cases, most amine starting material
recovered, and only 15% 1H NMR yield of the Giese
hydroalkylation product was detected with N, N-dimethylaniline as
radical precursor (Scheme 3). The inert reactivity of less
nucleophilic α-amino radical was further confirmed by the reaction
of carbamate and ester substrate in Scheme 3-2 and 3-4
(compared with 16 in Table 2). Those control experiments
demonstrated that the subtle characters of α-silyl amines as α-
amino radical precursors for this three-component conjunctive
cross-coupling.
To gain more insight into the mechanism, we synthesized the
ligated Ar–NiII–I complex 52[21] and found that the stoichiometric
reaction of the (o-tolyl)-Ni(II) complex 52 with 1a and methyl
acrylate 2b failed to yield the desired product 36 (Scheme 4-1).
Considering that dtbbpy was not the optimal ligand for this
process, we performed a control experiment with catalytic
NiCl2•glyme and dtbbpy as ligand and isolated 24% yield of 36
expectedly (Scheme 4-2). Moreover, to exclude the possibility of
decomposition of (o-tolyl)-Ni(II) complex, the catalytic efficiency of
(o-tolyl)-Ni(II) complex 52 was further examined by adding
another different aryl iodide and the result shown a good reactivity
(Scheme 4-3). All the above-performed reactions suggested that
Ar–Ni(II) might not be a reactive intermediate for the described
catalytic cycle, in other words, Ni0/NiII/NiIII pathway (path b in
Scheme 2) is rather unlikely. [9a, 21]
Scheme 4. Preliminary experiments on mechanistic study.
Conclusion
In summary, a dual photoredox/nickel-catalyzed conjunctive
cross-coupling of electron-deficient alkenes with α-silyl amines
and aryl halides has been developed. This three-component
reaction displayed very broad substrate scope and good
functional group compatibility. Acrylates, acrylonitrile as well as α,
β-unsaturated ketone and acrylamide were readily incorporated
in this three-component conjunctive cross-coupling. Additionally,
aryl halides including both iodides and bromides were compatible.
This protocol benefits from its good selectivity, mild, base-free and
redox-neutral conditions, and it is further characterized by the
unprecedented tolerance of primary alkyl radicals, which were
reluctant to cooperate in previous reports. The developed
dicarbofunctionalization (DCF) process allows a rapid buildup of
molecular complexity, especially provides an efficient and concise
synthetic way for α-aryl substituted γ-amino acid derivatives.
Further mechanistic studies on explanation of the high reactivity
and selectivity and asymmetric version are currently ongoing in
our laboratory.
Scheme 3. Control experiments of other α-amino radical precursors for this
three-component conjunctive cross-coupling.
5
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10.1002/anie.202006439
Angewandte Chemie International Edition
RESEARCH ARTICLE
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Acknowledgements
We thank Huazhong University of Science and Technology
(startup funding, 3004013135) and Hubei Technological
Innovation Project (2019ACA125) for financial support. We are
also grateful to the Analytical and Testing Centre of HUST for data
characterizing.
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Keywords: metallaphotoredox catalysis
• three-component
reactions • 1,2-dicarbofunctionalization • alkenes • conjunctive
cross-coupling
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RESEARCH ARTICLE
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RESEARCH ARTICLE
Entry for the Table of Contents
A photoredox/nickel dual catalyzed three-component conjunctive cross-coupling of alkenes with α-silyl amines and aryl halides is
reported here. This catalytic process allows for applying primary alkyl radicals in three-component dicarbofunctionalization (DCF) of π-
bond system, and characterized by the mild, base-free and redox-neutral conditions, as well as broad substrate scope and functional
group compatibility. Our developed method provides a fast and efficient way to synthesize structurally valuable α-aryl substituted γ-
amino acid moieties.
8
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