Metal-Free α-C(sp3)-H Aroylation of Amines via a Photoredox Catalytic Radical-Radical Cross-Coupling Process

Article abstract of DOI:10.1021/acs.orglett.1c00226

Here we describe an unprecedented metal-free C(sp3)-H aroylation of amines via visible-light photoredox catalysis, which provides a straightforward route for the construction of a useful α-amino aryl ketone skeleton. Additionally, a number of selected products exhibit good biological activity for protecting PC12 cell damage, which shows that this skeleton has the potential to become a new neuroprotective agent. Finally, a series of mechanism experiments indicate that this transformation undergoes a photoredox catalytic radical-radical cross-coupling pathway.

Full text of DOI:10.1021/acs.orglett.1c00226

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Letter
Metal-Free α‑C(sp3)−H Aroylation of Amines via a Photoredox
Catalytic Radical−Radical Cross-Coupling Process
Guo-Qiang Xu,* Teng-Fei Xiao, Guo-Xuan Feng, Chen Liu, Baoxin Zhang, and Peng-Fei Xu*
Cite This: Org. Lett. 2021, 23, 2846−2852
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ABSTRACT: Here we describe an unprecedented metal-free
C(sp3)−H aroylation of amines via visible-light photoredox
catalysis, which provides a straightforward route for the
construction of a useful α-amino aryl ketone skeleton. Additionally,
a number of selected products exhibit good biological activity for
protecting PC12 cell damage, which shows that this skeleton has
the potential to become a new neuroprotective agent. Finally, a
series of mechanism experiments indicate that this transformation
undergoes a photoredox catalytic radical−radical cross-coupling
pathway.
α-Amino aryl ketones constitute an important structural motif
that widely exists in pharmaceutically active compounds,
clinical drugs, and complex natural products,1 such as
buprobion, amfepramone, and pyrocalerone (Scheme 1a),
and they also serve as a valuable intermediate for the synthesis
of versatile 2-amino alcohols2 and various nitrogen-containing
heterocycles.3 Among the various synthetic methods,4−6 the
catalytic α-amination of aryl ketones provided a promising
approach for the in situ construction of the α-amino aryl
ketone motif via fragment coupling of carbonyl and an amine
substrate.7 However, this approach often requires specific
nitrogen electrophiles or activated aryl ketone derivatives for
the corresponding products. In particular, it is challenging for
all of these methods to access the cyclic α-amino aryl ketone
skeleton (Scheme 1a, right),4−8 which has greatly hampered
the exploration of the biological activity of this skeleton.
To fulfill these unmet needs, organic chemists turned their
attention to the direct acylation of C(sp3)−H bonds in
saturated cyclic amines9 due to the prevalence of these
skeletons in biologically active compounds and auxiliaries in
asymmetric synthesis.10,11 For instance, Doyle and Joe
reported the direct C(sp3)−H acylation of N-aryl amines by
using nickel and photoredox catalysis, providing a straightfor-
ward method for installing a diverse range of aliphatic acyl
groups onto saturated aza-heterocycles under mild conditions
(Scheme 1b).9c However, the most common method for
installing valuable aroyl groups onto saturated aza-heterocycles
is still the α-lithiation of carbamate-protected cyclic amines
(Scheme 1c),12 which suffers from the issue of a very low
temperatures and the use of stoichiometric amounts of strong
bases, such as n-butyl lithium. All of these limitations block the
applications of such transformation to substrates with sensitive
functional groups. Therefore, the development of a mild and
practical method for rapidly constructing biologically valuable
α-amino aryl ketones is still formidably challenging yet highly
Scheme 1. C(sp3)−H Aroylation of Saturated Aza-
Heterocycles
Received: January 21, 2021
Published: March 25, 2021
https://doi.org/10.1021/acs.orglett.1c00226
© 2021 American Chemical Society
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a
desired by synthetic chemists, medicinal chemists, and
pharmaceutical research.
Table 1. Optimization of the Reaction Conditions
Radical−radical cross-coupling reactions are among the
most promising synthetic tools for the rapid construction of
new chemical bonds, which have immense potential to enable
unconventional bond constructions or disconnections.13
However, the selectivity of the cross-coupling of two different
reactive radicals remains an active challenge due to the
unavoidable homocoupling of the involved radical species.
Recently, visible-light-mediated photoredox catalysis has
emerged as a powerful platform to simultaneously generate
two synthetically useful radical intermediates with low
concentration in one redox catalytic cycle under mild
conditions,14−16 which largely eliminates the homocoupling
reactions of either of the two radicals. However, this field
remains in its infancy compared with the classical transition-
metal-catalyzed cross-coupling reaction. In addition, most of
the reported methods still rely heavily on the use of catalysts
containing precious metals like Ru and Ir. Herein we describe
an unprecedented method for the direct cross-coupling of aroyl
radical and α-amino radical by employing an inexpensive
organic photocatalyst (Scheme 1d), which enables the metal-
free α-C(sp3)−H aroylation of saturated aza-heterocycles with
commercially available aroyl chloride.17 There are three critical
points for this protocol: (1) A variety of aroyl groups could be
easily installed onto cyclic and acyclic tertiary amines under
metal-free conditions through this photoredox catalytic
C(sp3)−H functionalization strategy, which is reported for
the first time. (2) The selectivity of the radical−radical cross-
coupling reaction could also be well controlled by organic
photoredox catalysis without the assistance of a transition
metal, which is well proved in this reaction. (3) The biological
experiments show that these α-amino aroyl ketone products
have a good bioactivity for conferring the protection of PC12
cells against oxidative insults, indicating that this newly
constructed skeleton has the potential to be developed into a
new neuroprotective agent.
b
entry
changes from standard conditions
none
Ru(bpy)3(PF6)2 instead of 4CzIPN
Ir(ppy)2(dtbbpy)(PF6) instead of 4CzIPN
no visible light
no 4CzIPN
no EtCO2K
under air
add TEMPO (1.0 equiv)
yield (%)
1
2
3
4
5
6
7
8
86
32
68
0
trace
0
0
0
a
Unless otherwise noted, the reaction was carried out with 1a (0.1
mmol), 2a (0.3 mmol), 4CzIPN (0.5 mol %), and EtCO2K (3.0
equiv) in DCM (2 mL) at 25 °C under a N2 atmosphere for 3 h.
b
Isolated yield.
a
Table 2. Substrate Scope of Aroyl Chlorides
With this speculation in mind, we evaluated the feasibility of
the proposed reaction between N-phenylpyrrolidine (1a) and
benzoyl chloride (2a) as model substrates in the presence of
4CzIPN and NaOAc. After surveying the reaction conditions,
including the photocatalyst, base, reaction temperature, and
rotational speed (see the Supporting Information), we were
pleased to find that the use of 4CzIPN and EtCO2K in
dichloromethane promoted the direct aroylation of C(sp3)−H
in amine at room temperature (25 °C) under a N2 atmosphere
to afford the desired cross-coupling product 3a in 86% yield
(Table 1, entry 1). When organic photocatalyst 4CzIPN was
replaced by the precious metal photocatalyst Ru(bpy)3(PF6)2
or Ir(ppy)2(dtbbpy)(PF6), the yield of the desired product
decreased (Table 1, entries 2 and 3). Control experiments
demonstrated that light, a photocatalyst, and a base were
critical for this transformation (Table 1, entries 4−6). The fact
that no desired C−H aroylation product was detected when
the reaction mixture was open to the air (Table 1, entry 7) or
when TEMPO was added to the reaction mixture (Table 1,
entry 8) demonstrated that this transformation proceeded by a
radical mechanism.
a
Unless otherwise noted, the reaction was carried out with 1a (0.1
mmol), 2 (0.3 mmol), 4CzIPN (0.5 mol %), and EtCO2K (3.0 equiv)
in DCM (2 mL) at 25 °C under a N2 atmosphere for 3 h; isolated
yield.
radical cross-coupling protocol. Pleasingly, the aroyl chlorides
with electron-donating groups were successfully transformed
into the corresponding products in excellent yields (3ab−3ae,
73−97%), and even the electron-withdrawing groups such as
fluoride, chloride, and bromide on the para position of the
benzene ring in aroyl chlorides were well tolerated in good
yields (3af−3ah, 70−79%). To our delight, some biologically
and pharmaceutically relevant functional groups such as
trifluoromethyl- (3ai, 76%; 3an, 82%) and trifluoromethoxy-
(3aj, 61%) substituted aroyl chloride also reacted smoothly. In
addition, both electron-donating groups (3ak, 70%; 3al, 72%;
3ao, 88%) and electron-withdrawing groups (3am, 72%; 3ap,
84%) on the meta and ortho positions of the aroyl chloride
component were compatible. Apart from the single substituted
aroyl chloride partners, the reaction with aroyl substrates
bearing two substituents also smoothly proceeded in good
yield (3aq−3at, 71−89%). More excitingly, other heteroar-
With the optimal conditions established, we examined the
generality and functional group tolerance of the aroyl chloride
component in this novel cross-coupling method. As shown in
Table 2, a variety of aroyl chlorides bearing electron-rich or
electron-deficient substituents were amenable to this radical−
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omatic carbonyl chlorides, such as 2-naphthoyl chlorides, 2-
thiophenecarbonyl chlorides, and 2-furoyl chloride, can also
successfully undergo such a cross-coupling reaction to furnish
the corresponding products in good yields (3au−3aw, 64−
67%). Besides various aroyl chlorides, aliphatic acyl chlorides,
such as propionyl chloride and phenylacetyl chloride, were also
examined in this cross-coupling protocol, and the correspond-
ing products were obtained in moderate yields (3ax, 57%; 3ay,
42%).
80%) owing to the higher stability of this configuration. In
addition, morpholine and piperazine derivatives were found to
be suitable substrates (3ta, 79%; 3ua, 50%). Seven- and eight-
membered and fused cyclic amine substrates afforded α-amino
aryl ketone products in high yields (3va, 81%; 3wa, 50%; 3xa,
78%). Furthermore, the para-methoxyphenyl group, which can
be easily removed under oxidative conditions to unmask the
free amine, was well compatible with this radical−radical cross-
coupling (3da, 64%; 3ya, 71%; 3za, 76%; 3zea, 40% yield). In
addition to various cyclic amines, acyclic aryl amines could also
be smoothly transformed into corresponding C(sp3)−H
aroylation products in good yields (3zaa−3zea, 40−58%).
To demonstrate the potential utilities of this protocol in
organic synthesis, synthetic transformations of the products
were investigated (Scheme 2). Initially, the reaction of 1a and
We then investigated the scope of the tertiary amine
coupling partner (Table 3). A variety of N-aryl pyrrolidines
a
Table 3. Substrate Scope of the Tertiary Arylamines
Scheme 2. Gram-Scale Reaction and Synthetic
Transformations
2a was performed on a 10 mmol scale, offering the desired
C(sp3)−H aroylation product 3aa in 92% yield with 60%
conversion of 1a. Moreover, this versatile scaffold could further
transform into a series of new compounds that were previously
difficult to obtain. For example, cyclic amino alcohol 4 was
successfully achieved with the reduction with NaBH4, and
alkene-bearing cyclic amines 5 also could be easily synthesized
with the Wittig reaction. In addition, cyclic amino alcohol 6
could be attained via the Grignard addition with PhMgBr at 0
°C. In view of the significance of hybrid systems in drug
discovery, the valuable diaryl methane 7 pharmacophore was
constructed on the aromatic amine ring of this scaffold under
metal-free conditions via the direct C(sp2)−H functionaliza-
tion strategy. More importantly, after the removal of the p-
methoxyphenyl (PMP) group, the C(sp3)−H aroylation
product 3zda was converted to phenyl(piperidin-2-yl)-
methanone 8, a critical intermediate for the preparation of
the top-selling pharmaceutical Concerta.18
a
Unless otherwise noted, the reaction was carried out with 1 (0.1
mmol), 2a (0.3 mmol), 4CzIPN (0.5 mol %), and EtCO2K (3.0
equiv) in DCM (2 mL) at 25 °C under a N2 atmosphere for 3 h;
isolated yield.
bearing electron-rich (3ba−3da, 3ha−3ka, 51−75%) or
electron-deficient (3ea−3ga, 58−66%) substituents on the
para, meta, and ortho positions of the aromatic ring were well
tolerated. Aside from the substituents on the benzene ring,
both 1-naphthyl- and 2-naphthyl-substituted cyclic amines
could be smoothly transformed into the corresponding
coupling products with good yields (3la, 47%; 3ma, 53%).
Furthermore, a variety of N-phenylpiperidine derivatives
bearing substituents in saturated nitrogen heterocycles
smoothly delivered the corresponding C−H aroylation
products in moderate to excellent yields, and only one
diastereoisomer was obtained for compounds 3oa−3sa (40−
In view of the wide distribution of the α-amino aryl ketone
scaffold in a variety of marketed pharmaceuticals and bioactive
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molecules, we selected some representative products to test
their cellular activities (Figure 1A). After the cell activity
Scheme 3. Spin-Trapping Experiments
Figure 1. Cytotoxicity screening of some representative products. (A)
Structure of some selected products, (B) cytotoxicity of selected
products for PC12 cells, and protection of tested products against (C)
H2O2- and (D) 6-OHDA-induced PC12 cell damage.
coupling is exhibited in Scheme 4. It is well established that
photoredox catalyst 4CzIPN (I) readily absorbs photons upon
Scheme 4. Proposed Mechanism
screening, the selected aroylation products had no cytotoxicity
toward PC12 cells under different concentrations (Figure 1B).
A further cell model test had proved that most of these
products could effectively prevent the PC12 cell from either
H2O2-induced damage (Figure 1C) or 6-OHDA-induced
damage (Figure 1D). These preliminary results indicate that
the new skeleton constructed by our protocol has the potential
to become a new neuroprotective agent that can treat some
adult neurodegenerative disorders, such as Alzheimer’s disease
(AD), Parkinson’s disease (PD), and amyotrophic lateral
sclerosis (ALS).19
To gain insight into the reaction mechanism, we carried out
a series of preliminary mechanistic studies. On the basis of the
Stern−Volmer luminescence quenching studies of each
component, it was found that only the amine substrate
quenched the excited photocatalyst 4CzIPN*. (See the
Supporting Information.) A significant primary kinetic isotope
effect (kH/kD) was observed with a value of 2.6 (see the
Supporting Information), indicating that the cleavage of the
C(sp3)−H bond was involved in the rate-limiting step of this
redox cross-coupling. When N-methyl-N-phenylmethacryla-
mide 9, a good radical capture reagent, was added to the
reaction mixture, the radical−radical cross-coupling and radical
cyclization products were simultaneously obtained in 21 and
55% yield, respectively (Scheme 3a). Furthermore, when
DMPO, a good spin-trapping reagent, was added to the
reaction mixture, both the aroyl radical and the α-amino
radical were successfully captured to deliver compound 12 and
stable radical species 11, which were detected by electron
paramagnetic resonance (Scheme 3b).20 This result strongly
demonstrated that the two nucleophilic radicals could be
generated effectively and stayed in the system for a reasonable
amount of time under this photoredox catalytic conditions.
Finally, the measured quantum yield of the model reaction was
0.31 (see the Supporting Information), implying that the
alternative chain pathway was not likely to be efficient.21
On the basis of a series of mechanistic experiments, a
detailed proposed mechanism for the radical−radical cross-
visible-light irradiation to generate the oxidation excited state
*4CzIPN (II), [E1/2(*P/P−) = +1.35 V]. *4CzIPN (II) is a
strong oxidant, and upon mixing with amine (1), it can accept
an electron to form the corresponding amine radical cation
(IV). The resultant [4CzIPN]− (III) is a strong reductant and
is capable of undergoing a single-electron transfer to aroyl
chloride (2), generating the aroyl chloride radical anion (VI)
as well as regenerating 4CzIPN (I) and thereby completing the
photoredox catalytic cycle. The bond energy of the C−H bond
adjacent to the nitrogen atom in IV is lowered by ∼40 kcal/
mol, and thus deprotonation by EtCO2K to give an α-amino
radical (V) is viable. In addition, an aroyl radical (VII) is
generated after a chloride anion leaves the aroyl chloride
radical anion (VI). Finally, the desired α-amino aryl ketone
product 3 is formed by the cross-coupling of the α-amino
radical (V) and the aroyl radical (VII).
In summary, the direct C(sp3)−H aroylation of amines via a
metal-free radical−radical cross-coupling strategy was first
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developed by utilizing organic photoredox catalysis. A series of
novel α-amino aryl ketones were rapidly synthesized with this
protocol, and the synthetic application value of this method
was displayed by several transformations. Remarkably, some of
the products could promote the proliferation of nerve cells,
which further showcased the broad applicability of this novel
reaction. Moreover, a series of mechanistic studies demon-
strated that the formidably challenging radical−radical cross-
coupling reaction could be well controlled without using an
expensive and toxic transition-metal at an ambient temper-
ature.
ACKNOWLEDGMENTS
■
We are grateful to the NSFC (21801102, 21632003, and
21871116), The Fundamental Research Funds for the Central
Universities (lzujbky-2019-51, lzujbky-2020-sp07), and the
Natural Science Foundation of Gansu Province
(20JR10RA612).
REFERENCES
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00226.
Materials and methods, experimental procedures, useful
information, optimization studies, 1H NMR spectra, 13
NMR spectra, and MS data (PDF)
C
Accession Codes
CCDC 2045384 (3ae) and 2045383 (3va) contain 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 Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: + 44
1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
■
Guo-Qiang Xu − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, P. R. China;
orcid.org/0000-0002-9683-4581; Email: gqxu@
lzu.edu.cn
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Peng-Fei Xu − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, P. R. China;
orcid.org/0000-0002-5746-758X; Email: xupf@
lzu.edu.cn
Authors
Teng-Fei Xiao − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, P. R. China
Guo-Xuan Feng − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, P. R. China
Chen Liu − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, P. R. China
Baoxin Zhang − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, P. R. China;
orcid.org/0000-0003-2854-6796
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00226
Notes
The authors declare no competing financial interest.
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