Merging Photoredox/Nickel Catalysis for Cross-Electrophile Coupling of Aziridines with Pyridin-1-ium Salts via Dearomatization

Article abstract of DOI:10.1021/acs.orglett.1c01077

Merging photoredox/nickel catalysis enabling the cross-electrophile coupling of aziridines with pyridin-1-ium salts involving dearomatization for the synthesis of β-(1,4-dihydropyridin-4-yl)-ethylamines, especially including bioactive motif-based analogue

Full text of DOI:10.1021/acs.orglett.1c01077

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Merging Photoredox/Nickel Catalysis for Cross-Electrophile
Coupling of Aziridines with Pyridin-1-ium Salts via Dearomatization
Chong-Hui Xu, Jin-Heng Li,* Jian-Nan Xiang, and Wei Deng*
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ABSTRACT: Merging photoredox/nickel catalysis enabling the cross-electrophile coupling of aziridines with pyridin-1-ium salts
involving dearomatization for the synthesis of β-(1,4-dihydropyridin-4-yl)-ethylamines, especially including bioactive motif-based
analogues, is described. This method allows incorporation of a 1,4-dihydropyridin-4-yl group and formation a N−H amino group to
construct highly valuable β-(1,4-dihydropyridin-4-yl)-ethylamine frameworks in a single step through the C2−N bond regioselective
cleavage and dearomatization alkylation cascades with precise regioselectivity and excellent functional group tolerance, and
represents an appealing cross-electrophile coupling strategy to accomplish transformations between two electrophiles, including
aziridines and pyridin-1-ium salts, by avoiding prefunctionalization.
he cross-coupling reaction has been well-recognized as
proceeded via the classical oxidative insertion, transmetalation
Tone of the most powerful cornerstones in synthesis for and reductive elimination process, and its success and
the facile and modular formation of C−C bonds.1 Not
selectivity control both rely on the Pd catalyst and the
combined additives of a catalytic base, a sterically demanding
triarylphosphine ligand and a phenol additive. Subsequently,
the similar strategy has been expanded to various organo-
metallic reagents, including organoboron, organozinc, (pin)2B2
and (pin)BSiMe2Ph, for allowing the ring opening/cross-
coupling of aziridines using the palladium or nickel catalysis.5
Recently, Xiao, Chen, and co-workers developed a visible light
photoredox/nickel-cocatalyzed cross-coupling of 2-arylaziri-
dines with potassium benzyltrifluoroborates involving a radical
process to prepare β-substituted amines through the C2−N
bond cleavage and the C(sp3)−C(sp3) bond formation
(Scheme 1A-a).5e Alternatively, Sigman, Doyle and co-workers
have illustrated a conceptually novel strategy based on the Ni-
catalyzed reductive cross-electrophile coupling of styrenyl
aziridines with aryl iodides through selective cleavage of the
C2−N bonds, enabling the formation of highly enantioen-
riched 2-arylphenethylamines (Scheme 1A-b).6a Very recently,
they developed a photoredox reductive quenching cycle
strategy to realize cross-electrophile coupling of aliphatic
aziridines with aryl iodides based on the photoredox and nickel
surprisingly, the cross-coupling reaction has been thoroughly
explored and led to wide applications in pharmaceutical and
functional material synthesis since its discovery in 1960s.2
Despite the remarkable progress, a key challenge is that the
ability to precisely control its selectivity for accessing the
resulting adducts containing highly reactive functional groups
(e.g., N−H free amino groups) still remains unconquered,
thereby limiting its broad synthetic applications to some
extent. Thus, the development of new strategies to
revolutionize the classical cross-coupling technology for the
facile preparation of the highly reactive functional group-based
molecules remains highly desirable.
To address the aforementioned issues, new typical function-
alized electrophilic reagents (e.g., aziridines)3−7 beyond the
conventional organohalides have been devised to establish new
efficiently versatile ring opening/cross-coupling methods as
appealing alternatives to the classical cross-coupling reaction1
in the past decades for directly and regioselectively forging
complex molecules accompanying the formation of highly
reactive functional groups (e.g., β-substituted amines).
However, such ring opening/cross-coupling approaches are
comparatively underdeveloped, with the vast majority of which
confined to limited nucleophilic reaction partners.5 The first
method for the cross-coupling of unsubstituted and 2-alkyl-
substituted aziridines with arylboronic acids using Pd catalysis
leading to the regioselective formation of β-aryl alkylamines
has been reported by Michael and co-workers.5a This method
Received: March 29, 2021
Published: April 7, 2021
https://doi.org/10.1021/acs.orglett.1c01077
© 2021 American Chemical Society
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a
Scheme 1. Cross Coupling of Aziridines
Table 1. Optimization of Reaction Conditions
entry
standard reaction conditions
yield (%)
1
2
none
70
0
without Ru(bpy)3Cl2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Ru(bpy)3(PF6)2 instead of Ru(bpy)3Cl2
[Ir(ppy)2(dtbbpy)]PF6 instead of Ru(bpy)3Cl2
NaI/PPh3 instead of Ru(bpy)3Cl2
Eosin Y instead of Ru(bpy)3Cl2
without blue LEDs light (in dark)
white light instead of blue LEDs light
without NiBr2·DME
NiBr2 instead of NiBr2·DME
NiCl2 instead of NiBr2·DME
without L1
L2 instead of L1
L3 instead of L1
L4 instead of L1
without Et3N
Na2HPO4 or Na2CO3 instead of Et3N
MeCONMe2 instead of MeCONMe2/MeCN
MeCN instead of MeCONMe2/MeCN
none
63
50
57
15
0
<5
trace
10
<5
trace
30
40
trace
trace
trace
43
cooperative catalysis, affording β-phenethylamine derivatives
via the C3−N bond cleavage (Scheme 1A-c).6b However, the
utilities of these protocols all are limited because of the
requirement of prefunctionalized reaction partners (e.g.,
organometallics, aryl iodides). Although the transition-metal-
catalyzed aryl C(sp2)−H coupling of aziridines with function-
alized arenes (e.g., 2-arylpyridines, aromatic acids) has been
developed in recent years,7 the directing groups are pivotal to
enable the success of the reaction.
We envisioned that direct use of electrophilic arenes, such as
pyridin-1-ium salts,8 to replace the common aryl halide
derivatives, would establish new cross-electrophile coupling
methods to allow transformations of aziridines. Herein, we
report a new visible light photoredox/nickel-cocatalyzed cross-
electrophile coupling of aziridines with pyridin-1-ium salts for
producing β-(1,4-dihydropyridin-4-yl)-ethylamines. By means
of the photoredox reductive quenching cycle strategy, a variety
of aziridines undergo the C2−N bond cleavage and
dearomatization alkylation cascades with pyridin-1-ium salts
to enable the formation of C(sp3)−C(sp3) bonds, which has a
different regioselectivity from the precedent work reported by
the Doyle group. Notably, the resulting products, especially β-
aryl ethylamines, are important structural units in natural
products and pharmaceuticals,9 as well as consist of the
unsaturated 1,4-dihydropyridin-4-yl group and the highly
reactive amino group which provide the potential to build
and modify pharmaceutically important molecule derivatives.8
We initially conducted the ring opening reaction using 2-(p-
tolyl)-1-tosylaziridine 1a and 1-cyclohexyl-2,4,6- triphenyl-
pyridin-1-ium tetrafluoroborate 2a as the model substrates
for optimization of reaction conditions (Table 1). We found
that the reaction of aziridine 1a and pyridin-1-ium 2a afforded
the desired product 3aa in a satisfactory yield (70%) in the
presence of Ru(bpy)3Cl2 (1 mol %), NiBr2·DME (5 mol %),
2,6-di(1H-pyrazol-1-yl)pyridine L1 (10 mol %) and Et3N (2
equiv) in anhydrous MeCONMe2/MeCN (1:4; 2 mL) at
room temperature for 12 h (entry 1). Further screening
showed that the cooperative catalytic system, including
Ru(bpy)3Cl2, NiBr2·DME, 2,6-di(1H-pyrazol-1-yl)pyridine L1
and Et3N (2 equiv), were crucial for the success of this reaction
because omission of each one resulted in no reaction (entries
2, 7, 9, 12, and 16). Other photocatalysts, such as
Ru(bpy)3PF6, [Ir(ppy)2(dtbbpy)]PF6, NaI/PPh3 and Eosin
Y, showed reactivity, but they all were less efficient than
Ru(bpy)3Cl2 (entries 2−6). The reaction is sensitive to blue
light as white light had no effect (entry 8). Using NiBr2 and
NiCl2 instead of NiBr2·DME resulted in lower yields (entries
55
62
b
20
a
Standard reaction conditions: 1a (0.2 mmol), 2a (1.2 equiv),
Ru(bpy)3Cl2 (1 mol %), NiBr2·DME (5 mol %), L1 (10 mol %), Et3N
(2 equiv), anhydrous MeCONMe2/MeCN (1:4; 2 mL), room
temperature, and 12 h. 1a (1 mmol) and 24 h.
b
10−11). Substituted bipyridine ligands L2 and L3 are highly
reactive (entries 12−13), but bipyridine L4 as ligand was inert
(entry 15). Notably, other inorganic bases, including Na2HPO4
and Na2CO3, completely inhibited the reaction, suggesting that
Et3N may serve as a single electron transfer reagent to effect
the reaction. Using MeCONMe2 or MeCN as the medium led
to less efficiency than a mixed MeCONMe2/MeCN solvent
(entries 18−19). Gratifyingly, the reaction was consistent with
the loading of 1a up to 1 mmol, giving 3aa in good yield (entry
20).
With the optimized reaction conditions in hand, we set out
to explore the substrate scope of this ring opening protocol
using various aziridines 1 and pyridin-1-ium tetrafluoroborates
2 (Scheme 2). Initially, we evaluated the substitution effect on
2 position of 1-tosylaziridine 1 in the presence of pyridin-1-ium
salt 1a, Ru(bpy)3Cl2, NiBr2·DME, L1 and NEt3 (2 equiv)
under blue LEDs light (3ba−3wa). The results showed that an
aryl group presented at 2 position was crucial for making the
reaction successful (3ba−3ua, 3wa−3ya) since an alkyl group
led to no reactivity (3va). Moreover, a wide range of
t
substituents, including bulking Bu, MeO, Ph, Br, Cl, F, CF3,
and CO2Et, on the 2-aryl ring were well tolerated, and the
electronic and steric hindrance effects both affected the
reaction (reactive order: electron-donating group > electron-
withdrawing, para > meta > ortho; 3ba−3ma). The use of
aziridine 1c bearing a electron-donating p-MeO group afforded
3ca in 72% yield, whereas aziridines 1h−i possessing an
electron-withdrawing p-CF3 or CO2Et group resulted in the
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to good yields (3na−pa). The introduction of two or three
substituents on the 2-aryl ring were also highly reactive (3qa−
ta; 69−75% yield). For 1,2,3-trisubstituted aziridines 1v−x the
reaction successfully executed to deliver 3wa−xa in moderate
yields. Strikingly, the method could be used to ring opening of
vinyl-containing aziridines 1u and 1y, affording the corre-
sponding products 3ua and 3ya in which the CC bond
remained untouched.
Scheme 2. Variations of the Aziridines (1) and Pyridin-1-
ium Tetrafluoroborates (2)
a
The scope of pyridin-1-ium tetrafluoroborates 2 was
subsequently investigated under the optimized conditions
(3ab−ak). We found that a number of pyridin-1-ium salts
bearing a substituent, including c-butyl 2b, c-pentyl 2c, N-Boc
piperidin-4-yl 2d, n-butyl 2e, and phenyl 2f, on the nitrogen
atom successfully provided the corresponding products 3ab−
af. Notably, our method could be applicable to the
construction of the bioactive molecules,10 such as dehydroa-
bietylamine derivative 3ai,10a tryptamine derivative 3aj,10b and
rizatriptan derivative 3ak.10c Use of 2,4,6-tri(p-toly)-pyridin-1-
ium tetrafluoroborate 2g or 2,6-di(p-toly)-4-(p-chlorophenyl)-
pyridin-1-ium tetrafluoroborate 2h also delivered ring opening
products 3ag−ah in moderate yields.
The control experiments showed that the cross-electrophile
coupling reaction was completely inhibited when using a
radical scavenger, such as TEMPO and 2,6-di-tert-butyl- 4-
methylphenol (BHT) (eq 1; Scheme 3). The results suggest
that the reaction includes a radical process.
Scheme 3. Control Experiments and Possible Reaction
Mechanisms
The possible mechanism for this cross-electrophile coupling
protocol was proposed on the basis of the current results and
the precedent literatures (Scheme 3).5−7 Initially, coordination
of the NiIIBr2·DME species with a ligand L1 affords the
reactive Ni0 species, which then undergoes the regioselective
oxidative insertion of the C2−N bond of aziridine 1 to give the
NiII intermediate A,5 attributing to the electronic and steric
hindrance effect of the ligand and substrates. Reaction of the
intermediate A with the 1,4-dihydropyridin-4-yl radical D,8e
which is generated from the reaction between pyridin-1-ium
salt 2 and the radical cation of NEt3 via a single electron
transfer (SET) process,5e,6 delivers the NiIII intermediate B.
Reductive elimination of the intermediate B results in the
formation of the NiI intermediate C. Finally, SET reduction of
the intermediate C by the reduced species Ru(I) affords
a
Reaction conditions: 1 (0.2 mmol), 2 (1.2 equiv), Ru(bpy)3Cl2 (1
mol %), NiBr2·DME (5 mol %), L1 (10 mol %), Et3N (2 equiv),
anhydrous MeCONMe2/MeCN (1:4; 2 mL), room temperature, and
12 h. The diastereoselectivity (dr value given in the parentheses) was
determined by H NMR and HPLC analysis.
b
1
formation of 3ha−ia, respectively, in decreasing yields (40−
42%). The reaction was compatible with aziridines 1f, 1k, 1m
bearing a Cl group at para, meta, or ortho position, which
afforded the corresponding products 3fa, 3ka, 3ma,
respectively, in 64%, 58%, and 47% yields. The reaction with
aziridines 1n−p containing a phenyl, a naphthalen-2-yl or a
benzofuran-2-yl at 2 position proceeded efficiently in moderate
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Metal-Catalyzed Cross-Coupling Reactions; Wiley-VCH: Weinhein,
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product 3 and regenerates the active Ni(0) species/the Ru(II)
photocatalyst.
In summary, we have developed a new method to access β-
(1,4-dihydropyridin-4-yl)-ethylamines via a photoredox/nick-
el-cocatalyzed cross-electrophile coupling of aziridines with
pyridin-1-ium salts through dearomatization. This method
features broad substrate scope of aziridines (e.g., 2-aryl
aziridines, 2-vinyl aziridines, 2,3-disubstituted aziridines) and
pyridin-1-ium salts. Moreover, this method allows the synthesis
of highly valuable β-aryl-β-(1,4-dihydro-pyridin-4-yl)-ethyl-
amine building blocks and bioactive molecule-based analogues
from readily available starting materials, which illustrates
promising potential application areas in natural product and
drug synthesis.
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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.1c01077.
Experimental procedures, characterization of all com-
pounds, NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Jin-Heng Li − State Key Laboratory of Chemo/Biosensing and
Chemometrics, Hunan University, Changsha 410082, China;
Key Laboratory of Jiangxi Province for Persistent Pollutants
Control and Resources Recycle, Nanchang Hangkong
University, Nanchang 330063, China; State Key Laboratory
of Applied Organic Chemistry, Lanzhou University, Lanzhou
730000, China; orcid.org/0000-0001-7215-7152;
Email: jhli@hnu.edu.cn
(3) (a) Huang, C. Y.; Doyle, A. G. The Chemistry of Transition
Metals with Three-Membered Ring Heterocycles. Chem. Rev. 2014,
114, 8153−8198. (b) Takeda, Y.; Sameera, W. M. C.; Minakata, S.
Palladium-Catalyzed Regioselective and Stereospecific Ring-Opening
Cross-Coupling of Aziridines: Experimental and Computational
Studies. Acc. Chem. Res. 2020, 53, 1686−1702.
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with nucleophiles using Lewis acid or Lewis base catalysis, see:
(a) Yudin, A. K. Aziridines and Epoxides in Organic Synthesis; Wiley-
VCH: Weinheim, 2006. (b) Hu, X. E. Nucleophilic Ring Opening of
Wei Deng − State Key Laboratory of Chemo/Biosensing and
Chemometrics, Hunan University, Changsha 410082, China;
Email: weideng@hnu.edu.cn
Authors
́
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Zhang, W.-X.; Xi, Z. Transition-Metal-Catalyzed Cleavage of C-N
Single Bonds. Chem. Rev. 2015, 115, 12045−12090.
Chong-Hui Xu − State Key Laboratory of Chemo/Biosensing
and Chemometrics, Hunan University, Changsha 410082,
China; Key Laboratory of Jiangxi Province for Persistent
Pollutants Control and Resources Recycle, Nanchang
Hangkong University, Nanchang 330063, China
Jian-Nan Xiang − State Key Laboratory of Chemo/Biosensing
and Chemometrics, Hunan University, Changsha 410082,
China
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Coupling of N-Sulfonylaziridines with Boronic Acids. J. Am. Chem.
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Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Nos. 21625203 and 21871126), and the Jiangxi Province
Science and Technology Project (No. 20182BCB22007) for
financial support.
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