Visible-Light Promoted Selective Imination of Unactivated C-H Bonds via Copper-nitrene Intermediates for the Synthesis of 2 H-Azirines

Article abstract of DOI:10.1021/acs.orglett.9b03103

A novel strategy to trap iminyl radicals with copper ions has been developed at room temperature, the resulted high-valent Cu(III) imine intermediate resets quickly to form nitrene and then to furnish a 2H-azirine. This protocol with dual copper/photoredox catalyst enables the selective imination of unactivated C-H bonds under mild conditions with a broader scope. Moreover, this method also uncovers a novel ring-expansion rearrangement from cyclobutyl oxime derivatives to give the α-acylamino cyclopentanones.

Full text of DOI:10.1021/acs.orglett.9b03103

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Visible-Light Promoted Selective Imination of Unactivated C−H
Bonds via Copper-nitrene Intermediates for the Synthesis of
2H‑Azirines
Liyan Feng, Chao Yang, and Wujiong Xia*
State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology (Shenzhen), Shenzhen 518055,
China
S
* Supporting Information
ABSTRACT: A novel strategy to trap iminyl radicals with copper ions has been developed at room temperature, the resulted
high-valent Cu(III) imine intermediate resets quickly to form nitrene and then to furnish a 2H-azirine. This protocol with dual
copper/photoredox catalyst enables the selective imination of unactivated C−H bonds under mild conditions with a broader
scope. Moreover, this method also uncovers a novel ring-expansion rearrangement from cyclobutyl oxime derivatives to give the
α-acylamino cyclopentanones.
ince the smallest aza-cycloalkene was discovered from the
Neber rearrangement reaction, the assembly of 2H-azirines
intramolecular or intermolecular radical addition to π-
systems,7 intramolecular hydrogen atom transfer (HAT),8
and C−C bond activation (Scheme 1A).9 Leonori reported a
direct coupling reaction of aminyl radicals and aryl organo-
metallic reagents through the combination of photoredox and
transition metal catalysis, revealing the reciprocity of iminyl
nitrogen radicals with metallic acceptor.10 Survey of the
literature indicated that the Cu (I)-catalyzed cyclopropanation
through a copper-carbene species and rearrangement of Ir-
nitrene complex furnished the 2H-azirines. Therefore, we
hypothesized that the iminyl radicals formed by photocatalysis
would be captured by Cu(I) species resulting in the high-
valent Cu(III) imine intermediate and will undergo reductive
elimination to afford 2H-azirines similar to the Ir/Ru catalysis
process.5,11
To evaluate the hypothesis, we selected oxime 1a as the
model substrate and fac-Ir(ppy)3 (1 mol %) as the photo-
sensitizer for the initial investigations (Table 1). To our
delight, when the reaction mixture was treated with blue LEDs
at room temperature in the presence of CuBr as cocatalyst and
Cs2CO3 as base in N,N-dimethylformamide (DMF) (0.1 M),
the desired product 2a was obtained in 53% yield (Table 1,
S
has attracted extensive attention for its wide synthetic
application because of the high ring strain and active CN
double bond.1 However, the typical methods including Neber
rearrangement, elimination of aziridine derivatives2 or
hydrazonium salts,3 and pyrolysis or photolysis conversions
of vinyl azides4 suffer from some inherent deficiencies, such as
the limitations of oxime substrates, precarious additions, and
tedious processes for the preparation of hydrazonium salts and
vinyl azides (Figure 1). To circumvent these restrictions, Ir/
Ru-catalyzed decarboxylative synthesis of 2H-azirines from
isoxazol-5(4H)-ones was developed by Ohe and Peters,
respectively (Figure 1).5 However, the conversions are limited
to β-ketoesters, and the method is only suitable for preparation
of 2H-azirines with quaternary carbon at α-position. So, it is
worth exploring a more simplified synthetic tactic with broader
scope and milder reaction conditions for the synthesis of
azirines from oxime derivatives through direct selective
imination of unactivated C−H bonds.
In the past few years, reductive or oxidative single electron
transfer (SET) of O-acyl oximes and O-aryl oximes by
photoredox or transition metal catalysis to form iminyl radicals
and subsequent transformations have been well developed.6
Behavior of these highly reactive nitrogen-centered radicals
could be classified into three categories including the
Received: August 30, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03103
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
b
entry
solvent
base
copper catalyst
yield (%)
1
2
3
DMF
DMA
CH3CN
others
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2HPO4
Na2CO3
others
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr2
Cu(CN)4PF6
others
--
53
66
23
<20
35
30
<20
42
35
<60
0
c
4
5
6
7
d
8
9
10
11
12
e
f
g
CuBr
0
a
The reaction was carried out with 5 W blue LEDs at 0.1 M
b
c
concentration. Isolated yield. Other solvents include tetrahydrofur-
an, toluene, methanol, 1,4-dioxane, dichloromethane, dimethyl
sulfoxide, N-methyl pyrrolidone, and 1,3-dimethyl-2-imidazolidinone.
Figure 1. Approaches to 2H-azirines and synthetic applications.
d
e
Scheme 1. Reactions of Nitrogen-Centered Radicals
Other bases include CsF, CsHCO3, DBU, and 2,6-lutidine. Other
copper salts include CuCl, CuSO4, Cu(CF3SO3)2, CuCN, Cu(OAc)2,
f
g
and CuO. Pd(OAc)2 or Rh2(OAc)4 instead of CuBr. In the absence
of copper or photocatalyst or visible light.
of the method in organic synthesis (2i). Furthermore, the
cyclization to form spirocyclic products (2r−2x) with five- and
six-membered rings containing azirines could be achieved with
good efficiency. Notably, both of the indoline (2p) and ether
(2m) were well tolerated without further oxidation.
The yield of the product (2q) containing the pyrazole group
decreased (32%) probably due to the complexation of pyrazole
with copper catalyst. As for the aromatic moieties, substituents
containing electron-withdrawing (2j, 2k, and 2s), electron-
donating group (2t), halogen (2v, 2w), and vinyl (2u) were all
compatible with the dual catalysts conditions. Finally, a radical
clock was treated with the standard conditions, and the
corresponding product (2y) was obtained in good yield
without ring opening, which might exclude the existence of α-
carbon radicals via 1,3-HAT. Imination of benzylic C−H
bonds successfully delivered product 2z in 70% yield as a single
regioisomer.
Derivatives containing cyclobutyl substituents underwent an
intriguing rearrangement with the system, giving the α-amino
cyclopentanone product instead of spirocyclic azirine (Scheme
3). The structure of 4a was further confirmed by the X-ray
crystallographic analysis. We next sought to investigate the
scope of such a unique rearrangement. Derivatives with halide
substitutes at para-, meta-, and ortho-sites of the phenyl ring
did not interrupt the ring expansion reaction (4b−4d).
Electronically distinct substituted aromatic moieties with
electron-donating (4e−4g), electron-withdrawing (4h, 4i),
and naphthyl (4j) groups were also tolerated well to afford the
corresponding products in good yields. In relation to
heteroaromatic substrates, e.g., furan-, thiophene-, and
pyridine-derived oxime derivatives were converted readily in
good efficiency (4k−4n). The cyclobutanes substituted by a
methyl group at the γ-position were found to transfer smoothly
entry 1). The reaction conditions were optimized by varying
several parameters including solvents, bases, and cocatalysts.
The results indicated that N,N-dimethylacetamide (DMA) was
the ideal solvent (Table 1, entries 1−4), Cs2CO3 was the best
base (Table 1, entries 2, 5−7), and CuBr was the suitable
cocatalyst (Table 1, entries 8−10). Other transition metals like
Pd(OAc)2 and Rh2(OAc)4 did not catalyze the reaction (Table
1, entry 11). No desired product 2a was obtained when the
reaction was conducted in the absence of either copper,
photocatalyst, or light.
Under the optimized conditions, scope of the aromatic
oxime derivatives derived from aromatic ketones without active
groups was investigated (Scheme 2). Generally, the aliphatic
moieties with tertiary carbons (2e−2m) to form C−N bond
outperformed secondary carbons (2a−2d) under standard
conditions. It was worth noticing that alkenes (2d, 2g)
including terpene (2h) were tolerated well to give excellent
yields of the product (up to 82%), which demonstrated the
potential application of the strategy in synthesis of complex
compounds through inter/intramolecular cyclization reac-
tions.12 The good yields of the reaction performed at both
microscale and gram scale identified the potential application
B
DOI: 10.1021/acs.orglett.9b03103
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
a b
,
Scheme 2. Scope of the Reaction
Scheme 3. Scope of Ring-Expansion Rearrangement
a
Reaction conditions: 1 (0.2 mmol), fac-Ir(ppy)3 (1 mol %), CuBr
(20 mol %), DMA (2 mL), and Cs2CO3 (1.5 equiv) under argon at
b
room temperature with 5 W blue LEDs for 10 h. Isolated yields.
c
The reaction was performed at 3 mmol-scale and irradiated by 5 W
blue LEDs at room temperature for 24 h.
to the corresponding product (4o). We took advantage of
a
these substances as models to demonstrate the competitive
Reaction conditions: 3 (0.3 mmol), fac-Ir(ppy)3 (1 mol %), CuBr
−
(20 mol %), DMA (3 mL), and Cs2CO3 (1.5 equiv) under argon at
reaction of p-CF3C6H4CO2 with other acids. Aromatic acid
b
room temperature with 5 W blue LEDs for 10 h. Isolated yields.
gave moderate yields of the products 4p and 4q with very low
yield of 4o (<10%). The yield of 4r was poor when aliphatic
acid was added instead. To our surprise, the C−O ether bond
fragmentation product 4t was found under the same conditions
when we installed a phenolic hydroxyl group at cyclobutane’s
C3 position (3t), giving us a view of this novel ring-expansion-
rearrangement reaction, and the mechanism study would
continue in our laboratory.
We next turned our attention to investigate the mechanism
of the dual copper/photoredox platform. The product 2q
(Scheme 2) revealed an alternative pathway to 1,3-HAT
inconsistent with Lei and Wei’s works.13 Furthermore,
operating the identical reaction with additional styrene or
phenylacetylene made no significant difference in the yield of
2a. The racemic product 2e from oxime with high ee value
(85% ee) supported the intermediacy of nitrene complex
(Scheme 4A). A radical inhibition experiment in the presence
of TEMPO indicated the involvement of nitrogen-centered
radicals (Scheme 4B). However, the Stem−Volmer fluores-
cence quenching experiments further demonstrated the
synergistic effect of dual copper and fac-Ir(ppy)3 containing
a SET pathway and Cu(I) to Cu(III) cycle (Supporting
Information).14
c
The reaction was performed with corresponding acid (3 equiv)
instead of 5a and Cs2CO3 (3.0 equiv).
To gain some more insights into the reaction pathway of
ring-expansion, we treated another iminyl radical precursor 1a′
with the standard conditions, but no corresponding product
was observed (Scheme 4C), which suggested the existence of
an active copper species, p-CF3C6H4CO2Cu that might really
promote the rearrangement.
Based upon the above experiments, a plausible reaction
pathway for dual copper/photoredox cycles was illustrated in
Scheme 5. The O-benzoyl ketoxime was reduced by visible-
light excited *IrIII to release the nitrogen-centered radical 1′,
which was trapped by Cu(I) instead of 1,5-HAT (for 1a). The
intermediate II was then oxidized by IrIV species to forge III
and completed the photocatalytic cycle in the meantime. The
active high-valence copper imine complex was isomerized to
form the nitrene complex IV in the presence of base. The
isomer IV′ underwent reductive elimination to furnish product
2 and the copper cycle.5
The α-acylamino ketone was reported as a new class of
ecdysone agonists of which, with a cyclohexane, had a superior
C
DOI: 10.1021/acs.orglett.9b03103
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
In conclusion, we have developed a novel selective imination
of unactivated C−H bond enabled by dual copper and
photoredox catalysis. The method allows the preparation of
2H-azirines without conventional blemishes and direct syn-
thesis of α,α-aryl-acylamino cyclopentanone under mild
conditions. The simple transfer of the products to useful
molecules presents the potential value of the method in
organic synthesis and medicinal chemistry. Meanwhile, the
capture of iminyl radicals by copper to afford nitrene species
would offer a new pathway for C−N coupling and cyclization
reactions.
Scheme 4. Control Experiments
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03103.
1
Experimental details, characterization data, H, 19F, and
13C NMR spectra, and X-ray structure of 4a (PDF)
Scheme 5. Plausible Mechanism
Accession Codes
CCDC 1936471 contains 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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: xiawj@hit.edu.cn.
ORCID
Liyan Feng: 0000-0003-0001-9062
Wujiong Xia: 0000-0001-9396-9520
Notes
The authors declare no competing financial interest.
potency,15 but these ring containing α-acylamino ketones were
hard to prepare due to the low yields of synthetic steps or
expensive initial materials. Finally, to demonstrate the
advantages and potential synthetic application value of our
protocol, α-acylamino ketone 6 was prepared through further
transformation of 1r by simple synthetic steps in 42% total
yield (Scheme 6).
ACKNOWLEDGMENTS
■
We are grateful for the financial support from the National
Natural Science Foundation of China (No. 21672047), State
Key Laboratory of Urban Water Resource and Environment
(No. 2018DX02), and The Science and Technology Plan of
Shenzhen (JCYJ20180306171926120).
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Scheme 6. Synthetic Application
■
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