Radical Aza-Cyclization of α-Imino-oxy Acids for Synthesis of Alkene-Containing N-Heterocycles via Dual Cobaloxime and Photoredox Catalysis

Article abstract of DOI:10.1021/acs.orglett.0c00224

Nitrogen-containing heterocycles are prevalent in both naturally and synthetically bioactive molecules. We report herein an unprecedented protocol for radical aza-cyclization of α-imino-oxy acids with pendant alkenes via synergistic photoredox and cobaloxime catalysis. With or without alkenes as the intermolecular cross-coupling partners, the transformation provides a variety of corresponding alkene-containing dihydropyrrole products in satisfactory yields. In the presence of external alkenes, the tandem reaction generates E-selective coupling products with excellent chemo- and stereoselectivity.

Full text of DOI:10.1021/acs.orglett.0c00224

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Letter
Radical Aza-Cyclization of α‑Imino-oxy Acids for Synthesis of
Alkene-Containing N‑Heterocycles via Dual Cobaloxime and
Photoredox Catalysis
Jia-Lin Tu, Jia-Li Liu, Wan Tang, Ma Su, and Feng Liu*
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ABSTRACT: Nitrogen-containing heterocycles are prevalent in both naturally and synthetically bioactive molecules. We report
herein an unprecedented protocol for radical aza-cyclization of α-imino-oxy acids with pendant alkenes via synergistic photoredox
and cobaloxime catalysis. With or without alkenes as the intermolecular cross-coupling partners, the transformation provides a
variety of corresponding alkene-containing dihydropyrrole products in satisfactory yields. In the presence of external alkenes, the
tandem reaction generates E-selective coupling products with excellent chemo- and stereoselectivity.
Scheme 1. Aza-Cyclization of Oxime Derivatives for
Synthesis of Alkene-Containing N-Heterocycles
xidative decarboxylation of carboxylic acids to generate
Ocarbon-centered radicals is a burgeoning area in organic
synthesis.1−3 In these pioneering studies, Li,1 MacMillan,2 and
others3 have demonstrated that Ag and photoredox catalysis
could be effective methods to enable radical transformations.
Furthermore, Studer and Leonori showcased that the photo-
redox decarboxylation of α-imino-oxy acids could readily give
iminyl radicals,4,5 thus allowing access to N-heterocycles by
radical cyclization. On the other hand, the Heck-type reaction
via cobalt-catalyzed radical-olefin coupling was recognized as
an effective and green method for synthesis of alkene
derivatives.6−8 One of the key breakthroughs in this field can
be traced to a report by Wu who achieved decarboxylative
Heck-type coupling of aliphatic acids and terminal alkenes
through the synergistic combination of photoredox and
cobaloxime catalysis.7 In a parallel report, Ritter demonstrated
a similar photoinduced protocol for olefin synthesis.8
Heck-type cyclization of nitrogen electrophiles via palladium
catalysis is a powerful strategy for synthesis of nitrogen-
containing heterocycles,9,10 which are ubiquitous motifs in
both naturally and synthetically bioactive compounds.11 The
Pd-catalyzed cyclization of oxime esters with pendant alkenes
was first developed by Narasaka and co-workers, providing a
direct method for the synthesis of substituted pyrroles
(Scheme 1a).12 Following this seminal work, the access to
other heterocyclic/aromatic species with other types of oxime
esters was further achieved.13 Recently, Bower reported the
cyclization of γ,δ-unsaturated oxime esters via an oxidative
addition or a radical process for the construction of C(sp3)−N
Received: January 16, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00224
© XXXX American Chemical Society
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A

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a b
,
a b
,
Scheme 2. Scope of the α-Imino-oxy Acids
Scheme 3. Variations of the Pendant Alkenes
a
Reaction conditions: 1 (0.20 mmol), Mes-Acr+ (5 mol %),
Co(dmgH)2Cl2 (10 mol %), and KOH (0.20 mmol) in HFPI (2
mL, used without dehydration), 35 °C, household blue LEDs (22 W),
b
72 h. Isolated yield. E/Z and diastereoselectivity (dr) ratios
c
1
determined by the crude H NMR spectra. Toluene/HFIP (1:1, 2
mL) used as cosolvent.
Scheme 4. Proposed Mechanism
a
Reaction conditions: 1 (0.20 mmol), Mes-Acr+ (5 mol %),
Co(dmgH)2Cl2 (10 mol %), and KOH (0.20 mmol) in HFPI (2
mL, used without dehydration), 35 °C, household blue LEDs (22 W),
b
72 h. Isolated yield. Diastereoselectivity (dr) ratios determined by
the crude H NMR spectra. 1aa (1.16 g, 4 mmol). Toluene/HFIP
c
d
1
(1:1, 2 mL) used as cosolvent.
bonds, significantly extending the Narasaka−Heck reaction to
the formation of stereogenic heterocycles (Scheme 1a).14,15
In contrast to the use of oxime esters in aza-Heck reactions
by a reductive process with low-valent transition metals, we
envisioned that a different approach involving an oxidative
decarboxylation of α-imino-oxy acids via dual photoredox and
cobaloxime catalysis could provide an alternative strategy and
beyond for the synthesis of functionalized alkene-containing N-
heterocycles via radical aza-cyclization, which to the best of our
knowledge remains elusive. Thus, we herein report an iminyl-
radical-mediated cyclization of α-imino-oxy acids with pendant
alkenes by synergistic photoredox and cobaloxime catalysis
under mild reaction conditions, with acetone, H2, and CO2 as
the easily removable byproducts. The radical transformation,
featured with cyclization and subsequent intermolecular
coupling, significantly extends the applicability of the radical
reaction for synthesis of N-heterocycles (Scheme 1b).
acid. After extensive screening of reaction parameters (see
Tables S1−S5 in the Supporting Information for details), we
were pleased to find that, with 5 mol % of Mes-Acr+ (N-
methyl-9-mesityl acridinium perchlorate) and 10 mol % of
Co(dmgH)2Cl2 as the synergistic catalyst system, KOH (1.0
equiv) as the base, and HFPI (hexafluoroisopropanol) as the
solvent, the reaction readily furnished the desired product 2a
in 80% yield upon irradiation by household blue LEDs at 35
°C. Notably, the control experiments revealed that the dual
photoredox and cobaloxime catalysts and light were all
essential for the success of the reaction.
As shown in Scheme 2, the optimized conditions were then
applied to the reaction of other α-imino-oxy acid derivatives
that possess pendant 1,2,2-trisubstituted alkenes. The sub-
strates with various aromatic substitutions proved to be
suitable for the reaction, affording the expected dihydropyrrole
products 2b−o in good to excellent yields. Note that the aryl
halides (2c−e and 2k), especially iodides (e.g., 2e) which are
highly sensitive to Pd-/Cu-catalyzed reaction conditions, were
all well compatible with the dual photoredox and Co catalysis,
thus allowing further transformation of these products into
We commenced our study by exploring the radical aza-
cyclization of α-imino-oxy acid 1aa in the presence of
photoredox and cobaloxime catalysts. The substrate, such as
1aa, can be readily prepared by condensation of the
corresponding ketone with 2-(aminooxy)-2-methylpropanoic
B
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a b
,
Scheme 5. Scope of Cyclization/Heck-Type Coupling of α-Imino-oxy Acids with Alkenes
a
Reaction conditions: 1 (0.20 mmol), 4 (1.0 mmol), Mes-Acr+ (5 mol %), Co(dmgH)2(4-CN-Py)Cl (10 mol %), H2O (40 μL), and K3PO4 (20
b
mol %) in HFPI/TMB (1:1, 2 mL, TMB = 1,3,5-trimethylbenzene), 35 °C, household blue LEDs (22 W), 36 h. Isolated yield. E/Z and
c
d
1
diastereoselectivity (dr) ratios determined by the crude H NMR spectra. 1cg (1.24 g, 4 mmol). 1 (0.20 mmol) and alkene (0.30 mmol).
e
Toluene/DCM (1:1, 2 mL) used as cosolvent.
more complex molecules via cross-coupling. The cyclization
was also applicable to sulfur-containing heterocycles as
exemplified by the synthesis of 2p in excellent yield. In the
examples of 2q and 2r, this protocol demonstrated that N-
heterobicyclic/-tricyclic scaffolds could be accessible in
satisfactory yields. Moreover, alkylidene cycloalkanes of various
ring sizes readily underwent radical cyclization to give the
corresponding products with good efficiency (2s−w). To
demonstrate the synthetic utility of the reaction, a gram-scale
reaction (1.16 g of 1aa) was conducted. The reaction still
proceeded very well, giving the desired product 2a in 75%
yield.
To further showcase the generality of the reaction, we went
on to test the aza-cyclization of α-imino-oxy acid with a variety
of pendant alkenes other than symmetrical 1,2,2-trisubstituted
alkenes. As depicted in Scheme 3, the reaction proceeded
smoothly to give the desired products in acceptable yields with
moderate to excellent E/Z selectivity (3b−j). It is worth
pointing out that the cyclization onto pendant cyclohexenes
produced cis-figured heterobicyclic/polycyclic molecules (3d−
e). Strikingly, 3f bearing a trisubstituted alkene moiety was
achieved with an excellent E-selectivity. The successful
cyclization of 1,1-disubstituted alkenes (e.g., 3g) proved to
be practicable for construction of quaternary amino-substituted
stereocenters. The protocol was also applicable to dialkyl-
substituted α-imino-oxy acids, furnishing the desired E-
selective products with acceptable efficiency (3h−j).
To gain insight into the mechanism of this visible-light-
mediated reaction, fluorescence quenching experiments were
conducted.16 As expected, the α-imino-oxy acid 1cg quenched
the photoexcited Mes-Acr+ (Mes-Acr+*) effectively but styrene
did not. Moreover, the released H2 can be detected by the GC
spectrum.16 On the basis of our observations and previous
reports,4,7 a simplified mechanism is depicted in Scheme 4.
The initial step involves a single oxidation of the carboxylate
derived from the α-imino-oxy acid 1 and base by Mes-Acr+*,
generating an iminyl radical A with loss of CO2 and acetone,
followed by 5-exo cyclization to deliver an alkyl radical B. The
reduced photocatalyst Mes-Acr• could be single-electron
oxidized by a CoIII complex to close the photoredox catalytic
cycle, as well as the generation of a CoII complex. On the other
hand, the alkyl radical B can react with the CoII complex to
form an organocobalt(III) complex C. The critical β-H
elimination step readily occurs to furnish the Heck-type
product 3 and a CoIII−H intermediate. The reaction of the
CoIII−H complex with a proton leads to H2 extrusion and
completion of the cobalt catalytic cycle. In addition, the
homolytic cleavage involving two CoIII−H to release H2 may
also take place.17
To expand the practicability of this radical reaction system,
we turned our attention to investigate sequential cyclization/
Heck-type coupling of α-imino-oxy acids with terminal alkenes,
which could enable synthesis of dihydropyrroles with high
diversity and complexity. Extensive examination and opti-
C
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mization of the reaction parameters was performed.16
Fortunately, best results could be afforded using Mes-Acr+ (5
mol %) and Co(dmgH)2(4-CN-Py)Cl (10 mol %) as the dual
catalyst system, K3PO4 (20 mol %) as the catalytic base, H2O
(40 μL) as the additive, and HFPI/TMB (1:1, TMB = 1,3,5-
trimethylbenzene) or toluene/DCM (1:1) as the cosolvent.
The scope of this two-component reaction is outlined in
Scheme 5. A series of cyclization/couplings could be
accomplished to give the desired E-selective products in
acceptable yields (5a−z and 5ba−bc). Notably, a high
efficiency was maintained when performing the reaction on a
gram scale, affording 5g in 62% yield (1.24 g of 1cg). A broad
generality and functional-group compatibility was observed.
For instance, styrene derivatives bearing either electron-
withdrawing or electron-donating groups on the phenyl ring
were all well tolerated (5k−r). Interestingly, the β-H
elimination of organocobalt(III) intermediates is site-selective,
only providing the thermodynamically stable internal alkenes,
and we did not find any terminal alkene products (5s−v). We
next tested the reaction of α-imino-oxy acids with pendant
internal alkenes which tend to undergo β-H elimination
immediately when forming the CoIII complex C. To our
delight, the intermolecular coupling also took place, thus
furnishing the desired products (5w−y) though the yield of 5y
is quite poor. We further applied this strategy to the late-stage
modification of terminal alkenes derived from natural products
or drug molecules. The reaction proceeded smoothly to furnish
the structural modified products with excellent stereo- and site-
selectivity (5ba−bc). To the best of our knowledge, this
cascade reaction represents the first example of the
combination of aza-cyclization and intermolecular Heck-type
coupling.
Pharmaceutical Sciences, Soochow University, Suzhou 215123,
People’s Republic of China
Jia-Li Liu − Jiangsu Key Laboratory of Neuropsychiatric Diseases
and Department of Medicinal Chemistry, College of
Pharmaceutical Sciences, Soochow University, Suzhou 215123,
People’s Republic of China
Wan Tang − Jiangsu Key Laboratory of Neuropsychiatric
Diseases and Department of Medicinal Chemistry, College of
Pharmaceutical Sciences, Soochow University, Suzhou 215123,
People’s Republic of China
Ma Su − Jiangsu Key Laboratory of Neuropsychiatric Diseases
and Department of Medicinal Chemistry, College of
Pharmaceutical Sciences, Soochow University, Suzhou 215123,
People’s Republic of China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00224
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Natural Science Foundation of the
Jiangsu Higher Education Institutions of China (Grant No.
18KJA350001) and the Priority Academic Program Develop-
ment of the Jiangsu Higher Education Institutes (PAPD).
REFERENCES
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In summary, we have developed an iminyl-radical-mediated
cyclization method with the merger of cobalt catalysis and
photoredox organocatalysis. The reaction is external-oxidant-
free, occurs under mild conditions with extrusion of acetone,
H2, and CO2, exhibits wide functional-group compatibility, and
enables synthesis of a range of alkene-containing dihydropyr-
roles with high diversity. The reaction could extend to
coupling with external alkenes and shows excellent chemo-
and stereoselectivity. Further mechanistic understanding of the
reaction is ongoing in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00224.
Experimental details, characterizations, and copies of 1H
and 13C NMR spectra for all compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Feng Liu − Jiangsu Key Laboratory of Neuropsychiatric Diseases
and Department of Medicinal Chemistry, College of
Pharmaceutical Sciences, Soochow University, Suzhou 215123,
People’s Republic of China; orcid.org/0000-0003-2669-
5448; Email: fliu2@suda.edu.cn
Authors
Jia-Lin Tu − Jiangsu Key Laboratory of Neuropsychiatric
Diseases and Department of Medicinal Chemistry, College of
D
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