Photocatalytic Visible-Light-Induced Nitrogen Insertion via Dual C(sp3)-H and C(sp2)-H Bond Functionalization: Access to Privileged Imidazole-based Scaffolds

Article abstract of DOI:10.1021/acs.orglett.0c03269

Here we have demonstrated a visible-light-mediated metal-free organic-dye-catalyzed dehydrogenative N-insertion leading to highly substituted imidazoles and privileged dihydroisoquinoline-based imidazole derivatives via C(sp3)-H and C(sp2)-H bond functionalization. A sustainable, convenient, metal-free azidation/C-H aminative cyclization approach in the absence of stoichiometric oxidants is presented. This protocol involves a rare photoinduced iminyl radical as a key intermediate for the "N"insertion.

Full text of DOI:10.1021/acs.orglett.0c03269

pubs.acs.org/OrgLett
Letter
Photocatalytic Visible-Light-Induced Nitrogen Insertion via Dual
C(sp3)−H and C(sp2)−H Bond Functionalization: Access to Privileged
Imidazole-based Scaffolds
Srilaxmi M. Patel, Ermiya Prasad P., Manickam Bakthadoss,* and Duddu S. Sharada*
Cite This: Org. Lett. 2021, 23, 257−261
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ABSTRACT: Here we have demonstrated a visible-light-mediated
metal-free organic-dye-catalyzed dehydrogenative N-insertion
leading to highly substituted imidazoles and privileged dihydroi-
soquinoline-based imidazole derivatives via C(sp3)−H and C-
(sp2)−H bond functionalization. A sustainable, convenient, metal-
free azidation/C−H aminative cyclization approach in the absence
of stoichiometric oxidants is presented. This protocol involves a
rare photoinduced iminyl radical as a key intermediate for the “N”
insertion.
photosynthesis has hugely influenced the scientific community
hotochemical reactions have vast potential in green
Pchemistry. Nature’s ability to convert solar power in to mimic nature in the development of photoredox systems in all
areas of science, including organic chemistry.1 Visible-light-
promoted photoredox catalysis has become one of the
promising tools for selective organic transformations, with
potential to unlock distinct reaction pathways due to its unique
features such as mild conditions, trace or no byproducts, and
economical and ecological friendliness in organic synthesis.2
Photoactive catalysts have emerged as an attractive and
sustainable tool for C−H activation for C−C/C−X bond
formation via visible-light-induced single-electron transfer
(SET) processes.3 This cutting-edge platform allows the
photoexcitation of photocatalysts with visible light and chemical
energy conversion, prompting an SET event, to generate
reactive free-radical intermediates for synthetically valuable
transformations.4 Conspicuously, MacMillan and coworkers
engaged photoredox catalysis to activate native functional
groups toward C−C/C−X bond formation and have widely
explored visible-light photocatalysis with transition metals and
organocatalysts via SET, hydrogen-atom transfer (HAT), radical
decarboxylative coupling via dual catalysis (Ni/Ir), and
reductive quenching cycles to develop numerous efficient
methods for plenteous C(sp3)−H bond functionalization.5
Scheme 1. Photoredox Approach for Benzylic C−H
Azidation and Our Strategy
Scheme 2. Hypothesized Approach for “N” Insertion via
C(sp3)−H and C(sp2)−H Functionalization
Received: September 29, 2020
Published: December 29, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03269
© 2020 American Chemical Society
Org. Lett. 2021, 23, 257−261
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Letter
a
Table 1. Optimization of Reaction Conditions
b
entry
catalyst (5 mol %)
[N] source
base/additive
light source
60W bulb
time (h)
yield (%)
1
2
3
4
5
6
7
8
rose Bengal
eosin Y
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
IBA-N3
NaN3
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
−
−
−
−
48
48
48
48
48
48
48
48
48
48
48
48
36
60
48
50
70
48
55
40
35
45
30
60W bulb
60W bulb
60W bulb
60W bulb
60W bulb
60W bulb
60W bulb
3W blue LED
other light source
60W bulb
60W bulb
60W bulb
60W bulb
rhodamine B
riboflavin
Ru(bpy)3Cl2
Ir(ppy)3
eosin Y
eosin Y
eosin Y
eosin Y
eosin Y
eosin Y
eosin Y
eosin Y
eosin Y
−
−
−
−
9
45
10−20
20
c
10
11
12
13
14
15
Et3N
DIPEA
CBrCl3
CCl4
−
30
60
65
ND
dark
a
b
Reaction conditions: 3a (0.36 mmol), [N] source (1.08 mmol), and 2 mL of CH3CN solvent. Isolated yields after column chromatography.
c
Other light sources afforded green LED (20%), red LED (trace), CFL variable wattages (11W, 15W, 18 W) around 20%, sunlight (10%). ND =
not detected.
Photocatalytic transformation has mostly been reported using
metal complexes such as ruthenium and iridium polypyridyl
complexes;6 however, transition-metal-based photocatalysts
demonstrate disadvantages such as low sustainability, potential
toxicity, and high cost. Most recently, some of the organic dyes
like rose bengal, eosin Y, rhodamine B, and riboflavin have been
recognized as superior alternatives due to their easy accessibility,
low cost, and low toxicity.7 In organic dyes, eosin Y has been
widely used in visible-light-promoted organic transformations
involving SET.8 On the contrary, the photoredox-catalyzed C−
H functionalization has been extensively developed, especially
for the C−H bond adjacent to the nitrogen atom, leading to the
synthesis of N-heterocycles.9
the Zhdankin reagent as an azide source in the presence of a
copper photoredox catalyst (Scheme 1).16 In a continuation of
our recent interests in photoredox catalysis for C−H
functionalization17 and azide-based chemistry,18 we envisaged
that it would be of great importance to investigate a light-
induced “N” insertion strategy via iminyl radical cyclization
involving dual C(sp3)−H and C(sp2)−H amination (Scheme
2).
Herein we disclose a visible-light-promoted “N” insertion
leading to highly substituted imidazole derivatives by a tandem
azidative/cycloamination strategy. Imidazole scaffolds shows
high biological activity and exist in many pharmaceuticals and
natural products.19
In the past few decades, C−H activation leading to C−N
bond formation has emerged as a powerful tool for the synthesis
of nitrogen-containing bioactive molecules and pharmaceuti-
cally important compounds.10,11 Very recently, radical chemistry
has gained importance due to its sustainable features, and, in
particular, “N” radical species have gained importance in their
applicability in C−N bond formation,12 specifically with photo/
electrotechniques. Among them, iminyl radicals represent
valuable synthons among N-centered radicals.13 Therefore,
various approaches have been developed starting from vinyl-
azides, oximes, and cyanide derivatives. Keeping sustainability in
view, light-induced photoredox strategies for generating these
radicals are of immense focus. Recently, the formation of an α-
azidyl radical has been a promising approach for iminyl radical
generation and α-C−N bond construction. Yu et al. have
reported light-induced N-bromosuccinimide (NBS)-mediated
iminyl radical cyclization to quinazolinones from α-azidyl
benzamide via an α-azidoradical.14 Later on, they reported an
interesting “N” insertion protocol utilizing the iminyl radical
strategy, leading to quinoxalines via the light-induced tandem
azidation/cyclization of N-arylenamines,15 featuring step-
economic operation in which two C−N bonds were formed in
one step. Greaney et al. reported benzylic C−H azidation using
To check our hypothesis, we choose 3a as a model substrate
and treated it with rose bengal in CH3CN in the presence of
TMSN3 under a 60W CFL bulb, resulting in the complete
disappearance of the starting material within 48 h to the desired
product 4a (50% yield, Table 1, entry 1). We screened the
reaction with different photocatalysts such as eosin Y,
rhodamine B, riboflavin, Ru(bpy)3Cl2, and Ir(ppy)3, which
resulted in moderate to good yields (35−70%) of 4a (Table 1,
entries 2−6). For sp3 C−H azidation, we investigated different
azide sources like IBA-N3 and NaN3, which afforded a moderate
yield of the product 4a (45 and 30%, Table 1, entries 7 and 8).
Subsequently, we switched the light source to blue LEDs, which,
however, significantly decreased the yield (38%, Table 1, entry
9). Trying our protocol with other light sources afforded a poor
yield of the product 4a (Table 1, entry 10). With further testing
with bases and additives, there was no improvement in the yield
of the product (Table 1, entries 11−14). Importantly, when the
reaction was conducted in the dark, no conversion was observed,
indicating that photocatalysis is crucial for the transformation
(Table 1, entry 15). Finally, the reaction with eosin Y in CH3CN
in the presence of TMSN3 under 60W CFL bulb proved to be
the best among all optimized conditions.
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a b
,
Scheme 3. Scope of N-Benzylenamine Esters in Visible-Light-
Induced “N” Incorporation
Scheme 4. Scope of CF3-based Enamines
a b
,
a
Conditions: 3 (0.36 mmol), eosin Y (0.018 mmol), TMSN3 (1.08
b
mmol) in dry CH3CN (2 mL), white CFL 60 W. Yields are reported
for compounds isolated after silica gel column chromatography.
Scheme 5. Control Experiments
a
Figure 1. Electrochemical oxidation and reduction curves in dry
CH3CN solution of THIQ enamine (3a), eosin Y, and TMSN3 at a scan
rate of 100 mV/s.
Conditions: 3 (0.36 mmol), eosin Y (0.018 mmol), TMSN3 (1.08
b
mmol) in dry CH3CN (2 mL), white CFL 60 W. Yield of the
product after silica gel column chromatography. Detected by HRMS
c
analysis.
Scheme 6. Plausible Reaction Mechanism
Under the optimized conditions, the substrate scope was
investigated. Initially we started investigation with tetrahydroi-
soquinoline (THIQ) enamines generated from THIQs and
dialkylbut-2-ynedioate (Scheme 2). THIQ enamines 3a−d
proceeded smoothly to give privileged imidazo-fused dihydroi-
soquinoline (DHIQ) scaffolds (4a−d) in 66−70% yields
(Scheme 3). DHIQ is an important core structure of
pharmaceuticals and natural products.20
Pleased by the results, we envisioned applying the optimal
reaction conditions to other benzylamine-based enamines (3e
and 3f), which resulted in the generation of highly substituted
imidazoles 4e and 4f in moderate yields (62 and 65%). Similarly,
electron-donating-group-substituted enamines 3g and 3h
afforded the products 4g and 4h in good yields (60 and 65%).
Furthermore, employing weakly electron-donating groups such
as −F and −Cl at the ortho and para positions of enamines (3i−
m) gave the corresponding products 4i−m in moderate yields
(50−56%). Furthermore, the CF3− substituent on the phenyl
ring of enamine (3n) was also found to be accomplished for the
synthesis of highly substituted imidazole 4n in moderate yield
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(46%). On the contrary, when we have examined enamines
derived from monoactivated alkynes (3o and 3p) and terminal
alkynes (3q) under optimized conditions, they have afforded a
trace amount of corresponding products 4o−q, which was
confirmed by HRMS analysis (Scheme 3). Keeping in view the
relevance of imidazole skeletons in pharmaceuticals and
biologically important molecules, we have examined the gram-
scale reaction of our protocol with 3a, which furnished a 52%
yield of the product 4a.
To further diversify the skeleton, we have applied our
azidation/C−H aminative cyclization approach to enamines
derived from 1,3-dicarbonyls (with −COCF3), resulting in the
corresponding CF3-substituted imidazoles 4r−v in good yields
64−75% (Scheme 4). The trifluoromethyl-substituted hetero-
cycles are very important structural motifs in agrochemicals,
pharmaceuticals, organic materials, and tracers for positron
emission tomography; furthermore, owing to their metabolic
stability, strong electron-withdrawing power, and high lip-
ophilicity, they can increase the strength of a compound’s
interactions with a target protein.21
physicochemical properties of fluorinated compounds and in
imaging. Overall, this sustainable method would open new
avenues for industrial applications in making value-added
heterocycles.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03269.
Experimental procedures, 1H and 13C NMR spectra, and
characterization data of compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Duddu S. Sharada − Indian Institute of Technology (IIT)
Hyderabad, Sangareddy, Telangana 502 285, India;
orcid.org/0000-0001-5861-4126; Email: sharada@
chy.iith.ac.in
To understand the probable mechanism of the visible-light-
promoted azidation/C−H aminative cyclization strategy, some
control experiments were performed, as shown in Scheme 5.
When the model reaction was carried out in the presence of
TEMPO and BHT as radical scavengers, the reaction was
completely inhibited, thus indicating a radical pathway.
To understand the mechanical aspects of this reaction, we
measured the oxidation potential (Eox) and reduction potential
(Ered) based on the cyclic voltammetry (CV) for THIQ-based
enamine (3a), eosin Y. and TMSN3 at a scan rate of 100 mV·s−1
(vs Ag/AgCl) (Figure 1). The Eox is calculated to be 1.52 V for
3a, and the Eox and Ered are calculated to be 1.6 and −1.13 V for
eosin Y. On the basis of the value of the more oxidation potential
value of eosin Y (1.6 V vs SCE), 3a is oxidized to radical cation I
via the reductive quenching cycle by the SET mechanism.
Subsequently, I is oxidized to produce the iminium ion II, which
affords the product 4a via the azidation/C−H aminative
cyclization strategy. The Ered for TMSN3 is calculated to be
−1.02 V vs SCE, and hence TMSN3 is crucial in the oxidation of
the eosin Y radical anion to eosin Y to complete the reductive
quenching cycle.
Manickam Bakthadoss − Department of Chemistry,
Pondicherry University, Puducherry 605 014, India;
orcid.org/0000-0003-4184-3947; Email: bhakthadoss@
yahoo.com
Authors
Srilaxmi M. Patel − Indian Institute of Technology (IIT)
Hyderabad, Sangareddy, Telangana 502 285, India;
orcid.org/0000-0001-7665-9731
Ermiya Prasad P. − Indian Institute of Technology (IIT)
Hyderabad, Sangareddy, Telangana 502 285, India;
orcid.org/0000-0002-9034-0468
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03269
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the Council of Scientific and Industrial
Research (CSIR 02(0297)/17/EMR-II), New Delhi, IIT
Hyderabad for financial support. S.M.P. thanks UGC, and
E.P.P. thanks CSIR New Delhi, India for the award of a research
fellowship. For the cyclic voltametry studies, we thank Prof. Ch.
Subrahmanyam and Dr. Palyam Subramanyam, IIT Hyderabad,
India.
On the basis of the controlled experiments, the cyclic
voltammetry results, and literature reports, we have formulated
a plausible reaction mechanism for the synthesis of 2,4,5-
trisubstituted imidazoles, as shown in Scheme 6. Initially, in the
presence of white CFL light, eosin Y is photoexcited. The THIQ
enamine (3a) is oxidized to the THIQ enamine radical cation
(I) by the SET mechanism via a reductive quenching cycle.
Subsequently, I is oxidized to the intermediate iminium ion (II),
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