Visible-Light Photoredox Catalyzed Double C-H Functionalization: Radical Cascade Cyclization of Ethers with Benzimidazole-Based Cyanamides

Article abstract of DOI:10.1021/acs.orglett.0c03853

A visible-light photoredox catalyzed radical cascade cyclization of simple ethers with cyanamides is developed at room temperature. This strategy involves sequential inert Csp3-H/Csp2-H functionalizations through intermolecular addition reaction of oxyalkyl radicals to N-cyano groups followed by radical cyclization of iminyl radicals in situ generated with C-2 aryl rings. This method allows for efficient synthesis of tetracyclic benzo[4,5]imidazo[1,2-c]quinazolines. Importantly, this is the first example of an intermolecular-intramolecular radical cascade cyclization reaction of cyanamides.

Full text of DOI:10.1021/acs.orglett.0c03853

pubs.acs.org/OrgLett
Letter
Visible-Light Photoredox Catalyzed Double C−H Functionalization:
Radical Cascade Cyclization of Ethers with Benzimidazole-Based
Cyanamides
Si Jiang, Xiao-Jing Tian, Shu-Yao Feng, Jiang-Sheng Li,* Zhi-Wei Li, Cui-Hong Lu, Chao-Jun Li,
and Wei-Dong Liu
Cite This: Org. Lett. 2021, 23, 692−696
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ABSTRACT: A visible-light photoredox catalyzed radical cascade cyclization of simple ethers with cyanamides is developed at room
temperature. This strategy involves sequential inert Csp3-H/Csp2-H functionalizations through intermolecular addition reaction of
oxyalkyl radicals to N-cyano groups followed by radical cyclization of iminyl radicals in situ generated with C-2 aryl rings. This
method allows for efficient synthesis of tetracyclic benzo[4,5]imidazo[1,2-c]quinazolines. Importantly, this is the first example of an
intermolecular−intramolecular radical cascade cyclization reaction of cyanamides.
Photoredox synthesis constitutes a powerful and sustainable
yanamide chemistry has been increasingly attracting great
Cinterest in the chemists’ community due to the versatile tool to form chemical bonds and complex organic molecular
architectures.7 The photoredox catalyzed intramolecular
radical additions to the N-CN moiety have been disclosed.8
Our interest in photochemistry9 and heterocycle synthesis10
promoted us to radical transformations of N-cyano-
benzimidazoles. We report herein a visible-light photoredox
catalyzed intermolecular radical addition to the N-CN part of
N-cyanobenzimidazoles and subsequent radical cyclization of
the iminyl radicals in situ generated. Our strategy involves a
double C−H functionalization process and enables ready
access to tetracyclic products, benzo[4,5]imidazo[1,2-c]-
quinazolines. Benzimidazoles11 and quinazolines12 are priv-
ileged structural cores prevalent in natural compounds and
bioactive molecules.
reactivities of cyanamides as building blocks1 for organic
synthesis. Thus, cyanamides can be used for nucleophilic
additions, cycloadditions, aminocyanation, electrophilic cyan-
ation, and radical reactions. Recently, radical cascade reactions
of cyanamides have emerged as a powerful strategy to assemble
polycyclic N-heterocycle frameworks. Malacria and co-workers
pioneered the introduction of N-acylcyanamides as viable
radical acceptors for the construction of tri- and tetracyclic
quinazolinone derivatives (Scheme 1a).2 The methods
typically relied on the toxic tin-based mediators initiated
radical generation from iodoaryls,2a,b iodovinyls,2c azides,2d
and phenylselenyls.2e The Cui group incorporated the
cyanamide moiety into unactivated alkenes to develop new
radical cascade cyclizations through the alkene difunctionaliza-
tion strategy using Togni’s reagent,3 phosphine oxides,4 and
1,3-dicarbonyls5 as radical precursors (Scheme 1b). Zhu et al.
reported radical relay reactions of N-cyanamide alkenes to
readily access functionalized γ-lactams (Scheme 1c).6 How-
ever, these seminal works are restricted to intramolecular
radical reactions of cyanamides. To the best of our knowledge,
the intermolecular version of cyanamides is underexplored to
date, except with thiyl radical to give a rearranged N-acyl
isothioureas, rather than thiylated quinazolinones generated via
radical cascade cyclization (Scheme 1d).
In terms of polarity matching, N-cyanobenzimidazoles
would readily couple with nucleophilic radicals. Ethers is
widely used to generate nucleophilic carbon centered radicals
through oxidation.13 We initially chose N-cyano-2-phenyl
Received: November 21, 2020
Published: January 13, 2021
https://dx.doi.org/10.1021/acs.orglett.0c03853
© 2021 American Chemical Society
Org. Lett. 2021, 23, 692−696
692

Organic Letters
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Letter
a
Scheme 1. Intra- and Intermolecular Radical Addition to
Cyanamides
Table 1. Optimization of Reaction Conditions
b
entry
variation from general conditions
none
[Ir(dtbbpy)(ppy)2]PF6
fac-Ir(ppy)3
Eosin Y−H2
Eosin Y−Na2
yield (%)
1
2
3
4
5
6
7
74
70
62
c
68
c
70
c
Methylene blue
Riboflavin
68
c
68
8
9
THF (0.25 mL) in DCE (0.25 mL)
THF (0.25 mL) in EtOAc (0.25 mL)
TBHP
62
65
64
54
68
81
75
85
10
11
12
13
14
15
16
17
TBPB
1.5 equiv of DTBP
2.0 equiv of DTBP
2.5 equiv of DTBP
for 14 h
w/o photocatalyst
in dark
trace
N.R.
a
General conditions: 1a (0.1 mmol), 2a (0.5 mL), DTBP (3.0 equiv),
Ir[(dFppy)2(dtbbpy)]PF6 ([Ir−F]) (1 mol %), r.t., 25 W blue LED
b
c
(460−470 nm), 12 h. Isolated yields. Photocatalyst (3 mol %).
DTBP = di-tert-butyl peroxide, DCE = 1,2-dichloroethane, TBHP =
tert-butyl hydroperoxide (70% solution in water), TBPB = tert-butyl
peroxyl benzoate, N. R. = no reaction.
benzimidazole (1a) and tetrahydrofuran (2a) as model
substrates using 3.0 equiv of di-tert-butyl peroxide (DTBP)
as the oxidant for photoredox transformation under irradiation
by 25 W blue light LED lamp. An array of photocatalysts,
including the extensively studied Ir-/Ru-based complexes and
organocatalysts, were screened. All the photocatalysts tested
except phenothiazine could promote this photochemical
reaction (see the ESI, Table S1). The catalysts [Ir-
(dFppy)2(dtbbpy)]PF6 ([Ir−F]), Ir(dtbbpy)(ppy)2]PF6, and
fac-Ir(ppy)3 (1 mol % loading) afforded good yields of 62−
74% (Table 1, entries 1−3). Likewise, the organocatalysts, like
Eosin Y series, methylene blue, and riboflavin, achieved
comparable efficacies with 3 mol % being used (Table 1,
entries 4−7). The use of THF mixed, respectively, with DCE
and EtOAc in 1:1 volume ratio, led to slight decrease in the
yields (Table 1, entries 8 and 9). It is worth noting that the
type of oxidant exerted a significant impact on the reaction
efficiency. The peroxides, TBHP, TBPB, and DTBP, could
trigger the radical cascade cyclization, with the former being
less effective (Table 1, entries 10 and 11). The amount of
oxidant was optimized to be 2.0 equiv, and the time of
irradiation was kept for 14 h (Table 1, entries 12−15).
Notably, the blue light with the wavelength ranging from 420
to 470 nm could efficiently facilitate the transformation (see
the ESI, Table S5). Under the optimal conditions, 85% of
compound 3 was obtained. Besides, without either photo-
catalyst or light irradiation, only trace or none of 3 was
detected by GC-MS.
cyanobenzimidazoles tested could smoothly undergo the
visible-light initiated oxidative radical cascade cyclization,
providing 6-functionalized tetracyclic benzo[4,5]imidazo[1,2-
c]quinazolines in moderate to good yields. The substituents on
the C-2 aryl rings of benzimidazoles 1, -Me, -OMe, -F, -Cl, -Br,
and -CF3, could be well tolerated in this photochemical
oxidative reaction. It is worthwhile to note that the electron-
rich groups favored the reaction while the electron-deficient
ones diminished the reaction yields. Moreover, it was found
that the functional groups located at the ortho-, meta-, and
para-position of the benzimidazolyl C-2 aryl ring afforded
comparable yields (Scheme 2, for -Me, compounds 4, 7, and
10; for -Cl, compounds 6, 8, and 14), indicating that the steric
effect imposed little influence on the reaction efficiency.
Notably, this cascade cyclization possessed an excellent
regioselectivity, and the in situ generated iminyl radicals
preferentially attacked the aryl rings at the para- position of the
substituents with the meta-substituted subtrates (Scheme 2,
compounds 7−9). Benzimidazoles 1, with 2,4-dimethyl and
3,5-dimethyl attached at the C-2 aryl ring, reacted well under
the standard conditions to furnish compounds 17 and 18 in
82% and 83% yields, respectively. Similarly, compounds 19 and
20 bearing dichloro groups were obtained in 65% and 67%
yields, respectively. Furthermore, the introduction of sub-
stituents to the fused benzene ring of benzimidazoles enriched
the substrate scope with respect to benzimidazoles 1, with high
reaction efficiencies (Scheme 2, compounds 21−23).
Next, other ethers 2 such as 1,3-dioxolane, 1,4-dioxane, and
2-methyltetrahydrofuran, as radical precursors were also
explored. To our delight, these substrates delivered their
individual cyclization products 24−26 in 35−72% yields under
Having established the optimal reaction conditions, we
turned our attention to exploring the generality of this
photoredox process. As is shown in Scheme 2, all the N-
693
https://dx.doi.org/10.1021/acs.orglett.0c03853
Org. Lett. 2021, 23, 692−696

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Letter
a
Scheme 2. Substrate Scope
Scheme 3. Control Experiments
a
Reaction conditions: 1a (0.2 mmol), 2a (1.0 mL), DTBP (2.0
equiv), [Ir−F] (1 mol %), r.t., 25 W blue LED (460−470 nm), 14 h.
b
The r.r. (regioisomeric ratio) determined by GC. Yield for 1 mmol
scale.
the standard conditions. It should be noted that 2-methyl-
tetrahydrofuran gave two inseparable regioisomeric products
26 with a 1:0.7 ratio (determined by GC). Besides, 80% yield
of product 3 in a 1 mmol scale verified the applicability of this
photochemical method.
Figure 1. ON/OFF experiments.
indispensable to the high reaction efficiency and also indicates
that a radical-chain process is unlikely to be a predominant
pathway, albeit can not be excluded, for the present
photoredox reaction. Furthermore, fluorescence quenching
experiments were conducted to ascertain whether the photo-
catalyst first reacted with DTBP under photoirradiation (see
the Supporting Information for details).
On the basis of the above preliminary experimental results
combined with the previous literatures,13d−f,15 a plausible
mechanism involved in photoredox catalysis is proposed in
Scheme 4. First, the photocatalyst, [Ir−F], is excited by blue
light irradiation to result in the formation of the excited
species, [Ir−F]*, which would then reduce the oxidant DTBP
to a tert-butoxyl radical and a tert-butoxyl anion via a single
electron transfer (SET) process, along with the generation of a
radical cation, [Ir−F]•+. The resultant tert-butoxyl radical
undergoes hydrogen atom transfer (HAT), selectively
abstracting the most hydridic hydrogen atom from tetrahy-
drofuran to afford a nucleophilic ether carbon-centered radical,
R·. Subsequently, the radical R· can participate in intermo-
lecular nucleophilic addition to the cyano group of 1a to
produce an iminyl radical, A, which is then transformed into
To shed light on the plausible mechanism for this novel
radical cascade cyclization, a series of control experiments were
carried out (Scheme 3). When 3 equiv of the radical inhibitor
2,6-di(tert-butyl)-4-methylphenol (BHT) was added under the
standard conditions, the reaction was almost completely
inhibited, with the possible benzylated tetrahydrofuran being
detected by GC-MS (m/e 290.25) (Scheme 3a). The addition
of a commonly used radical trapper, 2,2,6,6-tetramethyl-1-
piperidinyloxyl (TEMPO, 3 equiv), to the standard reaction
system led to only trace of the target product 3, and also the
adduct aminoxylated tetrahydrofuran was found by GC-MS
(m/e 227.20) (Scheme 3b). Furthermore, the adduct 2-(2,2-
diphenyl vinyl)tetrahydrofuran (m/e 250.15) was observed in a
considerable amount14 when the standard reaction was carried
out in the presence of 1,1-diphenylethylene (DPE, 3 equiv)
(Scheme 3c). These experimental results imply the involve-
ment of radical species in the present transformation.
To preliminarily unveil the role of the photoirradiation, an
on/off blue light irradiation experiment was performed (Figure
1). The result shows that continuous exposure to visible light is
694
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Org. Lett. 2021, 23, 692−696

Organic Letters
pubs.acs.org/OrgLett
Letter
Xiao-Jing Tian − Hunan Provincial Key Laboratory of
Scheme 4. Plausible Mechanism for Photochemical Radical
Cascade Cyclization
Material Protection for Electric Power and Transportation,
School of Chemistry and Food Engineering, Changsha
University of Science and Technology, Changsha 410114,
China
Shu-Yao Feng − Hunan Provincial Key Laboratory of
Material Protection for Electric Power and Transportation,
School of Chemistry and Food Engineering, Changsha
University of Science and Technology, Changsha 410114,
China
Zhi-Wei Li − Hunan Provincial Key Laboratory of Material
Protection for Electric Power and Transportation, School of
Chemistry and Food Engineering, Changsha University of
Science and Technology, Changsha 410114, China
Cui-Hong Lu − Hunan Provincial Key Laboratory of Material
Protection for Electric Power and Transportation, School of
Chemistry and Food Engineering, Changsha University of
Science and Technology, Changsha 410114, China
Chao-Jun Li − Department of Chemistry and FQRNT Centre
for Green Chemistry and Catalysis, McGill University,
Montreal, Quebec H3A 0B8, Canada; orcid.org/0000-
0002-3859-8824
the intermediate B through radical cyclization. The species B
would be further oxidized by the [Ir−F]•+ in situ generated
through another SET reaction, thus providing an intermediary
cation, C, and concomitantly regenerating the Ir-based
photocatalyst. Finally, the intermediate C deprotonates by
the tert-butoxyl anion to yield the product 3.
Wei-Dong Liu − National Engineering Research Center for
Agrochemicals, Hunan Research Institute of Chemical
Industry, Changsha 410007, China
In conclusion, we have disclosed a radical cascade cyclization
reaction of simple ethers with benzimidazole-based cyanamides
through visible light photoredox catalyzed double C−H
functionalization. The protocol includes intramolecular radical
addition of oxyalkyl radicals to the cyano moieties and the
subsequent intramolecular cyclization of the iminyl radical in
situ generated and allows for ready access to benzo[4,5]-
imidazo[1,2-c]quinazolines. To the best of our knowledge, this
is the first example of an intermolecular−intramolecular radical
cascade cyclization reaction of cyanamides. Our method will
provide an alternative strategy for the construction of
imidazoquinazolines from the view of sustainable chemistry
and could find its applications in medicinal research and
material developments. Extensive investigation on the radical
chemistry of benzimidazole-based cyanamides is under way in
our laboratory.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03853
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We would thank the Financial support from National Key
R&D Program of China (No. 2017YFB0307200), Hunan
Provincial Key Laboratory of Agricultural Chemicals (HKLA-
OF2020001), Scientific Research Fund of Hunan Provincial
Education Department (19C0091), Young Teachers Develop-
ment Project of CSUST (2019QJCZ039), International
Cooperative Extended Project for “Double First-Class”,
CSUST (2018IC21), Hunan Provincial Graduate Student
Teaching Reform and Research Project (JG2018B081), Hunan
Provincial Graduate Student Scientific Research Innovation
Project (CX20190698), and National Undergraduate Training
Programs for Innovation and Entrepreneurship of China
(202010536017).
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03853.
Experimental details, characterization data for new
compounds, copies of NMR spectra (PDF)
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