Metal-Free Visible-Light Promoted Radical Cyclization to Access Perfluoroalkyl-Substituted Benzimidazo[2,1-a]isoquinolin-6(5H)-ones and Indolo[2,1-a]isoquinolin-6(5H)-ones

Article abstract of DOI:10.1002/adsc.201901016

A metal-free visible-light-induced cyclization procedure was developed for the rapid synthesis of perfluoroalkyl-substituted benzimidazo[2,1-a]isoquinolin-6(5H)-ones and perfluoroalkyl-substituted indolo[2,1-a]isoquinolin-6(5H)-ones under mild reaction conditions. In this procedure, the formation of electron-donor-acceptor (EDA) complex is critical for the visible-light promoted process to avoid the utilization of external photocatalysts. (Figure presented.).

Full text of DOI:10.1002/adsc.201901016

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DOI: 10.1002/adsc.201901016
Metal-Free Visible-Light Promoted Radical Cyclization to Access
Perfluoroalkyl-Substituted Benzimidazo[2,1-a]isoquinolin-6(5H)-
ones and Indolo[2,1-a]isoquinolin-6(5H)-ones
Fan-Lin Zeng,+a Kai Sun,+a Xiao-Lan Chen,a,* Xiao-Ya Yuan,a Shuai-Qi He,a
Yan Liu,a, b Yu-Yu Peng,c Ling-Bo Qu,a Qi-Yan Lv,a,* and Bing Yua,*
a
College of Chemistry, School of Life Sciences, Zhengzhou University, Zhengzhou 450001, People’s Republic of China
E-mail: chenxl@zzu.edu.cn; qiyanlv@zzu.edu.cn; bingyu@zzu.edu.cn
College of Biological and Pharmaceutical Engineering, Xinyang Agriculture & Forestry University, Xinyang, 464000, People’s
b
Republic of China
c
Hunan Provincial Key Laboratory of Materials Protection for Electric Power and Transportation, Changsha University of
Science and Technology, Changsha 410114, People’s Republic of China
+
Fan-Lin Zeng and Kai Sun contributed equally
Manuscript received: August 14, 2019; Revised manuscript received: September 24, 2019;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.201901016
Abstract: A metal-free visible-light-induced cyclization procedure was developed for the rapid synthesis of
perfluoroalkyl-substituted benzimidazo[2,1-a]isoquinolin-6(5H)-ones and perfluoroalkyl-substituted indolo
[2,1-a]isoquinolin-6(5H)-ones under mild reaction conditions. In this procedure, the formation of electron-
donor-acceptor (EDA) complex is critical for the visible-light promoted process to avoid the utilization of
external photocatalysts.
Keywords: Visible-light; Radical cascade reaction; Metal free; Photocatalyst free; Perfluoroalkylation
Introduction
Nitrogen-containing heterocycles are important and
promising compounds due to their potential biological
activities.[1] Consequently, numerous procedures have
been developed for the construction of N-heterocycles
in the past decades.[2] On the other hand, in the recent
years visible-light-promoted synthesis has emerged as
a powerful and environmentally friendly strategy for
various organic transformations.[3] Particularly, the
synthesis of N-heterocycles under visible-light-medi-
Figure 1. Selected examples of benzimidazo-isoquinolin-6(5H)-
ones.
ated conditions have been well developed recently.[4]
Notably, benzimidazo-isoquinolin-6(5H)-ones (A) as a
significant structural scaffold was widely found in
biologically active molecules and functional
materials.[5] Figure 1 shows some representative com- conventional condensation methods were found to be
pounds containing benzimidazo-isoquinolin-6(5H)-one efficient for the construction of the target polycycles.[7]
scaffold with various pharmacological activities, such However, those reactions suffer from tedious prefunc-
as anti-inflammatory, antidiabetic.[6]
tionalization steps, harsh reaction conditions as well as
As a consequence of its importance, substantial practical inconvenience. Gratifyingly, transition-metal
efforts have been contributed to the construction of catalysis strategies have been reported as promising
benzimidazo-isoquinolin-6(5H)-ones. For instance, the alternatives for the synthesis of this important scaffold
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In most cases, an exogenous photocatalyst, e.g.,
transition-metal complex, or organic dye, is required to
harvest visible-light energy.[14] Alternatively, electron-
donor-acceptor (EDA) complexes, composed of elec-
tron donors and acceptors through molecular non-
covalent interactions, can be effectively excited by
visible-light.[15] As a result, in some visible-light
promoted reactions external photocatalysts, especially
those expensive and toxic metal complexes, could be
avoided through the formation of EDA complexes.[16]
With our ongoing interests on green chemistry and
radical reactions,[17] we herein disclosed a metal-free
procedure to synthesize perfluoroalkyl-substituted ben-
zimidazo[2,1-a]isoquinolin-6(5H)-ones and indolo[2,1-
a]isoquinolin-6(5H)-ones via visible-light-induced rad-
ical cyclization reaction under mild conditions (Sche-
me 1c-d). To the best of our knowledge, this is the first
example for the preparation of perfluoroalkyl-substi-
tuted benzimidazo[2,1-a]isoquinolin-6(5H)-ones and
indolo[2,1-a]isoquinolin-6(5H)-ones. All these synthe-
sized products are new compounds.
Scheme 1. Synthesis of benzimidazo[2,1-a]isoquinoline-6(5H)-
ones and indolo[2,1-a]isoquinolin-6(5H)-ones.
in recent years. For example, Song and co-workers
reported an elegant Cp*Rh(III)-catalyzed [4+2] annu-
Results and Discussion
lation reaction of 2-arylimidazoles and α-diazoketoest- We initiated our study by establishing optimal exper-
ers to access benzimidazole[2,1-a]isoquinolines imental conditions using the model reaction of N-
(Scheme 1a).[8] Recently, our group developed an methacryloyl-2-phenylbenzoimidazole (1a) with C4F9I
efficient AgNO3 catalyzed decarboxylative cascade (2b) under visible-light irradiation. After extensive
cyclization reaction for the construction of alkylated/ experimentation, the optimal reaction conditions were
acylated
benzimidazo[2,1-a]isoquinolin-6(5H)-ones thus established as follows: 1a (0.2 mmol), 2b
(Scheme 1b).[9] Despite these achievements, it should (0.4 mmol), tetramethylethylenediamine (TMEDA,
be pointed out that these methods still suffer from 2 equiv.) in the CH3CN (2 mL) under irradiation of
°
some drawbacks, including the requirement of expen- 25 W blue LEDs under N2 atmosphere at 35 C for
sive metal catalysts, stoichiometric oxidant and high 12 h (see the Supporting Information for more details).
reaction temperatures. In the standpoint of green and
With the optimized conditions in hand, the substrate
sustainable organic synthesis,[10] the development of scope for this visible-light promoted reaction to access
straightforward, convenient and eco-friendly synthetic perfluoroalkyl-substituted benzimidazo[2,1-a]isoquino-
methods for the preparation of structurally diverse lin-6(5H)-ones was investigated, as illustrated in
benzimidazo-isoquinolin-6(5H)-ones is of significance Table 1. Initially, the suitability of various perfluor-
and highly desired.
oalkyl was studied under the standard conditions. It
Fluorinated functional groups are increasingly was pleased to see that seven perfluoroalkyl iodides
applicable in the fields of drugs, agrochemical indus- (ICnF2n+1, n=3–8, 10) react smoothly with 1a to give
tries as well as material sciences.[11] In particularly, the the corresponding products 3a–g in moderate to good
introduction of fluorinated alkyl moiety to heterocycle yields (52–80%). Inspired by these exciting results,
scaffolds has a profound impact on their physicochem- other fluoroalkyl iodides, including ICF2COOEt and
ical and biological properties, resulting in enhanced ICF2CF2Cl were examined. To our delight, the desired
lipophilicity, bioavailability and metabolic stability.[12] products 3h–i were obtained in 45% and 65% yields,
Among those fluorine-containing functional groups, respectively. Afterward, the reactivity of functionalized
perfluoroalkyl groups (Rf) are versatile and valuable 2-arylbenzoimidazoles was evaluated under the opti-
moieties for the development of potential mized conditions. Notably, substrates 1 bearing elec-
i
pharmaceuticals.[13] Consequently, the development of tron-donating groups (À Me, À Et, À Pr, À OMe) and
efficient and convenient protocols for the installation electron-withdrawing groups (À F, À Cl, À Br, À CF3,
of Rf into target molecules is highly desired. However, À CN) were all compatible with the optimal conditions,
examples that enable the preparation of perfluoroalkyl- delivering the corresponding products 3j–u in moder-
substituted benzimidazo[2,1-a]isoquinolin-6(5H)-ones ate to good yields (42–72%). Generally, substrates 1
have not been reported so far.
bearing electron-donating groups showed better reac-
tivity than those attached with electron-donating
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Table 1. Substrate scope for the synthesis of perfluoroalkyl-
substituted benzimidazo[2,1-a]isoquinolin-6(5H)-ones.[a]
Table 2. Substrate scope for perfluoroalkyl-substituted indolo
[2,1-a]isoquinolin-6(5H)-ones.[a]
[a] Reaction conditions: 4 (0.2 mmol), 2 (0.8 mmol) and
TMEDA (4 equiv.) in CH3CN (3 mL) with the irradiation
°
of 25 W blue LEDs under N2 atmosphere at 35 C for 12 h.
Isolated yields were given.
valuable perfluoroalkyl-substituted indolo[2,1-a]iso-
quinolin-6(5H)-ones from the functionalized 2-arylin-
doles and perfluoroalkyl iodides. As it can be seen in
Table 2, N-methacryloyl-2,3-diphenyl indole (4a) re-
acted smoothly with C4F9I (2b) to yield the product 5a
in moderate yield (65%). Encouraged by this result,
other perfluoroalkyl iodides and ICF2COOEt were
employed to react with 4a. It was observed that the
desired products 5b–e were generated in moderate to
excellent yields (60–71%). Moreover, the reactivity of
[a] Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol) and
TMEDA (2 equiv.) in CH3CN (2 mL) with the irradiation
°
of 25 W blue LEDs under N2 atmosphere at 35 C for 12 h.
Isolated yields were given.
groups. Additionally, a scale-up reaction for the syn- various substrates 4 with ICF2COOEt were examined.
thesis of 3b was performed via our designed flow The results showed that the optimal conditions were
reactor.[18] Delightfully, a good yield (56%) of the applicable to those substrates to access the products
desired product 3b was obtained, demonstrating this 5f–j in moderate to excellent yields (55–80%).
metal-free visible-light promoted cyclization reaction
Several control experiments were conducted to gain
is a robust protocol with great potential in practical more insights into the reaction mechanism of this
applications (details see the Supporting Information). visible-light promoted cyclization reaction. When the
Notably, some entries of Table 1 gave very low yields model reaction was treated with radical scavengers,
(3h, 3s, 3u). In such cases, the decomposition of the i.e., 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) or
starting material 1 into the corresponding precursors 2- 2,6-di-tert-butyl-4-methylphenol (BHT), the reactions
phenylbenzimidazoles was observed. Among all the were totally suppressed, indicating that a radical path-
newly synthetic products, the structure of 3b was way might be involved (Scheme 2).
further confirmed by X-ray crystallography (hydrogen
Additionally, the electron paramagnetic resonance
(EPR) experiment was carried out. When the radical
atoms were not shown for clarity).[19]
Indolo[2,1-a]isoquinolin-6(5H)-ones moiety is a spin trapping reagent tert-butyl-α-phenylnitrone (PBN)
core structure of nature products with various bio- was added to the mixture of TMEDA and n-perfluor-
logical activities.[20] In the following research, we also obutyl iodide in the presence of blue light irradiation, a
made an attempt to extend this visible-light promoted clear signal was observed. According to the previous
cyclization reaction for the construction of biologically report,[21] the signal should be attributed to the
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by radical cation 7 via an intermolecular single
electron transfer (SET) process to form carbocation 10,
which was finally converted to the final product 3 by
deprotonation.
Scheme 2. Control experiments.
Conclusion
In conclusion, we have developed an efficient and
convenient visible-light-induced radical cyclization
reaction for the synthesis of perfluoroalkyl-substituted
benzimidazo[2,1-a]isoquinolin-6(5H)-ones and per-
fluoroalkyl-substituted indolo[2,1-a]isoquinolin-6(5H)-
ones from perfluoroalkyl iodides and easily available
starting materials. To the best of our knowledge, this is
the first example for the preparation of perfluoroalkyl-
substituted benzimidazo[2,1-a]isoquinolin-6(5H)-ones
and indolo[2,1-a]isoquinolin-6(5H)-ones. Various fluo-
roalkyl iodides were successfully employed as the
radical precursors to initiate this radical addition/
cyclization reaction. The remarkable merits of this
photochemical strategy include one-pot procedure, no
external added photocatalysts, wide reaction substrates,
mild reaction conditions, easy scaleup as well as
experimental simplicity. Additional biological studies
and the extension of this visible-light promoted radical
cyclization reaction is currently underway in our
laboratory.
Figure 2. EPR spectra in the presence of PBN.
Experimental Section
General Procedure for the Synthesis of 3and 5: In a 25 mL
Schlenk tube, 1 or 4 (0.2 mmol) was dissolved in MeCN (2 mL,
0.1 M), then 2 (2.0 equiv. or 4.0 equiv.) and TMEDA (2.0 equiv.
or 4.0 equiv.) were added. The mixture was allowed to stir with
Scheme 3. Plausible mechanism.
°
irradiation of 25 W blue LEDs under N2 atmosphere at 35 C
for 12 h. The reaction was monitored by TLC. After substrate 1
(or 4) was completely consumed, the solvent was removed
under reduced pressure. The residue was purified by column
chromatography on silica gel to afford the desired product 3 (or
5).
corresponding adduct PBNÀ C4F9, suggesting perfluor-
*
oalkyl radical ( Rf) was generated under the reaction
conditions. Moreover, no signal was observed without
TMEDA under the identical conditions, suggesting the
importance of TMEDA (Figure 2). Furthermore, the
formation of EDA complex from C4F9I and TMEDA
19
was confirmed by using F NMR titration experiment,
Acknowledgements
and the Job’s plot analysis revealed that donor/acceptor
molar ratio for the formation of EDA complex is 1:1,
with a binding constant of 0.908 MÀ 1 in CDCl3 (see the
Supporting Information for details).[22]
We acknowledge the Centre of Advanced Analysis & Computa-
tional Science (Zhengzhou University) for the characterization
and financial support from NSFC (21501010, 21971224), China
Postdoctoral Science Foundation (2019M652561), Key Re-
search Projects of Universities in Henan Province (19A350011,
20A150006), Henan Province Young Talents Elevation Program
(2019HYTP023) and Hunan Provincial Key Laboratory of
Materials Protection for Electric Power and Transportation
(2019CL03).
Based on experimental results and previous reports,
a plausible mechanism was proposed for this visible-
light promoted cyclization reaction (Scheme 3). Ini-
tially, EDA complex was formed from TMEDA and
*
perfluoroalkyl iodide. Then perfluoroalkyl radical ( Rf)
*
and radical cation TMEDA+ (7) were generated under
*
the irradiation of visible-light. Then, the addition of Rf
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Metal-Free Visible-Light Promoted Radical Cyclization to
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Adv. Synth. Catal. 2019, 361, 1–7
F.-L. Zeng, K. Sun, X.-L. Chen*, X.-Y. Yuan, S.-Q. He, Y.
Liu, Y.-Y. Peng, L.-B. Qu, Q.-Y. Lv*, B. Yu*