Visible-Light Photocatalytic Tri- A nd Difluoroalkylation Cyclizations: Access to a Series of Indole[2,1- A[isoquinoline Derivatives in Continuous Flow

Article abstract of DOI:10.1021/acs.orglett.1c00476

A process for achieving photocatalyzed tri- A nd difluoromethylation/cyclizations for constructing a series of tri-or difluoromethylated indole[2,1-a]isoquinoline derivatives is described. This protocol utilized an inexpensive organic photoredox catalyst and provided good yields. Moreover, the combination of continuous flow and photochemistry, designed to provide researchers with a unique green process, was also shown to be key to allowing the reaction to proceed (product yield of 83% in flow vs 0% in batch).

Full text of DOI:10.1021/acs.orglett.1c00476

pubs.acs.org/OrgLett
Letter
Visible-Light Photocatalytic Tri- and Difluoroalkylation Cyclizations:
Access to a Series of Indole[2,1‑a]isoquinoline Derivatives in
Continuous Flow
Xin Yuan, Xiu Duan, Yu-Sheng Cui, Qi Sun, Long-Zhou Qin, Xin-Peng Zhang, Jie Liu, Meng-Yu Wu,
Jiang-Kai Qiu,* and Kai Guo*
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ABSTRACT: A process for achieving photocatalyzed tri- and
difluoromethylation/cyclizations for constructing a series of tri- or
difluoromethylated indole[2,1-a]isoquinoline derivatives is de-
scribed. This protocol utilized an inexpensive organic photoredox
catalyst and provided good yields. Moreover, the combination of
continuous flow and photochemistry, designed to provide
researchers with a unique green process, was also shown to be key to allowing the reaction to proceed (product yield of 83% in
flow vs 0% in batch).
Scheme 1. Overview of the Fluoroalkylation/Cyclization/
Indole Strategy Employed in This Study
ue to their synthetic utility and various biological activities,
nitrogen-containing heterocycles, particularly fused indole
D
derivatives, are of great importance in organic synthesis and
pharmaceuticals.1−3 The compounds have attracted consid-
erable attention from both synthetic and medicinal chemists.4 In
the past few years, much effort has been devoted to constructing
the indole[2,1-a]isoquinoline core structure, and this effort has
predominantly relied on a cyclization strategy chiefly employing
transition metal complexes (e.g., Pd,5,6 Mn7) as catalysts
(Scheme 1A). However, the utility of these protocols for
large-scale synthesis is still rather limited due to relatively high
toxicity levels and costs of the transition metal complexes. Thus,
it is highly desirable to design green and sustainable synthetic
routes to construct indole[2,1-a]isoquinoline derivatives. The
resurgence of visible-light-mediated photoredox catalysis and
electrocatalysis have resulted in an operationally simple strategy
for the construction of these compounds.8−10 Notably, Xu’s
group have developed a powerful transformation for the
synthesis of the indole[2,1-a]isoquinoline skeleton via an
iridium (Ir)-based catalyzed radical cascade cyclization reac-
tion.11 Due to the high costs of the common metal catalysts
used, i.e., of the Ru and Ir complexes, the relatively inexpensive
organic donor−acceptor fluorophore photocatalysts, which also
display broad redox capabilities, offer an intriguing alter-
native.12−14
containing heterocycles.20,21 Recently, practical fluoralkylation
has been realized by the action of visible-light catalysis on a
variety of fluorinating sources such as Togni, Umemoto, and
The methods for the incorporation of fluorine atoms into
organic molecules have attracted considerable attention because
the fluorine-containing compounds widely exist in pharmaceut-
icals and agrochemicals and materials.15−18 However, almost all
of the classical protocols suffer from harsh conditions and
require expensive metal catalysts or toxic solvents.19 On the
other hand, visible-light photoredox catalysis also offers a novel
and efficient method to access the construction of fluoro-
Received: February 8, 2021
Published: February 24, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00476
© 2021 American Chemical Society
Org. Lett. 2021, 23, 1950−1954
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Langlois reagents.22−26 Well-designed sources of CF3/CF2H are
still not available, as recent studies have highlighted the
problems with the currently available ones.27,28 Moreover, we
previously reported a useful method for carrying out
trifluoromethylations/cyclizations of 1,7-enynes by using
Ph2SCF3OTf as a CF3 source in continuous flow.29 In 2017,
Akita and co-workers reported a shelf-stable easy-to-handle
sulfonium salt, namely, Ph2SCF2HBF4 (S-difluoromethyl-S-
di(p-xylyl)sulfonium tetrafluoroborate).30
a
Table 1. Optimization of the Reaction Conditions
b
entry
deviation from standard conditions
yield (%)
1
2
3
none
83
17
53
28
21
40
51
0
The use of light energy impairs the overall sustainability of the
photocatalytic reactions as dictated by the Bouguer−Lambert−
Beer law. Photochemical processes and continuous-flow
chemistry have, when used in combination, led to the
development of various reactions.31−33 In continuous-flow
chemistry, continuous reactions are carried out in tubes or a
microreactor. The keys to the success of carrying out reactions
using continuous flow have been shown to involve achieving an
improved mixing ability and more efficient heat transfer as well
as the ability to scale up such reactions.34 Compared to the
traditional batch reactions, continuous flow technology offers
many advantages. This technology has been used in the
screening and optimization of various reactions.35,36 Jamison
and Stephenson et al. have realized their unprecedent works in
this area.37 However, to the best of our knowledge, there has
been no report on the construction of indole[2,1-a]isoquinoline
derivatives in continuous flow under the condition of metal-free
photocatalysts and green solvent without any other bases.
Inspired by these achievements, we set out to and successfully
developed photocatalyzed tri- and difluoromethylation/cycliza-
tion process for the construction of a series of tri- or
difluoromethylated indole[2,1-a]isoquinoline derivatives in
good yields under mild conditions via a noble metal-free
protocol in continuous flow.
Initially, we commenced our study by employing (S)-3,5,12-
trimethyl-5-(2,2,2-trifluoroethyl)indolo[2,1-a]isoquinolin-
6(5H)-one (1a) and diphenyl(trifluoromethyl)sulfonium tri-
fluoromethane-sulfonate (2a) as the model set of substrates in
CH3CN to test the reaction conditions (Table S1, entry 8).
Although the desired product 3a was observed, the reaction
generally proceeded slowly. Thus, we set up a continuous-flow
photoreactor (Figure S2) made according to the needs of the
reaction to speed up the efficiency of the transformation (Table
S1, entry 7). Next, we investigated solvents of the reaction. To
find lower toxicity and less costly green solvent, a series of other
solvents including THF, DMSO, MeOH, 1,4-dioxane, and DMF
were screened, but acetone was indicated from the results to be
the best choice for this reaction (Table S1, entries 1−12). The
use of EtOH reduced the onset potential of reaction due to its
poor ability to dissolve both photocatalyst and reagents (Table
1, entry 3). To our delight, the desired indole[2,1-a]isoquinoline
(3a) product was obtained in 10 min in 83% yield in acetone at
room temperature when using the organic photocatalyst (4s,6s)-
2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile (4CzIPN)13 as
the photocatalyst, a PFA tube (ID = 600 μm, volume = 1.0 mL),
a flow rate of 100 μL/min, and 50 W blue LED irradiation
(Table 1, entry 1). In further optimization studies, fac-Ir(ppy)3
displayed significantly lower catalytic efficacy (Table 1, entry 7).
However, when Ph2SCF3OTf was replaced with CF3SO2Na as
the source of CF3, the yield of the product 3a decreased to 28%
while extra water was needed to achieve a clear reaction solution
(Table 1, entry 4); the poorer yield was attributed to the
presence of this extra water. The addition of bases resulted in less
reactivity for this reaction (Table 1, entries 6 and 7). From
MeOH as the solvent
EtOH as the solvent
CF3SO2Na as the CF3 source
Et3N as additive (2.0 equiv)
pyridine as additive (2.0 equiv)
fac-Ir(ppy)3 as the catalyst
in batch
c
4
5
6
7
d
8
9
without catalyst
2
10
11
12
two injection system
tube (ID = 800 μm)
200 μL/min
76
75
49
a
Standard reaction conditions: 1a (0.2 mmol), 2a (0.22 mmol),
4CzIPN (1.0 mol %) in 2.0 mL of acetone irradiated with light from
50 W blue LEDs (455 nm) at room temperature inside a 1.0 mL
reactor of a flow system (PFA tube, ID = 600 μm, 100 μL/min). See
the Supporting Information for more details. The isolated yield of
each recrystallized product was calculated based on 1a. CF3SO2Na as
the CF3 source; here another 0.5 mL of H2O was needed for
achieving a dissolution of the reaction mixture. Air, 5 h.
b
c
d
control experiments, both light and the photocatalyst were
concluded to be crucial to the success of the reaction (Table S4,
entries 1−4). Using a batch condition, however, failed to deliver
product 3a by 19F NMR, even when a longer reaction time was
used (Table 1, entry 8). We speculate the continuous flow
system was the most efficient as well as mixing ability compared
to the batch. However, the mechanism of the phenomenon is
not clear. The flow conditions were also examined, and use of a
thicker pipe (ID = 800 μm) and faster rate (200 μL/min)
provided lower yields (Table 1, entries 11 and 12).
With optimized conditions in hand, we investigated the
scopes of indole substrates and CF3 sources for the photo-
catalytic di/trifluoromethylation/cyclization reaction. As shown
in Scheme 2, a variety of functional groups were observed to be
well tolerated, forming products bearing various substituted 2-
arylindoles in the flow system. Notably, changing the electronic
properties of the substituent (R1) at the para position of the 2-
phenyl moiety of the N-substituted 2-aryl indole was found to
have little influence on its catalytic efficiency. Electron-neutral
substituents (−Me), electron-withdrawing groups (−F, −Cl,
−Br), and an electron-donating group (−OMe) were all
compatible with this reaction, giving the corresponding products
in 52−83% yields (3a−3g). Subsequently, the electronic nature
of the substituent located on the C3 position of the indole ring
was investigated; for two cases, products formed efficiently
regardless of the electronic nature of the substituent (3h and 3i).
Various substituents at the C5 position of the indole ring were
also readily tolerated in this system, delivering the correspond-
ing products in good to moderate yields (3j−3n). Besides these
examples, substrates containing different groups at the R4
position also gave the corresponding products in moderate
yields (3o−3q).
Due to their special chemical and biological properties,
difluoromethyl compounds are significant and widely used in the
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Scheme 2. Overview of the Trifluoromethylation/Cyclization
Reaction
Scheme 3. Overview of the Difluoromethylation/Cyclization
Reaction
a
,b
a,b
a
a
Reaction conditions: 1 (0.2 mmol), 2a (0.22 mmol), 4CzIPN (1.0
mol %), and acetone as the solvent (2.0 mL) in a PFA tube (ID = 600
μm, volume = 1.0 mL) at a flow rate of 100 μL/min under 50 W blue
Reaction conditions: 1 (0.2 mmol), 2c (0.22 mmol, tests using
Ph2SCF2HBF4 as a CF2H source), 4CzIPN (1.0 mol %), 2.0 mL of
acetone as the solvent in a PFA tube (ID = 600 μm, volume = 1.0
mL) at a flow rate of 100 μL/min under 50 W blue LED irradiation at
b
LED irradiation at room temperature after 10 min. The isolated yield
of each recrystallized product was calculated on the basis of 1.
b
room temperature after 10 min. The isolated yield of each
recrystallized product was calculated on the basis of 1.
pharmaceutical and agrochemical industries.37 Therefore, we
attempted to test the Ph2SCF2HOTf reagent (2b) as a CF2H
source but it decomposed about 2 h later when stored at room
temperature or in solvents. We were able to test the S-
(difluoromethyl)sulfonium reagent as the CF2H source as it was
easily synthesized and stable.30 We tested the ability to use it to
carry out the photocatalyzed difluoromethylation of 1 and give
potentially useful CF2H-substituted isoquinoline products
(Scheme 3). The reaction of various forms of 1 bearing different
functional groups such as Me, OMe, F, Cl, and Br among others
afforded the corresponding CF2H-substituted isoquinoline
compounds (4a−4p) in 34−66% yields. Imidazole[2,1-a]-
isoquinoline derivative products 6 are also suitable to this
transformation from 5 (for details see the Supporting
Information).
After finishing these, we next turned our attention to a
mechanistic interrogation to determine the formation of C−C
bond activation and CF3/CF2H radicals. A series of control
reactions were carried out to determine and understand the
reaction mechanism of the electrocatalytic fluoromethylation/
cyclization reaction (Figure 1). First, the radical-trapping
reagent 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) serving
as a radical scavenger was added to the reaction mixture under
standard reaction conditions (Figure 1a). As expected, the
reaction was completely quenched, and the corresponding 3a
failed to be detected, which indicated that a radical process
occurred in this transformation. Second, Stern−Volmer studies
were carried out to understand the process of the oxidative
quenching mechanism. The results suggested that the excited-
state PC* was quenched by 1a more efficiently than by 2a, which
indicated a reductive quenching mechanism (Figure 1b−e).
Figure 1. Mechanistic studies. (a) Radical trapping experiment. (b)
Fluorescence quenching experiments with 4CzIPN and various
concentrations of 1a. (c) Fluorescence quenching experiments with
4CzIPN and various concentrations of 2a. (d) Fluorescence quenching
experiments with 4CzIPN and various concentrations of 2b. (e) Stern−
Volmer plots of 4CzIPN with different quenchers.
Furthermore, we conducted a scale-up (1.0 mmol) reaction
based on 1a under standard conditions (Scheme 4). To our
delight, we could obtain the desired product 3a with the yield of
80%. The satisfactory result indicated that the application of
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a,b
Scheme 4. Scale-Up Experiment
FAIR data, including the primary NMR FID files, for
compounds 3a−3r, 4a−4p, and 6a−6e (ZIP)
Experimental procedures, more optimization of reaction
conditions, the equipment of the reaction, X-ray
crystallography structure of compound 3e, character-
ization data, copies of 1H NMR, 13C NMR, and 19F NMR
spectra for the products (PDF)
a
Reaction conditions: 1a (1.0 mmol), 2a (1.1 mmol), 4CzIPN (1.0
mol %), and acetone as the solvent (10.0 mL) in a PFA tube (ID =
600 μm, volume = 1.0 mL) at a flow rate of 100 μL/min under 50 W
Accession Codes
b
CCDC 2039357 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 Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
blue LED irradiation at room temperature. The isolated yield of
recrystallized product was calculated on the basis of 1a.
continuous-flow technology was also suitable for the scale-up
reaction.
On the basis of related literature reports11,29 and the above-
mentioned observations, we proposed a possible mechanism for
this photocatalyzed fluoroalkylation/cyclization reaction
(Scheme 5). Initially, photocatalyst PC (4CzIPN) excited by
AUTHOR INFORMATION
■
Corresponding Authors
Jiang-Kai Qiu − College of Biotechnology and Pharmaceutical
Engineering, Nanjing Tech University, Nanjing 211816,
China; Email: qiujiangkai@njtech.edu.cn
Scheme 5. Possible Mechanism
Kai Guo − College of Biotechnology and Pharmaceutical
Engineering, Nanjing Tech University, Nanjing 211816,
China; orcid.org/0000-0002-0013-3263; Phone: (+86)-
25-5813-9926; Email: guok@njtech.edu.cn; Fax: (+86)-
25-5813-91926
Authors
Xin Yuan − College of Biotechnology and Pharmaceutical
Engineering, Nanjing Tech University, Nanjing 211816,
China
Xiu Duan − College of Biotechnology and Pharmaceutical
Engineering, Nanjing Tech University, Nanjing 211816,
China
Yu-Sheng Cui − College of Biotechnology and Pharmaceutical
Engineering, Nanjing Tech University, Nanjing 211816,
China
Qi Sun − College of Biotechnology and Pharmaceutical
Engineering, Nanjing Tech University, Nanjing 211816,
China
Long-Zhou Qin − College of Biotechnology and Pharmaceutical
Engineering, Nanjing Tech University, Nanjing 211816,
China
Xin-Peng Zhang − College of Biotechnology and
Pharmaceutical Engineering, Nanjing Tech University,
Nanjing 211816, China
Jie Liu − College of Biotechnology and Pharmaceutical
Engineering, Nanjing Tech University, Nanjing 211816,
China
Meng-Yu Wu − College of Biotechnology and Pharmaceutical
Engineering, Nanjing Tech University, Nanjing 211816,
China
visible light irradiation (PC*) reduced Ph2SCF3OTf generate a
CF3 radical by way of a single electron transfer (SET) process.
Then, the CF3• radical added to the CC bond of the indole
derivative (1a) to give a new carbon radical intermediate I,
which underwent an intramolecular cyclization to give the
radical intermediate II. Subsequently, II interacted with PC− to
form the cation III via a single electron transfer (SET) process.
At last, the deprotonation of carbocation III to afford the
cyclization product 3a.
In summary, we have developed a photocatalyzed fluoroalky-
lation/cyclization reaction under mild conditions in continuous
flow. A vast array of tri- or difluoromethylated indole[2,1-
a]isoquinoline derivatives were obtained in moderate to good
yields by using readily accessible Ph2SCF3OTf or Ph2SCF2HBF4
reagents as the CF3/CF2H sources. Detailed mechanistic studies
provided strong support for the radical fluoroalkylation/
cyclization sequence. It is particularly worthy of note that the
robustness of the strategy involving photocatalysis and
continuous flow was shown for this reaction to clearly
outperform the batch performance (83% vs 0%). Moreover,
this radical sequence provides a highly valuable methodology for
fluorinated diketone synthesis and could be further extended for
use in industrial applications.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00476
Author Contributions
All authors have given approval to the final version of the
manuscript.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00476.
■
sı
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (Grant No. 21702103, 21522604)
and the youth in Jiangsu Province Natural Science Fund (Grant
No. BK20150031).
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