CF3SO2Na-Mediated, UV-Light-Induced Friedel-Crafts Alkylation of Indoles with Ketones/Aldehydes and Bioactivities of Products

Article abstract of DOI:10.1021/acs.orglett.9b04272

A concise, one-step route to produce 3,3′-diindolylmethanes (DIMs) from simple indoles and ketones or aldehydes is reported. The key step is the ready formation of indole derivatives that involves the in situ conversion of CF₃SO₂Na r

Full text of DOI:10.1021/acs.orglett.9b04272

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Letter
CF3SO2Na-Mediated, UV-Light-Induced Friedel−Crafts Alkylation of
Indoles with Ketones/Aldehydes and Bioactivities of Products
Tianbao Yang,∥ Huiai Lu,∥ Yixuan Shu, Yifeng Ou, Ling Hong,* Chak-Tong Au, and Renhua Qiu*
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ABSTRACT: A concise, one-step route to produce 3,3′-diindolylmethanes (DIMs) from simple indoles and ketones or aldehydes is
reported. The key step is the ready formation of indole derivatives that involves the in situ conversion of CF3SO2Na reagent to ·CF3
under oxygen or air (1.0 atm) and UV irradiation. It is disclosed that most of the obtained DIMs show anticancer activities in human
bladder cancer cell lines EJ and T24.
ndole moieties are common in a great number of
pharmaceuticals and biologically important natural prod-
Because of their biological potential, DIMs have received
much attention in organic synthesis, and several highly efficient
methods have been developed for their production.12−14 One
of them is the Cu-catalyzed cross-coupling of asymmetry
substituted indole (Scheme 2a).12d By means of organo-
catalysis, Huo et al.12e developed a synthetic method to
generate DIMs from sodium triphenylphosphine-m-sulfonate
(TPPMS) and CBr4 (Scheme 2b). Later, Toy et al.12a used a
novel approach of “halogen bond donor” to catalyze Friedel−
Crafts reactions of indoles with aldehydes and ketones for the
direct production of DIMs. Moreover, a concise method has
been realized with specific active starting materials for the
synthesis of DIMs at 80−100 °C without the need of a catalyst
(Scheme 2c).12b,c In recent years, photocatalysis has been
demonstrated to be an effective approach for the construction
of useful organic skeletons under mild conditions. The first Rh-
6G-catalyzed and photoinduced aerobic oxidative cross-
coupling of indoles to DIMs was achieved by Zhang et al.
using active glycine derivatives (Scheme 2d).9 Nonetheless,
most of the existing methods involve the use of a transition
metal, an acid or a base, a Lewis acid, or substrate activation.
Thus a simple, mild, and general protocol to afford DIMs is
meaningful.
I
ucts.1 It is especially so for the diindolylmethane derivatives
(DIMs),2 which exhibit a wide range of bioactivities, such as
antileishmanial,3 antistaphylococcal,4 and anticancer.5 For
example (Scheme 1), 3,3′-diindolylmethane (A1) is a novel
Scheme 1. Biologically Active DIMs
Herein we demonstrate a highly efficient method for the
synthesis of DIMs from simple indoles and aldehydes or
ketones directly using easily handled, greatly abundant, and
preventive for breast cancers and has been used in therapeutic
treatment,6 and 3,3′-((4-methoxyphenyl)methylene)bis(1H-
indole) (5b) could serve as an orphan nuclear receptor.7
Furthermore, vibrindole A (A2) is useful for the treatment of
fibromyalgia, chronic fatigue, and irritable bowel syndrome.8
As for natural products, arsindoline A (A3)9 and arsinoline B
(A4)10 from a marine-derived bacterium strain CB101 and
their analogues have been reported.11
Received: November 28, 2019
https://dx.doi.org/10.1021/acs.orglett.9b04272
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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a
Scheme 2. Synthetic Approaches toward DIMs
Table 1. Optimization of Reaction Conditions for 3a
entry
2a (equiv)
CF3SO2Na (equiv)
time (h)
yield (%)
b
1
2
3
4
5
6
7
8
46
46
46
46
46
1
2
3
4
5
0.1
0.5
0.7
1
2
2
2
2
2
2
24
24
24
24
24
19
19
19
19
19
24
24
24
24
24
36
44
61
57
63
36
60
60
b
b
b
b
b
9
59
77
81
10
11
12
13
14
15
5
5
5
5
2
2
2
2
c
NR
NR
e
d
34
f
5
2
NR
a
Reaction conditions: indole 1a (0.3 mmol, 1.0 equiv), acetone 2a
(1.5 mmol, 5.0 equiv), CF3SO2Na (0.6 mmol, 2.0 equiv), toluene (1.0
mL, 0.3 M), O2 (1.0 atm), UV irradiation (350−380 nm, 26 W lamp),
b
c
d
e
rt, 24 h; isolated yield. GC yield. No light. N2 atmosphere. Air
f
atmosphere. No CF3SO2Na.
a
Scheme 3. Substrates Scope with Alkyl Ketone
commercially available neutral salt CF3SO2Na as a mediator.
The reaction is conducted at room temperature under UV
irradiation and 1 atm pressure. The method does not involve
any use of a transition metal, photocatalyst, base, or acid. It
shows a broad substrate scope and gram-scalable ability. It is
noted that most of the obtained DIMs show anticancer
activities in human bladder cancer cell lines EJ and T24.
Finally, a possible mechanism is proposed for the synthesis.
We first attempt to synthesize 3,3′-(propane-2,2-diyl)bis-
(1H-indole) 3a by treating a mixture of indole 1a with acetone
2a (1.0 mL, also as a solvent) and 1.0 equiv of CF3SO2Na
under UV irradiation in an oxygen atmosphere, and the yield of
3a is 57% (Table 1, entries 1−4). Next, we optimize the
amount of CF3SO2Na, and 2.0 equiv of the salt is the best
(63%, entry 5). Afterward, the reaction is carried out at room
temperature by adding 5.0 equiv of acetone 2a, and the 3a
yield is 77% at 19 h (entry 10) and 81% at 24 h (entry 11).
The reaction does not take place without light or oxygen
(entries 12 and 13). When the reaction is conducted in air (1
atm), the yield is low (34%, entry 14). In addition, in the
absence of CF3SO2Na, there is no reaction (entry 15). The X-
ray structure of 3a is shown in Scheme 3.
Adopting the optimized conditions, we explored the scope of
the substrates (Scheme 3). With the attachment of the
electron-deficient fluorine atom on the indole, there is an
apparent decrease in reactivity (3b, 17%), plausibly due to the
lowering of the electron density of aromatic rings. In the case
of introducing a 5-methoxy group on the indole, the product
yield increases to 49% (3c). The insertion of a cyano group
results in a good product yield (3d, 84%). With 5-NO2 and 6-
NO2 groups on the rings, the yields of products 3e and 3f are
significantly different, 70 and 38%, respectively. In the case of
having a 7-methoxy group on the rings, the yield of 3g is 55%.
As for alkyl ketones, cyclopentanone and cyclohexanone give
3h and 3i in 40 and 30% yield, respectively. Compared with
a
Reaction conditions: indole 1 (0.3 mmol, 1.0 equiv), ketone 2 (1.5
mmol, 5.0 equiv), CF3SO2Na (0.6 mmol, 2.0 equiv), toluene (1.0 mL,
0.3 M), O2 (1.0 atm), UV irradiation (350−380 nm, 26 W lamp), rt,
24 h; isolated yield.
the previous protocol,14a our approach gives a better yield of
3a (81%). (The yield of using Bi(NO3)3·5H2O as the catalyst
is 67%.)
Aromatic ketones are also well adopted in this reaction
(Scheme 4). Acetophenones with bromine and iodine show
similar reactivities (4a−c, 58−62%). Acetonaphthones with
methyl sulfide and naphthyl groups give 4d and 4e in much
lower yield (31 and 26%, respectively). With the thiophene
derivative, the yield of 4f is 36%, but in the cases of furan and
pyrrole, there is no yield of any product. However, our system
provides excellent selectivity for 4a,b. Nonetheless, when HCl
was used, the yields of 4a and 4b become 37 and 53%,
respectively, with two side products.13
Compared with the ketones that are less reactive, the
aldehydes show much higher efficiency. No matter whether an
B
https://dx.doi.org/10.1021/acs.orglett.9b04272
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a
gram scale. It was demonstrated that they can be successfully
prepared in 96 (1.24 g) and 87% (1.53 g) yield, respectively
(Scheme 6).
Scheme 4. Substrates Scope with Aromatic Ketones
Scheme 6. Gram-Scale Experiment
a
Reaction conditions: indole 1a (0.3 mmol, 1.0 equiv), ketone 6 (1.5
mmol, 5.0 equiv), CF3SO2Na (0.6 mmol, 2.0 equiv), toluene (1.0 mL,
0.3 M), O2 (1.0 atm), UV irradiation (350−380 nm, 26 W lamp), rt,
24 h; isolated yield.
To reveal the synthetic mechanism, we did a series of
control experiments. First, 2.0 equiv of 2,2,6,6-tetramethylpi-
peridinooxy (TEMPO) or butylated hydroxytoluene (BHT)
was added to the reaction system under standard conditions,
and there was no or only a trace amount of desired product,
respectively (Scheme 7a,b). It is envisioned that 1,1-diphenyl-
electron-donating or an electron-withdrawing group is attached
on the aromatic rings (e.g., methoxy, bromine, chlorine), the
aldehydes readily give DIMs in good yield under an air
atmosphere (5a−e, 76−89%) (Scheme 5). 3-Nitrobenzalde-
a
Scheme 7. Control Experiments
Scheme 5. Substrate Scope with Aldehydes
a
Reaction conditions: indole 1 (0.3 mmol, 1.0 equiv), aldehyde 7 (1.5
mmol, 5.0 equiv), CF3SO2Na (0.6 mmol, 2.0 equiv), toluene (1.0 mL,
0.3 M), air (1.0 atm), UV irradiation (350−380 nm, 26 W lamp), rt,
24 h; isolated yield.
ethylene does not capture the CF3 radical but rather diverts the
reaction to form benzophenone, as detected by GC−MS
(Scheme 7c). Therefore, we speculate that there is the
generation of a highly active ·CF3 radical. When the N−H
bond of the simple indole was replaced with an N-methyl
bond, there was no detection of the expected product (Scheme
7d). The result indicates the necessity of the N−H bond for
the ready conversion of the generated nitrogen radical to a
carbon radical through a 1,3-H shift.
On the basis of the results of the control experiments and
those of the literature,17 we proposed a possible mechanism, as
illustrated in Scheme 8. At the beginning, upon UV irradiation,
CF3SO2Na is oxidized to generate ·CF3 radical under an O2-
containing atmosphere,18 and ·CF3 attacks the amino hydrogen
of indole to form nitrogen radical A and CF3H.19 By a 1,3-H
shift (detected by 19F NMR; see the SI), radical A readily
isomerizes to carbon radical B. Then, radical B reacts with
acetone to generate oxygen radical C, which reacts with
hyde and 4-nitrobenzaldehyde could also participate in this
reaction (5g,h, 80−87%). As for heteroaryl aldehydes such as
thiophene-2-carbaldehyde, furfural, and 9-ethyl-9H-carbazole-
4-carbaldehyde, 5i, 5j, and 5k are produced in 87, 43, and 87%
yield, respectively. Notably, if the reaction of these aldehydes
was conducted under an O2 atmosphere, then there would be
many side products, and the corresponding yields would be
much lower.
The product bis(indolyl)methanes 5a is an antioxidant that
can scavenge the 1,1-diphenyl-2-picrylhydrazyl (DPPH)
radical by donating an electron.15 It was reported that 5f is a
potent apoptogenic agent in leukemic cells through the
inhibition of MAPK signaling and the suppression of the
intrinsic and possibly caspase-independent apoptotic path-
ways.16 To illustrate their potential for practical application in
terms of facile fabrication, 5a and 5f were synthesized on a
C
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Scheme 8. Possible Reaction Mechanism
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04272.
Detailed experimental procedures, compound character-
ization data, and NMR spectra (PDF)
Accession Codes
CCDC 1965538 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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
CF3SO2Na and H2O to generate ·CF3 and active indole D.
Indole D can undergo β-elimination to generate intermediate
E, whereas the other indole reacts with intermediate E20 to
form intermediate F, which isomerizes to produce 3a.
It was demonstrated before that DIMs are heterocyclic
compounds possessing high bioactivities;2−5 we hence
screened the compounds for anticancer activities in human
bladder cancer cell lines T24 and EJ using the CCK-8 assay. It
was found that compounds 3b, 3d, 3f, 3i, 4a, 4c, 4f, 5a, 5b, 5d,
and 5j can reduce >50% of the viability of the cancerous cell
line (Figure 1). A further investigation of their bioactivities,
especially those of 3d, 4a, 5a, and 5j, is underway in our
laboratory. (For details of bioactivity experiments, see the SI.)
AUTHOR INFORMATION
Corresponding Authors
■
Ling Hong − Huazhong University of Science and
Technology, Wuhan, P. R. China; Email: lhong@
mail.hust.edu.cn
Renhua Qiu − Hunan University, Changsha, P. R. China;
orcid.org/0000-0002-8423-9988;
Email: renhuaqiu@hnu.edu.cn
Other Authors
Tianbao Yang − Hunan University, Changsha, P. R.
China
Huiai Lu − Huazhong University of Science and
Technology, Wuhan, P. R. China
Yixuan Shu − Huazhong University of Science and
Technology, Wuhan, P. R. China
Yifeng Ou − Hunan University, Changsha, P. R. China
Chak-Tong Au − Hunan Institute of Engineering,
Xiangtan, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.9b04272
Author Contributions
∥T.Y. and H.L. contributed equally to this work.
Notes
The authors declare no competing financial interest.
Figure 1. Anticancer activities of DIMs in human bladder cancer cell
lines EJ and T24.
ACKNOWLEDGMENTS
■
We thank Prof. Nobuaki Kambe (Osaka University) for the
helpful discussion. We thank the Natural Science Foundation
of China (nos. 21676076, 21878071, and 21971060), Hu-
Xiang High Talent of Hunan Province (2018RS3042), and
Recruitment Program for Foreign Experts of China
(WQ20164300353) for financial support.
In summary, a concise and mild method without the need
for a base, acid, or photocatalyst is developed to synthesize
DIMs under UV irradiation and an oxygen or air atmosphere.
The key step is the ready formation of indole derivatives
involving the in situ generation of ·CF3 from readily available
CF3SO2Na. In addition, a variety of ketones and aldehydes are
well tolerated in this protocol, and the condensation adducts
are obtained with high regioselectivity. The yield of the gram-
scale synthesis could be up to 96%, and most of the obtained
DIMs exhibit anticancer activities in human bladder cancer cell
lines EJ and T24.
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