Visible-Light-Induced Trifluoromethylation of Isonitrile-Substituted Indole Derivatives: Access to 1-(Trifluoromethyl)-4,9-dihydro-3H-pyrido[3,4-b]indole and β-Carboline Derivatives

Article abstract of DOI:10.1002/adsc.201800568

A visible-light-induced trifluoromethylation of isonitrile-substituted indole derivatives has been developed from the reaction of isonitrile-substituted indoles with Togni II reagent, affording 1-(trifluoromethyl)-4,9-dihydro-3H-pyrido[3,4-b]indoles in mo

Full text of DOI:10.1002/adsc.201800568

Title: Visible-Light-Induced Trifluoromethylation of Isonitrile-Substituted
Indole Derivatives: Access to 1-(Trifluoromethyl)-4,9-dihydro-3H-
pyrido[3,4-b]indole and β-Carboline Derivatives
Authors: Min Shi, Jiaxin Liu, Long-Hai Li, Liu-Zhu Yu, Lisha Tang, and
Qin Chen
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800568
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10.1002/adsc.201800568
Advanced Synthesis & Catalysis
.
Updates
DOI: (will be filled in by the editorial staff)
Visible-Light-Induced Trifluoromethylation of Isonitrile-Substituted
Indole Derivatives: Access to 1-(Trifluoromethyl)-4,9-dihydro-3H-
pyrido[3,4-b]indole and β-Carboline Derivatives
Jiaxin Liu,a Longhai Li,a Liuzhu Yu,a Lisha Tang,b Qin Chen,b* and Min Shia*
a
State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, University of Chinese
Academy of Sciences, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, People’s Republic of China.
b Research Center for Molecular Recognition and Synthesis, Department of Chemistry, Fudan University, 220 Handan Lu,
Shanghai 200433, People’s Republic of China,
Fax: (+86)-21-6416-6128; e-mail: chenq@fudan.edu.cn; mshi@mail.sioc.ac.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http:// /adsc.201######.((Please delete if not
appropriate))
Abstract:
A
visible-light-induced trifluoromethylation of
isonitrile-substituted indole derivatives has been developed from
the reaction of isonitrile-substituted indoles with Togni II
reagent,
affording
1-(trifluoromethyl)-4,9-dihydro-3H-
Figure 1. Structures of some β-carboline natural products.
pyrido[3,4-b]indoles in moderate to good yields. The further
transformations to β-carboline derivatives and a harmacine
derivative have been performed, demonstrating the potential
synthetic utility of this method. A preliminary biological study
indicated that the CF3-containing harmine analogue significantly
stimulated the secretion of glucagon-like peptide-1 (GLP-1),
suggesting an improvement in treating diabetes
In recently reported trifluoromethylation reactions, many
commercially available reagents have been used as trifluoromethyl
sources to participate in the photo-induced trifluoromethylation
reactions such as Togni II reagent,[11] TMSCF3,[12] Umemoto
reagent,[13] CF3SO2Cl,[14] and Langlois reagent.[15]
Keywords: visible-light catalyst; trifluoromethylation; β-
carboline derivatives; Togni II reagent; biological study
Over the past decade, visible-light photoredox catalysis
has been discovered by MacMillan,[1a] Yoon[1b] and
Stephenson.[1c] Due to its efficient, mild, green characteristics,
it has been intensively studied and broadly applied in organic
synthesis with significant achievements.[2] Currently, it has
become
molecules
a
powerful synthetic tool to construct complex
under mild Organofluorine
conditions.[3]
Scheme 1. Previous work and this work on the synthesis of
dihydro-β-carboline.
compounds have been extensively studied because of its
unique physical and chemical properties.[4] Introducing
fluorine or fluorine-containing group into organic compounds
might display improved membrane permeability and increased
bioavailability than those of non-fluorinated analogues as
usual.[5] For this reason, trifluoromethyl group as an important
building block has been widely used in drugs and drug
candidates due to its special solubility and lipophilicity.[6]
Thus far, the development of new strategies for introducing
trifluoromethyl group into organic compounds has drawn a
particular interest and many excellent works have been
reported.[7] In this aspect, MacMillan’s group has described a
novel protocol for the asymmetric α-trifluoromethylation of
aldehyde via cooperative photo- and organocatalysis in 2009.[8]
Subsequently, the trifluoromethylation of olefins has also been
achieved.[9] Moreover, the process of trifluoromethylation via
synergistic photocatalysis and transition metal catalysis has
been also reported by Sanford.[10]
Isonitriles have
a
broad synthetic applications in
multicomponent reactions.[16] In 2008, Studer and co-workers first
reported the radical trifluoromethylation of isonitriles using Togni
II reagent as the CF3 source and Bu4NI as an initiator, providing
the trifluoromethylated phenanthridines in moderate to good
yields.[17] After that, several related investigations on isonitriles
have been also disclosed.[18] These intriguing findings inspired us
to use isonitriles as accepters to realize trifluoromethylation under
visible-light photoredox catalysis.
The indole structure widely exists in biomolecules and drugs
due to its unique biocompatibility and bioactivities.[19] As a
branch of indole derivatives, β-carboline derivatives such as (±)-
eleagnine, harmine and (±)-harmacine have a wide bioactivities
in antitumor, receptor inhibition and antidiabetic (Figure 1).[20]
However, the limited substrate scope for the synthesis of β-
carboline derivatives has impaired their potential applications. In
the meantime, some of the synthetic methods were also carried
1
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10.1002/adsc.201800568
Advanced Synthesis & Catalysis
out under harsh conditions (Scheme 1a).[21] On the basis of these
circumstances, we envisaged to develop a new method to
synthesize trifluoromethylated dihydro-β-carboline in the
presence of Togni II reagent upon visible-light photoredox
catalysis. Herein, we wish to report a trifluoromethylation
reaction of isonitrile-substituted indole derivatives[22] via visible-
formation of 3a (Table 1, entry 17). A scale up of this reaction
has been indicated on page S19 in the Supporting Information.
light photoredox catalysis to produce
a
series of
trifluoromethylated dihydro-β-carboline derivatives, which
exhibit the potential usefulness in pharmaceutical chemistry
(Scheme 1b).
Table 1. Optimization of the reaction conditions for the synthesis
of 3a
Scheme 2. Substrates scope of the synthesis of 3.a,b
With the optimized reaction conditions in hand, the
substrate scope and functional group tolerance were next
examined. As shown in Scheme 2, various substituted indoles
regardless of whether they have electron-poor or -rich
substituents on the aromatic rings were all compatible,
affording the corresponding products 3a-3n in moderate to
good yields. When N-substituted indoles were used in this
reaction, the desired products 3o and 3p were obtained in 37-
53% yields after a prolonged reaction time. For N-Boc-
protected substrate, only trace of the desired product 3q was
produced due to the electronic effect, suggesting that the
substituent on nitrogen atom caused a significant impact on
the nucleophilicity of C-2 position in indole 1. The use of 7-
aza-indole derivative also afforded trace of 3r presumably due
to the same reason. In the case of cyclic alkyl group
substituted substrate, the desired product 3s could be given in
50% yield. Alkyl carbon chain substituted substrate was also
tolerated, furnishing the desired product 3t in 58% yield.
When 2-methyl-substituted indole derivative 1u was used as
substrate, only trace of unknown product was formed and most
of starting materials were recovered. Surprisingly, when the
carbon chain of isonitrile was extended from two carbon atoms
to three carbon atoms, the corresponding products 3v and 3w
were formed via a radical-initiated dimerization in 37% and
41% yields, respectively, rather than the desired cyclization
products. These two products may have isomers around the
C=N double bond. On the basis of 19F NMR spectroscopy,
they should have a symmetrical structure. Due to the lack of
enough H atoms around the C=N double bond, we can not
identify their real conformation at the present stage.
Initially, we investigated the reaction outcome of 1a with
1.5 eq of Togni II reagent 2a in the presence of TMEDA using
5 mol% of methylene blue (MB) as the photosensitizer in
MeCN (Table 1, entry 1). We found that the desired product
3a was obtained in 50% yield. However, MB itself could also
catalyze the reaction, giving 3a in 25% yield (Table 1, entry 2).
Moreover, we also realized that TMEDA itself could catalyze
this reaction independently even without irradiation of blue
LED (Table 1, entry 3). Therefore, we optimized the reaction
conditions by using metal complexes as the photosensitizers
and found that the use of fac-Ir(ppy)3 (5 mol%) gave 3a in
54% yield (Table 1, entries 4-7). Using 15 mol% of fac-
Ir(ppy)3 produced 3a in 83% NMR yield (72% isolated yield)
(Table 1, entry 8). Others CF3-sources such as Togni I reagent
2b, Umemoto reagent 2c, and CF3SO2Cl 2d did not perform as
well as that of 2a (Table 1, entries 9-11). The examination of
solvent effect revealed that MeCN is the best choice (Table 1,
entries 12 and 13). Increasing and reducing the employed
amounts of 2a did not further improve the yield of 3a (Table 1,
entries 14 and 15). The control experiments indicated that no
reaction occurred in the dark conditions (Table 1, entry 16)
and the photocatalyst of fac-Ir(ppy)3 was essential to the
We recognized that product
3
could be further
transformed to β-carboline derivatives that have a wide range
2
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10.1002/adsc.201800568
Advanced Synthesis & Catalysis
of biological activities upon oxidation. Thus, several products
3 were converted into β-carboline derivatives 4 upon treatment
with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). The
reactions proceeded smoothly, giving the desired products 4a-
4e in good yields, ranging from 59% to 80% (Scheme 3). The
structure of 4a has been unambiguously confirmed by X-ray
diffraction. The corresponding ORTEP drawing is shown in
Figure 2 and its CIF data are presented in the Supporting
Information. It should be noted that β-carboline derivative 4d
has a similar structure as that of the natural product harmine.
(A) STC-1 cells were treated with solvent control (DMSO), positive control
(1.0 μM PMA) and compound (100 and 10 μM harmine or 4d) for 2 hours.
Then the concentration of GLP-1 in the culture medium was measured. (B)
STC-1 cells were treated with 20, 40, 60, 80, 100 μM 4d, respectively. The
culture media were collected and measured of the release of GLP-1. (C) The
release of lactate dehydrogenase (LDH) was measured, which indicates the
integrity of cell membrane. (D) The effect of 4d on the activity of DPP-IV was
evaluated by Cayman’s DPP-IV Inhibitor Screening Assay. 100 μM sitagliptin
was included as a positive control. The data are represented as mean ± SD.
Statistical significance was calculated using Student’s t-test. **P<0.01; N.S.,
not significant.
Figure 2. X-ray crystal structure of 4a.
Figure 3 4d stimulates the release of GLP-1 in STC-1 cells
Furthermore, to evaluate the synthetic utility of the
obtained product 3, we further investigated the synthesis of 6a
from 3a as a short total synthesis of harmacine derivative
since a variety of natural product shares a characteristic 6-5-6-
5-cyclic core structure (Scheme 4). Firstly, to a THF solution
of CuCl was added a THF solution of KOtBu, and the
resulting mixture was stirred for 0.5 hour at room temperature,
and then was added 0.5 mL toluene followed by cooling to -78
oC. Allenylboronic acid pinacol ester was added to the mixture
followed by addition of a MeOH/THF solution of 3a. The
o
reaction mixture was stirred at -78 C for four hours. Then, it
was warmed to -40 oC and was further stirred for 36 hours.
After isolation and purification, the desired product 5a was
acquired in 82% yield. A gold(I)-catalyzed cyclization of 5a in
DCE successfully produced the desired product 6a in 56%
yield.
Since harmine has various types of pharmacological
activities, such as antitumor,[23] antidepression[24] and
antidiabetic,[20b,25] we were intrigued by the potential
biological activities of 4d. Therefore, we subsequently
examined its effect on an in vitro model for diabetes in the
secretion of glucagon-like peptide-1 (GLP-1), which plays an
important role in limiting postprandial glucose level. Although
harmine had no significant effect on the secretion of GLP-1,
intriguingly, 4d effectively stimulated GLP-1 release in mouse
intestinal cell line STC-1 with an EC50 of 14.25 μM (Figures
2A & 2B). Furthermore, 4d did not exhibit significant
cytotoxicity in STC-1 cells (Figure 2C). We also conducted a
preliminary exploration on the mechanism of 4d-stimulated
GLP-1 release. As shown in Figure 2D, 4d barely inhibited the
activity of DPP-IV, which is an enzyme that degrades GLP-1
rapidly. Further investigations of its antidiabetic activities and
mechanisms are under way.
The effect of 4d on diabetes was also evaluated by using
another in vitro model-glucose consumption. Neither harmine
nor 4d promoted glucose consumption in L6 skeletal muscle
cells (Figure S1A). We also evaluated its cytotoxicity in
human lung cancer cell line A549. As shown in Figure S1B,
4d moderately inhibited the proliferation of lung cancer cells
with half maximal inhibitory concentration (IC50) of 29.83 μM,
which was less potent than that of harmine (IC50 = 10.22 μM).
Scheme 4. Transformation: two step synthesis of harmacine
derivative.
On the basis of the previous reports, a plausible reaction
mechanism is proposed in Scheme 5. Initially, the
photosensitizer IrIII was excited to *IrIII upon visible light
irradiation, which was oxidized by Togni II reagent 2a to give
CF3 radical I and IrIV species via a single-electron-transfer
(SET) process. Subsequently, the addition of CF3 radical to the
isonitrile group in 1a generated the imidoyl radical II. This
radical intermediate underwent an intramolecular cyclization
at the C-2 position of indole to afford intermediate III, which
produced the cationic intermediate IV along with regeneration
of IrIII species through another SET process. Deprotonation of
intermediate IV furnished the desired trifluoromethylation
product 3a.
3
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10.1002/adsc.201800568
Advanced Synthesis & Catalysis
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In summary, we have developed a novel visible-light-
induced trifluoromethylation of isonitrile-substituted indole
derivatives, giving a variety of 1-(trifluoromethyl)-4,9-dihydro-
3H-pyrido[3,4-b]indole derivatives in moderate to good yields.
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Advanced Synthesis & Catalysis
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5
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10.1002/adsc.201800568
Advanced Synthesis & Catalysis
Updates
Visible-Light-Induced
Trifluoromethylation
of
Isonitrile-Substituted Indole Derivatives: Access to
1-(Trifluoromethyl)-4,9-dihydro-3H-pyrido[3,4-
b]indole and β-Carboline Derivatives
Adv. Synth. Catal. Year, Volume, Page – Page
Jiaxin Liu,a Longhai Li,a Liuzhu Yu,a Lisha
Tang,b Qin Chen,b* and Min Shia*
6
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