Visible-Light-Promoted Cascade Alkene Trifluoromethylation and Dearomatization of Indole Derivatives via Intermolecular Charge Transfer

Article abstract of DOI:10.1021/acs.orglett.8b01899

An intramolecular dearomatization of indole derivatives has been developed via an electron donor-acceptor complex formed between indole derivatives and Umemoto's reagent. Without the requirement of any catalyst and additive, diverse trifluoromethyl-substi

Full text of DOI:10.1021/acs.orglett.8b01899

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Visible-Light-Promoted Cascade Alkene Trifluoromethylation and
Dearomatization of Indole Derivatives via Intermolecular Charge
Transfer
Min Zhu,†,‡ Kai Zhou,† Xiao Zhang,*,† and Shu-Li You*,†,‡
†State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of
Sciences, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
‡School of Physical Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210, China
S
* Supporting Information
ABSTRACT: An intramolecular dearomatization of indole derivatives has been developed via an electron donor−acceptor
complex formed between indole derivatives and Umemoto’s reagent. Without the requirement of any catalyst and additive,
diverse trifluoromethyl-substituted spiroindolenines bearing a quaternary stereogenic center were obtained in good yields (up to
90%) merely upon the illumination of two starting materials in 1,2-dichloroethane solution at room temperature. This work
provides facile access to spiroindolenines bearing a trifluoromethyl group enabled by visible light.
piroindolenines, encountered as common substructures in
ors, thus providing a novel strategy for the direct alkylation of
Salkaloid natural products, constitute an important class of indoles (a, Scheme 1).11 Inspired by this pioneering work and
biologically active molecules.1 Meanwhile, they also occupy a
prominent position in drug discovery research for new lead
compounds.2 Because of their high value in both synthetic and
pharmaceutical chemistry, continuing efforts have been
devoted to the development of their synthetic methods.3
Among them, the dearomatization reaction of indole
derivatives represents a straightforward and practical strategy
to assemble such scaffolds.4 For instance, alkylation reaction of
indoles via intramolecular reactions including allylic sub-
stitution,5 cross-coupling,6 additions to alkynes,7 and others8
have been developed. Despite these great advances, the
currently available approaches largely depend on the
nucleophilic property of the indole moiety and the assistance
of catalysts under thermal conditions. Developing new
strategies beyond these thermal pathways in a catalyst-free
fashion remains elusive but highly desirable.
Scheme 1. EDA Complex Consisting of Indole As the
Electron Donor
Visible light, which is abundant and available in nature, has
long been appreciated as a mild energy source to drive
chemical transformations.9 Of particular interest are the
electron donor−acceptor (EDA, also called charge-transfer)
complexes capable of absorbing visible light and promoting
reactions involving open shell odd-electron species without any
external photocatalyst.10 However, due to the problems
associated with unproductive, fast, and reversible electron
transfer from the donor to the acceptor, the EDA complex-
enabled synthetic chemistry is limited. In this regard, one
recent elegant example from the Melchiorre group demon-
strated that indoles are suitable electron donors combined with
electron-deficient benzyl or phenacyl bromides as the accept-
as part of our continuing efforts toward dearomatization
reactions, we began to explore the feasibility of indole
derivatives as the electron donor in the intramolecular
dearomatization reactions (b, Scheme 1). To achieve this,
several challenges must be overcome: (a) possible competitive
reactions including both intermolecular dearomatization and
direct hydrofunctionalization of alkenes and (b) unfavorable
energetic barrier and steric congestion caused during the
Received: June 18, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01899
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
dearomatization process. Herein, we report the results from
this work.
reagents 2b and 2c were also tested;15 it was found that the
reaction between 1a and 2c delivered the dearomative product
in 54% NMR yield, while no reaction occurred between 1a and
2b. Varying the light source to 23W CFL or increasing the
substrate concentration resulted in a slight drop in yield
(entries 17 and 18). The reaction carried out in air merely led
to a mixture without any observation of the desired product
(entry 19). Finally, the control experiment verified that visible
light is essential (entry 20).
Fascinated by the ability of the trifluoromethyl group in
altering the intrinsic properties of organic compounds, our
attempt was launched with the investigation of the reaction
between indoles with Umemoto’s reagent 2a, with the goal of
incorporating the CF3 functionality into the spiroindolenines
(Table 1).12−14 However, the initial results were disappointing.
a
With the optimized reaction conditions in hand, we next
explored the substrate scope. As illustrated in Scheme 2,
Table 1. Optimization of the Reaction Conditions
a
Scheme 2. Substrate Scope
b
entry
2
solvent
DMF
CH3CN
MeOH
CHCl3
DCM
DCE
1,4-dioxane
Et2O
toluene
DCE
base
time (h)
yield (%)
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2a
2a
2a
2a
48
24
48
2
2
2
24
24
24
15
15
24
48
48
24
24
4
43
72
56
78
80
83
57
nd
nd
75
77
75
9
10
11
12
13
14
15
16
17
18
19
20
K2HPO4
K2CO3
Cs2CO3
tBuOK
Et3N
DCE
DCE
DCE
c
52
c
DCE
DCE
DCE
DCE
DCE
DCE
DCE
59
nd
54
77
77
nd
nd
c
c
d
e
15
24
24
f
g
a
General conditions: 1a (0.05 mmol), 2 (0.075 mmol), and base
(0.075 mmol) in solvent (0.5 mL, 0.1 M) were stirred at room
temperature under visible light. Unless otherwise noted, 24W blue
LEDs were used as the light source. The product was observed in the
form of two diastereoisomers, and the dr value was determined as
b
c
1.3:1 by 19F NMR. Isolated yield. NMR yield determined by 19F
d
NMR with PhCF3 as the internal standard. Light source: 23W CFL.
DCE (0.25 mL, 0.2 M). Open to air. In dark. nd = not detected.
e
f
g
a
General conditions: 1 (0.20 mmol) and 2a (0.30 mmol) in DCE
(2.0 mL, 0.1 M) were stirred at room temperature under the
irradiation of 24W blue LEDs. Unless otherwise noted, the reaction
Different indoles including those bearing a nitrogen atom on
the linkage or seven-membered carbon linked ones were not
compatible. Gratifyingly, exposure of substrates 1a and 2a in
DMF to blue LEDs provided the desired spiroindolenines in
43% yield after 2 days in the form of two diastereoisomers with
a ratio of 1.3:1 (entry 1). Further experiments revealed the
solvents had a profound effect on the reaction outcome and
DCE gave the best yield with a much shorter reaction time
(83% yield, entry 6). The reaction is quite robust and performs
well in the presence of diverse bases including Et3N, which
might serve as a potential competitive electron donor (entries
10−14). Other trifluoromethylating reagents such as Togni’s
b
c
time was 2 h. Isolated yield. The product was observed in the form
of two diastereoisomers, and the dr value was determined by 19F
d
e
NMR. Reaction time: 8 h. Reaction time: 12 h.
electron-donating or electron-withdrawing groups at various
positions of the phenyl moiety (4-OMe, 4-Me, 4-F, 4-Cl, 4-Br,
4-CO2Me, 4-CN, 4-NO2, 3-Me, 2-OMe, 2-Me, 2-CF3) or 1-
naphthyl group at the C2 position of indole were well
tolerated. The resultant dearomative products 3b−o were
obtained in 43−86% yields as diastereoisomeric mixtures
(1.2:1 to 6:1). Typically, the substrates bearing strong
B
DOI: 10.1021/acs.orglett.8b01899
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Organic Letters
Letter
electron-withdrawing groups such as −CO2Me, −CN, −NO2,
and −CF3 required a prolonged reaction time. It is worth
noting that the diastereoselectivity is highly dependent on
specific structure. For example, the incorporation of a
substituent at the ortho-position of the phenyl moiety could
dramatically increase the diastereoselectivity of the products.
Furthermore, the reactions between indoles bearing an
t
aliphatic group such as Me- or Bu- at the C2 position and
Umemoto’s reagent 2a proceeded smoothly, delivering the
corresponding spiroindolenines 3p and 3q in 58% and 55%
yields with 2:1 and 7:1 dr, respectively. Meanwhile, indoles
bearing 4-Cl, 5-Me, 5-Cl, 5-Br, 6-Cl, 7-Me were all compatible
with this protocol, in all cases, leading to their corresponding
products in good to excellent yields (58−90%, 1.1:1−1.3:1 dr,
3r−w). The structure of the minor isomer in 3a has been
confirmed by X-ray diffraction analysis.16
To our great delight, the reaction of 1a in a 2.52 mmol scale
with 2a also proceeded smoothly, delivering product 3a in 70%
yield within 12 h, which highlights the robustness and
practicality of this method (eq 1, Scheme 3). Furthermore,
Figure 1. (a) Optical absorption spectra of the reaction components.
(b) Job’s plot between 1a and 2a (measured wavelength: 425 nm).
(c) Determination of the association constant (KEDA): nonlinear
curve-fitting methodology (measured wavelength: 425 nm). (d)
Light/dark cycle experiments for the model reaction.
Scheme 3. Gram-Scale Reaction and Transformations of
Product 3a
trapping agent 5,5-dimethyl-1-pyrroline N-oxide (DMPO), the
spectrum recorded was identified as EPR signals of adduct
CF3-DMPO.16 In addition, the light-dark interval experiment
verified that constant illumination of light is an essential
element for product formation (d, Figure 1).
On the basis of all these experimental results, a plausible
mechanism was proposed. As exemplified by the reaction
between 1a and 2a, the combination of two starting materials
delivers the transient complex I, which upon visible-light
irradiation undergoes single-electron transfer from donor to
acceptor (II). The CF3 radical generated through S-CF3 bond
cleavage then proceeds via an addition to terminal alkene (III)
to afford the intermediate IV. Ultimately, the radical−radical
recombination occurs to provide the desired product 3a after
deprotonation (Scheme 4). Herein, the substituents intro-
Scheme 4. Proposed Mechanism
several transformations based on spiroindolenine 3a were
carried out. Upon the treatment with LiCl, selective removal of
one of the methyl ester groups in 3a occurred at 120 °C to give
compound 4 in 76% yield with 1.6:1 dr (eq 2, Scheme 3).
Interestingly, the spirocycle 5 bearing three contiguous
stereogenic centers could be obtained in 70% yield as a single
diastereoisomer through the reduction of the imine moiety of
3a in the presence of NaBH3CN and AcOH (eq 3, Scheme 3).
To gain insight into the reaction process, a series of
mechanistic experiments were performed. First, UV/vis
absorption spectrometry showed a bathochromic shift by
mixing the DCE solution of indole 1a with Umemoto’s reagent
2a, which was consistent with the sharp color change visually
(a, Figure 1). Then, a 1:1 ratio between 1a and 2a in the EDA
complex was established based on the Job’s plot with UV/vis
absorption experiments, in which maximal absorption appeared
at 50% molar fraction of indole 1a (b, Figure 1).17 Meanwhile,
the association constant KEDA was calculated to be 4.5 M−1 in
DCE via the nonlinear curve-fitting methodology (c, Figure
1).18 All of these above results support the formation of a
donor−acceptor complex between 1a and 2a. Next, the
reaction was monitored by electron paramagnetic resonance
(EPR) spectroscopy. Upon the addition of free radical spin-
duced at the C-2 position might render the radicals coupling
process in a diastereoselective manner due to the effect of
geometrical preferences. Notably, the radical chain mechanism
might also be operative in this case.19
In summary, we here introduced a novel method for the
intramolecular dearomatization reaction of indoles enabled by
visible-light promoted intermolecular charge transfer. Upon
C
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mixing two starting materials in DCE solution, the cascade
sequence involving trifluoromethylation of alkenes coupled
with indole dearomatization is achieved merely by illumination
of visible light. This method features extremely mild and
simple reaction conditionsno heating and is free of catalyst
and additivesallowing access to a wide range of spiroindo-
lenines bearing trifluoromethyl (CF3) group in good yields.
The amenable capability to scale-up and flexible manipulation
of the resultant products further demonstrate its synthetic
utility. In addition, mechanistic studies suggest an unprece-
dented EDA complex formed between the indole substrate and
Umemoto’s reagent. To the best of our knowledge, this work
constitutes a previously elusive reaction type in EDA complex-
enabled chemical transformations. Further exploration of
visible-light promoted dearomatization reactions are currently
underway in our laboratory.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01899.
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Experimental procedures and analysis data for all new
compounds (PDF)
Accession Codes
CCDC 1844566 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.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: zhangxiao@sioc.ac.cn.
*E-mail: slyou@sioc.ac.cn.
ORCID
Shu-Li You: 0000-0003-4586-8359
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Key R&D Program of China
(2016YFA0202900), the National Basic Research Program of
China (2015CB856600), the NSFC (21332009), the Program
of Shanghai Subject Chief Scientist (16XD1404300), the
Shanghai Sailing Program (18YF1428900), and the CAS
(XDB20000000, QYZDY-SSW-SLH012) for generous finan-
cial support.
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DOI: 10.1021/acs.orglett.8b01899
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