Activation Relay on Rhodium-Catalyzed C-H Aminomethylation in Cooperation with Photoredox Catalysis

Article abstract of DOI:10.1021/acs.orglett.9b01261

A site selective C-H aminomethylation at indole's C3 position has been achieved by merging rhodium(III)-catalyzed C-H activation and photoredox catalysis in a one-pot manner. An investigation of the mechanistic insights rationalized the essence of the activation relay and the combination mode.

Full text of DOI:10.1021/acs.orglett.9b01261

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Activation Relay on Rhodium-Catalyzed C−H Aminomethylation in
Cooperation with Photoredox Catalysis
Ruixing Liu, Jiaxin Liu, Yin Wei, and Min Shi*
State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic
Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: A site selective C−H aminomethylation at indole’s C3 position has been achieved by merging rhodium(III)-
catalyzed C−H activation and photoredox catalysis in a one-pot manner. An investigation of the mechanistic insights
rationalized the essence of the activation relay and the combination mode.
irect constructions of carbon−carbon (C−C) bonds and
because it can provide easy access to reactive radical or cationic
Dcarbon−hetero (C−X) bonds from C−H bonds are species under mild conditions from abundant and native
functional groups (FG).7 When these two powerful synthetic
methods were taken together, innovative activation modes could
be established in C−H bond functionalizations.8
highly efficient, atom- and step-economical processes.1 Exten-
sive research into the design of diversified directing groups
(DG), ligands (L), and ingenious synthetic strategies and the
development of transition metal (TM) catalysts such as
palladium,2 rhodium,3,4 ruthenium,5 and others6 have made
C−H bond activation more sophisticated and practical (Scheme
1a). Photoredox catalysis plays a pivotal role in synthetic events
The aminomethylated moiety, considered as the modified
amino group, is a crucial component and functional group in a
wide range of medicinally relevant compounds, including
pharmaceuticals, agrochemicals, and bioactive natural prod-
ucts.9 Amino reagents, such as organic azide,10 dioxazolone,11
and isocyanate,12 have been extensively used to build C−N
bonds in the C−H functionalizations. However, amino-
methylation has been rarely reported in metal-catalyzed C−H
bond activations.13 Triphenylhexahydrotriazine (THT), an
equivalent to imine, can be easily accessed from aniline and
paraformaldehyde under mild conditions. As a tertiary amine or
an imine equivalent (after dissociation), it can be excited and
oxidized by a photosensitizer to generate the corresponding
cationic radical intermediate 2a*, which is a highly electrophilic
species (Scheme 1b).
Scheme 1. C−H Bond Activation and Our Working
Hypothesis
Because the C−H bond of indole’s C2 position can be
activated by a transition metal catalyst with the assistance of an
N-tethered directing group, we envisioned that the merger of
these two catalytic cycles into one process would yield a new C−
H bond activation mode for indole 1a through an activation
relay. This working hypothesis is based on the following. (i) In
the classical activation mode, C−H bond functionalizations at
indole’s C2 position have been well developed using pyrimidine
as the directing group.14 The generation of a unique
Received: April 10, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01261
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Letter
functionalization reagent (FG) upon photoredox catalysis might
lead to a breakthrough with regard to the traditional activation
modes. (ii) THT (Ep = 1.05 V) could be oxidized with an
appropriate photosensitizer.15 In this respect, we need to
address several challenges to realize this breakthrough, such as
the selection of the appropriate metal catalyst in the first step of
C−H bond activation at the C2 position and the matched
photosensitizer to generate the desired active imino species
(Scheme 1c).
To our delight, the merger of these two catalysis modes is
successful in the site selective C−H aminomethylation at the C3
poisition of indole using pyrimidine as a directing group
(Scheme 1d). Because this occurrence of C3 aminomethylation
of indole is initiated by Rh-catalyzed C−H bond activation at the
C2 position, we termed this C−H activation mode the activation
relay. In this C−H bond functionalization, we reckoned that the
C3 position is also partially activated by the rhodium catalyst in
the formed cyclometalated species. A further illustration of this
concept will be presented in the mechanistic investigation
section.
desired product (Table 1, entries 6−8). The use of organic
dyes16 as photosensitizera is our first choice because they are
practically useful and much cheaper than metal−polypyridyl
complexes such as fac-Ir(ppy)3 and suitable for ambient
atmosphere without deterioration. Eosin Y [ET(S*/S•−) =
0.86 V vs a saturated calomel electrode (SCE) in acetonitrile]
has a wide range of applications and excellent catalyst
performance in the family of xanthene dyes. Although its
potential is lower than that of THT, Eosin still can oxidize THT
due to its dissociation equilibrium in the solvent. The other
transition metals were tested instead of Rh(III), but no reactions
occurred using these metal catalysts (Table 1, entry 8). An
examination of solvent effects revealed that 1,2-dichloroethane
(DCE) is an alternative option in this transformation (Table 1,
entry 9). Temperature is also crucial to this transformation
because the reaction becomes sluggish if it is carried out at 25 °C
(Table 1, entry 10). In addition, we have also tested several
LEDs with different powers and identified no influence on the
yield of 3a.17
Having established the optimal reaction conditions, we next
began to investigate the substrate scope of various substituted
indoles, and the results are shown in Scheme 2. When indoles
Our studies commenced with easily available indole 1a (0.1
mmol, 1.0 equiv) and THT 2a (0.05 mmol, 0.5 equiv) as the
model substrates, [Cp*RhCl2]2 and Eosin Y as the catalyst
combination, and pivalic acid as an additive in acetonitrile (1.0
mL) at 60 °C upon irradiation with white light-emitting diode
(LED) light for 5 h, giving desired aminomethylation product 3a
in 95% yield (Table 1, entry 1). The structure of product 3a was
Scheme 2. Substrate Scope
a
Table 1. Examination of the Reaction Conditions
b
c
entry
catalyst
standard conditions
without [RhCp*Cl2]2
yield (%)
1
2
95
0
3
without Eosin Y
0
4
5
6
7
8
9
10
without PivOH
33
17
0
0
0
fac-Ir(ppy)3 instead of Eosin Y
Rose Bengal instead of Eosin Y
fluorescein instead of Eosin Y
other metal catalysts instead of [Cp*RhCl2]2
DCE instead of MeCN
d
93
41
25 °C instead of 60 °C
a
Reaction conditions: 1a (0.10 mmol), 2a (0.05 mmol), PivOH (0.20
mmol), [Cp*RhCl2]2 (4 mol %), Eosin Y (20 mol %), MeCN (1.0
b
mL), 60 °C, 12 h, ambient atmosphere. All of the reactions were
carried out on a 0.10 mmol scale in solvent (1.0 mL) at 60 °C for 12 h
c
d
unless otherwise specified. Isolated yield. Other metal catalysts are
[Cp*IrCl2]2, [Cp*Co(CO)I2], and [Ru(p-cymene)Cl2]2.
determined by its X-ray diffraction. The examination of the
necessity of these catalysts revealed that the catalyst
combination of [Cp*RhCl2]2 and Eosin Y is essential in this
reaction, indicating the activation relay at the C3 position
through this cooperative catalysis (Table 1, entries 2 and 3). The
use of pivalic acid can significantly improve the yield of 3a
(Table 1, entry 4). Other photosensitizers, including a metal−
polypyridyl complex and organic dyes, were also examined, and
we found that fac-Ir(ppy)3 was less effective than Eosin Y;
however, the use of Rose Bengal and fluorescein did not give the
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Scheme 3. Control Experiments
bearing a pyrimidine directing group were substituted with
halogen atoms, Me, OMe, NO2, and OBn at positions C4−C6,
the reactions proceeded smoothly to furnish corresponding
aminomethylation products 3 in moderate to good yields
ranging from 77% to 96%. When indole was substituted with CN
(substrate 1i) and CHO (substrates 1j and 1p), no reaction
occurred presumably due to the fact that they can interfere with
the excited Eosin Y. We also examined the scope of other
directing groups such as pyridine, other pyrimidine derivatives,
and heterocycles containing a nitrogen atom. The use of
pyridine as a directing group afforded aminomethylated
products 3t−3x with results similar to those seen upon using
pyrimidine as a directing group. Other pyrimidine derivatives
could also deliver desired products 3r and 3s in good yields
under the standard conditions. To our delight, this protocol
could be extended to other heterocycles containing a nitrogen
atom. For example, indoles using pyrazine, thiazole, benzothia-
zole, and benzoxazole as directing groups afforded products 3ab,
3ac, 3ad, and 3ae, respectively, in good yields. The substrates
could be changed from indole to pyrrole with pyrimidine or
pyridine as a directing group, furnishing desired products 3y−
3aa in moderate yields ranging from 65% to 76%. In addition, we
also investigated the scope of THTs. A range of THTs with a
variety of substituents at the para position of the benzene ring
was tested, affording desired products 3af−3al in good yields
ranging from 77% to 94%. The electronic property of these
substituents did not significantly impact the reaction outcome
regardless of whether they are electron-donating or -with-
drawing ones. In the case of THT containing a heterocycle like
quinoline, the reaction also proceeded efficiently, providing
desired product 3am in 72% yield. Furthermore, this novel
aminomethylation process is compatible with the late-stage
modification of two drugs, fenofibrate and loratadine, affording
corresponding products 3an and 3ao in 75% and 63% yields,
respectively. All of these results demonstrated a broad substrate
scope and good functional group tolerance in this amino-
methylation process.
that indole can undergo electrophilic metalation, such as
electrophilic palladation, at position C3 also to afford the C3-
functionalized product.18 Thus, we replaced the pyrimidine
directing group with a benzyl group (substrate 4) or methyl
group (substrate 5), which cannot be used as a directing group
because neither has a coordination atom. We also introduced a
methyl group at position C2 (substrate 6) to block out the
Rh(III)-catalyzed C−H bond activation forming cyclometalated
species. These experiments all failed to give the corresponding
products, suggesting that the C−H activation step is
indispensable and the possibility of electrophilic metalation
can be ruled out (see Scheme S1 for more details) (Scheme
3a).18 Therefore, the activation relay is in principle not an
electrophilic metalation pathway. Furthermore, according to ref
14d, we prepared the corresponding cyclometalated complex 7
in the C−H activation step and identified that treating complex
7 with 2a could produce 3a in 95% yield under the standard
conditions (Scheme 3b). We next attempted to isolate the key
intermediate of this reaction. Fortunately, stirring complex 7 and
2a in DCM at room temperature gave complex 8 in 82% yield
(Scheme 3b). Protonolysis of complex 8 by PivOH at 60 °C
afforded desired product 3a in 92% yield (Scheme 3b).
Furthermore, complex 8 could be also used to replace
[Cp*RhCl2]2 as the catalyst, giving 3a in 93% yield under
otherwise identical conditions. All of these control experiments
suggested that complex 8 may be the real active catalytic species
in the mechanistic paradigm.
The Stern−Volmer experiment indicated that the fluores-
cence of Eosin Y was quenched by 2a, suggesting the SET
process between Eosin Y and 2a gives a high-electron affinity
cationic radical species 2a* (Scheme 3c).15,19 At the same time,
the nucleophilicity of position C3 was enhanced in cyclo-
metalated complex 7.20 The two factors resulted in site selective
C−H activation taking place exclusively at position C3.
Moreover, several other experiments were conducted to
investigate the SET process of Eosin Y and 2a. First, using
hexamethylenetetramine 9 or methyl group-substituted THT 10
instead of THT, the reaction did not take place, perhaps because
9 and 10 are unable to dissociate to give the reactive monomer
To gain more insights into the reaction mechanism, several
control experiments were performed. It has been well-known
C
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under the reaction conditions (Scheme 3d).21 The kinetic
isotope effect (KIE = 1.3) observed in parallel reactions using 1a
and 1a-d suggested that C−H activation at position C3 is not the
rate-limiting step (Scheme 3e). On the contrary, the kinetic
isotope effect (KIE = 4.1) observed in parallel reactions using 1a
and 1a-d3 indicated that C−H bond activation at position C2
catalyzed by the Rh(III) catalyst was the rate-limiting step
(Scheme 3e).
Scheme 5. Synthetic Application
On the basis of generally accepted mechanisms of C−H bond
activation and the conducted control experiments, a plausible
mechanistic paradigm was proposed (Scheme 4). Eosin Y was
Scheme 4. Proposed Mechanism
position C2 as well as using Eosin Y as a photosensitizer in the
photoredox catalysis. Efforts to apply this novel metal-
laphotocatalysis to synthesize other useful compounds are
underway.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b01261.
Experimental procedures and characterization data for all
compounds (PDF)
Accession Codes
excited upon photoirradiation with LED light, and THT 2a was
oxidized by Eosin Y* to give cationic radical species 2a*, which
is a high-electron affinity species. Substrate 1a was activated by
the rhodium(III) complex with the assistance of PivOH to
deliver cyclometalated complex 7, which reacted with 2a* to
afford rhodium species 11. A SET process between 11 and Eosin
Y•− furnished rhodium(III) species 8 and regenerated Eosin Y.
Rhodium(III) complex 8 underwent a proton demetalation by
pivalic acid to regenerate the Rh(III) catalyst and release desired
product 3a. Increasing the reaction temperature could accelerate
the proton demetalation process. High-electron affinity cationic
radical species 2a* and the activation relay dominated this
specific site selectivity.
The synthetic utility of obtained aminomethylation product
3a was briefly examined. This new aminomethylation procedure
could be conveniently performed in a gram scale manipulation,
giving desired product 3a in 90% yield. Removal of a pyrimidine
directing group was readily achieved upon treatment with
NaOEt in DMSO to afford corresponding product 12 in 81%
yield. Considering the fact that C2 unsubstituted indole can
undergo a C−H bond activation process again, we introduced a
benzoxazole moiety at position C2 under the catalysis of
Cu(OAc)2 to afford product 13 in 66% yield.22 Treatment of 3a
with propargyl bromide in the presence of Cs2CO3 and
subsequently with a gold(I) catalyst gave carbazole derivative
14 in 74% yield. In addition, reductive amination of 3a with
formaldehyde and NaBH4 in methanol provided methylated
product 15 in 85% yield (Scheme 5).
CCDC 1552046 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.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mshi@mail.sioc.ac.cn.
ORCID
Min Shi: 0000-0003-0016-5211
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful for financial support from the National
Basic Research Program of China [(973)-2015CB856603], the
Strategic Priority Research Program of the Chinese Academy of
Sciences (Grant XDB20000000 and sioczz201808), and the
National Natural Science Foundation of China (20472096,
21372241, 21572052, 20672127, 21421091, 21372250,
21121062, 21302203, 20732008, 21772037, 21772226, and
21861132014).
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■
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and photoredox catalysis into one reaction system in a unique
way. The site selective aminomethylation for the C−H bond at
indole’s C3 position can be achieved using THT as the reactant
and using [Cp*RhCl2]2 as the C−H bond activation catalyst at
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