Synthesis of Indole-Fused Polycyclics via Rhodium-Catalyzed Undirected C-H Activation/Alkene Insertion

Article abstract of DOI:10.1021/acs.orglett.9b02198

A Rh(III)-catalyzed undirected C-H activation/alkene insertion to synthesize diversified indole-fused polycyclics has been developed. Intramolecular electrophilic cyclization generated a 3-indolyl rhodium species that went through an aryl-to-aryl 1,4-rhodium migration to realize the C-H activation. The subsequent [4 + 2] carboannulation or hydroarylation of alkenes could be achieved, respectively, by simply adjusting the additives of the reaction.

Full text of DOI:10.1021/acs.orglett.9b02198

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Indole-Fused Polycyclics via Rhodium-Catalyzed
Undirected C−H Activation/Alkene Insertion
Songjin Guo, Rui Pan, Zhe Guan, Panpan Li, Libo Cai, Siwei Chen, Aijun Lin,* and Hequan Yao*
Department of Medicinal Chemistry, School of Pharmacy and State Key Laboratory of Natural Medicines (SKLNM), China
Pharmaceutical University, Nanjing 210009, P.R. China
S
* Supporting Information
ABSTRACT: A Rh(III)-catalyzed undirected C−H activation/alkene insertion to synthesize diversified indole-fused
polycyclics has been developed. Intramolecular electrophilic cyclization generated a 3-indolyl rhodium species that went
through an aryl-to-aryl 1,4-rhodium migration to realize the C−H activation. The subsequent [4 + 2] carboannulation or
hydroarylation of alkenes could be achieved, respectively, by simply adjusting the additives of the reaction.
ransition-metal-catalyzed C−H activation/alkene inser-
diversified indole-fused polycyclics in high atom and step
economy (Figure 1d). In this transformation, the in situ
generated 3-indolyl rhodium species via rhodium-catalyzed
cyclization of 2-ethynylanilines undergoes an aryl-to-aryl 1,4-
rhodium migration to achieve the C−H activation, affording an
aryl rhodium species, which could add across the alkenes to
realize the [4 + 2] carboannulation or hydroarylation of
alkenes by simply adjusting the additives of the reaction.
We initiated our investigation with 2-alkynylaniline 1a as the
model substrate (see the Supporting Information (SI) for
details). Using [Cp*RhCl2]2 (5.0 mol %) and Cu(OAc)2·H2O
(2.1 equiv) in DMAC under argon atmosphere, the [4 + 2]
carboannulation product 3a and the hydroarylation product 4a
were achieved in 45% and 28% yields (Table 1, entry 1). The
structures of the products 3a and 4a were determined by
single-crystal X-ray analysis (see the SI for details). To our
delight, when the reaction was operated with 0.3 equiv of
Cu(OAc)2·H2O under oxygen atmosphere, product 3a could
be obtained in a yield up to 82% (Table 1, entry 2).15 Other
copper salts, such as CuOAc, CuTc, or Cu(eh)2, impacted the
yield of product 3a (Table 1, entries 3−5), and Cu(TFA)2
significantly inhibited the reaction (Table 1, entry 6).
Diversity-oriented synthesis (DOS) is of obvious value in
synthetic organic chemistry, which has been identified as an
efficient strategy for achieving structural complexity and
molecular diversity with the same starting materials. We then
looked for appropriate reaction conditions to synthesize
product 4a (Table 1, entries 7−12). Product 4a could be
achieved in 68% yield when NaOAc was tested under argon
atmosphere (Table 1, entry 7). Other additives, such as
T
tion has been widely applied for the synthesis of
functional molecules and complex cyclic compounds,1 which
could efficiently circumvent the multistep preparation of the
preactivated starting materials, rendering the overall reaction
atom and step economical. Recently, Glorius,2 Guimond,3
Rovis,4 Cramer,5 and Wang6 have independently described a
rhodium- or ruthenium-catalyzed C−H activation/[4 + 2]
annulation of alkenes to access the six-membered aza-
heterocycles with imines or amides as the directing groups
(DGs) (Figure 1a). Moreover, a cobalt-catalyzed carboxylate-
directed C−H activation/alkene insertion of benzoic acids and
alkenes has been realized by Daugulis’s group (Figure 1a).7
Inspired by Murai’s pioneering work on the ruthenium-
catalyzed cross-coupling reaction between aromatic ketones
and alkenes,8 heteroatom chelation-assisted C−H activation/
hydroarylation of alkenes has been extensively studied in the
last two decades (Figure 1b).9 However, in these previous
works, the directing groups were necessary, which could well
guarantee the C−H activation. To the best of our knowledge,
the undirected C−H activation/alkene insertion,10 especially
the annulation or hydroarylation, has rarely been achieved until
now (Figure 1c).
Indole-fused polycyclic scaffolds widely exist in natural
products and pharmaceuticals with diverse bioactivities11 and
are utilized in organic synthesis.12 Nevertheless, most of the
existing methods to construct these frameworks either
employed elaborately prefunctionalized indoles as the reactants
or underwent multistep and complicated process.13 Thus,
exploring a practical and effective method to rapidly assemble
them is still highly desirable, yet challenging. Based on our
continuous interest in alkene functionalization,14 herein we
disclose an unprecedented rhodium(III)-catalyzed undirected
C−H activation/alkene insertion reaction to synthesize
Received: June 25, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02198
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Subsequently, we sought to explore the scope and generality
of the reaction (Scheme 1). The products 3b−h with various
substituents at the C4- or C5-position of the phenyl ring were
achieved in 51−75% yields (Scheme 1a). The N-mesyl-
protected 2-ethynylaniline 1i could also participate to offer 3i
in 40% yield. To further increase the molecular diversity, we
then embarked on the modification of the alkene moiety
(Scheme 1b). The products 3j and 3k were obtained in slightly
low yields due to the steric effect of the olefins. In addition to
forming indole-fused dihydrobenzofurans, other intriguing
indole-fused heterocycles, such as indole-fused dihydropyrans
3l and 3m, indole-fused isochroman 3n, and indole-fused
benzofuranone 3o were all achieved in moderate to good yields
by altering the alkene chains.
Controlling the regioselectivity of the C−H activation with
similar characteristic is always a meaningful and challenging
task in organic synthesis. To our delight, when the C-8
position of the benzene ring was fixed with different
substituents, such as alkanes, esters, ethers and tert-
butyldimethylsilyl (TBDMS) ether, the products 3p−w could
be generated exclusively in good efficiency (Scheme 1c).
The scope of hydroarylation products 4 was then
investigated (Scheme 1d). The products 4b−e with methyl,
methoxy, and ester groups on the C4- or C5-position of the
anilines were isolated in moderate to good yields. N-Mesyl-
protected 2-ethynylaniline 1f also performed well to give the
product 4f in 70% yield. The substrate 1g with an unsymmertic
phenyl unit provided the product 4g in 54% yield. Increasing
the steric hindrance of the alkenes caused a slight decrease in
reactivity, offering products 4h and 4i in 57% and 50% yield,
respectively. Furthermore, the indole-fused chroman 4j could
also be reliably synthesized in moderate yield.
Figure 1. Transition-metal-catalyzed C−H activation/alkene inser-
tion.
a
Table 1. Screening of Reaction Conditions
To gain insight into the transformation, various control
experiments were then performed (Scheme 2). First, the
potential intermediate 2a was synthesized and examined under
conditions A or B, while no desired product 3a or 4a was
observed (Scheme 2a,b). These results ruled out the possibility
of 2a as the intermediate of the reaction. When compound 5
reacted with allyltrimethylsilane 6 or diazo compound 8, only
product 7 or 9 was achieved (Scheme 2c,d). It should be noted
that the indole C3-functionalized products were not detected.
These two intermediate capturing experiments indicated the
existence of aryl rhodium species, which could be generated
from 3-indolyl rhodium species via an aryl-to-aryl 1,4-rhodium
migration process. When 1p was subjected to conditions A in
the presence of 0.3 mL of D2O, the compounds [D]n-2p and
[D]1-3p with deuterium installed on the benzene ring B or C
were observed (Scheme 2e), which further demonstrated the
existence of 3-indolyl rhodium species and aryl rhodium
species, and the process of 1,4-rhodium migration was
reversible. In conditions B, [D]n-4a with deuterium incorpo-
rated on the methyl group was detected when the reaction was
quenched by D2O (Scheme 2f); this result indicated that an
alkyl rhodium species was formed. The kinetic isotope effect
(KIE) experiment between 1a and D3-1a suggested that the
C−H activation was not involved in the rate-limiting step
(Scheme 2g).
b
b
3a yield
4a yield
entry
additive (equiv)
atmosphere
(%)
(%)
1
2
3
4
5
6
7
8
Cu(OAc)2·H2O (2.1) Ar
Cu(OAc)2·H2O (0.3) O2 (1 atm)
CuOAc (0.3)
CuTc (0.3)
Cu(eh)2 (0.3)
Cu(TFA)2 (0.3)
NaOAc (2.1)
CsOAc (2.1)
AgOAc (2.1)
AgTFA (2.1)
K3PO4 (2.1)
NaOAc (2.1)
45
82
70
63
28
ND
c
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
Ar
Ar
Ar
Ar
Ar
Ar
ND
ND
ND
ND
68
52
trace
ND
ND
ND
ND
ND
ND
23
9
trace
trace
trace
75
10
11
12
d
a
Reaction conditions: 1a (0.05 mmol), [Cp*RhCl2]2 (5.0 mol %),
additive (2.1 equiv), DMAC (3.0 mL), 100 °C (oil bath temper-
b
c
d
ature), 10 h. Isolated yields. ND = not determined. 80 °C. CuTc =
copper(I) thiophene-2-carboxylate; Cu(TFA)2 = copper(II) trifluor-
oacetate; Cu(eh)2 = copper(II) 2-ethylhexanoate.
On the basis of the above experiment results and previous
reports,2−9 a plausible pathway is proposed (Scheme 2h).
Initially, the active rhodium(III) species promotes the
intramolecular electrophilic cyclization of the nitrogen and
the alkyne, furnishing the 3-indolyl rhodium intermediate II.16
Subsequently, the aryl-to-aryl 1,4-rhodium migration occurs to
CsOAc, AgOAc, AgTFA, and K3PO4, were less effective (Table
1, entries 8−11). By reducing the temperature to 80 °C, the
yield of the product 4a could be further increased to 75%
(Table 1, entry 12).
B
DOI: 10.1021/acs.orglett.9b02198
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Organic Letters
Letter
Scheme 1. Substrate Scope*
*
a
(a−c) Substrate scope of the [4 + 2] carboannulation of alkenes. (d) Substrate scope of the hydroarylation of alkenes. Reaction conditions A: 1
(0.05 mmol), [Cp*RhCl2]2 (5.0 mol %), Cu(OAc)2·H2O (30.0 mol %), DMAC (3.0 mL), 100 °C (oil bath temperature) under oxygen
b
atmosphere, 10 h. Reaction conditions B: 1 (0.05 mmol), [Cp*RhCl2]2 (5.0 mol %), NaOAc (2.1 equiv), DMAC (3.0 mL), 80 °C (oil bath
temperature) under argon atmosphere, 10 h. All cited yields are isolated yields. 4.0 mmol scale. 3.0 mmol scale. 70 °C. dr = 2:1. dr = 1.5:1.
c
d
e
f
g
fulfill the C−H bond activation,17 affording the aryl rhodium
species III or IV. Proto-demetalation of intermediate II will
form the side products 2, which could not reverse to generate
intermediate II again. The alkene coordinates and inserts into
the Rh−C bond of intermediate III, giving rise to the alkyl
rhodium species V. In conditions A, the indole C3 C−H
activation offers the seven-membered rhodacycle complex VI,
which upon C−C reductive elimination provides the desired
C
DOI: 10.1021/acs.orglett.9b02198
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Letter
Scheme 2. Reaction Mechanism
products 3. It is worth noting that the choice of Cu(OAc)2/O2
as the additives is crucial for the formation of products 3
because it could efficiently eliminate the HOAc to avoid the
protonation process and oxidize the rhodium(I) species to
regenerate the active rhodium(III) species simultaneously. In
conditions B, the alkyl rhodium complex V undergoes direct
proto-demetalation process to provide products 4 and
regenerates the active rhodium(III) catalyst to the next
catalytic cycle.
In conclusion, we have presented a convenient method for
the divergent construction of indole-fused polycyclic frame-
works via a rhodium(III)-catalyzed undirected C−H activa-
tion/alkene insertion reaction. The in situ generated 3-indolyl
rhodium species enabled the C−H activation through an aryl-
to-aryl 1,4-rhodium migration process. The resulting aryl
rhodium added across the alkenes, realizing the [4 + 2]
carboannulation of alkenes with Cu(OAc)2 and O2 as the
additives and the hydroarylation of alkenes with NaOAc as the
additive. The primary mechanism study revealed that the C−H
D
DOI: 10.1021/acs.orglett.9b02198
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02198.
Full experimental details, characterization data of new
compounds, and copies of NMR spectra (PDF)
Accession Codes
CCDC 1823178 and 1823251 contain 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 Authors
■
*E-mail: hyao@cpu.edu.cn.
*E-mail: ajlin@cpu.edu.cn.
ORCID
Aijun Lin: 0000-0001-5786-4537
Hequan Yao: 0000-0003-4865-820X
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation of China (21572272), the Foundation of
The Open Project of State Key Laboratory of Natural
Medicines (SKLNMZZCX201818), and the Innovation
Team of “the Double-First Class” Disciplines
(CPU2018GY35 and CPU2018GY04).
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