Access to Structurally Diverse Quinoline-Fused Heterocycles via Rhodium(III)-Catalyzed C-C/C-N Coupling of Bifunctional Substrates

Article abstract of DOI:10.1021/acs.orglett.6b01032

Rhodium(III)-catalyzed C-H activation of heteroarenes and functionalization with bifunctional substrates such as anthranils allows facile construction of quinoline-fused heterocycles under redox-neutral conditions. The couplings feature broad substrate scope and provide step-economical access to two classes of quinoline-fused condensed heterocycles.

Full text of DOI:10.1021/acs.orglett.6b01032

Letter
pubs.acs.org/OrgLett
Access to Structurally Diverse Quinoline-Fused Heterocycles via
Rhodium(III)-Catalyzed C−C/C−N Coupling of Bifunctional Substrates
Songjie Yu,† Yunyun Li,† Xukai Zhou, He Wang, Lingheng Kong, and Xingwei Li*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
S
* Supporting Information
ABSTRACT: Rhodium(III)-catalyzed C−H activation of heteroarenes and functionalization with bifunctional substrates such as
anthranils allows facile construction of quinoline-fused heterocycles under redox-neutral conditions. The couplings feature broad
substrate scope and provide step-economical access to two classes of quinoline-fused condensed heterocycles.
used heterocycles such as indolo[2,3-b]quinoline are
extended π-systems widely found in pharmaceuticals and
Scheme 1. Representative Methods for Synthesis of
Quinoline-Fused Heterocycles
F
in natural products,1 and they have explicitly exhibited a broad
spectrum of biological activities including antifungal, anti-
inflammatory, antibacterial, cytotoxicity, and antimalarial
activities,2 among others (Figure 1).3 These fascinating
Figure 1. Representative biologically active pyrido[2,3-b]indoles.
biological activities have called for considerable efforts in
developing more efficient synthetic strategies because most of
the existing methods suffer from highly functionalized starting
materials, harsh conditions, low atom-economy, and lack of
substrate generality (Scheme 1).4 Therefore, the development
of novel strategies for the construction of these useful scaffolds
in a green, efficient, and atom-economic fashion is highly
desirable.
Transition-metal catalysts have exhibited profound potentials
in C−H activation of arenes5 for the construction of condensed
heterocycles. However, metal-catalyzed synthesis of quinoline-
fused heterocycles such as indolo[2,3-b]quinoline and benzo-
[b][1,8]naphthyridin-2-one via a C−H activation pathway is
unknown. As a continuation of our interest in C−H activation
chemistry,6 we pondered the employment of Rh(III) catalysis7
for this purpose starting from readily available bifunctional
substrates. Through the retrosynthetic analyses of this
molecular architecture, the key step in the synthesis of such a
scaffold boils down to the construction of a pyridine ring via
C−N and C−C formations, which have been well exemplified
in Rh(III) catalysis (Scheme 1).8 A strategy can thus be
envisioned to fulfill this synthetic target by taking advantage of
an electrophilic aminating reagent that delivers a proximal
electrophilic carbonyl group upon amination. This bifunction-
ality electronically matches that in an electron-rich arene. For
this purpose, anthranils9 have been identified as bifunctional
aminating reagents via a transannulation strategy. Thus,
electrophilic C−H amination occurs first,10 followed by
Friedel−Crafts cyclization−condensation.11 We now report
our findings in Rh(III)-catalyzed efficient synthesis of diverse
Received: April 10, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01032
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Organic Letters
Letter
a,b
quinoline-fused heterocycles via C−H activation of different
classes of arenes.
Scheme 2. Amination−Annulation of Indoles
We commenced our studies by examining the reaction
parameters of the coupling of N-pyrimidinylindole (1a) with
anthranil (2a) using [Cp*RhCl2]2/AgSbF6 as a catalyst (Table
1). The desired indolo[2,3-b]quinoline 3aa was isolated in 35%
a
Table 1. Optimization Studies
b
entry
cat. (mol %)
additive
solvent
yield (%)
1
2
[Cp*RhCl2]2 (4)
[Cp*CoI2CO] (8)
[Cp*CoCl2]2 (4)
[Cp*RhCl2]2 (4)
[Cp*RhCl2]2 (4)
[Cp*RhCl2]2 (4)
[Cp*RhCl2]2 (4)
[Cp*RhCl2]2 (4)
[Cp*RhCl2]2 (4)
[Cp*RhCl2]2 (3)
[Cp*RhCl2]2 (3)
[Cp*RhCl2]2 (3)
HOPiv
HOPiv
HOPiv
HOAc
TFA
DCE
35
DCE
NR
NR
31
3
DCE
4
DCE
5
DCE
trace
79
6
HOPiv
HOPiv
HOPiv
HOPiv
HOPiv
HOPiv
TFE
7
MeOH
EtOH
HFIP
MeOH
MeOH
MeOH
95
8
83
9
89
10
92
c
11
74
a
Reaction conditions: indole (0.2 mmol), anthranil (0.4 mmol),
12
39
a
[Cp*RhCl2]2 (3 mol %), AgSbF6 (20 mol %), and HOPiv (0.4 mmol)
in MeOH (3 mL) at 120 °C. Isolated yield.
Reaction conditions: 1a (0.2 mmol), anthranil 2a (0.4 mmol),
catalyst, AgSbF6 (0.04 mmol), and additive (0.4 mmol) in a solvent (3
b
b
c
mL) at 120 °C. Isolated yield. 100 °C.
crucial role in ensuring annulation between arenes and an
electrophilic coupling partner.11 For example, electron-poor
arenes such as 2-phenylpyridine only underwent amination
with anthranil with no further cyclization.12 We reasoned that
N-pyridyl-2-pyridone is sufficiently nucleophilic at the 5-
position.13 Meanwhile, the vicinal C(6)−H should readily
undergo activation when catalyzed by Rh(III).14 Thus, this may
lead to the synthesis of benzo[b][1,8]naphthyridin-2-ones,
another class of useful condensed heterocycles (Scheme 3).15
Indeed, reaction of N-pyridyl-2-pyridone and an anthranil
under modified conditions afforded a benzo[b][1,8]-
naphthyridin-2-one in high yield (5ag). Electron-donating
groups at different positions of the 2-pyridone ring are
compatible, and the reaction also tolerated steric perturbation
at the 4 position (5cg and 5dg). In addition, the arene substrate
has been extended to an isoquinolone, affording an even larger
π-conjugation system (5hg). Next, the scope of the anthranil
was investigated. The reaction proceeded smoothly with high
efficiency and good functional group tolerance (5ga−ik, 76−
99%).
To demonstrate the synthetic utility of the catalytic reactions,
gram-scale synthesis of 3aa has been realized in high yield
under a reduced catalyst loading (eq 1). Surprisingly, attempts
to remove the pyrimidyl DG by treatment of 3aa with NaOEt
in DMSO afforded an ethoxymethyl-protected indole (6)
instead of the expected NH indole (eq 2). Formation of 6 was
proposed to occur via Pummerer rearrangement, where DMSO
participated in the rearrangement to provide the methylene unit
in 6 (see the Supporting Information for the mechanism of this
transformation). This unexpected compound was then hydro-
lyzed in aqueous HCl to give the NH indole 7 in excellent
yield, which can be readily transferred to neocryptolepine,4c an
alkaloid with pronounced antiplasmodial activity.1a
yield in DCE (entry 1). Switching the rhodium catalyst to
related cobalt(III) ones, however, led to no desired reaction
(entries 2 and 3). PivOH proved to be an optimal and
necessary additive (entries 4, 5, and 12), which likely facilitated
both the C−H activation and the cyclization processes. Further
screening revealed that protic solvents tend to favor this
reaction. To our delight, the yield of the isolated 3aa was
dramatically improved to 95% when MeOH was chosen as a
solvent (entries 6−9). A similar yield was obtained when the
catalyst loading was lowered to 3 mol %, while lowering the
reaction temperature gave a diminished yield (entries 10 and
11).
With the establishment of optimal reaction conditions, we
next investigated the scope and generality of this coupling
system (Scheme 2). It was found that N-pyrimidinylindoles
bearing both electron-donating and -withdrawing substituents
at different positions all coupled smoothly with simple anthranil
(2a), and the corresponding products were isolated in 73−92%
yields. In addition to a pyrimidinyl DG, a pyridyl group also
offered comparable directing effects (3oa and 3pa). Notably,
this protocol was applicable to the synthesis of a pyrrolo[2,3-
b]pyridine (3qa) in good yield starting from a pyrrole. The
scope of anthranil was next examined, and introduction of
electron-donating and -withdrawing groups into different
positions of the anthranil ring was fully tolerated (3ab−3ag,
62−97%). In contrast, subjection of 3-methyl-1-(pyrimidin-2-
yl)-1H-indole to the standard conditions gave no amination
product (3ra), indicating that annulation and aromatization
offered important driving forces for the reaction.
It has been demonstrated that nucleophilicity of the site
vicinal to the C−H bond that undergoes activation plays a
B
DOI: 10.1021/acs.orglett.6b01032
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Organic Letters
Letter
a,b
Scheme 3. Amination−Annulation of 2-Pyridones
Scheme 4. Proposed Mechanism
pyridones. These couplings feature the employment of
bifunctional arenes and a bifunctional aminating reagent
under redox-neutral conditions. These efficient and concise
protocols to access such important scaffolds may find
applications in the synthesis of complex biologically active
products.
a
Reaction conditions: 2-pyridone (0.2 mmol), anthranil (0.4 mmol),
[Cp*RhCl2]2 (3 mol %), AgSbF6 (20 mol %), and HOPiv (0.6 mmol)
in DCE (3 mL) at 120 °C for 20 h. Isolated yield after column
chromatography.
b
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01032.
Experimental procedures, characterization data, derivati-
1
zation reactions, mechanistic studies, and H, 13C, and
19F NMR spectra of the products (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: xwli@dicp.ac.cn.
Author Contributions
†S.Y. and Y.L. contributed equally.
Notes
Rhodacyclic complexes 8 were then used as a catalyst for the
C−H activation of an indole, and the corresponding annulated
product 3aa was isolated in excellent yield (eq 3), indicating
relevancy of C−H activation in the coupling. On the basis of
previous work,11,12 a plausible pathway is proposed starting
from an active [RhCp*(OPiv)L]+ species (L = a weakly
coordinating species, Scheme 4). Cyclometalation of N-
pyrimidinylindole affords a rhodacycle A, to which anthranil
coordinates to give intermediate B, which undergoes
elimination of a formyl group with concomitant formation of
a nitrido species C.12 The Rh−aryl bond then migratorily
inserts into the nitrene to give a tripodal intermediate D,12
which undergoes protonolysis to lead to an aminated
intermediate E. Friedel−Crafts cyclization eventually delivers
the annulated product 3aa, and this annulation process is
favored in a protic solvent.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge financial support from the Dalian Institute of
Chemical Physics, Chinese Academy of Sciences, and the
NSFC (Nos. 21525208 and 21472186).
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DOI: 10.1021/acs.orglett.6b01032
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