Rh(III)-Catalyzed C-C/C-N Coupling of Imidates with α-Diazo Imidamide: Synthesis of Isoquinoline-Fused Indoles

Article abstract of DOI:10.1021/acs.orglett.6b01284

Imidate esters and diazo compounds have been established as bifunctional substrates for the construction of biologically active fused heterocycles via rhodium-catalyzed C-H activation and C-C/C-N coupling. This reaction occurs under mild conditions with high efficiency, step economy, and low catalyst loading.

Full text of DOI:10.1021/acs.orglett.6b01284

Letter
pubs.acs.org/OrgLett
Rh(III)-Catalyzed C−C/C−N Coupling of Imidates with α‑Diazo
Imidamide: Synthesis of Isoquinoline-Fused Indoles
He Wang,† Lei Li,† Songjie Yu, Yunyun Li, and Xingwei Li*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
S
* Supporting Information
ABSTRACT: Imidate esters and diazo compounds have been established as bifunctional substrates for the construction of
biologically active fused heterocycles via rhodium-catalyzed C−H activation and C−C/C−N coupling. This reaction occurs
under mild conditions with high efficiency, step economy, and low catalyst loading.
soquinoline-fused indoles are important structural motifs in
diverse functional molecules. For example, they exhibit
Scheme 1. Synthesis of Indoloisoquinolines via C−H
Activation/Annulation
I
important biological activities including analgesic, anti-inflam-
matory, and antioxidant effects (Figure 1).1 They also have found
Figure 1. Representative biologically active indoloisquinolines.
applications as materials in organic optoelectronic devices.2
Among such heterocycles, 7H-indolo(2,3-c)isoquinolines (Fig-
ure 1) are known to have potential antitumor activities and have
been used in the treatment of tumors.1b However, only very
limited methods have been reported for the synthesis of 7H-
indolo(2,3-c)isoquinoline derivatives,3 which typically start from
highly functionalized starting materials and require harsh
conditions with low step economy. Therefore, development of
highly efficient strategies for the preparation of these compounds
under mild conditions is of great significance.
Recently, direct C−H activation of arenes has been extensively
investigated as a powerful strategy for the high atom- and step-
economical syntheses of complex structures.4 However, to date,
synthesis of indoloisoquinolines via a C−H activation process
has been rare. In 2014, Roy and co-workers reported a two-step
synthesis of indoloisquinolines via Cu- and Pd-cocatalyzed
intramolecular C−H functionalization of indoles, which
occurred under high catalyst loading and relatively harsh
conditions (Scheme 1).5 On the other hand, electrophilic diazo
compounds have been widely applied as a coupling partner in
Rh(III)-catalyzed C−H functionalization of arenes.6 For
instance, in 2012, Yu and co-workers demonstrated the first
rhodium-catalyzed intermolecular coupling of diazomalonates
with arenes via C−H activation.7 Subsequently, the groups of
Rovis,8 Glorius,9 and others10 developed annulative couplings
between arenes and diazo compounds via Rh(III)-catalyzed C−
C/C−N bond formation. Afterward, diverse heterocycles were
synthesized via Rh(III)-catalyzed C−H activation.11 As a
continuation of our interest in C−H activation chemistry,12 we
reasoned that α-diazo imidamide as a precursor of a
dielectrophilic carbene13 can electronically match an arene
bearing a protic NH directing group, leading to synthesis of such
an indolo(2,3-c)isoquinoline scaffold (Scheme 1).14 In this
system, the C−C bond formation occurs first via C−H
alkylation15 followed by intramolecular C−N formation. We
now report our Rh(III)-catalyzed efficient synthesis of
indoloisquinolines via this strategy with aromatization as a
driving force.
We embarked on our studies by screening the reaction
parameters of the coupling of ethyl benzimidate (1a) with α-
diazo imidamide 2a (Table 1). Using [RhCp*Cl2]2/AgSbF6 as a
catalyst, desired product 3aa was isolated in 52% yield in DCE at
80 °C (entry 1). Introduction of PivOH proved to be beneficial
and necessary (entries 2−4), which likely facilitated both the C−
Received: May 2, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01284
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a b
,
Table 1. Optimization Studies
Scheme 2. Substrate Scope of Aryl Imidates
b
entry
n
additive (equiv)
solvent
t (°C)
yield (%)
1
2
4
4
4
4
4
4
2
2
2
1
2
2
DCE
80
80
80
80
80
80
80
40
25
40
40
40
52
67
47
95
PivOH (1)
TsOH (1)
PivOH (1)
PivOH (1)
PivOH (1)
PivOH (1)
PivOH (1)
PivOH (1)
PivOH (1)
PivOH (1)
PivOH (1)
DCE
3
DCE
4
MeOH
MeOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
c
5
37
6
98
98
97
50
96
7
8
9
10
11
12
d
nd
e
87
a
Reactions were carried out using [RhCp*Cl2]2 (1 mol %)/AgSbF6 (4
mol %), 1a (0.2 mmol), and 2a (0.24 mmol) in a solvent (3 mL)
b
under nitrogen at 40 °C for 12 h. Isolated yield after column
c
chromatography. Reaction was performed with 3-diazo-1-methyl-
d
e
indolin-2-one. No rhodium catalyst was used. No AgSbF6 was used.
a
Reaction conditions: 1 (0.2 mmol), 2 (0.24 mmol), [Cp*RhCl2]2 (1
mol %), AgSbF6 (4 mol %), PivOH (0.2 mmol), EtOH (3 mL), 40 °C
H activation and the cyclization processes. Screening of the
solvents revealed that EtOH was optimal (entry 6), and the same
yield was obtained when the catalyst loading was decreased to 2
mol % (entry 7). Poor conversion was observed when the diazo
compound was replaced with 3-diazo-1-methylindolin-2-one
(entry 5). The reaction proceeded well even at 40 °C (entry 8).
The reaction is highly efficient, and even 1 mol % loading of the
rhodium catalyst can suffice (entry 10). Control experiments
indicated that [RhCp*Cl2]2 was necessary (entry 11), but
omission of AgSbF6 still gave a good yield (entry 12).
b
c
under N2 for 12 h. Isolated yield. [Cp*RhCl2]2 (2 mol %), AgSbF6
d
(8 mol %), 40 °C. [Cp*RhCl2]2 (2 mol %), AgSbF6 (8 mol %), 60
e
f
g
n
i
°C. With MeOH (3 mL). With PrOH (3 mL). With PrOH (3
h
mL). [Cp*RhCl2]2 (2 mol %), AgSbF6 (8 mol %), MeOH (3 mL),
60 °C.
a b
,
Scheme 3. Substrate Scope of 3-Diazoindolin-2-imines
With the establishment of the optimal conditions, we first
defined the scope and generality with respect to aryl imidates
(Scheme 2). Aryl imidates bearing both electron-donating and
-withdrawing groups at the para position of the phenyl ring all
coupled smoothly with diazo 2a to afford the annulated products
(3ba−3ha) in good to excellent yields. The molecular structure
of 3fa was unambiguously confirmed by X-ray crystallography
(CCDC 1482471). Introduction of a meta substituent was also
tolerated, and the reaction occurred at the less hindered site,
furnishing the products in excellent yields (3ia−3ka). An ortho
fluoro group was also compatible (3la, 65%) at a slightly higher
temperature. Besides the ethyl ester, other alkyl esters of the
imidate also coupled smoothly in high yields (3ma−3na),
although the isopropyl imidate reacted with lower efficiency
(3oa). In the coupling of these alkyl esters, the corresponding
alcohol was employed as the solvent to avoid transesterification.
The imidate substrate is not limited to alkyl esters, and even
benzophenone NH imines all reacted with high efficiency (3pa
and 3qa), wherein using electronically biased diarylmethanimine
substrates afforded two regioisomeric products, 3ra and 3ra′.
Notably, the arene substrate was smoothly extended to a
thiophene ring in good yield (3sa).
a
Reaction conditions: 1 (0.2 mmol), 2 (0.24 mmol), [Cp*RhCl2]2 (1
mol %), AgSbF6 (4 mol %), PivOH (0.2 mmol), EtOH (3 mL), 40 °C
b
c
We next examined the scope of the diazo substrate. It was
found that introduction of electron-donating and halogen groups
at the 4-, 5-, 6-, and 7-positions of the indole ring was fully
tolerated (Scheme 3). However, introduction of a 4-chloro
under N2 for 12 h. Yield of isolated product. [Cp*RhCl2]2 (2 mol
%), AgSbF6 (8 mol %), 60 °C. [Cp*RhCl2]2 (2 mol %), AgSbF6 (8
mol %), MeOH (3 mL), 60 °C.
d
B
DOI: 10.1021/acs.orglett.6b01284
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
substituent of indole retarded the coupling (3ac, 37%), as a result
of the electronic and steric effects. Other N-substituted indoles,
such as N-ethyl and N-benzyl indoles, coupled with high yields
(3al, 3am). Notably, N-unprotected diazo indole was also viable
for this transformation albeit with slightly lower efficiency (3ak).
Product 3mf with potent antitumor activity was synthesized in
good yield.5
Scheme 4. Proposed Mechanism
To demonstrate the synthetic utility of the catalytic system,
gram-scale synthesis of 3aa was performed in high yield. Further
hydrolysis of 3aa in concentrated hydrochloric acid/1,4-dioxane
led to isoquinolone 4 in excellent yield (eq 1).
Several experiments have been performed to explore the
mechanism. To probe this C−H activation process, an
intermolecular kinetic isotope effect experiment was measured
using 1a and 1a-d5 in the coupling with 2a (eq 2). A rather large
such important fused heterocycles may find applications in the
synthesis of complex biologically active products.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01284.
Crystallographic data for 3fa (CIF)
General procedures, characterization data, and copies of
the NMR spectra of all new products (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: xwli@dicp.ac.cn.
Author Contributions
†H.W. and L.L. contributed equally.
Notes
kH/kD value of 5.7 indicated that cleavage of the C−H bond is
likely involved in the turnover-limiting step. Furthermore,
rhodacyclic complex 516 was designated as a catalyst for the
coupling of imidate 1a with diazo 2a, and the corresponding
annulated product was isolated in excellent yield (eq 3),
indicating the relevancy of C−H activation. Moreover, an
intermolecular competition between 1b and 1h under standard
conditions pointed to the conclusion that an electron-rich
imidate reacted preferentially (eq 4).
On the basis of these preliminary results, a plausible pathway is
proposed starting from an active [RhCp*(OPiv)X] (X = OPiv or
SbF6) species (Scheme 4). Coordination and C−H activation of
the imidate ester deliver rhodacycle A. Subsequent coordination
of the diazo substrate is followed by extrusion of N2 to give a
rhodium carbenoid intermediate B. Migratory insertion of the
Rh−Ar bond into the carbene generates a six-membered spiro-
rhodacycle C that undergoes protonolysis, leading to alkylated
intermediate D. An intramolecular nucleophilic addition/
elimination process eventually releases the Rh(III) species and
furnishes product 3aa.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge the financial support from the Dalian Institute
of Chemical Physics, Chinese Academy of Sciences, the NSFC
(No. 21525208), Postdoctoral Science Foundation of China
(2015M571333), and for new technology of methanol
conversion from Dalian Institute of Chemical Physics.
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DOI: 10.1021/acs.orglett.6b01284
Org. Lett. XXXX, XXX, XXX−XXX