Ruthenium(II)-Catalyzed Oxidative Double C-H Activation and Annulation Reaction: Synthesis of Indolo[2,1- a]isoquinolines

Article abstract of DOI:10.1021/acs.orglett.9b02871

The first metal-catalyzed double aryl C(sp²)-H bond activation of antipyrine and alkyne annulation reaction is reported. This Ru(II)-catalyzed reaction was accomplished in the presence of 20 mol % phosphine ligand tricyclohexylphosphine tetrafluoroborate to afford indolo[2,1-a]isoquinolines that are very important compounds because of their bioactivity and interesting optical properties.

Full text of DOI:10.1021/acs.orglett.9b02871

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Ruthenium(II)-Catalyzed Oxidative Double C−H Activation and
Annulation Reaction: Synthesis of Indolo[2,1‑a]isoquinolines
Somadrita Borthakur,† Bipul Sarma,‡ and Sanjib Gogoi*,†
†Applied Organic Chemistry, Chemical Sciences & Technology Division, CSIR-North East Institute of Science and Technology,
Jorhat 785006, AcSIR, India
‡Department of Chemical Sciences, Tezpur University, Tezpur 784028, India
S
* Supporting Information
ABSTRACT: The first metal-catalyzed double aryl C(sp2)−H bond
activation of antipyrine and alkyne annulation reaction is reported.
This Ru(II)-catalyzed reaction was accomplished in the presence of 20
mol % phosphine ligand tricyclohexylphosphine tetrafluoroborate to
afford indolo[2,1-a]isoquinolines that are very important compounds
because of their bioactivity and interesting optical properties.
n past few decades, the transition metal-catalyzed activation
2
Iof the aryl C(sp )−H bond followed by alkyne annulation
reactions has emerged as an excellent method for the efficient
synthesis of various important heteroaromatic compounds,
which are otherwise difficult to synthesize by using conven-
tional synthetic methods.1 There are several examples of the
metal-catalyzed reactions for the synthesis of heterocyclic
scaffolds that proceed via C−H/N−H bond or C−H/O−H
bond activation and alkyne annulation.1 Very recently, the
metal-catalyzed double activation of C(sp2)−H bonds and
Figure 1. Examples of important indolo[2,1-a]isoquinolines.
alkyne annulation reactions have also proven to be potential
tools for the efficient synthesis of polyheteroaromatic
compounds. In the recent past, the polyaromatic and
polyheteroaromatic compounds have been considered as very
derivatives (Scheme 1, eq 1).5 A Rh(III)-catalyzed synthesis
of polyarylated naphthyls and anthrylazoles by the double C−
useful compounds for the development of organic semi-
conductors and luminescent materials because of the excep-
tional p-conjugation of these cyclic compounds.2 These stable
polycyclic compounds with condensed aromatic rings have the
ability to enhance the transport of charges, and they exhibit
intense fluorescence. Among these polyheteroaromatic com-
pounds, the indolo[2,1-a]isoquinolines have in particular
attracted a considerable amount of attention from both
synthetic chemists and medicinal chemists because of their
presence as the key scaffold in several biologically active
compounds and pharmaceuticals and their utility in organic
light-emitting diodes as hole-transporting materials (HTMs)
(Figure 1).3,4
H activation of phenylazoles and alkyne annulation reaction
was also developed (Scheme 1, eq 2).6 To pursue our interest
in the development of new metal-catalyzed C−H activation
reactions,7 herein, we report a Ru(II)-catalyzed double
C(sp2)−H bond activation of antipyrine and disubstituted
alkyne annulation reaction for the synthesis of polyheteroar-
omatic compound indolo[2,1-a]isoquinoline (Scheme 1, eq 3).
At the beginning, the annulation reaction was studied to
construct indolo[2,1-a]isoquinoline 3aa using antipyrine 1a
and alkyne 2a as the starting compounds (Table 1). Screening
of some of the catalysts using Cu(OAc)2 as the additive
revealed the [{RuCl2(p-cymene)}2] catalyst to be the most
efficient catalyst that afforded a 30% yield of 3aa (entry 3 and
Table SI-1). Further studies of the additives provided an
inferior yield of 3aa (entries 5−7). Fortunately, after a variety
of phosphine ligands had been surveyed, the P(Cy)3·HBF4
ligand provided the highest yield of 3aa (entry 9 and Table SI-
1). Then, these standardized reaction conditions were first
examined with various substituted antipyrine derivatives 1b−m
Transition metal-catalyzed double C(sp2)−H activation and
alkyne annulation reaction is an excellent route for the efficient
synthesis of polyheteroaromatic compounds. However, despite
the importance of these polyheteroaromatic compounds,
examples of such metal-catalyzed routes for their synthesis
are very limited. For example, recently, Cheng, Chuang, and
co-workers developed a Rh(III)-catalyzed double C−H
activation reaction of (Z)-N-hydroxybenzamidines and alkyne
annulation to synthesize 1H-benzo[de][1,8]naphthyridine
Received: August 13, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02871
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Scheme 1. Examples of Double C(sp2)−H Activation and
desired products 3ka−ma, respectively, with 2a in good yields.
The reactions of 1k and 1m with alkyne 2a were highly
regioselective. Subsequently, the standard Ru(II)-catalyzed
reaction conditions were studied for the annulation of alkynes
2a−i with antipyrine (1a). All of the representative diaryl-
substituted symmetrical alkynes possessing substituents such as
methyl (2b), methoxy (2c), and fluoro (2d) at the para
position of the phenyl rings turned out to be suitable starting
compounds for this reaction to provide products 3ab−ad,
respectively, with 1a in moderate to good yields (Scheme 3).
The unsymmetrically substituted diaryl alkynes bearing
substituents methyl and fluoro (2e) and methyl and methoxy
(2f) at the para position of the phenyl ring provided a mixture
of isomers 3ae and 3af with 1a, which could not be separated
by normal silica gel column chromatography. The reaction of
unsymmetrical aryl alkyl group-containing alkyne 2g with
antipyrine (1a) provided only one isomer, 3ag. However,
similar unsymmetrical disubstituted alkynes 2h and 2i
provided a mixture of products 3ah (10:1) and 3ai (2.5:1),
respectively, with 1a. The dialkyl-substituted alkynes and
terminal alkynes were not good starting compounds for the
performance of this annulation reaction. The tested hetero-
cycle-containing alkyne 1,2-di(thiophen-3-yl)ethyne, the ester-
containing alkyne ethyl 3-phenylpropiolate, and the silyl group-
containing alkyne trimethyl(phenylethynyl)silane could not
afford the corresponding annulated products. At the same time,
the readily available acetanilide afforded only 12% of product
3aa with 2a under the optimized conditions. The structures of
all of the synthesized indolo[2,1-a]isoquinolines were clearly
established by NMR spectroscopy and X-ray crystallography
studies of 3aa.8 The regioselectivity of compounds 3ag−ai
Alkyne Annulation Reactions
with alkyne 2a to afford the corresponding indolo[2,1-
a]isoquinoline derivatives 3ba−ma, respectively (Scheme 2).
The antipyrines substituted at the para position of the phenyl
ring with substituents such as methyl (1b), isopropyl (1c),
methoxy (1d), fluoro (1e), chloro (1f), and trifluoromethyl
(1g) afforded 3ba−ga, respectively, with 2a in good yields.
Similarly, the antipyrines possessing substituents such as
methyl (1h), fluoro (1i), and chloro (1j) at the meta position
of the antipyrine phenyl ring also reacted smoothly with 2a to
provide products 3ha−ja, respectively. These annulation
reactions of 1h−j with 2a were found to be highly
regioselective owing to the selective less sterically hindered
C(sp2)−H bond activation. The antipyrines possessing two
substituents at positions 3 and 4 (1k and 1m) and positions 3
and 5 (1l) of the phenyl ring were also tested to provide the
1
were determined by comparing the H NMR spectra of these
compounds with those of some other synthesized compounds
(Supporting Information). The regioselectivity of the cycliza-
tion of unsymmetrical alkynes 2g−i follows the reported metal-
catalyzed alkyne annulation reactions, where, in the alkyne
insertion step in the C−M bond, the metal preferentially forms
a bond with the electron rich carbon center of the alkyne.9
a
Table 1. Optimization of the Reaction Conditions for 3aa
b
entry
catalyst
Pd(OAc)2
[RuCl2(PPh3)3]
[{RuCl2(p-cymene)}2]
[(Cp*RhCl2)2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
additive
ligand
3aa (%)
1
2
3
4
5
6
7
8
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
CsOAc
−
−
−
−
−
−
−
0
0
30
14
13
0
11
42
77
28
54
43
CuBr2
AgOAc
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
P(Cy)3
P(Cy)3·HBF4
DCYPE
( )-BINAP
( )-BINOL
9
10
11
12
a
Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), catalyst (5.0 mol %), additive (0.5 mmol), ligand (20 mol %), and tAmOH (5.0 mL) heated
b
at 100 °C for 8 h under air. Isolated yields.
B
DOI: 10.1021/acs.orglett.9b02871
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a
a
Scheme 2. Reactions of Antipyrenes 1b−m with Alkyne 2a
Scheme 3. Reactions of Antipyrine (1a) with Alkynes 2a−i
a
Reaction conditions: 1 (0.5 mmol), 2a (1.0 mmol), Ru(II) catalyst
(5.0 mol %), P(Cy)3·HBF4 (20 mol %), Cu(OAc)2·H2O (0.5 mmol),
t
and AmOH (5.0 mL) heated at 100 °C for 8 h under air.
The deuterium labeling experiment of antipyrine (1a)
without using the alkyne, performed under the optimized
conditions using CD3OD as the solvent, could not provide the
deuterium−hydrogen exchanged compound 1a-D2, which is
shown in Scheme 4 (eq 1). This reaction indicates the
nonreversible cycloruthenation step of this Ru-catalyzed
reaction. Moreover, the intermolecular and competitive parallel
kinetic isotope effect experiments provided a kH/kD of 4.0 and
a kH/kD of 3.4, respectively (Scheme 4, eqs 2 and 3). These
experiments indicate the metal-catalyzed C(sp2)−H bond
activation step to be the rate-limiting step of this reaction.
On the basis of our observation and evidence from the
literature, a probable mechanism of Ru(II)-catalyzed formation
of 3aa is presented in Scheme 5. Initially, the active Ru(II)
catalyst forms Ru complex B via amine group-directed
irreversible activation of the C(sp2)−H bond.10 Then,
metal−alkyne coordination, followed by migratory alkyne
insertion into the Ru−C bond and subsequent oxidation of
the metal Ru(II) to Ru(IV) because of the cleavage of the
weak N−N bond, provides a six-membered Ru(IV) complex
C.11 Next, reductive elimination of the Ru metal and further
C(sp2)−H activation of the substituted phenyl ring of the
a
Reaction conditions: 1a (0.5 mmol), 2 (1.0 mmol), Ru(II) catalyst
(5.0 mol %), Cu(OAc)2·H2O (0.5 mmol), P(Cy)3·HBF4 (20 mol %),
t
and AmOH (5.0 mL) heated at 100 °C for 8 h under air.
resulting indole derivative might have formed a nine-
membered Ru complex D. Subsequent contraction of the
C
DOI: 10.1021/acs.orglett.9b02871
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provide indolo[2,1-a]isoquinolines with good yields. This
ligand-directed reaction has opened up a new synthetic route
to access important polyheteroaromatic indolo[2,1-a]-
isoquinolines.
Scheme 4. Isotopically Labeled Experiments
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.9b02871.
Experimental procedures, spectroscopic data, and copies
1
of H NMR, 13C NMR, and HRMS spectra of the
synthesized compounds (PDF)
Accession Codes
CCDC 1547364 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 Author
■
*E-mail: skgogoi1@gmail.com or sanjibgogoi@neist.res.in.
ORCID
Sanjib Gogoi: 0000-0002-2821-3628
Notes
Scheme 5. Possible Mechanism
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank CSIR New Delhi for the financial support
via Project OLP 2020. The authors thank the Director of
CSIR-NEIST for his constant support. S.B. thanks CSIR for
the SRF.
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