Oxazolinyl-Assisted Ru(II)-Catalyzed C?H Functionalization Based on Carbene Migratory Insertion: A One-Pot Three-Component Cascade Cyclization

Article abstract of DOI:10.1002/adsc.201801362

A rare, ruthenium-catalyzed, oxazolinlyl assisted C?H functionalization and three-component cascade cyclization for the synthesis of isoquinolinones via a metal-carbene migratory insertion is reported. The transformation is unique since it involves the fo

Full text of DOI:10.1002/adsc.201801362

Title: Oxazolinyl-assisted Ru(II)-Catalyzed C-H Functionalization
Based on Carbene Migratory Insertion: A One-pot Three-
component Cascade Cyclization
Authors: Gangam Srikanth Kumar, Nandkishor Prakash Khot, and
Manmohan Kapur
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10.1002/adsc.201801362
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Oxazolinyl-assisted Ru(II)-Catalyzed C-H Functionalization
Based on Carbene Migratory Insertion: A One-pot Three-
component Cascade Cyclization
Gangam Srikanth Kumar,a Nandkishor Prakash Khot,a and Manmohan Kapura,*
a
Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal Bypass Road, Bhauri,
Bhopal 462066, MP, India.
E-mail:mk@iiserb.ac.in
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
other transition metals such as manganese and
ruthenium is quite underdeveloped.[12-13]
Abstract.
A rare, ruthenium-catalyzed, oxazolinlyl
assisted C-H functionalization and three-component
cascade cyclization for the synthesis of isoquinolinones
via a metal-carbene migratory insertion is reported. The
transformation is unique since it involves the formation of
multiple bonds in one pot via C-H functionalization and
ring opening of oxazolines. Detailed mechanistic
investigations reveal interesting insights on the mode of
transformation, involving reversible C-H activation,
migratory insertion of the diazo compound and cascade
cyclization as the key step of the transformation.
Keywords: C-H functionalization; carbene-migratory
insertion; ruthenium-carbene; multicomponent reaction;
isoquinolinone
Scheme 1. Ru(II)-Catalyzed, Oxazolinyl Assisted C-H
Functionalization with Diazo Compounds.
Transition metal-catalyzed C-H functionalization
has emerged as a powerful tool for achieving greater
complexity in organic molecules due to the rapid
development of the outstanding level of sophistication
in recent years.[1-2] Despite the remarkable advances
in C-H functionalizations, the development of more
sustainable approaches via efficient catalytic systems
still remains an attractive and long-standing interest.
Primarily, the merging of C-H functionalizations with
other efficient and sustainable approaches like
multicomponent reactions or cascade transformations,
is expected to be an ideal tool in organic synthesis for
rapid construction of molecular complexity from
simple starting materials.[3-4]
In recent years, diazo compounds have emerged as
versatile coupling partners in transformations
involving C-H functionalization to achieve the rapid
construction of complex entities (Scheme 1).[5]
Following pioneering reports by the research groups
of Yu, Glorius, Cui, and Rovis on the Rh(III)-
catalyzed intermolecular cross-coupling of diazo
compounds (Scheme 1)[6] C-H functionalizations
based on migratory insertions have witnessed great
advancements in last few years.[5b] However, most of
the reported methods employ rhodium,[6-8] copper[9]
and iridium[10] complexes as the catalysts; few of
them use cobalt complexes[11] whereas the use of
Despite the economic advantages and unique mode
of action of ruthenium(II) catalysts,[14] it came to us as
a surprise that the only few ruthenium catalyzed C-H
functionalization based on carbene migratory
insertion protocols have been reported.[13] Li and co-
workers developed the first Ru-(II) catalyzed C-H
activation of aryl imidamides with diazo
compounds.[13a] Barring few reports, the use of
ruthenium catalysis failed to provide the desired
products in a majority of the reported Rh(III)
catalyzed protocols. The lack of development in this
field is presumably because diazo compounds are
capable of displaying divergent reactivity with
different catalytic manifolds and under ruthenium
catalysis and acceptor-acceptor diazo compounds
undergo dimerization followed by reactions with
nucleophiles to afford furfurylation products.[15] To
explore the full potential of metal-carbene chemistry,
development of efficient ruthenium-catalyzed C-H
functionalizations of arenes with diazo compounds is
highly desirable.
The use of intrinsic functional groups of a molecule
as the directing group in C-H functionalization
represents a robust approach for building molecular
complexity from simple, readily-available building
blocks.[2] In this regard, oxazolinlyl moieties are a
1
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10.1002/adsc.201801362
Advanced Synthesis & Catalysis
superior choice as directing groups in C-H
Subsequently, we sought to explore the versatility
functionalization owing to their ubiquitous of the transformation. Importantly, the reaction
availability, easy preparation and prevalence in worked well with most of the aryl oxazolines as well
numerous bioactive compounds.[16-18] The ring as the diazo-compounds screened for the substrate
opening of oxazolines in C-H functionalization scope and displayed an excellent chemo- and
transformations to access N-heterocycles in a single regioselectivity profile, with remarkable functional
step remains unexplored. We envisioned that the group tolerance (Table 1). The cross-coupling of
ruthenium-catalyzed C–H functionalization of aryl various electronically-diverse oxazoles (electron-rich,
oxazolines with diazo compounds would lead to electron-neutral, as well as electron-poor substrates)
diverse nitrogen heterocycles in a one-pot fashion via proceeded smoothly to afford the isoquinolinones in
the ring opening of oxazoles (Scheme 1). To the best good to moderate yields (3aa-ai, Table 1). Along with
of
our
knowledge,
ruthenium-catalyzed electronic factors, steric factors were also well
multicomponent C–H functionalization of aryl tolerated, ortho-Me and MeO- substituted aryl
oxazolines in the synthesis of isoquinolinones in a oxazolines are found to be viable substrates in the
single step is not reported. With our continued interest transformation (3ca-3da, Table 1). Notably, densely
in Ru(II)-catalyzed C-H functionalizations,[19] we substituted aryl oxazolines also delivered the
report herein, a step-efficient ruthenium-catalyzed, corresponding isoquinolinones (3al, 3db, Table 1).
oxazolinlyl assisted C-H functionalization involving a
three-component cascade cyclization for the synthesis Table 1. Substrate Scope.a
of isoquinolinones via a metal carbene migratory
insertion (Scheme 1). Along-with mechanistic
insights, the notable highlights of the work are: (i) the
use of Ru(II) catalyst as an efficient alternative to
Rh(III) and Ir(III) catalysts in carbene chemistry, (ii)
three-component cascade cyclization, (iii) the ring
opening of aryl oxazolines for the synthesis of
isoquinolinones.
To probe the feasibility of envisioned transition
metal-catalyzed
multicomponent
C–H
functionalization of aryl oxazolines, we selected 2-
phenyl-4,5-dihydrooxazole (1a) and methyl 2-diazo-
3-oxobutanoate (2a) as the model substrates for the
transformation (see the Supporting Information (SI)
for details). To our delight, in preliminary
experiments, a catalytic system comprising of
[RuCl2(p-cym)]2, AgSbF6, CsOAc and AcOH
delivered the isoquinolinone 3ad as the product (see
SI for further details). We anticipated that the
formation of the isoquinolinone involves an initial C-
H functionalization, carbene migratory insertion
followed by acetate-mediated annulation. We felt that
the reactivity could be improved by employing
stoichiometric amounts of CsOAc, and a significant
improvement was actually observed (see SI for
further details). Switching to other acetate sources
afforded inferior results, and the best results were
obtained with CsOAc. Systematic screening of the
solvent system revealed that DCE is the optimal
solvent for the transformation (see SI for further
details). The effect of a protic source on the
transformation was found to be crucial and reaction-
efficiency significantly improved upon the use of
protic additives. Among these, (PhO)2P(O)OH was
found to be the most effective. An attempt to lower
the reaction temperature resulted in diminished yield
(see SI for further details). Different catalytic systems
such as Pd(OAc)2 and MnBr(CO)5 failed to provide
the desired product, whereas [Cp*RhCl2]2 provided
the desired product in comparable yield. It is worth
mentioning that the reaction displayed exclusive
selectivity and di-alkylated products were not
observed in the transformation.
aUnless otherwise mentioned all reactions were performed
with 1 (0.3 mmol), 2 (0.6 mmol), catalyst (0.015 mmol),
AgSbF6 (0.105 mmol) CsOAc (0.6 mmol and
b
(PhO)2P(O)OH (0.45 mmol) in 2.0 mL DCE. Reaction
c
1
performed on 1 mmol scale. ratio determined by H NMR
of the crude reaction mixture. ddiethyl 2-diazomalonate was
used.
The oxazolines bearing meta-substituents also
provided the corresponding products in good yields
with substituent dependent site-selectivity (3al, 3db,
3be, Table 1). The reaction of m-methoxy
aryloxazoline afforded a mixture of regioisomeric
products (3be, Table 1). Moreover, the reaction of 2-
(naphthalen-1-yl)-4,5-dihydrooxazole delivered the
cyclic scaffolds of isoquinolinones (3bg-3am, Table
2
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10.1002/adsc.201801362
Advanced Synthesis & Catalysis
1). The reaction was however found to be sensitive probe the C-H activation process, kinetic isotopic
towards pyridyl-substituted aryl oxazolines (3bj, effect studies were undertaken. A moderately low
Table 1). The scope of substituted diazoketoesters value of 1.65 was obtained for parallel experiments,
was also probed and the reaction worked well for whereas a value of 0.93 was obtained via competitive
most of the diazo compounds that were scanned for studies thereby indicating that the C-H cleavage is
the transformation (Table 1). Notable exception is 3- unlikely to be the rate-limiting step (Scheme 2c).
diazopentane-2,4-dione, which failed to deliver the Further, when the reaction was performed with
desired product (3ha, Table 1). Interestingly, the isotopically labeled oxazoline, a fast H/D scrambling
reaction of diethyl 2-diazomalonate furnished the was detected (see SI for further details). Based on our
tricyclic products through cascade cyclization albeit mechanistic studies and literature precedence,[6]
a
in rather low yield (3fa, Table 1). The reaction of plausible reaction mechanism for the transformation
5,5-dimethyl-2-phenyl-4,5-dihydrooxazole afforded is depicted in Scheme 3. The reaction begins with the
C-H alkylated products as the reaction did not generation of an active cationic Ru(II) species which
undergo cascade cyclization (3bh, 3bi, 3ga, Table 1). coordinates to oxazolinlyl moiety 1, and a reversible
The C-H alkylated products formed presumably C-H bond cleavage forms the five-membered
because the SN2 type nucleophilic attack of acetate ruthenacycle A. Then, the formation of ruthenium
anion is unlikely to occur at the 3o carbon center. We carbene intermediate B occurs via extrusion of N2
also employed CsOPiv, CsF, and CsOBz as followed by subsequent ruthenium-carbene migratory
nucleophiles for the ring opening of the oxazolines. insertion to deliver the ruthenacycle C. This is then
The reaction with the use of the CsOPiv and CsF did followed by proto-demetallation to afford D.
not result in any transformation, whereas the use of Nucleophilic attack of oxazolinlyl nitrogen onto the
CsOBz provided the expected product in 51% yield carbonyl functional group and acetate mediated ring
(3an). The reaction of 4,4-dimethyl-2-phenyl-4,5- opening of the aryl oxazoline occurs in an SN2 type
dihydrooxazole under the optimized conditions did fashion to afford isoquinolinones in a single step. The
not provide the desired product and starting material attack of the nitrogen onto the carbonyl is likely to be
mostly remained unreacted (3ao, Table 1).
a reversible step and the SN2 type nucleophilic attack
Given the versatile reactivity of Ru(II)-catalyzed of acetate anion on the intermediate E seems to be
three-component cascade cyclization and to gain key more facile than the initial attack of the acetate to the
insight into the mechanism of the transformation, a O-CH2 group to cleave the endocyclic C-O bond.
series of experiments were conducted. To this end, we Intermediate E was detected in ESI-MS (see the SI
performed reversibility experiments and kinetic for details) which also lent credence to the postulated
isotope effect (KIE) studies (Scheme 2). First, pathway.
quenching studies were performed in the presence and
absence of the coupling partner with D2O to
determine the reversibility of the C-H metallation step.
Scheme 2. Mechanistic studies.
In the absence of the coupling partner, the reaction
resulted in about 78% deuterium incorporation into
the starting material at both the ortho-positions Scheme 3. Plausible reaction pathway and Hammett
(Scheme 2a). In the presence of the coupling partner, studies.
deuterium content of about 70% at the ortho position
along with 35% deuterium content at the α-methylene
positions of the carbonyl group was observed, which
To get more insight on the formation of
could be attributed to the deuteration via keto-enol ruthenacycle, MS studies were performed (Scheme 3
tautomerization (Scheme 2b). The high levels of (I)). The ruthenacycles A and C were detected in ESI-
deuterium incorporation indicate that the formation of HRMS, thereby indicating that the oxazolinlyl
the ruthenacycle is a reversible reaction. To further assisted C-H functionalization was the initial step of
3
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10.1002/adsc.201801362
Advanced Synthesis & Catalysis
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Acknowledgements
Funding from SERB-India (EMR/2016/004298/OC) and CSIR-
India (02(205)/14/EMR-II) is gratefully acknowledged. GSK and
NPK thank CSIR-India, for research fellowships. We also thank
the Director, IISER Bhopal, for funding and infrastructural
facilities.
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[20] Crystal
Structure
submitted
to
Cambridge
Cystallographic Data Centre. CCDC deposition
number:
1854709
(compound
3ai).
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801362
Advanced Synthesis & Catalysis
COMMUNICATION
Oxazolinyl-assisted
Ru(II)-Catalyzed
C-H
Functionalization Based on Carbene Migratory
Insertion: A One-pot Three-component Cascade
Cyclization.
Adv. Synth. Catal. Year, Volume, Page – Page
Gangam Srikanth Kumar, Nandkishor Prakash
Khot, and Manmohan Kapur*
6
This article is protected by copyright. All rights reserved.