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org/OrgLett Letter

Iridium(III)-Catalyzed C(3)−H Alkylation of Isoquinolines via Metal

Carbene Migratory Insertion
Neha Jha, Roushan Prakash Singh, Paridhi Saxena, and Manmohan Kapur*
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ABSTRACT: An Ir(III)-catalyzed C(3)−H alkylation of N-acetyl-1,2-dihydroiso-

quinolines with diverse acceptor−acceptor diazo compounds has been achieved under
a single catalytic system via metal carbene migratory insertion. Moreover, further
synthetic transformations of the alkylated products such as aromatization, selective
decarboxylation, and decarbonylation lead to the formation of several synthetically
viable isoquinoline derivatives having immense potentials.

I soquinoline derivatives, being ubiquitous fragments in

biologically active compounds, exhibit a wide range of
pharmacological properties such as anti-infective, neuronal
Scheme 1. Transition-Metal-Catalyzed C−H Alkylation of
Heteroarenes

hyperexcitability, antimalarial, and anti-HIV activities.1 Con-

ventional methods of synthesis and functionalization, although
prevalent, suffer from lengthy multistep synthesis, lower
synthetic output, and limited scope.2 In this regard, a
transition-metal-catalyzed site-selective C−H bond functional-
ization approach assists in designing innovative routes for
atom- and step-economical synthesis of such heterocyclic
scaffolds.3 In particular, C−H bond functionalization via
transition metal-carbene migratory insertion has evolved as a
unique technique for accessing derivatized heterocycles.4 Diazo
compounds act as carbene precursors, which, following
insertion into preformed metalacycles, aids in direct C−C
bond formation. After the initial breakthrough by Yu and co-
workers, who reported Rh-catalyzed intermolecular chelation-
assisted carbene insertion of α-diazomalonates with aromatic
C(sp2)−H bonds,5a several pioneering works by the research
groups of Rovis,5b Glorius,5c and Wang5d demonstrated the
successful exploration of diazo compounds in C−H function-
alization, employing the chelation-assisted strategy (Scheme low reactivity of these heterocycles.6 Reports of C(3)−H
1). Following this, significant progress has been made in functionalization of isoquinolines are very limited, and to
coupling different sets of diazo compounds with arenes/ address such reactivity challenges, our group has contributed
heteroarenes employing varied catalytic systems of Rh, Ir, Co,
and Ru.4d,f In particular, α-diazomalonate derivatives have
emerged as efficient coupling partners in C−C bond formation Received: September 9, 2021
under Rh, Ir, and Co catalysis and have been effective in easy Published: November 10, 2021
derivatization.4d,f On the other hand, facile construction of C−
C bonds via directed functionalization in π-deficient hetero-
cycles (like quinolines, isoquinolines, pyridines, etc.) is a
challenging task owing to the reduced coordination ability and

© 2021 American Chemical Society https://doi.org/10.1021/acs.orglett.1c03054

8694 Org. Lett. 2021, 23, 8694−8698
Organic Letters
Scheme 2. Substrate Scope for Alkylationa,h,i
a
Reaction conditions: 1 (0.1 mmol), 2/4/6/8 (0.12 mmol), catalyst (3 mol %), Ag-salt (12 mol %) and acid additive (0.2 equiv) in 1 mL of HFIP
at 60 °C in a sealed tube. bReaction time: 4−6 h.. cSet at 2 mmol scale; yield of 3c: 62%. dReaction time: 1−3 h. eReaction time: 5−6 h. fReaction
time: 3−6 h. gUnidentified compound formed. hYields are isolated yields after column chromatography. iN-Acetyl-1,2-dihydroisoquinolines exist as
rotational isomers.
significantly to this area in recent years.7 We also noted that
despite many known elegant advances pertaining to C−H
alkylation, there is no report on site-selective C(3)−H
alkylation of N-acetyl-1,2-dihydroisoquinolines.
We, hence, report a site-specific Ir(III)-catalyzed, heter-
oatom-directed C(3)−H alkylation of N-acetyl-1,2-dihydroi-
soquinolines with α-diazomalonates. To the best of our
knowledge, this is also a rare report where a single catalytic
system efficiently couples with a wide variety of acceptor−
acceptor diazo compounds, namely α-diazotized Meldrum’s
acid, α-diazodiketones, α-diazo-β-ketoesters, and α-diazodime-
done to generate numerous derivatized isoquinoline scaffolds
(Scheme 1). The transformation requires a low Ir(III) loading,
and the catalytic system works efficiently with a broad
substrate scope. We also followed this up by diversification
of the alkylated products, to achieve simultaneous removal of
the activating tether and subsequent aromatization. In
addition, we have also achieved selective decarboxylation and
decarbonylation of C(3)−H alkylated products, thereby
further enhancing the synthetic utility of the transformation.
To initiate our investigations, we employed N-acetyl-1,2-
dihydroisoquinoline and an α-diazo-β-ketoester as the standard
substrates to optimize our reaction condition (see the
Supporting Information (SI) for further details). Following
some previous results,8 we initiated our screening with
[Cp*RhCl2]2 in the presence of a series of Ag(I)-additives.
Although this system worked with considerable success for α-
diazo-β-ketoesters, it could not be extrapolated to work with
other acceptor−acceptor diazo systems. Also, in most of the
cases, the products could not be purified beyond 90% purity.
We then attempted to test the transformation with N-acetyl-
1,2-dihydroisoquinoline (1b) and dimethyl diazomalonate
(2a). Upon several attempts, the best results were obtained
by using [Cp*IrCl2]2 (3 mol %) as the catalyst and AgBF4 (12
pubs.acs.org/OrgLett Letter
mol %) along with Boc-Pro-OH (20 mol %) as the additives.9
This resulted in the formation of the desired C(3)-alkylated
product in an optimum yield of 77%. Hence, with these
optimal conditions in hand, we evaluated the substrate scope
for the alkylation reaction. Various electronic and steric
parameters were screened with a variety of 1-substituted
isoquinolines generating the alkylated products in good to
moderate yields (3a−3f, Scheme 2). It must be noted here that
steric congestion played an important role in the reaction
outcome with 1-tert-butyl-N-acetyl-1,2-dihydroisoquinoline
failing to yield the desired product (3g, Scheme 2). Next, we
explored the scope of α-diazomalonate esters to bring forth the
synthetic utility of the transformation. The reaction was rather
sensitive to the steric congestion on the α-diazodiesters with a
decrease in yield observed upon increasing the bulk of the
substituents (3h−3j, Scheme 2). Also, tert-butyl-α-diazomalo-
nate was not a good addition since it failed to generate the
desired product (3k, Scheme 2). With C(5)-substituents, good
to moderate yields of the alkylated products were obtained
(3l−3m, 3o, Scheme 2). The C(6)- and C(7)-substituted
isoquinolines reacted smoothly to afford the alkylated products
albeit in good yields (3p−3q, 3s, Scheme 2). Halogen-
substituted isoquinolines transformed easily to the desired
products, thereby increasing the prospect of postfunctionaliza-
tion (3n, 3r, 3t, Scheme 2). It must be noted here that, in the
case of bromo-substituted isoquinolines, the product yield lies
between 50% and 60% or even lower, despite the complete
consumption of the substrate. This is mainly due to an in situ
degradation of these substrates under the reaction conditions.
To further expand the scope of the transformation, various
acceptor−acceptor α-diazo compounds were tested as the
requisite coupling partners.
8695 https://doi.org/10.1021/acs.orglett.1c03054
Org. Lett. 2021, 23, 8694−8698
Organic Letters pubs.acs.org/OrgLett
To our surprise, N-deacylated-C(3)-alkylated products were
obtained upon coupling N-acetyl-1,2-dihydroisoquinolines
with α-diazotized Meldrum’s acid.
A number of substrates were thus prepared forming the
desired products in good yields (5a−5d, Scheme 2). Even the
bromo substituent on the isoquinoline was well-tolerated (5e,
Scheme 2). Further expansion of the substrate scope led us to
evaluate the efficacy of α-diazo-β-ketoesters as the coupling
partner. The reaction worked best with Boc-Leu-OH as the
additive and was found to be compatible with methyl, ethyl,
and benzyl congeners of the ketoesters (7a−7c, Scheme 2).
Notably, 1-substituted isoquinoline gave a complex mixture of
inseparable diastereomers whose relative ratio changed with
each silica gel chromatography, probably resulting from the
epimerization of the product (7d, Scheme 2). Additionally, we
attempted to apply the developed strategy to alkylate
isoquinolines with α-diazodiketones. Desired products with
good yields were obtained under the given reaction condition,
thereby providing access to a variety of C(3)-alkylated
diketone products. Substitutions on the diazo substrates
afforded good results (9a, 9c, Scheme 2). C(1)- and C(5)-
substituted isoquinolines also formed products with compara-
ble yields (9b, 9d−9e, Scheme 2). Hence, wide compatibility
regarding the substrates can be observed, thereby enriching the
substrate scope. Notably, an aliphatic α-diazodicarbonyl
compound such as α-diazodimedone also provided access to
the desired product molecule (9f, Scheme 2). Unfortunately,
the reaction with α-diazoacetylacetone led to the formation of
an unidentified compound in place of the C(3)-alkylated
product (9g, Scheme 2).
The highlight of the methodology was removal of the
tethered directing group with concomitant aromatization to
achieve 3-alkyl-substituted isoquinolines. The aromatized
products 10 and 11 were thus obtained upon treatment of
3b and 7b with DDQ in toluene and 1,4-dioxane respectively
(Scheme 3A). Also, the synthetic potential of the methodology
was further enhanced by selective decarbonylation of α-diazo-
β-ketoester’s alkylated products. The treatment of 7 under
acidic conditions led to decarbonylation (and transesterifica-
tion) to afford the respective products in good yields.
The scope of this decarbonylation reaction was explored in
the presence of different alcoholic solvents to generate various
Scheme 3. Synthetic Transformations
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Letter
transesterification products (12a−12c, Scheme 3B). The 1-Me
substituted isoquinoline also underwent tandem aromatization
and decarbonylation in a single pot (12d, Scheme 3B).
Concurrently, we also attempted to achieve selective
decarboxylation of the alkylated product 7c (Scheme 3C).
After initial setbacks with simple esters (see the SI for details),
we were delighted to find that the introduction of a benzyl
ester solved this problem. Upon hydrogenolysis with Pd/C, the
elusive decarboxylated product 13 was achieved with moderate
yield. Next, in order to gain insights into the mechanistic
pathway of this Ir(III)-catalyzed C−H alkylation, a series of
control experiments were performed (Scheme 4). The
Scheme 4. Control Experiments
tendency of Ir(III)-complexes to catalyze traditional carbene
transfer reactions with diazo compounds prompted us to carry
out experiments with various carbene acceptors. The reaction
with cyclohexene under standard reaction conditions did not
result in cyclopropanation or allylic C−H insertion of the
cyclohexene in either the presence or absence of the
isoquinoline. The formation of 3b in the presence of N-
acetyl-1,2-dihydroisoquinoline (1b) was completely inhibited
with 1b and 2a being recovered in 47% and 53% yields
respectively (Scheme 4A). This might result from the reduced
electrophilicity of the Ir-center, upon coordination with the
alkene. A related experiment performed in the absence of
isoquinoline resulted in complete decomposition of the diazo
compound (Scheme 4A). Similar experiments were performed
upon replacing cyclohexene with anisole. In contrast to the
experiment with cyclohexene, C−H alkylated product 3b was
obtained in 65% yield. No C−H insertion product of the diazo
to the electron-rich anisole was observed. This clearly indicated
the precedence for the C−H activation step to metal-carbene
formation (Scheme 4B; also see Supporting Information for
MS studies).
A control reaction to check for the C(3)-site-selectivity of
alkylation was then performed. The C(3)-blocked 1,2-dihydro-
N-acetylisoquinoline did not furnish any product, with the
starting material remaining unreacted (Scheme 4C). This
indicates that the metalation is directed by the N-acetyl group
and is not a result of an electrophilic metalation at C(4)
followed by a migration to C(3). Studies to check for the
reversibility of metalation indicated the C−H activation step to
https://doi.org/10.1021/acs.orglett.1c03054
Org. Lett. 2021, 23, 8694−8698
Organic Letters pubs.acs.org/OrgLett
be reversible (∼50% D at C(3), Scheme 4D). Also, the lower
deuterium content of the recovered starting material (∼8% D)
in the presence of the diazo compound suggested the steps
following C−H activation to be faster than the reverse step
(Scheme 4D). Additionally, due to the rapid initial rate of
metalation, a proper study to check for the kinetic isotope
effect in the C−H metalation step could not be carried out.
On the basis of our mechanistic studies and previous
reports,10 a plausible mechanism for the Ir(III)-catalyzed
C(3)−H alkylation is depicted in Scheme 5. Initially,
Scheme 5. Plausible Catalytic Cycle
[Cp*IrCl2]2 generates the active cationic Ir(III) species I
with the assistance of Ag(I) and Boc-Pro-OH.11 A chelation-
controlled proximal C−H activation of 1b follows to yield the
five-membered iridacycle intermediate II. Further coordination
of the diazo compound with the iridacycle generates the
intermediate III, which either can follow a 1,2-aryl migration
pathway to give V (path a) or can lead to an Ir-carbene
intermediate IV (path b).5a,c,12 To elaborate, a 1,1-carbene
migratory insertion between the Ir−C bond transpires from IV,
which leads to the formation of the intermediate V. A
protodemetalation step assisted by Boc-Pro-OH generates the
C(3)-alkylated N-acetylisoquinoline along with the regener-
ation of the active catalyst. Intermediates II and V were
detected via ESI-HRMS, indicating that the formation of the
metalacycle II is preceded by the metal carbene complex
formation. It must be noted here that the presence of HFIP is
vital for the transformation, since it assists in stimulating the
weakly coordinating acetyl group via H-bonding, thereby
favoring proximal C−H activation.13
To conclude, we have successfully developed a versatile and
efficient Ir(III)-catalyzed route for C(3)−H alkylation of N-
acetyl-1,2-dihydroisoquinolines with a wide spectrum of
acceptor−acceptor α-diazo compounds. The report involves
reactions with a wide range of diazo compounds such as α-
diazomalonates, α-diazodicarbonyls, α-diazo-β-ketoesters, α-
diazotized Meldrum’s acid, and α-diazodimedone with
excellent compatibility and divergent substrate scope under a
single catalytic system. Additionally, diverse synthetic manip-
ulations of the C−H alkylated products such as aromatization,
decarboxylation, and decarbonylation were carried out to
demonstrate the synthetic utility of the transformation. This
8697
Letter
method can be looked upon as an effective approach to yield
C(3)-alkylated isoquinolines starting from the parent isoquino-
lines.
■ ASSOCIATED CONTENT
* Supporting Information
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c03054.
Experimental details, spectral characterization (PDF)
FAIR data, including the primary NMR FID files, for
compounds Il; Im; Io; Ip; Iq; Is; 1g; 1l; 1p−1u; 3a−3t;
5a−5e; 6c; 7a−7d; 8a; 8c; 9a−9f; 10; 11; 12a−12d; X;
13 (ZIP)
Accession Codes
CCDC 1900717 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
Manmohan Kapur − Department of Chemistry, Indian
Institute of Science Education and Research Bhopal, Bhopal
462066 MP, India; orcid.org/0000-0003-2592-6726;
Email: mk@iiserb.ac.in
Authors
Neha Jha − Department of Chemistry, Indian Institute of
Science Education and Research Bhopal, Bhopal 462066 MP,
India
Roushan Prakash Singh − Department of Chemistry, Indian
Institute of Science Education and Research Bhopal, Bhopal
462066 MP, India
Paridhi Saxena − Department of Chemistry, Indian Institute of
Science Education and Research Bhopal, Bhopal 462066 MP,
India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c03054
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
Funding from SERB-India (STR/2019/0000072), (EMR/
2016/004298), and CSIR-India (02(0361)/19/EMR-II) is
gratefully acknowledged. N.J. and P.S. thank IISERB for
Research Fellowships, and R.P.S. thanks IISERB for a BSMS-
Fellowship. We thank the CIF, IISERB for the analytical data.
We also thank the Director, IISERB, for funding and
infrastructure facilities.
■
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