Ir(III)-Catalyzed Carbenoid Functionalization of Benzamides: Synthesis of N-Methoxyisoquinolinediones and N-Methoxyisoquinolinones

Article abstract of DOI:10.1021/acs.orglett.6b01072

A mild and efficient Ir(III)-catalyzed C-H carbenoid functionalization strategy has been developed to access N-methoxyisoquinolinediones and N-methoxyisoquinolinones. The reaction proceeds efficiently in high yield at room temperature over a broad range of substrates without requirement of any additional oxidants or a base.

Full text of DOI:10.1021/acs.orglett.6b01072

Letter
pubs.acs.org/OrgLett
Ir(III)-Catalyzed Carbenoid Functionalization of Benzamides:
Synthesis of N‑Methoxyisoquinolinediones and
N‑Methoxyisoquinolinones
Ravindra S. Phatake, Pitambar Patel,*,† and Chepuri V. Ramana*
Organic Chemistry Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune, India 411008
S
* Supporting Information
ABSTRACT: A mild and efficient Ir(III)-catalyzed C−H carbenoid
functionalization strategy has been developed to access N-methoxyiso-
quinolinediones and N-methoxyisoquinolinones. The reaction proceeds
efficiently in high yield at room temperature over a broad range of
substrates without requirement of any additional oxidants or a base.
ransition metal catalyzed C−H functionalization is an
presence of air at rt to afford N-methoxyisoquinolinediones.5
Teconomic step and straightforward approach for the Interestingly, molecules having the isoquinolinedione moiety are
synthesis of N-heterocyclic compounds.1 In this regard, the use
known for their potent biological activity. Examples include
aldose reductase (ALR2) inhibitors, antitumor activity against
the human pancreatic carcinoma cell line, potent and selective
inhibitors of cyclin-dependent kinase 4, and inhibitors of
Lckkinase.9 Furthermore, the same Ir(III)-catalytic system was
applied for the synthesis of N-methoxyisoquinolinones.
of various coupling partners such as alkenes, alkynes, and allenes
has been studied extensively. Over the past couple of years, diazo
compounds have been successfully employed as versatile and
efficient coupling partners in C−H activation/annulation
reactions for the synthesis of various N-heterocyclic com-
pounds.2 The very first examples of Rh(III)-catalyzed C−H
functionalization of arenes with diazomalonates was reported by
Yu et al.3 Following this, the amicability of diazocarbonyl
compounds in Rh(III)-catalyzed C−H activation and annulation
cascade has been aptly explored by several research groups to
synthesize various N-heterocyclic compounds and/or hetero-
cyclic N-oxides.4 Very recently, Yi and co-workers have reported
the synthesis of N-methoxyisoquinolinedione via the Rh(III)-
catalyzed carbene insertion C−H annulation approach.5
In recent years, Cp*Ir(III) has been extensively used for
constructing C−C and C−Het bonds via C−H activation.6
However, only a handful of reports are available for C−H
carbenoid functionalization using the Ir(III)-catalytic system,
which were mostly limited to only the C−H alkylation reaction.7
Thus, the development of a mild and efficient one-pot process for
the synthesis of privileged N-heterocycles via the Ir(III)-
catalyzed C−H carbenoid functionalization approach is of
prime research interest. Recently, we have reported an Ir(III)-
catalyzed C−H annulation of N-hydroxyoximes with α-
diazocarbonyl compounds to give isoquinoline N-oxide.8
Continuing our efforts to develop a mild and efficient Ir(III)-
catalytic system for the synthesis of N-heterocyclic compounds
via the C−H carbenoid functionalization strategy, we disclose
here the broadly applicable Ir(III)-catalyzed C−H functionaliza-
tion of benzamides with α-diazotized Meldrum’s acid in the
At the outset of our studies, N-methoxybenzamide 1a and 5-
diazo-2,2-dimethyl-1,3-dioxane-4,6-dione (α-diazotized mel-
drum’s acid) 2 were taken as model substrates for reaction
optimization. After screening various reaction parameters, we
were pleased to observe that the desired N-methoxyisoquinoline-
dione 3a could be obtained in 90% yield using 2.0 mol % of
[IrCp*Cl2]2 and 8.0 mol % AgNTf2 in 1,2-dichloroethane (1,2-
DCE) at room temperature (see the Supporting Information for
details). When the reaction time was reduced to 1 h, 60% of
product 3a was obtained (Table 1, entry 2). The reaction
efficiency decreased to 68% when the catalyst loading was
reduced to 1.0 mol % (Table 1, entry 3). Both the metal catalyst
and silver additive were found to be essential for the reaction
(Table 1, entries 4−5). A very poor yield was obtained, when
LiNTf2 was used in lieu of the silver species (Table 1, entry 6).
Interestingly, commonly used Rh- and Ru-catalytic systems were
found to be ineffective under the present conditions (Table 1,
entries 7−8). Surprisingly, a reaction with other N-substituted
benzamides such as N-(tert-butyl)benzamides, N-methylbenza-
mide, or N-hydroxybenzamide was found to be sluggish.
With the optimal conditions in hand, we next investigated the
scope of substituted benzamides for the present reaction. For
Received: April 13, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01072
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Letter
a
Table 1. Selected Observation during Reaction Optimization
Scheme 2. N-Methoxyisoquinolinone Synthesis
b
entry
deviation from standard conditions
none
3a (%)
1
2
3
4
5
6
7
8
95 (90)
60
reaction time 1 h instead of 6 h
1.0 mol % of [Ir] instead of 2.0 mol %
no [IrCp*Cl2]2
good yields (3h, 3i). Additionally, the structure of 3i was
confirmed by single crystal X-ray diffraction studies. It was
observed that substitution at the meta-position plays a crucial role
in controlling the regioselectivity of the present C−H annulation.
For instance, when m-methylbenzamide was used for 3j, C−H
activation occurred predominantly at the less hindered position,
whereas m-chloro benzamide gave the corresponding re-
gioisomers 3k-1 and 3k-2 in a 1.2:1 ratio. Also, 2,3-dimethoxy-
benzamide 3l and polyaromatic naphthalene benzamide 3m were
found to be compatible under the present reaction conditions.
Furthermore, heterocyclic amide derived from thiophene 3n and
benzofuran 3o underwent C−H annulations efficiently to furnish
the corresponding products in high yield. However, the reaction
was found to be sluggish when N-methoxymethacrylamide was
used under the present Ir-catalytic conditions.
68
0
no AgNTf2
12
LiNTf2 instead of AgNTf2
[RhCp*Cl2]2 instead of [IrCp*Cl2]2
[Ru(p-Cymene)Cl2]2 instead of [Ir]
15
<5
<5
a
Reaction conditions: 1a (0.15 mmol) and 2 (1.1 equiv) in 1,2-
b
dichloroethane (1,2-DCE) (1.0 mL). Yields are based on 1H NMR of
crude reaction mixture (CH2Br2 as an internal standard); isolated
yields are given in parentheses.
this, various substituted N-methoxybenzamides were treated
with α-diazotized Meldrum’s acid 2 to furnish the corresponding
N-methoxyisoquinolinedione derivatives (Scheme 1). Overall,
After successful exploration of the N-methoxyisoquinoline-
dione synthesis, we next focused on extending the present
Ir(III)-catalytic system to synthesized isoquinolinones. Isoqui-
nolinones and pyridinone structural units are widely present in
many natural products. Some of their derivatives possess
potential biological activity and are privileged scaffolds in
medicinal chemistry.10 Based on our previous report of Ir(III)-
catalyzed isoquinoline N-oxide synthesis,8 we envisioned the
feasibility of C−H annulations of benzamide with previously
used Ohira−Bestmann’s diazo phosphonate 4 to give N-
methoxyisoquinolinones. In this context, Wang and co-workers
have documented an elegant method for the synthesis of
isoquinolinone and pyridinones via Rh(III)-catalyzed C−H
annulations of benzamide with the diazo compounds.11
a
Scheme 1. Benzamide Substrate Scope
As expected, treatment of N-methoxybenzamide 1a with the
diazocompound 4 under the present Ir(III)-catalytic conditions
afforded the desired N-methoxyisoquinolinone 5a in 62% yield.
The product yield was increased up to 90% by running the
reaction at 35 °C for 10 h (Scheme 2). With the adequate results
in hand, the scope of various benzamides was investigated next.
We were happy to observe that a wide range of benzamides
containing both electron-donating and -withdrawing groups
underwent C−H annulations smoothly to furnish the corre-
sponding N-methoxyisoquinolinone derivatives 5a−5k in good
to very good yields (Scheme 3). Next, amides derived from
naphthalene 5l, benzofuran 5m, and thiophene 5n were found to
be compatible with the present conditions. Furthermore, the
reaction of N-methoxymethacrylamide under standard con-
ditions gave the corresponding pyridinone 5o in high yields.
Then the scope of other α-diazocarbonyl compounds has been
also investigated. In the case of the methyl 3-diazo-2,4-
dioxopentanoate the product 5p was obtained in moderate
yield. Similarly, the cyclic α-diazocarbonyl compounds furnished
the corresponding tetrahydrophenanthridinone derivatives 5q,
5r in good yields.
a
Reaction conditions: 1 (0.15 mmol), 2 (1.2 equiv) in 1,2-DCE (1
mL). Isolated yields are given.
the reaction proceeded smoothly at room temperature regardless
of the position as well as electronic nature of the substituents on
the aryl ring. Benzamides having both electron-donating 3b−3c
and electron-withdrawing 3d−3f functionality at the para-
position worked well and furnished the corresponding products
in high yield. However, the benzamides bearing a strongly
electron-withdrawing nitro group resulted in a slightly lower
yield of 3g. Similarly, benzamides with an ortho-substituent were
found to be quite compatible and gave the desired product in
Next, a series of preliminary experiments were carried out in
order to gain mechanistic insight into the present reaction
(Scheme 4). The reversibility of the C−H activation step was
determined by performing the reaction in the absence of 2 with
B
DOI: 10.1021/acs.orglett.6b01072
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a
Scheme 3. Scope of N-Methoxyisoquinolinone Synthesis
Scheme 5. Proposed Catalytic Pathway
4, eq 2). Together, these studies suggested that C−H bond
cleavage is most likely the rate-determining step.13
Based on the experimental results and precedent literature
reports,4,7b,8,14,15 a plausible catalytic pathway for N-methoxy
isoquinolinedione formation is proposed in Scheme 5. First, a
cationic [Cp*Ir(III)] species will react with benzamide through
the key C−H bond cleavage step to form the five-membered
iridacyclic intermediate I with the spontaneous loss of the ortho
proton.14 Coordination of the diazo compound with I will afford
the diazonium species II, and then the release of N2 will form the
Ir-carbene species III. Subsequently migratory insertion of
carbene to the Ir−C bond would form the six-membered
iridacyclic intermediate IV. Alternatively, intermediate IV will
form via intramolecular 1,2-migratory insertion of the aryl group.
Next, protonation of IV delivers the alkylated intermediate V and
regenerates the reactive [Cp*Ir(III)] species. Intermediate V
then undergoes annulations via tandem addition, elimination,
decarboxylation, and protonation to furnish the desired product
3.15 In the case of isoquinolinone synthesis, the catalytic cycle is
identical up to the addition product, after which it undergoes
dehydration similarly to a previous report of Rh(III)-catalysis.12
In conclusion, we have developed the first Ir(III)-catalyzed C−
H carbenoid functionalization strategy to synthesize N-methoxy-
isoquinolinediones from N-methoxybenzamide and diazotized
Meldrum’s acid. The reaction proceeds efficiently at room
temperature under atmospheric conditions and releases easily
removable N2, CO2, and acetone as byproducts. Additionally, the
Ir(III)-catalytic system was extended for the synthesis of
phosphorylated N-methoxyisoquinolinone derivatives by using
α-diazocarbonyl compounds instead of diazotized Meldrum’s
acid. Cleavage of the N−OMe bond will give the corresponding
isoquinolinedione or isoquinolinone.16 Further exploration of Ir-
catalyzed N-heterocycles synthesis and detailed mechanistic
investigations for the C−H carbenoid functionalization strategy
are currently underway.
a
Reaction conditions: 1 (0.15 mmol), diazo compound (1.2 equiv) in
1,2-DCE (1 mL). Isolated yields are given.
Scheme 4. Preliminary Mechanistic Investigation
DCE/D2O (20:1) as solvent (Scheme 4, eq 1). Analysis of the 1H
NMR of the reaction after 12 h shows <10% deuterium
incorporation at the ortho positions (Scheme 4, eq 1). This result
indicates that the C−H bond activation is largely irreversible.12
Next, a significant kinetic isotope effect (KIE) was observed from
the intermolecular competition reaction (KH/KD = 4.0) (Scheme
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01072.
C
DOI: 10.1021/acs.orglett.6b01072
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Organic Letters
Letter
(5) For a report on [Rh(III)]-catalyzed N-methoxyisoquinolinedione
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Yi, W. Chem. Commun. 2015, 51, 668.
Experimental procedure, characterization of new com-
pounds (1H, 13C NMR spectra) and X-ray crystallographic
data (PDF)
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X-ray data for 3i (CIF)
X-ray data for 5n (CIF)
X-ray data for 5c (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: patel.pitambar@gmail.com (P.P.).
*E-mail: vr.chepuri@ncl.res.in (C.V.R.).
Present Address
†Natural Product Chemistry Group, CSTD, CSIR-North East
Institute of Science and Technology, Jorhat, India-785006.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
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We thank the CSIR for funding this project under 12 FYP
ORIGIN Program (CSC0108) and a research fellowship to
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