Iridium(III)-Catalyzed Regiocontrolled Direct Amidation of Isoquinolones and Pyridones

Article abstract of DOI:10.1002/adsc.201701244

Iridium(III)-catalyzed highly regiocontrolled C3/C8 amidation of isoquinolones and C6 amidation of 2-pyridones has been successfully accomplished with various azides. The optimized method is operationally simple with a broad substrate scope. The protocol has been found to be scalable. (Figure presented.).

Full text of DOI:10.1002/adsc.201701244

Title: Iridium Catalyzed Regiocontrolled Direct Amidation of
Isoquinolones and Pyridones
Authors: Debapratim Das and Rajarshi Samanta
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10.1002/adsc.201701244
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Iridium Catalyzed Regiocontrolled Direct Amidation of
Isoquinolones and Pyridones
Debapratim Das and Rajarshi Samanta*
Department of Chemistry, Indian Institute of Technology Kharagpur. Kharagpur 721302, India
E-mail: rsamanta@chem.iitkgp.ernet.in
Phone: +91-3222-283310; Fax: +91-3222-282252
Received:
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
catalyzed activation of corresponding C-H bond via
the carbonyl group coordination. The key aspect for
Abstract. Iridium catalyzed highly regiocontrolled C3/C8
amidation of isoquinolones and C6 amidation of 2-
pyridones has been successfully accomplished with various
azides. The optimized method is operationally simple with
a broad substrate scope. The protocol has been found to be
scalable.
the
C3/C6
position
functionalization
of
isoquinolone/2-pyridone moiety is the proper
directing group placement at the corresponding
nitrogen atom. Since the Buchwald-Hartwig
amination of arylhalides, significant progress has
been observed in the transition metal catalyzed
amination of unactivated C-H bonds.[7-8] Despite
admirable advancement on transition metal catalyzed
direct regioselective functionalization of isoquinolone
and pyridone scaffold, at per our best of knowledge
there is no report on direct transition metal catalyzed
site-selective amidation of isoquinolone scaffold. In
continuation of our recent studies on iridium catalysis
and amination,[9] herein we report a site-selective
iridium catalyzed C3 and C8 amidation of
isoquinolone and C6 amidation of 2-pyridone
(Scheme 1, eq 4).
Keywords: Regiocontrol; Amidation; Isoquinolone;
Pyridone; Iridium(III)
Transition metal catalyzed site selective functional
group introduction into the heteroatom containing
organic molecules becomes an attractive area for
synthetic
chemists.[1]
Nitrogen
containing
heterocycles like quinolones and pyridones are
widely present in several natural products,
pharmaceutical compounds, agrochemicals and
functional materials.[2] Consequently, development of
effective methods to directly introduce important
functional groups in regioselective fashion to the
isoquinolone[3] and pyridone[4-6] scaffolds is
demanding area of research.
a
Recently, the Hong group elegantly described the
transition metal catalyst controlled site-selective
arylation[3a-b] of isoquinolone moieties (Scheme 1, eq
1). Interestingly, they also revealed proper directing
group guided regioselective alkynylation of 4-
quinolone derivatives.[3d] Quite recently, Patil and co-
workers also showed the catalyst controlled C4 and
C8-selective alkynylation of isoquinolone derivatives
(Scheme 1, eq 2).[3e] In this context, another nitrogen
containing important heterocyclic scaffold 2-pyridone
moiety was also widely explored for C3[4], C4[5] and
C6-selective[6] direct functionalization under
transition metal catalyzed conditions by us and other
groups in recent years. Incidentally, during C6-
selective functionalization of 2-pyridone scaffold,
introduction of functional groups like alkyl[6h], aryl[6e,
6k]
or allyl[6n,6o] groups at the C3 position of
isoquinolone scaffold was also described in the
literature (Scheme 1, eq 3). Based on previous
Scheme 1. Site Selective C-H Functionalization of
Isoquinolones.
pioneering works on isoquinolone[3,6] and pyridone[4-6]
we hypothesized that C8 selectivity of isoquinolone
can be achieved through the transition metal
,
1
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10.1002/adsc.201701244
Advanced Synthesis & Catalysis
Based on the above assumptions, we started our
investigation with 2-(pyridin-2-yl)isoquinolin-1(2H)-
one (1a) and p-toluenesulfonyl azide (2a) in presence
of [Ru(p-cymene)2Cl2]2 (2 mol%), AgSbF6 (8 mol%)
in 1,2-dichloroethane at 85 °C (Table 1, entry 1). We
were glad to find that the desired C3-amidated
product was formed albeit in lower yield. Further, the
reaction was screened with another transition metal
catalyst [Cp*RhCl2]2 to improve the yield (Table 1,
entry 2). Gratifyingly, the desired product was
isolated with improved 62% yield. When the reaction
was performed under [Cp*IrCl2]2 catalyst and
AgSbF6 as halide abstractor, the reaction proceeded
with satisfying 81% desired product yield (Table 1,
entry 3). To improve the yield further, reaction
conditions were screened with additional 20 to 50
mol% acetate source (Table 1, entries 4-5).
efficiently proceeded with various aryl sulfonylazides
(Scheme 2, 3a-3d). Further, aliphatic sulfonylazides
also worked smoothly (Scheme 2, 3e-3f).
Interestingly, sterically more crowded sulfonylazide
like (1R)-(−)-10-camphorsulfonylazide provided
good yield of the desired product (Scheme 2, 3f). To
our delight, chemically different other azides like
benzoyl azide and diphenyl phosphoryl azide
afforded the C3-amidated quinolones with good to
moderate yield (Scheme 2, 3g-3h). Notably, coupling
of isoquinolone with aziodoformate also worked
albeit in poor yield (Scheme 2, 3i). But, other azides
like phenyl azide or benzyl azide did not furnish the
desired products. Furthermore, except 3g there was
no other probable Curtius rearranged product
observed during the reaction with benzoyl azide.[10]
C6-haloisoquinolones offered very good yields of the
desired products keeping the window open for further
modification of isoquinolone ring (Scheme 2, 3j-3k).
Additionally, 2-pyrimidyl protected isoquinolone also
afforded C3-amidated product in 83% yield (Scheme
2, 3l).
Table 1. Optimization for the synthesis of iridium
catalyzed amidation of isoquinolnea)
Entry Solvent Ag salt
Additive
(mol%)
Yieldb)
1c)
2d)
3
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
MeCN
EtOH
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgNTf2
AgOAc
AgNO3
AgSbF6
AgSbF6
-
-
-
15
62
81
4
NaOAc (20) 83
NaOAc (50) 91
NaOAc (50) 53
NaOAc (50) 87
NaOAc (50) trace
NaOAc (50) trace
NaOAc (50) 15
NaOAc (50) 33
NaOAc (50) trace
NaOAc (50) n.d.
5
6e)
7
8
9
10
11
12
13
dioxane AgSbF6
DMSO AgSbF6
a)Reaction Conditions: 1a (0.1 mmol), 2a (0.12 mmol),
[Cp*IrCl2]2 (2 mol%), Ag salt (8 mol%), NaOAc (50
mol%), 12 h, 85 °C, 0.1 M. b)Isolated Yields. c)Catalyst
used [Ru(p-cymene)Cl2]2 (2 mol%) d)Catalyst used
[Cp*RhCl2]2 (2 mol%). e)Cp*IrCl2]2 (1 mol%).
Finally, we were happy to obtain 91% isolated yield
of desired product with 50 mol% acetate additive.
However, the decrease in catalyst loading lowered the
yield (Table 1, entry 6). Furthermore, AgNTf2 as
silver salt provided comparable yield in 87% (Table 1,
entry 7). Other silver salts did not provide isolable
amount of desired product (Table 1, entries 8-9).
Other solvents having different polarity were not
found much successful in this transformation (Table
1, entries 10-13).
With the optimized reaction conditions in our hand,
the generality of the regiocontrolled amidation was
screened with the 2-pyridyl protected isoquinolone
and 2-pyridone derivatives (Scheme 2). Reaction was
Scheme 2: C3 and C6 selective amidation of isoquinolones
and 2-pyridones; Reaction Conditions: 1 (0.1 mmol), 2
(0.12 mmol), [Cp*IrCl2]2 (2 mol%), AgSbF6 (8 mol%),
NaOAc (50 mol%), 12 h, 85 °C, 0.1 M. a) 1a in 3 mmol
scale, 36 h. b) Reaction time 24h.c) N3CO2Et was used 0.3
2
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10.1002/adsc.201701244
Advanced Synthesis & Catalysis
d)
e)
f)
mmol. at 60 °C. at 100 °C. at 80 °C. Pym = 2-
pyrimidyl
Next, we examined the possibility of C8 amidation of
isoquinolone derivative 4 (Scheme 3). Strikingly, the
C8 amidated product was obtained in 42% yield from
the parent isoquinolone scaffold without any
protection group under the developed conditions
(Scheme 3, 5a). Further, the NH-alkyl protected
isoquinolone derivatives afforded desired products in
excellent yields (Scheme 3, 5b-5c). C4-Halogen
substituted iosquinolone derivatives accomplished the
desired C8 amidated products in excellent yields
(Scheme 3, 5d-5e). Furthermore, alkyne, alkene or
aryl substitution at this position of isoquinolone
accomplished desired products in good to excellent
yields (Scheme 3, 5f-5h). Isoquinolone having
electron withdrawing group like cyano group at its
C6 position also afforded desired product albeit in
moderate yield and at higher temperature (Scheme 3,
We next explored the site-selective amidation of the
2-pyridone scaffold. Importantly, most electron
deficient C6 position of 2-pyridone ring was
amidated under the optimized conditions with
admirable degree of regioselectivity (Scheme 2, 3m-
3ab). Electronically and sterically variant functional
groups at the C3, C4 and C5 position of pyridyl
protected 2-pyridone furnished the expected C6
amidated products with moderate to excellent yields.
Electron donating groups at the C3 and C4 position of
2-pyridone moiety were well tolerated with moderate
to very good yields (Scheme 2, 3n-3r). However,
electron withdrawing groups like CN, CF3 or acetyl
functional group at the C3 position of 2-pyridone and
free hydroxyl group at the C4 position did not furnish
the corresponding desired products in isolable
amount. Halogens at the C5 position of 2-pyridone
scaffold accomplished the desired products in
moderate to excellent yield (Scheme 2, 3s-3t).
Further, sulfonylazides having wide steric and
electronic profile afforded desired C6 amidated 2-
pyridones under developed conditions (Scheme 2, 3u-
3ab) in good to excellent yields. For practical utility,
1a could be converted into its C3-amidated product
3a with 30-fold increased scale in 79% desired
product yield (Scheme 2, 3a).
5i).
Importantly,
more
conjugated
3,4-
diphenylisoquinolone or phenanthridone moieties
also furnished desired amidated product in excellent
yields (Scheme 3, 5j-5k). Subsequently, various
aromatic and aliphatic sulfonyl azides worked
uninterruptedly to provide desired C8 amidated
products with excellent yields (Scheme 3, 5l-5p).
Nitrogen containing relevant 4-quinolone scaffold
was also amidated at its C5 position in high yield
(Scheme 3, 5q). The structure of the C8 amidated
product 5b was unequivocally confirmed by single x-
ray crystallography (See supporting information for
more details).[11] For scalability, 4b could be
converted into its C8-amidated product 5b with 25-
fold increased scale in 85% desired product yield
(Scheme 3, 5b).
Scheme 4: Transformations of C6 amidated 2-pyridone
molecule
To confirm the extended synthetic utility of this
developed reaction, further required modifications
were carried out (Scheme 4). The pyridyl protecting
group from the product 3m was successfully removed
via quaternization-reduction[12] to accommodate C6
amidated free pyridone derivative 6 in good yield
(Scheme 4i).
Scheme 3: C8 selective amidation of isoquinolones and 4-
pyridone; Reaction Conditions: 4 (0.1 mmol), 2 (0.12
mmol), [Cp*IrCl2]2 (2 mol%), AgSbF6 (8 mol%), NaOAc
(50 mol%), 6 h, 40 °C, 0.1 M. a) 1a in 2.5 mmol scale, 36 h.
b) at 80 °C.
Scheme 5: C8 Amidated isoquinolone product
modification to bioactive compound.
3
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10.1002/adsc.201701244
Advanced Synthesis & Catalysis
Furthermore, the compound 3m was partially reduced
under atmospheric hydrogenation conditions to
provide compound 7 (Scheme 4ii).
coordination with the nitrogen atom of pyridine ring
of 1a, followed by acetate assisted C-H bond
cleavage[14c-e] furnishes cyclometalated intermediate
A. Afterwards, tosyl azide (2a) reacts with complex
A to produce five-membered complex B. Further,
release of N2 and migratory insertion of complex B
produced six-membered cyclic complex C. Finally,
In addition to directing group deprotection and
functional group transformations, C8 amidated
isoquinolone derivative 5b was undergone tosyl
group
deprotection
to
obtain
8-amino-2-
methylisoquinolone 8. Importantly, compound 8
could be easily extended to the known antitumor
agent 9 (Scheme 5).[13]
protodemetalation of C produces our desired
amidated product 3a. Alternatively, formation of an
iridium nitrenoid species from B can occur through
oxidative manner followed by insertion of the
nitrenoid moiety to the the iridacycle may produce
C.[14e-g] For the formation of C8 amidated product,
coordination of active iridium complex with the keto
group of 4b and acetate assisted C-H bond cleavage
generates the iridacycle complex D. Presumably, next
few steps follow the similar way as previously
described to provide
E
and F. Subsequent
protodemetalation of F forms desired compound 5b.
In summary, we have developed the iridium-
catalyzed direct regioselective C3/C8-amidation of
isoquinolones and C6-amidation of 2-pyridones using
various azides. The substrate scope was broad with
wide functional group tolerance. This amidation
approach does not require extra oxidants and release
N2 as sole by-product. Due to ubiquitous availability
of amidated isoquinolones and pyridones in bioactive
natural products and pharmaceuticals, this protocol is
expected to gather significant attention from industry
and academia.
Scheme 6: Kinetic isotope effect
To understand the plausible mechanism for this
regioselective amidation, kinetic-isotope effect was
calculated in competitive and parallel experiments
1
(Scheme 6i). KIE value was obtained 1.08 by H
NMR analysis of the mixture of recovered starting
materials from competitive experiments, while it was
found 1.04 by isolating remaining starting materials
from parallel experiments. Here in, both the studies
recommended that C-H bond activation at C6-
position of 2-pyridone was not the rate determining
step in this transformation. No significant H/D-
scrambling was observed at the C6 position of 2-
pyridone moiety when 1m was exposed with
DCE/D2O under standard reaction conditions
(Scheme 6ii). This outcome reveals that more likely
C-H bond metallation step is irreversible.
Experimental Section
Representative Method for the Synthesis of 3a and
5b:
1a (0.1 mmol) was taken in a 10 mL screw cap vial
charged with a magnetic stirring bar and dissolved in
1 mL 1,2-DCE. Then [(Cp*IrCl2)2] (2 mol%),
AgSbF6 (8 mol%), NaOAc (50 mol%) and tosyl azide
(0.12 mmol) were added to the reaction mixture. The
reaction mixture was allowed to stir at 85 °C for 12 h
under air. After completion of the reaction, it was
directly loaded to the silica gel column and the
product was purified by eluting with hexane-ethyl
acetate mixture (1:1 to 0.5:9.5) to get product 3a as
pale yellow solid in 91% yield (35.6 mg). In a similar
manner, compound 4b was allowed to react under
above mentioned conditions at 40 ºC for 6 h. The
reaction mixture was directly loaded to the silica gel
column and the product 5b was purified by eluting
with hexane-ethyl acetate mixture (9:1 to 1:1) in 86%
yield (28.2 mg) as white solid.
Figure 1: Plausible Mechanism
Acknowledgements
Based on the experiments and previous literatures [10a,
14], a plausible mechanism is shown in Figure 1.
Initially, an active iridium complex is generated via
ligand exchange with the help of Ag-salt. Next, upon
This work is supported by the SERB, India (YSS/2014/000383 and
SR/FST/CSII-026/2013 for 500 MHz NMR facility). Fellowship
received from CSIR, India (D.D.) is gratefully acknowledged.
4
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10.1002/adsc.201701244
Advanced Synthesis & Catalysis
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5
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10.1002/adsc.201701244
Advanced Synthesis & Catalysis
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