Catalyst Controlled Divergent C4/C8 Site-Selective C-H Arylation of Isoquinolones

Article abstract of DOI:10.1021/acs.orglett.5b01840

The catalyst-controlled C4/C8 site-selective C-H arylation of isoquinolones using aryliodonium salts as the coupling partners was developed. The C4-selective arylation was successfully achieved via an electrophilic palladation pathway. A completely differ

Full text of DOI:10.1021/acs.orglett.5b01840

Letter
pubs.acs.org/OrgLett
Catalyst Controlled Divergent C4/C8 Site-Selective C−H Arylation of
Isoquinolones
Soyoung Lee,†,‡ Shinmee Mah,†,‡ and Sungwoo Hong*,‡,†
†Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 305-701, Korea
‡Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 305-701, Korea
S
* Supporting Information
ABSTRACT: The catalyst-controlled C4/C8 site-selective C−H arylation of
isoquinolones using aryliodonium salts as the coupling partners was
developed. The C4-selective arylation was successfully achieved via an
electrophilic palladation pathway. A completely different selectivity pattern
was observed using an Ir(III) catalytic system, which resulted in C−C bond
formation exclusively at the C8 position. The isoquinolone scaffold can be conveniently equipped with various aryl substituents
at either the C4 or C8 position.
methods for C−H functionalization at the C3 position were
ransition-metal-catalyzed direct and regioselective C−H
Tbond functionalization is a rapidly evolving research field achieved by installation of suitable directors, such as N-pyridyl or
that is useful in organic synthesis and total synthesis.1 Multisite-
selective C−H functionalization has received considerable
N-pyrimidyl groups on the nitrogen atom of isoquinolones
(Scheme 1b).10
Driven by the need for a more efficient synthetic route, we
were particularly interested in investigating catalytic systems that
would enable modulating the site selectivity on unfunctionalized
isoquinolone substrates. We envisioned that C8-regiocontrol
could be achieved in isoquinolone arylation guided by
coordination of the carbonyl group to the transition-metal
catalyst. We also hypothesized that the bias of isoquinolone to
undergo C8−H functionalization might be overridden by taking
advantage of the inherent nucleophilic characteristics of
isoquinolones upon treatment with an electrophilic metal
catalyst to promote the reaction at the C4 position.11 During
our studies, an unprecedented and remarkable switch in the site
selectivity was observed by the action of the catalytic system,
which enabled facile installation of aryl groups in a highly
selective and efficient fashion. Herein, we report the catalyst-
controlled divergent C4/C8 site-selective C−H arylation of
isoquinolones without recourse to extra directing groups
(Scheme 1c).
attention because this approach provides strategically attractive
synthetic routes for the rapid derivatization of medicinally
important privileged scaffolds and ultimately streamlines late-
stage drug modification. The isoquinolone scaffold is a
prominent structural motif present in a variety of natural and
bioactive compounds.2,3 Many elegant examples of the
construction of the isoquinolone framework via annulative
couplings of benzamides with alkynes have been reported using
various catalytic systems (Scheme 1a).4−9 However, there
remain distinct challenges to regio- and chemoselective C−H
functionalization for the introduction of aryl groups into the
isoquinolone core due to difficulties associated with controlling
the C−H bond at precise locations in the presence of
electronically or sterically similar C−H bonds. Recently, catalytic
Scheme 1. Synthetic Strategies for Arylated Isoquinolones
The interaction of Pd(II) with isoquinolone 1a was initially
investigated using H/D exchange experiments (Scheme 2).12 A
significant level of deuterium incorporation (after 24 h, 32% D)
was observed at the C4 position as shown in Scheme 2 (see the
Supporting Information). It is conceivable that the C4-
Scheme 2. Pd(II)-Catalyzed H/D Exchange Study
Received: June 26, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01840
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
deuteriated product may arise from an electrophilic palladation
pathway.
mediate, Cu catalytic systems were also screened but no desired
product was obtained.14
This result prompted us to explore the feasibility of an
expeditious synthetic approach for the installation of an aryl
group at the C4 position of isoquinolones via the presumed
electrophilic palladation pathway. Our efforts began by
examining a possible collection of C−H arylation conditions
using the Pd-catalytic system and iodobenzene as a coupling
partner (Table 1). The use of Pd catalysts initiated arylation to
The scope of both the aryliodonium salts and isoquinolone
substrates was next investigated to extend the utility of this
methodology. Consistent with the previous observation, the C4-
arylation process occurred almost exclusively at the C4 position
and could tolerate the presence of a variety of functional groups
from electron-donating (alkyl and methoxy) to electron-
withdrawing (ester, halides, and trifluoromethyl) groups
(Scheme 3). The reaction scope was extended to the
Table 1. Optimization of C4-Selective Arylation of
Isoquinolone
a
a
Scheme 3. Reaction Scope for C4 Arylation of Isoquinolone
yield (%)
cat.
aryl source
(1.2 equiv)
entry (10 mol %)
additive
solvent
3a
3a′
21
8
b
1
2
3
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
PhI
DMF
DMF
17
5
b
PhI
PhB(OH)2
Cs2CO3 DMF/
H2O
4
5
6
7
8
9
Pd(OAc)2
Pd(OPiv)2
Pd(OPiv)2
Pd(OPiv)2
Pd(TFA)2
Pd(OPiv)2
Cu(OTf)2
Ph2IBF4
Ph2IBF4
Ph2IPF6
Ph2IBF4
Ph2IBF4
Ph2IBF4
Ph2IBF4
hexanes
hexanes
DME
51
69
55
78
23
25
2
2
2
1
1
8
DME
DME
PivOH
DME
DME
10
a
Isoquinolone, aryliodonium salts (1.2 equiv) and Pd(OPiv)2 (10 mol
a
b
1a, iodonium salt (1.2 equiv), and catalyst (0.1 equiv) in solvent (0.1
%) in DME (0.1 M) at 120 °C for 24 h: isolated yields. Reaction was
conducted with Ph2IPF6 (1.2 equiv) in benzene (0.1 M).
b
M) at 120 °C: yields were determined by 1H NMR. 1a, iodobenzene
(2 equiv), Pd (0.1 equiv), Ag2CO3 (3 equiv), and CsOPiv (3 equiv) in
DMF (0.1 M) at 120 °C.
aryliodonium salt bearing an ortho-substituted aryl group, but
the product was obtained in a modest yield (3m, 41%), which
may due to steric factors. The bromo group was well tolerated to
afford the synthetically versatile 3f, 3l, and 3q, thereby providing
an opportunity for streamlining late-stage synthetic routes. The
resilience of the bromo group indicates that reactive Pd(0)
species is not likely to be formed under the reaction conditions.
In addition, the N-substituents of isoquinolone tolerated the
inclusion of benzyl and 2-oxobutyl groups (3r and 3s).
No obvious effects on the reaction were observed upon
addition of galvinoxyl or TEMPO, which suggests that a radical
mechanism is unlikely to be operative.14,15 On the basis of the
experimental results and previous studies, the aforementioned
electrophilic palladation pathway involving a PdII/IV catalytic
cycle most likely accounts for the observed C4-regioselectivity
(Scheme 4).14 The initial addition of Pd(II) to isoquinolone
would be prone to proceed via electrophilic palladation, followed
by deprotonation by the pivalate ligand to afford the C4-
palladated species I. The oxidation of the Pd(II) complex to a
Pd(IV) intermediate is readily promoted by aryliodonium salt,
and the subsequent reductive elimination of II delivered the C4-
arylated isoquinolone 3.
some extent. However, mixtures of the coupling products (3a
and 3a′) were obtained (entries 1 and 2). The low level of C3/C4
regioselectivity for arylation can be attributed to the Pd0/II
mechanisms, which may follow two feasible pathways: (1) an
electrophilic palladation pathway leading to C4-arylation or (2) a
carbopalladation process generating a Heck-type product (C3-
arylation).13 We reasoned that both the selectivity and reactivity
may be enhanced by promoting the electrophilic palladation
pathway and preventing the carbopalladation process. Therefore,
we investigated the PdII/IV catalytic cycle, and a breakthrough was
observed with aryliodonium salts.14 By systematic optimization
of the reaction conditions, it was found out that [Ph2I]BF4 not
only increased the yield of 3a but also promoted a nearly
exclusive reaction at the C4-position of isoquinolone. Altering
the iodonium salt counterion demonstrated that anion −BF4 was
optimal for the reaction efficiency and regioselectivity. Among
the Pd species screened, Pd(OPiv)2 was the most effective for
promoting the reactivity (see the Supporting Information). A
survey of solvents revealed that DME provided the highest yield
and the best regioselectivity. With the aim of tuning the
electrophilicity of Pd(II), the ligand effect was investigated, but
the addition of phosphine ligands or acid additives led to lower
yields under the reaction conditions. The optimized catalytic
conditions allowed for the direct installation of phenyl group
using Pd(OPiv)2 (10 mol %) and Ph2IBF4 (1.2 equiv) in DME to
afford 3a in 78% yield. In considering C−H functionalization
examples involving a highly electrophilic aryl−Cu(III) inter-
Next, we speculated that C8-regiocontrol could be achieved
using a coordinating amide moiety as a directing group, and this
prediction was tested with a range of transition-metal catalysts
(Table 2). Our initial attempts at C−H arylation were not
successful with aryl iodide. Intriguingly, when the arylation was
carried out using aryliodonium salts in the presence of Ru(II)
catalyst, a completely different selectivity pattern was observed
B
DOI: 10.1021/acs.orglett.5b01840
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 4. Plausible Mechanism for C4 Arylation
Scheme 5. Arylation Reaction of C8 of Isoquinolone
Table 2. Optimization Conditions for Arylation at the C8
a
Position of Isoquinolone
4a
entry
1
cat.
ligand
additive
solvent
(%)
(CO)
AgSbF6
hexanes
37
Ru(PPh3)3H2
2
3
[RuCl2(p-
hexanes
hexanes
5
3
cymene)]2
[Rh(1,5-COD)
Cl]2
AgSbF6
4
5
6
7
8
[RhCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
AgSbF6
AgSbF6
AgNTf2
AgSbF6
AgSbF6
hexanes
hexanes
hexanes
PivOH
AcOH
AcOH
18
44
28
71
93
30
b
9
AgSbF6 Cu(OAc)2·
H2O
b
10
[IrCp*Cl2]2
[IrCp*Cl2]2
AgSbF6 CsOAc
AgSbF6
AcOH
AcOH
24
c
11
trace
a
a
1, aryliodonium salt (1.2 equiv), [IrCp*Cl2]2 (5 mol %), and AgSbF6
(20 mol %) in AcOH (0.1 M) at 100 °C for 24 h; isolated yields.
Aryliodonium salt (3 equiv), [IrCp*Cl2]2 (10 mol %), and AgSbF6
1a, Ph2IPF6 (1.2 equiv), cat. (5 mol %), and AgSbF6 (20 mol %) in
1
solvent (0.1 M) at 100 °C for 24 h: yields were determined by H
NMR. Additive (3 equiv) was added. Iodobenzene was used.
b
b
c
(40 mol %) were used.
that successfully resulted in C−C bond formation exclusively at
the C8 position. Promising results were obtained using the Ir(III)
complex, which exclusively afforded a C8-arylated product,
which highlights the favorable coordination effect of the carbonyl
group on the Ir catalyst. It is worth noting that the Ir(III)-
catalyzed reaction with diaryliododium salts is unprecedented.
[IrCp*Cl2]2 was determined to be the most effective catalyst for
promoting the C8-arylation reaction. The use of AcOH as the
solvent was necessary to achieve a higher conversion. Anion
−BF4 was also optimal for the reaction efficiency. A systematic
investigation of the catalytic systems resulted in optimized
conditions involving the treatment of [IrCp*Cl2]2 (5 mol %) and
AgSbF6 (20 mol %) in AcOH with an excellent yield of 93%.
Next, studies of the C8 arylation reactions were extended to
include various functionalized aryliodonium salts and isoquino-
lone substrates (Scheme 5). In general, variation in both the
aryliodonium salts and isoquinolone substrates did not
significantly affect the reaction efficiency, permitting the
construction of a series of C8-arylated isoquinolones with
complete site selectivity. For example, alkyl, phenyl, fluoride,
bromide, chloride, ester, trifluoromethyl, methoxy, nitro, and
sulfone groups were all viable under the reaction conditions, and
yielded the C8-arylated isoquinolones. In some cases, the use of
the arylmesityliodonium salts improved the product yields.
Thiophene could also be efficiently installed at the C8 position
with similar efficiency to afford the desired product 4n.
Nearly complete conversion was observed when H/D
exchange experiments were carried out with the Ir catalytic
system, indicating a reversible and fast C−H cleavage step
(Scheme S1 in the SI). The C8−H coupling reaction appears to
be initiated by chelate-directed C−H bond activation of the
substrate, leading to iridacycle complex I (Scheme 6).16
Iridacycle I would be oxidized by the aryliodonium salt to afford
arylrhodium complex II. Subsequent reductive elimination in II
affords the arylated product 4 with the regeneration of the active
Ir(III) species.
For broad utility, we preliminarily explored the possibility of
extending this catalytic system to C3 arylation by investigating
the influence of N-directing groups on the reaction sites. Indeed,
the arylation of an isoquinolone substrate containing an N-
pyridyl directing group proceeded smoothly using the iridium
catalytic system, which resulted in the exclusive formation of the
C3-arylated product (Scheme 7).
In summary, we developed the catalyst-controlled site-
selective C−H arylation of isoquinolone using aryliodonium
C
DOI: 10.1021/acs.orglett.5b01840
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Scheme 6. Plausible Reaction Pathway of C8 Arylation
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Scheme 7. Preliminary Study of C3 Arylation Reaction
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salts as the coupling partners. This strategy has been verified in
divergent C4/C8 arylation, which can be broadly applied for the
rapid derivatization of isoquinolones of high synthetic utility.
The Pd(II)-catalyzed C4-selective arylation was successfully
realized via an electrophilic palladation pathway. The use of the
Ir(III) catalytic system enables catalytic cross-coupling at the C8
position.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b01840.
Experimental procedure and characterization of new
compounds (1H and 13C NMR spectra) (PDF)
(14) For selected examples of C−H arylation using aryliodonium salt,
see: (a) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am.
Chem. Soc. 2005, 127, 7330. (b) Deprez, N. R.; Sanford, M. S. J. Am.
Chem. Soc. 2009, 131, 11234. (c) Tang, D. T.; Collins, K. D.; Ernst, J. B.;
Glorius, F. Angew. Chem., Int. Ed. 2014, 53, 1809. (d) Topczewski, J. J.;
Sanford, M. S. Chem. Sci. 2015, 6, 70. (f) Phipps, R. J.; Grimster, N. P.;
Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 8172. (e) Bigot, A.;
Williamson, A. E.; Gaunt, M. J. J. Am. Chem. Soc. 2011, 133, 13778.
(f) Zhang, F.; Das, S.; Walkinshaw, A. J.; Casitas, A.; Taylor, M.; Suero,
M. G.; Gaunt, M. J. J. Am. Chem. Soc. 2014, 136, 8851.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: hongorg@kaist.ac.kr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported financially by the Institute for Basic
Science (IBS-R010-G1) and the National Research Foundation
of Korea (NRF) funded by the Ministry of Education, Science
and Technology (NRF-2010-0022179 and 2011-0020322).
(15) Neufeldt, S. R.; Sanford, M. S. Adv. Synth. Catal. 2012, 354, 3517.
(16) Kim, J.; Chang, S. Angew. Chem., Int. Ed. 2014, 53, 2203.
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D
DOI: 10.1021/acs.orglett.5b01840
Org. Lett. XXXX, XXX, XXX−XXX