Rhodium-catalyzed Synthesis of 1-Arylisoquinoline Derivatives through Annulative Coupling of 3-Aryl-1, 2-benzisoxazoles and Alkynes

Article abstract of DOI:10.1246/cl.170618

Direct annulative coupling of 3-aryl-1, 2-benzisoxazoles and alkynes efficiently proceeds in the presence of a Cp^?Rh(III) catalyst to produce 2-(1-isoquinolinyl)phenols of interest in medicinal chemistry as well as materials chemistry. The products may also be useful precursors of quinoline-based bidentate ligands.

Full text of DOI:10.1246/cl.170618

Advance Publication Cover Page
Rhodium-catalyzed Synthesis of 1-Arylisoquinoline Derivatives
through Annulative Coupling of 3-Aryl-1,2-benzisoxazoles and Alkynes
Teppei Noguchi, Yuji Nishii, and Masahiro Miura*
Advance Publication on the web July 28, 2017
doi:10.1246/cl.170618
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2017 The Chemical Society of Japan
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Publication manuscripts.

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Rhodium-catalyzed Synthesis of 1-Arylisoquinoline Derivatives
through Annulative Coupling of 3-Aryl-1,2-benzisoxazoles andAlkynes
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1
Teppei Noguchi, Yuji Nishii, and Masahiro Miura*
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Department of Applied Chemistry and Frontier Research Base for Global Young Researchers
Graduate School of Engineering, Osaka University, Suita Osaka 565-0871
E-mail: miura@chem.eng.osaka-u.ac.jp
o
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Direct
annulative
coupling
of
3-aryl-1,2-
5
5
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0
1
2
reaction temperature of 80 C (entry 8). Addition of any
bases considerably retarded the reaction (entries 9 and 10).
Negligible yield was obtained when [Cp*RhCl ] was used
benzisoxazoles and alkynes efficiently proceeds in the
presence of a Cp*Rh(III) catalyst to produce 2-(1-
isoquinolinyl)phenols of interest in medicinal chemistry as
well as materials chemistry. The products may also be
useful precursors of quinoline-based bidentate ligands.
2
2
53 as the catalyst (entry 11).
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5
a
5
Table 1. Optimization study
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Keywords: C-H activation, Rhodium, Isoquinoline
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Isoquinolines are an important class of aromatic
molecules of which skeletons are found in many
biologically active compounds as well as of vital use to
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1
various manufactured products. Transition-metal-catalyzed
2
aromatic C–H bond activation using imines or oxime
3
derivatives as directing groups has emerged as a powerful
synthetic tool for the facile construction of isoquinoline
skeletons. Especially, there has been considerable attention
to the latter reaction systems since the N–O bond of oxime
directing groups can act as an internal oxidant, which4
regenerates the catalytically active high-valent species.
Similar phenomena have merged in the Rh-catalyzed
reactions using hydrazone or azide directing groups, where
5
the N–N bond behaves as the oxidant.
6
7
Recently, we and Zhu et al. independently reported
the Rh- and Co-catalyzed 1-aminoisoquinoline syntheses,
8
respectively, using 1,2,4-oxadiazoles bearing a labile N–O
linkage within the ring system. As part of our successive
work, we herein report a Rh-catalyzed annulative coupling
of 3-aryl-1,2-benzisoxazoles and alkynes to give 2-(1-
isoquinolinyl)phenols. This type of compounds has been an
56
a
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Reaction conditions: 1a (0.1 mmol), 2a (0.11 mmol), catalyst
b
(4.0 mol%), and PhCF (0.5 mL). Determined by GC analysis.
important structural motif for ion channel and receptor
3
c
d
e
9
DCE = 1,2-dichloroethane Isolated yield (1.0 mmol scale).
(4.0 mol%) was used instead of
[Cp*Rh(MeCN) ][SbF ] . Not detected.
modulators
as well as components of organic
10
[Cp*RhCl2]2
electroluminescent devises. Additionally, they have been
employed as precursors in synthesizing various
isoquinoline-based ligands including axially chiral
scaffolds
asymmetric
phosphination, and amination.
f
3
6 2
1
1
We then examined the reaction of 1a with various
alkynes under the optimal conditions (Table 2). 4,4’-
Disubstituted diphenylacetylenes bearing electron-donating
and -withdrawing groups 2b-2d were compatible to the
present protocol, giving the corresponding isoquinolines
3ab-3ad in high yields. The bromo function of 2e remained
intact during the reaction to afford 3ae in an almost
quantitative yield. The ortho- and meta-substituents on 2f
and 2g somewhat encumbered the reaction, and a higher
reaction temperature was required to reach the adequate
yield of 3af and 3ag. An aliphatic alkyne 2h could be
adopted successfully to give 3ah. An unsymmetrically
substituted alkyne 2i furnished a mixture of regioisomers,
while the phenyl group was preferentially installed to the
as exemplified in recent Pd-catalyzed
12
transformations such
14
as
arylation,
1
3
At the outset, optimization study was carried out for
the reaction of 3-phenyl-1,2-benzisoxazole (1a) with
diphenylacetylene (2a) in the presence of a Rh catalyst
(Table 1). The desired coupling product 3aa was first
obtained in 20% yield
using
4
mol% of
[Cp*Rh(MeCN) ][SbF6]2
pentamethylcyclopentadienyl) in 1,4-dioxane at 110
(Cp*
=
C
3
o
(entry 1). The product structure was confirmed by X-ray
1
5
crystallography.
Solvent screening was then conducted
and a significant increase of the yield was observed when
the reaction was performed in PhCl (entry 6). A further
investigation revealed that PhCF3 was more sufficient
affording an almost quantitative conversion even at a lower
1
5
nitrogen side to give 3ai as the major product. Terminal

2
4
g
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1
2
3
4
alkynes were not suitable for the present reaction (not
shown).
30 N–O bond cleavage take place in a stepwise or concerted
31 manner. The resulted Rh(III) phenoxide complex may be
32 protonated to regenerate the catalytically active
33 Cp*Rh(SbF6)2 and liberate an annulated product 3.
a
Table 2. Substrate scope for alkynes
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3
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Alternatively, the alkoxide complex may directly mediate
the C–H bond activation of 1 to close the catalytic cycle.
The annulated product 3fa, whose protrusive methyl
substituent would prevent the free rotation along the
isoquinoline-phenol bond, was further transformed into a
P–N bidentate compound 6 as a representative derivatization
(Scheme 2). Phosphine oxide 5 was prepared in two steps
from 3fa though triflation and Ni-catalyzed phosphination,
and subsequent deoxygenation by trichlorosilane gave the
desired phosphine 6.
1
7
a
Table 3. Substrate scope for oxadiazoles
5
6
a
Reaction conditions: 1a (0.2 mmol), 2 (0.22 mmol),
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[Cp*Rh(MeCN) ][SbF ] (4.0 mol%), PivOH (20 mol%), and
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3
6 2
a
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4
4
5
5
5
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0
1
2
Reaction conditions: 1 (0.2 mmol), 2a (0.22 mmol),
PhCF (2.0 mL). Isolated yields are shown.
3
[Cp*Rh(MeCN) ][SbF ] (4.0 mol%), PivOH (20 mol%), and
PhCF (2.0 mL). Isolated yields are shown.
3
6 2
3
1
1
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1
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We also evaluated the substrate scope for isoxazoles
(Table 3). 3-(4-Substituted phenyl)-1,2-benzisoxazoles 1b-
1d reacted with 2a smoothly to afford the corresponding
annulated products 3ba-3da in high yields. For a meta-
substituted isoxazole 1e, the cyclization proceeded
predominantly at the uncongested position to give 3ea as the
single product. This protocol was suitable for the synthesis
of a 1,8-substituted isoquinoline such as 3fa which would be
Scheme 1. Proposed reaction mechanism for the coupling
reaction of oxadiazole 1 with alkyne 2
a
useful scaffold for some axially chiral pyridine
compounds. Thieno-fused pyridine 3ga was also accessible,
albeit the yield was moderate. Quinolinylphenol 3ha
bearing a chloro function at the phenol ring was obtained in
a good yield.
A proposed mechanism for the present catalytic system
is illustrated in Scheme 1. The reaction is initiated by the
isoxazole-directed ortho C–H bond cleavage where another
isoxazole 1 may participate as an external base (product 3
can replace from the second cycle), giving the
corresponding five-membered intermediate. After insertion
of alkyne 2 into the Rh–C bond, C–N bond formation and
5
3

3
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Selected recent examples for C-H activation using internal
oxidant to construct N-heterocyclic compounds, see; a) Y. Tan, J.
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In summary, the annulative coupling reaction of 3-aryl-
1,2-benzisoxazoles and alkynes in the presence of a Rh(III)
catalyst to furnish 2-(1-isoquinolinyl)phenols has been
developed, in which the N–O bond of isoxazole moiety
plays a crucial role for the catalytic turnover. The products
are of interest in medicinal chemistry as well as materials
chemistry and also as potential precursors for synthesizing a
series of isoquinoline-based bidentate ligands.
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Scheme 2. Preparation of an N–P bidentate ligand
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This work was supported by JSPS KAKENHI (Grant Nos.
JP 17H01202 and JP 17H06092).
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Supporting
Information
is
available
on
http://dx.doi.org/10.1246/cl.******.
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References and Notes
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06 15 CCDC 1556784 (3aa) and 1556786 (3ak): these data can be
07
08
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
09 16 D. R. Stuart, M. Bertrand-Laperle, K. M. N. Burgess, K. Fagnou
10
J. Am. Chem. Soc. 2008, 130, 16474.
11 17 HPLC analysis confirmed that 5 retained its chirality at ambient
12
13
14
temperature; however, separation condition could not be
determined for the phosphine 6. For detail, see the Supporting
Information.