Palladium-Catalyzed Synthesis of Isoquinolinones via Sequential Cyclization and N-O Bond Cleavage of N -Methoxy- o -alkynylbenzamides

Article abstract of DOI:10.1055/s-0032-1318159

A palladium-catalyzed controlled 6-endo-dig cyclization process has been developed for the chemoselective synthesis of isoquinolin-1-ones from N-alkoxy-o-alkynylbenzamides. The mechanism and scope of the reaction have also been investigated. Deuterium-labeling studies were used to confirm the intramolecular 1,5-hydrogen shift as a key step in the transformation. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1318159

LETTER
▌475
letter
Palladium-Catalyzed Synthesis of Isoquinolinones via Sequential Cyclization
and N–O Bond Cleavage of N-Methoxy-o-alkynylbenzamides
Palladium-Catalyzed Synthesis of Isoquinolinones
Manita Jithunsa, Masafumi Ueda,* Naoki Aoi, Shoichi Sugita, Tetsuya Miyoshi, Okiko Miyata*
Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe, Hyogo 658-8558, Japan
Fax +81(78)4417554; E-mail: miyata@kobepharma-u.ac.jp
Received: 06.12.2012; Accepted after revision: 14.01.2013
found that the intramolecular cyclization of Weinreb am-
Abstract: A palladium-catalyzed controlled 6-endo-dig cyclization
ides bearing an alkyne moiety proceeded predominantly
process has been developed for the chemoselective synthesis of iso-
quinolin-1-ones from N-alkoxy-o-alkynylbenzamides. The mecha-
nism and scope of the reaction have also been investigated.
via the O-nucleophilic attack of the carbonyl group in the
presence of CuCl2/NCS to form isobenzofuran-1-ones.10
Deuterium-labeling studies were used to confirm the intramolecular Interestingly, however, much less is known about influ-
1,5-hydrogen shift as a key step in the transformation.
encing the chemoselective nucleophilic attack of the am-
ide nitrogen over the carbonyl oxygen in Weinreb
amides.11 It was envisaged that the coordination of a pal-
ladium catalyst to both the N-alkoxyamide and alkyne
would lead to the formation of a product resulting from
the opposing chemo- and regioselectivities. Herein, we re-
port the development of a method for the palladium-cata-
lyzed cyclization of N-alkoxy-o-alkynylbenzamides to
afford isoquinolin-1-ones exclusively.
Key words: alkynes, regioselectivity, palladium, cyclization,
amides
Isoquinolinones, which are also known as 1-oxo-1,2-di-
hydroisoquinolines, are one of the key structural units
found in plant alkaloid derivatives.1 These structures can
also be found in synthetic molecules that possess a range
of biological activities.2 Isoquinolinone itself has been
used as a basic building block for the synthesis of more
complex isoquinolinone ring systems.3 The development
of practical synthetic strategies for the construction of iso-
quinolinone systems has been extensively explored by a
number of material, organic, and pharmaceutical chemists
because of the widespread occurrence and utility of this
structural motif. Of these methods, the use of an intramo-
lecular reaction is one of the most convenient tools for the
preparation of substituted isoquinolinone derivatives.4 To
date, several methods have been developed for the con-
struction of the isoquinolinone framework involving the
cyclization reaction of benzamide derivatives.5 The cycli-
zation of o-alkynylbenzamides in particular represents a
straightforward and powerful strategy for the direct syn-
thesis of isoquinolinones. Although a variety of different
methods has been reported for the intramolecular annula-
tion of o-alkynylbenzamide using either a base,6 electro-
phile,7 or transition-metal catalyst,6,8 these methods often
suffers from a lack of regioselectivity because of compet-
itive cyclization processes that can occur through either
the 5-exo or 6-endo cyclization modes. Moreover, the ox-
ygen and nitrogen atoms of the amide moieties involved
in these methods can both behave as nucleophiles, leading
to a lack of chemoselectivity in the cyclized products. The
development of a method providing exclusive control
over chemo- and regioselective outcomes of the reaction
is therefore both desirable and challenging.
Our study towards the development of a method for the
palladium-catalyzed intramolecular addition of Weinreb
amides to alkynes started with an investigation of the re-
action of N-methoxy-N-methyl-2-(2-phenylethynyl)-
benzamide (1a) with PdCl2(PPh3)2 (Table 1).
The treatment of 1a with 20 mol% of PdCl2(PPh3)2 in re-
fluxing 1,2-dichloroethane for 24 hours led to the forma-
tion of the cyclized product N-methylisoquinolin-1-one
2a via cyclization, elimination of the methoxy group, and
protonation at the 4-position, albeit in low yield (Table 1,
entry 1).11,12 The survey of catalysts revealed that
PdCl2(PPh3)2 is a superior catalyst over the other catalysts
such as PdBr2(PPh3)2, Pd(OAc)2, Pd(PPh3)4, FeCl3, FeCl2,
ZnCl2, Zn(OTf)2, InCl3, PtCl2, and AuCl3. To allow for the
reaction to be conducted at a higher temperature, toluene
and chlorobenzene were investigated as the reaction sol-
vent. Unfortunately, however, the use of these solvents re-
sulted only in a reduction in the chemical yield (Table 1,
entries 2 and 3). It is noteworthy that the addition of ben-
zoquinone to the catalytic reaction led to a significant im-
provement in the chemical yield (Table 1, entry 4).13
A
control reaction performed in the absence of the palladium
catalyst did not provide any of the desired product, con-
firming the critical role of the palladium catalyst in the re-
action (Table 1, entry 5). It was envisaged that the yield of
2a could be improved by the addition of a protic additive.
With this in mind, the reaction was conducted in the pres-
ence of isopropyl alcohol and pleasingly provided the de-
sired product in an 81% yield (Table 1, entry 6).
Moreover, the reaction was found to be tolerant to an at-
mosphere of molecular oxygen, with these conditions pro-
viding a slightly enhanced yield of 2a (Table 1, entry 7).
Although a reduction in the catalyst loading to 10 mol%
was tolerated (Table 1, entry 8), further reduction of the
During the course of our ongoing investigations based on
the reactivity of the nitrogen–oxygen bond,9 we recently
SYNLETT 2013, 24, 0475–0478
Advanced online publication: 29.01.2013
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9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1318159; Art ID: ST-2012-U1025-L
© Georg Thieme Verlag Stuttgart · New York

476
M. Jithunsa et al.
LETTER
reaction by varying the nature of the substituent on the
triple-bond terminus (Table 2).
Table 1 Optimization Studies for the Palladium-Catalyzed Cycliza-
tion of 1aa
Ph
H
The cyclization reaction of Weinreb amide 1b bearing a p-
fluorophenyl group gave the desired isoquinolinone 2b in
89% yield, whereas the introduction of an electron-donat-
ing group to the phenyl ring led to a decrease in the yield
of the reaction (Table 2, entries 1–3). Although aliphatic
substituents were well tolerated under the optimized con-
ditions, a higher temperature was needed in the case of the
cyclohexyl substituent likely because of steric hindrance
(Table 2, entries 4 and 5).
PdCl2(PPh3)2
additive
Ph
Me
N
N
reflux, 24 h
OMe
Me
O
O
2a
1a
Entry PdCl2(PPh3)2 Solvent Additive (equiv)
(mol%)
Yield
(%)b
1
20
20
20
20
–
DCE
toluene
PhCl
DCE
DCE
DCE
DCE
DCE
DCE
–
28
23
16
66
–
Further examination of a variety of different substituents
on the benzene ring demonstrated the scope and feasibility
of this reaction for the construction of isoquinolinone de-
rivatives (Scheme 1). This new Pd(II)-catalyzed cycliza-
tion protocol was also tolerant of substrates bearing
halogen groups on the benzene ring. For example, sub-
strates bearing fluoro and chloro groups on the benzene
ring at positions para and meta to the carbonyl group were
well tolerated, providing the cyclized products 2g–j, re-
spectively, in isolated yields of 76–94%. Similarly, the
application of a substrate bearing a fluoro group ortho to
the carbonyl group produced 2k in 70% yield, albeit fol-
lowing an extended reaction time. When substrates con-
taining electron-rich aromatic rings were subjected to the
cyclization conditions, the desired isoquinolinones 2l–n
were obtained in relatively lower yields, indicating the
preference of the reaction for electron-deficient ring
systems.
2
–
3
–
4
benzoquinone (5)
benzoquinone (5)
5
6
20
20
10
5
benzoquinone (5), i-PrOH (3) 81
benzoquinone (5), i-PrOH (3) 85
benzoquinone (5), i-PrOH (3) 81
benzoquinone (5), i-PrOH (3) 66
7c
8c
9c,d
a Reaction conditions: 1a (0.2 mmol) in DCE (0.05 M) under an Ar
atmosphere.
b Isolated yield.
c Reaction was carried out under an O2 atmosphere.
d Reaction was conducted over 48 h.
catalyst loading to 5 mol% had an adverse impact on the
yield of the product 2a (Table 1, entry 9).
With our optimized conditions in hand,14 we proceeded to
investigate the scope of this Weinreb amide cyclization
Ph
PdCl2(PPh3)2
benzoquinone, i-PrOH
R2
R2
Ph
Me
N
N
CH2Cl2, O2, reflux
24 h
Me
OMe
O
O
1g–n
2g–n
Table 2 Palladium-Catalyzed Cyclization of Substrate 1 with the
Acetylene Unitsa
Ph
Cl
Ph
F
Ph
R1
N
PdCl2(PPh3)2
N
N
R1
F
Me
Me
Me
benzoquinone, i-PrOH
Me
O
O
O
N
N
DCE, O2, reflux
2g 94%
2h 91%
2i 76%
OMe
Me
O
1b–f
O
2b–f
Ph
Ph
N
N
Entry
Substrate 1
Product 2
Yield (%)b
Cl
Me
Me
O
F
O
2ka 70%
1
1b R1 = 4-FC6H4
1c R1 = 4-MeC6H4
1d R1 = 4-MeOC6H4
1e R1 = n-Bu
2b
2c
2d
2e
2f
89
54
62
46
45
2j 79%
Me
2
Ph
Ph
Ph
3
N
N
N
Me
Me MeO
Me
Me
4
O
O
O
2nb 31%
2l 62%
2m 60%
5c
1f R1 = cyclohexyl
a Conditions: 1b–f (0.2 mmol), PdCl2(PPh3)2 (0.2 equiv), benzoqui-
none (5 equiv), i-PrOH (3 equiv) in DCE (0.05 M) under an O2 atmo-
sphere.
Scheme 1 Palladium-catalyzed cyclization: scope of the substituent
a
on the aromatic ring. Reagents and conditions: The reactions was
conducted over 48 h; b Chlorobenzene was used as the solvent.
b Isolated yield.
c Chlorobenzene was used as the solvent.
Synlett 2013, 24, 475–478
© Georg Thieme Verlag Stuttgart · New York

LETTER
Palladium-Catalyzed Synthesis of Isoquinolinones
477
To elucidate the mechanism of the reaction, deuterium- sequently undergo protodepalladation to form 2a as a
labeling experiments were performed as shown in Scheme minor pathway. Although the roles of benzoquinone and
2. Surprisingly, when the reaction of 1a was conducted molecular oxygen are unclear, benzoquinone would act as
with deuterated isopropyl alcohol, the product 2a-d was ligand for the palladium catalyst.13
isolated containing only 8% of deuterium at the 4-position
In summary, we have successfully developed a new meth-
(Scheme 2, eq. 1). To determine the source of the hydro-
od for the synthesis of isoquinolin-1-ones involving the
gen atom at the 4-position, compound 1a-d3 containing a
palladium-catalyzed cyclization of the Weinreb amide de-
rivatives of o-alkynyl benzoic acids via an N–O bond
deuterium-labeled methoxy group was subjected to the
palladium-catalyzed cyclization reaction in the presence
cleavage and 1,5-hydrogen shift mechanism. Mechanistic
of isopropyl alcohol (Scheme 2, eq. 2). This reaction re-
studies indicated that an intramolecular rearrangement of
sulted in 69% deuterium incorporation at the 4-position of
the hydrogen atom takes place. Further mechanistic study
and substrate scope are in progress in our laboratory. The
present reaction highlights the utility of Weinreb amides
the isoquinolinone 2a-d, indicating that the hydrogen
atom at the 4-position was derived predominantly from an
intramolecular hydrogen shift from the methoxy group.
as nucleophiles.
D
Ph
PdCl2(PPh3)2
benzoquinone
i-PrOH-d8
Acknowledgment
Ph
Me
N
(1)
(2)
This work was supported by Grants-in-Aid from the Ministry of
Education, Culture, Sports, Science and Technology of Japan
(MEXT), the MEXT-Supported Program for the Strategic Research
Foundation at Private Universities. M.U. is grateful to the Mitsub-
ishi Chemical Award in Synthetic Organic Chemistry of Japan.
N
DCE, O2, reflux
Me
OCH3
Ph
O
O
1a
2a–d 84%, 8% D
D
PdCl2(PPh3)2
benzoquinone
i-PrOH
Ph
Me
N
References and Notes
N
DCE, O2, reflux
Me
OCD3
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O
1a-d3
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2a–d 66%, 69% D
Scheme 2 Labeling experiments
Based on the experimental results, we have proposed the
following plausible mechanism for the transformation.
Alkyne activation of the N-methoxy-N-methyl-2-(2-
phenylethynyl)benzamide (1a) by the palladium catalyst
leads to the π complex A (Scheme 3). Subsequent intra-
molecular nucleophilic attack of the nitrogen atom of the
Weinreb amide onto the triple bond occurs in the 6-endo-
dig mode to generate intermediate B, which undergoes a
1,5-hydorgen shift to generate C with the concomitant
formation of formaldehyde. Liberation of the catalyst then
provides isoquinolinone 2a. Alternatively, chloride anion
mediated N–O bond cleavage would lead to the genera-
tion of vinylpalladium intermediate D, which would sub-
(3) Bisagni, E.; Landras, C.; Thirot, S.; Huel, C. Tetrahedron
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and Lactams; Patai, S.; Rappoport, Z., Eds.; John Wiley and
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(c) Mao, C.-L.; Barnish, I. T.; Hauser, C. R. J. Heterocycl.
H
H
H
ClPd
ClPd
H
Ph
Ph
O
Cl–
N+
+N
Me
Me
H
Ph
HCHO
O
O
Ph
B
C
••
N
Me
N
Me
PdCl
PdCl
N
OMe
O
2a
O
Ph
Ph
Cl–
A
HCl
i-PrOH
Me
+N
Me
H
O
O
B
O
D
H
H
HCHO
Scheme 3 Proposed mechanism for the cyclization of the 2-alkynylbenzamides
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 475–478

478
M. Jithunsa et al.
LETTER
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(14) General Procedure for the Palladium-Catalyzed
Synthesis of Isoquinolinone
To a solution of N-alkoxy-o-alkynylbenzamide 1 (0.20
mmol) in DCE (4 mL) was added i-PrOH (0.6 mmol), p-
benzoquinone (1.0 mmol), and PdCl2(PPh3)2 (0.04 mmol)
under O2 atmosphere. After being refluxed for 24 h, the
reaction mixture was concentrated in vacuo. The residue was
purified by flash column chromatography on silica gel
eluting with EtOAc–hexane (1:3) and/or toluene–Et2O (3:1).
Representative spectroscopic data of selected products are as
follows.
2-Methyl-3-phenylisoquinolin-1(2H)-one (2a)
Yellow solid; mp 66–67 °C (EtOAc–hexane; lit.5f 63 °C). 1H
NMR (300 MHz, CDCl3): δ = 8.45 (br d, J = 7.5 Hz, 1 H),
7.64 (br t, J = 8.1 Hz, 1 H), 7.51–7.39 (m, 7 H), 6.46 (s, 1 H),
3.44 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ = 163.3, 143.8,
136.3, 136.1, 132.2, 128.8, 128.7, 128.5, 127.7, 126.5,
125.7, 124.7, 107.5, 34.1. IR (KBr): νmax = 1652, 1619 cm–1.
ESI-HRMS: m/z calcd for C16H13NO [M + H]+: 236.1069;
found: 236.1066.
3-(4-Fluorophenyl)-2-methylisoquinolin-1(2H)-one (2b)
Yellow solid; mp 135–137 °C (EtOAc–hexane). 1H NMR
(300 MHz, CDCl3): δ = 8.44 (d, J = 7.8 Hz, 1 H), 7.64 (t, J =
7.8 Hz, 1 H), 7.51–7.45 (m, 2 H), 7.42–7.37 (m, 2 H), 7.17
(t, J = 8.4 Hz, 2 H), 6.44 (s, 1 H), 3.41 (s, 3 H). 13C NMR (75
MHz, CDCl3): δ = 164.6, 163.3, 161.3, 142.7, 136.2, 132.3,
132.2, 130.7, 130.6, 127.8, 126.7, 125.8, 124.9, 115.9,
115.6, 107.7, 34.1. IR (KBr): νmax = 1650, 1619 cm–1. ESI-
HRMS: m/z calcd for C16H13ONF [M + H]+: 254.0976;
found: 254.0967.
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131, 4198.
7-Chloro-2-methyl-3-phenylisoquinolin-1(2H)-one (2h)
White solid; mp 148–150 °C (EtOAc–hexane). 1H NMR
(300 MHz, CDCl3): δ = 8.37 (d, J = 8.4 Hz, 1 H), 7.49–7.45
(12) The transition-metal-catalyzed synthesis of heterocycles via
N–O bond cleavage has been reported, see: (a) Nakamura, I.;
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Hwang, S.; Lee, J.-E.; Lee, S. S.; Shin, S. Angew. Chem. Int.
Ed. 2010, 49, 1611. (d) Hirano, K.; Satoh, T.; Miura, M.
Org. Lett. 2011, 13, 2395. (e) Guimond, N.; Gorelsky, S. I.;
(m, 4 H), 7.42–7.37 (m, 3 H), 6.36 (s, 1 H), 3.40 (s, 3 H). 13
NMR (75 MHz, CDCl3): δ = 162.8, 145.4, 138.6, 137.6,
135.8, 129.7, 129.2, 128.7, 128.6, 127.1, 124.9, 123.2,
C
106.4, 34.1. IR (KBr): νmax = 1649, 1624 cm–1. ESI-HRMS:
m/z calcd for C16H13ONCl [M + H]+: 270.0680; found:
270.0673.
Synlett 2013, 24, 475–478
© Georg Thieme Verlag Stuttgart · New York

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