Synthesis of 3-methyleneisoindolin-1-ones via palladium-catalyzed C-Cl bond cleavage and cyclocarbonylation of ortho-chloro ketimines

Article abstract of DOI:10.1016/j.tetlet.2013.07.017

PdCl₂(PCy₃)₂-catalyzed cyclocarbonylative coupling of ortho-chloro arylketimines with CO has been investigated to develop an efficient method for the synthesis of isoindolin-1-ones. The developed synthetic method has the a

Full text of DOI:10.1016/j.tetlet.2013.07.017

Tetrahedron Letters 54 (2013) 5159–5161
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Tetrahedron Letters
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Synthesis of 3-methyleneisoindolin-1-ones via palladium-catalyzed
C–Cl bond cleavage and cyclocarbonylation of ortho-chloro
ketimines
a
a
a
a,b,
⇑
Jia Ju , Chuanmei Qi , Liyao Zheng , Ruimao Hua
a
Department of Chemistry, Tsinghua University, Key Laboratory of Organic Optoelectronics & Molecular Engineering of Ministry of Education, Beijing 100084, China
State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
b
a r t i c l e i n f o
a b s t r a c t
Article history:
PdCl (PCy ) -catalyzed cyclocarbonylative coupling of ortho-chloro arylketimines with CO has been
2
3 2
Received 16 March 2013
Revised 17 June 2013
Accepted 3 July 2013
Available online 16 July 2013
investigated to develop an efficient method for the synthesis of isoindolin-1-ones. The developed syn-
thetic method has the advantages of having easily available starting materials, high atom-economy,
and high selectivity.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Carbon monoxide
ortho-Chloro ketimine
Cyclocarbonylation
Isoindolin-1-ones
Palladium
Catalytic activation of the C–Cl bond of aryl chlorides and its
application in the C–C bond formation is one of the interesting
and challenging research topics in organic synthesis,1 since such
type of transformation has a higher atom-efficiency by comparison
with the use of aryl iodides and bromides. Also, aryl chlorides are
typically cheaper and more commercially available aryl halides
with a lower toxicity than that of aryl iodides and bromides. With
bromides as substrates.8 However, there is no report on the con-
struction of this type of skeleton via the C–Cl bond cleavage. Most
recently, Lloyd–Jones and Booker–Milburn, as well as Wang devel-
oped an elegant approach for the synthesis of 3-methyleneisoindo-
lin-1-ones via Pd-catalyzed C–H activation of benzamides and
1
0
coupling with alkenes. However, the substrates are limited to
the purpose of developing high-atom efficient C–C bond formation
2
procedures, our previous work disclosed that PdCl
2
(PCy
cross-coupling
3
)
2
was an
efficient catalyst in the Sonogashira2 and Heck
a,b
2c,d
R'
R
N
R'
N
reactions of aryl chlorides.
R
[
Pd]
Cl
3
-Methyleneisoindolin-1-one is core structural unit in some
O
3
,4
3a
natural products, such as fumaridine (Scheme 1). Also, it is a
valuable component for the construction of numerous valuable
polyheterocycles, including some natural products, such as len-
4
,5
4
g
4e
4a,d
noxamine, aristoyagonine, and aristolactam alkaloids.
Some
R'
N
synthetic 3-methyleneisoindolin-1-ones also show outstanding
R'
R
N
[
4
c,6
biological activities.
For example, A is a good muscarinic recep-
R
[
Pd]
Pd]
6
a
tor ligand. The double bond in methyleneisoindolinone facilitates
Cl
it for
p
-conjugated extend structures,7 such as B, a promising
7a
O
building block for organic optoelectronic materials.
HCl
A variety of synthetic routes to isoindolin-1-ones have been
R'
CO
8
,9
developed,
including several examples using aryl iodides or
N
R
[
Pd] Cl
O
⇑
Corresponding author. Fax: +86 10 62771149.
E-mail address: ruimao@mail.tsinghua.edu.cn (R. Hua).
Scheme 1. Proposed mechanism.
0
040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.017

5
160
J. Ju et al. / Tetrahedron Letters 54 (2013) 5159–5161
Table 1
Table 2
Substrate scope
a
a
Optimization of reaction conditions
Entry
Ketimine 1
Product 2
Cl
N
cat. Pd/base
toluene, 8h
Cl
+
CO
N
N
N
N
1
1b
1c
2b, 72%
2c, 72%
2d, 56%
Cl
Cl
Cl
1a
2a
O
O
Entry
Catalyst
Base
CO(atm)
Yieldb (%)
N
2
3
1
2
3
4
5
6
7
8
9
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
2
2
2
2
2
2
2
2
2
2
(PPh
(PCy
(dppe)(3)
(PCy
(PCy
(PCy
(PCy
(PCy
(PCy
(PCy
3
)
)
2
(3)
(3)
CS
CS
CS
2
CO
2
CO
2
CO
3
3
3
10
10
10
10
10
10
10
5
Trace
81
Trace
72
54
<10
50
Cl
F
Cl
3
2
O
)
3 2
)
3 2
)
3 2
)
3 2
)
3 2
)
3 2
)
3 2
(3)
(3)
(3)
(3)
(3)
(3)
(3)
(1)
(0.5)
2 3
K CO
Na
Bu
3
PO
N
4
N
1d
N
3
F
Cl
Pyrrolidine
O
CS
2
CS
2
CS
2
CS
2
CS
2
CO
3
CO
3
CO
3
CO
3
CO
3
89
1
10
5
Trace
28
1
1
1
0c
1
N
N
4
2e, 31%
PdCl
PdCl
2
(PCy
(PCy
3 2
)
95(84)d
41
1e
Cl
2
2
)
3 2
10
Cl
Cl
O
a
Unless otherwise noted, reactions were carried out using 1.0 mmol 1a, catalyst,
and 1.1 equiv of base in 1.0 mL of toluene in a 25 mL autoclave with CO at 130 °C for
N
5
6
7
8
N
N
2f, 81%
2g, 75%
2h, 83%
2i, 61%
8
h.
1
f
b
Yields of 2a are based on GC by using n-C22
Reactions were carried out at 115 °C.
Isolated yields.
H46 as internal standard.
Cl
Cl
O
c
d
Ph
N
1g
Ph
N-methoxybenzamides and active alkenes. Also, the use of stoichi-
ometric benzoquinone as oxidant and acetic acid as solvent makes
the reaction still not practical in the view of green chemistry. In
O
Ph
N
2
N Ph
continuation of our interest in the C–Cl bond activation and cyclo-
1h
1
1
Cl
carbonylation, we became interested in the development of an
alternative synthetic strategy toward 3-methyleneisoindolin-1-
O
OMe
Cl
1
2
one derivatives via palladium-catalyzed cyclocarbonylation of
ortho-chloro ketimines.
N
OMe
Cl
N
N
1
i
As a model reaction, ortho-chloro ketimine (1a) was employed
as the substrate, while a variety of catalysts and bases were
employed to optimize the reaction conditions (Table 1). Gas chro-
matography (GC) was used to give the yield of each entry by using
O
Cl
Cl
N
9
2j, 50%
1
j
n-C22
To start our study, three Pd(II) catalysts with different ligands
were used with Cs CO as base to explore an efficient catalyst sys-
tem. A common catalyst PdCl (PPh showed rather low activity
entry 1), while a remarkable yield (81%) of the desired product
2a) was obtained by simply replacing the PPh ligand with PCy
entry 2). Catalyst with a bidentate ligand 1,2-bis(diphenylphos-
H46 as internal standard.
O
a
Reactions were carried out using 1.0 mmol of 1, 1.0 mol % of PdCl
.1 equiv of Cs CO in 1.0 mL of toluene in a 25 mL autoclave with 5.0 atm of CO at
2
(PCy
3 2
) , and
2
3
1
1
2 3
2
3 2
)
30 °C for 8 h.
(
(
(
3
3
With the optimized reaction condition in hand, the generality
for the synthesis of isoindolin-1-ones was next examined
Table 2). Dichloro ketimine 1b and 1c were used to afford
phino)ethane (dppe) also showed low activity (entry 3). These re-
sults revealed that the Pd(II) catalyst with trialkylphosphine ligand
1
3
(
PCy
comparable with our previous studies.
By using PdCl (PCy as catalyst, we next surveyed several
bases (entries 4–7). Another carbonate K CO was also suitable
for the reaction besides Cs CO , but gave a lower yield (72%).
Na PO displayed much lower efficiency (54%), and organic bases
such as Bu N and pyrrolidine showed low activity. By using the
PdCl (PCy /Cs CO catalytic system, we further conducted our
3
was an efficient catalyst for the C–Cl bond activation, which is
chloro-substituted products 2b and 2c in 72% yield. Notably, chloro
groups not in the ortho position were inert in the system. This
selectivity in the C–Cl bond cleavage indicates that the C–Cl bond
activation is facilitated by the coordination to Pd using the N atom
in the ketimine (vide infra). Fluoro-substituted ketimine 1d gave
the fluoro-having products 2d in 56%, indicating that the C–F bond
remained intact under the reaction conditions. By using 1e as the
substrate, two isomers are expected to be formed, but only one
of them was obtained in 31% isolated yield, and unfortunately
the stereochemistry of the C@C double bond could not be con-
firmed by 2D NOESY experiment. Ketimines with bulkier N-substi-
tutes or N-aryl substitutes were also employed and the reaction
proceeded smoothly to afford the corresponding 3-methyleneiso-
indolin-1-ones 2f–j in moderate to good yields.
2
3 2
)
2
3
2
3
3
4
3
2
3
)
2
2
3
optimization by varying other reaction conditions. To our delight,
a higher yield (89%) was obtained by reducing the CO pressure to
5
atm (entry 8). However, only trace amount of product was
detected when the reaction was conducted under 1 atm CO (entry
). Decreasing the temperature from 130 °C to 115 °C made the
9
reaction sluggish and gave much lower yield (28%, entry 10).
Interestingly, a much satisfactory yield (95%) was obtained by
reducing the catalyst loading from 3 mol % to 1.0 mol % (entry
A proposed mechanism was shown in Scheme 1, ortho-chloro
ketimine makes an oxidative addition to the Pd catalyst to afford
a five-membered palladacyclic intermediate. Subsequently, CO
insertion occurs and a six-membered palladacyclic intermediate
1
1), may be due to the suppression of the side reactions. However,
further reducing the catalyst loading to 0.5 mol % gave disappoint-
ing yield (41%, entry 12).

J. Ju et al. / Tetrahedron Letters 54 (2013) 5159–5161
5161
is obtained. At last, a reductive elimination of the intermediate
proceeds to yield the product and catalytic species is regenerated.
The byproduct hydrochloric acid is absorbed by the added base.
In summary, we have developed a facile route to construct
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3
-methyleneisoindolin-1-ones from readily available ortho-chloro
(a) Couture, A.; Deniau, E.; Grandclaudon, P.; Hoarau, C. J. Org. Chem. 1998, 63,
arylketimines. The reaction proceeds efficiently via the C–Cl
bond cleavage and the cyclocarbonylation by using the
PdCl (PCy ) /Cs CO catalytic system.
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1
a (Table 1, entry 11): To a 25 mL autoclave equipped with a mag-
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netic stirrer, 1a (194.5 mg, 1.0 mmol), PdCl
.01 mmol), Cs CO (360.1 mg, 1.1 mmol), and dry toluene
1.0 mL) were added sequentially under nitrogen. The autoclave
was sealed and CO was introduced at an initial pressure of
.0 atm at room temperature. The autoclave was stirred at 130 °C
2 3 2
(PCy ) (8.0 mg,
0
(
2
3
5
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in a heating jacket for 8 h. After the autoclave was cooled to room
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luted with CH
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Cl (4.0 mL), and then n-octadecane (92.5 mg,
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0
.36 mmol) was added as an internal standard for GC analysis.
After GC and GC–MS analyses, volatiles were removed under re-
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chromatography with petroleum ether/ethyl acetate (mixture ratio
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4
:1) as eluent to afford 2a (156.5 mg, 84%) as a pale yellow oil.
Acknowledgments
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This project was supported by the National Natural Science
Foundation of China (21032004, 20972084), and the Bilateral Sci-
entific Cooperation between Tsinghua University & K.U. Leuven.
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Supplementary data
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1
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Supplementary data (general method, characterization data and
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2. For reviews, see: (a) Grigg, R.; Mutton, S. P. Tetrahedron 2010, 66, 5515; (b) Wu,
X.-F.; Neumann, H.; Beller, M. Chem. Rev. 2013, 113, 1.
1
13
charts of H, C NMR for all products) associated with this article
can be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2013.07.017.
1
1
3. The characterization data of the products are reported in Supplementary data.
References and notes
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