Preparation of isoindolinones via a palladium-catalyzed diamination

Article abstract of DOI:10.1016/j.tetlet.2016.11.113

A Pd(II)-catalyzed cyclization using oxidative olefin diamination was developed for the preparation of isoindolinones from ortho-olefinic N-methoxybenzamides. Using the optimized reaction conditions, the desired products were obtained in up to 90% yield using NFSI as the oxidant. This reaction provides an efficient and direct access to isoindolinones with amine functionality, an important drug skeleton.

Full text of DOI:10.1016/j.tetlet.2016.11.113

Accepted Manuscript
Preparation of Isoindolinones via a Palladium-Catalyzed Diamination
Yu Li, Xuezhen Kou, Chenghao Ye, Xinghua Zhang, Guoqiang Yang, Wanbin
Zhang
PII:
S0040-4039(16)31604-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.11.113
TETL 48399
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
26 September 2016
21 November 2016
28 November 2016
Please cite this article as: Li, Y., Kou, X., Ye, C., Zhang, X., Yang, G., Zhang, W., Preparation of Isoindolinones
via a Palladium-Catalyzed Diamination, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.
2016.11.113
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Preparation of Isoindolinones via a
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Yu Li, Xuezhen Kou, Chenghao Ye, Xinghua Zhang, Guoqiang Yang, and Wanbin Zhang

1
Tetrahedron Letters
Preparation of Isoindolinones via a Palladium-Catalyzed Diamination
Yu Lia, Xuezhen Koub, Chenghao Yeb, Xinghua Zhanga,, Guoqiang Yangb,, and Wanbin Zhangb,
aSchool of Chemical and Environmental Engineering, Shanghai Institute of Technology, 100 Haiquan Road, Shanghai 201418, China
bSchool of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A Pd(II)-catalyzed cyclization using oxidative olefin diamination was developed for the
preparation of isoindolinones from ortho-olefinic N-methoxybenzamides. Using the optimized
reaction conditions, the desired products were obtained in up to 90% yield using NFSI as the
oxidant. This reaction provides an efficient and direct access to isoindolinones with amine
functionality, an important drug skeleton.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Palladium
Diamination
Isoindolinone
Oxidation
Cyclization
———
 Xinghua Zhang. Tel.: +86-021-6087-7211; fax: +86-021-6087-7211; e-mail: xhzhang@sit.edu.cn
 Guoqiang Yang. Tel.: +86-021-5474-7486; fax: +86-021-5474-3265; e-mail: gqyang@sjtu.edu.cn
 Wanbin Zhang. Tel.: +86-021-5474-3265; fax: +86-021-5474-3265; e-mail: wanbin@sjtu.edu.cn

2
Tetrahedron
1. Introduction
THF at 80 oC, the desired diamination product was obtained in 84%
yield (entry 1). Other ether solvents such as 1,4-dioxane, DME
and diethyl ether only gave the product 2a in moderate yield or a
trace amount, respectively (entries 2-4). Solvents such as EtOAc,
DCE and DCM also afforded 2a in moderate to good yield
(entries 5-7). When the reaction was carried out in other solvents,
only a trace amount of product 2a or a mixture of unidentified
products was obtained (entries 8~11). A survey of reaction
temperatures revealed that the best result could be obtained when
the reaction was carried out at 80 oC. Lower or higher
temperatures resulted in a slight decrease in yield (entries 12~14).
When the reaction was conducted under an oxygen atmosphere,
product yield was similar to that of reactions carried out under air
(entry 15). However, a nitrogen atmosphere led to a stark
reduction in yield (entry 16), suggesting that oxygen may have
beneficial effects on this diamination. We believe that oxygen
can regenerate the Pd(II) catalyst from the inactive Pd(0) species,
which is formed as a result of side reactions.[13] Using other
nitrogen sources instead of NFSI such as TsNH2 and BocNH2,
and employing an additional oxidant PhI(OAc)2, failed to give
the desired corresponding diamination products.
Diamines reside within a wide assortment of potent drugs,
bioactive natural products, and organocatalysts.[1,2] Among them,
isoindolinones bearing amine functionality are an important
skeleton. These types of isoindolinones represent a structural
motif found in biologically active natural products and drug
candidates such as a drug for the treatment of cardiac arrhythmias
A and a modulator of serotonin receptors B (Figure 1).[3]
Therefore a reliable and efficient synthetic pathway for the
preparation of this skeleton is highly desired.
Figure 1. Representative isoindolinones with amine
functionality.
Table 1. Solvent and Temperature Effects.a,b
The direct diamination of alkenes is one of the most efficient
methods for the synthesis of diamines.[1] Several olefin-
diamination reactions have been developed over the past few
decades.[1,4-8] Some examples concerning 1,2- and 1,4-
diaminations have also been reported for conjugated alkenes.[1]
Diaminations using palladium and copper catalysis have been
widely studied, especially the former.[4-8] Shi and co-workers
T (oC)
80
Solvent
THF
Yield (%)
84
have carried out
a number of pioneering investigations
Entry
1
concerning Pd(0)- and Cu(I)-catalyzed 1,2-diaminations using
diaziridinones as nitrogen sources.[5] In 2005, Lloyd-Jones and
Booker-Milburn reported a Pd(II)-catalyzed intermolecular 1,2-
diamination of dienes using ureas as nitrogen sources.[6] In the
2
80
1,4-Dioxane
DME
62
3
80
47
same year, the Mũniz group described
a Pd-catalyzed
4
80
Et2O
Trace
51
intramolecular diamination of olefins using a high-valent
palladium mechanism.[7] Forest el al. have also developed high-
valent palladium chemistry for olefin cyclization diamination.[8]
The groups of Chemler, Zhang and Studer developed a series of
radical-based Cu-catalyzed diamination reactions.[9] Despite these
successes, appropriate nitrogen sources remain limited. The use
of different types of nitrogen sources to satisfy various
requirements for the synthesis of useful compounds is therefore
worth further exploration. N-Methoxyl amide is a powerful
directing group and the nucleophilic nitrogen can act as a
nitrogen source because the methoxyl group can be easily
removed.[10][11] In continuation of our efforts to develop
palladium-catalyzed syntheses of various heterocycles,[11,12] we
herein report a Pd(II)-catalyzed diamination cyclization of ortho-
olefinic N-methoxybenzamide for the preparation of
isoindolinones bearing amine functionality (Scheme 1).
5
80
EtOAc
DCM
6
80
73
7
80
DCE
66
8
80
CH3CN
DMSO
Toluene
CH3OH
Trace
NR
9
80
10
11
12
13
14
15c
16d
80
ND
ND
80
70
60
90
80
80
THF
THF
THF
THF
THF
82
79
62
82
52
a Reactions were carried out on a 2.0 mmol scale using 1.5 equiv of NFSI,
0.05 equiv of Pd(OAc)2 and 0.075 equiv of BPY in solvent (2 mL) in a sealed
tube under air atmosphere.
b NR = no reaction. ND = not detectable, a mixture of unidentified products.
c Under O2.
d Under N2.
Scheme 1. Diamination for preparation of isoindolinone with
amine functionality.
Next, the screening of different ligands and palladium sources
was carried out in THF at 80 oC (Table 2). A mixture of
unidentified products was obtained when no ligand was used
(entry 1 vs 2). Reactions with p,p’-disubstituted bispyridine
ligands gave lower yields (entries 3 and 4). Phenanthroline and
its derivative were also tested as ligands giving poor results
(entries 5 and 6). A pyridine-oxazoline ligand was also used and
2. Results and discussion
Initial studies were performed using ortho-olefinic N-
methoxybenzamide 3a and N-fluorobenzenesulfonimide (NFSI)
as the other nitrogen source. Firstly, different solvents and
temperatures were screened with Pd(OAc)2 and bispyridine (BPY)
as the catalyst (Table 1). When the reaction was conducted in

3
showed similar catalytic activity to BPY (entry 7), giving the
desired product in 77% yield with 7% ee. An enantioselective
version of this reaction appears challenging and new ligands are
likely required to induce enantioselectivity. The monodentate
ligand, pyridine, inhibits the reaction (entry 8). The results of
reactions catalyzed by different Pd(II) salts showed that
Pd(OAc)2 was the best Pd(II) source (entry 2 vs 9~14). Strongly
coordinating anions of Pd salts significantly decrease the
catalytic activity (entries 10~12), most likely due to that the BPY
ligand or substrate was inhibited from coordinating with the
palladium center.
an increase in steric bulk led to a reduction in product yields
(2i-m). The influence of protecting groups on the amide nitrogen
was also studied. Only the N-alkoxyl amides can be used as the
intramolecular nitrogen source (2a, 2l). Other protecting groups
such as tosyl, boc, and alkyl groups completely inhibited the
reactions and the starting materials were recovered intact (2m-o).
It should be disclosed that substrates bearing H or Ph as R’
yielded a mixture, which could not be separated in pure form.
Table 3. Substrate Scope.a,b
Table 2. Ligand and Pd Source Effects.a
Entry
1
L
Pd Source
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
PdCl2
Yield (%)
--
ND
84
2
BPY
3
4,4'-DM-BPY
4,4'-DMO-BPY
Phen
46
4
74
5
ND
47
6
o,o’-DM-Phen
iPr-Pyox
Py
7c
77
8
Trace
67
9
BPY
10
11
12
13
14
NR
NR
34
BPY
Pd(OH)2
a Reactions were carried out on a 2.0 mmol scale using 1.5 equiv of NFSI,
0.05 equiv of Pd(OAc)2 and 0.075 equiv of BPY in solvent (2 mL) in a sealed
tube under air atmosphere.
BPY
PdBr2
BPY
Pd(CH3CN)2Cl2
59
BPY
b NR = no reaction.
Pd(PPh3)2Cl2
49
BPY
a Reactions were carried out on a 2.0 mmol scale using 1.5 equiv of NFSI,
0.05 equiv of Pd(OAc)2 and 0.075 equiv of ligand in solvent (2 mL) in a
sealed tube under air atmosphere.
b NR = no reaction. ND = not detectable, a mixture of unidentified products.
c ee = 7%.
Scheme 2. Deprotection of N-methoxyl group.
Based on the above results, the optimal reaction conditions
leading to 2a were found to be when using Pd(OAc)2 as the Pd
source and BPY as the ligand, and performing the reaction in
THF at 80 oC. With the optimized reaction conditions identified,
a variety of substrates was examined for the Pd-catalyzed
diamination reaction (Table 3). It was found that substrates
bearing electron-withdrawing groups at the benzene ring could
give the corresponding isoindolinones 2 in good to excellent
yields (2b-e). The highest yield (90%) was obtained when a
fluoride group was present at the para position of the amide. In
contrast, the use of electron-donating groups led to a sharp
decrease in reactivity (2f-h), possibly due to the weaker
coordinating ability of the amide nitrogen with Pd(II). The steric
bulk of the substituent at the olefin noticeably affects the yield;
The OMe group could be removed by SmI2-promoted
reductive cleavage of the O-N bond in 89% yield (Scheme 2).

4
Tetrahedron
explain the experimental results. Investigations concerning the
biological activity of the obtained products are currently ongoing.
Acknowledgments
This work was partly supported by the National Nature
Science Foundation of China (Nos. 21302124, 21302127,
21232004), Shanghai Chenguang Project (No.14CG11), and
Science and Technology Commission of Shanghai Municipality
(Nos. 14XD1402300 and 15Z111220016). We thank the
Instrumental Analysis Center of SJTU.
Scheme 3. Reaction results with 1 equiv of NFSI.
References and notes
When only 1.0 equivalent of NFSI was used, the amounts of
byproducts increased (Scheme 3). Two major byproducts were
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4
produced by
hydroamination and isoquinolin-1(2H)-one 5 generated via an
aza-Wacker-type reaction.[12g] Based on this information, we have
proposed a mechanism for this reaction (Scheme 4). Substrate 1a
coordinates with the catalyst to form complex 6, which
undergoes aminopalladation to produce either the six-membered
intermediate 8 or the five-membered intermediate 7. Intermediate
8 can undergo sequential β-H elimination and reductive
elimination to give isoquinolin-1(2H)-one 5 and a Pd(0) species,
which can be oxidized to regenerate Pd(II) by the O2 oxidant or
NFSI. This may explain why a lower yield was obtained when
the catalytic reaction was carried out under a N2 atmosphere
compared to the equivalent reaction under an O2 or air
atmosphere. The intermediate 7 can be protonated by HX
(generated in other steps) to form product 4, or can be oxidized
by NFSI to generate a Pd(IV) species 9. The aminopalladation
steps should be reversible, so that using a smaller amount of
NFSI would lead to an increase in the yields of 5 and 4.
Reductive elimination of 9 produces the desired diamination
product 2a.
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Scheme 4. Proposed reaction mechanism.
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In summary, an efficient diamination of ortho-olefinic N-
methoxybenzamide with NFSI using a palladium catalyst was
developed, giving the amine-functionalized isoindolinones in
good yields. The reactions could be carried out under relatively
mild conditions, allowing for the synthesis of a variety of
isoindolinones. A plausible mechanism has been proposed to

5
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Supplementary Material
Supplementary data
associated
(experimental
and
characterization data. Copies of the H and 13C NMR spectra of
the products produced in this study) with this article can be
found, in the online version, at http://
1
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6
Tetrahedron
A Pd(II)-catalyzed olefin diamination was
developed using N-methoxyl amide as the
intramolecular nitrogen source.
The desired products were obtained in up to 90%
yield using NFSI as the oxidant.
This reaction provides an efficient and direct access
to isoindolinones with amine functionality, an
important drug skeleton.