Palladium-catalyzed insertion of N-tosylhydrazones for the synthesis of isoindolines

Article abstract of DOI:10.1039/c3cc40577j

Isoindolines are synthesized by palladium-catalyzed coupling reaction of N-(2-iodobenzyl) anilines with α,β-unsaturated N-tosylhydrazones. The reaction has several potential advantages: (1) toleration of a wide range of functional groups, (2) easy to handle and with mild conditions, (3) enriches the isoindoline family, (4) two new bonds form in one step.

Full text of DOI:10.1039/c3cc40577j

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Palladium-catalyzed insertion of N-tosylhydrazones for
the synthesis of isoindolines†
Ping-Xin Zhou,a Jian-Yi Luo,a Lian-Biao Zhao,b Yu-Ying Yea and Yong-Min Liang*a
Cite this: Chem. Commun., 2013,
49, 3254
Received 23rd January 2013,
Accepted 27th February 2013
DOI: 10.1039/c3cc40577j
www.rsc.org/chemcomm
Isoindolines are synthesized by palladium-catalyzed coupling reaction For example, migration of vinyl groups could generate Z3-allyl-
of N-(2-iodobenzyl) anilines with a,b-unsaturated N-tosylhydrazones. palladium intermediates that can be trapped with nucleophiles
The reaction has several potential advantages: (1) toleration of a such as secondary amines and sodium diethylmalonate.7
wide range of functional groups, (2) easy to handle and with mild Previously, we verified that Z3-allylpalladium intermediates
conditions, (3) enriches the isoindoline family, (4) two new bonds can also be formed from palladium-catalyzed dediazotization
form in one step.
of the arylvinyldiazoacetate, which is then attacked by amines.8 As
we all know, N-tosylhydrazones could decompose to give unstabi-
Isoindolines and their derivatives display a variety of biological lized diazo substrates in the Bamford–Stevens reaction, which
activities and interesting chemical properties. For instance, expanded the scope of palladium-catalyzed coupling reaction
the isoindoline structure is present in molecules which act of diazo compounds.9 In this work we report a related coupling
as modulators of estrogen, inhibitors of selective serotonin using a,b-unsaturated N-tosylhydrazones and N-(2-iodobenzyl)
reuptake, spin probes for studying cancer, antitumor, herbicidal, anilines to construct isoindoline derivatives.
anti-inflammatory and anesthetic agents.1 Moreover, they play
We hypothesize that the reaction starts with oxidative addition of
an important role in cycloaddition reactions and organic light- palladium to the N-(2-iodobenzyl) anilines to afford intermediate A
emitting diodes.2 Therefore, the study of these compounds (as shown in Scheme 1), which can dediazotize the diazo compound
continues to be an area of great interest in organic chemistry. B (generated in situ from N-tosylhydrazone) to afford a palladium
A variety of synthetic procedures have been reported, however, carbene complex C. Then, migratory insertion of the aryl group into
these methods usually suffer from long reaction time, high the palladium carbene at the carbonic carbon atom leads to the
temperature, expensive catalysts or high catalyst loadings.3 In Z1-allylpalladium complex D, which can isomerize to the
addition, the protecting groups on the nitrogen of the products Z3-allylpalladium E. The intermediate E species is then trapped
of these methods are often Cbz, Boc, Ts,4 or the products can’t
allow for incorporation of aromatic moieties on the isoindoline
ring,5 which limits the versatility of the isoindoline. Hence,
development of new, efficient and straightforward methods for
the preparation of diverse isoindolines is highly desirable.
Palladium-catalyzed insertion of diazo compounds has been
shown to be a powerful method for the C–C bond-forming reaction,
which is analogous to insertion of a CO. Migratory insertion of Pd
carbene species is considered to be the key step for these cross-
coupling reactions. A series of palladium-catalyzed reactions involving
benzyl, vinyl, aryl and acyl group migratory insertion have
been reported by Van Vranken, Barluenga and Wang et al.6–9
a State Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, China. E-mail: liangym@lzu.edu.cn; Fax: +86-931-8912582
b College of Chemical Engineering, Northwest University for Nationalities,
Lanzhou 730030, China
† Electronic supplementary information (ESI) available: Experimental procedures
and analysis data for new compounds. CCDC 918081 (3l). For ESI and crystal-
lographic data in CIF or other electronic format see DOI: 10.1039/c3cc40577j
Scheme 1 Plausible catalytic cycle.
c
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Table 1 Optimization of conditions for the palladium-catalyzed reaction of 1a
and 2aa
Entry
Equiv. of 2a
Base
Solvent
Yieldb
1
2
3
4
5
6
7
8
1.75
2.00
2.25
2.50
2.25
2.25
2.25
2.25
2.25
2.25
2.25
2.25
2.25
2.25
t-BuOLi (4.75 equiv.)
t-BuOLi (5.00 equiv.)
t-BuOLi (5.25 equiv.)
t-BuOLi (5.50 equiv.)
t-BuOLi (5.25 equiv.)
t-BuOLi (5.25 equiv.)
t-BuOLi (5.25 equiv.)
t-BuOLi (5.25 equiv.)
t-BuOLi (5.25 equiv.)
K2CO3 (5.25 equiv.)
Cs2CO3 (5.25 equiv.)
t-BuOK (5.25 equiv.)
t-BuONa (5.25 equiv.)
t-BuOLi (5.25 equiv.)
THF
THF
THF
THF
THF
DCE
MeCN
Dioxane
Toluene
THF
THF
THF
THF
THF
72
77
88
88
25c
76
52
85
45
86
82
0
9
10
11
12
13
14
0
0d
a
Reaction conditions: 1a (0.3 mmol), Pd2(dba)3ÁCHCl3 (2.5 mmol%),
b
PPh3 (15 mmol%), solvent (4 ml). Yield of the isolated product.
c
d
1.0 equiv. of BTAC used as an additive. Without palladium catalysis.
with an amine nucleophile and the Pd(0) catalyst is regenerated
with the aid of base.10
Initially, we studied the cross-coupling reaction by employing
N-(2-iodobenzyl)-3,4-dimethylaniline 1a and N-tosylhydrazone 2a
with Pd2(dba)3ÁCHCl3/PPh3 as a catalyst and t-BuOLi as base in
THF at 60 1C (Table 1, entry 1). To our delight, the desired coupling
product was isolated in 72% yield. Increasing the amount of
lithium tert-butoxide and N-tosylhydrazone relative to 1a led to
improvement in the yield (Table 1, entries 2 and 3). Using
2.25 equiv. of 2a gave a good yield but when the amount of 2a
was increased to 2.50 equiv., the yield of 3a did not increase further
(Table 1, entry 4). Then 1.0 equiv. of BTAC was used as an additive
to enhance the solubility of the lithiated sulfonylhydrazone, but led
to a diminished yield (Table 1, entry 5). Next, several other solvents,
such as DCE, MeCN, dioxane and toluene, were examined, how-
ever, they were all less efficient than THF (Table 1, entries 6–9).
Additionally, it was found that the yield could not be further
improved by employing different bases (Table 1, entries 10–13).
Various palladium catalysts including Pd(II) and Pd(0) were
screened. From the results, Pd(OAc)2 afforded good yield and
PdCl2(MeCN)2 was isolated in low yield. As for Pd(0), both Pd2(dba)3
and Pd(PPh3)4 worked efficiently for this reaction. It is worth noting
that the ligand PPh3 was essential for this reaction. Only a trace
amount of product was detected when XPhos was employed as a
ligand, and no reaction occurred in the absence of PPh3 (for details,
see the ESI†). Finally, the reaction could not proceed without
palladium catalysis (Table 1, entry 14).
Scheme 2 Palladium-catalyzed cross-coupling of N-(2-iodobenzyl) aniline deriva-
tives with N-tosylhydrazones. Reaction conditions: 1 (0.3 mmol), 2 (0.675 mmol,
2.25 equiv.), t-BuOLi (1.575 mmol, 5.25 equiv.), THF (4 ml), Pd2(dba)3ÁCHCl3
(2.5 mmol%), PPh3 (15 mmol%), 60 1C, 4.5–5.5 h. Yield of the isolated product.
amine (Scheme 2, 3f). In the case of R1, both electron-donating
and electron-withdrawing groups were well suited on the aromatic
ring (Scheme 2, 3g–k and 3s), except 3q, which contains an ortho-
substituent. Notably, the halogen substituents are tolerated
under the Pd-catalyzed conditions (Scheme 2, 3g–i), which allows
further transition-metal-catalyzed coupling reaction. As for the
N-tosylhydrazones, a series of substituents and functional groups,
including phenyl, heterocycle and ortho-substituted N-tosylhydra-
zones, could react smoothly with N-(2-iodobenzyl)-3,4-dimethyl-
aniline 1a to afford the corresponding isoindolines in moderate to
good yields (Scheme 2, 3l–p, 3r and 3t). The structure of 3l was
further established by X-ray diffraction.
With the optimal conditions in hand, we examined the scope
of this reaction with respect to the amine. The yield of isoindoline
was dramatically affected by the nucleophilicity of the amine.
Electron-donating groups led to moderate to good yields
(Scheme 2, 3a–d); however, the electron-withdrawing group gave
a lower yield, which may be due to less nucleophilicity of the
Scheme 3 Palladium-catalyzed cross-coupling of 1a with non-aromatic N-tosyl-
hydrazones. a2.0 equiv. of NEt3 was used as co-base, t-BuOLi was decreased to
3.25 equiv.
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S.-T. Lee, Chem. Mater., 2003, 15, 3148; (d) Z. Chen, P. Mu¨ller and
To further expand the scope of the reaction, we investigated
non-aromatic a,b-unsaturated N-tosylhydrazones (Scheme 3).
To our disappointment, when the H-substituted N-tosylhydra-
zones were used as substrates under the standard conditions,
the desired product was obtained in poor yield. In pioneering
studies, Van Vranken and co-workers demonstrated that
triethylamine used as co-base in palladium-catalyzed reaction
of diazo compounds proved useful for carbenylative amina-
tions. Indeed, when 2.0 equiv. of NEt3 was added, it resulted
in 53% yield. While as for methyl-substituted a,b-unsaturated
N-tosylhydrazones a similar yield was afforded both in the
presence and absence of Et3N.
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In summary, we have reported a new, efficient and straight-
forward method for the synthesis of isoindolines by palladium-
catalyzed coupling reaction of N-(2-iodobenzyl) anilines with
tosylhydrazones derived from a,b-unsaturated aldehydes. The
reaction has several potential advantages: (1) a wide range of
functional groups are tolerated and the yields are moderate to
good. (2) The reaction is easy to handle and the conditions are
mild. (3) By changing the substituent on the protecting groups
of the nitrogen and aromatic moieties on the isoindoline ring, a
series of products with diverse substituents were synthesized,
which enriched the isoindoline family. (4) Two new bonds are
formed in a one-step reaction. Future work on three-component
coupling reaction involving aryl halide, amine and vinyl hydra-
zone is in progress and will be reported in due course.
We thank the National Science Foundation (NSF 21072080
and 21272101) and National Basic Research Program of China
(973 Program) 2010CB833203 and ‘‘111’’ program of MOE and
PCSIRT: IRT1138 for financial support. Lian-Biao Zhao thanks
the Natural Science Foundation of Gansu (No. 096RJZA006)
PRC for supporting this study.
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