C-H Activation under the Guise of Diels-Alder Reaction: Annulation toward the Synthesis of Benzo[e]isoindole-1,3-diones

Article abstract of DOI:10.1021/acs.orglett.6b03757

A new paradigm in the coupling of external alkenes with internal electron-deficient alkenes has been investigated in which an unprecedented annulation of vinylarenes on maleimides takes place. The reaction is carried out via a tandem in situ activation of both olefinic and aromatic C-H bonds of styrenes driving the reaction in a pseudo-Diels-Alder mode.

Full text of DOI:10.1021/acs.orglett.6b03757

Letter
pubs.acs.org/OrgLett
C−H Activation under the Guise of Diels−Alder Reaction: Annulation
toward the Synthesis of Benzo[e]isoindole-1,3-diones
,†
†
‡
Mehdi Sheykhan,* Maryam Shafiee-Pour, and Masoumeh Abbasnia
†
Chemistry Department, University of Guilan, P.O. Box 41335-1914, Rasht, Iran
‡
School of Chemistry, College of Science, University of Tehran, P.O. Box 14155-6455, Tehran, Iran
S Supporting Information
*
ABSTRACT: A new paradigm in the coupling of external alkenes with
internal electron-deficient alkenes has been investigated in which an
unprecedented annulation of vinylarenes on maleimides takes place. The
reaction is carried out via a tandem in situ activation of both olefinic and
aromatic C−H bonds of styrenes driving the reaction in a pseudo-Diels−
Alder mode.
7
e
π-Extended polycyclic compounds due to their salient proper-
ties are indispensable scaffolds which have been widely used
both in industry and academia. Regarding their growing
enamides with maleimides. However, the first report to
couple maleimides with simple straight-chain olefins via a Pd-
catalyzed reaction was released by White in which these entities
1
7f
applications, long-standing interest has been aroused for their
could engage in a cycloaddition reaction. Despite all of their
benefits, previous procedures unanimously demonstrated the
preparation of functionalized succinimides, and to date, all
endeavors to preserve the double bond of maleimide through
its reaction with olefins have been in vain. To retrieve the
double bond of maleimide, Stahl devised a protocol by which
one could oxidize the cyclohexyl moiety installed on N-
2
construction. In past decades, most efforts directed toward
their synthesis comprised metal-catalyzed annulation of interna3l
alkynes, which are a good deal more active than alkenes.
However, to the best of our knowledge, vinylarenes have been
obscure in this field. Previously, a few Pd-catalyzed reactions
emerged in which external alkenes were exploited as annulating
4
8
reagents. Nevertheless, the aforementioned reports, for the
substituted maleimides to its arene counterpart. Nonetheless,
most part, were concerned with the involvement of only
olefinic C−H bonds of vinylarenes. In our study, we managed
to activate an aromatic C−H bond with a higher energy barrier
together with an olefinic C−H bond. This startling discovery
was achieved via an unexpected Pd-catalyzed C−H activation
reaction of styrene with maleimide. Maleimides are among
even this catalytic system fails for NH maleimides. Herein, we
describe a method in which hydrofunctionalization, in contrast
to the former work, did not occur but rather the maleimide core
survived. This approach also provides a way by which one can
preclude a stepwise reaction to make an aromatic ring on
maleimides.
5
motifs that have been extensively used in ongoing research, yet
Initially, we commenced reacting maleimide with styrene
with the aim of olefinating maleimide. Much to our surprise,
the reaction proceeded further, and an unprecedented
annulation occurred. Benzo[e]isoindole-1,3-diones, formed
through this strategy, are efficient GSK-3β inhibitors that
have been considered a powerful remedial pathway for
study of their reaction with vinylarenes has lagged behind. The
major reason behind this scarcity might lie in the ease in the
polymerization of both maleimides and styrenes which renders
6
their reaction extremely arduous.
Nevertheless, some compounds showed promise for hydro-
functionalization of maleimide through the reaction with
9
a−c
9d−f
7
treatment of diabetes,
Alzheimer’s disease,
Down’s
alkenes. In this context, Kiyooka took the first step in this
9
g
9h
9i,j
syndrome, bipolar disorder, and colorectal cancer.
Compared to traditional pathways to reach benzo[e]-
isoindole-1,3-diones, which suffered from tedious several-step
direction and coupled styrene with N-benzylmaleimide with the
7
a
aid of Ir. Another example was disclosed by Kim et al., who
7b
reacted maleimides with acrylamides using Rh as the catalyst.
10
synthetic procedures and very low yields (overall yield <7%),
Rh-catalyzed reaction of maleimides with enol carbamates has
7c
our procedure is operationally simple, single step, and catalytic
and provides high yields.
been also reported. Taking the lead from prior work, Miura
reported cross-coupling of maleimides with external alkenes
7d
bearing electron-deficient groups via a Ru-catalyzed reaction.
Very recently, Zhang showed that cobalt was as effective as its
Received: December 16, 2016
counterparts having the aptitude to catalyze coupling of
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03757
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
To start with, styrene 1a was treated with N-methylmalei-
mide 2a with 10 mol % of Pd(OAc) and 1 equiv of Cu(OAc) ·
Scheme 1. Scope of the Reaction
2
2
H O as the oxidant in EtOAc to furnish the desired product 3a
2
in 21% yield (Table 1, entry 1). Switching from EtOAc to DMF
Table 1. Screening Reaction Conditions in the Synthesis of
a
Benzo[e]isoindole-1,3-diones 3
entry
oxidant
solvent
additive
yield (%)
1
2
3
4
5
6
Cu(OAc) ·H O
EtOAc
DMF
21
53
2
2
Cu(OAc) ·H O
2
2
Cu(OAc) ·H O
DMSO
40
2
2
Cu(OAc) ·H O
H O
2
trace
45
2
2
Cu(OAc) ·H O
xylene
2
2
Cu(OAc) ·H O
CH CN
58
2
2
3
b
7
Cu(OAc) ·H O
CH CN
trace
51
2
2
3
8
9
Cu(NO ) ·2.5H O
CH CN
3
2
2
3
CuCl2
CuCl
CuCl
AgOAc
TBHP
DTBP
BP
CH CN
18
3
10
11
12
13
14
15
16
17
18
19
20
21
22
CH CN
70
3
c
CH CN
NR
68
3
CH CN
3
CH CN
N.R.
16
3
CH CN
3
CH CN
trace
trace
N.D.
77
3
K S O
CH CN
2
2
8
3
d
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CH CN
K CO
3
3
2
e
CH CN
AcOH
AcOH
AcOH
AcOH
AcOH
3
f
CH CN
75
3
g
h
i
CH CN
trace
14
3
a
CH CN
All reactions were run under the following conditions: styrene 1 (0.3
3
mmol, 3.0 equiv), maleimide 2 (0.1 mmol), Pd(OAc) (10 mol %),
CH CN
78
2
3
a
CuCl (1.0 equiv), and acetic acid (0.1 mL) in 0.5 mL of CH CN were
3
b
Reactions were performed using styrene (0.3 mmol), N-metheylma-
leimide (0.1 mmol), Pd(OAc) (10 mol %), and oxidant (1 equiv) in
heated at 100 °C for 6 h. Maleic anhydride (3 mmol, 10 equiv) was
2
b
c
used.
0
.5 mL of solvent. 10 mol % of oxidant was used. Absence of
d e f g
Pd(OAc) . 1 equiv. 0.1 mL of acid was used. Under O balloon. 0.1
mmol of styrene. Reaction proceeded at 70 °C. The reaction was run
2
2
h
i
shown in Scheme 1, styrenes containing a neutral methyl group
served well under the reaction conditions (3b). Also, when α-
substituted styrenes underwent the reaction, high yields were
obtained (3c,d). Electron-rich p-methoxystyrene also afforded
the corresponding product 3e in 75% yield. Furthermore,
halogen groups were well tolerated in this reaction, preparing
the ground work for later functionalization (3f,g). Unfortu-
nately, the reaction failed for styrene bearing nitro group (3h).
It is noteworthy that this reaction was not limited to N-
protected meleimides but could also be extended to a free NH
maleimide (3i−k). N-Substituted maleimides also reacted
successfully under the reaction conditions to give effective
access to products 3l−n.
for 6 h.
increased the yield to 53% (entry 2). Further survey of solvents
indicated that CH CN should be the solvent of choice (entries
3
3
−6). Upon decreasing the oxidant loading to 10%, the yield
diminished sharply (entry 7). Also, among different copper
salts, CuCl seemed to be the most effective oxidant (entries 8−
1
0). In the next step, control experiments showed that
Pd(OAc) was crucial for the viability of our reaction (entry
2
11). Moreover, utility of other oxidants in place of CuCl led to
a drop in the yield (entries 12−16). Conducting the reaction in
the presence of a base completely suppressed the reaction,
whereas using HOAc improved the yield to 77% (entries 17
We then turned our attention to the reaction of maleic
anhydride with styrene. Gratifyingly, keeping with our trend
when maleic anhydride was used in lieu of maleimides, the
anhydride segment remained intact despite its tendency to be
and 18). Using O as the atmosphere of the reaction instead of
2
air had a negligible effect on the yield (entry 19). Eventually,
lowering the amount of styrene and the reaction temperature
both resulted in lower yields (entries 20 and 21). In contrast,
when the reaction time was decreased to 6 h, approximately the
same yield was attained (entry 22).
Having found the optimal conditions, we then moved on to
investigate the scope of the reaction (Scheme 1). To this end,
different styrenes were exposed to the reaction conditions. As is
11
cleaved under Pd catalyst, and instead, its double bond took
part in the reaction and culminated in derivatives 3o−q.
Naphtho[1,2-c]furan-1,3-dione derivatives are privileged struc-
tures due to their utility in the frameworks of numerous
1
2a−g
pharmaceuticals.
They also benefited from luminescence
1
2h
properties, which allow them to be vastly used in industry.
B
DOI: 10.1021/acs.orglett.6b03757
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Earlier, most of these products have been prepared from
Scheme 3. Plausible Mechanism
13
brominated styrenes. It is also noteworthy that although
compound 3o is commercially available (available from Sigma-
Aldrich, product ID T153397), it is highly expensive. Bear in
mind that this reaction was previously conducted through a
Diels−Alder mode; nonetheless, the aromatization product was
only achievable at exceedingly high temperatures such as 220
1
4
°
C. This approach allows one to use an economical route to
achieve naphtho[1,2-c]furan-1,3-dione and its derivatives. This
promising result would also set the scene for further
manipulation of the molecule to reach more complex all-
carbon skeletons through a Pd-catalyzed reaction or naph-
thoisocoumarins via Ni-, Ru-, or Rh-catalyzed reaction with
1
5
internal alkynes.
Keeping in mind the aptitude of styrene in undergoing a
Diels−Alder reaction, as a first step we set out to corroborate
whether the reaction proceeded through a C−H activation or a
Diels−Alder mechanism. After precise scrutiny, it was found
that the presence of both Pd, which was needed to promote C−
H activation, and the copper salt, which played the role of an
oxidant, was vital to render the reaction feasible (Scheme 1).
In addition, when the reaction was exposed to Diels−Alder
Scheme 4. Annulation of Styrene on Maleic Acid
Accompanied by a Spontaneous Condensation
conditions, i.e., AlCl (1 equiv) in refluxing 1,2,4-trichlor-
3
1
6
obenzene (TCB), no product was observed even after a
prolonged time at as temperatures as high as 180 °C (Scheme
2). As further evidence of this, when 1,4-benzoquinone and 1,4-
Scheme 2. Control Experiments
bonds in the reaction of maleimides/maleic anhydride with
styrenes in a single step. This convenient strategy could also be
applied to maleic acid, rendering the reaction intriguing by
spanning the reaction conditions for another partner in place of
its anhydride peers.
ASSOCIATED CONTENT
Supporting Information
■
*
S
naphthoquinone were subjected to the standard reaction
conditions, no such an annulation occurred, verifying that the
reaction proceeded through a mechanism that was perhaps a
Diels−Alder reaction. Despite all investigations, we could not
certainly rule out the probability of a Diels−Alder reaction. For
further exploration in the mechanism, see the Supporting
Information.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03757.
Experimental details, characterization data of all com-
1
13
pounds, and H and CNMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
On the basis of the experimental data and precedents, a
putative mechanism is depicted in Scheme 3. We envisaged that
■
Pd(OAc) was first added to the olefin to produce intermediate
2
*E-mail: sheykhan@guilan.ac.ir. Fax: +981333367262.
ORCID
1
. The following extrusion of AcOH would furnish an alkenyl-
17
Pd-OAc intermediate 2 whose carbopalladation with
maleimide resulted in intermediate 3. The catalytic cycle was
not intercepted at this stage through a β-hydride eliminaton;
Mehdi Sheykhan: 0000-0002-1438-7643
Notes
18
instead, a migratory insertion of Pd into the adjacent aryl ring
occurred, which led to the cycloadduct 4. Eventually, a β-
hydride elimination and the subsequent oxidative aromatization
gave rise to the formation of thus-formed product.
Finally, we are pleased to report our achievement involving a
dicarboxylic acid as the second partner. When maleic anhydride
was supplanted by maleic acid, a cyclization together with the
dehydration occurred to afford 3o in a moderate yield (Scheme
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the research council of the University of
Guilan for the financial support of this work.
■
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DOI: 10.1021/acs.orglett.6b03757
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Org. Lett. XXXX, XXX, XXX−XXX