Palladium-catalyzed cross-dehydrogenative coupling of maleimides with simple arenes: A fast track to highly substituted maleimides

Article abstract of DOI:10.1039/c6ra24420c

Pd-catalyzed cross-dehydrogenative coupling of N-substituted maleimides with simple arenes is explored. The protocol provides a versatile and atom-economic method for construction of a range of highly functionalized maleimides. The study unveils that a co

Full text of DOI:10.1039/c6ra24420c

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Palladium‐catalyzed cross‐dehydrogenative coupling of
maleimides with simple arenes: A fast track to highly substituted
maleimides
Received 00th January 20xx,
Accepted 00th January 20xx
Farnaz Jafarpour*a and Mitra Shamsianpoura
DOI: 10.1039/x0xx00000x
www.rsc.org/
Pd‐catalyzed cross‐dehydrogenative coupling of N‐substituted
maleimides with simple arenes is explored. The protocol provides a
versetile and atom‐economic method for construction of a range of
Previous works
Both coupling partners must be prefunctionalized
O
O
O
Ar
Br
Br
Br
highly functionalized maleimides. The study unveils that
combination of TFA/PivOH is critical for diarylation.
a
Pd2(dba)3, PA-Ph
Pd(PhCN)2Cl2
THF
R
N
R
N
N
R
Cs2CO3, THF
Br
Ar
O
O
+
+
O
Direct C‐H bond functionalization reactions in lieu of pre‐
functionalizations, have found extensive applications since this
strategy presents an atom‐economic way to construct complex
molecules from simple starting materials which increases the
overall efficiency of multistep synthetic sequences.1 Likewise,
palladium catalyzed cross‐dehydrogenative coupling reactions
have proven to be one of the most powerful methodologies in
modern organic chemistry.2 In this regard , much effort has
been made toward the palladium(II)‐catalyzed oxidative cross‐
coupling of arenes and olefin bonds. Although these studies
showcase the ability of palladium to perform direct arylations
with simple unactivated arenes, however, there are several
problems associated with direct arylation of disubstituted
olefinic bonds to construct tetrasubstituted olefins.3 The
difficulty of generating tetrasubstituted alkenes using Heck
coupling may be rationalized to steric congestion around double
bonds.
Bisaryl‐substituted maleimides have received significant
attention for two main reasons; (a) they belong to the group of
organic photochromic compounds with potential applications
for optoelectronic devices4 and (b) these compounds belong to
an important class of substrates found in several natural
products as well as pharmaceuticals with diverse biological
activities such as cancer therapy or inhibitory effect on the
growth of fungi and bacteria.5 With an array of interesting
properties, several research groups have aimed at construction
of these structural motifs. Aryl‐substituted maleimides are
Ar-B(OH)2
Ar3In
Pd(OAc)2, AgOAc
PivOH, TFA
This work
O
H
R
N
+
Ar
H
H
O
Neither coupling partners must be prefunctionalized
Scheme 1. Methods for bisarylation of maleimides
typically synthesized via multistep ring closing reactions.6 In
recent decade transition metal‐catalyzed methods for synthesis
of 3,4‐disubstituted maleimides have been developed by
several researches. However, in most synthetic approaches
functionalization of maleimides or the arene coupling partner is
a pre‐requisite, and the more synthetically viable preparation of
these privileged scaffolds via direct arylation of
unfunctionalized maleimides with arenes continues to be
problematic (Scheme 1).7
Based on these results and in a continuation of our efforts
aimed at the development of palladium‐catalyzed C‐H
functionalization reactions,8 herein we devise a new catalytic
system which allows for palladium‐catalyzed C‐H
functionalization of simple unactivated arenes followed by
cascade vicinal diarylation of the olefinic bond of maleimides.
The present study uncovers a straightforward derivatization at
3‐ and 4‐positions of the maleimide core for one‐pot
construction of highly substituted maleimides precluding
installment of any disposal functionalities.
To test the hypothesis, we focused on oxidative arylation of N‐
methylmaleimide using toluene (Table 1). We were pleased to
observe that the desired diarylated product was obtained
employing a catalytic system comprising Pd(OAc)2, K2S2O8 and
a. School of Chemistry, College of Science, University of Tehran, P.O. Box 14155‐
6619, Tehran, Iran. E‐mail: Jafarpur@khayam.ut.ac.ir
Electronic Supplementary Information (ESI) available: [Characterization data,
experimental procedures and copies of spectra]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 1
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Table 1. Screening of the reaction conditionsa
Table 2. Scope of diarylation of N‐substituted maleimidesa
OCH3
H3CO
CH3
Me
H3C
Entry [Pd]
L
[O]
K2S2O8
K2S2O8
Cu(OAc)2 TFA /PivOH
TBP
BP
Ag2CO3
Ag2O
AgNO3
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
Solvent
TFA
TFA /PivOH
Yield (%)
O
O
O
1
2
3
4
5
6
7
8
9
Pd(OAc)2
10
43
38
trace
16
50
52
0
54
trace
35
50
0
N
CH3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
N
CH3
N
CH3
O
O
O
TFA /PivOH
TFA /PivOH
TFA /PivOH
TFA /PivOH
TFA /PivOH
TFA /PivOH
PivOH
, 54%
, 63%
3b
3a
H3CO
H3C
, 66%
3c
Me
F
H3C
OCH3
CH3
CH3
O
N
O
O
N
O
O
N
O
CH3
CH3
10 Pd(OAc)2
11 Pd(OAc)2
12 Pd(TFA)2
13 PdCl2
14 Pd(dba)2
15 Pd(acac)2
16 Pd(OAc)2
17 Pd(OAc)2
, 78%
3f
H3C
F
, 21%
3d
, 51%
3e
TFA
CH3
CH3
CH3
TFA /PivOH
TFA /PivOH
TFA /PivOH
TFA /PivOH
TFA /PivOH
TFA /PivOH
H3C
H3C
H3C
O
N
O
O
N
O
O
N
O
0
40
52
50
Phen
PPh3
H3C
, 56%
3h
, 52%
3g
H3C
H3C
,42%
3i
CH3
CH3
O2N
OCH3
aReaction conditions: N‐Methylmaleimide 1a (0.1 mmol), toluene 2a (4 mmol),
catalyst (20 mol%), oxidant (0.3 mmol), ligand (20 mol%), TFA (1 mmol), PivOH (0.6
mmol), 110 °C, 24 h.
H3CO
O
N
O
O
N
O
O
N
O
CH3
H3CO
O2N
, 0%
3l
, 40% (45%)b
3j
3k
, 72%
TFA, albeit in a 10% yield (entry 1). To our delight a combination
of TFA/PivOH built up the yield fundamentally to 43% (entry 2).
An oxidant screen revealed silver salts as the best choice of
oxidants (entries 3‐9). Accordingly, various silver salts were
tested and the best result was obtained with AgOAC where, the
desired product was gained in a 54% isolated yield (entries 6‐9).
In the absence of Ag salts however, the reactions did not
proceed. Furthermore, the results showed that the presence of
trifluoroacetic acid is essential to conduct the arylation process
(entries 10‐11). Among the Pd(II) catalysts tested, Pd(OAc)2
turned out to be the best, while no product could be detected
in the presence of PdCl2 and Pd(dba)2 (entries 12‐15). Ligands,
such as phen, pph3, py or bpy, led to the comparable or lower
yields of the arylated maleimide (16‐17). The best result was
obtained from the reaction of maleimide 1a (0.1 mmol) with
toluene 2a (4 mmol) using Pd(OAc)2 (20 mol %) and AgOAc (3
equiv) in PivOH/TFA at 110 °C for 24 h.
OCH3
aAll reactions were run under the optimized reaction conditions. bThe yield of the
reaction with bromobenzene as the coupling partner is given in parentheses.
Having identified the optimized conditions, we next
investigated the scope of the proposed cross‐dehydrogenative
diarylation approach using various electron‐rich and –deficient
arenes (Table 2). We were pleased to find that a range of alkyl,
alkoxy, aryl and halo substituted arenes smoothly underwent
the diarylation process to give the desired multifunctionalized
imides in moderate to good yields. To our delight, the catalytic
system was also very effective toward construction of bis(3,4‐
dimethoxyphenyl)maleimide 3c, the key structural motif in
permethyl ningalin B analogue which exhibits promising P‐
glycoprotein (P‐gp)‐modulating activity in Pgp‐over‐expressing
breast cancer cell lines without causing any cytotoxicity toward
normal cells (Scheme 2).9 Fluorobenzene was also tolerated in
this reaction, leaving behind a good precursor for further
functionalizations, albeit in low yield (3d). With bromobenzene
however, bromide was engaged in the reaction course and
replaced with imide unit to afford 3,4‐diphenylmaleimide 3j as
the sole product. Interestingly, employing biphenyl as coupling
partner, gave rise to highly π–extended maleimide 3e which is
proved to exhibit red‐shifted photoluminescence bands.10
Scheme 2. P‐glycoprotein inhibitor of permethyl ningalin B analogue.
2 | J. Name., 2012, 00, 1‐3
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OCH3
OCH3
O
Ar
Ar
O
O
H
O
OCH3
Pd(OAc)2, AgOAc
N
CH3
N
N
CH3
CH3
PivOH, TFA
110 C, 24 h
O
N
R
Pd(OAc)2
TFA
H
H
3
O
O
O
Ar
Ar
[Ag]
3n, 33%
3m, 37%
OCH3
OCH3
Pd(0)
CH3
H
(F3COCO)Pd
O
H3C
Pd(OCOCF3)2
OCH3
H
O
O
O
O
N
R
H3C
CH3
OCH3
H
H
Pd(OCOCF3)
Pd(OAc)2, AgOAc
PivOH, TFA
Ar
N
N
CH3
N
CH3
Pd(OCOCF3)
H
110 C, 24 h
Ar
O
Ar
O
O
O
O
H
3o, 41%
3p, 39%
H3C
OCH3
O
N
Ar
Scheme 3. Coupling of N‐methylmaleimide with anisole and 2‐methylanisole.
O
N
R
Pd(OCOCF3)
H
R
H
O
Furthermore, maleimides possessing N‐aryl and ‐benzyl
protecting groups also served as good coupling partners in this
CDC reaction to afford diaryl maleimides in good to high yields
O
N
R
Scheme 5. Proposed reaction mechanism.
(3f‐3k). Cumene also led to relate adduct 3i, albeit in moderate
yield. Unfortunately, no product was detected for the coupling
reaction of highly electron‐deficient arene and maleimide (3l).
It should be mentioned that the treatment of N‐
methylmaleimide with methoxy substituted arenes, anisole and
2‐methylanisole, provided a mixture of mono‐ and diaryl
maleimides (Scheme 3). Possibly, introducing highly electron
rich substituents on the olefinic bond, decreases its reactivity
for the next arylation reaction and a mixture of products gains.
Further investigations on the aforementioned reaction revealed
that replacing palladium(II) acetate with palladium(II)
trifluoroacetate in the absence of pivalic acid resulted the
monoarylation of N‐methyl maleimide core where no diarylated
product could be detected (Scheme 4).
Conclusions
In conclusion, we have developed a concise and efficient
palladium‐catalyzed method for direct diarylation of N‐
alkyl(aryl) maleimides in one step with simple unactivated
arenes. It is the first report on significant waste free arylation of
maleimides with diverse biological as well as photophysical
activities. Furthermore, in the present approach direct
diarylation of olefinic bond to construct a tetrasubstituted
alkene through a CDC reaction which is rarely precedented is
flourished.
The proposed mechanism for the CDC coupling involves a
Pd(II)/Pd(0) catalytic cycle (Scheme 5). The first step comprises
insertion of metal into the unactivated C‐H bond through two
Acknowledgements
most commonly invoked mechanisms: electrophilic addition or We acknowledge the financial support from the University of
oxidative insertion. Next olefin insertion is followed by β‐ Tehran.
hydride elimination to afford the monoarylated adduct which in
turn, inserts to the aryl palladium species. A second β‐hydride
Notes and References
elimination and reductive elimination/deprotonation generates
diaryl maleimide and palladium (0) catalyst which on oxidation
regenerates Pd(II) to render the C–H bond functionalization
catalytic. For an evidence for conversion of monoaryl adducts
to diaryl ones in the course of the reaction, samples of the
reaction mixture of the oxidative Heck coupling of maleimide
and toluene were taken after 6 and 12 h of the reaction progress
and mono/diarylmaleimide ratios of 3.3 and 1.1 were obtained,
respectively.
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Scheme 4. Monoarylation of N‐methyl maleimide via oxidative cross‐coupling reaction.
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Palladium-catalyzed cross-dehydrogenative coupling of maleimides
with simple arenes: A fast track to highly substituted maleimides
Farnaz Jafarpour and Mitra Shamsianpour
A combination of PivOH/TFA, accelerates an unprecedented palladium-catalyzed CDC diarylation of
unfunctionalized maleimides with simple arenes.