Efficient and general protocol for Sonogashira cross-coupling reactions of maleimides

Article abstract of DOI:10.1002/ejoc.201101811

Maleimides are involved for the first time in Sonogashira cross-coupling reactions. Sonogashira conditions have been developed to allow subsequent coupling of various terminal alkynes at room temperature in moderate to excellent yields. These results open

Full text of DOI:10.1002/ejoc.201101811

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201101811
Efficient and General Protocol for Sonogashira Cross-Coupling
Reactions of Maleimides
Agathe Souffrin,[a] Cécile Croix,[a] and Marie-Claude Viaud-Massuard*[a]
Keywords: Cross-coupling / Alkynes / Substituent effects / Synthetic methods
Maleimides are involved for the first time in Sonogashira
cross-coupling reactions. Sonogashira conditions have been
developed to allow subsequent coupling of various terminal
alkynes at room temperature in moderate to excellent yields.
These results open the way to innovative synthesis strategies
for various difunctionalized maleimide derivatives.
a palladium-catalyzed polyannulation reaction from an ap-
propriate diacetylenic moiety and 3,4-dibromomaleimide
precursors[7] or an iron-catalyzed double aminocarb-
onylation of an internal alkyne, followed by dehydrogena-
tion with DDQ.[8]
Introduction
Maleimides are important building blocks in organic
synthesis. They constitute a class of derivatives of the par-
ent maleimide where the NH group is replaced with alkyl
or aryl groups. They are an important family of natural and
synthetic products with valuable pharmacological proper-
ties. Currently, indolocarbazole alkaloids and biosyntheti-
cally related 3,4-bisindolylmaleimides are the maleimides
that have been described in greatest detail due to their phar-
maceutical interest (anticancer, antibacterial, antiviral, anti-
microbial, and antigenic activities).[1] Among these com-
pounds, Rebeccamycin, a well-known topoisomerase I in-
hibitor, exhibits antitumor activity against P388 leukemia,
L1210 leukemia, and B16 melanoma implanted in mice,
and it inhibits the growth of human lung adenocarcinoma
cells (A549).[2] Besides their pharmaceutical importance,
3,4-disubstituted maleimides have also found application in
materials science as components of red light-emitting di-
odes (LEDs) because of their intense color.[3] They have
also been used in the development of photocatalysts immo-
bilized on surfaces.[4]
Palladium-catalyzed cross-coupling reactions provide a
powerful method for forming carbon–carbon bonds in or-
ganic synthesis.[9] Despite the progress achieved in this area,
some limitations still exist for maleimides, especially in the
case of Sonogashira cross-coupling reactions. To the best of
our knowledge, no Sonogashira reactions have been re-
ported for dibromomaleimides. Because of the impressive
impact of Sonogashira coupling on modern organic chemis-
try,[10] we decided to explore for the first time this palla-
dium-catalyzed coupling with maleimide derivatives.
Furthermore, Sonogashira coupling opens the way to an
innovative approach to the synthesis of various disubsti-
tuted maleimides. We developed Sonogashira reaction con-
ditions for the maleimide scaffold and subsequent couplings
with various terminal alkynes.
Due to their attractive properties, several research groups
have synthesized difunctionalized maleimides. One of the
most widely used synthetic approaches involves con-
structing the central maleimide core by condensing substi-
tuted arylacetamides with arylglyoxalates esters in the pres-
ence of a strong base.[5] Disubstituted maleimides are also
prepared from an appropriate heteroaryl moiety and 3,4-
dihalogenomaleimide precursors by using Grignard or lithi-
ated reagents or palladium-catalyzed cross-coupling reac-
tions (Suzuki, Stille, Heck, Negishi).[6] Other methods use
Results and Discussion
Typical Sonogashira conditions involve the use of
PdCl2(PPh3)2 or Pd(PPh3)4 as a catalyst, CuI as a cocata-
lyst, and an excess amount of base is also used as solvent.
Often, an excess amount of the terminal alkyne is needed
to obtain the final products in good yields, especially with
electron-deficient halogenated substrates. Maleimides are
sensitive to bases, and so our starting point for this study
was to investigate the influence of various bases on Sonoga-
shira cross-coupling reactions with maleimides.[11] The most
widely used bases in Sonogashira couplings are amines [di-
isopropylethylamine (DIPEA), diisopropylamine (DIPA),
propylamine (PA), triethylamine (TEA), diethylamine
[a] UMR CNRS 6239: Génétique, Immunothérapie, Chimie et
Cancer; Equipe 5: Synthèse Organique et Thérapeutique,
Université de Tours, UFR des Sciences Pharmaceutiques
31, avenue Monge, 37200 Tours, France
Fax: +33-247367229
(DEA),
pyrrolidine],
tetrabutylammonium
fluoride
E-mail: marie-claude.viaud-massuard@univ-tours.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101811.
(TBAF), and carbonate bases such as potassium carbon-
ate.[12] These different bases were therefore studied in the
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A. Souffrin, C. Croix, M.-C. Viaud-Massuard
SHORT COMMUNICATION
palladium-catalyzed Sonogashira reaction of 1-benzyl-3,4- Table 2. Sonogashira cross-coupling reactions of 1-benzyl-3,4-di-
bromo-1H-pyrrole-2,5-dione (1) with alkynes 2b–t.[a]
dibromo-1H-pyrrole-2,5-dione (1) with phenylacetylene
(2a) by using the smooth conditions developed by Thorand
and Krause: PdCl2(PPh3)2 (5 mol-%), CuI (10 mol-%), 2a
(2.5 equiv.), and base (2.5 equiv.) in THF at room tempera-
ture.[13] The results are summarized in Table 1. The best
yield was obtained with DIPEA (Table 1, Entry 7). Under
these conditions 1-benzyl-3,4-bis(phenylethynyl)-1H-pyr-
role-2,5-dione (3a) was isolated in excellent yield (95%) af-
ter 3 h. Coupling product 3a was obtained in excellent yield
when the reaction was carried out with tertiary amines like
DIPEA or TEA (Table 1, Entries 6 and 7). When secondary
or primary amines were used, opening of the maleimide
core by the base was observed, and the coupling product
was not obtained (Table 1, Entries 1–4) except with DIPA
(Table 1, Entry 5). Indeed, due to the steric hindrance of
DIPA, 3a was obtained in good yield (66%). Moderate to
good yields were also obtained with mineral bases com-
bined with longer reaction times (Table 1, Entries 8–11).
Table 1. Base effects on Sonogashira cross-coupling reaction of 1-
benzyl-3,4-dibromo-1H-pyrrole-2,5-dione (1) with phenylacetylene
(2a).[a]
Entry
Base
Time [h][b]
Yield [%][c]
1
2
3
4
PA
pyrrolidine
piperidine
DEA
1
1
1
0
0
0
0
1
5
6
7
8
9
10
11
DIPA
TEA
DIPEA
K2CO3
Cs2CO3
CsF
4
3
3
6
24
24
2
66
92
95
75
69
52
45
TBAF
[a] All reactions were carried out with PdCl2(PPh3)2 (5 mol-%) and
CuI (10 mol-%) in THF at room temperature with 1 (1 equiv.), 2a
(2.5 equiv.), and base (2.5 equiv.). [b] Complete consumption of 1.
[c] Yield is given for isolated and chromatographed material.
Recently, sustainable chemistry has become an important
endeavor for organic chemists. Our Sonogashira methodol-
ogy can also be performed in aqueous media with the use
of tetrabutylammonium chloride as a phase-transfer agent,
though under different conditions [CsF in THF/water
[a] All reactions were carried out with PdCl2(PPh3)2 (5 mol-%) and
(1:1)]. We only managed to get the desired product in a CuI (10 mol-%) in THF at room temperature with 1 (1 equiv.), al-
kyne (2.5 equiv.), and DIPEA (2.5 equiv.). [b] Yield is given for iso-
lower 32% yield after a reaction time of 12 h.
lated and purified material. [c] Further studies have shown that
Having optimized the reaction conditions for the Sono-
other conditions [5 equiv. of 2b or use of 1-benzyl-3,4-diiodo-1H-
gashira reactions of 1, we decided to prepare new maleim-
ide derivatives by using terminal alkynes 2b–t. As shown in
Table 2, in most cases, the desired products were obtained
pyrrole-2,5-dione or use of Pd(PPh3)4] do not improve the yield.
[d] Further studies have shown that the use of 5 equiv. of 2e im-
proves the yield to 57%. [e] Degradation of 2i.
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Sonogashira Cross-Coupling Reactions of Maleimides
in good to excellent yields (Table 2, Entries 1, 5, 6, and 10– tained in a moderate yield (56%) after 3 h. Encouraged by
15). Furthermore, the reaction proceeded very quickly, as this result, the optimized conditions were applied to the
starting material 1 was completely consumed after 1 h (ac- Sonogashira reaction of 4 with alkynes 2b, 2n, and 2q. The
cording to TLC monitoring). In general, coupling reactions desired products were obtained in moderate to good yields
with alkyl acetylenes yielded the expected products in mod- (Table 3, Entries 1–3) after 1 h. As with 1, we observed the
erate yields (Table 2, Entries 2 and 3). For aryl alkynes, the same electronic influence of the substituents on the phenyl
product yield depended on the substitution pattern of the ring of the terminal alkynes (Table 3, Entries 3 and 4).
phenyl ring. Electron-rich phenylacetylenes gave better
yields (Table 2, Entries 10–15) than electron-poor alkynes
such as p-trifluoromethylphenylacetylene (Table 2, En-
tries 16–18) or ethynyl p-tolyl sulfone, where an electron-
Conclusions
withdrawing group such as sulfur dioxide is directly at-
In conclusion, we have developed an efficient and general
tached to the terminal alkyne (Table 2, Entry 19). As is well
method for the Sonogashira cross-coupling reaction of 1-
known, Sonogashira cross-coupling does not proceed well
benzyl-3,4-dibromo-1H-pyrrole-2,5-dione (1) and 3,4-di-
for electron-poor alkynes.[14] When π deficient heterocycles
bromo-1H-pyrrole-2,5-dione (4) with terminal alkynes. This
such as pyridine were attached to the terminal alkynes, the
reaction provides rapid access to a wide range of new malei-
final products were obtained in poor yields (Table 2, En-
mide derivatives in moderate to excellent yields.
try 7). The use of 3-ethynylaniline (2j) resulted in complete
The exploration of the Sonogashira coupling has given
us the opportunity to reveal, for the first time, alkynyl car-
bon–carbon bond formation by using maleimides. These re-
sults open the way to a novel strategy for the synthesis of
deactivation of the catalyst and no coupling product was
formed (Table 2, Entry 9).
When the nitrogen atom on the maleimide is not pro-
tected, Sonogashira cross-coupling reactions also offer an
various difunctionalized maleimide derivatives. Moreover,
interesting strategy. While deprotection of N-benzyl-pro-
this work could be extended, after deprotection of the TMS
protecting group, by using maleimide derivative 3b in other
Sonogashira cross-coupling reactions, with different haloge-
nated compounds, or in click chemistry reactions: this pro-
tected amines is quite straightforward in organic chemistry,
deprotection of N-benzylamides is more challenging, essen-
tially because of the presence of incompatible functional
groups on the molecular scaffold, such as alkynes. Indeed,
spective study is currently under investigation by our team.
the most commonly employed methods include hydro-
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and detailed spectroscopic data for
all new compounds.
genolysis with catalytic Pd/C. Even under these conditions,
deprotection is not guaranteed. Strongly reducing condi-
tions, such as Na/NH3, have been used.[15] These limitations
have led us to develop Sonogashira conditions on the un-
protected maleimide. Similar coupling of 3,4-dibromo-1H-
pyrrole-2,5-dione (4) with 2a was achieved under our opti-
Acknowledgments
mized conditions (Table 3, Entry 1). The product was ob-
Financial support by the Centre National de la Recherche Sci-
entifique (CNRS) and the Région Centre. Thanks also to Monika
Ghosh for translation assistance.
Table 3. Sonogashira cross-coupling reactions of 3,4-dibromo-1H-
pyrrole-2,5-dione (4) with alkynes 2a, 2b, 2n, and 2q.[a]
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Received: December 15, 2011
Published Online: March 19, 2012
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