Synthesis of 3,4-disubstituted maleimides by selective cross-coupling reactions using indium organometallics

Article abstract of DOI:10.1021/ol900063p

Unsymmetrical 3,4-disubstituted maleimides have been synthesized by palladium-catalyzed cross-coupling reactions of indium organometallics with 3,4-dihalomaleimides. The synthesis was performed by stepwise or sequential one-pot palladium-catalyzed cross-c

Full text of DOI:10.1021/ol900063p

ORGANIC
LETTERS
2009
Vol. 11, No. 6
1285-1288
Synthesis of 3,4-Disubstituted
Maleimides by Selective Cross-Coupling
Reactions Using Indium
Organometallics†
Latifa Bouissane, Jose´ Pe´rez Sestelo,* and Luis A. Sarandeses*
Departamento de Qu´ımica Fundamental, UniVersidade da Corun˜a,
E-15071 A Corun˜a, Spain
qfsarand@udc.es; sestelo@udc.es
Received January 13, 2009
ABSTRACT
Unsymmetrical 3,4-disubstituted maleimides have been synthesized by palladium-catalyzed cross-coupling reactions of indium organometallics
with 3,4-dihalomaleimides. The synthesis was performed by stepwise or sequential one-pot palladium-catalyzed cross-coupling reactions with
various triorganoindium reagents. This method was used to prepare a wide variety of alkyl, aryl, heteroaryl, and alkynyl 3,4-disubstituted
maleimides in good yields and with high selectivity and atom economy.
3,4-Disubstituted maleimides are an important family of
natural and synthetic products with valuable pharmacological
properties.1 They are potent agents for the inhibition of
protein kinases, especially PKC, an important target in cancer
chemotherapy,2 and some members of this family are in
clinical trials as anticancer drugs.3 Other compounds exhibit
antibacterial, antiviral, antimicrobial, and antigenic activities.4
Furthermore, 3,4-bisindolylmaleimides have found applica-
tions as light emitting diodes (LED)5 and have also been
used in the development of photocatalysts immobilized on
surfaces.6
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Culbert, A. A.; Cross, D. A. E.; Corcoran, S. L.; Yates, J. W.; Pearce, N. J.;
Rausch, O. L.; Murphy, G. J.; Carter, P. S.; Cox, L. R.; Mills, D.; Brown,
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Holder, J. C. Chem. Biol. 2000, 7, 793–803. (c) Hudkins, R. L.; Johnson,
N. W.; Angeles, T. S.; Gessner, G. W.; Mallamo, J. P. J. Med. Chem. 2007,
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† Dedicated to Professor Luis Castedo on the occasion of his 70th
birthday.
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10.1021/ol900063p CCC: $40.75
Published on Web 02/16/2009
2009 American Chemical Society

The synthesis of 3,4-disubstituted maleimides has generally
been carried out by two main approaches: a linear synthetic
sequence based on the formation of the maleimide ring in
the last steps of the synthesis7,8 or by selective functional-
ization of a 3,4-dihalomaleimide by Grignard addition and
cross-coupling reaction.9,10 Generally, the cross-coupling
reactions afford symmetrical 3,4-disubstituted maleimides,11
and only one example, using alkylzinc reagents, has proved
to be selective in the monocoupling reaction.12
Table 1. Palladium-Catalyzed Mono Cross-Coupling Reactions
of Indium Organometallics with 1 and 2
During the past few years, we have shown that indium
organometallics are useful reagents in metal-catalyzed cross-
coupling reactions.13 The main features of triorganoindium
reagents (R3In) in cross-coupling reactions are their high
efficiency, versatility, and chemo- and stereoselectivity.
Additionally, R3In are particularly effective in the synthesis
of functionalized heterocyclic compounds.14 In this com-
munication, we report the synthesis of unsymmetrically 3,4-
disubstituted maleimides by selective cross-coupling reac-
tions of R3In with 3,4-dihalomaleimides.
Our study began with an investigation into the reactivity
and selectivity of triorganoindium reagents in the palladium-
catalyzed cross-coupling reaction with 3,4-dibromomaleimide
1 (Table 1). Initially, the reaction of R3In with 1, using the
most commonly used commercially available palladium
catalysts Pd(Ph3P)4 or Pd(Ph3P)2Cl2, under reflux gave the
double cross-coupling product as the major product. Further
screening of the reaction conditions showed that on using
Pd(PhCN)2Cl2 (5 mol %) as the catalyst15 the monocoupling
product could be obtained regioselectively at rt in good yields
after 2-6 h, using only 40 mol % of the triorganoindium
reagent as the nucleophile. For example, the reaction of tri-
n-butylindium with 1 afforded the monocoupling product 3
in 81% yield (Table 1, entry 1). The reaction of arylindium
reagents (4-methoxyphenyl, 1-naphthyl) with 1 gave similar
yields and selectivities (78-79%, entries 2 and 3). Interest-
ingly, the 3-bromo-4-indolylmaleimide 6 was prepared by
reaction of tri(5-methoxy-3-indolyl)indium with 1, and this
reaction gave 75% yield (entry 4). These results demonstrate
the high selectivity of the system R3In:Pd(PhCN)2Cl2 in the
coupling reactions with 3,4-dibromomaleimides and the high
atom economy of R3In in transferring all three groups to the
electrophile.
The reactivity of R3In with 3,4-dichloromaleimide 2 was
also studied.12Initial studies showed that the reaction occurs
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1988, 44, 2887–2892. (b) Brenner, M.; Mayer, G.; Terpin, A.; Steglich,
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Ortinau, S.; Rolfs, A.; Beller, M. Org. Biomol. Chem. 2008, 6, 992–997.
a The reaction product (10) was obtained along with 32% of the
symmetrical cross-coupling product.
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Org. Lett., Vol. 11, No. 6, 2009

efficiently using Pd(PhCN)2Cl2 (5 mol %) as the catalyst,
although longer reaction times are required and slightly lower
yields obtained in comparison to the analogous dibromide.
We believe that the lower reactivity favors the double cross-
coupling product, which is the secondary product in all
reactions.16
Table 2. Palladium-Catalyzed Cross-Coupling Reactions of
Indium Organometallics with 3-Bromo- and
3-Chloro-4-Substituted Maleimides 3-11
Under these conditions, the reaction of arylindium (phenyl,
4-methoxyphenyl, 1-naphthyl) reagents with 2 produced the
selective cross-coupling products 7-9 in good yields
(67-71%, Table 1, entries 5-7). The reaction using tri(ph-
enylethynyl)indium afforded the monocoupling product 10
in 40% yield, accompanied by 32% of the symmetrical cross-
coupling product (Table 1, entry 8). Interestingly, the reaction
with an alkylindium derivative such as tri(n-hexyl)indium
gave the 3-alkyl-4-chloromaleimide 11 in a satisfactory 58%
yield (Table 1, entry 9). Overall, these results demonstrate
the high versatility of R3In (sp, sp2, sp3) in cross-coupling
reactions with 3,4-dihalomaleimides, and they represent the
first general method for the synthesis of 3-halo-4-substituted
maleimides by cross-coupling reactions.
To prepare unsymmetrically 3,4-disubstituted maleimides,
we explored a second cross-coupling reaction using the
previously prepared 3-halo-4-substituted maleimides 3-11.
In the first experiments, the reaction of 3-bromomaleimides
3-6 with R3In afforded the corresponding products in low
yields. Further research showed that good yields could be
obtained on using Pd(DPEphos)Cl2 (5 mol %)17 as the
catalyst and by performing the reactions under reflux for
5-8 h. Under these conditions, the 3-bromo-4-substituted
maleimides 3-6 reacted with aryl-, alkyl-, or alkynylin-
dium reagents (50 mol %) to give the corresponding 3,4-
disubstituted maleimides, i.e., alkyl-aryl (12 and 13,
80-89%yield, Table2, entries1and2), 1-naphthyl-alkynyl
(14, 84% yield, Table 2, entry 3), or 3-indolyl-1-naphthyl
(15, 88% yield, Table 2, entry 4).
Further evidence for the high efficiency of indium orga-
nometallics in these reactions was provided by the synthesis
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2003, 68, 2518–2520. (e) Pena, M. A.; Pe´rez Sestelo, J.; Sarandeses, L. A.
Synthesis 2003, 780-784. (f) Rodr´ıguez, D.; Pe´rezSestelo, J.; Sarandeses,
L. A. J. Org. Chem. 2004, 69, 8136–8139. (g) Riveiros, R.; Rodr´ıguez, D.;
Pe´rez Sestelo, J.; Sarandeses, L. A. Org. Lett. 2006, 8, 1403–1406. (h)
Riveiros, R.; Pe´rez Sestelo, J.; Sarandeses, L. A. Synthesis 2007, 3595–
3598. (i) Caeiro, J.; Pe´rez Sestelo, J.; Sarandeses, L. A. Chem.-Eur. J.
2008, 14, 741–746. (j) Riveiros, R.; Saya, L.; Pe´rez Sestelo, J.; Sarandeses,
L. A. Eur. J. Org. Chem. 2008, 1959–1966.
(14) (a) Pena, M. A.; Pe´rez Sestelo, J.; Sarandeses, L. A. J. Org. Chem.
2007, 72, 1271–1275. (b) Mosquera, A.; Riveiros, R.; Pe´rez Sestelo, J.;
Sarandeses, L. A. Org. Lett. 2008, 10, 3745–3748.
(15) This catalyst has been already useful in selective palladium-
catalyzed cross-coupling reactions: Zhang, L.; Meng, T.; Fan, R.; Wu, J. J.
Org. Chem. 2007, 72, 7279–7286.
a Reactions performed with Pd(DPEphos)Cl2 (5 mol %) as catalyst.
b Reactions performed with Pd(Ph3P)4 (5 mol %) as catalyst.
Org. Lett., Vol. 11, No. 6, 2009
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cedure.14b,18 For this reason, we explored the possibility of
synthesizing unsymmetrically 3,4-disubstituted maleimides
in a one-pot procedure. It was found that the reaction of
dibromomaleimide 1 with 40 mol % of R3In in the presence
of Pd(PhCN)Cl2 (5 mol %) in THF at rt, followed by the
addition of a different indium organometallic reagent after
completion of the first coupling (TLC test), afforded, after
12 h at rt, the disubstituted product in good yields. These
results show that a variety of aryl-, heteroaryl-, alkyl-, and
alkynylindium reagents can be coupled efficiently with 1,
and the results are summarized in Table 3 (68-89%). To
the best of our knowledge, this constitutes the first one-pot
approach to 3,4-disubstituted maleimides by cross-coupling
reactions.
Table 3. Sequential Cross-Coupling of Triorganoindium
Reagents with 1
In summary, a new method for the synthesis of 3,4-
disubstituted maleimides using palladium-catalyzed cross-
coupling reactions with indium organometallics was devel-
oped. The synthesis was performed by selective stepwise or
sequential one-pot procedures from 3,4-dibromo- or 3,4-
dichloromaleimides. The reactions give good yields, have
high selectivity, and have a high atom economy with respect
to the organic groups. Following this method, a wide variety
of unsymmetrically 3,4-disubstituted maleimides possessing
alkyl, aryl, heteroaryl (including 3-indolyl), and alkynyl
groups in their structure were synthesized. Further applica-
tions of this method in the synthesis of novel maleimides
are now under investigation.
Acknowledgment. This research was supported by the
SpanishMinisteriodeEducacio´nyCiencia(CTQ2006-06166),
Xunta de Galicia (INCITE08PXIB103167PR), and FEDER.
of unsymmetrically 3,4-disubstituted maleimides by reaction
of R3In with the 3-chloro-4-substituted maleimides 7-11.
The yields were relatively poor on using the same reaction
conditions as before, but the use of Pd(Ph3P)4 (5 mol %) as
catalyst and performing the reactions in a sealed tube at 80
°C for 8 h led to increases in the yields. The cross-coupling
reactions of heteroaryl- (3-indolyl, 2-thiophenyl), aryl-, and
alkylindium reagents afforded the corresponding 3,4-disub-
stituted maleimides (16-20) in good yields (82-91%, Table
2, entries 5-9). Unfortunately, the cross-coupling reactions
of trivinylindium with bromo- or chloromaleimides gave
unstable cross-coupling products in low yields.
Supporting Information Available: Experimental pro-
cedures, spectroscopic and analytical data, and copies of
NMR spectra for compounds prepared. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL900063P
(16) In the reactions with 1 and 2, the use of an excess of R3In (>40
mol %) increases the yield of the symmetrical cross-coupling products.
(17) DPEphos ) bis([o-(diphenylphosphino)phenyl] ether. (a) Kranen-
burg, M.; van der Burgt, Y. E. M.; Kamer, P. C. J.; van Leeuwen,
P. W. N. M.; Goubitz, K.; Fraanje, J. Organometallics 1995, 14, 3081–
3089. (b) Huang, Z.; Qian, M.; Babinski, D. J.; Negishi, E. Organometallics
2005, 24, 475–478.
One particular feature of the cross-coupling reactions using
indium organometallics is their suitability for the construction
of two different carbon-carbon bonds in a one-pot pro-
(18) (a) Pena, M. A.; Pe´rez, I.; Pe´rez Sestelo, J.; Sarandeses, L. A. Chem.
Commun. 2002, 2246-2247. (b) Pena, M. A.; Pe´rez Sestelo, J.; Sarandeses,
L. A. Synthesis 2005, 485-492.
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