An Efficient Rhodium-Catalyzed Carbonylative Annulation of Internal Alkynes and Anilines To Produce Maleimides

Article abstract of DOI:10.1002/cctc.201601092

A selective and efficient procedure for the carbonylative synthesis of polysubstituted maleimides was developed. With rhodium as the catalyst and acetylacetone (acac) as the ligand, various desired maleimide derivatives were isolated in moderate to excellent yields with good functional group tolerance from the corresponding internal alkynes and anilines.

Full text of DOI:10.1002/cctc.201601092

Accepted Article
Title: An Efficient Rhodium-Catalyzed Carbonylative Annulation of
Internal Alkynes and Anilines to Produce Maleimides
Authors: Xiao-Feng Wu, Fengxiang Zhu, Yahui li, and Zechao Wang
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10.1002/cctc.201601092
ChemCatChem
COMMUNICATION
An Efficient Rhodium-Catalyzed Carbonylative Annulation of
Internal Alkynes and Anilines to Produce Maleimides
Fengxiang Zhu,[a] Yahui Li,[a] Zechao Wang,[a] and Xiao-Feng Wu*[a]
Abstract: A selective and efficient procedure on carbonylative
synthesis of polysubstituted maleimides has been developed. With
rhodium as the catalyst and acetylaceton as the ligand, various
desired maleimide derivatives were isolated in moderate to excellent
yields with good functional group tolerance from the corresponding
internal alkynes and anilines.
alkynes, isocyanates and CO for the synthesis of polysubstituted
maleimides.10a Unsymmetrical maleimides can be prepared in
excellent yields in
a rapid and atom-economical manner
(Scheme 1, eq. 1). Later on, Fe(CO)5 was found to be a proper
catalyst for this transformation as well.10b A rhodium-catalyzed
carbonylation of alkynes with pyridin-2-ylmethylamine for the
synthesis of maleimides was developed by Chatani’s group.11
Two molecules of CO were incorporated into the final products
and the coordination of the pyridine nitrogen to the rhodium
center was found to be essential for the success of this reaction
(Scheme 1, eq. 2). Recently, Beller and co-workers reported a
novel procedure on iron-catalyzed cyclization of alkynes with CO
to succinimides.12 Under their reaction conditions, when
diphenylacetylene and cyclohexylamine or benzylamine were
applied as the substrates, N-substituted maleinimides were
formed (Scheme 1, eq. 3).
Approximately more than 70% of all pharmaceuticals and
agrochemicals bearing at least one heterocyclic ring, which can
be explained by two reasons: 1) the synthetic accessibility of
heterocyclic scaffolds and its physicochemical properties, driving
these values of lipophilicity and solubility toward the optimal
balanced range regarding uptake and bioavailability; 2)
heterocycles seem to be perfect bioisosteres of other iso- or
heterocyclic rings as well as of several different functional
groups which delivering through their similarity in structural
shape and electronic distribution equal or even better biological
efficacy. Hence, the development of new synthetic procedures
for heterocycles synthesis is still considered as the core interest
of organic chemists.1 Among all the heterocyclic compounds,
maleimide derivatives is an important class of heterocycles
which have been widely used in pharmaceutical engineering,2
natural rubbers,3 resins4 and aerospace industry (Figure 1).5
Except these applications, N-arylmaleimide products due to their
excellent heat resistance have also been applied in the
engineering plastics.6 Typically, maleimides can be prepared
from maleic anhydride by treatment with amines followed by
dehydration. Although numbers of alternative procedures have
been developed, new synthetic methodologies are still under
demand.7
On the other hand, carbon monoxide is one of the
cheapest and most abundant C1 source. By transition metal-
catalyzed carbonylative transformations, CO can be easily
incorporated into the parent molecules and contribute to
increase the diversity of accessible compounds in many ways.
Due to the high synthetic values and academic interests,
numerous novel carbonylation procedures have been
established and even industrialized during the past decades.8
And the combination of carbonylation and heterocycles
synthesis is attractive as well.9 High valued heterocycles can be
prepared with cheap CO as one of the reactants. Indeed,
carbonylation procedures have been reported for the synthesis
of maleimide derivatives. In 2006, Kondo and co-workers
reported an interesting ruthenium-catalyzed cocyclization of
Figure 1. Selected examples of bio-active maleimides.
With all above discussed backgrounds and our continual
interests in carbonylative synthesis of heterocycles, here we
wish to report our new results on rhodium-catalyzed
carbonylative synthesis of polysubstituted maleimides (Scheme
1, eq. 4). With readily available anilines and internal alkynes as
the substrates, the desired products were isolated in good yields
in general.
Initially, we choosing aniline and hex-3-yne as the model
substrates in toluene, different rhodium catalysts were tested
(Table 1, entries 1-5). As shown in Table 1, no desired 3,4-
diethyl-1-phenyl-1H-pyrrole-2,5-dione could be detected with
[Rh(COD)Cl]2, [Rh(OAc)2]2, or [Cp*RhCl2]2 as the catalyst (Table
1, entries1-3). To our delight, 21% and 31% of the desired
product can be obtained in the presence of Rh(acac)(COD) or
Rh(acac)3 as the catalyst (Table 1, entries 4-5). With this
exciting primary reactivity results in hand, we started the ligands
[a]
F. Zhu, Y. Li, Z. Wang, Prof. Dr. X.-F. Wu
Leibniz-Institut für Katalyse e.V. an der Universität Rostock,
Albert-Einstein-Strasse 29a, 18059 Rostock (Germany)
E-mail: Xiao-Feng.Wu@catalysis.de
Supporting information for this article is given via a link at the end of
the document.
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10.1002/cctc.201601092
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COMMUNICATION
effects testing which have been known hold strong influences on
transition-catalyzed carbonylation reactions (Table 1, entries 6-
9).13 Among all the tested ligands, acetylaceton gave the best
conversion of starting materials and 71% yield of the desired
product can be observed (Table 1, entry 9). In the case of
phosphine ligands, 20-30% of the corresponding α,β-
unsaturated amides can be detected (Table 1, entries 6-8).
Nitrogen ligands such as 1,10-phen. and bipyridine were found
not effective here. Then, the effects of the solvents were
checked with acetylaceton as the ligand (Table 1, entries 10-13).
Interestingly, 95% of yield can be achieved with DMF as the
media (Table 1, entry 13). However, the reaction was totally
inhibited in DMSO (Table 1, entry 11). Notably, the same results
can be obtained with 1% of Rh(acac)3 and the loading can even
be as low as 0.5 mol% (Table 1, entries 14 and 15).
13
Rh(acac)3
Rh(acac)3
Rh(acac)3
acac
acac
acac
DMF
DMF
DMF
95
94
87
14[c]
15[d]
[a] aniline (0.2 mmol), hex-3-yne (0.22 mmol), catalysis (2 mol%), PPh3 (6
mol%), 120 oC, CO (10 bar), solvent (1 mL), 24h. [b] GC yields using
hexadecane as the internal standard. [c] Rh(acac)3 (1 mol%). [d] Rh(acac)3
(0.5
mol%).
PPh3:
triphenylphosphane;
DPEphos:
bis(2-
diphenylphosphinophenyl)ether; DPPE: 1, 2-bis(diphenylphosphino)ethan;
acac: acetylaceton; Cp*: pentamethylcyclopentadienyl; COD: 1,5-
cyclooctadiene.
With the best reaction conditions in hand, we started the
limitation and generality testing of this new procedure (Tables 2
and 3). Under our standard reaction conditions, good to
excellent yields of phenyl-1H-pyrrole-2,5-diones can be
produced from aniline and the corresponding internal alkynes
(Table 2). Diaryl acetylenes with electron-donating or electron-
withdrawing substituents are all shown to be suitable substrates
here, and give the desired maleimides in good yields (Table 2,
entries 6-9). It is important to mention that terminal alkynes
(phenylacetylene, ethynylcyclohexane, hex-1-yne) were tested
with aniline under our conditions as well, but no wished products
can be detected.
Table 2. Rh-catalyzed carbonylative synthesis of maleimides: Substrate scope
of alkynes.[a]
Entry
Alkyne
Product
Yield (%)
93
1
Scheme 1. Transition metal-catalyzed carbonylative synthesis of maleimides.
Table 1. Optimization of the Reaction Conditions.[a]
2
3
4
5
6
7
8
94
81
89
84
86
87
81
Entry
1
[Catal]
[Rh(COD)Cl]2
[Rh(OAc)2]2
[Cp*RhCl2]2
Rh(acac)3
RhCOD(acac)
Rh(acac)3
Rh(acac)3
Rh(acac)3
Rh(acac)3
Rh(acac)3
Rh(acac)3
Rh(acac)3
Ligand
Solvent
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH3CN
DMSO
Yield(%)[b]
-
-
2
-
-
-
3
-
4
-
31
21
21
18
25
71
80
-
5
-
6
PPh3
DPPP
DPEPhos
acac
acac
acac
acac
7
8
9
10
11
12
9
77
THF
43
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[a] aniline (0.2 mmol), alkynes (0.22 mmol), Rh(acac)3 (1 mol%), acetylaceton
(3 mol%), 120 oC, CO (10 bar), DMF (1 mL), 24 h, isolated yield.
intermediates will be formed after the insertion of another
molecular of CO. Finally, the final maleimides were eliminated
through reductive elimination and complete he catalytic cycle.
Subsequently, different anilines were tested with hex-3-yne
as the model substrate (Table 3). Anilines with electron-donating
or electron-withdrawing functional groups are all suitable
substrates for this methodology. Good to excellent yields can be
achieved in all the tested cases. However, aliphatic amines
cannot be applied here instead of aniline.
Table 3. Rh-catalyzed carbonylative synthesis of maleimides: Substrate scope
of anilines.[a]
Scheme 2. Proposed reaction pathway.
Entry
1
Aniline
Product
Yield (%)
91
In conclusion, an efficient rhodium-catalyzed carbonylative
annulation of anilines with internal alkynes for the
straightforward synthesis of maleimide derivatives has been
developed. With rhodium as the catalyst and acetylaceton as the
ligand, various polysubstituted maleimides were isolated with
high yields.
2
3
4
5
84
87
83
89
Acknowledgements
The authors thank the Chinese Scholarship Council for financial
support. We also appreciate the general supports from
Professor Matthias Beller and the help from Mr. Jie Liu both in
LIKAT. The analytic supports of Dr. W. Baumann, Dr. C. Fisher,
S. Buchholz, and S. Schareina are gratefully acknowledged.
General procedure: Under an open atmosphere or under argon,
a 4 mL screw-cap vial was charged with Rh(acac)3 (1 mol%),
acetylaceton (3 mol%), aniline (0.2 mmol), alkyne (0.22 mmol),
dry DMF (1 mL) and an oven-dried stirring bar. The vial was
closed by Teflon septum and phenolic cap and connected with
atmosphere with a needle. Then the vial was fixed in an alloy
plate and put into Paar 4560 series autoclave (300 mL). At room
temperature, the autoclave is flushed with carbon monoxide for
three times and 10 bar of carbon monoxide was charged. The
autoclave was placed on a heating plate equipped with magnetic
stirring and an aluminum block. The reaction is allowed to be
heated under 120 oC for 24 hours. Afterwards, the autoclave
was cooled to room temperature and the pressure was carefully
released. The reaction solution was quenched with distilled
water and extracted with ethyl acetate three times. The
combined organic phases were washed with saturated NaCl
solution and dried over Na2SO4. The crude product was purified
by column chromatography (ethyl acetate/pentante = 1:30) to
give the pure product.
6
83
7
8
9
86
77
86
[a] anilines (0.2 mmol), alkyne (0.22 mmol), Rh(acac)3 (1 mol%), acetylaceton
(3 mol%), 120 oC, CO (10 bar), DMF (1 mL), 24 h, isolated yield.
Based on our results, a possible reaction is proposed
(Scheme 2). At the beginning, the real rhodium catalyst was
generated from the precursor in the presence of ligand and CO.
Then the generated rhodium catalyst reacted with aniline to give
the corresponding three-membered rhodium cycle which
subsequently reacted with internal alkynes to the desired five-
membered cycle. A six-membered cycle as one of the key
Keywords: domino reaction • carbonylation • maleimides •
annulation • heterocycle synthesis
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Fengxiang Zhu,Yahui Li, Zechao
Wang, and Xiao-Feng Wu*
Page No. – Page No.
An Efficient Rhodium-
Catalyzed Carbonylative
Annulation of Internal Alkynes
and Anilines to Produce
Maleimides
A selective and efficient procedure on carbonylative synthesis of
polysubstituted maleimides has been developed. With rhodium
as the catalyst and acetylaceton as the ligand, various desired
maleimide derivatives were isolated in moderate to excellent
yields.
This article is protected by copyright. All rights reserved.