Palladium-catalyzed aerobic oxidative carbonylation of alkynes with amines: a general access to substituted maleimides

Article abstract of DOI:10.1039/c8cc05802d

A catalytic oxidative carbonylation reaction was developed for the synthesis of polysubstituted maleimides from alkynes and amines with air as a green oxidant. This novel transformation proceeds in the presence of palladium chloride without the need for expensive ligands or additives and has a broad substrate scope affording a variety of maleimides in good to high yields.

Full text of DOI:10.1039/c8cc05802d

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Palladium-Catalyzed Aerobic Oxidative Carbonylation of Alkynes
with Amines: A General Access to Substituted Maleimides
Ji Yang,a,+ Jiawang Liu,a,+ Ralf Jackstell,a and Matthias Bellera*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
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A catalytic oxidative carbonylation reaction was developed for the catalysts which allow for carbonylation of internal alkynes with
synthesis of polysubstituted maleimides from alkynes and amines amines, affording a variety of maleimides (Scheme 1, b).[10]
with air as green oxidant. This novel transformation proceeds in However, as a general drawback only internal alkynes could be
the presence of palladium chloride without need for expensive applied in these methodologies.
ligands or additives and has a broad substrate scope affording a
variety of maleimides in good to high yields.
O
O
HN
N
Substituted maleimides represent interesting building blocks
N
SO2NH2
which are widely found in bioactive natural products and drug
molecules (Figure 1).[1] In addition, this class of compounds are
also applied in engineering,[2, 3] natural rubbers,[4] resins,[5] and
the aerospace industry.[6] In general, the traditional industrial
process for manufacturing maleimides is the reaction of
amines with maleic and related anhydrides. However, this
methodology is mainly used for the preparation of non- or
symmetrically substituted maleimides.[7] Consequently, there is
still a need for new procedures to access polysubstituted
maleimides.
Cl
O
O
2-Arachidonoyl glycerol (2-AG)
Anti-inflammatory
H
N
O
O
O
F
N
R1
O
18F
R1=H, CH3, OCH3
N
O
Inhibited tumor growth
PET-CT imaging
Figure 1. Selective examples of bioactive maleimides
.
As one of the most important homogenous catalytic processes,
transition-metal-catalyzed carbonylation reactions allow for
direct conversion of easily available feedstocks, like olefins or
alkynes and carbon monoxide, into a variety of carbonylated
compounds with higher value, which are useful in organic
synthesis, pharmaceutical as well as medicinal chemistry.[8] In
2006, Kondo and co-workers reported an interesting
ruthenium-catalyzed co-cyclization of internal alkynes,
isocyanates, and CO for the synthesis of multiple substituted
maleimides in excellent yields (Scheme 1, a).[9a] Later on,
Fe(CO)5 was also found to be a good catalyst for this
transformation albeit with lower yield (Scheme 1, a).[9b] In the
past decade, our group also developed iron and rhodium
Recently, we and other groups became interested in the
oxidative carbonylation of olefins and alkynes.[11] We thought
the later reaction offers a more practical approach to this
interesting class of products (Scheme 1, c). Notably, oxidative
carbonylations are among the most important reactions in the
field of palladium catalysis, since their discovery by Tsuji and
co-workers in 1964.[12] Although these transformations have
found varied use,[13] the main drawback is the use of
(over)stoichiometric amounts of oxidants and/or additional
copper salts. Clearly, among all the known oxidants air is the
ideal, green reagent. Herein, we report the first general Pd-
catalyzed oxidative carbonylation of alkynes with amines in the
presence of air for the synthesis of various maleimides in high
yields.
In our initial studies we investigated the oxidative carbony-
lation of phenylacetylene 1a and aniline 2a as a benchmark
system. Although carbon monoxide is an abundant and
inexpensive C1 source, its use under oxidative conditions
requires certain safety measures. Hence, all catalytic reactions
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Table 1 Pd-catalyzed oxidative aminocarbonylation of alkynes: Variation of alkynes.a
should be performed either with a diluted amount of CO or in
the presence of a significant excess carbon monoxide. After
variation of solvents, palladium precursors, temperature, and
pressure, we found that simple PdCl2 (2.0 mol%) in the
presence of air (5 bar) gave the desired product 1,3-diphenyl-
1H-pyrrole-2,5-dione 3aa in 92% GC yield at 120 °C in toluene.
Surprisingly, there is almost no by-product observed in this
reaction. Obviously, a control experiment without palladium
salt revealed no desired product. At the same time, we found
that this transformation does not require any ligands, which
makes the reaction system very convenient.
Entry
1
Alkynes
Product
Yield/%
92
2
3
4
74
85
83
84
5
6
7
87
63
87
91
92
91
81
Scheme 1 Synthesis of substituted maleimides via carbonylation reactions
With these optimized conditions in hands, we proceeded to
explore the substrate scope for this novel methodology. First,
different alkynes including terminal and internal alkynes were
studied with aniline as the reaction partner, affording a variety
of poly-substituted maleimides in good to high yields (63-92%).
As shown in Table 1, the reactions of aromatic terminal
alkynes with electron-donating (1b) or electron-withdrawing
8
(1c-1f) functional groups afforded the corresponding products
9
in a straightforward manner. Notably, this reaction tolerates
halide substituents (chloride, bromide). In general, substrates
bearing electron-withdrawing functional groups gave higher
yields compared to electron-rich aryl acetylenes. For aromatic
internal alkynes (1g), the yield decreased, and about 35% of
the original alkyne remained. On the other hand, aliphatic
10
11
12
terminal alkynes with different carbon chains (1h-1l) afforded
the desired products in good yields (81-92%). It is worth noting
that internal alkynes (1m, 1n) were also transformed affording
the multiple-substituted maleimides in good yields.
Next, the scope with respect to amines was investigated and
the results are summarized in Table 2. Aromatic amines (2b-2h)
with either electron-donating (OMe, Me) or electron-
withdrawing (F, Cl, Br, CF3) functional groups on the phenyl
ring provided the corresponding products (3ab-3ah) in high
yields (71-95%).
2 | J. Name., 2012, 00, 1-3
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13
82
71
11
84
aReaction conditions: 1 (1.5 mmol), 2 (1.0 mmol), PdCl2 (2.0 mol%), CO (15 bar), air (5
bar), toluene (2.0 mL), 120 oC, 12 h. b Methylamine solution, 2.0 M in THF, 1.0 mmol.
14
Aromatic amines bearing chloro- or bromo-atoms on the
phenyl ring (2c, 2d), which are often sensitive to palladium
catalysis, also worked well, without adverse effect on the
reaction. At the same time, the steric hindrance of the
substituent on the amine also has a certain influence on the
reaction, the yield of 2-methylaniline (2g) is moderately lower
than that of unsubstituted aniline. Bioactive amines (2i, 2j)
yielded the corresponding products in 87-91%. Similarly, for
aliphatic amines (2k, 2l) this transformation gave the
corresponding products in high yields (76-84%).
aReaction conditions: 1 (1.5 mmol), 2 (1.0 mmol), PdCl2 (2.0 mol%), CO (15 bar),
air (5 bar), toluene (2.0 mL), 120 oC, 12 h.
Table 2 Pd-catalyzed oxidative aminocarbonylation of alkynes: Variation of amines.a
With respect to the mechanism it is interesting to note that
the groups of Gabriele,[14] Xia,[15] and Muldoon[11c] reported
related carbonylations to 2-ynamides in the presence of halide
additives. However, under our conditions, the corresponding
ynamides were not observed by GC-MS as intermediates to a
significant extent. Hence, on the basis of previous mechanistic
studies for oxidative carbonylations,[16] we propose the
following pathway for this transformation (Scheme 2). First,
Entry
1
Amines
Product
Yield/%
91
2
3
84
81
the palladium acyl complex
B was generated from palladium (II)
A
in the presence of amine and CO. Subsequently, π-
coordination of the carbon- carbon triple bond to the metal
center, followed by the insertion of the alkyne into the
palladium carbon bond, affords palladium intermediates
Then, the palladium species undergoes CO insertion to give
the acyl palladium species . Finally, the maleimide is
eliminated through reductive elimination of intermediate to
C.
C
4
95
91
78
71
91
87
76
D
E
give the palladium (0) which is oxidized to palladium (II) in the
presence of air to finish the catalytic cycle.
5
6
7
8
9
Scheme 2 Proposed catalytic cycle
.
10b
In conclusion, we have developed a ligand-free palladium
catalyzed oxidative carbonylation of alkynes with amines to
give poly-substituted maleimides in good to high yields (63-
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Qi, Y. Lan and A. Lei, Chem. Commun., 2016, 52, 13307-
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terminal oxidant without other co-oxidants.[17]
Notes and references
The author thanks the Chinese Scholarship Council for financial Support
(J.Y).
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