Chemical fixation of carbon dioxide by copper catalyzed multicomponent reactions for oxazolidinedione syntheses

Article abstract of DOI:10.1039/c4gc02089h

The quest to reduce greenhouse gases has triggered the development of new chemical fixation of carbon dioxide. Given the importance of CO₂ based transformation chemistry, we demonstrate the fixation of CO₂ for oxazolidinedione synthesis via a novel multicomponent synthesis. In the presence of a catalytic amount of Cu₂O, various 2-bromo-3-phenylacrylic acid derivatives reacted with CO₂ and amines are transformed to the corresponding oxazolidinedione derivatives in high yields. This journal is

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Chemical Fixation of Carbon Dioxide by Copper
Catalyzed
Multicomponent
Reactions
for
Cite this: DOI: 10.1039/x0xx00000x
Oxazolidinedione Syntheses
a[+]
a
a
Siddharth Sharma,b Ajay K. Singh, Devendra K. Singh, Dong-Pyo Kim*
[+]
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
The quest to reduce greenhouse gases has triggered the from nucleophilic attack of imines to arynes captured CO2 as a route to
development of new chemical fixation of carbon dioxide. Given biologically important functionalized benzoxazinones.4 More recently
the importance of CO2 based transformation chemistry, we Kobayashi et al. utilized a similar strategy for the synthesis of
demonstrate fixation of CO2 for oxazolidinedione synthesis via a isocoumarins via new NHC-Cu catalyzed reactions involving ortho-
novel multicomponent synthesis. In the presence of a catalytic arynes, terminal alkynes, and carbon dioxide.5
amount of Cu2O, various 2-bromo-3-phenylacrylic acid
derivatives reacted with CO2 and amines are transformed to the
corresponding oxazolidinediones derivatives in high yields.
Introduction
With the alarming rise in global temperature, sustainable technologies
need to give serious consideration to fixing carbon dioxide, a prominent
greenhouse gas.1 It is a C1 building block for chemical synthesis because
of its ubiquitous, low cost and nontoxic nature. It has a tremendous
potential as fuels, polymers or other chemicals through renewable energy
Figure 1. Some biologically important oxazolidinedione derivatives.
utilization.2 However, CO2 is a less electrophilic and thermodynamically
stable molecule. Therefore, strong nucleophiles have been required such
The decades of significant efforts toward exploring technologies for
as Grignard reagents and organolithium compounds for the activation. In
CO2 transformation, however, have allowed only a handful of
the past decade transition-metal mediated chemical fixation of CO2 has
heterocyles to be synthesized, which is considered to be one of the most
emerged as a potential approach towards synthesis of a variety of useful
prominent areas of organic synthesis.4-6 Hence, development of efficient
commodity chemicals such as carboxylic acids by the activation of C-H
methods utilizing CO2 in combination with multicomponent reaction
bonds in heterocycles synthesis.3 Recently, Yoshida and coworkers
(MCR) for the synthesis of heterocyles such as oxazolidinedione is
highly desirable for its applications from pharmaceuticals to polymers,
which could potentially open access to
oxazolidinediones scaffold.
a library of diverse
aDepartment of Chemical Engineering, Pohang University of Science
and Technology (POSTECH), Pohang, Korea 790-784
Fax: (+82)-54-279-5528
Oxazolidinedione is a versatile component of many biologically
active compounds. A vast number of pharmaceuticals containing these
skeletons are being used for therapeutic purposes (Figure 1). For
instance, it is used for anticonvulsant drugs such as ethadione,
paramethadione, and trimethadione.7 It has also been reported recently
for their bioactivities such as sodium channel blocker, anti-diabetic and
anti-cancer.8
Herein we describe the use of CO2 as a C1 source in the three-
component reaction involving amines and 2-bromo-3-phenylacrylic acid
derivatives for the synthesis of oxazolidinediones with copper catalyst.
Diverse oxazolidinediones were synthesized in good to excellent yields,
E-mail: dpkim@postech.ac.kr
Homepage: http://camc.postech.ac.kr
bDepartment of Chemistry, U.G.C. Centre of Advance Studies in
Chemistry, Guru Nanak Dev University, Amritsar 143005, India.
[+] These author contributed equally
Electronic Supplementary Information (ESI) available: Detailed
e
xperimental procedure, characterization, NMR spectral details, GC
spectral result, and the supplementary results. See
DOI: 10.1039/c000000x/
reported that CO2 could readily be incorporated by a three-component
coupling reaction using arynes and imines, where generated zwitterions
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DOI: 10.1039/C4GC02089H
where amine component has been changed from aliphatics to aromatics. Table 1: Optimization of reaction conditions for the formation of
This catalytic system is a simple and practical protocol with great oxazolidinedione via CO2 fixation multicomponent reactions of
potential for further applications especially in medicinal chemistry.
alkylacrylic acid with amine.a
Result and Discussion
Originally, we were encouraged by the result reported on the base
mediated reaction of amine and CO2 for the synthesis of carbamic acid
type reactive intermediate.9 We anticipated that such an intermediate
could be incorporated in alkene to generate newer heterocycles by metal
catalysts.10 To prove our working hypothesis, studies were initiated with
benchmark reactions of 2-bromo-3-(4-methoxyphenyl)acrylic acid11 1a
and p-anisidine 2a’ under CO2 transformation conditions for
oxazolidinedione synthesis (3aa’) (Table 1), involving optimization with
respect to catalysts, bases, solvents, and temperature. Several metal
catalysts were initially investigated for the reaction of 1a as a model
substrate in DMF at 80oC in the presence of Cs2CO3 (2.0 equiv relative
to amount of 1a) as a base under atmospheric CO2 pressure for 12 h
(Table 1). The reaction did not proceed in the absence of the metal salt
(Table 1, entry 1). Palladium salt, which was expected to activate the
cross coupling reaction, hardly worked for this reaction (Table 1, entry
7). Hence, a series of various copper catalysts were investigated under
identical reaction condition at 80 °C in Cs2CO3 as a base. As shown in
Table 1, DMF (Table 1, entries 2-6), and Cu2O catalyst showed the best
activity with isolated yield of 81% (Table 1, entry 5). The isolated
product was characterized by NMR and GC-MS. It was further
confirmed by single crystal X-ray diffraction study (Figure 2,
Supplementary information section S1.3.1, S1.4 and Figure S1).
Entry
1
Catalyst
-
Solvent
DMF
Base
Yieldb
0
Cs2CO3
2
3
4
5
6
CuI
CuBr
DMF
DMF
DMF
DMF
DMF
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
56
45
23
81
39
CuCl
Cu2O
Cu(OAc)2
7c
Pd(OAc)2
Cu2O
DMF
DMF
Cs2CO3
K2CO3
K3PO4
KOtBu
DBU
0
8
69
29
0
9
Cu2O
DMF
10
11
12
13
14
15
16
17d
18e
19
Cu2O
DMF
Cu2O
DMF
77
13
67
34
68
12
51
32
46
Cu2O
DMF
DMAP
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cu2O
DMSO
Dioxane
DMA
Toluene
DMF
Cu2O
Cu2O
Encouraged by this result, we investigated the effect of bases and
solvents with Cu2O as an optimum catalyst. Different bases such as
K2CO3, K3PO4, 4-Dimethylaminopyridine (DMAP), Potassium tert-
butoxide (KOtBu) and 1,8-Diazabicycloundec-7-ene (DBU) were used
(entries 8-12) to find that the best result was obtained with inorganic
base Cs2CO3 although DBU was equally capable of accelerating the
reaction.
Cu2O
Cu2O
Cu2O
DMF
Cu2O/N-rGO
DMF
(a)1a (0.50 mmol), 2a (0.60 mmol), Cu/Pd source (1.0 mol %), CO2
(1 atm), solvents (2 ml) at 80 °C for 12 h. (b)Isolated yield. (c)1,3-
bis(4-methoxyphenyl)urea (4) was isolated (12% yield). (d)Reaction
temperature was 60°C. (e)Catalyst loading was 0.5 mol%.
In the preliminary examination of solvents such as DMSO, dioxane,
DMA, toluene (entries 13-16), nonprotic polar solvents were found to
promote the reaction smoothly, and DMF was revealed as the best
solvent for the model reaction. We also found that a milder reaction
temperature at 60°C and a lower catalyst loading (0.5 mol%) resulted in
a
lower yield (entries 17-18). An alternative attempt to utilize
heterogeneous catalyst for CO2 fixation reaction via Cu2O/N-doped
reduced graphene oxide (Cu2O/N-rGO) catalyst was not successful only
with moderate yield (entry 19). It is noted in this regard that this reaction
is very simple with relatively high yield. The preliminary result is all the
more interesting as no further addition of any ligand was required with
metal catalyst.
Figure 2. Single-crystal X-ray diffraction analysis for (3aa’). Thermal
ellipsoids are shown at 30% probability level.
As shown in Figure 3, the scope of CO2 fixation multicomponent
reaction of 2-bromo-3-alkylacrylic acids with amines can be extended to
the formation of various products by employing different amines and
various bromoacrylic acid derivatives under the optimized conditions: 1
mol% of Cu2O catalyst, 2 equiv. of Cs2CO3 base, DMF solvent.
Four types of 2-bromo-3-alkylacrylic acid derivatives with p-
methoxyphenyl (1a), phenyl (1b), p-tolyl (1c), and p-chlorophenyl (1d)
substitutes were first synthesized by multistep reactions (See
supplementary information section S1.2). Then, the synthesized
bromoacrylic acid compounds were reacted with aliphatic and aromatic
amines under the derived optimal conditions (See supplementary
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Figure 3. Copper-catalyzed cascade synthesis of oxazolidinediones via information section S1.3). In the synthesis of oxazolidinedione with
CO2 fixation multicomponent reactions; [a]1 (1.0 mmol), 2 (1.2 mmol), various aliphatic amines, benzyl amine, and allyl amine produced the
Cu2O (1.0 mol %), Cs2CO3 (2.0 mmol) CO2 (1 atm), solvents (4 mL) at corresponding oxazolidinediones (3ad’, 3bd’, 3bg’) in high yields (79-
80 °C for 12 h. [b]Isolated yield.
83%), while the use of ammonia instead of aliphatic amines did not
allow isolation of the product (3ah’). Furthermore, we synthesized
aromatic amine containing oxazolidinedione ring systems, and
comparatively moderate to high yields in the range of 58-86% of
oxazolidinediones were obtained as listed in Figure 3. Mostly, p-OCH3
electron donating group on aromatic amines (3aa’, 3ba’, 3ca’) furnished
the products with superior yields over 80% in comparison to yields in
range of 68-73% for the p-Cl electron withdrawing group presented on
the amines (3ac’, 3cc’, 3dc’). Alternatively, the bromoacrylic acid
derivatives with p-methoxyphenyl, phenyl, p-tolyl, p-chlorophenyl
groups on the alkene gave moderate to high yields (58-88%),
irrespective of the electron-withdrawing (3ac’, 3cc’, 3cf’, 3dc’) or
electron-donating (3aa’, 3ba’, 3ca’, 3da’) nature of the group on the
phenyl ring.
3aa’ (Yield 81%)
3ac’ (Yield 68%)
3ah’ (Yield 0%)
3ab’ (Yield 72%)
3ae’ (Yield 78%)
3ad’ (Yield 83%)
3bd’ (Yield 79%)
3ba’ (Yield 73%)
3be’ (Yield 71%)
Scheme 1. Proposed reaction pathways for the synthesis of
oxazolidinedione via CO2 fixation multicomponent reactions
To further enhance the synthetic profile of the three component
coupling reactions of 2-bromo-3-alkylacrylic acid (1a), amine (2a), and
CO2, we also performed a scale-up synthesis of this copper-catalyzed
reaction to obtain 2.3 gram product (3aa’) with 72 % yield by the
identical protocol with no chromatography filtration step as
aforementioned, indicating further upscaling potential. (See
supplementary information scheme S1).
3cb’ (Yield 84%)
3bb’ (Yield 78%)
3bg’ (Yield 82%)
3cc’ (Yield 73%)
3ce’ (Yield 77%)
3ca’ (Yield 54%)
Scheme 1 shows hypothetical reaction mechanism. Firstly, the
amine and the CO2 react together to form an intermediate as a conjugate
base of carbamic acid I.9b Further, the corresponding 2-bromo-3-
alkylacrylic acid coordinates with a Cu(I) ion and forms II in the
presence of base (Cs2CO3). Next, 2-bromo-3-alkylacrylic acid Cu
complexes II undergo intramolecular oxidative addition followed by
complex formation with carbamic acid I to generate coper complex III,
and subsequent reductive elimination of copper complex III provides the
intermediate IV. Intramolecular nucleophilic attack of amino to carbonyl
in IV affords oxazolidinedione, freeing the copper catalyst. Eventually,
in this proposed mechanism, the corresponding oxazolidinedione
derivative contains carbon dioxide that is inserted into a heterocyclic
ring.
3cf’ (Yield 58%)
3da’ (Yield 80%)
3dc’ (Yield 71%)
3db’ (Yield 82%)
3de’ (Yield 81%)
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To gain a better insight into this Cu catalyzed three-component
reaction with carbon dioxide, control experiments were performed.
Normally, Cu-catalysed three component reaction was carried out at
atmospheric pressure of CO2. To prove the origin of inserted carbon
dioxide, isotope-labelling experiments with C18O2 were conducted to
investigate the presence of carbon dioxide in the oxazolidinedione
molecule (Scheme 2).10 As a result, the 18O-labeled oxazolidinedione
(MW 329) was detected by mass spectral analysis, and the non-labeled
oxazolidinedione (MW 325, MW 327) was not detected at all (See
supplementary information Figure S2). This result clearly supports the
proposed reaction mechanism by demonstrating that two oxygen atoms
were originated from carbon dioxide, indicating the participation of
whole CO2 molecule in forming the heterocyclic ring during the three
component reaction.
Acknowledgements
This work was supported by a National Research Foundation of Korea
(NRF) grant funded by the Korean Government (MEST) (2008-
0061983).
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Scheme 2. Mechanistic prove for the synthesis of oxazolidinedione via
CO2 fixation multicomponent reactions by isotopic labelling
experiments.
Conclusion
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synthesize oxazolidinedione derivatives in good-to-high yields.
A
number of aliphatic and aromatic amines as well as acrylic acid
derivatives can be transformed in high yields to pharmaceutically
relevant oxazolidinedione compounds even on a large scale. This
catalyst system does not need any sensitive ligands or expensive
additives. The results indicate that carbon dioxide can conceptually be
further utilized in various multicomponent reactions. Therefore, we
anticipate that this work would contribute substantially to the
development of next-generation CO2 utilization.
Experimental Details.
To a solution of a substituted 2-bromo-3-phenylacrylic acid (1.0 mmol),
amines (1.2 mmol) Cu2O (1.0 mol%) and DMF (4mL) in a Schlenk flask
was added Cs2CO3 (2.0 mmol, 2eq.). The inside of the reaction container
was purged with CO2 by a balloon three times (~1.0 atm). The reaction
mixture was stirred at 80 °C for 12 hours. Aqueous solution of NaHCO3
was added to reaction mixture and the water layer was separated with
separatory funnel using CHCl3. The combined organic layer was dried
over anhydrous Na2SO4, concentrated under reduced pressure. The pure
corresponding oxazolidinone was obtained with no further purification.
Oxazolidinone have been further crystallize by the methanol.
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