Synthesis of oxazolidin-2-ones via a copper(I)-catalyzed tandem decarboxylative/carboxylative cyclization of a propiolic acid, a primary amine and an aldehyde

Article abstract of DOI:10.1002/adsc.201100608

A facile approach to polysubstituted oxazolidin-2-ones is presented via a copper(I)-catalyzed tandem decarboxylative/carboxylative cyclization of a propiolic acid, a primary amine and an aldehyde (PA²-coulpling). This new multicomponent coupling constitutes an efficient methodology to provide the corresponding oxazolidin-2-ones in good yields. Copyright

Full text of DOI:10.1002/adsc.201100608

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DOI: 10.1002/adsc.201100608
Synthesis of Oxazolidin-2-ones via a Copper(I)-Catalyzed
Tandem Decarboxylative/Carboxylative Cyclization of a Propiolic
Acid, a Primary Amine and an Aldehyde
Huangdi Feng,a,b Denis S. Ermolat’ev,a,* Gonghua Song,b
and Erik V. Van der Eyckena,*
a
Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, Katholieke Universiteit
Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium
Fax : (+32)-16-327-990; phone: (+32)-16-327-406; e-mail: denis.ermolatev@chem.kuleuven.be or
erik.vandereycken@chem.kuleuven.be
Shanghai Key Laboratory of Chemical Biology, East China University of Science and Technology, 130 Meilong Road,
b
Shanghai 200237, Peopleꢀs Republic of China
Received: August 1, 2011; Revised: September 18, 2011; Published online: January 19, 2012
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100608.
Abstract: A facile approach to polysubstituted oxa- constitutes an efficient methodology to provide the
zolidin-2-ones is presented via a copper(I)-catalyzed corresponding oxazolidin-2-ones in good yields.
tandem decarboxylative/carboxylative cyclization of
a propiolic acid, a primary amine and an aldehyde Keywords: carboxylative cyclization; decarboxylative
(PA2-coulpling). This new multicomponent coupling coupling; oxazolidinones; three-component coupling
Introduction
In the past decades, a variety of protocols has been
reported for the syntheses of oxazolidin-2-ones in-
Oxazolidin-2-ones are largely utilized as latent 1,2- cluding the cyclization of carbonyl compounds with a-
amino alcohols and as chiral auxiliaries in enantiose- amino acids or 1,2-amino alcohols,[3] the [2+3]cou-
lective synthesis.[1] Moreover, oxazolidin-2-ones have pling between heterocumulenes and oxiranes or aziri-
also a wide application in pharmaceutical science: for dines,[4] cyclocarbamations[5] and Au-catalyzed cycliza-
example, Linezolid has been reported as the first tion of N-Boc-propargylic amines.[6] The cycloaddition
member of a new class of antibacterial agents that procedure of propargylic amines with CO2 is a very
possess potent activity against Gram-positive bacteria, attractive alternative as CO2 is an easily available, re-
and an array of various oxazolidin-2-ones have been newable and environmentally benign substrate.[7] Al-
described as antibacterial compounds (Figure 1).[2] though a variety of methods for these carboxylation
Therefore, the development of an efficient and green reactions has been developed, high CO2 pressure or/
method for the synthesis of oxazolidin-2-ones has at- and noble metal catalyst are required, and most pro-
tracted much attention in the chemical community.
tocols are limited to the use of terminal alkynes.[8]
Results and Discussion
Following the success of the tandem A3-coupling/car-
boxylative cyclization for the synthesis of oxazolidin-
2-ones[9] and the C C and C N bond formation via
decarboxylative coupling of propiolic acids,[10] we
were wondering whether it would be possible to gen-
erate the oxazolidin-2-one framework in a one-pot
fashion via reaction of a propiolic acid, an aldehyde
and a primary amine (PA2-coupling) in which the car-
À
À
Figure 1. Examples of biologically active oxazolidin-2-ones.
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Huangdi Feng et al.
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Scheme 1. One-pot synthesis of oxazolidin-2-ones.
boxylic acid should serve as the source of CO2 conditions we could isolate the desired compound 6a
(Scheme 1). in an excellent yield of 92% after 22 h of oil bath
Our initial study applied phenylpropiolic acid in heating (Table 1, entry 8). Switching to other Cu cata-
combination with cyclohexanecarbaldehyde and amyl- lysts resulted in noticeably lower yields (Table 1, en-
amine. The feasibility of this tandem reaction was in- tries 8–14). A relatively high amount of CuI was re-
vestigated under microwave irradiation, employing quired with an optimum of 30 mol% (Table 1, en-
different catalysts and solvents (Table 1, entries 1–7). tries 8, 15 and 16). Further increasing the catalyst
To our great satisfaction the desired oxazolidin-2-one loading did not result in a higher yield (Table 1,
6a was formed in each case together with the propar- entry 17). In addition, we found that the reaction time
gylic amine. The best result was obtained when and temperature were important parameters for this
30 mol% of CuI was used in EtOH under microwave tandem reaction. When decreasing the reaction time
irradiation at a ceiling temperature of 858C and a to 6 h, the yield was drastically reduced (Table 1,
maximum power of 80 W for 80 min (Table 1, entry 18). This could not be fully compensated by an
entry 7). However, as the irradiation time was already increase of the reaction temperature to 1008C
long (Table 1, compare entries 2 and 7) we decided to (Table 1, entry 19).
switch to conventional heating. Applying the same
Table 1. Optimization of the conditions.[a]
Entry
Catalyst (mol%)
Solvent
Temperature [oC]
Time
Yield[b] [%]
1
2
3
4
5
6
7
8
CuI (30)
CuI (30)
CuI (30)
CuI (30)
CuBr (30)
AgNO3 (10)
CuI (30)
toluene
EtOH
THF
100
85
80
75
85
85
85
85
85
85
85
85
85
85
85
85
85
85
100
70
40 min
40 min
40 min
40 min
40 min
40 min
80 min
22 h
22 h
22 h
22 h
22 h
22 h
22 h
22 h
22 h
22 h
6 h
6 h
22 h
trace[c]
37[c]
5[c]
9[c]
15[c]
8[c]
57[c]
92
52
23
6
16
11
5
78
83
87
61
77
73
EtOAc
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
CuI (30)
9
CuBr (30)
CuCl (30)
CuOAc (30)
10
11
12
13
14
15
16
17
18
19
20
Cu
N
CuOTf (30)
CuTc (30)
CuI (10)
CuI (20)
CuI (40)
CuI (30)
CuI (30)
CuI (30)
[a]
Reactions were performed using phenylpropiolic acid (2 mmol), amylamine (1.5 mmol), cyclohexanecarbaldehyde
(1 mmol) and solvent (1.5 mL) under conventional heating conditions.
Isolated yields based on cyclohexanecarbaldehyde.
[b]
[c]
Microwave irradiation, 80 W.
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Synthesis of Oxazolidin-2-ones via a Copper(I)-Catalyzed Tandem
Table 2. Scope and limitations of the protocol.[a]
Entry
R1
R2
R3
Product
Yield[b] [%]
1
2
3
4
5
6
7
8
phenyl
phenyl
phenyl
phenyl
phenyl
phenyl
phenyl
phenyl
phenyl
phenyl
phenyl
phenyl
phenyl
phenyl
phenyl
phenyl
phenyl
phenyl
phenyl
Me
ethyl
isopropyl
amyl
amyl
hexyl
heptyl
nonyl
undecyl
cyclohexylmethyl
3,4-dimethoxyphenethyl
3-methoxylphenyl
amyl
amyl
amyl
amyl
amyl
octyl
PMB
cyclopentyl
heptyl
heptyl
octyl
amyl
amyl
amyl
amyl
amyl
amyl
amyl
amyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
hexyl
decyl
i-butyl
Ph
4-methylphenyl
i-butyl
i-butyl
i-butyl
i-propyl
3-ethylpropyl
cyclopropyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
6{1}
6{2}
6{3}
6{4}
6{5}
6{6}
6{7}
6{8}
92
89
91
93
89
88
87
0
73
67
70
62
65
68
65
36
85
71
84
39
41
51
55
54
57
85
83
9
6{9}
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
6{10}
6{11}
6{12}
6{13}
6{14}
6{15}
6{16}
6{17}
6{18}
6{19}
6{20}
6{21}
6{22}
6{23}
6{24}
6{25}
6{26}
6{27}
hexyl
naphthyl-2-
4-methylphenyl
4-methoxyylphenyl
[a]
Reactions were performed using propiolic acid (2 mmol), amine (1.5 mmol), aldehyde (1 mmol) and ethanol (1.5 mL)
under conventional heating at 858C for 22 h.
Isolated yields based on cyclohexanecarbaldehyde.
[b]
With the optimized conditions at hand (Table 1, To the best of our knowledge, there are no literature
entry 8) we evaluated the scope of this PA2 coupling examples describing a carboxylative cyclization to ox-
protocol (Table 2). In general, moderate to good azolidin-2-ones when aliphatic propargylic amines or
yields were obtained by reaction of a variety of pro- aliphatic alkynes are involved.
piolic acids, primary amines and aldehydes in the
A tentative mechanism for this tandem decarboxy-
presence of 30 mol% CuI in ethanol. Primary aliphat- lative/carboxylative cyclization is proposed in
ic amines gave the corresponding products in good Scheme 2. In the first step, propiolic acid 1 undergoes
yields (Table 2, entries 1–7). However, no product was a Cu(I)-catalyzed decarboxylation affording copper
obtained when the aromatic 3-methoxyaniline was acetylide a and CO2 (5). Then the copper acetylide a
used (Table 2, entry 8). It was envisaged that aliphatic attacks the in situ formed imine resulting in the for-
amines may increase the effective concentration of mation of the intermediate propargylamine 4. After
CO2 in solution by the formation of the carbamic that, a Cu(I)-catalyzed addition of CO2 5 released
acids with CO2.[11] To further investigate the scope of from the propiolic acid to propargylic amine 4 gives
the reaction, we then investigated different aldehydes. the intermediate b, which undergoes a Cu(I)-cata-
Both aliphatic and aromatic aldehydes were explored lyzed cyclization into c. Subsequent protonolysis de-
in combination with various amines, and moderate to livers finally the desired product the oxazolidin-2-one
good yields were obtained (Table 2, entries 9–19). Fi- 6. In order to verify that the product 6 was formed
nally, we evaluated the reaction of different propiolic via an intermolecular carbonylation of propargylic
acids. The desired oxazolidin-2-ones 6 were obtained amine 4 and released CO2, we set up two experiments
in moderate to good yields (Table 2, entries 20–27). (Scheme 2). Applying our optimized conditions, the
Adv. Synth. Catal. 2012, 354, 505 – 509
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Experimental Section
General Information
All solvents and reagents were purchased from commercial
sources and were used without prior purification. All micro-
wave irradiation experiments were carried out in a dedicat-
ed CEM-Discover monomode microwave apparatus, operat-
ing at a frequency of 2.45 GHz with continuous irradiation
power from 0 to 300 W. The reactions were carried out in
10-mL glass tubes, sealed with a Teflonꢂ septum and placed
in the microwave cavity. The reaction mixture was irradiated
at the required ceiling temperature using maximum power
for the stipulated time, and the reaction mixture tempera-
tures were measured by the external IR sensor. The reaction
tube was cooled to ambient temperature with air jet cooling.
TLC analysis was performed on aluminum backed plates
SIL G/UV254. The products were purified by silica gel
1
(200–300 mesh) column chromatography. H and 13C NMR
spectra were recorded on a 300 MHz or 600 MHz NMR in-
1
strument. The H chemical shifts are reported in ppm rela-
tive to tetramethylsilane. High-resolution mass spectra were
recorded by using an ion source temperature 150–2508C as
required. High-resolution EI-mass spectra were performed
with a resolution of 10000.
General Procedure for the Synthesis of Oxazolidin-2-
ones 6
Propiolic acid
1 (2.0 mmol) was dissolved in ethanol
(1.5 mL) applying a vial along with a stirring bar, and then
amine 2 (1.5 mmol), aldehyde 3 (1.0 mmol) and copper
iodide (0.30 mmol) were added. The reaction vessel was
sealed and heated in an oil-bath for 22 h at a temperature of
858C. The resulting reaction mixture was loaded on a
column and flashed on silica gel (7–9% ethyl acetate-hexane
mixture) to afford the desired product 6
5-Benzylidene-4-cyclohexyl-3-pentyloxazolidin-2-one 6{1}:
1H NMR (300 MHz, CDCl3): d=7.62 (d, J=7.74 Hz, 2H),
7.60 (t, J=15.09, 2H), 7.20 (t, J=14.52, 1H), 5.50 (s, 1H),
4.26 (s, 1H), 3.70–3.57 (m, 1H), 3.11–3.02 (m, 1H), 1.87–
1.55 (m, 8H), 1.40–1.08 (m, 9H), 0.93 (s, 3H); 13C NMR
(75.5 MHz, CDCl3): d=155.4, 145.6, 133.7, 128.4, 126.7,
104.1, 63.4, 41.7, 40.7, 28.8, 27.9, 26.9, 26.4, 26.2, 26.1, 26.0,
22.3, 14.0; HR-MS (EI): m/z=327.2217, calcd. for
C21H29NO2 [M+H]: 327.2198.
Scheme 2. Proposed mechanism for the PA2 coupling.
addition of propargylic amine 4’ to the synthesis re-
sulted in the mixture of products A and B, and the
ratio of A/B was determined as 3/5 by GC-MS [Eq.
(1)]. Further experiment using 1’ showed that both
the products C and D were obtained in a 1:1 ratio as
determined by GC-MS [Eq. (2)]. From these results,
we are quite confident that the oxazolidin-2-one is
generated via the formation of an intermediate prop-
Supporting Information
argylic amine 4/intermolecular carboxylative cycliza- General experimental methods, spectroscopic characteriza-
tion and copies of 1H NMR and 13C NMR spectra for all
tion.
compounds are available in the Supporting Information.
Conclusions
Acknowledgements
In conclusion, the Cu(I)-catalyzed tandem decarboxy-
lative/carboxylative cyclization of a propiolic acid, a
The authors wish to thank the F.W.O. [Fund for Scientific Re-
search – Flanders (Belgium)] and the Research Fund of the
Katholieke Universiteit Leuven for financial support to the
laboratory. D.S.E. is grateful to the F.W.O. for providing a
postdoc fellowship. H. D. F. thanks the China Scholarship
Council for financial support.
primary amine and an aldehyde (PA2 coupling) con-
stitutes an efficient approach for the synthesis of oxa-
zolidin-2-one under mild reaction conditions. Interest-
ingly, this procedure is applicable to a wide variety of
aldehydes, primary amines and propiolic acids.
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Synthesis of Oxazolidin-2-ones via a Copper(I)-Catalyzed Tandem
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