Organocatalyzed carboxylative cyclization of propargylic amides with atmospheric CO2 towards oxazolidine-2,4-diones

Article abstract of DOI:10.1039/c8gc03929a

The metal-free carboxylative cyclization of propargylic amides with CO₂ to oxazolidine-2,4-diones was achieved for the first time employing 1,5,7-triaza-bicyclo-[4.4.0]dec-5-ene (TBD) as an organocatalyst. This method allows for the efficient a

Full text of DOI:10.1039/c8gc03929a

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DOI: 10.1039/C8GC03929A
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Organocatalyzed Carboxylative Cyclization of Propargylic Amides
with Atmospheric CO2 towards Oxazolidine-2,4-diones
Received 00th January 20xx,
Accepted 00th January 20xx
Hui Zhou,* Sen Mu, Bai-Hao Ren, Rui Zhang and Xiao-Bing Lu
DOI: 10.1039/x0xx00000x
www.rsc.org/
The metal-free carboxylative cyclization of propargylic amides
with CO2 to oxazolidine-2,4-diones was achieved for the first time
employing 1,5,7-triaza-bicyclo-[4.4.0]dec-5-ene (TBD) as
organocatalyst. The method allows for the efficient and selective
synthesis of a variety of (Z) 5-alkylidene 1,3-oxazolidine-2,4-diones,
and a variety of functional groups are well-tolerated under mild
reaction conditions. Theoretical studies reveal that the
bifunctional activity (base/H-bond donor) of TBD plays a key role
in accelerating this reaction.
Oxazolidine-2,4-diones are important motifs in organic
chemistry, due to their widespread presence in natural
products and the actual uses in medicine and agriculture as
antiepileptic agents, anti-inflammatory agents, and
herbicides.1 Traditional synthetic methods of oxazolidine-2,4-
diones mostly require multistep reactions and relatively harsh
conditions, in which toxic and hazardous compounds such as
phosgene or isocyanates are usually involved.1a,2 In view of
environmental-friendly point, catalytic transformations of CO2
generating high value-added chemicals and polymers provide a
greener alternative to this area.3 Up to now, several examples
have been described in the literature on the construction of
oxazolidine-2,4-diones using CO2 as a feedstock, as shown in
Scheme 1. Among them, Saliu and co-workers reported that
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) mediated the
carboxylation of N-substitued-2-chloroacetamide with CO2 in
one-step procedure (Scheme 1A).4 Later on, Ma group
reported that K2CO3 involved the carboxylation of propargylic
amides with CO2, selectively yielding 5-alkylidene cyclic
oxazolidine-2,4-diones under ambient conditions (Scheme
1B).5 Recently, Zhang and coworkers presented a tandem
phosphorus mediated carboxylative condensation of primary
Scheme 1. CO2 involved synthesis of oxazolidine-2,4-diones
carboxylative reagent, and one-pot NaOMe-catalyzed
cyclization to construct functionalized oxazolidine-2,4-diones
(Scheme 1C).6
In contrast to the above processes mediated by
stoichiometric organic/inorganic bases, approach to catalytic
carboxylation reactions using CO2 as carboxylative agent is
highly desired. Up to now, the only catalytic precedent
reported by Kim et al is Cu2O catalyzed three-component
reaction of amines, 2-bromo-3-phenylacrylic acid and CO2 in
the presence of two equivalent of CsCO3 (Scheme 1D)7. Herein,
we firstly present an effective metal-free catalytic strategy to
prepare oxazolidine-2,4-diones by the carboxylative cyclization
of propargylic amides with atmospheric CO2 at room
temperature, employing 1,5,7-triaza-bicyclo-[4.4.0]dec-5-ene
(TBD) as organocatalyst. Notably, this mild method is a
convenient and operationally simple protocol to afford
functionalized 5-alkylidene 1,3-oxazolidine-2,4-diones with
high chemo- and stereoselectivity (Scheme 1E).
amines and α-ketoesters using atmospheric CO2 as
a
Dr. H. Zhou, S. Mu, B.-H. Ren, R. Zhang, Porf. Dr. X.-B. Lu,
State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian
116024, China. E-mail: zhouhui@dlut.edu.cn
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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Table 2. TBD-catalyzed carboxylative cyclization of functionalized propargylic amides
with CO2
DOI: 10.1039/C8GC03929A
Table 1. Nitrogen Lewis bases catalyzed carboxylative cyclization of N-benzyl-
a
a
3-phenylpropiolamide 1a with CO2
O
O
Bn
N
R2
O
O
TBD
(5.0 mol%)
O
N
R1
O
Cat.
(5.0 mol%)
O
+
C
O
HN R2
O
C O
THF, 25 oC, 1 h
+
O
R1
O
NHBn
25 oC, 1.0 atm
1a
(Z)-2a
1
2
N
N
N
N
N
O
O
O
N
N
N
H
N
N
N
N
Bn
N
Bn
N
Bn
O
O
O
N
DBN
DBU
TBD
MTBD
DMAP
O
O
O
F
H3C
O
Entry
Cat.
DMAP
DBN
DBU
TBD
MTBD
TBD
TBD
TBD
TBD
TBD
-
solvent
DMF
DMF
DMF
DMF
DMF
DMSO
DCM
CH3CN
THF
t (h)
Yield (%)b
NRc
16
b
2d
2g
Yield: 99%
2b
2e
Yield: 83%
2c
Yield: 70%
O
O
O
1
2
1
1
1
1
1
1
1
1
1
4
4
Bn
Bn
Bn
Bn
Bn
O
N
O
O
N
N
O
O
O
O
Cl
Br
Yield: 98%
Yield: 99%
2f
Yield: 98%
3
23
O
O
O
Bn
4
50
O
N
O
O
N
N
O
O
O
O
O
Yield: 80% (Z/E=3.8:1)
NC
O2N
5
33
c
2i
2j
Yield: 98%
2h
Yield: 78%
6
16
O
O
Bn
N
Bu
N
O
O
7
44
O
F3C
O
2k
2k
X-ray structure of
2l
Yield: 82%
Yield: 99%
8
75
O
O
9
98
O
N
O
N
10d
11
THF
5
O
O
d
b
2n
Yield: 63%
2m
X-ray structure of
2m
Yield: 78%
THF
NRc
O
O
PMB
N
a
O
N
O
General reaction conditions: Propargylic amide 1a (0.5 mmol), Cat. (0.025
mmol, 5 mol%), Solvent (0.2 mL), CO2 (1.0 atm), 25 oC. Determined by 1H-
NMR spectroscopy. c No reaction. d Hydrous THF used as solvent. DMAP = 4-
dimethylaminopyridine, DBN = 1,5-Diazabicyclo[4.3.0]non-5-ene, DBU = 1,8-
Diazabicyclo[5.4.0] undec-7-ene, TBD = 1,5,7-triaza-bicyclo-[4.4.0]dec-5-ene,
MTBD = 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene.
b
O
O
b
d
2o
X-ray structure of
2o
2q
2p
Yield: 83%
Yield: 60%
O
O
O
O
O
Bn
Bn
O
N
N
N
O
O
O
O
Et
O
2s
S
b
b
e
Yield: 64%
2r
Yield: 98%
Yield: 98%
Initially, we systematically examined the carboxylative
cyclization of N-benzyl-3-phenylpropiolamide 1a with CO2 as a
benchmark reaction, employing common and commercially
available nitrogen Lewis bases as organocatalysts in a variety
of solvents at ambient conditions. The results are summarized
in Table 1. When using DMAP as organocatalyst, the reaction
didn’t occur in DMF solution (Table 1, entry 1). To our delight,
this carboxylative cyclization took place when changing to DBN
or DBU, and the desired oxazolidine-2,4-dione 2a as the sole
product was obtained in 16% and 23% yield within 1 h,
respectively (Table 1, entries 2 and 3). In addition, the absolute
stereostructure of (Z)-2a was clearly confirmed based on the
previous literature.5 By further using TBD or MTBD, we found
that the product 2a was produced in higher yield (Table 1,
entries 4 and 5). The solvent effect has also been examined in
the presence of TBD (Table 1, entries 6-9). We found that THF
was the optimal solvent for this reaction, and up to 98% yield
was obtained within only 1 h. It should be pointed out that this
process is usually carried out under strictly water-free
conditions. When using wet THF as solvent, only 5% yield of 2a
a General reaction conditions: Propargylic amide 1 (0.5 mmol), TBD (0.025 mmol, 5
mol%), THF (0.2 mL), CO2 (1.0 atm), 25 oC. Yields were determined by 1H-NMR
b
c
spectroscopy of the crude mixture. Reaction time: 6 h. The ratio of Z/E within
parentheses was determined by 1H-NMR spectroscopy of the crude mixture. CO2
(2.0 MPa), 80 oC, DMSO (0.2 mL). e DBU as organocatalyst.
d
was obtained within 4 h (Table 1, entry 10). Moreover, no
reaction was observed in the absence of catalyst (Table1, entry
11).
The substrate scope of the reaction was then explored using
anhydrous THF as solvent at standard conditions (5.0 mol%
o
TBD loading, 25 C, and 1.0 bar of CO2). The results are shown
in Table 2. A range of propargylic amides with electron-
donating (2b and 2c) and electron-withdrawing (2d-2k) groups
on phenyl ring, were tolerated in this process, providing the
desired products in moderate to good yields with excellent
stereoselectivity. Note that the nitro group attached on phenyl
ring 1i showed a relatively lower stereoselectivity to form 2i in
80% isolated yield. Meanwhile, various functionalized alkyl (-R2)
amides were also found to be suitable reaction partners (Table
2 | J. Name., 2012, 00, 1-3
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2, 2l-2q). It is interesting to note that the reaction of N-
propargylic precursor 1m containing two carbon-carbon triple
bonds, gave the desired oxazolidine-2,4-dione 2m with high
chemoselectivity, which could be applied for in vivo
bioorthogonal reactions through the use of click chemistry.8 In
addition, the presence of a thiophene group on the acetylenic
carbon atom did not hamper the successful preparation of 2n,
and an isolated yield of 98% could be obtained by a prolonging
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DOI: 10.1039/C8GC03929A
Scheme 3. Plausible reaction mechanism
reaction time of
6 hours. When employing DBU as
organocatalyst, proprargylic derivative 1s with ester group was
also applicable in this process. Furthermore, the absolute (Z)
configuration of 2k, 2m and 2o were clearly proved by X-ray
crystallographic analysis, respectively.
To gain more insight into the reaction mechanism, a series
of control experiments were investigated by means of In-situ
FTIR and 1H-NMR spectroscopy (Supporting Information.
Figure S1-S5). Noting that CO2 could be activated by strong
organic bases, especially, organic guanidines,9 and the
corresponding TBD-CO2 adduct was firstly isolated in THF
solution due to the hydrogen bonding interaction.10 Figure S1
showed that TBD also could rapidly react with free CO2 in
CH2Cl2 solution and the carbonyl peak of TBD-CO2 adduct at
1713 cm-1 gradually increased within 2 hours. Meanwhile, TBD
as organic base could also activate propargylic amides. In
Figure S2, the peak associated to carbonyl group of 1a
smoothly shifts towards lower frequencies, from 1655 cm-1
after 2.0 h to 1622 cm-1. Furthermore, the interaction of TBD
1
and 1a was proved by H-NMR titration experiments, in which
the -NH- signal (δ 6.20 ppm) completely disappears in the Scheme 2. Plausible reaction mechanism. The Gibbs free energy in solution are
presence of 1.0 equivalent TBD, while the ArCH2- signal (δ 4.55
a
relative to the energy sum of TBD, CO2, and 1n
ppm) undergoes a modest downshift of -0.05 ppm (Figure S5).
hydrolysis,10, 12 which leads to form the corresponding [TBDH]+
bicarbonate salt, it is necessary to carry out this process in an
anhydrous reaction condition. During the subsequent attack of
oxygen anion in the intermediate A on the C≡C bond of
propargylic amide, the step should overcome an energy barrier
of 20.1 kcal/mol to form an alkenyl anion intermediate B.
Finally, the [TBDH]+ cation provides the proton to the alkenyl
anion via transition state TS3 with an energy barrier of 11.9
kcal/mol, leading to generate 5-alkylidene cyclic oxazolidine-
2,4-diones and the recovery of free TBD. The overall reaction is
exothermic by 5.4 kcal/mol and the insertion step of free CO2
to N-H bond of propargylic amides is the rate determining step
via the dual activation by TBD through hydrogen bonding,
which is in well agreement with the experimental results.
Moreover, propargylic amide 1a due to the low nucleophilicity
of the nitrogen atom, is very stable under CO2 atmosphere,
and no observable change in the absorption intensity at 1655
cm−1 was found (Figure S3). When TBD was subsequently
added into the solution, the carbonyl peak of 1a at 1655 cm-1
gradually decreased and the carbonyl peak of desired
oxazolidine-2,4-diones 2a at 1818 cm−1 and 1743 cm−1
simultaneously increased (Figure S4).
On the basis of preliminary mechanistic studies and previous
reports,11 a plausible mechanism is proposed to account for
this transformation (Scheme 2). Meanwhile, density functional
theory (DFT) B3LYP-D3(BJ) was employed to investigate the
mechanism, and its potential energy curves are illustrated in
Supporting Information, Figure S10. In the first step of this
process, the hydrogen attached to the nitrogen of TBD
activates the carbonyl group of free CO2, and the imine
nitrogen simultaneously activates the propargylic amides by
attracting the hydrogen of its amide group through a lone pair
interaction. Then, in the transition state TS1 with an energy
barrier of 25.6 kcal/mol, both C-N bond formation and proton
transfer occur at the same time, and a new [TBDH]+carbamate
ionic pair intermediate A is formed. It is worth noting that the
low transformation barriers for the CO2 addition of TBD and
the decarboxylation of TBD-CO2 adduct show the reversible
CO2 binding with TBD under room temperature (Supporting
Information, Figure S9). Because TBD-CO2 adduct is sensitive to
Conclusions
In conclusion, we have developed a high efficient cyclization of
propargylic amides with atmospheric CO2 employing
commercially available TBD as organocatalyst, allowing a facile
access to (Z) 5-alkylidene oxazolidinones in good yields with
excellent chemo- and stereoselectivity. To the best of our
knowledge, the reported system is the first metal-free catalyst
for this transformation. The reaction operates under very mild
o
reaction conditions (25 C, pCO2=1.0 atm, 5 mol% catalyst) and
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Conflicts of interest
There are no conflicts to declare
Acknowledgements
This work is supported by National Natural Science Foundation
of China (Grant No. 21402021), the Fundamental Research
Funds for the Central Universities (DUT18LK55) and the
Program for Changjiang Scholars and Innovative Research
Team in University (IRT-17R14). X.-B. Lu gratefully
acknowledges the Chang Jiang Scholars Program (No.
T2011056) from Ministry of Education, People’s Republic of
China.
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Organocatalyzed Carboxylative Cyclization of Propargylic Amides with Atmospheric CO2 towards Oxazolidine-2,4-diones
View Article Online
DOI: 10.1039/C8GC03929A
Hui Zhou,* Sen Mu, Bai-Hao Ren, Rui Zhang and Xiao-Bing Lu
A facile and practical TBD-catalyzed carboxylative cyclization of propargylic amides with atmospheric CO2 has been developed for the
formation of (Z) 5-alkylidene 1,3-oxazolidine-2,4-diones.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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