Synthesis of 5-vinylideneoxazolidin-2-ones by DBU-mediated CO 2-fixation reaction of 4-(benzylamino)-2-butynyl carbonates and benzoates

Article abstract of DOI:10.1021/ol800663v

A CO₂-fixation reaction of 4-(benzylamino)-2-butynyl carbonates and benzoates, carried out in the presence of DBU, provides substituted 5-vinylideneoxazolidin-2-ones. The reaction has been successfully applied to the CO₂-recycling process and fixation of atmospheric CO₂.

Full text of DOI:10.1021/ol800663v

ORGANIC
LETTERS
2008
Vol. 10, No. 10
2083-2086
Synthesis of 5-Vinylideneoxazolidin-
2-ones by DBU-Mediated CO2-Fixation
Reaction of 4-(Benzylamino)-2-butynyl
Carbonates and Benzoates
Masahiro Yoshida,*,† Yuki Komatsuzaki,‡ and Masataka Ihara*,§
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokushima, 1-78-1
Sho-machi, Tokushima, 770-8505, Japan, Graduate School of Pharmaceutical
Sciences, Tohoku UniVersity, Aobayama, Sendai, 980-8578, Japan, and Institute of
Medicinal Chemistry, Hoshi UniVersity, 2-4-41 Ebara, Shinagawa, 142-8501, Japan
yoshida@ph.tokushima-u.ac.jp
Received March 22, 2008
ABSTRACT
A CO2-fixation reaction of 4-(benzylamino)-2-butynyl carbonates and benzoates, carried out in the presence of DBU, provides substituted
5-vinylideneoxazolidin-2-ones. The reaction has been successfully applied to the CO2-recycling process and fixation of atmospheric CO2.
A number of 5-substituted oxazolidinones are shown to have
high potency as biologically active molecules and are widely
used in the pharmaceutical industry.1 Consequently, much
attention and extensive study have been focused on the
synthesis of oxazolidinones. The chemical fixation of CO2
with aziridines2 or propargylic amines3 is one of the most
useful and efficient methods. We have recently developed a
palladium-catalyzed CO2-fixation of 4-(benzylamino)-2-
butenyl carbonates (Scheme 1).4 The reaction proceeds
through a pathway involving decarboxylation-fixation of
liberated CO25 to afford 5-vinyloxazolidinones. We expected
that this process could be applied for the propargylic substrate
bearing an amino group at the propargylic position. We report
here a DBU-mediated CO2-fixation reaction of 4-(benzy-
lamino)-2-butynyl carbonates and benzoates. It is noteworthy
that the reaction undergoes under palladium-free conditions
to afford the 5-vinylideneoxazolidin-2-ones in good yields.
The initial reactions were carried out using a cyclohexyl-
substituted propargylic carbonate 1a in the presence of CO2.
(2) (a) Kawanami, H.; Matsumoto, H.; Ikushima, Y. Chem. Lett. 2005,
34, 60. (b) Hancock, M. T.; Pinhas, A. R. Synthesis 2004, 2347. (c) Shen,
Y.-M.; Duan, W.-L.; Shi, M. Eur. J. Org. Chem. 2004, 3080. (d) Miller,
A. W.; Nguyen, S. T. Org. Lett. 2004, 6, 2301. (e) Sudo, A.; Morioka, Y.;
Sanda, F.; Endo, T. Tetrahedron Lett. 2004, 45, 1363. (f) Sudo, A.; Morioka,
Y.; Koizumi, E.; Sanda, F.; Endo, T. Tetrahedron Lett. 2003, 44, 7889. (g)
Kawanami, H.; Ikushima, Y. Tetrahedron Lett. 2002, 43, 3841. (h) Tascedda,
P.; Dunach, E. Chem. Commun. 2000, 449.
† The University of Tokushima.
‡ Tohoku University.
§ Hoshi University.
(1) (a) Park, C.-H.; Brittelli, D. R.; Wang, C. L.-J.; Marsh, F. D.;
Gregory, W. A.; Wuonola, M. A.; McRipley, R. J.; Eberly, V. S.; Slee,
A. M.; Forbes, M. J. Med. Chem. 1992, 35, 1156. (b) Brickner, S. J.;
Hutchinson, D. K.; Barbachyn, M. R.; Manninen, P. R.; Ulanowicz, D. A.;
Garmon, S. A.; Grega, K. C.; Hendges, S. K.; Toops, D. S.; Ford, C. W.;
Zurenko, G. E. J. Med. Chem. 1996, 39, 673. (c) Lohray, B. B.; Baskaran,
S.; Rao, B. S.; Reddy, B. Y.; Rao, I. N. Tetrahedron Lett. 1999, 40, 4855.
(d) Selvakumar, N.; Srinivas, D.; Khera, M. K.; Kumar, M. S.; Mamigi,
R. N. V. S.; Sarnaik, H.; Charavaryamath, C.; Rao, B. S.; Raheem, M. A.;
Das, J.; Iqbal, J.; Rajagopalan, R. J. Med. Chem. 2002, 45, 3953. (e)
Barbachyn, M. R.; Ford, C. W Angew. Chem., Int. Ed. 2003, 42, 2010.
(3) (a) Maggi, R.; Bertolotti, C.; Orlandini, E.; Oro, C.; Sartori, G.; Selva,
M. Tetrahedron Lett. 2007, 48, 2131. (b) Feroci, M.; Orsini, M.; Sotgiu,
G.; Rossi, L.; Inesi, A. J. Org. Chem. 2005, 70, 7795. (c) Shi, M.; Shen,
Y.-M. J. Org. Chem. 2002, 67, 16. (d) Bacchi, A.; Chiusoli, G. P.; Costa,
M.; Gabriele, B.; Righi, C.; Salerno, G. Chem. Commun. 1997, 1209. (e)
Costa, M.; Chiusoli, G. P.; Rizzardi, M. Chem. Commun. 1996, 1699. (f)
Coppola, G. M.; Damon, R. E. J. Heterocycl. Chem. 1995, 32, 1133. (g)
Mitsudo, T.; Hori, Y.; Yamakawa, Y.; Watanabe, Y. Tetrahedron Lett. 1987,
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(4) Yoshida, M.; Ohsawa, Y.; Sugimoto, K.; Tokuyama, H.; Ihara, M.
Tetrahedron Lett. 2007, 48, 8678.
10.1021/ol800663v CCC: $40.75
Published on Web 04/23/2008
2008 American Chemical Society

Scheme 1
Table 2. Reactions Using Various Substituted Substrates 1b-fa
When 1a was subjected to the reaction with 10 mol % of
Pd(PPh3)4 and 2 equiv of DBU under CO2 (1 atm) in MeCN
at 80 °C, the vinylideneoxazolidinone 2a was produced in
51% yield (entry 1 in Table 1). Further investigations have
Table 1. Initial Attempts for the Base-Mediated Fixation of 1a
entry
base
DBU
DBU
DBU
DBU
DBU
DBU
DABCO
NEt3
solvent
time (h)
yielda (%)
a Reactions were carried out in the presence of 2 equiv of DBU in
acetonitrile under CO2 (1 atm) at 80 °C for 0.5-12 h.
1b
2
3
4
5
6
7
8
9
MeCN
MeCN
DMSO
DMF
6
12
9
10
48
48
14
48
48
48
51
99
81
86
58 (80)
59 (92)
60
79
58 (73)
N.R.
atm) yielded the vinylideneoxazolidinone 2a in 92% yield
(entry 1). Diethyl-substituted propargylic carbonate 1c was
transformed to 2c in 90% yield (entry 2). The product 1c
was similarly yielded from the reaction of diethyl-substituted
benzoate 1d in 99% yield (entry 3). Reactions of the
carbonate 1e and benzoate 1f, which have no substituents at
the propargylic position, also afforded the corresponding
oxazolidinone 2e in 81% and 99% yields, respectively
(entries 4 and 5).
THF
CH2Cl2
MeCN
MeCN
MeCN
MeCN
TMEDA
10
a The yields in parentheses are based on recovered starting material.
b The reaction was carried out in the presence of 10 mol % Pd(PPh3)4.
We then examined the required amount of DBU for the
above CO2-fixation reaction. As a result, it was clear that
the reaction successfully proceeded even in the catalytic
amount of DBU (10 mol %) to afford the product 2a in
moderate yield (Scheme 2).
made clear that the reaction successfully proceeded in the
absence of palladium catalyst. Thus, oxazolidinone 2a was
obtained in 99% yield when only 2 equiv of DBU was
employed (entry 2). The reaction using various solvents
resulted in the production of 2a in moderate to good yields
(entries 3-6). Other amine bases such as DABCO, Et3N,
and TMEDA were also effective for the reaction (entries
7-9), but no reaction proceeded in the absence of base (entry
10).
Scheme 2
The results of the reactions using various substrates 1b-f
are shown in Table 2. The reaction of 1b, having a benz-
oyloxy group as the leaving group, with DBU under CO2 (1
(5) For other examples about the palladium-catalyzed CO2-recycling
reactions, see:(a) Yoshida, M.; Ihara, M. Chem. Eur. J. 2004, 2886. (b)
Yoshida, M.; Ihara, M. Angew. Chem., Int. Ed. 2001, 40, 616. (c) Yoshida,
M.; Fujita, M.; Ishii, T.; Ihara, M. J. Am. Chem. Soc. 2003, 125, 4874. (d)
Yoshida, M.; Fujita, M.; Ihara, M. Org. Lett. 2003, 5, 3325. (e) Yoshida,
M.; Ohsawa, Y.; Ihara, M. J. Org. Chem. 2004, 69, 1590. (f) Yoshida, M.;
Ohsawa, Y.; Ihara, M. Tetrahedron 2006, 62, 11218.
It is known that DBU reacts with CO2 to form DBU-CO2
zwitterionic carbamic complex 3, which exhibits high activity
for various CO2-fixation reactions.4,6 To examine the effect
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Org. Lett., Vol. 10, No. 10, 2008

of DBU in the synthesis of vinylideneoxazolidinone, the
reaction of propargylic benzoate 1b with DBU-CO2 com-
plex 3 was attempted. When 1b was subjected to the reaction
with 2 equiv of 3 in MeCN at 50 °C, the corresponding
oxazolidinone 2a was produced in 52% yield (91% yield
based on recovered starting material) (Scheme 3). This result
Scheme 5
Scheme 3
to afford the carbamate-DBU complex 4. Intramolecular
SN2′ substitution of 4 produces the vinylideneoxazolidinone
2 with the regeneration of DBU.
To further highlight the potential of this process, we tried
the fixation of atmospheric CO2 (Scheme 6). Direct fixation
implies that the CO2-fixation process proceeds through the
formation of DBU-CO2 complex 3.
We next attempted the reaction in the absence of an
external CO2 source, to confirm whether a CO2-recycling
process4,5 occurs under the palladium-free conditions (Scheme
4). When propargylic carbonate 1a was subjected to the
Scheme 6
Scheme 4
of air containing CO2 into the organic molecules has received
much attention from the viewpoint of its potential use as an
abundant carbon source and global warming problems, but
few examples about this methodology were reported.9 When
the reaction of propargylic benzoate 1a was carried out under
air bubbling conditions with 10 equiv DBU for 14 days, the
CO2-fixed vinylideneoxazolidinone 2a was obtained along
with the by-produced oxazolidinone 510 in 43% and 40%
yields, respectively. The product 5 would be formed by
intramolecular nucleophilic attack of the carbamate anion
to the alkyne in the carbamate-DBU complex 4, followed
by successive protonation of the resulting intermediate 6.11
Although the reaction time was too long, the result clearly
indicates that air containing CO2 has been incorporated into
the propargylic substrate.
reaction with 5 equiv of DBU under argon atmosphere in a
sealed tube, the desired oxazolidinone 2a was produced in
81% yield. The substrate 1e was also transformed to the
corresponding product 2e in 85% yield. From these results,
it was clear that CO2 component in the substrate was
efficiently utilized as a CO2 source. To the best of our
knowledge, this is the first example of a CO2-recycling
reaction under transition metal-free conditions.
A plausible mechanism for the reaction is shown in
Scheme 5. The substrate 1 reacts with DBU-CO2 complex
3, a reactive species formed from DBU and CO2 in situ,7,8
(6) (a) Pe´rez, E. R.; da Silva, M. O.; Costa, V. C.; Rodrigues-Filho,
U. P.; Franco, D. W. Tetrahedron Lett. 2002, 43, 4091. (b) Pe´rez, E. R.;
Santos, R. H. A.; Gambardella, M. T. P.; de Macedo, L. G. M.; Rodrigues-
Filho, U. P.; Launay, J.-C.; Franco, D. W. J. Org. Chem. 2004, 69, 8005.
(c) Dinsmore, C. J.; Mercer, S. P. Org. Lett. 2004, 6, 2885.
(7) It is expected that the corresponding carbamate complexes are formed
in situ when other amines such as Et3N, pyridine, and DABCO are
employed.
(9) It is known that zinc and copper complexes can fix atmospheric CO2:
Sun, W. Y.; Kong, L. Y.; Zhang, Z. H.; Kawaguchi, H.; Okamura, T.; Doi,
M.; Ueyama, N.; Ford, C. W Angew. Chem., Int. Ed. 2005, 44, 4352.
(10) The stereochemistry of 5 was determined unambiguously by NOE
correlation, see the Supporting Information.
(8) In the CO2-recycling reaction (Scheme 4), it is presumed that the
CO2 source for the initial formation of DBU-CO2 complex 3 would be
derived from extremely low levels of CO2 in the solvent. The related
(11) (a) Similar cyclization reactions have been reported: Arcadi, A.;
Inesi, A.; Marinelli, F.; Rossi, L.; Verdecchia, M. Synlett 2005, 67. (b)
Asao, N.; Iso, K.; Yodha, S. S. Org. Lett. 2006, 84149.
observation has been reported, see ref 6c
.
Org. Lett., Vol. 10, No. 10, 2008
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In conclusion, we have developed a methodology for the
synthesis of 5-vinylideneoxazolidin-2-ones by DBU-mediated
CO2-fixation reaction. Substituted oxazolidinones are attractive
and important compounds in both medicinal and synthetic
organic chemistry, and our methodology would provide a new
protocol for the synthesis of substituted oxazolidinones. Further
studies about this type of reaction and synthetic application of
the resulting oxazolidinones are now in progress.
from the Japan Society for the Promotion of Science (JSPS)
and Takeda Science Foundation. We are grateful to a
reviewer for helpful suggestions about the reaction mecha-
nism.
Supporting Information Available: Starting material
1
preparations, spectral data, and copies of H and 13C NMR
spectra of all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This study was supported in part by a
Grant-in-Aid for the Encouragement of Young Scientists (B)
OL800663V
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Org. Lett., Vol. 10, No. 10, 2008