Synthesis of oxazolidine-2,4-diones by a tandem phosphorus-mediated carboxylative condensation - Cyclization reaction using atmospheric carbon dioxide

Article abstract of DOI:10.1039/c5cc01530h

The oxazolidine-2,4-dione motif is found frequently in biologically important compounds. A tandem phosphorus-mediated carboxylative condensation of primary amines and α-ketoesters/base-catalyzed cyclization reaction have been developed. These processes provide a novel and convenient access to various oxazolidine-2,4-diones in a one-pot fashion using atmospheric carbon dioxide and readily available substrates under very mild and transition-metal-free conditions.

Full text of DOI:10.1039/c5cc01530h

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Synthesis of oxazolidine-2,4-diones by a tandem
phosphorus-mediated carboxylative
condensation–cyclization reaction using
atmospheric carbon dioxide†
Cite this: Chem. Commun., 2015,
51, 6175
Received 19th February 2015,
Accepted 1st March 2015
Wen-Zhen Zhang,* Tian Xia, Xu-Tong Yang and Xiao-Bing Lu
DOI: 10.1039/c5cc01530h
www.rsc.org/chemcomm
The oxazolidine-2,4-dione motif is found frequently in biologically efficiency, the use of transition metals involves drawbacks
important compounds. A tandem phosphorus-mediated carboxylative including their associated cost, toxicity, and raises the important
condensation of primary amines and a-ketoesters/base-catalyzed issue of removing metal impurities from the products, especially
cyclization reaction have been developed. These processes provide in the synthesis of pharmaceutical compounds. Therefore, the
a novel and convenient access to various oxazolidine-2,4-diones in a development of a transition-metal-free methodology to convert
one-pot fashion using atmospheric carbon dioxide and readily available carbon dioxide into value-added compounds is desirable.8
substrates under very mild and transition-metal-free conditions.
Intrigued by the development of a convenient access to
oxazolidine-2,4-dione and as a continuation of our interest in
Oxazolidine-2,4-diones are important structural motifs frequently carbon dioxide utilization,9 we envisioned that oxazolidine-2,4-
found in medicinally relevant and biologically active molecules.1–5 dione I could be easily synthesized by cyclization of carbamate II,
These compounds have been identified as having diverse properties which might be obtained by an insertion reaction of a metal
such as antitumor,1 cardiotonic,2 antidiabetic,3 and anti-inflammatory carbenoid and carbamic acid formed in situ from primary amines
activity.4 For example, vinzolidine shows broad inhibitory activity and carbon dioxide (eqn (1), Scheme 1).10,11 However, our initial
against many cancer cell lines.1 Anticonvulsants ethosuximide and investigation revealed that the Rh2(OAc)4 catalyzed reaction of
trimethadione were found to exhibit life-span-extending activity.5 amine, carbon dioxide and methyl 2-diazo-2-phenylacetate gave
Vinclozolin has long been established as a common fungicide no carbamate product II (see ESI†). Instead, non-carboxylative
used to control diseases in fruits and vegetables. With regard to product III was exclusively formed from the insertion of the N–H
oxazolidine-2,4-diones synthesis, most of the traditional strategies bond of the amine into the metal carbenoid, due to that metal
suffer from harsh reaction conditions, multi-steps and the use of
very toxic compounds like phosgene and isocyanates. Therefore,
a mild, convenient and environmentally friendly method for the
synthesis of oxazolidine-2,4-diones is highly desired.
Recently, the development of homogeneous transformation
of carbon dioxide into valuable fine chemicals has drawn
considerable attention since carbon dioxide is an abundant,
nontoxic and renewable carbon resource.6 Reactions of carbon
dioxide with relatively weak carbon nucleophiles, C–H bonds,
halide electrophiles have been successfully developed to access
functionalized carboxylic acids and derivatives.7 Due to the
thermodynamic and kinetic stability of carbon dioxide, high-
energy starting materials or transition-metal catalysts are often
used to facilitate these reactions. Despite their good catalytic
State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian,
116012, P. R. China. E-mail: zhangwz@dlut.edu.cn; Fax: +86 411 8498 6256;
Tel: +86 411 8498 6257
Scheme 1 Synthesis of oxazolidine-2,4-diones via a tandem phosphorus-
mediated carboxylative condensation–cyclization sequence using atmospheric
carbon dioxide.
† Electronic supplementary information (ESI) available: Experimental details and
spectroscopic data. CCDC 1044132. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c5cc01530h
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carbenoid is electrophilic12 and the nitrogen atom in amine
shows a much higher nucleophilicity than the oxygen atom in
unstable carbamic acid. Very recently, Jiang and co-workers
reported an elegant synthesis of carbamate by the reaction of amine,
carbon dioxide and N-tosylhydrazones promoted by potassium
carbonate,13 in which a carbocation generated by decomposition
of carbene in a protic solvent was proposed as a key intermediate.
The reaction proceeded under relatively harsh reaction conditions
(4 MPa of carbon dioxide and 120 1C), presumably because of the
low nucleophilicity of carbamic acid.
Table 1 Synthesis of oxazolidine-2,4-diones from various primary amines (1),
atmospheric carbon dioxide and ethyl benzoylformate (2a)
On the other hand, the carbamic acid shows much higher
acidity or electrophilicity than the amine and thus prefers to
react with an active nucleophile. It was reported that Kukhtin–
Ramirez addition of tris(dimethylamino)phosphine to a-ketoester
gives adduct IV,14 which reacts formally as a carbene but proves to
serve as a nucleophile to react with many electrophilic reagents.15,16
We reasoned that in our designed reaction system of eqn (2) in
Scheme 1, adduct IV would rapidly react with carbamic acid V
rather than the amine via proton transfer. It should be noted that
proton transfer from phenols, amides and carboxylic acids to the
Kukhtin–Ramirez adduct has been recently testified to be feasible
by Radosevich and co-workers’ elegant studies.16 The produced
alkoxyphosphonium species VI would then conduct nucleophilic
displacement with the carbamate group to yield target product II
(Scheme 1). Therefore, this reaction system would offer an access to
oxazolidine-2,4-diones from atmospheric carbon dioxide under very
mild reaction conditions. Herein, we report a new and convenient
synthesis of oxazolidine-2,4-diones via a tandem phosphorus-
mediated carboxylative condensation/base-catalyzed cyclization
sequence in a one-pot fashion using atmospheric carbon dioxide and
readily available substrates under transition-metal free conditions.
In initial experiments with p-toluidine (1a), atmospheric
carbon dioxide and ethyl benzoylformate (2a), we found that
upon employing tris(dimethylamino)phosphine (3) the conden-
sation reaction proceeded rapidly and carbamate product 4a was
obtained exclusively in excellent yield, which probably attributed
to the high affinity of the Kukhtin–Ramirez adduct toward in situ
formed carbamic acid rather than amine. To avoid a tedious
isolation procedure for 4a, the residue from the condensation
reaction was directly used in the next NaOMe-catalyzed cycliza-
tion reaction. After an easy workup to remove the water-soluble
byproduct hexamethylphosphoramide, the tandem sequence
afforded oxazolidine-2,4-dione 5a in 72% isolated yield in a
a
Reaction conditions: primary amine 1 (1.2 mmol), ethyl benzoylfor-
mate (1.0 mmol), carbon dioxide (1 atm), THF (10 mL), À78 1C to rt,
b
1.5 h. Reaction conditions: NaOMe (0.1 mmol), toluene, 110 1C, 1 h.
c
Yields of isolated products are given. 81% yield of 4c was isolated in the
first step, compound 6c was isolated as the main product. 80% yield of
4f was isolated in the first step, compound 6f was isolated as the main
product.
d
one-pot fashion. It is noteworthy that as a carboxylative reagent, substitution in 4c and 4f may hinder the cyclization step due
carbon dioxide is totally incorporated in the oxazolidine-2,4- to steric reasons. In Jiang and co-worker’s carbamate synthesis
dione product as the carboxylate moiety. Other phosphorus(III) using the coupling reaction of amine, carbon dioxide and
reagents such as P(OMe)3 only gave a trace product and PEt3 N-tosylhydrazones,13 anilines were not suitable substrates due
proved to be ineffective in this reaction system.
to their low basicity and nucleophilicity. The difference in the
With these optimal reaction conditions in hand, the substrate reactivity of anilines in their and our reactions might result
scope with respect to the primary amine was investigated (Table 1). from the mechanistic distinctions in terms of key intermediates.
Alkyl (1a–c) or halide (1d–g) substituted anilines undergo the Benzyl amines bearing a wide range of functional groups includ-
carboxylative condensation reaction with atmospheric carbon ing electron-donating alkyl and alkoxy, and electron-withdrawing
dioxide and ethyl benzoylformate in the presence of tris(dimethyl- trifluoromethyl substituents all participate in the tandem reaction
amino)phosphine smoothly. With the exception of 5c and 5f, other efficiently to provide the corresponding oxazolidine-2,4-dione
3-aryl substituted oxazolidine-2,4-dione products (5a–b, 5d–e, 5g) products (5h–p) in moderate to good yields. The structure
were obtained in moderate to good yields. The ortho of product 5n was determined unambiguously by single crystal
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of tris(dimethylamino)phosphine and a-ketoester toward in situ
formed carbamic acid, the condensation reaction can be easily
carried out using atmospheric carbon dioxide under mild reaction
conditions. Further mechanistic investigations and extension of
this strategy to other reactions involving carbon dioxide incorpora-
tion are ongoing in our laboratory.
This work was supported by the National Natural Science
Foundation of China (21172026), and the Scientific Research
Fund of Liaoning Provincial Education Department (No. L2012024).
X.-B. L. gratefully acknowledges the Chang Jiang Scholars
Program (no. T2011056) from Ministry of Education of the
People’s Republic of China.
Fig. 1 ORTEP plot of 5n shown with ellipsoids at the 30% probability level;
most hydrogen atoms are omitted for clarity.
Table 2 Synthesis of oxazolidine-2,4-diones from benzyl amine, atmo-
spheric carbon dioxide and various a-ketoester (2)a
Notes and references
1 (a) M. S. Aapro, D. S. Alberts and S. E. Salmon, Cancer Chemother.
Pharmacol., 1983, 10, 161; (b) B. J. Takasugi, S. E. Salmon,
R. L. Nelson, L. Young and R. M. Liu, Invest. New Drugs, 1984, 2, 49.
2 J. M. Cox, H. D. Chu, C. Yang, H. C. Shen, Z. Wua, J. Balsells, A. Crespo,
P. Brown, B. Zamlynny, J. Wiltsie, J. Clemas, J. Gibson, L. Contino,
J. M. Lisnock, G. Zhou, M. Garcia-Calvo, T. Bateman, L. Xu, X. Tong,
M. Crook and P. Sinclair, Bioorg. Med. Chem. Lett., 2014, 24, 1681.
3 (a) R. C. Schnur and M. Morville, J. Med. Chem., 1986, 29, 770;
(b) R. L. Dow, B. M. Bechle, T. T. Chou, D. A. Clark, B. Hulin and
R. W. Stevenson, J. Med. Chem., 1991, 34, 1538; (c) Y. Momose,
T. Maekawa, T. Yamano, M. Kawada, H. Odaka, H. Ikeda and
T. Sohda, J. Med. Chem., 2002, 45, 1518.
4 R. T. Lewis, A. M. Macleod, K. J. Merchant, F. Kelleher, I. Sanderson,
R. H. Herbert, M. A. Cascieri, S. Sadowski, R. G. Ball and K. Hoogstee,
J. Med. Chem., 1995, 38, 923.
5 K. Evason, C. Huang, I. Yamben, D. F. Covey and K. Kornfeld,
Science, 2005, 307, 258.
6 For reviews, see: (a) J. Louie, Curr. Org. Chem., 2005, 9, 605; (b) M. Mori,
Eur. J. Org. Chem., 2007, 4981; (c) T. Sakakura, J.-C. Choi and H. Yasuda,
Chem. Rev., 2007, 107, 2365; (d) M. Aresta and A. Dibenedetto, Dalton
Trans., 2007, 2975; (e) A. Correa and R. Martin, Angew. Chem., Int. Ed.,
2009, 48, 6201; ( f ) S. N. Riduan and Y. Zhang, Dalton Trans., 2010,
39, 3347; (g) A. Behr and G. Henze, Green Chem., 2011, 13, 25;
(h) K. Huang, C.-L. Sun and Z.-J. Shi, Chem. Soc. Rev., 2011, 40, 2435;
(i) M. Cokoja, C. Bruckmeier, B. Rieger, W. A. Herrmann and F. E. Kuhn,
Angew. Chem., Int. Ed., 2011, 50, 8510; ( j) X.-B. Lu and D. J. Darensbourg,
Chem. Soc. Rev., 2012, 41, 1462; (k) W.-Z. Zhang and X.-B. Lu, Chin.
J. Catal., 2012, 33, 745; (l) Y. Tsuji and T. Fujihara, Chem. Commun.,
2012, 48, 9956; (m) L. Zhang and Z. Hou, Chem. Sci., 2013, 4, 3395;
(n) N. Kielland, C. J. Whiteoak and A. W. Kleij, Adv. Synth. Catal., 2013,
355, 2115; (o) M. Aresta, A. Dibenedetto and A. Angelini, Chem. Rev.,
2014, 114, 1709.
7 For the selected examples, see: (a) M. Shi and K. M. Nicholas, J. Am.
Chem. Soc., 1997, 119, 5057; (b) T. Mita, J. Chen, M. Sugawara and
Y. Sato, Angew. Chem., Int. Ed., 2011, 50, 1393; (c) K. Ukai, M. Aoki,
J. Takaya and N. Iwasawa, J. Am. Chem. Soc., 2006, 128, 8706;
(d) T. Ohishi, M. Nishiura and Z. Hou, Angew. Chem., Int. Ed.,
2008, 47, 5792; (e) C. S. Yeung and V. M. Dong, J. Am. Chem. Soc.,
2008, 130, 7826; ( f ) L. J. Goossen, N. Rodriguez, F. Manjolinho and
P. P. Lange, Adv. Synth. Catal., 2010, 352, 2913; (g) D. Yu and
Y. Zhang, Proc. Natl. Acad. Sci. U. S. A., 2010, 107, 20184;
(h) J. Takaya and N. Iwasawa, J. Am. Chem. Soc., 2008, 130, 15254;
(i) C. M. Williams, J. B. Johnson and T. Rovis, J. Am. Chem. Soc.,
2008, 130, 14936; ( j) S. Li, W. Yuan and S. Ma, Angew. Chem., Int.
Ed., 2011, 50, 2578; (k) T. Fujihara, T. Xu, K. Semba, J. Terao and
Y. Tsuji, Angew. Chem., Int. Ed., 2011, 50, 523; (l) L. Zhang, J. Cheng,
B. Carry and Z. Hou, J. Am. Chem. Soc., 2012, 134, 14314;
(m) T. Fujihara, Y. Tani, K. Semba, J. Terao and Y. Tsuji, Angew.
Chem., Int. Ed., 2012, 51, 11487; (n) T. G. Ostapowicz, M. Schmitz,
M. Krystof, J. Klankermayer and W. Leitner, Angew. Chem., Int. Ed.,
2013, 52, 12119; (o) I. I. F. Boogaerts and S. P. Nolan, J. Am. Chem.
Soc., 2010, 132, 8858; (p) L. Zhang, J. Cheng, T. Ohishi and Z. Hou,
Angew. Chem., Int. Ed., 2010, 49, 8670; (q) H. Mizuno, J. Takaya and
N. Iwasawa, J. Am. Chem. Soc., 2011, 133, 1251; (r) K. Sasano,
J. Takaya and N. Iwasawa, J. Am. Chem. Soc., 2013, 135, 10954;
a
Reaction conditions: benzyl amine (1.2 mmol), a-ketoester 2 (1.0 mmol),
carbon dioxide (1 atm), THF (10 mL), À78 1C to rt, 1.5 h; then NaOMe
(0.1 mmol), toluene, 110 1C, 1 h. Yields of isolated products are given.
X-ray diffraction (Fig. 1).17 The presence of the bromo groups in
5g and 5o provides a handle for further functionalization using
traditional methods such as cross-coupling reactions. As expected,
primary aliphatic amines are also found to be suitable substrates
(5q–t), and the cyclopropyl group is compatible with the reaction
conditions (5t).
Moreover, the tandem condensation–cyclization reaction of
benzyl amine, atmospheric carbon dioxide and several a-ketoesters
can also be carried out (Table 2). The use of alkyl, chloro and fluoro
substituted ethyl benzoylformates leads to the formation of the
corresponding oxazolidine-2,4-dione products in moderate to good
yields (5u–v, 5x–y). The more electron-rich substrates including
methoxy substituted ethyl benzoylformate (2w) and alkyl substituted
a-ketoester (2z) are inert under these conditions. The reactions of
these two substrates at increased temperature (60 1C) gave complex
mixtures and no desired carbamate products were detected in the
condensation step.
In summary, we have developed a novel, convenient, and
transition-metal-free access to biologically important oxazolidine-
2,4-diones via a phosphorus-mediated carboxylative condensation
of readily available primary amines and a-ketoesters using carbon
dioxide as a carboxylative reagent, and a NaOMe-catalyzed cycliza-
tion sequence in a one-pot fashion. Due to the high nucleophilic
affinity of the Kukhtin–Ramirez adduct formed by the reaction
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(s) A. Correa and R. Martin, J. Am. Chem. Soc., 2009, 131, 15974; 10 For review, see: D. B. DellAmico, F. Calderazzo, L. Labella,
(t) T. Fujihara, K. Nogi, T. Xu, J. Terao and Y. Tsuji, J. Am. Chem. Soc., F. Marchetti and G. Pampaloni, Chem. Rev., 2003, 103, 3857.
2012, 134, 9106; (u) T. Leon, A. Correa and R. Martin, J. Am. Chem. 11 For the synthesis of 5-alkylidene-oxazolidine-2,4-diones from carbon
Soc., 2013, 135, 1221; (v) K. Sekine, T. Ishida and T. Yamada, Angew.
Chem., Int. Ed., 2012, 51, 6989; (w) T. Moragas, J. Cornella and
dioxide, see ref. 8h and S. Sharma, A. K. Singh, D. Singh and D.-P. Kim,
Green Chem., 2015, 17, DOI: 10.1039/C4GC02089H.
R. Martin, J. Am. Chem. Soc., 2014, 136, 17702; (x) Y. Tani, 12 For review, see: M. P. Doyle, M. A. McKervey and T. Ye, Modern
T. Fujihara, J. Terao and Y. Tsuji, J. Am. Chem. Soc., 2014, 136, 17706.
8 For the transition-metal-free incorporation of CO2, see: (a) H. Yoshida,
Catalytic Methods for Organic Synthesis with Diazo Compounds, Wiley-
Interscience, New York, 1998.
H. Fukushima, J. Ohshita and A. Kunai, J. Am. Chem. Soc., 2006, 13 W. Xiong, C. Qi, H. He, L. Ouyang, M. Zhang and H. Jiang, Angew.
128, 11040; (b) H. Zhou, W.-Z. Zhang, C.-H. Liu, J.-P. Qu and X.-B. Lu, Chem., Int. Ed., 2015, 54, 3084.
J. Org. Chem., 2008, 73, 8039; (c) S. N. Riduan, Y. Zhang and J. Y. Ying, 14 (a) V. A. Kukhtin, Dokl. Akad. Nauk SSSR, 1958, 121, 466; (b) F. Ramirez,
Angew. Chem., Int. Ed., 2009, 48, 3322; (d) Y. Kayaki, M. Yamamoto and
T. Ikariya, Angew. Chem., Int. Ed., 2009, 48, 4194; (e) G. Chen, C. Fu and
S. Ma, Org. Lett., 2009, 11, 2900; ( f ) O. Vechorkin, N. Hirt and X. Hu, Org.
Pure Appl. Chem., 1964, 9, 337; (c) F. Ramirez, Acc. Chem. Res., 1968,
1, 168; (d) F. H. Osman and F. A. El-Samahy, Chem. Rev., 2002, 102,
629.
Lett., 2010, 12, 3567; (g) S. Minakata, I. Sasaki and T. Ide, Angew. Chem., 15 (a) F. Ramirez, A. S. Gulati and C. P. Smith, J. Org. Chem., 1968,
Int. Ed., 2010, 49, 1309; (h) G. Chen, C. Fu and S. Ma, Org. Biomol. Chem.,
2011, 9, 105; (i) C. Das Neves Gomes, O. Jacquet, C. Villiers, P. Thuery,
M. Ephritikhine and T. Cantat, Angew. Chem., Int. Ed., 2012, 51, 187;
( j) K. Inamoto, N. Asano, Y. Nakamura, M. Yonemoto and Y. Kondo,
Org. Lett., 2012, 14, 2622; (k) W.-J. Yoo, M. G. Capdevila, X. Du and
S. Kobayashi, Org. Lett., 2012, 14, 5326; (l) L.-L. Zhao, S.-Y. Wang,
X.-P. Xu and S.-J. Ji, Chem. Commun., 2013, 49, 2569.
9 (a) W.-Z. Zhang, W.-J. Li, X. Zhang, H. Zhou and X.-B. Lu, Org. Lett.,
2010, 21, 4748; (b) X. Zhang, W.-Z. Zhang, X. Ren, L.-L. Zhang and
X.-B. Lu, Org. Lett., 2011, 13, 2402; (c) X. Zhang, W.-Z. Zhang, L.-L.
Shi, C.-X. Guo, L.-L. Zhang and X.-B. Lu, Chem. Commun., 2012,
33, 13; (b) D. N. Harpp and P. Mathiaparanam, J. Org. Chem., 1972,
37, 1367; (c) A. J. Muller, K. Nishiyama, G. W. Griffin, K. Ishikawa
and D. M. Gibson, J. Org. Chem., 1982, 47, 2342; (d) D. V. Griffiths,
H. A. R. Jamalia and J. C. Tebby, Phosphorus Sulfur Relat. Elem., 1985,
25, 173; (e) C. K. McClure and P. Mishra, Tetrahedron Lett., 2002,
43, 5249; ( f ) W. Zhang and M. Shi, Chem. Commun., 2006, 1218;
(g) I. P. Romanova, A. V. Bogdanov, V. F. Mironov, G. R. Shaikhutdinova,
O. A. Larionova, S. K. Latypov, A. A. Balandina, D. G. Yakhvarov, A. T.
Gubaidullin, A. F. Saifina and O. G. Sinyashin, J. Org. Chem., 2011,
76, 2548; (h) M. T. Corbett, D. Uraguchi, T. Ooi and J. S. Johnson,
Angew. Chem., Int. Ed., 2012, 51, 4685.
48, 6292; (d) X. Zhang, W.-Z. Zhang, L.-L. Shi, C. Zhu, J.-L. Jiang and 16 (a) E. J. Miller, W. Zhao, J. D. Herr and A. T. Radosevich, Angew.
X.-B. Lu, Tetrahedron, 2012, 68, 9085; (e) Y.-B. Wang, Y.-M. Wang,
W.-Z. Zhang and X.-B. Lu, J. Am. Chem. Soc., 2013, 135, 11996;
( f ) C.-X. Guo, W.-Z. Zhang, S. Liu and X.-B. Lu, Catal. Sci. Technol.,
2014, 4, 1570; (g) W.-Z. Zhang, L.-L. Shi, C. Liu, X.-T. Yang,
Y.-B. Wang, Y. Luo and X.-B. Lu, Org. Chem. Front., 2014, 1, 275.
Chem., Int. Ed., 2012, 51, 10605; (b) S. R. Wang and A. T. Radosevich,
Org. Lett., 2013, 15, 1926; (c) W. Zhao, D. M. Fink, C. A. Labutta and
A. T. Radosevich, Org. Lett., 2013, 15, 3090; (d) W. Zhao, P. K. Yan
and A. T. Radosevich, J. Am. Chem. Soc., 2015, 137, 616.
17 CCDC 1044132 (5n).
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