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Synthesis of 1,3-oxazoles and benzoxazoles

Name Reactions

Van Leusen Oxazole Synthesis

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Recent Literature

Complementary  methods for direct arylation of  with high regioselectivity at both C-5 and C-2 have been developed for a wide range of aryl and heteroaryl bromides, chlorides, iodides, and triflates. Using task-specific phosphine ligands, palladium-catalyzed C-5 arylation of oxazoles is preferred in polar solvents, whereas C-2 arylation is preferred by nonpolar solvents.
N. A. Strotman, H. R. Chobanian, Y. Guo, J. He, J. E. Wilson, Org. Lett., 2010, 12, 3578-3581.

N. A. Strotman, H. R. Chobanian, Y. Guo, J. He, J. E. Wilson, Org. Lett., 2010, 12, 3578-3581.

A quaternary ammonium hydroxide ion exchange resin catalyzes the reaction of p-tolylsulfonylmethyl isocyanide (TosMIC) with aromatic aldehydes to give 5-aryloxazoles. The base and the p-tolylsulfinic acid byproduct can be removed by simple filtration, resulting in oxazoles in high yield and purity.
B. A. Kulkarnia, A. Ganesan, Tetrahedron Lett., 1999, 40, 5637-5638.

An improved one-pot van Leusen oxazole synthesis using tosylmethyl isocyanide (TosMIC), aliphatic halides and various aldehydes in ionic liquids allows the preparation of 4,5-disubstituted oxazoles in high yields. The recovered ionic liquids could be reused as solvent for six runs without significant loss of yields.
B. Wu, J. Wen, J. Zhang, J. Li, Y.-Z. Xiang, X.-Q. Yu, Synlett, 2009, 500-504.

Pd(PPh₃)₄ efficiently catalyses both direct arylation and alkenylation of oxazoles. The method is regio- and stereospecific with respect to bromoalkenes and tolerates a wide range of functional groups.
F. Besselièvre, S. Lebrequier, F. Mahuteau-Betzer, S. Piguel, Synthesis, 2009, 3511-3512.

A straightforward route allows the synthesis of 2-(hetero)arylated and 2,5-di(hetero)arylated oxazoles through regiocontrolled palladium-catalyzed direct (hetero)arylation of ethyl oxazole-4-carboxylate with iodo-, bromo-, and chloro(hetero)aromatics.
C. Verrier, T. Martin, C. Hoarau, F. Marsais, J. Org. Chem., 2008, 73, 7383-7386.

C. Verrier, T. Martin, C. Hoarau, F. Marsais, J. Org. Chem., 2008, 73, 7383-7386.

An efficient intermolecular reaction of gold carbene intermediates generated via gold-catalyzed alkyne oxidation using nitriles as both the reacting partner and the reaction solvent offers a generally efficient synthesis of 2,5-disubstituted oxazoles with broad substrate scope. The overall reaction is a [2 + 2 + 1] annulation of a terminal alkyne, a nitrile, and an oxygen atom from an oxidant.
W. He, C. Li, L. Zhang, J. Am. Chem. Soc., 2011, 133, 8482-8485.

A facile one-pot, transition-metal-free process enables the synthesis of various polysubstituted oxazoles via t-BuOOH/I₂-mediated domino oxidative cyclization from readily available starting materials under mild conditions.
H. Jiang, H. Huang, H. Cao, C. Qi, Org. Lett., 2010, 12, 5561-5563.

In a practical and simple synthesis of 2,5-disubstituted oxazoles via an iodine-catalyzed tandem oxidative cyclization, a wide range of common commercial aromatic aldehydes can be used as reaction substrates, which displayed excellent functional group compatibility.
C. Wan, L. Gao, Q. Wang, J. Zhang, Z. Wang, Org. Lett., 2010, 12, 3902-9305.

A simple and efficient Cs₂CO₃-mediated reaction of aromatic and unsaturated primary amides with 2,3-dibromopropene allows the synthesis of 2-aryl-5-alkyl-substituted oxazoles in a single step in good yields.
N. Yasmin, J. K. Ray, Synlett, 2009, 2825-2827.

A modular and practical synthesis of highly substituted oxazoles consists of a sequential copper-catalyzed amidation of vinyl halides followed by cyclization promoted by iodine. A wide variety of functionalized oxazoles and polyazoles can be obtained in a selective manner from simple and easily accessible precursors.
R. Martín, A. Cuenca, S. L. Buchwald, Org. Lett., 2007, 9, 5521-5524.

An efficient one-pot propargylation/cycloisomerization tandem process provides a rapid and efficient access to substituted oxazoles from propargylic alcohols and amides with use of p-toluenesulfonic acid monohydrate (PTSA) as a bifunctional catalyst.
Y.-M. Pan, F.-J. Zheng, H.-X. Lin, Z.-P. Zhan, J. Org. Chem., 2009, 74, 3148-3151.

Zn(OTf)₂ catalyzed the cyclization of propargyl alcohols with anilines and phenols in toluene at 100°C without additive and gave various indole and benzofuran products with different structures. The cyclization of propargyl alcohols and amides gave oxazoles. Mechanisms for the different substituation patterns are discussed.
M. P. Kumar, R.-S. Liu, J. Org. Chem., 2006, 71, 4951-4955.

An expedient and mild method for the direct conversion of aldehydes to 2,4-disubstituted oxazoles relies on the oxidation of an oxazolidine formed from the condensation of serine with an aldehyde and proceeds through a 2,5-dihydrooxazole intermediate. In contrast to standard methods that start from carboxylic acids, the use of aldehydes as starting materials does not require intermediate purification.
T. H. Graham, Org. Lett., 2010, 12, 3614-3617.

3-Oxazoline-4-carboxylates as easily available synthetic intermediates can be oxidized to yield oxazole-4-carboxylates. Furthermore, derivatization of 3-oxazoline-4-carboxylates with Grignard reagents enables a facile preparation of 4-keto-oxazole derivatives.
K. Murai, Y. Takahara, T. Matsushita, H. Komatsu, H. Fujioka, Org. Lett., 2010, 12, 3456-3459.

A highly efficient copper-catalyzed tandem oxidative cyclization gives polysubstituted oxazoles from readily available starting materials under mild conditions. This is an attractive alternative method for the synthesis of oxazole derivatives.
C. Wang, J. Zhang, S. Wang, J. Fan, Z. Wang, Org. Lett., 2010, 12, 2338-2341.

A small library of compounds with oxazole and thiazole scaffolds and structural diversity in both positions 2 and 5 has been synthesized. Double acylation of a protected glycine affords intermediate α-amido-β-ketoesters, which in turn can be dehydrated to afford 1,3-oxazoles or reacted with Lawesson’s reagent to furnish 1,3-thiazoles.
J. F. Sanz-Cervera, R. Blasco, J. Piera, M. Cynamon, I. Ibáñez, M. Murguía, S. Fustero, J. Org. Chem., 2009, 74, 8988-8996.

Substituted oxazol-5-ylethanones can be synthesized in a consecutive three-component sequence starting with amidation of propargylamine with an acid chloride followed by cross-coupling with another acid chloride. Therefore, this diversity-oriented one-pot approach to substituted oxazoles can be considered as an amidation-coupling-cycloisomerization (ACCI) sequence.
E. Merkul, O. Grotkopp, T. J. J. Müller, Synthesis, 2009, 502-507.

The reaction of 1-(methylthio)acetone with different nitriles in the presence of triflic anhydride gave 2-substituted 5-methyl-4-methylthio-1,3-oxazoles in good yield. The methylthio group at the C4 position can easily be removed with Raney nickel. 4-Methylsulfonyl derivatives were prepared by the oxidation of the MeS group with m-CPBA.
A. Herrera, R. Martinez-Alvarez, P. Ramiro, D. Molero, J. Almy, J. Org. Chem., 2006, 71, 3026-3032.

The reaction of aldehydes and ketones, including aliphatic and aromatic ones, with amides of α-isocyano-β-phenylpropionic acid in toluene in the presence of lithium bromide gives 2,4,5-trisubstituted oxazoles in good to excellent yield.
G. Cuny, R. Gamez-Montano, J. Zhu, Tetrahedron, 2004, 60, 4879-4885.

An experimentally simple, general, efficient, and ligand-free synthesis of substituted benzimidazoles, 2-aminobenzimidazoles, 2-aminobenzothiazoles, and benzoxazoles via intramolecular cyclization of o-bromoaryl derivatives is catalyzed by copper(II) oxide nanoparticles in DMSO under air. The heterogeneous catalyst can be recovered and recycled without loss of activity.
P. Saha, T. Ramana, N. Purkait, M. A. Ali, R. Paul, T. Punniyamurthy, J. Org. Chem., 2009, 74, 8719-8725.

A copper(II)-catalyzed conversion of bisaryloxime ethers to 2-arylbenzoxazoles involves a cascade C-H functionalization and C-N/C-O bond formation under oxygen atmosphere.
M. M. Guru, M. A. Ali, T. Punniyamurthy, Org. Lett., 2011, 13, 1194-1197.

An efficient method for the transformation of N-benzyl bisarylhydrazones and bisaryloxime ethers to functionalized 2-aryl-N-benzylbenzimidazoles and 2-arylbenzoxazoles involves a copper(II)-mediated cascade C-H functionalization/C-N/C-O bond formation under neutral conditions. Substrates having either electron-donating or -withdrawing substituents undergo the cyclization at moderate temperature.
M. M. Guru, M. A. Ali, T. Punniyamurthy, J. Org. Chem., 2011, 76, 5295-5308.

Lawesson’s reagent is an efficient promoter in the solvent-free microwave-assisted synthesis of 2-substituted benzoxazoles and benzothiazoles from carboxylic acids and 2-aminophenol or 2-aminothiophenol, respectively. Various aromatic, heteroaromatic and aliphatic carboxylic acids react under the conditions developed with good yields.
J. A. Seijas, M. P. Vázquez-Tato, M. R. Carballido-Reboredo, J. Crecente-Campo, L. Romar-López, Synlett, 2007, 313-316.

Dess-Martin periodinane (DMP) efficiently mediates the intramolecular cyclization of phenolic azomethines at ambient temperature leading to substituted benzoxazoles and benzothiazoles. Treatment of the reaction mixtures sequentially with Amberlyst A-26 thiosulfate resin and diisopropylaminomethyl resin (PS-DIEA) removes excess reagent and byproducts, to give pure products.
D. S. Bose, M. Idrees, Synthesis, 2010, 398-402.

A highly efficient Pd/Cu-catalyzed C-H arylation method for a range of heterocycles has been discovered. The efficiency and low loading of a combination of a palladium catalyst and a well-defined copper cocatalyst together with the mild reaction conditions demonstrate this method to be practically useful and mechanistically interesting.
J. Huang, J. Chan, Y. Chen, C. J. Borths, K. D. Baucom, R. D. Larsen, M. M. Faul, J. Am. Chem. Soc., 2010, 132, 3674-3675.

A new method for a direct, copper-catalyzed arylation of heterocycle C-H bonds by aryl iodides allows the conversion of electron-rich five-membered heterocycles and electron-poor pyridine oxides. The best results are obtained by using a combination of lithium tert-butoxide as base and copper iodide as catalyst.
H.-Q. Do, O. Daugulis, J. Am. Chem. Soc., 2007, 129, 12404-12405.

A versatile one-pot domino acylation annulation reaction of 2-bromoanilines with acyl chlorides in the presence of Cs₂CO₃, catalytic CuI, and 1,10-phenanthroline under microwave conditions was applied to the synthesis of benzoxazoles. These copper-catalyzed approaches complement existing strategies for benzoxazole synthesis, which typically utilize 2-aminopheonls as precursors.
R. D. Viirre, G. Evindar, R. A. Batey, J. Org. Chem., 2008, 73, 3452-3459.

A general method for the formation of benzoxazoles and benzothiazoles via a copper-catalyzed cyclization of ortho-haloanilides is reported. Optimal conditions for cyclization used a catalyst combination of CuI and 1,10-phenanthroline as ligand. The mechanism is believed to proceed via an oxidative insertion/reductive elimination pathway through a Cu(I)/Cu(III) manifold. The rate of reaction of ortho-haloanilides follows the order I > Br > Cl, consistent with oxidative addition being the rate-determining step.
G. Evindar, R. A. Batey, J. Org. Chem., 2006, 71, 1802-1808.

A simple and straightforward method for the direct carboxylation of aromatic heterocylces such as oxazoles, thiazoles, and oxadiazoles using CO₂ as the C1 source requires no metal catalyst and only Cs₂CO₃ as the base. A good functional group tolerance is achieved.
O. Vechorkin, N. Hirt, X. Hu, Org. Lett., 2010, 12, 3567-3569.

A convenient, copper-catalyzed C-H and C-N bond activation enables an efficient and conceptually new method for oxidative amination of azoles with tertiary amines. This protocol can be performed in the absence of external base and only requires atmospheric oxygen as oxidant.
S. Guo, B. Qian, C. Xia, H. Huang, Org. Lett., 2011, 13, 522-525.