Synthesis of 1,3-oxazoles
Complementary methods for direct arylation of oxazoles 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 in nonpolar solvents.
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.
An MCM-41-immobilized phosphine-gold(I) complex as catalyst enables a [2 + 2 + 1] annulation of terminal alkynes, nitriles, and oxygen atoms using 8-methylquinoline N-oxide as oxidant under mild conditions to provide 2,5-disubstituted oxazoles in very good yields with broad substrate scope. The heterogeneous catalyst can easily be recovered by simple filtration and recycled for at least eight times without significant loss of activity.
W. Yang, R. Zhang, F. Yi, M. Cai, J. Org. Chem., 2017, 82, 5204-5211.
Valuable substituted oxazoles can be synthesized from readily available α-bromoketones and benzylamines by visible-light photocatalysis at room temperature. This process requires 1 mol % of [Ru(bpy)3]Cl2 as photocatalyst, K3PO4 and CCl3Br.
T. Chatterjee, J. Y. Cho, E. J. Cho, J. Org. Chem., 2016, 81, 6995-7000.
The hypervalent iodine reagent PhI(OTf)2, generated in situ, has been successfully utilized in a metal-free intramolecular oxidative cyclization of N-styrylbenzamides. In remarkably short reaction times, the desired 2,5-disubstituted oxazoles were isolated in high yields.
C. Hempel, B. J. Nachtsheim, Synlett, 2013, 24, 2119-2123.
Copper(II) triflate as catalyst enables a coupling of α-diazoketones with amides to provide 2,4-disubstituted oxazoles. The synthetic versatility of this approach is exemplified in the synthesis of an analogue of balsoxin.
M. R. Reddy, G. N. Reddy, U. Mehmood, I. A. Hussein, S. U. Rahman, K. Harrabi, B. V. S. Reddy, Synthesis, 2015, 47, 3315-3320.
A metal-free annulation of alkynes, nitriles, and O-atoms, using PhIO as oxygen source, in the presence of TfOH or Tf2NH enables a regioselective assembly of 2,4-disubstituted and 2,4,5-trisubstituted oxazole compounds. The present reaction could be applied to a facile synthesis of an anti-inflammatory drug.
A. Saito, A. Taniguchi, Y. Kambara, Y. Hanzawa, Org. Lett., 2013, 15, 2672-2675.
Ring expansion of keto aziridines provides the corresponding 2,5-diaryl oxazoles in the presence of dicyclohexyl carbodiimide and iodine in refluxing acetonitrile. A plausible mechanism is proposed.
H. A. Samimi, S. Mohammadi, Synlett, 2013, 24, 223-225.
A N-bromosuccinimide-mediated direct synthesis of 2,5-diaryloxazoles starting from N-H ketoaziridines proceeds via in situ formation of N-bromoketoaziridines followed by generation of azomethine ylides.
H. S. Samimi, F. Dadvar, Synthesis, 2015, 47, 1899-1904.
ZnI2 and FeCl3 mediate a direct approach to the selective and regiocontrolled synthesis of 2-oxazolines and 2-oxazoles in very good yields under mild reaction conditions by cyclization of acetylenic amides. Various functionalities were well tolerated.
G. C. Senadi, W.-P. Hu, J.-S. Hsiao, J. K. Vandavasi, C.-Y. Chen, J.-J. Wang, Org. Lett., 2012, 14, 4478-4481.
A base-induced transformation reaction of 2-acyl-3-alkyl-2H-azirines provides oxazoles via a deprotonation-initiated mechanism followed by nucleophilic addition to the imine functionality. Intermediacy of ketenimine is consistent with both experimental and computational results, at least under strongly basic reaction conditions.
Y. Ning, Y. Otani, T. Ohwada, J. Org. Chem., 2017, 82, 6313-6326.
A dual catalytic approach offers readily access to substituted heterocycle aldehydes via oxygen radical addition to vinyl-gold intermediates under Fe catalyst assistance. This system offers good functional group compatibility for the synthesis of substituted oxazole, indole, and benzofuran aldehydes.
H. Peng, N. G. Akhmedov, Y.-F. Liang, N. Jiao, X. Shi, J. Am. Chem. Soc., 2015, 137, 8912-8915.
A three-component cyclization of 2H-azirines, alkynyl bromides, and molecular oxygen under visible-light photoredox catalysis at room temperature provides a wide range of substituted oxazoles in good yields.
L . Chen, H. Li, P. Li, L. Wang, Org. Lett., 2016, 18, 3646-3649.
A broad range of functionalized oxazoles were synthesized in good yields from enamides via phenyliodine diacetate (PIDA)-mediated intramolecular cyclization. The oxidative carbon-oxygen bond formation process is heavy-metal-free.
Y. Zheng, X. Li, C. Ren, D. Zhang-Negrerie, Y. Du, K. Zhao, J. Org. Chem., 2012, 77, 10353-10361.
A highly efficient method for the synthesis of oxazole derivatives from simple amides and ketones proceeds through a C-N bond formation followed by a C-O bond formation closing the ring. Because of the simple and readily available starting materials, easy operation, and high bioactivity of oxazoles, this strategy can be broadly applied to medicinal chemistry.
M. Zhang, L. Huang, H. Huang, X. Li, W. Wu, H. Jiang, Org. Lett., 2014, 16, 5906-5909.
The use of iodosobenzene (PhIO) as an oxidant realizes an intermolecular oxidative C(sp2)-O bond formation between enamines and various carboxylic acids, including N-protected amino acids. This direct β-acyloxylation of enamine compounds tolerates a wide range of functional groups and furnishes various β-acyloxy enamines that can be conveniently converted to oxazoles via cyclodehydration.
X. Liu, R. Cheng, F. Zhao, D. Zhang-Negrerie, Y. Du, K. Zhao, Org. Lett., 2012, 14, 5480-5483.
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.
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 copper(II)-catalyzed oxidative cyclization of enamides gives oxazoles via vinylic C-H bond functionalization at room temperature. Various 2,5-disubstituted oxazoles bearing aryl, vinyl, alkyl, and heteroaryl substituents could be synthesized in good yields. This reaction protocol is complementary to a previously reported iodine-mediated cyclization of enamides to afford 2,4,5-trisubstituted oxazoles.
C. W. Cheung, S. L. Buchwald, J. Org. Chem., 2012, 77, 7526-7537.
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.
Hexafluorophosphoric acid promotes the formation of 1,3,4-oxadiazolium hexafluorophosphate salts from N′-acyl-N-aroyl-N-arylhydrazides or N′-acyl-N-acyl-N-arylhydrazides under mild conditions. A subsequent reaction with cyanamide in propan-2-ol in the presence of triethylamine generates 1,5-disubstituted 3-amino-1H-1,2,4-triazoles in good yields.
B. Wong, A. Stumpf. D. Carrera, C. Gu, H. Zhang, Synthesis, 2013, 45, 1083-1093.
A series of propargylic amides were transformed to the corresponding alkylideneoxazolines by a gold(I) catalyst. A subsequent autoxidation to hydroperoxides bearing the heteroaromatic oxazoles followed by reduction to the corresponding alcohols with sodium borohydride enables a highly efficient, and atom-economic access to a series of functionalized 2,5-disubstituted oxazoles.
A. S. K. Hashmi, M. C. B. Jaimes, A. M. Schuster, F. Rominger, J. Org. Chem., 2012, 77, 6394-6408.
Palladium-catalyzed direct alkynylations of heteroarenes with inexpensive gem-dichloroalkenes as user-friendly electrophiles set the stage for a modular, step-economical synthesis of diversely decorated heteroaryl alkynes.
L. Ackermann, C. Kornhaass, Y. Zhu, Org. Lett., 2012, 14, 1824-1826.
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.
A tandem reaction of a vinyliminophosphorane with various acyl chlorides gives unexpectedly 2,4,5-trisubstituted oxazoles in a one-pot fashion.
H. Xie, D. Yuan, M.-W. Ding, J. Org. Chem., 2012, 77, 2954-2958.
I2-catalyzed C-O bond formation and dehydrogenation with TBHP enables a general method for the synthesis of oxazolines and oxazoles from β-acylamino ketones. Depending on the base, either oxazolines or oxazoles were selectively produced.
W.-C. Gao, F. Hu, Y.-M. Huo, H.-H. Chang, X. Li, W.-L. Wei, Org. Lett., 2015, 17, 3914-3917.
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.
A facile gold-catalyzed heterocyclization provides 2-amino-1,3-oxazoles functionalized at the nitrogen atom as well as at the fifth position of the heterocyclic ring in good to moderate yields. The reaction is based on intermolecular trapping of intermediate α-oxo gold carbenes with various cyanamides.
V. A. Rassadin, V. P. Boyarskiy, V. Yu. Kukushkin, Org. Lett., 2015, 17, 3502-3505.
Highly substituted oxazoles can be synthesized from readily accessible ynamides in the presence of ytterbium(III) trifluoromethanesulfonate, N-iodosuccinimide, and acetonitrile. Hydroamidation and iodo-imidation of ynamides to ketene aminals are also demonstrated. The reactions are scalable to the gram scale, testifying the robustness of the transformations.
An unprecedented Tf2NH-catalyzed formal [3 + 2] cycloaddition of ynamides with dioxazoles enables a a metal-free assembly of various polysubstituted 4-aminooxazoles. This approach features a low-cost catalyst, exceptionally mild reaction conditions, a very short reaction time, broad substrate scope, and high efficiency.
Y. Zhao, Y. Hu, C. Wang, X. Li, B. Wan, J. Org. Chem., 2017, 82, 3935-3942.
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.
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 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 Regel-type transition-metal-free direct C-2 aroylation of (benzo)oxazoles, (benzo)thiazoles and 1,3,4-oxadiazoles with acid chlorides is catalyzed by N,N-dimethyl-4-aminopyridine (DMAP) and affords the corresponding 2-ketoazoles in good yields.
P. Lassalas, F. Marsais, C. Hoarau, Synlett, 2013, 24, 2233-2240.