Transition-metal-free synthesis of oxazoles: valuable structural fragments in drug discovery

Abstract

Oxazole, a central structural motif of numerous complex natural products and pharmaceuticals, is closely associated with the development of contemporary drug discovery research due to a diverse portfolio of biological functions. The remarkable medicinal potential and ubiquitous prevalence of oxazoles in synthetic drugs have provided an impetus for their easy accessibility and much effort has been exerted to develop new and efficient methods. In this regard, metal-free reactions for the synthesis of oxazole heterocycles have emerged as an eminent concept over the years due to the toxicity, price or scarcity of some transition-metal-catalyzed reactions. In this review, the various concepts that have proved useful for the development of robust and transition-metal-free methodologies for the construction of oxazole skeleton are presented. A brief description of mechanistic investigations and synthetic utility of these motifs have also been discussed.

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Aliya Ibrar

Aliya Ibrar received her M.Sc and M.Phil degrees in Organic Chemistry from Quaid-i-Azam University, Islamabad, Pakistan. She completed her Ph.D. degree in Organic Chemistry from the same university under the supervision of Prof. Dr Aamer Saeed, working on the design and synthesis of coumarinyl-based bioactive heterocycles. She is the recipient of the Indigenous 5000 Ph.D. Fellowship from the Higher Education Commission of Pakistan. She has also been a visiting research fellow at the University of Oxford (UK), working in the group of Prof. S. G. Davies. Currently, she is an assistant professor of organic chemistry at the COMSATS Institute of Information Technology, Abbottabad, Pakistan. Her current research interests include heterocyclic chemistry, focused mainly on the development of new synthetic methodologies, and medicinal chemistry with a particular interest in the discovery and development of bioactive five- and six-membered heterocycles.

1. Introduction

Oxazoles represent an important class of five-membered heterocyclic aromatic compounds.^1–3 The increasing interest in the exploitation of oxazole ring system is due to its widespread prevalence in numerous complex natural products as well as in a number of organic building blocks.^4–10 A significant number of oxazole-enriched natural products have been isolated from several marine invertebrates and microorganisms.^11–13 They also serve as key structural units of numerous pharmaceuticals which display a diverse range of biological functions such as antiviral, antifungal, antibacterial, antiproliferative,^14–18 antileukemia, anticancer, analgesic, and enzyme inhibitory activities.^19–28 Synthetic oxazoles are also important in the development of drug research portfolio due to good TRPV1 antagonistical activity,²⁹ anti-inflammation potential,³⁰ anti-HIV,³¹ and antitubercular activities.³² In addition, oxazoles are also used as agrochemicals, fluorescent dyes, corrosion inhibitors,^33,34 in photography,³⁵ and polymer industries.^36–38 The remarkable biological potential and prevalence of oxazoles in natural products and synthetic drugs have generated significant interest in the synthesis of functionalized oxazole ring systems. Fig. 1 illustrates the representative examples of oxazole-containing natural products and bioactive molecules.

Fig. 1 Selected examples of oxazole-containing natural products and pharmaceutical agents.

Considering the significance and utility of oxazole functionality, several research groups have contributed a range of important methods for the synthesis of decorated oxazoles. The synthetic routes to oxazoles can be broadly classified as: (i) intramolecular oxidative cyclization of acyclic precursors to oxazoles, and (ii) transition-metal-catalyzed functionalization of the oxazole ring to the desired derivatives. The classic methods, including the cyclodehydration of α-acylamino ketones (Robinson–Gabriel reaction),^39,40 or the Hantzsch,⁴¹ and Conforth cyclizations,^42,43 among others, often have drawbacks such as harsh reaction conditions, long reaction times, less substrate scope or modest to poor yields. Transition-metal catalysts have also enabled the synthesis of oxazoles under mild reaction conditions,^44–57 however, lack of general applicability, harsh reaction conditions, high reaction temperatures, hindered reaction scope, use of less abundant and expensive reagents or catalysts, toxicity and price or scarcity of some metals have prompted the search for new metal-free methodologies.^58–62

This review summarizes the transition-metal-free approaches used to construct oxazole skeleton in the past decade (2006–2015). Several examples of fused-oxazole derivatives have also been included in addition to a brief mechanistic discussion and synthetic utility wherever relevant and if unveiled in the original manuscript. Oxazole is a weakly basic aromatic compound with three potential points of structural diversity, C-2, C-4 and C-5 (Fig. 2). This review outlines the important developments in the synthesis of oxazole ring endowed with multiple substituents.

Fig. 2 The oxazole unit with its numbering pattern.

2. Transition-metal-free synthesis of oxazoles

This section deals with the metal-free synthesis of oxazole compounds with multiple substituents at various positions.

2.1. Ketones and nitriles as starting materials

Martínez-Alvarez and co-workers developed a straightforward one-pot synthesis of 2,4,5-trisubstituted and 2,5-disubstituted 1,3-oxazoles (2 & 3) by reacting 1-(methylthio)acetone (1) and nitriles in the presence of triflic anhydride (Scheme 1).⁶³ The heterocyclic products were obtained in good yields. The functionalization of the methylthio group at the C-4 position of the oxazole ring produced 2,5-disubstituted oxazole derivatives by the reduction reaction using RANEY® nickel. The reaction scope was examined under mild conditions (0 °C, 36 h) with a range of nitriles. The reaction productivity was found unaffected when a variety of substituted nitriles were employed as coupling partners, however, higher temperatures significantly hindered the reactions leading to the considerably lower yields of the oxazole products. In addition, the versatility of the MeS group allowed an easy access to C-4 unsubstituted oxazoles by the reductive desulfuration of oxazoles (3) with RANEY® nickel in ethanol at room temperature.⁶⁴

Scheme 1

Lee and co-workers have shown an efficient strategy for the direct conversion of deoxybenzoin into 2-alkyl-4,5-diphenyloxazoles and 2-aryl-4,5-diphenyloxazoles (6) using Koser's reagent, [hydroxy(tosyloxy)iodo]benzene (HTIB) from readily available starting materials such as ketones and nitriles (Scheme 2). The approach was highly productive in terms of reaction yields under solvent-free microwave irradiation conditions.⁶⁵ The reaction compatibility was investigated with both aliphatic and aromatic nitriles. The yields of the corresponding 2-alkyl-4,5-diphenyloxazoles and 2-aryl-4,5-diphenyloxazoles were satisfactory, and comparable or superior (in some cases) to the literature reported results where the oxazoles were obtained from ketones. However, ketones like acetophenone and propiophenone did not produce the desired oxazole products. Based on the experimental results, neutral and eco-friendly nature of the reaction conditions, the authors believed that this method could potentially serve as a useful alternative to the existing methods.

Scheme 2

Kawano and Togo developed a smooth and efficient iodoarene-mediated one-pot synthesis of 2,4,5-trisubstituted oxazoles (8) from ketones using m-chloroperbenzoic acid (MCPBA) and trifluoromethanesulfonic acid in acetonitrile or propionitrile (Scheme 3).⁶⁶ Under optimized reaction conditions, the scope and generality of the ketone substrates were tested. Both electron-donating and electron-withdrawing groups on the aryl ring of ketone were tolerated affording the polysubstituted oxazoles in moderate to good yields over variable time. Propiophenone and nonanophenone were also investigated as useful substrates under the same conditions, and the corresponding 2,4-dimethyl-5-phenyloxazole and 2-methyl-4-heptyl-5-phenyloxazole were afforded in moderate yields.

Scheme 3

The proposed mechanism for this transformation is illustrated in Scheme 4. Aryl iodonium species 9 is generated by the oxidation of iodoarene by MCPBA and TfOH which reacts with the enolate form of ketone to furnish the corresponding α-keto iodonium species 10. Finally, α-keto iodonium species 10 reacts with nitrile to provide the oxazole through the intermediate 11.

Scheme 4

In a subsequent study, Ishiwata and Togo investigated the synthesis of 2,5-disubstituted and 2,4,5-trisubstituted oxazoles (12) using oxone and nitriles. Alkyl aryl ketones were employed as substrates for this one-pot iodoarene-mediated operation (Scheme 5).⁶⁷ A range of different iodoarenes such as iodobenzene, 4-chloroiodobenzene, 4-methoxyiodobenzene, 3-trifluoromethyliodobenzene and 4-iodobenzoic acid were tested and the results indicated that the iodobenzene and 4-chloroiodobenzene were effective producing oxazoles in best yields. On examination of the reaction scope, it was revealed that the dialkyl ketones and silyl ethers were less effective producing corresponding oxazoles in low yields (∼10–20%). However, when the reactions were performed in propionitrile instead of acetonitrile, the oxazole products were obtained in moderate yields.

Scheme 5

In Lai and Taylor's investigations, Ritter reaction of α-oxo tosylates (13) and nitriles (14) delivered a range of oxazoles (15) (Scheme 6).⁶⁸ The authors explored an unexpected scandium trifluoromethanesulfonate-catalyzed formation of oxazole by the reaction of methyl mandelate-derived tosylate with allyl(trimethyl)silane in acetonitrile. They assumed that the heterocyclic product is formed via Ritter reaction instead of the expected allylation product. The optimized reaction conditions were successfully applied to expand the scope and a diverse variety of trisubstituted oxazoles was synthesized. Both the ketones and nitrile substrates were varied to a large extent giving desired oxazoles in good yields except the electron-rich substituted products where lower yields were obtained due to the problems associated with the isolation of the final compounds. In addition, indole-substituted oxazoles (18 & 20) were also furnished in moderate yields (Scheme 7).

Scheme 6

Scheme 7

Kumar et al. disclosed a new and concise synthesis of 5-(3′-indolyl)oxazoles (23) using relatively benign reagent [hydroxy(2,4-dinitrobenzenesulfonyloxy)iodo]benezene (HDNIB) (Scheme 8).⁶⁹ The reaction sequence includes the reagents such as 3-acetyl-1-benzenesulfonylindole (21) and nitriles (benzonitrile, alkylnitriles, and heteroaryl nitriles). The products were obtained in moderate yields. The deprotection of the benzenesulfonyl moiety of oxazole 22 by sodium hydroxide yielded compound 23.

Scheme 8

Wu and co-workers developed an efficient protocol involving methyl ketones (24), benzoins (25) and ammonium acetate which was used to build an oxazole skeleton (26) in a one-pot process (Scheme 9).⁷⁰ After screening several reaction parameters, the authors identified the optimal conditions (acetophenone 1.0 equiv.; benzoin 1.1 equiv.; ammonium acetate 2.5 equiv.; iodine 2.5 equiv. in DMSO at 120 °C) which were applied to a diverse range of substrates. A high degree of reactivity was observed when electron-deficient substituents on the aryl ring were tolerated. Similar results were obtained when heterocyclic methyl ketones were employed as substrates and the corresponding oxazoles were furnished in good yields. The authors also noticed that the sterically hindered substrates such as 2-acetonaphthone gave the corresponding oxazole in lower yield which indicated that the reaction is influenced by the steric factors. Additionally, unsaturated methyl ketones such as benzalacetone and 4-nitrobenzalacetone were also viable substrates for one-pot operation. However, 3-acetyl-1-methylpyrrole showed no reactivity. The authors assumed that the unreactive nature of the substrate could possibly be due to the N-iodination of the pyrrole ring which may further lead to the undesired reactions such as nucleophilic attack at C-5 of the pyrrole ring.⁷¹ It was also noticed that the reaction in greatly influenced by the electronic properties of the substituents on the aromatic rings of methyl ketones. In this regard, when electron-rich groups were investigated, two types of oxazoles were formed.

Scheme 9

The proposed mechanism for this reaction using acetophenone, benzoin and ammonium acetate is illustrated in Scheme 10. Due to the high reactivity of 25 towards oxidation than 24, the compound 27 is produced by the oxidation of 25. Then, iodination and oxidation of compound 24 generated the phenylglyoxal 28. Compound 29 is obtained after the addition of ammonium acetate to 27 which gave compound 30 or its enolizational isomer 31 by reacting with 28. Compound 31 was subsequently converted to 32 via intramolecular nucleophilic reaction. Dehydration of 32 afforded the final product 26.

Scheme 10

Saito and co-workers explored the synthesis of poly-substituted oxazoles (35 or 36) by the reaction of carbonyl compounds (33 or 34) with nitriles in a single step.⁷² The reactions were performed under mild conditions in the presence of trifluoromethanesulfonic acid (TfOH) or bis(trifluoromethanesulfonyl)imide (Tf₂NH), iodosobenzene (PhI = O). A range of substrates were tested to evaluate the reaction scope and the desired oxazoles were obtained in good yields (Scheme 11).

Scheme 11

Another important method for the synthesis of 2,5-disubstituted oxazoles (39) was developed by Gao et al. enabling the sp³ C–H functionalization of the readily accessible methyl ketones (37) and benzylamines (38). These I₂-mediated reactions gave heterocyclic compounds in good yield under metal- and peroxide-free conditions (Scheme 12).⁷³ During the course of reaction optimization, presence of iodine was identified as essential element of this oxidative cyclization process as there was no reaction without iodine. While exploring the reaction scope with a range of aryl methyl ketones incorporating both electron-donating (4-OMe, 4-OEt, 3-OMe, 2,4-OMe₂, 3,4-OCH₂O, 3,4-OCH₂CH₂O) and electron-withdrawing (4-NO₂, 4-Ph) substituents, it was noticed that the reaction afforded the expected oxazoles in 78–91% yield. Generally, better yields were obtained with electron-rich substrates. Unprotected phenol, sterically demanding 2-naphthyl methyl ketone and 1-naphthyl methyl ketone were also viable starting materials as their corresponding heterocyclic products were obtained in 80%, 82% and 84% yields, respectively. Moreover, heteroaryl ketones, including benzofuryl, furyl, thienyl, and morpholinyl were also discovered as useful reaction partners. However, unsaturated methyl ketones were inert under these conditions.

Scheme 12

Similarly, reaction scope was expanded with different benzylamine derivatives where electronic and steric factors were found to exert a strong impact on the reaction profile. Electron-deficient benzylamines were more reactive. Likewise, presence of a substituent at the para-position greatly favored the reaction whereas meta-substituted benzylamines were impotent. The authors also exemplified the diversity of reaction scope by investigating halo-substituted benzylamines along with several heteroaryl amines under the optimized conditions, affording the corresponding oxazoles in good yields. The only limitation of the reaction was the inertness of n-BuNH₂ which failed to produce the corresponding alkylated oxazole.

In a recent report, Togo and co-workers synthesized 2,5- and 2,4,5-trisubstituted oxazoles (41) from alkyl aryl ketones (40) in good yield. This one-pot procedure utilizes iodine, oxone, and trifluoromethanesulfonic acid in nitriles (Scheme 13).⁷⁴ In general, the reaction tolerated a wide range of different substrates and the scope of the reaction was reasonably broad. The synthetic utility of the present protocol was validated by preparing oxaprozin (44) in two steps (46% overall yield) from benzyl phenyl ketone (42) (Scheme 14).

Scheme 13

Scheme 14

2.2. Amides as starting materials

Zhan and co-workers developed a highly efficient PTSA-catalyzed propargylation/cycloisomerization tandem reaction for the synthesis of substituted oxazoles (47) from propargylic alcohols (45) and amides (46). The reaction was completed rapidly under mild conditions and was tolerant of air generating water as the only by-product (Scheme 15).⁷⁵ The reaction versatility was explored using a diverse range of secondary propargylic alcohols incorporating both terminal and internal alkyne groups. Moreover, several other functional groups, such as TMS, chloro, bromo, vinyl, ester and methoxy were also tested under the standard reaction conditions. The products of propargylation/cycloisomerization reaction were obtained in good yields with complete regioselectivity. Propargylic alcohol incorporating an electron-rich group at the aryl ring afforded the desired oxazole in 94% yield along with the substrates bearing electron-deficient groups (bromo and ester functionalities) at the aryl ring where the corresponding oxazoles were produced in 89% and 78% yields, respectively. Internal propargylic alcohols also gave good results. Furthermore, sterically encumbered groups such as 1-naphthyl readily underwent propargylation/cycloisomerization tandem reaction delivering the substituted oxazoles in high yields. However, propargylic alcohols with aliphatic groups such as 3-phenylprop-2-yn-1-ol and 4-phenylbut-3-yn-2-ol were unreactive. On the other hand, a diverse range of amides (aromatic and aliphatic) were also investigated to expand the reaction scope. The electronically rich amides were favorable in this tandem reaction.

Scheme 15

Pummerer cyclization of N-[4-(phenylsulfinyl)-1-propylbut-2-ynyl]acetamides (48) for the preparation of a series of substituted 5-[2-(phenylthio)vinyl]-1,3-oxazoles (49) was developed by Zhou and co-workers (Scheme 16).⁷⁶ The reaction scope for this methodology includes the utility of several aliphatic and aromatic groups at various positions of the starting material under standard reaction conditions: amide (0.5 mmol), TFAA (0.75 mmol) in CH₂Cl₂ (3 mL) at −78 °C → r.t under N₂ atmosphere for 4 h.

Scheme 16

Yasmin and Ray demonstrated a simple synthesis of 2-aryl-5-alkyl-substituted oxazoles (51) in a one-pot operation by the reaction of aromatic primary amides (46) with 2,3-dibromopropene (50). This one-pot synthetic approach was assisted by a base (Scheme 17).⁷⁷ The scope of this methodology was investigated by varying both substrates, amides and dibromopropenes. Initially, the reactivity of the amide substrates was examined in the noncatalytic reaction and the results were quite promising producing oxazoles in moderate to good yields. When α,β-unsaturated carboxyamides, such as cinnamide and α-phenylcinnamide were evaluated, the 2-styryloxazoles were obtained with good yields. On the other hand, 2,3-dibromopropenes were explored to expand the reaction scope. In all cases, the corresponding oxazoles were obtained in moderate yields under standard reaction conditions.

Scheme 17

The authors explained the mechanism of 2,5-disubstituted oxazole formation by the help of Hacksell model.⁷⁸ Initially, amidic NH₂ reacts with the allylic bromine of 2,3-dibromopropene (50) to generate a secondary amide intermediate 52 which on HBr elimination afforded intermediate 53. The N-propa-1,2-dienylamide intermediate 53 undergoes 5-endo-dig cyclization by amide oxygen (via enolization) to produce a substituted oxazoline intermediate 54 that finally isomerizes at the exocyclic double bond to form 2,5-disubstituted oxazoles 51 (Scheme 18).

Scheme 18

Zhou et al. reported a catalyst-free synthesis of 2,5-disubstituted oxazoles (56) from N-allylbenzamides (55) via intramolecular oxidative cyclization reaction (Scheme 19).⁷⁹ The prepared heterocyclic analogues were obtained in good yields. The authors developed a set of optimal reaction conditions which were utilized to investigate the reaction scope. A wide range of N-allylbenzamide substrates underwent intramolecular cyclization producing oxazole compounds in good chemical yields. The authors observed that the substrates featuring strong electron-withdrawing substituents on the aromatic moiety show strong reactivity as compared to the strong electron-releasing groups which inhibited the reactions even at longer times. However, steric factors were not operative with no influence on the reaction yields.

Scheme 19

Hempel and Nachtsheim were able to synthesize 2,5-disubstituted oxazoles (58) in good yield through an intramolecular oxidative cyclization of N-styrylbenzamides (57) catalyzed by hypervalent iodine reagent PhI(OTf)₂ (Scheme 20).⁸⁰ An intensive screening for the optimized reaction conditions was performed and several electron-donating and electron-deficient aromatic functional groups in the substrate were investigated under these reaction conditions. The final 2,5-diaryl oxazole compounds were obtained in up to 77% yield. The substrates featuring substituents in the 3-position were relatively less reactive and gave lower yields except a 3-nitro substituted substrate, where the corresponding oxazole product was acquired in 72% yield.

Scheme 20

The proposed mechanism for this cyclization is illustrated in Scheme 21. The in situ generated PhI(OTf)₂ activates the alkene moiety of the enamide to furnish complex 59 or iodonium ion 60 which on 5-endo-cyclization forms alkyl iodane 61 which is converted to oxazoline 62 by the nucleophilic attack of acetate (pathway A).⁸¹ Finally, elimination of AcOH afforded the desired oxazole. Alternatively, oxazole could directly be formed from alkyl iodane 61 through elimination, liberating iodobenzene and triflate (pathway B).

Scheme 21

Ghosh and co-workers developed a photo-thermochemical synthesis of 4-bromo-2,5-trisubstituted oxazoles (64) from N-arylethylamides (63) by using N-bromosuccinimide–dichloroethane system. The oxazole products were obtained in 42–82% yield (Scheme 22).⁸² The substrates employed in this one-pot process had easy availability and were readily synthesized from corresponding acid chlorides and amines. The scope of the reaction was entertained by exploiting various R¹ and R² groups. The highest reactivity was observed when R¹ = p-Cl-C₆H₄ and R² = H, whereas lowest isolated yield was recorded for compound with R¹ = p-OMe-C₆H₄ and R² = p-Cl, respectively. In addition to aromatic substitution, some alkyl and heteroaryl substituted oxazoles were also prepared in moderate yields.

Scheme 22

The authors also proposed a mechanism for their photo-thermochemical method which starts with the benzylic bromination of the substrate 63, followed by O–C bond formation through intramolecular nucleophilic substitution. Subsequently, a second benzylic bromination followed by HBr elimination, afforded the oxazole ring (Scheme 23).

Scheme 23

Wan and co-workers developed a divergent synthesis of oxazolidines 70 and iodoalkylidenedihydrooxazoles 71 via a 5-exo-dig process (Scheme 24).⁸³ The strategy involves the NIS-mediated iodocyclization of N-sulfonyl propargylamides (69). The subsequent oxidation of iodoalkylidenedihydrooxazoles 71 led to the corresponding oxazoles 72 in the presence of molecular oxygen. The scope of this iodocyclization tolerated a range of electron-withdrawing and electron-donating substituents on aryl rings at various positions of propargylamides. However, with aliphatic substituents such as cyclopentyl as R², both reactions failed to undergo the cyclization, probably due to the electronic nature of aliphatic substituents. Likewise, substrates bearing heteroaryl substituents such as furyl were also inert under standard reaction conditions.

Scheme 24

The authors proposed a plausible mechanism for this divergent iodocyclization methodology as depicted in Scheme 25. The reaction starts with the coordination of 69 with I⁺, thereby enhancing the electrophilicity of the alkyne moiety to produce intermediate 73 which on subsequent 5-exo-dig cyclization generates intermediate 74. In two different solvents, the intermediate 74 generates the desired products. In path A, using DCM as solvent, the succinimide anion attacks the more electrophilic carbon of the iminium ion to produce the final product 70. Whereas, in more polar solvent like DMF, the succinimide anion traps the tosyl group of intermediate 74 to furnish the desired product 71.

Scheme 25

Adimurthy and co-workers demonstrated an iodine-catalyzed approach for the preparation of 2,5-disubstituted oxazoles (76) from N-arylethylamides (75). The process involves an intramolecular C(sp³)–H activation under metal-free conditions (Scheme 26).⁸⁴ Under optimized reaction conditions, various N-arylethylamide substrates bearing halogens (F, Cl, & Br) at the para-position of aryl ring were tolerated. In addition, ortho-methoxy phenyl and pyridyl substituted amides were also productive substrates, however, the products were furnished in slightly reduced yields. Moreover, the methodology was extended by utilizing various groups attached to the carbonyl carbon of N-arylethylamides. In this case, the electron-rich groups (Me and OMe) gave comparatively low yields. Hetero-aromatic and aliphatic aldehydes also contributed positively. In general, the methodology was versatile in nature due to broad functional group tolerance.

Scheme 26

Based on the literature data,^85,86 the authors proposed a possible mechanism which starts with the reaction of 75 with iodine delivering N-iodo intermediate 77. The homolytic cleavage of 78 in the presence of peroxide gave intermediate 79. 1, 5 proton shift followed by the elimination of hydroiodic acid in the presence of iodine radical generated intermediate 80 which on subsequent addition, substitution and elimination processes (through 81 and 82) afforded the desired oxazole product (Scheme 27).

Scheme 27

Yu et al. developed a facile and step-economical one-pot protocol for the synthesis of trisubstituted 5-(trifluoromethyl)oxazoles (86) (Scheme 28).⁸⁷ After analyzing different reaction parameters such as oxidant, additive, solvent, and temperature, optimized conditions were identified. Several different substrates incorporating electron-rich, and electron-deficient aryl groups at the α-position of the amide group. The products were obtained in moderate to good yields. The present protocol was ranked as quite general due to the simultaneous functionalization of three sequential Csp²–H, Csp³–H, and Csp²–H bonds along with the selective installation of different functional groups.

Scheme 28

2.3. Aldehydes as starting materials

Graham explored a versatile strategy for the direct synthesis of 2,4-disubstituted oxazoles (88) from aldehydes (87) (Scheme 29).⁸⁸ The method relies on the oxidation of an oxazolidine formed from the condensation of serine with an aldehyde and proceeds through a 2,5-dihydrooxazole intermediate. Two different methods have been developed for the synthesis of oxazole derivatives. With these two conditions, the scope of this transformation was evaluated. Apart from the parent aldehyde (benzaldehyde), halogen-substituted benzaldehydes were also effective leading to the corresponding oxazoles in good yields under both set of conditions (condition A: (i) Ser-OMe·HCl (1 equiv.), Et₃N (2 equiv.), MgSO₄ (1 equiv.), THF, r.t, 12 h, then filter; (ii) BrCCl₃ (3 equiv.), DBU (3 equiv.), CH₂Cl₂, 0 °C to r.t, 12 h) and (condition B: Ser-OMe·HCl (1 equiv.), K₂CO₃ (2 equiv.), DMA, r.t, 12 h, then BrCCl₃ (3 equiv.), DBU (3 equiv.), 0 °C to r.t, 12 h). In addition, both electron-deficient and electron-rich benzaldehydes afforded the corresponding oxazoles. Heteroaromatic substituted aldehydes were also tolerated. These include pyridine, quinoline, furan, and thiophene substituents. Furthermore, the scope of this transformation was extended to the oxazoles (89) bearing 2-alkenyl and 2-alkynyl groups. Cinnamaldehyde and α-methyl cinnamaldehyde were also a part of this exploration affording the corresponding oxazoles in 72% and 70% yield, respectively, whereas, 2,4-hexadienal afforded the 2-pentadienyl oxazole in 60% yield (Scheme 30).

Scheme 29

Scheme 30

The authors proposed a mechanistic approach for this methodology where condensation of an aldehyde with an aminoalcohol yields the oxazolidine, being reported as a mixture of ring-chain tautomers 90 and 91.⁸⁹ Oxidation of the oxazolidine gave intermediate 92,^90–92 which on isomerization delivered intermediate 93 (oxazoline).⁹³ A second oxidation affords oxazole 88 (Scheme 31).

Scheme 31

Wang and co-workers demonstrated the use of iodine as a catalyst in a practical and simple oxidative cyclization operation for the synthesis of 2,5-disubstituted oxazoles (95) from readily available starting materials such as aldehydes (87) and 2-amino-1-phenylethanone hydrochloride (94) (Scheme 32).⁹⁴ The authors examined different catalytic systems, however, iodine with TBHP was found as the most effective combination for the reaction. Having established the optimal conditions, the scope of different aldehydes was explored including both the nature of the substituents on the aryl ring as well as the aryl part itself. It was found that the electron-rich groups showed slight preference over electron-deficient substituents in terms of the product yield. Similarly, the steric factors were also found operative but to a limited extent. Moreover, the aryl aldehyde substrates could be easily replaced with other aldehydes such as (Z)-3-phenylacrylaldehyde and 2-naphthaldehyde and the corresponding heterocyclic products were afforded in 76% and 75% yields, respectively. Furthermore, when the heterocyclic aldehydes were chosen as substrates, the corresponding oxazoles were obtained in moderate to good yields.

Scheme 32

The authors also successfully showed the practical application of this methodology by synthesizing annuloline (97), a natural product isolated from the roots of ryegrass. Under standard reaction conditions, preparation of annuloline was achieved by the reaction of 94 with 96 in one step, with a yield of 75% (Scheme 33).

Scheme 33

Zhong and co-workers utilized α-isocyanoacetamides (98) and aliphatic aldehydes (87) for a highly efficient enantioselective synthesis of oxazoles (100) (Scheme 34).⁹⁵ This process is catalyzed by chiral phosphoric acid (99) and the heterocyclic products were obtained in toluene at −40 °C in the presence of 5 Å molecular sieves. The products were obtained in excellent yields (85–98%) and good to excellent enantioselectivities (up to >99% ee) under this catalytic system. After screening a library of chiral Bronsted acids, the catalyst with triphenylsilyl group at the 3,3′-positions was found as the optimal catalyst which was used for subsequent optimization of the reaction conditions. Overall, the final conditions are 5 mol% of (R)-99 in the presence of MS 5 Å in toluene at −40 °C. Under these conditions, the generality of the α-addition reaction was explored leading to the oxazole synthesis. Generally, a diverse range of aliphatic aldehydes including acetyldehyde, isobutyaldehyde, pivalaldehyde, and octanal were successfully employed demonstrating excellent yields and good to excellent enantioselectivities. By increasing the chain length, enantioselectivity could be improved. However, the aromatic benzaldehyde was unreactive in this addition reaction. Furthermore, different α-isocyanoacetamides were also probed in the reaction, and excellent yields and enantioselectivities were achieved. The substrate 2-isocyano-3-phenyl-1-(piperidin-1-yl)propan-1-one gave 99% ee.

Scheme 34

Meng et al. described a facile chemoselective approach for the easy accessibility of polyarylated oxazoles (101) using aromatic aldehydes and 2-cyano heteroarenes as starting materials. This one-pot metal-free protocol operates without the use of any external oxidant (Scheme 35).⁹⁶ In order to establish an optimized set of conditions, several parameters including temperature, reaction time, substrate ratio, and acid additives were varied. Finally, the title product was obtained in 60% yield when 3-bromobenzaldehyde and 2-cyanopyridine (1 : 2.5) were heated at 170 °C in AcOH (3 mL) for 10 h. To establish the reaction scope, aldehydes bearing halogen groups, electron-rich and electron-poor substituents at the aryl ring were taken into account and the results revealed the reactivity preference for aldehydes with electron-releasing groups. Aliphatic aldehydes were unreactive under optimized conditions. On the other hand, various combinations of 2-cyano N-heteroarene and aldehydes were explored and the corresponding heterocycles were obtained in acceptable yields. It was also noteworthy to observe the chemoselective generation of heterocyclic products when 2-cyano N-heteroarenes were reacted with two different aldehydes simultaneously.

Scheme 35

2.4. Enamides as starting materials

Reissig and co-workers developed a one-pot three-component synthesis of alkoxy-substituted enamides (102) that could easily be converted to 2,4-substituted 5-acetyloxazoles (103) (Scheme 36).⁹⁷ This methodology was found as an effective approach to install different substituents at 2- and 4-position of the resulting oxazoles. The cyclization of enamides afforded the corresponding oxazole compounds in excess trifluoroacetic acid by heating at 80 °C. The heterocyclic derivatives were afforded in moderate to good yields. Several different substituents such as electron-deficient heteroaryl, alkynyl, and acetyl were successfully introduced at the C-2 position. Similarly, the C-4 position was functionalized with aromatic and aliphatic substituents. In addition, benzyl and trimethylsilylethyl-protected enamides were also investigated in this reaction.

Scheme 36

Zheng et al. reported a facile route toward the synthesis of oxazoles (105) using enamides (104) as the starting material through phenyliodine diacetate-mediated intramolecular oxidative cyclization approach (Scheme 37).⁹⁸ The functionalized oxazoles were obtained in moderate to good yields. After extensive screening, the authors became successful in identifying the optimal conditions (PIDA 1.3 equiv.; BF₃·Et₂O 2.0 equiv.; DCE, reflux), which were used for the exploration of the reaction scope. Substrates bearing either an electron-donating or electron-withdrawing functional group on the aryl ring, were efficiently transformed into their corresponding oxazole products. In addition, various ester groups such as benzoyloxycarbonyl group was also successfully tolerated. Replacement of aryl group with an alkyl substituent afforded the desired alkyl-substituted oxazoles but in lower isolated yields. In the same way, ester group had been replaced with a ketone functionality.

Scheme 37

Panda and Mothkuri conveniently synthesized two different series of 2,5-disubstituted- and 2,4,5-trisubstituted oxazoles (107) using NBS/Me₂S system in the presence of a mild base (Scheme 38).⁹⁹ A range of easily accessible enamide substrates (106) was employed to achieve this annulation. Similar method was introduced by Du and Zhao by using phenyliodinediacetate (PIDA) to accomplish intramolecular cyclization of enamides in the presence of BF₃·Et₂O,¹⁰⁰ however, according to the authors, the presented methodology was less attractive to produce 2,5-disubstituted oxazoles which is potentially a limitation of the reaction scope. Moreover, several other methods are available for similar transformations,¹⁰¹ however, these are mostly substrate specific (leading to either 2,5-disubstituted- or 2,4,5-trisubstituted oxazoles) and are dependent on the selective starting materials (i.e. β-halo or β-mercapto or β-benzyloxy enamides) to furnish either 2,5 or 2,4,5-substituted oxazoles.

Scheme 38

The authors successfully implemented their procedure to several substrates (108) incorporating electron-rich and electron-poor substituents at the aryl ring, yielding 2,5-substituted oxazoles (109) in one-pot with good to excellent yields. Heteroaromatic enamides were also efficiently transformed to their corresponding products, however, the methodology was limited to N-styrylbenzamides, where formation of required oxazole was not observed. The authors attributed this limitation to the presence of an electron-deficient group at the β-position in the enamide substrate that hinders the reaction to proceed. Similarly, 2,4,5-trisubstituted oxazoles (109) were successfully obtained in good yields (Scheme 39).

Scheme 39

2.5. Amines as starting materials

Jiang and co-workers unveiled an efficient and facile one-pot, transition-metal-free domino approach for the preparation of oxazoles (111). On investigation of various reaction conditions, DMSO was found as the most effective solvent while 80 °C was found as the optimal temperature (Scheme 40).¹⁰² Under these conditions, the generality of this one-pot process was investigated for the synthesis of polysubstituted oxazoles from various terminal aryl alkenes and benzylamine. All the olefins, regardless of their electronic or steric properties, proceeded efficiently affording the desired 1,5-diaryl oxazoles in good yields. In addition, various benzylamine derivatives were also probed to elevate the reaction scope. On investigation, it was revealed that the electron-deficient groups on the aromatic ring were more favorable as compared to the electron-rich substituents. The reaction yields were slightly influenced by varying the position of the substituents (para-, meta-, and ortho-positions).

Scheme 40

The authors proposed a mechanism for this reaction where TBHP/I₂-mediated oxidation of phenyl styrene 110 afforded intermediate 112, which was easily converted to intermediate 113 under Kornblum oxidation conditions.^103,104 On addition of the benzylamine to 113 produced intermediate 114 or its enolizable isomer 115. The intramolecular nucleophilic addition of 115 led to the generation of 116 which was converted to the final product (111) via deprotonation and oxidation (Scheme 41).

Scheme 41

Zhu and co-workers explored an organocatalytic domino process for the facile formation of C–N, C–O and C=N bonds via dual sp³ C–H activation to access oxazole compounds (118). This methodology works under metal-free and mild conditions. The key starting materials involved were 1,3-dicarbonyl compounds (34) and different benzylamines (38) (Scheme 42).¹⁰⁵ During the catalyst screening, the authors found that n-Bu₄NI was the most effective as the reaction did not occur when n-Bu₄NCl or n-Bu₄NBr were used which clearly depicts the importance of iodide ligand. Having optimized reaction parameters in hand, the authors exposed the methodology to other relevant 1,3-dicarbonyl compounds and various benzylamines. The replacement of the model substrate (ethyl acetoacetate) with methyl to tert-butyl acetoacetate, produced oxazoles with acceptable yields. In addition, β-keto esters incorporating a range of alkyl groups were also reacted with benzylamine delivering the desired products in 67–76% yield. However, when 1,3-diketone was introduced in this reaction as a substrate, the corresponding oxazole was obtained in reduced chemical yield. The authors also employed the asymmetric 1,3-diketone as a substrate, delivering the oxazole compound in a regioselective fashion. Next, scope of the cascade reaction was broadened with different benzylamines and the results revealed that both electron-donating and electron-withdrawing benzylamines were equally effective leading to the oxazole products in 50–73% isolated yield.

Scheme 42

2.6. Enamines as starting materials

Zhao et al. uncovered the synthesis of 4,5-disubstituted-2-(trifluoromethyl)oxazoles (121) by the reaction of β-monosubstituted enamines (119) with phenyliodine bis(trifluoroacetate) (PIFA) (120).¹⁰⁶ This approach conveniently allows the incorporation of the trifluoromethyl moiety in PIFA into the final products (Scheme 43). Under the best identified conditions, the authors investigated the scope and limitations¹⁰⁷ of this process by exploiting various β-monosubstituted enamines,¹⁰⁸ incorporating a terminal carbonyl functionality. The yields of the final heterocyclic products revealed that the presence of either electron-rich or electron-deficient substituents in the α-phenyl ring of enamine does not affect the reaction to any significant extent. In addition, the α-phenyl ring in 119 could be replaced by an alkyl substituent such as methyl, benzyl, or cyclohexenylmethyl group. Likewise, an acyl group could also be exploited instead of β-carboxylic ester group.

Scheme 43

The authors justified the reaction approach by proposing a mechanism for this transformation, which starts with the formation of β-iodo iminium salt 122 by the reaction of β-monosubstituted enamines 119 with PIFA.¹⁰⁹ Next, the attack of trifluoroacetate anion onto the sp³ carbon center in 122 yields intermediate 123.¹¹⁰ The subsequent proton transfer from the iminium center to the carbonyl oxygen of the trifluoroacetate moiety, produces 124 which leads to 125. Finally, the protonation of the hydroxyl group by the ammonium proton in 125, and the aromatization affords the heterocyclic oxazoles 121 (Scheme 44).

Scheme 44

In another study, Liu et al. developed a β-acyloxylation of enamine compounds (127) using iodosobenzene (PhIO) as an oxidant. The resulting β-acyloxy enamines (128) were efficiently transformed to the corresponding oxazoles (129) via cyclodehydration (Scheme 45).¹¹¹ Having optimized the reaction conditions, several enamines and carboxylic acids were tolerated to examine the scope and versatility of the methodology. A range of enamine substrates incorporating electron-poor groups including acyl or benzoyl groups were investigated and converted to β-acyloxy derivatives which finally furnished the desired oxazoles in good yields. The authors have also developed a one-pot protocol for the preparation of oxazoles using easily accessible β-monosubstituted enamine and N-protected amino acids in chlorobenzene, at reflux conditions. The process successfully tolerated a range of amino acids. These reactions produced oxazole products in moderate to good yields.

Scheme 45

2.7. Imines as starting materials

Lin and co-workers achieved a new type of trisubstituted oxazoles (131) by the chemoselective O-acylation and intramolecular Wittig reaction with ester functionalities using in situ formed phosphorus ylides as key intermediates (Scheme 46).¹¹² A range of acyl imines (130) and acyl chlorides (aliphatic and aromatic) were tested. The authors were surprised when they used an acyl chloride with (R² = 4-BrC₆H₄, 4-MeOC₆H₄, 2-furyl, c-hexyl, or i-propyl) and the corresponding oxazoles were delivered as a mixture of major and minor isomers. Similarly, different acyl imines were also successfully employed yielding the oxazoles in pleasing yields.

Scheme 46

2.8. Isocyanides as starting materials

Yu and co-workers were able to develop an efficient, highly straightforward and mild protocol to access a range of 4,5-disubstituted oxazoles (134) in ionic liquids (Scheme 47).¹¹³ The key starting materials used to synthesize oxazole products through one-pot Van Leusen protocol were tosylmethyl isocyanide (TosMIC) (132), aliphatic halides (133) and aldehydes (87). The heterocyclic products were obtained in high yields. In order to evaluate the scope of this methodology, TosMIC and primary aliphatic halides including allyl bromide and benzyl halides were tested to furnish monoalkyl products in good yields. Secondary alkyl halide were also effective in producing monosubstituted heterocycles in good yield. However, tertiary alkyl halides failed to work in this sequence due to the steric hindrance. With regard to the aldehyde reactivity, aliphatic aldehydes gave slightly lower yields as compared to the aromatic and heterocyclic aldehydes. In addition, aromatic aldehydes with electron-donating groups produced compounds with higher yields and the substrates with sterically hindered groups were less productive in terms of the obtained yields. The key advantage of this methodology is the reusability of the ionic liquids up to six runs without significant loss of yields.

Scheme 47

2.9. Diazoesters as starting materials

Yu and co-workers developed a new and efficient method for the preparation of 2-keto-5-aminooxazoles (137) from α-diazocarbonyl esters (135) and α-isocyanoacetamides (136) without using any catalytic system (Scheme 48).¹¹⁴ After developing a set of optimal reaction conditions, the authors investigated the versatility of this process. A diverse range of α-diazocarbonyl esters and α-isocyanoacetamides were examined. Several α-diazocarbonyl esters with aliphatic and aromatic substituents with various steric and electronic properties were tested and the corresponding 2-keto-5-aminooxazoles were obtained in moderate to good yields. The electron-rich substituted esters gave better yields as compared to the electron-poor diazocarbonyl compounds. The increase in the carbon chain showed a detrimental effect on the isolated yields of oxazoles. Moreover, the benzyl group produced heterocyclic product in good yield, however, the R² group was non-influential on the yields even with electronic and steric effects. The amine part of the oxazole ring was varied by introducing different substituted isocyanoacetamides.^115,116 such as morpholinyl, piperidinyl, and pyrrolidinyl groups.

Scheme 48

The authors proposed a mechanism for this transformation which starts with the formation of ketene 138 from α-diazocarbonyl ester through the Wolff rearrangement reaction.¹¹⁷ Then ketene 138 reacts with isocyanoacetamide 136 to give the nitrilium intermediate 139 which on cyclization furnishes the 2-keto-5-aminooxazole 137 after tautomerization (Scheme 49).

Scheme 49

2.10. Vinyliminophosphoranes as starting materials

Ding and co-workers reported an unexpected synthesis of 2,4,5-trisubstituted oxazoles (144) by the reaction of vinyliminophosphorane (141) with a range of acyl chlorides in an aza-Wittig/Michael/isomerization one-pot process (Scheme 50).¹¹⁸ While undertaking the reaction of vinyliminophosphorane (1 equiv.) with various acyl chlorides (1.2 equiv.) in toluene followed by the hydrolysis to afford dihydrooxazoles 145, however, the final product was verified as an oxazole 144. The oxazole products were delivered in good chemical yields regardless of the nature of acyl chloride (aromatic or aliphatic) used. In addition, several azides and aromatic aldehydes were employed which ultimately yielded vinyliminophosphoranes with different substituent pattern.

Scheme 50

The proposed mechanism for the synthesis of oxazoles 144 indicated that the initial reaction of iminophosphorane 141 with acyl chloride leads to the generation of N-acylated aminophosphonium salt, which on subsequent hydrolysis afforded an amide intermediate 146. An intramolecular Michael addition of 146 under acidic conditions produced intermediate 148, which on isomerization gave oxazole 144 (Scheme 51).

Scheme 51

2.11. Amino acids as starting materials

Wang and co-workers described a decarboxylative cyclization approach for the easy accessibility of poly-substituted oxazoles (151) by using readily available primary α-amino acids (149) and 2-bromoacetophenones (150). The whole process was simple and straightforward where the desired oxazoles were prepared under mild and metal-free conditions (Scheme 52).¹¹⁹ To expand the reaction scope, amino acids including phenylglycine, glycine, alanine, norvaline, valine, isoleucine, leucine and phenylalanine were tolerated and the yields of the corresponding products were acceptable, whereas, primary α-amino acids such as lysine, arginine and serine containing active hydrogen on the pendant chains were unreactive. The scope was broad in terms of different substituents present on the aryl ring as well as nature of the substituent with regard to the steric properties. Heterocyclic substrate such as 2-bromo-1-(pyridin-4-yl)ethanone also proved a competent reaction partner although the corresponding oxazole was isolated in 52% yield.

Scheme 52

Bathula et al. described an easy approach for the synthesis of di- and tri-substituted oxazoles (153) under metal- and catalyst-free conditions using N-acylated amino acids (152) and NBS (Scheme 53).¹²⁰ After optimizing the general conditions, the authors investigated several amide derivatives of phenylalanine and the results indicated that both aliphatic and aromatic substitutions were equally productive. Similarly, amides of aspartic acid were subjected to the standard reaction conditions, the oxazoles with new substitution patterns (two ester groups at C-4 and C-5) were obtained in good yields. Similar results were demonstrated by the amides of β-alanine for the synthesis of 2,5-disubstituted oxazoles.

Scheme 53

Boto and co-workers reported a one-pot metal-free iodine-promoted radical decarboxylation–oxidation–enolization cyclization methodology to widely access a range of 2,5-disubstituted oxazoles (155) endowed with different alkyl and aryl groups (Scheme 54).¹²¹ N-Acylamino acids (154) were employed as substrates in this domino process under mild reaction conditions. The feasibility of this reaction was investigated by employing N-benzoylphenylalanine as the substrate, using different solvents, amounts of iodine and additives under irradiation with visible light and/or heating to afford the 2,5-diphenyloxazole. Next, optimized reaction conditions were used to exploit the suitability of benzamides bearing different substituents. Moreover, vinyl and alkyl (tert-butyl) groups were proved as useful substituents providing enough stabilization of cationic intermediates. However, sec-butyl and methyl led to a complex mixture of products due to the possible decomposition of the enamide intermediate. Similarly, the amino acid chain substituents were also varied and it was observed that the alanine, leucine, and aspartic benzamides were successfully transformed to their corresponding oxazole derivatives.

Scheme 54

Recently, Huang and co-workers developed a metal-free iodine-mediated methodology for the preparation of polysubstituted oxazoles (156) (Scheme 55).¹²² Simple, inexpensive and easily available α-amino acids (149) and methyl ketones (37) were employed as key starting materials. Although, similar reactions are reported to achieve oxazole products, the authors identified an efficient additive (p-aminobenzenesulfonic acid) that greatly enhanced the reaction efficiency. Under optimized reaction conditions (I₂/PABS oxidant system) in DMSO, the authors expanded the substrates scope of this oxidative cyclization to access a range of 2,5-disubstituted oxazoles. Several acetophenones featuring both electron-poor or electron-rich groups on the aromatic rings participated efficiently in the reactions. The isolated yields were remarkably high. The halogen substituents at various positions (2-, 3- or 4-position) also showed good reactivity. Moreover, 1- and 2-naphthyl groups produced similar results, however, 4-methylpentan-2-one furnished the oxazole product in slightly lower yield (42%). On the other hand, several amino acids were also well tolerated.

Scheme 55

2.12. Alkynes as starting materials

In another study, Saito and co-workers successfully disclosed a metal-free synthesis of 2,4-disubstituted and 2,4,5-trisubstituted oxazoles (158) via [2 + 2 + 1] annulation of alkynes (157), nitriles, and O-atoms. This regioselective transformation was accomplished by using PhIO with TfOH or Tf₂NH (Scheme 56).¹²³ Two different sets of reaction conditions were optimized and diversity of alkynes and nitriles (14) were investigated under the PhIO/acid-mediated conditions A (TfOH as acid) or B (Tf₂NH as acid). Both terminal and internal alkynes were successfully tolerated regardless of the nature of nitriles (MeCN, propionitrile, succinonitrile, benzonitrile). These substrates provided access to 2,4-disubstituted and 2,4,5-trisubstituted oxazoles in a regioselective fashion. The authors also observed that when all the reactions were conducted under conditions B, the transformations were completed at ambient temperatures and in some cases improved yields of the products were also obtained.

Scheme 56

In view of the literature reports,¹²⁴ and the obtained results, the authors proposed a plausible mechanistic pathway for this annulation reaction (Scheme 57). The compound 161 was formed by the iodooxidation of alkyne 157 activated by PhI(OH)OTf and the subsequent ligand exchange in 160.¹²⁵ The nucleophilic vinylic substitution of 160 with R³CN generates 161 which on subsequent hydrolysis affords 162 and/or 163, which are converted to 165. The authors also believed that the vinylic substitutions of 161 with R³CONH₂ derived from R³CN and H₂O might be possible as an alternative route to 163. Finally, the reductive elimination of 165 releases the target oxazoles.

Scheme 57

2.13. Aziridines as starting materials

Samimi and Mohammadi introduced a synthetic strategy for the expansion of keto aziridine ring (166) delivering the corresponding 2,5-diarylated oxazoles (167) in the presence of dicyclohexyl carbodiimide (DCC) and iodine under reflux conditions in acetonitrile (Scheme 58).¹²⁶ Having established the standard reaction conditions, scope of the methodology involved the reaction of different substituted keto aziridines with DCC. Both aliphatic and aromatic keto aziridines were equally viable substrates. All the products were afforded in good yields.

Scheme 58

The authors proposed a reaction mechanism which starts with the reaction of aziridine with dicyclohexyl carbodiimide to afford intermediate 168. Iodine-promoted ring cleavage of the aziridine C–C bond by coordinating with the carbonyl group gave 169, in the same manner as the interaction of diphenyliodonium iodide with the carbonyl group of N-alkyl keto aziridines as reported by Padwa.¹²⁷ Ring closure then lead to 2,3-dihydrooxazole 170 followed by elimination to form the oxazole. Alternatively, 167 could be accessed through the ring closure of intermediate 171 (Scheme 59).

Scheme 59

2.14. 1,3-Dicarbonyl compounds as starting materials

Naresh and Narender developed an iodine-mediated oxidative cyclization of β-ketoesters (34) and primary amines (38) under metal- and peroxide-free conditions to furnish polysubstituted oxazoles (172) (Scheme 60).¹²⁸ Under optimized reaction conditions, series of β-keto ester and benzylamine substrates featuring both electron-rich and electron-poor functional groups were well tolerated. The expected oxazole heterocycles were obtained in good yields. It was noted that ketoesters bearing aliphatic groups produced oxazoles in better yields compared to the aromatic substituents. Furthermore, 1,3-diketone (acetyl acetone) also proved a viable starting material although the corresponding oxazole was obtained in <10% isolated yield. On the other hand, amine scope was also examined and it was found that aromatic and heteroaromatic amines were competent substrates, however, aliphatic amines limited the methodology as the desired oxazole product was not observed.

Scheme 60

3. Transition-metal-free synthesis of fused-oxazoles

Fused oxazoles represent a privileged class of heterocyclic compounds and have garnered considerable attention due to their synthetic utility and a diverse set of biological activities against a range of different targets.¹²⁹ These skeletons are prevalent structures of numerous natural products,¹³⁰ pharmaceutical drugs and important bioactive molecules.¹³¹ In addition, these structures find wide applications as melatonin receptor agonists,¹³² natural antimycobacterials,¹³³ Rho kinase inhibitors,¹³⁴ non-nucleoside reverse transcriptase inhibitors,¹³⁵ amyloidogenesis inhibitors,¹³⁶ elastase inhibitors,¹³⁷ and antitumor agents.¹³⁸ As a consequence, several methods have been developed for the efficient synthesis of these heterocycles.

This section represents the developments in the metal-free synthesis of oxazole fused heterocycles from readily available and inexpensive starting materials.

3.1. Schiff bases as starting materials

Prakash and co-workers described an organoiodine-mediated approach for the synthesis of 2-(3-aryl-1-phenyl-4-pyrazolyl)-benzoxazoles (174) using a less toxic oxidant, iodobenzene diacetate (IBD) through an oxidative intramolecular cyclization of the appropriate Schiff's bases (173) in methanol (Scheme 61).¹³⁹ Initially, the synthesis of benzoxazoles was carried out in dichloromethane, but the product yield was 24% only, however, switching the solvent to methanol, an enhanced yield of 60% was acquired. A range of potentially biologically active pyrazole based Schiff bases were investigated to explore the reaction scope. The electron-rich and electron-deficient functional groups along with halogen moieties worked efficiently delivering the benzoxazole products in 55–88% isolated yield.

Scheme 61

Few years later, Bose and Idrees unearthed a DMP-promoted strategy for the synthesis of benzoxazole derivatives (176) by the intramolecular cyclization of phenolic azomethines/Schiff bases (175) at ambient temperature (Scheme 62).¹⁴⁰ The yields of the reaction were increased by developing a solution-phase strategy where the reaction mixtures were sequentially treated with Amberlyst A-26 thiosulfate and diisopropylaminomethyl resin (PS-DIEA). The general reaction scope and diversity were assessed by using several substituted azomethines under standard reaction conditions and the results were impressive affording benzoxazoles in good yields. Moreover, the presence of both electron-rich and electron-poor substituents was non-influential on the fate of the reaction in terms of the obtained yields. Some other solvents like acetonitrile, tetrahydrofuran and methanol were also found effective for this reaction. Overall, the presented strategy was evaluated as efficient, clean, and with simple work-up procedure.

Scheme 62

3.2. Imines as starting materials

Chen and co-worker reported a divergent and regioselective synthesis of two isomeric forms, 3-substituted benzisoxazoles (178) and 2-substituted benzoxazoles (179) from o-hydroxy aryl N–H ketimines (177) through the formation of a common intermediate containing N–Cl bond formation, followed by treatment with a suitable base (Scheme 63).¹⁴¹ Various bases and different solvents were used to optimize the reaction conditions after using NCS/NaOCl as activating agents for the formation of intermediate compounds and found K₂CO₃ as a superior base for benzisoxazole and IPA for benzoxazole. It was also investigated that first N–Cl imine formation is not necessary before addition of a base. The reaction can be carried out in one-pot by mixing substrate, NCS and base in a solvent at ambient temperature.

Scheme 63

The synthesis of benzisoxazoles was performed using the optimized reaction conditions such as o-hydroxy N–H ketimine (1 equiv.), NCS (1.5 equiv.), K₂CO₃ (2 equiv.), in THF at ambient temperature for 12 h. Substrate effect was also investigated where electron-deficient groups enormously facile the reaction with product yield of 99%. On the other hand, synthesis of benzoxazole derivatives was carried out by mixing o-hydroxy N–H ketimine (1 equiv.), NaOCl (10%, 3 equiv.) in IPA at ambient temperature for 12 h. The reactions appeared spontaneous because yellow color of N–H ketimine faded upon addition of NaOCl. The experiments concluded that electron-donating groups favor the high yield of product (100%) as compared to electron-withdrawing groups.

The authors proposed the mechanism for benzoxazoles synthesis which involves a Beckmann-type rearrangement (Scheme 64). Treatment of substrate 177 with NaOCl yielded phenoxide intermediate 180 that further upon concerted cyclization formed spiro-enone intermediate 181. The electron-rich substituents facilitated this step by donation of electrons to the hydroxyl aromatic ring. It was also suggested that aqueous media weakens the nucleophilicity of phenoxide and species favor the rearrangement via net [1,2]-aryl migration rather N–O bond formation. It is worth noting that the conventional Beckmann rearrangement requires strong acidic conditions and dehydrating media at elevated temperatures. However, the current protocol assisted in the formation of benzoxazoles under very mild and rapid conditions at ambient temperature.

Scheme 64

3.3. Amides as starting materials

Yu and co-workers explored an intramolecular oxidative coupling of electron-rich N-phenyl benzamides (183) mediated by phenyliodine bis(trifluoroacetate) (PIFA) as an oxidant and TMSOTf as a catalyst (Scheme 65).¹⁴² A number of different solvents and additives (single or in combination) were used at different temperatures to optimize the reaction conditions. The reaction was preceded by dropwise addition of PIFA in a stirred solution of substituted phenyl amides and TMSOTf in MeCN at room temperature. Several substituents (electron-rich and electron-poor) gave pleasing yields of the benzoxazole products (184).

Scheme 65

They demonstrated two different mechanisms for the synthesis of benzoxazoles (Scheme 66). In path (a), PIFA attacked at proton of amide nitrogen and intermediate 185 is formed which further gives nitrenium ion (186). Next step involves the nucleophilic attack of carbonyl oxygen at phenyl ring to form cyclic product (187) that on deprotonation yielded the target compound 184. In the path (b), single electron transfer (SET) from 183 to PIFA occurred and finally through intermediate 187 afforded the product 184. These both mechanisms support only the electron rich 4-alkoxy-substituted substrates for this reaction. Electron-deficient groups or with higher oxidation potential may follow any other path.

Scheme 66

In the same year, Deng and co-workers developed a metal-free approach for the synthesis of 2-arylbenzoxazoles (192) (Scheme 67).¹⁴³ The readily available benzamides (190) and cyclohexanones (191) were employed as substrates with a combination of KI, p-TsOH in DMSO gave superior results. To expand the reaction scope, they performed the reaction of benzamides with various cyclohexanones. The substituents at the para-position of the carbonyl group gave optimum results. The chain length of the alkyl groups had no profound effect on the outcome of the reactions. However, the presence of a phenyl group slightly improved the yield. The sterically hindered cyclohexanones (with methyl group at 2-position) were poorly tolerated. On the other hand, several functional groups on the benzamide substrates were compatible under optimized conditions generating a library of benzoxazole compounds. The transformation with salicylamide was smooth affording the desired product in 67% yield.

Scheme 67

3.4. Amidines as starting materials

In the quest of developing new synthetic methodologies for benzoxazole compounds (194), Yadav and co-workers uncovered a mild and efficient visible-light-mediated approach (Scheme 68).¹⁴⁴ o-Phenolic amidines (193) were cyclized to their corresponding 2-aminobenzoxazoles using CBr₄ as an oxidant. They investigated the substrate scope with various electron-neutral, electron-rich and electron-poor functional groups and the 2-aminobenzoxazoles were afforded in good to excellent yields (80–92%). This methodology also tolerated several structurally diverse cyclic and acyclic secondary amines. In addition, it was also noted that various electronic properties of the substituents had no visible effect on the yield of the cyclized products.

Scheme 68

The authors proposed a plausible mechanism for this cyclization as illustrated in Scheme 69. The photo-irradiation of CBr₄ delivered Br˙ and ˙CBr₃ radicals which initiate the reaction by the abstraction of phenolic H to produce 195. The aminyl radical 196 is formed by the intramolecular cyclization which undergoes 1,2-H shift to generate a more stable carbon radical 197. The oxidation of intermediate 197 provided a highly stabilized carbocation 198, which on subsequent aromatization afforded the heterocyclic product 194.

Scheme 69

3.5. Phenols as starting materials

Cheon and co-workers explored a cyanide-catalyzed synthesis of 2-substituted benzoxazoles (200) in good yields under ambient conditions. Schiff bases of 2-aminophenol (199) and aldehydes (87) were employed as efficient starting materials with air as the only oxidant (Scheme 70).¹⁴⁵ Later, they developed the synthesis of desired benzoxazoles in one-pot without the isolation of Schiff base intermediates. The authors investigated the substrate scope using various aromatic aldehydes and the corresponding benzoxazoles were isolated in good yields. The role of various substituents in terms of their electronic properties suggested that yields of the benzoxazole products are not much affected. This method was further extended to the heteroaromatic aldehydes for the preparation of benzoxazoles. In addition, alkyl substituted benzoxazoles were also obtained under these conditions.

Scheme 70

Nieddu and Giacomelli developed a new microwave-assisted strategy to prepare a series of benzoxazole derivatives (204) from carboxylic acids (201) and aminophenols (199) using cyanuric chloride (Scheme 71).¹⁴⁶ The reaction conditions were optimized in two steps. Firstly, the benzoic acid was activated by treating with TCT (2,4,6-trichloro-1,3,5-triazine, cyanuric chloride) derivatives and then reacting with 2-aminophenol to form amide intermediate that upon cyclization yielded the benzoxazole product. Diverse chlorinating agents (TCT derivatives, CDMT) were used to check their activation efficiency in different combination of ratios along with various solvents. Under optimized reaction conditions, a range of 2-substituted benzoxazoles endowed with aliphatic and aromatic groups were prepared using this methodology. Natural α-amino acids and α-hydroxy derivatives were also used to introduce chiral substitution at 2-position of benzoxazoles but the low yields of products were obtained.

Scheme 71

Yoon and co-workers revealed a new eco-friendly system for the synthesis of benzoxazoles (206) from 2-aminophenols (199) and 2-acyl pyridazine-3(2H)-ones (205) as acyl transfer agent (Scheme 72).¹⁴⁷ The reactions were performed under mild, metal- and catalyst-free conditions with quantitative recovery of 205 at the end of reaction. Under optimized reaction conditions, the scope of reaction involving both 2-aminophenols and 2-acyl-4,5-dichloropyridazin-3(2H)-ones was investigated. The products were furnished in good yields.

Scheme 72

A range of 2-substituted benzoxazoles (208) were efficiently synthesized by Zeng and co-workers by an indirect anodic oxidation of a Schiff base (207). They performed the electrochemical synthesis under constant current conditions (Scheme 73).¹⁴⁸ A catalytic amount of NaI was used as a redox catalyst and a biphasic system (buffer/CH₂Cl₂) as a solvent. After developing an optimized set of conditions, the scope of this electrochemical reaction was explored using different benzaldehyde and o-aminophenols featuring several electron-releasing and electron-accepting substituents. The desired 2-substituted benzoxazoles were furnished in good yields.

Scheme 73

Recently, another direct approach to benzoxazoles (211) and benzobisoxazoles (214) was introduced by Rubin and co-workers who employed phenols (209) and nitroalkanes (210) as efficient substrates for PPA-catalyzed cyclization (Scheme 74).¹⁴⁹ The process was developed in one-pot under metal- and oxidant-free conditions involving direct ortho-C–H functionalization of phenols, followed by Beckman rearrangement and intramolecular cyclocondensation. Based on the optimized results, several nitroalkanes were tested in the reaction with phenol. The final products were afforded in good yields. Similarly, a range of different para-substituted phenols such as p-ethylphenol, p-cumenol were tested and the results were promising in terms of isolated yields. Resorcinols also reacted selectively showing a strong preference for the electrophilic attack at only one of the ortho-positions.

Scheme 74

The authors also tried their methodology for the preparation of benzobisoxazoles (BBOs). The reaction of resorcinols (212) with excess nitroethane (213) afforded the corresponding benzobisoxazoles (214) in moderate yields (Scheme 75). The initial annulation into benzoxazole happened smoothly, however, the subsequent cyclization occurred at prolonged heating conditions.

Scheme 75

3.6. Amines as starting materials

Foroumadi and co-workers reported a novel, efficient and solvent-free method for the synthesis of benzoxazole derivatives (217) (Scheme 76).¹⁵⁰ In a model reaction to establish the favorable conditions, they used 2-fluoro-5-nitroaniline (215) and benzoyl chloride (216) as substrates in the presence of various bases. The best optimized reaction conditions obtained were as follow: 2-fluoro-5-nitroaniline (1 equiv.), benzoyl chloride (1 equiv.), K₂CO₃ (1 equiv.), and 130 °C. The effect of various substitutions on reaction efficiency was studied and concluded that the presence of electron-donating and electron-withdrawing groups have not any tremendous effect and all benzoyl chloride derivatives shown equivalent behavior regarding the reaction time and yield.

Scheme 76

The proposed reaction mechanism revealed that first 216 reacts with 215 to form the corresponding amide intermediate 218 that upon intramolecular cyclization with removal of fluoride delivered the target compound 217 (Scheme 77).

Scheme 77

Majumdar and co-workers demonstrated a catalyst-free synthesis of coumarin-, quinolone- and pyridine-annulated oxazole derivatives (222, 224) through an intramolecular C–O bond formation in the presence of a base (Schemes 78 and 79).¹⁵¹ The reaction conditions for intramolecular cyclization were optimized by using a variety of bases and solvents at different temperatures. The best reaction conditions were concluded by treating intermediate with Cs₂CO₃ (1.5 equiv.) in DMSO solvent at 130 °C.

Scheme 78

Scheme 79

The proposed mechanism for the formation of products 222, 224 involves initial attack of a base on proton of amide nitrogen to form intermediate 225 that is resonance stabilized by the keto group (conformer 226). The bromide of aromatic ring is removed by amide oxyanion through an intramolecular aromatic nucleophilic displacement to yield the final product 222. While, the synthesis of product 224 was achieved through Peng's mechanism. In the presence of a base, a benzyne like intermediate 227 is formed followed by an intramolecular nucleophilic addition of amide to the intermediate 228 affording the product 224 (Scheme 80).

Scheme 80

Inspired by the recent work on fused oxazoles, Hajra and co-workers developed a redox-neutral domino strategy that provided access to hexahydropyrrolo[2,1-b]oxazoles (230) (Scheme 81).¹⁵² This diastereoselective synthesis involves the direct functionalization of inert sp³ C–H bond of a cyclic amine under transition metal-free conditions. The optimized reaction conditions were established in order to explore the general applicability of the reaction. Initially, various aldehydes featuring electron-rich and electron-deficient functional groups were efficiently reacted with pyrrolidine to generate the desired products in good yields. All the fused products were obtained as a single diastereomers. Aldehydes bearing Me, OMe and SMe functionalities afforded the title products in high yields. On the other hand, aldehydes incorporating halogen groups such as F, Cl, Br were also found as competent partners affording the corresponding products in moderate to high yields. A substituent at the ortho-position of the phenyl ring also afforded the corresponding product with a comparable yield. Heterocyclic aldehydes such as 2-thiophene carboxaldehyde was also compatible under optimized reaction conditions.

Scheme 81

This protocol also tolerates piperidine which reacted with different aldehydes and the corresponding 2,3-disubstituted hexahydrooxazolo[3,2-a]pyridines (232) were obtained in moderate yields (Scheme 82). However, L-prolinol, morpholine, and aliphatic aldehydes were inert under the present domino protocol.

Scheme 82

3.7. Miscellaneous

Another recent example of fused oxazoles such as tetrahydrofuro[3,2-d]oxazoles (235) was developed by Ahmed and co-workers (Scheme 83).¹⁵³ This highly efficient, metal-free diastereoselective synthesis was achieved under microwave irradiation. The reactions were performed without the addition of external additives or co-oxidants. The authors employed aryl/alkyl glyoxals (233), β-naphthol (234) and pyrrolidine (229) as the key starting materials. Having established the suitable reaction conditions, the scope was primarily explored by varying 2-oxoaldehydes. In all the reactions, the desired products (tetrahydrofuro[3,2-d]oxazoles) were obtained in good yields. However, in case of 2-oxoaldehydes incorporating electron-poor substituents (2-Cl and 2-CF₃) at the ortho-position, F, Cl, Br and CF₃ at meta-position, and CF₃, NO₂ at para-position gave slightly lower yields. Moreover, the reactions involving different aliphatic groups were also compatible in this reaction.

Scheme 83

4. Concluding remarks

The development of highly efficient methods for the preparation of oxazole heterocycles under metal-free conditions is important in both synthetic and medicinal chemistry. In this review, we have detailed significant recent advances in the synthesis of oxazoles, especially highlighting those methods in which the construction of oxazole compounds is particularly attractive due to reasonably mild conditions and easy accessibility of the inexpensive and stable starting materials. Several elegant approaches have been developed for the construction of oxazoles using ionic liquids, easily available amino acids such as phenylglycine, glycine, alanine, norvaline, valine, isoleucine, leucine and phenylalanine in addition to the cascade methods which are particularly attractive for industry. Furthermore, these metal-free approaches efficiently produced several fused-oxazoles including benzoxazoles, coumarin-, quinolone- and pyridine-annulated oxazole compounds. A range of cyclizative agents were shown to perform these transformations with remarkable efficiency. The stereo-controlled construction of fused heterocycles namely hexahydropyrrolo[2,1-b]oxazoles and tetrahydrofuro[3,2-d]oxazoles from basic chemicals was also achieved through microwave-assisted protocols. Notably, despite these recent advancements in the methods enabling to achieve highly decorated oxazole heterocycles in an attractive and straightforward fashion, there is still much room for improvement due to the limited functional group compatibility and hindered substrate scope in some reactions. Because of the endless pursuit of sustainable and green chemistry, we strongly believe that this timely review will inspire researchers and stimulate further interest in the ways to develop new and challenging methodologies in this field.

Conflict of interest

The authors declare no financial conflict of interest.

Abbreviations

BBOs	Benzobisoxazoles
CDMT	2-Chloro-4,6-dimethoxy-1,3,5-triazine
CFL	Compact fluorescent lamp
DBU	1,8-Diazabicycloundec-7-ene
DCC	Dicyclohexyl carbodiimide
DCE	1,2-Dichloroethane
DMA	Dimethylacetamide
DMF	N,N-Dimethylformamide
DMP	Dess–Martin periodinane
DMSO	Dimethyl sulfoxide
HDNIB	Hydroxy(2,4-dinitrobenzenesulfonyloxy)iodobenezene
HIV	Human immunodeficiency virus
HTIB	Hydroxy(tosyloxy)iodo]benzene
IBD	Iodobenzene diacetate
MCPBA	m-Chloroperbenzoic acid
MS	Molecular sieves
MW	Microwave
NBS	N-Bromosuccinimide
NCS	N-Chlorosuccinimide
PABS	p-Aminobenzenesulfonic acid
PIFA	Phenyliodine bis(trifluoroacetate)
PIDA	(Diacetoxyiodo)benzene
PPA	Polyphosphoric acid
PTSA	p-Toluenesulfonic acid
SET	Single electron transfer
TBHP	tert-Butyl hydroperoxide
TCT	2,4,6-Trichloro-1,3,5-triazine
TFAA	Trifluoroacetic anhydride
Tf2NH	Bis(trifluoromethanesulfonyl)imide
TfOH	Trifluoromethanesulfonic acid
THF	Tetrahydrofuran
TosMIC	Tosylmethyl isocyanide
TRPV	Transient receptor potential vanilloid
r.t	Room temperature

Acknowledgements

A. Ibrar is thankful to the Higher Education Commission of Pakistan for financial support.

Notes and references

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