Hubbry Logo
OxazoleOxazoleMain
Open search
Oxazole
Community hub
Oxazole
logo
8 pages, 0 posts
0 subscribers
Be the first to start a discussion here.
Be the first to start a discussion here.
Contribute something
Oxazole
Oxazole
Oxazole
View on Wikipedia
from Wikipedia
Oxazole
Full structural formula
Skeletal formula with numbers
Ball-and-stick model
Space-filling model
Names
Preferred IUPAC name
1,3-Oxazole[1]
Identifiers
3D model (JSmol)
103851
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.005.474 Edit this at Wikidata
EC Number
  • 206-020-8
485850
MeSH D010080
UNII
  • InChI=1S/C3H3NO/c1-2-5-3-4-1/h1-3H ☒N
    Key: ZCQWOFVYLHDMMC-UHFFFAOYSA-N ☒N
  • InChI=1/C3H3NO/c1-2-5-3-4-1/h1-3H
    Key: ZCQWOFVYLHDMMC-UHFFFAOYAD
  • C1=COC=N1
Properties
C3H3NO
Molar mass 69.06 g/mol
Density 1.050 g/cm3
Boiling point 69.5 °C (157.1 °F; 342.6 K)
Acidity (pKa) 0.8 (of conjugate acid)[2]
Hazards
GHS labelling:[3]
GHS02: FlammableGHS05: Corrosive
Danger
H225, H318
P210, P233, P240, P241, P242, P243, P264+P265, P280, P303+P361+P353, P305+P354+P338, P317, P370+P378, P403+P235, P501
Supplementary data page
Oxazole (data page)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Oxazole is the parent compound for a vast class of heterocyclic aromatic organic compounds. These are azoles with an oxygen and a nitrogen separated by one carbon.[4] Oxazoles are aromatic compounds but less so than the thiazoles. Oxazole is a weak base; its conjugate acid has a pKa of 0.8, compared to 7 for imidazole.

Preparation

[edit]

The classic synthetic route the Robinson–Gabriel synthesis by dehydration of 2-acylaminoketones:

The Robinson–Gabriel synthesis
The Robinson–Gabriel synthesis

The Fischer oxazole synthesis from cyanohydrins and aldehydes is also widely used:

Fischer Oxazole Synthesis
Fischer Oxazole Synthesis

Other methods are known including the reaction of α-haloketones and formamide and the Van Leusen reaction with aldehydes and TosMIC.

Biosynthesis

[edit]

In biomolecules, oxazoles result from the cyclization and oxidation of serine or threonine nonribosomal peptides:[5]

Where X = H, CH
3 for serine and threonine respectively, B = base.
(1) Enzymatic cyclization. (2) Elimination. (3) [O] = enzymatic oxidation.

Oxazoles are not as abundant in biomolecules as the related thiazoles with oxygen replaced by a sulfur atom.

Reactions

[edit]

With a pKa of 0.8 for the conjugate acid (oxazolium salts), oxazoles are far less basic than imidazoles (pKa = 7). Deprotonation of oxazoles occurs at C2, and the lithio salt exists in equilibrium with the ring-opened enolate-isonitrile, which can be trapped by silylation.[4] Formylation with dimethylformamide gives 2-formyloxazole.

Electrophilic aromatic substitution takes place at C5, but requiring electron donating groups.

Nucleophilic aromatic substitution takes place with leaving groups at C2.

Diels–Alder reactions involving oxazole (as dienes) and electrophilic alkenes has been well developed as a route to pyridines. In this way, alkoxy-substituted oxazoles serve a precursors to the pyridoxyl system, as found in vitamin B6. The initial cycloaddition affords a bicyclic intermediate, with an acid-sensitive oxo bridgehead.

Use of an oxazole in the synthesis of a precursor to pyridoxine, which is converted to vitamin B6.[6]


In the Cornforth rearrangement of 4-acyloxazoles is a thermal rearrangement reaction with the organic acyl residue and the C5 substituent changing positions.

  • Various oxidation reactions. One study[7] reports on the oxidation of 4,5-diphenyloxazole with 3 equivalents of CAN to the corresponding imide and benzoic acid:
Oxazoline CAN oxidation
In the balanced half-reaction three equivalents of water are consumed for each equivalent of oxazoline, generating 4 protons and 4 electrons (the latter derived from CeIV).

See also

[edit]

Additional reading

[edit]
  • Fully Automated Continuous Flow Synthesis of 4,5-Disubstituted Oxazoles Marcus Baumann, Ian R. Baxendale, Steven V. Ley, Christoper D. Smith, and Geoffrey K. Tranmer Org. Lett.; 2006; 8(23) pp 5231 - 5234. doi:10.1021/ol061975c

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Oxazole

View on Grokipedia
from Grokipedia
Oxazole is a five-membered heterocyclic with the molecular formula C₃H₃NO, consisting of three carbon atoms, one oxygen atom at position 1, and one atom at position 3, arranged in a ring with two double bonds that confer through delocalization of 6π electrons. This structure renders oxazole a , with its conjugate acid exhibiting a pKa of 0.8 under standard conditions. As a colorless liquid at , oxazole has a of approximately 69.5 °C, a of 1.050 g/cm³, and is miscible with alcohols and ethers while showing limited in water. In , oxazole serves as a fundamental scaffold and building block for synthesizing more complex molecules, owing to its electron-rich heteroaromatic nature that facilitates diverse reactivity patterns, including and metal-catalyzed couplings. Its derivatives are particularly prominent in , where they exhibit a broad spectrum of pharmacological activities, such as antibacterial, , antiviral, , and anticancer effects, making oxazole-based compounds key components in numerous FDA-approved pharmaceuticals. For instance, oxazole moieties are integral to drugs targeting microbial infections and certain cancers, underscoring the ring's role in enhancing and binding affinity in therapeutic agents. Beyond pharmaceuticals, oxazoles find applications in for dyes, polymers, and agrochemicals due to their stability and tunable electronic properties.

Structure and Properties

Molecular Structure

Oxazole is a five-membered heterocyclic with an oxygen atom at position 1, a atom at position 3, and carbon atoms at positions 2, 4, and 5. The oxazole ring is planar and exhibits aromatic character due to the delocalization of 6 π s across the five ring atoms, satisfying (4n + 2, where n = 1). In this system, the oxygen atom contributes two electrons from one of its s occupying a p-orbital to the ring plane, the pyridine-like contributes one from its p-orbital (with its held in an in-plane sp² orbital, unavailable for π conjugation), and each of the three carbon atoms contributes one to the π system. This results in a stable, akin to but modulated by the heteroatoms. Computational models provide insight into the bond lengths and angles that reflect this aromatic delocalization. (DFT) calculations at the B3LYP/6-311++G(2df,2p) level yield the following optimized geometrical parameters for the unsubstituted oxazole ring: Bond lengths (Å):
BondLength
O1–C21.374
C2–N31.388
N3–C41.374
C4–C51.451
C5–O11.368
Selected bond angles (°):
AngleValue
C2–N3–C4104
C5–O1–C2104
These values show bond length alternation consistent with partial double-bond character (e.g., shorter C–O and C–N bonds around 1.37 compared to a typical C–C of ~1.45 ), supporting the aromatic π electron distribution. In comparison to related heterocycles, oxazole displays lower overall ring than owing to oxygen's greater relative to , which withdraws more effectively from the π system. This manifests in reduced basicity, with the pKa of the protonated oxazolium (at the site) being 0.8, versus 2.5 for thiazolium. Isoxazole, with adjacent and oxygen atoms, exhibits an even lower profile and basicity (pKa ≈ -3 for its conjugate acid), though the reversed heteroatom positioning alters local charge distribution at C4 and C5. Oxazole lacks significant tautomerism due to the fixed positions of its s and does not readily interconvert between isomers like 2H- or 4H-oxazole under standard conditions; occurs selectively at the atom, forming the oxazolium cation.

Physical Properties

Oxazole appears as a colorless at standard conditions. It has a of 69–70 °C at 760 mmHg, a of −85 °C, and a of 1.05 g/cm³ at 25 °C. The compound exhibits good solubility in organic solvents, being miscible with and , while its solubility in water is limited to approximately 10 g/100 mL at . Oxazole possesses a characteristic pungent . Its thermodynamic properties include a standard heat of formation of −11.48 kcal/mol in the liquid phase and a dipole moment of 1.92 D. Under ambient conditions, oxazole is non-explosive and generally stable, though it shows sensitivity to and gradual oxidation by air over time.

Spectroscopic Properties

Oxazole displays characteristic ultraviolet-visible (UV-Vis) absorption in the far-UV region, with a maximum (λ_max) at approximately 200-210 nm arising from π-π* transitions within its aromatic . The molar absorptivity (ε) at this band is around 5000 M⁻¹ cm⁻¹, reflecting moderate intensity due to the heteroaromatic π-electron delocalization. (IR) spectroscopy provides key vibrational signatures for the oxazole ring, particularly the heteroatom-containing bonds. The C=N stretching vibration appears as a medium-to-strong band between 1560 and 1600 cm⁻¹, while the C-O stretch is observed at 1040-1080 cm⁻¹, aiding in structural confirmation of the five-membered heterocycle. These bands are influenced by the ring's partial double-bond character and electronegative heteroatoms. Nuclear magnetic resonance (NMR) offers precise assignments for oxazole's protons and carbons, revealing the electronic environment of the ring. In ¹H (typically in CDCl₃), the proton at position 2 (H-2, adjacent to both O and N) resonates at ~7.9 ppm, while H-4 (~7.2 ppm) and H-5 (~7.4 ppm) appear upfield due to their positions relative to the oxygen. The ¹³C spectrum shows C-2 at ~143 ppm (deshielded by the adjacent heteroatoms), C-4 at ~124 ppm, and C-5 at ~128 ppm, consistent with the ring's aromatic π-system. These shifts serve as benchmarks for identifying oxazole derivatives.
Position¹H NMR Shift (ppm)¹³C NMR Shift (ppm)
2~7.9~143
4~7.2~124
5~7.4~128
Substitutions on the oxazole ring modulate these NMR shifts, with electron-withdrawing groups (e.g., nitro or carbonyl) causing deshielding (downfield shifts) at C-2 by 5-15 ppm through inductive withdrawal of from the electron-deficient carbon. Mass spectrometry of oxazole under typically shows the molecular [M]⁺ at m/z 69 as the base peak, indicating stability of the intact ring. Common fragmentation involves loss of CO (28 Da) to yield a prominent at m/z 41 (C₂H₃N⁺), followed by further to m/z 40, highlighting the ring's tendency to cleave at the C-O bond. The observed π-π* transitions in UV-Vis spectroscopy stem from the of the oxazole ring, which features 6 π-electrons delocalized across the five-membered heterocycle.

Synthesis

Laboratory Methods

The Robinson-Gabriel synthesis represents a classical method for constructing oxazoles through the acid-catalyzed dehydration of α-acylamino ketones. This approach typically employs strong acids such as concentrated or phosphorus oxychloride (POCl₃) to promote intramolecular cyclization, yielding 2,5-disubstituted oxazoles as the primary products. The reaction proceeds via initial protonation of the , followed by nucleophilic attack from the nitrogen and subsequent elimination of water. Independently discovered by Robinson in 1909 and in 1910, this method remains a staple in due to its simplicity and broad substrate tolerance for aryl and alkyl substituents. The general transformation is illustrated by the equation: \ceR−C(O)−CH2−NH−C(O)−R′−>[H2SO4orPOCl3]R′NOC−R+H2O\ce{R-C(O)-CH2-NH-C(O)-R' ->[H2SO4 or POCl3] \frac{R'}{N} \frac{O}{C-R} + H2O} where the oxazole ring features R' at the 2-position and R at the 5-position. Yields are generally moderate to good (50-80%), though side products from over-dehydration can occur with sensitive substrates. This synthesis is particularly useful for preparing oxazoles in campaigns, as it accommodates functional groups compatible with acidic conditions. Another established laboratory route is the reaction of α-haloketones with primary amides, known as the Bredereck synthesis, which affords 2,4-disubstituted oxazoles. In this process, the amide nitrogen displaces the halide to form an intermediate , which then cyclizes with loss of water under heating or basic conditions. Developed by Bredereck in , it is effective for introducing diverse substituents at the 2- and 4-positions, with the halide typically being or . The method is operationally straightforward, often conducted in refluxing or without solvent, and provides access to oxazoles not easily obtainable via other routes. The reaction can be represented as: \ceX−CH2−C(O)−R+R′−C(O)−NH2−>[heat]R′NOC−HRC−H+HX+H2O\ce{X-CH2-C(O)-R + R'-C(O)-NH2 ->[heat] \frac{R'}{N} \frac{O}{C-H} \frac{R}{C-H} + HX + H2O} where X is a , resulting in a 2-R'-4-R-oxazole. Typical yields range from 60-85%, and the approach has been applied in the synthesis of bioactive heterocycles. The Van Leusen reaction offers a versatile modern alternative for synthesizing 2-substituted oxazoles from aldehydes and tosylmethyl (TosMIC) under basic conditions, such as with or tert-butoxide in or DMSO. TosMIC acts as a for the oxazole C-4 and C-5 carbons, with the base promoting and condensation to form an intermediate that aromatizes upon tosyl group elimination. First reported in 1972, this method excels in and compatibility, delivering products in 70-90% yields for aromatic and aliphatic aldehydes. Post-2010 advancements have introduced palladium-catalyzed cyclizations of propargyl amides as efficient routes to oxazoles, often integrated with Sonogashira coupling for alkyne installation. In these protocols, propargyl amides undergo intramolecular hydroamination or carbopalladation, followed by β-hydride elimination to form the oxazole ring under mild conditions (e.g., Pd(OAc)₂ with phosphine ligands in toluene at 80-100°C). A 2014 study demonstrated a consecutive aminolysis-Sonogashira-cyclization sequence for (hetero)arylated oxazoles with yields up to 75%, highlighting improved efficiency over classical methods for complex substrates. These catalytic approaches minimize waste and enable late-stage diversification in synthetic sequences. Due to their volatility (boiling points typically 70-120°C at ), oxazoles are commonly purified by under reduced pressure (e.g., 10-20 mmHg) to prevent or loss during handling. This technique effectively separates the target from polar byproducts or unreacted starting materials, often achieving >95% purity without for small-scale preparations.

Biosynthetic Pathways

Oxazoles occur naturally in various bioactive compounds, particularly in and marine metabolites produced by bacteria and marine organisms. For instance, oxazolomycin A is an isolated from * JA3453, featuring a characteristic 5-substituted oxazole ring as part of its peptide-polyketide hybrid structure. Similarly, ulapualide A, a tris-oxazole from the marine Hexabranchus sanguineus, exemplifies oxazole-rich metabolites derived from marine ecosystems, often linked to dietary sponges. These products highlight the prevalence of oxazoles in secondary metabolites with and cytotoxic properties. The primary biosynthetic pathway for oxazole incorporation in these compounds involves non-ribosomal peptide synthetases (NRPS), often in hybrid systems with synthases (PKS), where oxazole rings form through cyclodehydration of or residues. In such pathways, NRPS modules activate like serine, followed by intramolecular cyclization to generate oxazolines, which are then oxidized to aromatic oxazoles. This process is catalyzed by dedicated cyclodehydratase domains within the NRPS machinery, enabling precise incorporation during chain elongation. A representative example is the of inthomycins A and B in Streptomyces sp. SYP-A7193, where the hybrid PKS/NRPS system assembles the chain with an oxazole derived from serine. The enzymatic mechanism relies on cyclodehydratase enzymes that facilitate dehydration of the serine/threonine side chain onto the peptide backbone, often involving cysteine residues in the enzyme active site for nucleophilic attack, followed by oxidation to aromatize the ring. In the patellamide pathway from cyanobacterial symbionts of marine ascidians, although primarily ribosomal, the analogous cyclodehydratase PatD performs ATP-dependent heterocyclization on serine to form oxazolines, with subsequent dehydrogenase-mediated oxidation yielding oxazoles; this mechanism shares similarities with NRPS systems. The genetic basis for these pathways resides in NRPS gene clusters, first characterized in Streptomyces species during the 1990s with the elucidation of modular NRPS architectures, and refined through 2020s genomic mining that identified oxazole-specific clusters like itm in Streptomyces. Biological production via typically yields 1-10 mg/L of oxazole-containing natural products in wild-type strains, offering advantages over by inherently producing enantiopure heterocycles from L-amino acids. For example, initial of oxazolomycin clusters achieves around 0.5 mg/L, underscoring the efficiency gains possible through engineering while highlighting the native pathway's precision.

Reactivity

Electrophilic Substitution

reactions on the oxazole ring are limited due to its overall electron-deficient nature, arising from the heteroatoms' influence on the π-electron , with the C-2 position being particularly electron-poor. The ring's aromatic stability allows for such substitutions when activated, but they generally require electron-donating groups or specific conditions to proceed efficiently. Early investigations in the mid-20th century, including studies from the onward, established the fundamental patterns of reactivity for these transformations. Regioselectivity favors the C-5 position as the most electron-rich site, followed by C-4, reflecting the distribution of influenced by the oxygen and nitrogen's inductive effects. Computational analyses of electrostatic potentials confirm this preference, with C-5 exhibiting the highest negative potential suitable for electrophilic attack. In contrast, direct substitution at C-2 is rare without prior activation, as the position's partial positive charge discourages approach by electrophiles. Halogenation exemplifies this regioselectivity, particularly in 5-substituted oxazoles, where bromination occurs selectively at C-4. For instance, treatment of 5-substituted oxazoles with Br₂ in DMF provides the 4-bromo derivatives in high yields, with the solvent playing a key role in suppressing over- or side reactions; this method is scalable and achieves >95:5. Similar selectivity is observed for iodination via lithiation followed by electrophilic , though classical with Br₂ on the parent oxazole is less straightforward and often leads to low yields or ring degradation. The Vilsmeier-Haack demonstrates mixed in 2,5-unsubstituted oxazoles. Reaction of 4-methyloxazole with the Vilsmeier reagent (POCl₃/DMF) affords a 1:1 mixture of 4-methyl-5-formyloxazole and 4-methyl-2-formyloxazole, highlighting competition between C-5 and C-2 sites under these conditions. This reaction introduces an group useful for further elaboration, though separation of isomers is necessary. Nitration of the parent oxazole is challenging, as the ring resists standard mixed acid conditions (HNO₃/H₂SO₄) due to insufficient . However, activated derivatives, such as 2-dimethylamino-4-phenyloxazole, undergo at C-5 in moderate yields, underscoring the need for electron-donating substituents to facilitate the process. Friedel-Crafts exhibits poor reactivity on oxazoles, with the electron-deficient ring deactivating further upon initial substitution, limiting multiple acylations. Attempts on neutral oxazoles typically result in low conversion or side reactions like ring opening, making this transformation impractical without prior activation.

Nucleophilic Reactions

Oxazoles exhibit susceptibility to nucleophilic attack due to the electron-deficient nature of the ring, particularly at the C-2 position, which is influenced by the pKa of the conjugate acid (oxazolium ) being approximately 0.8. This low pKa value indicates that oxazoles are weakly basic and can be protonated under mildly acidic conditions, enhancing their reactivity toward nucleophiles by forming a positively charged oxazolium intermediate that facilitates attack at electron-poor sites. Under strong basic conditions, oxazoles undergo at the C-2 position, leading to ring opening and formation of a ring-opened enolate-isonitrile intermediate, which highlights the instability of the oxazole ring under such conditions. (SNAr) is feasible at the C-2 position when activated by good leaving groups such as . For instance, 2-chlorooxazoles react with primary (RNH₂) to displace the , yielding 2-aminooxazoles in 60-70% yields under mild heating. This addition-elimination mechanism is regioselective for the C-2 site due to the electron-withdrawing effects of the ring and oxygen, making it a useful route for synthesizing amine-substituted derivatives. Representative examples include the conversion of ethyl 2-chlorooxazole-4-carboxylate to the corresponding 2-(alkylamino) analogs, with yields optimized by using excess amine in polar solvents. In recent years, nucleophiles have gained attention for applications involving azoles, particularly in and protein labeling. Activated azoles bearing electron-withdrawing groups can undergo efficient addition under physiological conditions, forming stable thioether linkages.

Cycloadditions and Rearrangements

participate in inverse electron demand Diels-Alder reactions as 2-azadienes, particularly with electron-deficient dienophiles such as alkynes. The cycloaddition involves the C2-N3 and C4=C5 bonds of the oxazole ring, yielding a bridged 7-oxa-2-azabicyclo[2.2.1]heptadiene adduct. For instance, the reaction of unsubstituted oxazole with dimethyl acetylenedicarboxylate (DMAD) forms the corresponding bicyclic diester, which undergoes spontaneous retro-Diels-Alder fragmentation with loss of (HCN) to produce dimethyl pyridine-3,4-dicarboxylate. This sequence provides a versatile route to substituted pyridines, with the reaction efficiency enhanced by Lewis or Brønsted acid coordination to the oxazole , which lowers the LUMO energy and activation barrier. In 1,3-dipolar cycloadditions, oxazoles act as dipolarophiles, with diazomethane adding across the electron-rich C4=C5 double bond to afford fused pyrazolooxazole systems. This regioselective [3+2] cycloaddition proceeds under mild conditions, yielding 6H-pyrazolo[1,5-c]oxazoles as stable adducts, which can serve as precursors for further heterocyclic transformations. The reaction's selectivity arises from the partial positive charge on C5, facilitating approach of the diazomethane's terminal carbon. The Cornforth rearrangement involves the base-promoted migration in 2-(acylaminomethyl)oxazoles, leading to N-substituted . Under or conditions mimicking basic catalysis, the oxazole ring opens via of the , followed by cyclization and to form the imidazole core. This method, optimized for diversity-oriented synthesis, efficiently converts oxazoles bearing α-acylamino substituents into 1,4- or 1,5-disubstituted imidazoles, with yields exceeding 70% for electron-neutral aryl variants. Seminal work by Cornforth established the foundational thermal variant, while recent adaptations expand its scope to pharmaceutical intermediates. Thermal [4+2] cycloreversions of oxazoles occur at elevated temperatures around 200°C, decomposing the ring into and carbonyl fragments. This retro-hetero-Diels-Alder process cleaves the O1-C2 and N3-C4 bonds, generating an α-oxo intermediate that fragments to R-CN and R'-C=O equivalents, where R and R' derive from the 2- and 5-substituents, respectively. The reaction is particularly clean for 2,5-disubstituted oxazoles, providing a synthetic equivalent for carbonyl- assembly, though it competes with pathways in unsubstituted cases. Recent (DFT) studies using the B3LYP functional have elucidated the frontier orbital interactions governing these cycloadditions. For unsubstituted oxazole, the -LUMO gap is calculated at 6.64 eV, with the localized on the C4=C5 bond and the LUMO on the C2=N3 region, favoring inverse demand pathways with electron-poor partners. Substituents like phenyl at C5 reduce the gap to 4.80 eV, enhancing reactivity by raising the energy and promoting better orbital overlap in [4+2] transitions. These insights confirm oxazole's role as a moderate azadiene, with activation barriers for Diels-Alder cycloadditions around 20-30 kcal/mol under .

Applications and Derivatives

Pharmaceutical Uses

Oxazole derivatives play a significant role in pharmaceutical design due to their ability to mimic bonds and participate in hydrogen bonding, enhancing binding affinity to biological targets. The 2,5-disubstituted oxazole motif is commonly incorporated into inhibitors, where it serves as a hinge-binding element that interacts with the ATP-binding pocket of enzymes like receptors (VEGFRs). In antimicrobial applications, oxazole-containing peptides such as microcin B17, a natural product from , inhibit bacterial (a ) through its /oxazole rings, which intercalate into DNA and stabilize the cleavage complex. Synthetic analogs inspired by these motifs have been developed to target bacterial topoisomerases, offering potential against multidrug-resistant strains by disrupting with minimal host toxicity. These compounds draw from biosynthetic pathways in natural antibiotics, where oxazoles are post-translationally formed from serine or residues. Oxazoles are also prominent in anti-inflammatory agents, exemplified by oxaprozin, an FDA-approved non-steroidal drug (NSAID) introduced in 1992 for treating and . Oxaprozin acts as a (COX) inhibitor, reducing synthesis to alleviate and ; structure-activity relationship (SAR) studies indicate that phenyl substitution at the C-4 position of the oxazole ring enhances its selectivity for COX-2 over COX-1, minimizing gastrointestinal side effects compared to non-selective NSAIDs. As of 2025, at least eight FDA-approved drugs incorporate oxazole scaffolds, spanning indications from treatment to disorders. The pharmaceutical pipeline emphasizes , with oxazole derivatives explored as targeted therapies, including inhibitors of and tubulin that show promise in preclinical models for cancers like and . Oxazole-based pharmaceuticals generally exhibit low toxicity profiles, attributed to their metabolic stability and rapid clearance, but certain derivatives like 2-aminooxazoles may induce reactions or renal damage at high doses, necessitating careful SAR optimization in .

Material and Synthetic Applications

Oxazole derivatives have found significant utility as components in ligands for , particularly in palladium-catalyzed cross-coupling reactions. Oxazole-phosphine hybrid ligands, such as PhMezole-Phos (a phosphine substituted with a 4,5-dimethyl-2-phenyl oxazole moiety), enable highly efficient direct C2-alkenylation of oxazoles with alkenyl acetates at parts-per-million levels of palladium loading, achieving yields up to 95% under mild conditions. These ligands enhance catalyst stability and selectivity, facilitating Buchwald-Hartwig-type aminations and Suzuki-Miyaura couplings with improved turnover numbers exceeding 10,000 in the , which broadens the scope for constructing complex molecular architectures in synthetic chemistry. In materials chemistry, fluorescent oxazole derivatives serve as key chromophores in organic light-emitting diodes (s), leveraging their rigid heterocyclic structure for efficient electron delocalization and high . For instance, phenanthro[9,10-d]oxazole-anthracene hybrids exhibit deep-blue emission with external quantum efficiencies (EQE) of up to 5.9% in non-doped OLED devices, attributed to balanced charge transport and reduced non-radiative decay. Similarly, 2-aryloxybenzooxazole derivatives demonstrate solid-state quantum yields as high as 0.67, making them suitable for pigments in display technologies where color purity and stability are critical. Oxazoles are incorporated into high-performance polymers, notably polybenzoxazoles (PBOs), which exhibit exceptional thermal stability due to their rigid, aromatic backbone. PBO fibers, such as those derived from poly(p-phenylene benzobisoxazole), maintain structural up to decomposition temperatures exceeding 650°C and are widely used in composites for their high tensile strength (up to 5.8 GPa) and low density, enabling lightweight components in and . These materials also feature temperatures above 300°C in variants, supporting applications in high-temperature environments like parts. As synthetic building blocks, oxazoles enable diversity-oriented synthesis (DOS) for generating compound libraries through efficient multicomponent reactions. A versatile approach involves the conversion of oxazole-5-trifluoroacetamides to Boc-protected variants, followed by and diversification, yielding libraries of over 100 oxazole-5-s with high purity for screening in materials discovery. Hantzsch-like multicomponent reactions, adapting the classical protocol, combine α-haloketones, , and aldehydes to form substituted oxazoles in one pot, streamlining access to structurally diverse heterocycles for precursors and functional materials. Emerging applications in include oxazole-based nonionic , which offer biodegradability and reduced environmental persistence compared to traditional petroleum-derived analogs. Derivatives such as N-(2-hydroxyethyl)oxazole amides demonstrate over 90% biodegradation within 28 days under guidelines, making them promising for eco-friendly detergents and emulsifiers in the 2020s. These leverage oxazole's polarity and stability to achieve low critical concentrations (around 0.1 mM) while minimizing aquatic toxicity.

References

  1. https://www.sciencedirect.com/topics/chemistry/oxazole
  2. https://www.tandfonline.com/doi/full/10.1080/2314808X.2023.2171578
  3. https://www.chemicalbook.com/ChemicalProductProperty_EN_CB8420295.htm
  4. https://www.sciencedirect.com/science/article/abs/pii/S0223523417310760
  5. https://pubs.rsc.org/en/content/articlehtml/2025/md/d4md00777h
  6. https://bmcchem.biomedcentral.com/articles/10.1186/s13065-019-0531-9
  7. https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/slct.202403179
  8. https://link.springer.com/article/10.1007/s11164-024-05245-1
  9. https://pmc.ncbi.nlm.nih.gov/articles/PMC8895684/
  10. https://www.chemicalbook.com/article/what-is-oxazole.htm
  11. https://pubs.aip.org/aip/jcp/article/157/21/214305/2842283/Core-spectroscopy-of-oxazole
  12. https://www.nature.com/articles/s41598-020-59889-1
  13. https://pmc.ncbi.nlm.nih.gov/articles/PMC10675556/
  14. https://pubs.acs.org/doi/10.1021/jm801331y
  15. https://www.thieme-connect.de/products/ebooks/pdf/10.1055/sos-SD-011-00361.pdf
  16. https://parchem.com/chemical-supplier-distributor/oxazole-038355
  17. https://webbook.nist.gov/cgi/cbook.cgi?ID=C288426&Units=CAL&Mask=37
  18. https://www.sciencedirect.com/science/article/pii/S0040402001991276
  19. https://webbook.nist.gov/cgi/cbook.cgi?ID=C288426&Mask=400
  20. https://webbook.nist.gov/cgi/cbook.cgi?ID=C288426&Mask=80
  21. https://pubs.rsc.org/en/content/articlelanding/1969/j2/j29690000270
  22. https://link.springer.com/article/10.1007/BF00961751
  23. https://webbook.nist.gov/cgi/cbook.cgi?ID=C288426&Mask=200
  24. https://pubchem.ncbi.nlm.nih.gov/compound/Oxazole
  25. https://www.sciencedirect.com/topics/chemistry/robinson-gabriel-synthesis
  26. https://onlinelibrary.wiley.com/doi/10.1002/anie.196206622
  27. https://www.organic-chemistry.org/namedreactions/van-leusen-oxazole-synthesis.shtm
  28. https://pmc.ncbi.nlm.nih.gov/articles/PMC2888422/
  29. https://pubs.acs.org/doi/10.1021/ja00264a052
  30. https://www.mdpi.com/1660-3397/18/4/203
  31. https://journals.asm.org/doi/10.1128/AEM.01388-20
  32. https://pubmed.ncbi.nlm.nih.gov/32801183/
  33. https://pmc.ncbi.nlm.nih.gov/articles/PMC4268494/
  34. https://www.pnas.org/doi/10.1073/pnas.1614191114
  35. https://microbialcellfactories.biomedcentral.com/articles/10.1186/s12934-025-02726-9
  36. https://pubs.acs.org/doi/10.1021/i300001a005
  37. https://pubs.acs.org/doi/10.1021/op700176n
  38. https://onlinelibrary.wiley.com/doi/abs/10.1002/jhet.5570180618
  39. https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/oxazole
  40. http://www.mch.estranky.sk/file/268/2015jhetchem52-425-39.pdf
  41. https://pubs.acs.org/doi/10.1021/ol202648r
  42. https://www.sciencedirect.com/science/article/pii/B9780080965192000862
  43. https://triggered.stanford.clockss.org/ServeContent?doi=10.3987%252Fr-1983-07-1335
  44. https://pubs.rsc.org/en/content/articlelanding/2014/cc/c3cc48467j
  45. https://pubs.acs.org/doi/10.1021/jo00898a040
  46. https://pmc.ncbi.nlm.nih.gov/articles/PMC7048806/
  47. https://pmc.ncbi.nlm.nih.gov/articles/PMC6722960/
  48. https://www.ncbi.nlm.nih.gov/books/NBK548334/
  49. https://chemrxiv.org/engage/api-gateway/chemrxiv/assets/orp/resource/item/66a52715c9c6a5c07a26b95c/original/structural-optimization-of-oxaprozin-for-selective-inverse-nurr1-agonism.pdf
  50. https://pubmed.ncbi.nlm.nih.gov/34525925/
  51. https://theses.hal.science/tel-02918015v1/file/Sramel_Peter_2017_ED222.pdf
  52. https://pubs.acs.org/doi/10.1021/acs.orglett.6b02619
  53. https://pubs.rsc.org/en/content/articlelanding/2020/tc/d0tc01811b
  54. https://www.sciencedirect.com/science/article/abs/pii/S0143720820318246
  55. https://onlinelibrary.wiley.com/doi/full/10.1155/adv/1175941
  56. https://www.sciencedirect.com/science/article/abs/pii/S003238611731073X
  57. https://pubs.acs.org/doi/abs/10.1021/jo900425w
  58. https://www.sciencedirect.com/science/article/abs/pii/S0040402022002307
  59. https://onlinelibrary.wiley.com/doi/10.1002/jhet.2288
Add your contribution
Related Hubs
Contribute something
User Avatar
No comments yet.