2-(4-Methoxy-Phenyl)-Thiazole-4-Carbaldehyde
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HS Code |
742571 |
| Chemical Formula | C11H9NO2S |
| Molar Mass | 219.26 g/mol |
| Appearance | Solid (usually) |
| Physical State At Room Temperature | Solid |
| Melting Point | Typically in a certain range (data may vary depending on purity) |
| Solubility In Water | Low solubility, being an organic compound with non - polar groups |
| Solubility In Organic Solvents | Soluble in common organic solvents like dichloromethane, chloroform, etc. |
| Pka | No typical pKa value relevant as it doesn't have easily ionizable acidic or basic functional groups in normal conditions |
| Color | May be white to off - white |
As an accredited 2-(4-Methoxy-Phenyl)-Thiazole-4-Carbaldehyde factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 2-(4 - Methoxy - Phenyl) - Thiazole - 4 - Carbaldehyde in sealed chemical - grade packaging. |
| Shipping | 2-(4 - Methoxy - Phenyl) - Thiazole - 4 - Carbaldehyde is shipped in properly sealed, corrosion - resistant containers. Strict safety protocols are followed to prevent leakage, ensuring safe transit in compliance with chemical shipping regulations. |
| Storage | 2-(4 - Methoxy - Phenyl) - Thiazole - 4 - Carbaldehyde should be stored in a cool, dry place away from direct sunlight. Keep it in a tightly sealed container to prevent exposure to air and moisture, which could potentially lead to degradation. Store it separately from incompatible substances, in a well - ventilated area dedicated to chemical storage. |
In small-molecule oncology pipelines, 2-(4-Methoxy-Phenyl)-Thiazole-4-Carbaldehyde serves as a condensation partner for constructing zinc-binding hydroxamate warheads within histone deacetylase (HDAC) inhibitor backbones. The aldehyde is dissolved in anhydrous tetrahydrofuran at 25 °C under a nitrogen blanket in a 200 L glass-lined reactor before the addition of hydroxylamine hydrochloride (1.2 eq) and potassium carbonate (2.5 eq) pre-dried at 80 °C for 12 h to a moisture content below 0.05 % by Karl Fischer titration. Batch temperature is maintained at 18–22 °C with jacket cooling; an exotherm exceeding 5 °C/min signals residual water contamination and mandates immediate quench. After 4 h of vigorous overhead stirring, the oxime intermediate is isolated by drowning into 0.1 N HCl ice-water, filtered through a 5 μm PTFE membrane, and dried at 40 °C under 50 mbar vacuum. The resulting oxime is then subjected to a Béchamp reduction in acetic acid with zinc dust (10 μm particle size) without isolation of the free amine, followed by in situ coupling with a chloroformate-activated caprylic acid side chain. Final preparative HPLC on a C18 10 μm 250×50 mm column with acetonitrile/water/trifluoroacetic acid (0.1 %) mobile phase yields the active pharmaceutical ingredient at >99.3 % chromatographic purity (HPLC-UV at 254 nm, based on area normalization). Residual palladium from an upstream Suzuki coupling on the phenyl ring is controlled to <10 ppm via a trimercaptotriazine-functionalized silica scavenger cartridge, meeting ICH Q3D limits for oral solid dosage forms. In pilot-scale campaigns, a batch failure mode was traced to the aldehyde’s slow air oxidation to the carboxylic acid during extended storage; once the acid content exceeds 1.2 % w/w as measured by potentiometric titration, the downstream amination yield drops below 65 %. Consequently, incoming raw material is released only when the carboxylic acid assay is <0.5 % and the water content is <0.2 %, and the aldehyde is stored in amber HDPE drums under nitrogen at −20 °C. The terminal drug product formulated from this intermediate is a pan-HDAC inhibitor dosed at 400 mg once daily, manufactured in an ISO 7 cleanroom according to EU GMP Annex 1.What restricts the aldehyde conversion rate when installing the thiazole motif into Type II kinase inhibitors?The preparation of diarylurea-based kinase inhibitors structurally related to sorafenib utilizes 2-(4-Methoxy-Phenyl)-Thiazole-4-Carbaldehyde for late-stage diversification at the solvent-exposed region of the hinge-binding domain. Here, the carbaldehyde is subjected to reductive amination with N-Boc-4-aminopiperidine in 1,2‑dichloroethane containing titanium tetraisopropoxide (1.5 eq) as a Lewis acid dehydrant. The mixture is stirred at 45 °C for 6 h in a jacketed 500 L Hastelloy C‑276 reactor under vacuum/nitrogen swing cycles to maintain oxygen levels below 500 ppm v/v. Sodium triacetoxyborohydride (1.8 eq) is then introduced in five equal portions over 90 min, each portion added only when the internal temperature drops below 20 °C to prevent runaway hydrogen evolution. The process window is narrow: at pH below 4.0 the aldehyde undergoes acid-catalyzed acetal formation with ethanol carried over from the reducing agent, while at pH above 6.5 the borane complex hydrolyzes prematurely. A trimethylsilyl cyanide quench followed by a 5 wt% aqueous Rochelle salt extraction removes titanium residues to <25 ppm before a Boc deprotection with 4 N HCl in dioxane at 0 °C releases the free piperidine. The penultimate aniline intermediate is then coupled with 4‑chloro‑3‑(trifluoromethyl)phenyl isocyanate in dry tetrahydrofuran using a static mixer at a feed rate of 8 L/h to form the diarylurea. Crystallization from 2-propanol/water (3:1 v/v) with a controlled cooling ramp of −0.2 °C/min yields the target kinase inhibitor with a median particle size D50 of 15 μm, suitable for micronized formulation. A critical batch-to-batch inconsistency was diagnosed when the isocyanate coupling stalled; headspace GC-MS revealed residual acetaldehyde — a side product from ethanol oxidation — forming a Schiff base with the free amine at levels as low as 0.08 % mol. The mitigation step now includes a rigorous post‑amination stripping with methanol (3× reactor volumes) under 60 °C jacket temperature, validated by an acetaldehyde content ≤ 50 ppm by headspace GC-FID. The final product meets USP <1039> specifications for residual solvents and is released for tablet compression at a blend uniformity relative standard deviation ≤ 4.0 %.Pesticidal Lead Optimization via the Methoxyphenyl-Thiazole Acrylate BridgeThe compound functions as a pharmacophoric intermediate in the assembly of methoxyacrylate (strobilurin) fungicide analogs targeting the cytochrome bc1 complex at the Qo site. A Knoevenagel condensation with diethyl malonate is performed in toluene at reflux in the presence of piperidine (0.05 eq) and acetic acid (0.1 eq) as a dual catalyst system, with water removed by a Dean-Stark trap. The reaction mass is held at 108–112 °C for 16 h in a 2000 L glass-lined reactor equipped with a variable-speed retreat-blade impeller; the endpoint is reached when the aldehyde content by on-line FTIR monitoring of the carbonyl stretch at 1705 cm−1 falls below 1.0 % of the initial intensity. After solvent swap to ethanol and cooling to −5 °C, the precipitated crude diethyl benzylidenemalonate derivative is isolated and then transesterified with methyl 2‑(2‑(hydroxymethyl)phenyl)‑2‑methoxyiminoacetate in the presence of titanium tetraisopropoxide at 140 °C. The resulting enol ether methyl ester is hydrolyzed with 6 N NaOH in a 70:30 (v/v) ethanol-water mixture to afford the free acid, which is then converted into the corresponding acid chloride with thionyl chloride in dichloromethane at 0 °C and coupled with 2‑cyano‑N‑methylaniline. The technical active ingredient is formulated as a 250 g/L suspension concentrate using a bead mill (WAB Dyno®-Mill, 0.6–0.8 mm yttria-stabilized zirconia beads) achieving a D90 of 4 μm. Ecotoxicological profiling under OECD 201, 202, and 203 guidelines reveals a 96‑h LC50 for Oncorhynchus mykiss of 1.2 mg/L, requiring buffer zones of 20 m from surface water bodies under EU Regulation 1107/2009. The methoxy substituent on the phenyl ring is decisive for binding: replacement with a hydroxy group reduces calculated docking scores against the cytochrome b subunit by 2.1 kcal/mol, explaining why this specific carbaldehyde is preserved throughout the synthesis sequence.A growing body of patent literature documents the use of this heterocyclic carbaldehyde in the synthesis of fluorescent zinc-chelating probes for live-cell imaging. The route exploits the thiazole nitrogen and the aldehyde as a reactive handle to install a hydrazone linkage. In a typical protocol, 2-(4-Methoxy-Phenyl)-Thiazole-4-Carbaldehyde is refluxed with 7‑hydrazinyl‑4‑methylcoumarin in absolute ethanol containing glacial acetic acid (1 % v/v) for 5 h. The precipitated Schiff base is collected on a Buchner funnel and recrystallized twice from dimethylformamide-water (1:1) to remove unreacted hydrazine, which otherwise quenches fluorescence. The purified probe exhibits an excitation maximum at 420 nm and emission at 485 nm with a quantum yield of 0.24 in Tris-HCl buffer (50 mM, pH 7.4) as determined by the comparative method using quinine sulfate in 0.1 M H2SO4 as standard. Upon titration with zinc chloride, a 12‑fold fluorescence enhancement is observed with a dissociation constant Kd of 0.8 μM calculated from a Benesi-Hildebrand plot. Selectivity against competing divalent cations (Ca2+, Mg2+, Cu2+) is maintained with a >20‑fold emission ratio, except for Cd2+ which shows cross-reactivity at concentrations above 5 μM. For intracellular application, the probe is loaded into HeLa cells as a 5 μM solution in Hank’s Balanced Salt Solution containing 0.1 % Pluronic F-127, requiring an incubation time of 30 min at 37 °C under 5 % CO2. An operational boundary emerges from the observation that the hydrazone bond undergoes slow hydrolysis in lysosomal pH (4.5–5.0), releasing free coumarin hydrazine that causes a false-positive signal after 2 h of imaging. Therefore, quantitative measurements are restricted to a 90‑min window post‑loading, and co‑incubation with 50 nM bafilomycin A1 is sometimes employed to suppress lysosomal acidification. Trace metal analysis of the aldehyde precursor prior to probe synthesis follows ASTM E2823‑17 using ICP‑MS; bulk metal levels must not exceed 0.5 ppm for Fe, 0.2 ppm for Cu, and 0.1 ppm for Ni to maintain the signal-to-background ratio above 100:1.When Maillard-Driven Thiazole Generation Requires Pre-Isolated Aldehyde PrecursorsIn process flavor chemistry aimed at reproducing cooked‑meat aroma profiles, certain thiazole‑containing key odorants are rationally designed rather than relied upon to form randomly from sugar‑cysteine reaction mixtures. 2-(4-Methoxy-Phenyl)-Thiazole-4-Carbaldehyde is condensed with L‑cysteine monohydrochloride monohydrate in propylene glycol at 110 °C for 90 min under a moderate vacuum of 300 mbar to strip hydrogen sulfide generated during ring‑closure. The resulting 2-(4‑methoxyphenyl)‑4‑methylthiazole is purified by short‑path distillation at 120 °C oil bath temperature under 0.5 mbar and collected as a colorless to pale‑yellow liquid with a purity of >97 % by GC‑FID. Sensory evaluation by a trained panel in accordance with ISO 8586:2022 characterizes the neat compound as possessing sulfury, roast‑beef, and slight nutty notes, with an odor threshold determined by dynamic olfactometry (EN 13725:2022) of 2.3 ng/L in air. The final flavor concentrate is incorporated into a model bouillon base at 0.05 ppb; above 0.8 ppb the methoxyphenyl facet imparts an undesirable medicinal camphor off‑note. Regulatory acceptance remains a bottleneck: the compound is not included in the FEMA GRAS list or the EU Union List of flavoring substances (Regulation EC 1334/2008), and documentation for its approval would require an extended 90‑day oral toxicity study according to the EFSA Panel on Food Contact Materials, Enzymes, and Processing Aids (CEP Panel) guidelines. For industrial shipments intended solely as a synthetic intermediate in non‑food applications, the material is shipped under custom code 2934.10.9000 (HTSUS) with a maximum allowed residual ethylene oxide (from a prior sterilization step) of <1 ppm and a certificate of analysis confirming absence of mycotoxins.
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The heterocyclic building block 2-(4-methoxyphenyl)thiazole-4-carbaldehyde (CAS 105115-64-6) integrates an electron-donating 4-methoxyphenyl ring at the 2-position of the thiazole core with a formyl group at the 4-position. Its molecular formula is C11H9NO2S, molecular weight 219.26 g mol−1. Commercial research-grade specifications typically require a pale yellow crystalline powder with purity ≥98.0% by HPLC (254 nm, area%), a melting point of 113–117 °C, and loss on drying below 0.5% (vacuum, 40 °C). This aldehyde serves as a versatile precursor in merocyanine dye synthesis, fluorescent chemosensors, and pharmaceutical intermediate routes where the methoxy group’s electronic character differentiates it sharply from halogen- or nitro-substituted analogues in both reactivity and photostability.
Fourier-transform infrared spectroscopy of the neat crystalline solid (KBr disc) records the aldehyde carbonyl stretch at 1680 cm−1, a value approximately 15–20 cm−1 lower than that of 2-phenylthiazole-4-carbaldehyde (ν(C=O) 1698 cm−1) and 30 cm−1 lower than the 4-nitro derivative (1710 cm−1). The bathochromic shift reflects increased electron density on the thiazole ring donated by the methoxy group through the 2-aryl linkage, which attenuates the carbonyl double-bond character. This red-shifted carbonyl absorption is accompanied by a diagnostic C–O–C asymmetric stretch at 1245 cm−1 and thiazole ring vibrations at 1480 cm−1. The relationship between substituent Hammett σp constants and ν(C=O) is linear across a series of para-substituted derivatives, confirming that the methoxy group (σp = −0.27) provides the strongest resonance donation among the common electron-releasing substituents used in thiazole-aldehyde building blocks.
| Compound | CAS | MW (g mol−1) | mp range (°C) | ν(C=O) (cm−1) | σp |
|---|---|---|---|---|---|
| 2-Phenylthiazole-4-carbaldehyde | 16650-55-8 | 189.24 | 54–57 | 1698 | 0.00 |
| 2-(4-Methoxyphenyl)thiazole-4-carbaldehyde | 105115-64-6 | 219.26 | 113–117 | 1680 | −0.27 |
| 2-(4-Nitrophenyl)thiazole-4-carbaldehyde | 88546-59-8 | 234.23 | 160–164 | 1710 | 0.78 |
The aldehyde undergoes Knoevenagel condensation with active methylene compounds such as malononitrile, ethyl cyanoacetate, and Meldrum’s acid in the presence of a weak base catalyst. In a representative protocol, stirring equimolar amounts of the aldehyde and malononitrile in absolute ethanol with piperidine (5 mol%) at ambient temperature for 3 h delivers the 2-(4-methoxyphenyl)-4-(2,2-dicyanovinyl)thiazole in isolated yields exceeding 85% after filtration and cold ethanol wash. When ethyl cyanoacetate is employed under identical conditions, the reaction requires gentle reflux (78 °C) and 8 h to reach 80% conversion, owing to the reduced acidity of the α-protons (pKa 13.1 vs 11.1 for malononitrile in DMSO). The methoxy group retards the condensation rate by a factor of approximately 2–3 relative to the 4-nitro analogue, which reacts quantitatively with malononitrile within 1 h without external heating. This kinetic attenuation is advantageous when chemoselectivity is required in polyfunctional substrates; the methoxy aldehyde preferentially reacts with malononitrile in the presence of aliphatic aldehydes, enabling sequential functionalisation strategies. Batch-to-batch variation in reaction rate correlates with residual acetic acid from the synthetic route; pre-neutralisation of the aldehyde with 1% aqueous NaHCO₃ wash is recommended to maintain reproducible kinetics on multi-kilogram campaigns.
Differential scanning calorimetry (performed on a Netzsch DSC 204 F1 Phoenix under nitrogen at 10 K min−1) detects a sharp melting endotherm with onset 113.5 °C, peak 116.2 °C, and enthalpy of fusion 98 J g−1. A broad exothermic decomposition initiates at 218 °C with peak at 245 °C, releasing 1.2 kJ g−1; this thermal liability necessitates controlled heating when used in polycondensation melt processes that exceed 200 °C. Under ambient fluorescent laboratory lighting (400–700 nm), the solid powders remain unchanged for 72 h as assessed by HPLC, but solutions in chlorinated solvents rapidly develop yellow-brown discoloration indicative of radical-mediated oxidation of the methoxy moiety. Long-term storage specifications mandate amber borosilicate vials, argon headspace (O₂ < 5 ppm), and temperature −20 ± 5 °C. Pre-weighing for moisture-sensitive reactions is executed inside a glovebox with dew point ≤ −50 °C. Incompatible substances include strong bases (promote aldol self-condensation), primary amines (immediate Schiff base formation exotherm), and concentrated nitric acid (exothermic nitration/decomposition). Published accelerated stability data under ICH Q1A guidelines for this specific aldehyde configuration is limited; however, analogous thiazole-4-carbaldehydes show <2% degradation after 6 months at 25 °C / 60% RH in sealed aluminised pouches.
The dominant commercial route involves Hantzsch condensation between 4-methoxybenzothioamide and ethyl bromopyruvate in refluxing ethanol, giving ethyl 2-(4-methoxyphenyl)thiazole-4-carboxylate. Subsequent reduction with diisobutylaluminum hydride (DIBAL-H) in anhydrous THF at −78 °C furnishes the target aldehyde after quenching with Rochelle salt and flash chromatography (silica gel, hexane/ethyl acetate 4:1). Alternative Vilsmeier–Haack formylation of 2-(4-methoxyphenyl)thiazole with POCl₃/DMF proceeds with moderate regioselectivity, generating the 4-formyl isomer alongside the 5-formyl regioisomer (~5–8%), which must be resolved by fractional crystallisation or preparative HPLC. Critical impurity control includes: unreacted thioamide (<0.1%, LC-MS m/z 168.2 [M+H]⁺), residual ethyl ester (<0.2%), and the over-oxidised 2-(4-methoxyphenyl)thiazole-4-carboxylic acid (<0.5%, single peak at retention time 4.2 min on C18, 50% acetonitrile/water + 0.1% TFA). Safety assessments on representative production lots confirm heavy metals below 20 ppm (USP <231> method II), residual solvents compliant with USP <467> Option 1 (THF <720 ppm, ethanol <5000 ppm, hexane <290 ppm), and sulfated ash <0.1%. A dedicated HPLC purity method employing a 250 × 4.6 mm, 5 µm C18 column, isocratic 60:40 acetonitrile/water, 1.0 mL min−1, with UV detection at 254 nm, resolves the aldehyde (tR 6.8 min) from all known process impurities with resolution >2.0. Specification limits for any single unknown impurity are ≤0.3%, total impurities ≤1.5%.
For fluorescence sensing applications (e.g., cysteine detection via Michael addition/cyclization cascade), the choice between methoxy and nitro substitution dictates the probe’s quantum yield, Stokes shift, and signal-to-noise ratio. A pyrazoline fluorophore constructed from 2-(4-methoxyphenyl)thiazole-4-carbaldehyde and phenylhydrazine in acetic acid under microwave irradiation (120 °C, 20 min) displays an absorption maximum at 345 nm (ε 28 000 M−1 cm−1) and emission at 430 nm in acetonitrile, with a fluorescence quantum yield (Φf) of 0.22 determined relative to quinine sulfate in 0.5 M H₂SO₄ (Φref 0.546). The corresponding nitro analogue, under identical conditions, exhibits a red-shifted absorption 370 nm, emission at 420 nm, and Φf dropping to 0.04, primarily due to non-radiative decay facilitated by the nitro group’s electron-withdrawing character. This order-of-magnitude difference persists across multiple fluorophore architectures (benzoxazole, coumarin, BODIPY conjugates), making the methoxy thiazole aldehyde the preferred electrophilic partner when designing sensors requiring low detection limits. Additionally, the methoxy derivative’s larger Stokes shift (85 nm versus 50 nm) reduces self-absorption interference in high-concentration labelling experiments (> 10 µM). In cellular imaging contexts, the 4-methoxyphenyl motif enhances lipophilicity (calculated logP 2.8) and reduces cytotoxicity compared to the nitro variant (IC₅₀ in HeLa cells > 100 µM after 24 h incubation, MTT assay). Although published systematic photodegradation quantum yields for the neat aldehyde are absent, accelerated light exposure tests (ICH Q1B Option 2, 1.2 million lux·h) on methoxy-containing thiazole derivatives indicate <5% photolysis, ensuring adequate photostability for confocal microscopy sessions.
