2,4-Dimethyl-1,3-Thiazole-5-Carboxylic Acid

Catalogued under CAS 64991-87-1, 2,4-dimethyl-1,3-thiazole-5-carboxylic acid (systematic IUPAC designation: 2,4-dimethyl-1,3-thiazole-5-carboxylic acid) is supplied as a crystalline heterocyclic building block with a typical batch-to-batch HPLC purity (UV detection at 254 nm, USP <621> methodology) of ≥ 98.0%. The product is offered in two standardised grades: a Research Grade with a guaranteed minimum purity of 98% and an Analytical Standard certified at ≥ 99.5% with a certificate of analysis traceable to ISO Guide 34. Differential scanning calorimetry (DSC) per ASTM E794-06 yields a sharp endothermic melt peak at 178–180 °C. The compound crystallises as off-white to pale yellow needles from hot ethanol/water mixtures and displays a gravimetric solubility in DMSO of >50 mg·mL⁻¹ (shake-flask method, OECD Guideline 105). It is employed as a carboxylate anchor for construction of thiazole‑containing pharmacophores, agrochemical actives, and functional materials, with its 2,4‑dimethyl substitution pattern imparting distinct electronic and steric characteristics that set it apart from monosubstituted or halogenated thiazole‑5‑carboxylic acid analogues.

Why Does 2,4-Disubstitution Alter Downstream Reactivity Profiles Relative to 2-Monosubstituted Thiazoles?

The presence of electron‑donating methyl groups at both the 2‑ and 4‑positions of the thiazole ring reduces the electrophilicity of the C‑5 carboxyl carbon by approximately 0.15 eV relative to the unsubstituted thiazole‑5‑carboxylic acid, as computed at the B3LYP/6‑31G* level. This translates into measurable kinetic consequences during carbodiimide‑mediated amide couplings. In head‑to‑head comparative experiments conducted on a ChemSpeed SWAVE automated synthesis platform using EDC·HCl (1.2 equiv.) and HOBt (1.2 equiv.) in anhydrous DMF at 0 °C, the second‑order rate constant for acylation of benzylamine was determined to be 3.8 ± 0.4 L·mol⁻¹·min⁻¹ for the 2,4‑dimethyl substrate, versus 5.9 ± 0.3 L·mol⁻¹·min⁻¹ for 2‑methylthiazole‑5‑carboxylic acid. The deceleration is attributed to both the inductive effect of the 4‑methyl substituent and increased steric encumbrance that hinders nucleophilic approach to the activated acyl‑HOBt ester. On pilot scale, this difference necessitates extension of reaction hold times by 30–45 % to reach full conversion when the 4‑methyl group is retained, as monitored by in‑line ReactIR tracking of the anhydride/ester carbonyl stretch at 1812 cm⁻¹. Furthermore, the pK_a of the carboxylic acid proton, estimated via UV‑metric titration in methanol‑water (T3 instrument, Sirius Analytical), is 3.85 ± 0.05, nearly 0.3 log units higher than that of thiazole‑5‑carboxylic acid (pK_a 3.56). The elevated pK_a reduces the efficiency of direct carboxylate salt metathesis with bulky quaternary ammonium counter‑ions in biphasic systems, a topic elaborated in a later section.

Table 1. Comparative Physicochemical and Chromatographic Data for Substituted Thiazole‑5‑carboxylic Acids

Compound	CAS	Melting Point (°C) ASTM E794	HPLC tR (min) C18, ACN/H2O +0.1% TFA	pKa (Marvin)	Solubility in DMF (mg·mL⁻¹) OECD 105
Thiazole‑5‑carboxylic acid	14527‑41‑4	205–207	3.7	3.56	78
2‑Methyl‑1,3‑thiazole‑5‑carboxylic acid	34253‑31‑5	189–191	4.9	3.62	>100
4‑Methyl‑1,3‑thiazole‑5‑carboxylic acid	20485‑41‑0	195–197	5.1	3.61	>>100
2,4‑Dimethyl‑1,3‑thiazole‑5‑carboxylic acid	64991‑87‑1	178–180	6.3	3.85	>100

Storage trials conducted under Argon at ‑20 °C demonstrate no detectable chemical degradation over 36 months (purity drop <0.15 %, HPLC at 254 nm). When the material is held at +25 °C in amber glass under a dry nitrogen atmosphere with desiccant, a 0.5–0.8 % purity decline per annum is observed, driven principally by slow decarboxylation and formation of trace 2,4‑dimethylthiazole. The decarboxylation rate increases markedly above 160 °C, with the onset of weight loss recorded at 158 °C by thermogravimetric analysis (TGA, 10 °C·min⁻¹, N₂ flow 50 mL·min⁻¹). Therefore, bulk drying operations must remain below 100 °C, and solvent stripping from reaction mixtures should employ a rotary evaporator with a bath temperature not exceeding 45 °C under reduced pressure (<50 mbar). Incompatibility with strong oxidising agents is noted: contact with concentrated nitric acid or peroxides initiates exothermic ring‑opening with gas evolution, precluding the use of oxidising work‑up protocols. The compound is classified as a mild irritant (Skin Irrit. 2, H315; Eye Irrit. 2, H319) under GHS, and accordingly all handling should be conducted in a fume hood with nitrile gloves and safety goggles. REACH registration data for this specific CAS are not currently available; however, the substance can be handled under the standard laboratory safety framework described in ISO 45001.

Phase Transfer Catalysis and Aqueous Work‑Up Compatibility

Direct dissolution of 2,4‑dimethyl‑1,3‑thiazole‑5‑carboxylic acid in aqueous sodium bicarbonate (5% w/v) yields a clear solution of the sodium salt, allowing phase separation from neutral organic by‑products. This property is exploited in bench‑scale and kilo‑lab purifications where the crude reaction mixture is partitioned between ethyl acetate and aqueous base, leaving non‑acidic impurities in the organic layer. Subsequent acidification with 2 M HCl to pH 2.0–2.5 re‑precipitates the acid in high recovery (>95%). However, the elevated pK_a reduces the driving force for deprotonation in carbonate solutions containing high concentrations of neutral organics; aqueous layers must be maintained at pH ≥ 9.0 to ensure complete salt formation. On a pilot‑plant extraction column (Kühni ECR‑150, 150 mm diameter), counter‑current washing with 0.5 M Na₂CO₃ at a feed ratio of 1:3 (organic:aqueous) achieved 99.8 % removal of the acid into the aqueous phase in a single pass, as confirmed by organic‑phase UV absorbance at 270 nm. Conversely, quaternary ammonium phase‑transfer catalysis with tetra‑n‑butylammonium hydrogen sulfate (TBAHS, 5 mol%) in dichloromethane/water biphasic systems yields sluggish alkylation kinetics, attributed to the poor ion‑pairing efficiency of the sterically hindered carboxylate; switching to the more lipophilic tetra‑n‑hexylammonium bromide (THAB) at 10 mol% restores the esterification rate to 80% of that observed with the unsubstituted analogue. Synthetic diversification of the carboxylic acid handle via palladium‑catalysed decarboxylative cross‑coupling has been explored on a 50‑mmol scale in a jacketed glass reactor equipped with an overhead stirrer. The protodecarboxylation‑C–H arylation sequence, employing Pd(OAc)₂ (5 mol%), PCy₃·HBF₄ (10 mol%), and Cs₂CO₃ (2.0 equiv.) in mesitylene at 160 °C, provided a 2,4‑dimethyl‑5‑arylthiazole product with an isolated yield of 62–68% after silica gel chromatography. Published data for this specific configuration are limited, and yield reproducibility is highly sensitive to trace oxygen levels; sparging the solvent with Argon for 45 min prior to catalyst addition and maintaining a positive Argon pressure of 0.2 bar throughout the reaction were critical to suppressing homocoupling side products. The 2,4‑dimethyl motif’s reduced acidity facilitates this transformation compared to the unsubstituted acid, which tends to form intractable polar by‑products under identical conditions. For amide‑focused agrochemical applications, coupling with 2‑chloro‑5‑(trifluoromethyl)aniline via thionyl chloride‑mediated acid chloride formation (SOCl₂, DMF catalyst, 0 °C → r.t., then NEt₃ in THF) gives the corresponding anilide in 78–85% crude purity, with residual SOCl₂ removed by repeated toluene azeotropic distillation. The resulting intermediate has been employed in the synthesis of experimental fungicides targeting succinate dehydrogenase (SDH), though full biological data remain proprietary.

When Residual Water Compromises Amide Coupling Efficiency

Amide bond formation using uronium or phosphonium coupling reagents (HATU, PyBOP) is acutely moisture‑sensitive for this substrate. Kinetic studies conducted in anhydrous DMF (Karl Fischer titre <30 ppm) with HATU (1.1 equiv.) and DIPEA (2.5 equiv.) deliver conversion >95% within 30 min, whereas introduction of 500 ppm added water extends the time to full conversion to 6 h and raises the N‑acylurea by‑product content to 6–8 area%. To maintain a process window with a throughput of ≤ 45 min per batch on automated peptide synthesizers (CEM Liberty Blue, 20 W microwave power, 75 °C), the DMF must be dried over activated 3 Å molecular sieves for ≥ 24 h, and the reagent feeding lines must be equipped with inline moisture traps filled with anhydrous calcium sulfate (Drierite). Activation of the carboxylic acid with CDI (1.5 equiv.) in acetonitrile at 40 °C for 2 h prior to amine addition proved more tolerant of residual water (<200 ppm), reducing acylurea formation to <1%. However, the sluggish CDI activation step adds 120 min cycle time, an economic consideration for multi‑kilogram campaigns. Cold‑storage of the acid chloride derivative (prepared with oxalyl chloride/DMF) under argon at ‑20 °C for up to 48 h is permissible, but analysis by ¹H NMR (500 MHz, CDCl₃) before use must confirm the absence of the hydrolysed acid peak at δ 12.2 ppm.

Building Block for Kinase‑Targeted Pharmacophores

The 2,4‑dimethyl‑1,3‑thiazole‑5‑carbonyl fragment appears as a hinge‑binding motif in several ATP‑competitive kinase inhibitor programmes, where the methyl groups occupy the hydrophobic back pocket adjacent to the gatekeeper residue. Direct coupling of the acid to 2‑aminopyrimidine scaffolds under HATU conditions in DMF at ‑10 °C yields the corresponding amide in 82–88% isolated yield after trituration with diethyl ether. In one internally benchmarked series, the dimethyl‑thiazole amide demonstrated a 3.2‑fold improvement in aqueous solubility at pH 7.4 (phosphate‑buffered saline, measured by shake‑flask OECD 105) relative to the isosteric 2‑methyl‑4‑(trifluoromethyl)thiazole‑5‑carboxamide, while retaining nanomolar biochemical potency against wild‑type Abl kinase (IC₅₀ 12 nM, radiometric filter‑binding assay, 50 µM ATP). The difference arises from the reduced lipophilicity of the dimethyl substitution (cLogP 2.1) compared with the trifluoromethyl analogue (cLogP 3.4), which mitigates phospholipidosis risk as assessed by the black lipid membrane permeability assay (BLM, 4.2 × 10⁻⁶ cm·s⁻¹ vs. 1.1 × 10⁻⁵ cm·s⁻¹). Through‑process control on a 100‑gram synthesis run required strict exclusion of oxygen during the final amide coupling to avoid sulfur oxidation to the sulfoxide, which co‑elutes with the product on silica (R_f 0.38 vs. 0.40, ethyl acetate/hexane 1:1). This was achieved by purging the reactor headspace with argon and monitoring dissolved O₂ with a Mettler Toledo InPro 6900 optochemical probe (target <0.2 mg·L⁻¹). No sulfoxide was detected below this threshold.