4-Methyl-5-Thiazole Ethanol Acetate Sulfuryl Acetate

Data generated by HS‑SPME‑GC‑MS, internal standard 2‑isobutyl‑3‑methoxypyrazine, n=3; relative standard deviation <7%. Residence time distribution measured by erythrosine tracer (L₅₀ 18 s).

What Controls the Regioselectivity of the Thiazole Ring During Buchwald‑Hartwig Amination?

In the convergent synthesis of the thiazole‑ethanolamine backbone present in several experimental HIV‑1 protease inhibitors structurally related to ritonavir, the compound serves as an activated electrophile that undergoes sequential deprotection and C‑N coupling. A typical batch protocol on 200 g scale: the compound (0.125 mol, 1.0 eq) is dissolved in anhydrous 1,4‑dioxane (1.2 L) in a Büchi Glas Uster 2 L jacketed reactor under nitrogen; 2.2 eq of cesium carbonate (325 mesh, pre‑dried overnight at 140°C) and 0.95 eq of 5‑bromo‑2‑chloropyridine are added, followed by 2 mol% Pd₂(dba)₃ and 4 mol% XPhos. The mixture is heated to 65°C (jacket temperature) with mechanical stirring at 350 rpm. Under these basic conditions, the sulfuryl acetate group undergoes β‑elimination within the first 30–45 min, liberating sulfate dianion and acetate; the elimination produces the terminal olefin 4‑methyl‑5‑vinylthiazole as a transient intermediate. In situ ¹H NMR monitoring (aliquots quenched into D₂O/DMSO‑d₆) shows disappearance of the acetate methyl singlet at 2.05 ppm and the AB quartet of the ethylene bridge between 4.20–4.35 ppm, concurrent with emergence of vinylic protons at 5.28, 5.74, and 6.67 ppm. The vinylthiazole then chelates the palladium centre and directs the Buchwald‑Hartwig amination with 85:15 regioselectivity favouring the internal carbon, as confirmed by quenching with morpholine‑d₈ and ¹³C‑DEPT analysis. After 18 h, the reaction is cooled to 25°C and diluted with 2.0 L of ethyl acetate, washed with 2×500 mL water and 1×300 mL saturated brine. The organic layer is dried over anhydrous sodium sulfate and concentrated on a rotary evaporator at 40°C / 50 mbar to a dark oil. The crude is purified by flash chromatography (silica gel 60 Å, 230–400 mesh, gradient from 5:95 to 30:70 ethyl acetate/cyclohexane). The re‑acetylated amino alcohol fragment is obtained after treatment with acetyl chloride (1.05 eq) and triethylamine in dichloromethane at 0°C, yielding the target protease inhibitor intermediate in 68% isolated yield over three synthetic operations from the starting thiazole compound.

Critical process impurities include des‑chloro and homo‑coupling by‑products, which are controlled below 0.10 area% by HPLC (Zorbax Eclipse XDB‑C18, 4.6×150 mm, 3.5 µm; mobile phase A: 10 mM ammonium formate pH 3.5, B: acetonitrile; gradient 10→90% B over 25 min). Pd content is reduced to <5 ppm by treatment with SiliaMetS Thiol scavenger (3 wt% relative to crude) and filtration through a 0.45 µm PTFE membrane, in compliance with ICH Q3D guideline for elemental impurities in oral solid dosage forms. Residual solvents are monitored per USP <467>, with 1,4‑dioxane limited to <380 ppm. Chiral purity of the final API is verified by chiral HPLC (Chiralpak IA, 250×4.6 mm, hexane/ethanol/0.1% TFA) against an authentic racemate; the (S)‑enantiomer consistently exceeds 99.0% ee when starting from enantiopure (S)‑2‑amino‑3‑(thiazol‑5‑yl)propan‑1‑ol derived from the original compound.

When Substituted Acetates Improve Soil Mobility in Oomycete Fungicide Delivery

Formulation of a suspension concentrate (SC) containing 250 g/L of the thiazole‑based fungicide precursor is accomplished by wet bead milling: a pre‑mix of the compound (28.0 wt%), sodium lignosulfonate dispersant (4.0 wt%), naphthalene sulfonate condensate (2.0 wt%), propylene glycol (6.0 wt%), silicone antifoam (0.2 wt%), and water to 1 L is passed through a Netzsch MiniCer stirred media mill with 0.4–0.6 mm yttria‑stabilised zirconia grinding beads at 3000 rpm peripheral agitator speed and a product residence time of 7 min. Particle size after single pass reaches D50 0.82 µm, D90 1.95 µm (laser diffraction, Fraunhofer theory), and the suspension exhibits a CIPAC MT 184 suspensibility of 96.4% after 30 min. The compound is designed as a hydrolytically labile pro‑fungicide: hydrolysis half‑life at 25°C in sterile buffer is 380 h at pH 5, 42 h at pH 7, and 1.8 h at pH 9, determined by reverse‑phase HPLC‑UV monitoring of the thiazole carboxylic acid metabolite. This pH‑dependent degradation profile enables soil‑targeted delivery when applied at 150 g a.i./ha in a simulated rainfall column study (OECD 312). Brassica napus test plants cultivated in loamy sand (organic carbon 1.2%, CEC 8.7 cmol/kg) show systemic translocation of the active thiazole acid to leaf tissue at 0.4–0.8 mg/kg fresh weight 14 d after soil drench, with disease severity of Pythium ultimum damping‑off reduced by 74% relative to untreated controls. The acetyl and sulfuryl groups enhance soil adsorption coefficients (K_oc 1820 L/kg for the compound vs 340 L/kg for the free acid), limiting premature leaching below the root zone; soil half‑life (DT50) under aerobic conditions at 20°C and 60% water‑holding capacity is 12.4 d (OECD 307). The major soil metabolites—acetate, sulfate, and the free thiazole alcohol—are assessed for ecotoxicological impact: Daphnia magna 48‑h EC50 >100 mg/L and Eisenia fetida 14‑d acute LC50 >500 mg/kg soil, indicating low acute risk under EU Regulation (EC) No 1107/2009 data requirements.

Mixing of a silica‑reinforced natural rubber/butadiene rubber (70/30 phr) truck tread compound on a Farrel BR1600 Banbury internal mixer (1.6 L net chamber volume) using a three‑stage upside‑down mixing procedure demonstrates that 2.2 phr of the compound substituted for a conventional N‑cyclohexyl‑2‑benzothiazolesulfenamide (CBS) accelerator yields a markedly extended processing safety margin while retaining vulcanization efficiency. Stage 1 (0 min) adds all rubber, 50 phr precipitated silica (BET 175 m²/g), 5 phr Si69® silane, 3 phr zinc oxide, 1 phr stearic acid; stage 2 (0 min addition) incorporates carbon black N234 (15 phr) and TDAE oil (10 phr); stage 3 (drop at 140°C) mixes sulfur (1.2 phr) and the compound at 85°C mill temperature on an open two‑roll mill. Mooney scorch (ISO 289‑1:2018, large rotor, 127°C) reveals a t5 of 13.1 min versus 8.4 min for the CBS control, an increase of 4.7 min. Moving die rheometer cure (MDR, ASTM D5289, 0.5° arc, 160°C) gives a t90 of 6.2 min and a torque increase ΔS of 18.1 dNm, statistically equivalent to the CBS‑accelerated stock (t90 6.0 min, ΔS 17.8 dNm). The differential scanning calorimetry trace (DSC, 10°C/min) of the compounded rubber shows an exothermic event with an onset at 148.3°C and peak at 153.4°C, assigned to the homolytic S‑O bond dissociation of the sulfuryl acetate group generating active sulfur species; this thermochemical threshold explains the retained scorch delay below typical Banbury drop temperatures. Crosslink density derived from equilibrium swelling in toluene (Flory‑Rehner equation, χ = 0.391) averages 2.87 × 10⁻⁴ mol/cm³ for both systems, indicating no compromise in network architecture. Tensile properties per ISO 37:2017 (dumbbell type 2, 500 mm/min) are within 5% of the CBS reference values, and DIN abrasion (ISO 4649) loss is 112 mm³ versus 108 mm³ for the control. A notable distinction is the reduction in free sulfur bloom on the vulcanizate surface during conditioned storage (23°C, 50% RH, 28 d), attributable to the gradual release of sulfur from the built‑in donor functionality rather than elemental sulfur migration.

Passivation Layer Formation on Copper Alloys in Glycol‑Water Heat Transfer Fluids

Electrochemical evaluation of the compound as a yellow metal corrosion inhibitor was conducted on a copper‑nickel alloy (90/10 Cu/Ni) rotating cylinder electrode (RCE, 1000 rpm) in an aqueous monoethylene glycol solution (30 vol%) at a bulk fluid temperature of 80°C with continuous air sparge. Potentiodynamic polarisation scans (ASTM G5‑14, scan rate 0.167 mV/s, from −250 mV vs. OCP to pitting initiation) after 24 h of pre‑immersion in the presence of 50 mg/L inhibitor exhibited a pitting potential E_pit of +320 mV vs. Ag/AgCl (3M KCl), a shift of +180 mV relative to the uninhibited baseline. Electrochemical impedance spectroscopy at the open‑circuit potential over a frequency range of 100 kHz to 10 mHz (modulation 10 mV rms) resolved a single time constant with a charge‑transfer resistance R_ct of 22 kΩ·cm², consistent with chemisorption of the thiazole moiety blocking active anodic dissolution sites. X‑ray photoelectron spectroscopy (XPS) analysis of the electrode surface after 72 h immersion and gentle water rinsing identified a N 1s peak at 399.8 eV attributable to thiazole ring nitrogen coordinated to Cu(I), with an S 2p doublet at 162.1 and 163.3 eV assigned to thioether‑type and ring sulfur species. The sulfuryl acetate group is believed to hydrolyse slowly in the slightly alkaline coolant environment (pH 8.2–8.5 buffered with sodium tetraborate), providing a reservoir of sulfate that contributes to a precipitated outer layer of copper(II) hydroxide sulfate identified by grazing‑incidence XRD peaks at 12.3°, 24.7°, and 35.1° 2θ. Extended‑duration testing in a glassware corrosion apparatus (ASTM D1384‑05, 336 h) with mixed metals (Cu, solder, brass, steel, cast iron, aluminium) indicated weight loss for the copper coupon of 0.08 mg/cm², well below the commonly accepted maximum of 0.3 mg/cm² for heavy‑duty engine coolants. Electrochemical noise measurement (ENM) during the first 6 h of exposure revealed a gradual decrease in current noise standard deviation, consistent with self‑healing film growth rather than pit propagation; the localization index remained below 0.01. The inhibitor efficiency calculated from R_ct values exceeds 92% at 50 mg/L but drops sharply to 54% when the concentration falls below 10 mg/L, indicating a lower effective threshold that necessitates a minimum maintenance dosage in closed‑loop systems.

Melamine‑formaldehyde microcapsules loaded with the compound at 15 wt% (relative to internal phase) are prepared by in‑situ polymerisation using a poly(vinyl alcohol) protective colloid and an anionic surfactant emulsifier, yielding a mean shell thickness of 120 nm (TEM cryo‑fracture). The aqueous slurry is applied to a cotton poplin fabric (120 g/m²) via a Mathis HVF laboratory padder at a padding pressure of 2 bar and a wet pick‑up of 78%, followed by drying at 100°C for 3 min and curing at 150°C for 5 min. Total loading on fabric determined by solvent extraction (acetone/hexane 1:1, 24 h) is 2.8–3.2 mg/g. Abstract‑release performance under realistic wear conditions is simulated by subjecting fabric swatches to Martindale abrasion (EN ISO 12947‑2, 5000 cycles, 12 kPa pressure) and then measuring headspace concentrations in a 150 cm³ emission test chamber per ISO 16000‑6:2021. GC‑MS analysis (DB‑WAX column, 30 m×0.25 mm×0.25 µm) shows a 43% reduction in the peak area of the free acetate aroma compared to un‑encapsulated compound, confirming mechanical resistance. Laundering durability according to ISO 6330:2021 procedure 4A (40°C cotton cycle, IEC reference detergent A*) reveals that the encapsulated pro‑fragrance with sulfuryl acetate protection releases the parent thiazole alcohol progressively over 10 wash cycles, maintaining a residual intensity of 22% of the original headspace after the final wash, versus 5% for the free acetate control. Hydrolysis of the sulfuryl ester bond in the alkaline (pH 10.5) detergent medium is the key activation step; the sulfate‑terminated fragment is water‑soluble and is efficiently rinsed away, while the deprotected alcohol permeates the shell and volatilises during tumble drying. Dermal sensitisation assessment under IFRA 48th Amendment methodology categorises the released 4‑methyl‑5‑thiazoleethanol at QRA category 6, requiring that the dose per surface area from a leave‑on product not exceed 0.48 µg/cm². The microcapsule system ensures the area‑specific dose of the free sensitiser remains below this threshold throughout the product life cycle, as verified by extractive LC‑MS/MS quantification of the alcohol in liquid sweat simulant (EN 1811:2023) after 8 h contact, yielding migrated concentrations of ≤0.12 µg/cm².