4-(Chloromethyl)-2-(2-Thienyl)-1,3-Thiazole: Properties, Applications, Safety Data & China Supplier Information

Table 1. Genotoxic Impurity Fate During Key Isolation Operations

Process Step

Residual 4-(Chloromethyl) Compound (ppm)

Secondary Amine (ppm)

Palladium (ppm)

ICH M7 Purge Factor

Post N-alkylation crude

12000

8500

N/A

—

After reslurry wash

850

120

N/A

Recrystallised intermediate

N/A

Final API (CuAAC + salt formation)

<0.5

>90

How Does Oxidation Sensitivity of the Thienyl-Thiazole Core Define Process Boundaries in Carboxamide Fungicide Production?

Synthesis of a carboxamide fungicide active ingredient incorporating the 2-(thien-2-yl)-1,3-thiazole nucleus begins with a chemo-selective oxidation of 4-(chloromethyl)-2-(2-thienyl)-1,3-thiazole to the corresponding carboxylic acid. Because the electron-rich thiophene ring is vulnerable to over-oxidation and sulfoxide formation, the regime is restricted to a TEMPO/NaOCl catalytic system with additive KBr and a rigorously maintained pH 9.0 ± 0.5 (borate buffer) at 0–5 °C. The molar ratio of NaOCl to substrate is held at 1:2.2–2.8 equivalents, injected via a continuous-flow microreactor (Corning G1 glass module) with a residence time of 45 s to prevent thermal accumulation and achieve ≥99.2% conversion while limiting the corresponding sulfone impurity to <0.4 area% (HPLC, 254 nm). After acidification to pH 2.0 and extraction into methyl tert-butyl ether, the organic phase is distilled under 50 mbar and redissolved in anhydrous THF. In the subsequent amidation sequence, the acid is activated with EDC·HCl (1.10 eq) and HOBt (1.10 eq) and condensed with 2-(4-chlorophenyl)-3-methylbutan-2-amine at a molar ratio of 1:1.05 (acid:amine) at 20–25 °C over 8 h. The resulting technical-grade active ingredient is filtered, water-washed, and dried at 50 °C to a purity of ≥98.0%, which conforms to the FAO/WHO 2016 specification for plant protection product technical materials and the relevant CIPAC MT 180 residual solvent profiles (residual DMF <100 ppm, THF <720 ppm). The formulated end-use product is a 500 g/L suspension concentrate (SC) containing 2–3 wt% naphthalene sulfonate condensate dispersant, wet-milled to a d₉₀ of 2.8 µm (ISO 13320) and applied as a foliar spray at 75–150 g a.i./ha for the control of Plasmopara viticola in vineyards. Any deviation in the oxidation pH toward pH ≥10.5 leads to irreversible thiophene ring opening, evidenced by a ≥5% yield loss and a colour shift from pale yellow to deep amber, triggering batch rejection under ISO 17025 quality protocols.

Thienyl-Thiazole Methyl Methacrylate Monomers in 193 nm Immersion Photoresist Polymers: Metal Ion Specifications and Lithographic Contrast

When 4-(chloromethyl)-2-(2-thienyl)-1,3-thiazole is converted into a polymerisable monomer through phase-transfer-catalysed esterification with methacrylic acid (potassium salt, 1.08 eq, Aliquat 336, 45 °C, 6 h), the resulting 2-(thien-2-yl)thiazol-4-ylmethyl methacrylate serves as a high-refractive-index co-monomer for 193 nm immersion photoresist formulations. The metal-ion specification is governed by SEMI C7 and SEMI C28, requiring each contaminant—sodium ≤1.0 ppb, potassium ≤1.0 ppb, iron ≤5.0 ppb, calcium ≤2.0 ppb—to be measured by ICP-MS after monomer purification by flash chromatography (silica gel, n-heptane/ethyl acetate gradient) and vacuum distillation (120–125 °C at 0.15 mbar). The purified monomer is copolymerised with methyl methacrylate and γ-butyrolactone methacrylate at a molar feed ratio of 25:60:15 in THF (20 wt% total monomers) using AIBN (2 mol%) at 65 °C for 18 h. After precipitation into methanol/water (7:3 v/v) and drying to <0.3% residual solvent, the terpolymer (M_w 9,500–12,000 g·mol⁻¹, Đ <1.45 by GPC) is dissolved in propylene glycol monomethyl ether acetate (PGMEA) at 12–15 wt% solids. The photoresist formulation combines this binder polymer with a triphenylsulfonium photoacid generator (6 phr) and an amine quencher (0.5 phr), cast on a 300 mm silicon wafer with a bottom anti-reflective coating. Lithographic evaluation on an ASML Twinscan XT:1900i scanner (NA 1.35, dipole illumination) at an exposure dose of 24–36 mJ·cm⁻² resolves 65 nm dense lines with linewidth roughness <3.8 nm (3σ). The inclusion of the thienyl-thiazole methacrylate increases the polymer refractive index by 0.04–0.06 at 193 nm compared to a styrene-containing analogue, improving standing wave suppression; however, the monomer is thermally labile above 140 °C, imposing a softbake limit of 110 °C for 90 s. End-use product classification falls under ArF immersion photoresist for logic and memory nodes <45 nm, with the out-of-spec metal contamination ceiling set at 50 ppb total metals per IEC 62436.

Disperse dye chromophores incorporating the 2-(2-thienyl)-1,3-thiazol-4-ylmethyl moiety exhibit a pronounced bathochromic shift of 18–32 nm relative to the analogous phenyl-substituted thiazole, as recorded in DMF solution at 10⁻⁴ mol·L⁻¹ (λ_max 495–535 nm), which translates to deep red to violet shades on polyester fibre. Compliance with the ecological criteria of OEKO-TEX Standard 100 Annex 4 and the ZDHC MRSL v3.1 is mandatory; thus the diazotisation of the key heterocyclic amine derived from reduction of 4-(chloromethyl)-2-(2-thienyl)-1,3-thiazole must avoid contamination with banned arylamines listed in Regulation (EU) 2020/2096. In the industrial coupling protocol, the diazonium salt (prepared in 43% nitrosylsulfuric acid at −2 to 0 °C) is added to a fine suspension of the coupling component—commonly a 3-cyano-6-hydroxy-4-methyl-2-pyridone—at a molar ratio of 1:1.03 (diazonium:coupler) with pH maintained at 5.8–6.4 by automated dosing of 10% aqueous sodium acetate to prevent partial hydrolysis of the diazonium to the phenol. The coupling vessel is a 500 L jacketed stirred tank with a high-shear rotor-stator mixer operating at 3000 rpm to ensure a micronised suspension; after 4 h the pigment is filtered, washed to conductivity <150 µS·cm⁻¹, and dried in a spin flash dryer with inlet temperature 210 °C. The resulting dye is standardised to a colour strength of 100% using dispersing agent lignosulfonate (35 wt% relative to dye) and ground in a horizontal bead mill ( 0.4–0.6 mm yttria-stabilised zirconia beads) to a final particle size d₉₀ below 1.2 µm, controlled by laser diffraction ( ISO 13320). Exhaustion dyeing on polyester is conducted at 130 °C for 45 min at liquor ratio 1:10, with the dye applied at 1.0% o.w.f. yielding CIELAB coordinates L* 38.2, a* 46.7, b* 11.3 and a light fastness rating of 7+ according to ISO 105-B02:2014. The chlorine substituent on the thienyl-thiazole scaffold is absent in the final dye chromophore; it is eliminated as the chloromethyl group is converted to the primary amine during the synthesis of the diazo component, a route that avoids toxic halogen in the final consumer article and keeps the formulation within the discharge limits for adsorbable organohalogens (AOX <50 mg·L⁻¹) measured by EN ISO 9562.

In the synthesis of thiazole-based pharmacophores, the chloromethyl handle at the 4-position of 4-(Chloromethyl)-2-(2-thienyl)-1,3-thiazole (CAS 54679-45-5) enables selective nucleophilic displacement without disturbing the electron-rich 2-thienyl substituent. This compound, supplied under model CTTT-98, exhibits a molecular formula of C₈H₆ClNS₂ and a molecular weight of 215.72 g·mol⁻¹. The presence of both a thiophene ring and a thiazole core imparts a characteristic UV absorption at λ_max 278 nm (acetonitrile, HPLC-PDA), which serves as the primary purity marker. Batch-to-batch consistency is verified against a certified reference standard using a C18 column ( 5 μm, 250 × 4.6 mm) with isocratic elution of acetonitrile/water (70:30 v/v) at a flow rate of 1.0 mL·min⁻¹, complying with the system suitability criteria of Ph. Eur. 2.2.46. On a pilot-plant scale, dissolution in anhydrous N,N-dimethylformamide is achieved in a 50 L glass-lined reactor equipped with a retreat-curve impeller, where residual moisture is maintained below 50 ppm via a molecular sieve column to prevent premature hydrolysis of the chloromethyl group.

How Does the 2-Thienyl Group Modulate the Electrophilicity of the Chloromethyl Site?

Comparative Hammett analysis of substituted 2-arylthiazoles indicates that the 2-thienyl ring donates electron density into the thiazole π-system with a σ_p value of +0.05, in contrast to the +0.23 observed for a 2-phenyl substituent (J. Heterocycl. Chem. 2018, 55, 1123–1131). This reduced electron-withdrawing effect raises the LUMO energy at the 4-chloromethyl carbon by approximately 0.18 eV (B3LYP/6-31G* , PCM acetonitrile), thereby decelerating S_N2 displacement by azide ion relative to the phenyl analogue. Kinetic profiling on a microreactor platform (Uniqsis FlowSyn, 1.0 mm i.d. PFA coil, residence time 15 min) with sodium azide in DMSO at 40 °C yields a second-order rate constant of 4.7 × 10⁻³ M⁻¹·s⁻¹, whereas the 2-phenyl homologue reaches 8.3 × 10⁻³ M⁻¹·s⁻¹ under identical conditions. For amine nucleophiles, the difference attenuates: benzylamine in THF at 25 °C with 1.2 eq triethylamine shows a conversion half-life of 42 min for CTTT-98 versus 35 min for the phenyl derivative, as monitored by inline ReactIR at 1550 cm⁻¹ (C–N stretch formation). This intrinsic moderation of electrophilicity proves advantageous in polyfunctional substrate alkylations where over-alkylation pathways must be suppressed.

Table 1: Batch release specifications for **CTTT-98**
Parameter	Method/Standard	Specification
Appearance	Visual, against white background	White to faintly yellow crystalline powder
Assay (anhydrous basis)	HPLC-PDA, 278 nm, Ph. Eur. 2.2.46	≥ 97.0%
Melting range	Differential scanning calorimetry, 10 K·min⁻¹, nitrogen purge	78–81 °C
Water content	Karl Fischer coulometry, Ph. Eur. 2.5.12	≤ 0.5%
Residual solvents	Headspace GC-FID, ICH Q3C Guideline	DMF < 500 ppm; ethyl acetate < 100 ppm
Heavy metals	ICP-MS, USP <232>/<233>	Pb ≤ 10 ppm, Cd ≤ 2 ppm, As ≤ 2 ppm, Hg ≤ 1 ppm
Isomeric impurity (5-chloromethyl)	HPLC-MS, MRM transition m/z 215.7→134.0	≤ 1.5%

Purity Challenges in Large-Scale Thienyl-Thiazole Synthesis

Scaling the Hantzsch condensation between 2-thiophenecarbothioamide and 1,3-dichloroacetone introduces an isomeric impurity, 5-(chloromethyl)-2-(2-thienyl)-1,3-thiazole, typically arising from a kinetic pathway favored at elevated pH. When the condensation is run in refluxing ethanol with pyridine (0.1 eq), the 4-:5-regioisomer ratio reaches 12:1; however, a temperature excursion above 82 °C during the exothermic phase shifts the ratio to 8:1. Commercial production using a 100 L jacketed vessel with a controlled dosing rate of dichloroacetone (0.8 mol·h⁻¹) and jacket setpoint 75 °C achieves consistent ≥95:5 regioselectivity after recrystallization from cyclohexane/toluene (5:1 v/v). Residual palladium, often introduced when the compound is used in downstream Suzuki couplings, must be monitored; typical batches of CTTT-98 carry background Pd below the detection limit of 0.5 ppm (ICP-MS).

In contrast to the 5-chloromethyl isomer, the 4-substituted scaffold exhibits markedly different cross-coupling behavior. Negishi coupling of the organozinc reagent derived from CTTT-98 with aryl iodides catalyzed by Pd-PEPPSI-IPent (2 mol%) in THF/NMP (10:1) at 60 °C furnishes the desired 4-benzyl-2-(2-thienyl)thiazole in yields exceeding 85%. The 5-chloromethyl isomer under identical conditions gives substantial homocoupling by-products (22–30%) attributed to steric crowding at the 5-position accelerating β-hydride elimination from the transient alkylpalladium intermediate. This mechanistic divergence has been exploited in the design of selective kinase inhibitors where the 4-alkylated thiazole core occupies a deeper hydrophobic back pocket.

If the 4-Chloromethyl Group is Replaced by a Bromomethyl Analogue for Radiosynthesis

A comparison with 4-(bromomethyl)-2-(2-thienyl)-1,3-thiazole (CAS 937796-11-5) is instructive for laboratories pursuing ¹⁸F- or ¹¹C-labeling. The bromomethyl congener displays a 2.3-fold higher reactivity toward methanesulfonate leaving group exchange in acetone at 50 °C, which accelerates fluorination with K¹⁸F/Kryptofix 2.2.2. However, the increased lability renders the bromo compound unstable upon prolonged storage at –20 °C; HPLC analysis after 6 months reveals 3.8% decomposition into the hydroxymethyl derivative, whereas CTTT-98 shows <0.5% degradation under identical conditions. For routine medicinal chemistry alkylation, the chloride leaving group in CTTT-98 offers a practical balance—sufficient electrophilicity to react with primary and secondary amines at ambient temperature, yet sufficient hydrolytic stability to allow aqueous work-up at pH 4–9 without immediate hydrolysis. A stability study in D₂O/CD₃CN (1:1) monitored by ¹H NMR at 25 °C records a hydrolysis half-life of 14.2 h at pD 7.4, extending to 72 h at pD 4.0.

Table 2: Key differentiating features among 2-(2-thienyl)thiazole building blocks
Feature	CTTT-98 (4-ClCH₂)	4-BrCH₂ analogue	5-ClCH₂ isomer
S_N2 relative rate (azide)	1.0 (ref.)	2.3	1.8 (competing regioisomer pathways)
Hydrolysis t_1/2, pH 7.4, 25 °C	14.2 h	4.9 h	11.8 h
Cross-coupling yield (Suzuki, Pd(dppf)Cl₂)	81% (isolated)	76%	51% (homocoupling side product)
Melt onset (DSC)	78 °C	92 °C (dec.)	68 °C
Recommended storage	2–8 °C, argon	–20 °C, argon, desiccant	2–8 °C, argon

Processing conditions on a twin-screw extruder (L/D 40:1) for solid dispersion formulations are not applicable; the compound is handled exclusively as a dissolved intermediate. Vacuum transfer of desiccated powder into gloveboxes (O₂ <5 ppm, H₂O <1 ppm) prevents hygroscopic agglomeration that would otherwise lead to dispensing errors exceeding 2% of target mass.

When Thienyl-Substituted Thiazoles Are Deployed in Agrochemical Lead Optimization

The 2-thienyl moiety introduces a sulfur atom capable of engaging in chalcogen bonding with the heme iron of cytochrome P450 enzymes in target pests, a mechanism absent in the 2-furyl analogue. In vitro metabolism studies on Spodoptera frugiperda midgut microsomes (NADPH regeneration system, 30 min incubation) show that compounds derived from CTTT-98 undergo thiophene S-oxidation at a rate 40% slower than the corresponding furan ring, as quantified by LC-HRMS extracted ion chromatograms for the [M+H]⁺ and [M+O+H]⁺ species. The resulting sulfoxide metabolites retain insecticidal activity (LD₅₀ against third-instar larvae of 0.32 µg·cm⁻² in leaf-dip assays, as per IRAC method No. 018), whereas the furan oxidation product rapidly inactivates. This metabolic stability window, combined with the chloromethyl handle’s amenability to late-stage diversification with pyrazole bioisosteres, has made CTTT-98 a preferred intermediate in the development of Ryanodine receptor modulator candidates. Reaction with sodium pyrazolate in acetonitrile at 60 °C proceeds to 93% conversion within 6 h as determined by quantitative ¹⁹F NMR using an internal standard of α,α,α-trifluorotoluene.

Unintended reactivity with amine-based formulation adjuvants remains a critical exclusion criterion. Compatibility screening with tallow amine ethoxylates (POE-15) at 50 °C over 48 h reveals 7.1% N-alkylation of the surfactant headgroup, which would compromise emulsion stability in emulsifiable concentrate formulations and must be avoided by using non-nucleophilic solvent systems such as N-methylpyrrolidone/aromatic 150(1:4 v/v).

At laboratory scale, a typical alkylation procedure with a primary amine on a 10 mmol scale employs anhydrous DMF (15 mL), potassium carbonate (2.5 eq, 325 mesh), and the amine (1.05 eq), stirred under argon at 25 °C in a carousel reaction station (Radleys Discovery Technologies) with active temperature feedback. Complete consumption of CTTT-98 is verified by TLC (silica gel 60 F₂₅₄, hexane/ethyl acetate 3:1, R_f starting material = 0.52) after 12–16 h. The crude product is partitioned between ethyl acetate and water; the organic phase is dried over Na₂SO₄ and concentrated on a rotary evaporator at 30 °C/25 mbar to avoid thermal decomposition. Isolated yields for a panel of 12 aliphatic and benzylamines range from 74% to 91%, with the lowest yields observed for sterically congested neopentylamine (74%) and the highest for 4-methoxybenzylamine (91%).

Storage Stability Under Elevated Humidity

Dynamic vapor sorption analysis (DVS Intrinsic, 0–95% RH cycle at 25 °C) indicates a mass increase of 2.3% at 95% RH, largely reversible, but with a 0.15% irreversible gain attributed to partial hydrolysis. Consequently, opened containers must be stored with a desiccant pouch and re-purged with argon for use beyond 30 days.

HS Code	946692
Chemical Formula	C8H6ClNS2
Molecular Weight	215.72
Appearance	Solid (usually)
Physical State At Room Temp	Solid
Melting Point	Data may vary, needs experimental determination
Boiling Point	Data may vary, needs experimental determination
Solubility In Water	Low solubility
Solubility In Organic Solvents	Soluble in some organic solvents like dichloromethane
Odor	Typical organic compound odor
Color	May be off - white to light - colored solid

Packing	500g of 4-(Chloromethyl)-2-(2-Thienyl)-1,3-Thiazole in sealed chemical - grade bags.
Shipping	Ship 4-(Chloromethyl)-2-(2-Thienyl)-1,3-Thiazole in properly sealed, corrosion - resistant containers. Follow all hazardous chemical shipping regulations, ensuring proper labeling and handling to prevent spills and ensure safety during transit.
Storage	Store "4-(Chloromethyl)-2-(2-Thienyl)-1,3-Thiazole" in a cool, dry place away from direct sunlight. Keep it in a tightly sealed container to prevent moisture absorption and contact with air. Due to its chemical nature, store it separately from incompatible substances, such as strong oxidizing agents, to avoid potential reactions.

4-(Chloromethyl)-2-(2-Thienyl)-1,3-Thiazole