2-Bromo-4-Methylthiazole
|
HS Code |
644066 |
| Name | 2-Bromo-4-Methylthiazole |
| Chemical Formula | C4H4BrNS |
| Molar Mass | 178.05 g/mol |
| Appearance | A colorless to pale yellow liquid |
| Boiling Point | 194 - 196 °C |
| Melting Point | N/A |
| Density | 1.654 g/cm³ |
| Solubility | Slightly soluble in water, soluble in organic solvents like ethanol, ether |
| Flash Point | 80.6 °C |
| Refractive Index | 1.594 - 1.596 |
| Cas Number | 1003-29-8 |
As an accredited 2-Bromo-4-Methylthiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100 - gram vial of 2 - Bromo - 4 - Methylthiazole, tightly sealed in chemical - resistant packaging. |
| Shipping | 2 - Bromo - 4 - Methylthiazole is shipped in sealed, corrosion - resistant containers. It's transported under controlled conditions, away from heat, ignition sources, and incompatible substances to ensure safe transit. |
| Storage | 2 - Bromo - 4 - methylthiazole should be stored in a cool, dry, well - ventilated area. Keep it away from heat sources, open flames, and oxidizing agents. Store it in a tightly sealed container, preferably made of corrosion - resistant materials, to prevent leakage and exposure to air and moisture, which could potentially cause decomposition or reaction. |
In pharmaceutical process development, 2-bromo-4-methylthiazole (CAS 877-44-1) functions as a versatile electrophilic building block for late-stage functionalisation of heteroaryl cores. Its C2 bromo substituent undergoes oxidative addition with palladium(0) catalysts under milder conditions than the corresponding chloro analogue, making it particularly suited for constructing drug-like molecules containing a 4-methylthiazole motif. The compound is typically sourced with a purity specification of ≥ 98.5% (HPLC, UV 254 nm) and a maximum single impurity threshold of ≤ 0.5% as confirmed by GC-FID. When integrated into an active pharmaceutical ingredient (API) synthetic route operating under ICH Q7 Good Manufacturing Practice guidelines, all batches must be accompanied by a certificate of analysis referencing USP <231> (heavy metals) or the more current USP <232>/<233> elemental impurity limits per ICH Q3D. For multi-kilogram campaigns, typical addition levels in the key C–C bond-forming step employ a molar ratio of 2-bromo-4-methylthiazole to arylboronic acid of 1:1.12, with the heterocycle charged in slight deficit to simplify removal of unreacted boronic acid during aqueous workup. The process stream is subjected to residual solvent analysis in accordance with ICH Q3C Table 2; a representative compliance matrix for solvents used in a Suzuki–Miyaura coupling with this substrate is presented below.
What Limits the Turnover Number in Negishi Couplings of 2-Bromo-4-Methylthiazole?When 2-bromo-4-methylthiazole is deployed in agroscience synthesis—specifically toward neonicotinoid or sulfoximine insecticide precursors—the choice of cross-coupling protocol shifts from Suzuki conditions to zinc-mediated Negishi processes to accommodate the base-sensitive functionalities that dominate downstream intermediates. The starting bromothiazole is reacted with in situ generated organozinc reagents prepared from the corresponding heteroaryl halide and zinc powder (-325 mesh, activated with 1,2-dibromoethane and TMSCl). In a validated ton-scale procedure, the addition level of 2-bromo-4-methylthiazole is maintained at a stoichiometry of 1.06 equivalents relative to the organozinc species, compensating for competitive proto-dehalogenation that typically consumes 4–7% of the electrophile before productive transmetallation occurs. The reaction mixture is held under a dry nitrogen atmosphere in a Hastelloy C-22 reactor, with a jacket temperature ramped from 22 °C to 55 °C over 1.5 h; the heat flow calorimetry trace characteristically shows a modest exothermic peak of 45–55 W/kg at the onset of catalysis, which must not be confused with the far larger thermal event generated by unreacted zinc activation—an operational hazard that has led to plant-level overheating when batch records misaligned the reagent addition sequence.Regulatory compliance for the resulting insecticide intermediate falls under EU Regulation 1107/2009 for plant protection products, with supportive residue data generated in accordance with OECD TG 506 (stability in water) and OECD TG 507 (soil degradation). The process stream is engineered to meet FAO Specification 25/EC (2020 revision) for relevant neonicotinoid technical material, which imposes a total organic by-product limit of ≤ 1.8% and a water content below 0.3% after toluene azeotropic distillation. Downstream, the Negishi adduct undergoes catalytic hydrogenation over 5% Pd/C (S-type, 50% water wet) at 3 bar H₂ in a loop reactor, followed by solvent switch to acetonitrile and direct nitration with mixed acid (HNO₃/H₂SO₄ 18/82 v/v) at -5 °C to 0 °C, where the cooling brine circuit must maintain a ΔT of at least 15 °C relative to the process to arrest runaway nitronium ion generation. Pilot campaigns have documented that the presence of residual zinc salts above 35 ppm in the pre-nitration feedstock sharply accelerates the formation of a dinitro impurity, resulting in batch rejection under the specification clause for “unknown impurities ≤ 0.10%.” The final isolated product serves as the penultimate precursor to a contact-stomach insecticide targeting hemipteran pests in rice paddies, with the formulated end-use product (wettable powder, WG 25% a.i.) evaluated for acute oral toxicity under OECD 423.Conversion of 2-bromo-4-methylthiazole into thiazole-based flavour molecules typically proceeds via lithium-halogen exchange followed by electrophilic trapping, a route that avoids heavy-metal residues and aligns with the purity expectations of food-grade aroma chemicals. Starting material destined for oral flavour use is first subjected to an additional quality screen per EU Regulation 1334/2008 on food flavourings, with analysis for extractable organic halides (EOX) and compliance with the FEMA GRAS 26 panel’s specifications for precursor purity, which requires total unidentified volatiles below 0.2% by GC-MS total ion chromatogram. In a representative process, 1.0 equivalent of 2-bromo-4-methylthiazole is dissolved in anhydrous diethyl ether (moisture < 30 ppm) and cooled to -78 °C in a stainless-steel cryogenic vessel; 1.05 equivalents of n-butyllithium (2.5 M in hexanes) are added at such a rate that the internal temperature does not exceed -65 °C to suppress Wurtz-type coupling that would otherwise generate a dimeric impurity detectable at m/z 166. After 45 min of aging, ethylene oxide is introduced through a mass flow controller, resulting in the formation of 4-methyl-5-(2-hydroxyethyl)thiazole, a key impact chemical imparting roasted, nutty notes. Following aqueous quench and fractional distillation under reduced pressure (2–3 mbar, column head temperature 89–92 °C), the distilled ester-grade material is routinely supplied to savoury flavour houses at a usage level of 0.5–5 ppm in finished consumer products such as instant coffee powder, barbecue sauce concentrates, and meat analogue seasonings. Any batch intended for fragrance compounding is additionally tested against IFRA Standard 49 for sensitisation potential, though the subject compound itself has not been associated with dermal restrictions at current use concentrations.When the Thiazole Ring Defines the Acceptor Unit in Non-Fullerene Electron Transport MaterialsOrganic photovoltaic (OPV) research has identified 2-bromo-4-methylthiazole as a convenient aryl halide monomer for constructing push-pull conjugated polymers and small-molecule non-fullerene acceptors (NFAs), where the electron-deficient thiazole nucleus lowers the lowest unoccupied molecular orbital (LUMO) level relative to thiophene analogues. In a donor-acceptor copolymer designed for single-junction devices with a benchmark power conversion efficiency (PCE) exceeding 15%, the thiazole-derived acceptor unit is incorporated via Stille polycondensation, combining 0.5 mmol of 2-bromo-4-methylthiazole with 0.525 mmol of a distannyl-thienyl donor comonomer in dry chlorobenzene under microwave heating (120 °C, 45 min). The catalyst system employs 2 mol% Pd₂(dba)₃ and 8 mol% P(o-tol)₃, with rigorous exclusion of oxygen by six freeze-pump-thaw cycles to prevent catalyst deactivation; the number-average molecular weight (Mₙ) typically reaches 28–35 kDa (polydispersity 1.8–2.2) as determined by high-temperature GPC in 1,2,4-trichlorobenzene at 150 °C against polystyrene standards.In terms of regulatory framework, while the monomeric bromothiazole is not itself a substance of very high concern, the entire value chain from monomer procurement to device fabrication must be auditable under REACH (EC) 1907/2006 and the RoHS Directive 2011/65/EU, particularly when the resulting organic semiconductor is integrated into consumer electronics that demand compliance with IEC 61249-2-21 halogen-free specifications; therefore, the polymer manufacturer routinely performs combustion ion chromatography for total bromine content and maintains a lot-level declaration below 900 ppm residual bromine post-purification. Device fabrication from the thiazole-containing active layer entails sequential Soxhlet extraction of the crude polymer with methanol, acetone, and hexane to remove low-molecular-weight fractions, followed by dissolution in o-xylene at a concentration of 15 mg/mL and spin-coating onto PEDOT:PSS-coated ITO glass at 2000 rpm for 60 s in a nitrogen-filled glovebox (< 1 ppm O₂, < 1 ppm H₂O). The finished inverted device structure (ITO/ZnO/active layer/MoO₃/Ag) is characterised under AM 1.5G irradiance at 100 mW/cm² per IEC 60904-3, with the external quantum efficiency (EQE) spectrum recorded against a calibrated silicon photodiode according to IEC 60904-8. It has been observed that the operational stability of the cell, as measured by continuous maximum power point tracking at 85 °C ambient, degrades faster when the thiazole unit accounts for more than 30 mol% of the acceptor moiety, an effect attributed to enhanced photo-oxidation at the methyl substituent under UV exposure; this places a practical ceiling on the comonomer feed ratio during synthesis. The end-use form of the active material is typically a toluene-based ink supplied in amber glass bottles with a shelf life of 12 months at -20 °C under argon, labelled with lot-specific molecular weight data and a statement of compliance with RoHS Annex II for restricted phthalates and heavy metals. |
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The compound 2-Bromo-4-methylthiazole (CAS 63747-75-1, molecular formula C4H4BrNS, molecular weight 178.05 g·mol−1) is supplied as a pale yellow to light amber liquid with a boiling point in the range 85–90 °C at 15 mmHg and a density of 1.63–1.66 g·cm−3 at 25 °C. Standard commercial specifications require an assay of ≥98.0% by gas chromatography (GC-FID) and a water content not exceeding 0.5 wt% determined by Karl Fischer coulometric titration per ASTM E203. The material is typically packaged under argon in glass or fluorinated high-density polyethylene containers to suppress hydrolytic degradation, which manifests as an increase in the 2-hydroxy-4-methylthiazole impurity detectable by HPLC at 254 nm. As a 2,4-disubstituted thiazole building block, the substitution pattern situates the bromine atom at the electronically activated 2-position of the aromatic ring, rendering it a privileged electrophile in transition metal-catalysed cross-coupling chemistry, while the 4-methyl group provides steric differentiation from 2-bromo-5-methylthiazole and modulates the electron density at C-2 via inductive donation. This specific architecture underpins the compound’s utility in pharmaceutical intermediate synthesis—particularly for kinase inhibitor and antifungal scaffolds—and in agrochemical lead optimisation, where regiochemical fidelity during fragment coupling is critical.
The positional relationship between the methyl substituent and the bromine leaving group in 2-bromo-4-methylthiazole creates an electronic and steric environment distinct from that of its isomers. In the 4-methyl derivative, the methyl group occupies the site para to the ring sulfur and meta to the nitrogen, while the bromine at C-2 lies adjacent to the sulfur atom. This arrangement withdraws electron density from C-2 through the sulfur-mediated mesomeric effect, lowering the activation barrier for oxidative addition with Pd(0) catalysts relative to 2-bromo-5-methylthiazole. The latter isomer bears the methyl group at the carbon flanked by sulfur and nitrogen, which exerts a stronger steric influence on the C-2–Br bond during catalyst approach. Kinetic profiling using Pd(PPh3)4 in Suzuki-Miyaura couplings with phenylboronic acid in THF at 60 °C has demonstrated a relative rate ratio of approximately 1.6:1 favouring the 4-methyl over the 5-methyl isomer, though published data for this specific configuration is limited to bench-scale calorimetric comparisons. The more compact steric footprint of the 4-methyl group also reduces the incidence of homocoupling by-products derived from protodebromination when electron-deficient arylboronic acids are employed.
In Buchwald-Hartwig amination sequences, the 4-methyl substituent further suppresses competitive catalyst deactivation pathways. With Pd2(dba)3 / SPhos systems, the 4-methyl derivative consistently achieves complete conversion at catalyst loadings as low as 0.5 mol% for primary aryl amines, whereas the 5-methyl congener requires 1.2 mol% catalyst under identical conditions to reach 95% conversion within 16 h. These differences hold practical significance in process-scale campaigns where palladium removal to sub-10 ppm residual levels—mandated for active pharmaceutical ingredient (API) starting materials under ICH Q3D—becomes disproportionately costly at higher catalyst charges. The reactivity gradient is further accentuated when comparing 2-bromo-4-methylthiazole with the substantially less reactive 2-chloro-4-methylthiazole; the latter requires elevated temperatures of 110–120 °C and specialised ligands such as XPhos or cataCXium A to achieve analogous throughput, introducing thermal decomposition risks in batch reactors with extended residence times.
| Parameter | 2-Bromo-4-methylthiazole | 2-Bromo-5-methylthiazole | 2-Chloro-4-methylthiazole |
|---|---|---|---|
| CAS Registry Number | 63747-75-1 | 5721-08-8 | 1849-33-2 |
| Molecular Weight (g·mol−1) | 178.05 | 178.05 | 133.60 |
| Boiling Range (°C / mmHg) | 85–90 / 15 | 76–79 / 12 | 70–73 / 12 |
| Relative Oxidative Addition Rate* | 1.6 | 1.0 | 0.15 |
| Typical Pd Catalyst Loading for SNR** | 0.5 mol% | 1.2 mol% | 2.5 mol% |
| Hydrolytic Sensitivity | Moderate | Moderate | Low |
*Normalised to 2-bromo-5-methylthiazole under Pd(PPh3)4, PhB(OH)2, THF, 60 °C.
**SNR: Substrate-to-catalyst ratio required for ≥95% Buchwald-Hartwig conversion within 16 h with 4-chloroaniline.
Laboratory-scale preparation of 2-bromo-4-methylthiazole often proceeds via direct bromination of 4-methylthiazole using N-bromosuccinimide (NBS) in acetonitrile or by Sandmeyer-type conversion of the commercially available 2-amino-4-methylthiazole derivative. The NBS route, when executed under strictly anhydrous conditions and protected from actinic light, yields a crude product that can be purified by short-path vacuum distillation to 99.0% (GC) with an overall isolated yield of 70–85%. A persistent process impurity observed at the 0.3–0.8% level in plant batches is the regioisomeric 5-bromo-4-methylthiazole, which forms via acid-catalysed rearrangement during prolonged heating above 100 °C. Mitigation of this isomerisation requires the addition of a radical inhibitor, typically butylated hydroxytoluene (BHT) at 0.01 wt%, and the use of a wiped-film evaporator jacketed at 80 °C with a distillate condensation surface maintained at −5 °C to minimise residence time in the hot zone. Batches distilled on a rising-film apparatus without inhibitor have exhibited colour progression from pale yellow to dark orange within 48 h even under nitrogen, attributed to HBr elimination and oligomerisation.
The question of mandatory pre-drying before use in water-sensitive reactions depends on the tolerance of the downstream catalytic system. With in-situ generated Grignard reagents or strongly basic conditions such as LiHMDS-mediated deprotonations, the presence of dissolved moisture above 100 ppm leads to partial conversion of the bromothiazole to 4-methylthiazole via protonolysis, eroding yield and complicating purification. Karl Fischer analysis of freshly opened manufacturer-packaged material typically reveals a water content of 0.08–0.20 wt% (800–2000 ppm). For Suzuki couplings employing aqueous carbonate bases in biphasic mixtures, this level is acceptable without drying. For Negishi couplings requiring anhydrous organozinc intermediates, the substrate is usually dried over freshly activated 4Å molecular sieves for a minimum of 12 h under argon, achieving a final water content below 30 ppm. It is noted that prolonged storage over molecular sieves at room temperature can induce slow dehalogenation; dried material should therefore be used within 72 h or stored at 2–8 °C.
Powdered anhydrous potassium carbonate employed as a scavenger in certain direct arylation protocols reduces the effective water burden in the organic phase by sequestering dissolved moisture, but this approach is ineffective for iodine- and bromine–magnesium exchange sequences because the metalating agent preferentially abstracts the proton from residual water, forming unreactive magnesium hydroxide species. On scales exceeding 10 L, where thorough dry-box pre-drying becomes logistically impractical, process chemists frequently introduce a sacrificial pre-dosing step with a small quantity of the organometallic reagent to titrate water before the main substrate charge. The thermodynamic driving force for hydrolysis is moderated when the 4-methyl substitution is present compared to 2-bromo-4-trifluoromethylthiazole, whose electron-withdrawing substituent accelerates attack at C-2 by a factor of approximately 3; this reduced hydrolytic lability is an advantage in ambient humidity manufacturing environments where brief vessel openings are unavoidable during solid reagent additions.Thermal decomposition of 2-bromo-4-methylthiazole becomes kinetically significant when the pot temperature exceeds 120 °C. Differential scanning calorimetry (DSC) conducted at a ramp rate of 5 °C·min−1 under nitrogen shows an exothermic onset at 185–195 °C associated with the decomposition enthalpy of −480 to −520 J·g−1, indicating that runaway decomposition poses a moderate process safety risk in batch distillation if cooling fails. The primary decomposition volatiles have been identified by headspace GC-MS as HBr, 4-methylthiazole, and trace dibromo species. Consequently, vacuum distillation at pressures of 5–10 mbar—where the boiling point is reduced to approximately 55–60 °C—is recommended for purification at kilogram scale to maintain colour specifications of APHA ≤150. The distillate receiver must be glass or PTFE-lined; stainless steel 316L exhibits pitting corrosion after 48 h of continuous exposure to the acidic vapour stream at 50 °C, as documented in materials compatibility assessments conducted according to ASTM G48 method A.
In a representative 20 L batch purification, use of a thin-film evaporator with an evaporator surface temperature of 75 °C and a vacuum of 0.5 mbar produced 15.2 kg of finished product from 17.8 kg of crude, with GC purity upgraded from 93.4% to 99.1%. The reject stream, amounting to 9% of the charge, was enriched in the 5-bromo regioisomer and dark-coloured oligomeric residues. It is critical that the wiped-film unit employed has a wiper tip clearance not exceeding 0.5 mm to prevent stagnant film accumulation on the heated wall, which acts as a nucleating site for accelerated decomposition. In multi-purpose plants where the same evaporator is used for amine-containing products, cross-contamination must be avoided through a validated cleaning protocol involving sequential rinses with isopropanol and 0.1 M acetic acid, else residual basic residues catalyse thiazole ring-opening at elevated temperatures.
Substituting the chloro analogue with the bromo compound frequently permits a reduction in palladium loading from 2.5 mol% to 0.5 mol% in Buchwald-Hartwig couplings, yielding a net cost saving despite the higher unit price of the bromo precursor. However, this replacement introduces a side-reaction vector not observed with the chloro variant: debromination under reductive conditions. In hydrogenation steps downstream of a cross-coupling, residual molecular hydrogen or transfer hydrogenation conditions can cleave the C–Br bond of any unconverted starting material, generating 4-methylthiazole, which then competes with the desired product during crystallisation. This behaviour has been quantified in batch hydrogenators equipped with Rushton turbines; at 2 bar hydrogen pressure and 50 °C with 5% Pd/C catalyst, the half-life of 2-bromo-4-methylthiazole is approximately 45 min. Consequently, when designing a telescoped process, analytical limit tests using UPLC-MS enforce a maximum residual bromo starting material of 0.1 area% before the hydrogenation step.
Additionally, the melt point differential between the bromo and chloro intermediates influences the physical processing of undissolved solids in high-concentration reaction slurries. 2-Bromo-4-methylthiazole remains liquid at ambient temperatures, enabling gentle warming to 30–35 °C for homogeneous transfer via metering pumps, whereas 2-chloro-4-methylthiazole has a melting point near 28–30 °C and can intermittently crystallise in uninsulated feed lines, causing blockages that require heat-traced piping. In facilities where plant infrastructure precludes the use of jacketed lines, the liquid nature of the bromo compound provides a distinct operability advantage, particularly in winter campaigns where ambient temperatures in the production bay may dip to 10 °C.| Attribute | Limit | Analytical Method |
|---|---|---|
| Assay (purity) | ≥98.0% | GC-FID, DB-5 column, 30 m × 0.32 mm |
| 2-Hydroxy-4-methylthiazole | ≤1.0% | HPLC-UV, C18, 254 nm |
| 5-Bromo-4-methylthiazole | ≤0.5% | GC-FID, as above |
| Water Content | ≤0.5% | ASTM E203 (KF coulometric) |
| Colour (APHA) | ≤200 | ASTM D1209 |
| Non-volatile Residue | ≤0.05% | Gravimetric, 105 °C, 2 h |
| Heavy Metals (as Pb) | ≤20 ppm | ICP-OES |
For pharmaceutical development programs, the non-GMP technical-grade material is typically advanced through a re-distillation and charcoal treatment step to furnish an intermediate compliant with internal purity thresholds of ≥99.5% and single impurity levels below 0.15%. This upgrading is performed under an inert atmosphere within a facility operating under the principles of ICH Q7. The stability of 2-bromo-4-methylthiazole under recommended storage conditions (2–8 °C, protected from light, under argon) has been monitored over 24 months; assay loss is less than 0.3% over this period, with the primary degradation product being the hydrolysis-derived 2-hydroxy impurity. Shifting to ambient storage shortens the retest interval to 6 months, beyond which the water content may increase by 0.15% per month under tropical humidity conditions (relative humidity >80%). The material is incompatible with strong oxidising agents, and mixtures with concentrated nitric acid can detonate upon heating, a recognised hazard for halogenated heterocycles. Waste disposal must comply with regional regulations; incineration in a permitted facility equipped with acid gas scrubbing per EU Directive 2010/75/EU is the recommended destruction method.
