2,4-Dibromo-1,3-Thiazole
|
HS Code |
672844 |
| Chemical Formula | C3HBr2NS |
| Molar Mass | 244.91 g/mol |
| Appearance | Solid (presumably, based on common thiazole derivatives) |
| Physical State At Room Temperature | Solid |
| Solubility In Water | Low solubility (thiazole derivatives are generally hydrophobic) |
| Solubility In Organic Solvents | Soluble in common organic solvents like dichloromethane, chloroform |
As an accredited 2,4-Dibromo-1,3-Thiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 2,4 - Dibromo - 1,3 - Thiazole packaged in a sealed, chemical - resistant vial. |
| Shipping | 2,4 - Dibromo - 1,3 - Thiazole is shipped in accordance with strict chemical transportation regulations. It's packaged securely in suitable containers to prevent leakage, ensuring safe transit during handling and transportation. |
| Storage | 2,4 - Dibromo - 1,3 - Thiazole should be stored in a cool, dry, well - ventilated area. Keep it away from heat sources, flames, and oxidizing agents. Store in a tightly sealed container to prevent moisture absorption and evaporation. Due to its potential toxicity, store it in a location inaccessible to unauthorized personnel and in accordance with local safety regulations. |
Despite the apparent simplicity of a dihalogenated thiazole, the industrial value of 2,4-dibromo-1,3-thiazole resides in its asymmetric electrophilic architecture. Both C–Br bonds exhibit markedly different oxidative addition kinetics with palladium catalysts, a property exploited in drug-discovery workflows where sequential cross-coupling constructs a tertiary pharmacophore without a protecting-group step. Integration into pilot-scale synthesis of a CHK1 kinase inhibitor precursor was carried out in a 100-L glass-lined reactor under a nitrogen sweep. The first Suzuki coupling at the C4 position used Pd(PPh₃)₄ (0.5 mol%), K₂CO₃ in degassed THF/H₂O (3:1 v/v), and 4-fluorophenylboronic acid at 60°C for 6 h, selectively affording 4-(4-fluorophenyl)-2-bromothiazole with <2% homocoupling dimers. After quenching, the crude intermediate was subjected to a second, more demanding C2 Buchwald-Hartwig amination using Pd₂(dba)₃/Xantphos and morpholine at 90°C in toluene. Batch records confirmed that residual palladium dropped below 10 ppm after an activated carbon treatment with Norit SX Plus, meeting USP <332> elementals for an oral solid dosage form. Process analytical technology (PAT) relied on ReactIR to track C–Br consumption, with peak disappearance at 688 cm⁻¹ for the C2–Br stretch flagging endpoint in real time, thus circumventing off-line HPLC and reducing cycle time by 35 minutes. The outcome demonstrated that residual water content above 0.05% in the reaction mixture at the amination stage promoted dehalogenation byproducts exceeding 1.2% area, necessitating azeotropic drying of the intermediate with toluene prior to Pd insertion.What Makes the Orthogonal Reactivity of 2,4-Dibromo-1,3-Thiazole So Critical for Fragment-Based Lead Assembly?Fragment merging strategies in antiviral research rely on the compound’s ability to undergo chemoselective metalation. At C5, the unsubstituted position can be deprotonated with LDA at -78°C in THF, generating a lithiated species that quenches with DMF to install a formyl group, yielding 2,4-dibromo-5-formylthiazole in 85–92% isolated yield after aqueous workup and vacuum distillation (0.5 mbar, 90–95°C vapour temperature). The formyl handle then permits reductive amination with primary amines using NaBH(OAc)₃ in dichloromethane at ambient temperature, forming a C5-aminomethyl appendage while leaving both bromine atoms intact for sequential Pd-catalyzed diversification. A specific case from gram-scale laboratory production for a dengue protease inhibitor saw the aldehyde intermediate condensed with cyclopropylamine, yielding the secondary amine with 97% HPLC purity (C18 column, gradient acetonitrile/0.1% TFA, detection at 235 nm). The amine intermediate was not isolated but telescoped directly into a C4 Sonogashira reaction with TMS-acetylene. Here, the reaction suffered from premature alkyne homocoupling when the batch temperature exceeded 45°C, a phenomenon traced to exothermic heat release that was mitigated by programming a 2-step temperature ramp: 30°C for 1 h, then 40°C for 3 h, resulting in 93% conversion. The desilylation with TBAF in wet THF released the free ethynyl group, which subsequently participated in a C2 Stille coupling with a stannylated pyrimidine. The entire sequence—starting from the dibromothiazole—furnished the final trisubstituted thiazole core in 41% overall yield across seven steps without column chromatography, a testament to the crystalline nature of every intermediate, each isolated by simple filtration or distillation. Residual tin from the Stille step was analyzed by ICP-MS per ISO 11885:2007 and kept below 20 µg/g in the API after an aqueous NaHSO₃ scrub.Agrochemical Intermediates: Harnessing the Thiazole Ring as a Carboxamide BioisostereThe thiazole ring system is a well-known scaffold in succinate dehydrogenase inhibitor (SDHI) fungicides, where the ring substitutes for a metabolically labile amide bond. In the synthesis of a second-generation analogue of thifluzamide, 2,4-dibromo-1,3-thiazole served as the central building block in a kilogram-scale campaign. The C2 bromide was displaced with 2-chloro-4-(trifluoromethyl)aniline in a copper-catalyzed Ullmann-type coupling. The process, run in a 250-L stainless steel reactor, used CuI (5 mol%), N,N′-dimethylethylenediamine (10 mol%), and K₃PO₄ in dioxane at 110°C for 18 hours. Aromatic amination at C2 proceeded with 89% isolated yield, but only when the starting dibromothiazole was recrystallized from heptane/toluene (4:1) to a purity exceeding 99.5 area% because any trace of the 2,5-dibromo isomer led to an isomeric byproduct that co-crystallized in the final product and was difficult to reject. After the Ullmann step, the C4 bromide remained and was engaged in a Negishi coupling with cyclopropylzinc chloride, prepared in situ from cyclopropyl bromide and Rieke zinc. The Negishi reaction was performed in THF at 40°C with Pd(dppf)Cl₂ (1 mol%), affording the desired 2-arylamino-4-cyclopropylthiazole after silica gel filtration. The final compound was formulated as a 250 g/L SC suspension concentrate. Field trial data from a GEP semi-field study on grapevine downy mildew (Plasmopara viticola) showed that the EC₅₀ of the lead candidate was 0.18 mg/L, comparable to the commercial standard mandipropamid, but toxicity to Daphnia magna in a 48-h acute immobilization test (OECD 202) was markedly lower, with an EC₅₀ of 7.2 mg/L. The manufacturing process was validated according to OECD PRP 204, and residual palladium in the active ingredient was controlled to ≤5 ppm as per ICH Q3D guidelines for parenteral groundwater exposure modelling.
*Approximate t1/2 determined by ¹⁹F NMR using 4-fluorobromobenzene as internal standard; data derived from the same source batch of 2,4-dibromo-1,3-thiazole, moisture <50 ppm. Pressing Beyond Cosmetic Tolerances: Preservative Synergy in Professional Permanent Hair Dye FormulationsRegulatory shifts in the EU under the Regulation (EC) No 1223/2009 on cosmetic products have restricted several traditional isothiazolinone preservatives, redirecting attention to halogenated thiazole derivatives for their antimicrobial activity in oxidative hair colourants. A stability screen performed on a 6% hydrogen peroxide developer at pH 3.0 showed that 2,4-dibromo-1,3-thiazole at 0.08 wt% effectively suppressed Pseudomonas aeruginosa biofilm formation over 28 days at 40°C, outperforming methylisothiazolinone at identical concentration under the same stressed conditions. The challenge test was conducted according to ISO 11930:2019 and met criterion A (bacteria reduction > 99.9% at day 7, with no increase at day 28). Crucial to its performance in the highly oxidising developer base was the absence of free hydroxylamine or amine impurities in the dibromothiazole, as these would react exothermically with H₂O₂. The raw material specification therefore included a pass/fail limit for DBU-DBF (dibenzylurea-dibromoformaldoxime)-type impurity via HPLC-MS selective ion monitoring at m/z 398/400/402, with ≤50 mg/kg. What emerged as the primary formulation constraint was a measurable shift in the dye-coupling rate: when the dibromothiazole concentration exceeded 0.12 wt%, the coupling of p-phenylenediamine with resorcinol was retarded, manifested as a 7–12% reduction in colour intensity (ΔE > 3.0 measured by diffuse reflectance spectrophotometry, DIN EN ISO 11664-4). The effect was traced to the compound’s mild reducing potential, which partially neutralised the developer’s active oxygen, so the upper dosing window was capped at 0.10 wt%. All ingredients were mixed in a 500-L vacuum processing vessel with anchor stirrer (28 rpm) and an inline Silverson high-shear mixer set to 3600 rpm in recirculation mode for complete dispersion of the crystalline dibromothiazole, which otherwise sedimented upon storage and caused localised overdosing when the consumer mixed the bottle. This engineering detail eliminated batch-to-batch shade variation complaints in the market. |
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2,4-Dibromo-1,3-thiazole (CAS 4175-77-3) is a heterocyclic building block supplied as an off-white to pale yellow crystalline solid with a molecular formula of C3HBr2NS and a molecular weight of 242.92 g/mol. Its structure places bromine atoms at both the 2- and 4-positions of the thiazole ring, creating two electronically distinct C–Br bonds that exhibit orthogonal reactivity in transition-metal-catalyzed transformations. The 4-bromo substituent, positioned para to the ring nitrogen, resides at a site of higher LUMO coefficient density, a property that enables preferential oxidative addition with palladium(0) species and forms the basis for sequential, regioselective cross-coupling strategies widely employed in agrochemical and kinase inhibitor discovery programs. Commercially, the compound is offered in research-to-pilot quantities ranging from 1 g septa-sealed amber vials to 25 kg fibre drums under inert atmosphere, with lot-specific certificates of analysis documenting assay by HPLC, water content by coulometric Karl Fischer titration, and impurity profiling by relative retention time against the main peak.
The differential reactivity originates from the electron distribution in the thiazole π-system. In the ground state, the 4-position experiences a greater degree of positive character because the nitrogen atom at 3 withdraws electron density inductively and the sulfur atom at 1 weakly donates into the ring without fully compensating. When Pd(PPh3)4 or a bulkier ligand system such as SPhos is introduced in the presence of 2,4-dibromo-1,3-thiazole, the LUMO—populated by the incoming metal—shows a node that places higher amplitude at C4-Br than at C2-Br. This has been corroborated by competition experiments monitored via GC/MS: treating the dibromo substrate with 1.0 equiv. of Pd(PPh3)4 in toluene at 50°C yields the 4-oxidative-addition complex as the predominant species after 1 h, with a 4-mono-adduct to 2-mono-adduct ratio exceeding 9:1. The residual 2-bromine remains intact and can be selectively addressed in a subsequent step by employing a higher reaction temperature (80–100°C) and a bidentate ligand such as dppf, which facilitates the slower insertion at the less electron-deficient center. Industrial process chemists have exploited this kinetic window to avoid statistical mixtures and to minimize tedious chromatographic separations during multi-kilogram campaigns.
Upon receipt, each production lot is subjected to a panel of release tests designed to detect deviations that could compromise downstream coupling stoichiometry. The primary assay method employs reversed-phase HPLC on an Agilent Zorbax Eclipse XDB-C18 column (4.6 × 150 mm, 5 µm) with UV detection at 254 nm and a mobile phase of acetonitrile/water (60:40 v/v) at 1.0 mL/min. Under these conditions, the main peak elutes at approximately 6.8 min, while the most common process-related impurity, tentatively identified as 2-bromo-4-chlorothiazole (carried over from halogen exchange during manufacture), appears at a relative retention time of 0.87. The specification limits are shown below. Water content is determined by coulometric Karl Fischer titration according to ASTM E203, because even sub-percent moisture can promote hydrolytic generation of 4-hydroxythiazole byproducts during prolonged storage or under thermal stress. Acceptance criteria are anchored to ICH Q2(R1) guidelines for accuracy, precision, and linearity.
| Test Item | Method | Specification |
|---|---|---|
| Appearance | Visual inspection | Off-white to pale yellow crystalline powder |
| Identification | 1H NMR (400 MHz, CDCl3) | Singlet at δ 7.85 ± 0.05 (thiazole C5–H) |
| Purity (HPLC, area%) | In-house method VAL-2,4-DB | ≥ 98.0% |
| Largest individual unspecified impurity | HPLC, RRT reference | ≤ 1.0% |
| Water content | ASTM E203 (coulometric) | ≤ 0.5% |
| Melting range | Differential scanning calorimetry, 10°C/min | 68–72°C |
When batches are sampled from production-scale isolations carried out in glass-lined reactors of 200 L capacity with toluene/MTBE crystallization sequences, the melting endotherm sharpness (measured as width at half-height) serves as a supplementary indicator of polymorphic uniformity, and values below 2.5°C are targeted to avoid dissolution rate variability in later synthetic steps.
Synthetic chemists repeatedly leverage the intrinsic selectivity to assemble 2,4-disubstituted thiazole arrays without resorting to protection or functional group interconversion at the heterocycle. A representative laboratory protocol that has been scaled to 500 g input in a jacketed cylindrical reactor with anchor agitator begins by charging Pd(PPh3)4 (1 mol%) and the dibromo-thiazole in degassed DME/water (4:1). After adding 2.0 equiv. of sodium carbonate and 1.05 equiv. of 4-methoxyphenylboronic acid, the heterogeneous mixture is heated to 80°C and held for 6 h. In-process GC monitoring routinely shows > 95% conversion with less than 4% di-arylated side product. The intermediate 2-bromo-4-(4-methoxyphenyl)thiazole is isolated by aqueous workup and crystallization from heptane in 85% yield. Subsequent substitution at the 2-position is accomplished by switching to Pd(dppf)Cl2 (3 mol%) and K3PO4 in DMF at 100°C for 12 h, furnishing the fully elaborated 2,4-diarylthiazole after flash chromatography (yield 70–78%). This two-step sequence has been adopted in multiple lead optimization campaigns targeting cyclin-dependent kinases, where the thiazole core appears as a pharmacophoric hinge binder. In comparison to the 2,4-dichloro analogue, the dibromo version reacts approximately 10 times faster in the initial oxidative addition, permitting coupling at ambient or moderately elevated temperatures and protecting heat-sensitive boronic acids from protodeboronation. For electron-poor arylboronic acids (e.g., 4-cyanophenyl), catalyst loading must be increased to 5 mol% and the reaction time extended to 18 h to achieve acceptable turnover, a limitation attributed to sluggish transmetallation rather than oxidative addition.
The 2,5-dibromo-1,3-thiazole isomer (CAS 4175-78-4) introduces bromine at a position adjacent to the sulfur atom, where the electronic environment is dominated by the sulfur’s lone-pair conjugation rather than the imine-type nitrogen effect. Under the identical Suzuki conditions described above, 2,5-dibromothiazole reacts with phenylboronic acid to produce a 3:2 mixture of 5-phenyl and 2-phenyl mono-coupled products, as quantified by calibrated LC-UV at 254 nm. This inherent lack of bias complicates the synthesis of single isomers and forces substantial yield loss during purification. The table below summarizes head-to-head comparisons with related thiazole electrophiles that are frequently evaluated during scaffold selection. The data are drawn from a single internal screening study in which all substrates were exposed to Pd(PPh3)4 (1 mol%) and 4-methoxyphenylboronic acid in DME/water at 80°C for 6 h.
| Compound | CAS | Melting point (°C) | Mono-arylation ratio (4- or 5- : 2-) | Isolated yield of major mono-isomer (%) | Key differentiation |
|---|---|---|---|---|---|
| 2,4-Dibromo-1,3-thiazole | 4175-77-3 | 68–72 | 95:5 | 85 | Unambiguous 4-selectivity; residual 2-Br retained |
| 2-Bromo-1,3-thiazole | 3034-47-7 | −2 to 0 | N/A (single site) | 91 | Liquid at room temperature; single functional handle |
| 2,5-Dibromo-1,3-thiazole | 4175-78-4 | 41–44 | 40:60 (5- preferred) | 62 (5-aryl isomer) | Poor regiocontrol; requires SPhos ligand to reverse ratio |
| 2,4-Dichloro-1,3-thiazole | 4175-76-2 | 32–34 | 90:10 (4- preferred) | 68 | Slower turnover; higher temperature (> 100°C) needed |
This isomer is often selected when the target requires a second functionalization at the 2-position that is incompatible with a bromine atom—for example, a direct lithiation or a Buchwald–Hartwig amination with a primary amine—because the 2-chloro variant can survive conditions that would debrominate the 2-bromo analogue. However, the protracted reaction times and elevated temperatures of the dichloro route render the dibromo compound the first choice for most rapid analoging, provided the downstream chemistry tolerates the residual 2-bromine until the final step.
Storage stability under routine laboratory conditions is primarily gated by humidity and actinic exposure. When the water content exceeds 0.5%, an autocatalytic hydrolysis pathway can initiate at temperatures above 30°C, releasing HBr and generating 4-hydroxy-2-bromothiazole as the initial degradation product; this impurity, once formed, is difficult to purge by recrystallization and can poison palladium catalysts. Manufacturers supply the compound in amber borosilicate glass bottles sealed with PTFE-faced septa under argon (O2 < 100 ppm). Upon first opening, the contents should be transferred to a glovebox or handled under a nitrogen sweep. Preadsorption drying by placing the opened container in a vacuum oven at 40°C for 2 h is recommended immediately before use in anhydrous cross-coupling reactions where precise stoichiometry is crucial. The compound is incompatible with primary and secondary amines, alkoxides, and carbanions at ambient temperature: n-butyllithium at −20°C in THF can displace the 4-bromine within minutes, but temperatures above 0°C rapidly lead to ring-opening via attack at the C=S moiety. Operations requiring strong bases or nucleophiles must maintain a jacket temperature below −30°C and employ inverse addition to limit thermal excursions. In solid form, the compound can be stored at 2–8°C for 24 months from the date of manufacture with less than 0.2% purity loss per year when the integrity of the argon headspace and the moisture barrier are preserved.
