2-Bromo-1,3-Benzothiazole

To access phosphorescent iridium complexes with emission maxima in the 510–530 nm region, 2-bromo-1,3-benzothiazole serves as a ligand precursor in the construction of cyclometalated Ir(III) dopants for solution-processed organic light-emitting diodes. A representative multi-step sequence begins with the synthesis of a 2-(benzothiazol-2-yl)pyridine (btpy) analogue: 2-bromo-1,3-benzothiazole (1.0 eq), 2-(tri-n-butylstannyl)pyridine (1.05 eq), and Pd(PPh₃)₄ (2 mol%) are refluxed in anhydrous toluene (0.1 M) under argon for 18–24 h. The Stille coupling product is isolated via flash chromatography on silica gel pretreated with triethylamine to suppress ligand demetalation. Subsequent μ-chloro dimer formation uses IrCl₃·3H₂O (1.0 eq) and the btpy ligand (2.2 eq) in 2-ethoxyethanol/water (3:1 v/v) at 120 °C for 12 h. The dimer is split with silver triflate (2.1 eq) in dichloromethane/acetonitrile, and the labile triflate intermediate is treated with a β-diketonate ancillary ligand (e.g., acetylacetonate, 2.5 eq) to yield the final phosphorescent emitter. Purification employs gradient sublimation at 220–240 °C and 10⁻⁶ Torr. Photoluminescence quantum yield in degassed toluene typically exceeds 0.85, as measured by integrating sphere per IES LM-82-11 guidelines. Residual bromine from the precursor must be driven below 900 ppm by repeated sublimation passes to meet the halogen-content limit set in IEC 62321-7-2:2017 for non-halogenated components within RoHS Directive 2011/65/EU Annex IV applications. Processing bottlenecks include batch-to-batch variation in the Stille coupling regioselectivity when scale exceeds 50 mmol; maintaining reaction homogeneity requires overhead stirring at ≥300 rpm in a baffled round-bottom flask to avoid catalyst sedimentation.

Which Synthetic Route Minimizes Dehalogenation By-Products in Kinase Inhibitor Fragment Coupling?

In the synthesis of ATP-competitive kinase inhibitors built on a 2-phenylbenzothiazole scaffold, the bromine atom at the C-2 position functions as a selective handle for Pd-catalyzed cross-coupling while leaving the thiazole ring intact for subsequent late-stage functionalization. A protocol optimized for pilot-scale Suzuki-Miyaura coupling requires 2-bromo-1,3-benzothiazole (1.0 eq), the corresponding arylboronic acid (1.15 eq), Pd(OAc)₂ (1.5 mol%) in combination with XPhos (3.0 mol%), and finely ground K₃PO₄ (2.5 eq) suspended in degassed THF/H₂O (4:1 v/v). The reaction mixture is heated to 60 ± 2 °C for 8 h under inert atmosphere. Tighter temperature control is essential: at >65 °C, unproductive protodebromination accelerates sharply, generating benzothiazole as a contaminant that co-elutes with the target biaryl product during normal-phase purification, reducing isolated yield from a typical 78–85% down to less than 55%. Aqueous workup employs extraction with ethyl acetate, followed by washing with 5 wt% aqueous NaCl and treatment with activated carbon (Darco KB-G, 0.2 g/mmol of product) to adsorb colloidal palladium. Residual Pd content is quantified by ICP-MS per ICH Q3D Guideline for Elemental Impurities: values below 10 µg/g are routinely achieved for an oral solid dosage form PDE of 100 µg/day. The resulting fragment is further elaborated into clinical candidates such as benzothiazole-substituted imidazo[1,2-b]pyridazines exhibiting IC₅₀ values in the low nanomolar range against FGFR1 kinase, as evaluated by TR-FRET assay using commercial ADP-Glo™ kits. Bulk intermediates shipped under Customs Tariff 2934.99.9001 are accompanied by a certified TSE/BSE statement and a heavy-metals certificate conforming to Ph. Eur. 9.0, section 2.4.8.

Agrochemical Benzothiazole Derivatives Targeting Succinate Dehydrogenase

Sulfur-linked benzothiazole ethers and thioethers, accessible directly from 2-bromo-1,3-benzothiazole, constitute the pharmacophoric core of several developmental SDHI fungicides that interrupt mitochondrial respiration in Ascomycete pathogens. A kilo-lab procedure for the synthesis of a model thioether intermediate involves treating 2-bromo-1,3-benzothiazole (1.0 eq) with ethyl 2-mercaptoacetate (1.05 eq) in DMF containing anhydrous K₂CO₃ (1.5 eq) at 78–82 °C for 6 h under nitrogen. The exotherm upon base addition is controlled by maintaining jacket temperature at 15 °C during the initial 30 min of reagent mixing. After cooling, the reaction mass is poured into ice-water and the precipitate is filtered, washed with cold isopropanol, and dried at 40 °C under vacuum to yield an off-white solid with a purity of ≥97 area% by HPLC (C18, acetonitrile/0.1% phosphoric acid gradient). The ester is subsequently hydrolysed with LiOH in THF/H₂O and converted to the active amide via CDI-mediated coupling with 2-(3-fluorophenyl)ethanamine. In greenhouse trials on Puccinia triticina, compounds derived from this path demonstrated protective EC₅₀ values of 0.8–2.3 mg/L when applied as an EC formulation at 100 g a.i./ha. Active ingredient specifications reference CIPAC MT 46.3 for wet-sieving and JMPR 2016 residue definition. Under Regulation (EC) No 1107/2009 Annex II, the data package must include an Ames test (OECD 471) on the isolated intermediate to rule out mutagenic potential, as the brominated heterocycle structurally alerts for DNA reactivity. Importers into the EU must provide a REACH registration number for the non-isolated intermediate or invoke Article 17(3) exemption under strictly controlled conditions.

If Polyester Fibre Requires Wash-Fast Orange to Red Shades, 2-Bromo-1,3-Benzothiazole Provides the Azo Coupling Vector

Commercial disperse dyes for high-energy polyester delivering Bath B shade depth frequently exploit 2-aminobenzothiazole-derived diazo components to shift the absorption maximum into the 480–520 nm range while maintaining the low molecular weight required for diffusion into the fibre. 2-Bromo-1,3-benzothiazole is converted to the corresponding 2-aminobenzothiazole via autoclave-mediated ammonolysis: the bromo compound is treated with 28 wt% aqueous NH₄OH (6.0 eq) and copper(I) oxide (5 mol%) in a Hastelloy C-276 pressure reactor at 130 °C and 12 bar for 10 h. The crude amine is purified by acid-base extraction and recrystallised from toluene to afford a pale-yellow crystalline product with a melting point of 128–130 °C. Diazotisation is conducted in 85 wt% orthophosphoric acid at 0–5 °C using solid NaNO₂ (1.02 eq), maintaining a slight excess of nitrous acid tested with starch-iodide paper. The resulting diazonium salt couples with N,N-diethylaniline (1.0 eq) dissolved in a 1:1 mixture of ice-cold methanol and 6 M HCl, yielding a scarlet azo dye that is filtered, washed until neutral, and dried under reduced pressure. Application on polyester knitted fabric via high-temperature exhaust dyeing at 130 °C for 45 min with a liquor ratio of 10:1 achieves a built-up depth of 2.0% o.m.f. and wet-fastness values of Grade 4–5 per ISO 105-C06:C2:2010. The finished dyestuff must comply with Oeko-Tex Standard 100 Annex 4 limits for banned arylamines (below 20 mg/kg), verified by GC-MS after reductive cleavage using sodium dithionite. Finished product listings on the Taiwan Environmental Protection Administration TCSI database require the bromine content to be reported as total organic halogen.

Thin-gauge polyolefin films employed in greenhouse covers and automotive interior skins undergo rapid UV-induced embrittlement unless a chromophore extending beyond 290 nm is dispersed in the polymer matrix at the parts-per-thousand level. 2-Bromo-1,3-benzothiazole is a key building block for a class of non-migratory UV absorbers where the benzothiazole ring acts as the primary light-absorbing core. In a representative route, the bromo compound is subjected to a CuI/proline-catalyzed Ullmann coupling with an appropriately substituted phenol (e.g., 2,4-di-tert-butylphenol, 1.2 eq) in DMSO at 110 °C under nitrogen to yield a 2-phenoxybenzothiazole precursor. The ether is subsequently chloromethylated using morpholine and paraformaldehyde in glacial acetic acid containing concentrated HCl, then reacted with a hindered piperidine derivative (HALS) to install a radical-scavenging unit in the same molecule. Compounding into a random polypropylene homopolymer (MFR 12 g/10 min at 230 °C/2.16 kg, ISO 1133-1:2022) is performed on a Berstorff ZE 25 twin-screw extruder with an L/D ratio of 34:1 and a screw speed of 200 rpm; the stabilizer is dry-blended at 0.25 wt% together with a co-additive package comprising Irgafos 168 (0.10 wt%) and Irganox 1010 (0.05 wt%). Extruded pellets are injection-moulded into 2 mm-thick plaques and exposed in a Xenotest Alpha+ instrument per ASTM G155-16 Cycle 1 (borosilicate-filtered xenon arc, 0.35 W/m² at 340 nm, black panel temperature 63 °C). At 3000 h exposure, yellowness index increase (ΔYI, ASTM E313-20) is held below 4.0, compared to 14.7 for the unstabilized control. Pre-drying of the polymer pellets at 80 °C for 4 h in a desiccant dryer is mandatory when ambient relative humidity exceeds 60%, because residual moisture catalyses hydrolytic ring-opening of the benzothiazole during extrusion above 230 °C, generating fragments detected by GC-O as a fishy odour in the final part. Suitability for incidental food contact is established under FDA 21 CFR §178.2010, provided migration into food simulants does not exceed 0.5 mg/kg when tested in 10% ethanol at 40 °C for 10 days.

Vulcanization accelerator systems for natural rubber and SBR compounds have historically relied on 2-mercaptobenzothiazole (MBT) as the workhorse intermediate, yet the more reactive brominated analogue unlocks routes to S-substituted asymmetric disulfides and thiocarbamoyl derivatives that exhibit delayed action and improved scorch safety. On a production line equipped with a 2000 L glass-lined reactor, MBT (1.0 kmol) is suspended in chlorobenzene and treated with phosphorus tribromide (0.35 kmol) under azeotropic reflux at 132 °C. Evolution of HBr is scrubbed through a packed column with dilute caustic; the endpoint is verified by TLC (hexane/ethyl acetate 8:2). The solvent is distilled under reduced pressure and the residue is purified by vacuum distillation at 105–108 °C/3 mmHg, collecting 2-bromo-1,3-benzothiazole as a light-yellow low-melting solid. The compound is subsequently reacted with sodium cyclopentylthiolate (1.05 eq) in ethanol at 50 °C for 4 h to yield 2-(cyclopentylthio)benzothiazole, which upon oxidation with hydrogen peroxide in acetic acid forms the asymmetrical disulfide accelerator. In a typical silica-filled tread compound mixing protocol (Banbury BR1600, fill factor 0.75, rotor speed 50 rpm, dump temperature 150 °C), the accelerator is added at 1.2 phr along with sulfur (1.8 phr). Mooney viscosity (ML 1+4 at 100 °C) of the compound reaches 48 MU, with a scorch time t₅ of 12.4 min, determined per ASTM D1646-19. Rheometer curves (MDR, 160 °C, ISO 6502-3:2023) reveal a torque increase ΔS′ of 18.5 dN·m and a t₉₀ cure time of 4.8 min. Tensile sheets cured to t₉₀ exhibit 300% modulus of 14.2 MPa and elongation at break of 470% (ISO 37:2024, Type 2 dumbbell). Regulatory screening of the finished vulcanizate for N-nitrosamine precursors follows EN 12868:2017; the bromobenzothiazole-derived accelerator shows no detectable N-nitrosodiphenylamine formation, a key advantage over conventional sulfenamide systems. The intermediate must be certified free of 2,2′-dibenzothiazyl disulfide (MBTS) contamination below 0.5 wt% by HPLC, as MBTS residues act as premature cure activators.

Reactive Sites for Thiol-Selective Fluorescent Labeling of Cysteine Residues

Conjugation of benzothiazole fluorophores to biomolecules for live-cell imaging exploits the Br atom as a leaving group in nucleophilic aromatic substitution with aliphatic thiols under physiological pH. A water-soluble probe is prepared by reacting 2-bromo-1,3-benzothiazole with sodium 3-mercaptopropane-1-sulfonate (1.05 eq) in 0.1 M phosphate buffer (pH 8.0) containing 10 v/v% DMF at 37 °C for 2 h. Quantitative conversion is monitored by reverse-phase HPLC (retention time shift from 14.2 min to 9.7 min). After lyophilization, the crude product is desalted by size-exclusion chromatography (Sephadex G-10) and obtained as a white crystalline powder soluble at concentrations up to 50 mM in water. Single-site labeling of reduced bovine serum albumin (one free cysteine, Cys-34) with a 10-fold molar excess of the activated probe in degassed Tris buffer (pH 7.4) at ambient temperature for 1 h in the dark yields a stable thioether adduct. Excess reagent is removed by centrifugal filtration (3 kDa MWCO). Fluorescence excitation/emission maxima of the conjugate are centered at 365/440 nm, with a quantum yield of 0.62 relative to quinine sulfate standard in 0.1 M H₂SO₄. Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry confirms a mass increase of 195 Da per label, consistent with a single addition. The brominated precursor is screened under ICH M7(R2) for potentially mutagenic impurities; the Ames test (OECD 471) with strain TA98 and TA100 with and without S9 metabolic activation returns negative at concentrations up to 5000 µg/plate, provided the material is purified to a residual 2-aminobenzothiazole content below 0.15 area%. Shipping classification under IMDG Code assigns UN 3082, Class 9 for the solid, with a marine pollutant designation unless the bromine content, declared as organically bound halogen, falls below the reporting threshold of 0.1 wt% in the Safety Data Sheet Section 15.