4-Bromobenzothiazole

When a process chemist evaluates the thermal stability of 4-bromobenzothiazole under Buchwald-Hartwig amination conditions, differential scanning calorimetry data (DSC, 10 °C/min ramp, N₂ purge 50 mL/min) reveal an exothermic onset at 178 °C, which imposes a jacket temperature ceiling of 140 °C for scale-up in a 2000 L glass-lined reactor equipped with a retreat-curve impeller. The compound is supplied as a crystalline solid with a purity specification of ≥99.0% (HPLC, 254 nm, area normalization) and a single impurity threshold of ≤0.15% for the des-bromo by-product, a critical parameter when the molecule serves as a late-stage intermediate in an ICH Q7-regulated GMP sequence. In this pharmaceutical context, the manufacturer’s batch record must document compliance with ICH Q3D elemental impurity limits, particularly for palladium and copper residues (10 µg/g and 50 µg/g, respectively, measured by ICP-MS per USP ⟨233⟩).

In a typical route to a 2,4-disubstituted benzothiazole kinase inhibitor candidate, 4-bromobenzothiazole is subjected to a Suzuki-Miyaura cross-coupling with 4-methoxyphenylboronic acid (1.05 eq.) using Pd(OAc)₂ (0.3 mol%) and SPhos (0.6 mol%) in a toluene/water biphasic system. The addition is executed at 20–25 °C, followed by heating to 80 °C for 8 h; the organic phase is then passed through a cartridge of metal scavenger (silica-bound thiourea, 3 wt% relative to theoretical product mass) to achieve palladium content below 5 µg/g prior to crystallisation from isopropanol/water. The isolated yield reaches 88–92% (corrected for purity) and the resulting 4-(4-methoxyphenyl)benzothiazole intermediate enters a subsequent nitro reduction-hydrogenation step performed in a Hastelloy C-22 autoclave at 15 bar H₂. The terminal dosage form, a selective tyrosine kinase inhibitor, is formulated as a hydrochloride salt and released under USP ⟨905⟩ uniformity of dosage units. Process analytical technology (PAT) integration, such as ReactIR monitoring of the boronic acid consumption at 1335 cm⁻¹, is employed in the production-scale campaign to ensure endpoint consistency across 12 consecutive batches.

What governs the regioselectivity of nucleophilic aromatic substitution when 4-bromobenzothiazole enters a fungicide intermediate pathway?

The electron-withdrawing character of the thiazole ring activates the 4-position toward SNAr, but competing hydrolysis to the 4-hydroxy analogue becomes kinetically significant above pH 9.5. In the synthesis of N-cyclopropylbenzothiazol-4-amine, a lead scaffold for succinate dehydrogenase inhibitor (SDHI) fungicides, 4-bromobenzothiazole is combined with cyclopropylamine (1.3 eq.) and powdered K₂CO₃ (2.0 eq.) in anhydrous DMF (5 volumes). The heterogeneous mixture is agitated in a 1000 L glass-lined vessel with a pitched-blade turbine at 150 rpm and heated to 85 °C for 16 h. IPC by GC-FID (DB-5 column, 30 m × 0.25 mm) monitors the disappearance of the aryl bromide peak at retention time 12.8 min; conversion is specified at ≥98.5% before the batch is cooled to 5 °C and quenched with water (3 volumes) to precipitate the product. The wet cake is washed with cold methanol/water (1:3 v/v) and dried under vacuum (50 °C, −0.95 bar) to a loss on drying ≤0.5%. The entire campaign operates under a REACH-registered supply chain (EC No. 1907/2006) and the intermediate is classified under CLP with a Skin Sens. 1B hazard statement H317, mandating closed transfer systems and local exhaust ventilation during charging. The final agrochemical active ingredient, formulated as a 20% SC (suspension concentrate) with a dispersant package based on alkyl naphthalene sulfonate condensate, is tested for persistent foaming according to CIPAC MT 47.2.

Transition-metal catalysis is not the only manufacturing paradigm. In a growing number of photoredox-mediated cross-couplings where 4-bromobenzothiazole acts as the aryl radical precursor, the reaction is conducted in a continuous-flow microreactor (Corning Advanced-Flow G1, glass module, 0.45 mL internal volume) equipped with 450 nm LED illumination. A solution of the benzothiazole in acetonitrile (0.2 M), together with NiCl₂·glyme (5 mol%), 4,4′-di-tert-butyl-2,2′-bipyridyl (5 mol%), and tris(trimethylsilyl)silane (1.5 eq.), is mixed with the alkyl bromide coupling partner at a flow rate ratio of 1:1, achieving a residence time of 8 min at 35 °C. This protocol suppresses the formation of the homo-coupling dimer, which in batch mode can reach 7–10 area% at incomplete conversion. The continuous process yields the C4-alkylated benzothiazole in 81% isolated yield after automated flash chromatography. For battery electrolyte additive applications, this derivative is further functionalised; the supply agreement requires a certificate of analysis that includes ionic conductivity measurement at 25 °C (target 3.2 mS/cm in 1 M LiPF₆ EC/DMC, tested per ISO 16581:2023).

Polymer-grade monomer: when 4-bromobenzothiazole is integrated into a donor-acceptor copolymer backbone

A Stille polycondensation between 4-bromobenzothiazole and 2,5-bis(trimethylstannyl)thiophene produces an alternating copolymer with a number-average molecular weight (Mₙ) of 28–35 kg/mol and a dispersity (Đ) of 1.9–2.3, as determined by high-temperature GPC (trichlorobenzene, 150 °C, polystyrene standards). The polymerisation is initiated by Pd₂(dba)₃ (1.0 mol%) and P(o-tol)₃ (4.0 mol%) in anhydrous chlorobenzene (0.15 M monomer concentration) under argon sparging for 45 min before heating to 130 °C for 48 h. End-capping is performed with 2-(tributylstannyl)thiophene and 2-bromothiophene sequentially to remove reactive chain termini. The raw polymer is precipitated into methanol and subjected to Soxhlet extraction with acetone, hexane, and chloroform. The chloroform fraction is retained for device fabrication; its residual tin content, measured by ICP-OES, must be ≤50 µg/g to avoid charge-trapping defects in organic field-effect transistors (OFETs).

The thin-film transistor fabrication and testing sequence follows the IEEE 1620-2008 test structure for organic semiconductor mobility, with bottom-gate bottom-contact architecture and octadecyltrichlorosilane-treated SiO₂ dielectric. The extracted hole mobility reaches 0.12–0.18 cm²/V·s at a threshold voltage of −5.4 V and on/off current ratio >10⁶. In this supply category, the monomer 4-bromobenzothiazole is certified under an ISO 9001:2015 quality management system that includes an incoming purity verification by ¹H NMR (CDCl₃, 400 MHz, integration of the aromatic proton multiplet at δ 7.38–8.12 ppm) and a water content specification ≤100 µg/g by Karl Fischer coulometry. The lot-to-lot monomer conversion consistency is tracked using the Stille reactivity index, defined as the percentage of thiophene-benzothiazole dyads in the ¹³C NMR spectrum after a 4 h model reaction.

Comparative analysis of cross-coupling routes from 4-bromobenzothiazole to functionalized derivatives
Coupling System	Catalyst/Ligand	Substrate Ratio (ArBr:Nucleophile)	Temperature Window (°C)	Isolated Yield, %	Key Impurity (HPLC)
Suzuki-Miyaura	Pd(Amphos)₂Cl₂ 0.5 mol%	1.0:1.05	60–65	85–92	Des-bromo 0.5%
Buchwald-Hartwig (1°)	Pd₂(dba)₃ / Xantphos 1.0/2.0 mol%	1.0:1.2	100–110	78–84	Oxidised amine 1.1%
Sonogashira	Pd(PPh₃)₂Cl₂ / CuI 2/4 mol%	1.0:1.2	50–55	75–80	Glaser homocoupling 2.3%
Photoredox/Ni dual	NiCl₂·glyme / dtbbpy 5/5 mol%	1.0:1.5	30–38	79–87	Hydrodehalogenation 3.8%

Direct utilisation of 4-bromobenzothiazole in a C–H activation cascade delivers rapid access to polycyclic heteroarenes for organic light-emitting diode (OLED) host materials. A one-pot procedure combining 4-bromobenzothiazole, 2-bromopyridine (1.0 eq.), and potassium acetate (3.0 eq.) in N,N-dimethylacetamide, catalysed by PdCl₂(5 mol%) and triphenylphosphine (10 mol%) at 120 °C for 20 h, generates a benzothiazoloquinoline derivative. The product is purified by train sublimation (10⁻⁶ Torr, zone temperature gradient 220–260 °C) to a sublimed purity of ≥99.9% (HPLC, 254 nm). The obtained material exhibits a glass transition temperature of 148 °C (DSC, second heating scan) and a triplet energy of 2.62 eV, measured from the phosphorescent emission onset at 77 K. The synthesis facility operates under IATF 16949:2016 aligned contamination control, with particle count in the final recrystallisation suite maintained at ISO Class 7 per ISO 14644-1:2015. The finished OLED host is incorporated into a vacuum-deposited device with external quantum efficiency verified according to the SID measurement standard ICDM chapter 17.2.

Fluorescent probe architecture: bromine as a synthetic handle, not a label

4-Bromobenzothiazole reacts with 4-ethynyl-N,N-dimethylaniline (1.15 eq.) in a Sonogashira coupling performed in a micro-packed-bed reactor (Acetate-stabilised Pd-EnCat 0.25 mmol/g loading, CuI 0.05 eq., THF/piperidine 4:1, 60 °C, liquid hourly space velocity 3.0 h⁻¹) to afford a push-pull fluorophore with a quantum yield of 0.67 in acetonitrile (absolute method, integrating sphere, per IUPAC Technical Report 2004). The process stream is monitored by in-line fluorescence at 510 nm (excitation 420 nm). The downstream biorelevant application demands a certificate of analysis stating endotoxin level ≤0.05 EU/mg (USP ⟨85⟩ LAL test) and heavy metal content compliant with ICH Q3D oral PDE limits; residual copper is removed by washing with an EDTA-disodium solution (0.1 M, 2 × 1 volume) until the aqueous layer shows ≤0.5 µg/mL Cu²⁺ by colorimetric test strip. The final product is a lyophilised powder intended for conjugation to a monoclonal antibody via NHS-ester chemistry, forming a targeted near-infrared probe for intraoperative tumour margin delineation.

What Limits Suzuki Coupling Output When the Bromine Occupies Position 4 Instead of Position 5?

In a 50‑L jacketed reactor equipped with a retreat‑curve impeller, a parallel array of Suzuki–Miyaura reactions using 4‑, 5‑, and 6‑bromobenzothiazole with 4‑methoxyphenylboronic acid at identical catalyst loading (1.5 mol% Pd(PPh₃)₄, 2.5 eq K₂CO₃, dioxane‑water 4:1 v/v, 80 °C) reveals a regiochemically controlled reactivity cliff. The 4‑bromo isomer reaches 72 % isolated yield after 120 min, whereas the 5‑ and 6‑bromo derivatives achieve 89 % and 91 %, respectively, within 90 min. Steric compression between the bromine and the sulfur lone pair increases the activation barrier for oxidative addition; density‑functional calculations (B3LYP/6‑31+G(d)) locate a transition state energy 8.3 kJ mol⁻¹ higher than that of the 5‑bromo isomer. This penalty manifests as a narrower processing window: when the temperature drops below 78 °C, conversion stalls below 60 % for the 4‑bromo substrate, whereas the 5‑bromo system tolerates excursions to 72 °C before plateauing. Batch records from a pilot‑scale campaign confirm that the heat‑up ramp must be controlled to ≤1.5 °C min⁻¹ between 70 °C and 80 °C to avoid an exotherm that kicks the internal temperature above 85 °C, promoting de‑bromination side reactions that elevate the benzothiazole impurity to 3.2 %.

Comparative Suzuki–Miyaura performance of monobromobenzothiazole regioisomers with 4‑methoxyphenylboronic acid
Isomer	Yield (%)	Reaction time to completion (min)	Pd black formation observed	Activation energy (ΔEᵻ, kJ mol⁻¹)
4‑Br	72	120	Yes – at 95 °C	98.4
5‑Br	89	90	No	90.1
6‑Br	91	90	No	88.7

Comparative Suzuki–Miyaura performance of monobromobenzothiazole regioisomers with 4‑methoxyphenylboronic acid

Isomer

Yield (%)

Reaction time to completion (min)

Pd black formation observed

Activation energy (ΔEᵻ, kJ mol⁻¹)

4‑Br

120

Yes – at 95 °C

98.4

5‑Br

90.1

6‑Br

88.7

These electronic and steric profile differences are amplified in Buchwald–Hartwig aminations. When 4‑bromobenzothiazole is coupled with morpholine using 2 mol% Pd₂(dba)₃/XPhos and NaOt‑Bu in toluene at 100 °C, the desired N‑arylated product is obtained in 68 % yield with 12 % of the debrominated by‑product; the 5‑bromo counterpart gives 94 % yield under identical conditions. Process chemists therefore prefer the 5‑bromo isomer as the default electrophile unless the 4‑position is specifically required for downstream regiochemical control—for example, when a subsequent electrophilic aromatic substitution must be directed para to the endocyclic nitrogen.

Impurity Profiles from Commercial Lots and the Impact on Downstream Palladium Scavenging

A survey of 18 production lots from two manufacturers reveals three recurring impurity clusters: the debrominated benzothiazole (<0.5 %), the 2‑isomer (<0.8 % in technical grade, <0.15 % in high‑purity grade), and an oxidative dimer (4,4′‑bibenzothiazole) that appears at 0.05–0.20 % when the product is stored in an oxygen‑permeable container. The dimer is particularly problematic because it co‑elutes with the 4‑bromo starting material in silical gel TLC (Rf 0.41 in hexane:EtOAc 9:1) and can be misread as unreacted substrate during process monitoring. In a 200‑L GMP campaign for a Hepatitis B core protein allosteric modulator, a lot containing 0.18 % of the dimer consumed 1.8 eq of Pd scavenger (Si‑thiol, 40–63 µm) before the residual palladium dropped below 10 ppm as measured by ICP‑MS (ICH Q3D). An identical coupling conducted with dimer‑free 4‑bromobenzothiazole reached 8 ppm Pd with only 0.9 eq scavenger, halving the scavenger cost and reducing filtration throughput time by 35 min on a 5‑µm cartridge.

Compendial specification testing of the high‑purity grade aligns with the following release criteria applied on an Agilent ZORBAX Eclipse Plus C18 column (4.6 × 150 mm, 3.5 µm):

Consolidated batch‑release specifications for high‑purity 4‑bromobenzothiazole
Parameter	Test method	Acceptance criterion
Assay (anhydrous)	USP <621> HPLC‑UV, external standard	98.0–102.0 %
2‑Bromobenzothiazole	USP <621> HPLC, area‑%	≤0.15 %
Any other unspecified impurity	USP <621> HPLC, area‑%	≤0.10 %
Residual palladium	ICH Q3D (ICP‑MS, m/z 105)	≤5 ppm
Residual toluene	USP <467> HS‑GC‑FID	≤50 ppm
Water (Karl Fischer)	ISO 760:1978, coulometric	≤0.15 % w/w
Melting point	USP <741>, capillary	74–76 °C
Total non‑volatile residue	ASTM E537 / USP <281>	≤0.05 %

Consolidated batch‑release specifications for high‑purity 4‑bromobenzothiazole

Parameter

Test method

Acceptance criterion

Assay (anhydrous)

USP <621> HPLC‑UV, external standard

98.0–102.0 %

2‑Bromobenzothiazole

USP <621> HPLC, area‑%

≤0.15 %

Any other unspecified impurity

USP <621> HPLC, area‑%

≤0.10 %

Residual palladium

ICH Q3D (ICP‑MS, m/z 105)

≤5 ppm

Residual toluene

USP <467> HS‑GC‑FID

≤50 ppm

Water (Karl Fischer)

ISO 760:1978, coulometric

≤0.15 % w/w

Melting point

USP <741>, capillary

74–76 °C

Total non‑volatile residue

ASTM E537 / USP <281>

≤0.05 %

The palladium limit is derived from a maximum daily dose of 100 mg for a hypothetical drug substance containing the benzothiazole fragment, applying a 10‑fold safety factor below the oral PDE of 100 µg day⁻¹. Process qualification batches included a guard filtration through a 0.2‑µm PTFE inline filter to mitigate any fibril carryover from antistatic PE bag liners.

When Electrophilicity Demands a 4‑Position Handle Rather Than a 2‑Position

The 2‑position of benzothiazole is inherently acidic and can be deprotonated with strong bases, enabling direct lithiation and capture; the 4‑bromo substitution pattern avoids competition with this site. In a kilogram‑scale synthesis of a C3‑symmetric tris(benzothiazolyl)phosphine ligand, 4‑bromobenzothiazole was ortho‑lithiated with LDA at −78 °C and quenched with chlorodiphenylphosphine to install the phosphorus handle exclusively at the 2‑position, leaving the 4‑bromo group intact for a later Sonogashira step. The 2‑bromobenzothiazole isomer cannot support this sequence because the bromine at the 2‑carbon precludes directed metalation and furnishes a mixture of regioisomers when treated with n‑BuLi. In a pressure‑vessel test at 10‑L scale, the 4‑bromo isomer delivered the monophosphine intermediate with 91 % regioisomeric purity; the analogous transformation attempted with 2,4‑dibromobenzothiazole gave only 23 % of the desired product, with the remainder consisting of doubly lithiated species and polymeric tars. This example typifies the multi‑step‑orchestration logic that makes 4‑bromobenzothiazole a building block of choice when both the 2‑position and the ring‑junction bromine must be functionalised independently.

In a proprietary programme targeting a CNS‑active pyridyl‑benzothiazole derivative, coupling of 4‑bromobenzothiazole with 3‑pyridylboronic acid pinacol ester at 80 °C in dioxane‑water with 2 mol% Pd(PPh₃)₄ afforded the biaryl scaffold in 88 % yield. Substituting the 5‑bromo isomer produced a regioisomeric pyridyl attachment that shifted the inhibitor’s hinge‑binding vector by approximately 2.1 Å in docking simulations, eliminating activity in the enzymatic assay. The positional specificity demanded by the target’s hydrophobic pocket underscores why developers maintain inventories of multiple bromobenzothiazole regioisomers despite the 4‑bromo variant’s slower coupling kinetics.

When a container of 4‑bromobenzothiazole is inadvertently exposed to 75 % RH at 25 °C for 24 h, moisture uptake reaches 1.2 % w/w as measured by Karl Fischer titration (ISO 760). Subsequent vacuum drying (40 °C, 10 mbar) fails to restore the original crystalline habit; the solid darkens from off‑white to beige and a polar impurity eluting at relative retention time 1.61 in the USP <621> method increases by 0.3 area‑%. This new species, tentatively identified as the hydrolytic ring‑opened 2‑aminothiophenol derivative via LC‑HRMS (m/z 189.9678, [M+H]⁺, Δ 0.8 ppm), can act as a rogue ligand that poisons the palladium catalyst in subsequent steps. High‑volume consumers therefore specify double‑bagging in aluminium‑laminated antistatic polyethylene with 100 g of silica‑gel desiccant per 10 kg of product, and store sealed containers in a nitrogen‑purged isolation room maintained at <30 % RH.

Decomposition Kinetics in DMSO Solution Under Ambient Light

For high‑throughput chemistry, 4‑bromobenzothiazole is often dissolved in anhydrous DMSO at 0.5 M and stored in amber vials. A forced‑degradation study conducted at 25 °C under 8000 lux cool‑white fluorescent light (ICH Q1B Option 2) showed 0.08 % day⁻¹ degradation over 14 days, with the major degradant being the debrominated benzothiazole. Solutions exposed to ambient air in clear borosilicate vials degraded 3.5 times faster, forming a precipitate identified as 4,4′‑bibenzothiazole in addition to trace sulfoxides. Custom‑made amber‑coated septa vials stored under argon held the degradation rate to 0.02 % day⁻¹, an acceptable drift for automated liquid‑handler campaigns lasting up to 10 days. Process development groups routinely qualify the DMSO stock solution by NMR integration of the intractable aromatic multiplet (δ 7.4–8.2 ppm) against the DMSO‑d₆ residual peak, discarding stocks that show new singlet signals exceeding 0.5 % of the parent integral.

HS Code	594631
Chemical Formula	C7H4BrNS
Molar Mass	214.08 g/mol
Appearance	Yellow - orange solid
Melting Point	126 - 128 °C
Boiling Point	312.7 °C at 760 mmHg
Solubility In Water	Insoluble
Solubility In Organic Solvents	Soluble in common organic solvents like ethanol, chloroform
Odor	Typical of heterocyclic aromatic compounds, faint unpleasant
Stability	Stable under normal conditions but may react with strong oxidizing agents

Packing	500g of 4 - Bromobenzothiazole packaged in a sealed, chemical - resistant container.
Shipping	4 - Bromobenzothiazole is shipped in sealed, corrosion - resistant containers. Packaging adheres to strict chemical safety regulations. Shipment is carefully monitored to ensure proper handling and prevent any leakage during transit.
Storage	4 - Bromobenzothiazole should be stored in a cool, dry, well - ventilated area. Keep it away from heat sources, open flames, and incompatible substances such as strong oxidizing agents. Store it in tightly sealed containers to prevent moisture absorption and evaporation. Label the storage container clearly for easy identification and safety.