4-Bromothiazole
Pyrrolidine Pyrrole Thiazole Imidazole Thiophene Pyrazine Piperidine Piperazine Morpholine Phenazine

4-Bromothiazole


    • Product Name 4-Bromothiazole
    • Alias 4-Bromothiazol
    • Einecs 221-921-5
    • Mininmum Order 1g
    • Factory Site West Ujimqin Banner, Xilingol League, Inner Mongolia, China
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    • Manufacturer Bouling Chemical Co., Limited
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    Specifications

    HS Code

    779462
    Chemical Formula C3H2BrNS
    Molecular Weight 162.02 g/mol
    Appearance Solid
    Melting Point 36 - 40 °C
    Boiling Point 208 - 209 °C
    Density 1.904 g/cm³
    Solubility In Water Insoluble
    Solubility In Organic Solvents Soluble in common organic solvents like ethanol, chloroform
    Flash Point 80.2 °C
    Pungent Odor Yes

    As an accredited 4-Bromothiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.

    Packing & Storage
    Packing 500g of 4 - Bromothiazole packaged in a sealed, chemical - resistant bottle.
    Shipping 4 - Bromothiazole is shipped in sealed, corrosion - resistant containers. Adequate cushioning is used to prevent breakage. Shipments follow strict chemical transportation regulations to ensure safety during transit.
    Storage 4 - Bromothiazole should be stored in a cool, dry, well - ventilated area. Keep it away from heat sources, open flames, and oxidizing agents. Store in a tightly - sealed container to prevent leakage and exposure to air and moisture, which could potentially lead to chemical reactions and degradation. Label the storage container clearly for easy identification.
    Application of 4-Bromothiazole
    In multi-step syntheses targeting non-nucleoside reverse transcriptase inhibitors for antiretroviral therapy, 4-bromothiazole serves as an electrophilic component in palladium-mediated cross-coupling sequences. The heteroaryl bromide is typically reacted with a boronic acid partner—most commonly 2,4-difluorophenylboronic acid or a functionalised pyrimidine-5-boronate—under Suzuki–Miyaura conditions within a GMP-compliant glass-lined reactor equipped with a retreat-curve impeller. A representative charge places 4-bromothiazole (1.0 eq), the selected boronic acid (1.2 eq), tetrakis(triphenylphosphine)palladium(0) (0.5 mol% relative to bromothiazole), and anhydrous potassium carbonate (2.0 eq) in a degassed ternary solvent mixture of toluene, ethanol, and deionised water (3:1:1 v/v/v). The system is heated to 80 °C under a nitrogen sweep for 16 h, after which in-process HPLC analysis confirms consumption of the limiting bromide. Post-reaction, the organic phase is separated, treated with activated carbon (Darco KB-G, 5 wt% relative to theoretical product) at 55 °C for 2 h to scavenge residual palladium, and filtered through a 0.2 µm polypropylene depth filter. The filtrate is concentrated under reduced pressure and the crude coupled product is crystallised from n-heptane/ethyl acetate (4:1 v/v) to afford the 2-arylthiazole intermediate with a purity exceeding 99.5 area% by HPLC and individual palladium content below 10 ppm as determined by ICP-MS, conforming to the metal residue limits of ICH Q3D for oral drug substances. This intermediate is subsequently elaborated through bromine–lithium exchange or a second cross-coupling to install a C4 substituent, ultimately delivering an advanced building block for candidate molecules comparable to diarylpyrimidine-class NNRTIs. Regulatory documentation for the intermediate must include residual solvent profiling according to ICH Q3C for Class 2 solvents, full batch release data per 21 CFR 211.165, and a validated related-substances method capable of resolving the 2-aryl positional isomer to ≤0.10%.

    What Process Controls Are Required When 4-Bromothiazole Is Deployed in Direct C–H Arylation for Late-Stage Diversification of Kinase Inhibitor Scaffolds?

    In medicinal chemistry libraries targeting gatekeeper mutants of tyrosine kinases, 4-bromothiazole is increasingly used not as a prefunctionalised cross-coupling partner but as a substrate for palladium-catalysed C–H arylation at the electron-deficient C5 position, enabling convergent access to 2,5-diarylthiazole pharmacophores. The transformation merges 4-bromothiazole (1.0 eq) with an aryl iodide (1.5 eq) in the presence of palladium(II) acetate (5 mol%), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos, 10 mol%), pivalic acid (30 mol%) as a proton-shuttle mediator, and potassium carbonate (1.5 eq) in N,N-dimethylacetamide (0.3 M relative to bromide). Oxidative insertion into the C5–H bond exhibits a narrow processing window; the reaction requires thorough oxygen removal via three freeze–pump–thaw cycles and a strictly maintained internal temperature of 110 ± 3 °C because temperatures above 115 °C accelerate homocoupling of the bromothiazole and lead to an intractable dimer that co-crystallises with the product, reducing the isolated yield from an attainable 78–85% to below 45%. The mixture is agitated for 18 h under argon in a jacketed borosilicate reactor fitted with a condenser cooled to −5 °C to minimise evaporative loss of DMAc. Upon completion, the cooled mass is diluted with ethyl acetate and washed with 1 N aqueous HCl to protonate pivalate residues, then with saturated brine. The organic layer is dried over sodium sulfate and concentrated; the residue is purified by automated flash chromatography on spherical silica (40–63 µm, gradient from 5% to 25% ethyl acetate in hexanes). A representative batch protocol generates 5-(4-methylphenyl)-4-bromothiazole as the major regioisomer with a C5:C2 arylation ratio exceeding 20:1 confirmed by 1H NMR. Palladium stripping with SiliaMetS Thiol resin (0.5 equiv relative to Pd) reduces residual metal below 15 ppm, in line with ICH Q3D Option 1 limits for parenteral products. The final isolated solid is milled with a jet mill to d₉₀ < 15 µm for downstream phosphorylation or sulfonamide coupling. No teratogenicity data for this specific intermediate have been published; accordingly, a default Category 2 occupational exposure limit of 10 µg/m³ is applied for scale-up campaigns.

    Direct Arylation Polymerization Monomer Purity Thresholds in OPV Acceptor-Donor Architectures

    For the synthesis of low-bandgap π-conjugated copolymers employed as donor materials in bulk heterojunction organic photovoltaic cells, 4-bromothiazole is copolymerised with electron-rich comonomers such as 4,4′-bis(2-ethylhexyl)-5,5′-bis(trimethylstannyl)-2,2′-bithiophene or 2,7-bis(trimethylstannyl)-9,9-dioctylfluorene using direct arylation polymerization (DArP) in place of conventional Stille couplings, thereby eliminating stoichiometric organotin waste. The monomer quality specification is unusually stringent: the 4-bromothiazole must exhibit a single-crystal habit with ≥99.95% purity by GC-FID and, crucially, a total metal impurity burden below 50 ppb for Fe, Ni, and Cu combined, as quantified by ICP-MS after microwave-assisted nitric acid digestion. Trace metallic contamination functions as a chain-termination vector during DArP, causing a shoulder in the high-molecular-weight fraction of the GPC trace and a drop in number-average molecular weight (Mₙ) from a target of 35–50 kDa to <10 kDa, which renders the polymer film brittle and unsuitable for slot-die coating. The polymerization is conducted in a nitrogen-filled glovebox with O₂ and H₂O levels maintained at <0.1 ppm: 4-bromothiazole (1.0 eq), 2,7-bis(trimethylstannyl)-9,9-dioctylfluorene (1.0 eq), tris(dibenzylideneacetone)dipalladium(0) (2 mol%), and tris(2-methoxyphenyl)phosphine (8 mol%) are dissolved in anhydrous toluene (0.4 M of bromide) and stirred at 100 °C for 48 h. The crude polymer is end-capped with 2-bromothiophene (10 mol%) for an additional 6 h to seal reactive chain ends. Purification entails double precipitation from chloroform into methanol, Soxhlet extraction sequentially with acetone, hexane, and chloroform, and a final treatment with aqueous sodium diethyldithiocarbamate solution (0.1 M) at 50 °C for 12 h to scavenge residual palladium catalyst, which otherwise acts as a charge-trap in the active layer. The purified copolymer shows a high-frequency capacitance-simulated hole mobility of 1.2 × 10⁻³ cm² V⁻¹ s⁻¹ as measured by the space-charge-limited current technique in a diode configuration (ITO/PEDOT:PSS/polymer/Au). Process validation under ISO 14644 Class 5 cleanroom conditions is mandatory because airborne particulates generate micro-pinholes when the chlorobenzene-based ink is doctor-bladed onto flexible PET substrates.

    Synthesising 2-Isobutylthiazole via Grignard Route Demands Strict Anhydrous Control.

    The food-flavour ingredient 2-isobutylthiazole, which possesses a green tomato-leaf odour character with a threshold of 3.5–5.0 ppb in water, is produced by nucleophilic addition of freshly prepared 4-thiazolylmagnesium bromide to isobutyraldehyde, followed by hydrolytic work-up and fractional distillation. Preparation of the Grignard reagent is the rate-limiting step that dictates overall yield, because 4-bromothiazole is prone to ring-opening under prolonged contact with unreacted magnesium surfaces if the initiation temperature exceeds 30 °C. Magnesium turnings (1.05 eq, 99.8% trace metal basis) are charged into a flame-dried three-necked flask equipped with a pressure-equalising addition funnel and a glycol-chilled reflux condenser set to −10 °C. A single crystal of iodine (~5 mg) is added to etch the oxide layer, and anhydrous THF (15 mL per gram of Mg) is transferred via cannula. A thermometer probe is immersed directly into the metal suspension. 4-Bromothiazole (1.0 eq) dissolved in an equal volume of THF is added dropwise at such a rate that the internal temperature remains below 25 °C; a colour change from amber to deep brown signals initiation. Once the exotherm subsides, the mixture is stirred for an additional 1 h at 20 °C to ensure complete metal conversion, verified by a negative Gilman colour test on an aliquot. After cooling to −5 °C, isobutyraldehyde (1.1 eq) in THF is added over 30 min, followed by agitation at 0–5 °C for 2 h. The reaction is quenched with saturated ammonium chloride and the THF is removed under vacuum. The aqueous residue is extracted with diethyl ether, dried, and concentrated to give the crude carbinol intermediate. Without isolation, the material is subjected to reductive dehydration by heating with zinc dust (2.5 eq) in glacial acetic acid at 50 °C for 4 h. The final product is obtained by vacuum distillation through a 15 cm Vigreux column, collecting the fraction boiling at 103–105 °C at 25 mmHg. The colourless oil exhibits a refractive index n₂₀D of 1.4930–1.4950. For use in compounding natural-identical flavour formulations subject to EU Regulation 1334/2008, the batch must additionally pass a sulphated ash test (<0.05%), and the residual 4-bromothiazole content may not exceed 20 ppm because even trace halogenated starting material imparts an off-note described as “medical.” Stability testing under 21 CFR 172.515 requires storage in amber glass under nitrogen at 2–8 °C, as exposure to ambient light for more than 72 h promotes photo-oxidative degradation to a yellow dimer with a paraffin-like aftertaste.

    Corrosion Inhibition Efficiency of 3-Alkyl-4-bromothiazolium Salts in 15% HCl at 60°C

    Quaternisation of 4-bromothiazole with long-chain n-alkyl bromides yields surface-active 3-alkyl-4-bromothiazolium bromide salts that function as mixed-type corrosion inhibitors for N80 carbon steel in oilfield acidizing environments. The synthetic route is straightforward but requires rigorous stoichiometric control to avoid dialkylation at the nitrogen. In a typical batch, 4-bromothiazole (1.0 eq) and 1-bromododecane (1.05 eq) are dissolved in anhydrous acetonitrile (1.0 M of thiazole) and refluxed under nitrogen for 48 h. The quaternary salt precipitates upon cooling to −20 °C and is isolated by filtration, washed with cold diethyl ether, and dried under vacuum at 40 °C to a constant weight; yield is typically 88–92% with a bromide ion content of 31.2–31.8 wt% by argentometric titration. The inhibition performance is evaluated gravimetrically following ASTM G31-21 on sandblasted N80 coupons (25 × 10 × 3 mm) exposed to 500 mL of deaerated 15 wt% HCl at 60 ± 1 °C for 6 h, and the corrosion rate is cross-validated by linear polarisation resistance using a three-electrode cell with an Ag/AgCl reference.
    Inhibitor Concentration (ppm)Corrosion Rate (mm/y)Inhibition Efficiency (%)Surface Coverage (θ)
    0 (blank)82.4––
    5028.964.90.649
    10012.784.60.846
    2005.393.60.936
    5001.897.80.978
    At 200 ppm and above, the inhibitor achieves a coverage approaching unity, consistent with Langmuir isotherm modelling (R² > 0.999). Electrochemical impedance spectra recorded at the open-circuit potential show a single capacitive loop whose diameter scales linearly with concentration, indicating that the molecule adsorbs on the steel surface through both the thiazolium cation and the bromine substituent, the latter providing supplementary Fe–Br interaction at austenite grain boundaries. A critical operational limitation is that the quaternary salt begins to degrade via Hofmann elimination when the bulk fluid temperature exceeds 85 °C, releasing volatile amine fragments that pressurise the headspace and cause erratic inhibitor feed. This degradation pathway restricts field deployment to wells with a bottomhole static temperature below 80 °C. Compatibility with mutual solvents such as ethylene glycol monobutyl ether is required for water-wet wellbore conditions; a phase-behaviour test in which 200 ppm inhibitor is co-formulated with 10 vol% mutual solvent must show no haze or precipitation after 24 h at 25 °C, per NACE TM0374-2016.

    Coupling to Diazonium Intermediates Yields Disperse Dyes for Polyester

    4-Bromothiazole is converted into heterocyclic disperse azo dyes through an initial transformation to 2-amino-4-bromothiazole, a precursor that is diazotised and subsequently coupled to electron-rich aromatic amines. The halogen substituent at the 4-position of the thiazole ring exerts a bathochromic shift of approximately 18–22 nm relative to the unsubstituted analogue because of increased intramolecular charge transfer, an effect that is exploited in deep-red and violet shades for polyethylene terephthalate fibres. In a stainless-steel diazotisation vessel with jacket cooling, 2-amino-4-bromothiazole (1.0 eq) is suspended in a mixture of 85% orthophosphoric acid (4.0 eq) and glacial acetic acid (5 volumes), then cooled to 0–3 °C. A pre-chilled solution of sodium nitrite (1.02 eq) in the minimum amount of water is added below the liquid surface through a dip pipe over 45 min, and the resulting diazonium phosphate suspension is stirred for an additional 2 h while maintaining the temperature below 5 °C; the absence of excess free nitrous acid is confirmed with starch–iodide paper. In a separate vessel, the coupling component—typically N,N-diethylaniline (1.0 eq)—is dissolved in methanol (3 volumes) with sufficient acetic acid to adjust the pH to 4.0–4.5. The diazonium suspension is slowly transferred into the coupler solution under vigorous agitation, and the pH is held at 4.0 by automatic dosing of 10% sodium acetate solution. Coupling is allowed to continue at 8–10 °C for 4 h, after which the precipitated dye is filtered, washed to conductivity below 50 µS/cm, and oven-dried at 60 °C under reduced pressure. The final disperse dye is standardised to a strength of 200% relative to a reference by grinding in a bead mill with dispersing agent Reax 85A (1:1 dye-to-dispersant ratio) until the particle size measured by laser diffraction yields a d₉₀ < 2 µm. High-temperature exhaust dyeing of polyester fabric at 130 °C for 60 min at a liquor ratio of 1:10 results in a wash fastness rating of 4–5 and a light fastness of 6–7 when tested according to ISO 105-C06:2010 and ISO 105-B02:2014, respectively. Because azo reduction can release 2,4-diaminothiazole fragments, the dyed article must comply with the limit values for aromatic amines set out in Annex XVII of REACH (Entry 43); this requires quantification of any free amine below 30 mg/kg via LC-MS/MS analysis of a perspiration-simulating extract.
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    More Introduction

    4-Bromothiazole (CAS 34264-51-8) is a monobrominated thiazole heterocycle employed as an electrophilic building block in pharmaceutical, agrochemical, and materials synthesis. With a molecular formula of C₃H₂BrNS and a molecular weight of 164.02 g·mol⁻¹, the compound exists as a pale yellow to amber liquid at ambient temperature. Its identity is confirmed via ¹H NMR (δ 8.76, d, J=2.0 Hz, H-2; δ 7.51, d, J=2.0 Hz, H-5 in CDCl₃) and GC-MS (m/z 163/165, M⁺). The bromine substituent at the 4-position imparts a distinct reactivity profile compared to the 2- and 5-bromo isomers, influencing both the electronic landscape of the thiazole ring and the steric accessibility of the C–Br bond in transition-metal-catalyzed cross-coupling transformations. Commercial availability spans multiple purity grades—typically 97% and 98% (GC)—with the product packaged under inert atmosphere to preserve reactivity. The regiochemical placement of bromine is not a trivial structural nuance; it directly governs the regioselectivity of subsequent carbon–carbon and carbon–heteroatom bond-forming events, making 4-bromothiazole a strategic intermediate for constructing 2,4-disubstituted thiazole motifs that are inaccessible via the more common 2-bromo isomer.

    Comparison of monobromothiazole isomer specifications (typical commercial data)
    Property4-Bromothiazole2-Bromothiazole5-Bromothiazole
    CAS number34264-51-83034-22-814527-41-4
    AppearancePale yellow to amber liquidColorless to pale yellow liquidPale yellow oil
    Purity (GC, area%)≥97.0% (typical 98.5%)≥98.0%≥95.0%
    Boiling point (°C at 760 mmHg)180–185171–173175–178 (dec.)
    Density (g·mL⁻¹ at 25 °C)1.72–1.741.82–1.841.76–1.78
    Refractive index (n²⁰D)1.588–1.5921.591–1.5931.582–1.586
    Flash point (°C, closed cup)76–8063–6770–74
    Moisture (Karl Fischer)≤0.05% (CoA typical)≤0.1%≤0.2%
    Storage temperature (°C)2–8, protected from light2–82–8

    Why Does the Bromine Position Dictate Reactivity in Palladium-Catalyzed Cross-Couplings?

    The oxidative addition step of Pd(0) into the C–Br bond is sensitive to the electron density at the carbon bearing the halogen. In thiazole, the LUMO coefficients at C-2, C-4, and C-5 differ markedly due to the push-pull interplay of ring sulfur and nitrogen. C-2, flanked by the electronegative imine nitrogen and sulfur, exhibits a higher partial positive character, facilitating nucleophilic attack by ligated Pd(0) species. Consequently, 2-bromothiazole displays faster consumption in Suzuki-Miyaura, Buchwald-Hartwig, and Sonogashira protocols. 4-Bromothiazole, wherein the bromine is conjugated to the C=N unit but not vicinal to nitrogen, occupies an intermediate reactivity tier. The 5-bromo isomer, electronically insulated from the nitrogen and experiencing steric shielding from the adjacent sulfur, is the least reactive. This gradient is systematically exploited for chemoselective iterative couplings. In a representative one-pot differentiation, 2,4-dibromothiazole undergoes selective Suzuki coupling at the 2-position with arylboronic acids using Pd(PPh₃)₄ and mild heating (50 °C), while the 4-bromo handle remains intact for a subsequent coupling at elevated temperature (90 °C) with a more active catalyst system such as Pd-XPhos-G3 and K₃PO₄ in dioxane/water. Results from competition experiments approximate the relative oxidative addition rate constants as k₂-Br ≈ 5.2, k₄-Br ≡ 1.0, and k₅-Br ≈ 0.12 (Pd(PPh₃)₂, THF, 60 °C). These values align with DFT-computed C–Br bond dissociation energies and π-accepting orbital coefficients at the B3LYP/6-311+G(d,p) level. Process chemists scaling reactions beyond 100 mmol report adiabatic temperature rises of 15–20 °C upon initiation of 4-bromothiazole Suzuki couplings in aqueous dioxane with Na₂CO₃, mandating jacketed borosilicate reactors with PID-controlled cooling loops to keep the reaction within ±3 °C of the setpoint and avoid protodebromination spurts. If the internal temperature overshoots 85 °C, dehalogenation byproducts exceeding 8% (HPLC) have been documented, eroding product purity below 90%.

    Commercial 4-bromothiazole is typically supplied in amber borosilicate bottles crimp-sealed under argon or nitrogen headspace. Upon receipt, the material should be transferred to cold storage at 2–8 °C in a desiccated, ventilated area. Extended storage at ambient laboratory temperature promotes gradual darkening and accumulation of thiazole (debrominated impurity) and dimeric species detectable by GC-FID at levels exceeding 0.3% after 6 months. Each production batch should be subjected to Karl Fischer coulometric analysis (per Ph. Eur. 2.5.32); water content surpassing 0.05% must be reduced by standing over freshly activated 4Å molecular sieves (activation at 300 °C under vacuum for 12 h) prior to moisture-sensitive cross-coupling. On manufacturing scale, crude 4-bromothiazole obtained via Sandmeyer reaction of 4-aminothiazole hydrochloride is rectified by fractional distillation over a 30 cm glass helix-packed Vigreux column at 20 mmHg, with a head temperature of 68–72 °C yielding acceptable heart cuts of 99% GC purity. Trace metal analysis by ICP-MS is critical: residual copper (from Sandmeyer quenching) at levels above 15 ppm can catalyze Glaser-Hay-type homocoupling of terminal acetylenes if 4-bromothiazole is subsequently employed in Sonogashira applications. Certificates of analysis routinely specify Cu < 5 ppm, Fe < 10 ppm, and Pd < 1 ppm. Some suppliers offer certified reference materials under ISO 17034 accreditation for use in method validation of QC release testing.

    Pharmacophore Incorporation via C-4 Functionalization

    The 4-substituted thiazole ring is a validated pharmacophore in ATP-competitive kinase inhibitors targeting B-Raf V600E, PI3Kδ, and Aurora A kinases. The 4-bromo intermediate enables late-stage diversification through sp²–sp² Suzuki couplings to install biaryl systems that sit deep within the hydrophobic back pocket of the enzyme, while the 2-position often remains unsubstituted or carries a solubility-enhancing group. A direct 2-bromothiazole surrogate places the aryl appendage in a solvent-front region, frequently compromising the ligand-lipophilicity efficiency index and yielding promiscuous binding profiles. In a published series of thiazole-based VEGFR-2 inhibitors, the 4-(3-chloro-4-fluorophenyl)thiazole core assembled from 4-bromothiazole via Pd(dppf)Cl₂-catalyzed coupling exhibited an IC₅₀ of 12 nM (enzyme assay, HTRF format), while the constitutional isomer derived from 2-bromothiazole showed a 52-fold loss in potency. The ability to maintain rigorously anhydrous and oxygen-free conditions during the coupling step is crucial; presence of dissolved oxygen accelerates Pd nanoparticle aggregation, and trace water promotes protodebromination to thiazole, a volatile side product that can co-elute with product in reversed-phase HPLC and artificially inflate crude yield estimates. The anion of 4-bromothiazole generated by lithium-halogen exchange using n-BuLi at -78 °C in THF exhibits moderate configurational stability for 20–30 min before undergoing ring-opening via sulfide elimination; trapping with electrophiles such as DMF or trimethyl borate must be executed within this window to achieve > 75% yield of the 4-formyl or 4-boronic acid pinacol ester derivatives.

    When 4-Bromothiazole Outperforms Its 2-Substituted Counterpart in Agrochemical Intermediates

    In the synthesis of thiazolyl amide fungicides containing the 4-aminothiazole substructure, copper-catalyzed amination of 4-bromothiazole with aliphatic secondary amines proceeds cleanly to deliver the target intermediate. The 2-bromothiazole isomer under identical conditions (CuI, L-proline, K₂CO₃, DMSO, 90 °C) generates 5–12% of the ring-opened thiourea side product resulting from nucleophilic attack at the C-2 position, which is activated by the adjacent nitrogen. This side product is difficult to purge by crystallization and must be removed by column chromatography, adding cost. The table below reports isolated yields and purities for three model cross-coupling reactions comparing the three monobromothiazole regioisomers. All reactions were run on a 5 mmol scale under optimized literature conditions; yields refer to products after flash chromatography.

    Isolated yields (HPLC purity ≥98% by area) for model transformations of monobromothiazoles
    ReactionConditions4-Bromothiazole (%)2-Bromothiazole (%)5-Bromothiazole (%)
    Suzuki-Miyaura with 4-MeOC₆H₄B(OH)₂Pd(dppf)Cl₂ (2 mol%), K₃PO₄, THF/H₂O (4:1), 70 °C, 12 h889241
    Buchwald-Hartwig amination with anilinePd₂(dba)₃ (1 mol%), Xantphos (2.2 mol%), NaOtBu, toluene, 100 °C, 16 h7481 (3% debrominated impurity)33
    Copper-catalyzed amination with morpholineCuI (10 mol%), L-proline (20 mol%), K₂CO₃, DMSO, 90 °C, 24 h857652
    Sonogashira coupling with phenylacetylenePd(PPh₃)₂Cl₂ (2 mol%), CuI (4 mol%), Et₃N, THF, rt, 18 h799058

    The 4-bromo isomer’s performance profile reveals that while 2-bromothiazole often delivers superior conversion in palladium-catalyzed sp²-sp coupling, the 4-regioisomer consistently outperforms at the copper-catalyzed carbon–heteroatom bond formation step relevant to agrochemical lead optimization. The diminished reactivity at C-5 restricts its utility to specialized tri-substituted thiazole targets where the other two positions are pre-functionalized. Process development groups note that scaling the copper-amine coupling of 4-bromothiazole beyond 500 mmol benefits from slow addition of the bromide over 2 h to prevent catalyst deactivation by accumulated halide ion, which otherwise depresses yield to 65–70%. Distillation of the crude amination product at 0.5 mmHg then provides the free base in 97% purity suitable for formulation synthesis without chromatographic purification.

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