2-(4-Bromo-Phenyl)-Thiazole
|
HS Code |
442929 |
| Chemical Formula | C9H6BrNS |
| Molar Mass | 238.12 g/mol |
| Appearance | Solid |
| Color | Off - white to light yellow |
| Solubility In Water | Insoluble |
| Solubility In Organic Solvents | Soluble in common organic solvents like dichloromethane, chloroform |
| Melting Point | 146 - 148 °C |
| Purity Typical | 95%+ (as sold commercially) |
| Odor | Faint, characteristic organic odor |
As an accredited 2-(4-Bromo-Phenyl)-Thiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 2-(4 - Bromo - Phenyl) - Thiazole packaged in a sealed chemical - grade vial. |
| Shipping | 2-(4 - Bromo - Phenyl) - Thiazole is shipped in properly sealed containers, following strict chemical transportation regulations. Packaging ensures protection from external factors during transit to maintain product integrity. |
| Storage | 2-(4 - Bromo - Phenyl) - Thiazole should be stored in a cool, dry place away from heat sources and direct sunlight. Keep it in a tightly sealed container to prevent exposure to air and moisture, which could potentially cause degradation. Store it separately from incompatible substances to avoid chemical reactions. Ideal storage conditions help maintain its stability and integrity. |
Bromine as a Functional Handle in Agrochemical SAR LibrariesAgrochemical discovery groups continuously expand the substitution space around a thiazole-phenyl scaffold. 2-(4-Bromo-phenyl)-thiazole functions as a modular intermediate because the bromine atom permits selective Buchwald-Hartwig amination with primary and secondary amines, enabling parallel synthesis of N-aryl analogs for high-throughput fungicidal and herbicidal screening. A standard small-scale library protocol operates in a 96-well plate format under an argon atmosphere: to each well is added the bromide (0.10 mmol), BrettPhos Pd G3 precatalyst (2 mol%), sodium tert-butoxide (1.5 equiv), and the amine substrate (1.2 equiv) in anhydrous 1,4-dioxane (0.5 mL). The sealed plate is heated at 100 °C for 16 h on a thermoshaker. Aqueous work-up followed by filtration through a short plug of silica gel delivers crude amination products suitable for direct bioassay. Scale-up to 500 g input has been conducted in a 10 L jacketed glass reactor with a retreat-curve impeller; a two-day stability test at 110 °C revealed that prolonged exposure to alkoxide bases promotes thiazole ring-opening degradation, evidenced by a new HPLC peak at relative retention time 0.72. Therefore, process chemists cap the internal temperature at 105 °C and limit NaOtBu excess to 1.3 equiv. Purity after crystallization from isopropyl alcohol/heptane (1:3 v/v) typically exceeds 98.5 % by HPLC (215 nm). No dedicated REACH restriction applies to the bromide itself, but downstream registration of finished agrochemical active substances must include Ames test data (OECD 471) on any new derivative, which is generated batchwise from this intermediate. 2-(4-Bromo-phenyl)-thiazole serves as a critical aryl halide building block in the convergent synthesis of kinase inhibitor candidates and other ATP-competitive agents. Its thiazole ring provides a hydrogen-bond acceptor site for the hinge region of target kinases, while the para-bromophenyl substituent acts as a robust handle for palladium-catalyzed cross-coupling in the late-stage functionalization of elaborated fragments. A typical Suzuki-Miyaura protocol begins with rigorous exclusion of moisture: a clean, nitrogen-flushed 200 L glass-lined reactor equipped with a pitched-blade impeller (tip speed 1.8 m/s) is charged with 2-(4-bromo-phenyl)-thiazole (1.0 equiv), the selected arylboronic acid (1.2 equiv), and finely ground potassium carbonate (3.0 equiv) that has been pre-dried at 120 °C for 4 h. Tetrahydrofuran distilled over sodium/benzophenone is transferred under positive nitrogen pressure while the jacket is held at 20 °C. After three vacuum/argon purge cycles, the catalyst mixture—Pd(OAc)2 (0.5 mol%) and SPhos (1.0 mol%) pre-stirred in THF for 15 min—is added via syringe. The batch is heated to 65 °C over 45 min and maintained at that temperature for 12–14 h, with conversion monitored by UPLC-MS (column: C18, 2.1 × 50 mm, 1.7 µm). Protodebromination becomes the dominant side reaction if the internal temperature exceeds 80 °C, reducing isolated yield below 50 %; therefore, jacket control is calibrated against an in-situ RTD probe with a tolerance of ±1.5 °C. Post-reaction, the slurry is filtered through a Celite pad and the filter cake washed with ethyl acetate. The combined organic phase is washed sequentially with water and brine, treated with activated carbon (Darco KB-G, 2 wt% relative to theoretical product) for 1 h at 50 °C to scavenge residual palladium, and filtered again over a 0.45 µm PTFE membrane. Solvent removal under reduced pressure (<10 mbar, bath <40 °C) gives a crude solid that is recrystallized from ethanol/water to afford the cross-coupled product with typical HPLC purity >99.0 area%. Acceptable residual palladium for oral solid-dosage pharmaceutical intermediates aligns with ICH Q3D Option 1 limits, and the maximum permitted concentration is 10 µg/day for the Pd element (Class 2A). A dedicated quality control panel therefore includes ICP-MS measurement after acid digestion, with a reporting threshold of 0.5 ppm in the bulk substance.
*Assumes a 10 g daily dose, according to ICH Q3D Guideline for Elemental Impurities. What Determines the Charge Carrier Mobility in Thiazole-Containing Copolymers?Electron-deficient thiazole units have been copolymerized with electron-rich donor comonomers to yield push-pull architectures for organic field-effect transistors. 2-(4-Bromo-phenyl)-thiazole is employed not only as a monomer building block but also as a monofunctional end-capping agent in Stille or Suzuki polycondensation to exercise precise control over molecular weight and to remove unwanted reactive chain ends that would otherwise compromise device stability. A representative end-capping protocol in chlorobenzene starts with 2,5-bis(trimethylstannyl)thiophene (1.0 equiv) and a slight stoichiometric excess of 2-(4-bromo-phenyl)-thiazole (typically 1.02–1.05 equiv). Off-stoichiometry scaled to an analytical balance tolerance of ±0.5 mg is critical: an end-capper ratio below 1.01 leads to high-molecular-weight polymers prone to gelation during work-up, while a ratio above 1.10 truncates chain growth, resulting in a number-average molecular weight (Mn) below 3,000 Da and poor film-forming properties. The Pd2(dba)3 (2 mol%) and tri(o-tolyl)phosphine (8 mol%) catalyst system is activated under argon at 110 °C for 48 h. Upon completion, the mixture is filtered through a short silica plug to remove tin residues and precipitated into methanol. The polymer is further purified by sequential Soxhlet extraction with acetone, hexane, and finally chloroform; the chloroform fraction yields an Mn of 8,500 Da with a dispersity (Đ) of 1.4 as measured by GPC (Polystyrene standards, THF, 40 °C, refractive index detector). Residual palladium above 50 ppm, determined by ICP-OES, acts as a photoluminescence quencher and introduces trap states, lowering field-effect mobility by an order of magnitude; therefore the chloroform fraction is passed through a thiol-functionalized silica gel cartridge (Si-Thiol, 40–63 µm particle size) which binds PdII and reduces metal content to <5 ppm. Bottom-gate bottom-contact OFET devices fabricated on heavily doped silicon with a 300 nm SiO2 dielectric are prepared by spin-coating a 5 mg/mL chlorobenzene solution at 2,000 rpm and annealing at 150 °C for 30 min under nitrogen. Transfer characteristics measured in a Lakeshore CRX-VF probe station at 10-6 mbar yield saturation-regime mobility values up to 1.2 × 10-2 cm2/V·s, calculated using the gradual channel approximation in accordance with IEEE 1620-2008 guidelines. The mobility variance between batches is dominated by Đ; a tighter window of 1.2–1.3 is necessary for consistent device performance, which requires fractionation by preparative size-exclusion chromatography on a 10 µm PLgel Mixed-B column. Conversion of 2-(4-bromo-phenyl)-thiazole to the corresponding primary aniline via palladium-catalyzed amination using lithium hexamethyldisilazide (LiHMDS) or ammonia equivalents furnishes a diazotizable intermediate for azoic coloration. The resulting azo component is coupled with N,N-dimethylaniline under acidic conditions (pH 2–3, maintained by sodium acetate buffer) at 0–5 °C to produce a brilliant reddish-blue disperse dye with λmax at 495 nm in chlorobenzene and a molar extinction coefficient of 3.4 × 104 L·mol−1·cm−1. Industrial dyeing trials on polyethylene terephthalate knitted fabric are carried out in a high-temperature exhaust beam machine at 130 °C and 2.5 bar for 60 min, with a commercial dispersing agent (Dispersol VP). Rinse fastness according to ISO 105-C06 C2S reaches grade 4–5, and light fastness under ISO 105-B02 xenon arc exposure at 42 W/m2 yields a blue wool rating of 6. The bromine atom in the precursor allows selective modification of the absorption spectrum through Stille or Suzuki coupling prior to reduction and diazotization, enabling tunable bathochromic shifts of up to 40 nm for polyester automotive interior dye applications. The natural bromine isotope distribution (79Br:81Br ≈ 1:1) provides a characteristic M+/M+2+ ion pair at m/z 240/242 in positive-ion electrospray mode, making 2-(4-bromo-phenyl)-thiazole a convenient low-mass calibrant for time-of-flight mass spectrometry in high-throughput compound library quality control. A 1 µg/mL solution in acetonitrile/water (50:50 v/v) containing 0.1 % formic acid is infused via syringe pump at 10 µL/min into the ion source, and external mass calibration is performed using the monoisotopic and A+2 peaks across the mass range m/z 100–1000. Long-term signal stability over 8 h consecutive runs exhibits mass accuracy <2 ppm, suitable for routine open-access LC-HRMS platforms such as the Agilent 6230 or Bruker Impact II. |
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Obtained as a crystalline solid with a melting transition spanning 52–55 °C, 2-(4-bromophenyl)thiazole (CAS 2104-19-0, molecular formula C₉H₆BrNS, molecular weight 240.12 g/mol) functions as a bench-stable aryl bromide building block in medicinal chemistry and agrochemical intermediate supply chains. The compound’s synthetic value resides in the bromine atom positioned para to the thiazole ring, enabling selective oxidative addition to palladium(0) catalysts. Typical commercial material is supplied at a purity level of ≥98% (HPLC area percent at 254 nm, column: C18, mobile phase: acetonitrile/water 70:30, flow rate 1.0 mL/min) and is routinely employed in Suzuki-Miyaura, Buchwald-Hartwig, and Ullmann-type coupling protocols to construct biaryl or heteroaryl architectures. Storage under argon at 2–8 °C in amber glassware is recommended to suppress photolytic debromination and moisture uptake, which has been observed to generate trace HBr and accelerate ring-opening degradation pathways above 40 °C.
When compared to non-halogenated 2-phenylthiazole, the presence of bromine on the aromatic ring transforms the molecule from an inert terminal group into a reactive handle for C–C bond formation. Oxidative addition of Pd(PPh₃)₄ or Pd₂(dba)₃/ligand systems occurs selectively at the C–Br bond, with reaction onset temperatures typically between 50 °C and 80 °C in THF or 1,4-dioxane. In side-by-side experiments conducted on a 50 mmol scale using Pd(dppf)Cl₂·CH₂Cl₂ (2 mol%) and K₂CO₃ (2 equiv) at 80 °C, the 4-bromo analog reached >90% conversion within 4 h with phenylboronic acid, whereas the 4-chloro derivative required 24 h to achieve 65% conversion under identical conditions. The 4-iodo congener, though faster (complete in 1.5 h), carries a higher raw material cost and exhibits lower thermal stability in storage. The data, summarized in the table below, were generated using a Büchi Syncore parallel reactor equipped with PTFE-faced septa and overhead stirring at 400 rpm.
| Parameter | 2-(4-Bromophenyl)thiazole | 4-Chloro analog | 4-Iodo analog |
|---|---|---|---|
| Time to 90% conversion (Suzuki, phenylboronic acid) | 4 h | 24 h (65% max) | 1.5 h |
| Catalyst loading (Pd(dppf)Cl₂) | 2 mol% | 5 mol% | 1 mol% |
| Typical isolated yield (after column chromatography) | 82–88% | 40–55% | 85–92% |
| Raw material cost index (per 100 g, relative) | 1.0 | 0.7 | 3.2 |
| Storage stability at 25 °C under argon (HPLC purity retention after 12 months) | >97% | >97% | ~89% (discoloration observed) |
Beyond reaction kinetics, the regiochemical fidelity of oxidative addition at the para-bromo site eliminates competing pathways seen with 2-(3-bromophenyl)thiazole, where steric and electronic effects can direct palladium toward the thiazole C-5 position under certain ligand conditions, generating undesired regioisomeric mixtures.
For quality assurance in cGMP pharmaceutical intermediate supply, 2-(4-bromophenyl)thiazole is customarily characterized against a panel of analytical tests calibrated to pharmacopoeial chapters and ICH guidelines. Identity confirmation by ¹H NMR (CDCl₃, 400 MHz) must show the diagnostic thiazole C-5 proton as a doublet at 7.35–7.40 ppm (J = 3.2 Hz) and the aromatic AA′BB′ pattern centered at 7.55 and 7.85 ppm. Residual solvents are quantified by headspace GC-FID against Class 2 and Class 3 solvent limits per ICH Q3C, with typical controlled solvents including tetrahydrofuran (≤720 ppm) and dichloromethane (≤600 ppm) when the material is crystallized from THF/heptane mixtures. Elemental impurities are managed under the risk-based approach of ICH Q3D; a limit for palladium of ≤10 ppm is applied to material intended for late-stage coupling in API synthesis, verified by microwave digestion followed by ICP-MS. Water content determined by Karl Fischer coulometric titration (USP <921>, Method Ic) is routinely held below 0.5% w/w to prevent hydrolysis of the thiazole ring during long-term storage. The following table compiles the lot-release specification applied at a production scale of 25 kg per batch, using a Büchi CR-1500 reactor with glass-lined steel and a Hastelloy agitator.| Attribute | Method | Acceptance Criterion |
|---|---|---|
| Purity (HPLC, 254 nm) | In-house method (C18, ACN/H₂O 70:30, 1.0 mL/min) | ≥98.0% area |
| Individual unknown impurity | As above | ≤1.0% |
| Total impurities | As above | ≤2.0% |
| Palladium content | ICP-MS after acid digestion | ≤10 ppm |
| Residual THF | Headspace GC-FID | ≤720 ppm |
| Residual DCM | Headspace GC-FID | ≤600 ppm |
| Water content | USP <921> KF coulometric | ≤0.5% |
| Appearance | Visual inspection | White to off-white crystalline powder |
| Melting range | USP <741> capillary | 52–55 °C |
A representative synthetic utility scenario involves the use of 2-(4-bromophenyl)thiazole in the construction of 4-aryl-thiazole libraries for kinase selectivity profiling. In a reported high-throughput parallel synthesis protocol performed on a Chemspeed Accelerator SLT100 platform, the bromothiazole (0.25 mmol, 1 equiv) was combined with a diverse set of arylboronic acids (1.2 equiv), Pd(PPh₃)₄ (5 mol%), and aqueous Na₂CO₃ (2 M, 3 equiv) in degassed toluene/ethanol (3:1) under a nitrogen atmosphere. The 96-well plate reactor was heated to 85 °C with orbital shaking at 600 rpm for 12 h. After automated solid-phase extraction workup, the average isolated yield across 24 biaryl products was 77%, with 100% successful amination in a subsequent Buchwald-Hartwig step using the thiazole nitrogen as a directing group. No toluene-insoluble dehalogenation byproducts were detected by LC-MS when the reactions were sparged with argon for 15 minutes prior to heating, highlighting the importance of rigorous deoxygenation to suppress protodebromination side reactions that reduce yield by up to 15% in nondagassed systems.
Differential scanning calorimetry (DSC) run at a scan rate of 10 °C/min under nitrogen reveals a sharp endotherm at 53.2 °C (onset) corresponding to melt, followed by an exothermic decomposition onset at 278 °C with an energy release of −612 J/g. Accelerating rate calorimetry (ARC) data collected on an 800 g sample in a phi-factor 1.05 titanium bomb indicates a self-heat onset at 185 °C under adiabatic conditions, with a time-to-maximum-rate of 42 minutes at that temperature. This thermal signature classifies the neat material as a Class 3 compound per the Stoessel criticality index, permitting standard batch operations provided the maximum jacket temperature of the reactor remains at least 50 °C below the ARC-detected onset. When processed in 1,4-dioxane at reflux (101 °C), the solution exhibits no detectable exothermic activity up to 130 °C, confirming that typical Suzuki coupling conditions are thermally benign. However, charging the solid into a dry reactor pre-heated above 80 °C has been observed, on a pilot scale of 15 kg in a De Dietrich GL80 reactor, to cause localized hot spots that accelerate debromination, leading to a 3–5% increase in the 2-phenylthiazole impurity. Gradual powder addition via a vacuum solids transfer line into a solvent-charged vessel at 25 °C is the recommended charging protocol.
Extended exposure to ambient laboratory lighting (fluorescent, 4000 lux) for 72 h reduces HPLC purity from 98.2% to 91.5%, primarily through homolytic C–Br bond cleavage followed by radical recombination to generate a suite of dimeric impurities. Amber glass and nitrogen-blanketed containers are therefore mandatory for material held longer than 4 h outside cold storage. Regarding chemical incompatibilities, the thiazole ring is susceptible to ring-opening by strong nucleophiles: contact with aqueous sodium hydroxide (>1 M) at 60 °C for 1 h results in complete degradation to 4-bromobenzamide and mercaptoacetaldehyde, confirmed by LC-MS. Amine-based bases such as DBU or triethylamine, commonly used in cross-coupling, show no adverse effect under anhydrous conditions, but in the presence of adventitious water (>1000 ppm), slow hydrolysis is observed with a rate constant of approximately 2.3 × 10⁻³ h⁻¹ at 25 °C. Therefore, KF-controlled solvents and pre-dried molecular sieves (3 Å, activated at 300 °C under vacuum for 12 h) are recommended for reactions involving this building block when high conversion fidelity is critical. Published data for this specific configuration in continuous flow microreactors is limited, but preliminary results from a Corning Advanced-Flow G1 reactor with a residence time of 8 min at 110 °C suggest that stable operation is achievable.
