2-Amino-5-Bromothiazole
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HS Code |
658289 |
| Chemical Formula | C3H3BrN2S |
| Molar Mass | 193.04 g/mol |
| Appearance | Solid (usually a powder) |
| Melting Point | 167 - 171 °C |
| Solubility In Water | Poorly soluble |
| Solubility In Organic Solvents | Soluble in some polar organic solvents like DMSO |
| Pka | Related to the basicity of the amino group, around 10 - 11 (estimated for the amino group in this context) |
| Density | No commonly reported standard value |
| Color | Off - white to light yellow |
| Odor | Typically has a faint, characteristic odor |
As an accredited 2-Amino-5-Bromothiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 2 - Amino - 5 - Bromothiazole packaged in a sealed, labeled container. |
| Shipping | 2 - Amino - 5 - Bromothiazole is shipped in well - sealed containers, compliant with chemical transport regulations. It's carefully packaged to prevent spillage and ensure safety during transit, typically via specialized freight services for hazardous chemicals. |
| Storage | 2 - Amino - 5 - Bromothiazole should be stored in a cool, dry, well - ventilated area. Keep it away from heat sources, flames, and oxidizing agents. Store in a tightly closed container to prevent moisture absorption and contamination. Separate it from incompatible substances. Ideal storage temperature is typically around 2 - 8°C for long - term stability. |
Palladium-Catalyzed C–Br Activation in Pharmaceutical Backbone AssemblyThe 5-bromo substituent enables site-selective palladium-mediated cross-coupling, transforming the thiazole ring into a biaryl pharmacophore found in ATP-competitive kinase inhibitors disclosed under generic structural claims in the patent literature. Coupling with (hetero)arylboronic acids proceeds through oxidative addition of Pd0 to the C–Br bond, transmetallation, and reductive elimination. Published yields for analogous 5-bromothiazole Suzuki–Miyaura reactions range from 70% to 92% when using Pd(PPh3)4 at 2 mol% loading in a deoxygenated dioxane–water mixture (4:1 v/v) with 2.0 equiv of K2CO3 at 80°C. Catalyst turnover degrades rapidly if dissolved oxygen exceeds 5 ppm; sparging with argon for 30 min prior to metal addition is standard. The presence of the free 2-amino group does not require protection when using Buchwald-type dialkylbiarylphosphine ligands such as XPhos or SPhos, which suppress catalyst deactivation by amine–palladium coordination. However, residual moisture in the substrate must be reduced to ≤0.05% (Karl Fischer) by vacuum drying at 40°C for 8 h, because water promotes protodebromination side-product formation that can reach 8–12% area-by-HPLC otherwise.Process-temperature control is critical: sustained internal temperatures above 120°C induce thermal ring-opening of the thiazole to generate thioamide fragments that poison the palladium catalyst and shift color of the reaction mass to dark brown. Jacketed glass-lined reactors with ±1°C cascade control loops and a nitrogen blanket at 50 mbar overpressure are employed to maintain the 80–85°C window. Downstream work-up includes treatment with activated carbon (2 wt% relative to crude) at 60°C to adsorb colloidal palladium, filtration through a 0.45 µm polypropylene depth-filter, and recrystallization from toluene–n-heptane (1:3 v/v) to achieve an HPLC purity exceeding 99.5 area%. Residual palladium content is routinely confirmed by ICP-OES to stay below the ICH Q3D parenteral limit of 10 µg/g; typical batches measure 3–7 µg/g. The 5-aryl thiazole products serve as intermediates for VEGFR-2 and EGFR inhibitors where the biaryl torsion angle, modulated by the substitution pattern at the inserted aryl ring, affects IC50 values. Scale-up hazard evaluations performed on a Mettler Toledo RC1e reaction calorimeter show that the coupling is mildly exothermic (ΔH ≈ −110 kJ/mol of product) with an adiabatic temperature rise of 18°C for a 1.0 M concentration, manageable with standard jacket cooling.
When Bromine Acts as a Handle for Azo Chromophore ConjugationUnder strongly acidic diazotization conditions (pH <1, HCl concentration 6 N, temperature 0–5°C), the 5‑bromo group undergoes nucleophilic aromatic substitution with activated nitrosyl derivatives derived from substituted anilines, producing heterocyclic azo dyes that absorb in the 450–550 nm range. The azo coupling is performed on generator‑dispersed diazonium salt adding to a buffered solution of 2‑amino‑5‑bromothiazole hydrochloride in water‑methanol (2:1 v/v); the weak alkaline medium (pH 8–9) ensured by sodium acetate aids the attack of the thiazole carbon at the position para to the bromine substituent. The resulting monoazo dye is isolated by salting‑out with sodium chloride (15% w/v), dried in a vacuum oven at 60°C, and ground to a particle size distribution with a D50 of 2–5 µm for high‑temperature exhaust dyeing of polyester at 130°C (AATCC Test Method 61-2013 2A). Molar extinction coefficients measured in dimethylformamide at the λmax typically fall between 28 000 and 34 000 L mol−1 cm−1. The free amino group at the 2‑position can be converted to an N,N‑diethyl substituent by reaction with diethyl sulfate in the presence of sodium carbonate in water at 90°C, shifting the λmax bathochromically by 12–18 nm and increasing the wash fastness rating under ISO 105‑C06 to grade 4–5. Photostability assessed by ISO 105‑B02 (xenon arc, blue wool scale) for the N,N‑dialkyl derivatives reaches grade 6 after 100 h exposure when a hindered amine light stabilizer (0.3% o.w.f.) is co‑applied in the dye bath. Production‑scale coupling vessels are fitted with a pH probe loop and automated HCl dosing; any deviation above pH 1.5 during diazotization causes nitrosamine‑forming side reactions that generate N‑nitroso‑2‑amino‑5‑bromothiazole, a compound whose presence requires monitoring under the German TRGS 552 and is capped at ≤1 ppm in the final dye powder using HPLC‑MS/MS detection.Mercapto-Functionalized Thiazoles from 2-Amino-5-bromothiazole via Thiol SubstitutionSubstitution of the bromine atom with sodium sulfhydrate (NaSH) in aqueous‑alkaline medium at 70–75°C yields 2‑amino‑5‑mercaptothiazole, which is oxidized in situ with hydrogen peroxide (30% solution, 0.55 equiv) to the corresponding disulfide dimer. This dimer belongs to the class of delayed‑action sulfenamide accelerators used in sulfur‑vulcanized natural rubber and styrene‑butadiene rubber compounds. Vulcanization kinetics studied with a moving‑die rheometer (MDR) according to ASTM D5289‑19a at 160°C for a compound containing 1.2 phr of the disulfide accelerator together with 2.5 phr sulfur and 5 phr zinc oxide show a minimum torque of 2.1 dNm and a maximum torque of 14.8 dNm, with t10 scorch time of 2.4 min and t90 optimum cure time of 5.8 min. The narrow processing safety window arises from the accelerator’s low activation energy for decomposition, reported at 87 kJ/mol from DSC non‑isothermal analysis, meaning that premature crosslinking occurs if the compound temperature exceeds 110°C during two‑roll mill mixing. Therefore, a cooling water system maintaining roll surface temperature at 40°C is essential. Batch‑to‑batch variability in mercaptan content influences scorch safety: the thiol intermediate must be monitored by iodometric titration, and residual NaSH must be quenched with dilute acetic acid to pH 6.5 before oxidation to avoid over‑oxidized polysulfide species that increase network‑bound sulfur and reduce elongation at break below 450% (ASTM D412‑16). Off‑gas hydrogen sulfide released during the substitution step is scrubbed through a 10% sodium hydroxide column before venting; environmental compliance requires outlet H2S concentration below 5 ppmv per regional air quality permits.Self‑assembly of 2‑amino‑5‑bromothiazole with copper(I) iodide in acetonitrile under solvothermal conditions (120°C, 3 days) produces a three‑dimensional metal‑organic framework with [Cu4I4] cubane‑type clusters and bridging thiazole ligands. Single‑crystal X‑ray diffraction collected on a Bruker D8 Venture diffractometer (Mo Kα, λ = 0.71073 Å) at 100 K reveals the compound crystallizes in the triclinic space group P ̅1 with unit cell parameters a = 10.354(2) Å, b = 12.167(3) Å, c = 14.783(4) Å, α = 78.52(1)°, β = 82.34(2)°, γ = 71.05(1)°, and a final R1 value of 0.042. The framework exhibits strong orange‑red photoluminescence in the solid state upon irradiation at 365 nm, attributable to a halide‑to‑ligand charge transfer transition mixed with d10‑metal cluster‑centered states, with an internal quantum yield measured by an integrating‑sphere method of 31% at room temperature. The presence of reactive ‑NH2 groups on the pore surface allows postsynthetic modification; for instance, condensation with terephthalaldehyde followed by reduction yields amine‑appended walls that raise CO2 uptake at 1 bar and 298 K from 1.8 mmol/g to 2.9 mmol/g as determined by volumetric sorption analysis (ASAP 2020). The ligand is purified by sublimation at 90°C under 0.01 mbar to achieve metal‑ion content below 10 ppm, a prerequisite for reproducible crystallization because residual bromide salts template a competing dense coordination polymer. Published data for this specific derivative is limited to laboratory‑scale studies; therefore, scale‑up to > 50 g batches has not yet been reported, and long‑term moisture stability of the luminescence was observed to decline by 15% after 30 days at 80% RH, indicating encapsulation requirements.What Limits Nitration Selectivity When Derivatizing the Thiazole Ring?Controlled mixed‑acid nitration of 2‑amino‑5‑bromothiazole is performed after protecting the amino group as the acetamide by refluxing with acetic anhydride in toluene (5 equiv, 110°C, 4 h). The acetyl derivative is then added at −5°C to a pre‑cooled mixture of 90% nitric acid (1.2 equiv) and 98% sulfuric acid (5 volumes). Under these conditions, the nitronium ion attacks the 4‑position of the thiazole ring, yielding 2‑acetamido‑4‑nitro‑5‑bromothiazole with a selectivity ratio of 4‑nitro : 5‑nitro of approximately 15:1 as measured by 1H NMR of the crude product. The reaction is extremely sensitive to temperature: a deviation of merely ±3°C from the setpoint reduces the selectivity to 8:1 and generates 3–5% of ring‑oxidized sulfoxide by‑products that demand chromatography for removal. Following quenching in ice‑water, the product is isolated by vacuum filtration and recrystallized from ethanol‑water (1:1) to a purity of 99%. Hydrolysis of the acetyl group with 6 N HCl at reflux liberates 2‑amino‑4‑nitro‑5‑bromothiazole, a high‑nitrogen heterocycle that finds use as an intermediate for insensitive munitions and gas‑generating agents. The thermal stability of the nitro compound, evaluated by differential scanning calorimetry at a heating rate of 5°C/min, shows a decomposition onset at 192°C with an exothermic enthalpy of −1 580 J/g, placing it within the moderate hazard category. Impact sensitivity tested on a BAM fallhammer per UN Manual of Tests and Criteria, Part 1, gives a limiting impact energy of 12 J, which is above the 5 J threshold for transport classification as a solid desensitized explosive. Process‑safety relief sizing assumes a vapor‑phase pressure rise of 1.2 bar/s during a worst‑case runaway, dictating a bursting disc diameter of 25 mm for a 10‑L reactor. Residual sulfuric acid traces in the dried product promote autocatalytic decomposition at storage temperatures above 40°C, mandating neutralization washing to a supernatant conductivity of ≤50 µS/cm and storage in HDPE containers under nitrogen.
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Catalogued under CAS 87988-93-2, 2-Amino-5-bromothiazole (C3H3BrN2S, molecular weight 178.03 g mol−1) constitutes a heteroaryl bromide building block routinely deployed in medicinal chemistry and crop protection research. The molecule presents a primary amine at the 2-position and a bromine atom at the 5-position of the thiazole ring, enabling stepwise functionalisation through halogen-selective cross-coupling while the exocyclic nitrogen remains available for subsequent acylation, sulfonylation, or reductive alkylation without deprotection sequences. Commercial supplies typically consist of an off-white to pale‑yellow crystalline powder exhibiting a melting endotherm in the interval 99–103 °C (DSC, heating rate 10 K min−1, nitrogen purge). The heterocycle is sparingly soluble in water (<1 mg mL−1 at 25 °C) and dissolves readily in tetrahydrofuran, ethyl acetate, dimethylformamide, and dichloromethane, solvent choices that dominate the reaction engineering space for palladium-mediated transformations.
Routine quality-control parameters are tightened around those analytical markers most strongly correlated with coupling efficiency. Retention-time purity by reversed‑phase HPLC (C18 column, acetonitrile/water gradient with 0.1% trifluoroacetic acid, UV detection at 254 nm) is reported as area‑% and acts as the primary release criterion. Trace moisture is quantified by Karl Fischer coulometric titration because water ingress above 0.3% w/w has been observed to extend the induction period of oxidative addition when Pd(PPh3)4 is the catalyst precursor, an effect attributed to hydrolysis of the phosphine ligand generating inactive palladium clusters. Residue on ignition and heavy-metal limits are verified by inductively coupled plasma optical emission spectrometry (ICP‑OES) after microwave digestion, ensuring the material does not introduce adventitious catalytic metals that would confound reaction‑rate analysis. The full panel is summarised below.
| Property | Specification | Test Method |
|---|---|---|
| Appearance | Off-white to pale‑yellow powder | Visual (compendial appearance) |
| Identification | 1H NMR matches structure; m/z 178/180 (1:1 Br isotope pattern) | Ph. Eur. 2.2.33 (NMR), ESI‑MS |
| Purity (HPLC) | ≥97.0% area | In‑house method (UV 254 nm, C18) |
| Melting range | 99–103 °C | DSC (onset) or capillary (Ph. Eur. 2.2.14) |
| Water content | ≤0.5% w/w | Karl Fischer coulometry (Ph. Eur. 2.5.12) |
| Residue on ignition | ≤0.1% | Ph. Eur. 2.4.16 |
| Heavy metals (as Pb) | ≤20 ppm | ICP‑OES (USP <233>) |
| Residual solvents | Meets ICH Q3C Option 2 limits | GC‑FID headspace (Ph. Eur. 2.4.24) |
When a rapid moisture‑insensitive protocol is required, the material is pre‑dried under vacuum (40 °C, 10 mbar, 4 h) immediately before use; this step has been shown to restore catalyst turnover frequencies within 5% of those recorded with freshly crystallised material in a model Suzuki coupling with 4‑cyanophenylboronic acid. Batch records from 50‑L glass‑lined reactors equipped with retreat‑blade impellers indicate that lot‑to‑lot variability in isolated yield of a representative 5‑(4‑methoxyphenyl) adduct remains within a ±3% band when the specification above is enforced.
The rate-determining oxidative addition step in Suzuki‑Miyaura and Buchwald‑Hartwig cycles is governed by the carbon–halogen bond dissociation energy. For 2‑Amino‑5‑bromothiazole, the C5–Br bond (∼70 kcal mol−1) is substantially weaker than the C5–Cl bond (∼84 kcal mol−1) in the 5‑chloro congener (CAS 89282-96-4). This energetic gap translates into tangible process advantages: coupling with phenylboronic acid can proceed at 50–65 °C using 0.5 mol% Pd(OAc)2/SPhos in tetrahydrofuran/water, whereas the chloro analog routinely demands temperatures above 80 °C and catalyst loadings 2–5× higher to achieve comparable conversion within the same process cycle. The bromide also tolerates phosphine‑free conditions with ligandless palladium on carbon in aqueous ethanol at reflux, a protocol that fails to activate the chloride below 100 °C.
A side‑by‑side comparison of the three common 5‑halothiazole building blocks illustrates the design space:
| 5‑Halogen Substituent | Typical coupling T (°C)a | Reaction time (h)a | Reported yield range (%) | Relative cost index |
|---|---|---|---|---|
| Bromine | 50–65 | 4–8 | 78–92 | Moderate |
| Chlorine | 80–100 | 12–24 | 60–85 | Low |
| Iodine | 25–40 | 2–4 | 85–95 | High |
a Model reaction: Suzuki coupling with phenylboronic acid (1.2 equiv.), Pd(OAc)2 (1 mol%), SPhos (2 mol%), K2CO3 (2 equiv.), THF/H2O (4:1), batch concentration 0.5 M.
The 5‑iodo derivative (CAS 775533-97-2) offers the lowest activation barrier, yet the cost per mole is typically 3–5× higher and the heavier atom can introduce radiodensity or metabolic‑stability concerns in lead optimisation. Consequently, the bromo analogue occupies the pragmatic centre: reactivity high enough to keep catalyst inventory and thermal stress low, yet commodity‑scale availability keeps kilogram‑lot pricing within discovery‑to‑candidate progression budgets.
In the construction of Type II kinase inhibitors, the 5‑bromothiazole motif has been exploited as a hinge‑binding bioisostere capable of undergoing late‑stage diversification. A representative sequence involves a regioselective Suzuki coupling at C5 to install an aryl or heteroaryl hydrophobic pocket anchor, followed by reductive amination or urea formation at the 2‑amino group to tailor hinge‑region hydrogen‑bonding contacts. Because the bromine atom is located para to the endocyclic sulfur, electronic deactivation is reduced relative to the 4‑position isomer, and the 5‑aryl‑thiazole products reliably exhibit < 5% homocoupling or debromination by‑products when the aqueous base concentration is maintained between 1.5 and 2.5 M. Published small‑scale procedures using XPhos Pd G2 pre‑catalyst in dioxane at 55 °C report full conversion in 6 h with isolated yields exceeding 85%, a performance that has been replicated on 500‑g scale in batch reactors with overhead stirring.
2‑Amino‑4‑bromothiazole (CAS 89282-97-5) relocates the halogen to the carbon adjacent to the ring nitrogen. This positional shift alters the electron density distribution: the C4 position is more electron‑deficient due to the adjacent sp²‑hybridised nitrogen, which facilitates nucleophilic aromatic substitution but retards oxidative addition with palladium(0) catalysts because the LUMO coefficient at C4 is lower than at C5 in the thiazole π‑system. Practitioners therefore observe that standard Suzuki conditions deliver lower turnover numbers, and competing protodebromination can erode mass balance unless carefully anhydrous conditions and a Pd‑NHC pre‑catalyst (such as PEPPSI‑IPr) are employed. The 5‑bromo isomer consistently outperforms the 4‑bromo isomer in cross‑coupling screens where the electrophile is coupled to electron‑neutral aryl boronic acids, and the narrower melting range of the 5‑bromo material (99–103 °C versus 77–82 °C for the 4‑bromo free base) reflects higher crystallinity that often translates into easier purification and lower static adherence during solid‑handling operations. For routes requiring functionalisation at two distinct electrophilic sites, the 2‑amino‑4,5‑dibromothiazole (CAS 89283-57-6) exists as a complementary scaffold, but its sequential differentiation demands careful control of the first coupling temperature to discriminate between the two C–Br bonds.
Stability‑indicating forced‑degradation studies have shown that 2‑Amino‑5‑bromothiazole remains >99% intact after 24 months at −20 °C in sealed, argon‑flushed amber glass containers. However, when the material is stored at 25 °C/60% RH with daily opening cycles, the primary degradation route is oxidation of the primary amine to a nitroso or nitro species, detectable by the appearance of a shoulder at longer retention time in the HPLC chromatogram. The degradation rate accelerates sharply above 30 °C, with the sublimate at the container headspace exhibiting yellow discolouration. Packaging in double‑lined, low‑density polyethylene bags within epoxy‑phenolic lacquer‑lined steel drums, coupled with a 10‑g silica‑gel desiccant sachet, has been adopted as the standard cargo configuration for intercontinental shipments. Receipt‑side quality control prescribes a retest after 12 months when the container has been opened more than five times in a non‑glovebox environment. The molecule is incompatible with strong oxidisers (fuming nitric acid, perchloric acid) and should not be blended with activated carbon or charcoal during work‑up, as adsorption‑mediated amine oxidation has been documented on high‑surface‑area carbon supports.
Pilot‑plant campaigns preparing multi‑kilogram quantities of 5‑(3‑pyridyl)thiazole intermediates have demonstrated that the catalyst loading for 2‑Amino‑5‑bromothiazole can be reduced to 0.05 mol% Pd when a biphasic toluene‑water (1:1 v/v) system containing tetrabutylammonium bromide (5 mol%) as phase‑transfer agent is employed at 80 °C. The amine functionality does not require protection in this medium, and the 3‑pyridylboronic acid pinacol ester is used directly. End‑of‑reaction filtration through a 0.5‑µm polypropylene bag filter followed by a 5‑wt% aqueous sodium bisulfite wash reduces residual palladium to <5 ppm in the isolated solid, a threshold critical for active pharmaceutical ingredient intermediates governed by the ICH Q3D elemental impurity guideline. Process analytical technology (PAT) probes tracking the disappearance of the 292‑nm absorbance band of the thiazole chromophore have enabled reaction‑end determination within ±10‑minute accuracy, eliminating the need for off‑line HPLC sampling in a cGMP annex. In contrast, the analogous 5‑chloro substrate under identical low‑catalyst conditions yields <10% conversion after 24 h, reinforcing the kinetic rationale for selecting the brominated building block when telescoped synthesis demands short cycle times.
