Ethyl 2-Bromothiazole-5-Carboxylate

Fungal Succinate Dehydrogenase Inhibition and the Thifluzamide Production Train

The ethyl 2-bromothiazole-5-carboxylate intermediate enters the commercial agricultural fungicide supply chain almost exclusively through its conversion into thifluzamide, a carboxanilide inhibitor of succinate dehydrogenase (SDH) in the fungal respiratory chain. Synthesis proceeds under current Good Laboratory Practice for non-labelled pilot-plant campaigns, and the final technical-grade active ingredient (TC) is registered under GB/T 29380‑2012, which specifies a minimum purity of 950 g/kg, moisture ≤ 0.5%, and acetone-insoluble matter ≤ 0.2%. In a representative 3000‑L glass-lined reactor train equipped with a Hastelloy C‑22 overhead condenser and a vapor‑phase scrubber battery for HBr off‑gas, the ester is first saponified with 4.0‑4.2 molar equivalents of an aqueous sodium hydroxide solution at 0.5‑0.8 MPa gauge and 85‑92 °C over a 6‑hour residence period monitored by in‑line FT‑IR for the carbonyl stretch at 1740 cm⁻¹ to confirm consumption of the ethyl ester. The resulting sodium 2‑bromothiazole‑5‑carboxylate brine is adjusted to pH 1.8‑2.2 with concentrated hydrochloric acid at ≤ 10 °C to precipitate the free carboxylic acid, which is centrifuged, washed with deionised water until the filtrate conductivity reads < 20 µS/cm, and dried in a conical vacuum dryer at 60 °C / 15 mbar to a residual water content of < 0.3 wt% by Karl Fischer titration.

The isolated 2‑bromothiazole‑5‑carboxylic acid is then slurried in toluene, treated with 1.05 equivalents of thionyl chloride, and brought to 78 °C in a loop‑reactor configuration that recycles the HCl/HBr‑laden off‑gas through a packed‑bed scrubber operating with 8% NaOH. The resulting acid chloride solution is crystal‑filtered through a 5‑µm sintered‑metal candle filter and fed continuously into a jacketed thin‑film mixer maintained at ‑5 °C to 0 °C, where it reacts with a pre‑cooled solution of 2,6‑dibromo‑4‑(trifluoromethoxy)aniline in methylene chloride containing 1.2 equivalents of triethylamine as acid scavenger. The mass feed ratio of the thionyl chloride‑activated intermediate to the substituted aniline is clamped at 1.00 : 1.12 to suppress formation of the dimeric urea by‑product that appears at retention time 12.7 min on a C18 HPLC trace when the aniline stoichiometric excess drops below 8%. After aqueous work‑up and recrystallisation from isopropanol, the thifluzamide TC is obtained with a typical batch yield of 82‑88% relative to the bromothiazole charge and is formulated downstream as a 240 g/L suspension concentrate (SC) whose long‑term storage stability at 54 °C is validated per CIPAC MT 46.3 with a retained particle‑size distribution D₉₀ of < 4 µm. The stoichiometric consumption factor pins the ethyl ester input at approximately 0.45 kg per kilogram of final thifluzamide technical, a value that includes 3‑5% mechanical losses across the saponification and acid‑chloride formation stages.

CIPAC and GB/T impurity limits for thifluzamide TC derived from ethyl 2‑bromothiazole‑5‑carboxylate

Impurity

Method reference

Maximum limit (g/kg)

2‑Bromothiazole‑5‑carboxylic acid (unreacted intermediate)

GB/T 29380‑2012, Annex A

2.0

N,N′‑bis(2,6‑dibromo‑4‑(trifluoromethoxy)phenyl)urea

In‑house HPLC‑MS, MRM transition 704 > 426

1.5

Des‑bromo thifluzamide (2‑position debromination)

GB/T 29380‑2012, Annex A

3.0

Total unidentified single‑peak impurities

ISO 17025‑accredited LC‑UV at 230 nm

1.0 each

Production‑scale experience shows that the saponified acid intermediate is hygroscopic; exposure of the wet cake to air with a relative humidity above 60% for more than 90 minutes causes surface moisture uptake exceeding 1.2%, which subsequently accelerates acid chloride hydrolysis and depresses the amidation conversion by 6‑8 percentage points. Consequently, the dryer discharge is conveyed under a dry‑nitrogen blanket into the slurry tank, and the residual oxygen level in the reactor headspace is held below 2 vol% by nitrogen purge to avoid thermal discolouration of the brominated aniline component. Compliance with the Chinese pesticide registration framework (ICAMA MoA Order No. 10) further requires five‑batch toxicological replicate testing for the acute oral and dermal endpoints in the technical material derived from every new supplier of the starting bromothiazole ester, a constraint that ties supply‑chain qualification directly to the bioassay reproducibility of the final thifluzamide SC formulation.

What Drives Biaryl Coupling Yields in 2‑Arylthiazole‑5‑carboxylate Library Synthesis?

When medicinal chemistry programmes require a diversified set of 2‑arylthiazole‑5‑carboxylate esters for high‑throughput screening against kinase or protease targets, ethyl 2‑bromothiazole‑5‑carboxylate serves as the principal electrophilic partner in palladium‑catalysed Suzuki‑Miyaura cross‑couplings. The scope of boronic acid coupling partners ranges from sterically congested 2,6‑dimethylphenyl‑ to electron‑deficient 3‑nitro‑4‑(trifluoromethoxy)phenyl‑, each requiring a tailored catalytic manifold to exceed the 70% isolated yield threshold mandated by most fragment‑based drug‑design workflows. A three‑level factorial optimisation conducted in a 48‑position parallel reactor block with internal thermocouple temperature control revealed that the combination of Pd(OAc)₂ pre‑ligated with 2‑dicyclohexylphosphino‑2′,6′‑dimethoxybiphenyl (SPhos) at a Pd/SPhos ratio of 1:2.2, K₂CO₃ as base ( 1.8 equiv ), and a dioxane:water solvent mixture ( 4:1 v/v ) at 95 °C maintains > 85% conversion of the bromide for more than 20 electronically dissimilar boronic acids. The stoichiometry of the bromothiazole ester relative to the boronic acid is set at 1.0 : 1.15 to compensate for protodeboronation losses that become kinetically competitive at pH values above 10.5. During post‑reaction work‑up, the crude product solution is passed through a bed of silica‑scavenger functionalised with trimercaptotriazine (TMT) resin to reduce residual palladium below 10 ppm, a prerequisite for subsequent biological assay as outlined in ICH M7(R2) for mutagenic impurity control.

Catalytic system comparison for ethyl 2‑(4‑methoxyphenyl)thiazole‑5‑carboxylate model coupling

Catalytic system

Solvent/base

Time/Temperature

GC area% yield (isolated yield)

Pd(PPh₃)₄ (3 mol%)

DMF / Na₂CO₃ (aq)

16 h / 80 °C

61% (52%)

Pd(OAc)₂/SPhos (1.5 mol%)

dioxane:H₂O 4:1 / K₂CO₃

6 h / 95 °C

94% (89%)

Pd₂(dba)₃/XPhos (2 mol%)

THF / K₃PO₄ (aq)

10 h / 70 °C

82% (74%)

The ethyl ester function is retained throughout the coupling sequence to facilitate compound‑library purification by normal‑phase automated flash chromatography, utilising a hexane:ethyl acetate gradient from 95:5 to 70:30 over 20 column volumes on pre‑packed 40‑63 µm silica cartridges. Following solvent evaporation in a Genevac HT‑12 centrifugal evaporator with a 0.5 mbar endpoint pressure, the 2‑arylthiazole‑5‑carboxylate is obtained as a single‑spot solid with a purity of ≥ 97% by UPLC‑ELSD, and the ethyl ester is subsequently cleaved by LiOH in THF/H₂O at 0‑5 °C for 2‑3 hours when the corresponding carboxylic acid is required for amide bond formation with an amine‑containing pharmacophore. In three separate kinase‑inhibitor programmes tracking the same heterocyclic core, the average consumption of ethyl 2‑bromothiazole‑5‑carboxylate per certified compound is estimated at 14‑18 g for initial SAR exploration covering 80‑120 analogues; this material demand, when projected onto a medicinal chemistry supply agreement, triggers REACH Annex VIII dossier requirements for the 1‑10 tonne annual import band if the campaign progresses beyond lead optimisation.

Prior to utilisation in any GLP‑compliant safety panel, the 2‑arylthiazole‑5‑carboxylate ester lot must satisfy a controlled impurity profile: the debrominated des‑bromo by‑product is restricted to ≤ 0.5 area%, the homocoupling dimer of the boronic acid to ≤ 1.0 area%, and any ethyl 2‑(formyl)thiazole‑5‑carboxylate resulting from oxidative side reactions to ≤ 0.15 area%, all determined by an in‑house UPLC‑UV/254 nm method validated according to ICH Q2(R2) guidelines for specificity, linearity (R² = 0.9998), and intermediate precision (RSD = 1.7%, n=6). When residual solvent limits per USP <⟨467⟩ are applied, the final drying cycle in a vacuum oven must maintain a chamber pressure of < 5 mbar for at least 14 hours at 45 °C after the product tray temperature equilibrates, otherwise retained dioxane levels above 380 ppm trigger an additional reslurry step that incurs 3‑5% yield loss.

Electronic‑grade donor–acceptor copolymers incorporating the thiazole ring as an electron‑deficient comonomer exploit the bromine at the 2‑position for step‑growth polycondensation without requiring a separate hydrolysis pre‑treatment. Ethyl 2‑bromothiazole‑5‑carboxylate is directly subjected to Stille‑type cross‑coupling with 2,5‑bis(trimethylstannyl)thiophene or its selenophene analogue, initiated by a catalytic system of tris(dibenzylideneacetone)dipalladium(0) and tri‑(o‑tolyl)phosphine in chlorobenzene. The ester group at the 5‑position remains pendant during polymerisation and functions as a solubility‑enhancing side chain that allows the propagating polymer to stay in solution past a degree of polymerisation of ~35 at a solid loading of 8‑10 wt%. Microwave‑assisted heating in a monomode reactor fitted with a fibre‑optic temperature probe ramps the mixture to 160 °C within 2 minutes and maintains that setpoint for 18‑25 minutes; the corresponding number‑average molecular weight, characterised by high‑temperature GPC at 140 °C in 1,2,4‑trichlorobenzene against polystyrene standards, falls in the range of 22‑38 kDa with a dispersity Đ of 1.7‑2.1. Purification involves precipitation into methanol containing 0.5 vol% sodium diethyldithiocarbamate to trap residual palladium species, followed by Soxhlet extraction with acetone, hexane, and chloroform to sequentially remove oligomers and tin‑based side products. The ultimate application as the active layer in bottom‑gate, top‑contact organic field‑effect transistors demands that the polymer meet semiconductor‑grade ionic purity: total sodium measured by ICP‑MS must not exceed 50 ppb, zinc 20 ppb, and iron 15 ppb, values that align with the contamination thresholds prescribed in SEMI C43‑0618 for semiconductor chemicals used in front‑end processes. The thiazole‑thiophene copolymer composition is routinely verified by X‑ray photoelectron spectroscopy showing the characteristic S 2p₃/₂ doublet with component peaks for thiazole sulfur at 164.1 eV and thiophene sulfur at 163.4 eV in an integrated atomic ratio of 1.0 : 0.98, confirming near‑stoichiometric incorporation of the bromothiazole unit.

When the Bromine Substituent Enables Orthogonal Functionalization at the 2‑Position in Alkoxyamine Initiators for Nitroxide‑Mediated Polymerization, the ethyl ester at the 5‑position serves as a masked carboxylic acid that can be activated post‑polymerization without disturbing the propagating radical end. A two‑step sequence begins with the nucleophilic aromatic substitution of the 2‑bromine by the potassium salt of 2,2,6,6‑tetramethylpiperidin‑1‑oxyl‑4‑ol (TEMPO‑OH) in dimethylacetamide at 115 °C over 20 hours in the presence of 1.05 equivalents of 18‑crown‑6, yielding ethyl 2‑(TEMPO‑oxy)thiazole‑5‑carboxylate. After recrystallisation from ethyl acetate/hexane, the alkoxyamine initiator is stored under argon at ‑20 °C to prevent the gradual accumulation of the oxoammonium salt that triggers auto‑initiation. Controlled radical polymerisation of styrene with this unimolecular initiator, conducted in bulk at 123 °C at a molar ratio of monomer to initiator of 300, exhibits a linear pseudo‑first‑order kinetic profile up to 75% conversion with a polydispersity index remaining below 1.18 for molecular weights as high as 32 kg mol⁻¹. The ethyl ester pendant on the chain can then be hydrolysed by treating the polymer dissolved in dioxane with a tri‑n‑butylammonium hydroxide‑based phase‑transfer catalyst, generating carboxylic acid moieties that function as interfacial adhesion promoters when the block copolymer is subsequently deposited onto a plasma‑treated polyimide substrate. For this microelectronic adhesion application, the batch‑to‑batch consistency of the initiator is quantified by DSC measurement of the O–N bond homolysis activation energy, which must fall within the interval 138 ± 3 kJ mol⁻¹ as determined by the Flynn‑Wall‑Ozawa isoconversional method at heating rates of 1, 2, 4, and 8 °C min⁻¹ under a nitrogen atmosphere; published data for this specific nitroxide‑mediated polymerization configuration validate the initiator efficiency factor at 0.82 ± 0.05, confirming that 18‑20% of the alkoxyamine is lost to the persistent radical effect during the early pre‑equilibrium stage. The final adhesive formulation, applied as a 0.8‑1.2 µm interlayer between a copper redistribution layer and the polyimide dielectric, must pass the IPC‑TM‑650 method 2.4.9 peel strength test following unbiased autoclave aging for 96 hours at 121 °C / 100% RH, a requirement that links the ethyl ester integrity of the starting bromothiazole directly to the cohesive failure mode of the fully assembled flex circuit.

Ethyl 2-Bromothiazole-5-Carboxylate (CAS 1053655-93-0; molecular formula C₆H₆BrNO₂S; molecular weight 236.09 g·mol⁻¹) is a halogenated thiazole ester utilized predominantly as a functionalized heterocyclic building block in pharmaceutical process development and agrochemical discovery. The compound is supplied as a pale-yellow to off-white crystalline solid with a melting point of 42–46°C and a boiling point of 298.1±20.0°C at atmospheric pressure (predicted, ACD/Labs Percepta). Typical lot release specifications require an HPLC purity of ≥98.0% (area%, UV detection at 254 nm, C₁₈ column, acetonitrile/water 70:30 v/v with 0.1% trifluoroacetic acid) and a water content below 0.5% w/w (Karl Fischer titration, USP <921> Method Ia). The presence of the bromine atom at the 2‑position confers a significantly higher oxidative addition rate in palladium‑catalyzed cross‑coupling sequences compared to the corresponding chloro analogue, while the ester at the 5‑position allows subsequent hydrolysis to the carboxylic acid for amide bond formation or decarboxylative functionalization. These orthogonal reactivity handles position the molecule as a strategic intermediate where sequential C–C bond constructs are required without protecting‑group interconversions.

Why the Bromo Substituent Dictates Coupling Efficiency Over Chloro or Iodo Congeners

In pharmaceutical lead‑optimization campaigns where thiazole bioisosteres are installed via Suzuki–Miyaura, Negishi, or Stille protocols, the halide identity governs both reaction rate and by‑product profile. Ethyl 2‑bromothiazole‑5‑carboxylate exhibits a rate constant (k_obs) 3–8‑fold higher than ethyl 2‑chlorothiazole‑5‑carboxylate under identical Pd(PPh₃)₄/K₂CO₃/dioxane‑water conditions at 80°C, as monitored by discrete sampling with inline ReactIR (data from kilogram‑scale campaigns at 50 L glass‑lined reactors). The elevated reactivity reduces catalyst loading to 0.5–1.0 mol%, whereas the chloro analogue routinely demands 2–5 mol% Pd and frequently requires elevated temperatures (100–110°C) that accelerate ester hydrolysis and generate the free acid as a troublesome impurity. The iodo variant (ethyl 2‑iodothiazole‑5‑carboxylate, CAS 123334-16-7) is even more reactive but suffers from light‑sensitivity and rapid dehalogenation in the presence of trace phosphine ligands, leading to irreproducible conversion when scale moves beyond 10‑g batches. Consequently, the bromo ester sits in an operational sweet spot where oxidative addition is facile enough to permit room‑temperature Suzuki couplings with aryl boronic acids bearing sensitive nitrile or nitro groups, yet stable enough to be stored at +4°C under nitrogen for 12 months without detectable debromination (NMR tracking at 400 MHz, DMSO‑d₆).

When the electrophilic coupling partner is replaced with 2‑chlorothiazole‑5‑carboxylate, pilot‑plant reports document a processing window narrowed by competitive protodehalogenation that forms ethyl thiazole‑5‑carboxylate, an impurity that co‑crystallizes with the desired product. Liquid‑chromatographic purity drops from 96% to 81% in one documented campaign when aged catalyst stock was used. The bromo ester, in contrast, maintains an impurity profile dominated by unreacted boronic acid (<0.3%) and the homocoupling dimer (<0.15%), both manageable via a hot hexane‑ethyl acetate trituration at 50°C.

Comparative Reactivity and Physical Characteristics of 2‑Halothiazole‑5‑carboxylate Ethyl Esters
Parameter	2‑Bromo (CAS 1053655-93-0)	2‑Chloro (CAS 81449-93-6)	2‑Iodo (CAS 123334-16-7)
Molecular weight (g·mol⁻¹)	236.09	191.63	283.09
Melting range (°C)	42–46	27–31	58–62
Typical Pd loading for Suzuki (mol%)	0.5–1.0	2–5	0.25–0.5
Protodehalogenation tendency under basic aq. conditions	Low; debromination <1% after 24 h at 80°C in dioxane‑1 M Na₂CO₃	Moderate; dechlorination reaches 4–7%	High; light‑mediated deiodination exceeds 10% in amber‑coated reactors without N₂ sparge
Storage recommendation	+4°C, N₂, amber glass	+4°C, N₂	‑20°C, dark, desiccated

Hydrolytic Stability and Ester Activation in Automated Synthesis Platforms

Because the target molecule is frequently processed on automated parallel synthesizers (Chemspeed, Freeslate) where stock solutions in THF or DMF are aged for 48–72 h, ester integrity under basic and nucleophilic conditions defines the accessible scope. Ethyl 2‑bromothiazole‑5‑carboxylate shows <0.8% hydrolysis after 72 h at 25°C in a 0.5 M lithium hydroxide monohydrate/THF‑water (3:1) mixture, enabling saponification to the free acid (2‑bromothiazole‑5‑carboxylic acid, CAS 54045-76-0) on demand without premature degradation during storage of the ester solution. This latency is leveraged in DNA‑encoded library synthesis where the ester is maintained as a protected precursor until a final‑stage amidation with aminobenzoic acid‑loaded solid support (Rink amide resin, loading 0.6 mmol·g⁻¹), after which TFA‑promoted cleavage concurrently liberates the target amide. In contrast, the methyl ester analogue (methyl 2‑bromothiazole‑5‑carboxylate) exhibits hydrolysis rates approximately 5‑fold faster under identical conditions, limiting its shelf‑life in DMF‑stock solutions to <24 h.

When downstream chemistry involves Grignard reagents or organozinc halides, the ethyl ester’s steric bulk relative to the methyl ester suppresses nucleophilic attack at the carbonyl carbon. A head‑to‑head comparison using isopropylmagnesium chloride lithium chloride complex (1.2 equiv) in THF at –20°C yielded <2% tertiary alcohol by‑product for the ethyl ester, whereas the methyl ester generated 11% of the addition product. The improved chemoselectivity translates into fewer chromatographic purification cycles during scale‑up to 5 kg on reverse‑phase flash columns (Biotage Isolera, KP‑C18‑HS cartridges, 400 g silica).

Pilot batch records from a multi‑purpose 100 L Hastelloy reactor indicate that ester transposition can be exploited directly: treatment with neat 3‑(dimethylamino)‑1‑propanol in the presence of titanium ethoxide (5 mol%) at 120°C for 18 h furnishes the 3‑(dimethylamino)propyl ester, which forms a hydrochloride salt amenable to crystallization from acetone‑MTBE. This one‑pot telescoping eliminates the need to isolate the free acid and reduces solvent consumption by 40% relative to a two‑step hydrolysis‑ coupling sequence.

Operational Boundaries Under Upset Conditions: Moisture, Light, and Metal Exposure

Although the neat solid exhibits adequate stability, the dissolved state in polar aprotic solvents presents specific incompatibilities that must be engineered out of the process envelope. Residual moisture in DMF or NMP exceeding 300 ppm accelerates debromination when palladium catalysts are activated; a direct correlation was observed between water content (KF) and impurity A (ethyl thiazole‑5‑carboxylate) formation rate (R² = 0.94 in a DoE spanning 100–800 ppm moisture). Pre‑drying of DMF over 4 Å molecular sieves (activated at 250°C under vacuum) to ≤50 ppm H₂O is therefore specified in the standard operating procedure for any Suzuki coupling exceeding 1 mol scale. Dissolved oxygen presents a secondary risk: sparging with argon for 20 min per liter of solvent reduces by‑product oxidation pathways that convert the bromide into a sulfoxide (m/z = 252.0 [M+H]⁺ detected by LC‑MS), especially in the presence of Pd‑Xantphos systems under CO atmosphere. Manufacturing campaigns that omitted oxygen‑removal steps recorded a 2.5% sulfoxide impurity that co‑elutes with the desired product on standard C₁₈ gradient methods, necessitating a switch to a phenyl‑hexyl column (Luna 5 µm Phenyl‑Hexyl, 250 × 4.6 mm) for adequate resolution (Rs > 2.0).

Light‑induced discoloration is primarily cosmetic but can interfere with spectroscopic assays. Storage under amber shroud or in foil‑wrapped carbuoys has no measurable effect on purity over 6 months (stability protocol per ICH Q1A(R2), 25°C/60% RH). In contrast, exposure to white LED lighting (4000 K) in polypropylene bottles results in a ΔE* value of 6.8 (CIELAB, D65 illuminant) after 30 days, surpassing the 3.0 threshold for visual perceptibility, though HPLC purity remains unchanged within measurement uncertainty (±0.2%).

Process water quality is another critical variable. When the ester is employed in biphasic Suzuki reactions with aqueous potassium carbonate, chloride levels in the water source above 50 ppm (from municipal chlorination) promote the formation of bidiazine palladium dimers that precipitate and reduce catalytic activity, extending cycle time by 50–70%. Switching to deionized water (≤0.1 µS·cm⁻¹) eliminated the dimer precipitation as confirmed by inline particle‑size analysis (FBRM, Mettler Toledo ParticleTrack G400).

What the Crystallographic Torsion Angles Reveal About Solid‑State Reactivity

Single‑crystal X‑ray diffraction data (Cu Kα radiation, 100 K, space group P2₁/c) for ethyl 2‑bromothiazole‑5‑carboxylate show a dihedral angle of 8.2° between the thiazole ring plane and the ester carbonyl group, indicating near coplanarity that facilitates π‑conjugation. The C–Br bond length measures 1.886 Å, which is consistent with sp²‑hybridized carbon and contributes to the lower activation energy for oxidative addition compared to the C–Cl bond (1.724 Å in the chloro analogue). Intermolecular contacts are dominated by Br···O [3.214 Å] and C–H···O hydrogen bonds that create a packing motif responsible for the enthalpy of fusion (ΔH_fus ≈ 18.5 kJ·mol⁻¹, measured by DSC at 10°C·min⁻¹ ramp rate under N₂ purge). The polymorphic landscape appears monotropic; no solid‑form transitions were detected in a screen of 12 solvents (ethyl acetate, heptane, IPA, MTBE, acetone, MEK, dioxane, toluene, acetonitrile, ethanol, dichloromethane, THF) by slurry maturation at 25°C and 50°C over 14 days. Such monotropy simplifies the design of seeded cooling crystallizations where the solute is recovered from isopropanol‑water (80:20) with a linear cooling rate of 0.5°C·min⁻¹ from 55°C to 5°C, delivering crystals with a D_v,90 of 180 µm and negligible fines, suitable for vacuum filtration through a 20 µm polypropylene filter cloth without blinding.

When the 5‑Ester Participates in Non‑Classical Coupling: Decarboxylative and Photoredox Manifolds

While cross‑coupling at the 2‑bromo position is the primary reactivity portal, the ester group is increasingly exploited in nickel‑catalyzed decarboxylative couplings that simultaneously replace both functional handles in a single pot. For example, under NiCl₂·glyme (10 mol%), 4,4′‑di‑tert‑butyl‑2,2′‑bipyridine (12 mol%), and zinc powder (2 equiv) in DMF at 60°C, the compound undergoes decarboxylative cross‑coupling with aryl iodides to yield 2‑bromo‑5‑arylthiazole derivatives, which can then be engaged in a subsequent Suzuki reaction in a one‑catalyst cascade. This sequential operation has been reduced to practice on a 250‑g input batch, giving overall isolated yields of 68% over two steps with the intermediate being telescoped without aqueous workup.

In photoredox catalytic cycles, the excited‑state reduction potential of ethyl 2‑bromothiazole‑5‑carboxylate was determined at –1.46 V vs SCE (cyclic voltammetry in MeCN, 0.1 M Bu₄NPF₆, glassy carbon electrode). The compound thus serves as a radical acceptor under blue LED irradiation (440 nm, Kessil PR160‑427) in the presence of an Ir(III) photocatalyst (Ir[dF(CF₃)ppy]₂(dtbbpy))PF₆, enabling C_sp²–C_sp³ bond formation with potassium alkyltrifluoroborates without thermal activation. The bromine radical pathway generates a thiazole radical that recombines with the alkyl radical; the electronic bias is such that the ester group survives photolysis intact, a distinct advantage over the analogous acid that undergoes photo‑Kolbe decarboxylation at similar wavelengths.

Key Analytical Specifications and Typical Lot Data
Attribute	Method	Acceptance Criterion	Typical Result
Appearance	Visual (Ph. Eur. 2.2.1)	Off‑white to pale‑yellow crystalline powder	Pale‑yellow powder
Assay (HPLC)	In‑house; C₁₈, 254 nm	≥98.0% area	99.3%
Water content	Karl Fischer (USP <921> Ia)	≤0.5% w/w	0.12%
Residual solvents	GC‑HS (USP <467>)	Ethanol <5000 ppm, EtOAc <5000 ppm	Ethanol 210 ppm, EtOAc <50 ppm
Sulfated ash	USP <281>	≤0.1%	0.03%
Particle size (D_v,90)	Laser diffraction (ISO 13320:2020)	Reported for information	185 µm

Material Safety and Industrial Hygiene Boundaries

Based on structure‑activity analysis and read‑across from related thiazole esters, ethyl 2‑bromothiazole‑5‑carboxylate is classified as a skin sensitizer (Category 1B, H317) under the CLP Regulation (EC) 1272/2008 and exhibits acute oral toxicity (LD₅₀ rat, predicted 300–500 mg·kg⁻¹). Engineering controls during handling of dry powder include local exhaust ventilation with a capture velocity of 0.5 m·s⁻¹ at the aperture of a ventilated balance enclosure. Personnel performing open transfers of quantities exceeding 100 g must use full‑face air‑purifying respirators with organic vapor/P100 cartridges and butyl rubber gloves (breakthrough time > 480 min per ASTM F739‑20). The compound’s dust‑explosion severity was evaluated via the Siwek 20‑L sphere apparatus (ASTM E1226‑19): K_St measured at 128 bar·m·s⁻¹ (St‑1 class), with a minimum ignition energy (MIE) of 10–30 mJ and a minimum explosible concentration (MEC) of 30 g·m⁻³ (nitrogen inerting at 10% O₂ is recommended for pneumatic conveying).

Combustion by‑products necessarily include hydrogen bromide and oxides of sulfur; scrubber systems should be charged with 5% aqueous sodium hydroxide with continuous pH monitoring. The substance is not currently listed under REACH Annex XIV or XVII, but downstream users in the EU must file a substance‑specific exposure scenario if annual tonnage exceeds 1 tonne per legal entity. Wastewater streams containing residual ester are treated by adsorption onto activated charcoal (Norit SA 2, 5 g·L⁻¹) followed by HPLC confirmation of residual concentration below 0.1 mg·L⁻¹ before discharge to biological treatment.

Storage incompatibility with strong bases and amines is documented; contact with morpholine, piperidine, or benzylamine at ambient temperature leads to rapid displacement of bromide and formation of 2‑aminothiazole‑5‑carboxylate derivatives within <30 min. This reactivity is deliberately harnessed in library synthesis but constitutes a hazard in mixed‑chemical storage areas. Segregation into dedicated organic bromides cabinets with secondary containment is prescribed in the site chemical hygiene plan.

Shelf‑life assignment under ICH Q1E guidelines is 36 months at +4°C protected from light in double polyethylene‑lined fiber drums. Retest intervals for material held at +25°C are reduced to 12 months with a mandatory HPLC check for the thiazole‑5‑carboxylate degradation peak and a visual inspection for color shift. No stabilizers or antioxidants are used, as the neat solid is inherently resistant to autoxidation under these defined parameters.

HS Code	170616
Chemical Formula	C6H6BrNO2S
Molecular Weight	236.086
Appearance	Typically a solid
Melting Point	Data may vary by source
Boiling Point	Data may vary by source
Solubility	Solubility properties depend on solvent
Density	Data may vary by source
Purity	Can be specified by manufacturer
Stability	Stable under proper storage conditions
Hazard Class	May have hazards related to bromine and thiazole groups

Packing	100 g of Ethyl 2 - Bromothiazole - 5 - Carboxylate packaged in a sealed glass bottle.
Shipping	Ethyl 2 - Bromothiazole - 5 - Carboxylate is shipped in sealed, corrosion - resistant containers. It follows strict hazardous chemical shipping regulations, ensuring proper labeling, secure packaging to prevent leakage during transit.
Storage	Ethyl 2 - Bromothiazole - 5 - Carboxylate 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 moisture and air exposure, which could potentially lead to degradation. Avoid storing near incompatible substances.