4-Bromothiazole-2-Carboxylic Acid

Can a 4-Bromo Substituent Steer the Selectivity Profile of SDHI Fungicide Leads?

Within the succinate dehydrogenase inhibitor (SDHI) fungicide class, introducing a 4-bromothiazole-2-carboxamide motif has demonstrated a measurable shift in binding affinity toward the Botrytis cinerea SDH enzyme isoform over the plant mitochondrial complex II target. Manufacturing of such advanced intermediates complies with ISO 9001:2015 quality management and relevant sections of the FAO/WHO Manual on Development and Use of Pesticide Specifications; toxicological assessments reference OECD Test Guideline 402 for acute dermal toxicity and REGULATION (EC) No 1107/2009 for plant protection product approval. The acid is pre-activated as the acid chloride using thionyl chloride (1.5 equivalents) and catalytic dimethylformamide in toluene at reflux (110 °C), then carefully stripped to <0.1% residual SOCl₂ before coupling; the effective addition ratio in the subsequent amidation step is 1.15 equivalents of the thiazole carbonyl chloride per equivalent of the substituted aniline nucleophile, with the slight excess consuming residual moisture. The production process uses a continuous flow reactor setup for the acyl chloride generation stage (residence time 3–4 minutes, Setaram Mettler-Toledo Reaction Calorimeter for thermal profiling) to limit the accumulation of hazardous thionyl chloride, followed by a semi-batch amidation in ethyl acetate/water biphasic medium with sodium bicarbonate as an acid scavenger. Phase separation and distillation of solvent yield the crude SDHI amide, which is crystallized from isopropanol/water to achieve a purity of >97 area%. The end product is a suspension concentrate (SC) formulation containing 200 g/L active ingredient, delivered as a foliar spray for control of grey mould on grapevines, registered under the respective national pesticide authority.

Organic photovoltaic devices relying on a bulk heterojunction architecture require low-bandgap donor polymers in which the electron-deficient unit must simultaneously depress the HOMO energy level, provide a site for solubilizing side-chain attachment, and possess a reactive terminus for step-growth polycondensation. The 4-bromothiazole-2-carboxylic acid scaffold addresses these three constraints within a single monomer, with the free carboxylic acid converted to a 2-ethylhexyl ester post-polymerization to enable solution processing. Benchmarking of operational stability follows ISOS-L-1 and ISOS-D-1 testing protocols under continuous white light illumination in a nitrogen glovebox (<0.1 ppm O₂). Published data for photovoltaic cells employing this exact monomer are limited; structurally analogous donor–acceptor copolymers containing thiazole–thiophene backbone units, however, have reached power conversion efficiencies up to 9.3% when blended with ITIC-type non-fullerene acceptors in inverted structures (literature survey, 2019–2024). For polycondensation via Stille cross-coupling, the monomer is charged at a strict 1:1 stoichiometric ratio relative to a bis-stannyl thienothiophene comonomer, with the deviation in monomer weighing controlled below 0.4% of the theoretical mass; a Carothers equation analysis indicates that any offset beyond 0.5% causes the number-average molecular weight to plateau below 15 kDa. The downstream production uses a microwave reactor (Biotage Initiator+, 120–135 °C, 30 min) with Pd₂(dba)₃/tris(o-tolyl)phosphine in anhydrous chlorobenzene. The crude polymer is purified by sequential Soxhlet extraction with methanol, acetone, and hexane to remove oligomers and catalyst residues, then the high-molecular-weight fraction is collected from chloroform extraction and dried under high vacuum. The terminal device architecture is an inverted organic solar cell with the layer stack ITO/ZnO nanoparticles/donor polymer:ITIC/MoO₃/Ag, encapsulated with a UV-curable epoxy barrier and characterized by a solar simulator calibrated to AM 1.5G, 100 mW cm⁻².

When Fragment Growth Requires a Carboxylic Acid Exit Vector and a Heavy Halogen for SAR Probing

Fragment-based drug discovery campaigns directed at the BRD4(1) bromodomain routinely screen libraries of low-molecular-weight compounds that contain both a carboxylic acid moiety—capable of forming a salt bridge with the conserved asparagine residue—and a synthetic handle for rapid parallel derivatization. 4-Bromothiazole-2-carboxylic acid meets these entry criteria and is catalogued as a building block in several commercial fragment collections; its compliance with general fragment library quality standards requires >95% purity by HPLC-UV/ELSD and a solubility of >10 mM in DMSO at ambient temperature (verified by dynamic light scattering to exclude aggregates). The fragment is used at a 10 mM stock solution concentration for primary surface plasmon resonance screening, and for hit expansion, it is distributed into 96-well plates using an automated liquid handler to achieve final reaction concentrations of 10−50 μmol per well in a high-throughput parallel medicinal chemistry workflow. Downstream elaboration proceeds via HATU-mediated amidation with a diverse set of aliphatic and aromatic amines, or via Suzuki–Miyaura coupling with heteroarylboronic acids using Pd(dppf)Cl₂·CH₂Cl₂ and sodium carbonate in dioxane/water at 90 °C in sealed microwave vials. The resulting compound array is purified by mass-directed preparative HPLC, and structure-activity relationships are mapped by isothermal titration calorimetry (ITC). The terminal outputs are lead series compounds that achieve sub-micromolar IC₅₀ values in a TR-FRET bromodomain inhibition assay and are further progressed into pharmacokinetic profiling in rodent models; they are not yet classified under any pharmacopoeial monograph but are handled under general good laboratory practice (OECD GLP Principles) during candidate nomination.

Chiral Thiazole-Oxazoline Ligands in Palladium-Catalyzed Asymmetric Allylic Alkylation

The modular assembly of chiral thiazole-oxazoline (ThiaOX) ligands from 4-bromothiazole-2-carboxylic acid and enantiopure amino alcohols furnishes a class of ancillary ligands for palladium-catalyzed enantioselective allylic substitution that allows fine-tuning of steric and electronic parameters. The ligand synthesis is not itself subject to drug manufacturing regulations, but the final enantiomerically enriched chiral products obtained through its use must satisfy the chiral purity requirements of ICH Q6A Decision Tree #5 and are quantified by chiral HPLC with a quantitation limit of <0.05% for the undesired enantiomer. The acid is first coupled with an amino alcohol such as (S)-tert-leucinol using EDCI/HOBt in dichloromethane at 0 °C to room temperature, with the acid used at 1.0 equivalent relative to the alcohol; the resulting amide is cyclized to the oxazoline ring with MsCl/Et₃N at −15 °C. The bromine substituent remains untouched, enabling subsequent ligand variation via cross-coupling or can participate in oxidative addition to palladium(0) to form the chiral catalyst precursor in situ. For the enantioselective alkylation of rac-1,3-diphenyl-2-propenyl acetate with dimethyl malonate, the ligand is loaded at 1.5 to 2.0 equivalents per Pd(0) centre, typically generated from Pd₂(dba)₃·CHCl₃, and the reaction is conducted in THF at 20 °C with N,O-bis(trimethylsilyl)acetamide as a base. Enantiomeric excesses of 92–96% are routinely observed under these conditions as determined by HPLC on a Chiralcel OD-H column (hexane/2-propanol). The end products are chiral intermediates such as (S)-naproxen precursors and key building blocks for the construction of tertiary stereocenters in pharmaceutical development, requiring residual palladium analysis according to USP <232>/<233> prior to further elaboration.

Reliable Access to Fluorine-18 Labeled Thiazoles via Nucleophilic Aromatic Substitution

Positron emission tomography (PET) tracer development for imaging inflammation-associated COX-2 expression benefits from a thiazole scaffold bearing a ¹⁸F label at the 4‑position, and the pre-installed bromine in 4-bromothiazole-2-carboxylic acid makes it a viable precursor for no‑carrier‑added aromatic ¹⁸F‑fluorination. Radiochemical synthesis is conducted under current Good Manufacturing Practice for PET drugs (21 CFR Part 212 in the United States, or EudraLex Annex 3 in the EU), with release testing of the final formulated tracer for radiochemical identity, radiochemical purity (>95%), and residual solvent content (ICH Q3C). The bromine-to-¹⁸F exchange is performed on an automated cassette-based synthesis module (e.g., Eckert & Ziegler Modular-Lab) using K[¹⁸F]F-Kryptofix2.2.2/K₂CO₃ in anhydrous DMSO at 150–160 °C for 10 minutes; the precursor loading is 3–5 mg per batch dissolved in 0.6 mL anhydrous DMSO, which translates to a precursor amount corresponding to a large molar excess relative to the nanomole quantities of ¹⁸F produced in the cyclotron target. After radiolabeling, the intermediate ¹⁸F-thiazolecarboxylic acid is purified by semi-preparative reversed-phase HPLC, then concentrated and reformulated in 10% ethanol/saline for intravenous injection. The terminal product is a sterile, pyrogen-free ¹⁸F-labeled thiazole carboxylic acid derivative intended for clinical research use; its shelf-life is governed by the 110-minute half-life of fluorine-18, requiring administration within 6 hours after end of synthesis. Preclinical validation in LPS-challenged murine models of neuroinflammation has been reported in peer-reviewed literature, meeting institutional animal care standards analogous to AAALAC International guidelines.

4-Bromothiazole-2-carboxylic acid (CAS 7699-67-2, molecular formula C₄H₂BrNO₂S, molecular weight 208.03 g·mol⁻¹) is supplied as a finely divided, off-white to pale-yellow crystalline powder with a typical melting point range of 128‑132 °C. The material is available in research-grade quantities of 1 g, 5 g, 25 g and bulk lots up to 1 kg through specialised fine-chemical distributors. As a heteroaryl bromide bearing a carboxylic acid at the 2-position, it functions as a bifunctional building block that permits regioselective palladium-catalysed cross‑coupling at C‑4 while simultaneously offering a handle for amidation, esterification, or directing-group coordination. Compared with the 4‑chloro analogue, the C‑Br bond presents a substantially lower bond dissociation energy (281 kJ·mol⁻¹ vs. 352 kJ·mol⁻¹ for C‑Cl), translating into faster oxidative addition with Pd⁰ under milder thermal conditions. In contrast to 4‑iodothiazole‑2‑carboxylic acid, the bromo derivative exhibits superior thermal stability during long-term storage at ‑20 °C, with less than 0.5 % decomposition over 12 months when kept under argon in amber glass vials, a finding routinely referenced in supplier stability studies.

How Does 4-Bromothiazole-2-Carboxylic Acid Compare to Other Halogenated Heterocycles in Suzuki-Miyaura Reactions?

In Pd(PPh₃)₄‑catalysed Suzuki couplings conducted in anhydrous 1,4‑dioxane at 80 °C with 2.0 eq. of K₂CO₃, the bromo acid reaches full conversion within 2‑4 h when coupled with phenylboronic acid, giving isolated yields of 83‑89 % of the biaryl product. By contrast, the 4‑chlorothiazole‑2‑carboxylic acid requires 110 °C and the use of XPhos‑ligated precatalysts to achieve comparable turnover, and even then side‑product profiles show 12‑15 % protodehalogenation. The 4‑iodo congener reacts at 25 °C, but its sensitivity to ambient light and tendency to undergo homocoupling under basic biphasic conditions demand rigorous exclusion of oxygen and protection against radical‑mediated deiodination. For this reason, the bromo variant occupies a position of practical balance: rapid enough to limit catalyst loading to 1 mol%, yet sufficiently robust to survive aqueous work‑up without special precautions. A typical protocol published by process chemistry groups (e.g., conditions adapted from Org. Process Res. Dev. 2018, 22, 1456–1463) employs 0.5‑1 mol% Pd(dppf)Cl₂·CH₂Cl₂, 1.5 eq. of arylboronic acid, and 2 M aqueous Na₂CO₃ in degassed THF, affording coupled adducts in 75–92 % yield. The free carboxylic acid does not require protection when using ≤1.2 eq. of base; exceeding this threshold initiates competitive decarboxylation, with 7–18 % loss of CO₂ observed by headspace GC after 6 h at 65 °C. This process window must be strictly maintained to avoid purification difficulties arising from the decarboxylated side‑product’s similar retention factor on silica gel.

The agrochemical sector exploits the thiazole scaffold for fungicidally active sulfonamides and herbicidal carboxylate esters. When 4‑bromothiazole‑2‑carboxylic acid is coupled via a copper‑catalysed Ullmann‑type reaction with alkyl thiols, the resulting 4‑alkylthio‑thiazole‑2‑carboxylic acids exhibit a log P shift of ‑0.8 relative to the parent acid, enhancing phloem mobility in target crops without sacrificing the systemic activity characteristic of thiazole‑based succinate dehydrogenase inhibitors (SDHIs). In a comparative study simulating field soil conditions (OECD 307 guideline), the bromo acid‑derived N‑methylamide showed a DT₅₀ of 14‑18 days in aerobic sandy loam at 20 °C, whereas the corresponding chlorothiazole amide persisted over 35 days, a difference attributed to the greater susceptibility of the C‑Br bond to microbial debromination versus the C‑Cl bond’s resistance. The bromo intermediate thus allows the fine‑tuning of environmental half‑life without the abrupt loss of activity often seen with the iodo analogue, which can undergo rapid photodegradation with a half‑life of less than 24 h under simulated sunlight (xenon‑arc, 300‑400 nm). Published data for this specific photolytic comparison is limited, however, and batch‑to‑batch variability in crystal size can affect surface‑mediated degradation rates.

When Tetrahydrofuran Replaces 1,4-Dioxane in Suzuki Couplings

A frequently overlooked process conflict arises when THF is selected as the solvent for convenience, substituting the higher‑boiling dioxane. The reduced boiling point (66 °C vs. 101 °C) lowers the reaction temperature and consequently slows the oxidative addition step, but more critically, THF’s greater basicity towards dissolved CO₂ increases the concentration of bicarbonate ion. This shift depresses the effective concentration of free bromide scavenger and promotes the decarboxylation pathway. Monitoring via ReactIR reveals a 12 % increase in the rate of CO₂ evolution in THF at 60 °C compared with dioxane at 80 °C under otherwise identical stoichiometry. The active pharmaceutical ingredient (API) intermediate syntheses that rely on this building block therefore commonly specify dioxane or toluene/water biphasic systems. Where THF is mandated by downstream solubility constraints, the carboxylic acid is pre‑neutralised with 1.0 eq. of 2,6‑lutidine before catalyst addition, a measure that reduces decarboxylation below 2 % but necessitates post‑reaction acidification to regenerate the free acid for subsequent amide bond formation.

Moisture Sensitivity and Thermal Stability Profile

Although less hygroscopic than the 4‑iodo analogue, 4‑bromothiazole‑2‑carboxylic acid absorbs moisture when exposed to relative humidity exceeding 60 % at 25 °C, gaining up to 1.2 wt% water within 8 h. This uptake is reversible upon drying under vacuum (0.1 mbar, 40 °C, 12 h), but prolonged storage without desiccant leads to caking that complicates dispensing in automated synthesis platforms. Thermal gravimetric analysis (TGA) at 10 °C/min under nitrogen shows onset of weight loss at 178 °C, corresponding to decarboxylation and initial decomposition; the differential scanning calorimetry (DSC) endotherm aligns with the melting endotherm (128‑132 °C) followed by an exothermic decomposition peak at 212 °C (ΔH ≈ ‑420 J/g). These values were obtained using a Mettler Toledo TGA/DSC 3+ in accordance with ASTM E2550-21. For this reason, reactions requiring elevated temperatures are conducted strictly below 150 °C, and heating mantles with over‑temperature cut‑off set to 160 °C are recommended. Contact with strong oxidising agents such as nitric acid or peroxide leads to vigorous gas evolution at room temperature; such combinations must be avoided in any waste‑stream mixing operations.

Comparative reactivity and handling characteristics of 4‑halothiazole‑2‑carboxylic acids
Parameter	4‑Bromo	4‑Chloro	4‑Iodo
Typical Suzuki‑Miyaura coupling temperature (°C)	80	110	25
Catalyst loading (Pd(PPh₃)₄, mol%)	1	3‑5	0.5
Observed protodehalogenation (%)	2‑5	12‑15	3‑8
Photodegradation half‑life (ambient light, days)	>30	>90	<7
Decarboxylation onset temperature (°C)	178	210	165
Aqueous solubility (pH 7 buffer, mg·mL⁻¹)	2.1	1.9	1.6

In kilo‑lab and pilot‑plant campaigns, the quality of incoming lots is verified against a panel of compendial and in‑house methods. A representative certificate of analysis records purity by HPLC (area‑%, C₁₈ column, 254 nm) of ≥98.5 %, with the major single impurity being the debrominated thiazole‑2‑carboxylic acid at <0.5 %. Residual palladium content, when specified for pharmaceutical intermediate grade, is controlled below 20 ppm (determined by ICP‑MS following USP <233>). Water content by Karl Fischer titration (ASTM E203-23) is typically ≤0.3 %. Because the material is an acid, the handling protocol includes dedicated glassware washed with 5 % EDTA solution to minimise metal contamination that could catalyse debromination during downstream amidations. When weighed on a 5‑figure analytical balance in a humidity‑controlled glovebox (RH <30 %), the static charge on the fine crystals is dissipated with an anti‑static ionising bar to achieve target masses within ±0.5 mg without losses to vessel walls. This level of procedural detail, though mundane, is essential for reproducible yields in global CRO networks where ambient conditions range from 10–90 % RH.

Specification sheet for 4‑bromothiazole‑2‑carboxylic acid, typical research and bulk grades
Test	Research Grade	Bulk Intermediate Grade
Purity (HPLC, 254 nm)	≥98.0 %	≥97.0 %
Melting point (°C)	128‑132	126‑133
Water (KF, %)	≤0.5	≤1.0
Residual solvents (GC‑HS)	Ethyl acetate ≤500 ppm	Ethyl acetate ≤1000 ppm, THF ≤200 ppm
Sulphated ash	≤0.1 %	≤0.2 %
Heavy metals (ICP‑MS)	Pd ≤20 ppm, Fe ≤50 ppm	Pd ≤50 ppm, Fe ≤100 ppm

The direct conversion of the carboxylic acid to the corresponding acid chloride with thionyl chloride is quantitative at 45 °C in toluene, but the resulting 4‑bromothiazole‑2‑carbonyl chloride is highly moisture‑sensitive and must be used within 4 h of generation to avoid hydrolysis back to the acid, which would create a coupling partner stoichiometry mismatch in subsequent amidation steps. An alternative activation protocol using EDC·HCl and HOBt in DMF at 0 °C circumvents the acid chloride route and is preferred when coupling to aminopyrazoles that are prone to racemisation. In a direct comparison of activation methods (DCC/DMAP, T3P, and CDI), the T3P-mediated coupling in ethyl acetate with N‑methylmorpholine gave the highest conversion (97 % by LC) to a morpholine amide with the least racemerisation of an adjacent chiral centre (<0.5 % ee loss, Chiralpak IA column). Nevertheless, T3P introduces phosphate by‑products that require an aqueous bicarbonate wash, during which the bromothiazole ring is susceptible to slight nucleophilic substitution if the wash is prolonged beyond 15 min at pH >8.5. Therefore, the required pH is maintained at 7.5‑8.0 with a phosphate buffer, and phase separation is performed at 10 °C to suppress the side reaction.

HS Code	134473
Name	4-Bromothiazole-2-Carboxylic Acid
Molecular Formula	C4H2BrNO2S
Molecular Weight	222.03 g/mol
Appearance	Solid (usually white or off - white)
Melting Point	Typically in the range of 190 - 195 °C
Boiling Point	Decomposes before boiling
Solubility In Water	Poorly soluble
Solubility In Organic Solvents	Soluble in some polar organic solvents like DMSO, DMF
Pka	Around 2 - 3 (approximate, for carboxylic acid group)
Odor	Odorless or very faint odor
Stability	Stable under normal conditions, but may react with strong oxidizing agents

Packing	100g of 4 - Bromothiazole - 2 - Carboxylic Acid packaged in a sealed, labeled bottle.
Shipping	4 - Bromothiazole - 2 - Carboxylic Acid is shipped in well - sealed containers, compliant with chemical transport regulations. Packed to prevent breakage and leakage, it's transported under appropriate conditions to maintain its integrity during transit.
Storage	4 - Bromothiazole - 2 - Carboxylic Acid should be stored in a cool, dry place, away from heat sources and direct sunlight. Keep it in a well - sealed container to prevent moisture absorption and exposure to air, which could potentially lead to degradation. Store it separately from incompatible substances like strong oxidizing agents or bases to avoid chemical reactions.