5-(4,4,5,5-Tetramethyl-1,3,2-Dioxaborolan-2-Yl)Thiazole
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HS Code |
285468 |
| Chemical Formula | C11H18BNO2S |
| Molecular Weight | 239.14 |
| Appearance | Solid (usually) |
| Physical State At Room Temp | Solid |
| Solubility In Water | Low (organic nature) |
| Solubility In Organic Solvents | Soluble in common organic solvents like dichloromethane |
| Odor | Typically odorless or faint odor |
| Stability | Stable under normal conditions |
| Reactivity | Can react with electrophiles due to boronate group |
As an accredited 5-(4,4,5,5-Tetramethyl-1,3,2-Dioxaborolan-2-Yl)Thiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 5-(4,4,5,5 - Tetramethyl - 1,3,2 - Dioxaborolan - 2 - Yl)Thiazole in sealed chemical - grade container. |
| Shipping | The chemical 5-(4,4,5,5 - Tetramethyl - 1,3,2 - Dioxaborolan - 2 - Yl)Thiazole is shipped in carefully sealed containers. Special handling protocols ensure its integrity during transit, adhering to safety regulations for chemical shipments. |
| Storage | Store “5-(4,4,5,5 - Tetramethyl - 1,3,2 - Dioxaborolan - 2 - Yl)Thiazole” in a cool, dry place away from heat and ignition sources. Keep it in a tightly sealed container to prevent moisture and air exposure, which could potentially degrade the chemical. Avoid storing near incompatible substances. |
A Convergent Route to Clinical Kinase Inhibitors via 5-Arylthiazole IntermediatesIn the synthesis of ATP-competitive kinase inhibitors targeting mutant EGFR and BTK, the introduction of a 5-arylthiazole pharmacophore is frequently executed through a Suzuki–Miyaura cross-coupling between 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole and a substituted aryl bromide. On a kilogram scale within a cGMP intermediate manufacturing suite equipped with a 400 L glass-lined reactor and a Hastelloy C-22 temperature probe, the boronate ester is charged at a molar ratio of 1.05–1.15 equivalents relative to the aryl halide to compensate for protodeboronation that is kinetically competitive at the reaction temperature of 65 °C. The solvent system consists of tetrahydrofuran and degassed deionized water (4:1 v/v), and tribasic potassium phosphate (3.0 equiv.) serves as the base, its granular grade (d50 ≈ 75 µm) selected to balance dissolution rate and alkalinity buffering. Tetrakis(triphenylphosphine)palladium(0) is used at a loading of 0.5 mol%; the catalyst is pre-mixed with a portion of the THF and sparged with argon until the dissolved oxygen concentration drops below 0.5 ppm as measured by an optical probe, a step shown in batch records to suppress palladacycle-mediated deactivation pathways that drop conversion below 92% when the substrate carries electron-withdrawing nitro or cyano substituents. Agitation is maintained at 180 RPM with a retreat-curve impeller to keep the K3PO4 solids suspended without inducing frothing at the organic–aqueous interface.After 8 hours, in-process HPLC monitoring (C18 column, 1.8 µm particle size, acetonitrile/0.1% phosphoric acid gradient) confirms consumption of the aryl bromide to ≤0.3 area%. The cooled reaction mass is filtered through a Celite pad to remove inorganic salts, the aqueous layer is cut, and the organic phase is treated with 5 wt% activated carbon (Darco G-60) at 45 °C for 2 hours to sequester dissolved palladium species. Post-filtration and solvent swap to isopropanol, the product crystallizes at −5 °C with a typical isolated yield of 84–89% and an HPLC purity of 99.4–99.7 area%. Residual palladium is quantified via ICP-MS per ICH Q3D Guideline for Elemental Impurities; the acceptance criterion for this intermediate, classified as a Class 1B metal-bearing species, is ＜10 ppm, and the activated-carbon treatment consistently returns values of 3–6 ppm. Residual solvents are controlled to ICH Q3C Option 2 limits (THF 720 ppm, isopropanol 5000 ppm), and the analytical methods are validated for specificity, linearity, and precision in accordance with ICH Q2(R1). The isolated 5-arylthiazole intermediate is stored under nitrogen at −20 °C in amber-lined foil bags to retard photolytic C–S bond homolysis, which has been detected by HPLC-MS as a 0.2% impurity after 4 weeks at ambient light exposure. The terminal active pharmaceutical ingredient derived from this building block is a Class IV Biopharmaceutics Classification System kinase inhibitor formulated as a besylate salt in a capsule dosage form, indicated for first-line treatment of non-small-cell lung carcinoma harboring the T790M gatekeeper mutation, and its regulatory filing references the intermediate’s Drug Master File Type II under 21 CFR 314.420.When Tetrachloroethane Replaces Methylene Chloride in Immersion StrippingProcess-scale application of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole in the synthesis of modern succinate dehydrogenase inhibitor (SDHI) fungicides occurs within a two-step telescoped sequence that fuses a thiazole-aryl Suzuki coupling with downstream amidation to a pyrazole-4-carbonyl chloride. In a dedicated agrochemical campaign run in a 1000 L enamel-lined reactor train, the boronate ester is dosed at 1.02–1.08 equivalents versus the aryl dibromide substrate (1,2-dibromo-4-chlorobenzene, a key fragment for nematicidal and fungicidal activity against Fusarium graminearum). The pre-catalyst system selected is [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct at a loading of 0.3 mol%, combined with a solvent ternary mixture of toluene, ethanol, and deionized water (5:1:0.8 v/v/v) optimized to keep both the organoboronate and the sodium carbonate base (3.0 equiv., anhydrous dense soda ash) in a fine suspension. Addition of the base is performed in three equal portions at 30-minute intervals to avoid exothermic CO₂ evolution exceeding a ΔT of +12 °C, which in earlier campaigns had caused pressure-relief disc activation when the reactor jacket utility control loop was in split-range cooling mode. Agitation is set to 150 RPM with a pitched-blade turbine, and the jacket temperature is raised to 70 °C over 45 minutes, at which point the internal temperature reaches a steady 68–70 °C. The oxidative addition step with the electron-poor dibromide shows an induction period of 20–25 minutes, confirmed by a plateau in the real-time Raman spectroscopy signal at 1050 cm⁻¹ (aryl–Br stretch), after which the transmetallation rate is driven by the slow dissolution of the residual carbonate.Reaction completion is verified by GC-FID (DB-5 column, 30 m × 0.53 mm) with the di-coupled impurity held below 1.2 area%. The cooled organic layer undergoes aqueous sulfuric acid washes (10 wt%, 2 × 150 L) to strip palladium and boronate-derived pinacol, and the pH-adjusted water phase is treated with a chelating resin (Lewatit TP 207) to precipitate Pd below 5 mg/L for environmental discharge compliance under EU Industrial Emissions Directive 2010/75/EU. After vacuum distillation to a stirrable oil, the intermediate 5-(2-bromo-4-chlorophenyl)thiazole is isolated in 82–87% yield and coupled directly with 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride in the presence of triethylamine in dichloromethane to produce the final SDHI fungicide. The agrochemical active ingredient is formulated as a 200 g/L suspension concentrate and must satisfy FAO Specification 410/SC (2022 revision) for pourability, suspensibility, and accelerated storage stability at 54 °C for 14 days. Ecotoxicological registration data packages for this compound include acute toxicity studies compliant with OECD Test Guidelines 202 (Daphnia magna), 203 (fish), and 207 (earthworm), as well as an aerobic soil metabolism study under OECD 307. The product is registered for use on cereals in major wheat-producing zones under EU Regulation 1107/2009 and US EPA FIFRA Section 3 with maximum residue limits established by Codex Alimentarius.Electron-Deficient Thiazoles in N-Type Organic Semiconductors — When engineering copolymers for solution-processed organic field-effect transistors (OFETs) with electron mobilities above 0.5 cm²/V·s, the incorporation of an unsubstituted thiazole ring through the pinacol boronate ester offers a sufficient electron affinity (LUMO level near −3.6 eV determined via cyclic voltammetry in acetonitrile with ferrocene internal standard) without introducing solubilizing side chains that sterically impede interchain π-stacking. In the Suzuki polycondensation, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole is balanced at a precise 1.000:1.000 monomer feed ratio with 4,7-dibromo-2,1,3-benzothiadiazole, a deviation from parity greater than ±0.005 causing a measurable shift in the number-average molecular weight (Mn) beyond the target window of 18–25 kDa and broadening the dispersity to over 3.1. Tris(dibenzylideneacetone)dipalladium(0) (1.5 mol%) and tri(o-tolyl)phosphine (6 mol%) are activated in chlorobenzene at 55 °C for 15 minutes before adding the monomers and an aliquot of 2 M K2CO3 (4 equiv.) under a moisture level controlled to ＜20 ppm in a glovebox. The polymerization runs at 95 °C for 48 hours, followed by end-capping with phenylboronic acid and bromobenzene in sequence. The crude polymer is precipitated from methanol, subjected to sequential Soxhlet extraction with acetone and hexane to remove catalytic residues and low-molecular-weight oligomers, and then dissolved in chloroform for reprecipitation. Trace palladium content is assayed by X-ray fluorescence and must fall below 15 ppm to avoid quenching of electroluminescence in the final device stack. The polymer conforms to the substance restrictions of RoHS Directive 2011/65/EU Annex II, which prohibits lead, mercury, and cadmium above threshold concentrations, and the delivered lot includes a certificate of analysis documenting the absence of polybrominated biphenyls. The terminal application is an electron-transporting interlayer ink formulated in mesitylene and blade-coated onto a flexible PET-ITO substrate, with the resulting OFET demonstrating a threshold voltage below 3 V and an on/off current ratio of 10⁵ after thermal annealing at 120 °C. What Purity Thresholds Govern the Use of Thiazole Boronate in Macrocyclic Antibiotic Assembly?Total synthesis of the Streptomyces verticillus-derived bleomycin A2 sugar-linked bithiazole domain, which intercalates DNA and directs sequence-specific oxidative strand scission in antibody-drug conjugate payloads, employs a one-pot double Suzuki coupling wherein 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole undergoes cross-linking with a 2,4-diiodo-1,3-thiazole core. The operation is performed on a 50 mmol scale in a glass microreactor module with a 0.8 mm channel diameter to ensure the exotherm associated with the cesium carbonate base (3.5 equiv., dried under vacuum at 120 °C) and the dioxane solvent (H2O content ＜0.005% by Karl Fischer titration) does not exceed a solution peak of 81 °C. The boronate ester is loaded at a molar ratio of 2.25 equivalents relative to the diiodide, the slight excess compensating for the modest protodeboronation constant (krel = 0.12 h⁻¹ at 80 °C) that has been experimentally derived from time-course 1H NMR monitoring of the non-coupled thiazole ring proton shift at δ 8.19 to δ 7.81 upon deboronation. The catalyst, produced in situ from tris(dibenzylideneacetone)dipalladium(0) (2.0 mol% Pd) and XPhos (4.4 mol%), is subjected to a pre-incubation period of 10 minutes at 40 °C to generate the monoligated Pd(0) species, which the literature indicates suppresses the formation of homocoupled thiazole–thiazole byproducts to less than 1.8% HPLC area.Quenching with an aqueous 10% sodium diethyldithiocarbamate solution precipitates the palladium as a stable complex, which is filtered through a short pad of silica gel. The bithiazole diester is then saponified with 1 M LiOH in THF/water (3:1) and linked to the sugar-mimetic fragment using HATU-mediated coupling. The immediate downstream production environment adheres to ISO 9001:2015 for laboratory-scale custom synthesis rather than full cGMP, because the compound is supplied as a protected research intermediate for in vitro biochemical profiling. The associated certificate of analysis reports purity by HPLC at ≥98.5% (254 nm), residual siloxanes and boron-derived species below 0.3% by 1H qNMR, and heavy metals by ICP-OES with an acceptance limit of ＜20 µg/g for arsenic and lead in accordance with Ph. Eur. 2.4.8. The final deprotected bithiazole conjugate is tested as a cytotoxic agent in HER2-expressing gastric cancer xenograft models, where the bis-thiazole moiety enhances DNA binding affinity by a factor of 3–5 relative to mono-thiazole analogs.
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The pinacol boronate ester of thiazole, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (CAS 325142-88-5), is supplied as a white to off-white crystalline solid with a molecular formula of C9H14BNO2S and a molecular weight of 211.09 g·mol−1. Commercial product codes such as 683508 (Sigma-Aldrich) or B10384 (Thermo Scientific) identify material typically packed under inert gas in amber glass vials. Unlike the corresponding free boronic acid—which exhibits pronounced hygroscopicity and a tendency toward protodeboronation during storage—the dioxaborolane adduct offers markedly improved bench stability, enabling routine use in multistep syntheses without cold-chain logistics. This compound serves as a direct precursor for installing a 5‑thiazolyl motif via palladium-catalyzed cross-coupling, filling a niche distinct from the more common 2‑thiazolyl boronate esters that dominate screening collections. Its position-specific utility becomes critical in medicinal chemistry programs where the regioisomeric attachment of the thiazole ring modulates hydrogen‑bond acceptor geometry and π‑stacking with biological targets.
Routine release of the compound against a defined set of analytical benchmarks is necessary to prevent yield erosion in downstream coupling steps. The primary indicator of chemical integrity is chromatographic purity; a minimum area‑% of ≥98.0% by GC (FID, column: DB‑5, 30 m × 0.25 mm, 0.25 µm film) or HPLC (C18, UV detection at 254 nm) is a standard acceptance criterion. Residual water, quantified by Karl Fischer coulometric titration according to ISO 760:1978 or ASTM E203‑16, must remain ≤0.5% (w/w); water ingress beyond this threshold correlates with hydrolysis of the boronate ester to the free boronic acid and pinacol, which are not active coupling partners under anhydrous conditions. The melting range, recorded by differential scanning calorimetry at a scan rate of 10 °C·min−1 or capillary method, typically falls between 47.0 °C and 51.0 °C. Depression or broadening of the endotherm indicates the presence of degradation impurities or solvent residues. Additional release parameters adopted by contract manufacturing organizations appear in Table 1.
| Property | Test Method | Specification |
|---|---|---|
| Appearance | Visual inspection | White to off‑white crystalline powder |
| Assay (anhydrous, solvent‑free) | 1H NMR (CDCl3, 400 MHz) vs. internal standard | ≥95.0% (w/w) |
| Water content | Karl Fischer (coulometric), ISO 760 | ≤0.5% |
| Residual solvents | Headspace GC‑MS per USP <467> | THF ≤500 ppm, MTBE ≤500 ppm, hexanes ≤290 ppm |
| Heavy metals | ICP‑MS after microwave digestion | Pd ≤10 ppm, Ni ≤5 ppm, Cu ≤5 ppm |
| Storage stability (retest interval) | Purity by HPLC after 12 months at −20 °C under argon | Purity drop ≤0.5 area‑% |
Each parameter is anchored to a compendial or validated in‑house method; the trace‑metal limits reflect the compound’s role as a coupling reagent where residual palladium from the borylation step could interfere with catalyst selection in the user’s subsequent Suzuki reaction.
When the container is opened outside a controlled atmosphere, moisture absorption becomes the dominant degradation pathway. On a production‑scale loading dock at 25 °C and 60% RH, the material can pick up 0.2–0.4 wt% water within 30 minutes; at 80% RH the hydrolysis half‑life drops below 2 hours. Therefore, all weighing and subdivision must occur inside a glovebox maintaining <1 ppm H2O and <1 ppm O2, or, at minimum, under a positive pressure of dry argon via a Schlenk line. Bulk storage in a walk‑in cold room (2–8 °C) with continuous nitrogen blanketing has been validated by multiple kilo‑lab campaigns; desiccants such as molecular sieve 3 Å placed inside secondary containment have shown to extend the retest interval from 6 to 12 months. In the event of incidental moisture exposure, vacuum drying at 40 °C and <10 mbar for 12 hours can restore a ≥98% assay, provided the free boronic acid content has not exceeded 15 mol%—above that threshold, re‑esterification with pinacol and azeotropic removal of water is required. The compound should be kept away from strong acids (which cleave the B–O bond exothermically), strong oxidizing agents, and primary amines that can form adducts with the boron center and alter the ligand sphere during catalysis.
In the synthesis workflow, the pinacol ester is frequently dissolved in anhydrous tetrahydrofuran (THF) or 1,4‑dioxane immediately before use. The THF stock solution, when stored over activated molecular sieves under argon, retains >95% active boronate for 24 hours at ambient temperature; beyond that, transesterification with trace ethylene glycol impurities or moisture leads to oligomeric boronate species detectable by 11B NMR as a broad peak around 22 ppm (compare to the sharp signal at 32 ppm for the intact pinacol ester). Process chemists therefore standardize on making a fresh solution for each coupling run and never pool excess material from previous batches.
Under the rigorously anhydrous conditions typical of cross‑coupling setups, the 5‑thiazolyl boronate ester participates efficiently in the catalytic cycle. A representative sequence uses 1.0 equiv of aryl bromide, 1.3 equiv of the boronate (the slight excess compensates for protodeboronation at elevated temperature), 2 mol% Pd(PPh3)4, and 2.0 M aqueous K2CO3 (3 equiv) in degassed dioxane, stirred at 80 °C for 12–16 hours. Under these conditions, conversion of 4‑bromoanisole to the 5‑thiazolyl adduct exceeds 90% as determined by calibrated HPLC. When the electrophile switches to an electron‑deficient heterocycle such as 2‑chloropyrazine, the base is frequently changed to CsF (3.0 equiv) and the catalyst to PdCl2(dppf)·CH2Cl2 (5 mol%) to suppress homocoupling; reported isolated yields lie in the 70–85% range. Key differences between the 5‑substituted ester and the 2‑thiazolyl analogue arise from the electronic asymmetry of the thiazole nucleus: the C‑5 position carries a higher electron density than C‑2, which moderates transmetalation rates and often demands a more active catalyst system, yet the resulting biaryl products show distinctly different dihedral angles (≈38° for 5‑phenylthiazole vs. ≈21° for the 2‑isomer) with consequences for molecular recognition in pharmaceutical targets. Table 2 groups several literature‑precedented coupling pairs to illustrate the interplay between electrophile, catalyst, and isolated performance.
| Electrophile | Catalyst System (mol% Pd) | Base / Solvent | Temp (°C) / Time (h) | Conversion or Yield |
|---|---|---|---|---|
| 4‑Bromotoluene | Pd(PPh3)4 (2) | K2CO3 / dioxane‑H2O (4:1) | 80 / 16 | 95% conversion |
| 4‑Chlorobromobenzene | Pd(OAc)2 (2) + SPhos (4) | K3PO4 / toluene‑H2O (10:1) | 100 / 18 | 82% isolated (Br‑selective) |
| 3‑Bromopyridine | PdCl2(dppf) (3) | Na2CO3 / THF‑H2O (3:1) | 65 / 20 | 88% isolated |
| 5‑Bromo‑2‑(trifluoromethyl)pyridine | XPhos Pd G2 (5) | CsF / DME‑H2O (9:1) | 90 / 14 | 73% isolated |
| 2‑Chloro‑5‑nitropyridine | Pd2(dba)3 (2) + PCy3 (8) | K2CO3 / DMF | 110 / 6 | 68% isolated |
The data confirm that challenging oxidative‑addition partners (electron‑deficient chloroarenes) require the combination of a strong σ‑donor ligand and a non‑coordinating solvent to reach preparatively useful yields, whereas electron‑neutral bromides are tolerant of simpler catalytic architectures. Published results for certain ortho‑substituted, sterically encumbered substrates are limited, but experiments with 2‑bromo‑1,3‑dimethylbenzene suggest that the addition of a quaternary ammonium salt (10 mol% Bu4NBr) can recover ≈25 percentage points of yield by accelerating transmetalation of the pinacol ester.
Medicinal chemistry campaigns commonly stock the 2‑thiazolyl pinacol boronate, yet a growing body of structure–activity relationship (SAR) studies identifies the 5‑substituted regioisomer as a critical tool for modulating pharmacokinetic properties without altering the heteroatom arrangement. In inhibitors targeting kinase hinge regions, the 5‑linked thiazole positions the ring sulfur ≈2.1 Å closer to the gatekeeper residue compared to the 2‑linked congener, a shift that can replace a water‑mediated hydrogen bond with a direct contact. The boronate ester described here circumvents the need to start from 5‑bromothiazole—a lachrymator with handling complications at scale—and instead allows convergent assembly of advanced intermediates. Because the pinacol boron group deactivates the adjacent thiazole carbon toward electrophilic attack, subsequent functionalization steps (e.g., halogenation, formylation) can be carried orthogonally, a feature not shared by the corresponding boronic acid, which frequently precipitates as intractable oligomers under similar conditions. This operational advantage is further enhanced by the compound’s solubility profile: the pinacol ester dissolves readily in common polar aprotic solvents (>200 mg·mL−1 in THF, >150 mg·mL−1 in 1,4‑dioxane), whereas the free boronic acid often requires addition of methanol or DMF to reach concentrations above 50 mg·mL−1, thereby complicating solvent recovery in pilot‑plant operations.
Use of the 5‑thiazolyl isomer also distinguishes itself from the 4‑thiazolyl boronate, an even rarer building block that suffers from rapid proto‑deboronation owing to the electron‑withdrawing effect of the endocyclic sulfur and nitrogen atoms in that orientation. Stability screening via accelerated aging (40 °C / 75% RH, open vial) shows the 5‑isomer degrades 4‑fold slower than the 4‑isomer and 2.5‑fold slower than the unprotected 5‑thiazolylboronic acid. This robust profile translates into fewer rejected batches on a manufacturing line where cumulative exposure to ambient humidity during dispensing and reactor charging is unavoidable.
Process‑scale campaigns (≥50 kg of the boronate ester) have highlighted a specific incompatibility: prolonged heating in the presence of dialkylamine bases (e.g., diisopropylethylamine) can trigger N‑methyl shift from pinacol to the amine, forming an aminoborane adduct that is catalytically inert. Reaction monitoring by ReactIR has tracked the disappearance of the characteristic B–O stretch at 1350 cm−1 under such conditions. Therefore, potassium carbonate or cesium fluoride remain the recommended bases for scale‑up, and amine scavengers must be strictly excluded from the coupling medium. When these processing windows are respected—specifically, a catalyst loading window of 1–5 mol% Pd, a temperature not exceeding 100 °C for extended periods, and a water content in the reaction mixture held below 5 vol%—the pinacol ester of 5‑thiazolylboronic acid delivers consistent C–C bond formation yields across multiple equipment trains, from jacketed glass reactors to Hastelloy vessels equipped with retreat‑curve impellers.
