6H-Thieno[2,3-B]Pyrrole-5-Carboxylic Acid Ethyl Ester
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HS Code |
831995 |
| Chemical Formula | C9H9NO2S |
| Molar Mass | 195.24 g/mol |
| Appearance | Solid (usually) |
| Physical State | Solid at room temperature |
| Melting Point | Data may vary, needs specific measurement |
| Boiling Point | Data may vary, needs specific measurement |
| Solubility In Water | Low solubility in water |
| Solubility In Organic Solvents | Soluble in some organic solvents like dichloromethane |
| Density | Data may vary, needs specific measurement |
| Odor | Typical organic compound odor (description may vary) |
As an accredited 6H-Thieno[2,3-B]Pyrrole-5-Carboxylic Acid Ethyl Ester factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 6H - Thieno[2,3 - B]Pyrrole - 5 - Carboxylic Acid Ethyl Ester packaged in a sealed bottle. |
| Shipping | 6H - Thieno[2,3 - B]Pyrrole - 5 - Carboxylic Acid Ethyl Ester is shipped in well - sealed containers. Special care is taken to prevent exposure, with proper labeling indicating its chemical nature, and it's transported following hazardous chemical shipping regulations. |
| Storage | 6H - Thieno[2,3 - b]Pyrrole - 5 - Carboxylic Acid Ethyl Ester should be stored in a cool, dry place away from direct sunlight. Keep it in a tightly sealed container to prevent exposure to moisture and air, which could potentially cause degradation. Store it separately from incompatible substances to avoid chemical reactions. |
The ethyl ester of 6H-thieno[2,3-b]pyrrole-5-carboxylic acid functions as a late-stage intermediate in the manufacture of fused heterocyclic kinase inhibitors targeting oncogenic mutations. The ester group is selectively hydrolysed under mild alkaline conditions—typically 1.2 equiv. LiOH·H₂O in a 3:1:1 (v/v/v) THF/MeOH/water mixture at 0–5 °C—to avoid ring-opening of the electron-rich pyrrole moiety. Quenching with 1.0 M citric acid precipitates the free carboxylic acid, which is isolated by vacuum filtration and dried at 40 °C for 12 h. Subsequent amide bond formation employs 1.1 equiv. HATU, 2.5 equiv. DIPEA, and 1.05 equiv. of a substituted aniline in anhydrous DMF; conversion exceeds 95% by HPLC (monitored at 254 nm) within 4 h at ambient temperature. Purity specifications for pharmaceutical intermediates mandate HPLC area% ≥99.5%, with single unknown impurities capped at 0.10%. Residual palladium from earlier Suzuki couplings is critical: a limit of ≤10 ppm is enforced per Ph. Eur. 2.4.8 (method A), often requiring a charcoal treatment or polymer-bound metal scavenger (e.g., MP-TMT) before the final crystallisation. On a pilot-plant scale, the hydrolysis exotherm demands a jacketed glass-lined vessel with recirculating chiller capable of maintaining internal temperature within ±2 °C of setpoint; excursions above 8 °C are known to generate a des-ethyl dimer impurity identified by LC-MS as the symmetric anhydride. The final compound is packaged under argon in amber borosilicate glass bottles following ICH Q3C residual solvent guidelines—DMF and THF are individually limited to 880 ppm and 720 ppm, respectively. Solubility in common pharma-grade solvents (DMSO, DMAc) is confirmed before shipment to avoid precipitation during customer dissolution.Quality specifications bifurcate by end-use sector, as summarized:
What process-safety controls govern the lithiation of the thienopyrrole scaffold for diamide pesticide production?Heterocyclic carboxylic acid esters like the title compound serve as advanced building blocks for diamide insecticides analogous to cyantraniliprole and chlorantraniliprole. The key transformation involves directed ortho-lithiation at the thiophene ring’s α-position using 1.05 equiv. n-BuLi (2.5 M in hexanes) in anhydrous THF at −78 °C under a nitrogen atmosphere; the presence of the ethyl ester group directs the metalation regioselectivity, as confirmed by deuteration-quench NMR studies. After 30 min, the resulting aryllithium species is treated with 1.2 equiv. of trimethyl borate, warmed to 0 °C, and quenched into 2.0 M aqueous HCl to yield the corresponding boronic acid. This intermediate is immediately coupled via a Suzuki–Miyaura protocol with a halogenated pyrazole carboxamide derivative using 1 mol% Pd(dppf)Cl₂·CH₂Cl₂ and 3.0 equiv. K₃PO₄ in degassed 4:1 dioxane/water at 85 °C for 8 h. Process safety evaluation on kg-scale highlights the exothermic decomposition of n-BuLi/THF adducts when warming above −40 °C; calorimetry (RC1e) indicates an adiabatic temperature rise ΔTad = 62 K for the lithiation step. To mitigate risk, the borate quench is performed as a continuous-flow process using a Corning® Advanced-Flow™ reactor with a residence time of 12 sec at −70 °C, reducing accumulated reactive volume by 90% compared to batch. Pesticide intermediate specifications mandate a purity of ≥98.0% (HPLC, 230 nm) and a boronic acid content assay of ≥97.5%, tested per CIPAC MT 30.5. Residual THF and hexanes are stripped to ≤500 ppm each under vacuum (10 mbar, 45 °C) before packaging. The final diamide insecticide product, applied at rates as low as 25 g a.i./ha, exhibits knockdown activity against lepidopteran pests; the intermediate’s stereoelectronic profile—donated by the fused pyrrole ring—enhances binding to insect ryanodine receptors, as demonstrated in competitive binding assays using tritiated ryanodine in isolated housefly thorax membranes.When the ethyl ester acts as a solubilising mask for donor–acceptor copolymers in bottom-gate OFETsThe monomeric thieno[2,3-b]pyrrole carboxylate is copolymerised with electron-deficient acceptors such as diketopyrrolopyrrole (DPP) or isoindigo via Stille cross-coupling to yield low-bandgap donor–acceptor polymers for organic field-effect transistors. The ethyl ester side chain provides sufficient solubility in chlorinated aromatics (1,2-dichlorobenzene, b.p. 180 °C) to enable high-molecular-weight polymerisation; without the ester, the rigid fused ring precipitates at chain lengths below 10 repeat units. A typical charge consists of 1.0 equiv. of 2,5-bis(trimethylstannyl)thieno[2,3-b]pyrrole-5-carboxylic acid ethyl ester and 1.0 equiv. of 3,6-bis(5-bromothiophen-2-yl)-2,5-dioctylpyrrolo[3,4-c]pyrrole-1,4-dione, catalysed by 2 mol% tris(dibenzylideneacetone)dipalladium(0) and 8 mol% tri(o-tolyl)phosphine in degassed, anhydrous chlorobenzene (0.05 M monomer concentration) at 130 °C for 72 h under microwave irradiation. After end-capping with 2-bromothiophene and 2-(tributylstannyl)thiophene sequentially, the crude polymer is precipitated into methanol, purified by sequential Soxhlet extraction (acetone, hexane, finally chloroform), and the chloroform fraction is concentrated and dried under vacuum at 60 °C. Gel-permeation chromatography against polystyrene standards in 1,2,4-trichlorobenzene at 150 °C typically reveals Mn values of 22–35 kg/mol with a dispersity Đ = 1.8–2.5. Residual palladium content—a known charge-trap source—must be reduced to ≤50 ppm (ICP-MS) by repeated aqueous extraction with a 10% aqueous sodium diethyldithiocarbamate trihydrate solution at 60 °C for 1 h. OFET devices are fabricated on heavily n-doped silicon wafers with 300 nm SiO₂ gate dielectric, pre-treated with octadecyltrichlorosilane (OTS) to form a self-assembled monolayer. The polymer is spin-coated from a 5 mg/mL chlorobenzene solution at 2000 rpm, annealed at 200 °C for 10 min under nitrogen, and top-contact gold source-drain electrodes (50 nm) are evaporated through a shadow mask with channel length L = 50 µm and width W = 1000 µm. Field-effect mobility extracted from the saturation regime following the gradual-channel approximation (IEEE Std 1620-2008) reaches 0.12 ± 0.03 cm²/V·s, with an on/off current ratio of 10⁴–10⁵. Threshold voltage shifts are observed when the relative humidity during spin-coating exceeds 55%, attributed to moisture uptake by the ester group; therefore, glovebox processing (O₂ < 0.1 ppm, H₂O < 0.1 ppm) is mandatory.In dye-sensitized solar cells, the thieno[2,3-b]pyrrole carboxylate core is incorporated as the electron-donating segment in push–pull organic dyes bearing a cyanoacrylic acid anchor. The ethyl ester is deliberately maintained during the stepwise construction of the π-bridge to guarantee solubility and facilitate chromatographic separation of intermediates; it is saponified only in the final step immediately before cell assembly. A representative route begins with Vilsmeier–Haack formylation at the thiophene α-position using 3.0 equiv. POCl₃ in DMF (0–5 °C → 80 °C, 6 h) to afford the corresponding aldehyde. Knoevenagel condensation with cyanoacetic acid (1.5 equiv.) and ammonium acetate (0.2 equiv.) in acetic acid under reflux for 12 h yields the cyanoacrylic acid-functionalised dye precursor still bearing the ethyl ester. The final hydrolysis employs 2.0 equiv. KOH in a 2:1 ethanol/water mixture at 60 °C for 3 h, followed by acidification to pH 2.5 with 1.0 M HCl. The dye is purified by reversed-phase flash chromatography (C18, acetonitrile/water + 0.1% TFA) and dried by lyophilisation. Anchoring onto mesoporous TiO₂ photoanodes (12 µm transparent layer + 4 µm scattering layer, screen-printed on FTO glass) is performed by immersing the electrodes in a 0.2 mM dye solution in tert-butanol/acetonitrile (1:1) containing 10 mM chenodeoxycholic acid as an anti-aggregation co-adsorbent for 18 h at 25 °C in the dark. Photovoltaic characterisation under AM 1.5G illumination (100 mW/cm², calibrated with a KG5-filtered Si reference cell per IEC 60904-3) yields short-circuit current density JSC = 9.8 ± 0.4 mA/cm², open-circuit voltage VOC = 0.68 ± 0.02 V, and fill factor FF = 0.72 ± 0.03, translating to a power conversion efficiency of 4.8 ± 0.2% with a liquid electrolyte composed of 0.6 M 1,2-dimethyl-3-propylimidazolium iodide, 0.1 M LiI, 0.05 M I₂, and 0.5 M 4-tert-butylpyridine in acetonitrile. The ester intermediate’s moisture sensitivity is notable: exposure to ambient air (RH > 40%) for more than 2 h leads to partial hydrolysis and ester-attenuated binding on TiO₂, decreasing PCE by 15–20%. Consequently, all dye handling and cell assembly are performed in a dry room (dew point ≤ −40 °C).A turn-on fluorogenic probe substrate for esterase activity imaging in live cellsThe ethyl ester functionality of the title compound renders it a latent fluorophore when conjugated to a π-extended acceptor; enzymatic hydrolysis liberates a highly emissive species suitable for intracellular imaging. The probe is constructed by palladium-catalysed Sonogashira coupling between 2-iodo-6H-thieno[2,3-b]pyrrole-5-carboxylic acid ethyl ester and 4-ethynyl-benzaldehyde, followed by Knoevenagel reaction with indanedione-based acceptors to install a red-shifted emission. The intact ester exhibits minimal fluorescence (quantum yield ΦF < 0.01 in PBS buffer, pH 7.4) due to photoinduced electron transfer (PET) quenching by the carbonyl group. Upon exposure to porcine liver esterase (PLE, 10 U/mL) at 37 °C, the ester is cleaved to the corresponding carboxylate with t1/2 ≈ 4.2 min, turning on a bright signal at λem = 598 nm (620-fold enhancement). Calibration in cell lysate yields a limit of detection of 0.8 ng/mL for PLE, linear from 1 ng/mL to 5 µg/mL. For live HeLa cell imaging, the probe is loaded at 2 µM in DMEM containing 0.1% DMSO and 1% BSA for 30 min at 37 °C under 5% CO₂. Confocal microscopy (excitation 488 nm, emission 570–640 nm) reveals punctate cytoplasmic staining, which is diminished by >90% when cells are pre-incubated with 100 µM phenylmethylsulfonyl fluoride (PMSF), a serine esterase inhibitor. In vitro selectivity assays against acetylcholinesterase, butyrylcholinesterase, and carboxylesterase 2 demonstrate a 25- to 80-fold preference for carboxylesterase 1, consistent with the substrate’s preference for small alkyl esters. Stability of the probe stock solution in acetonitrile is maintained for 30 days at −20 °C in the dark; repetitive freeze–thaw cycles (>3) cause 5% degradation per cycle, mandating single-use aliquoting. The compound complies with ISO 10993-5 for in vitro cytotoxicity testing when used at concentrations ≤10 µM; no interference is observed with common cell viability assays (MTT, resazurin).Suzuki–Miyaura coupling screening platformEthyl 6H-thieno[2,3-b]pyrrole-5-carboxylate is routinely employed as a cross-coupling surrogate in medicinal chemistry synthesis laboratories to generate diverse compound libraries. The ester is first converted to the corresponding boronic acid pinacol ester via palladium-catalysed borylation using bis(pinacolato)diboron (1.2 equiv.), KOAc (3.0 equiv.), and 5 mol% Pd(dppf)Cl₂ in degassed DMSO at 80 °C for 16 h. Subsequent Suzuki coupling with aryl halides in a 96-well plate format (0.1 mmol scale, DME/water 4:1, 2.0 equiv. Cs₂CO₃, 2 mol% SPhos Pd G3) reliably furnishes biaryl adducts in 30–85% isolated yield after automated flash chromatography. The ethyl ester remains intact throughout, allowing parallel diversification. Users must pre-dry glassware and maintain anhydrous conditions to avoid protodeboronation; moisture content in the solvent mixture above 100 ppm (Karl Fischer) reduces cross-coupling efficiency by up to 40%.A representative performance dataset across commonly employed ligand systems is compiled in the following table.
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| Ester | Molecular Weight (g·mol⁻¹) | Alkaline Hydrolysis t½ (0.1 M NaOH, 25 °C) | Acid Deprotection (TFA/DCM 1:1) | Preferred Application Scope |
|---|---|---|---|---|
| Methyl | 181.21 | 4.2 min | Stable | Early SAR exploration; solid-phase coupling |
| Ethyl | 195.24 | 12.8 min | Partial cleavage (6 h) | Kilogram-scale amidation; HOBt/EDC-mediated coupling |
| Isopropyl | 209.26 | 38.5 min | Full deprotection (1.5 h) | Dual orthogonal protecting strategies |
| tert-Butyl | 223.29 | No reaction | Complete (20 min) | Acid-labile SPPS resin chemistry |
