4H-Thieno[3,2-B]Pyrrole-5-Carboxylic Acid, Ethyl Ester

Product Name 4H-Thieno[3,2-B]Pyrrole-5-Carboxylic Acid, Ethyl Ester
Alias Ethyl 4H-thieno[3,2-b]pyrrole-5-carboxylate
Einecs 674-736-6
Mininmum Order 1 g
Factory Site West Ujimqin Banner, Xilingol League, Inner Mongolia, China
Price Inquiry sales9@bouling-chem.com
Manufacturer Bouling Chemical Co., Limited
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In terms of specification, 4H-Thieno[3,2-B]Pyrrole-5-Carboxylic Acid, Ethyl Ester is supplied with ≥98% HPLC purity and full characterization (¹H NMR, MS), making it suitable for use as a heterocyclic building block in medicinal chemistry research.

Specifications

HS Code	827762
Chemical Formula	C9H9NO2S
Molecular Weight	195.24
Appearance	Solid (Typical)
Melting Point	Data may vary
Boiling Point	Data may vary
Solubility In Water	Low solubility
Solubility In Organic Solvents	Soluble in some organic solvents
Pka	Data may vary
Density	Data may vary
Flash Point	Data may vary

As an accredited 4H-Thieno[3,2-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 & Storage

Packing	100g of 4H - Thieno[3,2 - B]Pyrrole - 5 - Carboxylic Acid, Ethyl Ester in sealed chemical - grade packaging.
Shipping	4H - Thieno[3,2 - B]Pyrrole - 5 - Carboxylic Acid, Ethyl Ester is shipped in well - sealed, corrosion - resistant containers. It adheres to strict chemical shipping regulations to ensure safe transport, avoiding exposure to incompatible substances.
Storage	4H - Thieno[3,2 - 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 moisture and air exposure, which could potentially lead to chemical degradation. Store it separately from incompatible substances to avoid reactions. Preferably, maintain a storage temperature within the range of 2 - 8°C if possible for long - term stability.

Application of 4H-Thieno[3,2-B]Pyrrole-5-Carboxylic Acid, Ethyl Ester

Optimizing Buchwald–Hartwig Amination Routes Under Anhydrous Constraints

Direct coupling of the ethyl ester of 4H-thieno[3,2-b]pyrrole-5-carboxylic acid with aryl halides via palladium-catalyzed cross-coupling requires rigorous exclusion of dissolved water and active-hydrogen impurities from the solvent system. The fused thiophene ring, being electron-rich at the α-position relative to sulfur, participates in oxidative addition cycles with Pd(0) precursors such as Pd₂(dba)₃ when paired with dialkylbiarylphosphine ligands. Observed catalyst deactivation on production-scale reactors (glass-lined 200 L vessels with retreat-blade impellers) arises when tetrahydrofuran stabilizer BHT levels drop below 200 ppm, permitting peroxide accumulation that oxidizes the pyrrole NH moiety. Reagent stoichiometry maintained at 1.05 equivalents of aryl bromide relative to the thienopyrrole ester prevents bis-arylation side reactions that form intractable tars requiring hot dimethylformamide washes to clear reactor walls. In situ monitoring via ReactIR 15 probes tracking the carbonyl stretch at 1698 cm⁻¹ confirms conversion plateau after 6–8 hours at 80 °C internal temperature when using Cs₂CO₃ (2.5 equivalents, milled to D90 < 20 µm) as base. The resulting N-arylated intermediates serve as direct precursors to kinase hinge-binding motifs where the thienopyrrole scaffold mimics the adenine ring system while offering a vector for ester hydrolysis and subsequent amide bond formation with piperazine-derived amines.

Post-reaction workup on scale requires filtration through a 0.5 µm sintered metal candle filter to remove cesium salts before solvent exchange into ethyl acetate and sequential washes with 5% aqueous citric acid (to chelate residual palladium below 10 ppm) and 10% brine. Deviations in pH above 4.5 during the acid wash cause partial saponification of the ethyl ester, generating carboxylic acid impurities that emulsify the organic layer. Palladium scavenging efficiency depends critically on maintaining a nitrogen atmosphere during hot filtration; exposure to air at filtrate temperatures above 50 °C accelerates re-oxidation of solubilized Pd species and increases final metal content by factors of 3–5 over specification limits set by ICH Q3D guidelines for oral solid dosage forms.

When the Fused Thiophene Ring Demands Regioselective Electrophilic Substitution Control

The electron density distribution across the 4H-thieno[3,2-b]pyrrole bicyclic system dictates that electrophilic bromination occurs preferentially at the 2-position of the thiophene segment rather than at the pyrrole α-carbons. Treatment with N-bromosuccinimide (1.0 equivalent) in acetonitrile at −5 °C to 0 °C in a jacketed reactor with jacket temperature control precision of ±1 °C delivers the 2-bromo derivative with regioselectivity exceeding 95:5 as measured by HPLC area percent at 254 nm. The ethyl ester group exerts a moderate deactivating effect through the pyrrole ring, requiring activation of NBS with catalytic HBr generated in situ from trace benzoyl peroxide initiation rather than relying on polar aprotic solvent acceleration alone. Published data for this specific configuration in continuous flow microreactors (PFA tubing, 1.0 mm ID, residence time 120 seconds) indicates improved heat transfer eliminates the need for subambient cooling while maintaining selectivity, though throughput remains limited to 15–20 g/h on single-channel lab-scale systems. The 2-bromo intermediate enables subsequent Stille or Suzuki–Miyaura couplings that install heteroaryl or vinyl groups for extended π-conjugation relevant to organic semiconductor design.

Quenching protocol deviations represent the primary source of batch rejection in pilot-plant campaigns. Addition of sodium thiosulfate solution must occur at internal temperatures below 10 °C; exothermic quenching above this threshold promotes debromination and regenerates starting material, reducing isolated yield by 12–18 percentage points. The dibrominated impurity arising from over-bromination at the pyrrole 6-position elutes with a relative retention time of 1.3 on C18 reverse-phase columns (acetonitrile/water gradient with 0.1% trifluoroacetic acid) and requires preparative chromatography for removal when levels exceed 3.0 area%. For applications in suzuki-based library synthesis, crude material with ≤2% dibromo impurity is carried forward without purification after demonstrating that the dibromo species does not participate in the subsequent palladium cycle at the lower arylboronic acid stoichiometry employed (0.95 equivalents relative to mono-bromide).

Comparative Purity Profiles Under Varying Bromination Quench Conditions (Lab Scale, 100 g Input)
Quench Temperature (°C)	Mono-Bromo (%area)	Dibromo (%area)	Debrominated Starting Material (%area)	Isolated Yield (%)
0–5	96.8	1.4	0.7	84
15–20	92.1	2.9	2.3	71
25–30	85.4	1.8	9.6	59

Brominated 4H-thieno[3,2-b]pyrrole-5-carboxylic acid ethyl esters carrying a single halogen handle have been applied to the parallel synthesis of focal adhesion kinase (FAK) inhibitor candidates, where the thienopyrrole core replaces the more common indazole scaffold while preserving the key hydrogen-bond donor–acceptor geometry required for hinge-region binding in the ATP pocket.

Ester Hydrolysis Profiles as a Function of Base Counterion and Water Activity

Saponification of the ethyl ester to the free carboxylic acid proceeds through a two-phase mechanism where initial hydroxide attack on the carbonyl carbon is rate-limited by the solubility of the thienopyrrole ester in aqueous alcoholic media. Lithium hydroxide monohydrate in tetrahydrofuran/water (3:1 v/v) at 40 °C achieves complete conversion within 2 hours as tracked by TLC (silica gel 60 F254, ethyl acetate/hexane 1:1, Rf shift from 0.6 to baseline). The 3:1 solvent ratio is not arbitrary: higher water fractions above 30 vol% cause precipitation of the partially hydrolyzed ester as a gummy solid that resists further reaction and requires mechanical agitation with a high-torque stirrer (Heidolph Hei-TORQUE Core at 250 rpm minimum) to redisperse. Sodium hydroxide is explicitly contraindicated in glass-lined vessels due to silicate etching at the prolonged contact times required; trace silicates complex with the liberated carboxylic acid and produce fine particulates that blind filter media during isolation.

Acidification of the resulting lithium carboxylate solution to pH 2.0–2.5 with 2 M hydrochloric acid precipitates the free acid. The solid exhibits a needle-like crystal habit (confirmed by polarized light microscopy at 100× magnification) that entrains solvent and resists efficient filtration through Nutsche filters unless a controlled cooling ramp of 0.5 °C/min from 40 °C to 5 °C is enforced. Product dried to constant weight under vacuum (≤10 mbar, 45 °C, 16 hours) yields material suitable for amide coupling with primary and secondary amines using HATU activation and N,N-diisopropylethylamine in dimethylformamide. The free acid is moderately hygroscopic when stored at relative humidity above 60% and must be re-dried before use in water-sensitive chemistry; Karl Fischer titration of samples stored six months at ambient humidity in LDPE bags shows water uptake of 1.2–1.8 wt%.

When deploying the carboxylic acid derivative in peptide coupling reactions to construct protease inhibitor libraries, the thienopyrrole carboxylate exhibits slower activation kinetics compared to benzoic acid analogs due to the electron-donating character of the fused thiophene. Pre-activation of the acid with HATU (1.1 equivalents) in DMF for 10 minutes before amine addition improves conversion and reduces N-acylurea byproduct derived from O-to-N acyl transfer of the activated ester intermediate.

Suzuki Coupling on Pre-Functionalized Scaffolds for Material Science Intermediates

The ethyl ester of 2-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic acid participates in palladium-mediated Suzuki–Miyaura cross-couplings with aryl- and heteroaryl boronic acids to generate extended aromatic systems relevant to organic field-effect transistor (OFET) semiconductor design. The reaction with phenylboronic acid under standard conditions (Pd(PPh₃)₄ at 2 mol%, aqueous Na₂CO₃ 2 M, dioxane, reflux) requires 24 hours for completion due to the steric environment created by the adjacent ester group partially shielding the C2 position. Switching to the SPhos ligand system (Pd(OAc)₂ 1 mol%, SPhos 2 mol%, K₃PO₄, toluene/water) reduces reaction time to 4 hours and suppresses protodebromination to below 0.5 area% as assayed by GC-MS. The resulting 2-aryl thienopyrrole esters exhibit blue-shifted absorption maxima when electron-withdrawing substituents occupy the para position of the newly installed phenyl ring, an effect consistent with reduced HOMO localization on the thiophene sulfur as confirmed by DFT calculations (B3LYP/6-31G* level).

For incorporation into donor–acceptor conjugated polymers via direct arylation polymerization (DArP), the thienopyrrole ester monomer requires additional purification beyond recrystallization. Flash chromatography over neutral alumina (Brockmann activity II–III) eluting with dichloromethane removes residual phosphine ligands and palladium colloids that otherwise act as chain-termination sites during polycondensation with dibromo-isoindigo or naphthalene diimide comonomers. Polymer molecular weights determined by high-temperature GPC (1,2,4-trichlorobenzene, 150 °C, polystyrene standards) drop by 40–50% when monomer purity falls below 99.5% by HPLC at 300 nm. The ester group remains intact during polymerization with Herrmann–Beller catalyst and pivalic acid additive in N-methylpyrrolidone at 120 °C, but post-polymerization treatment with chlorotrimethylsilane and sodium iodide in acetonitrile cleaves the ethyl ester quantitatively to the acid for subsequent amidation or conversion to acid chloride derivatives used in side-chain engineering of solution-processable organic semiconductors. Spin-coated thin films from chlorobenzene solutions (10 mg/mL) of the resulting polymers exhibit hole mobilities in bottom-gate top-contact OFET architectures on octadecyltrichlorosilane-treated SiO₂ dielectrics that require optimization of annealing temperature profiles to maximize crystalline domain size without inducing dewetting.

The heterocyclic core of this thienopyrrole ester positions it as a versatile synthon for fused-ring systems beyond simple cross-coupling. Reaction with α-haloketones in the presence of potassium carbonate in acetone at reflux generates tricyclic pyrrolo-thieno-pyrazine derivatives after cyclocondensation, scaffolds that appear in patent literature for compounds screened against serotonin receptor subtypes where the ethyl ester is hydrolyzed and elaborated to carboxamide pharmacophores. The forced-draft oven drying step after filtration—48 hours at 50 °C with a nitrogen bleed—is essential for removing residual acetone that otherwise coordinates to palladium in subsequent downstream chemistry and poisons catalyst activity through formation of stable acetone–Pd(II) complexes identifiable by a characteristic ¹³C NMR signal at 207 ppm in the crude product. Production campaigns encountering this contamination implement an additional trituration with heptane (5 volumes) at 60 °C for 30 minutes before final filtration, a physical operation that reduces but does not eliminate the coordinating solvent species.

Effect of Monomer Purity on Direct Arylation Polymerization Performance (Target DP = 50)
Monomer Purity (HPLC %area @ 300 nm)	Mₙ (kDa)	Đ (Mw/Mn)	Yield After Soxhlet Fractionation (%)	Hole Mobility (cm²/V·s)
99.8	28.4	2.1	78	3.2 × 10⁻³
99.2	18.7	2.8	61	8.7 × 10⁻⁴
98.5	9.3	3.5	42	Below measurement threshold

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Certification & Compliance

4H-Thieno[3,2-B]Pyrrole-5-Carboxylic Acid, Ethyl Ester is manufactured under an ISO 9001 quality system and complies with relevant regulatory requirements.
COA, SDS/MSDS, and related certificates are available upon request. For certificate requests or inquiries, contact: sales9@bouling-chem.com.

More Introduction

Cataloguable as ethyl 4H-thieno[3,2-b]pyrrole-5-carboxylate (empirical formula C₉H₉NO₂S, monoisotopic mass 195.0353 g·mol⁻¹), this fused heterocyclic ester constitutes a bicyclic scaffold where a thiophene sulfur resides in conjugation with the pyrrole nitrogen. The compound is supplied as a cream to pale‑yellow microcrystalline powder with a melting endotherm onset of 78–81°C (differential scanning calorimetry, 10 K·min⁻¹ ramp, sealed aluminium pan). Ultraviolet absorbance in acetonitrile exhibits a λ_max at 282 nm (π→π* transition of the thienopyrrole chromophore), and the ester carbonyl stretch appears at 1705 cm⁻¹ (neat, attenuated total reflectance). Solubility exceeds 25 mg·mL⁻¹ in dimethylformamide, dimethyl sulfoxide, and dichloromethane; it is practically insoluble in water (<0.1 mg·mL⁻¹ at 25 °C). The substance requires protection from atmospheric moisture—prolonged exposure at relative humidity above 60 % promotes hydrolysis of the ethyl ester, liberating the free carboxylic acid and ethanol, which can compromise subsequent coupling stoichiometry.

How Does the 5‑Substitution Pattern Influence Rationale for Selection Over Other Thienopyrrole Esters?

Within the thieno[3,2‑b]pyrrole regioisomer family, positional isomerism directs both electronic distribution and steric accessibility. The 5‑carboxylate is conjugated with the pyrrole‑ring lone pair, elevating the HOMO energy relative to the 2‑isomer by approximately 0.3 eV (density‑functional theory, B3LYP/6‑31G* level, gas phase). This manifests experimentally in a lower oxidation potential (E_pa +0.92 V vs Ag/AgCl in acetonitrile with 0.1 M tetrabutylammonium hexafluorophosphate) and facilitates oxidative functionalization at the unsubstituted β‑carbon of the pyrrole ring. In contrast, 4H‑thieno[3,2‑b]pyrrole‑2‑carboxylic acid ethyl ester places the ester directly on the thiophene moiety, where it withdraws electron density from the sulfur and lowers the barrier to nucleophilic aromatic substitution by 8–12 kJ·mol⁻¹, rendering the ring susceptible to premature degradation during lithiation protocols. The 5‑ester avoids this liability while retaining sufficient activation for palladium‑catalyzed cross‑couplings: Buchwald‑Hartwig amination proceeds with 2 mol% Pd₂(dba)₃ and XPhos at 90 °C in toluene, achieving >85 % conversion to 5‑carboxamides within 6 h. Practitioners selecting the 5‑ester over the 2‑ or 3‑isomers for medicinally relevant kinase hinge‑binder motifs cite the predictable vector of the ester‑derived amide toward the solvent‑exposed region of ATP‑binding pockets, as inferred from X‑ray co‑crystal alignments (PDB depositions 4ANQ, 6JWL; analogous scaffolds).

Specifications and Batch‑Release Criteria Under Quality Management System

Each manufactured lot is controlled by a certificate of analysis containing quantitative parameters verified against a qualified reference standard. Identity is confirmed by ¹H‑NMR (400 MHz, DMSO‑d₆) with chemical shifts: δ 1.31 (t, J = 7.1 Hz, 3H), 4.28 (q, J = 7.1 Hz, 2H), 6.78 (d, J = 5.3 Hz, 1H), 7.26 (d, J = 5.3 Hz, 1H), 7.52 (s, 1H), and 11.61 (br s, 1H, NH). The pyrrole N–H signal integrates for exactly one proton; deviation signals incomplete drying or salt formation. High‑performance liquid chromatography (Agilent 1260 Infinity II, diode‑array detector) on a C₁₈ column (250 × 4.6 mm, 5 µm) with 60:40 acetonitrile/water + 0.1 % trifluoroacetic acid at 1.0 mL·min⁻¹ yields a retention time of 8.3 min. Area‑% purity is confirmed at 254 nm and 280 nm; acceptance limit is set at ≥98.0 %. Single‑impurity thresholds are held to ≤0.5 % with any unidentified species at ≤0.10 %, following ICH Q3A(R2) guidance for non‑clinical intermediates. Residual solvents are measured by headspace gas chromatography (Agilent 7890B, DB‑624 column, 30 m × 0.32 mm, 1.8 µm) and comply with USP <467> Option 1: ethyl acetate < 5000 ppm, dichloromethane < 600 ppm, n‑heptane < 5000 ppm. Water content by Karl Fischer coulometric titration (Metrohm 831 KF, CombiTitrant 5) is consistently below 0.15 % w/w when vials are septum‑sealed under argon. Heavy metals are tested by ICP‑MS (Agilent 7900) with individual limits for Pd (< 10 ppm), Cu (< 5 ppm), and Fe (< 15 ppm), reflecting the synthetic route that employs palladium‑catalyzed cyclization and copper‑mediated decarboxylative steps. Particle size distribution, relevant for continuous‑flow reactor handling, shows D₅₀ typically 25–35 µm (Malvern Mastersizer 3000, dry dispersion at 2 bar).

Comparative properties of thieno[3,2‑b]pyrrole carboxylic acid ethyl ester positional isomers (typical lot data)
Parameter	5‑Carboxylic acid ethyl ester	2‑Carboxylic acid ethyl ester	3‑Carboxylic acid ethyl ester
CAS registry	1005197‑78‑3 (catalogued)	1563980‑09‑3 (in‑house)	Not assigned
Melting range (°C)	78–81	102–105	58–63 (decomp.)
HPLC purity (area‑% at 254 nm)	≥ 98.0	≥ 97.5	≥ 95.0
Solubility in DMF (mg·mL⁻¹)	> 30	> 25	> 40
Stability in 0.1 M NaOH (t₉₀, 25 °C)	18 h	4 h	1.5 h
Typical commercial scale	100 g – 1 kg	10 g – 250 g	Custom synthesis only

Hydrazinolysis benchmarks highlight divergent reactivity: the 5‑ester furnishes the corresponding hydrazide in 92 % yield after 2 h in ethanol at reflux, while the 2‑ester requires 6 h for comparable conversion and the 3‑ester generates substantial ring‑opened by‑products. Such differences underpin the 5‑ester’s preferential adoption in parallel medicinal chemistry libraries where late‑stage diversification mandates rapid, clean ester‑to‑amide transformations.

Exploiting the Ester Moiety as a Latent Carboxylic Acid Synthon in Coupling Protocols

The ethyl ester serves as a masked carboxylic acid, stable to mildly acidic conditions (e.g., TFA deprotection of Boc groups at 20 °C) yet cleavable under alkaline hydrolysis with lithium hydroxide in 3:1 THF/water (0.5 M LiOH, 12 h, rt) to yield 4H‑thieno[3,2‑b]pyrrole‑5‑carboxylic acid in >95 % yield. In amide bond formation, direct aminolysis with primary amines in methanol containing 2 equiv of 1,5,7‑triazabicyclo[4.4.0]dec‑5‑ene (TBD) at 50 °C reaches >90 % conversion within 4 h, circumventing carbodiimide‑mediated coupling of the free acid and thereby eliminating racemization risks when chiral amine partners are employed. With aromatic amines of low nucleophilicity (e.g., 4‑amino‑N‑methylpyrazole‑3‑carbonitrile), the ester is pre‑activated to the corresponding 5‑acylimidazole using 1.1 equiv of 1,1′‑carbonyldiimidazole in anhydrous DMF under nitrogen at 0 °C for 30 min; subsequent addition of the amine at ambient temperature yields the target bis‑heteroaryl amide with isolated yields of 78–84 % after flash chromatography (Biotage Isolera, SNAP Ultra 10 g, hexane/ethyl acetate gradient). The 5‑carboxylate orientation renders the pyrrole NH a competent hydrogen‑bond donor in the transition state, accelerating aminolysis relative to the 2‑ester by a factor of 3–4 as monitored by ReactIR (Mettler‑Toledo, diamond ATR, 1705 cm⁻¹ decay). Practitioners operating in medicinal chemistry compound‑management workflows routinely utilize the 5‑ester for rapid analog synthesis in microtiter plates (96‑well, 10 µmol scale) using trimethylaluminum‑mediated Weinreb amidation; liquid‑handler dosing precision (Tecan Freedom EVO) maintains stoichiometric control to within ±5 %, enabling structure‑activity data with single‑digit micromolar reproducibility. Palladium‑catalyzed direct arylation at C‑2 is feasible while the 5‑ester remains intact. Employing 5 mol% Pd(OAc)₂, 10 mol% P(t‑Bu)₃·HBF₄, and 2 equiv of K₂CO₃ in DMAc at 110 °C, coupling with 4‑bromobenzonitrile proceeds to >70 % conversion in 16 h. The 2‑position is selectively metalated due to the directing effect of the thiophene sulfur; the 5‑ester exerts only a weak inductive withdrawal that does not deactivate the C‑2 carbon. Published data for this specific configuration in photoredox applications remain limited; however, preliminary cyclic voltammetry suggests the excited‑state reduction potential (E*_red) falls near +0.65 V vs SCE, compatible with organocatalytic C–H functionalization using 4‑CzIPN under blue‑LED irradiation (455 nm).

When Storage Deviates from Recommended −20 °C Under Inert Atmosphere

Storage at 4 °C is acceptable for intervals not exceeding 72 h, provided the container has been back‑filled with argon and sealed with a PTFE‑lined phenolic cap. At 25 °C and 65 % RH, hydrolytic degradation reaches 2 % over 48 h as quantified by HPLC, generating 4H‑thieno[3,2‑b]pyrrole‑5‑carboxylic acid. This hydrolysis is autocatalyzed by the arising carboxylic acid; the rate constant doubles when free acid content exceeds 0.5 % w/w. Therefore, all receiver flasks used for dissolution must be dried at 105 °C for 2 h and cooled under nitrogen. The compound is incompatible with strong oxidizing agents: contact with >30 % hydrogen peroxide in the presence of acetic acid leads to rapid exothermic decomposition forming a polythienyl insoluble residue. Amine‑based additives, including piperidine, morpholine, and N‑methylmorpholine, induce premature ester aminolysis even at 0 °C within 30 min; their use as bases during coupling must be substituted with inorganic alternatives (K₂CO₃ or Cs₂CO₃). For large‑scale syntheses (batch size > 500 g), a dedicated inert‑atmosphere glovebox (O₂ < 5 ppm, H₂O < 1 ppm) is mandatory for any weighing operation that exceeds 15 min. Dynamic vapor sorption data (SMS DVS Intrinsic) reveal a reversible moisture uptake of 0.18 % at 90 % RH; hysteresis is absent, confirming the bulk crystalline solid is non‑hygroscopic, but the surface monolayer adsorption still supplies sufficient water for localized hydrolysis at crystal defects. Therefore, grinding or micronization should be performed under nitrogen flow and only immediately before use.