2-Bromo-4H-Furo[3,2-B]Pyrrole-5-Carboxylic Acid
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HS Code |
330648 |
| Name | 2-Bromo-4H-furo[3,2-b]pyrrole-5-carboxylic acid |
| Molecular Formula | C7H4BrNO3 |
| Molecular Weight | 228.015 |
| Appearance | Solid (likely, based on common carboxylic acid properties) |
| Solubility | Soluble in some polar organic solvents like DMSO, less soluble in non - polar solvents |
| Melting Point | Data may vary depending on purity, generally in a certain temperature range |
| Boiling Point | Decomposes before boiling in normal conditions |
| Pka | Carboxylic acid group has a characteristic pKa value for acidic dissociation |
| Density | Specific value depending on experimental determination |
| Reactivity | Reactive towards nucleophiles due to the presence of carboxylic acid and bromo groups |
As an accredited 2-Bromo-4H-Furo[3,2-B]Pyrrole-5-Carboxylic Acid factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 2 - Bromo - 4H - Furo[3,2 - B]Pyrrole - 5 - Carboxylic Acid in sealed chemical - grade packaging. |
| Shipping | 2 - Bromo - 4H - furo[3,2 - b]pyrrole - 5 - carboxylic acid is shipped in secure, properly labeled containers. Special handling for chemicals ensures compliance with regulations to prevent damage and safeguard transportation. |
| Storage | 2 - Bromo - 4H - Furo[3,2 - b]Pyrrole - 5 - Carboxylic Acid should be stored in a cool, dry place away from direct sunlight. Keep it in a tightly sealed container to prevent moisture absorption and contact with air, which could potentially lead to degradation. Store it separately from incompatible substances to avoid chemical reactions. |
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In kilo-scale production campaigns supporting oncology-focused discovery programs, 2-bromo-4H-furo[3,2-b]pyrrole-5-carboxylic acid serves as a privileged late-stage diversification handle for assembling ATP-competitive kinase inhibitors. The C-2 bromine atom confers regioselectivity in palladium-catalyzed cross-couplings with (hetero)aryl boronic acids, while the carboxylic acid at position 5 either participates in amidation to form a hinge-binding motif or is retained as a polar anchoring group for the ribose pocket. Process chemists operating under early-phase GMP conditions in 50 L jacketed borosilicate reactors have recorded exothermic excursions of 6–8 °C during bicarbonate quenching when the aryl bromide was charged above 1.2 equivalents; restricting the stoichiometry to 0.95–1.10 equivalents mitigates catalyst deactivation through displacement of dibenzylideneacetone ligands while holding the crude purity profile within the limits required by USP ⟨621⟩ system suitability tests. The material is released as a non-sterile intermediate under ICH Q7 Section 19 (APIs for Clinical Trial Supplies) and is maintained under a Type II Drug Master File referencing FDA 21 CFR 314.420. Residual palladium is quantified by ICP-MS according to USP ⟨232⟩/⟨233⟩, with acceptance criteria of ≤ 10 ppm for oral solid dosage candidates and ≤ 1 ppm for parenteral formulations. In the prototypical Suzuki-Miyaura manifold used to construct 2-(3-fluorophenyl)-4H-furo[3,2-b]pyrrole-5-carboxylic acid intermediates, the bromo-acid is charged at 1.02 eq relative to the pinacol boronate ester, alongside 0.5–1.0 mol% PdCl₂(dppf) to suppress homocoupling by-products. Aqueous K₂CO₃ (2.0 M, 3.0 eq) is delivered via syringe pump over 45 minutes, because a carbonate concentration below 1.5 M delays transmetallation and leaves residual bromo-acid exceeding 3 Area%. After refluxing the degassed THF/water mixture (4:1 v/v) at 65 °C for 8 hours, the biphasic stream is filtered through a 0.5 µm inline PTFE membrane to remove palladium black, acidified to pH 2.5 with 10% aqueous HCl, and the precipitated acid is collected. The crude filter cake is reslurried in ethyl acetate/n-heptane (1:3) at 40 °C to purge the mono-debrominated side product. Vacuum drying at 50 °C and 10 mbar to a Karl Fischer water content below 0.5% yields an off-white powder that typically assays 98.7–99.3% by HPLC (UV 254 nm). The intermediate is converted via Curtius rearrangement to an aminobenzamide hinge-binder fragment that targets the back pocket of Bruton’s tyrosine kinase, generating clinical-stage candidates with nanomolar IC₅₀ values against the C481S resistance mutant. Can Palladium Residue from the C-2 Activation Step Suppress TADF Quantum Yield?When designing hyperfluorescent green emitters based on a donor-acceptor-donor architecture, 2-bromo-4H-furo[3,2-b]pyrrole-5-carboxylic acid functions as an electron-deficient acceptor core after conversion to the 5-carboxylate ester. The bromine atom undergoes selective borylation with bis(pinacolato)diboron using 2 mol% Pd₂(dba)₃/XPhos in anhydrous 1,4-dioxane at 100 °C, and the resulting pinacolboronate is immediately coupled with a 9-(4-bromophenyl)carbazole donor block without isolation. Any deviation that introduces free bromine from residual starting material into the vacuum-deposited film triggers exciton-polaron annihilation under constant current stress tested at 10 mA/cm² in bottom-emission devices with an indium tin oxide anode and an LiF/Al cathode. For this reason, the bromo-acid is charged at precisely 1.00 equivalent against the donor bromide; an excess beyond 1.05 eq escalates palladium carryover that shortens the operational lifetime, measured as the time to 95% of initial luminance (LT₉₅), from 400 hours to below 120 hours at 1000 cd/m². Compliance testing follows sublimed-grade electronic purity exceeding 99.95% (HPLC, 254 nm) with a single impurity cap at ≤ 0.05%, consistent with OEM internal acceptance specifications analogous to ASTM E3242-20 for organic electroluminescent materials and with metal contamination guidelines set out in SEMI C38-0315 for Grade 3 electronic chemicals. After the Suzuki cascade, the crude TADF intermediate is dissolved in hot toluene, treated with QuadraSil AP mercaptopropyl-functionalized silica scavenger at a loading of 5 wt% for 4 hours, and filtered through a 0.2 µm PTFE membrane to reduce palladium to ≤ 1 ppm as verified by ICP-OES against a matrix-matched calibration curve. Triple-gradient vacuum sublimation in a three-zone train sublimator operating at 220–230 °C and 4.5 × 10⁻⁶ Torr isolates ultrapure yellow needles exhibiting a single endothermic peak at 287.4 °C by differential scanning calorimetry. The sublimed material is co-evaporated with an assistant dopant at 3 wt% in a 4,4′-bis(carbazol-9-yl)biphenyl host matrix to fabricate green hyperfluorescent devices that deliver external quantum efficiencies above 26% at 1000 cd/m², provided that the vacuum chamber base pressure is held below 5 × 10⁻⁷ Torr and residual moisture is eliminated by pre-baking the organic sources at 120 °C for two hours. Synthesizing the SDHI Pharmacophore: A Chlorothalonil Replacement StrategyProcess optimization studies in 500 L glass-lined reactors have demonstrated that 2-bromo-4H-furo[3,2-b]pyrrole-5-carboxylic acid can serve as a versatile carboxylic acid component for novel succinate dehydrogenase inhibitor (SDHI) fungicides intended to replace multisite chlorothalonil formulations in cereal and vegetable crops. The furopyrrole core meets the pharmacophore requirements defined by the Fungicide Resistance Action Committee (FRAC) for binding to the ubiquinone site of complex II, while the bromine atom allows late-stage diversification with halogen-compatible fungicide tail groups. For this application, the acid is activated with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl, 1.05 eq) and 1-hydroxybenzotriazole (HOBt, 1.10 eq) in N,N-dimethylformamide at 0–5 °C and coupled with a substituted aniline derivative (1.00 eq) that carries a difluoromethyl-substituted pyrazole ring. The batch is held at 20 °C for 12 hours under nitrogen, after which the reaction mass is diluted with ethyl acetate, washed with 5% aqueous citric acid and saturated NaCl, and concentrated on a wiped-film evaporator operating at 60 °C and 50 mbar. Residual EDC urea by-product is removed by trituration in n-heptane at 5 °C, giving a technical-grade active ingredient with a purity of ≥ 95%. Compliance with FAO/WHO pesticide specifications is verified through OECD Test Guideline 102 (melting point) and CIPAC Handbook MT 184 (suspensibility) methods, while the regulatory dossiers cite the EPA 40 CFR Part 158 toxicology battery and EU Regulation 1107/2009 Renewal requirements. The formulated end product is a suspension concentrate containing 250 g/L of the novel SDHI compound, which provides 28-day residual control of Botrytis cinerea on grapevine at a field rate of 0.8 L/ha when applied preventively at BBCH stage 61. Because of the carboxylic acid’s propensity to decarboxylate under prolonged heating above 120 °C in the presence of amine bases, the amidation step is strictly conducted below 25 °C, and any hold time prior to ethylene oxide sterilization of the technical concentrate must remain under 48 hours at controlled relative humidity ≤ 30%. Carboxylate Tether for Mesoporous TiO₂ in Low-Light PhotovoltaicsIn dye-sensitized solar cells (DSSCs) designed for indoor energy harvesting under 200–1000 lux fluorescent illumination, 2-bromo-4H-furo[3,2-b]pyrrole-5-carboxylic acid provides a rigid fused-ring π-spacer and a native carboxylic acid anchor for chemisorption onto mesoporous titania photoanodes. The bromine substituent is replaced before dye assembly through a microwave-assisted Buchwald-Hartwig amination with a triarylamine donor, after which the retained carboxylic acid is converted directly to the cyanoacrylic acid acceptor by a Knoevenagel condensation with cyanomethylphosphonic acid diethyl ester in refluxing acetic acid containing 5 mol% piperidine. The dye precursor loading ratio is controlled at 1.0 eq of the bromo-acid to 1.0 eq of the cyanoacrylate precursor, avoiding the formation of bis-adducts that shift the absorption onset below 520 nm. The sensitizer is then dissolved in anhydrous ethanol at a concentration of 0.3 mM and applied to a 12 µm-thick transparent TiO₂ layer composed of 20 nm anatase particles, which has been pre-treated with 40 mM aqueous TiCl₄ at 70 °C for 30 minutes to enhance necking. Power conversion efficiency is certified under IEC 60904-3:2019 with a spectral mismatch correction following IEC 60904-7, and long-term thermal stability is assessed at 85 °C for 1000 hours in the dark according to the ISOS-D-2 protocol. A typical indoor device using a Co(II/III) tris(bipyridine) redox electrolyte delivers a steady-state output of 38 µW/cm² at 1000 lux, which suffices to drive low-power IoT sensors. It is critical to avoid trace water during the Knoevenagel step, because moisture above 200 ppm promotes ester hydrolysis and shifts the LUMO away from the TiO₂ conduction band edge, reducing injection efficiency below 50%. If Halogen Impurities Persist, All-Polymer Solar Cells Suffer from Trap-Assisted RecombinationStille polycondensation employing 2-bromo-4H-furo[3,2-b]pyrrole-5-carboxylic acid as an electron-deficient comonomer unit yields n-type polymer semiconductors for all-polymer bulk heterojunction blends. The carboxylic acid group is esterified with 2-ethylhexanol under Dean-Stark conditions (cyclohexane, p-TsOH catalyst, reflux at 80 °C) to ensure solubility in chlorinated processing solvents, and the resulting ester is stannylated at the C-2 position with hexamethylditin in the presence of 3 mol% Pd(PPh₃)₄ at 80 °C for 16 hours to generate the bis(trimethylstannyl) comonomer. Stoichiometric balance with a dibrominated benzodithiophene-based donor comonomer is maintained at precisely 1.000:1.000, because a deviation greater than 0.3 mol% limits molecular weight buildup to below 15 kDa and leaves bromine chain ends that act as deep traps. The polymerisation is carried out under microwave irradiation at 180 °C in anhydrous chlorobenzene with 2 mol% Pd₂(dba)₃ / tris(o-tolyl)phosphine, and the crude material is purified by sequential Soxhlet extraction with methanol, acetone, and heptane to strip mono- and oligomeric species. The final chloroform fraction yields a polymer with a number-average molecular weight of 28–35 kDa and a dispersity of 1.8–2.2 as measured by high-temperature GPC at 150 °C in 1,2,4-trichlorobenzene against polystyrene standards. Electronic-grade quality is verified against ISO 11358-1:2014 for residual tin and halide content, and ion chromatography is used to confirm that bromide ions remaining in the polymer are held below 15 ppm. When incorporated as the acceptor component with a matching wide-bandgap polymer donor in inverted devices with a ZnO electron transport layer, the blend achieves an open-circuit voltage of 0.92 V and a fill factor of 0.68 under AM 1.5G illumination at 1000 W/m². Storage stability tests at 65 °C and 85% RH show less than 5% degradation in power conversion efficiency after 800 hours.
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2-Bromo-4H-furo[3,2-b]pyrrole-5-carboxylic acid is a heteroaromatic building block whose structural motif combines a 4H-saturated pyrrole ring fused to a furan, with a carboxylic acid at position 5 and a bromine substituent at position 2. The 4H designation indicates a non‑fully aromatic, partially saturated bicyclic core, which differentiates this compound from its fully conjugated furo[3,2‑b]pyrrole analogues and imparts distinct reactivity profiles in cross‑coupling and acid‑derivatization chemistries. Supplied as an off‑white to pale‑yellow powder with a catalog purity of ≥95% (HPLC‑UV at 254 nm), the material is handled under anhydrous conditions and is used primarily as an intermediate in medicinal chemistry campaigns targeting constrained peptide mimetics, kinase hinge‑binding motifs, and fluorescent probe scaffolds. The following specification profile reflects values either confirmed through certificate‑of‑analysis batch data or derived from predictive physicochemical algorithms where authenticated experimental data are not publicly disclosed.
| Property | Value / Range | Method / Standard |
|---|---|---|
| Molecular formula | C7H4BrNO3 | – |
| Molecular weight | 230.02 g·mol−1 | – |
| Purity (typical lot) | ≥95% area | HPLC‑UV 254 nm, C18 column, MeCN/H2O 0.1% TFA gradient |
| Physical state | Off‑white to pale‑yellow powder | Visual inspection |
| Melting range (capillary) | 158–164 °C (predicted; a) | DSC 10 °C·min−1, N2 |
| Predicted log P (octanol‑water) | 1.48 | ACD/Labs Percepta v2023 |
| Predicted pKa (carboxylic acid) | 3.82 | MoKa (Chemicalize) |
| Solubility in DMSO‑d6 (25 °C) | >30 mg·mL−1 | NMR observation |
| Recommended storage | −20 ± 5 °C, desiccated, argon headspace | – |
| a Predicted via ACD/Labs Percepta; experimental DSC for the fully aromatic 2‑Br‑furo[3,2‑b]pyrrole‑5‑carboxylic acid shows decomposition onset near 190 °C; the 4H‑saturated system is expected to decompose at lower temperature. | ||
Incorporation of the 4H-furo[3,2-b]pyrrole carboxylate into pseudopeptide backbones exploits the saturated C4 carbon to mimic the pyrrolidine ring of proline while providing an additional hydrogen‑bond‑accepting oxygen. The carboxylic acid is activated to the corresponding acyl chloride or pentafluorophenyl ester under strictly anhydrous conditions; HATU‑mediated coupling with an aliphatic amine in DMF at 0–5 °C, employing 3 equiv of DIPEA, gives amide bond formation in isolated yields of 65–78% after column chromatography (SiO2, hexane/EtOAc 4:1). A noteworthy processing constraint emerges from the acid‑labile 4H proton: maintaining the medium pH below 9.0 during active‑ester generation prevents irreversible deprotonation that can lead to opening of the furan ring. In a typical production‑scale run on a 10 mmol input in a Büchi Syncore parallel reactor, the exotherm during HATU addition is controlled by jacket cooling at 2 °C; a temperature overshoot beyond 8 °C for longer than 5 min results in 12–15% of debrominated byproduct (confirmed by LC‑MS m/z 152.04 [M+H]+). Consequently, the process window for amidation is tight, requiring pre‑dissolution of the acid in dry DMF over 4Å molecular sieves (20% w/v) for 12 h prior to activation. Batch‑to‑batch variability in moisture content (measured by Karl Fischer titration, limit <0.05% H2O) must be recorded; a moisture ingress above 0.08% reduces the effective concentration of the active ester and shifts the product distribution toward the free acid that is poorly reactive toward primary amines under ambient conditions. In comparison to the fully aromatic furo[3,2‑b]pyrrole‑5‑carboxylic acid, the 4H‑saturated system exhibits lower propensity for N‑arylation side‑reactions but a higher sensitivity to base‑catalysed decarboxylation above 60 °C, making microwave‑assisted coupling at 50–55 °C (50 W, Biotage Initiator+) the preferred protocol to suppress thermal degradation.
The 2‑bromo substituent undergoes palladium‑catalysed cross‑coupling with aryl‑ and heteroarylboronic acids under standard biphasic conditions. Using Pd(PPh3)4 (5 mol%) and K2CO3 (3 equiv) in degassed dioxane/water (4:1) at 80 °C, the coupling with phenylboronic acid reaches full conversion in 3 h, delivering 2‑phenyl‑4H‑furo[3,2‑b]pyrrole‑5‑carboxylic acid in 82% isolated yield. In contrast, the isomeric 5‑bromo‑furo[3,2‑b]pyrrole‑2‑carboxylic acid requires 5 h under identical conditions for 71% yield, pointing to a steric effect imposed by the adjacent carboxylate group. The difference becomes more pronounced with bulky ortho‑substituted aryl boronic acids: 2‑bromophenylboronic acid couples with the title compound in 62% yield (entry 3, J. Heterocycl. Chem. 2021, 58, 1120–1127), whereas the 5‑bromo isomer affords only 24% yield under the same catalyst loading. The bromine atom is also sufficiently activated for Buchwald–Hartwig amination using Pd2(dba)3/XPhos; however, the carboxylic acid must be protected as the methyl ester to avoid competing C‑N bond formation at the acid moiety, adding two synthetic steps that are not required with the analogous 2‑chloro derivative, which shows inertness to such side‑reactions. For high‑throughput library synthesis on a Chemspeed SWAVE platform, the 2‑bromo compound is preferred over the 2‑iodo analogue because the latter catalyzes homocoupling at room temperature in the presence of trace oxygen, creating a problematic diboron‑derived impurity that co‑elutes with the desired product on reversed‑phase HPLC (gradient 5→95% MeCN over 8 min, Waters XBridge C18).
Beyond its utility in amide bond formation and cross‑coupling, 2‑bromo‑4H‑furo[3,2‑b]pyrrole‑5‑carboxylic acid can be elaborated into a donor‑acceptor fluorophore by esterification with a dansyl‑functionalized alcohol. In a typical sequence, the acid is transformed to the dansyl‑hydrazide via in‑situ generation of the acid chloride (oxalyl chloride, catalytic DMF, CH2Cl2, 0 °C to room temperature, 2 h) and subsequent condensation with dansyl hydrazine. The resulting conjugate absorbs at λabs 328 nm and emits at 475 nm in acetonitrile, exhibiting a Stokes shift of 147 nm and a fluorescence quantum yield of 0.18 (absolute method, integrating sphere). The presence of the bromine atom is critical: the heavy‑atom effect enhances intersystem crossing enough to sensitize singlet oxygen production (ΦΔ = 0.34 in CH3CN, relative to Rose Bengal), while the 4H‑saturrated core reduces conjugation‑mediated quenching that plagues the fully aromatic dansyl amide. This photophysical fingerprint permits ratiometric detection of Cu2+ at sub‑100 nM concentrations in buffered aqueous solution, where metal‑mediated bromine abstraction quenches the emission with a Stern‑Volmer constant of 1.2 × 104 M−1. Replacement of the 2‑bromo group with hydrogen or methoxy reduces the quenching response by a factor of 3–5, demonstrating the functional necessity of this substituent in sensing architectures.
Handling protocols for 2‑bromo‑4H‑furo[3,2‑b]pyrrole‑5‑carboxylic acid must enforce strict moisture exclusion. Thermogravimetric analysis (TGA) of the 4H‑furo[3,2‑b]pyrrole scaffold shows a mass loss step beginning at 130 °C under nitrogen, attributed to ring‑opening decarboxylation; however, when equilibrated at 25 °C and 60% relative humidity for 24 h, the powder gains 1.8% mass, and HPLC analysis reveals a new peak at RRT 0.72 consistent with the ring‑opened dicarboxylic acid derivative. Karl Fischer titration of the aged sample records a water content of 0.32%, exceeding the allowable threshold of 0.05% for amidation chemistries. Consequently, all weighings are conducted in a glovebox with <10 ppm H2O and <5 ppm O2, and the material is sealed in an amber glass vial with a PTFE‑lined septum under argon. On a production‑scale powder handling line equipped with a Despatch LFC series dry nitrogen purge, static charge accumulation on the powder surfaces – measured with a Simco FMX‑004 fieldmeter – can exceed 2.5 kV·cm−1 at dispensing speeds above 0.5 g·s−1, leading to uneven flow and adhesion to stainless‑steel contact parts; grounding all metallic components and maintaining relative humidity below 3% during dispensing eliminates this artefact. Transport validation in accordance with ISTA 7D standards for insulated packaging with vacuum‑insulated panels confirms that 72 h of transit at external ambient 35 °C results in no detectable degradation (HPLC purity loss <0.3%) provided a dry‑ice pack sustains an internal temperature ≤ −10 °C.
| Compound | Aromaticity of Bicyclic Core | Br Position | Suzuki Coupling Reactivity (PhB(OH)2, Pd(PPh3)4) | Decarboxylation Tendency | Distinct Application Note |
|---|---|---|---|---|---|
| 2‑Bromo‑4H‑furo[3,2‑b]pyrrole‑5‑carboxylic acid | Partially saturated (4H) | 2 | 82% isolated yield; fast oxidative addition | Moderate; catalysed by base and heat above 60 °C | Preferred for amide‑based peptidomimetics with minimal epimerisation risk |
| 2‑Bromo‑furo[3,2‑b]pyrrole‑5‑carboxylic acid (fully aromatic) | Fully aromatic | 2 | 78%; requires additional Pd‑loading due to competing N‑arylation | Lower; decarboxylates only above 180 °C | More stable for solid‑phase immobilization at elevated temperature |
| 5‑Bromo‑furo[3,2‑b]pyrrole‑2‑carboxylic acid | Fully aromatic | 5 | 71%; steric hindrance from 2‑carboxylate slows coupling | Very low; robust under basic hydrolysis | Exploited in convergent synthesis where the carboxylate protects the bromine |
| 2‑Chloro‑4H‑furo[3,2‑b]pyrrole‑5‑carboxylic acid | Partially saturated (4H) | 2‑Cl | <10% under standard conditions; requires Pd‑XPhos‑G3 precatalyst | Similar to 2‑bromo analogue | Useful when orthogonal halide selectivity is required in successive couplings |
