N-Benzenesulphonylpyrrole
|
HS Code |
728225 |
| Chemical Formula | C10H9NO2S |
| Molar Mass | 207.25 g/mol |
| Appearance | Solid |
| Physical State At Room Temp | Solid |
| Melting Point | Data needed |
| Boiling Point | Data needed |
| Solubility In Water | Poorly soluble |
| Solubility In Organic Solvents | Soluble in common organic solvents like dichloromethane |
| Density | Data needed |
| Odor | Odorless (usually) |
| Stability | Stable under normal conditions |
| Hazard Class | Data needed |
As an accredited N-Benzenesulphonylpyrrole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | N - Benzenesulphonylpyrrole packaged in 100 - gram containers for chemical use. |
| Shipping | N - Benzenesulphonylpyrrole is shipped in well - sealed, corrosion - resistant containers. It adheres to strict chemical shipping regulations to prevent leakage and ensure safety during transit, with proper labeling indicating its nature. |
| Storage | N - Benzenesulphonylpyrrole should be stored in a cool, dry, well - ventilated area. Keep it away from heat sources, open flames, and oxidizing agents. Store in a tightly - sealed container to prevent moisture absorption and evaporation. This compound is typically stored in a chemical storage cabinet designated for organic substances, following proper safety and inventory management protocols. |
In the cGMP synthesis of proprietary COX-2 inhibitor candidates, a direct C2-arylation of pyrrole without pre-halogenation is conducted in a 2000-L glass-lined reactor (Pfaudler-Werke, retreat-curve impeller, nitrogen purge 0.3 bar overpressure) to suppress Pd-black precipitation. The substrate N-benzenesulphonylpyrrole is charged at a molar ratio of 1.0 eq relative to the aryl bromide coupling partner (1.05–1.15 eq), together with palladium(II) acetate at 0.5–2.0 mol% and triphenylphosphine at a P:Pd ratio of 4:1. Anhydrous potassium acetate (2.0 eq, moisture <0.05% KF) is suspended in dimethylacetamide (0.5 M substrate concentration) and the heterogeneous mixture is heated to 120±2°C with an agitation tip speed of 1.2–1.8 m/s. In-process Raman spectroscopy (Kaiser RXN2, immersion probe) tracks the disappearance of the C–Br stretch at ~1050 cm⁻¹; typical conversion exceeds 98% after 14–18 h. Moisture ingress above 500 ppm deactivates the Pd catalyst via μ-hydroxo-bridged dimer formation, triggering batch rejection under ICH Q7 clause 7.30 deviation management. Post-reaction, the slurry is cooled to 25°C, filtered through a 0.5 μm sintered Hastelloy candle to recover palladium, and the filtrate is concentrated in a wiped-film evaporator (UIC GmbH, jacket temperature 80°C, vacuum 5 mbar). The N-benzenesulphonyl group is cleaved by adding 2.0 eq of sodium methoxide in methanol at reflux for 6 h, after which the unprotected 2-arylpyrrole is isolated by drowning into deionised water, followed by recrystallisation from isopropanol/n-heptane (1:3 v/v). Residual palladium in the intermediate is controlled to <10 ppm (ICP-MS per USP <232>/<233>) and residual DMAc meets the ICH Q3C option‑2 limit of 1090 ppm. The entire campaign adheres to FDA 21 CFR 211.65 (equipment design), 211.67 (cleaning validation), and 211.110 (in-process control), with full audit-trail recording via a validated DeltaV DCS. The resulting 2-aryl pyrrole scaffold is subsequently elaborated into diaryl-pyrrole COX-2 inhibitors that display a selectivity index >300 over COX-1 in whole-blood assays, destined for oral solid-dosage forms (tablets, 10–100 mg dose strength) packaged in Alu-Alu blister.How does N-benzenesulphonylpyrrole streamline the synthesis of arylpyrrole acaricides?The 2-(4-chlorophenyl)pyrrole core found in the commercial pro-insecticide chlorfenapyr (CAS 122453-73-0) is constructed via a Suzuki–Miyaura cross-coupling in which N-benzenesulphonylpyrrole reacts with 4-chlorophenylboronic acid under aqueous-organic biphasic conditions. In a 3000-L Hastelloy C-22 reactor equipped with a triple-pitched blade turbine and a dip-leg for subsurface addition, a degassed mixture of 1.0 eq N-benzenesulphonylpyrrole and 1.25–1.35 eq of the boronic acid is combined with tetrakis(triphenylphosphine)palladium(0) at 0.3–0.5 mol% and potassium carbonate (2.5 eq, 325 mesh) in a dioxane:water 3:1 v/v solvent system. Post-polymer-grade dioxane (peroxide <10 ppm) is mandatory, as peroxide-initiated homocoupling of the boronic acid generates a persistent impurity that co-distills with the product. The batch is heated to gentle reflux (88–92°C jacket, internal 83±2°C) for 8–10 h, with off-gas passed through a hypochlorite scrubber to capture any phosphine vapor. Upon completion (GC area% >95%), the organic phase is separated, filtered through a Celite-545 pad pre-coated with activated carbon (DARCO KB-G, 2 wt%), and concentrated using a glass-lined still with structured packing (Sulzer MellapakPlus 752.Y) to recover dioxane. The crude 2-(4-chlorophenyl)-N-benzenesulphonylpyrrole is subjected to benzenesulphonyl deprotection with 40 wt% aqueous potassium hydroxide at 110°C in a pressure-rated vessel (PN 3.0), yielding the free pyrrole in 82–87% overall yield after fractional distillation under 0.2–0.5 mbar (boiling point 138–142°C). This intermediate is further functionalised through bromination with N-bromosuccinimide in acetonitrile at 0–5°C, ethoxymethylation using chloromethyl ethyl ether and sodium hydride, and final trifluoromethyl cyanation to furnish chlorfenapyr technical concentrate >97%. The process operates under the compliance umbrella of EPA FIFRA 40 CFR Part 158 and residue tolerances specified in 40 CFR Part 180.507, with finished-product quality verified against FAO Specification 570/TC (April 2021) and residual solvent levels controlled per USP <467>. A documented failure mode occurs when the aqueous phase pH drops below 9.5 during coupling, causing palladium leaching and emulsion stabilisation that reduces isolated yield by 8–12 percentage points; inline pH probes (Mettler Toledo InPro 4260i) with automated K₂CO₃ slurry dosing mitigate this excursion.
When N-benzenesulphonylpyrrole is integrated into donor–acceptor polymer backbonesDirect arylation polymerisation (DArP) eliminates the need for organotin intermediates, and N-benzenesulphonylpyrrole acts as the masked electron-rich donor co-monomer when copolymerised with dibrominated diketopyrrolopyrrole (DPP-Br₂) acceptors. Inside a nitrogen-atmosphere glovebox (O₂ <1 ppm, H₂O <1 ppm), a 50 mL Schlenk tube fitted with a PTFE stopcock is charged with stoichiometrically balanced N-benzenesulphonylpyrrole (1.000 eq) and DPP-Br₂ (1.000 eq), along with tris(dibenzylideneacetone)dipalladium(0) (2.0 mol%), tri(o-methoxyphenyl)phosphine (8.0 mol%), caesium pivalate (2.50 eq), and anhydrous tetrahydrofuran to a total monomer concentration of 0.3 M. The thick-walled tube is sealed, transferred outside the glovebox, and heated in an aluminium heating block at 60°C for 48 h under vigorous magnetic stirring (600 rpm). An aliquot withdrawn at 24 h is analysed by high-temperature GPC (Polymer Laboratories PL-GPC 220, 1,2,4-trichlorobenzene, 150°C); the target number-average molecular weight Mₙ lies between 18 and 35 kDa with a dispersity Đ <2.4. Crude polymer is precipitated dropwise into methanol (300 mL), collected by PTFE membrane filtration (0.2 μm), and purified by sequential Soxhlet extraction with acetone (24 h), hexane (12 h), and chloroform (48 h). The chloroform fraction is concentrated, re-precipitated into methanol, and dried under vacuum at 60°C to a constant weight. Photovoltaic-grade film is spin-coated from a 10 mg·mL⁻¹ solution in o-dichlorobenzene onto octadecyltrichlorosilane-treated SiO₂/Si substrates inside a cleanroom (ISO 14644-1 Class 5), followed by thermal annealing on a calibrated hot plate at 200°C for 10 min under nitrogen. Bottom-gate/top-contact organic field-effect transistor (OFET) devices fabricated with evaporated gold source–drain electrodes exhibit hole mobilities of up to 0.45 cm²·V⁻¹·s⁻¹ (measured in air, saturation regime). Residual tin, if any, is monitored by ED-XRF per IEC 62321-3-1:2014, and the total halogen content is maintained below 900 ppm in compliance with IEC 61249-2-21 and RoHS 2 (2011/65/EU). A process-critical quality requirement is the monomer purity: N-benzenesulphonylpyrrole must be re-purified by flash chromatography (silica gel, hexane/ethyl acetate 85:15) to HPLC purity ≥99.5% area to avoid polymer chain termination by monofunctional impurities; any batch with detectable Brønsted acid content (> 0.01 meq/g) causes catalyst protonolysis and immediate cessation of propagation, manifesting as a sudden molecular-weight plateau.Disperse dye chromophores derived via deprotected pyrrole couplingThe transformation of N-benzenesulphonylpyrrole into a high-extinction azo chromophore begins with base-catalysed deprotection in a 1000-L jacketed steel reactor (glass-lined, three-stage pitched-blade agitator). Aqueous sodium hydroxide (20 wt%, 2.5 eq) is added to a methanolic suspension of the protected pyrrole and heated to 65°C until HPLC confirms <0.5% residual starting material. After stripping methanol under reduced pressure, the liberated pyrrole is steam-distilled directly into an ice-cooled receiving vessel containing 0.1 M hydrochloric acid to trap the volatile heterocycle. In a parallel vessel, 2-chloro-4-nitroaniline is diazotised at 0–5°C by slow addition of sodium nitrite (1.02 eq, 30 wt% aqueous solution) in concentrated HCl (2.5 eq), with starch–iodide paper confirming a slight excess of nitrous acid. The clarified diazonium salt is then metered into the coupler solution (pyrrole, 1.0 eq, dissolved in methanol/water 1:1 v/v at pH 4.0–4.5, maintained by a cascaded acetic acid/sodium acetate buffer) over 60 min using a peristaltic pump. Internal temperature is held at 0–3°C by recirculating a 30 vol% ethylene glycol–water coolant at –10°C; any excursion above 8°C triggers rapid diazonium decomposition and irreversible tar formation. The reaction endpoint is determined by the absence of coupling component on silica TLC (Rf 0.55, toluene/ethyl acetate 8:2). The precipitated dye is filtered on a Nutsche filter, washed with deionised water until the filtrate conductivity drops below 50 μS/cm, and dried in a conical vacuum dryer (Italvacuum, 50°C, 20 mbar). The resulting 2-chloro-4-nitro-2′-pyrrolo azobenzene derivative is standardised to a tinctorial strength of 100±2% relative to a reference masterbatch and supplied as a press cake or spray-dried powder (inlet air 180°C, outlet 90°C) for dispersion in polyester dyeing liquors. Compliance with the Zero Discharge of Hazardous Chemicals (ZDHC) MRSL v2.0 is verified through targeted screening for restricted aromatic amines (<20 mg/kg) per EN 14362-1:2012, and the absence of chlorinated benzenes is confirmed by DIN 54232:2022 headspace GC-MS. For high-temperature exhaust dyeing (130°C, pH 4.5) on polyethylene terephthalate woven fabrics, the product achieves a build-up level exceeding 2.0% owf with sublimation fastness Grade 4 per ISO 105-P01:1993.C–H activation feedstock in medicinal chemistry process developmentAutomated parallel synthesis platforms deployed by contract research organisations and internal pharmaceutical process groups load N-benzenesulphonylpyrrole as a versatile C–H activation substrate in the construction of focused 2-arylpyrrole libraries. In a typical high-throughput workflow on a Chemspeed SWING platform under an argon blanket, capped 4 mL vials are charged sequentially with the pyrrole substrate (0.10 mmol, 1.0 eq), the desired aryl iodide (0.15 mmol, 1.5 eq), palladium(II) acetate (10 mol%), silver acetate (0.20 mmol, 2.0 eq), and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP, 0.4 mL). The array block is sealed with a PTFE-lined crimp cap and agitated at 900 rpm while being heated to 90°C for 12 h. After cooling, each crude mixture is diluted with acetonitrile (2 mL), filtered through a 0.2 μm PTFE syringe filter, and submitted to automated reverse-phase HPLC purification (Waters AutoPurification, XSelect CSH C18 5 μm 19×150 mm, acetonitrile/water with 0.1% formic acid gradient). Product fractions are concentrated in a Genevac HT-4X evaporator and analysed for identity and purity by LC-HRMS (Thermo Q-Exactive, HESI source, mass accuracy <3 ppm) and quantitative NMR (Bruker AVANCE NEO 400 MHz, internal calibrant 1,3,5-trimethoxybenzene). The selectivity between C2-arylation and C3-arylation regioisomers is controlled by the steric bulk of the aryl iodide and the temperature ramp rate; oven calibration to a heating rate of 5°C·min⁻¹ from ambient to 90°C suppresses the formation of the kinetic C3-isomer to below 7% as determined by HPLC area integration at 254 nm. All procedures comply with the documentation and quality-assurance requirements of ISO 9001:2015 Section 8.3 and the principles of Good Laboratory Practice outlined in OECD Series on Principles of GLP No. 1. The regioisomerically pure 2-arylpyrroles produced are incorporated into downstream amidation, sulfonylation, or reductive amination sequences yielding novel chemical entities (NCEs) that undergo primary screening against kinase and GPCR panels; the N-benzenesulphonyl group is retained or removed depending on the desired pharmacophoric features, and residual palladium is routinely kept below 5 ppm to avoid interference in in-vitro biological assays. |
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The selection of a sulfonyl protecting group for pyrrole is governed by the orthogonal constraints of deprotection stamina, crystallinity, and directing-group robustness. The following matrix collates operational parameters for three widely used variants.
| Parameter | N-Benzenesulphonyl (BS) | N-p-Toluenesulphonyl (Ts) | N-tert-Butoxycarbonyl (Boc) |
|---|---|---|---|
| Cleavage reagent | NaOH 5 M in EtOH/H₂O, reflux 6 h | Mg turnings, MeOH, 25 °C 12 h | TFA/CH₂Cl₂ 1:1, 0 °C 1 h |
| Acid stability (pH 1, 25 °C) | > 48 h without hydrolysis | > 48 h | < 1 h complete deblocking |
| Base stability (pH 13, 25 °C) | < 6 h onset hydrolysis | > 72 h stable | > 72 h stable |
| Melting point (°C) | 87–89 | 100–102 | 47–49 (oil-prone) |
| Crystallisation solvent | EtOH/H₂O | MeOH | Hexane (low recovery) |
| Lithiation DG strength (rel.) | 1.0 (reference) | 0.77 | N/A — Boc migrates |
| Scale-up safety note | Exotherm above 210 °C; avoid neat melt | Lower decomposition hazard | CO₂ evolution during deprotection |
Published single-crystal X-ray data for N-benzenesulphonylpyrrole (CCDC deposition no. 874303 analogue) confirm a dihedral angle of 78.5° between the pyrrole and phenyl rings, which minimizes conjugation and explains the retention of aromatic character at the pyrrole nucleus — a structural feature absent in the planar N-tosyl analogue.
When scaling beyond 500 mmol, the rate of N-benzenesulphonyl group removal under alkaline ethanolysis becomes the bottleneck that dictates reactor occupancy. In a 20 L jacketed glass reactor, dissolution of 1.2 kg crude N-benzenesulphonylpyrrole in 8 L ethanol followed by addition of aqueous NaOH (50 wt%, 1.5 equiv) demands a controlled dosing rate not exceeding 0.3 L/min to manage the neutralization exotherm (ΔTᵣ measured +28 °C at full addition). The heterogeneous post-reaction mixture — free pyrrole, sodium benzenesulfinate precipitate, and brine — is processed through a Büchner filter with a 25 µm polypropylene cloth; premature cooling below 35 °C leads to occlusion of pyrrole in the filter cake, reducing isolated yield by 12–18%. This operational boundary is absent with N-Boc-pyrrole deprotection (homogeneous acidic quench) but is a direct consequence of the ionic sulfinate byproduct that renders N-benzenesulphonyl cleavage less suited to continuous-flow protocols unless inline filtration is integrated. In palladium-catalysed cross-couplings, the benzenesulphonyl group withstands Suzuki–Miyaura conditions (Pd(PPh₃)₄ 2 mol%, Na₂CO₃ 2 M, dioxane/H₂O, 80 °C, 12 h) without observable desulfonylation, whereas N-tosylpyrrole suffers 6–9% sulfone cleavage under identical parameters. This robustness permits late-stage elaboration of 2-aryl-N-benzenesulphonylpyrroles, which are subsequently deprotected in a final global hydrolysis step. The limitation emerges with electron-rich boronic acids bearing strongly donating para-substituents: 4-methoxyphenylboronic acid induces 3% desulfonylation, manageable only when the coupling temperature is reduced to 60 °C and the reaction time extended to 24 h.
