1-(Phenylsulfonyl)-1H-Pyrrole

Accelerating Pyrrolo[2,3-d]pyrimidine Assembly via Directed Ortho-Lithiation

When 1-(Phenylsulfonyl)-1H-pyrrole enters the supply chain for Janus kinase (JAK) and epidermal growth factor receptor (EGFR) inhibitor families, its electron‑withdrawing benzenesulfonyl group imposes a regiospecific ortho‑lithiation manifold that avoids competing C‑2 substitution. Process‑scale lithiation‑formylation is conducted in anhydrous THF (Karl Fischer water content < 50 ppm) at a substrate concentration of 0.3–0.5 M. The solution is chilled to ‑78 °C under argon and treated dropwise with lithium diisopropylamide (1.05–1.15 eq, 2.0 M in THF/heptane/ethylbenzene) over 45–60 min, maintaining the internal temperature within a ±3 °C window. Deviation beyond this band raises the 3,4‑diformyl impurity to 8–12 area% (HPLC). Dimethylformamide (1.2 eq) is introduced as the electrophilic quench, after which the cold bath is removed and the batch reaches 20–25 °C within 3 h. Aqueous work‑up with saturated ammonium chloride, extraction into ethyl acetate, and vacuum distillation delivers 3‑formyl‑1‑(phenylsulfonyl)pyrrole in 85–92% isolated yield with GC purity ≥ 98.5%. The aldehyde is subsequently condensed with cyanoacetamide in ethanol using sodium ethoxide (1.05 eq) at reflux (78–80 °C, 12–16 h) to construct the pyrimidine ring, yielding the 4‑amino‑5‑cyanopyrrolo[2,3‑d]pyrimidine scaffold. Cleavage of the benzenesulfonyl protecting group proceeds with aqueous potassium hydroxide (2.5 eq) in methanol/water (3:1 v/v) at 65 °C for 5 h, producing the free N–H intermediate required for final‑stage N‑alkylation. Compliance with ICH Q3A(R2) mandates that any unspecified impurity remains below 0.10%, while potential genotoxic impurities are controlled according to ICH M7 option‑4 purge factor calculations. In‑process monitoring applies Ph. Eur. 2.2.29 liquid chromatography with a C18 column (UV detection at 254 nm); the retention time of the des‑formyl by‑product is verified against a reference standard. Kilo‑lab reactors equipped with low‑temperature jackets and precise feed‑forward control are necessary because the lithiation exotherm must be compensated within 30 seconds to prevent outlet temperature overshoot. The terminal intermediate is qualified as a regulatory starting material for active pharmaceutical ingredients such as tofacitinib analogues, and the batch release documentation includes residual solvents per USP <467> and palladium content (if introduced in a subsequent Heck coupling) below 20 ppm measured by ICP‑MS conforming to USP <232> and <233>.

The production of phenylpyrrole fungicides—exemplified by fludioxonil and fenpiclonil—relies on a 3‑cyanopyrrole building block that must tolerate palladium‑catalysed cross‑coupling without premature N‑deprotection. 1‑(Phenylsulfonyl)‑1H‑pyrrole satisfies this requirement by stabilising the pyrrole nitrogen during bromination and the subsequent Suzuki–Miyaura coupling. A commercial‑scale bromination charges 1.0 kg (4.6 mol) of the starting material into a glass‑lined reactor together with dichloromethane (6 L), cooled to 0–5 °C. N‑Bromosuccinimide (1.05 eq, 0.86 kg) is added portion‑wise over 90 min while maintaining the jacket at ‑5 °C; after a further 3 h of stirring, a sodium metabisulfite solution quench removes residual bromine. The organic layer is washed, dried over magnesium sulfate, and concentrated to a low‑melting solid. Recrystallisation from cyclohexane/toluene (4:1 v/v) yields 3‑bromo‑1‑(phenylsulfonyl)pyrrole with a melting point of 78–80 °C and purity 99.0% (GC). Cyanation is performed in N‑methyl‑2‑pyrrolidone using copper(I) cyanide (1.2 eq) at 150–155 °C for 8 h; after diluting with ethyl acetate and filtering through Celite, the 3‑cyano intermediate is isolated in 82% yield. The decisive Suzuki coupling combines 100 mmol of this intermediate with 105 mmol of 4‑bromo‑2,2‑difluoro‑1,3‑benzodioxole, tetrakis(triphenylphosphine)palladium(0) (2.0 mol%), and sodium carbonate (200 mmol) in a toluene/ethanol/water (3:1:1) solvent mixture at gentle reflux (85 °C internal) for 18 h. The coupled adduct is obtained in 88% yield after column chromatography. Benzenesulfonyl deprotection employs sodium hydroxide (3.0 eq) in ethylene glycol/water at 110 °C for 4 h, followed by acidification to precipitate fludioxonil technical (purity > 95% after recrystallisation). Compliance with EU Regulation 1107/2009 and the FAO/WHO JMPR monograph criteria governs active ingredient equivalence. Residual NMP must be controlled below 530 ppm according to ICH Q3C, and the nitrile‑related impurity profile is validated by GC‑FID with a limit of quantification of 50 ppm. The terminal formulated product is a flowable concentrate or water‑dispersible granule for seed treatment in cereals and vegetables, where the batch release protocol also includes suspension stability (CIPAC MT 184) and wet sieve retention (< 0.2% on a 75 µm screen).

What Determines the Quantum Yield of Sulfonic Acid Photogeneration in 248 nm Resist Formulations?

When incorporated into chemically amplified photoresists for KrF lithography, 1‑(phenylsulfonyl)‑1H‑pyrrole operates as a non‑ionic photoacid generator (PAG) that undergoes homolytic N–S bond scission upon irradiation at 248 nm. The liberated benzenesulfonic acid (pKa < ‑2.8) subsequently catalyses the deprotection of tert‑butoxycarbonyl‑ or tert‑butyl ester‑protected resins. A typical screening formulation dissolves poly(4‑hydroxystyrene‑co‑tert‑butyl acrylate) (molecular weight Mw 8 000–12 000 g/mol) in propylene glycol monomethyl ether acetate, loading the PAG at 5–12 wt% relative to solid polymer and adding a photobase such as tri‑n‑octylamine at 0.5–1.0 wt% to suppress dark film loss. The resist is spin‑cast to a thickness of 0.8–1.2 µm, soft‑baked at 130 °C for 90 s, and exposed through a binary mask on a 248 nm stepper (numerical aperture 0.63). Exposure doses in the range 15–35 mJ/cm² are followed by a post‑exposure bake at 120 °C for 60 s and development with 0.26 N tetramethylammonium hydroxide for 60 s using a single‑puddle process. The acid generation quantum yield (Φ_acid) measured in acetonitrile by Rhodamine B base titration at 254 nm is approximately 0.25 ± 0.03; this value is influenced by solvent cage recombination of the benzenesulfonyl radical and the pyrrolyl radical, and in a rigid polymer matrix the efficiency can drop by 30–50% because restricted free volume hinders radical diffusion. When the PAG load falls below 3 wt%, the sensitivity curve shifts to > 50 mJ/cm² and the linewidth roughness (LWR) increases beyond 6 nm (3σ), failing the ITRS specification for the 90 nm node. Process qualification follows ASTM F 1353-08 to determine film thickness loss and contrast, while outgassing risk is assessed by residual gas analysis per ISO 14644-9. The patterned resist stack ultimately defines gate‑level contact holes or isolation trenches in logic devices, where critical dimension uniformity must stay below 10% across a 300 mm wafer. Waste streams containing the PAG are treated as non‑halogenated organic by‑products and must comply with local VOC emission limits per the EU Industrial Emissions Directive 2010/75/EU.

Electrochemical deposition of polypyrrole from a precursor carrying a removable benzenesulfonyl group enables the fabrication of high‑surface‑area films with significantly fewer α–β crosslinks than films grown directly from pyrrole monomer. A standard three‑electrode cell is assembled with an indium tin oxide (ITO) working electrode (sheet resistance < 10 Ω/sq), a platinum mesh counter electrode, and a Ag/AgCl reference electrode (3 M KCl). The deoxygenated electrolyte contains 0.1 M 1‑(phenylsulfonyl)pyrrole and 0.1 M tetrabutylammonium hexafluorophosphate in anhydrous acetonitrile (water < 30 ppm). Potentiostatic deposition is conducted at +1.20 V to +1.35 V versus Ag/AgCl, and the charge is integrated to a total of 0.8–1.2 C/cm², which yields a film thickness of 0.6–0.9 µm as verified by stylus profilometry. After growth, the wash‑coated electrode is immersed in 0.1 M NaOH in methanol/water (1:1 v/v) at 40 °C for 3 h; the disappearance of the asymmetric S=O stretching band at 1170 cm⁻¹ in the ATR‑FTIR spectrum signals complete deprotection. The resulting porous poly(pyrrole) exhibits a specific capacitance of 240–320 F/g at a scan rate of 5 mV/s in 1 M H₂SO₄ electrolyte, evaluated by cyclic voltammetry according to ISO 21885:2019. Galvanostatic charge‑discharge cycling over 10 000 cycles at 1 A/g shows capacitance retention above 85%. Adhesion to the current collector, measured by the cross‑cut tape test ASTM D3359, achieves classification 4B when a (3‑aminopropyl)triethoxysilane primer is applied to the ITO surface before deposition. The electrode is subsequently assembled into a symmetrical supercapacitor coin cell with a cellulose separator and 1 M tetraethylammonium tetrafluoroborate in propylene carbonate; the device delivers an energy density of 5–8 Wh/kg at a power density of 500 W/kg. Heavy‑metal content—lead, cadmium, and mercury—remains below 10 ppm each as mandated by RoHS Directive 2011/65/EU, and the electrochemical stability window is verified to 2.5 V by linear sweep voltammetry at 1 mV/s. Flexible supercapacitor modules fabricated in this way are qualified for wearable energy storage where repeated bending to a radius of 5 mm must not alter capacitance by more than 10% after 1 000 cycles.

When 2‑Lithiation Outcompetes S_NAr Pathways: A Route to Lamellarin‑Class Marine Alkaloids

The 5,6‑dihydropyrrolo[2,1‑a]isoquinoline core of lamellarin D and its congeners demands a pyrrole unit that can be selectively functionalised at the C‑2 position without interference from the nitrogen centre. 1‑(Phenylsulfonyl)‑1H‑pyrrole meets this demand through a directed C‑2 lithiation‑alkylation‑arylation cascade. Anhydrous THF containing the substrate (1.0 eq, 0.25 M) and hexamethylphosphoramide (1.5 eq) is cooled to ‑40 °C, and lithium 2,2,6,6‑tetramethylpiperidide (LiTMP, freshly prepared from 1.1 eq TMP and 1.1 eq n‑butyllithium at 0 °C) is added dropwise. After 1 h of metalation, a protected isovanillin equivalent (1.2 eq) in THF is introduced at ‑78 °C, giving the benzylic alcohol in 70–80% yield after aqueous work‑up. The alcohol is oxidised to the corresponding ketone with Dess–Martin periodinane (1.5 eq) in dichloromethane at 20 °C over 2 h. With the ketone in hand, the benzenesulfonyl group is retained while a copper‑catalysed Ullmann N‑arylation with ethyl 2‑iodobenzoate (1.2 eq) proceeds in N,N‑dimethylformamide at 120 °C using copper(I) iodide (10 mol%) and N,N‑dimethylethylenediamine (20 mol%) as the ligand; this forms the N‑aryl pyrrole intermediate in 65% yield. The benzenesulfonyl group is subsequently removed with potassium hydroxide (2.0 eq) in ethanol/water (4:1 v/v) at 80 °C over 6 h, followed by acid‑catalysed intramolecular aldol condensation to forge the isoquinoline ring. The final lamellarin D methyl ether is obtained after global demethylation with boron tribromide (3.0 eq) in dichloromethane at 0 °C. Throughout this synthesis, in‑process controls specified under cGMP for advanced intermediates require HPLC purity determination at each step (area% by Ph. Eur. 2.2.29), and any single unidentified impurity must not exceed 0.15%. Residual copper from the arylation step is controlled to < 50 ppm (ICP‑OES) before the final deprotection, as post‑purification removal efficiency drops sharply once the heterocyclic chelation sites are unmasked. The terminal compound serves as a reference standard for topoisomerase I inhibition assays and is supplied with a certificate of analysis stating elemental composition and solvent residues according to the ICH Q3C guideline.

3‑Borylated 1‑(Phenylsulfonyl)pyrrole Intermediates for Fragment‑Based Drug Discovery Platforms

Fragment screening libraries require heteroarylboronic ester building blocks stable enough to withstand automated liquid handling and high‑throughput Suzuki–Miyaura coupling in aqueous dimethyl sulfoxide. Conversion of 1‑(phenylsulfonyl)‑1H‑pyrrole into its 3‑(4,4,5,5‑tetramethyl‑1,3,2‑dioxaborolan‑2‑yl) derivative is accomplished through a directed ortho‑metalation–borylation sequence that avoids competing 2‑substitution. In a nitrogen‑purged vessel, the substrate (1.0 eq) is dissolved in anhydrous 2‑methyltetrahydrofuran, cooled to ‑50 °C, and treated with lithium bis(trimethylsilyl)amide (1.2 eq, 1.0 M in THF). The solution is stirred for 1 h to achieve complete deprotonation, after which 2‑isopropoxy‑4,4,5,5‑tetramethyl‑1,3,2‑dioxaborolane (1.5 eq) is injected at a rate that maintains the internal temperature below ‑40 °C. The cooling bath is removed and the mixture is allowed to warm overnight to 20–25 °C. Quenching with saturated ammonium chloride, extraction with ethyl acetate, and crystallisation from heptane/methyl tert‑butyl ether (5:1) furnishes the pinacol boronate ester as a white crystalline solid with HPLC purity ≥ 98%. This borylated intermediate is compatible with high‑throughput experimentation: a standard microscale coupling partitions the boronate (50 μmol), a aryl bromide diversity partner (55 μmol), PdCl₂(dppf)·CH₂Cl₂ (2 mol%), and tribasic potassium phosphate (3 eq) into a 96‑well plate, adds dimethyl sulfoxide/water (9:1), and heats the sealed plate at 65 °C for 4 h. Conversions routinely exceed 75% as judged by LC‑UV at 254 nm. The coupling products retain the benzenesulfonyl group, which can be removed later to reveal the N–H pyrrole for additional derivatisation. Quality assurance for fragment library supply applies ICH M7 principles to purge potential mutagenic impurities; residual palladium is quantified by ICP‑MS according to USP <232> and <233> and must remain below 10 ppm. Boron content is verified by ¹H and ¹¹B NMR spectroscopy, and the lot is released only when LC‑MS confirms the expected [M+H]⁺ ion with mass error < 3 ppm. The final output is a validated fragment plate where each well contains a dry film of the intermediate re‑dissolved in DMSO‑d₆ at 100 mM, ready for surface plasmon resonance or thermal shift screening against kinase and epigenetic target panels.