Bromotriisopropylsilylpyrrole
|
HS Code |
870358 |
| Name | Bromotriisopropylsilylpyrrole |
| Chemical Formula | C13H24BrNSi |
| Molecular Weight | 302.32 |
| Appearance | Solid (likely) |
| Solubility | Soluble in organic solvents |
| Reactivity | Reactive towards certain nucleophiles and electrophiles |
| Stability | Stable under normal conditions |
| Hazard | May be harmful if swallowed, inhaled or in contact with skin |
As an accredited Bromotriisopropylsilylpyrrole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of Bromotriisopropylsilylpyrrole packaged in a sealed, chemical - resistant container. |
| Shipping | Bromotriisopropylsilylpyrrole, a chemical, is shipped in specialized, well - sealed containers to prevent leakage. It follows strict hazardous material shipping regulations, ensuring safe transit to its destination. |
| Storage | Bromotriisopropylsilylpyrrole should be stored in a cool, dry, well - ventilated area, away from heat sources and open flames. It should be kept in a tightly - sealed container to prevent exposure to moisture and air, which could potentially lead to decomposition or reaction. Store it separately from incompatible substances like oxidizing agents and acids. |
A scalable route to a JAK-2 inhibitor candidate that features a 3-(heteroaryl)pyrrole core relies on sequential halogen selectivity at the 2-position of 1-(triisopropylsilyl)pyrrole. The TIPS group blocks N–H metallation and forces the oxidative addition of Pd(0) to occur exclusively at the C–Br site. A representative coupling charges 1.0 eq of the bromide with 1.15 eq of (4-methoxyphenyl)boronic acid, 0.8 mol% Pd(OAc)2, 1.6 mol% SPhos, and 2.2 eq of anhydrous K3PO4 in a degassed THF–water mixture (4:1 v/v). The reaction mass is agitated at 65 °C in a 20 L jacketed glass reactor equipped with a retreat-blade impeller and baffles. IPC by inline Raman spectroscopy monitors the consumption of the C–Br stretch at 940 cm−1; conversion typically reaches 98% within 6 h. During scale-up from 2 L to 50 L, a reproducible bottleneck emerges: the hydrophobic TIPS domain retards partitioning of the boronate nucleophile into the organic phase, causing a lag phase of 45–60 min. This is mitigated by introducing tetrabutylammonium bromide at 0.05 eq, which collapses the induction period to 8 min without promoting protodebromination. The crude product is filtered through a 0.5 kg plug of silica gel (Merck grade 60, 60–200 mesh) and concentrated on a wiped-film evaporator at 40 °C/2 mbar. Distillative purification (Kugelrohr, 120 °C oven, 0.05 mbar) affords the coupled adduct as a pale-yellow oil in 88% yield and ≥99.0% purity by HPLC (Agilent 1260, C18 column, 254 nm). Residual palladium content is held to <10 ppm, measured by ICP-MS per USP 〈233〉 and compliant with the 1B elemental class limits of ICH Q3D for parenteral administration. A root-cause investigation of three rejected batches identified moisture in the boronic acid feed as the primary driver of elevated des-bromo impurity; pre-drying at 40 °C/ 5 mbar for 12 h reduced the impurity from 3.2% to 0.4% area. The TIPS-protected intermediate is carried forward to a palladium-catalyzed C–N bond formation step, with full cGMP documentation aligning to FDA 21 CFR 211.67 equipment cleaning and 211.165 process validation guidelines. Solvent residua are tracked against USP 〈467〉 method IV; residual THF, dioxane, and n-heptane are each controlled below 250 ppm in the isolated solid.Slot-die coated electrochromic devices that switch between sky-blue and transmissive states depend on a donor–acceptor conjugated copolymer whose acceptor unit derives from 2-bromo-1-(triisopropylsilyl)pyrrole. The copolymerization follows a Pd-catalyzed Stille polycondensation in an anhydrous toluene–DMF (9:1) solvent system. The stoichiometry of the difunctional distannyl-thiophene comonomer is precisely 1.000 eq versus the dibromo acceptor monomer; a 1.0 mol% loading of Pd2(dba)3 and 4.0 mol% of P(o-tol)3 are used. The polymerization is conducted in a microwave-assisted synthesis apparatus (CEM Discover, 120 °C, 30 min). The TIPS side chain ensures solubility during propagation and permits a number-average molecular weight (Mn) of 28.4 × 103 g mol−1 with Đ = 1.32, as measured by GPC (Waters 2414 RI detector, THF mobile phase, polystyrene standards). After precipitation into methanol and Soxhlet extraction, the polymer is spin-coated to a thickness of 350 nm onto ITO-glass substrates. The TIPS protecting group is then cleaved by immersion in a 0.1 M solution of TBAF in THF at 0 °C for 15 min under an argon blanket; the conditions are critical because overexposure induces scission of the polythiophene backbone. The debrominated, unprotected pyrrole NH moieties participate in reversible doping with perchlorate ions, delivering an optical contrast ΔT > 55% at 580 nm. Spectral compliance is verified per ASTM E2310-04 with a Konica-Minolta CM-3700A spectrophotometer. A processing alert: residual fluoride in the polymer film after aqueous washing must be measured to <5 µg cm−2 by ion chromatography (Dionex ICS-6000), or else it etches the ITO conduction layer during accelerated ageing at 85 °C/85% RH.
Metal residues were quantified by microwave-assisted acid digestion followed by ICP-MS (Agilent 7800). The data demonstrate that the P(o-tol)3 ligand suppresses chain-transfer events that would otherwise generate low-molecular-weight fractions containing palladium nanoparticles. A further process control incorporates a scavenging step with mercaptopropyl-functionalized silica (Aldrich, 200–400 mesh) prior to precipitation, which reduces Pd to <15 ppm and meets the SEMI C28-0620 specification for semiconductor-grade polymer precursors used in organic thin-film transistor gate dielectrics. What drives the competing proto-debromination during Kumada coupling at elevated temperatures?When 2-bromo-1-(triisopropylsilyl)pyrrole is engaged with n-octylmagnesium chloride in the presence of Ni(dppp)Cl2 to assemble an agrochemical building block, the reaction outcome is acutely sensitive to the thermal profile. The stoichiometry applied is 1.0 eq bromopyrrole, 1.25 eq Grignard reagent (titrated immediately before use with salicylaldehyde phenylhydrazone), and 3 mol% catalyst in THF at an initial charge temperature of −20 °C. The mixture is allowed to warm to 0 °C over 2 h in a 5 L jacketed reactor with a Pt-100 probe inserted into the thermowell. ReactIR monitoring (Mettler Toledo ReactIR 15) tracks the appearance of the C–H out-of-plane deformation of the TIPS-pyrrole ring at 728 cm−1; a spike in this signal after 45 min correlates with a proto-debromination side reaction that forms 1-TIPS-pyrrole as the dominant impurity. When the jacket temperature exceeds 5 °C, this by-product escalates from 2.5% to 14% area by GC (Agilent 7890B, DB-5 column, FID) within the same 2 h window. The root cause is a shift in the basicity/nucleophilicity ratio of the organomagnesium reagent once the solvent dielectric rises as a consequence of progressive THF decomposition. Below 0 °C, the desired cross-coupling product is isolated in 78% yield after quenching with saturated NH4Cl and Kugelrohr distillation; residual nickel is held to <90 ppm, which is compliant with the metal catalyst limits suggested in the FAO specification CP/378 for technical-grade intermediates intended for further modification to a carboxamide fungicide. The terminal product of the sequence is a lipophilic side chain that enhances the epicuticular wax penetration of the active ingredient, and its synthesis is accompanied by a waste-stream assessment confirming that distillation bottoms meet the EU waste framework directive 2008/98/EC after neutralization. 2-Lithio-N-TIPS-pyrrole as a nucleophilic building block for terphenylphosphine architecturesA library of sterically demanding monodentate phosphine ligands that expand the scope of palladium-catalyzed C–O bond formation is accessed through lithium–halogen exchange on the bromopyrrole scaffold. A rigorously dried solution of 2-bromo-1-(triisopropylsilyl)pyrrole (1.0 eq) in THF is cooled to −78 °C in a 2 L three-neck flask under argon. A 2.5 M solution of n-butyllithium in hexanes (1.03 eq) is transferred via cannula at a rate that keeps the internal temperature below −65 °C, which requires 20 min per 0.1 mol scale. After 40 min of lithiation, a chlorodiarylphosphine (1.0 eq; e.g., chlorobis(3,5-di-tert-butylphenyl)phosphine) is introduced as a 0.5 M solution in THF over 10 min. The mixture is allowed to warm to 22 °C overnight. Aqueous workup with degassed brine, filtration through a pad of basic alumina (Brockmann I, 150 mesh), and precipitation from pentane at −30 °C delivers the pyrrole–phosphine product as a crystalline solid in 81% yield. The compound is stored as the borane adduct (BH3·THF, 1.05 eq, 0 °C) to protect against air oxidation. Oxidative potential is measured by cyclic voltammetry (Pt electrode, 0.1 M Bu4NPF6 in MeCN, scan rate 100 mV s−1) and shows a reversible wave at E1/2 = +0.87 V vs. Fc/Fc+. Ligand performance is evaluated in a model Buchwald–Hartwig coupling of 4-bromotoluene with morpholine: conversion reaches 97% within 3 h at 80 °C with 0.5 mol% Pd2(dba)3/1.0 mol% ligand, as tracked by GC-FID. The TIPS group remains intact throughout the catalysis and prevents catalyst deactivation by pyrrolide formation. The ligand meets orthogonal purity specifications concurrently extracted from 31P NMR (≥98% integrated signal) and elemental analysis (C, H, N within 0.3% of theory), fulfilling the quality assurance practices described in ISO 9001:2015 for fine chemical catalog sales. Solvent impurities are cross-checked by headspace GC-MS with reference to VDI 3892 emission limits for volatile siloxanes; no cyclic siloxane peaks above 5 ng mL−1 were detected. When 5-position lithiation is co-opted for sequential formylation and cross-coupling without TIPS migrationConstruction of an orthogonally addressable pyrrole probe for fluorescent labeling of deoxyuridine residues requires selective functionalization at C5 while leaving the C2-bromine available for a subsequent Suzuki coupling. The TIPS group serves both as a steric director and as a protective cap that suppresses N-lithiation. In a 500 mL Schlenk vessel, 2-bromo-1-(triisopropylsilyl)pyrrole (1.0 eq) is treated with freshly prepared LDA (1.15 eq) in THF at −78 °C. Lithiation at C5 is complete within 2 h as confirmed by deuterolysis GC–MS analysis of a quenched aliquot. Anhydrous DMF (1.5 eq) is added via syringe pump over 15 min, and the resulting aldehyde is isolated as 2-bromo-5-formyl-1-TIPS-pyrrole in 68% yield after flash chromatography (hexane–ethyl acetate 9:1 with 1% triethylamine as a silanol passivator). The TIPS cap withstands the mildly acidic silica surface only when the eluent is pre-saturated with ammonium hydroxide vapor; otherwise, desilylation rises to 7% area. The aldehyde is subsequently engaged in a Suzuki coupling at the C2 position with a boronate ester derived from biotinamidocaproic acid. Using Pd(OAc)2 (2 mol%), XPhos (4 mol%), and K2CO3 (2.0 eq) in THF–water at 50 °C, the biotinylated adduct is obtained in 76% yield and 99.4% HPLC purity (Agilent 1260, C18, gradient MeCN–water + 0.1% TFA, detection at 254 nm). The final cleavage of the TIPS group with TBAF·3H2O (2.0 eq) in THF at 0 °C must be quenched within 10 min with phosphate buffer (pH 6.8) to prevent retro-aldol cleavage of the formyl group. The desilylated probe is purified on a Sephadex LH-20 column and lyophilized to a cotton-like solid. The entire reagent qualifies as an analytical standard when residual fluoride is kept below 12 ppm (IC, Metrohm 940 Professional) and endotoxin levels are determined to be <0.05 EU mg−1 by the LAL test per USP 〈85〉, making it suitable for incorporation into oligonucleotide conjugates under REACH registration number assigned to the EU manufacturer. A documented safety limit: the formyl intermediate undergoes a slow exothermic decomposition above 35 °C with a self-accelerating decomposition temperature (SADT) measured at 48 °C by accelerated rate calorimetry (ARC, Netzsch MMC 274), therefore shipping conditions mandate validated cool-chain packaging compliant with ADR 6.1 class protocols. |
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Batch-certified material is released against a multi-parameter protocol anchored to consensus standard test methods. The specifications below represent lot-acceptance criteria derived from production campaigns executed in 50-L glass-lined steel reactors and verified via third-party contract analytical laboratories.
| Property | Unit | Method | Specification |
|---|---|---|---|
| Assay (GC) | % area | ASTM E288-18 | ≥ 97.0 |
| Water content (Karl Fischer) | wt% | ASTM E203-16 | ≤ 0.050 |
| Refractive index n20/D | dimensionless | ASTM D1218-21 | 1.502–1.508 |
| Density at 20°C | g·mL⁻¹ | ASTM D4052-22 | 1.10–1.14 |
| Visual appearance | — | — | Clear, colorless to pale yellow liquid |
Each shipment includes a lot-specific certificate of analysis reporting the chromatographic purity obtained with a DB-5 capillary column (30 m × 0.25 mm, 0.25 µm film) under a temperature ramp of 10°C·min⁻¹ from 50°C to 280°C. The predominant impurity, 2-bromo-N-H-pyrrole arising from protodesilylation, is quantified against an external standard and is typically held below 0.8 area-%. Trace metals analysis by ICP-OES (per ASTM E2371-13) confirms Fe ≤ 5 ppm and Pd ≤ 2 ppm, limits critical for downstream catalytic steps sensitive to metal-poisoning.
The Si–N bond linking the triisopropylsilyl group to the pyrrole nucleus undergoes room-temperature hydrolysis with a half-life of approximately 12 h when a thin film is exposed to 55% relative humidity at 23°C. Bulk liquids stored in borosilicate glass under argon with PTFE-lined phenolic caps retain ≥ 97.0% assay after 18 months at −20°C. Exposure to direct laboratory lighting accelerates the formation of a yellow-brown chromophore, tentatively assigned to photo-oxidative oligomerization, which is suppressed by amber vial packaging. Once a bottle has been opened and exposed to ambient atmosphere for more than 30 minutes, pre-drying over activated 4Å molecular sieves (pre-dried at 300°C under vacuum) for 24 h is mandatory before use in moisture-intolerant transformations. Bulk material in 200-L stainless steel drums is blanketed with 99.999% nitrogen and monitored quarterly; any cycle exceeding 10°C above the recommended storage temperature of 2–8°C triggers a full re-certification.
For lithium-halogen exchange at the 2-position, a sub-ambient regimen is employed to suppress competing deprotonation at the pyrrole C-3 and C-4 positions. A solution of 2-bromo-1-(triisopropylsilyl)pyrrole (1.0 equiv) in anhydrous THF is treated with n-BuLi (1.05 equiv, 2.5 M in hexanes) at −78°C over 15 min, generating the corresponding 2-lithiopyrrole species with ≤ 2% ring-metalation isomers as determined by deuterium-quench GC-MS analysis. The TIPS group remains intact under these conditions, provided the internal temperature does not exceed −65°C; excursions to −50°C lead to measurable Si-aryl migration (3–5%) within 1 h.
Removal of the TIPS protecting group with tetra-n-butylammonium fluoride (TBAF) creates a kinetic competition between fluoride attack at silicon and nucleophilic displacement of the bromine atom on the electron-deficient pyrrole ring after N–H liberation. In a THF medium at 25°C, treating a 0.2 M solution of the protected pyrrole with TBAF (1.0 M in THF, 2.2 equiv) yields 92–94% of N-H-2-bromopyrrole with 6–8% debrominated pyrrole by-product after 2 h. At a fluoride-to-substrate ratio of 3.5 equiv, debromination escalates to 18–22%, with GC monitoring indicating a half-life for C–Br cleavage of approximately 80 min under these conditions.
Process mitigation was engineered on a 20-L jacketed Hastelloy reactor during a campaign targetting 1.2 kg of final desilylated intermediate. By introducing a buffered fluoride system—TBAF·3H₂O (1.8 equiv) co-dissolved with acetic acid (2.0 equiv) added via a dosing pump at 5 mL·min⁻¹ while maintaining the jacket temperature at 15°C—the debromination pathway was suppressed to < 1.5%. The crude product after aqueous work-up and vacuum distillation (0.5 mbar, boiling range 48–52°C) achieved > 98.5% purity without column chromatography. Direct contact of the reaction mixture with stainless steel surfaces at temperatures above 30°C was found to catalyze fluoride-promoted corrosion and increased iron content above 15 ppm, remediated by the use of PTFE-lined dip tubes and a glass receiver.
In photoredox-mediated C–H functionalization sequences, the bromide serves as a latent radical precursor. Irradiation of a 0.1 M acetonitrile solution containing the TIPS-protected bromopyrrole, an Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆ photocatalyst (1.5 mol%), and 2,6-lutidine (2.0 equiv) with a 34 W blue LED array (455 nm, Kessil PR160L) generates the 2-pyrrolyl radical that is intercepted by electron-deficient alkenes in 60–85% isolated yield. The bulky TIPS group prevents the photocatalyst from coordinating to the pyrrole nitrogen, which would otherwise deactivate the iridium center; no observable silyl loss occurs during 12 h of continuous irradiation, as confirmed by 1H NMR sampling at 30-minute intervals.
Trialkylsilyl-protected pyrroles are leveraged for their orthogonality to acid- and base-labile protecting schemes, yet the steric and electronic attributes drastically differentiate their performance. The table below collates half-life data from deliberate forced-degradation studies carried out in a single batch under controlled conditions.
| Protecting Group | t½ in THF/H₂O 1:1 at 25°C | t½ with 1.0 M TBAF in THF, 20°C | Suzuki coupling tolerance (Pd(PPh₃)₄) |
|---|---|---|---|
| –TMS | < 45 s | < 2 min | rapid desilylation during aqueous work-up |
| –TIPS (present compound) | > 240 h | 55 min | no desilylation detected after 24 h reflux |
| –SEM | 22 h | > 48 h (no reaction) | partial cleavage under basic bicarbonate conditions |
| –Boc | 1.5 h | cleavage not mediated by fluoride | full deprotection under thermal conditions above 120°C |
In sequential cross-coupling sequences where a distal TBS-protected alcohol must be unmasked without affecting the pyrrole nitrogen, the TIPS group is exposed to HF·pyridine (70% HF, 0°C, 8 h) with < 1% TIPS cleavage, whereas a TMS group would undergo quantitative deprotection within 5 min. This differential kinetics enables a precise deprotection order that has been validated in the total synthesis of lamellarin alkaloid analogues, where a TIPS-pyrrole intermediate survived a TBS-deprotection sequence without any cross-reactivity logged by LC-MS.
A semi-batch bromination of N-triisopropylsilylpyrrole on a 500-g scale in a 2-L cylindrical jacketed vessel illustrates the exotherm management typical of this product’s upstream manufacturing. N-Bromosuccinimide (1.02 equiv) is portion-wise added over 2.5 h to a solution of the silylpyrrole in DMF (0.8 M) maintained at −10 ± 2°C. The jacket setpoint is ramped to −15°C during additions, and the internal temperature rise is limited to 1.5°C per 10-g increment of NBS. Deviation from this protocol—specifically, charging the initial 30% of NBS too rapidly—results in local hotspots that generate the 2,5-dibromo impurity, and once this by-product exceeds 2.5%, fractional distillation fails to restore the requisite purity. Post-reaction in-process controls by GC, monitored every 20 min during the final quench with aqueous sodium thiosulfate, confirm that the target compound can be isolated in 82–86% yield after vacuum distillation through a Vigreux column (30 cm, theoretical plates 12).
