Tert-Butyl 2-(Tetramethyl-1,3,2-Dioxaborolan-2-Yl)-1H-Pyrrole-1-Carboxylate
|
HS Code |
338099 |
| Chemical Formula | C15H24BNO4 |
| Molar Mass | 293.17 g/mol |
| Appearance | Solid (usually white or off - white) |
| Solubility In Organic Solvents | Soluble in common organic solvents like dichloromethane, toluene |
| Melting Point | Typically in the range of 70 - 80 °C |
| Stability | Stable under normal conditions, but sensitive to strong acids and bases |
| Purity | Can be obtained with high purity (e.g., >95% in commercial products) |
| Application | Used in cross - coupling reactions for the synthesis of pyrrole - containing compounds |
As an accredited Tert-Butyl 2-(Tetramethyl-1,3,2-Dioxaborolan-2-Yl)-1H-Pyrrole-1-Carboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of Tert - Butyl 2-(Tetramethyl - 1,3,2 - Dioxaborolan - 2 - Yl)-1H - Pyrrole - 1 - Carboxylate in sealed vial. |
| Shipping | **Shipping Description for Tert - Butyl 2 - (Tetramethyl - 1,3,2 - Dioxaborolan - 2 - Yl)-1H - Pyrrole - 1 - Carboxylate**: This chemical is shipped in accordance with strict hazardous material regulations. Packed in secure containers to prevent leakage, ensuring safe transport. |
| Storage | Store "Tert - Butyl 2-(Tetramethyl - 1,3,2 - Dioxaborolan - 2 - Yl)-1H - Pyrrole - 1 - Carboxylate" in a cool, dry place away from heat and ignition sources. Keep it in a tightly sealed container to prevent exposure to moisture and air, which could potentially degrade the chemical. Store it separately from incompatible substances to avoid reactions. |
In multi-kilogram production of targeted oncology intermediates, the boronic ester is charged at a 1.08–1.15 molar equivalent relative to the aryl bromide partner—a stoichiometric overage empirically determined to compensate for protodeboronation side reactions observed during 500 L glass-lined batch campaigns. The Suzuki coupling is catalyzed by 0.3 mol% tetrakis(triphenylphosphine)palladium(0) suspended in a rigorously degassed toluene/ethanol/water ternary system (3:1:1 v/v) at precisely 75 °C jacket temperature. An in-line attenuated total reflectance Fourier-transform infrared probe monitors the disappearance of the C–Br stretching band at 1,070 cm⁻¹ to determine reaction endpoint; typical cycle time ranges from 8 to 12 hours depending on the electronic character of the aryl electrophile. Upon phase separation at 55 °C, the organic layer is washed with a 5% w/w aqueous ethylenediaminetetraacetic acid disodium salt solution to sequester residual palladium below the 100 μg/day oral permissible daily exposure threshold mandated by the ICH Q3D guideline for Class 1B elemental impurities. The crude 2-aryl-N-Boc-pyrrole is concentrated under reduced pressure (50 mbar, 45 °C bath) and recrystallized from isopropanol/water (4:1) to yield a white to off-white crystalline solid with chemical purity exceeding 99.0% by HPLC area at 254 nm (RP-C18, acetonitrile/0.1% phosphoric acid gradient). Residual solvent profiles are validated against USP <467> procedure A, with headspace GC-FID confirming toluene below 890 ppm and ethanol below 5,000 ppm. The N-Boc protecting group is subsequently cleaved in a separate vessel using 3.0 equivalents of trifluoroacetic acid in dichloromethane at 0–5 °C, producing the free pyrrole hydrochloride salt as a pivotal building block for ATP-competitive kinase inhibitor scaffolds targeting mutant epidermal growth factor receptor variants. This intermediate is further elaborated through amide bond formation or reductive amination sequences to deliver active pharmaceutical ingredient candidates evaluated in Phase I/II clinical settings under ICH Q7 GMP guidelines. Lot-to-lot variability in palladium content, as tracked by inductively coupled plasma mass spectrometry per USP <233>, remains the critical quality attribute driving specification tightness at commercial scale.What Enables Pyrrole-Containing Host Materials to Achieve High Triplet Energy in Phosphorescent OLEDs?Vacuum-processable small-molecule hosts for blue and green phosphorescent organic light-emitting diodes demand triplet energies (**ET**) exceeding 2.8 eV to prevent back energy transfer from the emissive iridium dopant to the host matrix. The introduction of an electron-donating pyrrole moiety linked to a high-bandgap dibenzofuran or dibenzothiophene core via Suzuki coupling with this pinacol boronate ester provides a synthetic route to materials exhibiting a glass transition temperature (**Tg**) above 120 °C, a prerequisite for morphological stability during device operation at 85 °C panel temperature. The coupling protocol employs 1.05 equivalents of the boronate relative to dibromocarbazole or bromodibenzofuran, catalyzed by 1.0 mol% tris(dibenzylideneacetone)dipalladium(0) and 2.4 mol% 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos) in anhydrous tetrahydrofuran at 40 °C under a positive argon blanket. Aqueous workup with 10% w/w sodium chloride is followed by flash chromatography over neutral alumina (Brockmann activity I, eluent: toluene/ethyl acetate 9:1) to remove ligand-derived phosphine oxide contaminants. The isolated material undergoes gradient sublimation in a four-zone tube furnace operating at 1.2 × 10⁻⁶ mbar, with zone temperatures set to 240 °C/220 °C/180 °C/25 °C, yielding a purity exceeding 99.95% as determined by differential scanning calorimetry melting endotherm sharpness and supported by high-performance liquid chromatography–mass spectrometry. Metallic impurity ceilings are stringently enforced: sodium and potassium below 0.5 ppm each, total transition metals below 1.0 ppm by glow discharge mass spectrometry, in alignment with the electronic-grade material specifications harmonized under the RoHS Directive 2011/65/EU and its amending Delegated Directive (EU) 2015/863. The sublimed host is co-evaporated with a phosphorescent emitter such as fac-tris(2-phenylpyridine)iridium(III) at a rate of 1.0–2.0 Å/s onto a pre-cleaned indium tin oxide anode substrate in a Kurt J. Lesker cluster tool at a base pressure of 5 × 10⁻⁷ Torr. The resulting emissive layer, typically 30–40 nm thick, sits between a hole-transport layer of N,N′-di(1-naphthyl)-N,N′-diphenylbenzidine and an electron-transport layer of bathophenanthroline, comprising a bottom-emission OLED stack. External quantum efficiency benchmarks are measured with a calibrated integrating sphere and a Keithley 2400 source meter following procedures consistent with the IEC 62341-2-1:2019 standard for OLED display optical measurement. Specific published luminous efficiency metrics for this exact composition remain limited; however, fabricated devices typically target current efficiencies exceeding 40 cd/A at 1,000 cd/m² luminance. The commercial end product comprises rigid and flexible active-matrix OLED display panels deployed in smartphone and wearable device screens where high color gamut compliance (DCI-P3 ≥ 98%) is mandatory.Benzylpyrrole Fungicide Intermediate Synthesis via High-Dilution CouplingA critical intermediate in the preparation of 3-cyano-4-(2,2-difluoro-1,3-benzodioxol-4-yl)pyrrole-based agricultural fungicides—structurally related to fludioxonil—is assembled by coupling the Boc-protected pyrrole-2-boronate with 4-bromo-2,2-difluoro-1,3-benzodioxole. To suppress homocoupling and protodeboronation side reactions that compromise isolated yields on a metric-ton scale, the process relies on a high-dilution protocol wherein the boronate is fed as a 20% w/w solution in toluene to the reactor over 4 hours while maintaining the aqueous base concentration at 1.5 M potassium carbonate. The catalyst, palladium(II) acetate (0.15 mol%) supported on activated charcoal, is selected for ease of recovery by filtration across a 5 μm sintered metal candle filter. Reaction temperature is held at 68 °C with a temperature rise limit of 2 °C/min; exceedances trigger automatic cooling interlocks to prevent exothermic excursions beyond the THF solvent autoignition threshold. The batch is post-treated with 3% w/v activated carbon (Norit SX Plus) at 60 °C for 90 minutes, then polish-filtered and crystallized from cyclohexane at a controlled cooling rate of 0.5 °C/min. The resulting crystalline intermediate achieves an assay of 96.5–98.0% by gas chromatography with flame ionization detection (DB-5 column, 15 m × 0.25 mm, 0.25 μm film). Regulatory oversight follows the multigenerational testing framework of OECD Test No. 416 for reproductive toxicity screening and the residue chemistry guidelines under US EPA OPPTS 860.1340. The intermediate is further converted to the active ingredient via alkaline hydrolysis of the nitrile group followed by decarboxylation, then formulated as a 500 g/L flowable concentrate for seed treatment or as a water-dispersible granule. The formulated product is applied at rates of 2.5–5.0 g a.i./100 kg seed for the control of Fusarium and Tilletia spp. in winter wheat, meeting the specifications of CIPAC MT 184 for suspension stability.
When the Pyrrole-Boronate is Employed to Construct Sterically Demanding Buchwald LigandsThe synthesis of dialkylbiaryl monophosphine ligands bearing a 2-(N-Boc-pyrrol-2-yl)phenyl backbone begins by coupling the boronic ester with 2-bromoiodobenzene in a sequential Suzuki–C–P cross-coupling sequence. The first step proceeds with 1.02 equivalents of the boronate and 0.5 mol% [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in dioxane at 85 °C. Following aqueous workup, the purified N-Boc-2-(2-bromophenyl)pyrrole is lithiated with 1.1 equivalents of n-butyllithium at −78 °C and quenched with di-tert-butylchlorophosphine to install the -P(t-Bu)₂ functionality. The Boc group survives the lithiation step when the temperature is rigorously maintained below −65 °C; excursions result in irreversible pyrrole α-deprotonation and subsequent ring-opening byproducts. The final ligand, after deprotection, finds application in palladium-catalyzed C–N bond formation for electron-deficient aniline substrates at catalyst loadings as low as 0.05 mol%. Technical performance is assessed by the turnover number achieved in a model coupling of 4-chlorobenzotrifluoride with morpholine in toluene at 110 °C, with a benchmark exceeding 15,000 under optimal conditions. Published kinetic data for this exact ligand architecture are limited; however, comparative studies with commercially available SPhos indicate a 20–30% rate enhancement with ortho-substituted aryl chlorides due to the conformationally restricted pyrrole substituent. The material is offered on a gram-to-kilogram scale for research and pilot use, packaged under argon in flame-sealed ampoules to prevent phosphine autoxidation.No general-purpose mixing description is required for the ligand synthesis; the complexity resides entirely in the cryogenic lithiation step. The only applicable downstream purification note is the precipitation of the phosphonium tetrafluoroborate salt from diethyl ether to improve handling stability.Optimizing Charge Transfer in Bulk Heterojunction Blends with Pyrrole-Appended DonorsSolution-processed organic photovoltaic cells leveraging a donor:acceptor architecture benefit from low-bandgap copolymers wherein electron-rich pyrrole units alternate with electron-deficient benzothiadiazole or diketopyrrolopyrrole comonomers. The N-Boc-pyrrole-2-boronate is polymerized with 4,7-dibromo-2,1,3-benzothiadiazole under Stille or Suzuki polycondensation conditions using 1.0 equivalent each of boronate and dibromide, 2 mol% tetrakis(triphenylphosphine)palladium(0), and a phase transfer catalyst aliquot 336 in a chlorobenzene/2 M aqueous sodium carbonate biphasic medium at 95 °C for 48 hours. The crude polymer is end-capped with phenylboronic acid and bromobenzene sequentially to suppress reactive termini, then purified by Soxhlet extraction with methanol, acetone, and hexane to remove low molecular weight fractions. The number-average molecular weight (**Mn**) determined by high-temperature gel permeation chromatography in 1,2,4-trichlorobenzene at 150 °C against polystyrene standards typically falls between 15,000 and 25,000 g/mol, with a dispersity of 1.8–2.2. Concomitant in-situ deprotection occurs during the aqueous basic polymerization, liberating the N-H pyrrole unit that can participate in hydrogen-bond-directed self-assembly in the active layer. Blends with [6,6]-phenyl-C61-butyric acid methyl ester (PCBM) in a 1:1.5 weight ratio are spin-coated from chlorobenzene onto PEDOT:PSS-coated ITO glass. Devices are completed by thermal evaporation of a lithium fluoride/aluminum cathode (0.6 nm/100 nm). Power conversion efficiencies are measured under AM 1.5G illumination at 100 mW/cm² using a Class AAA solar simulator, with current density–voltage curves recorded by a Keithley 2400 source meter in accordance with IEC 60904-1:2020. Direct certification data for this specific alternating copolymer is sparse; however, analogous pyrrole-thiadiazole polymers have delivered open-circuit voltages around 0.72 V and short-circuit current densities approaching 8.5 mA/cm². The packaged module configuration targets building-integrated photovoltaic applications where conformality and weighting constraints rule out crystalline silicon panels.Note on analytical methodology: For all Suzuki-based processes described, residual boron species are monitored by 11B NMR (160 MHz, DMSO-d6) or by conversion to boric acid and titration with mannitol; pinacol release is quantified by GC headspace analysis. The information provided represents aggregated process experience from pilot and production environments; site-specific optimization remains necessary. |
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| Parameter | Specification | Method/Standard Reference |
|---|---|---|
| Molecular weight | 293.17 g/mol | High-resolution mass spectrometry (ESI+) |
| CAS registry number | 905966-49-2 | American Chemical Society SciFinder |
| Appearance | White to off-white crystalline powder | Visual inspection under D65 illuminant |
| Melting range | 54–58 °C | DSC, ISO 11357-1; capillary, ASTM E794-06 |
| Purity (HPLC) | ≥98.0% (λ = 254 nm) | RP-C18 column, acetonitrile/water gradient |
| Loss on drying | ≤0.5% (w/w) | Karl Fischer coulometry (ISO 15512) |
| Storage temperature (long-term) | −20 ± 5 °C under argon | Stability study: 6 months with <1% degradation |
The transmetalation step in Suzuki-Miyaura coupling with pinacol boronates does not proceed through the fully formed boronic acid unless deliberate hydrolytic pre-activation is applied. Under anhydrous conditions with a fluoride base such as CsF (3.0 equiv), the tetracoordinate boronate intermediate generated from the pinacol ester undergoes direct transmetalation with arylpalladium(II) halide complexes, often exhibiting slower kinetics than the corresponding free boronic acid but offering superior functional group tolerance because protodeboronation of the C2-pyrrole unit—a known vulnerability of electron-rich heteroaryl boronic acids—is substantially suppressed. Kinetic profiling by in-situ IR monitoring in a typical model system (4-bromobenzotrifluoride, Pd(dppf)Cl₂ 1.5 mol%, anhydrous DMF, 80 °C) reveals a transmetalation half-life of approximately 45–60 minutes for the pinacol ester, compared to ≤15 minutes for the free acid under identical anhydrous conditions; however, the free acid shows concurrent protodeboronation exceeding 12% by 1H NMR after 1 hour, while the ester remains unchanged. This delayed activation profile is deliberately exploited when coupling partners contain base-sensitive ester or nitrile functionalities that would be compromised by the prolonged basic aqueous conditions required for in situ boronate hydrolysis.
In pharmaceutical intermediate synthesis conducted on 50–100 kg scale, the preference for the pinacol ester over the neopentyl glycol ester or the free acid arises from the balance of crystallinity, hydrolytic latency, and the ease of removing the liberated pinacol (boiling point 212 °C) via azeotropic distillation or aqueous washes. By contrast, N-methyliminodiacetic acid (MIDA) boronates—which require a two-step “slow release” hydrolysis with 3M NaOH at 60 °C—introduce a discontinuous processing sequence that complicates batch cycle time. The pinacol ester therefore occupies a narrow operational window in flow chemistry where controlled hydrolysis in a packed-bed column with a weak base (e.g., KHCO₃ in THF/water 4:1) enables continuous transmetalation without accumulating the free, protodeboronation-prone boronic acid.
The title compound is manufactured predominantly through direct sp² C–H borylation of N-Boc-pyrrole using bis(pinacolato)diboron (B₂pin₂, 1.05 equiv) and a catalyst system consisting of [Ir(OMe)(cod)]₂ (0.75 mol% Ir) and 4,4′-di-tert-butyl-2,2′-bipyridine (dtbpy, 1.5 mol%) in methyl tert-butyl ether (MTBE) at 50 °C over 16–20 h. Pilot-plant campaigns at 80–120 kg input routinely report isolated yields of 78–85% after crystallization from heptane/MTBE. This method circumvents the classical halogen-metal exchange route that would require lithiation of N-Boc-2-bromopyrrole at −78 °C with n-BuLi (1.1 equiv) followed by trapping with triisopropyl borate—a sequence notorious for generating 2,2′-bipyrrole byproducts via oxidative coupling of the transient 2-lithiopyrrole. The C–H activation pathway also avoids the stoichiometric use of organolithium reagents, reducing the thermal hazard footprint (adiabatic temperature rise for n-BuLi quench exceeds 120 K in the event of cooling failure) and eliminating lithium salt waste streams.
Competing direct boronation methods employing silica-supported phosphine ligands or heterogeneous Pd/C catalysts with B₂pin₂ have been evaluated but deliver inferior regioselectivity, with C3-borylated isomer contamination reaching 7–12% (HPLC). The homogeneous iridium-dtbpy system consistently provides a C2:C3 ratio greater than 97:3, a critical quality attribute when the downstream cross-coupling product is destined for an active pharmaceutical ingredient requiring an impurity threshold below 0.15% for the regioisomeric derivative. Effective removal of residual iridium (<5 ppm in the isolated product) is achieved by silica gel filtration and treatment with N-acetylcysteine-functionalized scavenger resin (loading 0.5 wt% relative to product), validated by ICP-MS per USP <232>/<233>.
Exposure to ambient moisture during weighing operations can reduce effective boron content by 5–10% within a single laboratory shift if relative humidity exceeds 60%. In production suites without humidity control, transferring the material from a resealable container inside a nitrogen-purged glovebag fitted with a dew-point sensor (<−40 °C dew point) is mandatory. Once hydrolyzed, the free boronic acid impurity (≥1.0%) self-condenses to form boroxine species detectable as a broad 11B NMR resonance at +18 ppm (pinacol ester: +31 ppm). Such contaminated lots produce erratic coupling yields and should be re-purified by recrystallization from anhydrous dichloromethane/hexane (1:3 v/v) or by trituration with cold pentane.
A decisive advantage of the pre-isolated pinacol ester over in situ trapping strategies—where B(OR)₃ is added directly to a lithiated pyrrole—manifests in the precision of stoichiometry during library-scale parallel synthesis. Weighing the solid, crystalline reagent on a five-decimal place balance allows a coupling stoichiometry of 1.00 ± 0.02 molar equivalents, whereas solutions of lithiated pyrrole exhibit titer variability of ±8–12% batch-to-batch. For array syntheses in 96-well plates using 10 μmol substrates, this translates to a hit-rate improvement from 65% to 93% (LCMS-conversion ≥90%) when switching from in situ borylation to the pre-formed pinacol ester. The operational simplicity is accompanied by a critical limitation: the C–B bond in this electron-rich heteroaryl system undergoes protolytic cleavage in the presence of Brønsted acids stronger than acetic acid (pKa <4.8). Thus, global deprotection of a synthesis intermediate prior to coupling is contraindicated; the Boc group must be removed only after the C–C bond-forming step, typically using TFA/CH₂Cl₂ (20% v/v, 25 °C, 1 h) followed by neutralization with triethylamine to prevent decomposition of the coupled pyrrole.
In continuous-flow Suzuki reactions carried out with a coil reactor (PFA, 0.8 mm ID, 15 mL volume) and a back-pressure regulator set at 75 psi, the pinacol ester has been successfully coupled with 4-bromobenzonitrile using Pd(OAc)₂ (1 mol%) and SPhos (2 mol%) in 10% aqueous K₂CO₃/THF at 110 °C, achieving a residence time of 8 minutes and steady-state conversion of 94% without observable clogging or palladium black precipitation over 16 hours of continuous operation. By comparison, the potassium trifluoroborate analogue affords 80% conversion under identical conditions due to slower hydrolysis of the trifluoroborate to the active boronate, and requires pre-treatment with TMSOK for activation.
| Boronate Species | Physical Form | Air/Moisture Sensitivity | Typical Activation Protocol | Recommended Storage |
|---|---|---|---|---|
| Free boronic acid (2-BocNH-pyrrole-2-B(OH)₂) | Off-white amorphous solid | High; protodeboronation >5% per hour in CD₃OD/D₂O at 25 °C | Direct use with aq. Na₂CO₃; 0.5–2 h coupling | −20 °C under argon, desiccated |
| Pinacol ester (this product) | White crystalline powder | Moderate; <0.5% hydrolysis after 24 h at 25 °C / 50% RH in sealed vial | Anhydrous or aq. K₂CO₃/THF; 8–24 h coupling | −20 °C under argon; 2–8 °C short-term |
| MIDA boronate | Colorless free-flowing powder | Low; bench-stable >6 months at 25 °C / 60% RH | Two-stage: dilute NaOH hydrolysis (60 °C), then coupling | 20–25 °C, tightly closed |
| Potassium trifluoroborate | White microcrystalline powder | Low; negligible protodeboronation at pH 7 | TMSOK (1.2 equiv) in anhydrous THF, or aq. Cs₂CO₃ with heating | 20–25 °C, desiccated |
Incompatibility with strong organic bases such as DBU or NaH during solvent drying operations must be observed; prolonged contact with molecular sieves (type 4A, 8–12 mesh) stored in contact with the ester solution in anhydrous DMF at 25 °C has been reported to induce slow hydrolytic cleavage due to residual alkalinity, diminishing active boron content by 3–7% per week. A more robust drying protocol uses anhydrous MgSO₄ added immediately before filtration and reaction charge. The compound’s infrared spectrum (attenuated total reflectance) shows characteristic absorbance for the Boc carbonyl at 1698 cm⁻¹ and the pinacol C–O stretch at 1143 cm⁻¹; disappearance of the latter upon silica gel chromatography indicates full hydrolysis and can be used as a rapid quality check in production environments without immediate access to NMR.
