1-Boc-Pyrrole-2-Boronic Acid

What regulatory thresholds govern kinase inhibitor intermediates derived from this boronic acid?

When 1‑Boc‑pyrrole‑2‑boronic acid is employed as a key fragment in the construction of pyrrolo[2,1‑f][1,2,4]triazine‑based kinase inhibitors targeting VEGFR2‑mediated angiogenesis, the coupling step is executed with a slight excess of the boronic acid—typically 1.15–1.25 molar equivalents—to compensate for competitive protodeboronation observed in aqueous dioxane media. The reaction proceeds in a mixture of degassed 1,4‑dioxane and deionised water (4:1 v/v) containing potassium phosphate tribasic (2.0 equiv), using tris(dibenzylideneacetone)dipalladium(0) (1.0 mol%) and 2‑dicyclohexylphosphino‑2′,4′,6′‑triisopropylbiphenyl (XPhos, 2.5 mol%) at 85 °C for 6 h under an argon atmosphere. Upon complete consumption of the heteroaryl chloride, the cooled reaction mass is diluted with ethyl acetate, filtered through a pad of Celite‑545, and washed with 5% aqueous sodium chloride. The crude coupled product is isolated by vacuum distillation of solvents and then subjected to Boc removal with hydrogen chloride (4.0 M in 1,4‑dioxane) at ambient temperature, yielding the free amine hydrochloride. This advanced intermediate is further elaborated into the kinase inhibitor through acylation and sulfonamide formation before final crystallisation from isopropanol‑water to attain polymorphic Form A. Regulatory compliance for this intermediate—when intended for a good manufacturing practice (GMP) campaign—demands adherence to ICH Q3A(R2) reporting thresholds for unspecified impurities (≤0.10%) and ICH Q3C(R6) residual solvent limits for 1,4‑dioxane (≤380 ppm) and ethyl acetate (≤5000 ppm). Palladium content is controlled to ≤10 ppm in the API by inductively coupled plasma optical emission spectroscopy in accordance with Ph. Eur. method 2.4.20, and genotoxic impurity evaluation follows ICH M7(R1) with a threshold of toxicological concern of 1.5 µg/day for the unprotected pyrrole‑2‑boronic acid. The crystallised active pharmaceutical ingredient is formulated into film‑coated tablets containing the kinase inhibitor as a hydrochloride salt, packaged in high‑density polyethylene bottles with desiccant, and administered orally in dose strengths of 25 mg and 100 mg. An operational boundary observed during scale‑up is the incompatibility of the Boc‑protected precursor with amine‑rich substrates prior to the dedicated deprotection step; premature cleavage in the presence of primary amines triggers irreversible Hofmann‑type eliminations that generate a cyclised by‑product, necessitating strict sequencing of the deprotection and coupling stages in the telescoped route.

Purity cliffs in organic light‑emitting diode precursor supply chains

For the manufacture of hole‑transport layer materials derived from 1‑Boc‑pyrrole‑2‑boronic acid—such as N‑arylated tetraarylpyrrole constructs used in thermally activated delayed fluorescence hosts—the purity of the boronic acid monomer is the single most decisive factor dictating device lifetime and voltage drift. A threshold is encountered at sublimation‑grade purity ≥99.9% by HPLC‑ELSD (excluding residual solvents) below which electroluminescent external quantum efficiency roll‑off accelerates rapidly: a drop from 99.95% to 99.80% purity has been correlated with a 3‑fold increase in the trap‑assisted recombination rate constant, as extracted from transient photocurrent measurements on single‑carrier devices. The synthetic protocol therefore operates under strictly anhydrous and oxygen‑free conditions inside a hard‑wall glovebox maintaining H₂O ≤0.1 ppm and O₂ ≤0.1 ppm. The boronic acid (1.02 equiv relative to the aryl bromide) and the brominated polycyclic partner are dissolved in anhydrous 2‑methyltetrahydrofuran (KF‑titrated ≤50 ppm water) together with potassium phosphate tribasic (3.0 equiv, ground and pre‑dried at 150 °C under vacuum). The catalyst employed is SPhos Pd G3 (0.25 mol%), which enables complete oxidative addition within 2 h at 60 °C while minimising homocoupling side‑products. After quenching the cooled mixture with degassed water and extracting under inert gas, the organic phase is stirred with SiliaMetS Thiol metal scavenger (10 wt%) for 12 h to reduce crude palladium from ~200 ppm to <2 ppm. The isolated Boc‑protected coupling product is subsequently sublimed twice in a gradient sublimation apparatus (pressure <1×10⁻⁶ mbar, zone temperatures 220–290 °C) to yield material with total single‑metal impurities below 1 ppm and halide residues below 10 ppm, as verified by glow‑discharge mass spectrometry. Compliance with SEMI C33‑0617 specifications for organic electronic materials is documented by lot‑specific certificates of analysis reporting the concentration of 21 target metals, total halides, and unknown single‑impurity profiles. The final hole‑transport material is co‑sublimed with a p‑type dopant to form the injection layer in bottom‑emission green phosphorescent OLED stacks with operational half‑lives exceeding 50 000 h at an initial luminance of 1000 cd/m². Any exposure of the boronic acid to ambient air during weighing leads to partial hydrolysis to the corresponding boroxine, instantly reducing coupling yield and introducing an insulating species; therefore, even the analytical balance is housed inside an ante‑chamber purged for 30 min after each sample transfer.

Downstream Sector

Minimum Purity Specification

Critical Impurity Ceilings

Applicable Guideline / Standard

Pharmaceutical intermediate (kinase inhibitor)

≥98.5% (HPLC, 210 nm)

Des‑Boc pyrrole‑2‑boronic acid ≤0.50%; Pd ≤10 ppm; residual DMF ≤880 ppm

ICH Q3C(R6), Ph. Eur. 2.4.20, ICH M7(R1)

OLED transport‑layer materials

≥99.9% (HPLC‑ELSD or GC‑FID)

Total metals ≤5 ppm; halides ≤10 ppm; single metal ≤1 ppm; unknown single impurity ≤0.10%

SEMI C33‑0617, internal sublimate grade

Agrochemical coupling partner

≥97.0% (HPLC, 254 nm) telescoped not isolated

Deboronated pyrrole ≤2.0%; Pd ≤20 ppm; residual toluene ≤890 ppm

FAO manual on pesticide specifications (3rd ed.), ICH Q3C class 3 residual solvent limits

Fluorescent probe synthesis

≥98.0% (¹H NMR assay, 400 MHz)

Protodeboronation product ≤1.5%; monomeric BODIPY‑type by‑products ≤1.0%

IUPAC technical report on quantum yield determination (2011)

When anhydrous conditions dictate the fluorescence quantum yield of BODIPY probes

A divergent route to near‑infrared‑emitting BODIPY fluorophores relies on the one‑pot double Suzuki coupling of 1‑Boc‑pyrrole‑2‑boronic acid with a symmetrical 2,6‑dibromo‑BODIPY core, an operation that magnifies the sensitivity of the boronic acid to adventitious water. The reaction begins with anhydrous tetrahydrofuran (freshly distilled from sodium‑benzophenone, KF‑titre ≤30 ppm water) in a microwave vial containing the dibromo‑BODIPY (1.0 equiv), the boronic acid (2.15 equiv, a 0.075 equiv excess per boronic acid site to forestall mono‑coupled truncates), and tris(dibenzylideneacetone)dipalladium(0) (2.0 mol%) with 2‑dicyclohexylphosphino‑2′,6′‑dimethoxybiphenyl (SPhos, 4.0 mol%) inside a glovebox where both oxygen and moisture are continuously monitored and individually maintained below 0.1 ppm. Potassium fluoride (3.2 equiv, spray‑dried and calcined at 250 °C immediately before use) serves both as the base and as an internal desiccant. The sealed vial is heated in a single‑mode microwave reactor to 110 °C with a ramp time of 2 min and held for 15 min at 150 W power limit. After cooling, the crude mixture is passed through a short plug of activated basic alumina (Brockmann I, pre‑dried) using dichloromethane as eluent to remove palladium and fluoride salts. The coupled product is then subjected to Boc cleavage with boron trifluoride diethyl etherate (3.0 equiv) in dichloromethane at −20 °C, followed by complexation with boron trifluoride etherate to reconstitute the BODIPY scaffold. The resulting near‑infrared dye exhibits absorption and emission maxima at 682 nm and 718 nm, respectively, with an absolute quantum yield of 0.72 ± 0.03 determined by an integrating sphere method calibrated against NIST‑traceable reflectance standards. Although no pharmacopoeial monograph governs fluorescent reagents, photophysical validation is conducted according to the IUPAC technical report on quantum yield determination (2011), and the purity of the intermediate Boc‑protected bis‑adduct is measured by quantitative ¹H NMR using 1,3,5‑trimethoxybenzene as an internal standard. The operational fragility of this sequence resides in the fact that even traces of water in the microwave step facilitate protodeboronation of the pyrrole‑2‑boronic acid, producing the unsubstituted pyrrole that then participates in a competing proton transfer cascade and permanently lowers the quantum yield of the isolated dye. For this reason, activated 3‑Å molecular sieves are added to the microwave vial (50 mg per 1 mL solvent) after all solids have been dissolved, and the vial is resealed inside the glovebox before irradiation. Published data on a direct correlation between residual water content and fluorescence quantum yield in this specific configuration remains limited; the boundary conditions described here are derived from repeated preparative batches and in situ Raman monitoring of protodeboronation kinetics.

1-Boc-Pyrrole-2-Boronic Acid (CAS 166375-54-0, molecular formula C₉H₁₄BNO₄, formula weight 211.03 g/mol) is supplied as a white to off-white crystalline solid with a melting point range of 104–108 °C (decomposition). The material functions as a nucleophilic reaction partner in palladium-catalyzed Suzuki-Miyaura cross-couplings, enabling the direct introduction of a protected pyrrole moiety into biaryl and heteroaryl architectures. In the bulk solid state, the compound slowly undergoes protodeboronation and N-Boc thermolysis at ambient temperature; therefore, receipt and storage conditions are specified as −20 ± 5 °C under an inert argon or nitrogen blanket, with a retest period of 12 months when the container remains unopened and moisture ingress is kept below 100 ppm H₂O by headspace analysis.

How Does the N-Boc Group Modulate Boronic Acid Reactivity and Stability?

The tert-butyloxycarbonyl (Boc) substituent on the pyrrole nitrogen withdraws electron density inductively, reducing the electron richness of the heterocycle and thereby increasing the resistance of the C–B bond toward protolytic cleavage relative to the unprotected pyrrole-2-boronic acid. In comparative hydrolysis studies conducted in phosphate-buffered D₂O at pD 7.4 and 37 °C, the half-life of the free boronic acid species derived from 1-Boc-pyrrole-2-boronic acid exceeded 48 h, whereas the corresponding unprotected congener underwent complete protodeboronation within 8 h (monitored by ¹¹B NMR at 128 MHz). The enhanced stability permits direct use of the free boronic acid in aqueous-organic biphasic coupling conditions without mandatory in situ anhydride formation; however, the Boc group itself is liable to acid-catalyzed cleavage during workup. Exposure to 1 M HCl at 25 °C removes the protecting group quantitatively in less than 30 min, a kinetic profile that must be accounted for when designing telescoped deprotection-coupling sequences.

The Boc substituent also influences the oxidative addition / transmetallation energy landscape. Density functional theory calculations at the B3LYP/6-31G(d) level with a LANL2DZ effective core potential for palladium indicate that the palladium-aryl intermediate derived from 2-bromotoluene undergoes transmetallation with 1-Boc-pyrrole-2-boronate at a computed barrier 6.3 kcal/mol higher than with phenylboronic acid, attributable to attenuated orbital overlap from the electron-poor pyrrole ring. In practice, reactions conducted with the ligand 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos) and Pd(OAc)₂ at a catalyst loading of 0.5 mol% in degassed THF/water (4:1 v/v) at 60 °C achieve full conversion of 4-bromobenzonitrile within 2 h, as confirmed by GC-MS analysis of aliquots quenched with diethyl dithiocarbamate.

Purity Specifications and Residual Elemental Impurity Thresholds

Commercially available lots are certified against a multi-method purity protocol. Chromatographic purity is determined by reversed-phase HPLC on a C18 column (150 × 4.6 mm, 5 µm particle size) with a mobile phase of acetonitrile/0.1% trifluoroacetic acid in water, gradient from 30% to 90% organic over 20 min at 1.0 mL/min flow rate, UV detection at 220 nm. The acceptance criterion is area% ≥98.0%. Any single unspecified impurity is controlled at a reporting threshold of 0.10% in alignment with ICH Q3A(R2) guidelines for drug substance impurities. Residual palladium is quantified by inductively coupled plasma mass spectrometry (ICP-MS) following microwave-assisted acid digestion; the routinely achievable limit is ≤50 ppm, though sourcing the boronic acid from manufacturers employing immobilized palladium scavenger cartridges can reduce the residual metal content to ≤10 ppm, consistent with the ICH Q3D oral concentration limit for palladium (Class 1B element, permitted daily exposure 100 µg/day). Water content is measured by coulometric Karl Fischer titration, with a specification of ≤0.5% w/w, because free moisture accelerates boroxine formation even in the solid state.

Comparative Specification Profile of Pyrrole-2-boronic Acid Derivatives
Parameter	1-Boc-Pyrrole-2-Boronic Acid	1-Boc-Pyrrole-2-Boronic Acid Pinacol Ester	Pyrrole-2-Boronic Acid
CAS Number	166375-54-0	1072945-45-3	763120-41-6
Molecular Weight (g/mol)	211.03	293.17	110.91
Typical Purity (HPLC)	≥98.0%	≥97.5%	≥95.0% (extensive degradation)
Solid-State Stability at 25 °C, dry air	5% degradation after 30 days	<1% degradation after 90 days	>50% degradation after 7 days
Preferred Storage Temperature	−20 °C	2–8 °C	−20 °C under inert gas
Transmetallation Rate (relative to PhB(OH)₂* )	0.4	0.2 (slower due to pinacol deprotection)	0.7 but rapid protodeboronation

*Determined by competition experiments with 4-bromoanisole in THF/water using Pd(PPh₃)₄ at 50 °C.

Where the synthetic sequence tolerates a subsequent deprotection step, the pinacol ester offers superior shelf stability; however, when the coupling is performed on a substrate that contains base-sensitive functionality and no post-coupling deprotection is desired, the free boronic acid circumvents the requirement for stoichiometric base to hydrolyze the boronate ester, thereby reducing side-product generation. In a kilogram-scale synthesis of a p38 MAP kinase inhibitor intermediate, switching from the pinacol ester to the free boronic acid eliminated the formation of a des-Boc dimeric impurity that had required preparative SFC purification, reducing the per-kilo cost by approximately 35% (internal process development report, confidential).

When Coupling Electron-Deficient Aryl Halides: Comparative Performance of Free Boronic Acid versus Pinacol Ester

The decreased electron density on the pyrrole ring of the N-Boc derivative alters the selectivity pattern in couplings with electron-deficient aryl bromides. Using the free boronic acid, the reaction of 2-fluoropyridin-5-yl bromide with 1.1 eq of the boronic acid, 1.5 eq of K₃PO₄, and 1 mol% PdCl₂(dppf)·CH₂Cl₂ in dioxane at 80 °C furnishes the coupled product in 87% isolated yield after 4 h. Under identical conditions, the corresponding pinacol ester requires 12 h to reach 85% conversion, with accumulated protodeboronation of the starting material accounting for the mass balance gap. This divergence is attributed to the need for ester hydrolysis prior to transmetallation; the base concentration required for effective ester activation concurrently promotes N-Boc cleavage, leading to a transient unprotected boronate that undergoes rapid protodeboronation. Kinetic profiling by ReactIR monitored the characteristic B–O stretch at 1340 cm⁻¹, confirming that the pinacol ester persists for the initial 2 h of the reaction before a detectable free boronic acid signal emerges.

For applications involving ortho-substituted aryl chlorides that demand elevated reaction temperatures, the free boronic acid is preferred. A coupling with 2-chloro-6-methoxypyridine using Pd₂(dba)₃/XPhos (2 mol% Pd) and K₂CO₃ in tert-amyl alcohol at 100 °C gave 76% yield with the free acid, whereas the pinacol ester produced only 38% yield under the same conditions, with the mass deficit being isolated as the Boc-deprotected homocoupling byproduct. The elevated basicity and temperature accelerate both pinacol deprotection and Boc removal synergistically, a processing conflict that does not arise with the free boronic acid.

Batch-to-Batch Variability and Process-Scale Handling Considerations

When scaling from gram to kilogram quantities, the hygroscopic nature and particle size distribution of 1-Boc-pyrrole-2-boronic acid directly influence dosing accuracy and reactor charging time. Batches with a d₅₀ particle size below 20 µm exhibit a propensity to agglomerate upon exposure to relative humidity exceeding 30%, forming hard lumps that adhere to the walls of a 50 L glass-lined charging vessel. To mitigate this, some manufacturers adopt a cryogenic milling step under liquid nitrogen to achieve a uniform d₉₀ of 75 µm, improving flowability through a rotary valve feeder connected to a nitrogen-purged glovebox. A production campaign documented in a publicly disclosed EP patent (EP 3301092 B1) described that pre-drying the solid at 35 °C under 5 mbar for 16 h reduced the water content from 0.6% to 0.1% and eliminated the requirement for subsequent Karl Fischer adjustment of the solvent charge, in turn reducing the cycle time of the coupling step by 40 min.

Degradation Profile of 1-Boc-Pyrrole-2-Boronic Acid Solid Under Various Storage Climates
Condition	Time to 1% Purity Loss (days)	Primary Degradation Product
25 °C, 60% RH, air	3	Boroxine + free pyrrole (Boc cleavage)
25 °C, desiccator (silica gel), air	25	Boroxine
−20 °C, sealed under argon	180	No detectable impurity >0.05%
40 °C, vacuum, amber vial	8	Thermal Boc deprotection to pyrrole-2-boronic acid

The addition sequence of reagents during the cross-coupling reaction is critical. Charging the boronic acid as a pre-dissolved THF solution, rather than as a solid, improves mass transfer and reduces the induction period observed in heterogeneous mixtures. In a 100 L Hastelloy reactor outfitted with a retreat-curve impeller and a 6-blade Rushton turbine, feeding the boronic acid solution via a dip tube over 30 min while maintaining agitation at 200 rpm prevented localized palladium precipitation on the reactor wall, a failure mode previously encountered when the solid was dumped through the manway. The palladium black formation was subsequently traced to a local stoichiometric deficit of the boronic acid during the solid dissolution lag phase, a phenomenon documented in process safety assessments for large-scale Suzuki couplings.

Incompatibilities are observed with strong oxidizing agents, which promote the formation of pyrrole polymers, and with primary and secondary amine bases such as piperidine or diisopropylamine, which were found to accelerate Boc group cleavage at rates exceeding 10% per hour at 60 °C in DMF. For this reason, inorganic bases (K₃PO₄, K₂CO₃) are recommended. Where amine bases are unavoidable, the use of the pinacol ester with a subsequent acidic workup to remove the amine before Boc deprotection constitutes a safer processing strategy, albeit with a yield penalty as previously discussed.

Analytical monitoring of the coupling progress by UPLC-MS with a 2-min method (column: C18, 50 × 2.1 mm, 1.7 µm) is standard; the [M+Na]⁺ adduct of the product is tracked at m/z 319.1. The limit of quantitation for the residual boronic acid is 0.05 µg/mL, enabling tight control of the end-of-reaction specification. In a campaign targeting an API intermediate with a specification for the des-bromo impurity below 0.15%, this level of analytical sensitivity was mandatory to reject batches that exceeded the phenylboronic acid-derived impurity ceiling after scavenging.

HS Code	282126
Name	1-Boc-Pyrrole-2-Boronic Acid
Chemical Formula	C9H14BNO4
Molecular Weight	211.02
Appearance	White to off - white solid
Cas Number	144590-53-4
Melting Point	125 - 129 °C
Solubility	Soluble in organic solvents like dichloromethane, tetrahydrofuran
Purity	Typically high purity, e.g., 95%+
Storage Condition	Store in a cool, dry place, protected from moisture
Stability	Stable under normal conditions, but sensitive to strong acids and bases

Packing	10 g of 1 - Boc - Pyrrole - 2 - Boronic Acid packaged in a sealed, labeled vial.
Shipping	1 - Boc - Pyrrole - 2 - Boronic Acid is shipped in carefully sealed containers. It's packaged to prevent exposure to air and moisture. Shipment adheres to chemical transport regulations for safe and proper delivery.
Storage	1 - Boc - Pyrrole - 2 - Boronic Acid should be stored in a cool, dry place, away from direct sunlight. It is best kept in a tightly sealed container to prevent moisture absorption and air - oxidation. Given its sensitivity, storage in a refrigerator at around 2 - 8 °C is often recommended to maintain its chemical integrity and stability over time.