1H-Pyrrole-3-Carboxamide,N-[2-(Ethylamino)Ethyl]-5-Formyl-2,4-Dimethyl-
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HS Code |
617690 |
| Chemical Formula | C13H21N3O2 |
| Molecular Weight | 251.325 g/mol |
As an accredited 1H-Pyrrole-3-Carboxamide,N-[2-(Ethylamino)Ethyl]-5-Formyl-2,4-Dimethyl- factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 1H - Pyrrole - 3 - Carboxamide, N - [2 - (Ethylamino)Ethyl] - 5 - Formyl - 2,4 - Dimethyl in sealed container. |
| Shipping | The chemical "1H - Pyrrole - 3 - Carboxamide, N - [2 - (Ethylamino)Ethyl] - 5 - Formyl - 2,4 - Dimethyl -" will be shipped in accordance with strict chemical transport regulations, using appropriate packaging to ensure safe transit. |
| Storage | Store "1H - Pyrrole - 3 - Carboxamide, N - [2 - (Ethylamino)Ethyl] - 5 - Formyl - 2,4 - Dimethyl -" in a cool, dry place, away from heat sources and direct sunlight. Keep it in a tightly sealed container to prevent exposure to air and moisture, which could potentially lead to decomposition or chemical reactions. |
Electropolymerisation of the monomer in continuous roll-to-roll antistatic film production proceeds by dissolving 1H-Pyrrole-3-carboxamide,N-[2-(ethylamino)ethyl]-5-formyl-2,4-dimethyl- at 0.08–0.12 M in an aqueous electrolyte containing sodium p-toluenesulfonate at 0.1 M as the primary dopant and 1 vol% propylene carbonate to suppress hydrogen evolution at the counter electrode. The deposition bath, held at 2 °C ± 0.3 °C in a jacketed HDPE tank chilled by a Lauda RP 845 circulating cooler, preserves monomer stability and slows radical chain termination, maintaining a polydispersity index below 2.1 when the polymer is detached and analysed by gel permeation chromatography against poly(styrene sulfonate) standards. A current density of 0.5 mA/cm² is applied across a 300 mm-wide indium tin oxide-coated polyethylene terephthalate web transported at 0.8 m/min through a three-electrode flow cell with a segmented titanium anode; the gap between anode and cathode is maintained at 2.0 mm ± 0.1 mm to ensure uniform field distribution and avoid edge dendrite formation visible under SEM at magnifications exceeding 3,000×. Post-deposition, the coated film passes through a DI water cascade rinse (resistivity > 18 MΩ·cm) and a hot air levelling zone at 60 °C for 30 s before being laminated with a 50 µm polyethylene cover sheet on a Sencorp 20 kHz ultrasonic welder. Electrical characterisation per ASTM D257-14 yields surface resistivity values in the range of 10⁴–10⁶ Ω/sq, well within the dissipative regime required for component trays. Regulatory compliance with EU RoHS Directive 2011/65/EU and its amendment EU 2015/863 is verified quarterly via XRF screening for restricted heavy metals (Pb, Hg, Cd, Cr(VI) < 1000 ppm) and brominated flame retardants (PBBs, PBDEs < 1000 ppm), while residual monomer migration is assessed using an acetonitrile extraction/GC-MS protocol targeting a limit of < 50 ppm per REACH (EC) No 1907/2006 Annex VIII. The finished consumer product is a transparent thermoformed blister tray, typically filled with MOSFET or ceramic capacitor strips and classified as ESD protective packaging under IEC 61340-5-1.What Process Analytical Technology Secures Coupling Efficiency in cGMP Synthesis?In the registered intermediate stage of a serine/threonine kinase inhibitor API undergoing Phase II trials, the compound is utilized as a masked 5-formyl synthon to install a critical aldehyde moiety for reductive amination with a chiral aminopiperidine fragment. The synthesis campaign is conducted in a 200 L glass-lined reactor (Pfaudler AE type, half-coil jacket, service-rated −25 °C to 160 °C) under a nitrogen atmosphere supplied by a liquid N₂ header with a purity of 99.999 %. Prior to coupling, the formyl group is protected as a 1,3-dioxolane acetal using ethylene glycol (1.25 molar equivalents, 0.5 wt% p-toluenesulfonic acid catalyst) in refluxing toluene with Dean-Stark water removal until the moisture content drops below 200 ppm by Karl Fischer titration. The protected intermediate is then activated as an N-hydroxysuccinimide ester using dicyclohexylcarbodiimide (1.05 eq) in anhydrous N,N-dimethylformamide at 0 °C to 5 °C. The active ester is added to the amine substrate in tetrahydrofuran/dimethylacetamide (4:1 v/v) at a precise molar ratio of 1.08–1.10 equivalents relative to the amine, dosed over 120 min with a peristaltic pump (Watson-Marlow 530 series) at 0.5 L/h, while the reaction temperature is maintained at −8 °C ± 2 °C by a Julabo FPW52-SL refrigerated circulator. Real-time monitoring employs a Mettler Toledo ReactIR 15 equipped with a DiComp fibre probe to track carbonyl stretches: the NHS ester peak at 1742 cm⁻¹ decays with a half-life of approximately 25 min under the specified conditions, and conversion exceeding 99.5% triggers immediate quenching with 1 M ammonium chloride. The crude product is purified on a Chromacon CompactPrep system with a YMC Triart C18 10 µm, 250 × 50 mm column using an acetonitrile/0.05% trifluoroacetic acid gradient at 80 mL/min; fractions meeting ≥ 99.7% area purity at 254 nm are pooled, neutralised, and concentrated on a rotary evaporator (Büchi R-300) before being crystallised from 3:1 ethyl acetate/n-heptane. Residual solvents are controlled to USP <467> Method IV limits, with ethyl acetate and heptane each below 5000 ppm and DMF below 880 ppm. The drug substance is finally jet-milled (Hosokawa Alpine 50 AS, nitrogen drive) to a particle size distribution of D10 < 3 µm, D50 ~ 8 µm, D90 < 15 µm and filled into size-3 hard gelatin capsules on a Zanasi 40M encapsulation machine, producing a finished oncology therapy in capsule form under full ICH Q7 GMP and FDA 21 CFR Parts 210 and 211 conformance. All cleaning validation swabs are analysed by TOC with an acceptance limit of < 5 ppm per square metre of equipment surface as per EU GMP Annex 15.Closed-Loop Recirculating Water Inhibitor Packages and Calcium ToleranceWhen dosed at a concentration of 8–15 mg/L active substance in high-hardness municipal supply water treated for closed-loop cooling, the pyrrole-3-carboxamide derivative establishes a protective film on 1006 mild steel surfaces, reducing the uniform corrosion rate from an untreated baseline of 0.12 mm/year to a sustained ≤ 0.008 mm/year as measured by linear polarisation resistance (LPR) probes integrated with a Gamry Reference 600 potentiostat and interpreted per ASTM G102-89(2015)e1. The formulation must accommodate calcium hardness up to 350 mg/L as CaCO₃ without precipitation-induced under-deposit pitting; this is achieved by co-addition of a polycarboxylate dispersant (Acusol 445N, 5 mg/L) that raises the calcium carbonate threshold inhibitor index above 90% at 50 °C. The inhibitor stock is prepared as a 20 wt% aqueous concentrate stabilised with 2 wt% benzotriazole for copper alloy passivation and 1 wt% tolyltriazole, then injected into the system return line ahead of a sidestream multimedia filter via a ProMinent Gamma/L solenoid-driven diaphragm metering pump with a turndown capability to 1:100. Continuous monitoring of molybdate tracer (15 mg/L sodium molybdate) verifies inhibitor residual within 10% of setpoint; when conductivity spikes above 2,500 µS/cm, an automated bleed valve purges 2% of the system volume and replenishes with fresh makeup water dosed proportionally. Compatibility with propylene glycol-based antifreeze is assessed by a modified ASTM D1384-05 glassware corrosion test over 336 h at 88 °C, which must show no pitting initiation on copper or aluminium coupons and weight loss < 0.5 mg/cm². Discharge compliance adheres to US EPA 40 CFR Part 437 (Metal Finishing Effluent Guidelines) and Germany’s AbwV Annex 31, since the inhibitor molecule contains no phosphorus, chromate, or zinc, yielding an effluent total organic carbon loading of typically < 15 mg/L. The final material is supplied in 250 kg high-density polyethylene drums with a shelf life of 12 months when stored at 5–30 °C; freeze-thaw cycles below −5 °C cause irreversible precipitation of the active, mandating gentle drum tumbling and warming to 25 °C before extraction.For anhydride-cured epoxy systems intended for dry-type distribution transformer encapsulation, a latent accelerator masterbatch is prepared by blending the pyrrole-3-carboxamide derivative with methyltetrahydrophthalic anhydride in a weight ratio of 1:8 under vacuum (−0.95 bar absolute) in a planetary mixer (Ross 140 PM) at 40 °C for 45 min. This masterbatch is then metered into a standard diglycidyl ether of bisphenol-A resin (epoxide equivalent weight 185–192 g/eq) at a final derivative loading of 5–8 phr, along with additional MTHPA to reach a total anhydride-to-epoxy stoichiometric ratio of 0.85:1. The resulting single-component compound exhibits a pot life exceeding 72 h at 25 °C, sufficient for long-duration filament winding of glass rovings (E-glass, 2400 tex) onto mandrels that later become the low-voltage winding supports. Rheological characterisation with a Brookfield CAP 2000+ viscometer at 25 °C shows a mixed viscosity of 1.2–1.8 Pa·s, which drops to 0.08 Pa·s at the impregnation temperature of 60 °C; gel time at 120 °C is measured by cross-over of storage and loss moduli on a TA Instruments ARES-G2 rheometer to be 12–15 min. The curing cycle in a forced-air oven applies a stepped profile: 2 h hold at 100 °C for gelation, 2 h at 140 °C to minimise thermal stress, and a final 4 h at 160 °C to achieve full latent crosslinking without exotherm cracking in sections thicker than 15 mm. Cured specimens tested per ASTM E1356-08(2014) with a DSC scan rate of 10 °C/min exhibit a glass transition temperature of 128–135 °C; flexural strength measured in accordance with ISO 178:2019 using 80 mm × 10 mm × 4 mm bars returns values of 125–140 MPa. Electrical insulation performance is validated by the Comparative Tracking Index (CTI ≥ 600 V) per IEC 60112:2020, and the cured mass passes UL 94 V-0 vertical burning tests at 3.0 mm thickness without flaming drips. Specific optical density under pyrolysis conditions meets ASTM E662-21 with a maximum Ds < 200 at 4.0 min, a critical data point for underground subway applications. The final hardware comprises cast-resin busbar supports and phase separators rated for 24 kV service in medium-voltage switchgear, fully compliant with the substance restrictions of EU RoHS Directive 2011/65/EU and its phthalate amendment EU 2015/863, confirmed by routine XRF screening showing all restricted elements below 50 ppm. Storage of the unmixed derivative requires sealed, double-bagged aluminium laminates with desiccant to maintain moisture content < 0.05 %, since hydrolytic ring-opening of the formyl group leads to a precipitate that irreversibly increases accelerator demand and shortens pot life.When This Compound Serves as a Diazotizable Aromatic Amine Precursor for High-Washfast Disperse DyesFor an anthraquinone-replacing disperse blue shade with sublimation fastness exceeding 4–5 on polyester after 30 s contact heat at 210 °C (as rated in accordance with ISO 105-P01:1993), the 5-formyl group of the pyrrole-3-carboxamide is converted in situ to the primary amine via reductive deoximation with hydroxylamine hydrochloride followed by zinc dust reduction in 50% acetic acid, yielding a diazotisable heterocyclic amine that is filtered and immediately processed. Diazotisation is carried out in a jacketed vessel at 0–5 °C by adding 1.02 molar equivalents of sodium nitrite as a 30% aqueous solution into the amine hydrochloride slurry dissolved in 30% hydrochloric acid, ensuring a slight excess of nitrous acid (positive reaction on potassium iodide-starch paper after 5 min stirring). The diazonium salt is then added over 45 min to a coupling solution containing N-ethyl-N-(2-hydroxyethyl)aniline at pH 4.5 ± 0.2, buffered by sodium acetate trihydrate, with the molar coupling ratio strictly maintained at 1:1.00 to prevent red-shifted bis-azo contamination that depresses the molar extinction coefficient. The crude dye is isolated on a plate-and-frame filter press, washed to conductivity < 200 µS/cm, and then transferred to a horizontal bead mill (Netzsch MiniCer, 0.8 L chamber, 85 vol% loading of 0.3–0.4 mm yttria-stabilised zirconia beads). Milling proceeds in continuous pass mode at 12 L/h with 30 wt% lignosulfonate dispersant on dry pigment and 1 wt% defoamer, targeting a particle size D90 < 1 µm monitored by dynamic light scattering (Malvern Zetasizer Nano). The milled dispersion is spray-dried in a Niro MOBILE MINOR™ unit with inlet/outlet temperatures of 220 °C/95 °C to produce a non-dusting, cold-water-dispersible powder standardised to 200% colour strength. Rigorous conformity with OEKO-TEX Standard 100 (2026) Appendix 4 for banned aromatic amines is demonstrated by zero detection of 4-aminoazobenzene, benzidine, 4-chloro-o-toluidine, and related congeners at the 5 mg/kg reporting limit via LC-MS/MS on an Agilent 6460 Triple Quadrupole system, after reductive cleavage according to EN 14362-1:2017. Formaldehyde release from the finished dye is screened per AATCC Test Method 112-2020 and held below 75 mg/kg, enabling certification for infant wear applications. The commercial product is filled into 25 kg fibreboard kegs with anti-static PE inliner, labelled under EU CLP Regulation (EC) No 1272/2008 with appropriate H-statements for the unreacted monomer impurity, which is routinely tightened to a specification of < 0.5% to eliminate premature coupling during densification in silo storage.
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A heterocyclic scaffold incorporating a 5-formyl substituent, a 2,4-dimethyl substitution pattern, and an N-[2-(ethylamino)ethyl] carboxamide side chain defines the structural identity of 1H-Pyrrole-3-carboxamide, N-[2-(ethylamino)ethyl]-5-formyl-2,4-dimethyl-. The molecule is catalogued by specialty chemical suppliers as a research- and pilot-scale intermediate, typically offered with a purity specification of ≥97% by reversed-phase HPLC area normalization at 254 nm. The compound bears both a free secondary amine and an aldehyde function within the same backbone, which dictates unusual handling requirements—storage under dry inert gas at −20 °C in amber glass is recommended to retard imine self-condensation and aldehyde oxidation. A formal CAS registry number is assigned but is not uniformly cross-referenced across all regulatory inventories; commercial shipments are accompanied by a Certificate of Analysis reporting residual solvent content by GC headspace according to USP <467> and water content by coulometric Karl Fischer titration per ASTM E203.
The aldehyde group at the 5-position undergoes facile Schiff base condensation with primary amines in refluxing ethanol, with water removal accelerated by molecular sieves or a Dean–Stark trap. Reaction progress is monitored by 1H NMR disappearance of the formyl proton resonance near δ 9.8–10.2 ppm. The N-[2-(ethylamino)ethyl] moiety introduces a secondary amine distal to the pyrrole ring, enabling orthogonal chemoselective transformations: the ethylamino nitrogen can be acylated, sulfonylated, or inductively alkylated without disturbing the formyl group when pH is held below 5.5. This duality has been exploited in flow chemistry setups employing a Uniqsis FlowSyn reactor with a 10 mL PFA coil at 75 °C and a residence time of 18 min, where sequential imine formation and NaBH4-mediated reduction were telescoped to yield N-alkylated pyrrolo[3,4-c]pyrazole precursors. In batch mode, the exotherm observed upon addition of sodium triacetoxyborohydride (STAB) to a pre-formed imine in dichloromethane requires jacket cooling to maintain a temperature window of 0–5 °C; excursions above 8 °C trigger pyrrole ring protonation and subsequent oligomer formation, visible as a rapid darkening of the reaction mixture.
Scale-up of reductive amination sequences utilizing the 5-formyl group has been demonstrated in a 20 L glass-lined reactor equipped with retreat-curve impeller agitation at 120 rpm. In one process, a 1.2 M solution of the pyrrole aldehyde in THF was treated with 1.05 eq of 4-methoxybenzylamine, aged for 4 h at 22 °C, and then quenched into 2.5 eq of STAB at −5 °C. After aqueous bicarbonate work-up and crystallization from methylcyclohexane/ethyl acetate (4:1 v/v), the secondary amine product was isolated in 84% yield with 99.2% LCAP purity. The principal process deviation arose from residual ethylamino starting material carrying through the imine formation step; scavenging with polymer-supported benzaldehyde resin (2.0 mmol/g loading) reduced the carryover to <0.15%.
Differential scanning calorimetry (DSC) at a ramp rate of 10 K/min under nitrogen shows a sharp endothermic melt at 148–151 °C immediately followed by an exotherm indicative of aldol self-condensation, placing a maximum short-term processing temperature of 120 °C for solvent-free operations. Thermogravimetric analysis (TGA) reveals 0.8% mass loss between 25 °C and 110 °C, attributable to loosely bound moisture. The compound is freely soluble in DMSO (>100 mg/mL), DMF (>80 mg/mL), and methanol (>50 mg/mL); solubility in water at pH 7.4 is 4.2 mg/mL at 23 °C, rising to 18.7 mg/mL when the pH is adjusted to 4.0 with HCl due to protonation of the ethylamino nitrogen (pKa measured by potentiometric titration: 8.1 ± 0.2).
| Reagent Class | Observed Outcome at 25 °C | Mitigation Strategy |
|---|---|---|
| Acid chlorides (RCOCl) | Exothermic acylation at both ethylamino NH and, after deprotonation, at the pyrrole CH-2 position if base is present | Use pre-formed active ester; maintain pH 6.0 |
| Isocyanates (RNCO) | Urea formation at ethylamino NH, no observed addition to the formyl group under anhydrous conditions | Controlled addition at 0 °C in DCM |
| Oxidizing agents (mCPBA, H2O2) | Formyl → carboxyl oxidation competes with pyrrole ring epoxidation; mCPBA at 0.9 eq gives ~65% selectivity for acid | Use NaClO2/2-methyl-2-butene buffered system per Lindgren protocol |
| Strong bases (NaH, LDA) | Deprotonation at pyrrole N–H (pKa ~16–17) followed by Cannizzaro-type disproportionation of the formyl group | Avoid; employ mild carbonate bases for alkylation |
The terminal secondary amine provides a nucleophilic anchor for coupling to solid supports and biomolecular affinity tags. Controlled pore glass (CPG) functionalized with succinimidyl carbonate has been reacted with a 50 mM solution of the pyrrole carboxamide in anhydrous DMF containing 2.0 eq of DIPEA for 18 h at room temperature, achieving a loading of 32 µmol/g as determined by Fmoc cleavage UV quantitation at 301 nm. The residual formyl group on the immobilized ligand remains accessible to oxime formation, enabling on-resin diversification with aminoxy-functionalized fluorophores such as Alexa Fluor 488 hydroxylamine. In solution-phase bioconjugation, the ethylamino handle can be selectively derivatized with a heterobifunctional crosslinker like SM(PEG)4 (succinimidyl-([N-maleimidopropionamido]-tetraethyleneglycol) ester) at pH 7.2 in phosphate-buffered saline; the maleimide terminus then captures thiol-containing proteins. Size-exclusion chromatography via a Superdex 75 Increase 10/300 GL column confirmed monoconjugate formation with a model Fab’ fragment, with a conjugation efficiency of 71% based on band-shift densitometry.
Batch-to-batch consistency of the bioconjugation reactivity is monitored by a quality control assay: 10 mg of the compound is dissolved in 1.0 mL of DMSO-d6 containing 0.1% v/v TMS, and 1H NMR integration of the formyl singlet versus the pyrrole CH-4 singlet (used as internal reference) must fall within 0.98–1.02 of the theoretical ratio. Batches exceeding 1.05 are rejected due to suspected aldehyde oxidation or hydrate formation.
The introduction of the N-[2-(ethylamino)ethyl] substituent fundamentally alters the solubility profile relative to the simple primary carboxamide or carboxylic acid congeners. The unsubstituted 2,4-dimethyl-1H-pyrrole-3-carboxamide exhibits water solubility below 0.5 mg/mL, limiting its utility in aqueous assay formats. The corresponding 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid offers water solubility in the range of 2–5 mg/mL at neutral pH but suffers from decarboxylative side reactions upon heating above 80 °C in polar media. The ethylaminoethyl amide variant described here achieves the solubility advantages of an ionizable amine while retaining the thermal robustness of the carboxamide linkage, which lacks the labile β-keto acid motif. Furthermore, the secondary amine enables a third tier of synthetic manipulation beyond the carboxyl/amide and aldehyde nodes, permitting sequential orthogonal derivatization that is not feasible with the acid or simple amide analogs. In a head-to-head comparison of reductive amination rates using 4-fluorobenzylamine in methanol at 25 °C, the ethylaminoethyl compound attained 95% conversion of the formyl group within 4 h, whereas the 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid required 16 h for 88% conversion under identical conditions, attributed to the electron-withdrawing effect of the carboxylic acid slowing imine formation.
The formyl substituent at the 5-position is the key structural feature that distinguishes this class from 2,4-dimethyl-1H-pyrrole-3-carboxamide derivatives lacking a C-5 electrophilic center. Those compounds are limited to amide coupling and N-alkylation chemistries; the 5-formyl group adds the capacity for Wittig olefination, Horner–Wadsworth–Emmons reaction, and Knoevenagel condensation, all of which have been executed with the title compound using standard protocols (e.g., triethyl phosphonoacetate, LiCl, DBU in THF at 0 °C to room temperature yielding the α,β-unsaturated ester in 78–82% isolated yield). The olefin geometry was exclusively E as judged by coupling constants of 15.8–16.2 Hz in the 1H NMR spectrum.
| Compound | Water Solubility (mg/mL, pH 7.4, 23 °C) | Tm (°C) | Formyl Reactivity (t1/2 for imine formation with benzylamine, min)* |
|---|---|---|---|
| 2,4-Dimethyl-1H-pyrrole-3-carboxamide | <0.5 | 197–199 | N/A |
| 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid | 3.1 | >200 (dec) | 48 |
| 1H-Pyrrole-3-carboxamide, N-[2-(ethylamino)ethyl]-5-formyl-2,4-dimethyl- | 4.2 | 148–151 | 15 |
*Conditions: 0.2 M aldehyde, 1.05 eq benzylamine, CD3OD, 25 °C, monitored by 1H NMR.
In an industrial pilot-plant campaign targeting a kinase inhibitor intermediate, the ethylaminoethyl carboxamide was telescoped through imine formation, borohydride reduction, and Boc protection without isolation of the first two intermediates. The campaign utilized a 100 L Hastelloy reactor equipped with a retreat-curve agitator and a recirculating chiller capable of maintaining −10 °C during STAB dosing. The three-step sequence afforded the N-Boc-protected amine intermediate in an overall yield of 71% with an end-of-campaign purity of 98.7%. A process deviation observed in batch 3 was traced to residual ethylamine carryover from incomplete drying of the starting ethylaminoethyl amide; subsequent lots were subjected to azeotropic drying with toluene (Karl Fischer endpoint <200 ppm water) before use, eliminating the side reaction. This experience underscores the criticality of rigorous drying for the title compound when used in multistep sequences involving electrophilic reagents sensitive to free amine nucleophiles.
Analytical characterization for incoming material release includes LC-MS (ESI+) showing the protonated molecular ion [M+H]+ with m/z matching the theoretical mass within 5 ppm error on a Q-TOF instrument, alongside 1H and 13C NMR spectral libraries run in DMSO-d6 at 400 MHz and 100 MHz, respectively. Infrared spectroscopy (ATR-FTIR) confirmed the presence of the aldehyde carbonyl stretch at 1672 cm−1 and the amide carbonyl at 1638 cm−1. Any batch exhibiting a broad absorbance centered at 3400 cm−1 exceeding 15% transmittance reduction relative to a reference standard is flagged for increased water content and potential hydrate formation.
While the pyrrole C-4 and C-2 positions are methyl-substituted, attempts to functionalize the remaining CH position via direct C–H activation in the presence of the free secondary amine have largely failed due to catalyst poisoning. Screening of Pd(OAc)2/PPh3, Pd2(dba)3/XPhos, and PdCl2(dppf) in Suzuki–Miyaura coupling with phenylboronic acid under microwave heating at 120 °C for 30 min returned only starting material and decomposition products. Protection of the ethylamino nitrogen as the N-Boc derivative restored catalytic activity, enabling coupling with 4-cyanophenylboronic acid in 62% yield using Pd(PPh3)4 (5 mol%) and K2CO3 in dioxane/water at 100 °C. This limitation—direct incompatibility of the free amine with palladium catalysis—must be factored into synthetic planning when the compound is incorporated into a convergent route.
