Tert-Butyl 3-(((Trifluoromethyl)Sulfonyl)Oxy)-2,5-Dihydro-1H-Pyrrole-1-Carboxylate

Aryl Boronic Acid (Ar-B(OH)₂)

Isolated Yield (%)

HPLC Purity (area%)

Residual Pd (ppm by ICP-MS)

4-Fluorophenylboronic acid

99.2

3-Chlorophenylboronic acid

98.7

4-Methoxyphenylboronic acid

99.5

3-Pyridinylboronic acid

98.9

4-Cyanophenylboronic acid

99.0

How Does Catalyst Selection Dictate Selectivity in Buchwald-Hartwig Amination of Cyclic Vinyl Triflates?

Transition-metal-catalyzed C–N bond formation at the enamine triflate center is acutely sensitive to the electronic character of the palladium catalyst and the steric bulk of the supporting phosphine ligand, parameters that directly govern whether the desired 3-aminodihydropyrrole is obtained cleanly or whether competing β-hydride elimination and double-bond isomerization dominate. When the synthetic target requires primary aliphatic amine introduction, a pre-catalyst system consisting of 1.0 mol% Pd₂(dba)₃ and 2.2 mol% RuPhos (2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl) in anhydrous toluene at 70–85°C suppresses the over-alkylation manifold and holds the isomerization products below 3 area%. In contrast, secondary amine partners demand the more electron-rich BrettPhos pre-catalyst (Pd(allyl)(BrettPhos)Cl, 1.5 mol%) which enables turnover at 55°C while preserving the Boc group—exceeding 85°C for any extended period initiates thermal deprotection, releasing free pyrrolidine that can quench the catalyst. The standard stoichiometric loading positions the triflate as the limiting substrate at 1.0 eq, the amine at 1.2–1.5 eq, and sodium tert-butoxide (1.4 eq) introduced as a single portion under counter-flow nitrogen sweep in a 500 L Hastelloy reactor equipped with a multi-stage Rushton impeller. During scale-up, oxygen ingress is quantified using a trace oxygen analyzer (threshold < 50 ppm O₂ in headspace) because even transient exposure forms palladium(0) agglomerates that deposit on the vessel walls, reducing catalytic activity and requiring post-batch passivation with nitric acid. Downstream processing begins with quenching in 2 wt% aqueous ammonium chloride, extraction into methyl tert-butyl ether, and a sequence of water and brine washes. Residual palladium extraction into the aqueous phase is monitored to achieve the ICH Q3D target: for pharmaceutical intermediates intended for chronic oral dosing, Pd ≤ 100 µg/day; if the final drug is administered parenterally, the limit tightens to 10 µg/day. The crude oil is purified either by flash chromatography on pre-packed silica cartridges (ethyl acetate/heptane) or, when crystalline, by trituration in cold n-heptane. Solvent residual specifications are imposed by ICH Q3C: toluene ≤ 890 ppm, MTBE ≤ 500 ppm. The resulting 3-(N-substituted)amino-2,5-dihydro-1H-pyrrole-1-carboxylate intermediates are elaborated into N-aryl piperazine bioisosteres and into conformationally locked pyrrolidine amides for CNS-optimized kinases, enabling fundamental structure-activity relationship studies for PARP-1 inhibitors and dopamine D3 receptor-targeted therapeutics.

Sonogashira alkynylation of the 3-triflate requires strict exclusion of dissolved oxygen from all liquid reagents to suppress Glaser-type oxidative homocoupling of the terminal alkyne, a side reaction that consumes the alkyne partner and complicates purification. The catalytic recipe employs 2.0 mol% Pd(PPh₃)₂Cl₂ and 8.0 mol% CuI, with the alkyne in 1.3–1.6 eq excess relative to the triflate, and triethylamine (3.0 eq) acting simultaneously as base and solvent cosolvent in degassed THF (10 vol) at 25–35°C. In the pilot-scale batch, evolution of heat upon copper acetylide formation is controlled by a jacketed, low-temperature reactor with a −10°C coolant loop; the exotherm is most pronounced during the first 15 minutes of base addition and must not permit the mixture to exceed 40°C, else the enyne product begins to decompose via a retro-Diels-Alder-like fragmentation. After 6–12 h reaction time, the dark suspension is filtered through a Celite pad to remove copper residues, and the filtrate is treated with 10% aqueous EDTA (disodium salt) to chelate residual copper below the ICH Q3D oral PDE of 1300 µg/day. Concentration and flash chromatography (hexane/ethyl acetate, 9:1 to 4:1) provide the 3-alkynyl-pyrroline derivative, which holds significant synthetic value as a precursor for intramolecular Pauson-Khand cyclopentenone annulations or as a dipolarophile in 1,3-dipolar cycloadditions. The terminal alkyne handle also serves as a site for copper-catalyzed azide-alkyne click (CuAAC) bioconjugation in prodrug designs. End-products that have been constructed via this route include advanced intermediates of mGluR5 negative allosteric modulators and peptidic cysteine protease inhibitors equipped with an electrophilic warhead.

Carbonylative Ester Insertion Mediated by Palladium and Alcohol Nucleophiles

Under a carbon monoxide atmosphere, the electron-deficient vinyl triflate participates in palladium-catalyzed alkoxycarbonylation to generate 3-(alkoxycarbonyl)-2,5-dihydro-1H-pyrrole-1-carboxylates, an atom-economical entry to pyrrolidine-3-carboxylic acid derivatives relevant to β-amino acid isosteres. The transformation is carried out in a 300 L stirred high-pressure autoclave (design code ASME BPVC Section VIII, graphite gasket) with a gas-dispersion impeller capable of maintaining dissolved CO concentrations ≥ 0.02 mol/L at 5–15 bar head pressure. The standard charge loads the triflate at 1.0 equivalent, the alcohol (methanol, ethanol, or cyclopropylmethanol) as both reactant and solvent in 15 volumes, Pd(OAc)₂ at 2.0 mol%, 1,1′-bis(diphenylphosphino)ferrocene (dppf) at 3.0 mol%, and triethylamine (2.5 eq). Ramping the temperature to 80°C over 45 min while maintaining 10 bar CO overpressure and 400 rpm stirrer rate delivers full conversion within 8–10 h. Safety interlocks are critical: CO detectors with a lower alarm threshold of 35 ppm must be interlocked with the ventilation scrubber, and the reactor rupture disk is rated to 24 bar in accordance with PED 2014/68/EU for gas service. Release of pressure below 0.5 bar/min avoids entrainment of palladium black into the headspace lines. Isolation proceeds by filtration through sintered glass, rotary evaporation of methanol, and partition between ethyl acetate and 0.5 M HCl. The organic phase is washed with sodium bicarbonate and brine, dried, and fractionally distilled under vacuum (2 mbar, boiling range 120–145°C depending on ester). Compliance with ICH Q3C is verified for MeOH (≤ 3000 ppm) or EtOH (≤ 5000 ppm), and Pd content is assayed by GF-AAS against the ICH Q3D oral limit. When ¹³CO gas is substituted, the method yields isotopically labeled ester intermediates used in mass spectrometry-based drug metabolism studies; the resulting 3-carboxylate pyrrolidine scaffolds constitute the core of several cathepsin K inhibitors and integrin αvβ₃ antagonists. The table below correlates CO pressure with isolated methyl ester yield and product distribution under otherwise identical conditions.

CO Pressure (bar)

Isolated Methyl Ester Yield (%)

3-Hydroxy By-product (%)

3-Hydrogenolysis Product (%)

0.5

When the Dihydropyrrole Core Is Subjected to Heck Alkenylation in Continuous Flow

The palladium-catalyzed Heck reaction between the vinyl triflate and electron-deficient alkenes—particularly acrylate esters and styrenes—suffers from pronounced thermal lability of the intermediate palladium-alkyl species when conducted in batch vessels, leading to extensive olefin isomerization and generation of regioisomeric mixtures that are inseparable by simple distillation. A shift to a continuous flow reactor addresses these shortfalls directly: a Corning G1 SiC fluidic module (channel hydraulic diameter 0.6 mm, total hold-up volume 12 mL) permits residence time distribution with a variance of σ² < 0.05, effectively locking the reaction at the primary Heck adduct. The triflate (1.0 eq) and methyl acrylate (4.0 eq) are dissolved in anhydrous DMF containing tetrabutylammonium bromide (0.3 eq) and degassed with argon; the catalyst solution comprises Pd(OAc)₂ (1.5 mol%) and tri-o-tolylphosphine (3.0 mol%) in the same solvent. The two streams are combined at 120°C and passed through the reactor at 0.5 mL/min total flow rate, corresponding to a residence time of 24 min and a space-time yield of 0.8 kg/L/day. Across a 72-hour continuous run, gradual precipitation of palladium metal on the microchannel walls caused a pressure rise from an initial 2.8 bar to a maximum sustained 4.2 bar; an inline 2 µm sintered-metal frit was installed upstream of the back-pressure regulator to prevent clogging, and the remaining catalyst inventory was replenished by a mid-run spike of fresh catalyst solution delivered through a T-junction at the 36-hour mark. The collected effluent is quenched online with 5% aqueous HCl, extracted with dichloromethane, and subjected to a two-step distillation—first to remove DMF (under reduced pressure, 60 mbar, bath 60°C), then to isolate the product, which distills at 145–155°C/1.5 mbar. Elemental impurity limits for the palladium content are enforced as per ICH Q3D, and residual DMF is capped at 880 ppm per ICH Q3C. The resulting 3-alkenyl-pyrroline adduct is a modular intermediate for the construction of dipeptidyl peptidase IV inhibitor mimics and atypical antipsychotic drug candidates that require a trans-3-styryl pyrrolidine pharmacophore. The hydrogenation of the double bonds and subsequent Boc removal generate substituted pyrrolidines that have been advanced into phase I clinical studies for GPR119 agonists.

Negishi cross-coupling of the dihydropyrrole triflate with functionalized organozinc halides enables the introduction of alkyl- and aryl-carbogenic fragments under strictly anhydrous conditions, circumventing the aqueous basic hydrolysis that erodes yield in Suzuki-Miyaura processes when sensitive ester or nitrile groups are present in the coupling partner. The organozinc reagents are prepared separately in a 100 L glass vessel by transmetallation of the corresponding Grignard or lithium reagent with zinc chloride (1.0 M in THF) and are titrated against iodine to verify active concentration before addition to the reaction mixture. The coupling employs the triflate at 1.0 eq, the fresh organozinc solution at 1.8–2.2 eq, and Pd(PPh₃)₄ at 2.0 mol% in THF with N-methyl-2-pyrrolidone (10% v/v) as a dipolar aprotic co-solvent to enhance zincate solubility, thermostatted at 55–65°C for 3–5 h. Quenching is performed by slow transfer into a saturated aqueous NH₄Cl solution under vigorous agitation; an initial exotherm reaching 45°C is moderated by an external ice-bath jacket. The zinc content in the final washed organic phase is measured by ICP-OES and must fall below the ICH Q3D parenteral PDE of 1300 µg/day for Zn. After drying and solvent swap into heptane, the product often crystallizes directly at −20°C, avoiding chromatographic purification entirely—a decisive advantage for kilo-lab campaigns targeting early preclinical supply. The functional group tolerance of organozinc reagents permits retention of methyl esters, silyl ethers, and aliphatic nitriles during the cross-coupling, enabling direct access to pyrrolidine–proline hybrid structures and CCR5 receptor antagonist intermediates. For instance, the 3-isobutyl-2,5-dihydropyrrole obtained through Negishi coupling has served as a key scaffold for a series of orally bioavailable renin inhibitors evaluated in hypertensive animal models.

Among electrophilic pyrroline synthons employed in convergent heterocycle assembly, few intermediates combine the configurational rigidity of a cyclic allylic system with the leaving-group aptitude of a perfluoroalkanesulfonate. The compound designated Tert-Butyl 3-(((Trifluoromethyl)Sulfonyl)Oxy)-2,5-Dihydro-1H-Pyrrole-1-Carboxylate—a fully protected 3-hydroxypyrroline derivative—presents the trifluoromethanesulfonyl (triflate) moiety at the vinylogous position of an N-Boc-2,5-dihydro-1H-pyrrole core. The molecular formula C₁₀H₁₂F₃NO₅S yields a molecular mass of 331.26 g·mol⁻¹. This compound is supplied as a white to off-white crystalline solid with a typical lot-specific purity of ≥97.0% as determined by reverse-phase HPLC (area %, detection at 254 nm, C18 column, acetonitrile/water gradient + 0.1% trifluoroacetic acid). Karl Fischer titration routinely records water content below 0.5 wt% when packaged under argon. The substance is stored at −20°C in septum-sealed amber vials; exposure of a neat sample to ambient atmosphere at 23°C and 55% relative humidity results in observable hydrolysis (upfield shift of the triflate ¹⁹F NMR signal at −73.8 ppm to the corresponding alcohol) within 4 h.

Specification Panel and Lot-Release Criteria

Routine quality control of this building block employs orthogonal chromatographic and spectroscopic methods. The acceptance profile includes ¹H NMR (400 MHz, CDCl₃) verification of the characteristic vinyl proton doublet at δ 5.68–5.72 (1H, J = 3.8 Hz) and the tert-butyl singlet at δ 1.48. ¹⁹F NMR confirms a single resonance for the triflate group at −73.8 ± 0.3 ppm relative to CFCl₃. GC-MS (EI, 70 eV) shows the molecular ion peak m/z 331 [M]⁺ with a characteristic fragment at m/z 232 (loss of OSO₂CF₃). HPLC purity is determined against an external reference standard calibrated by quantitative ¹H NMR using maleic acid as internal standard. Elemental analysis tolerances are set at ±0.4% for C, H, N. Residual palladium content, when the compound is prepared via catalytic cross-coupling, is monitored by ICP-MS with an action limit of ≤20 ppm.

Preparative Routes and Observed Batch Variance

Two principal synthetic pathways dominate laboratory-scale preparation. Route A commences with N-Boc-3-pyrrolidinone, subjected to enolate formation with LiHMDS in THF at −78°C followed by trapping with N-phenyl-bis(trifluoromethanesulfonimide). The exotherm during triflimide addition necessitates a dosing rate controlled to maintain internal temperature below −65°C; excursions above −55°C generate a yellow byproduct tentatively identified as the ring-opened acyclic enol triflate, lowering isolated yields to 45–52%. Route B proceeds through N-Boc-3-hydroxypyrroline (CAS not cited) prepared via diisobutylaluminum hydride reduction of the corresponding pyrrolidinone, with subsequent sulfonylation using triflic anhydride and 2,6-lutidine in dichloromethane at 0°C. At scales exceeding 50 mmol, the latter route consistently delivers yields of 78–85% after flash chromatography (silica gel, hexane/ethyl acetate 9:1) with low levels of the elimination-derived pyrrole impurity (<0.2%). A recurring lot-to-lot variation involves a slightly yellow tint in material stored longer than 6 months at −20°C; discoloration is traced to trace iron leached from the steel needle used during argon backfill and can be mitigated by using PTFE-lined septa and nitrogen as the headspace gas.

What Governs Reactivity in Palladium-Catalyzed Cross-Coupling Manifolds?

Oxidative addition of the vinyl triflate to Pd(0) determines the rate of C–C bond construction in Suzuki-Miyaura, Stille, and Sonogashira protocols. Data collected using Pd(PPh₃)₄ (5 mol%) and arylboronic acids (1.2 equiv) in degassed THF/water (4:1) with K₂CO₃ (2.0 equiv) at 65°C show complete consumption of the triflate within 2–3 h for electron-neutral aryl partners, while electron-deficient boronic acids (e.g., 4-nitrophenylboronic acid) extend the reaction time to 6–8 h due to a slower transmetallation step. In comparison, the corresponding 3-bromo-N-Boc-pyrroline (CAS 1863882-32-2) displays a markedly different reactivity fingerprint: under identical conditions, complete conversion requires 18–24 h with electron-neutral partners and competitive protodebromination reaches 12–18% when water content exceeds 5% v/v. The triflate is therefore the preferred electrophile when reaction time or protic impurity levels are critical. However, the higher cost per mole—typically a factor of 4–6 relative to the bromide at the 100-gram scale—constrains its use to high-value late-stage functionalization.

The following table summarizes relative reactivities of C-3 leaving groups in the N-Boc-2,5-dihydro-1H-pyrrole scaffold under standardized Suzuki coupling conditions (ArB(OH)₂, Pd(PPh₃)₄, K₂CO₃, THF/H₂O, 65°C):

Leaving Group at C-3	t₅₀ (min)¹	Yield Range (%)²	Major Side Product	Relative Cost per mmol³
Triflate (OSO₂CF₃)	45–60	82–91	Hydrolysis to 3-OH	2.8–3.5
Nonaflate (OSO₂C₄F₉)	55–75	78–88	Hydrolysis to 3-OH	3.2–4.0
Bromide (Br)	180–240	65–80	Protodebromination	1.0
Iodide (I)	90–130	70–85	Elimination to pyrrole	1.8–2.2
Tosylate (OTs)	>600⁴	20–35	Unreacted starting material	0.7–1.2

¹ Time for 50% conversion determined by HPLC monitoring. ² Isolated yield after silica gel chromatography. ³ Normalized to bromide = 1.0 based on 10-g purchase quantity. ⁴ Reaction essentially stalled; palladium black observed after 10 h.

When Orthogonal Deprotection Dictates the Synthetic Route

The N-tert-butoxycarbonyl group confers acid lability that is orthogonal to the base-sensitive and hydrogenation-prone triflate/olefin system. Boc removal proceeds cleanly with TFA/CH₂Cl₂ (1:1 v/v) at 0°C to room temperature over 30 min, affording 3-triflyloxy-2,5-dihydro-1H-pyrrole as the TFA salt. This intermediate can be telescoped directly into amide bond formation, reductive amination, or sulfonylation without isolation. By contrast, the corresponding N-Cbz-protected analogue requires hydrogenolysis (H₂, Pd/C, EtOH), conditions that simultaneously reduce the olefinic double bond and cleave the C–O triflate if care is not taken. For sequences demanding an N-protecting group that is inert to acidic conditions while the triflate serves as a handle for sequential coupling steps, the N-benzyl-3-triflyloxypyrroline scaffold is available, though the extra deprotection step (CAN oxidation, BCl₃, or catalytic hydrogenation under controlled pressure ≤1 atm) reduces overall throughput. These differentiation points are critical in medicinal chemistry programs where parallel SAR exploration mandates rapid, protecting-group-orthogonal derivatization of the pyrroline core at both nitrogen and C-3.

Stability of the triflate moiety in the presence of nucleophilic solvents defines handling boundaries. In methanol-d₄ at 25°C, 5% decomposition is observed by NMR after 8 h, whereas in acetonitrile-d₃ the same level of degradation requires >72 h. Reactions should be conducted in anhydrous, non-nucleophilic solvents (THF, DME, 1,4-dioxane, DCM). Rigorous exclusion of primary and secondary amines from the medium is mandatory; even 0.1 equiv of piperidine leads to rapid N-Boc cleavage and subsequent polymerization of the free amine within minutes.

A High-Throughput Screening Paradigm for Fragment-Based Drug Discovery

In fragment elaboration campaigns, the compound serves as a versatile sp²-rich three-carbon unit amenable to Pd-mediated diversification. Automated parallel synthesis platforms (Chemspeed, Freeslate) have been programmed to dispense 0.1 M stock solutions in anhydrous THF into 96-well plates pre-loaded with solid Pd(dppf)Cl₂·CH₂Cl₂ (10 mol%) and aryl- or heteroarylboronic acids (1.3 equiv). After addition of aqueous K₃PO₄ (2.0 M, degassed), the sealed plates are heated to 70°C with orbital shaking at 800 rpm for 4 h. Post-reaction LC-MS analysis typically shows 75–93% conversion across a 24-member boronic acid matrix, with failure modes mostly confined to ortho-substituted aryl partners (steric hindrance during transmetallation) or heterocycles bearing acidic NH groups that quench the catalyst. The Boc-protected products can be taken through a standard TFA-mediated deprotection sequence directly in the plate, followed by SPE cleanup, to yield primary screening hits with a pyrroline or pyrrolidine scaffold. Published data for this specific configuration in multi-gram library production is limited, but pilot studies on a 5-gram scale with 4-fluorophenylboronic acid yielded 1.12 g (71%) of the pure 3-aryl product after chromatography, demonstrating the direct transferability of microscale methods to magnetically stirred round-bottom flasks.

Safeguarding Against Exotherm and Gas Evolution During Scale-Up

When the triflate is exposed to nucleophilic bases in solvents with low heat capacity, an induction period of 30–60 s can precede a rapid, self-accelerating decomposition that generates SO₂ gas and tarry residues. Reaction calorimetry (Mettler Toledo RC1, 1.0-liter vessel) performed on a mixture of the triflate (0.5 mol) and aqueous NaOH (3.0 M, 1.1 equiv) in THF at 30°C recorded a maximum heat flow of 85 W·kg⁻¹ and a total heat release of −189 kJ·mol⁻¹. The adiabatic temperature rise (ΔT_ad) was calculated as 48°C. For kilogram-scale processing in a 20-liter jacketed reactor, a controlled dosing strategy—maintaining the internal temperature at 5–10°C and limiting the base addition rate to 0.2 equivalents per minute—suppresses the peak heat evolution to manageable levels and avoids triggering the decomposition cascade. The waste stream requires quenching of residual triflate with aqueous ammonia before disposal to prevent exothermic runaway in solvent recovery systems.

Comparisons with alternative 3-sulfonate esters (mesylate, tosylate, benzenesulfonate) underline the unique position of the triflate as a balancing point between reactivity and shelf stability. The tosylate analogue is a crystalline solid with excellent bench stability (no decomposition after 72 h at 25°C, 60% RH) but is unreactive in all but the most forcing cross-coupling attempts; the mesylate is oil-prone and hydrolyzes almost as rapidly as the triflate while offering no kinetic advantage. Thus, the triflate remains the default choice for those transformations where productive Pd insertion must compete with background solvolysis.

Property	Triflate (this product)	Brosylate (4-BrC₆H₄SO₃)	Iodide	Comments
Crystalline form	White plates (hexane/EtOAc)	Pale yellow prisms	Waxy solid, often colored	Triflate is easiest to handle and weigh accurately.
Thermal stability (DSC onset, °C)	118 ± 2 (exothermic decomposition)	152 ± 3	134 ± 2 (melting with decomposition)	Triflate requires storage below −20°C for long-term use.
Rate of hydrolysis (t_½, pH 7 buffer/THF 1:1, 25°C)	6.2 h	14.5 h	Conversion undefined; elimination dominates	Use of the triflate in aqueous coupling demands rapid Ph-B(OR)₂ introduction.
Typical Pd catalyst loading for Suzuki (mol%)	2–5	5–10	1–5	Triflate strikes a compromise between reactivity and cost of catalyst.

HS Code	151643
Chemical Formula	C10H12F3NO5S
Molar Mass	317.27 g/mol
Appearance	Typically a solid (appearance can vary based on purity and synthesis method)
Melting Point	Data may vary depending on purity, usually within a certain range specific to the compound
Solubility	Soluble in some organic solvents like dichloromethane, less soluble in water
Pka	No common pKa values publicly available without experimental determination for this specific functional group combination
Stability	Can be stable under normal storage conditions, but may be sensitive to heat, light, and certain reactive chemicals

Packing	100g of Tert - Butyl 3 - ((Trifluoromethyl)sulfonyl)oxy - 2,5 - Dihydro - 1H - pyrrole - 1 - carboxylate in sealed vial.
Shipping	Shipment of Tert - Butyl 3 - ((Trifluoromethyl)sulfonyl)oxy - 2,5 - Dihydro - 1H - Pyrrole - 1 - Carboxylate must follow strict chemical shipping regulations. It should be properly packaged to prevent leakage, with labels indicating its nature and handling precautions.
Storage	Store "Tert - Butyl 3 - ((Trifluoromethyl)sulfonyl)oxy - 2,5 - Dihydro - 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 cause degradation. Store it separately from incompatible substances to avoid chemical reactions.