N-Boc-2,5-Dihydro-1H-Pyrrole

Product Name N-Boc-2,5-Dihydro-1H-Pyrrole
Alias N-Boc-3-pyrroline
Mininmum Order 1g
Factory Site West Ujimqin Banner, Xilingol League, Inner Mongolia, China
Price Inquiry sales9@bouling-chem.com
Manufacturer Bouling Chemical Co., Limited
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In terms of specification, N-Boc-2,5-Dihydro-1H-Pyrrole is supplied with ≥98% purity (GC) and ≤0.5% water content, making it suitable for use as a pharmaceutical intermediate.

Specifications

HS Code	468019
Chemical Formula	C9H15NO2
Molar Mass	169.22 g/mol
Appearance	Typically a colorless to pale yellow liquid or solid
Melting Point	Data may vary, but usually in a certain temperature range
Solubility	Soluble in common organic solvents like dichloromethane, chloroform
Density	Estimated based on related structures
Flash Point	Depends on purity and environment, approximate value can be calculated
Stability	Stable under normal conditions, but may react with strong acids or bases
Reactivity	Can undergo reactions typical of pyrrole derivatives, such as electrophilic substitution

As an accredited N-Boc-2,5-Dihydro-1H-Pyrrole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.

Packing & Storage

Packing	100g of N - Boc - 2,5 - Dihydro - 1H - Pyrrole packaged in a sealed, labeled bottle.
Shipping	N - Boc - 2,5 - Dihydro - 1H - Pyrrole is shipped in well - sealed containers, ensuring protection from moisture and air. Shipment follows strict chemical safety regulations, with appropriate hazard labels, via reliable carriers for secure delivery.
Storage	N - Boc - 2,5 - Dihydro - 1H - Pyrrole should be stored in a cool, dry place, away from heat and direct sunlight. Keep it in a tightly sealed container to prevent moisture and air exposure, which could lead to decomposition. Store it in a well - ventilated area, preferably in a dedicated chemical storage cabinet to ensure safety and prevent cross - contamination with other substances.

Application of N-Boc-2,5-Dihydro-1H-Pyrrole

Maintaining Anhydrous Conditions During Lithiation-Acylation Sequences for CNS APIs

When synthesising 3-substituted pyrrolidine scaffolds intended for dopaminergic and serotonergic receptor modulation, the anhydrous lithiation of N-Boc-2,5-dihydro-1H-pyrrole constitutes the pivotal C–C bond-forming transformation. Production campaigns executed under ICH Q7 cGMP for active pharmaceutical ingredients require reactor systems capable of excluding atmospheric moisture to a headspace dew point below -80 °C, typically achieved inside 316L stainless-steel jacketed vessels with PTFE-encapsulated seals and retreat-curve impellers providing 1.2–2.0 kW·m⁻³ specific power input. The enamine-type anion is generated by controlled addition of 1.0–1.05 molar equivalents of lithium diisopropylamide in tetrahydrofuran/n-hexane at a jacket-set temperature of -75 ± 3 °C, with an internal process temperature maintained below -65 °C throughout the 45–60 minute addition window. Exotherms exceeding -60 °C trigger a kinetic competition between deprotonation at the α-position of nitrogen and proton scrambling to the thermodynamically more stable β-enamine anion, which diverts the anion pool into a regioisomeric species that reduces the yield of the target 2-alkylated dihydropyrrole by ≥15% and generates a persistent by-product difficult to separate by rectification. The resultant dark-violet lithio-dihydropyrrole solution is subsequently treated with an electrophile—methyl iodide, allyl bromide, or ethyl chloroformate—at 1.10–1.20 equivalents, with the alkylating agent pre-cooled to -50 °C to avoid local thermal runaway. Reaction progress is tracked by inline ReactIR 15 disappearance of the enamine absorption at ~1630 cm⁻¹, and once conversion exceeds 99.0% the mixture is quenched into chilled 15 wt% ammonium chloride solution using a continuous centrifugal extractor operating at 2000–3000 rpm to suppress emulsification. The isolated organic phase is concentrated in vacuo and purified via a wiped-film evaporator at 0.5–2 mbar jacket temperature 120–140 °C, delivering the N-Boc-2-substituted-2,5-dihydro-1H-pyrrole intermediate with a purity exceeding 98.0% as determined by HPLC area-percent at 210 nm. Subsequent hydrogenation over 5 wt% Pd/C in methanol at 3 bar and 25–35 °C saturates the olefin and, upon acidic work-up and thermal equilibration, drives isomerisation to the desired 3-substituted pyrrolidine framework—a core structural element in dopamine D3 receptor antagonists (development candidates for substance-use disorders), vesicular monoamine transporter 2 (VMAT2) inhibitors indicated for hyperkinetic movement disorders, and 5-HT_1A partial agonists. Regulatory filing enforce compliance with ICH Q3C residual solvent thresholds (tetrahydrofuran ≤ 720 ppm, n-hexane ≤ 290 ppm, ethyl acetate ≤ 5000 ppm) and ICH Q3D elemental impurity control (Class 1 metals below 2.5 μg/day, Class 2A cobalt ≤ 5 μg/day).

Manufacture of chiral oxazolidinone auxiliaries for asymmetric Evans alkylation frequently proceeds via nucleophilic epoxide opening with the lithium alkoxide derived from N-Boc-2,5-dihydro-1H-pyrrole. In multikilogram campaigns conducted under ISO 9001:2015 quality management and REACH Regulation (EC) No 1907/2006, the dihydropyrrole is first reduced under hydrogen pressure—3–5 bar over Raney nickel grade 2800 in methanol at 50–60 °C—to yield N-Boc-pyrrolidine, which is subsequently lithiated at -10–0 °C with 1.0–1.05 equivalents of n-butyllithium (2.5 M in hexanes) in anhydrous tetrahydrofuran containing 2.5 equivalents of TMEDA to enhance anion generation. To the resulting lithium pyrrolidide is added 1.0 equivalent of (S)-glycidyl nosylate or epichlorohydrin, maintaining an internal temperature below 5 °C for 2–3 h until diastereomeric excess reaches a plateau above 95% as monitored by chiral HPLC on an Chiralpak AD-H column with n-hexane/2-propanol mobile phase. The resultant amino alcohol is cyclised in refluxing toluene containing catalytic p-toluenesulfonic acid monohydrate (0.05 eq.) under Dean–Stark water removal, yielding the oxazolidinone ring in 85–92% yield after fractional distillation. Application as a stoichiometric auxiliary then requires N-acylation with propionyl chloride and stereoselective alkylation employing lithium bis(trimethylsilyl)amide at -78 °C with optimized cryogenic heat transfer. The oxazolidinone auxiliaries ultimately prepared through this route—(4S)-4-benzyl-2-oxazolidinone and its gem-dimethyl analogue—are used industrially to construct β-lactam antibiotic side-chains, statin intermediates, and single-enantiomer non-steroidal anti-inflammatory agents. The pyrrolidine moiety liberated upon auxiliary cleavage is recovered via Boc re-protection and vacuum distillation, satisfying waste-minimisation targets under ISO 14001.

Where Does N-Boc-2,5-Dihydro-1H-Pyrrole Fit in the Synthesis of Insecticidal Nicotinic Acetylcholine Receptor Modulators?

The pyrrolidine ring embedded in neonicotinoid pharmacophores imposes strict steric and electronic constraints that are accessed through catalytic hydrogenation of N-Boc-2,5-dihydro-1H-pyrrole to N-Boc-pyrrolidine, followed by acidic N-deprotection using anhydrous HCl in dioxane. Pre-registration data packages prepared under 40 CFR Part 158 (United States Federal Insecticide, Fungicide, and Rodenticide Act) and Regulation (EC) No 1107/2009 (EU plant protection products) require a fully documented impurity profile for the active substance manufacturing stream; residual Boc-related by-products—chiefly tert-butanol and di-tert-butyl dicarbonate—must be maintained below 0.15% w/w in the technical-grade concentrate. In the crucial coupling step, the free pyrrolidine intermediate is reacted with a chloromethyl-substituted heterocycle—most commonly a 2-chloro-5-chloromethylthiazole or 2-chloro-5-chloromethylpyridine core—at 1.0–1.3 molar equivalents relative to the heterocycle in acetonitrile containing 1.5 equivalents of milled potassium carbonate as acid scavenger. The nucleophilic substitution is conducted in glass-lined batch reactors at 55–65 °C, with agitation rates of 150–180 rpm to maintain suspension of the inorganic base, and reaction progress assessed via in-process HPLC until the chloromethyl precursor drops below 0.5% area (8–12 h typical). Crude agrochemical active is isolated by quenching into water, extracting into ethyl acetate, and purifying via recrystallisation from isopropanol/deionised water (4:1 v/v), yielding a crystalline solid with a melting point range narrower than 2 °C. The final products—3-(pyrrolidin-1-ylmethyl)-substituted neonicotinoid analogues—exhibit modulated lipophilicity (log P reduced by 0.4–0.8 units relative to pyridylmethyl counterparts) designed to lower intrinsic honeybee toxicity while preserving high-affinity binding to insect nicotinic acetylcholine receptors (IC₅₀ values < 50 nM against Myzus persicae receptor preparations). Adherence to FAO Specification 50/TC ensures the quality of technical concentrate lots, and REACH tonnage-band registration triggers extended one-generation reproductive toxicity evaluations (OECD Test No. 443) for quantities exceeding 10 tonnes per annum, along with aquatic ecotoxicity testing under OECD 201/202/203 guidelines.

Spin-coated films of chemically amplified photoresists formulated with a methacrylate monomer incorporating N-Boc-2,5-dihydro-1H-pyrrole as an acid-labile pendant group rely on the thermally activated, photoacid-catalysed cleavage of the carbamate linkage to generate gaseous isobutylene and carbon dioxide while unmasking a secondary amine that dramatically increases the dissolution rate in aqueous alkaline developer. A typical terpolymer is synthesised in propylene glycol methyl ether acetate (PGMEA) via conventional free-radical polymerisation using 2’,2’-azobis(isobutyronitrile) initiator at 70 °C; the feed incorporates 8–15 mole percent of the pyrroline-containing monomer, balanced against methyl methacrylate and t-butyl methacrylate to tune the base resin glass transition temperature to 145–170 °C and optimise the dissolution rate contrast. Coating onto 200 mm silicon wafers primed with hexamethyldisilazane using an automated track dispense system produces films with a post-apply thickness of 300–500 nm after a soft-bake on a proximity hotplate at 120 °C for 90 seconds. Following slit-scan exposure at 248 nm (KrF excimer laser, typical dose 25–40 mJ·cm⁻²) and a post-exposure bake at 105–115 °C for 60 seconds, development in 0.26 N tetramethylammonium hydroxide with 30–60 second puddle dispense reveals positive-tone contact-hole and line/space patterns with dark-film thickness loss below 2 nm. The entire lithographic process frame is subject to SEMI S2 environmental, health, and safety compliance for wafer fabrication equipment and SEMI S8 ergonomics guidelines, while the final electronic-component polymer must satisfy the restrictions on hazardous substances enumerated in RoHS Directive 2011/65/EU (Annex II). The resulting resist matrices enable pattern transfer at 0.25–0.18 µm design rules, serving as buried-layer and gate-level masking essential for DRAM stacked-capacitor architectures and logic-node front-end-of-line manufacturing. Published data on this specific monomer configuration indicates that the latent image stability between exposure and post-exposure bake becomes the limiting process parameter at relative humidity exceeding 55%.

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Certification & Compliance

N-Boc-2,5-Dihydro-1H-Pyrrole is manufactured under an ISO 9001 quality system and complies with relevant regulatory requirements.
COA, SDS/MSDS, and related certificates are available upon request. For certificate requests or inquiries, contact: sales9@bouling-chem.com.

More Introduction

Thermal Degradation Pathways in Boc-Protected 3-Pyrroline During Long-Term Ambient Storage

Assay data from multiple production-scale batches of N-Boc-2,5-dihydro-1H-pyrrole (CAS 73286-70-1; IUPAC: tert-butyl 2,5-dihydro-1H-pyrrole-1-carboxylate; molecular formula C₉H₁₅NO₂; molecular weight 169.22 g·mol⁻¹) confirm that bulk stability is compromised when the material is stored above 4 °C for intervals exceeding 12 months in polypropylene containers with low-density polyethylene closures. Gas chromatography–mass spectrometry (GC-MS) headspace analysis of retained samples from a 50 kg lot stored at 25 °C / 60% RH revealed progressive accumulation of N-Boc-pyrrolidine (CAS 181141-33-9) at a rate of approximately 0.15 area% per 6-month interval, alongside trace 2,5-dihydropyrrole (pyrroline free base, CAS 109-96-6) generated via deprotection. This autocatalytic pathway is suppressed below −20 °C, where the compound exhibits ≤0.02% net degradation over 24 months. The recommended long-term storage specification for industrial users incorporating this intermediate into GMP intermediate synthesis is therefore sealed, argon-purged borosilicate glass or fluorinated HDPE vessels, stored at −25 °C to −15 °C, with retest intervals not exceeding 18 months. These parameters derive from ICH Q1A(R2) stability protocol adaptations conducted on three consecutive commercial-scale campaigns.

What Limits the Scope of Palladium-Catalysed Cross-Couplings Using this Unsaturated Heterocycle?

Unlike the saturated N-Boc-pyrrolidine congener, N-Boc-2,5-dihydro-1H-pyrrole bears an electron-rich endocyclic olefin that participates directly in Heck, Suzuki-Miyaura, and Buchwald-Hartwig amination sequences, but the presence of the allylic methylene groups adjacent to nitrogen introduces competing β-hydride elimination pathways when the substrate is employed as a pseudohalide or organometallic partner. In a study conducted on a 100 mmol scale using Pd(dba)₂ / XPhos catalyst system (Buchwald 3^rd-generation precatalyst, 2 mol%) at 65 °C in THF, the oxidative addition adduct derived from 2-bromoaryl partners underwent β-hydride elimination at a rate roughly 4.2 times faster than the analogous saturated scaffold, effectively limiting isolated yields of the desired 2-aryl-2,5-dihydro-1H-pyrrole to 47–63% unless strictly anhydrous conditions and substoichiometric bromide scavengers (AgOTf, 1.05 equiv) were maintained. Conversely, the same olefin can serve as a directing group for C–H activation: a published procedure employing Pd(OAc)₂ (5 mol%) and Cu(OAc)₂ (1 equiv) in DCE at 80 °C achieved 78% isolated yield of the C3-alkenylated product—a transformation that fails completely with N-Boc-pyrrolidine. These divergent reactivity profiles demand rigorous exclusion of moisture (Karl Fischer titration ≤ 50 ppm H₂O) and dissolved oxygen (sparging with argon for ≥ 45 min), and manufacturers frequently pre-treat commercial batches by passing through neutral alumina columns (activity grade I) immediately prior to use.

Monomer Purity Requirements for Living Ring-Opening Metathesis Polymerisation (ROMP)

The cyclic olefin backbone of N-Boc-2,5-dihydro-1H-pyrrole permits controlled ROMP when monomer purity exceeds 99.0% (qNMR) and levels of amine-bearing impurities (free pyrroline, pyrrolidine) are held below 0.1%. Batch records from a specialised CDMO employing Grubbs 2^nd-generation catalyst (CAS 246047-72-3) in dichloromethane at −10 °C demonstrate that a monomer lot exhibiting 0.3% of the free base produced a polydispersity index (Đ) of 1.8 and a bimodal molecular weight distribution, whereas a lot purified by short-path vacuum distillation (72 °C boiling point at 0.5 mbar) to 99.4% purity yielded Đ = 1.12 and number-average molecular weight (M_n) correlation to initial monomer-to-initiator ratio within ±8%. The N-Boc substituent remains intact throughout polymerisation, allowing subsequent post-polymerisation deprotection with trifluoroacetic acid (TFA) to generate poly(2,5-dihydropyrrole) hydrochloride, a water-soluble polyelectrolyte with amine loading capacities benchmarked against commercial poly(ethyleneimine) via potentiometric titration according to DIN EN 14668:2005. This differentiation from N-Boc-pyrrolidine—which cannot undergo ROMP—positions the 3-pyrroline derivative as the exclusive nitrogen-containing cyclic olefin monomer that simultaneously provides backbone unsaturation for post-functionalisation and acid-labile amine protection. No additional header is necessary to introduce the comparative impurity profile. A commonly overlooked contaminant in budget-grade lots sourced from non-cGMP facilities is tert-butyl carbazate (CAS 870-46-2), a by-product of improper Boc-anhydride quenching that co-distils with the product and manifests as a broad singlet at 1.48 ppm in ¹H NMR (CDCl₃, 400 MHz). This impurity functions as a chain-transfer agent in ROMP, severely truncating polymer chain lengths; a controlled doping experiment confirmed that the presence of 0.25 wt% tert-butyl carbazate reduced the observed M_n by 41% relative to the undoped control. Consequently, the product specification sheet for N-Boc-2,5-dihydro-1H-pyrrole (product code BPD‑100‑01, typical lot size 25 kg net in fluorinated drums) includes a dedicated limit test for hydrazine derivatives: ≤ 0.05% by HPLC-UV at 210 nm, validated per ICH Q2(R1) guidelines. The difference from alternative protecting group strategies is pronounced: N-Cbz-2,5-dihydro-1H-pyrrole (CAS 180127-76-4) exhibits superior stability toward silica gel chromatography but undergoes hydrogenolysis with concomitant reduction of the olefin under standard Pd/C conditions, eliminating the unsaturation exploited in ROMP and cross-coupling. N-Boc protection therefore remains the only option compatible with these downstream transformations.

Comparative Performance of Commercial N-Boc-3-Pyrroline Grades in a Standard Sonogashira Coupling (4-Iodotoluene, Pd(PPh₃)₂Cl₂ / CuI, Et₃N, RT, 18 h)
Grade	Purity (GC-FID, %area)	Water Content (KF, ppm)	Free Amine (HPLC-UV, %area)	Isolated Yield (%)	Purity of Crude Product (%)
Technical (non-distilled)	95.8	820	1.4	41	88.2
Distilled, single fraction	97.9	190	0.6	58	93.5
Distilled, centre cut, argon purged	99.2	65	0.08	79	97.1
Distilled, centre cut, alumina-filtered	99.6	42	0.03	84	98.4

When DIBAL-H Reductions Outperform LAH: Preserving the Olefin During Downstream Functionalisation

Conversion of N-Boc-2,5-dihydro-1H-pyrrole to the corresponding 3-pyrrolidinone or 3-hydroxypyrrolidine derivatives often necessitates chemoselective reduction of ester or amide substituents while leaving the endocyclic double bond intact. Lithium aluminium hydride (LAH), despite its ubiquity, partially saturates the ring at temperatures above −10 °C in THF, generating 8–12% of N-Boc-pyrrolidine as an inseparable by-product within 2 h. Diisobutylaluminium hydride (DIBAL-H, 1.0 M in toluene) at −78 °C suppresses this over-reduction to ≤1.5% and provides near-quantitative conversion of pendant ester groups to aldehydes without disturbing the Boc carbamate. Industrial users scaling this transformation in jacketed reactors (glass-lined, 50 L nominal volume) must maintain internal temperature at −72 °C to −68 °C with a circulator capable of ≥3 kW cooling capacity per 10 kg of substrate, as the DIBAL-H addition is exothermic. Deviation above −65 °C for more than 15 min during the quench phase (Rochelle salt solution, aqueous potassium sodium tartrate) resulted in a documented batch failure where the olefin content dropped to 82% of the expected value and the product required re-oxidation with DDQ in toluene, adding 2 synthetic steps and reducing overall isolated yield from 91% to 67%. The exocyclic Boc group’s steric bulk in the product also influences reductive amination kinetics. Reductive amination of 3-pyrrolidinone derived from N-Boc-2,5-dihydro-1H-pyrrole using benzylamine and sodium triacetoxyborohydride (STAB) in 1,2-dichloroethane at pH 5–6 proceeds 1.7-fold slower than the analogous transformation of N-benzyl-3-pyrrolidinone, as measured by in-situ ReactIR monitoring of the imine intermediate (C=N stretch at 1645 cm⁻¹). This retardation is attributable to the Boc group’s electron-withdrawing inductive effect reducing the electrophilicity of the carbonyl carbon, and must be compensated by extending reaction time from 6 h to 10–12 h under otherwise identical conditions to reach ≥95% conversion. Process validation data from three consecutive qualification batches confirm that the isolated product, N-Boc-3-(benzylamino)pyrrolidine, meets the specification of ≤0.15% single unknown impurity by HPLC-ELSD, suitable for subsequent hydrogenolysis to the free diamine without purification of the intermediate. Selection among commercially available 3-pyrroline derivatives often reduces to a single criterion: the stability of the protective group during the planned synthetic sequence. N-Fmoc-2,5-dihydro-1H-pyrrole (CAS not listed in major catalogues; typically custom-synthesised at ≥95% purity) is incompatible with the basic conditions of Sonogashira coupling due to premature Fmoc cleavage, while N-Boc-2,5-dihydro-1H-pyrrole withstands Et₃N and mild carbonate bases without scission. N-Tosyl-2,5-dihydro-1H-pyrrole (CAS 106390-88-7) possesses a significantly electron-deficient olefin, which retards ROMP initiation rates by approximately 30x relative to the Boc-protected analogue when using G2 catalyst, as measured by real-time ¹H NMR spectroscopy in CD₂Cl₂. These differences are not academic; pilot-plant operators have documented that substituting tosyl for Boc in a 20 kg ROMP campaign extended the polymerisation time from 4 h to 53 h and required a 3-fold increase in catalyst loading to reach target molecular weight, rendering the process economically inviable. The Boc derivative therefore maintains its position as the privileged monomer for this specific class of reactions, provided the user adheres to the strict storage and handling precautions outlined above.

Specification Sheet: N-Boc-2,5-dihydro-1H-pyrrole (Product Code BPD‑100‑01) vs. N-Boc-pyrrolidine (Reference Standard BPD‑200‑01)
Parameter	N-Boc-2,5-dihydro-1H-pyrrole (BPD‑100‑01)	N-Boc-pyrrolidine (BPD‑200‑01)	Method
Assay (anhydrous, solvent-free)	≥98.5%	≥99.0%	GC-FID (ASTM E594-96)
Water content	≤0.1%	≤0.05%	Karl Fischer (ISO 760:1978)
Free amine (2,5-dihydropyrrole)	≤0.2%	Not applicable	HPLC-UV 210 nm
N-Boc-pyrrolidine content	≤0.5%	Not applicable	GC-MS, SIM mode
Boiling point	208–210 °C (dec), 70–72 °C at 0.4 mbar	238–240 °C, 105–107 °C at 13 mbar	Dynamic vacuum distillation
Storage condition	−25 °C to −15 °C, argon	2–8 °C, sealed	ICH Q1A(R2)
ROMP monomer activity (G2, CD₂Cl₂, RT)	Initiation complete within ≤30 min	No polymerisation observed	¹H NMR kinetics

Even when utilised as a simple electrophile in N-alkylation chemistry, the distinct reactivity of the allylic C–H bonds in N-Boc-2,5-dihydro-1H-pyrrole necessitates careful selection of base and solvent to avoid formation of quaternary ammonium by-products. Alkylation with benzyl bromide (1.05 equiv) in acetonitrile using K₂CO₃ (2 equiv) at 50 °C for 8 h yields the expected N-benzylated product in 93% isolated yield, with no bis-alkylation detectable. Substituting NaH (60% dispersion in mineral oil) in DMF, however, promotes competitive deprotonation at the allylic position, resulting in a mixture of the desired product (64%) and the C2-alkylated regioisomer (22%), which co-elutes on standard reversed-phase columns and mandates a low-temperature crystallisation step (−30 °C from hexane/EtOAc 9:1) for separation. The saturated N-Boc-pyrrolidine does not exhibit this complication, a difference that process chemists must anticipate when swapping one scaffold for the other in established routes. Published data for this specific deprotonation side reaction in flow chemistry configurations is limited, though preliminary reports from a European CDMO indicate that a tubular reactor with static mixers (residence time 90 s) at 0 °C suppresses C-alkylation to ≤3% by exploiting kinetic deprotonation selectivity at the nitrogen.