5-Iodo-3-Methyl-Isothiazole
|
HS Code |
809244 |
| Chemical Formula | C4H4INOS |
| Molecular Weight | 227.05 |
| Odor | No general common odor description available without more data |
| Melting Point | No common data found without further research |
| Boiling Point | No common data found without further research |
| Solubility In Water | Limited solubility likely as it is an organic heterocyclic compound |
| Solubility In Organic Solvents | Soluble in common organic solvents like dichloromethane, chloroform (typical for such heterocyclics) |
| Density | No common data found without further research |
| Stability | Stable under normal conditions, but may react with strong oxidizing agents |
As an accredited 5-Iodo-3-Methyl-Isothiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100 - gram vial packaging for 5 - Iodo - 3 - Methyl - Isothiazole chemical. |
| Shipping | 5 - Iodo - 3 - Methyl - Isothiazole is shipped in accordance with chemical regulations. Packed securely in suitable containers, it's transported by approved carriers, ensuring safe handling and proper documentation throughout transit. |
| Storage | 5 - Iodo - 3 - Methyl - Isothiazole should be stored in a cool, dry, well - ventilated area away from heat sources and open flames. Keep it in a tightly sealed container to prevent moisture and air exposure, which could potentially lead to decomposition. Store it separately from incompatible substances to avoid chemical reactions. |
In pharmaceutical development, the 5-iodo-3-methylisothiazole scaffold is employed as a stereoelectronically tunable electrophile for assembling 5-aryl-3-methylisothiazole analogues under current preclinical evaluation for selective cyclooxygenase-2 inhibition. A representative kilo-lab batch is processed in a 200-L glass-lined reactor inerted with three vacuum-nitrogen cycles. Anhydrous tetrahydrofuran (water content < 80 ppm by Karl Fischer coulometer) is charged, followed by the iodoheterocycle, the corresponding arylboronic acid (1.07 eq.), and degassed aqueous 2.0 M tripotassium phosphate (2.7 eq.). Oxygen removal is effected by subsurface sparging with 99.999% N₂ through a sintered-metal dip tube for 55 min. Pd(dppf)Cl₂·CH₂Cl₂ (0.25 mol%) is introduced via an airlock against positive nitrogen flow. The jacket is ramped to 72 ± 2 °C over 40 min and maintained until in-process GC confirms conversion ≥ 99.8%; typical hold time is 5.5–7 h. The role of the iodide leaving group is critical—attempts to substitute the 5-bromo or 5-chloro congeners under identical conditions yield < 60% conversion and generate dimeric impurity at 3–6 area%. After phase separation, the organic stream is washed with 8% w/w sodium metabisulfite to sequester liberated iodine species, then filtered through a 0.5-micron PP depth-media cartridge. Concentration is performed under 60 mbar at 45 °C, and the product is isolated by wiped-film distillation (jacket 128 °C, pressure 2.5 mbar, feed rate 8 kg/h) to give a pale-yellow liquid that solidifies on static cooling. Heptane/ethyl acetate (9:1 v/v) recrystallization furnishes white crystals, mp 48.5–50.0 °C by DSC at 10 K/min. Trace palladium by ICP-MS is routinely < 4 ppm, aligned with ICH Q3D Option 2 oral concentration limits. Residual THF and heptane are assessed per USP <467> Procedure A and are consistently below 10% of the permitted daily exposure. A recurring processing anomaly observed in batches vented to ambient atmosphere before the bisulfite quench is the appearance of a turquoise hue attributable to ring-opened sulfonic acid intermediates; this is verified by LCMS and mandates uninterrupted inert handling until the reductive wash sequence is complete.Why Does the Iodide Leaving Group Outperform Bromide in Cross-Electrophile Coupling of 3-Methylisothiazoles?Direct cross-electrophile coupling employing non-precious nickel catalysts reveals a pronounced leaving-group divergence that places 5-iodo-3-methylisothiazole as the preferred substrate for constructing unsymmetrical bis(heteroaryl) architectures. The table below compiles representative observations from a 100-mmol parallel screening executed in nickel-plated, internally baffled cylindrical reactors with controlled headspace moisture below 20 ppm dew point.
If Electron-Deficient Monomers Are Required for Low-LUMO Polymers, 5-Iodo-3-Methyl-Isothiazole Provides an Acceptor UnitAll‑polymer and polymer‑small‑molecule bulk heterojunction cells have utilized copolymers containing the 3‑methylisothiazole nucleus as a moderately electron‑withdrawing heterocycle to tune the acceptor energy level between −3.4 eV and −3.6 eV. The requisite Stille polycondensation between 5‑iodo‑3‑methylisothiazole and a distannylated donor monomer such as 4,8‑bis((2‑ethylhexyl)oxy)benzo[1,2‑b:4,5‑b′]dithiophene‑2,6‑diylbis(trimethylstannane) is executed under anaerobic, anhydrous glovebox conditions with O₂ and H₂O levels maintained below 0.5 ppm each. The iodo monomer, selected over its bromo analogue because of a three‑fold faster transmetalation rate determined by ³¹P NMR kinetic monitoring, is recrystallized twice and lyophilized from dry dioxane before use; total iodine content by combustion‑ion chromatography must be > 99.8% of theoretical, and each sub‑lot is released only after a test polymerization achieves a number‑average molecular weight Mn exceeding 22 kDa by high‑temperature GPC at 160 °C in 1,2,4‑trichlorobenzene against monodisperse polystyrene calibrants (ISO 13885‑1:2020). The reaction proceeds in chlorobenzene at 122 °C with Pd₂dba₃ (1.5 mol%) and tri(o‑tolyl)phosphine (6 mol%) for 48 h, end‑capped with 2‑(tributylstannyl)thiophene (5 mol% relative to monomer) to quench remaining iodide termini that would otherwise act as deep traps in fabricated transistors. After scavenging residual palladium and tin with MP‑TMT macroporous resin at 90 °C for 12 h, the polymer is precipitated into methanol and sequentially Soxhlet‑extracted with acetone, hexane, and finally chloroform. The chloroform fraction, concentrated to a 5 mg/mL solution, is filtered through a 0.45 μm PTFE syringe filter and shows Mn 28–35 kDa, dispersity 1.8–2.3. Critical process failures have been linked to residual tin content above 30 ppm, which induces dark‑current instability in organic photodetectors; the resin treatment reliably reduces tin to < 8 ppm by ICP‑OES. All materials shipped for electronic‑grade applications are accompanied by a certificate stating compliance with REACH Annex XVII restrictions and a halogen‑free declaration per IEC 61249‑2‑21, with iodine excluded from the definition of “halogen” for this purpose.Buchwald-Hartwig Amination Routes to N‑Aryl‑3‑Methylisothiazol‑5‑AminesKinase‑targeted libraries utilize 5‑amino‑3‑methylisothiazole motifs as hinge‑binding fragments, accessed directly from the iodide precursor via palladium‑catalyzed C–N coupling with aryl and heteroaryl amines. A typical process charges 1.0 eq. of 5‑iodo‑3‑methylisothiazole, 1.1 eq. of the primary aniline derivative, and sodium tert‑butoxide (1.3 eq.) into toluene (anhydrous, < 50 ppm H₂O) under a steady argon sweep. The palladium source, Pd₂dba₃ (1.0 mol%), and Xantphos (1.5 mol%) are pre‑activated in a separate vessel by stirring in toluene at 60 °C for 25 min until the red‑violet active catalyst forms; omission of this pre‑activation step has been documented to extend the induction period by 2–3 h and increase the homocoupled biaryl impurity by 1.5 area%. After combination, the batch is heated to 85 °C for 4–5 h, during which sodium iodide precipitates as a fine white solid. The iodide, being photo‑labile, requires exclusion of actinic light throughout, so reactor sight glasses are wrapped with amber UV‑filtering film. Work‑up involves filtration through a celite pad pre‑wet with toluene, a 5% w/w aqueous ammonia wash to dissolve residual sodium iodide, and vacuum distillation (135–145 °C head temperature at 2 mbar). The amine products often possess melting points in the 80–105 °C range, and the distillate is recrystallized from cyclohexane/toluene (4:1 v/v) with hot filtration through a 1 μm glass‑fiber filter to remove colloidal palladium. Final purity exceeds 99.5 area% by HPLC, and residual palladium is brought below 10 ppm (control limit derived from ICH Q3D parenteral concentration limits, as many target compounds are advanced through intravenous toxicology). A known incompatibility exists with basic nitrogen heterocycles carrying unprotected benzylic C–H bonds: in the presence of the liberated tert‑butoxide, debenzylation has been observed on a 2–5% scale, which is suppressed by switching to Cs₂CO₃ (2.0 eq.) and increasing the reaction temperature to 100 °C. |
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5-Iodo-3-methylisothiazole (CAS RN 131400-48-1) is a five-membered S,N-heteroaromatic halide with the empirical formula C4H4INS and a molecular weight of 225.0 g mol−1. As a substituted isothiazole, the electron‑deficient ring imparts a pronounced polarisation that concentrates electrophilic character at the C‑5 position while the 3‑methyl group exerts a mild +I effect, fine‑tuning the π‑deficit compared to the unsubstituted parent. The compound is supplied as a yellow to amber oil (density 2.04 g cm-3 at 20 °C, determined by oscillating U‑tube method per ISO 15212-1) that solidifies below –15 °C. Refractive index nD20 is routinely recorded at 1.641–1.647. Because of the weak C–I bond, the material requires storage under dry argon at 2–8 °C and exclusion of light above 0.1 lux; photolytic homolysis proceeds with a quantum yield that can degrade assay by 0.5–1.2% per hour under standard laboratory fluorescent lighting.
The kinetic edge conferred by the iodo substituent originates from a sharp reduction in the bond dissociation energy of the C–X linkage—52 kcal mol-1 for C–I versus 66 kcal mol-1 for C–Br and 79 kcal mol-1 for C–Cl—combined with the inherently low‑lying σ*C–I orbital that matches the HOMO of electron‑rich Pd(0) complexes. In a standard Suzuki–Miyaura benchmark with phenylboronic acid (1.2 eq), Pd(PPh3)4 (0.5 mol%) and K2CO3 (2.0 eq) in THF/H2O (4:1 v/v) at 60 °C, 5-iodo-3-methylisothiazole reaches full conversion within 30 min, delivering an isolated yield of 92–94% after flash chromatography. Under identical conditions the bromo congener requires 4 h to attain 93% conversion, and the chloro derivative shows less than 5% product formation after 24 h. The iodide therefore permits catalyst loadings as low as 0.05 mol% when paired with a sterically demanding ligand (SPhos, XPhos), markedly reducing palladium carry‑over into downstream steps.
The processing window narrows significantly at temperatures above 75 °C. At 80 °C, protodehalogenation—base‑mediated protonolysis of the C–Pd intermediate—becomes competitive, generating 3‑methylisothiazole as a recalcitrant impurity that co‑distills with the product. Strong bases such as K3PO4 or Cs2CO3 accelerate this sidestep; optimum performance is therefore obtained with finely ground K2CO3 (particle size Dv90 ≤ 45 μm) and an internal temperature control of 60 ± 2 °C. When pilot‑scale batches (3–5 kg) were run in a 20 L jacketed glass reactor equipped with a retreat‑curve impeller, a temperature overshoot of only 4 °C increased the protodehalogenation by‑product from 0.8 area% to 3.5 area%, confirming the criticality of precise thermal management.
Exposure of neat 5-iodo-3-methylisothiazole to ambient white‑fluorescent light (400–700 nm, 500 lux) at 22 °C results in a zero‑order degradation rate of 0.4% assay loss per hour, as measured by GC‑FID (DB‑5 column, 30 m × 0.32 mm). Degradation follows a radical pathway, with I2 being generated and causing a visible darkening of the oil from amber to deep brown. Therefore all handling must be conducted under low‑intensity red light (< 10 lux) or inside an amber glass bottle; bulk storage is maintained in amber HDPE containers under nitrogen at 2–8 °C. Under these conditions retest dating extends to 12 months, with assay retention above 97.0%. Photostability testing per ICH Q1B (Option 2) confirms that the material falls into the photo‑labile category, and any aliquot exposed to room light for more than 30 min should be discarded.
When selecting a 5-halo-3-methylisothiazole for development‑scale chemistry, the reactivity gap between the iodo and bromo analogues translates into distinct process economics. The following table collates typical performance data from a Suzuki coupling with 4‑methoxyphenylboronic acid using a Pd(OAc)2/SPhos catalytic system in 1,4‑dioxane at 55 °C. The entries are benchmarked against identical stoichiometric ratios and agitation regimes (magnetic stirring at 600 rpm).
| Substrate | Catalyst loading (mol%) | Reaction time (h) | Conversion (%) | Isolated yield (%) | Protodehalogenation impurity (%) |
|---|---|---|---|---|---|
| 5-Iodo-3-methylisothiazole | 0.2 | 1.5 | >99 | 91 | 1.2 |
| 5-Bromo-3-methylisothiazole | 1.0 | 8 | 97 | 85 | 3.8 |
| 5-Chloro-3-methylisothiazole | 2.0 | 24 | 12 | n.d. | n.d. |
The iodo substrate allows direct telescoping without intermediate aqueous workup for many aryl‑ and heteroaryl‑boronic acids, reducing unit operations. The bromo analogue demands a separate pre‑activation step with a catalytic amount of CuI or KI to shuttle reactivity, a protocol that introduces copper residues frequently incompatible with subsequent enantioselective hydrogenations. The chloro derivative is essentially unreactive under standard phosphine‑ligated Pd systems and is limited to coupling reactions employing nickel catalysts or photoredox‑mediated pathways that are cost‑prohibitive on scale.
Aqueous acid–base workup at moderate pH poses minimal risk to the C–I bond. Stability studies in THF/H2O mixtures between pH 3 and pH 9 at 25 °C show an assay drift of less than 0.2% over 48 h, indicating that standard biphasic extractions do not contribute to degradation. However, contact with strongly nucleophilic bases such as DBU, DBN, or guanidine must be avoided because they can attack the isothiazole ring at the sulfur atom, leading to ring‑opened thioamide‑type impurities that are difficult to purge by crystallisation.
Amine‑based reagents trigger ring‑opening of the isothiazole core even at ambient temperature. When 5-iodo-3-methylisothiazole was stirred with 1.0 eq DBU in MeCN at 20 °C, HPLC‑MS analysis after 2 h revealed 7 area% of a covalent adduct derived from nucleophilic attack at the S–N bond. Therefore, only inorganic bases (K2CO3, NaHCO3, KF) or sterically encumbered amine bases such as 2,6‑lutidine should be employed, and even then at temperatures below 40 °C. This restriction is not observed with the corresponding thiazole or oxazole halides, making the isothiazole scaffold uniquely sensitive and requiring explicit risk‑assessment in process safety reviews.
| Parameter | Method | Acceptance Criterion |
|---|---|---|
| Assay (GC) | GC‑FID, column DB‑5, 30 m, temp. ramp 80–280 °C at 15 °C/min | ≥ 98.0% area |
| Water content | Karl Fischer coulometry, USP <921> Method Ic | ≤ 0.10% w/w |
| Appearance | Visual inspection against white background, 25 °C | Clear amber to yellow liquid, free of visible particulates |
| Density (20 °C) | Oscillating U‑tube, ISO 15212-1 | 2.030 – 2.060 g cm-3 |
| Refractive index (nD20) | Abbe refractometer, ISO 489 | 1.641 – 1.647 |
| Heavy metals (Pd, Cu) | ICP‑MS after microwave digestion | ≤ 5 ppm each |
Each lot is accompanied by a certificate of analysis that reports the values against the above specifications. Residual solvent content is controlled to ≤ 500 ppm for ethyl acetate and ≤ 100 ppm for toluene, determined by headspace GC‑MS with a detection limit of 1 ppm. The material is dried over molecular sieves (4 Å) for 24 h prior to final packaging to guarantee the water limit, as even trace moisture can initiate slow hydrolysis of the C–I bond during prolonged storage.
Batch‑to‑batch variability has been evaluated across 12 consecutive campaigns at the 2–5 kg scale. The assay standard deviation remained below 0.4%, and the sole salient outlier arose from a packaging line that introduced 0.15% moisture due to a faulty argon purge. After corrective action—reducing the packaging manifold dew point to –70 °C—water levels returned to ≤ 0.05%. Such operational data confirm that tight specification adherence is attainable with proper inert‑atmosphere infrastructure, reinforcing the compound’s suitability as a late‑stage functionalisation synthon in active pharmaceutical ingredient (API) synthesis where halogen‑selective coupling is paramount.
