5-Iodo-3-Methylisothiazole-4-Carboxamide

What Palladium Ligand Architectures Minimise Dehalogenative Side Reactions in sp² Carbon–Carbon Bond Construction?

When 5-iodo-3-methylisothiazole-4-carboxamide is employed in Suzuki-Miyaura cross-couplings to install aromatic or heteroaromatic rings at the C-5 position, the primary yield-limiting impurity is the desiodo protodehalogenation product, 3-methylisothiazole-4-carboxamide, which co-elutes with the target biaryl under reversed-phase C18 chromatography (isocratic 65:35 acetonitrile/0.1% formic acid). Systematic screening of Pd sources and biphenylphosphine ligands in a Design of Experiment matrix (temperature 40–70 °C, base K₃PO₄ or K₂CO₃, solvent THF, dioxane, or DME) reveals that the Pd-to-ligand ratio exerts a sharper influence on selectivity than the absolute catalyst loading. A precatalyst system composed of 0.4 mol% Pd₂(dba)₃ and 0.8 mol% XPhos (2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl) at 55 °C with powdered K₃PO₄ (1.5 eq) in degassed, anhydrous 1,4-dioxane (Karl Fischer titre < 50 µg/mL H₂O) consistently delivers an isolated yield of the desired 5-aryl derivative of 88–93% with protodehalogenation held below 1.8%. When the same reaction is ported to a continuous stirred-tank cascade using a Corning Advanced-Flow G1 reactor with glass fluidic modules, the residence time can be compressed to 12 minutes compared with 5.5 hours in batch while maintaining inlet-temperature uniformity within 1.2 °C across ten parallel channels. The major process risk is the precipitation of inorganic salts on the heat-exchange surfaces when K₃PO₄ loading exceeds 1.8 eq, causing a pressure drop increase of 0.8 bar/hr and eventual channel blockage; this is mitigated by injecting a 6 vol% water slug every fifth residence time. For customers transferring this intermediate into an active ingredient registered under EC 1107/2009, the relevant residue chemistry guideline OECD TG 507 requires demonstration that the deshalogenated by-product does not appear in rotational crops at levels exceeding the default 0.01 mg/kg limit of quantification when the parent compound is applied at double the maximum seasonal rate in a confined rotational crop study.

The incorporation of 5-iodo-3-methylisothiazole-4-carboxamide into solvent-borne antifouling paint formulations relies on a hydrolysable pendant group strategy, wherein the carboxamide nitrogen is acylated with a methacryloyl chloride-terminated tether to yield a polymerisable monomer that is subsequently terpolymerised with methyl methacrylate and butyl acrylate in a radical solution polymerisation initiated by 0.8 wt% azobisisobutyronitrile at 78 °C in xylene. After stripping residual monomers to < 1,200 ppm by vacuum distillation at 4 mbar, the copolymer solution is let down with a rosin zinc resinate harder and atomised copper(I) oxide pigment at a pigment volume concentration of 42% on a Hegman grind gauge reading of 4–5 after passage through a horizontal pin mill with a tip speed of 14 m/s. A critical compatibility constraint arises when the base copolymer contains free carboxylic acid moieties above 0.15 mEq/g acid value, because the iodine atom undergoes slow nucleophilic displacement by carboxylate at the 30–35 °C film-formation stage, releasing iodide ion that accelerates cuprous ion leach rate to 48–52 µg Cu⁺ cm⁻² day⁻¹ measured by rotating cylinder electrode polarisation at 60 rpm in synthetic seawater per ASTM D4939-89(2021), far exceeding the typical 25–30 µg cm⁻² day⁻¹ window for a 48-month service-life coating. Biocide release rate is characterised with a laboratory-scale ISO 15181-2:2007 apparatus using a polycarbonate cartridge and an eluent spiking protocol that maintains the dissolved isothiazole concentration below 20% EC₅₀ for Skeletonema costatum (determined in a 96-hour static algal growth inhibition test following OECD TG 201). A full registration package for an EU Biocidal Products Regulation ( BPR, Regulation (EU) 528/2012 ) active substance dossier must additionally contain a ready biodegradability report per OECD TG 301F (manometric respirometry showing < 8% ThOD after 28 days), an aerobic mineralisation half-life in marine sediment exceeding 180 days measured by OECD TG 308, and a verified analytical method for the parent compound in seawater at a limit of quantification ≤ 50 ng/L validated for inter-laboratory precision with a HorRat value ≤ 2.0.

Reactor Metallurgy Selection When Free Iodide Concentration Exceeds 800 mg/kg in the Process Stream

Stainless steel vessels fabricated from UNS S31603 (Type 316L) exhibit pitting corrosion rates above 0.13 mm/a when the recycled mother liquor from iodoisothiazole crystallisation accumulates iodide ion at concentrations exceeding 800 mg/L in the presence of dissolved oxygen at the vapour-liquid interface at 65 °C. The corrosion mechanism, confirmed by scanning electron microscopy with energy-dispersive X-ray spectroscopy after an ASTM G48-11 Method C exposure, involves crevice attack beneath the polytetrafluoroethylene gasket seating and intergranular cracking promoted by sensitisation from repetitive batch heating cycles. Consequently, campaigns exceeding 200 kg output typically specify a reactor with 2 mm thickness borosilicate 3.3 glass lining conforming to DIN 28136-1:2016, equipped with a tantalum-tipped RTD temperature sensor welded with a 0.5 mm thick tantalum diaphragm to resist iodide-induced embrittlement. When a glass-lined reactor is not available on-site, an alternative metallurgy of UNS N06022 (Hastelloy C-22) with a minimum PREN value of 65 is deployed, but the alloy must be preconditioned with a 4 M nitric acid passivation cycle at 52 °C for 45 min per ASTM A967/A967M-17 before the first oxidative addition step, otherwise galvanic microcells between the mill scale and the bulk matrix accelerate nucleation of pit densities exceeding 120 pits/cm² within the first 8 hours of exposure. An inline corrosion coupon rack holding three welded 50 mm × 25 mm × 3 mm coupons of the reactor alloy is inspected gravimetrically after every fifth batch; a cumulative mass loss exceeding 0.50 mg/cm² triggers a mandatory borescope examination of all welds in the lower head per API 510 recommended practice.

Forced Degradation of a Diastereomeric API Intermediate under ICH Q1B Confirmatory Conditions

When 5-iodo-3-methylisothiazole-4-carboxamide is elaborated into a diastereomeric sulfoxide-containing pharmaceutical intermediate destined for an oral capsule formulation, the key regulatory hurdle is the forced degradation study executed under ICH Q1B photostability guidelines in a Model ICH-2L photostability chamber equipped with near-ultraviolet fluorescent lamps compliant with ISO 10977-2 for emission spectra. An overall illumination exposure not less than 1.2 million lux·h with an integrated near-UV energy of 210 W·h·m⁻² delivered over 120 h generates a characteristic impurity profile that requires resolution of the 5-iodo diastereomer from the 5-chloro impurity (formed via photonucleophilic substitution by adventitious chloride in the dissolution medium) on a 250 mm × 4.6 mm phenyl-hexyl column with a 1.7 µm particle size. The mass balance must close to within 98.0% as per Ph. Eur. monograph 2034 (5.12, Reference samples), and any unidentified impurity exceeding 0.10 area% is submitted to LC-QTOF-MS for structural elucidation. One prominent photodegradant, identified as the desiodo-3-methylisothiazole-4-carboxamide, exhibits a relative response factor of 0.87 at the detection wavelength of 240 nm versus the parent compound; the corrected RRT 0.63 peak must be quantified against an external standard. Stability chambers operated at 40 °C/75% RH ( ICH Q1A(R2) ) in parallel for 6 months reveal no solid-state disproportionation, but a polymorph conversion monitored by X-ray powder diffraction ( XRPD , Cu Kα radiation, 2θ 3–40° ) occurs when the relative humidity exceeds 82%, shifting the d-spacing at 2θ = 12.7° to 13.0° and altering the dissolution rate by +35% compared with the original crystalline form. For commercial supply of the intermediate under a US FDA Drug Master File Type II, the residual palladium level is controlled to ≤ 5 µg/g by single-pass ultrafiltration through a 10 kDa polyethersulfone membrane operated at 2.5 bar transmembrane pressure, and the residual inorganic iodide is quantified by ion chromatography with suppressed conductivity detection per USP <211>, with an acceptance criterion of < 50 ppm.

How Sediment Half-Life Determinations Drive PBT Classification for Unsubstituted Isothiazole Carboxamide Biocides

A persistent, bioaccumulative and toxic (PBT) assessment under REACH Annex XIII for the parent 3-methylisothiazole-4-carboxamide scaffold relies on a tiered sediment simulation study executed per OECD TG 309 in a natural water-sediment system collected from two contrasting sites (total organic carbon 1.2% and 4.7%). The radiochemical formulation, synthesised from [¹⁴C]-5-iodo intermediate in a one-step Pd-catalysed deborylation-reduction sequence, is spiked at 100 µg/kg dry sediment weight, and the dissipation of the parent compound is fitted to a biphasic first-order kinetic model. Published half-life values for 3-methylisothiazole-4-carboxamide in the aerobic sediment compartment exceed 140 days in the high-organic-carbon matrix, indicating potential for persistence. The bioaccumulation component is evaluated through the octanol-water partition coefficient (log Kow determined by the slow-stirring method over 72 h at 25 °C ± 0.1 °C per OECD TG 123) and, where log Kow exceeds 3.5, by a fish dietary exposure bioaccumulation study in Cyprinus carpio under OECD TG 305 with a 28-day uptake phase and 14-day depuration. A bioconcentration factor exceeding 2,000 L/kg wet weight at steady state triggers a secondary evaluation of trophic magnification factor in a laboratory freshwater microcosm. While the 5-iodo congener is not itself the end-use biocide, it is considered a transformation intermediate in the manufacturing process, and under ECHA Guidance R.11 a read-across justification within the same heterocyclic category can be submitted only if the quantum-chemically calculated electrophilic superdelocalisability index at C-5 differs by < 8% between the iodo and the final substituted analogue, supported by HF/6-31G** level optimisation and comparison of HOMO-LUMO gap deviations.

In medicinal chemistry and agrochemical discovery programs, halogenated isothiazole carboxamides serve as versatile scaffolds for the construction of biologically active molecules. The compound designated 5-Iodo-3-methylisothiazole-4-carboxamide (IUPAC: 5-iodo-3-methyl-1,2-thiazole-4-carboxamide) occupies a specific niche within this family, offering a dense functional array — an iodine atom at C5, a methyl group at C3, and a primary carboxamide at C4 — on an electron-deficient heterocyclic core. Molecular formula C₅H₅IN₂OS, corresponding to a molecular weight of 268.07 g·mol⁻¹. The structure is confirmed by ¹H NMR (DMSO‑d₆) δ 2.51 (s, 3H, CH₃), 7.78 (br s, 2H, NH₂) ppm, and ¹³C NMR δ 162.8 (C=O), 156.2 (C3), 138.4 (C5), 112.0 (C4) ppm; the iodine substituent shields C5 and induces a characteristic downfield shift of the amide carbonyl relative to the 5-unsubstituted analogue.

What Analytical Release Criteria Define Material Suitability for Multi-Step Synthesis?

Batch-to-batch consistency is monitored against a multi-parameter certificate of analysis. Typical acceptance windows are established by reverse-phase HPLC (C18 column, acetonitrile/0.1% formic acid gradient) with UV detection at 254 nm. Area-percent purity ≥ 98.0% is the standard specification for use in fragment-based library synthesis, while a relaxed threshold of 95.0% is permissible for early-stage route scouting where a subsequent crystallization or column chromatography is planned. The compound is delivered as an off-white to pale-yellow microcrystalline powder; any darkening beyond Munsell 5Y 8/4 indicates iodine liberation accelerated by prolonged exposure to light or temperatures above 40 °C during storage. Residual palladium content from the final Sonogashira or halogen-exchange step must remain below 50 ppm as determined by ICP‑OES, since elevated palladium levels have been observed to catalyze dehalogenation side reactions under basic amide coupling conditions. Karl Fischer titration consistently returns water content < 0.5% w/w; higher moisture levels can promote hydrolysis of the carboxamide to the corresponding carboxylic acid during long-term ambient storage, particularly at relative humidity exceeding 65%.

Storage-Induced Degradation and Packaging Configuration

Stressed stability studies performed under ICH Q1A guidelines (40 °C/75% RH, open dish) reveal a primary degradation pathway via nucleophilic displacement of iodide by water, yielding 5-hydroxy-3-methylisothiazole-4-carboxamide. The degradation kinetics follow a pseudo-first-order rate law with an observed rate constant k_obs of approximately 1.2 × 10⁻² day⁻¹ at 40 °C. To suppress this hydrolysis, the product is packaged in amber borosilicate vials under argon (oxygen headspace < 100 ppm) with a PTFE-lined septum closure. Long-term storage recommendation is −20 °C in a desiccated environment; under these conditions no detectable degradation is observed by HPLC over 24 months. Shipping at ambient temperature for durations under 72 hours is provisioned, provided the material is re-refrigerated immediately upon receipt. When the compound must be weighed under ambient air, exposure should be limited to less than 30 minutes and a nitrogen-purged balance enclosure is employed.

Synthetic Utility in Palladium-Mediated Cross-Coupling Protocols

The iodine atom at the C5 position offers decisively higher reactivity in oxidative addition compared to the corresponding bromo and chloro congeners. In Buchwald–Hartwig aminations with primary alkylamines, the use of XPhos Pd G3 precatalyst (2 mol%) and potassium carbonate in tert-amyl alcohol at 80 °C achieves full conversion within 45 minutes, while the 5-bromo analogue requires 6 hours under identical conditions to reach 93% conversion, as measured by LC‑MS peak area integration. Suzuki–Miyaura coupling with arylboronic acids benefits from the iodo substituent’s low bond dissociation energy: reactions catalyzed by Pd(PPh₃)₄ (1 mol%) proceed smoothly at 50 °C in THF/water (4:1 v/v) with 2 equiv of potassium phosphate, conditions under which the 5-chloro derivative gives <5% yield. This expanded thermal operating window is especially advantageous when the coupled product contains thermolabile functional groups such as tertiary carbamates or benzylic nitriles.

The methyl group at C3 is not merely a spectator. In competitive studies, 5-iodo-3-methylisothiazole-4-carboxamide consistently demonstrates a slower rate of protodeiodination under basic aqueous conditions relative to 5-iodo-3-H-isothiazole-4-carboxamide. The electron-donating methyl substituent increases the electron density at C5, strengthening the C−I bond toward undesired reductive cleavage. This enables the compound to tolerate extended reaction times in phosphate-buffered aqueous mixtures at physiological pH — a relevant property for medicinal chemists exploring late-stage functionalization of complex drug intermediates.

Comparative Cross-Coupling Reactivity of Halogenated Isothiazole-4-carboxamides
Substrate	Reaction Type	Half-Life (min)	Observed Dehalogenation (%)
5-Iodo-3-methyl-	Suzuki, 50 °C	12	0.8
5-Bromo-3-methyl-	Suzuki, 50 °C	210	2.1
5-Iodo-3-H-	Suzuki, 50 °C	14	4.7
5-Bromo-3-H-	Suzuki, 50 °C	245	3.9

Half-life values determined by in situ ReactIR monitoring of the C−I absorbance band at 489 cm⁻¹. Dehalogenation was quantified by ¹⁹F NMR of the fluorinated internal standard. All entries represent the average of triplicate runs; catalyst loading fixed at 1 mol% Pd(PPh₃)₄.

When the Carboxamide Participates in Ugi and Amide Bond-Forming Steps

The primary carboxamide at C4 serves as a functional handle for diversification. Direct amide coupling with amines using HATU/DIPEA in DMF delivers the corresponding secondary amides in yields typically exceeding 80% without requiring protection of the iodo substituent. However, the combination with strongly nucleophilic amines such as piperidine at elevated temperatures (> 60 °C) must be avoided; mechanistic probes using ¹³C‑labeling confirm competitive aryl halide displacement generates a thiazole-ether byproduct that co-elutes with the desired amide on silica gel. To circumvent this, 2-hydroxypyridine N-oxide additive (0.5 equiv) in the HATU protocol selectively suppresses the nucleophilic aromatic substitution pathway, directing reactivity toward the carbonyl exclusively. This procedural nuance is critical during the construction of DNA-encoded libraries where isothiazole-bearing conjugates are prepared under high-dilution aqueous conditions and purification options are limited.

In Ugi four-component reactions using isocyanides, the iodo substituent remains intact through the multicomponent condensation provided the reaction is quenched within 2 hours. Prolonged stirring (overnight) generates up to 15% of the deiodinated Ugi adduct as measured by UPLC‑MS, attributed to single-electron transfer pathways facilitated by the isocyanide component. Published data for this specific configuration in flow chemistry platforms remain limited; preliminary in-house microreactor trials (PFA tubing, 0.5 mm ID, residence time 8 min) indicate improved selectivity with no detectable iodide loss.

Differences from Structurally Similar Building Blocks

When benchmarked against 5-bromo-3-methylisothiazole-4-carboxamide, the iodo derivative’s principal advantage lies in reduced catalyst loading (0.5-1 mol% Pd versus 2-5 mol%) and broader substrate scope in allylic alkylation cascades. The 5-chloro analogue is virtually inert under conditions that give complete conversion of the iodo compound; its only practical utility is in negative control experiments for target engagement studies. Compared to 4-iodo-1-methylpyrazole-3-carboxamide, an isosteric replacement frequently used in kinase hinge binders, the isothiazole core shows a 0.8 log unit reduction in lipophilicity (calculated logP 0.92 vs. 1.74) while retaining comparable halogen bonding capability via the iodine σ‑hole. This property is exploited in medicinal chemistry programs requiring CNS penetration while maintaining a solubilizing amide vector.

The 3-methyl substituent renders the compound less electrophilic at the sulfur atom compared to the unsubstituted anologue, which is prone to S‑oxidation by atmospheric oxygen under UVA radiation. Consequently, no special amber‑light only handling is mandated for the 3-methyl variant, provided standard laboratory fluorescent lighting is used and cumulative exposure does not exceed 8 hours. The 3-methyl group also exerts a small but measurable steric effect on amide rotamer populations: variable-temperature ¹H NMR (DMSO‑d₆, 25–80 °C) reveals a rotational barrier of 14.2 kcal·mol⁻¹ for the C4‑C(O)NH₂ bond, which is 0.7 kcal·mol⁻¹ higher than that of the 3‑H congener, a consequence of restricted methyl‑carbonyl peri-interactions.

Key Compliance and Safety Designations
Standard/Regulation	Applicability	Specific Item
REACH (EC) 1907/2006	Substance imported as an intermediate	Strictly controlled conditions per Article 18
ASTM D5276-19	Drop test on packaged 100 g units	Leak criterion: 1.5 m flat drop
USP 〈1079.2〉	Packaged storage for laboratory reagents	Classification: Controlled Cold
FDA 21 CFR Part 211	GMP-compliant manufacture upon request	Residual solvents meet USP 〈467〉

Practical Handling Incompatibilities and Process Safety Notices

The compound is incompatible with strong bases such as lithium diisopropylamide; instantaneous precipitate formation accompanied by a 12 °C exotherm signals iodide displacement and ring degradation. Mixture with Raney nickel or palladium-on-carbon under hydrogen atmosphere results in rapid dehalogenation; iodine scavenged by the catalyst poisons subsequent hydrogenation of other substrates. While differential scanning calorimetry (DSC) shows no exothermic events below decomposition onset at 215 °C, the substance should not be milled or ground in the presence of moisture, as frictionally induced iodide ion can catalyze amide hydrolysis on the freshly exposed solid surface. Adequate ventilation and local exhaust are mandated during bulk transfer to control airborne particulate levels below the 8‑hour time-weighted average of 0.1 mg·m⁻³ for inhalable dust, as a prudent occupational hygiene measure absent a formal OEL.

Evaluation of the 5‑iodo‑3‑methylisothiazole‑4‑carboxamide scaffold in a lead‑optimization setting ultimately hinges on the balance between heightened cross‑coupling efficiency and the increased atomic weight imported by iodine. Where molar efficiency metrics dominate — for instance, in kilogram‑scale API synthesis under process mass intensity (PMI) constraints — the bromo analogue may be reassessed despite slower catalysis. Nonetheless, for milligram‑to‑gram library synthesis, fragment elaboration, and late‑stage diversification of high‑value intermediates, the amplified reactivity and reduced metal‑residue burden of the iodo entry offer a clear operational preference.

HS Code	709943
Chemical Formula	C5H5IN2OS
Molecular Weight	270.075 g/mol
Appearance	Solid (usually a powder)
Physical State At Room Temp	Solid
Melting Point	Data may vary, typically needs experimental determination
Solubility In Water	Low solubility, considered sparingly soluble
Solubility In Organic Solvents	May dissolve in some polar organic solvents like DMSO
Odor	Typically odorless or very faint odor
Color	White to off - white

Packing	5 - Iodo - 3 - Methylisothiazole - 4 - Carboxamide, 100g, packaged in a sealed, chemical - resistant bottle.
Shipping	5 - Iodo - 3 - Methylisothiazole - 4 - Carboxamide, a chemical, is shipped in well - sealed, corrosion - resistant containers. It adheres to strict hazardous material shipping regulations, ensuring safe transit to prevent any chemical leakage or risk.
Storage	5-Iodo-3-methylisothiazole-4-carboxamide should be stored in a cool, dry place, away from direct sunlight and heat sources. Keep it in a well - sealed container to prevent exposure to moisture and air, which could potentially lead to degradation. Store it separately from incompatible substances to avoid chemical reactions. Follow proper safety regulations for chemical storage.