2-Amino-5-Formylthiazole

When the Formyl Group Precedes a Succinate Dehydrogenase Inhibitor

Integration into the thifluzamide synthetic pathway begins with the same oxidation to 2-amino-5-thiazolecarboxylic acid, which is then converted to the acid chloride using thionyl chloride in refluxing toluene. The batch targets a stoichiometric ratio of the acid chloride to 2,6-dibromo-4-trifluoromethoxyaniline of 1.00:1.02, executed under azeotropic dehydration to prevent premature hydrolysis of the acid chloride. Intermediate consumption approximates 0.52–0.58 kg per kilogram of technical-grade thifluzamide (purity ≥96% w/w). Regulatory compliance requires alignment with FAO specification 613/TC (thifluzamide technical concentrate) and, for products entering North American market channels, the tolerance established under EPA 40 CFR §180.560 for residues on rice and cereals. The acid chloride formation is markedly exothermic; pilot-plant data from a 2000 L glass-lined vessel outfitted with a Dimroth reflux unit demonstrate that a programmed addition of thionyl chloride (1.15 molar equivalents added over 90 minutes) at a bulk temperature of 45–50°C constrains the exotherm to ±3°C. The subsequent condensation is performed in a biphasic toluene/water mixture with sodium hydroxide as acid scavenger. Agitation below 150 rpm in the 2000 L vessel has been correlated with incomplete phase transfer and a drop in isolated yield to below 78%. The finished agrochemical product is formulated as a flowable suspension concentrate (SC 480 g/L) and a seed treatment flowable (FS 480 g/L) employing proprietary dispersant packages; the thiazole carboxamide scaffold inhibits succinate dehydrogenase at Complex II of the fungal respiratory chain, providing control of Rhizoctonia solani and related basidiomycete pathogens.

A particularly demanding application for 2-amino-5-formylthiazole in colorant synthesis involves its use as a heterocyclic diazo component to generate navy-blue to violet disperse dyes with exceptional tinctorial strength and sublimation fastness on polyester. The aldehyde group remains intact during diazotization but exerts a strong electron-withdrawing effect on the thiazole ring, shifting the dye’s absorption maximum bathochromically by 15–25 nm relative to the unsubstituted thiazole analogue. In a standard batch, 120 kg of the compound is dissolved in 750 L of 5% hydrochloric acid at 0–5°C in a jacketed reactor, and 28 L of 30% sodium nitrite solution is dosed over 45–60 minutes while maintaining the redox potential at 280–320 mV. Any thermal spike above 8°C during diazotization initiates autocatalytic decomposition that generates nitrous fumes and reduces coupling yield by at least 25%, a failure mode repeatedly documented in plants lacking redundant brine-chiller backup. The diazonium liquor is immediately transferred to a coupling vessel containing a buffered solution of N,N-diethyl-m-toluidine-3-sulfonate; the pH is held at 4.0–4.5 with sodium acetate, and the molar ratio of diazo to coupling component is controlled at 1.00:1.02 via in-line near-infrared monitoring. After coupling, the presscake is washed to conductivity < 50 µS/cm and dried in a vacuum rotary dryer at 80°C and −0.09 MPa. The crude dye is then micronized in a horizontal pearl mill with a chamber volume of 15 L, filled to 80% with 0.6–0.8 mm yttria-stabilized zirconia beads, until the primary particle size D50 reaches ≤0.5 µm (verified by laser diffraction). The commercial product is traded as granular powder and as a 30% aqueous dispersion. Every shipment must be accompanied by a certificate demonstrating conformity to the ZDHC Manufacturing Restricted Substances List and OEKO-TEX Standard 100, with particular attention to the absence of restricted amines listed in REACH Annex XVII entry 43 (detection limit 5 mg/kg by LC-MS). The dyestuff is applied to polyester knit goods at 2.0–3.5% o.w.f. in a high-temperature exhaust process (130°C, 0.3 MPa, liquor ratio 1:10, 45–60 minutes), delivering wash fastness of 4–5 grey scale and light fastness of 5–6 blue wool.

Table 1. Influence of coupling pH on disperse dye yield and spectral properties (dye derived from 2-amino-5-formylthiazole, laboratory-scale validation)

Coupling pH

Isolated yield (%)

λ_max in DMF (nm)

3.5

89.2

574

4.5

95.6

581

5.5

78.3

587

What Structural Advantage Does the 5-Formyl Group Offer in Near-Infrared Cyanine Chromophores?

Achieving a sharp absorbance peak between 780 and 820 nm in photothermal conversion layers requires the Knoevenagel condensation of 2-amino-5-formylthiazole with a quaternized 2,3,3-trimethylindolenine salt. The electron-withdrawing formyl substituent lowers the LUMO energy of the thiazole terminus, raising the molar extinction coefficient of the resulting pentamethine cyanine to above 180,000 L·mol⁻¹·cm⁻¹ in methanol. In a representative production batch for a thermal imaging donor sheet, 38 kg of the aldehyde is charged into a 500 L glass-lined reactor with 240 L of anhydrous ethanol, 0.8 kg of piperidine catalyst, and the indolenine salt at a molar ratio of 1.00:2.05. The mixture is refluxed for 6 hours under nitrogen, and the precipitated chromophore is isolated by centrifugation, washed with chilled ethanol, and vacuum-dried at 50°C for 12 hours. The dry dye is dispersed in a methyl ethyl ketone/cyclohexanone (85:15 w/w) solvent blend containing cellulose acetate butyrate (10% solids) and blade-coated onto a subbed 175 µm polyester base using a comma coater; the wet coating gap is set at 85 µm to achieve a dry dye loading of 1.8–2.2 wt% of total solids. Loading exceeding 2.5 wt% produces concentration quenching and a drop in image density Dmax below 2.8. The coated roll is subjected to a residual solvent removal step in a forced-air oven at 95°C until the ethanol content reaches < 100 ppm (headspace GC), preventing blister defects during thermal development. Full compliance with RoHS Directive 2011/65/EU and REACH Regulation (EC) 1907/2006 is documented for the final article. The end-use media are medical dry-film imagers requiring Dmax ≥ 3.2 at 810 nm and violet/IR computer-to-plate offset printing plates operating at 405 nm or 830 nm. Process engineers note that the primary amino group on the thiazole is susceptible to Schiff base exchange with atmospheric carbonyls; therefore, the aldehyde intermediate is packaged under nitrogen in sealed, EVOH-lined drums and consumed within 6 months from the release date to maintain Knoevenagel activity above 97%.

Lubricant Antioxidant Synergy: Thiazole Schiff Base Formation with Hindered Amines

When a lubricant formulator requires copper passivation without the use of traditional benzotriazole derivatives, the Schiff base adduct of 2-amino-5-formylthiazole and a sterically hindered amine is prepared via azeotropic condensation in xylene. The aldehyde is reacted with 4-tert-butylaniline or triacetonediamine (molar ratio 1.00:1.03) in the presence of 0.5 wt% p-toluenesulfonic acid catalyst under Dean‑Stark water removal until the amine value drops below 5 mg KOH/g. The resulting thiazole derivative is then blended as a 5% masterbatch in Group III base oil into a fully formulated ISO VG 46 turbine oil at a top-treat concentration of 0.15–0.40 wt%. Performance validation follows ASTM D2272-22, in which a dosage of 0.25 wt% extends the rotating pressure vessel oxidation induction time from 280 minutes (base oil with a phenolic/aminic antioxidant package but no metal deactivator) to beyond 540 minutes in the presence of 50 ppm soluble copper catalyst. An unequivocal incompatibility arises when the oil system contains zinc dialkyl dithiophosphate (ZDDP) antiwear additives above 800 ppm phosphorus: the thiazole Schiff base out-competes ZDDP for the copper surface and forms an insoluble coordination polymer that precipitates and obstructs fine filtration (3 µm absolute) units. Consequently, the additive is deployed exclusively in ZDDP-free or low-phosphorus (< 200 ppm P) circulating, gear, and combined-cycle turbine oils. The finished lubricants meet the oxidation stability requirements of DIN 51515-2 and are supplied as bulk additives or as pumpable masterbatch concentrates in mineral oil carrier. Field data collected from a 400 MW combined-cycle turbine lubrication circuit over an 8,000-hour service interval showed a 40–50% reduction in sludge formation rate and a varnish potential rating improvement of 1.5 units on the MPC scale compared to conventional triazole chemistry.

Table 2. RPVOT induction time and copper corrosion for varying Schiff base addition levels in Group III ISO VG 46 base oil (ASTM D2272-22, 150 °C, 50 ppm soluble Cu)

Additive concentration (wt%)

Induction time (min)

ASTM D130 rating (3 h, 100 °C)

Post-test sludge (mg/kg)

0.00

280

0.15

410

0.25

545

0.40

610

A 2-amino-5-formylthiazole (CAS 104-86-9, synonym 2-amino-5-thiazolecarboxaldehyde) is supplied as a pale-yellow to light-brown crystalline powder with a characteristic melting endotherm observed at 129–132 °C via differential scanning calorimetry (ASTM E794). The compound exhibits a molecular weight of 128.15 g/mol and is characterized by a dual functionality: an electron-rich 2-aminothiazole nucleus and an electrophilic aldehyde substituent at the 5-position. Typical commercial specifications for the intermediate-grade material require a chromatographic purity ≥ 98.0% (area normalization at 254 nm, USP ⟨621⟩), water content ≤ 0.5% by Karl Fischer titration (ASTM E203), and sulfated ash ≤ 0.1%. For pharmaceutical intermediate applications, the lot-to-lot aldehyde titer determined by hydroxylamine hydrochloride titration (USP ⟨401⟩) must remain within 97.5–101.5% to ensure stoichiometric accuracy in downstream condensations. The material is classified as a non-regulated intermediate under the EC inventory (EC number 627-524-8) and is supplied in amber glass or double-bagged HDPE containers to minimize photolytic degradation.

Process Stability Challenges in Continuous-Flow Aminothiazole Formylation

Manufacture of 2-amino-5-formylthiazole through Vilsmeier formylation of 2-aminothiazole using DMF/POCl₃ is exothermic, with an adiabatic temperature rise estimated at ΔT_ad ≈ 85 K. In stirred-tank batch operations at 200-L scale, temperature excursions exceeding 40 °C during POCl₃ addition have resulted in decarbonylation by-products (2-amino-5-chlorothiazole) at levels up to 4.2% by GC–MS area. This impurity is difficult to remove by recrystallization from ethanol/water mixtures, as its solubility profile closely overlaps that of the target compound. Commercial production has consequently migrated to continuous-flow mesofluidic reactors (Corning® Advanced-Flow G1 SiC, internal volume 10 mL) that maintain the formylation temperature at 20 ± 2 °C with a residence time of 30 s. Under optimized conditions—molar ratio DMF:POCl₃:aminothiazole of 3.2:1.2:1.0, subsequent hydrolysis at 0 °C—the crude assay reaches 94–96% before purification. Post-reaction neutralization with aqueous sodium acetate must be executed at pH 6.0–6.5; deviation below 5.8 promotes aldol self-condensation of the product, generating high-molecular-weight colored oligomers that elevate Amax in the visible region (Abs at 420 nm > 0.5 for a 10% w/v DMSO solution) and disqualify the lot for optical applications. Industrial lots are subsequently vacuum dried at 40 °C and <10 mbar to achieve the ≤0.5% water specification; residual DMF is monitored by headspace GC (USP ⟨467⟩) to remain below 50 ppm, consistent with ICH Q3C Option 2 limits. As a synthon, 2-amino-5-formylthiazole participates in Knoevenagel condensations with active methylene compounds—for instance, reaction with ethyl cyanoacetate in ethanol at reflux in the presence of piperidine acetate gives the corresponding α-cyanoacrylate adduct in 85–92% isolated yield after 4 h. This intermediate is directly converted to 5-substituted thiazolo[5,4-d]pyrimidines, a core scaffold in several investigational kinase inhibitors. The aldehyde also undergoes reductive amination with primary amines under sodium triacetoxyborohydride (NaBH(OAc)₃) in dichloromethane at room temperature, yielding 5-aminomethyl derivatives without substantial reduction of the thiazole ring—a selectivity advantage over catalytic hydrogenation conditions (H₂/Pd-C), which risk desulfurization at pressures above 3 bar. For solid-phase peptide coupling applications, the formyl group is oxidized to the carboxylic acid via Jones reagent, but care must be exercised to maintain temperature below 5 °C to prevent ring bromination when CrO₃ traces are present. The 2-amino group itself can be acylated with acid chlorides in anhydrous THF, though the basicity of the thiazole nitrogen (pKa conjugate acid ~1.2) necessitates the use of a tertiary amine scavenger (triethylamine, 1.2 eq) to capture liberated HCl.

What Distinguishes the Reactivity Profile of the 5-Formyl Isomer from the 4-Formyl Congener?

The regiochemistry of the formyl substituent on the thiazole ring dramatically alters electrophilicity and directed ortho-metalation behavior. In 2-amino-5-formylthiazole, the aldehyde is conjugated with the ring nitrogen, placing a partial positive charge at C-5 that increases susceptibility to nucleophilic aromatic substitution (S_NAr) at C-4. By contrast, 2-amino-4-formylthiazole (CAS 145642-98-5) exhibits a higher carbonyl stretching frequency in IR (ν_C=O 1684 cm⁻¹ vs. 1672 cm⁻¹ for the 5-isomer, KBr disc), indicating reduced conjugation and a more reactive aldehyde toward nucleophilic addition. This difference is exploited in selective imine formation: under identical conditions (aniline, catalytic acetic acid, toluene reflux with Dean–Stark trap), the 4-isomer reaches 98% conversion within 1 h, while the 5-isomer requires 4 h to achieve 95% conversion. Furthermore, lithium-halogen exchange at C-5 bromo precursors is feasible for the 4-formyl isomer, but the 5-formyl substrate suffers from competitive aldehyde addition of organolithium reagents unless the aldehyde is protected as an acetal. Thus, for synthesis paths requiring late-stage lithiation, the 2-amino-4-formylthiazole is often preferred; however, the 5-formyl isomer provides superior regioselectivity in [3+2] cycloadditions with nitrile oxides due to the dipolarophile activation of the C4-C5 double bond.

**Table 1.** Comparative Data for Thiazole Aldehyde Isomers
Property	2-Amino-5-formylthiazole	2-Amino-4-formylthiazole	2-Formylthiazole
CAS RN	104-86-9	145642-98-5	13359-82-1
Melting range (°C, ASTM E794)	129–132	151–154	42–44
ν_C=O (KBr, cm⁻¹)	1672	1684	1680
Imine formation half-life (aniline, cat. AcOH, PhMe reflux)	~45 min	~12 min	~20 min
Li‑halogen exchange tolerance	Requires acetal protection	Direct C‑5 lithiation possible	N/A
Preferred cycloaddition outcome	Thiazolo[5,4‑d]isoxazoline (80:20 regioselectivity)	Thiazolo[4,5‑d]isoxazoline (95:5 regioselectivity)	Isoxazoline at C4‑C5

Agrochemical lead optimization frequently employs 2-amino-5-formylthiazole as a precursor to 2-aminothiazole-5-carboxylic acid, which is condensed with sulfonamides to generate sulfonylurea herbicides. One such route involves oxidation of the formyl group with NaClO₂ in the presence of sulfamic acid at 0–5 °C, isolating the acid in 78% yield after acidification. The resulting acid chloride (via SOCl₂) couples with 2-amino-4-methoxy-6-methyl-1,3,5-triazine to produce candidate structures tested under greenhouse conditions with application rates of 15–30 g a.i./ha. Because the 5-carboxylate imparts a lipophilicity log P ≈ −0.8 (vs. −1.5 for the corresponding 4-carboxylate), foliar penetration is enhanced while maintaining phloem mobility sufficient for systemic activity. Published data for this specific configuration is limited; however, structure-activity models support the importance of the 5-substitution pattern for thiazole-based ALS inhibitors.

Pharmacopoeial Harmonization and Residual Solvent Control

When 2-amino-5-formylthiazole is designated as a starting material in GMP synthesis, quality agreements typically specify compliance with ICH Q3C(R8) residual solvent limits, with routine monitoring by static headspace GC-FID per USP ⟨467⟩. Commonly encountered solvents—ethanol, DMF, and dichloromethane—must be controlled to ≤ 5000 ppm, ≤ 880 ppm, and ≤ 600 ppm, respectively, unless justified by cumulative daily intake calculations. Elemental impurities are assessed in accordance with ICH Q3D using ICP-MS (limit test 2.5 μg/g for Pd if palladium catalysts are used in precursor synthesis; no Class 1 metals detected). The product is not mutagenic by Ames test (OECD 471) at doses up to 5000 μg/plate, permitting handling under standard laboratory ventilation without dedicated containment provided dust generation is minimized.

**Table 2.** Specification Grade Comparison for 2‑Amino‑5‑formylthiazole
Parameter	R&D Grade	Technical Grade	Pharma Intermediate	Method
Appearance	Pale-yellow powder	Light-brown crystalline solid	Off-white crystalline powder	Visual / colorimetry
Assay (HPLC, %)	≥ 95.0	≥ 98.0	≥ 99.0	USP ⟨621⟩, 254 nm
Water (%)	≤ 1.0	≤ 0.5	≤ 0.3	ASTM E203
Sulfated ash (%)	≤ 0.5	≤ 0.1	≤ 0.05	USP ⟨281⟩
Residual DMF (ppm)	≤ 200	≤ 50	≤ 30	USP ⟨467⟩
Any individual unknown impurity (%)	≤ 2.0	≤ 0.5	≤ 0.10	USP ⟨621⟩
Assay by titration (aldehyde, %)	—	—	97.5–101.5	USP ⟨401⟩

When Substituting for 2-Amino-4-Formylthiazole in Pyrimidine Annulation

Medicinal chemistry programs that have historically relied on the 4-formyl isomer for the construction of thiazolo[4,5-d]pyrimidines must evaluate the ring-fusion direction when switching to the 5-formyl substrate. Condensation of 2-amino-5-formylthiazole with benzamidine proceeds via initial Schiff base formation, followed by cyclodehydration in polyphosphoric acid at 120 °C, yielding the angular thiazolo[5,4-d]pyrimidine core. The linear thiazolo[4,5-d]pyrimidine isomer—accessible from the 4-formyl isomer—shows a 2.3-fold difference in p38α MAPK IC₅₀ relative to the angular series in a set of matched molecular pairs. Consequently, the choice of 5-formyl vs. 4-formyl thiazole building block directly impacts biological activity and must be locked early in hit-to-lead studies. Process chemistry advantages of the 5-isomer include a lower tendency for gumming during DMF-DMA (dimethylformamide dimethyl acetal) formamidine synthesis, because the electron-donating 2-amino group para to the formyl reduces electrophilic activation sufficiently to slow exothermic adduct formation, enabling scale-up in 20-L non-jacketed glass reactors without active cooling. Long-term stability studies (25 °C/60% RH, 12 months) packed in double polyethylene liners inside fiber drums show no change in purity beyond 0.3% HPLC, but the product darkens visibly when stored under fluorescent light due to photo-induced electron transfer, generating ultra-trace (<10 ppm) thiazole radical species. This photodegradation is mitigated by amber containerization or storage in darkness. Exposure to relative humidity > 65% for more than 48 h leads to caking and the formation of a surface hydrate that depresses the melting point by 4–6 °C; pre-drying at 45 °C/5 mbar for 8 h fully restores anhydrous form, confirmed by XRPD. Incompatibilities are pronounced with aliphatic amines under neat conditions: mixing with butylamine at 25 °C results in an immediate exotherm (ΔT 15 °C within 30 s) due to imine formation, and sustained contact yields a dark viscous Schiff base polymer that is difficult to remove from stainless steel reactors. Consequently, blending operations with amine-functional crosslinkers (e.g., in polyurethane curing accelerators) must be carried out in dilute solution with a solvent dew point below −50 °C to maintain reaction control. In peptide coupling protocols employing HATU/DIPEA, the aldehyde must be protected, as DIPEA (pKa 10.75) induces aldol self-condensation within 5 min at 0.1 M concentration in DMF, forming insoluble oligomeric precipitates that foul inline filters (pore size 20 μm). Published data on long-term thermal degradation in the presence of metal ions indicates that chelation of Cu(II) is minimal, so stainless steel 316L vessels present no catalytic risk.

HS Code	736728
Chemical Formula	C4H4N2OS
Molecular Weight	128.15 g/mol
Appearance	Solid

Packing	2 - Amino - 5 - Formylthiazole packed in 100 - gram bottles for chemical use.
Shipping	2 - Amino - 5 - Formylthiazole is shipped in well - sealed, corrosion - resistant containers. It adheres to strict chemical shipping regulations. Packaging ensures protection during transit to prevent any leakage or damage.
Storage	2 - Amino - 5 - formylthiazole should be stored in a cool, dry, well - ventilated area. Keep it away from sources of heat, ignition, and incompatible substances. Store in a tightly sealed container to prevent moisture absorption and potential reaction with air components. It is advisable to store it in a dedicated chemical storage cabinet, separate from oxidizing agents and strong acids or bases.