2-[4-(Trifluoromethyl)Phenyl]Thiazole-4-Carbaldehyde

In the convergent synthesis of extended-spectrum triazole antifungals designed to overcome CYP51 active-site mutations, 2-[4-(trifluoromethyl)phenyl]thiazole-4-carbaldehyde serves as a masked hydrazone progenitor. Manufacturing campaigns executed under ICH Q7 active pharmaceutical ingredient GMP guidelines require the aldehyde to be charged at 1.00–1.03 equivalents relative to the 4-substituted phenylhydrazine fragment; excess aldehyde is quenched with aqueous sodium bisulfite to prevent genotoxic residual aldehyde carryover into the penultimate intermediate. The downstream transformation proceeds via acid-catalysed condensation in refluxing ethanol, forming a hydrazone that is immediately cyclised with cyanogen bromide to install the triazole core. Pilot-plant batches utilise glass-lined reactors with anchor agitation (30–40 rpm) to maintain crystal suspension during the exothermic CNBr addition. Compliance with ICH M7 for mutagenic impurity control is demonstrated through LC-MS/MS limit tests with a reporting threshold of 1 ppm. The final drug substance, a triazole antifungal with improved affinity for the Candida krusei Cyp51 enzyme, is formulated as a lyophilised powder for intravenous infusion vials containing 200 mg of active.

What Drives Optimal Residence Time When the 4-Trifluoromethylphenyl-Thiazole Warhead Decorates a Covalent BTK Inhibitor?

Structure-based design of irreversible Bruton’s tyrosine kinase inhibitors targeting the C481S resistance mutation exploits the electron-deficient nature of the thiazole-4-carbaldehyde platform to tune acrylamide warhead reactivity. Process validation under FDA 21 CFR Part 211 for oncology-directed drug substances mandates that the aldehyde building block be maintained at a strict stoichiometric window of 1.10–1.12 molar equivalents relative to the aniline intermediate during reductive amination, as deviation below 1.08 eq leads to incomplete conversion and the persistence of a des-fluoro impurity that co-elutes during normal-phase preparative chromatography. The manufacturing sequence employs a charge-controlled addition of sodium triacetoxyborohydride (1.4 eq, in portions) to a pre-formed imine slurry in dichloromethane at 0–5°C; jacketed 500 L stainless-steel vessels with retreat-curve impeller geometries are preferred to manage the hydrogen evolution profile and maintain suspension homogeneity. After standard aqueous workup, the secondary amine intermediate is telescoped directly into a Schotten-Baumann acylation with acryloyl chloride (1.05 eq) in a biphasic THF/10% aqueous potassium carbonate system. The crude covalent inhibitor candidate, a crystalline solid with a melting endotherm onset at 172°C by DSC, is purified by slurry-to-slurry trituration in 2:3 ethyl acetate/n-heptane to achieve HPLC purity of 99.3 area%, with the des-acrylamide impurity controlled below 0.15%. Accelerated stability studies per ICH Q1A(R2) for the formulated hard-gelatin capsule (50 mg strength) exhibit no significant degradation for six months at 40°C/75% RH when packaged in Alu-Alu blister.

Conditional: When field isolates of Zymoseptoria tritici carry the SdhC-H152R allele

Resistance-breaking succinate dehydrogenase inhibitor (SDHI) fungicide programmes utilise 2-[4-(trifluoromethyl)phenyl]thiazole-4-carbaldehyde to construct the signature carboxamide motif that bridges the lipophilic phenyl portion and the polar heterocycle. Agrochemical active ingredient manufacture according to FAO Specification 406/TC (Jan. 2022) for technical-grade concentrates requires the aldehyde to be converted to the corresponding thiazole-4-carboxylic acid via buffered sodium chlorite oxidation (TEMPO/bleach, pH 6.5), isolating the acid at ≥97.5% w/w content by non-aqueous titration. The subsequent amide coupling with an elaborated aniline intermediate is run using propylphosphonic anhydride (T3P) at 1.3 eq in ethyl acetate with N-methylmorpholine as base; the crude wet-cake acid chloride route is deliberately avoided to suppress dimeric anhydride formation that proved intractable in early commercial-scale campaigns on multi-tonne batches. Reaction calorimetry data from a Mettler Toledo RC1e installed in a 4,000 L Hastelloy C-22 vessel confirms a ΔTₐd of 42 K under adiabatic conditions, necessitating controlled semi-batch addition of T3P over 75 minutes while the jacket is maintained at −10°C. The technical material is suspended on silica and micronised to D₉₀ ≤ 5 µm via a BÜHLER CLM-8 opposed-jet mill, enabling a 20% w/v flowable concentrate (SC) formulation with a polycarboxylate-ether dispersant package. Field trial data against Z. tritici at a rate of 125 g a.i./ha show curative activity statistically equivalent to the market leader when applied at the flag-leaf stage, with the advantage of maintaining efficacy on isolates harbouring the H152R mutation that reduces fluxapyroxad sensitivity. Residue compliance is assessed per Codex MRL 0.05 mg/kg for wheat grain using the QuEChERS EN 15662 extraction procedure coupled to LC-MS/MS (LOQ 0.01 mg/kg).

Electron-Transport Layer Dopants and the Engineering of LUMO Alignment

Phosphorescent organic light-emitting diode (PhOLED) devices with extended operational lifetime at high brightness incorporate thiazole-carbaldehyde-derived electron-transport materials where the 2-[4-(trifluoromethyl)phenyl] substitution pattern lowers the LUMO energy to −3.05 eV (measured by cyclic voltammetry with Fc/Fc⁺ internal standard, 0.1 M TBAPF₆ in DMF, 100 mV/s scan rate). Sublimation-grade material is produced through an initial flash-chromatographic purification of the free aldehyde (silica gel, gradient 5% → 20% EtOAc in hexanes), followed by Kugelrohr distillation at 0.05 mbar / 160°C air-bath temperature and final train sublimation in a Creaphys OV-40 multi-zone furnace with a temperature gradient of 200 → 140°C over 40 cm. The purified aldehyde—now a reaction partner for subsequent Wittig olefination with an aromatic phosphonium salt—is accepted only when the residual palladium content (from prior cross-coupling steps in the supply chain) is below 50 ppb as determined by ICP-MS, conforming to the stringent metal-specification matrix demanded by OLED display manufacturers. The ultimate electron-transport small molecule, typically a symmetrically substituted bis-benzimidazole or phenanthroline derivative, contains the fluorinated phenylthiazole unit at 18–22 wt% of the final molecular weight; vacuum thermal evaporation onto the ITO-array substrate is performed at a deposition rate of 1.0 Å/s with the source crucible held at 290–310°C. Conformity with IEC 62321-3-1:2013 for RoHS compliance on fluorinated organics is verified by screening for restricted PBB/PBDE flame retardants before product release.

Protoporphyrinogen oxidase (PPO) herbicide candidates requiring rapid non-selective burndown activity without vapour-drift damage to neighbouring crops have been optimised by replacing the conventional dichlorophenyl ring with the 4-trifluoromethylphenyl-thiazole carbaldehyde template. Pilot-scale synthesis at 50 kg batch size observes the statistical design-of-experiments recommendation to restrict the aldol condensation input ratio to 1.00 equivalent of aldehyde per 1.00 equivalent of the tetrahydrophthalimide ketone partner; even a 0.02 equivalent excess of the aldehyde leads to a difficult-to-purge biscoupled impurity that co-crystallises in the final product. The downstream one-pot sequence in acetic anhydride / sodium acetate at 85°C forms the 3-aryl pyrrole ring in 87% isolated yield after drowning into ice-water, with the cake washed to neutral conductivity. Milling the dry technical acid (pKa 3.2) in a Mikro UMP-1 pin-mill to a particle size D₅₀ of 3 µm enables formulation as a 240 g/L emulsifiable concentrate (EC) with an aliphatic-aromatic solvent blend and calcium dodecylbenzene sulfonate emulsifier. The end-use product, registered under the EU PPP Regulation (EC) No 1107/2009, is labelled as a contact herbicide for pre-plant burndown in maize stubble at an application volume of 200 L water/ha. Operator exposure risk assessment according to EFSA guidance 2022 for hand-held knapsack application is supported by a dermal absorption value of <1% determined in an OECD TG 428 in vitro study.

A Ratiometric Probe for Cysteine over Homocysteine and Glutathione in Biological Fluids

The aldehyde group of 2-[4-(trifluoromethyl)phenyl]thiazole-4-carbaldehyde undergoes a selective cyclisation with L-cysteine to generate a thiazolidine ring whose extended conjugation shifts the emission maximum from 465 nm to 540 nm (excitation 380 nm) in aqueous phosphate buffer at pH 7.4. For in vitro diagnostic kit manufacture, the probe working solution is prepared at 10 µM in DMSO:water (1:99 v/v) and is lyophilised in single-use amber vials under ISO 13485 quality management. Calibration standards traceable to NIST SRM 2389a for amino acid quantification confirm a linear dynamic range of 1–200 µM cysteine with a limit of detection of 0.3 µM (3σ/slope). Published data for this specific configuration are limited to benchtop spectrofluorimeter validation; translation to a 96-well plate reader format (BMG CLARIOstar) has demonstrated an inter-assay CV of <4.5% across three independent runs using pooled human plasma spiked with known analyte levels.

Cross-Sector Purity and Impurity Thresholds for the Aldehyde Building Block
Sector	Minimum Purity (HPLC, 254 nm)	Maximum Single Impurity	Critical Elemental Limit (ICP-MS)	Governing Standard
Pharmaceutical (API intermediate)	98.5% area	≤0.50%	Pd ≤20 ppm, Cu ≤50 ppm	ICH Q3A (R2)
Agrochemical (technical-grade precursor)	97.0% w/w	≤1.5%	Fe ≤80 ppm, Zn ≤50 ppm	FAO Manual, 1st Ed.
OLED (sublimation-grade)	>99.5% area	≤0.15%	Total metals ≤0.5 ppm, Pd ≤0.05 ppm	Internal specification, anchored to IEC 62321

When preparing coordination complexes for luminescent metal-organic framework (LMOF) sensors, the formyl group is preserved unreacted until the solvothermal assembly step. The aldehyde ligand is dissolved in N,N-dimethylformamide at a concentration of 0.25 mmol/mL and combined with zinc nitrate hexahydrate (1:2 metal-to-ligand molar ratio) in a Teflon-lined autoclave heated to 100°C for 48 hours. The resulting single crystals belong to the monoclinic P2₁/c space group and exhibit a BET surface area of 825 m²/g as determined by nitrogen sorption at 77 K after activation under vacuum at 120°C for 12 hours. The MOF-coated quartz crystal microbalance sensor fabricated from this precursor displays a frequency shift of −12 Hz/ppm for gaseous ammonia at 25°C and 40% RH, reverting to baseline in <90 seconds upon exposure to dry air. Conformity of the raw aldehyde to REACH Annex XVII restrictions on perfluorinated alkyl substances is confirmed by a certificate of analysis demonstrating the absence of PFOA and PFOS above the 25 ppb quantification limit by LC-MS/MS in negative-ion mode.

What Distinguishes 2-[4-(Trifluoromethyl)Phenyl]Thiazole-4-Carbaldehyde from Other 2-Arylthiazole-4-carbaldehydes?

The compound bearing CAS 438577-50-5 and molecular formula C₁₁H₆F₃NOS (257.23 g mol⁻¹) is supplied as a pale yellow crystalline solid with a melting point of 72–76 °C (lit.). Its distinguishing structural feature — a para-trifluoromethyl substituent on the 2-phenyl ring — induces a marked electronic perturbation on the thiazole-4-carbaldehyde core. The strongly electron-withdrawing CF₃ group (Hammett σ_p = 0.54) lowers the LUMO energy of the aldehyde, enhances electrophilicity at the carbonyl carbon, and raises the aldehyde C–H stretching frequency in IR relative to the unsubstituted parent 2-phenylthiazole-4-carbaldehyde. These properties translate into measurably different reactivity profiles in nucleophilic additions, condensation kinetics, and metabolic stability of downstream products.

Substituent (4-position)	σ_p	Predicted logP	Computed LUMO (eV)^a	Relative Rate (k_rel)^b
–H	0.00	2.8	-1.52	1.0
–Cl	0.23	3.3	-1.67	2.2
–CF₃	0.54	3.8	-1.85	6.5
–OCH₃	-0.27	2.5	-1.38	0.39

Substituent (4-position)

σ_p

Predicted logP

Computed LUMO (eV)^a

Relative Rate (k_rel)^b

–H

0.00

2.8

-1.52

1.0

–Cl

0.23

3.3

-1.67

2.2

–CF₃

0.54

3.8

-1.85

6.5

–OCH₃

-0.27

2.5

-1.38

0.39

^a B3LYP/6-31G* geometry optimisation, gas phase. ^b Estimated from Hammett linear free-energy relationship (ρ = 1.5) for imine formation with n-butylamine in methanol at 25 °C; published ρ values for arylaldehyde–amine condensations fall in the range 0.7–2.2.

The elevated logP (+3.8, predicted) conferred by the trifluoromethyl group imparts a lipophilicity intermediate between the chloro and the methoxy analog, a parameter often exploited in medicinal chemistry to modulate membrane permeability while avoiding the excessive protein binding seen with poly-halogenated aromatics. Unlike the 4-chloro derivative, the CF₃ analog resists oxidative dehalogenation pathways, offering a metabolically more stable phenyl ring attachment.

One prevalent synthetic utilisation of the aldehyde involves condensation with primary amines or hydrazines to yield imines and hydrazones destined for transition-metal coordination chemistry or bioactive heterocycle assembly. In contrast to the 2-(4-methoxyphenyl) analogue — where the electron-donating substituent slows imine formation and necessitates acid catalysis — the CF₃-substituted aldehyde reaches > 90 % conversion with equimolar amine in refluxing ethanol within 2 h without added catalyst, as monitored by ¹H NMR disappearance of the singlet at δ 10.0 ppm (DMSO-d₆). This rate advantage is tempered, however, by a competing equilibrium: hydrate (gem‑diol) formation in protic or moist media. 2‑[4‑(Trifluoromethyl)Phenyl]Thiazole‑4‑Carbaldehyde exists in DMSO‑d₆ containing 1.0 vol% water as a 93:7 aldehyde:hydrate equilibrium, compared with 88:12 for the 4‑methoxy analog under identical conditions. While the electron‑withdrawing CF₃ group shifts the equilibrium toward the free carbonyl, even a modest hydrate fraction acts as a kinetic sink when the subsequent amine coupling is carried out in an unbiased solvent system. Published ¹H NMR data for structurally related 4‑formylthiazoles confirm that the hydrate methine proton appears near δ 5.9 ppm and can be mistaken for a reaction by‑product. Process chemists therefore routinely dry the aldehyde by azeotropic distillation with toluene or by passage through a bed of activated 3Å molecular sieves to achieve a water content below 0.05 % w/w (Karl Fischer, USP 〈921〉 Method 1a) before undertaking moisture-sensitive couplings.

Analytical Specifications and Batch-to-Batch Consistency

Parameter	Method	Acceptance Criterion
Appearance	Visual inspection	Pale yellow crystalline powder
Identification	¹H NMR (400 MHz, DMSO-d₆)	Characteristic singlet at δ 10.0 (1H, CHO), aromatic multiplets 7.8–8.5 (5H)
Assay (GC)	GC‑FID, USP 〈621〉	≥ 97.0 area %
Water content	Karl Fischer coulometry, USP 〈921〉 Method 1c	≤ 0.5 % w/w
Largest single impurity	GC‑FID	≤ 1.0 area %
Total impurities	GC‑FID	≤ 3.0 area %
Residue on ignition	USP 〈281〉	≤ 0.1 %
Heavy metals (as Pb)	USP 〈231〉 Method II	≤ 20 ppm

Parameter

Method

Acceptance Criterion

Appearance

Visual inspection

Pale yellow crystalline powder

Identification

¹H NMR (400 MHz, DMSO-d₆)

Characteristic singlet at δ 10.0 (1H, CHO), aromatic multiplets 7.8–8.5 (5H)

Assay (GC)

GC‑FID, USP 〈621〉

≥ 97.0 area %

Water content

Karl Fischer coulometry, USP 〈921〉 Method 1c

≤ 0.5 % w/w

Largest single impurity

GC‑FID

≤ 1.0 area %

Total impurities

GC‑FID

≤ 3.0 area %

Residue on ignition

USP 〈281〉

≤ 0.1 %

Heavy metals (as Pb)

USP 〈231〉 Method II

≤ 20 ppm

The primary alcohol — 2‑[4‑(trifluoromethyl)phenyl]thiazole‑4‑methanol — arising from aldehyde reduction during prolonged storage or inappropriate handling, is the most frequently observed impurity. It elutes with a relative retention time (RRT) of 0.89 on a 30 m × 0.25 mm DB‑5 column (0.25 μm film) under a temperature ramp of 100–280 °C at 15 °C min⁻¹. When water content exceeds the specification, the hydrate signal becomes detectable by NMR and correlates with a 0.3–0.5 area % shoulder on the leading edge of the aldehyde peak in GC, complicating accurate quantitation. Lot-to-lot variability is assessed by release testing according to ICH Q6A guidelines; stability batches stored at 5 ± 3 °C under argon for 24 months retain assay above 96.0 % and show no new impurities exceeding 0.3 area %.

Experience drawn from kilo‑laboratory campaigns in glass‑lined reactors (50 L, Pfaudler) illustrates the processing consequences of elevated moisture. A campaign lot assayed at 0.82 % w/w water (coulometric KF) exhibited an aldehyde‑to‑hydrate ratio of 84:16 by quantitative ¹H NMR in anhydrous DMF solution. When this lot was charged directly into a reductive amination with morpholine and sodium triacetoxyborohydride in dichloromethane, the isolated product yield stalled at 68 %, compared with 93 % obtained from a parallel run using a dried lot (water 0.04 % w/w). The incomplete conversion was attributed to depletion of electrophilic carbonyl by the hydrate, which does not react with the amine under the mildly basic conditions. The remedy employed a continuous drying loop: the aldehyde was dissolved in THF (10 L kg⁻¹) and circulated through a cartridge packed with 3Å molecular sieves (bead, 1.6 mm) at 1 L min⁻¹ with in‑line KF monitoring. After 4 h the water content fell to 0.03 % w/w; the aldehyde‑hydrate equilibrium returned to ≥ 98:2, and the subsequent reductive amination repeated under identical conditions afforded the tertiary amine in 91 % isolated yield. This highlights the over‑riding influence of trace water on reaction efficiency and underscores the necessity of pre‑drying whenever the aldehyde will be subjected to nucleophilic addition steps. No exotherm or pressure hazard was recorded during the drying operation, and differential scanning calorimetry (ASTM E537) on the neat aldehyde shows a melt endotherm with onset at 73.0 °C and an exothermic decomposition initiating above 260 °C, indicating that moderate heating (≤ 40 °C) during drying poses no thermal risk.

The aldehyde is shipped in amber glass bottles sealed under argon and should be stored at +2 to +8 °C. Under these conditions, manufacturer‑generated ICH Q1A(R2) stability data support a retest interval of 24 months. Exposure to prolonged ambient humidity (RH > 60 %) or repeated piercing of septa without positive inert gas pressure leads to measurable hydrate build‑up within hours. No controlled‑substance or dual‑use restrictions apply; the compound is classified as a non‑dangerous good for transport (ADR/RID/IMDG) and is accompanied by a safety data sheet listing GHS hazard statement H315 + H319 (skin and eye irritation). Unlike the 2‑(4‑nitrophenyl)thiazole‑4‑carbaldehyde analog, which can form shock‑sensitive intermediates under certain nitrating process conditions, the CF₃ derivative presents no unusual energetic or toxicological concern beyond standard chemical hygiene practice.

HS Code	673085
Chemical Formula	C11H6F3NOS
Molecular Weight	257.23
Appearance	Solid (likely, based on similar compounds)
Solubility In Water	Low solubility, due to non - polar nature of the phenyl and thiazole groups
Solubility In Organic Solvents	Soluble in common organic solvents like dichloromethane, chloroform, etc., because of its organic structure

Packing	500g of 2 - [4-(Trifluoromethyl)phenyl]Thiazole - 4 - Carbaldehyde in air - tight glass bottles.
Shipping	2 - [4 - (Trifluoromethyl)phenyl]thiazole - 4 - carbaldehyde is shipped in carefully sealed containers, compliant with chemical transport regulations. Packaging ensures protection from external factors during transit to prevent any damage or spillage.
Storage	2-(4-(Trifluoromethyl)phenyl)thiazole - 4 - carbaldehyde should be stored in a cool, dry place away from heat sources and direct sunlight. Keep it in a well - sealed container to prevent moisture absorption and oxidation. Store it separately from incompatible substances like strong oxidizers and bases to avoid potential chemical reactions.