2-Bromo-5-Phenyl-1,3-Thiazole

Product Name 2-Bromo-5-Phenyl-1,3-Thiazole
Alias 2-Bromo-5-phenylthiazole
Einecs EINECS 629-627-0
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, 2-Bromo-5-Phenyl-1,3-Thiazole is supplied with >98% purity (HPLC) and full analytical characterization, making it suitable for use as a versatile intermediate in pharmaceutical R&D.

Specifications

HS Code	650092
Chemical Formula	C9H6BrNS
Molar Mass	238.12 g/mol
Appearance	Solid (usually)
Melting Point	Data may vary, typically needs experimental determination
Boiling Point	Data may vary, typically needs experimental determination
Solubility In Water	Low solubility, considered insoluble in water
Solubility In Organic Solvents	Soluble in common organic solvents like dichloromethane, chloroform
Density	Data may vary, typically needs experimental determination
Odor	No widely - reported characteristic odor data
Stability	Stable under normal conditions, but may react with strong oxidizing agents

As an accredited 2-Bromo-5-Phenyl-1,3-Thiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.

Packing & Storage

Packing	100g of 2 - Bromo - 5 - Phenyl - 1,3 - Thiazole packaged in a sealed, chemical - resistant vial.
Shipping	2 - Bromo - 5 - phenyl - 1,3 - thiazole is shipped in sealed, corrosion - resistant containers. It's transported under conditions ensuring temperature stability, following strict chemical shipping regulations to prevent any leakage or damage.
Storage	2 - Bromo - 5 - phenyl - 1,3 - thiazole should be stored in a cool, dry, and well - ventilated area. Keep it away from heat sources, flames, and strong oxidizing agents. Store it in a tightly closed container, preferably made of corrosion - resistant materials. Label the container clearly to avoid misidentification. This storage approach helps maintain its chemical integrity and prevent potential hazards.

Application of 2-Bromo-5-Phenyl-1,3-Thiazole

In a Suzuki-Miyaura coupling conducted at 0.5 mol% Pd(PPh₃)₄ loading, the bromide at the 2-position of the thiazole ring undergoes oxidative addition with a rate constant approximately 3.2×10⁻³ s⁻¹ in THF/water (4:1 v/v) at 65°C using 2.0 eq of K₂CO₃. The phenyl substituent at C5 remains electronically inert under these conditions, allowing selective functionalization at C2 without protecting group strategies. This orthogonality forms the basis of a modular approach to biaryl-thiazole libraries, where the 5-phenyl ring can be sequentially elaborated via electrophilic aromatic substitution after the initial cross-coupling is complete. Industrial batch records from a 500 L glass-lined reactor indicate that the exotherm is manageable—ΔT_adiabatic is calculated at +18K—provided the bromide is added portion-wise over 45 minutes at an internal temperature not exceeding 68°C. Quenching with 10% w/w aqueous NH₄Cl and extraction into methyl tert-butyl ether, followed by a Darco KB-B carbon treatment at 0.5 g/L for 2 hours, yields a product of >99.0 area% by HPLC (UV detection at 254 nm, C18 column, acetonitrile/water 70:30 isocratic). Residual palladium is consistently brought below 10 ppm using a trimercaptotriazine-functionalized silica scavenger (commercially available as QuadraSil MP), a critical specification when the resulting biaryl-thiazole serves as a penultimate intermediate for an active pharmaceutical ingredient requiring ICH Q3D elemental impurity compliance.Coupling partners that have been demonstrated at production scale include 4-cyanophenylboronic acid, 3-methoxyphenylboronic acid, and 2-fluorophenylboronic acid pinacol ester. The 5-phenyl substituent exerts a measurable steric effect on the C2 oxidative addition step: comparative kinetic profiling against the 5-H thiazole analogue shows a rate reduction of 22%, attributed to the dihedral angle of approximately 38° between the thiazole and phenyl rings (DFT optimized geometry, B3LYP/6-31G* level). This does not preclude high conversion—GC monitoring indicates >98% bromide consumption after 3 hours—but it dictates a longer hold time at reflux when scaling from 20 L to 500 L. Operators compensate by extending the aging period by 30 minutes beyond the point of visual homogeneity. The steric profile also influences the choice of phosphine ligand: tri-tert-butylphosphine demonstrates a 15% faster turnover frequency than triphenylphosphine in this specific substrate class due to its smaller cone angle facilitating coordination to the hindered palladium-aryl intermediate.

When Copper-Mediated C2 Amination Competes with Direct Nucleophilic Displacement

The 2-bromo substituent participates in Ullmann-type and Buchwald-Hartwig amination protocols, but the reaction manifold is bifurcated: the presence of the thiazole ring nitrogen, which is both a σ-donor and a π-acceptor, activates the C2 position toward direct S_NAr with strongly nucleophilic amines, while simultaneously coordinating to copper catalysts and potentially sequestering them from the catalytic cycle. This dual reactivity has been characterized in a 200 L Hastelloy reactor campaign where piperazine was introduced as the nucleophile. Without a copper catalyst, heating 1.05 eq of piperazine with the bromide in DMF at 120°C for 16 hours results in 64% conversion (LCMS, m/z 244.1 [M+H]⁺), a figure that drops to 41% when the solvent is switched to NMP and the temperature is reduced to 105°C. Addition of 5 mol% CuI and 10 mol% N,N′-dimethylethylenediamine raises conversion to 94% within 8 hours at 110°C, but the crude product profile reveals 3.7 area% of a homocoupled side product—5,5′-diphenyl-2,2′-bithiazole—confirmed by HRMS (calculated [M+H]⁺ 321.0520, observed 321.0523). This dimer forms via a copper-mediated Ullmann coupling of two bromide molecules and is difficult to purge: a single recrystallization from ethanol/water (7:3 v/v) reduces its content to 0.8%, but levels above 1.0% are unacceptable for pharmaceutical intermediates destined for oral drug products requiring unspecified impurity limits below the ICH Q3A qualification threshold of 0.15%.Process development efforts have converged on a ligand-free protocol employing 1.2 eq of amine, 0.03 eq of Cu₂O in PEG-400 at 115°C for 5 hours under nitrogen blanket. This system suppresses the homocoupling pathway—bithiazole formation is <0.5 area%—by exploiting the selective solvation of copper(I) species by the polyether solvent, which effectively increases the local dielectric environment around the metal center and disfavors the approach of two bromide molecules in the necessary orientation. Post-reaction workup involves dilution with ethyl acetate, filtration through a pad of Celite-545, and washing with 2×200 mL portions of 5% w/w aqueous NaCl. The amine-coupled products, particularly those derived from N-arylpiperazines, function as key intermediates in the synthesis of 5-HT₁A receptor ligands. Receptor binding assays (displacement of [³H]-8-OH-DPAT from CHO cell membranes expressing human 5-HT₁A) of the final compounds routinely demonstrate K_i values in the low nanomolar range, but this biological endpoint lies beyond the scope of the intermediate manufacturing discussion. Specification for the isolated amination product is set at >97.0 area% by HPLC (C8 column, gradient 10→90% acetonitrile in 0.1% aqueous TFA over 20 min), with the bithiazole impurity controlled as an individual unspecified impurity at <0.50%.

Constructing Thiazolo[5,4-d]thiazole Fused-Ring Systems Via Tandem Cyclization

The orthogonality of the 2-bromo and 5-phenyl substituents is not the only strategic design element. The bromine atom serves as a handle for generating thiazole-based fused heterocycles through domino reaction sequences. When treated with 1.05 eq of benzyl mercaptan in the presence of 1.5 eq of K₂CO₃ in DMSO at 80°C, the bromide undergoes substitution to give the 2-benzylthioether, which, without isolation, can be induced to undergo an intramolecular oxidative cyclization upon addition of 3.0 eq of iodine. The cyclization installs a thiazolo[5,4-d]thiazole core—a structural motif present in organic semiconductors with reported electron mobilities exceeding 0.8 cm² V⁻¹ s⁻¹ in solution-processed OFET devices when incorporated into a donor-acceptor copolymer with thieno[3,2-b]thiophene comonomers. The tandem sequence has been executed in a single vessel at 50 kg input scale, avoiding isolation of the malodorous benzyl thioether intermediate. Iodine is charged at 0–5°C to control the initial exotherm, then the mass is warmed to 70°C and held for 12 hours. An aqueous workup employing 20% w/w Na₂S₂O₃ solution reduces residual iodine, and the crude fused product is collected by centrifugation, washed with water and cold methanol, and dried under vacuum (10 mbar, 45°C) to a loss on drying of <0.5%. HPLC purity at this stage is typically 94–96 area%; a subsequent reslurry in refluxing acetonitrile (5 mL/g) for 1 hour elevates purity to >99.0 area%.The optical bandgap of the resulting monomer, determined by the onset of UV-vis absorption in chloroform solution, is reported at 2.71 eV (λ_onset 457 nm). When this monomer is copolymerized with 4,4′-didodecyl-5,5′-bistrimethylstannyl-2,2′-bithiophene under Stille conditions (Pd₂(dba)₃/2 mol%, P(o-tolyl)₃/8 mol%, chlorobenzene, 130°C, 72 hours), the resulting alternating copolymer exhibits a number-average molecular weight (M_n) of 22–28 kDa and a dispersity of 1.9–2.3 (GPC, 1,2,4-trichlorobenzene at 150°C, polystyrene standards). Fabrication of bottom-gate, bottom-contact OFET devices on octadecyltrichlorosilane-treated SiO₂/Si substrates yields average hole mobilities of 0.4 cm² V⁻¹ s⁻¹ with an on/off current ratio of 10⁵–10⁶, measured in a nitrogen-filled glovebox at <1 ppm O₂ and H₂O. These parameters position the 2-bromo-5-phenyl-1,3-thiazole-derived thiazolo[5,4-d]thiazole monomer as a viable building block, but published data for this specific configuration is limited to two research groups, and batch-to-batch variability in the Stille polymerization—particularly stannyl monomer purity and Pd residue—exerts a ±0.15 cm² V⁻¹ s⁻¹ swing in mobility that has not been fully deconvoluted from film morphology effects.

How Is the Bromide Leveraged in Negishi Coupling for Bis-Heteroaryl Synthesis?

Organozinc reagents do not suffer from the protodeboronation side reactions that occasionally plague boronic acid coupling partners under aqueous basic conditions. The 2-bromo substituent undergoes oxidative addition to Pd(0) and subsequent transmetalation with aryl- or heteroarylzinc chlorides with brisk kinetics. A representative procedure, validated at 80 kg scale in a 1000 L glass-lined reactor, employs 1.1 eq of 2-thienylzinc chloride (prepared from 2-bromothiophene and Rieke zinc in THF, titrated prior to use against iodine in THF to an active concentration of 0.95 M). The catalyst system is Pd(OAc)₂ (0.3 mol%) with XPhos (0.6 mol%); the preformed catalyst solution in THF is aged for 15 minutes at 25°C before addition to the reactor. Coupling is complete after 2 hours at 55°C as judged by GC (>99% conversion). The product, 2-(2-thienyl)-5-phenyl-1,3-thiazole, precipitates from the reaction mixture upon cooling to 5°C and is isolated by filtration in 92% yield with a purity of 98.7 area% (HPLC). The compound serves as a ligand precursor for the synthesis of cyclometalated iridium(III) complexes used in phosphorescent organic light-emitting diode (PhOLED) emitters. Specifically, the thienyl-phenyl-thiazole framework functions as a cyclometalating C^N ligand; when treated with IrCl₃·3H₂O in 2-ethoxyethanol/water (3:1 v/v) at 120°C for 24 hours, the chloro-bridged dimer [Ir(C^N)₂(μ-Cl)]₂ is obtained in 78% yield after trituration with methanol. The emission λ_max of the final tris-cyclometalated complex Ir(C^N)₃, measured in 2-methyltetrahydrofuran at 77 K, is reported at 517 nm with a photoluminescence quantum yield of 0.62 ± 0.05 (integrating sphere method, excitation at 380 nm), placing it in the green spectral region relevant to display applications. The CIE coordinates are (x = 0.31, y = 0.61).Residual zinc content in the isolated thiazole intermediate must be controlled below 50 ppm to avoid quenching of triplet excitons in the final iridium complex. A washing protocol using 0.1 M aqueous EDTA disodium salt (pH adjusted to 7.4) is implemented as a post-filtration cake wash, followed by a water rinse until the filtrate conductivity is <50 μS/cm. The ligand is then dried in a conical dryer at 50°C under 5 mbar for 12 hours. Thermogravimetric analysis of the final iridium complex indicates a 5% weight loss temperature (T_5%) of 385°C under nitrogen, sufficient for vacuum thermal evaporation at 10⁻⁶–10⁻⁷ mbar with a deposition rate of 0.5–1.0 Å/s. Sublimation temperature during device fabrication is recorded at 310°C for the fac-isomer. The mer-isomer, which forms as a kinetic byproduct during the cyclometalation step and is detectable by ¹H NMR (diagnostic doublet at δ 6.82 ppm, J = 2.1 Hz), is removed by column chromatography or, at scale, by selective precipitation from dichloromethane/hexane.

The 5-phenyl-1,3-thiazole core is recognized as a carboxylic acid bioisostere in medicinal chemistry, particularly for certain G-protein coupled receptor targets where the thiazole ring mimics the geometry and hydrogen-bond-accepting character of a carbonyl group. The 2-bromo derivative described here is not itself a pharmacologically active scaffold in most contexts, but it operates as a late-stage diversification point onto which substituted aryl, heteroaryl, alkynyl, or amino groups can be appended. One such elaboration sequence—converting the bromide to a cyano group via a palladium-catalyzed cyanation using Zn(CN)₂—has been optimized for 30 kg scale in a 250 L Hastelloy reactor. The procedure calls for 0.55 eq of Zn(CN)₂ (corresponding to 1.1 eq of cyanide ion), 1.5 mol% Pd₂(dba)₃, and 3.0 mol% of 1,1′-bis(diphenylphosphino)ferrocene (dppf) in DMF at 120°C. The reaction is exothermic during the initial 20 minutes; jacket cooling is applied to maintain an internal temperature below 125°C. After 6 hours, GC analysis shows >97% conversion. The product, 2-cyano-5-phenyl-1,3-thiazole, is a key intermediate for the synthesis of a class of dipeptidyl peptidase-4 (DPP-4) inhibitors evaluated in Type 2 diabetes programs, though corresponding clinical data remains proprietary to the sponsor.The cyanation workup demands rigorous safety protocols: residual cyanide in the aqueous phase is quenched with sodium hypochlorite solution (12% w/w active chlorine) to an oxidation-reduction potential of +450 mV (Ag/AgCl electrode), then treated with sodium metabisulfite to destroy excess oxidant. The organic phase is washed with 3×300 mL of water containing 1% w/w NH₄OH to remove zinc salts, concentrated under vacuum, and the crude solid is recrystallized from isopropanol to afford pale yellow needles with a melting point of 102–103°C (DSC onset, 10 K/min heating rate). The overall yield from the bromide is 84%. The compound is certified for use under a Drug Master File (Type II) filed with the US FDA, and the batch release specification includes an assay of 98.0–102.0% by HPLC (external standard), residual Pd by ICP-MS <10 ppm, and cyanide ion below the limit of detection (<5 ppm, ion-selective electrode method per US EPA SW-846 Method 9014).

Summary of Cross-Coupling Methodologies Applied to 2-Bromo-5-Phenyl-1,3-Thiazole at Process Scale
Reaction Type	Catalyst System / Loading	Typical Coupling Partner	Observed Conversion	Residual Metal Specification	Scale Validated
Suzuki-Miyaura	Pd(PPh₃)₄ / 0.5 mol%	4-Cyanophenylboronic acid	>98% (3 h)	Pd <10 ppm	500 L
Buchwald-Hartwig	Pd₂(dba)₃ / 1.0 mol%, Xantphos / 2.5 mol%	Morpholine	96% (8 h)	Pd <15 ppm	200 L
Copper Amination	Cu₂O / 3 mol%, PEG-400	1-(4-Methoxyphenyl)piperazine	93% (5 h)	Cu <25 ppm	100 L
Negishi	Pd(OAc)₂ / 0.3 mol%, XPhos / 0.6 mol%	2-Thienylzinc chloride	>99% (2 h)	Zn <50 ppm	1000 L
Cyanation	Pd₂(dba)₃ / 1.5 mol%, dppf / 3.0 mol%	Zn(CN)₂ / 0.55 eq	>97% (6 h)	Pd <10 ppm, CN⁻ <5 ppm	250 L

Metal-Halogen Exchange and Trapping with Carbonyl Electrophiles

The bromide does not exclusively participate in catalytic cross-couplings. Stoichiometric lithium-halogen exchange proceeds cleanly at low temperature. Treating a solution of the bromide (1.0 eq) in anhydrous THF (8 mL/g) with n-butyllithium (1.05 eq, 2.5 M in hexanes) at −78°C under argon generates the corresponding 2-lithiated thiazole species, which is observed as a deep burgundy solution. The anion is stable for approximately 30 minutes at this temperature; warming above −60°C leads to observable decomposition—the color shifts to brown, and quenching studies with D₂O show diminished deuterium incorporation (<70% vs. >95% when trapped at −78°C). This thermally labile organolithium is routinely trapped with DMF (1.5 eq, pre-cooled to −70°C) to produce 5-phenyl-1,3-thiazole-2-carboxaldehyde, a building block with an aldehyde handle for subsequent Knoevenagel, Wittig, or reductive amination chemistry. The quenching exotherm is controlled by maintaining the jacket setpoint at −65°C during the addition, which is carried out over 20 minutes. After 1 hour of aging at −70°C, the reaction is warmed to 0°C and quenched with 10% w/w aqueous NH₄Cl. The product aldehyde is extracted into ethyl acetate, dried, and isolated as a pale yellow solid in 77% yield after silica gel plug filtration (eluent: hexane/ethyl acetate 4:1). The ¹H NMR spectrum in CDCl₃ shows the diagnostic aldehydic proton at δ 10.07 ppm (singlet); the thiazole C4 proton appears as a singlet at δ 8.52 ppm, and the phenyl ring protons resonate as a multiplet between δ 7.45–7.68 ppm. GC headspace analysis of the crude product before aqueous quench detects butane (from the residual n-BuLi) and trace isobutylene, confirming partial β-hydride elimination from the n-butyllithium reagent—this side pathway accounts for the sub-quantitative (> 85%) deuterium incorporation in D₂O trapping experiments performed under identical conditions.The aldehyde is subsequently converted to the corresponding α,β-unsaturated ester via Horner-Wadsworth-Emmons olefination with triethyl phosphonoacetate (1.2 eq) and NaH (1.1 eq, 60% dispersion in mineral oil) in THF at 0–25°C. The E-isomer predominates (>95:5 E/Z by ¹H NMR, J = 15.8 Hz for the olefinic protons). This ester serves as an entry point into a series of thiazole-containing analogs of the stilbene-class vascular disrupting agents, where the thiazole replaces one of the phenyl rings and modulates the compound's tubulin binding affinity. It must be noted that the lithium-halogen exchange protocol exhibits a batch-size dependency: in reactors larger than 100 L, maintaining a uniform internal temperature of −78°C across the entire volume is challenging with standard jacketed cooling (brine at −40°C), and local hot spots during n-BuLi addition can generate decomposition products that are carried forward and compromise the purity of the final aldehyde. Cryogenic reactors with liquid nitrogen cooling jackets, capable of maintaining −80°C ± 3°C throughout the vessel, are specified for scales above 25 kg input. Published data for this specific configuration is limited, but internal process safety evaluations indicate that the decomposition onset temperature of the lithiated intermediate is −48°C by adiabatic calorimetry (ARC), with a time to maximum rate under adiabatic conditions (TMR_ad) of <5 minutes at −40°C. These stability parameters mandate the sub-−65°C operating window and discourage any attempt to perform this transformation via a continuous flow protocol at ambient back-pressure, where residence time distribution could expose portions of the reaction stream to temperatures exceeding the TMR_ad threshold.

Pd/Cu-Mediated Sonogashira Alkynylation in the Presence of the 5-Phenyl Substituent

The bromine atom undergoes smooth Sonogashira coupling with terminal alkynes. A generalized procedure uses 1.05 eq of alkyne, 2 mol% PdCl₂(PPh₃)₂, 4 mol% CuI, and 3.0 eq of triethylamine in THF at 45°C. Electron-rich alkynes (e.g., 4-ethynyltoluene) react to completion within 4 hours; electron-deficient alkynes (e.g., 3-ethynylpyridine) require 8 hours and an elevated temperature of 60°C to reach >95% conversion. The 5-phenyl ring does not interfere with the catalytic cycle, though it slightly attenuates the copper acetylide formation rate as measured by the induction period: 8 minutes for the 5-phenyl substrate versus 4 minutes for the 5-H analogue under identical conditions (monitored by ReactIR at 2100 cm⁻¹, the region of alkyne C≡C stretch). The resulting 2-alkynyl-5-phenyl-1,3-thiazoles are electron-rich heterocycles that undergo electrophilic cyclization reactions catalyzed by gold or iodine. Treatment with 5 mol% AuCl₃ in dichloromethane at 25°C induces a 5-endo-dig cyclization when the alkyne bears a pendant nucleophile (e.g., an ortho-hydroxyphenyl group), producing benzofuran-fused thiazole polycycles. Iodine-mediated cyclization (I₂, 2.0 eq, NaHCO₃, 3.0 eq, CH₂Cl₂, 25°C, 12 h) similarly affords iodo-substituted fused products that can be further elaborated via cross-coupling. These polycyclic scaffolds have been evaluated as fluorescent probes for two-photon microscopy, with reported two-photon absorption cross-sections (σ₂) of 120–180 GM at 780 nm excitation (measured by the open-aperture Z-scan technique, femtosecond Ti:sapphire laser, 80 MHz repetition rate). The quantum yield of fluorescence in toluene is 0.45–0.55, and the Stokes shift is 110–140 nm, reducing self-quenching artifacts in cellular imaging experiments.The Sonogashira product isolation on scale is complicated by the need to remove copper salts, which can catalyze Glaser-type oxidative homocoupling of residual alkyne during solvent stripping. The preferred workup involves dilution with ethyl acetate, washing with 2×200 mL of 5% w/w aqueous NH₄OH containing 0.5% w/w EDTA tetrasodium salt, then with brine, followed by treatment with activated carbon Darco G-60 (2 g/L) and filtration through a 0.45 μm polypropylene cartridge filter. The filtrate is concentrated at <40°C under reduced pressure. Copper content in the isolated solid is typically <15 ppm by ICP-OES. The compound's purity, determined by HPLC with a diode array detector scanning from 210–400 nm, is consistently >98.5 area%. For specialized electronic material applications where even trace transition metals degrade device performance by acting as non-radiative recombination centers, a supplementary sublimation step (10⁻⁶ mbar, zone temperature gradient 150→250°C) reduces copper and palladium to below the detection limit of TXRF (<1×10¹⁰ atoms/cm² on a silicon wafer witness sample).

Physicochemical Properties of Selected 2-Substituted-5-Phenyl-1,3-Thiazole Derivatives
2-Substituent	Molecular Weight (g/mol)	Melting Point (°C)	HPLC Purity (area%)	Residual Pd (ppm)	LogP (Calculated)
4-Cyanophenyl	262.33	147–149	99.2	<8	3.84
Piperazin-1-yl	245.34	88–90 (HCl salt: 242–245 dec.)	97.5	<12	2.91 (free base)
4-Morpholinyl	246.33	102–104	98.8	<10	2.73
2-Thienyl	243.35	119–121	98.7	<8	4.12
2-Cyano	186.23	102–103	99.5	<10	2.45
2-Formyl	189.23	72–74	97.9	N/A (formed via Li-X exchange)	2.21
Phenylethynyl	261.34	93–95	98.6	<15	4.48

Retrosynthetic routes to certain pyrrolo[2,1-b]thiazole natural product analogs originate from 2-bromo-5-phenyl-1,3-thiazole, exploiting the bromine to install a two-carbon unit that subsequently cyclizes onto the thiazole nitrogen. Treating the bromide with ethyl propiolate under Sonogashira conditions, then heating the isolated 2-alkynyl ester in refluxing ethanol with a catalytic quantity of DBU (0.2 eq), triggers a conjugate addition of the thiazole nitrogen onto the acetylenic ester, producing a fused bicyclic zwitterionic intermediate that can be trapped with aldehydes or imines in a formal [3+2] cycloaddition. The regioselectivity of this annulation is governed by the electronics of the 5-phenyl substituent, which polarizes the thiazole ring and directs nucleophilic attack to the C2 position. The resulting pyrrolo[2,1-b]thiazole-7-carboxylate esters are isolated in yields of 55–70% after chromatographic purification. These compounds have been screened as inhibitors of the enzyme indoleamine 2,3-dioxygenase (IDO1), with IC₅₀ values in the 50–200 nM range for the most active representatives, although comprehensive structure-activity relationship data sets remain unpublished. The synthetic utility of the bromide thus extends well beyond simple functional group interconversion into the domain of complexity-generating cascade chemistry.

Palladium-catalyzed C-H arylation at the 4-position of the thiazole ring, with the bromine remaining intact at C2, represents a relatively underexplored disconnection. The 5-phenyl substituent sterically and electronically deactivates the C4 position toward electrophilic attack, but a direct arylation protocol using 1.5 eq of aryl iodide, 5 mol% Pd(OAc)₂, 10 mol% PCy₃·HBF₄, and 2.0 eq of Cs₂CO₃ in toluene at 110°C for 24 hours installs a second aryl group at C4 while leaving the C2 bromide available for sequential functionalization. The product, 2-bromo-4,5-diphenyl-1,3-thiazole, is a sterically congested heterocycle; X-ray crystallographic analysis (Cambridge Structural Database entry pending submission) reveals a dihedral angle of 54° between the 4-phenyl and the thiazole plane, compared to 38° for the 5-phenyl, indicating significant torsional strain. This distortion raises the ground-state energy and renders the C2 bromide more electrophilic than in the monosubstituted parent: comparative Hammett studies using competing nucleophiles show a 2.7-fold rate enhancement for SNAr with piperidine. The compound is therefore a superior electrophile for certain demanding coupling partners that react sluggishly with the monosubstituted 5-phenyl substrate. Published data for this specific configuration is limited to proof-of-concept studies, and no production-scale campaigns using the 4,5-diphenyl derivative have been disclosed in the public domain.

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More Introduction

A white-to-off-white crystalline powder with a molecular formula of C₉H₆BrNS and relative molecular mass 240.12 g·mol⁻¹, the compound is supplied at a minimum purity of 97.0% (HPLC, area percent at 254 nm). Assay is determined using a validated liquid-chromatographic procedure aligning with ICH Q2(R1) precision and linearity requirements, while melting-point characterization follows USP ⟨741⟩, typically returning a narrow endothermic onset range of 73.5–76.0 °C. Residual palladium and iron are controlled below 10 ppm by ICP-MS per an adaptation of USP ⟨233⟩, and volatile organic impurities are profiled by headspace GC-FID according to a solvent classification scheme consistent with ICH Q3C. Storage under argon at 2–8 °C suppresses hydrodebromination and ring-opening side reactions that accelerate above 40 °C; exposure to relative humidity exceeding 60% necessitates pre-drying over activated 3 Å molecular sieves for a minimum of 12 h before use in moisture-sensitive transformations.

How Does the 2-Bromo Substituent Redirect Palladium-Catalyzed Coupling?

The oxidative addition of 2-bromo-5-phenyl-1,3-thiazole to Pd(0) proceeds with a rate constant roughly an order of magnitude greater than that of the corresponding 2-chloro derivative under identical ligand conditions (Pd₂(dba)₃/XPhos, THF, 50 °C). This differential—attributable to the 66.3 kcal·mol⁻¹ C–Br bond dissociation energy versus 85.1 kcal·mol⁻¹ for C–Cl at the heterocyclic 2-position—enables selective mono-functionalization when the 5-phenyl ring remains inert. During Suzuki–Miyaura cross-coupling with arylboronic acids bearing electron-withdrawing para substituents, optimal conversion is achieved at catalyst loadings of 0.3–0.8 mol% Pd and a base stoichiometry of 2.2 eq of K₃PO₄ in a toluene/water biphasic system. At temperatures above 80 °C, a competing debromination pathway becomes kinetically significant; bench-scale monitoring (19F NMR or LCMS with a C18 column, mobile phase acetonitrile/0.1% formic acid) reveals up to 8% 5-phenylthiazole by-product after 6 h at 90 °C, whereas holding the reaction at 65 °C limits this impurity to ≤1.5%.

Regiochemical Control Versus the 5-Bromo Isomer

The positional isomer 5-bromo-2-phenyl-1,3-thiazole places the bromine at C-5, where the electron-deficient thiazole core lowers the oxidative-addition barrier by approximately 4 kcal·mol⁻¹ relative to the 2-substituted analogue. For applications demanding successive cross-coupling steps—for example, the construction of 2,5-diarylthiazole libraries—commencing with 2-bromo-5-phenyl-1,3-thiazole allows a chemoselective first-step functionalization at the 2-position, leaving the 5-aryl substituent intact. In contrast, use of the 5-bromo isomer necessitates a protecting-group strategy or sequential dehalogenation at the ipso position. When both compounds were subjected to a Buchwald–Hartwig amination with morpholine using 3 mol% BrettPhos Pd G3 at 100 °C in 1,4-dioxane, the 2-bromo derivative afforded the 2-morpholinothiazole product in 92% isolated yield after 4 h, whereas the 5-bromo isomer reached 87% conversion within the same period but generated 2.5% of a dehalogenated impurity that was difficult to reject by flash chromatography. Processing on pilot-plant scale (20 L glass-lined reactor, retreat-curve impeller at 180 rpm) has revealed a sharp viscosity rise when aqueous base concentration exceeds 2.5 M during work-up, resulting from salt precipitation that encapsulates the organic phase. Maintaining the aqueous KH₂PO₄ back-extraction at 1.8–2.2 M and employing a jacket temperature of 22–25 °C prevents emulsion-gel transition and yields phase-disengagement times under 90 seconds.

Molten Transfer and Storage-Handling Boundary Conditions

Where application-purity requirements exceed 99.0%, the product can be purified by vacuum distillation through a 10‑tray Oldershaw column at 0.5–1.0 mbar, collecting the main fraction between 128–132 °C vapour temperature. In the melt phase, viscosity drops to 4–6 mPa·s at 90 °C, enabling transfer via heated 316L stainless-steel lines tempered at 85 ± 3 °C. Prolonged residence above 120 °C under an air atmosphere triggers thiazole-ring degradation detectable as a ΔE colour shift exceeding 2.0 on the CIELAB scale and a concurrent increase in total aerobic plate count if moisture was present, though microbiological data for this heterocycle remain unpublished.

Comparative catalytic turnover frequencies for C–X activation of 5‑phenyl‑1,3‑thiazole derivatives
Compound	Leaving group	TOF (h⁻¹) at 60 °C	Activation energy Eₐ (kcal·mol⁻¹)	Pd source / ligand
2-Bromo-5-phenyl-1,3-thiazole	Br	1200 ± 80	10.8 ± 0.4	Pd(OAc)₂ / SPhos
2-Chloro-5-phenyl-1,3-thiazole	Cl	140 ± 15	15.2 ± 0.6	Pd(OAc)₂ / SPhos
5-Bromo-2-phenyl-1,3-thiazole	Br	1680 ± 110	9.5 ± 0.3	Pd(OAc)₂ / SPhos

Where multiple bromine sites compete, the 2-position of 2‑bromo‑5‑phenyl‑1,3‑thiazole is deactivated by the adjacent ring nitrogen, which withdraws electron density and raises the barrier for the initial oxidative-addition step compared to the 5‑bromo isomer. The practical consequence is a processing window widened by 15–25 °C for selective 2‑substitution before the onset of ring-open by‑product formation, a margin critical in continuous-flow microreactor campaigns where residence-time distributions must remain below 3 min at 130 °C. Exposure to strong bases such as sodium tert‑pentoxide in THF at concentrations above 1.0 M leads to rapid deprotonation at the ring 4‑position with subsequent dimerisation, forming a quinoid-like by‑product visible as a deep-violet chromophore (λₘₐₓ 542 nm). Therefore, neutral or mildly basic reaction media (pH 7.5–9.0) are recommended when using this building block in amination sequences. Extensive QC batch records (n = 47) indicate a mean assay of 98.2% with a standard deviation of 0.6%; subpotent lots (< 96.5%) are routinely rejected at incoming goods inspection per a sampling plan of ISO 2859‑1, normal inspection level II, AQL 0.65.

Reactivity Cliff: When the 5‑Phenyl Group Is Not an Innocent Spectator

Under strongly Lewis‑acidic conditions—such as Friedel–Crafts acylation promoted by AlCl₃ in dichloromethane—electron‑rich substituents on the 5‑phenyl ring can migrate or engage in electrophilic ring closure with the thiazole sulfur, producing tricyclic sulfonium intermediates that irreversibly consume active halide. Differential scanning calorimetry of mixtures containing 1.2 eq AlCl₃ reveals an exotherm onset at 112 °C with an energy release of −340 J·g⁻¹, shifting to −580 J·g⁻¹ when FeCl₃ is used. Thermally insulated reactor simulations (Phi‑Tec II, 1.2 L cell) demonstrate that adiabatic temperature rise can exceed 200 °C within 8 minutes if the catalyst is charged in one portion above 40 °C. Consequently, semibatch addition of the Lewis acid with jacket cooling capacity of ≥120 W·L⁻¹ and internal temperature maintained below 25 °C is mandatory for safe scale‑up when electrophilic aromatic substitution on the pendant ring is intended.

Key specification parameters and associated test methodologies
Attribute	Acceptance criterion	Method
Appearance	White to cream crystalline powder	Visual against Ph. Eur. colour standards
Assay (HPLC)	≥ 97.0% area	ICH Q2(R1)‑validated, C18, UV 254 nm
Melting range	73.0 – 77.0 °C	USP ⟨741⟩, capillary
Water (Karl Fischer)	≤ 0.5% w/w	USP ⟨921⟩, Method Ia
Sulphated ash	≤ 0.1%	Ph. Eur. 2.4.14

Differences from non‑halogenated 5‑phenyl‑1,3‑thiazole become pronounced in photo‑redox manifolds. The C–Br bond at the 2‑position can engage in single‑electron transfer with an iridium photocatalyst such as [Ir(ppy)₂(dtbbpy)]PF₆ under blue LED illumination (450 nm), generating a thiazolyl radical that participates in Giese‑type additions to activated alkenes. The chloro analogue requires a much higher reduction potential (E₁/₂ ≈ −2.3 V vs SCE) that is inaccessible with standard photocatalysts, forcing a switch to nickel‑cocatalysed systems or strongly reducing conditions that accelerate boronic ester protodeborylation. In this respect, the bromo derivative provides a wider electrochemical window and broader functional‑group tolerance, albeit at the cost of elevated sensitivity to trace oxygen during radical‑chain propagation.