PIFA-Mediated Ring-Opening/Coupling Reaction of Benzoxazoles: Access to 2-Hydroxy Diarylureas

Abstract

An efficient method for synthesizing mixed unsymmetric 2-hydroxy diarylureas is developed via (bis(trifluoroacetoxy)iodo)benzene (PIFA)-mediated ring-opening/coupling of benzoxazoles with aryl isocyanates or isothiocyanates. This transition-metal-free protocol operates under mild conditions and utilizes Al₂O₃/H⁺ as a key additive, achieving high yields (up to 95%) with broad substrate scope. The reaction proceeds through a proposed PIFA-induced ring-opening of the benzoxazole followed by nucleophilic addition, providing direct access to pharmacologically and materially valuable 2-hydroxy diarylureas while avoiding the use of toxic reagents and high-pressure equipment. This strategy addresses limitations of traditional urea syntheses, offering operational simplicity and scalability.

 

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Key words

2-hydroxy diarylureas - ring-opening reaction - benzoxazoles - metal-free synthesis

The urea structural moiety is a privileged scaffold ubiquitous in functional materials, bioactive compounds, and natural products. It is found in the active cores of numerous therapeutic agents, including antitumor drugs,[1] native receptor antagonists,[2] allosteric modulators,[3] enzyme inhibitors,[4] anti-HIV drugs,[5] and anticonvulsants.[6] Urea derivatives are also employed as highly efficient and stable organocatalysts[7] and transition-metal ligands.[8] Beyond the field of medicinal chemistry, urea derivatives also find significant applications in organic materials.[9]

Among functionalized urea compounds, 2-hydroxy diarylurea derivatives represent an important subclass with broad applications in pharmaceutical synthesis, organic materials, and catalysis. The unique adjacent positioning of the hydroxy group and the urea moiety enables the formation of intricate hydrogen-bonding networks. This property is crucial for generating specific interactions with biological targets, making 2-hydroxy diarylureas key scaffolds for designing antitumor agents, enzyme inhibitors, and antiviral drugs. For example, in anti-HIV and anticonvulsant therapies, the 2-hydroxy diarylurea structure enhances drug-target binding efficiency by modulating molecular polarity and hydrogen-bonding capability.[10] In kinase inhibitor development (e.g., targeting SRPK3) (Figure [1]), this structural unit acts as a critical pharmacophore, utilizing hydrophobic interactions and hydrogen bonding to bind within hydrophobic pockets in the kinase domain, highlighting its potential in anticancer drug discovery.[11]

Figure 1 Representative 2-hydroxy diarylurea derivatives

The strong hydrogen bond donor ability of 2-hydroxy diarylureas also promotes their applications in materials science. They can be used to design self-assembled structures, fluorescent probes, and functional polymers. Intermolecular hydrogen bonds can guide ordered assembly, playing roles in optoelectronic materials or serving as signal transduction units in sensors. In the design of fluorescent probes (such as thiourea-based sensors for Hg²⁺) (Figure [1]), the introduction of a hydroxy group and aromatic rings can regulate the conjugated system, enabling selective recognition of metal ions and fluorescent responses, which are applied in environmental monitoring and bioimaging.[12]

Given the importance of functionalized ureas in the above-mentioned fields, the development of efficient synthetic methods is crucial. Traditional methods for urea synthesis typically rely on reagents such as phosgene, azides, carbamates, or carbonyldiimidazoles, which suffer from disadvantages such as high toxicity, instability, and difficult handling.[13] Alternative strategies have been explored, such as oxidative carbonylation of amines using carbon monoxide (CO)[14] or direct carbonylation of amines using carbon dioxide (CO₂).[15] However, these methods often require expensive metal catalysts and high-pressure conditions. Additionally, these approaches often have limitations with respect to the synthesis of asymmetric urea derivatives, and are particularly challenging for the synthesis of specific types such as 2-hydroxy diarylureas.

At present, the main approach for synthesizing 2-hydroxy diarylureas is via the reaction of o-aminophenols with isocyanates (Scheme [1a]).[16] Unfortunately, this method often suffers from issues such as complex reaction mixtures, low yields, and difficult purification, which severely hinder access to these valuable compounds. Hence, there is an urgent need to develop new synthetic strategies to enable the efficient and selective preparation of asymmetric 2-hydroxy diarylureas under mild conditions.

Scheme 1 Synthetic methods toward 2-hydroxy diarylureas

Inspired by the strategy reported in the literature of benzoxazole ring-opening as a powerful approach for constructing C–O and C–N bonds,[16] we have conceived a new method. Herein, we report an efficient approach for the synthesis of asymmetric 2-hydroxy diarylureas via (bis(trifluoroacetoxy)iodo)benzene-mediated benzoxazole ring-opening/coupling reactions under mild conditions (Scheme [1b]). This protocol features excellent substrate applicability and high yields, effectively circumventing the common by-product formation issues of existing methods. This work provides a practical and reliable solution for accessing these pharmacologically and materially valuable structures.

Table 1 Optimization of the Experimental Conditions^a

Entry	[O]	Solvent	Additive	Temp (°C)	Yield (%)b
1	PIFA	MeCN	–	80	56
2	PIFA	dioxane	–	80	37
3	PIFA	THF	–	80	18
4	PIFA	DCM	–	80	13
5	PIFA	DCE	–	80	34
6	PIFA	toluene	–	80	23
7	PIFA	DMF	–	80	NRc
8	PIFA	DMSO	–	80	NRc
9	PIFA	MeOH	–	80	73
10	PIFA	acetone	–	80	45
11	DIPA	MeOH	–	60	12
12	PhICl2	MeOH	–	60	23
13	IBX	MeOH	–	60	15
14	DTBP	MeOH	–	60	31
15	TBHP	MeOH	–	60	29
16	PIFA	MeOH	Cs2CO3	60	78
17	PIFA	MeOH	t-BuOK	60	75
18	PIFA	MeOH	NaOH	60	80
19	PIFA	MeOH	Al2O3/H+	60	87
20	PIFA	MeOH	CF3COOH	60	72
21	PIFA	MeOH	DBU	60	79
22	PIFA	MeOH	DABCO	60	64

^a Reagents and conditions: reactions were carried out in a 10 mL reaction tube with benzoxazole (1a) (12 mg, 0.1 mmol, 1.0 equiv), 3-methoxyphenyl isocyanate (2a) (15 mg, 0.1 mmol, 1.0 equiv), oxidant (1.0 equiv), additive (1.0 equiv), and solvent (1 mL) with stirring at the specified temperature 2 hours.

^b The yield of 3a was calculated based on 1a.

^c NR = no reaction.

In our initial studies, benzoxazole (1a) (12 mg, 0.1 mmol, 1.0 equiv), 3-methylphenyl isocyanate (2a) (15 mg, 0.1 mmol, 1.0 equiv), and (bis(trifluoroacetoxy)iodo)benzene (PIFA) (44 mg, 0.1 mmol, 1.0 equiv) were added to a 10 mL reaction tube (Table [1]). As shown in entry 1, stirring in acetonitrile as the solvent at 80 °C for 2 hours gave the target product 1-(2-hydroxyphenyl)-3-(3-methylphenyl)urea (3a) with an isolated yield of 56%. Next, in an effort to improve the reaction yield, a series of reaction solvents was screened (entries 2–10). No target product was formed in DMF or DMSO, while common solvents such as dioxane, THF, DCM, toluene, and acetone resulted in low yields. However, methanol (MeOH) provided the highest isolated yield of 73% for target product 3a, establishing it as the optimal solvent. Under the conditions of MeOH as the solvent and a reaction temperature of 60 °C, various oxidants were screened, including diacetoxyiodobenzene (DIPA), iodobenzene dichloride (PhICl₂), 2-iodoxybenzoic acid (IBX), di-tert-butyl peroxide (DTBP), and tert-butyl hydroperoxide (TBHP), but all led to low yields (entries 11–15), confirming PIFA as the best oxidant. Finally, a series of additives was evaluated (entries 16–22). Additives such as Cs₂CO₃, t-BuOK, NaOH, CF₃COOH, DBU, and DABCO gave good yields, with Al₂O₃/H⁺ providing the highest yield. The optimal reaction conditions were determined through screening as follows: MeOH as the solvent, Al₂O₃/H⁺ as the additive, PIFA (1.0 equiv) as the oxidant, benzoxazole (1a) (0.2 mmol), 3-methylphenyl isocyanate (2a) (0.2 mmol), a reaction temperature of 60 °C and a reaction time of 2 hours, to afford target product 3a in 87% yield.

On the basis of the optimized reaction conditions, we next explored the substrate generality for the preparation of 1-(2-hydroxyphenyl)-3-(phenyl)urea derivatives 3 from various substituted phenyl isocyanates or phenyl isothiocyanates and aryl oxazoles (Scheme [2]). First, we investigated the reactions of phenyl isocyanates possessing different substituents (such as methyl, methoxy, halogen, trifluoromethoxy) to prepare the target products 3a–h. As shown in Scheme [2], these substrates provided the corresponding 1-(2-hydroxyphenyl)-3-(phenyl)urea derivatives 3a–h in good to excellent yields (75–92%). The electronic effects of the substituents on the benzene ring of the phenyl isocyanates had no obvious impact on the yields of the target compounds, nor did the substitution positions. For example, products 3c (o-Cl), 3d (m-Cl) and 3e (p-Cl) were obtained in yields of 89%, 87% and 92%, respectively. Phenyl isothiocyanates and benzoxazoles also underwent this reaction. Unsubstituted, methyl-, tert-butyl-, and naphthyl-substituted derivatives afforded 1-(2-hydroxyphenyl)-3-(phenyl)thioureas 3i–l in good to excellent yields. In addition, a disubstituted phenyl isocyanate yielded the target compound 3m in a high yield of 84%. Next, we studied the reactions of phenyl isocyanates possessing different substituents and various substituted benzoxazoles, all of which were suitable for the reaction, giving the corresponding target products 3 in good yields (3p–r: 77–81%), and demonstrating the good substrate scope of this reaction. Products 3i and 3j were selected as a representative compounds from the library and were characterized by X-ray crystallography.[17]

Scheme 2 Studies on the substrate scope for the synthesis of 2-hydroxy diarylureas. Reagents and conditions: reactions were conducted in a 10 mL reaction tube with aryl oxazole 1 (0.2 mmol, 1.0 equiv), aryl isocyanate or aryl isothiocyanate 2 (0.2 mmol, 1.0 equiv), PIFA (86 mg, 0.2 mmol, 1.0 equiv), Al₂O₃/H⁺ (1.0 equiv), and MeOH (1 mL) with stirring at 60 °C for 2 hours. Yields of products 3 are calculated based on substrates 1.

To investigate the possible reaction mechanism, control experiments were performed (Scheme [3]). In the presence of TEMPO as a free-radical scavenger, the model reaction proceeded with difficulty under the standard conditions (Scheme [3a]). Compound 1a can react with PIFA to afford intermediate Int-1, which can be isolated (Scheme [3b]). When anhydrous methanol is used as the solvent, only a trace amount of Int-1 is observed. However, when 1 to 2 drops of water are added to anhydrous methanol, the formation of Int-1 can be clearly observed. Therefore, we speculate that the moisture present in methanol may be involved in the oxidative ring-opening reaction of the benzoxazole. Moreover, intermediate Int-1 can further react with the aryl isocyanate to yield product 3a (Scheme [3c]).

Scheme 3 Control experiments

According to a previous literature report,[18] taking the synthesis of 3a as an example, we have proposed a mechanism for the synthesis of asymmetric urea derivatives via a benzoxazole ring-opening/coupling reaction mediated by (bis(trifluoroacetoxy)iodo)benzene (Scheme [4]). The starting benzoxazole 1 undergoes an oxidative ring-opening reaction under the action of (bis(trifluoroacetoxy)iodo)benzene, generating phenoxyl and iodine radicals.[18] [19] These two species then undergo radical coupling to form intermediate Int-1. Next, intermediate Int-1 couples with 3-methylphenyl isocyanate 2 to form intermediate Int-II. Finally, intermediate Int-II undergoes cleavage of iodobenzene and acetic acid elimination under the catalysis of acidic Al₂O₃ to afford the target compound 3.

Scheme 4 Possible reaction mechanism

In summary, phenyl isocyanates or phenyl isothiocyanates and benzoxazoles have been selected as reaction materials, and asymmetric 2-hydroxy diarylurea derivatives have been synthesized via ring-opening/coupling reactions of the benzoxazoles mediated by (bis(trifluoroacetoxy)iodo)benzene. This method features readily available starting materials, good substrate scope, mild reaction conditions, and no requirement for transition-metal catalysts or high-pressure/corrosion-resistant equipment, affording good yields of the desired products. In addition, it provides a foundation for the further applications of 2-hydroxy diarylureas.

All chemicals and reagents were of commercial grade and were used without further purification. The reactions were monitored by thin-layer chromatography (TLC) using silica gel GF254. Column chromatography was performed with 200–300 mesh silica gel. All yields refer to those of isolated products after purification. The synthesized intermediates and products were fully characterized by spectroscopic data. The NMR spectra were recorded on Bruker DRX-600 spectrometer (¹H: 600 MHz, ¹³C: 151 MHz) using DMSO-d ₆ as the solvents. The following abbreviations are used to explain the multiplicities: (s) = singlet, (d) = doublet, (t) = triplet, (q) = quartet, (dd) = doublet of doublets, (dt) = doublet of triplets, (dq) = doublet of quartets, (ddd) = doublet of doublets of doublets, (m) = multiplet; chemical shifts (δ) are expressed in parts per million (ppm) and J values are given in hertz (Hz). IR spectra were recorded on an FT-IR Thermo Nicolet Avatar 360 using a KBr pellet. HRMS was performed on an Agilent LC/MSD TOF instrument. The melting points were measured using an XT-4A melting point apparatus without correction.

 

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Acidic Al₂O₃

The method for the preparation of acidic Al₂O₃ usually includes the following steps: impregnation of the Al₂O₃ carrier (such as γ-Al₂O₃) in sulfuric acid or sulfate solution, followed by drying and calcination. For example, Al₂O₃ particles (with a particle size of 3–4 mm) can be impregnated in 98% sulfuric acid for 8 h, then dried at 100 °C for 3 h, and finally calcined at 400 °C for 3 h to afford the acidic alumina catalyst. This method introduces acidic sites on the surface of Al₂O₃ through the loading of sulfuric acid, and is suitable for reactions such as catalytic dehydration.[20]

 

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Compounds 3; General Procedure

Under an air atmosphere, benzoxazole 1 (0.2 mmol, 1.0 equiv), aryl isocyanate or aryl isothiocyanate 2 (0.2 mmol, 1.0 equiv), (bis(trifluoroacetoxy)iodo)benzene (0.1 mmol, 1.0 equiv), Al₂O₃/H⁺ (1.0 equiv), and MeOH (1 mL) were added to a 10 mL reaction tube. The reaction tube was then placed in an oil bath and the contents were stirred at 60 °C for 2 h. After the reaction was complete, the solvent was removed from the mixture by vacuum distillation under reduced pressure. To the residue was added saturated NaCl solution (30 mL) and ethyl acetate (30 mL), and the solution was extracted three times. The combined organic layer was dried over anhydrous Na₂SO₄, filtered, and then distilled under reduced pressure. The crude residue was purified by silica gel column chromatography (PE/EtOAc = 6:1) to afford the desired product 3.

 

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1-(2-Hydroxyphenyl)-3-(m-tolyl)urea (3a)

Yield: 42 mg (87%); brown solid; mp 125.3–126.6 °C.

IR (KBr): 3551, 3369, 2549, 1931, 1745, 1247, 1043, 943, 854, 786, 762 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.01 (s, 1 H, OH), 9.29 (s, 1 H, NH), 8.22 (s, 1 H, NH), 8.10 (dd, J = 7.8, 1.8 Hz, 1 H, ArH), 7.35 (d, J = 2.4 Hz, 1 H, ArH), 7.28 (d, J = 8.1 Hz, 1 H, ArH), 7.20 (t, J = 7.7 Hz, 1 H, ArH), 6.91–6.78 (m, 4 H, ArH), 2.33 (s, 3 H, CH₃).

¹³C NMR (101 MHz, DMSO-d ₆): δ = 153.0, 146.0, 140.3, 138.4, 129.1, 122.8, 119.9, 119.6, 118.8, 116.8, 115.5, 114.9, 114.8, 21.7.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₄H₁₅N₂O₂: 243.1128; found: 243.1132.

 

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1-(2-Hydroxyphenyl)-3-(3-methoxyphenyl)urea (3b)

Yield: 47 mg (91%); brown solid; mp 136.2–137.6 °C.

IR (KBr): 3553, 3374, 2546, 1926, 1742, 1246, 1041, 940, 855, 784, 766, 755 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 9.96 (s, 1 H, OH), 9.32 (s, 1 H, NH), 8.16 (s, 1 H, NH), 8.04 (dd, J = 7.8, 1.8 Hz, 1 H, ArH), 7.21–7.16 (m, 2 H, ArH), 6.93–6.90 (m, 1 H, ArH), 6.84–6.73 (m, 3 H, ArH), 6.56–6.52 (m, 1 H, ArH), 3.73 (s, 3 H, OCH₃).

¹³C NMR (101 MHz, DMSO-d ₆): δ = 159.3, 154.2, 147.5, 137.3, 129.1, 125.4, 124.4, 121.8, 119.7, 117.9, 112.9, 109.5, 106.6, 54.3.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₄H₁₅N₂O₃: 259.1077; found: 259.1081.

 

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1-(2-Chlorophenyl)-3-(2-hydroxyphenyl)urea (3c)

Yield: 47 mg (89%); brown solid; mp 170.4–171.3 °C.

IR (KBr): 3567, 3376, 1742, 1245, 1048, 883, 764, 741, 637, 607 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 9.89 (s, 1 H, OH), 8.97 (s, 1 H, NH), 8.94 (s, 1 H, NH), 8.10 (dd, J = 8.3, 1.6 Hz, 1 H, ArH), 8.00 (dd, J = 8.0, 1.6 Hz, 1 H, ArH), 7.44 (dd, J = 8.0, 1.5 Hz, 1 H, ArH), 7.29 (ddd, J = 8.5, 7.4, 1.5 Hz, 1 H, ArH), 7.03 (td, J = 7.6, 1.6 Hz, 1 H, ArH), 6.89–6.79 (m, 2 H, ArH), 6.75 (ddd, J = 8.9, 7.1, 1.9 Hz, 1 H, ArH).

¹³C NMR (101 MHz, DMSO-d ₆): δ = 152.9, 146.6, 136.7, 129.7, 127.9, 127.8, 123.7, 122.9, 122.7, 122.6, 119.9, 119.5, 115.0.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₃H₁₂ClN₂O₂: 263.0582; found: 263.0578.

 

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1-(3-Chlorophenyl)-3-(2-hydroxyphenyl)urea (3d)

Yield: 46 mg (87%); brown solid; mp 136.4–137.5 °C.

IR (KBr): 3542, 3338, 1741, 1724, 1249, 1050, 880, 780, 740, 646, 603 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 9.94 (s, 1 H, OH), 9.46 (s, 1 H, NH), 8.16 (s, 1 H, NH), 7.98 (dd, J = 7.8, 1.8 Hz, 1 H, ArH), 7.68 (t, J = 2.1 Hz, 1 H, ArH), 7.25–7.14 (m, 2 H, ArH), 6.95–6.91 (m, 1 H, ArH), 6.81–6.73 (m, 2 H, ArH), 6.69 (td, J = 7.6, 1.8 Hz, 1 H, ArH).

¹³C NMR (101 MHz, DMSO-d ₆): δ = 152.7, 146.1, 141.9, 133.7, 130.8, 127.9, 122.4, 121.6, 119.6, 119.1, 117.6, 116.6, 114.8.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₃H₁₂ClN₂O₂: 263.0582; found: 263.0579.

 

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1-(4-Chlorophenyl)-3-(2-hydroxyphenyl)urea (3e)

Yield: 48 mg (92%); brown solid; mp 88.4–89.6 °C.

IR (KBr): 3573, 3363, 1732, 1250, 754, 757, 720, 683, 657 cm^–1.

¹H NMR (600 MHz, DMSO-d ₆): δ = 9.98 (s, 1 H, OH), 9.43 (s, 1 H, NH), 8.17 (s, 1 H, NH), 8.02 (dd, J = 7.9, 1.6 Hz, 1 H, ArH), 7.48 (dt, J = 8.7, 1.8 Hz, 2 H, ArH), 7.33–7.30 (m, 2 H, ArH), 6.84 (dt, J = 7.8, 1.5 Hz, 1 H, ArH), 6.80 (tt, J = 7.8, 1.5 Hz, 1 H, ArH), 6.75 (td, J = 7.6, 1.5 Hz, 1 H, ArH).

¹³C NMR (151 MHz, DMSO-d ₆): δ = 152.8, 146.1, 139.4, 129.1, 129.1, 128.0, 125.5, 122.3, 119.8, 119.6, 119.0, 114.8.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₃H₁₂ClN₂O₂: 263.0582; found: 263.0577.

 

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1-(4-Bromophenyl)-3-(2-hydroxyphenyl)urea (3f)

Yield: 54 mg (88%); brown solid; mp 143.4–144.8 °C.

IR (KBr): 3562, 3349, 2093, 1742, 1226, 1024, 923, 852, 801, 743, 691 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 9.99 (s, 1 H, OH), 9.45 (s, 1 H, NH), 8.19 (s, 1 H, NH), 8.03 (dd, J = 7.9, 1.7 Hz, 1 H, ArH), 7.44 (d, J = 2.2 Hz, 4 H, ArH), 6.85–6.83 (m, 1 H, ArH), 6.82–6.77 (m, 1 H, ArH), 6.74 (td, J = 7.5, 1.9 Hz, 1 H, ArH).

¹³C NMR (101 MHz, DMSO-d ₆): δ = 152.8, 146.1, 144.4, 139.8, 132.0, 128.0, 122.3, 120.2, 119.9, 116.8, 114.9, 114.8, 113.4.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₃H₁₂BrN₂O₂: 307.0077; found: 307.0081.

 

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1-(2-Fluorophenyl)-3-(2-hydroxyphenyl)urea (3g)

Yield: 42 mg (85%); yellow solid; mp 182.4–183.6 °C.

IR (KBr): 3561, 3327, 1928, 1742, 1246, 1039, 886, 800, 766, 742, 719 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 9.90 (s, 1 H, OH), 9.22 (d, J = 2.3 Hz, 1 H, NH), 8.73 (s, 1 H, NH), 8.18 (td, J = 8.3, 1.7 Hz, 1 H, ArH), 8.04 (dd, J = 7.9, 1.7 Hz, 1 H, ArH), 7.22 (ddd, J = 11.7, 8.1, 1.5 Hz, 1 H, ArH), 7.13 (td, J = 7.8, 1.5 Hz, 1 H, ArH), 7.02–6.95 (m, 1 H, ArH), 6.87–6.79 (m, 2 H, ArH), 6.75 (td, J = 7.6, 1.9 Hz, 1 H, ArH).

¹³C NMR (101 MHz, DMSO-d ₆): δ = 152.8, 152.5 (J _C–F = 240 Hz), 146.1, 142.8, 139.7, 128.0, 122.3, 122.2, 119.6, 119.4, 119.0, 114.8.

¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –129.28.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₃H₁₂FN₂O₂: 247.0877; found: 247.0872.

 

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1-(2-Hydroxyphenyl)-3-(4-(trifluoromethoxy)phenyl)urea (3h)

Yield: 47 mg (75%); yellow solid; mp 194.0–195.6 °C.

IR (KBr): 3566, 3362, 1742, 1226, 1088, 884, 849, 797, 766 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 9.97 (s, 1 H, OH), 9.51 (s, 1 H, NH), 8.20 (s, 1 H, NH), 8.04 (dd, J = 7.9, 1.7 Hz, 1 H, ArH), 7.57–7.53 (m, 2 H, ArH), 7.31–7.26 (m, 2 H, ArH), 6.87–6.73 (m, 3 H, ArH).

¹³C NMR (101 MHz, DMSO-d ₆): δ = 152.8, 146.1, 142.8, 139.7, 128.0, 122.3, 122.2, 120.6 (J _C–F = 236 Hz), 119.6, 119.4, 119.0, 114.8.

¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –57.13.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₄H₁₂F₃N₂O₃: 313.0795; found: 313.0791.

 

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1-(2-Hydroxyphenyl)-3-phenylthiourea (3i)

Yield: 46 mg (95%); yellow solid; mp 140.5–141.8 °C.

IR (KBr): 3554, 3347, 2093, 1790, 1225, 1025, 849, 783, 736, 690 cm^–1.

¹H NMR (400 MHz, acetone-d ₆): δ = 9.68 (s, 1 H, OH), 9.18 (s, 1 H, NH), 9.07 (s, 1 H, NH), 8.25 (dd, J = 8.0, 1.7 Hz, 1 H, ArH), 8.02 (ddt, J = 8.6, 3.5, 1.8 Hz, 2 H, ArH), 8.00 (t, J = 7.9 Hz, 2 H, ArH), 7.83 (m, 1 H, ArH), 7.66 (td, J = 7.7, 1.6 Hz, 1 H, ArH), 7.52 (dd, J = 8.0, 1.5 Hz, 1 H, ArH), 7.40 (td, J = 7.7, 1.5 Hz, 1 H, ArH).

¹³C NMR (101 MHz, acetone-d ₆): δ = 179.6, 150.1, 138.8, 128.8, 126.8, 126.5, 125.5, 125.5, 124.5, 124.4, 119.7, 116.6.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₃H₁₃N₂OS: 245.0743; found: 245.0747.

 

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1-(2-Hydroxyphenyl)-3-(naphthalen-2-yl)thiourea (3j)

Yield: 58 mg (78%); yellow solid; mp 167.3–168.4 °C.

IR (KBr): 3562, 3357, 2258, 1928, 1742, 1726, 941, 894, 797, 724, 689, 650 cm^–1.

¹H NMR (400 MHz, acetone-d ₆): δ = 9.38 (s, 1 H, OH), 8.70 (s, 1 H, NH), 8.53 (s, 1 H, NH), 8.13–8.10 (m, 1 H, ArH), 7.98 (dd, J = 7.5, 1.9 Hz, 1 H, ArH), 7.92 (d, J = 8.2 Hz, 1 H, ArH), 7.73 (d, J = 8.6 Hz, 1 H, ArH), 7.67–7.64 (m, 1 H, ArH), 7.61–7.55 (m, 3 H, ArH), 7.06 (td, J = 7.6, 1.6 Hz, 1 H, ArH), 6.91 (dd, J = 8.1, 1.5 Hz, 1 H, ArH), 6.84 (td, J = 7.7, 1.5 Hz, 1 H, ArH).

¹³C NMR (101 MHz, acetone-d ₆): δ = 180.8, 150.1, 134.6, 134.0, 128.2, 127.9, 127.2, 126.6, 126.6, 126.4, 125.9, 125.7, 125.3, 123.0, 119.7, 117.1.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₇H₁₅N₂OS: 295.0900; found: 295.0904.

 

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1-(2-Hydroxyphenyl)-3-(p-tolyl)thiourea (3k)

Yield: 37 mg (71%); yellow solid; mp 131.7–132.4 °C.

IR (KBr): 3577, 3318, 2978, 1746, 1256, 1050, 882, 808, 748, 630 cm^–1.

¹H NMR (600 MHz, DMSO-d ₆): δ = 9.86 (s, 1 H, OH), 9.82 (s, 1 H, NH), 8.99 (s, 1 H, NH), 7.95 (dd, J = 8.0, 1.6 Hz, 1 H, ArH), 7.40–7.38 (m, 2 H, ArH), 7.15 (d, J = 8.2 Hz, 2 H, ArH), 6.97 (td, J = 7.7, 1.6 Hz, 1 H, ArH), 6.87 (dd, J = 8.1, 1.4 Hz, 1 H, ArH), 6.77 (td, J = 7.7, 1.4 Hz, 1 H, ArH), 2.28 (s, 3 H, CH₃).

¹³C NMR (151 MHz, DMSO-d ₆): δ = 179.4, 137.0, 134.3, 129.4, 127.1, 125.7, 124.3, 118.9, 115.7, 21.0.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₄H₁₅N₂OS: 259.0900; found: 259.0900.

 

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N-(4-(tert-Butyl)phenyl)-3-(2-hydroxyphenyl)thiourea (3l)

Yield: 47 mg (78%); yellow solid; mp 134.5–135.6 °C.

IR (KBr): 3564, 3372, 2539, 2415, 1746, 1047, 881, 791, 713, 924 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 9.91 (s, 1 H, OH), 9.04 (s, 1 H, NH), 7.96 (dd, J = 8.1, 1.6 Hz, 1 H, NH), 7.43 (d, J = 2.2 Hz, 1 H, ArH), 7.37 (d, J = 2.2 Hz, 1 H, ArH), 6.98 (td, J = 7.7, 7.3, 1.6 Hz, 1 H, ArH), 6.88 (dd, J = 8.1, 1.5 Hz, 1 H, ArH), 6.78 (td, J = 7.6, 1.5 Hz, 1 H, ArH), 6.63 (dd, J = 7.7, 1.4 Hz, 1 H, ArH), 6.56 (dd, J = 7.4, 1.6 Hz, 1 H, ArH), 6.39 (td, J = 7.4, 1.9 Hz, 1 H, ArH), 1.29 (s, 9 H, C(CH₃)₃).

¹³C NMR (101 MHz, DMSO-d ₆): δ = 179.3, 149.9, 147.4, 144.4, 136.9, 125.6, 123.9, 119.9, 116.8, 114.8, 114.8, 34.6, 31.6.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₇H₂₁N₂OS: 301.1369; found: 301.1373.

 

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1-(3-Chloro-4-methylphenyl)-3-(2-hydroxyphenyl)urea (3m)

Yield: 46 mg (84%); brown solid; mp 196.2–197.6 °C.

IR (KBr): 3363, 3353, 1752, 1708, 1268, 741, 638, 603, 552, 516 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.03 (s, 1 H, OH), 9.40 (s, 1 H, NH), 8.16 (s, 1 H, NH), 8.01 (dd, J = 7.9, 1.7 Hz, 1 H, ArH), 7.71 (d, J = 2.2 Hz, 1 H, ArH), 7.23 (d, J = 8.3 Hz, 1 H, ArH), 7.14 (dd, J = 8.3, 2.2 Hz, 1 H, ArH), 6.67–6.45 (m, 2 H, ArH), 6.39 (td, J = 7.4, 1.8 Hz, 1 H, ArH), 2.25 (s, 3 H, CH₃).

¹³C NMR (400 MHz, DMSO-d ₆): δ = 152.88, 146.1, 139.5, 133.6, 131.6, 128.5, 128.0, 122.4, 119.9, 119.6, 118.2, 117.0, 114.8, 19.2.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₄H₁₄ClN₂O₂: 277.0738; found: 277.0741.

 

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1-(4-Chloro-2-hydroxyphenyl)-3-(o-tolyl)urea (3n)

Yield: 41 mg (75%); brown solid; mp 182.7–183.6 °C.

IR (KBr): 3562, 3354, 2547, 1928, 1733, 1268, 1946, 801, 747, 725, 689, 648 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.28 (s, 1 H, OH), 8.75 (s, 1 H, NH), 8.61 (s, 1 H, NH), 8.18 (d, J = 2.1 Hz, 1 H, ArH), 7.80 (dd, J = 8.1, 1.3 Hz, 1 H, ArH), 7.18–7.14 (m, 2 H, ArH), 6.95 (td, J = 7.4, 1.3 Hz, 1 H, ArH), 6.83 (m, 2 H, ArH), 2.24 (s, 3 H, CH₃).

¹³C NMR (101 MHz, DMSO-d ₆): δ = 153.1, 144.9, 137.7, 130.6, 129.9, 128.4, 126.5, 123.3, 123.0, 122.0, 121.1, 118.3, 115.7, 18.5.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₄H₁₄ClN₂O₂: 277.0738; found: 277.0740.

 

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1-(4-Bromo-2-hydroxyphenyl)-3-(3-chlorophenyl)urea (3o)

Yield: 56 mg (83%); brown solid; mp 198.2–199.6 °C.

IR (KBr): 3578, 3367, 1928, 1747, 1247, 1050, 881, 780, 747, 725, 680, 634 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.57 (s, 1 H, OH), 9.54 (s, 1 H, NH), 8.28 (s, 1 H, NH), 8.02 (d, J = 8.7 Hz, 1 H, ArH), 7.73 (d, J = 2.1 Hz, 1 H, ArH), 7.30 (t, J = 8.0 Hz, 1 H, ArH), 7.21 (dd, J = 8.0, 2.0 Hz, 1 H, ArH), 6.99 (d, J = 2.5 Hz, 1 H, ArH), 6.94 (dd, J = 8.7, 2.3 Hz, 1 H, ArH), 6.78–6.65 (m, 1 H, ArH).

¹³C NMR (101 MHz, DMSO-d ₆): δ = 152.6, 147.3, 145.6, 141.7, 136.7, 133.7, 130.9, 127.6, 122.2, 120.3, 117.7, 116.8, 113.3.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₃H₁₁BrClN₂O₂: 340.9687; found: 340.9683.

 

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1-(2-Chlorophenyl)-3-(2-hydroxy-5-methylphenyl)urea (3p)

Yield: 44 mg (80%); brown solid; mp 189.7–190.6 °C.

IR (KBr): 3578, 3380, 2981, 1740, 1246, 1047, 891, 797, 750, 703, 669 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 9.64 (s, 1 H, OH), 8.94 (s, 1 H, NH), 8.93 (s, 1 H, NH), 8.11 (dd, J = 8.3, 1.6 Hz, 1 H, ArH), 7.87 (d, J = 2.1 Hz, 1 H, ArH), 7.44 (dd, J = 8.0, 1.5 Hz, 1 H, ArH), 7.28 (ddd, J = 8.6, 7.4, 1.6 Hz, 1 H, ArH), 7.02 (ddd, J = 8.0, 7.3, 1.6 Hz, 1 H, ArH), 6.74 (d, J = 8.0 Hz, 1 H, ArH), 6.63 (ddd, J = 8.0, 2.2, 0.9 Hz, 1 H, ArH), 2.20 (s, 3 H, CH₃).

¹³C NMR (101 MHz, DMSO-d ₆): δ = 152.9, 144.4, 136.7, 129.7, 127.9, 127.8, 127.7, 123.7, 122.9, 122.6, 120.5, 114.8, 21.1.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₄H₁₄ClN₂O₂: 277.0738; found: 277.0742.

 

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1-(4-Chloro-2-hydroxyphenyl)-3-(3-methoxyphenyl)urea (3q)

Yield: 45 mg (77%); brown solid; mp 189.7–190.6 °C.

IR (KBr): 3563, 3350, 2574, 1927, 1745, 1268, 1048, 873, 827, 747, 736, 705 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.31 (s, 1 H, OH), 9.41 (s, 1 H, NH), 8.32 (s, 1 H, NH), 8.21–8.14 (m, 1 H, ArH), 7.24–7.15 (m, 2 H, ArH), 6.91 (ddd, J = 8.1, 2.0, 0.9 Hz, 1 H, ArH), 6.87–6.82 (m, 2 H, ArH), 6.55 (ddd, J = 8.3, 2.5, 0.9 Hz, 1 H, ArH), 3.75 (s, 3 H, OCH₃).

¹³C NMR (101 MHz, DMSO-d ₆): δ = 160.1, 152.7, 144.8, 141.3, 130.0, 129.6, 123.1, 121.3, 118.0, 115.6, 110.7, 107.8, 104.1, 55.3.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₄H₁₄ClN₂O₃: 293.0687; found: 293.0689.

 

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1-(2-Hydroxy-5-methylphenyl)-3-(4-(trifluoromethoxy)phenyl)urea (3q)

Yield: 50 mg (81%); purple solid; mp 201.2–202.4 °C.

IR (KBr): 3552, 3327, 2991, 1744, 1246, 1049, 938, 850, 781, 740, 633 cm^–1.

¹H NMR (400 MHz, acetone-d ₆): δ = 8.85 (s, 1 H, OH), 8.82 (s, 1 H, NH), 7.89 (s, 1 H, NH), 7.79 (s, 1 H, ArH), 7.69–7.64 (m, 2 H, ArH), 7.29–7.23 (m, 2 H, ArH), 6.77 (d, J = 8.0 Hz, 1 H, ArH), 6.69 (dd, J = 8.3, 2.1 Hz, 1 H, ArH), 2.23 (s, 3 H, CH₃).

¹³C NMR (101 MHz, acetone-d ₆): δ = 152.9, 144.0, 143.4, 139.2, 128.8, 123.2, 121.6, 120.4 (J _C–F = 232 Hz), 119.5, 119.4, 115.2, 20.0.

¹⁹F NMR (376 MHz, acetone-d ₆): δ = –58.92.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₅H₁₄F₃N₂O₃: 327.0951; found: 327.0955.

 

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(2-Aminophenoxy)(phenyl)-λ³-iodaneyl 2,2,2-Trifluoroacetate (Int-1)

Under an air atmosphere, benzoxazole 1 (0.2 mmol, 1.0 equiv), (bis(trifluoroacetoxy)iodo)benzene (PIFA) (0.1 mmol, 1.0 equiv), Al₂O₃/H⁺ (1.0 equiv), and MeOH (1 mL) were added to a 10 mL reaction tube. The reaction tube was then placed in an oil bath and the contents were stirred at 60 °C for 2 h. After the reaction was complete, the solvent was removed from the mixture by vacuum distillation under reduced pressure. To the residue was added saturated NaCl solution (30 mL) and ethyl acetate (30 mL), and the solution was extracted three times. The combined organic layer was dried over anhydrous Na₂SO₄, filtered, and then distilled under reduced pressure. The crude residue was purified by silica gel column chromatography (PE/EtOAc = 6:1) to afford Int-1.

Yield: 16 mg (37%); white solid; mp 172.1–175.4 °C.

¹H NMR (600 MHz, DMSO-d ₆): δ = 7.76 (t, J = 7.6 Hz, 1 H, ArH), 7.60 (d, J = 8.0 Hz, 2 H, ArH), 7.42 (t, J = 7.8 Hz, 2 H, ArH), 6.99 (t, J = 7.6 Hz, 1 H, ArH), 6.71 (d, J = 7.7 Hz, 1 H, ArH), 6.64 (d, J = 8.0 Hz, 1 H, ArH), 6.41 (dd, J = 8.0, 7.3 Hz, 1 H, ArH).

¹³C NMR (151 MHz, DMSO-d ₆): δ = 173.87, 154.35, 136.38, 135.19, 131.56, 129.50, 127.54, 123.59, 121.50, 116.51 (J _C–F = 235 Hz), 116.23, 114.94.

¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –77.13.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₄H₁₂F₃INO₃: 425.9808; found: 425.9812.

 

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Conflict of Interest

The authors declare no conflict of interest.

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Publication History

Received: 19 June 2025

Accepted after revision: 24 August 2025

Accepted Manuscript online:
24 August 2025

Article published online:
08 October 2025