A Facile Synthesis of 2-Aminobenzoxazines Based on Iodine­Catalyzed Desulfurative Cyclization

Abstract

A facile and environmentally benign access to N-aryl/alkyl-4H-benzoxazin-2-amines is achieved from 1-[2-(hydroxymethyl)phenyl/alkyl]-3-phenylthioureas under transition-metal-free conditions. The conversions occur smoothly in the presence of a catalytic amount of molecular iodine and hydrogen peroxide as the oxidant in tetrahydrofuran at room temperature to afford moderate to good yields (28–90%) of the desired products within 2 hours. This method reports the first examples of the catalytic transformations of 1-[2-(hydroxymethyl)phenyl/alkyl]-3-phenylthioureas into N-aryl/alkyl-4H-benzoxazin-2-amines based on desulfurative cyclization.

Benzoxazine and its derivatives are important scaffolds in biologically active molecules such as pharmaceuticals and agrochemicals (Figure [1]).[1] Previous methods for the synthesis of the benzoxazines include the cyclization of thioureas mediated by 1,3-dicyclohexylcarbodiimide (DCC),[2] and starting from isothiocyanates, hypervalent-­iodine(III)-mediated desulfurative cyclization,[3] cyclization using 1,1′-(ethane-1,2-diyl)dipyridinium bistribromide (EDPBT) as a brominating reagent,[4] cyclodesulfurization with triphenylbismuth dichloride,[5] a Cu₂O/TBAB-promoted approach in water,[6] and cyclization mediated by stoichiometric iodine in the presence of a base[7] (Scheme [1]). However, these methods suffer from harsh reaction conditions, moderate yields, and the use of expensive and/or stoichiometric amounts of reagents.[8] Therefore, the development of an efficient and environmentally benign method for the synthesis of benzoxazines is still highly desirable. It was assumed that the target molecules could be prepared using a catalytic amount of iodine in the presence of an oxidant.[9] In continuation of our studies directed toward the synthesis of heterocycles using iodine-based reagents,[10] we now describe the molecular-iodine-catalyzed synthesis of N-aryl/alkyl-4H-benzoxazin-2-amines 2 from 1-[2-(hydroxy­methyl)phenyl/alkyl]-3-phenylthioureas 1 under mild reaction conditions.

The optimization studies for the formation of benzoxazines from thioureas were conducted using 1-[2-(hydroxymethyl)phenyl]-3-phenylthiourea (1a)[2] as a model substrate (Table [1]). The reaction of thiourea 1a in the presence of 20 mol% of iodine, triethylamine (2 equiv), and hydrogen peroxide (2 equiv) in ethanol at room temperature for 2 hours produced the desired N-phenyl-4H-benzoxazin-2-amine 2a in 85% yield (entry 2). On performing the reaction in tetrahydrofuran the yield increased slightly to 90% (entry 3). When the catalytic amount of iodine was reduced to 10 mol%, the yield decreased to 76% (entry 4). Increasing the reaction time was not effective in improving the yield due to the formation of unknown impurities (entry 5). Control experiments without the use of an oxidant, a base or iodine resulted in decreased yields for each conversion (entries 8–10), respectively. When tert-butyl hydroperoxide (TBHP) was utilized instead of hydrogen peroxide, the yield decreased to 34% (entry 11). Some typical Lewis acids have also been tested as catalysts for this system. Although the reactions using copper(I) iodide and zinc iodide afforded moderate yields of 2a (entries 13 and 14), aluminum trichloride and boron trifluoride–diethyl ether complex gave lower yields (entries 12 and 15), respectively. A gram-scale reaction was performed to provide 2a in 78% yield (entry 3).

Table 1 Optimization of the Conditions for the Cyclodesulfurization of 1a ^a

Entry	Catalyst (mol%)	Oxidant (equiv)	Base (equiv)	Solvent	Time (h)	Yield (%)b
1	I2 (20)	H2O2 (2)	Et3N (2)	EtOH	1	58
2	I2 (20)	H2O2 (2)	Et3N (2)	EtOH	2	85
3	I2 (20)	H2O2 (2)	Et3N (2)	THF	2	90 (78)c
4	I2 (10)	H2O2 (2)	Et3N (2)	THF	2	76
5	I2 (10)	H2O2 (2)	Et3N (2)	THF	3	51
6	I2 (10)	H2O2 (2)	Et3N (2)	THF	1	67
7	I2 (10)	H2O2 (3)	Et3N (3)	THF	2	78
8	I2 (10)	none	Et3N (2)	THF	2	10
9	I2 (10)	H2O2 (2)	none	THF	2	44
10	none	H2O2 (2)	Et3N (2)	THF	2	7
11	I2 (20)	TBHP (2)	Et3N (2)	THF	2	34
12	AlCl3 (20)	H2O2 (2)	Et3N (2)	THF	2	8
13	CuI (20)	H2O2 (2)	Et3N (2)	THF	2	41
14	ZnI2 (20)	H2O2 (2)	Et3N (2)	THF	2	52
15	BF3·OEt2	H2O2 (2)	Et3N (2)	THF	2	12

^a All reactions were carried out with 1a (0.5 mmol) and solvent (2 mL, 0.5 M).

^b Yield of isolated product.

^c A gram-scale synthesis using 1a (2.0 g, 7.8 mmol) to give 2a (1.4 g, 6.2 mmol).

With optimized reaction conditions in hand (Table [1], entry 3), we next investigated the scope and limitations of the iodine-catalyzed cyclodesulfurization of thioureas 1 (Scheme [2]). Concerning the substituents R² on the aromatic ring derived from the isothiocyanate, both electron-donating (methyl and methoxy) and electron-withdrawing (bromo­, chloro, fluoro and trifluoromethyl) groups at ortho, meta­, and para positions tolerated the reaction to afford the corresponding benzoxazines 2b–h in good to excellent yields (66–85%). With regard to substituents R¹ on the aromatic moiety derived from 2-aminobenzyl alcohol, the presence of both electron-donating and electron-withdrawing (methyl and chloro) was tolerated in the reaction to afford the benzoxazines 2i–l in good to excellent yields (50–86%). Concerning substrate 1m with a non-aromatic N-substituent, N-benzylbenzoxazine 2m was obtained in a good yield of 69%. However, the reactions of other N-alkylthioureas afforded complex mixtures of products. Substrate 1o possessing a cyano substituent was transformed into the expected product 2o; however, substrate 1n with a nitro group did not react to afford benzoxazine 2n, instead the starting material 1n was recovered. The N-substituted thiourea 1p was transformed into the corresponding benz­oxazine 2p, albeit in a low yield (28%) under the optimized conditions.

The one-pot synthesis of benzoxazine 2a was performed starting from 2-aminobenzyl alcohol and phenyl­isothiocyanate as model substrates (Scheme [3]). The reaction of 2-aminobenzyl alcohol and phenylisothiocyanate in THF at room temperature for 3 hours afforded thiourea 1a, which was directly subjected to the standard cyclization conditions to provide the desired benzoxazine 2a in an isolated yield of 47%.

To demonstrate the applicability of the products, the further derivation of benzoxazine 2c was performed (Scheme [4]). The Suzuki–Miyaura cross-coupling of 2c with 4-chloroboronic acid provided product 3a in 61% yield.[11]

A plausible mechanism for the formation of benzoxazines 2 from thioureas 1 in the presence of molecular iodine is illustrated in Scheme [5]. The mechanism has been postulated based on control experiments (see Table [1], entries 8–10) and related reactions.[7] [8] [9] [12] [13] The reaction of triethylamine and thiourea 1a forms the thiolate ion I, which reacts with hypoiodous acid (IOH) derived from iodine and hydrogen peroxide[12] to generate the intermediate II.[13] Intramolecular nucleophilic attack of the alkoxide in III, derived from II by the action of IOH, on the iminium carbon formed cyclized intermediate IV.[7] The release of sulfur and iodide from IV then produced benzoxazine 2a. It is tentatively assumed that the failure of the nitro-group-containing thiourea 1n to react (see Scheme [2]) was due to inhibition of the conversion of intermediate I into II caused by the inductive effect of the strongly electron-donating nitro group.

In conclusion, we have described a molecular-iodine-catalyzed, facile and rapid access to benzoxazines 2 from thioureas 1 under mild reaction conditions (room temperature, 2 h). This method represents the first catalytic conversion of thioureas 1 into benzoxazines 2. The reactions occur smoothly by employing readily available reagents (I₂, H₂O₂, Et₃N, and THF). Surprisingly, twelve of the benzoxazines prepared in this study are novel compounds. This procedure is expected to serve as an efficient process for the construction of substituted benzoxazines toward the development of novel drug candidates.

Reagents were commercially available and were used without purification. THF was distilled over sodium. BW–200 (Fuji Silysia Chemical) silica gel was used for column chromatography. Melting points were determined using a J-Science RFS-10 melting point apparatus and are uncorrected. IR spectra were obtained using a JASCO Corporation FT/IR-460 Plus spectrophotometer as KBr disks. ¹H NMR (500 MHz) and ¹³C NMR (125 MHz) spectra were recorded on a JEOL-ECZ R-series 500 MHz spectrometer. ¹H NMR spectra are referenced to tetramethylsilane as an internal standard or to the solvent signal (DMSO-d ₆: 2.50 ppm). ¹³C NMR spectra are referenced to solvent signals (CDCl₃: 77.0 ppm or DMSO-d ₆: 39.52 ppm). High-resolution mass spectra (HRMS) were recorded on a Bruker microTOF instrument.

N-Phenyl-4H-3,1-benzoxazin-2-amines; General Procedure

To a solution of the N-[2-(hydroxymethyl)phenyl]-N′-phenylthiourea derivative 1 (0.50 mmol) and iodine (25 mg, 0.10 mmol, 20 mol%) in THF (2 mL, 0.5 M) was added triethylamine (101 mg, 1.0 mmol) and 30% aqueous hydrogen peroxide solution (113 mg, 1.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h and then quenched with saturated aq Na₂S₂O₃ and extracted with CH₂Cl₂. The organic layers were washed with brine, dried over Na₂SO₄ and the solvent evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane/EtOAc, 3:1 or 4:1) to afford the corresponding N-phenyl-4H-3,1-benzoxazine-2-amine 2.

N-Phenyl-4H-3,1-benzoxazin-2-amine (2a)[7]

Yield: 101 mg (90%); white solid; mp 143–145 °C (Lit.[4] 140–142 °C); R_f = 0.61 (hexane/EtOAc, 2:1).

¹H NMR (500 MHz, CDCl₃): δ = 7.41 (d, J = 8.1 Hz, 2 H, Ar), 7.29 (dd, J = 8.1, 8.1 Hz, 2 H, Ar), 7.24–7.20 (m, 1 H, Ar), 7.04 (t, J = 7.2 Hz, 1 H, Ar), 7.20–6.98 (m, 3 H, Ar), 5.23 (s, 2 H, CH₂).

¹³C NMR (125 MHz, CDCl₃): δ = 152.0, 141.3, 139.5, 129.2, 129.0 (2 C), 123.8, 123.2, 123.1, 121.4, 121.0, 120.4 (2 C), 67.8.

N-(3-Fluorophenyl)-4H-3,1-benzoxazin-2-amine (2b)

Yield: 94 mg (78%); pale yellow solid; mp 114–116 °C; R_f = 0.63 (hexane­/EtOAc, 2:1).

IR (KBr): 3060, 2995, 2870, 1694, 1604, 1491, 1409, 1315, 1265, 1136, 1029, 974, 893, 873, 787, 754, 687 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.37 (d, J = 11.4 Hz, 1 H, Ar), 7.24–7.19 (m, 2 H, Ar), 7.04–7.00 (m, 4 H, Ar), 6.73 (ddd, J = 8.3, 8.3, 2.1 Hz, 1 H, Ar), 5.25 (s, 2 H, CH₂).

¹³C NMR (125 MHz, CDCl₃): δ = 163.3 (d, ¹ J _C–F = 242.4 Hz), 151.4, 141.8 (d, ³ J _C–F = 10.8 Hz), 140.5, 130.03, 129.99 (d, ³ J _C–F = 9.6 Hz), 129.3, 123.9, 123.4, 121.0, 120.8, 109.7 (d, ² J _C–F = 21.6 Hz), 107.8 (d, ² J _C–F = 25.1 Hz), 68.0.

HRMS (ESI-negative): m/z [M – H]^– calcd for C₁₁H₁₀FN₂O: 241.0783; found: 241.0780.

N-(4-Bromophenyl)-4H-3,1-benzoxazin-2-amine (2c)[3]

Yield: 123 mg (81%); white solid; mp 169–170 °C (Lit.[4] 182–184 °C); R_f = 0.58 (hexane/EtOAc, 3:1).

¹H NMR (500 MHz, CDCl₃): δ = 7.39 (d, J = 8.6 Hz, 2 H, Ar), 7.27 (d, J = 8.6 Hz, 2 H, Ar), 7.24–7.21 (m, 1 H, Ar), 7.04–7.00 (m, 2 H, Ar), 6.96 (d, J = 8.1 Hz, 1 H, Ar), 5.23 (s, 2 H, CH₂).

¹³C NMR (125 MHz, CDCl₃): δ = 151.5, 140.5, 139.4, 131.9 (2 C), 129.3, 124.0, 123.3, 122.3 (2 C), 120.7, 120.6, 115.7, 68.0.

N-(2-Bromophenyl)-4H-3,1-benzoxazin-2-amine (2d)

Yield: 129 mg (85%); beige solid; mp 148–150 °C; R_f = 0.79 (hexane/ EtOAc, 3:1).

IR (KBr): 3458, 3057, 2873, 1675, 1590, 1497, 1462, 1408, 1266, 1032, 746 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 8.13 (d, J = 8.0 Hz, 1 H, Ar), 7.54 (dd, J = 8.0, 1.2 Hz, 1 H, Ar), 7.32 (ddd, J = 7.8, 7.8, 1.7 Hz, 1 H, Ar), 7.22 (ddd, J = 7.3, 7.3, 2.0 Hz, 1 H, Ar), 7.03–6.99 (m, 2 H, Ar), 6.95 (d, J = 8.0 Hz, 1 H, Ar), 6.92 (ddd, J = 7.7, 7.7, 1.7 Hz, 1 H, Ar), 5.23 (s, 2 H, CH₂).

¹³C NMR (125 MHz, CDCl₃): δ = 150.6, 140.1, 138.8, 132.5, 129.2, 128.2, 124.0, 123.9, 123.4, 122.3, 120.7, 120.6, 114.7, 67.9.

HRMS (ESI-negative): m/z [M – H]^– calcd for C₁₄H₁₀BrN₂O: 300.9982; found: 300.9962.

N-(2-Chlorophenyl)-4H-3,1-benzoxazin-2-amine (2e)

Yield: 90 mg (70%); white solid; mp 152–153 °C; R_f = 0.72 (hexane/ EtOAc, 2:1).

IR (KBr): 2871, 1680, 1592, 1500, 1463, 1410, 1271, 1036, 749 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 8.20 (d, J = 8.0 Hz, 1 H, Ar), 7.36 (dd, J = 8.0, 1.2 Hz, 1 H, Ar), 7.28 (ddd, J = 7.9, 7.9, 1.4 Hz, 1 H, Ar), 7.22 (ddd, J = 7.5, 7.5, 1.5 Hz, 1 H, Ar), 7.04–6.96 (m, 4 H, Ar), 5.23 (s, 2 H, CH₂).

¹³C NMR (125 MHz, CDCl₃): δ = 150.7, 140.3, 137.2, 129.2 (2xC), 127.6, 123.9, 123.8, 123.5 (2xC), 121.9, 121.0, 120.8, 67.9.

HRMS (ESI-negative): m/z [M – H]^– calcd for C₁₄H₁₀ClN₂O: 257.0487; found: 257.0483.

N-(4-Methylphenyl)-4H-3,1-benzoxazin-2-amine (2f)

Yield: 93 mg (78%); white solid; mp 113–116 °C; R_f = 0.65 (hexane/ EtOAc, 2:1).

IR (KBr): 2913, 2865, 1695, 1599, 1498, 1410, 1242, 1028, 830, 750 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.29 (d, J = 8.6 Hz, 2 H, Ar), 7.23–7.20 (m, 1 H, Ar), 7.10 (d, J = 8.6 Hz, 2 H, Ar), 7.01–6.98 (m, 3 H, Ar), 5.22 (s, 2 H, CH₂), 2.31 (s, 3 H, CH₃).

¹³C NMR (125 MHz, CDCl₃): δ = 152.3, 141.6, 136.7, 132.8, 129.6 (2 C), 129.2, 123.8, 123.0, 121.4, 121.0, 120.7 (2 C), 67.8, 20.9.

HRMS (ESI-negative): m/z [M – H]^– calcd for C₁₅H₁₃N₂O: 237.1033; found: 237.1028.

N-(3-Trifluoromethylphenyl)-4H-3,1-benzoxazin-2-amine (2g)

Yield: 107 mg (73%); pale yellow solid; mp 150–152 °C; R_f = 0.35 (hexane­/EtOAc, 2:1).

IR (KBr): 3447, 2965, 2848, 1664, 1592, 1484, 1428, 1404, 1335, 1304, 1255, 1236, 1169, 1122, 1072, 1029, 956, 888, 868, 777, 761, 715, 696 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.32 (d, J = 8.6 Hz, 1 H, Ar), 7.25–7.19 (m, 1 H, Ar), 7.00–6.87 (m, 3 H, Ar), 6.86 (dd, J = 6.3, 2.3 Hz, 1 H, Ar), 5.20 (s, 2 H, CH₂), 3.79 (s, 3 H, CH₃).

¹³C NMR (125 MHz, CDCl₃): δ = 156.0, 152.2, 141.7, 132.3, 129.1 (2 C), 123.7, 122.8, 122.4, 121.5, 120.9, 114.3 (2 C), 67.8, 55.6.

HRMS (ESI-negative): m/z [M – H]^– calcd for C₁₅H₁₀F₃N₂O: 291.0751; found: 291.0753.

N-(2-Methoxyphenyl)-4H-3,1-benzoxazin-2-amine (2h)[7]

Yield: 84 mg (66%); pale yellow solid; mp 100–102 °C (Lit.[4] 92–94 °C); R_f = 0.56 (hexane/EtOAc, 2:1).

¹H NMR (500 MHz, CDCl₃): δ = 8.40 (dd, J = 7.2, 2.0 Hz, 1 H, Ar), 7.25 (ddd, J = 7.6, 7.6, 1.4, 1 H, Ar), 7.12 (d, J = 8.0 Hz, 1 H, Ar), 7.01 (ddd, J = 7.5, 7.5, 1.2 Hz, 1 H, Ar), 7.00–6.96 (m, 3 H, Ar), 6.87–6.85 (m, 1 H, Ar), 5.24 (s, 2 H, CH₂), 3.85 (s, 3 H, CH₃).

¹³C NMR (125 MHz, CDCl₃): δ = 151.5, 148.0, 141.9, 129.1, 128.3, 123.7, 123.3, 122.7, 122.4, 121.4, 121.2, 119.2, 110.0, 67.7, 55.8.

6-Methyl-2-(phenylamino)-4H-3,1-benzoxazine (2i)

Yield: 102 mg (86%); white solid; mp 134–136 °C; R_f = 0.65 (hexane/ EtOAc, 2:1).

IR (KBr): 3475, 2860, 1686, 1598, 1503, 1393, 1313, 1266, 1218, 1031, 931, 814, 751, 697 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.41 (d, J = 7.4 Hz, 2 H, Ar), 7.29 (dd, J = 8.6, 7.4 Hz, 2 H, Ar), 7.04–7.01 (m, 2 H, Ar), 6.92 (d, J = 8.0 Hz, 1 H, Ar), 6.80 (s, 2 H, Ar), 5.19 (s, 2 H, CH₂), 2.30 (s, 3 H, CH₃).

¹³C NMR (125 MHz, CDCl₃): δ = 151.6, 139.5, 138.8, 132.8, 129.7, 129.0 (2 C), 124.4, 123.0, 121.4, 120.9, 120.2 (2 C), 67.8, 21.0.

HRMS (ESI-negative): m/z [M – H]^– calcd for C₁₅H₁₃N₂O: 237.1033; found: 237.1031.

6-Methyl-2-[(4-methoxyphenyl)amino]-4H-3,1-benzoxazine (2j)

Yield: 81 mg (61%); white solid; mp 117–119 °C; R_f = 0.37 (hexane/ EtOAc, 2:1).

IR (KBr): 2902, 1879, 1649, 1607, 1505, 1453, 1240, 1103, 1035, 939, 817, 745, 712 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.34–7.25 (m, 2 H, Ar), 7.01 (d, J=8.0 Hz, 1 H, Ar), 6.89 (d, J = 8.0 Hz, 1 H, Ar), 6.85 (dd, J = 6.9, 2.3 Hz, 2 H, Ar), 6.78 (s, 1 H, Ar), 5.16 (s, 2 H, CH₂), 3.78 (s, 3 H, CH₃), 2.29 (s, 3 H, OCH₃).

¹³C NMR (125 MHz, CDCl₃): δ = 155.9, 151.8, 143.3, 139.1, 132.4, 129.6, 124.2, 122.2 (2 C), 121.4, 120.8, 114.3 (2 C), 67.8, 55.6, 20.9.

HRMS (ESI-positive): m/z [M + H]⁺ calcd for C₁₆H₁₇N₂O₂: 269.1287; found: 269.1285.

7-Chloro-2-(phenylamino)-4H-3,1-benzoxazine (2k)

Yield: 65 mg (50%); white solid; mp 150–152 °C; R_f = 0.36 (hexane/ EtOAc, 4:1).

IR (KBr): 3451, 3056, 2821, 1694, 1652, 1592, 1483, 1385, 1250, 1201, 1079, 1023, 869, 801, 743, 694, 644 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.45 (d, J = 7.8 Hz, 2 H, Ar), 7.32 (dd, J = 7.8, 7.7 Hz, 2 H, Ar), 7.07 (t, J = 7.7 Hz, 1 H, Ar), 7.04 (d, J = 2.3 Hz, 1 H, Ar), 6.97 (dd, J = 8.1, 2.3 Hz, 1 H, Ar), 6.89 (d, J = 8.1 Hz, 1 H, Ar), 5.19 (s, 2 H, CH₂).

¹³C NMR (125 MHz, CDCl₃): δ = 152.5, 143.2, 138.5, 134.6, 129.1 (2 C), 124.7, 123.6, 123.1, 122.2, 120.2 (2 C), 119.5, 67.4.

HRMS (ESI-negative): m/z [M – H]^– calcd for C₁₄H₁₀ClN₂O: 257.0487; found: 257.0491.

7-Chloro-2-[(3-fluorophenyl)amino]-4H-3,1-benzoxazine (2l)

Yield: 86 mg (62%); white solid; mp 115–117 °C; R_f = 0.31 (hexane/ EtOAc, 4:1).

IR (KBr): 3468, 3185, 1649, 1584, 1478, 1429, 1388, 1250, 1148, 1080, 1043, 921, 853, 795, 768, 709, 679 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.45 (d, J = 11.0 Hz, 1 H, Ar), 7.23–7.21 (m, 1 H, Ar), 7.05–7.03 (m, 2 H, Ar), 7.00 (dd, J = 8.1, 2.3 Hz, 1 H, Ar), 6.91 (d, J = 8.1 Hz, 1 H, Ar), 6.76 (ddd, J = 9.2, 9.2, 2.4 Hz, 1 H, Ar), 5.21 (s, 2 H, CH₂).

¹³C NMR (125 MHz, CDCl₃): δ = 163.3 (d, ¹ J _C–F = 243.6 Hz), 151.8, 142.4, 140.5 (d, ³ J _C–F = 7.3 Hz), 134.7, 130.1 (d, ³ J _C–F = 9.6 Hz), 124.8, 123.5, 122.0, 119.3, 115.4, 110.1 (d, ² J _C–F = 21.6 Hz), 107.5 (d, ² J _C–F = 26.4 Hz), 67.6.

HRMS (ESI-negative): m/z [M – H]^– calcd for C₁₄H₉ClFN₂O: 275.0393; found: 275.0376.

N-(Phenylmethyl)-4H-3,1-benzoxazin-2-amine (2m)[14]

Yield: 82 mg (69%); yellow solid; mp 126–128 °C (Lit.[11] 131–132 °C); R_f = 0.24 (hexane/EtOAc, 4:1).

¹H NMR (500 MHz, CDCl₃): δ = 7.34–7.31 (m, 4 H, Ar), 7.28–7.26 (m, 1 H, Ar), 7.20 (ddd, J = 7.9, 7.9, 2.0 Hz, 1 H, Ar), 6.99–6.92 (m, 3 H, Ar), 5.12 (s, 2 H, CH₂), 4.53 (s, 2 H, CH₂).

¹³C NMR (125 MHz, CDCl₃): δ = 155.1, 142.8, 138.8, 129.1, 128.8 (2 C), 127.7 (2 C), 127.6, 123.6, 122.5, 121.9, 121.2, 67.7, 45.7.

N-(4-Cyanophenyl)-4H-3,1-benzoxazin-2-amine (2o)

Yield: 87 mg (70%); white solid; mp 163–165 °C; R_f = 0.51 (hexane/ EtOAc, 1:1).

IR (KBr): 3191, 3068, 2218, 1906, 1593, 1402, 1342, 1237, 1178, 1041, 934, 833, 756, 706 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.56 (d, J = 8.5 Hz, 1 H, Ar), 7.49 (d, J = 8.5 Hz, 1 H, Ar), 7.24 (ddd, J = 8.0, 7.5, 2.0 Hz, 1 H, Ar), 7.05 (dd, J = 8.0, 7.5 Hz, 1 H, Ar), 7.03 (d, J = 8.0 Hz, 1 H, Ar), 6.96 (d, J = 8.0 Hz, 1 H, Ar), 5.26 (s, 2 H, CH₂).

¹³C NMR (125 MHz, CDCl₃): δ = 150.8, 144.9, 139.6, 133.2, 132.9 (2 C), 129.4, 124.0, 123.9, 120.6, 120.5 (2 C), 119.4, 105.5, 68.1.

HRMS (ESI-positive): m/z [M + H]⁺ calcd for C₁₅H₁₂N₃O: 250.0975; found: 250.0979.

(Z)-N-(1-Methyl-1H-benzo[d][1,3]oxazin-2(4H)-ylidene)aniline (2p)

Yield: 33 mg (28%); mp 89–90 °C; white solid; R_f = 0.39 (hexane/EtOAc, 2:1).

IR (KBr): 3020, 2988, 2919, 2870, 1658, 1587, 1473, 1387, 1351, 1315, 1238, 1206, 1136, 1079, 1024, 764 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.36 (ddd, J = 7.7, 7.7, 1.7 Hz, 1 H, Ar), 7.28 (tt, J = 7.7, 7.7, 2.3 Hz, 1 H, Ar), 7.11 (dd, J = 7.7, 1.7 Hz, 1 H, Ar), 7.04−6.97 (m, 5 H), 4.97 (s, 2 H, CH₂), 3.49 (s, 3 H, CH₃).

¹³C NMR (125 MHz, CDCl₃): δ = 148.2, 147.6, 139.8, 129.3, 128.6 (2 C), 124.3, 123.4 (2 C), 122.5, 122.2, 121.8, 113.0, 66.9, 32.8.

HRMS (ESI-positive): m/z [M + H]⁺ calcd for C₁₅H₁₅N₂O [M – H]⁺: 239.1177; found: 239.1179.

N-Phenyl-4H-3,1-benzoxazin-2-amine (2a); One-Pot Synthesis

To a solution of 2-aminobenzyl alcohol (62 mg, 0.50 mmol) in THF (2 mL, 0.5 M) was added phenyl isothiocyanate (68 mg, 0.50 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 h. Next, iodine (25 mg, 0.10 mmol, 20 mol%), triethylamine (101 mg, 1.0 mmol), and 30% aqueous hydrogen peroxide solution (113 mg, 1.0 mmol) were added and the resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated aq Na₂S₂O₃ and extracted with CH₂Cl₂. The organic layers were washed with brine, dried over Na₂SO₄ and the solvent evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane/EtOAc, 3:1) to afford N-phenyl-4H-3,1-benzoxazin-2-amine (2a) (112 mg, 47%) as a white solid.

N-(4′-Chloro-[1,1′-biphenyl]-4-yl)-4H-3,1-benzoxazin-2-amine (3a)

To a solution of N-(4-bromophenyl)-4H-3,1-benzoxazin-2-amine (2c) (211 mg, 0.7 mmol), p-chlorophenylboronic acid (131 mg, 0.84 mmol) and potassium carbonate (242 mg, 1.75 mmol) in DMF/H₂O (3:1) was added tetrakis(triphenylphosphine) palladium (81 mg, 0.07 mol) at 60 °C under Ar. The reaction mixture was then stirred at 60 °C under Ar overnight. The reaction was quenched with water and extracted with diethyl ether. The combined organic layer was washed with brine, dried over Na₂SO₄ and the solvent evaporated in va­cuo. The residue was purified by silica gel column chromatography (n-hexane/EtOAc, 3:1) to afford N-(4′-chloro-[1,1′-biphenyl]-4-yl)-4H-3,1-benzoxazin-2-amine (3a).

Yield: 143 mg (61%); white solid; mp 183–185 °C; R_f = 0.24 (hexane/ EtOAc, 3:1).

IR (KBr): 3430, 2867, 1685, 1596, 1480, 1400, 1245, 1094, 1036, 816, 754 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.50–7.48 (m, 6 H, Ar), 7.38 (d, J = 8.6 Hz, 2 H, Ar), 7.26–7.22 (m, 1 H, Ar), 7.04–7.01 (m, 3 H, Ar), 5.26 (s, 2 H, CH₂).

¹³C NMR (125 MHz, CDCl₃): δ = 151.8, 141.0, 139.3 (2 C), 134.6, 133.0, 129.3, 129.0 (2 C), 128.1 (2 C), 127.5 (2 C), 123.9, 123.3, 121.3, 120.9, 120.7 (2 C), 67.9.

HRMS (ESI-negative): m/z [M – H]^– calcd for C₂₀H₁₄N₂ClO: 333.0800; found: 333.0803.

Conflict of Interest

The authors declare no conflict of interest.

• References

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Related studies including I₂/TBHP-mediated oxidative coupling of 2-aminobenzyl alcohols with isocyanides and cyclization of ureas derived from anthranilic acids and isocyanates using a polymer-supported carbodiimide have also been reported, see:
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For recent advances on iodine-mediated organic synthesis, see:
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Corresponding Author

Publication History

Received: 30 May 2021

Accepted after revision: 16 August 2021

Article published online:
05 October 2021

© 2021. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References

• 1a Gromachevskaya EV, Kvitkovskii FV, Kosulina TP, Kul’nevich VG. Chem. Heterocycl. Compd. 2003; 39: 137
  CrossrefSearch in Google Scholar
• 1b Djabrouhou N, Guermouche M.-H. J. Pharm. Biomed. Anal. 2014; 100: 11
  CrossrefPubMedSearch in Google Scholar
• 1c Zhang P, Terefenko EA, Fensome A, Wrobel J, Winneker R, Lundeen S, Marschke KB, Zhang Z. J. Med. Chem. 2002; 45: 4379
  CrossrefPubMedSearch in Google Scholar
• 1d Zhang P, Terefenko EA, Fensome A, Zhang Z, Zhu Y, Cohen J, Winneker R, Wrobel J, Yardley J. Bioorg. Med. Chem. Lett. 2002; 12: 787
  CrossrefPubMedSearch in Google Scholar
• 2 You S.-W, Lee K.-J. Bull. Korean Chem. Soc. 2001; 22: 1270
  CrossrefSearch in Google Scholar
• 3 Ghosh H, Yella R, Nath J, Patel BK. Eur. J. Org. Chem. 2008; 6189
  Crossref
• 4 Yella R, Patel BK. J. Comb. Chem. 2010; 12: 754
  CrossrefPubMedSearch in Google Scholar
• 5 Murata Y, Matsumoto N, Miyata M, Kitamura Y, Kakusawa N, Matsumura M, Yasuike S. J. Organomet. Chem. 2018; 859: 18
  CrossrefSearch in Google Scholar
• 6 Zhang J, Chen L, Dong Y, Yang J, Wu Y. Org. Biomol. Chem. 2020; 18: 7425
  CrossrefPubMedSearch in Google Scholar
• 7 Putta VP. R. K, Vodnala N, Gujjarappa R, Tyagi U, Garg A, Gupta S, Pujar PP, Malakar CC. J. Org. Chem. 2020; 85: 380
  CrossrefPubMedSearch in Google Scholar

Related studies including I₂/TBHP-mediated oxidative coupling of 2-aminobenzyl alcohols with isocyanides and cyclization of ureas derived from anthranilic acids and isocyanates using a polymer-supported carbodiimide have also been reported, see:
• 8a Wang H.-X, Wei T.-Q, Xu P, Wang S.-Y, Ji S.-J. J. Org. Chem. 2018; 83: 13491
  CrossrefPubMedSearch in Google Scholar
• 8b Buckman BO, Morrissey MM, Mohan R. Tetrahedron Lett. 1998; 39: 1487
  CrossrefSearch in Google Scholar

For recent advances on iodine-mediated organic synthesis, see:
• 9a Shantharjun B, Rajeswari R, Vani D, Unnava R, Sridhar B, Reddy KR. Asian J. Org. Chem. 2019; 8: 2162
  CrossrefSearch in Google Scholar
• 9b Hu S, Yang Z, Chen Z, Wu X.-F. Adv. Synth. Catal. 2019; 361: 4949
  CrossrefSearch in Google Scholar
• 9c Mani GS, Donthiboina K, Shankaraiah N, Kamal A. New J. Chem. 2019; 43: 15999
  CrossrefSearch in Google Scholar
• 9d Mani GS, Donthiboina K, Siddiq PS, Shankaraiah N, Kamal A. RSC Adv. 2019; 9: 27021
  CrossrefPubMedSearch in Google Scholar
• 9e Ghosh S, Chattopadhyay SK. Adv. Synth. Catal. 2019; 361: 4727
  CrossrefSearch in Google Scholar
• 9f Rong H.-J, Yang C.-F, Chen T, Wang Y.-Q, Ning B.-K. Tetrahedron Lett. 2019; 60: 150970
  CrossrefSearch in Google Scholar
• 9g For a review, see: Aggarwal T, Kumar S, Verma AK. Org. Biomol. Chem. 2016; 14: 7639
  CrossrefPubMedSearch in Google Scholar
• 10a Nariki H, Miyamura T, Matsui D, Sonoda M, Tanimori S. SynOpen 2020; 4: 99
  Thieme ConnectSearch in Google Scholar
• 10b Kamiya M, Sonoda M, Tanimori S. Tetrahedron 2017; 73: 1247
  CrossrefSearch in Google Scholar
• 10c Kashiwa M, Sonoda M, Tanimori S. Eur. J. Org. Chem. 2014; 4720
  Crossref
• 11 Liu J.-T, Simmons CJ, Xie H, Yang F, Zhao X.-l, Tang Y, Tang W. Adv. Synth. Catal. 2017; 359: 693
  CrossrefSearch in Google Scholar
• 12 Yusubov MS, Zhdankin VV. Resour.-Effic. Technol. 2015; 1: 49
  Search in Google Scholar
• 13 Yadav VK, Srivastava VP, Yadav LD. S. Tetrahedron Lett. 2018; 59: 252
  CrossrefSearch in Google Scholar
• 14 Garratt PJ, Hobbs CJ, Wrigglesworth R. Tetrahedron 1989; 45: 829
  CrossrefSearch in Google Scholar

• Supplementary Material