2-Nitroso-N-arylanilines: Products of Acid-Promoted Transformation of σ^H Adducts of Arylamines and Nitroarenes

Abstract

Anions generated from arylamines react with substituted nitrobenzenes to form σ^H adducts, which, under protonation with acetic acid, undergo transformation to 2-nitroso-N-arylamines, ­susceptible to reduction, condensation and cyclization reactions.

nucleophilic - additions - arenes - amines - nitroso group

References and Notes

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15

Melting points are uncorrected. ¹H and ¹³C NMR spectra were recorded on a Varian Mercury 400 instrument (400 MHz for ¹H NMR and 100 MHz for ¹³C NMR spectra) in CDCl₃. Chemical shifts (δ) are expressed in ppm referred to TMS, and coupling constants are given in Hz. ¹⁵N GHMBC experiment was performed on a Bruker 500 instrument in CDCl₃ at 273 K. Mass spectra (EI, 70 eV) were obtained on an AMD-604 spectrometer. Silica gel Merck 60 (230-400 mesh) was used for column chromatography.
2-Chloro-4-trifluoromethylonitrobenzene [20] (2d) and 4-chloro-2-methoxynitrobenzene [21] (2e) were obtained according to the literature. All other reagents are commercially available.
Preparation of 2-Nitroso- N -arylanilines 3a-i; General Procedure
To a cooled solution of t-BuOK (6 mmol, 672 mg) in DMF (2 mL) was added dropwise at -60 °C a solution of aniline 1 (2 mmol) in DMF (1 mL) and nitroarene 2 (2 mmol) in DMF (1 mL). The mixture was stirred at this temperature for 2-5 min, and then a cooled mixture of AcOH (1.5 mL) and DMF (1.5 mL) was added in one portion. The cooling bath was removed and the mixture was allowed to reach the ambient temperature, then it was poured into H₂O (ca. 50 mL) and extracted with EtOAc. The extract was washed with H₂O and brine, and dried with Na₂SO₄. After evaporation, the crude product mixture was subjected to column chromatography (SiO₂, hexane-benzene) to obtain products 3a-i. The representative examples of 3 are described below. 3a: Brown solid; mp 124-125 °C. ¹H NMR: δ = 7.09 (dd, J = 1.4, 10.2 Hz, 1 H), 7.05 (d, J = 1.7, 8.8 Hz, 1 H), 7.17-7.24 (m, 2 H), 7.39-7.45 (m, 2 H), 8.68 (br s, 1 H), 11.82 (br s, 1 H). ¹³C NMR: δ = 114.0, 119.1, 126.1, 130.0, 132.2, 135.0, 140.4 (br), 144.8, 154.9, one signal not observed. MS (EI): m/z (%) = 268 (7), 266 (11), 251 (66), 249 (100), 237 (18), 235 (26), 201 (22). HRMS (EI): m/z [M]⁺ calcd for C₁₂H₈ON₂ ³⁵Cl₂: 266.0014; found: 266.0024.
3d: Brown solid; mp 96-97 °C (hexane-benzene). ¹H NMR: δ = 2.38 (s, 3 H), 6.93 (d, J = 8.6 Hz, 1 H), 7.05 (d, J = 2.0 Hz, 1 H), 7.13 (br d, J = 8.2 Hz, 2 H), 7.23 (br d, J = 8.2 Hz, 2 H), 8.67 (br s, 1 H), 12.08 (br s, 1 H). ¹³C NMR: δ = 114.4, 118.5, 120.2, 124.9, 130.4, 133.4, 136.9, 141.8 (very br), 144.6, 154.9, one signal not observed. MS (EI): m/z (%) = 245 (6), 231 (42), 229 (100), 214 (22), 180 (25). HRMS (LSI): m/z [M + H]⁺ calcd for C₁₃H₁₂ON₂ ³⁵Cl: 247.0632; found: 247.0621. 3f: Brown solid; mp 106-107 °C. ¹H NMR (500 MHz, CDCl₃, -15 °C): δ = 2.37 (s, 3 H), 3.76 (s, 3 H), 6.35 (d, J = 2.1 Hz, 1 H), 6.57 (dd, J = 2.1, 9.2 Hz, 1 H), 7.17-7.25 (m, 4 H), 8.48 (d, J = 9.2 Hz, 1 H), 12.97 (br s, 1 H). ¹³C NMR: δ = 20.9, 55.7, 93.5, 109.3, 124.7, 130.2, 133.9, 136.4, 137.7, 142.4, 153.6, 167.0. ¹⁵N NMR (GHMBC, CDCl₃, δ relative to MeNO₂, 273 K): δ = -286.5 (N=O), 334 (J _NH = 91.9 Hz, NH). MS (EI): m/z (%) = 242 (16), 241 (15), 225 (100), 210 (15), 196 (15), 182 (21). HRMS (EI): m/z [M]⁺ calcd for C₁₄H₁₄O₂N₂: 242.1055; found: 242.1051.
Reduction of 3d with Zn/AcOH: To a solution of 2-nitroso-N-(4-tolyl)aniline 3d (0.15 mmol, 37.2 mg) in AcOH (1 mL), powdered Zn (150 mg) was added and the mixture was stirred at ambient temperature, while monitored by TLC. After the substrate had disappeared (ca. 1.5 h), the mixture was diluted with EtOAc (10 mL), filtered, washed with H₂O, sat. NaHCO₃ and H₂O, and then dried with Na₂SO₄. The solvent was evaporated and the crude product was purified by column chromatography (SiO₂, hexane-EtOAc, 5:1) to give 4a (26.2 mg, 75%).
4a: Brown solid; mp 65-66 °C(hexane) [Lit. [22] 66.5-67.5 °C (PE)]. ¹H NMR: δ = 2.68 (s, 3 H), 3.64 (br s, 2 H), 5.10 (br s, 1 H), 6.69 (d, J = 8.4 Hz, 1 H), 6.72-6.76 (m, 2 H), 6.89 (dd, J = 2.3, 8.4 Hz, 1 H), 7.04-7.08 (m, 3 H). ¹³C NMR: δ = 20.6, 116.9, 117.0, 121.7, 123.7, 123.8, 129.9, 130.0, 131.5, 138.6, 141.3. MS (EI): m/z (%) = 232 (100), 217 (59). HRMS (EI): m/z [M]⁺ calcd for C₁₃H₁₃N₂ ³⁵Cl: 232.0767; found: 232.0772.
Catalytic Hydrogenation of 3d: 2-Nitroso-N-(4-tolyl)aniline 3d (0.22 mmol, 55 mg), suspended (partially soluble) in MeOH (1 mL), Et₃N (0.44 mmol, 44 mg) and Pd/C (10%, 25 mg) were stirred under H₂ at r.t. for 30 min. The catalyst was filtered off and the solution was evaporated to dryness. The residue was diluted with EtOAc (10 mL) and H₂O (5 mL), and the organic layer was separated, washed with H₂O and dried with Na₂SO₄. After evaporation of the solvents, the crude product was purified by column chromatography (SiO₂, hexane-EtOAc, 4:1) to deliver 4b (37 mg, 84%).
4b: Brown solid; mp 77 °C(hexane). ¹H NMR: δ = 2.26 (s, 3 H), 3.67 (br s, 2 H), 5.26 (br s, 1 H), 6.65 (m, 2 H), 6.71-6.76 (m, 1 H), 6.78 (dd, J = 1.2, 7.8 Hz, 1 H), 6.95-7.00 (m, 1 H), 7.00-7.05 (m, 2 H), 7.08 (dd, J = 1.4, 7.8 Hz, 1 H). ¹³C NMR: δ = 20.4, 115.8, 116.1, 119.1, 123.8, 125.0, 128.8, 129.4, 129.8, 141.3, 142.62. MS (EI): m/z (%) = 198 (100), 183 (64), 91 (18). HRMS (EI): m/z [M]⁺ calcd for C₁₃H₁₄N₂: 198.1157; found: 198.1147.
Cyclization of 3a to 2,7-Dichlorophenazine ( 5): 2-Nitroso-N-(4-chlorophenyl)aniline 3a (0.1 mmol, 25 mg) in AcOH (3 mL) was refluxed for 1.5 h. After cooling down, the mixture was diluted with H₂O and the precipitated crude product was filtered off. Recrystallization from EtOH gave pure 5 (20 mg (80%).
5: Pale yellow solid; mp 265-266 °C (Lit. [23] 266-268 °C). MS (EI): m/z (%) = 250 (64), 248 (100), 213 (33).
Condensation of 3a with Methyl Malonate: 2-Nitroso-N-(4-chlorophenyl)aniline 3a (0.067 mmol, 18 mg), methyl malonate (0.14 mmol, 18 mg) and K₂CO₃ (75 mg) were stirred in MeCN (1 mL) at r.t. for 30 min. The mixture was diluted with MeCN, filtered and evaporated. The crude product was purified by column chromatography (SiO₂, hexane-EtOAc, 5:1) to obtain pure 6 (20 mg, 85%).
6: Yellowish crystals; mp 160-161 °C. ¹H NMR: δ = 4.03 (s, 3 H), 6.71 (d, J = 2.2 Hz, 1 H), 7.23-7.27 (m, 2 H), 7.35 (dd, J = 2.2, 8.6 Hz, 1 H), 7.60-7.65 (m, 2 H), 7.92 (d, J = 8.6 Hz, 1 H). ¹³C NMR: δ = 55.3, 115.2, 125.2, 129.5, 130.2, 130.9, 132.1, 132.8, 135.5, 136.3, 138.9, 148.8, 151.8, 163.4. MS (EI): m/z (%) = 350 (31), 348 (48), 263 (67), 261 (100), 226 (24), 191 (21). HRMS (EI): m/z [M]⁺ calcd for C₁₆H₁₀N₂O₃ ³⁵Cl₂: 348.0068; found: 348.0076.

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