Mendeleev Communications Electronic Version, Issue 5, 2001 1 Heterocyclization of N-[2-(cyclopent-1-enyl)phenyl]acetamides and ethyl N-[2-(cyclopent-1-enyl)phenyl]carbamates under the action of hydrogen peroxide Rail R. Gataullin,* Marat F. Nasyrov, Ol’ga V. Shitikova, Leonid V. Spirikhin and Il’dus B. Abdrakhmanov Institute of Organic Chemistry, Ufa Scientific Centre of the Russian Academy of Sciences, 450054 Ufa, Russian Federation.Fax: +7 3472 35 6066; e-mail: chemorg@anrb.ru 10.1070/MC2001v011n05ABEH001489 The oxidation of N-[2-(cyclopent-1-enyl)phenyl]acetamides and ethyl N-[6-methyl-2-(cyclopent-1-enyl)phenyl]carbamate with hydrogen peroxide in methanolic NaOH gave spiro[4H-3,1-benzoxazine-4,1'-cyclopentanes]. On the other hand, ethyl [2-(cyclopent- 1-enyl)phenyl]carbamate reacted with hydrogen peroxide in the presence of acetonitrile and NaOH to give ethyl 3a-hydroxy- 2,3,3a,8b-tetrahydrocyclopenta[b]indole-4(1H)-carboxylate, which was dehydrated with polyphosphoric acid to ethyl 2,3-dihydrocyclopenta[ b]indole-4(1H)-carboxylate.Benzoxazine derivatives exhibit considerable activity in the inhibition1 of chymase or reverse transcriptase of HIV-1.2 Recently, we have reported a convenient synthesis of 3,1-benzoxazines from ortho-(alk-1-enyl)anilides under the action of hydrogen chloride or bromine.3,4 At present, the cyclization of these anilides under the effect of oxidising agents as hydrogen peroxide has not been studied.In order to search for new methods of controllable heterocyclization of ortho-alkenylanilines, the effect of hydrogen peroxide on acetamides 1a,b and carbamates 1c,d† has been studied. Therefore, the reaction of 1a3 or 1c with hydrogen peroxide in the presence of sodium hydroxide in acetonitrile and methanol as solvents gave 8-methylspiro[4H-3,1-benzoxazine- 4,1'-cyclopentanes] 2a or 2c.‡ Under the same reaction conditions, carbamate 1d gave ethyl 3a-hydroxy-2,3,3a,8b-tetrahydrocyclopenta[ b]indole-4(1H)-carboxylate 4, the effect of polyphosphoric acid on which caused dehydration and gave ethyl 2,3-dihydrocyclopenta[b]indole-4(1H)-carboxylate 5.§ Compounds 1a–d were found to be sensitive to oxidation conditions.The interaction of 1d with H2O2 in the presence of Na2WO4 and H3PO4 resulted in 3,1-benzoxazinone 3. Under these conditions, amide 1b gives benzoxazine 2b in 85% yield.¶ Under the same conditions, anilides 1a and 1c did not react.To clarify the mechanism of the formation of 4, the wellknown reaction of aryl(cycloalk-1-enes) bearing no amine moiety with hydrogen peroxide, which leads to arylcycloalkylketones should be taken into account.5 Probably, 4 is formed by the intramolecular cyclization of intermediate A (Scheme 1), which was not detected in the reaction mixture most probably because of its high reactivity under alkaline conditions.The structure of compounds 1b–d, 2a–c, 3–5 was determined using spectral methods and elemental analyses. † General methods. 1H and 13C NMR spectra were recorded using a Bruker AM-300 spectrometer at 300.13 and 75.47 MHz (with Me4Si as an internal standard).IR spectra were recorded on a Specord M-80 spectrophotometer. The purity of initial compounds and reaction products was controlled with a Chrom 5 instrument and Silufol UV 25 plates. Mass spectra were recorded using an MH 1320 spectrometer (70 eV). Acetamide 1b was obtained according to the published method3 by the reaction of ortho-(cyclopent-1-enyl)aniline6 with acetic anhydride.General procedure for the synthesis of carbamates 1c and 1d. Ethyl chloroformate (1.3 g, 12 mmol) was added dropwise to a vigorously stirred mixture of ortho-(cyclopent-1-enyl)aniline6 or 2-methyl-6-(cyclopent- 1-enyl)aniline3 (10 mmol) and potassium carbonate (2.76 g, 20 mmol) in dichloromethane (20 ml) at 20 °C. After 1 h, water (2 ml) was added, the mixture was stirred, the precipitate was filtered off, and the filtrate was washed with water and dried (MgSO4).The solvent was evaporated in a vacuum, the products were isolated as a yellowish oil. 1c: yield 95%, mp 51–53 °C. 1H NMR (CDCl3) d: 1.30 (t, 3H, Me, J 7.31 Hz), 1.90–2.70 (m, 6H, 3CH2), 2.30 (s, 3H, Me), 4.15 (m, 2H, CH2), 5.90 (s, 1H, CH), 6.35 (s, 1H, NH), 7.10 (m, 3H, Ar). 13C NMR (CDCl3) d: 14.65 (Me), 18.34 (Me), 23.66 [C(4')], 33.51 [C(3')], 35.91 [C(5')], 61.14 (OCH2), 126.14 [C(5)], 126.73 [C(4)], 129.24 [C(2)], 130.91 [C(3)], 133.80 [C(6)], 136.37 [C(2')], 138.35 [C(1)], 141.33 [C(1')], 154.60 (C=O).Found (%): C, 73.19; H, 7.15; N, 5.43. Calc. for C15H19NO2 (%): C, 73.47; H, 7.76; N, 5.71. 1d: yield 95%, Rf 0.6 (hexane–EtOAc, 4:1). 1H NMR (CDCl3) d: 1.3 (t, 3H, Me, J 7.3 Hz), 2.0 (quint, 2H, CH2, J 7.8 Hz), 2.6 (br.s, 2H, CH2), 2.7 (br. s, 2H, CH2), 4.2 (q, 2H, CH2O, J 7.2 Hz), 5.9 (br. s, 1H, =CH), 7.0 (m, 1H, ArH), 7.1 (br. s, 1H, NH), 7.1–7.3 (m, 2H, ArH), 8.1 (d, 1H, ArH, J 8.1 Hz). 13C NMR (CDCl3) d: 14.3 (Me), 23.0, 33.5, 36.4 (3CH2), 61.0 (CH2O), 119.5 [C(6)], 122.7 [C(2')], 127.3 [C(4)], 127.5 [C(3)], 127.6 [C(2)], 129.9 [C(5)], 134.6 [C(1')], 140.3 [C(1)], 153.4 (C=O).Found (%): C, 72.68; H, 7.45; N, 5.99. Calc. for C14H17NO2 (%): C, 72.70; H, 7.41; N, 6.06. ‡ General procedure for the synthesis of spirobenzoxazinecyclopentanes 2a and 2c and tetrahydrocyclopentaindole 4. Acetamide 1a or carbamate 1c or 1d was added to a stirred solution of sodium hydroxide (0.2 g) in methanol (5 ml) and acetonitrile (5 ml).To the resulting mixture, an excess of a 50% hydrogen peroxide solution (1 g, 29.4 mmol) was added dropwise. Evolution of oxygen and an increase of the reaction temperature were observed upon standing for 2 h. A saturated sodium thiosulfate solution (10 ml) was added, extracted with dichloromethane and dried (MgSO4). The solvent was evaporated in vacuo, and the yellowish oily residue was purified by column chromatography using silica gel (5 g, eluent: hexane–EtOAc, 2:1) to give spirobenzoxazinecyclopentane 2a, which was recrystallised from ethyl acetate or spirobenzoxazinecyclopentane 2c, which crystallised upon standing or tetrahydrocyclopentaindole 4, which was obtained as an amorphous substance. 2a: yield 80%, mp 103 °C. 1HNMR (CDCl3) d: 1.7–2.0 (m, 2H, CH2), 2.1 (s, 3H, Me), 2.1–2.2 (m, 2H, CH2), 2.3 (s, 3H, Me), 2.4–2.5 (m, 2H, CH2), 2.9 (br.s, 1H, OH), 4.0 (d, 1H, CH, J 5.9 Hz), 7.0–7.3 (m, 3H, ArH). 13C NMR (CDCl3) d: 17.3, 21.8 (2Me), 20.6, 31.5, 34.4 (3CH2), 75.5 (CHOH), 90.2 [C(4)], 122.6 [C(6)], 123.5 [C(4a)], 125.4 [C(5)], 130.8 [C(7)], 132.4 [C(8)], 137.5 [C(8a)], 159.6 (C=N). MS, m/z: 231 (M+). Found (%): C, 72.45; H, 7.42; N, 6.30. Calc.for C14H17NO2 (%): C, 72.70; H, 7.41; N, 6.06. 2c: yield 63%, mp 105 °C. 1H NMR (CDCl3) d: 1.4 (t, 1H, Me, J 7.2 Hz), 1.7–2.2 (m, 6H, 3CH2), 2.3 (s, 3H, Me), 4.1 (br. s, 1H, CH–O), 4.4 (m, 2H, CH2), 5.0 (br. s, 1H, OH), 6.9–7.0 (m, 2H, ArH), 7.1 (d, 1H, ArH, J 8.1 Hz). 13C NMR (CDCl3) d: 14.2, 17.0 (2Me), 20.6, 31.4, 34.2 (3CH2), 64.3 (OCH2), 75.4 (CHOH), 93.5 [C(4)], 122.3 [C(4a)], 122.6 [C(6)], 123.2 [C(5)], 130.7 [C(7)], 131.7 [C(8)], 140.0 [C(8a)], 154.8 (C=O).Found (%): C, 68.42; H, 7.21; N, 5.40. Calc. for C15H19NO3 (%): C, 68.94; H, 7.33; N, 5.36. 4: yield 70%. 1H NMR (CDCl3) d: 1.3 (t, 3H, Me, J 7.6 Hz), 1.5–1.7 (m, 2H, CH2), 1.7–1.9 (m, 2H, CH2), 2.2–2.4 (m, 2H, CH2), 3.5–3.6 (m, 1H, CH), 4.3 (q, 2H, CH2, J 6.9 Hz), 7.0 (t, 1H, ArH, J 7.4 Hz), 7.1–7.3 (m, 3H, ArH), 7.6 (br.s, 1H, OH). 13C NMR (CDCl3) d: 14.6 (Me), 25.4 [C(2)], 34.0 [C(1)], 42.2 [C(3)], 53.2 [C(8b)], 61.9 (OCH2), 103.6 [C(3a)], 114.4 [C(5)], 123.2 [C(7)], 124.4 [C(8)], 129.0 [C(6)], 132.7 [C(8a)], 141.5 [C(4a)], 153.5 (C=O). Found (%): C, 67.83; H, 6.71; N, 5.78. Calc. for C14H17NO3 (%): C, 68.00; H, 6.93; N, 5.66. § Synthesis of tetrahydrocyclopentaindole 5.A mixture of tetrahydrocyclopentaindoline 4 (0.5 g, 2.02 mmol), phosphoric acid (85%) (3 g) and phosphorus pentoxide (2 g) was vigorously stirred and then left to stand for 10 h. The acid solution was neutralised with aqueous sodium hydroxide, extracted with benzene, and the organic extract was dried (NaOH). The solvent was evaporated to give crystalline tetrahydrocyclopentaindole 5.Yield 97%, mp 67 °C. 1H NMR (CDCl3) d: 1.4 (t, 3H, Me, J 6.2 Hz), 2.4 (q, 2H, CH2, J 7.0 Hz), 2.7 (t, 2H, CH2, J 6.8 Hz), 3.0 (t, 2H, CH2, J 6.6 Hz), 4.4 (q, 2H, CH2), 7.1–7.3 (m, 2H, ArH), 7.3 (d, 1H, J 7.4 Hz, H-8), 8.1 (d, 1H, H-5, J 6.2 Hz). 13C NMR (CDCl3) d: 14.5 (Me), 24.2, 27.5, 29.0 (3CH2), 62.8 (OCH2), 115.9 [C(5)], 118.7 [C(8)], 124.8 [C(6)], 125.1 [C(7)], 127.0 [C(8a)], 128.0 [C(8b)], 140.3 [C(3a)], 144.0 [C(4a)], 151.5 (C=O).Found (%): C, 74.01; H, 6.67; N, 6.00. Calc. for C14H15NO2 (%): C, 73.34; H, 6.59; N, 6.11.Mendeleev Communications Electronic Version, Issue 5, 2001 2 Finally, it must be concluded that the structure of products obtained (benzoxazine or indoline type) is dependent on the nature of protecting group and the type of catalysts used (tungstate –phosphoric acid or acetonitrile–alkali) despite that both of these systems are epoxydising.References 1 M.Gütschow, Sci. Pharm., 1999, 67, 524. 2 M. E. Pierce, R. L. Parsons, L. A. Radesca, Y. S. Lo, St. Silverman, J. R. Moore, Q. Islam, A. Choudhury, J. M. D. Fortunak, D. Nguyen, C. Luo, S. G. Morgan, W. P. Davis, P.N. Confalone, C. Chen, R. D. Tillyer, L. Frey, L. Tan, F. Xu, D. Zhao, A. S. Thomson, E. G. Corley, E. G. G. Grabowski, R. Robert and P. P. Reider, J. Org. Chem., 1998, 63, 8536. 3 R. R. Gataullin, I. S. Afonkin, I. V. Pavlova, A. A. Fatykhov, I. B. Abdrakhmanov and G. A. Tolstikov, Izv. Akad. Nauk, Ser. Khim., 1999, 398 (Russ. Chem. Bull., 1999, 48, 396). 4 R. R. Gataullin, I.S. Afonkin, A. A. Fatykhov, L. V. Spirikhin and I. B. Abdrakhmanov, Izv. Akad. Nauk, Ser. Khim., 2000, 118 (Russ. Chem. Bull., 2000, 49, 122). 5 E. N. Prilezhaeva, Reaktsiya Prilezhaeva. Elektrofil’noe okislenie (Prilezhaev Reaction. Electrophilic Oxidation), Nauka, Moscow, 1974, p. 332 (in Russian). 6 R. R. Gataullin, T. V. Kazhanova, A. A. Fatykhov, L. V. Spirikhin and I. B.Abdrakhmanov, Izv. Akad. Nauk, Ser. Khim., 2000, 171 (Russ. Chem. Bull., 2000, 49, 174). ¶ General procedure for the synthesis of spirobenzoxazinecyclopentane 2b and 3. A solution of sodium tungstate (50 mg, 0.17 mmol) in water (0.2 ml), one drop of conc. phosphoric acid and a solution of 50% of hydrogen peroxide (0.34 g, 4.98 mmol) were added to a solution of acetamide 1b or carbamate 1d (2.48 mmol) in methanol (5 ml).The reaction mixture was allowed to stand for 48 h at 30 °C, and then dichloromethane (50 ml) was added, washed with a saturated sodium thiosulfate solution followed by water and then the organic extracts were dried (MgSO4). The solvent was evaporated in vacuo to give an oil of spirobenzoxazinecyclopentanes 2b or 3, which crystallised on standing. 2b: yield 80%, mp 143 °C. 1H NMR (CDCl3) d: 1.7–2.0 (m, 2H, CH2), 2.0 (s, 3H, Me), 2.1–2.2 (m, 2H, CH2), 2.4–2.5 (m, 2H, CH2), 2.7 (br. s, Scheme 1 Reagents and conditions: i, H2O2, NaOH, MeCN+MeOH (1:1); ii, H2O2, Na2WO4, H3PO4; iii, PPA, 20 °C. NHC(O)R R1 1a–d a R = R1 = Me b R = Me, R1 = H c R = OEt, R1 = Me d R = OEt, R1 = H N O HO R1 R 2a–c N O HO O 3 H NHCO2Et A i, 1a–c ii, 1d i, 1d O N H OH CO2Et 4 iii N CO2Et 5 Received: 28th June 2001; Com. 01/1815 1H, OH), 4.1 (d, 1H, CH, J 4.62 Hz), 7.0 (d, 1H, J 7.59 Hz), 7.1–7.3 (m, 3H, ArH). 13C NMR (CDCl3) d: 21.5 (Me), 20.5, 31.6, 34.7 (3CH2), 75.9 (CHOH), 90.0 [C(4)], 123.5 [C(4a)], 123.6 [C(6)], 125.1 [C(7)], 125.8 [C(8)], 129.1 [C(5)], 139.1 [C(8a)], 160.3 (C=N). Found (%): C, 71.03; H, 6.82; N, 6.76. Calc. for C13H15NO2 (%): C, 71.87; H, 6.96; N, 6.45. 3: yield 85%, mp 216 °C. 1H NMR ([2H6]DMSO) d: 1.6–2.4 (m, 6H, 3CH2), 4.0 (m, 1H, CH–O), 4.9 (br. s, 1H, OH), 6.9 (d, 1H, H-5, J 8.2 Hz), 7.0 (t, 1H, ArH, J 7.6 Hz), 7.2 (t, 2H, ArH, J 7.4 Hz), 10.1 (s, 1H, NH). 13C NMR ([2H6]DMSO) d: 19.5, 32.1, 33.2 (3CH2), 74.6 (CHOH), 92.8 [C(4)], 113.5 [C(8)], 120.7 [C(4a)], 121.7 [C(6)], 126.5 [C(5)], 128.6 [C(7)], 136.0 [C(8a)], 150.7 (C=O). Found (%): C, 65.30; H, 6.02; N, 6.36. Calc. for C12H13NO3 (%): C, 65.74; H, 5.98; N, 6.39.