Cl Pt NH2R NH2R Cl 1 R = alkyl, aryl O O R1 2 R1 = H 3 R1 = SO2C6H4- p-Me O HN R2 4 R2 = C6H4- p-Me 5 R2 = CH2Ph 6 R2 = c-C6H11 i,ii OMe N R2 7 R2 = C6H4- p-Me 8 R2 = CH2Ph 9 R2 = c-C6H11 iii 2 1 iv N HNR2 R3O 10 R2 = C6H4- p-Me, R3 = H 11 R2 = CH2Ph, R3 = H 12 R2 = C6H4- p-Me, R3 = Me 13 R2 = CH2Ph, R3 = Me 14 R2 = c-C6H11, R3 = Me OMe N OR3 15 R3 = H 16 R3 = Me + 362 J. CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 362–363† Synthesis of 2-Aminotropone Oximes and 2-Alkoxytropone Imines† Tetsuo Nozoe,1‡ Lung Ching Lin,*ab Chih-Hsien Hsu,a Shwu-Chen Tsay,b Gholam H.Hakimelahib and Jih Ru Hwu*b,c aDepartment of Chemistry, National Taiwan University, Taipei, Taiwan 10671, Republic of China bInstitute of Chemistry, Academia Sinica, Nankang, Taipei, Taiwan 11529, Republic of China cDepartment of Chemistry, National Tsing Hua University, Hsinchu, Taiwan 30043, Republic of China A synthetic route was developed for preparation of 2-aminotropone oximes 10–14, a new class of compounds, from tropolone 2; 2-methoxytropone imines 7–9 and tropylium salts 17 were generated as the key intermediates.cis-Diamminedichloroplatinum analogues 1 are used as drugs for clinical cancer chemotherapy.2,3 In order for 1 to exhibit significant biological activity, the two amino groups must be in a cis configuration in 1.4,5 Here we report the preparation of 2-aminotropone oximes (e.g., 10–14), in which the two adjacent nitrogen atoms are attached to a planar nucleus and could coordinate to Pt to form cis-platinum complexes.Reaction of tropone with NH2OH.HCl and pyridine in methanol generates tropone oxime and 2-aminotropone.6 Under the same conditions, 2-alkyltropones can also be converted to 2-alkyltropone oximes and 2-alkyl-7-aminotropones, 7 yet tropolone 2 remains intact.8 By replacement of pyridine with various bases, including NaOH, NaOMe, NaOAc, Na2CO3 and Et3N, we were also unable to convert tropolone to the corresponding oximes by using NH2OH.HCl.The unusual resonance phenomenon associated with tropolone and an inherent intramolecular hydrogen bonding between the OH and the C�O groups9 may decrease its reactivity towards oxime formation. Furthermore, our attempts to oximate 2-(p-tolylsulfonyl)tropone and 2-aminotropone were also unsuccessful. Herein we report an indirect way to convert tropolone 2 to the desired 2-aminotropone oximes 10–14. To the best of our knowledge, this provides the only available up-to-date route for the preparation of 2-aminotropone oximes, an unprecedented class of compounds.After tosylation of 2,10 the resultant toluene-p-sulfonate 3 was treated with various amines,11 including p-toluidine, benzylamine and cyclohexylamine, in BuOH under reflux to give the corresponding 2-aminotropones 4–6 in 65–76% yields (Scheme 1). Methylation11 of 4–6 with dimethyl sulfate in toluene under reflux followed by treatment with NaHCO3 afforded the 2-methoxytropone imines 7–9 in 60–65% overall yields.Upon reaction with NH2OR.HCl (R=H or Me) and NaOMe in MeOH, 7–9 were converted to the desired oximes 10–14 in 24–54% yields. The spectroscopic data are summarized in Table 1. In these reactions, an unexpected by-product (i.e., 2-methoxytropone oxime 15 or 16) was generated and its structure was determined with the aid of single-crystal X-ray diffraction analysis.§ Formation of oximes 10–14 came from a nucleophilic attack of 7–9 by NH2OR (R=H or Me) at the C-2 position and formation of oximes 15 and 16 came from an attack at the C-1 position.Furthermore, we found that reactions of 2-aminotropones 4–6 with methyl fluorosulfonate gave the corresponding isolable tropylium salts 17 (Scheme 2).12 The desired oximes 10–14 can be obtained by treatment of 17 with NH2OH.HCl or NH2OMe.HCl. Moreover, we were able to synthesize 2-aminotropone imines 18–20 in high yields (a80%) by treating tropylium salts 17 with primary amines, including p-toluidine and benzylamine.13 These 2-aminotropone imines were also obtained in excellent yields (91–98%) by the reactions of 2-methoxytropone imines 7 and 8 with amines (Scheme 2 and Table 1).11 In conclusion, 2-methoxytropone imines 7–9 and tropylium salts 17 were prepared readily from tropolone 2 via toluene-p-sulfonate 3 and 2-aminotropones 4–6.These key intermediates (i.e., 7–9 and 17) were successfully converted to the 2-aminotropone oximes (10 and 11) and oxime methyl ethers (12–14) upon treatment with NH2OR.HCl (R=H or Me), and to 2-aminotropone imines 18–20 with primary amines.Use of the resultant new nitrogen-containing planar compounds to form cis-diamminedichloroplatinum analogues and to test their biological activity are under investigation in our laboratory. Experimental General Procedure for the Conversion of 2-Methoxytropone Imines (7–9) to 2-Aminotropone Oximes 10–14.·To a clear solution of NH2OH.HCl or NH2OMe.HCl (2.30 mmol) and NaOMe (2.30 mmol) in MeOH (20 mL) was added a 2-methoxytropone imine (7–9, 2.22 mmol).The reaction mixture was stirred at room temperature for 4.0 h. After the solvent was removed under reduced *To receive any correspondence. †This is a Short Paper as defined in the Instructions for Authors, Section 5.0 [see J. Chem. Research (S), 1997, Issue 1]; there is therefore no corresponding material in J. Chem. Research (M). ‡Deceased April 4, 1996. §Details of the X-ray crystal-structure determination will be reported elsewhere. Scheme 1 Reagents and conditions: i, for 2h3: p-MeC6H4SO2Cl, pyridine, 0 °C (96%); ii, for 3h4: p-MeC6H4NH2, BuOH, reflux (72%); for 3h5: PhCH2NH2, BuOH, reflux (76%); for 3h6: cyclohexylamine, BuOH, reflux (65%); iii, for 4–6h7–9: Me2SO4, toluene, reflux, NaHCO3 (aq) (60–65%); iv, for 7h10+15 and 8h11+15: NH2OH.HCl, NaOMe, MeOH; for 7–9h12–14+16: NH2OMe.HCl, NaOMe, MeOHO HN R2 OMe HN R2 SO3F– 17 MeOSO2F OMe N R2 NHR4 N R2 R4NH2 (R4 = C6H4- p-Me or CH2Ph) MeOH 10–14 + R4NH2, MeOH (R4 = C6H4- p-Me or CH2Ph) NH2OR3•HCl (R3 = H or Me) 4 R2 = C6H4- p-Me 5 R2 = CH2Ph 6 R2 = c-C6H11 7 R2 = C6H4- p-Me 8 R2 = CH2Ph 18 R2 = C6H4- p-Me, 19 R2 = C6H4- p-Me, 20 R2 = CH2Ph, R4 = CH2Ph R4 = C6H4- p-Me R4 = CH2Ph J.CHEM. RESEARCH (S), 1997 363 pressure, the residue was purified by use of column chromatography (EtOAc/hexanes=1:5 as eluent) to give a 2-aminotropone oxime (10–14) and a 2-methoxytropone oxime (15 or 16) in a pure form.The yields and spectroscopic data are listed in Table 1. This work was supported by the National Science Council of the Republic of China and Academia Sinica. Received, 7th March 1997; Accepted, 5th June 1997 Paper E/7/01621B References and notes 1 811-2-5-1, Kami-Yoga, Setagaya-Ku, Tokyo 158, Japan 2 B. Rosenberg, L. VanCamp, J. E. Trosko and V. H. Mansour, Nature (London), 1969, 222, 385. 3 K. R. Harrap, Cancer Treat.Rev., 1985, 12, 21. 4 S. J. Lippard, H. M. Ushay, C. M. Merkel and M. C. Poirier, Biochemistry, 1983, 22, 5165. 5 M. V. Keck and S. J. Lippard, J. Am. Chem. Soc., 1992, 114, 3386. 6 T. Machiguchi, T. Hasegawa, M. Ohno, Y. Kitahara, M. Funamizu and T. Nozoe, J. Chem. Soc., Chem. Commun., 1988, 838. 7 T. Nozoe, T. Mukai and I. Murata, Proc. Jpn. Acad., 1953, 29, 169. 8 T. Nozoe, T. Mukai, K. Takase and T. Nagase, Proc. Jpn. Acad., 1952, 28, 477. 9 W. von E. Doering and L.H. Knox, J. Am. Chem. Soc., 1951, 73, 828. 10 W. von E. Doering and C. F. Hiskey, J. Am. Chem. Soc., 1952, 74, 5688. 11 A. Zask, N. Gonnella, K. Nakanishi, C. J. Turner, S. Imajo and T. Nozoe, Inorg. Chem., 1986, 25, 3400. 12 P. Beak, J.-K. Lee and B. G. McKinnie, J. Org. Chem., 1978, 43, 1367. 13 cf. W. R. Brasen, H. E. Holmquist and R. E. Benson, J. Am. Chem. Soc., 1961, 83, 3125; K. Kikuchi, Y. Maki and K. Sato, Bull. Chem. Soc. Jpn., 1978, 51, 2338. Table 1 Conversion of 2-methoxytropone imines 7–9 to a mixture of oximes 10–16 or to 2-aminotropone imines 18–20 by the use of various nitrogen-containing reagents Found (calcd) (%) Products Mp Imine Reagent (% in yield)a dH (CDCl3) dC (CDCl vmax/cm–1 (T/°C) C H N 7 NH2OH.HCl 10 (28)+15 (50) 10: 2.31 (s, 3 H), 6.12–7.20 (m, 10 H), 7.46 (br s, 1 H); 15: 3.72 (s, 3 H), 5.80–7.11 (m, 5 H), 9.83 (br s, 1 H) 10: 21.9, 106.3, 117.6, 121.6, 125.8, 130.9, 132.9, 133.1, 135.8, 137.6, 145.8, 151.0; 15: 55.6, 104.9, 120.7, 124.2, 129.0, 131.1, 149.9, 157.0 10: 3315 (OH, NH), 1583 (C�N); 15: 3298 (OH), 1599 (C�N) 10: liq.; 15: 132–133 10: 74.26 (74.31) 15: 63.48 (63.57) 6.55 (6.24) 5.99 (6.00) 12.26 (12.38) 9.38 (9.27) 8 NH2OH.HCl 11 (24)+15 (50) 11: 4.43 (d, 2 H), 5.82–7.33 (m, 12 H) 11: 47.4, 103.4, 115.6, 119.1, 127.2, 127.4, 128.7, 132.0, 132.4, 137.4, 146.2, 150.1 11: 3352 (OH, NH), 1584 (C�N) 11: liq. 11: 74.18 (74.31) 6.31 (6.24) 12.49 (12.38) 7 NH2OMe.HCl 12 (54)+16 (30) 12: 2.33 (s, 3 H), 4.00 (s, 3 H), 6.11–7.28 (m, 9 H), 7.62 (br s, 1 H); 16: 3.84 (s, 3 H), 4.01 (s, 3 H), 5.82–6.94 (m, 5 H) 12: 20.9, 62.1, 105.3, 117.3, 120.7, 124.9, 129.9, 132.0, 132.2, 134.8, 136.6, 144.8, 148.4; 16: 560, 62.0, 105.2, 120.9, 124.3, 129.0, 131.0, 151.0, 151.2 12: 3152 (NH), 1583 (C�N); 16: 1590 (C�N) 12: liq.; 16: liq. 12: 74.88 (74.97) 16: 65.45 (65.44) 6.73 (6.71) 6.84 (6.71) 11.57 (11.66) 8.40 (8.48) 8 NH2OMe.HCl 13 (47)+16 (25) 13: 4.02 (s, 3 H), 4.49 (d, 2 H), 5.82–7.43 (m, 10 H), 7.87 (br s, 1 H) 13: 47.2, 62.0, 103.3, 116.5, 119.2, 127.2, 127.4, 128.8, 132.0, 132.5, 134.9, 137.8, 146.3, 148.6 13: 3360 (NH), 1584 (C�N) 13: liq. 13: 75.09 (74.97) 6.63 (6.71) 11.77 (11.66) 9 NH2OMe.HCl 14 (51)+16 (31) 14: 0.92–2.00 (m, 11 H), 3.43 (br s, 1 H), 3.96 (s, 3 H), 5.81–7.06 (m, 5 H) 14: 24.7, 25.7, 32.4, 50.8, 61.9, 115.4, 118.0, 131.8, 132.5, 145.4, 148.5 14: 3338 (NH), 1583 (C�N) 14: liq. 14: 72.44 (72.38) 8.63 (8.68) 12.15 (12.06) 7 p-MeC6H4NH2 18 (98) 18: 2.41 (s, 3 H), 2.49 (s, 3 H), 6.19–7.32 (m, 14 H) 18: 20.9, 114.5, 121.5, 122.6, 130.0, 133.2, 133.4, 142.5, 152.1 18: 3059 (NH), 1587 (C�N) 18: 143–144 18: 83.83 (83.96) 6.71 (6.71) 9.25 (9.33) 7 PhCH2NH2 19 (91) 19: 2.32 (s, 3 H), 4.54 (s, 2 H), 6.10–7.32 (m, 15 H) 19: 20.8, 47.2, 105.4, 119.9, 120.7, 120.9, 127.2, 127.4, 130.0, 131.9, 133.0, 133.7, 137.4, 148.4, 150.8, 155.1 19: 3265 (NH), 1582 (C�N) 19: 113–114 19: 84.09 (83.96) 6.80 (6.71) 9.24 (9.33) 8 PhCH2NH2 20 (95) 20: 4.62 (br s, 4 H), 6.27–7.33 (m, 16 H) 20: 50.0, 111.6, 119.1, 126.8, 127.2, 128.4, 133.8, 139.3, 153.2 20: 3055 (NH), 1591 (C�N) 20: 81–82 20: 84.03 (83.96) 6.56 (6.71) 9.38 (9.33) aAll data are satisfactory for the high- and low-resolution mass sp