Burgemeister, Thomas

Mahboobi, Siavosh

Wagner, W.

Wiegrebe, Wolfgang

English

University of Regensburg Publication Server

Nazlinin and 6-Azacyclodeca[5,4-£]indol-1 -amine 463 Non-Identity of Nazlinin and 6-Azacyclodeca[5,4-Ä]indol-l-amine Nicht-Identität von Nazlinin und 6-Azacyclodeca[5,4-Z>]indol-l-amin Siavosh Mahboobi*, Wolfgang Wagner, Thomas Burgemeister, and Wolfgang Wiegrebe Faculty of Chemistry and Pharmacy, University, D-93040 Regensburg/Germany Received February 17,1994 In 1991 Üstünes and coworkers have published isolation and structure elucidation of a new alkaloid from Nitraria Schoben (Zygophyllaceae), which was named nazlinin1). Its spectroscopic data led to the conclusion that nazlinin is 6-azacyclodeca[5,4-&]indol-l-amine (1) (the authors do not report upon measurements of optical activity). - Whilst the NMR-data of nazlinin can be attributed to structure 1, the base peak in its EI-MS at m/z = 171, in accordance with a Af-protonated 3,4-dihydro-ß-carbolinium-ion, cannot be explained straightforwardly by structure 1 (Scheme 1). Koomen et al.2) did not exclude the alternative structure of (+/-)-l-(co-amino-^-butyl)-l,2,3,4-tetrahydro-ß-carboline (2) which was synthesized by this group. The authors found the published NMR-data of nazlinin to be in complete agreement with those obtained for 2 in C D 3 O D containing more than two equivalents of F 3 C-COOD. Scheme 1 Moreover, 2+* is expected to give rise to a fragment ion at m/z 171 by benzylic/ß-cleavage 3 ) of high intensity, which is actually reported to be the base peak in the ms of nazlinin1). It remained open why the NMR-data published for nazli-nin strongly deviate from those obtained for 2 in C D 3 O D whilst those of (at least) diprotonated 2 and those of nazli-nin are identic2). In order to shed some additional light onto this problem we have synthesized compound 1 (Scheme 2). The l,2,3,4,6,7-hexahydro-12//-indolo[2,3-a]quinol-izine 3 4 ) was converted by benzyl chloroformate in M e O H / N a 2 C 0 3 to the ten-membered ring urethan 4 (mix-ture of rotamers)5) which was readily oxidized to ketone 5 by teft-butyl hypochlorite, according to lit.6). Reaction of 5 with O-methylhydroxylamine-HCl in pyridine afforded the oxime ether 6 which was reduced specifically by N a B H 4 and almost equimolar amounts of F 3 C - C O O H in T H F 7 ) leading to the amine-urethan 7 besides some 5. Surprising-ly, hydrogenation of the oxime ether 6 on Pd/C led to the tetracyclic starting material 3: this can be explained by hydrogenolysis of the urethan, transannular addition of the sec. amin at the C=N-OMe group and subsequent hydroge-nolysis of the benzylic C - N H - O C H 3 increment. - Hydroge-nolysis of the carbamate group of 7 afforded the title com-ponent 1. The chromatographic data of 1 are very similar CIC02CH2Ph 2NOCH3-HCI NOCH3 H OCHo C02CH2Ph »BuOCI C02CH2Ph NaBH4 TFA C02CH2Ph N H NH2 Pd/C/H2 Scheme 2 Arch. Pharm. (Weinheim) 327,463-465 (1994) © VCH Verlagsgesellschaft mbH, D-69451 Weinheim, 1994 0365-6233/94/0707-0463 $ 5.00 + .25/0 464 Mahboobi and coworkers Table: NMR-spectra in CD 3OD 1 1 + [D]TFA natural alkaloid [lit1)] 2 *-H or 2 + [D]TFA [lit2)] [lit2)] 3 0.79-0.95 (1H, m) 1.46-1.56 (1H, m) 1.03-1.16 (1H, m) 1.70 (2H, m) 1.5 (4H, m) 4 1.57-1.70 (2H, m) 1.67-1.89 (3H, m, + one 3-H) 1.83 (2H, m) 1.71 (lH,m) 2 1.95-2.07 (2H, m) 2.15-2.28 (1H, m) 2.32-2.43 (1H, m) 2.03 (1H, m) 2.30 (1H, m) 1.99 (1H, m) 5 2.55-2.63 (1H, m) 3.06-3.16 (1H, m) 3.00 (2H, m) 2.67 (4H, m) 7/8 2.81-2.90 (1H, m) 3.26-3.59 (5H, m, 3.10 (2H, m) 2.95 (lH,dxdxd, 2.90-3.02 (2H, m, + one 5-H) 3.45 (1H, m) J=12.3,8.9,5.2Hz) + one 5-H) 3.72 (1H, m) 3.31 (1H, m) 3.05-3.15 (1H, m) 3.17-3.29 (1H, m) 1 4.44 (1H, dd, 5.07 (1H, dd, 4.72 (1H, m) 4.02 (1H, m, ^=8.4, j!=6.0, J=8.4,3.5, J2=7.2Hz) J2=5.5Hz) 1.8Hz) 10/11 6.99-7.03 (1H, m) 7.13-7.17 (1H, m) 7.05 (1H, dt, 6.98 (2H, m) 7.09-7.11 (1H, m) 7.24-7.28 (1H, m) J=7.5, 1.5Hz) 7.15 (1H, dt, J=7.5,1.5Hz) 9/12 7.33-7.35 (1H, m) 7.48-7.50 (1H, m) 7.38 (1H, d, 7.27 (1H, m) 7.48-7.51 (1H, m) 7.67-7.69 (1H, m) J=7.5Hz) 7.48 (1H, d, J=7.5Hz) 7.36(lH,dxd, J=7.1,1.3Hz) with those reported for nazlinin, the spectroscopic data of 1, however, are absolutely different from those of nazlinin. By ^ ^ H - and ^/^C-correlation spectra all the signals can be attributed to atoms of compound 1. The resonance frequency of 1-H is of special importance: in 1 (base) it resonates as a dd at 4.44 ppm, whilst addition of F 3 C -COOD shifts this signal to 5.07 ppm without changing its shape, indicating that this dd results from a neighbouring CH2-group which is part of a cyclic system. In ß-carboline 2 1-H resonates as a m, probably because the mobility of the side chain at C - l is not restricted. Under these N M R -conditions bis-amine 1 is stable, whilst it is partially degra-ded by prolonged warming (8 d at 30-40°C) or by treatment with 0.1 N H C l (slow reaction at room temp., fast reaction at about 40°C), leading to more polar unknown compounds. In conclusion compound 1 is not identic with nazlinin, neither as a base nor as its dication. Financial support by Fonds der Chemischen Industrie is gratefully acknowledged. Experimental Part General remarks: m.p.: Biichi 512.- IR: FT Nicolet 510.- *H-NMR: Var-ian E M 390 (90 MHz), Bruker ARX 400 (400 MHz).- 1 3 C-NMR: Bruker ARX 400 (100.61 MHz); all NMR-spectra in CDC13, if not otherwise stat-ed.- MS: Varian MAT 112 S/SS, 70 eV.- Column chromatography (cc): SiCVflash, if not otherwise stated.- Al l reactions have been performed under N 2 . 1,2,3,4,6,7-Hexahydro-12H-indolo[2,3-a]chinolizine (3) 3 was prepared according to Costerousse et al4^ (1. step), Costerousse4^ and Tamelen4b) (2. step), and Rapoport4c) (3. step): colour-less crystals, m.p. 147-149°C (lit.4 c ): 147-149°C). For ^ - N M R data see lit.*»-6-Benzyloxycarbonyl-l -methoxy-6-azacyclodeca[5,4-b]indole (4) 1.46 g (6.46 mmole) 3 were dissolved in 10 ml of absol. THF and 1 ml of absol. MeOH. 3 g of Na 2 C0 3 were added, this suspension was cooled to 0°C and 1.21 g (7.11 mmole) of benzyl chloroformate were added drop-wise. The mixture was stirred for 2 h at room temp., poured into a mixture of 20 ml of CH 2C1 2 and 50 ml of ice water and stirred vigorously for 10 min. The org. phase was washed with a satd. aq. solution of NaHC0 3, then with water and dried (Na 2S0 4): 1.95 g (77%) yellowish oil. After cc (column: 2.5 x 40 cm2; C H ^ y e t h y l acetate = 95/5) 1.82 g (71%) 4: colourless oil.- C 2 4 H 2 8 N 2 0 3 (392.5).- IR (Film): v = 3315 (NH); 2933; 1684 (CO); 1464; 1422; 1337; 1258; 1094; 743 cm 1.- !H-NMR (90 MHz): 8 (ppm) = 0.70-2.36 (6H; m), 2.50-4.22 (6H; m), 3.27 (3H; s, OCH 3), 4.23-4.57 (1H; m), 4.87 (2/3H; d, J = 13 Hz, AB-system, CH2Ph, rotamer), 5.26 (2/3H; d, J = 13 Hz, AB-system, CH 2Ph, rotamer), 5.26 (2/3H; br s, CH 2Ph, rotamer), 7.02-7.68 (9H; m), 8.87 (1H, br s, NH-indole, ex-changeable).- MS (70 eV): m/z = 392 (92) [M + ' ] , 226 (19), 225 (77), 91 (100) [C 7H 7] + . 6-Benzyloxycarbonyl-6-azacyclodeca[5,4-b]indol-l-one (5) To the solution of 1.82 g (4.64 mmole) 4 in 10 ml of absol. CH 2C1 2 were added at 0°C 453 mg (4.87 mmole) of tert-butyl hypochlorite drop by drop under stirring (the solution became red but the colour faded away by the time). Stirring was continued for 10 min after the addition, then 2 g of Nazlinin and 6-Azacyclodeca[5,4-/?]indol-l-amine 465 solid NaHC0 3 were added, and the mixture was poured into a mixture of 10 ml of CH 2C1 2 and 10 g of ice immediately. The aqueous phase was thoroughly extracted with CH 2C1 2, the org. phase was washed with satd. NaHC03-solution and water. Evaporation of the solvent yielded 1.71 g (98%) brownish oil. After cc (column: 2.5 x 40 cm2; CH^yethyl acetate = 95/5): 1.06 g 5 (61%), colourless oil.- C 2 3 H 2 4 N 2 03 (376.5).- IR (Film): v = 3327 (NH); 2935; 1694 (CO); 1636 (CO); 1472; 1420; 1339; 1270; 1240; 1216; 1120; 741 cm 1 .- ! H-NMR (90 MHz): 8 (ppm) = 1.12-2.13 (5H; m), 2.76-3.04 (2H; m), 3.25-3.57 (3H; m), 3.58-3.83 (1H; m), 3.84-4.40 (1H; m), 4.99 (1H; br s, CH 2Ph, rotamer), 5.14 (1H; br s, CH 2Ph, rotamer), 6.91-7.82 (9H; m), 9.33 (1H; br s, NH-indole, exchangeable). -MS (70 eV): m/z = 376 (31) [M+*], 241 (12), 91 (100) [C 7H 7] + . 6-Benzyloxy-l -methoxyimino-6-azacyclodeca[5,4-b]indole (6) 1.10 g (2.93 mmole) 5 and 10 g 0-methylhydroxylamine«HCl were sus-pended in 50 ml of freshly distilled absol. pyridine and heated to reflux for 14 h. After cooling 20 g ice and 100 ml of CH 2C1 2 were added. The org. phase was 3 x extracted with 2N HCl and washed with half satd. NaHC0 3-solution. After evaporation of solvent: 1.12 g (94%) 6, dark brown oil. Purification by cc (column: 2.5 x 40 cm2; CH2Cl2/ethyl acetate = 98/2): 1.03 g (87%) colorless oil.- C 2 4 H 2 7 N 3 0 3 (405).- IR (Film): v = 3327 (NH), 2937; 1690 (CO); 1472; 1420; 1335; 1272; 1243; 1212; 1054; 745 cm 1.-*H-NMR (400 MHz): 8 (ppm) = 1.33-1.43 (1H; m), 1.49-1.57 (1H; m), 1.74-1.84 (2H; m), 2.84-2.92 (2H; m), 3.20-3.41 (4H; m), 3.61-3.67 (2H; m), 3.963 and 3.965 (3H; 2 x s, NOCH 3 , rotamers), 5.01 (1H; s, CH2Ph, rotamer), 5.15 (1H; s, CH 2Ph, rotamer), 7.06-7.19 (2H; m), 7.19-7.42 (6H; m), 7.49-7.57 (1H; m), 8.70 and 8.71 (1H; 2 x s, NH-indole, exchangeable, rotamers).- MS (70 eV): m/z = 405 (35) [M+*], 374 (33), 225 (11), 91 (100) [C 7HV] +. 6-Benzyloxycarbonyl-6-azacyclodeca[5,4]indol-l-amine (7) 130 mg (3.45 mmole) of NaBH 4 were slowly added at 0°C to 57 ml of absol. THF, being 0.06 molar in F 3 C-COOH. When the reaction had ceased 230 mg (0.57 mmole) 6 in 5 ml of absol. THF were added drop by drop at 0°C, then the mixture was refluxed for 90 min. After cooling and dilution with 50 ml of Et 20, 0.5 g of solid NaHC0 3 were added followed by washing with water.- Drying (Na2S04) and evaporation of the org. phase yielded 200 mg (93%) of yellowish oil which was purified by cc (column: 1.5 x 30 cm2; CHsCl^ tOH (about 1% of N H 3 gas) = 98/2): 122 mg (57%) of 7 as a colourless oil besides 15 mg (7%) of 5.- C 2 3 H 2 7 N 3 0 2 (377.5).- IR (Film): v = 3340 (NH); 2933; 1679 (CO); 1463; 1424; 1333; 1260; 1218; 1121; 735 cm 1.- !H-NMR (400 MHz): 8 (ppm) = 0.67-1.00 (1H; m), 1.13-1.82 (5H; m), 1.57 (2H; br s, NH 2 , exchangeable), 2.53-3.63 (5H; m), 3.93-4.02 (2/3 H; m, rotamer), 4.17-4.30 (4/3 H; m, rotamer), 4.79 (2/3 H; d, J = 12.4 Hz, AB-system, CH 2Ph, rotamer), 5.13 (2/3 H; d, J = 12.4 Hz, AB-system, CH2Ph, rotamer), 5.14 (2/3 H; s, CH2Ph, rotamer), 7.02-7.49 (9H; m), 8.58 (1H; br s, NH-indole, exchangeable).- MS (70 eV): m/z = 377 (100) [M+*], 243 (14), 225 (51), 198 (30), 91 (92) [C 7H 7] + . 6-Azacyclodeca[5,4-b]indol-l -amine (1) Under normal pressure 150 mg (0.40 mmole) urethan 7, dissolved in 2 ml of absol. MeOH, were stirred with 150 mg Pd/C (5%) under H 2 at 30°C for 10 min. The catalyst was filtered off using celite and was washed several times with warm MeOH until the reaction with Mayer's reagent was negative. Evaporation of solvent afforded a yellow oil (80 mg, 82%) which was purified by twofold cc (1.column: 1.5 x 10 cm2; ethyl acetate/propan-2-ole/NH3 (aq., 25%) = 55/30/15.- 2.column: C H ^ y E t O H (satd. with N H 3 gas) = 8/2): 25 mg (26%) colourless oil, precipitating from ethyl acetate/hexane = 2/1 as a colourless powder after scratching.- Mel-ting range: 83-90°C- 1 decomposes partially when we tried to get rid of solvent by drying at 30-40°C in vacuo.- C 1 5 H 2 1 N 3 (243.5).- Bis-picrate-2 MeOH: m.p. 231°C (decomp.): C 2 9 H 3 5 N 9 0 1 6 (765.6) calcd. C 45.5 H 4.61 N 16.5 found C 45.3 H 4.35 N 16.2.- IR (KBr): v = 3290 (NH); 2929; 1461; 1337; 1273; 1175; 1148; 1055; 747 cm"1.- ! H-NMR (400 MHz, CD3OD): 8 (ppm) = 0.79-0.95 (1H; m, 3-H), 1.46-1.56 (1H; m, 3-H), 1.57-1.70 (2H; m, 4-H), 1.95-2.07 (2H; m, 2-H), 2.55-2.63 (1H; m, 5-H), 2.81-2.90 (1H; m, 7-H or 8-H), 2.90-3.02 (2H; m, H-5, 7-H/8-H), 3.05-3.15 (1H; m, 7-H/8-H), 3.17-3.29 (1H; m, 7-H/8-H), 4.44 (1H; dd, J 1 = 8.4, J 2 = 7.2 Hz, 1-H), 6.99-7.03 (1H; m, 10-H/ll-H), 7.09-7.11 (1H; m, 10-H/l l -H) , 7.33-7.35 (1H; m, 9-H/12-H), 7.48-7.51 (1H; m, 9-H/12-H).-1 3 C-NMR (CD3OD): 8 (ppm) = 21.08 (C-3), 22.11 (C-8), 28.07 (C-4), 38.68 (C-2), 44.20 (C-5), 45.67 (C-7), 47.98 (C-l), 108.12 (pyrrol), 112.04 (C-10/C-11), 119.28 (C-10/C-11), 120.04 (C-9/C-12), 122.90 (C-9/C-12), 128.37 (pyrrol), 138.28 (pyrrol), 144.22 (pyrrol).- 1 3C-DEPT (CD 3OD, rel.Int.): 8 (ppm) = 21.03 (-84, CH 2), 21.88 (-92, CH 2), 28.81 (-82, CH 2), 38.46 (-56, CH 2), 44.19 (-89, CH 2), 45.59 (-91, CH 2), 47.99 (+82, CH), 112.11 (+89, CH), 119.29 (+100, CH), 120.11 (+100, CH), 122.99 (+94, CH).- MS (70 eV): m/z = 243 (31) [M+*], 226 (66), 225 (100), 197 (22).-FD-MS (MeOH): 243.0 [M+*].- To 4.0 mg (0.016 mmole) 1 dissolved in 1 ml of CD 3OD were added 4 JLLI (3.2 equiv) of [D]TFA: *H-NMR (400 MHz): 8 (ppm) = 1.03-1.16 (1H; m), 1.67-1.89 (3H; m), 2.15-2.28 (1H; m), 2.32-2.43 (1H; m), 3.06-3.16 (1H; m), 3.26-3.59 (5H; m), 5.07 (1H; dd, J 1 = 6.0, J 2 = 5.5 Hz, 1-H), 7.13-7.17 (1H; m), 7.24-7.28 (1H; m), 7.48-7.50 (1H; m), 7.67-7.69 (1H; m).- After alkalisation by Na 2 C0 3 1 was recovered unchanged so excluding a reaction of the skeleton. References 1 L. Üstünes, A. Özer, G.M. Laekeman, J. Corthout, L.A.C. Pieters, W. Baeten, A.G. Herman, M. Claeys, A.J. Vlietinck, / . Nat. Prod. 1991, 54, 959-966. 2 M.J. Wanner, A.W. Velzel, G.J. Koomen, / . Chem. Soc. Chem. Com-mun. 1993, 174-175. 3a M . Hesse, Indolalkaloide, Verlag Chemie, Weinheim, 1974, p. 103-216. 3b S. Mahboobi, Arch. Pharm. (Weinheim) 1992,325, 249-250. 3c J. Gynther, P. Peura, S. Salmi, Acta. Chem. Scand. 1985, B35, 849-859. 4a G. Costerousse, J. Buendia, E. Toromanoff, J. Martel, Bull. Soc. Chim. FranceII197S, 355-360. 4b E.E. Tamelen, P.E. Aldrich, T.J. Katz, Chem. Ind. 1956, 793. 4c J.E. Johansen, B.D. Christie, H. Rapoport, / . Org. Chem. 1981, 46, 4914-4920. 5a G. Schill, H. Löwer, C.U. Priester, U.F. Windhövel, H. Fritz, Tetrahe-dron 1987,43,3729-3745. 5b M.J. Calverley, J. Harley-Mason, S.A. Quarrie, P.D. Edwards, Tetra-hedron 1981,37, 1547-1556. 5c T. Koike, H. Takayama, S. Sakai, Chem. Pharm. Bull. 1991,39, 1677-1681. 6 S. Sakai, E. Yamanaka, L.J. Dolby, Heterocycles 1976,4,981 -984. 7 N . Umino, T. Iwakuma, M . Ikesaki, N . Itoh, Chem. Pharm. Bull. 1978,26, 2897-2898. [KPh615] 

Non-Identity of Nazlinin and 6-Azacyclodecal[5,4-b]indol-1-amine

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Non-Identity of Nazlinin and 6-Azacyclodecal[5,4-b]indol-1-amine

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