吲哚的合成060117概要.docx

1、吲哚的合成060117概要 经典化学合成反应标准操作吲哚的合成编者： 柏祝药明康德新药开发有限公司化学合成部目 录2. Fischer 吲哚合成 22.1 Fischer 吲哚合成反应示例 23. 从硝基苯的衍生物出发合成吲哚 33.1 邻甲基硝基苯衍生物合成吲哚 43.1.1 邻甲基硝基苯衍生物合成吲哚示例 43.2 邻甲酰基硝基苯衍生物合成吲哚 43.1.2 邻甲酰基硝基苯衍生物合成吲哚示例 53.3 邻氰甲酰基硝基苯衍生物合成吲哚示例 53.4 邻乙烯基硝基苯衍生物合成吲哚示例 63.5 邻位有氢的硝基苯衍生物直接用乙烯格氏试剂合成吲哚（Bartoli反应）示例 74. 从苯胺的衍生物出

2、发合成吲哚 74.1苯胺经佛克烷基化再还原关环合成吲哚 74.2 N-羟基苯胺DMAP催化下与丙炔酸酯缩合合成3-羧酸吲哚衍生物 94.3 Nenitzescu吲哚合成 95. 2-叠氮基-3-芳基丙烯酸酯环合合成2-羧酸吲哚衍生物 105.1 2-叠氮基-3-芳基丙烯酸酯环合合成2-羧酸吲哚衍生物示例 111. Introduction吲哚及其衍生物是一类非常有效的药物中间体。已有不少相关综述报道其合成方法1。我们将一些常用的合成方法简单的列举了出来，供大家在合成此类化合物的时候参考。 1 (a) G. W. Gribble, Contemp. Org. Synth., 1994, 145.

3、 (b) U. Pindur and R. Adam, J. Heterocycl. Chem., 1988, 25, 1. (c) C. J. Moody, Synlett, 1994, 681. (d) R. J. Sundberg, Indoles, Academic Press, San Diego, CA, 1996. (e) T. L. Gilchrist, J. Chem. Soc., Perkin Trans. 1, 1999, 2849. (f) G. W. Gribble, J. Chem. Soc., Perkin Trans. 1, 2000, 1045.2. Fisc

4、her 吲哚合成Fischer 吲哚合成法是一个常见的吲哚合成方法。通过苯腙在酸催化下加热重排消除一分子氨得到2取代或3取代吲哚衍生物。在实际操作中，常可以用醛或酮与等当量的苯肼在酸中加热回流得到苯腙，其在酸催化下立即进行重排、消除氨而得到吲哚化合物。常用的催化剂有氯化锌、三氟化硼、多聚磷酸等，常用的酸有AcOH， HCl, 三氟乙酸等。其机理大致如下：2.1 Fischer 吲哚合成反应示例 4-Bromophenylhydrazine hydrochloride 1 (21 g) was suspended in 150 mL of acetic acid, and the mixture

5、 was heated to reflux. Then a solution of cyclohexanone 2 (9.3 mL) in 10 mL of acetic acid was added dropwise. After the addition, the mixture was stirred under reflux for another 2 h. Water (50 mL) was added dropwise slowly, cooled to room temperature, the solid was filtered, washed with water, dri

6、ed, pale brown solid 3 (21.65g, 91 %) was obtained.Ref: (a) B. Robinson, Chem. Rev., 1963, 373. (b) B. Robinson, Chem. Rev., 1969, 227. (c) H. Ishii, Accts. Chem. Res., 1981, 233. (d) B. Robinson, The Fischer Indole Synthesis, 1982, 923. (e) D. L. Hughes, Org. Prep. Proced. Int., 1993, 607. (f) S. M

7、. Hutchins, K. T. Chapman, Tetrahedron Letters, 1996, 4869. (g) O. Miyata et al., ibid. 1999, 3601. (h) S. Wagaw et al., J. Am. Chem. Soc., 1999, 10251.3. 从硝基苯的衍生物出发合成吲哚对于2，3位没有取代基的吲哚，一般工业上大多采用硝基苯的衍生物出发合成，邻甲基、邻甲酰基、邻氰乙基、邻乙烯基、及邻位有氢的硝基苯衍生物都可通过相应的方法得到吲哚。3.1 邻甲基硝基苯衍生物合成吲哚该方法是目前最常用的，邻甲基硝基苯衍生物与DMF-DMA反应后得到

8、相应的烯胺，然后硝基可通过多种方法还原后加成得到吲哚。 还原方法一般通过加氢， 但当分子内有敏感官能团（比如：Br，I都可或烯烃等）存在时可通过化学还原如：NH2NH2-Raney Ni, 铁粉，TiCl3, 锌粉还原得到吲哚。3.1.1 邻甲基硝基苯衍生物合成吲哚示例To a solution of 4-methoxy-2-nitrotoluene 1 (17.9 g, 0.107 mol) in 200 mL of dry DMF was added DMFDMA (42 mL, 0.316 mol) and pyrrolidine (10 mL, 0.12 mmol). The mixt

9、ure was heated at 105 0C for 19 h under nitrogen, then cooled, diluted with water and extracted with ether (850 mL). The ether layer was extracted with water (325 mL), dried with sodium sulfate, and concentrated to give a deep red oil 2 which was dissolver in ethyl acetate (150 mL), and to the solut

10、ion was added 10% palladium on carbon (1.8 g). Hydrogenation at 50 p.s.i. with shaking for 3 h and then filtration through celite gave a light brown filtrate. This filtrate is evaporated to purple oil, which was purified by chromatography on silica gel (eluent: DCM) to give 6-methoxyindole Yield: 76

11、%Ref: (a) Feldman, et al, Synthesis, 1986, 735. (b) Kline.T.B. et al, J. Med. Chem., 1982, 908. (c) Schumacher, R.W. et al, Tetrahedron, 1999, 935. (d) bromidge, S.M., et al, J. Med. Chem., 1998, 1598. (e) Maehr, H. et al, J. Org. Chem. 1984, 1549. (f) Nicolaou, K.C. et al, J. Am. Chem. Soc., 2004,

12、10162. 3.2 邻甲酰基硝基苯衍生物合成吲哚该邻甲酰基硝基苯衍生物与硝基甲烷反应后得到相应的不饱和硝化物再还原后得到吲哚。 3.1.2 邻甲酰基硝基苯衍生物合成吲哚示例 To a solution of 2-nitro-benzaldehyde 1 (3.14 g, 0.02 mol) in nitromethane (40 mL) was added ammonia acetate (0.9 g, 0.012 mol) under N2 protected. Then it was heated to reflux for 1.25 h. After cooled to room te

13、mperature, it was poured into water and stirred for 30 min. Then it was extracted with DCM (50 mL3), and the combined organic layer was washed with brine, dried over Na2SO4 and evaporated under vacuum. The residue was purified by flash column chromatography to yield 1.2 g pure 2-(2-nitro-vinyl)-nitr

14、obenzene 2. Yield: 42%To a solution of 2-(2-nitro-vinyl)-nitrobenzene 2 (1.0 g, 0.005 mol) in ethanol (10 mL), glacial acetate acid (10 mL) and water (3 mL) was added iron powder (5.7 g, 0.1 mol) portionwise. After the addition, it was heated to 50 C for 30 min. After cooled to room temperature, aq.

15、 NaHSO3 was added to it and extracted with ether (50 mL3). The combined organic layer was washed with saturated aq. NaHCO3, dried over Na2SO4 and evaporated under vacuum. The residue was purified by flash column chromatography to yield 0.45 g 1H-indole 3. Yield: 75%Ref: (a) Sinhababu, Achintya K.; B

16、orchardt, Ronald T., J. Am. Chem. Soc., 1985, 7618, (b) He, Feng; Bo, Yunxin; Altom, Jason D.; Corey, E. J.; J. Am. Chem. Soc., 1999, 6771. 3.3 邻氰甲酰基硝基苯衍生物合成吲哚示例 To a solution of 2-nitro-1-naphthyl-acetonitrile (33g, 0.155 mol) in 630 mL of ethanol containing 10% water and 6.3 mL of pure acetic acid

17、 was added 19 g of 10% palladium-on-carbon. Then it was stirred at r.t. under 4 bars of hydrogen. After the reaction completed, the catalyst was filtered and the filtration was concentrated under reduced pressure. Then residue was dissolved in 250 mL of DCM, washed with 100 mL of 0.1 N KOH solution

18、and then dried over Na2SO4, evaporated under reduced pressure to give the crude product, which was purified by column chromatography using cyclohexane/EA=4:1 as eluant to yield 13 g of 3H-benzoeindole. Yield: 50% Ref: (a) Makosza, M. et al., Tetrahedron, 1995, 7263. (b) Bromidge, S.M. et al., J. Med

19、. Chem., 1998, 1598. 3.4 邻乙烯基硝基苯衍生物合成吲哚示例 To a solution of 2-bromo-4-methylnitrobenzene 1 (1.00 g, 4.61 mmol) and vinyltri-n-butyltin (1.61 g, 5.07 mmol) in toluene (25 mL) was added, under a positive flow of argon, bis(dibenzylideneacetone) palladium (0) (265 mg, 0.46 mmol) together with triphenylp

20、hosphine (498 mg, 1.90 mmol). The solution was heated at reflux (19 h) whereupon a red solution containing a black precipitate was formed. The reaction mixture was cooled to ambient temperature, and the solvent was removed to give black oil. The oil was dissolved in dichloromethane (50 mL), washed w

21、ith NH4OH (10%, aq, 3 x30 mL), and dried (MgSO4). Removal of solvent gave yellow oil containing a smaller amount of black viscous oil. The crude product was purified by chromatography (hexanes-EtOAc, 19:1) to give 2-ethenyl-4-methylnitrobenzene (589 mg, 3.61 mmol, 78%) as yellow oil 2.To an oven-dri

22、ed, threaded ACE glass pressure tube was added 2-ethenyl-4-methylnitrobenzene 2 (152 mg, 0.93 mmol), Pd(OAc)2 (13 mg, 0.06 mmol), triphenylphosphine (62 mg, 0.24 mmol), and 4 mL of MeCN. The tube was fitted with a pressure head, the solution was saturated with CO (four cycles to 4 atm of CO), and th

23、e reaction mixture was heated to 70 C (oil bath temperature) under CO (4 atm) until all starting material was consumed (15 h) as judged by TLC. The reaction mixture was diluted with HCl (aq, 10%, 10 mL) and extracted with Et2O (3x10 mL). The combined organic phases were washed with HCl (aq, 10%, 10

24、mL) and dried (MgSO4), and the solvent was removed to give the crude product. The crude product was purified by chromatography (hexanes-EtOAc, 9:1) to give 5-methylindole 3 (62 mg, 0.47 mmol, 51%) as faint yellow crystals.Ref: Soederberg, B. et al, J. Org. Chem., 1997, 5838 3.5 邻位有氢的硝基苯衍生物直接用乙烯格氏试剂合

25、成吲哚（Bartoli反应）示例 The 2-nitrotoluene (685 mg, 5 mmol) was placed in a twonecked round bottomed flask fitted with a gas inlet (argon) and rubber septum. The flask was purged several times with argon before adding THF (3540 ml) and cooling to between 40 and 45 C. The Grignard reagent (3 eq.) was then a

26、dded rapidly in one portion to the THF solution and stirring continued for a further 30 mins to 1 hour (exact length of time had little effect on yield). Saturated ammonium chloride solution was added to the reaction mixture (at ca. 40 C) before allowing the mixture to warm to room temperature. The

27、mixture was thoroughly extracted with diethyl ether (2 x 200 ml), the ether extracts combined and thoroughly washed with further ammonium chloride (300 ml), water (300 ml) and brine (300 ml) before drying (MgSO4) and concentrating in vacuo to give a dark brown gum, which was purified by flash column

28、 chromatography (hexane:ethyl acetate 9:1) to give 465 mg of 7-methyl-indole. Yield: 71%.Ref: (a) Adrian P. Dobbs, Martyn Voyle, Neil Whittall, Synlett, 1999, 1594, (b) Curtin, M.L et al, J.Med.Chem., 1998, 74.4. 从苯胺的衍生物出发合成吲哚从苯胺的衍生物合成吲哚虽不常用，但还是有一些方法被报道。4.1苯胺经佛克烷基化再还原关环合成吲哚To a stirred solution of b

29、oron trichloride (645 mg, 5.5mmol) in dry benzene (6 mL), a solution of 4-chloroaniline 1 (638mg, 5 mmol) in dry benzene (6 mL) was added dropwise under ice-cooling. To the resulting mixture containing 4-chloroaniline borontrichloride complex, chloroacetonitrile (0.38 mL, 6 mmol) and aluminum trichl

30、oride (734 mg, 5.5 mmol) were added successively. The mixture was then refluxed for 6 h under nitrogen, becoming a solution of two layers. The evolved hydrogen chloride was absorbed through a drying tube containing silica gel or calcium chloride to a surface of aqueous sodium hydroxide. After coolin

31、g, ice 2 N hydrochloric acid was added and a yellow precipitate was formed. To hydrolyze the ketimine of 2 the mixture was warmed at 80 C under stirring, until the precipitate had dissolved (ca. 30 min). The cooled mixture was extracted with chloromethane (three times) and the organic layer was wash

32、ed with water, dried (MgS04), and concentrated. The neutral fraction obtained (744 mg) was recrystallized to obtain pure 2 (674 mg). Yield: 66%. The acidic layer was made alkaline with 2 N sodium hydroxide and extracted with dichloromethane. Washing, drying, and evaporation of the solvent gave the basic fraction (170 mg). Thin-layer chromatographic purification (silica gel, chloroform containing 10% methanol) gave recovered 1 (103 mg).To a stirred solution of 5-chloro-2-amino-chloroacetophenone 2 (204 mg, l mmol) in dioxane (5 m