吲哚的合成.docx

1、吲哚的合成 经典化学合成反应标准操作吲哚的合成目 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、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. (b) U. Pindur and R. Adam, J.

3、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. Fischer 吲哚合成Fischer 吲哚合成法是一个常见的吲哚合成

4、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 was heated to reflux. Then a s

5、olution 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, dried, pale brown solid 3 (21.65g,

6、 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. Hutchins, K. T. Chapman, Tetr

7、ahedron 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

8、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 mixture was heated at 105 0C for 19

9、 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 solution was added 10% palladium on

10、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%Ref: (a) Feldman, et al, Synth

11、esis, 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, 10162. 3.2 邻甲酰基硝基苯衍生物合成吲哚该邻甲酰基硝

12、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 temperature, it was poured into w

13、ater 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)-nitrobenzene 2. Yield: 42%To a solu

14、tion 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. NaHSO3 was added to it and ext

15、racted 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.; Borchardt, Ronald T., J. Am. Che

16、m. 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 was added 19 g of 10% palladium-on-carbon. Then it was stirred at r.t. under 4 bars of hydrogen. After the reaction com