吲哚的合成-060117

1、经典合成反应标准操作吲哚的合成 药明康德新药开发有限公司 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

2、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 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. Fisch

4、er 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, drie

6、d, 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反应后得到相

8、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 mixtu

9、re was heated at 105 0C for 19 h under nitrogen, then cooled, diluted with water and extracted with ether (8×50 mL). The ether layer was extracted with water (3×25 mL), dried with sodium sulfate, and concentrated to give a deep red oil 2 which was dissolver in ethyl acetate (150 mL), and t

10、o the solution 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-methoxyindol

11、e Yield: 76%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. S

12、oc., 2004, 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

13、 to room temperature, it was poured into water and stirred for 30 min. Then it was extracted with DCM (50 mL×3), 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-

14、nitro-vinyl)-nitrobenzene 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 t

15、o room temperature, aq. NaHSO3 was added to it and extracted with ether (50 mL×3). 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:

16、(a) Sinhababu, Achintya K.; Borchardt, 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 a

17、nd 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 completed, the catalyst was filtered and the filtration was concentrated under reduced pressure. Then residue was dissolved in 250 mL of DCM, washed with

18、100 mL of 0.1 N KOH solution 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)

19、Bromidge, S.M. et al., J. Med. 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 m

20、mol) together with triphenylphosphine (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 dich

21、loromethane (50 mL), washed with 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%) a

22、s yellow oil 2.To an oven-dried, 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 c

23、ycles to 4 atm of CO), and the 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

24、 were washed with HCl (aq, 10%, 10 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., 1

25、997, 5838 3.5 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 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

26、. The Grignard reagent (3 eq.) was then added 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 allowin

27、g the mixture to warm to room temperature. The 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 dar

28、k brown gum, which was purified by flash column 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

29、。4.1苯胺经佛克烷基化再还原关环合成吲哚To a stirred solution of boron 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, chloroace

30、tonitrile (0.38 mL, 6 mmol) and aluminum trichloride (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 su

31、rface of aqueous sodium hydroxide. After cooling, 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 chlor

32、omethane (three times) and the organic layer was washed 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. Washi

33、ng, 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 mL) containing

34、 water (0.5 mL) was added sodium borohydride (1.1 mmol) and the solution was refluxed for 5.5 h. After removal of the solvent, water was added and the mixture was extracted with dichloromethane. The extract was dissolved in benzene and passed through a silica gel layer (ca. 2 g) to remove a polar fr

35、action. The eluate with benzene was concentrated giving indole 3 (one spot, on TLC, dichloromethane). Yield: 69%Ref: (a) T. Sugsawa, M. Adachi, K. Sasakura, A.Kitagawa, J. Org. Chem., 1979, 578, (b) Gonzalez, J.C. et al, Synthesis, 2002, 475.4.2 N-羟基苯胺DMAP催化下与丙炔酸酯缩合合成3-羧酸吲哚衍生物其机理可以理解为如下方式：To a solut

36、ion of N-benzyl-N-phenylhydroxylamine 1 (86.2 mg, 0.426 mmol) in THF (15.0 mL) was added 4A molecular sieves. DMAP (6.0 mg, 0.049 mmol) and methyl propiolate 2 (54 mg, 0.562 mmol) were added to it at 0°C. The reaction mixture was stirred at 0°C for 1 h, then at room temperature for 48 h. E

37、thyl acetate (5.0 mL) was added, and after filtration, the organic solution was washed with water (3 x 20 mL), brine, and then dried over magnesium sulfate. Following filtration, the organics are concentrated under reduced pressure and the resultant oil purified by flash column chromatography (hexan

38、es: ethyl acetate= 7:3) as eluent to give 1-benzyl-1H-indole-3-carboxylic acid methyl ester 3 (95.6 mg; 82% yield) as a white solid (m.p. 67.0-67.5°C).Ref: (a) R.Hwu, H.V. Patel, R.J. Lin, and M.O. Gray, J. Org. Chem., 1994, 15774.3 Nenitzescu吲哚合成Nenitzescu是一类比较特殊的吲哚合成方法，它的最终产物一般都是在N原子上有芳香环的化合物

39、。对于Nenitzescu反应而言，最后一步合环反应采用不同的溶剂会得到不同的合环产物。如下的化合物4和5所示。To a solution of (E)3-amino-but-2-enenitrile 1 (1.0 g, 12.2 mmol) in acetic acid (1.54 g, 25 mmol) and water (5 mL) was added aniline 2 (1.13 g, 12.2 mol) at r.t. After stirring for 30 min., the mixture was cooled in an ice bath and the product

40、 3 was collected on a filter, dried in vacuum. (The mixture also can be extracted with acetic ether if there was no precipitate appearance.)To the solution of 1,4-benzo quinone (0.96 g, 9.0 mmol) in acetic acid (4 mL) was added acetic anhydride (0.8 mL) at r.t. After stirring for 30 min., a solution

41、 of (E)3-Phenylamino-but-2-enenitrile 3 (1.18 g, 7.5 mmol) in acetic acid (4 mL) was added to it and the mixture was stirred overnight. Crude solid was collected after filtered, washed with a little acetic acid and water, dried in vacuum. The solid was purified by column chromatography on silica gel

42、 using EtOAc/petro ether (1:2) as eluent to yield 6-hydroxy-3-cynao-2-methyl-1-phenyl-indole 4. (30%)Ref: (a) R. K. Brown, The Chemistry of Heterocyclic Compounds, (b) W. J. Houlihan, Ed., 1972, 413, (c) G. R. Allen, Jr., Org. React. 1973, 337, (d) Synthetic applications: U. Kuecklander, W. Huehnerm

43、ann, Arch. Pharm. 1979, 515, (e) J. L. Bernier, J. P., Henichart, J. Org. Chem. 1981, 4197, (f) M. Kinugawa et al., J. Chem. Soc. Perkin Trans. I, 1995, 2677; (g) J. M. Pawlak et al., J. Org. Chem. 1996, 9055.5. 2-叠氮基-3-芳基丙烯酸酯环合合成2-羧酸吲哚衍生物通过叠氮基丙烯酸酯与芳香醛缩合可以得到2-叠氮基-3-芳基丙烯酸酯，其加热环合生成吲哚2-羧酸酯衍生物，一般而言只有富电子

44、的芳环（带推电子苯环，呋喃，噻吩，吡咯）可通过该方法环合。由于反应放出氮气，在环合时一定要严格控制2-叠氮基-3-芳基丙烯酸酯滴加速度及反应瓶敞口，否则很容易喷发出来。5.1 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To a solution of NaN3 (60 g, 0.92 mol) in 240 mL of DMF was added dropwise chloro-acetic acid methyl ester 1 (75 mL, 0.86 mol) at 0 °C. After the addition, it was allowed to warm