史上最全吲哚化學總結

史上最全吲哚化學總結：

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1. Introduction

吲哚及其衍生物是一類非常有效的藥物中間體。已有不少相關綜述報導其合成方法。我們將一些常用的合成方法簡單的列舉了出來，供大家在合成此類化合物的時候參考。

 

1 (a) G. W. Gribble, Contemp.Org. Synth., 1994, 145. 

(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. Fischer 吲哚合成

Fischer 吲哚合成法是一個常見的吲哚合成方法。通過苯腙在酸催化下加熱重排消除一分子氨得到2－取代或3－取代吲哚衍生物。在實際操作中，常可以用醛或酮與等當量的苯肼在酸中加熱回流得到苯腙，其在酸催化下立即進行重排、消除氨而得到吲哚化合物。常用的催化劑有氯化鋅、三氟化硼、多聚磷酸等，常用的酸有AcOH， HCl, 三氟乙酸等。其機理大致如下：

2.1  Fischer 吲哚合成反應示例

4-Bromophenylhydrazine hydrochloride 1 (21 g) was suspended in 150 mL of aceticacid, and the mixture was heated to reflux. Then a solution of cyclohexanone 2 (9.3 mL) in 10 mL of aceticacid was added dropwise.  After theaddition, 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,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 FischerIndole Synthesis, 1982, 923. (e) D. L. Hughes, Org. Prep. Proced.Int., 1993, 607. (f) S.M. 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. 從硝基苯的衍生物出發合成吲哚

對於2，3位沒有取代基的吲哚，一般工業上大多採用硝基苯的衍生物出發合成，鄰甲基、鄰甲醯基、鄰氰乙基、鄰乙烯基、及鄰位有氫的硝基苯衍生物都可通過相應的方法得到吲哚。

3.1 鄰甲基硝基苯衍生物合成吲哚

該方法是目前最常用的，鄰甲基硝基苯衍生物與DMF-DMA反應後得到相應的烯胺，然後硝基可通過多種方法還原後加成得到吲哚。還原方法一般通過加氫，但當分子內有敏感官能團（比如：Br，I都可或烯烴等）存在時可通過化學還原如：NH2NH2-RaneyNi, 鐵粉，TiCl3, 鋅粉還原得到吲哚。

3.1.1 鄰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 DMFwas added DMFDMA (42 mL, 0.316 mol) and pyrrolidine (10 mL, 0.12 mmol).  The mixture 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 sodiumsulfate, and concentrated to give a deep red oil 2 which was dissolverin ethyl acetate (150 mL), and to the solution was added 10% palladium oncarbon (1.8 g).  Hydrogenation at 50 p.s.i. with shaking for 3h 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 give6-methoxyindole 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. Soc., 2004, 10162.

 

3.2 鄰甲醯基硝基苯衍生物合成吲哚

該鄰甲醯基硝基苯衍生物與硝基甲烷反應後得到相應的不飽和硝化物再還原後得到吲哚。

 

3.1.2鄰甲醯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 water and stirredfor 30 min.  Then it was extracted withDCM (50 mL×3), and the combined organic layer was washed with brine, dried overNa2SO4 and evaporated under vacuum.  The residue was purified by flash columnchromatography to yield 1.2 gpure 2-(2-nitro-vinyl)-nitrobenzene 2. Yield: 42%

To a solution of 2-(2-nitro-vinyl)-nitrobenzene 2(1.0 g, 0.005 mol) inethanol (10 mL), glacial acetate acid (10 mL) and water (3 mL) was added ironpowder (5.7 g, 0.1 mol)portionwise.  After the addition, it washeated to 50 °C for 30 min.  After cooled to room temperature, aq. NaHSO3was added to it and extracted with ether (50 mL×3).  The combined organic layer was washed withsaturated aq. NaHCO3, dried over Na2SO4 andevaporated under vacuum.  The residue waspurified by flash column chromatography to yield 0.45 g 1H-indole 3.  Yield: 75%

 

Ref: (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 鄰氰甲醯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 containing10% 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 ofhydrogen.  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 and then dried over Na2SO4,evaporated under reduced pressure to give the crude product, which was purifiedby column chromatography using cyclohexane/EA=4:1 as eluant to yield 13 g of 3H-benzo[e]indole.  Yield: 50%

 

Ref: (a) Makosza, M. et al., Tetrahedron, 1995,7263. (b) Bromidge, S.M. et al., J. Med. Chem., 1998, 1598.

 

3.4 鄰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) intoluene (25 mL) was added, under a positive flow of argon,bis(dibenzylideneacetone) palladium (0)(265 mg, 0.46 mmol) together withtriphenylphosphine (498 mg, 1.90 mmol).  Thesolution was heated at reflux (19 h) whereupon a red solution containing a blackprecipitate was formed.  The reactionmixture was cooled to ambient temperature, and the solvent was removed to giveblack oil.  The oil was dissolved indichloromethane (50 mL), washed with NH4OH (10%, aq, 3 x30 mL), and dried(MgSO4).  Removal of solvent gave yellowoil containing a smaller amount of black viscous oil.  The crude product was purified bychromatography (hexanes-EtOAc, 19:1) to give 2-ethenyl-4-methylnitrobenzene(589 mg, 3.61mmol, 78%) as yellow oil 2.

To an oven-dried, threaded ACEglass pressure tube was added 2-ethenyl-4-methylnitrobenzene 2 (152 mg,0.93 mmol), Pd(OAc)2(13 mg, 0.06mmol), triphenylphosphine (62 mg, 0.24 mmol), and 4 mL of MeCN.  The tube was fitted with a pressure head, thesolution was saturated with CO (four cycles to 4 atm of CO), and the reactionmixture was heated to 70 °C(oil bath temperature) under CO (4 atm) until all starting material wasconsumed (15 h) as judged by TLC.  Thereaction mixture was diluted with HCl (aq, 10%, 10 mL) and extracted with Et2O (3x10 mL).  The combined organic phases were washed withHCl (aq, 10%, 10 mL) and dried (MgSO4), and the solvent was removed to give the crude product. The crude product was purified bychromatography (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 鄰位有氫的硝基苯衍生物直接用乙烯格氏試劑合成吲哚（Bartoli反應）示例

The 2-nitrotoluene (685 mg, 5mmol) was placed in a two–necked round bottomed flask fitted with a gas inlet(argon) and rubber septum. The flask was purged several times with argon beforeadding THF (35–40 ml) and cooling to between –40 and –45 °C. The Grignard reagent (3 eq.) was then addedrapidly in one portion to the THF solution and stirring continued for a further30 mins to 1 hour (exact length of time had little effect on yield). Saturatedammonium chloride solution was added to the reaction mixture (at ca. –40 °C) before allowing the mixture towarm to room temperature. The mixture was thoroughly extracted with diethylether (2 x 200 ml), the ether extracts combined and thoroughly washed withfurther ammonium chloride (300 ml), water (300 ml) and brine (300 ml) beforedrying (MgSO4) and concentrating in vacuo to give a dark brown gum, which was purifiedby flash column chromatography (hexane:ethyl acetate 9:1) to give 465 mg of7-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. 從苯胺的衍生物出發合成吲哚

從苯胺的衍生物合成吲哚雖不常用，但還是有一些方法被報導。

 

4.1苯胺經佛克烷基化再還原關環合成吲哚

 

Toa stirred solution of boron trichloride (645 mg, 5.5mmol) in drybenzene (6 mL), a solution of 4-chloroaniline 1(638mg, 5 mmol) in dry benzene (6 mL) was added dropwise underice-cooling. To the resulting mixture containing 4-chloroanilineborontrichloride complex, chloroacetonitrile (0.38 mL, 6 mmol) and aluminumtrichloride (734 mg, 5.5 mmol) were added successively. The mixture was thenrefluxed for 6 h under nitrogen, becoming a solution of two layers. The evolvedhydrogen chloride was absorbed through a drying tube containing silica gel orcalcium chloride to a surface of aqueous sodium hydroxide. After cooling, ice 2N hydrochloric acid was added and a yellow precipitate was formed. To hydrolyzethe ketimine of 2 the mixturewas warmed at 80 °Cunder stirring, until the precipitate had dissolved (ca. 30 min). The cooledmixture was extracted with chloromethane (three times) and the organic layerwas washed with water, dried (MgS04), and concentrated. The neutralfraction obtained (744 mg) was recrystallized to obtain pure 2 (674 mg). Yield: 66%. The acidiclayer was made alkaline with 2 N sodium hydroxide and extracted withdichloromethane. Washing, drying, and evaporation of the solvent gave the basicfraction (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-α-chloroacetophenone2(204 mg, l mmol) indioxane (5mL) containing water(0.5 mL) was added sodium borohydride (1.1 mmol) and the solution was refluxedfor 5.5 h. After removal of the solvent, water was added and the mixture wasextracted with dichloromethane. The extract was dissolved in benzene and passedthrough a silica gel layer (ca. 2 g)to remove a polar fraction. The eluate with benzene was concentrated givingindole 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-羥基苯胺DMAP催化下與丙炔酸酯縮合合成3-羧酸吲哚衍生物

To a solution of N-benzyl-N-phenylhydroxylamine1 (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 addedto it at 0°C.  The reaction mixture was stirred at 0°C for 1 h, then at room temperature for48 h. Ethyl acetate (5.0 mL) was added, and after filtration, the organicsolution was washed with water (3 x 20 mL), brine, and then dried overmagnesium sulfate. Following filtration, the organics are concentrated underreduced pressure and the resultant oil purified by flash column chromatography(hexanes: ethyl acetate= 7:3) as eluent to give 1-benzyl-1H-indole-3-carboxylicacid 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, 1577

 

4.3 Nenitzescu吲哚合成

Nenitzescu是一類比較特殊的吲哚合成方法，它的最終產物一般都是在N原子上有芳香環的化合物。對於Nenitzescu反應而言，最後一步合環反應採用不同的溶劑會得到不同的合環產物。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) wasadded aniline 2 (1.13 g,12.2 mol) at r.t..  After stirring for 30min., the mixture was cooled in an ice bath and the product 3was collected on a filter, dried invacuum.  (The mixture also can beextracted 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 of(E)3-Phenylamino-but-2-enenitrile3(1.18 g,7.5 mmol) in acetic acid (4 mL) was added to it and the mixture was stirredovernight.  Crude solid was collectedafter filtered, washed with a little acetic acid and water, dried invacuum.  The solid was purified by columnchromatography on silica gel 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 HeterocyclicCompounds, (b) W. J. Houlihan, Ed., 1972, 413, (c) G. R. Allen, Jr.,Org. React. 1973, 337, (d) Synthetic applications: U.Kuecklander, W. Huehnermann, 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-疊氮基-3-芳基丙烯酸酯環合合成2-羧酸吲哚衍生物

通過疊氮基丙烯酸酯與芳香醛縮合可以得到2-疊氮基-3-芳基丙烯酸酯，其加熱環合生成吲哚2-羧酸酯衍生物，一般而言只有富電子的芳環（帶推電子苯環，呋喃，噻吩，吡咯）可通過該方法環合。由於反應放出氮氣，在環合時一定要嚴格控制2-疊氮基-3-芳基丙烯酸酯滴加速度及反應瓶敞口，否則很容易噴發出來。

5.1 2-疊氮基-3-芳基丙烯酸酯環合合成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 wasadded dropwise chloro-acetic acid methyl ester 1 (75 mL, 0.86 mol) at 0 °C.  After the addition, it wasallowed to warm to r.t. and overnight. The reaction mixture was poured into 1.5 L of water and extracted with ether (500mL×3).  The combined organic layer waswashed with brine, dried over Na2SO4 and evaporated underreduced pressure to yield 78.4 gyellow oil azido-acetic acid methylester 2.  Yield: 90%

To 500 mL of methanol was added portionwise sodium (15.7 g, 0.68 mol).  After the addition, it was heated to refluxfor 30 min.  Then a solution of4-methoxy-benzaldehyde 3 (46.2 g, 0.34 mol) and azido-aceticacid methyl ester 2 (78 g,0.68 g) in 100 mL ofmethanol was added dropwise to it.  Afterthe addition, it was stirred at 5 °C for 2 h and overnight at r.t..  Then the reaction mixture was poured into icewater and stirred for 10 min. Deposited and filtered.  The solid was washed with water (50 mL×3),dried under vacuum to yield 54.3 g yellow solid 2-azido-3-(4-methoxy-phenyl)-acrylicacid methyl ester 4.  Yield: 69%

To 600 mL of xylene was slowly added dropwise asolution of compound 4 (54 g, 0.23 mol) in 400 mL of xylene atreflux.  After the addition, it wasreflux for 1 h and cooled to room temperature and stirred overnight.  The solvent was removed under reducedpressure and the residue was recrystallized with xylene to yield 28 g white solid 6-methoxy-1H-indole-2-carboxylic acid methyl ester 5. Yield: 59%

 

Reference: (a) Coowar, D. et al, J.Med. Chem., 2004, 6270, (b) Blair, J. B., et al, J. Med. Chem.,2000, 4701

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