3- Phenylindole

An important general method of preparing indoles, known as the Fischer Indole synthesis, consists in heating the phenylhydrazone of an aldehyde, ketone or keto-acid in the presence of a catalyst such as zinc chloride, hydrochloric acid or glacial acetic acid. Thus acetophenone phenylhydrazone (I) gives 2-phenylindole (IV). The synthesis involves an intramolecular condensation with the elimination of ammonia. The following is a plausible mechanism of the reaction  

An interesting application is the preparation of 1 2 3 4-tetrahydrocarb-azole (VI), which is formed when phenylhydrazine is added to a boiling solution of cyclohexanone in acetic acid the phenylhydrazone (V) intermediately pro duced undergoes ring closure directly  

Prepare acetophenonephenylhydrazone by warming a mixture of 20 g. of acetophenone (Section IV, 136) and 18 g. of phenylhydrazine on a water bath for 1 hour. Dissolve the hot mixture in 40 ml. of rectified spirit, and shake or stir to induce crystallisation. Cool the mixture in ice, filter and wash with 12 ml. of rectified spirit. Dry in a vacuum desiccator over anhydrous calcium chloride for at least half an hour. The yield of phenylhydrazone, m.p. 105-106°, is 28 g. 

Place an intimate mixture of 125 g. of powdered, anhydrous zinc chloride and 26-5 g. of acetophenonephenylhydrazone in a tall 500 ml. beaker in an oil bath at 170°. Stir the mixture vigorously by hand. After 3-4 minutes the mass becomes liquid and evolution of white fumes commences. Remove the beaker from the bath and stir the mixture for 5 minutes. Then stir in 100 g. of clean, white sand in order to prevent solidification to a hard mass. Digest the mixture for 12-16 hours on a water bath with 400 ml. of water and 12 ml. of concentrated hydrochloric acid in order to dissolve the zinc chloride. Filter off the sand and the crude 2-phenylindole, and boil the solids with 300 ml. of rectified spirit. Treat the hot mixture with a little decolourising carbon and filter through a pre-heated Buchner funnel wash the residue with 40 ml. of hot rectified spirit. Cool the combined filtrates to room temperature, filter off the 2-phenylindole and wash it three times with 10 ml. portions of cold alcohol. Dry in a vacuum desiccator over anhydrous calcium chloride. The yield of pure 2-phenylindole, m.p. 188-189°, is 16 g. 

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The Fischer Indolisation Reaction occurs when the phenylhydrazone of a suitable aldehyde or ketone undergoes cyclisation with loss of ammonia, under the influence of various reagents, such as zinc chloride, ethnnolic hydrogen chloride, or acetic acid. For example, the phenylhydrazone of acetophenone (p. 257) when heated with zinc chloride gives 2 phenylindole. ... 

For the mechanism of this reaction, see Robinson and Robinson,1918, H3i 639 1924, 145, 827.) The reaction is of wide application for example, the use of methyl-phenyl-hydrazine, CsH5(CHj)> -iN H, in the above reaction gives i-methyl-2-phenylindole, whereas pyruvic acid, CH CO COOH, when converted to its phenylhydrazone and then indolised, gives indole-2-carboxylic... 

As another example of nitrene formation, the reaction of o-nitrostilbene (96) with CO in the presence of SnCU affords 2-phenylindole (97). The reaction is explained by nitrene formation by deoxygenation of the nitro group with CO, followed by the addition of the nitrene to alkene. Similarly, the 2//-indazole derivative 99 was prepared by reductive cyclization of the A-(2-nitrobenzyli-dene)amine 98[89]. 

N,N -Dihexyl-2-phenylindole-3-acetamide from 3-phenyl-3-oxopropanoic Acid[4]... 

A further class of stabilisers are the amines, such as diphenylurea and 2-phenylindole. These materials are effective with certain emulsion polymers but rather ineffective with many other polymers. 

In 1912, Madelung reported that o-acetotoluidine 3 and o-benzotoluidine 5 provided the corresponding 2-methylindole 4 and 2-phenylindole 6 respectively when heated to 360-380 C with 2 molar equivalents of sodium ethoxide. ... 

Bruce and Sutcliffe obtained l-acetyl-2-methyl-3-phenylindole (123) by the action of acetyl chloride on 2-methyl-3-pheiiylindole magnesium iodide in ether.These authors were able to obtain l-benzoyl-2-benzyl-3-phenylindole (124) but not l-acetyl-2-benzyl-3-phenylindole (125) from 2-benzyl-3-phenylindole magnesium iodide by analogous procedures.3-Acetyl-2-phenylindole (126) and 3-propionyl-2-pheny]indole (127) have recently been prepared in fair yield by the acylation of 2-phenylindole magnesium iodide with acetyl and propionyl chloride, respectively. Le ete obtained a mixture of l-acetyl-3-ethylindole (128) and 2-acetyl-3-ethylindole (129) by the interaction of acetyl chloride with 3-ethylindole magnesium iodide in ether. 

MeOH with a Hannovia UV lamp in 1973 (73TL2451). Monitoring with H NMR spectroscopy, only two among many products appeared to contain an ethoxy group. After several separations, 3-ethoxy-2-phenylindole (147, 12%), 2-phenylindole (149, 35%), and an unknown ethoxy-containing 2-phenylindole (unknown 148, 3%) were isolated (Scheme 23). 

Its structural determination had to wait for 25 years until 1998 (98H2481), when we reached the stage where we could apply suitable characteristic reactions found in 1-hydroxyindole chemistry to the synthesis of the authentic 6-ethoxy-2-phenylindole (148). 

Methylindole is, however, incorporated into mixed dimers and trimers. It thus reacts with indole and with skatole to form mixed dimers, and 2 moles react with 1 mole of indole for form a mixed trimcr. Likewise indole forms a dimer with 1,2-dimethylindole, 2-phenylindole, and even with 2,5-dimethylpyrrole, ... 

Cyanoethylation of 2-phenylindole (79MI585) and dimethylindole (82AP901) gave the corresponding cyanoethyl derivatives 326 whose hydrolysis to the acids 327 and subsequent cycUzation with PPA gave 328. 

A solution of n-Bubi in hexane (2.5 M, 980 b, 2.2 mmol) is added dropwise to a mixture of N-trimethylsilyl-o-toluidine 1602 (200 mg, 1.12 mmol) in 10 mb dry hexane. The resulting yellow solution is heated under reflux for 6 h and then left to cool to room temperature. The dianion 1603 is then added via a caimula to a precooled solution of ethyl benzoate (176 mg, 1.17 mmol) in 4 mb THF. The reaction mixture is then warmed to room temperature and partitioned between 10 mb each of ether and ice-water. The aqueous layer is extracted with ether (4x10 mb) and the combined organic extracts are washed with 10 mb brine, dried (MgS04), and concentrated in vacuo. Flash chromatography with 95 5 hexane-EtOAc gives 140 mg (65%) 2-phenylindole 1605, m.p. 182-184°C [12] (Scheme 10.24). 

After hybridization and washing, the samples were stained with DAPI (4, 6-di-amidino-2-phenylindole), which apparently associates in the minor groove of double-stranded DNA (Kapuscinski 1990). DAPI from Sigma was used. Binding of DAPI to double-stranded DNA occurs with about a 20-fold fluorescence enhancement, which usually does not occur with single-stranded DNA (Haugland 1992). 

R. E. Hicks, R. I. Amann, and D. A. Stahl, Dual staining of natural bacterioplankton with 4, 6-diamidino-2-phenylindole and fluorescent oligonucleotide probes targeting kingdom-level 16S rRNA sequences, Appl. Environ. Microbiol. 571 2158 (1992). 

Fig. 6.8. Structures of some common fluorophores. DPH = diphenylhexatriene NBD = nitrobenzoxadiazole Tb-DTPA-csl24 = terbium diethylenetriaminepentacetate-carbostyril 124, DAPI = 4, 6-diamidino-2-phenylindole Nile red = 9-(diethylamino)-5H-benzo-[a]phenoxazin-5-one.

A nickel(II) species is also though to be an intermediate in the carbonyla-tion reaction of iodobenzene with (V-methylbenzaldimine and nickel carbonyl. Two addition modes of an ensuing aroylnickel(II) complex to the C=N double bond can be envisaged as routes to l-methyl-2-phenylindol-3-one and an ethylenediamine derivative (Scheme 47).7 5 The scope of this simple indole synthesis has not been assessed. 

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