3- indoles, synthesis from oximes

Hartwig and Tan reported a simple indole synthesis from an oxime acetate involving C-H functionalization (Scheme 3, equation 1) [22]. Buchwald described an excellent versatile carbazole synthesis that also involved C-H activation (equation 2) [23], as did Youn [24], Antonchick [25], Gault [26], and Shi [27], who synthesized 4-deoxy-carbazomycin B (equation 3). 

A Neber route to substituted indoles 532, complementary to the Fischer indole synthesis, was recently developed (equation 235). Formation of azirine 531 from the oxime was smoothly induced, for example using MsCl/DBU or DIAD/BU3P or PhsP, and the intermediate was isolated. Thermal rearrangement of the azirine (40 to 170 °C, depending on the azirine structure) produced the indoles 532 directly in usually good yields (84-88% from the azirine). 

Benzofurans and Other Annelated Furans.-A new synthesis of benzofurans (73) is by the reaction of the phosphonium salt (72) with acid chlorides RCOCl in the presence of triethylamine. The benzofuran (74) results from the condensation of hexafluorobenzene with acetylacetone. Three instances of the formation of benzofurans from O-aryl-hydroxylamines, i.e. the oxygen analogue of the Fischer indole synthesis, have been reported O-phenylhydroxylamine hydrochloride and benzenesulphonylacetone give a 2 1 mixture of compounds (73 R = CH2S02Ph) and (75), the oxime ether (76) is converted into the aldehyde (77 ... 

As discussed in Chapter 6, nitro compounds are converted into amines, oximes, or carbonyl compounds. They serve as usefid starting materials for the preparation of various heterocyclic compounds. Especially, five-membered nitrogen heterocycles, such as pyrroles, indoles, ind pyrrolidines, are frequently prepared from nitro compounds. Syntheses of heterocyclic compounds using nitro compounds are described partially in Chapters 4, 6 and 9. This chapter focuses on synthesis of hetero-aromadcs fmainly pyrroles ind indolesi ind saturated nitrogen heterocycles such as pyrrolidines ind their derivadves. 

Benzofuranyl)pyrroles, 2-(2-thienyl)pyrroles , 2,2 -dipyrroles, 3-(2-pyr-rolyl)indoles , 2-(2-benzimidazolyl)pyrroles and2-(2-, 3- and4-pyridyl)pyrroles were prepared using this method. Reaction of alkynes (for example, propyne) or allene with ketoximes in a superbase system (MOH/DMSO) leads to 2,5-di- or 2,3,5-trisubstituted pyrroles Pyrroles and dipyrroles were synthesized also from corresponding dioximes and acetylene in a KOH/DMSO system It has also been shown that 1,2-dichloroeth-ane can serve as a source of acetylene in pyrrole synthesis. Oxime 52 in the system acetylene/RbOH/DMSO at 70 °C afforded a mixture of three pyrroles 53-55 in low yields (equation 23). The formation of product 53 occurred through recyclization of pyrrolopy-ridine intermediate. ... 

Indole oximes are widely used in the synthesis of a-, /3- and y-carbolines. Synthesis of a-carbolines 302 was easily realized from 0-2,4-dinitrophenyl-substituted oximes 301... 

Experiments on the synthesis of 4,5,6,7-tetrahydroindole and 1 -vinyl-4, 5,6,7-tetrahydroindole from cyclohexanone oxime and acetylene on bench reactors of 5 and 25 L performed under a 1.5 atm pressure give positive answers to these questions. Thus, at 100°C and KOH concentration of 0.4 mol/L, the output of 1 L of catalyst solution can amount to 50-100 g of pyrroles per hour. This means that in a small 1 m3 reactor, it is possible to produce up to 400 tons of 4,5,6,7-tetrahydroindoles (1 and/or 2) per year, which is quite acceptable to meet an initial demand for these products. It can initiate, for instance, a cheap indole manufacture by catalytic dehydrogenation of tetrahydroindoles 1 and 2. 

Recent syntheses of indol-2-ones (oxindoles) include Chuang s p-toluenesulfo-nyl radical induced cyclization of allylsulfones and the oxidative free-radical reactions of a,a-dimethylsulfonyl substituted anilides [62], the tin-free synthesis of 3-aminoindolinones from O-benzyl oxime substituted amidocyclohexadienes [63], and Pudlo s 5-exo-trigl5-exo-trig tandem radical cyclization of acrylamides to give 3-pyrrolidinone substituted oxindoles, shown below [64]. 

Iminyl radicals, generated by microwave irradiation of ( -phenyl oxime ethers such as 224, cychzed onto the indole 2-position to afford indolopyridine derivatives (225) [117]. The most likely pathway involves a 6-endo cyclization and was further exploited into a formal synthesis of neocryptolepine from gramine in five steps. 

Baeyer confirmed his results by the total synthesis of oxindole, isatin and indole. Nitration ofphenylacetic acid, isolation of the o-nitro isomer, and reduction of the latter followed by ring closure gave oxindole. Reaction with nitrous acid ( .e. potassium nitrate and sulfuric acid) gave isatin oxime, from which by reduction, dehydrogenation with iron(lll) chloride and final hydrolysis, isatin itself was obtained. 

SCHEME 1.30 Synthesis of 4,5-dihydrobenz[ ]indoles from 1-tetralone oximes and... 

SCHEME 1.131 Synthesis of 4,5-dihydrobenzo[,g]indole and its N-vinyl derivative from a-tetralone oxime and vinyl chloride in the KOH/DMSO system. 

The synthesis of 4,5,6,7-tetrahydroindoles from cyclohexanone oxime and 1,2-dihaloethanes has been disclosed [303], The best overall yields (52%-61%) of NH- and N-vinyl-4,5,6,7-tetrahydroindoles are reached when molar ratio of cyclohexanone oxime-dichloroethane-KOH-DMSO is 1 1-2 7 10. For the successful synthesis of 4,5,6,7-tetrahydroindoles, it is important to add the alkali and dihaloethane to the solution of the ketoxime in DMSO in portions. Otherwise, the reaction of diether formation becomes appreciable. At the sacrifice of decreasing the yield to -30%, one can attain 94%-95% selectivity relative to the major product, 4,5,6,7-tetrahydro-indole. Like in the reaction with free acetylene, this is achieved mainly due to the addition of small amounts of water (10%-20%) to the reaction mixture. In this case, the water can be conveniently fed into the mixture by dissolving alkali in it, which simultaneously also facilitates the dispensing of both components. Somewhat poorer results are obtained with 1,2-dibromoethane under comparable conditions [303]. 

Mikhaleva, A.I., LA. Aliev, R.N. Nesterenko, and G.A. Kalabin. 1982. One-pot synthesis of 4,5-dihydrobenz[ ]indole and its 1-vinyl derivative from a-tetralone oxime and vinyl chloride. Zh Org Khim 18 (10) 2229-2230. 

The authors analyze conditions of typical syntheses, limitations of their applicability, and possibility of vinyl chloride or dichloroethane application instead of acetylene. They examine chemical engineering aspects of the first synthesis of tetrahydroindole and indole from commercially available oxime of cyclohexanone and acetylene. In addition, the book discusses new facets of pyrroles and N-vinyl pyrroles reactivity in the reactions with the participation of both the pyrrole ring and N-vinyl groups. 

Industrially feasible synthesis of indole from cyclohexanone oxime and... 

---