Indoles anilines

This article deals with the chemistry of carbazoles, and except for their formation from carbazoles as illustrations of the chemistry of carbazoles, it specifically excludes that of 1,2,3,4-tetrahydro-, 1,2,3,4,4a,9a-hexahydro-, 1,2,3,4,5,6,7,8-octahydro carbazoles, etc., because from the viewpoint of chemical reactivity, these are indoles, anilines, pyrroles, and so on. This article also excludes carbazoles with additional fused aromatic or heteroaromatic rings, again except for the formation of such systems as illustrations of carbazole reactivity. The physical and spectroscopic properties are not covered. 

Triphenylbismuth carbonate (2) displays remarkable chemoselecdvity, aUowing alcohol oxidation in the presence of benzenethiol, pyrrolidine, indole, aniline, dimethyl aniline and 3-pyrolidinocholesta-3,S-diene. The diol moiety in (3) is cleaved selectively without oxidizing the dithioacetal function (equation 3). The rate of the stoichiometric oxidative cleavage of ciJ-cyclohexane-l,2-diol to adipic aldehyde with Ph3BiC03 is faster than that of the trans isomer, suggesting the formation of a cyclic organobismuth intermediate (4 Scheme 1). ... 

The last result concerns the effect of the H2S partial pressure on aniline reactivity. H2S was found to inhibit aniline reactivity (Figure 5) aniline conversion dropped from 47% in the absence of H2S in the reacting gas phase to 15% at a H2S partial pressure of 132 kPa. We investigated the effect of the H2S partial pressure on aniline alone in order to evaluate whether the effect of H2S was modified by the inhibition exerted by indole. Aniline conversion also decreased with the increase of the H2S partial pressure. The same result was observed when dimethyldisulphide (instead of CS2) was used as H2S precursor [26]. 

Their synthesis began with protected dipeptide 220, reaction of which with o-iodoaniline and (V-iodosuccinimide in the absence of an acid-scavenger afforded the indole-aniline coupled product 221 as a single diastereomer. Larock annulation of 221 with tripeptide 222 obtained in two steps from serine-derived 223 through... 

Many other aromatic systems can be similarly electropolymerized, including thiophene, furan, carbazole, azulene, indole, aniline, phenol and thiophenol among others. 

Concerning non-metallic compounds, the antiknocking properties of nitrogen compounds such that derivatives of aniline, indole and quinoline, and certain phenol derivatives have been mentioned. 

Reactions of aromatic and heteroaromatic rings are usually only found with highly reactive compounds containing strongly electron donating substituents or hetero atoms (e.g. phenols, anilines, pyrroles, indoles). Such molecules can be substituted by weak electrophiles, and the reagent of choice in nature as well as in the laboratory is usually a Mannich reagent or... 

Another category Ic indole synthesis involves cyclization of a-anilino aldehydes or ketones under the influence of protonic or Lewis acids. This corresponds to retro.synthetic path d in Scheme 4.1. Considerable work on such reactions was done in the early 1960s by Julia and co-workers. The most successful examples involved alkylation of anilines with y-haloacetoacetic esters or amides. For example, heating IV-substituted anilines with ethyl 4-bromoacetoacetate followed by cyclization w ith ZnClj gave indole-3-acetate esterfi]. Additional examples are given in Table 4.3. 

A -(2 2-Diethoxyethyl)anilines are potential precursors of 2,3-unsubstituted indoles. A fair yield of 1-methylindole was obtained by cyclization of N-inethyl-M-(2,2-diethoxyethyl)aniline with BFj, but the procedure failed for indole itself[2], Nordlander and co-workers alkylated anilines with bromo-acetaldehyde diethyl acetal and then converted the products to N-trifliioro-acetyl derivatives[3]. These could be cyclized to l-(trifluoroacetyl)indoles in a mixture of trifluoroacetic acid and trifluoroacetic anhydride. Sundberg and... 

Gassman and co-workers developed a synthetic route from anilines to indoles and oxindoles which involves [2.3]-sigmatropic rearrangement of anilinosul-fonium ylides. These can be prepared from Ai-chloroanilines and ot-thiomcthyl-ketones or from an aniline and a chlorosulfonium salt[l]. The latter sequence is preferable for anilines with ER substituents. Rearrangement and cyclizalion occurs on treatment of the anilinosulfonium salts with EtjN. The initial cyclization product is a 3-(methylthio)indole and these can be desulfurized with Raney nickel. Use of 2-(methylthio)acetaldehyde generates 2,3-unsubstituled indoles after desulfurization[2]. Treatment of 3-methylthioindoles with tri-fiuoroacetic acid/thiosalieylie acid is a possible alternative to Raney nickel for desulfurization[3]. 

INDOLES FROM ANILINES via o-CHLOROACETYLATION-THE SUGASAWA SYNTHESIS... 

Boron trichloride, usually in conjunction with an additional Lewis acid, effects o-chloroacetylation of anilines. The resulting products are converted to indoles by reduction with NaBH4.[l], The strength of the Lewis acid required depends upon the substitution pattern on the ring. With ER substituents no additional... 

The stronger directing effects present in the indoline ring can sometimes be used to advantage to prepare C-substituted indoles. The aniline type of nitrogen present in indoline favours 5,7-substitution. After the substituent is introduced the indoline ring can be aromatized by dehydrogenation (see Section 15.2 for further discussion). A procedure for 7-acylation of indoline... 

The industrial source of indole has been isolation from coal-tar distillate (7). Several patents for the manufacture of indole have been issued with aniline and ethylene glycol (8), aniline and ethylene oxide (9), 2-ethy1ani1ine (10), and /V-ethy1ani1ine (11) as the starting materials. 

Transition-Metal Catalyzed Cyclizations. o-Halogenated anilines and anilides can serve as indole precursors in a group of reactions which are typically cataly2ed by transition metals. Several catalysts have been developed which convert o-haloanilines or anilides to indoles by reaction with acetylenes. An early procedure involved coupling to a copper acetyUde with o-iodoaniline. A more versatile procedure involves palladium catalysis of the reaction of an o-bromo- or o-trifluoromethylsulfonyloxyanihde with a triaLkylstaimylalkyne. The reaction is conducted in two stages, first with a Pd(0) and then a Pd(II) catalyst (29). 

The reaction between copper(I) acetylides and o-halogenophenols or -anilines provides a general and convenient route to 2-substituted benzofurans or indoles (Scheme 71g) (66JOC4071). 

Aniline, N-alkyl-o-allyl-indole synthesis from, 4, 321 Aniline, N-allyl-... 

Coe et al. reported an efficient modification for the preparation of /-substituted indole analogs for biology screening in good yield. The intermediate P-nitrostyrene 44, prepared from the condensation of 43 with DMFDMA, underwent methanolysis and reduction to provide the aniline acetal intermediate 45. Alkylation of amine 45 was carried out employing standard conditions of reductive alkylation to provide A-alkyl analogs represented by 46. The indole 47 was generated by formation of the oxonium ion (from 46) under acidic conditions, followed by cyclization, accompanied by loss of methanol. 

Aniline 77 was converted into its diazonium salt with nitrous acid and this was followed by reduction with stannous chloride to afford the corresponding arylhydrazine 78. Condensation of 78 with 3-cyanopropanal dimethylacetal 79 gave the arylhydrazone 80. Treatment of 80 with PPE resulted in cyclization to indole 81. The nitrile group was then reduced to the primary amine by catalytic hydrogenation. Reaction of the amine with excess formalin and sodium borohydride resulted in Imitrex (82). 

The Gassman indole synthesis involves an one-pot process in which hypohalite, a P-carbonyl sulfide derivative 2, and a base are added sequentially to an aniline or a substituted aniline 1 to provide 3-thioalkoxyindoles 3. Raney nickel-mediated desulfurization of 3 then produces the parent indole... 

In 1974, Gassman et al. reported a general method for the synthesis of indoles. For example, aniline 5 was reacted sequentially with r-BuOCl, methylthio-2-propanone 6 and triethylamine to yield methylthioindole 7 in 69% yield. The Raney-nickel mediated desulfurization of 7 then provided 2-methylindole 8 in 79% yield. The scope and mechanism of the process were discussed in the same report by Gassman and coworkers as well. 

The mechanism of the indolization of aniline 5 with methylthio-2-propanone 6 is illustrated below. Aniline 5 reacts with f-BuOCl to provide A-chloroaniline 9. This chloroaniline 9 reacts with sulfide 6 to yield azasulfonium salt 10. Deprotonation of the carbon atom adjacent to the sulfur provides the ylide 11. Intramolecular attack of the nucleophilic portion of the ylide 11 in a Sommelet-Hauser type rearrangement produces 12. Proton transfer and re-aromatization leads to 13 after which intramolecular addition of the amine to the carbonyl function generates the carbinolamine 14. Dehydration of 14 by prototropic rearrangement eventually furnishes the indole 8. 

The Gassman indole synthesis provides a single regioisomer when ortho/para substituted anilines are employed, the yields of which are quite good generally. This provides some advantage in the preparation of 7-substituted indoles compared to other methods which normally give low yields, that is, the Fischer indole process. ... 

A variety of 2-substituted indoles can be prepared by the Gassman process. For example, when methyl phenacyl sulfide 22 was employed with aniline, the 2-phenyl indole was obtained in 81% yield as shown here. 

The Gassman process has also been applied to the preparation of indoles which are devoid of a substituent at the 2 position. For example, indolization of aniline 5 with methylthioacetaldehyde 25 or methylthioacetaldehyde dimethyl acetal 26 furnished indole 27 however, a higher yield was obtained when the acetal 26 was employed. ... 

Many 3-substituted indoles have also been prepared with the use of a-alkyl or a-aryl-p-keto sulfides. Thus indolization of aniline 5 with 3-methylthio-2-butanone 27 furnished indolenine 28, presumably via the same mechanism discussed earlier. The indolenine 28 was relatively unstable and reduced to the indole 29 without purification. Tetrahydrocarbazole 32 was prepared in 58% overall yield. Smith et al. made excellent use of the Gassman process in the total synthesis of (-i-)-paspalicine and (+)-paspalinine. ... 

The Gassman indole synthesis has one serious limitation. Attempts to use anilines with an ortho/para- methoxy moiety failed to indolize. One means to overcome this was synthesis of the corresponding oxindoles followed by reduction to the indoles. ... 

The Hegedus indole synthesis involves one of the earlier (formal) examples of olefin hydroamination. An ortho-vinyl or ortho-nllyl aniline derivative 1 is treated with palladium(II) to deliver an intermediate resulting from alkene aminopalladation. Subsequent reduction and/or isomerization steps then provide the indoline or indole unit 2, respectively. 

Indoles 118 (99IZV400, 99RCB398) and indolizines 120 (99IZV2375, 99RCB2349) have been obtained by the condensation of suitably functionalized pyridinium salts 119 and aniline derivatives (Scheme 71). 

Studies on the Bischler-Napieralski cyclization of A -acetyltryptamine in the presence of indole have led to the isolation of numerous products, among which the indolocarbazole 186 could be found in 3.5% yield. This outcome was rationalized as a result of the intermediacy of a spiroindolenine species formed under these conditions [89H(28)175]. During detailed studies on the polymerization of indole, formation of a low yield of the related indolo[3,2-h]carbazole 187 was discovered in the product mixture originating from the treatment of indole with p-toluenesulfonic acid at elevated temperature [88JCS(P1)2387]. In an investigation of the condensation of p-benzoquinone with 4-substituted anilines, an indolo[3,2-h]carbazole derivative has been reported to be formed in 2% yield (80JOC1493). 

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