Indoles from ortho

Baeyer and Emmerling, Indole from ortho-Nitro Cinnamic Acid.—... 

The first relationship between members of the indole group and simpler benzene derivatives was that established by Baeyer and Emmerling, 1869, in synthesizing indole from ortho-mtro cinnamic acid by fusion with potassium hydroxide and iron filings. The steps in the synthesis are probably as follows ... 

Bartoli indole synthesis Formation of 7-substituted indoles from ortho-substituted nitro- or nitrosoarenes. 40... 

Larock indole synthesis Preparation of 2,3-disubstituted indoles from ortho-iodoanilines and disubstituted alkynes. 258... 

For a general, simple high yield indole synthesis from anilines and methylthioacetaldehyde etc. see JACS 95,588,591,2718,6508 (1973). For indoles from N-( /3 -hydroxy-ethyl aniline esters see BSC 2485(1973). For a 2-acyl-indoles in one step from orthoamino-ketones and alpha-haloketones or 2-carboxyindoles from sulfonamides of ortho-aminocarbonyls see JOC 38,3622-24(1972). Indole and 5-Br-indole in 4 steps from beta-naphthol see Chem. Het. Cpds. (Russ.) 753(1973). Indole-JOC 37,3622(1972). 

The initial indole derivatives 185 and 187 are synthesized from ortho-nitrotoluenes 191 (57CB1980 60CB2024 79JOC4003). Indolylcarboxylic... 

Isatin.—Furthermore, a di-ketone derivative of di-hydro indole-known as isatin is prepared from ortho-amino benzoyl formic acid as a lactam anhydride. 

Sonogashira reactions allow easy access to arenes with an alkynyl snbstitnent ortho to nitrogen, for example from ortho-iodo- and -bromo-nitrobenzenes, or ortho-iodo- and -bromo-A -acyl- (or N-sulfonyl)-arylamines, or even by conpUng acetylenes with 2-iodoaniUne itself.Conversion of orf/20-alkynyl-nitrobenzenes and -arylamines into indoles can be achieved in several ways, for example alkoxides add to the triple bond and form nitro-acetals, nitro-gronp rednction then acetal hydrolysis bringing ring closure. ... 

Finally, in this category there must be included cyclisations of the benzylic anions derived from ortho-isocyano-toluenes the scheme shows this route in its simplest form. However, the synthesis is very flexible, for example the initial benzylic anion can be alkylated with halides or epoxides before the ring closure, thus providing 3-substituted indoles and, additionally, the final A -hthioindole can be A -alkylated by adding a suitable electrophile before work-up. ... 

Somewhat related to the Madelung and Wender indole syntheses is the method developed by Smith and Visnick, which features the dilithio species from ortho-sXkyl-N-in-methylsilyl anilines reacting with carboxylic acid esters to give 2-substitnted and 2,3-disubstituted indoles [1, 2], The value of this indole synthesis is seen by its numerous applications by Smith and coworkers in the synthesis of indole alkaloids [3-12], The basic reaction and some examples are shown in Scheme 1. The requisite silylated anilines were prepared by lithiation (n-bntyllithinm, -78 °C) of the aniline followed by quenching with trimethylsilyl chloride. For the synthesis of 2,3-disubstituted indoles an inverse quench is preferred (equation 3). To lithiate ort/to-ethyl-A -methylsilyl aniline, n-butyllithium-tetramethylethylene-diamine (TMEDA) was required. Indole 1 is an intermediate in the synthesis of (H-)-cinchonamine. 

Although the cyclization of nitrenes to indoles via ortho-azidostyrenes justifiably is associated with Sundberg, several earlier workers described and studied this reaction. Notably, the researches of Smith [1-5], SmoUnsky [6-8], Abramovitch [9], Coffin and Robbins [10], and Isomura colleagues [11] describe the pyrolysis of ort/io-azidobiphenyls to carbazoles and, in a few cases, ort/io-azidostyrenes to indoles. A sampling of these pre-Sundberg reactions from the work of Smith and coworkers is shown in Scheme 1. The typical solvent used was kerosene, and the conversion of azides to carbazoles was also accomplished photochemically, albeit in lower yield. Other carbazoles prepared thermally were 1-4 in excellent yields. These workers also synthesized 4H-thieno[3,2-ii]indole (5) from 2-(o-azidophenyl)thiophene [3]. 

A formal [3 + 2] cydoaddition route leading to the preparation of di- and tri-substituted indoles 264 from ortho-haloanilines 261 and copper(I) acetylides 262 was introduced by Castro (Scheme 9.92) [75, 76, 111], simultaneously with the mentioned earlier coupling-cyclization reaction en route to benzofurans 57 (Scheme 9.21). It is believed that this stoichiometric in copper cascade reaction proceeded with the generation of an intermediary ortho-alkynylaniline 263 [77]. Attempts to turn this reaction into a more practical catalytic process, using basic conditions to generate Cu(I)-acetylide from a terminal alkyne in the presence of Cul, provided poor yields of the respective indoles 264. 

Substituted indoles from the reaction of ortho-substituted nitroarenes and vinyl Grignard reagents. 

As might be anticipated from the behaviour of the parent heterocycles, C-2 of indole, benzo[i]furan and benzo[i]thiophene (Table 13) is shifted to lower field than C-3. However, the shifts for C-2 (O, 144.8 Se, 128.8 S, 126.1 NH, 124.7 Te, 120.8) and C-7a (O, 155.0 Se, 141.3 S, 139.6 NH, 135.7 Te, 133.0) in the benzo[i] heterocycles vary irregularly (80OMR(l3)3l9), and the sequence is different to that observed for C-2 in the parent heterocycles, namely 0>Se>Te>S>NH. Also noteworthy is the upheld position of C-7, especially in indole and benzofuran, relative to the other benzenoid carbons at positions 4, 5 and 6. A similar situation pertains in the dibenzo heterocycles (Table 14), where not only are C-1 and C-8 shifted upheld in carbazole and dibenzofuran relative to the corresponding carbons in dibenzothiophene and fluorene, but similar, though smaller, shifts can be discerned for C-3 and C-6 in the former compounds. These carbon atoms are of course ortho and para to the heteroatom and the shifts reflect its mesomeric properties. Little variation in the carbon-hydrogen coupling constants is observed for these dibenzo compounds with V(qh) = 158-165 and V(c,h) = 6-8 Hz. 

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. 

With conventional methods, the formation of indole derivatives from anilines proceeds at the expense of both unsubstituted ortho positions in the phenyl ring. This leads to undesirable by-products. Particularly, the formation of by-products takes place during Fischer s synthesis of benzohet-erocycles. In the previously described ion-radical variant of the synthesis, only one indole isomer is formed—the isomer that corresponds strictly to the structure of the starting haloaniline. 

A similar cyclization can result from lithiation of an isonitrile lithiation of 553 requires two equivalents of LDA and the organolithium 554 can either be trapped with other electrophiles at low temperature or warmed to give an indole 555 (Scheme 219) . It is quite clear that isonitriles activate purely by conjugation, and indeed they promote deprotonation of methyl groups para to an isonitrile just as well as ortho. The ease with which isonitriles can be made from formamides suggests that these methods could be rather more widely used than they are. 

Current work is focused on the benzoheteropines with the fused pyrrole (or indole), thiophene or furan rings, i.e., ortho-fused 6 + 7 + 5 ring systems with carbons only on the six-membered ring, one heteroatom on the five-membered ring and one or more heteroatoms on the seven-membered ring. The variety of heteroatoms is limited to nitrogen, oxygen and sulfur. Several examples of the related cyclic systems with the other heteroatom distribution or peri-fusion are briefly summarized in Section 4.3. The current first specialized review covers synthetic, reactivity and structural aspects reported from the late 1989 until 2007. 

The UV spectrum [7max 238, 256 (sh), 293 (sh), 314, 362 (sh), and 390 (sh) nm] of rebeccamycin (337) indicated the presence of an indolo[2,3-fl]pyrrolo[3,4-c]carbazole-5,7(6H)-dione framework. This was also discernible from its IR spectrum. The H-NMR spectrum indicated the presence of an amide NH at 8 11.37 and an indole NH at 6 10.30, in addition to signals for aromatic protons and a sugar moiety. Unlike (+)-staurosporine (295) (see Scheme 2.74), where the lactam function deshielded only the ortho C-4 proton, the C-4 and C-8 aromatic protons in rebeccamycin are both deshielded due to the anisotropic deshielding effect of the phthalimide function. 

The method that has been most utilized for the preparation of aromatic carbazoles from noncarbazole precursors is the dehydrogenation of a tricyclic indole, usually a 1,2,3,4-tetrahydrocarbazole. The synthesis of the latter s is outside the scope of this article. The next most used precursors are biphenyls with an ortho nitrogen substituent, and the next, diphenylamines the synthesis of these precursors is also not dealt with in detail here. Finally, a variety of approaches utilizing precursor indoles have been described some of these have been used only once, whereas others have been used often enough that they can be described as general. 

---