Annelation of indoles

The annelation of indoles to produce carbazoles is also frequently a satisfactory synthetic process. Reaction of 5-, 6- or 7-methoxyindole with 2,5-hexanedione, for example, gives... 

The material in the succeeding chapters describes both the synthesis of the indole ring and means of substituent modification which are especially important in indole chemistry. The first seven chapters describe the preparation of indoles from benzenoid precursors. Chapter 8 describes preparation of indoles from pyrroles by annelation reactions. These syntheses can be categorized by using the concept of bond disconnection to specify the bond(s) formed in the synthesis. The categories are indicated by the number and identity of the bond(s) formed. This classification is given in Scheme 1.1. 

The electrochemical generation of a nitrilimine provides an entrance to a wide range of heterocyclic systems via anodic oxidation of aldehyde hydra-zones. The same reaction was used for annelation of various heterocyclic systems,86 e.g., substituted pyridines, quinolines, isoquinolines, indoles, imidazoles, benzimidazoles, and benzotriazoles. 

Annelation of a benzene ring on to the [6] face of the heterocyclic ring does not have any pronounced effect upon the chemical shifts of the heterocyclic protons (cf. Table 8). The rather unexpected heteroatom sequence for shifts to progressively lower field for both H-2 and H-3 remains NHparent heterocycles. The chemical shift of the indolic N—H is also very solvent dependent and as in pyrrole it is also coupled to the ring protons with /1>2 = 2.4 Hz and Ji>3 = 2.1 Hz. The assignment of the benzenoid protons H-5 and H-6 has caused some confusion in the literature as they have almost... 

Syntheses of category Ilac can properly be called the most important category of indole synthesis. Fundamentally, the reason for this is the use of aniline or its derivatives as starting materials. Besides the easy availability of many aniline derivatives, the aromatic starting material is monofunctional whereas many other annelation procedures require a specific ortho substitution pattern in the aromatic starting material. 

The cyclization steps are facilitated by the ready susceptibility of the pyrrole ring to electrophilic attack. Step-wise approaches such as these give much better yields than attempts at cyclizative annelation of pyrroles with potentially bifunctional reagents. For example, the cyclizative condensation of pyrrole with 2,5-hexanedione, which gives 4,7-dimethylindole (equation 138), is plagued with by-product formation to the extent that the indole is obtained in only 28% yield (68AJC2053). 

Pyrroles, H.M.L. Davies. Synthesis of Porphyrins with Exocy-clic Rings from Cycloalkenopyrroles, T.D. Lash. Palladium-Catalyzed Coupling Reactions of Indoles, A.R. Martin and Q. Zheng. Cycloaddition Reactions of Indole Derivatives, U. Pindur. Transition-Metal Mediated Synthesis of Carbazole Derivatives, H. J. Knoiker. Synthesis of [b]-Annelated Indoles by Thermal Electrocyclic Reactions, S. Hibino and E. Sugi-no. Total Synthesis of (-) and ent (-) Duocarmycin SA, D.L. Boger. Index. I... 

Annelation of steroidal dienamines with substituted phenacyl bromides (7 examples) or with benzenediazonium salts (11 examples) has been shown to lead to the corresponding furano- and indolo-steroids.89 Thus the A3,5-dienamine derived from A4-androstene-3,17-dione reacted with p-bromophenacyl bromide to yield the A5-androstano[3,4-h]furan (199) in 26% yield, and reaction of the same A3,5-dienamine with benzenediazonium fluoroborate at -45 °C led to formation of the hydrazone (200) which underwent Fischer-indole cyclization on treatment with phosphorus oxychloride to produce the A4-androstano[6,7-6]indole (201). The A3,5-dienamine derived from 17/3-acetoxyandrost-4-en-3-one has been converted into the benz[4,5,6]-steroid (202 R1 = Me, R2 = H) by reaction with methyl vinyl ketone and into the analogous benzsteroid (202 R1 = H, R2 = Me) on treatment with crotonal-dehyde.90 A route to the condensed pyrroline ring system (203) has been devised... 

An alternate route for the annelation of a pyrrole ring employs the base-catalyzed condensation of furan-, thiophene-, and selenophene-carbox-ald ydes with ethyl azidoacetate the bicyclic products are indole Isoster-es. The Isomeric (3,2-b)pyrroles can be similarly prepared from the corresponding 2-carboxaldehydes. 

Indole synthesis. A new approach to indoles involves annelation of o-iodoanilines with internal alkyncs catalyzed by Pd(OAc)2-(Q,H5)3P (1 1) with 1 cquiv. of LiCl (or Bu4NC1) and 5 equiv. of K2COj or Na2COj (equation I). R1 can be H, CH2, Ac,... 

Another class of indole syntheses involve annelations of pyrroles. One new example of this type of indole synthesis involved the electrocyelization of a 2-alkenyl-3-allenylpyrrole intermediate <04H(63)1765>. This was exploited for the synthesis of indole-4,7-quinones. 

---