Indoles from pyrroles

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. 

Sulfonamides (R2NSO2R ) are prepared from an amine and sulfonyl chloride in the presence of pyridine or aqueous base. The sulfonamide is one of the most stable nitrogen protective groups. Arylsulfonamides are stable to alkaline hydrolysis, and to catalytic reduction they are cleaved by Na/NH3, Na/butanol, sodium naphthalenide, or sodium anthracenide, and by refluxing in acid (48% HBr/cat. phenol). Sulfonamides of less basic amines such as pyrroles and indoles are much easier to cleave than are those of the more basic alkyl amines. In fact, sulfonamides of the less basic amines (pyrroles, indoles, and imidazoles) can be cleaved by basic hydrolysis, which is almost impossible for the alkyl amines. Because of the inherent differences between the aromatic — NH group and simple aliphatic amines, the protection of these compounds (pyrroles, indoles, and imidazoles) will be described in a separate section. One appealing proj>erty of sulfonamides is that the derivatives are more crystalline than amides or carbamates. 

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. 

While the Mori-Ban indole synthesis is catalyzed by a Pd(0) species, the Hegedus indole synthesis is catalyzed by a Pd(II) complex. In addition, the Mori-Ban indole synthesis is accomplished via a Pd-catalyzed vinylation (a Heck recation), whereas the Hegedus indole synthesis established the pyrrole ring via a Pd(II)-catalyzed amination (a Wacker-type process). Hegedus conducted the Pd-induced amination of alkenes [430] to an intramolecular version leading to indoles from o-allylanilines and o-vinylanilines [291-293, 295, 250, 251]. Three of the original examples from the work of Hegedus are shown below. 

To make tryptophan analogs, Gronowitz and coworkers conducted a pyrrole annulation from an aminoiodopyrimidine utilizing the Larock indole synthesis conditions (see Section 1.10.) [80]. They prepared heterocondensed pyrrole 115 by treating 4-amino-5-iodopyrimidine 114 with trimethylsilyl propargyl alcohol under the influence of a palladium catalyst The regiochemical outcome was governed by steric effects. 

Reduction of amides to aldehydes was accomplished mainly by complex hydrides. Not every amide is suitable for reduction to aldehyde. Good yields were obtained only with some tertiary amides and lithium aluminum hydride, lithium triethoxyaluminohydride or sodium bis 2-methoxyethoxy)aluminum hydride. The nature of the substituents on nitrogen plays a key role. Amides derived from aromatic amines such as JV-methylaniline [1103] and especially pyrrole, indole and carbazole were found most suitable for the preparation of aldehydes. By adding 0.25 mol of lithium aluminum hydride in ether to 1 mol of the amide in ethereal solution cooled to —10° to —15°, 37-60% yields of benzaldehyde were obtained from the benzoyl derivatives of the above heterocycles [1104] and 68% yield from N-methylbenzanilide [1103]. Similarly 4,4,4-trifluorobutanol was prepared in 83% yield by reduction of N-(4,4,4-trifluorobutanoyl)carbazole in ether at —10° [1105]. 

Tertiary amides derived from pyrrole, indole and carbazole were hydro-genolyzed to alcohols and amines by refluxing in ether with a 75% excess (0.88 mol) of lithiwn aluminum hydride. Benzoyl derivatives of the above heterocycles afforded 80-92.5% yields of benzyl alcohol and 86-90% yields of the amines [7704]. 

Using this information in conjunction with a study into the preferred conformations of iminium ions generated from catalysts 12 and 21, Houk suggests that the additional steric bulk of the ferf-butyl group causes the benzyl arm of the catalyst to shield better the Si face of the C=C double bond - a requirement for high ees in an open transition state. For both the Diels-Alder and pyrrole/indole alkylation... 

Heterocycles containing an NH group, such as pyrroles, indoles, imidazoles, triazoles, etc., can be linked to insoluble supports as N-alkyl, N-aryl, or N-acyl derivatives (Table 3.29). The optimal choice depends mainly on the NH acidity of the heterocycle in question. Increasing acidity will facilitate the acidolytic cleavage of N-benzyl groups and the nucleophilic cleavage of /V-acyl groups from these heterocycles. 

Table 11. Synthesis of Indoles from t 2-Pyrrole Complexes...

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