Indoles basicity

Crude oils contain nitrogen compounds in the form of basic substances such as quinoline, isoquinoline, and pyridine, or neutral materials such as pyrrole, indole, and carbazole. 

The nucleophilicity of the nitrogen atom survives in many different functional groups, although its basicity may be lost. Reactions of non-basic, but nucleophilic urea nitrogens provide, for example, an easy entry to sleeping-pills (barbiturates) as well as to stimulants (caffeine). The nitrogen atoms of imidazoles and indole anions are also nucleophilic and the NH protons can be easily substituted. 

Alkylation can also be accomplished with electrophilic alkenes. There is a dichotomy between basic and acidic conditions. Under basic conditions, where the indole anion is the reactive nucleophile, A-alkylation occurs. Under acidic conditions C-alkylation is observed. The reaction of indole with 4-vinylpyri-dine is an interesting illustration. Good yields of the 3-alkylation product are obtained in refluxing acetic acid[18] whereas if the reaction is done in ethanol containing sodium ethoxide 1-alkylation occurs[19]. Table 11.2 gives some examples of 3-alkylation using electrophilic alkenes. 

While catalytic reduction of the indole ring is feasible, it is slow because of the aromatic character of the C2-C3 double bond. The relative basicity of the indole ring, however, opens an acid-catalysed pathway through 3if-indoleninm intermediates. 

Indole is a neutral compound but can be protonated or deprotonated under strongly acidic or basic conditions, respectively. The piC of the conjugate acid is about —2.4 that of the neutral compound is about 16.7 (1). 

Indole is a heterocycHc analogue of naphthalene. The basic reactivity patterns of indole can be understood as resulting from the fusion of an electron-rich pyrrole ring with a ben2ene ring. 

This basic reactivity pattern is not greatiy affected by the presence of a 1- or 2- substituent, although electron-attracting substituents do diminish the reactivity. The pattern for substitution in 3-substituted indoles can be compHcated by the fact that the electrophile may preferentially attack the 3-position, even when it is already substituted. When this is the case, migration of either the new or the original substituent to C-2 may occur. 

Although only ppm levels of nitrogen are found in the mid-distillates, both neutral and basic nitrogen compounds have been isolated and identified in fractions boiling below 345°C (12). Pyrroles and indoles account for about two-thirds of the nitrogen. The remaining nitrogen is found in the basic pyridine and quinoline compounds. Most of these compounds are alkylated. 

Vinyl chloride reacts with sulfides, thiols, alcohols, and oximes in basic media. Reaction with hydrated sodium sulfide [1313-82-2] in a mixture of dimethyl sulfoxide [67-68-5] (DMSO) and potassium hydroxide [1310-58-3], KOH, yields divinyl sulfide [627-51-0] and sulfur-containing heterocycles (27). Various vinyl sulfides can be obtained by reacting vinyl chloride with thiols in the presence of base (28). Vinyl ethers are produced in similar fashion, from the reaction of vinyl chloride with alcohols in the presence of a strong base (29,30). A variety of pyrroles and indoles have also been prepared by reacting vinyl chloride with different ketoximes or oximes in a mixture of DMSO and KOH (31). 

Although it has not been possible to study the protonation of isoindole itself, it is clear that isoindoles are more basic than indoles or pyrroles. For example, 2,5-dimethyl-1,3-diphenylisoindole (40) has a p/sTa of 4-2.05 protonation of isoindoles occurs at positions 1 or 3. The pK for protonation of indolizine (10) at position 3 is 4-3.94 and that for carbazole (41) for protonation on nitrogen is estimated at -6.0. 

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. 

The BOM group is introduced onto an indole with the chloromethyl ether and sodium hydride in 80-90% yield. It is cleaved in 92% yield by catalytic reduction followed by basic hydrolysis, or by CF3COOH, HBr or 6 M HCl at... 

A large number of Brpnsted and Lewis acid catalysts have been employed in the Fischer indole synthesis. Only a few have been found to be sufficiently useful for general use. It is worth noting that some Fischer indolizations are unsuccessful simply due to the sensitivity of the reaction intermediates or products under acidic conditions. In many such cases the thermal indolization process may be of use if the reaction intermediates or products are thermally stable (vide infra). If the products (intermediates) are labile to either thermal or acidic conditions, the use of pyridine chloride in pyridine or biphasic conditions are employed. The general mechanism for the acid catalyzed reaction is believed to be facilitated by the equilibrium between the aryl-hydrazone 13 (R = FF or Lewis acid) and the ene-hydrazine tautomer 14, presumably stabilizing the latter intermediate 14 by either protonation or complex formation (i.e. Lewis acid) at the more basic nitrogen atom (i.e. the 2-nitrogen atom in the arylhydrazone) is important. 

The most common conditions employed in the Madelung process are sodium/potassium alkoxide or sodium amide at elevated temperature (200-400 C). The Madelung reaction could be effected at lower temperature when -BuLi or LDA are employed as bases/ The useful scope of the synthesis is, therefore, limited to molecules which can survive strongly basic conditions. The process has been successfully applied to indoles bearing alkyl substituents. ... 

Under basic conditions, the o-nitrotoluene (5) undergoes condensation with ethyl oxalate (2) to provide the a-ketoester 6. After hydrolysis of the ester functional group, the nitro moiety in 7 is then reduced to an amino function, which reacts with the carbonyl group to provide the cyclized intermediate 13. Aromatization of 13 by loss of water gives the indole-2-carboxylic acid (9). 

Some recent studies have underlined the effect that certain physical properties of the reaction medium have in governing the nature and yields of the products obtained when indole Grignard reagents react with alkyl or alkynyl halides. Such factors include the basicity and dielectric constant of the medium and its ability to solvate any of the reacting species. ... 

The idea that dichlorocarbene is an intermediate in the basic hydrolysis of chloroform is now one hundred years old. It was first suggested by Geuther in 1862 to explain the formation of carbon monoxide, in addition to formate ions, in the reaction of chloroform (and similarly, bromoform) with alkali. At the end of the last century Nef interpreted several well-known reactions involving chloroform and a base in terms of the intermediate formation of dichlorocarbene. These reactions included the ring expansion of pyrroles to pyridines and of indoles to quinolines, as well as the Hofmann carbylamine test for primary amines and the Reimer-Tiemann formylation of phenols. 

In a basic medium, it is possible to direet the ketovinylation at the a-position of the indole ring 240 to arrive at the 2-ketovinyl derivative 247 whieh furnishes the maeroeyele 248 by eondensation with eyanoaeetie ester (94CZ452). 

Problem 24.23 Which nitrogen atom in the hallucinogenic indole alkaloid jV,A -dimethyltryptamine is more basic Explain. 

Both 3-bromo- and 3-iodo-indoles have been selectively prepared by titrimetric addition to the heterocycle of the halogen dissolved in dimethylformamide. The mildly basic solvent is probably responsible for trapping the generated hydrogen halide (82S1096). 

Aromatic aldehydes react in basic as well acidic medium. Thus vanillin and primary amines yield Schiff s bases (cf. vanillin-potassium hydroxide reagent in Volume 1 a). Colored phenolates are formed at the same time. As would be expected secondary amines, indole derivatives and lysergic acid derivatives do not react. 

A novel method has been developed for the selective N-arylation of indoles with aryl electrophiles in the presence of potassium fluoride adsorbed onto basic alumina <96TL299>. 

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