Indole basicity

The psychoactive constituents of rauwolfia are alkaloids classified in three groups (1) weakly basic indole alkaloids, (2) intermediate basic indoline alkaloids, and (3) strong anhydronium bases. Approximately 50 alkaloids have been identified, but the principal indole alkaloids... 

One of the major subdivisions of plant alkaloids is termed the indole alkaloid group. All contain the basic indole heterocycle, and many have valuable pharmacological activity that can be exploited in drug materials. The indole portion is very often fused to another heterocycle we shall see some typical stractures in Section 11.9, where we shall consider them under fused heterocycles. 

Diels-Alder reaction of 2-bromoacrolein and cyclopentadiene using 10 mol% of titanium catalyst 74 gave the synthetically versatile (R)-bromoaldehyde adduct 75 in 94% yield, 67 1 exo. endo diastereoselectivity, and 93% ee. The absolute stereochemical outcome of the reaction is consistent with the proposed transition state assembly 76 in which the dienophile coordinates at the axial site of the metal, proximal to the indane moiety through Ji-attractive interactions. In this complex, the 7t-basic indole and the Ji-acidic dienophile can assume a parallel orientation facilitated by the octahedral geometry of the transition metal. The aldehyde would then react through a preferential s-cis conformation (Scheme 17.27).54... 

Yet another rearrangement of a tabersonine derivative has been reported. 19-Iodotabersonine (202), prepared from vindolinine, when heated with diazabi-cycloundecene in DMSO, gives mainly the expected A18-tabersonine, together with the cyclobutane derivative (203) and an optically inactive non-basic indole derivative, for which the structure (204) has been proposed.118 A much-improved yield of (204) (78%) can be obtained if the reaction is conducted in DMF in the presence of sodium acetate. One of the possible mechanisms for the formation of (204) is illustrated if correct, this requires the presence of water in the reaction mixture. 

This compound-cluster exhibits an extra ring attached to its basic indolic chemical structure. The resulting three-ring /3-carboline system has an unusually placed methoxy (CH3O) group, "in marked contrast to the orientation found in serotonin and the related tryptamines (Shulgin). 

Only those indoles that are sufficiently basic to be protonated by acetic acid are reduced under these conditions. Thus, 5-nitroindole and 2,3-diphenylindole are recovered unchanged,whereas 5,6-dimeth-oxyindole is cleanly reduced to 5,6-dimethoxyindoline in 86% yield with NaBHsCN/HOAc. " This differential reactivity has been exploited by Cava and Rawal in their synthesis of CC-1065 analogs in which only the more basic double bond in (23) is reduced (equation 61).Indeed, this same tactic has since been utilized by Boger," Moodyand Sundberg, and their coworkers, in their respective synthetic efforts towards CC-1065 and the related phosphodiesterase inhibitors PDE-I and PDE-II. Likewise, Joule and coworkers have utilized NaBHsCN/HOAc in a chemoselective reduction of the more basic indole double bond in benzodipyrrole (24 equation 62). ... 

While pyrrole has 6 Ti-electrons, indole, with 10 7t-electrons, is also an electron-rich aromatie heteroeycles. Indole is not as reactive as pyrrole because its electrons are more delocalized. An indole lone pair of electrons takes part in the delocalization essential to indole s aromaticity. Therefore, the indole nitrogen atom (p/fa = -3.5/ is not basic Indole loses its aromaticity when protonated. The protonation takes place predominantly at the C3 position to form the 3//-indolium ion, which combines with another molecule of indole to give oligomers. 

Sharp resolutions of the acids and to some extent of the basic indole derivatives also, have been accomplished using solvents XX and XXI... 

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). 

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