Indoles quaternary salts

An important method for construction of functionalized 3-alkyl substituents involves introduction of a nucleophilic carbon synthon by displacement of an a-substituent. This corresponds to formation of a benzylic bond but the ability of the indole ring to act as an electron donor strongly influences the reaction pattern. Under many conditions displacement takes place by an elimination-addition sequence[l]. Substituents that are normally poor leaving groups, e.g. alkoxy or dialkylamino, exhibit a convenient level of reactivity. Conversely, the 3-(halomethyl)indoles are too reactive to be synthetically useful unless stabilized by a ring EW substituent. 3-(Dimethylaminomethyl)indoles (gramine derivatives) prepared by Mannich reactions or the derived quaternary salts are often the preferred starting material for the nucleophilic substitution reactions. 

The methine chain is obtained by reacting ethyl o-formate (method A ) or ethylisoformanilide (method B) with a bis quaternary salt of bis-(2-thiazolyllbutane. Concerning dyes with fused thiazolo rings pyrrolo[2. lb]thiazoIe. thiazolo[2.3a]indole. thiazolo[2.3c]1.4-benzox-azine. the a carbon directly linked to the carbon 2 of the thiazoJe ring is also responsible for the classical syntheses giving trimethine or penta-methine dyes. 

Another useful reagent for the 3-aLkylation of indole is the /V,/V-dimethy1foTma1 diminium ion, which forms the useful intermediate gramine [87-52-5] (9). The C-3 substituent can subsequendy be modified by displacement of the dimethylarnino group by a nucleophile. Alternatively, gramine can be converted to its quaternary salt prior to substitution. A variety of carbanions can function as the nucleophile. 

Aminomethylindoles are particularly important synthetic intermediates. 3-Dimethyl-aminomethylindole (gramine) (153) and especially its quaternary salts readily undergo displacement reactions with nucleophiles (Scheme 60). Indole-2,3-quinodimethanes, generated from 2-methylgramine as shown in Scheme 61, undergo intermolecular cycloaddition reactions with dienophiles to yield carbazole derivatives (82T2745). 

The introduction of a nitrogen atom into the benzene ring of indole affords a center, not present in indole itself, at which quaternary salt formation occurs readily, and the base 95 is converted into a quaternary salt (96) on the pyridine-type nitrogen atom. ... 

Tetrahydro-y-carbolines may be prepared by an internal Mannich-type reaction between 2-j8-aminoethyhndoles and formaldehyde. Kebrle et al. prepared 27 by the reaction of 2-lithio-l-methyl-indole with A-benzyl-A-ethylaminoacetone followed by debenzyl-ation treatment of 27 with formaldehyde led to the formation of the tetrahydro-y-carboline 28. Similarly, when the quaternary salts (30) of the Mannich bases (29) are heated at 100°, 1,2,3,4-tetrahydro-y-carbohnium salts (31) are formed. 

Fischer s base, a typical starting material, is commercially available and is also obtained in situ from the corresponding quaternary salt, substituted indolines 4 can be prepared by TV-alkylation of 2,3,3-trimethyl-3//-indole followed by alkali treatment, or by exhaustive alkylation of 2,3-dimethylindole (N- and C-alkylation) followed by alkali treatment (Scheme 3). Further, methylation of indoline 5 with methyl iodide leads to C-methylation on the methylene group or the Plancher rearrange-... 

The final phase of our syntheses of vinblastine and analogous compounds required closure of the piperidine ring in the seco cleavamine part of the indole-indoline compounds 162 and 163. We had originally studied this reaction with the simple indolic C-16 and C-20 unsubstituted C-16 epimeric carbomethoxy seco cleavamines 164 and 165 and found that on cyclization they produced, through conformations 166 and 167, almost exclusively quaternary salts 168 and 169, which on debenzylation gave... 

Aminomethylindoles are particularly important synthetic intermediates. 3-Dimethylaminomethyl-indole (gramine) (353) and especially its quaternary salts readily undergo displacement reactions with nucleophiles (Scheme 62). 

The 2H-and 3//-pyrroles and -indoles are considerably more basic than the corresponding H-isomers and they readily undergo alkylation to give the quaternary salts, which are then highly susceptible to nucleophilic attack. Thus, for example, methylation of the trialkyl-3//-indole (507), followed by reaction with aqueous base, yields the indolin-2-ol (508). A similar reaction sequence results from the acylation of (507) under Schotten-Baumann conditions to give (509 X = OH). When the benzoylation is conducted in benzene in the absence of the base, the 2-chloroindoline (509 X = C1) is formed and acylation of (507) with a carboxylic acid anhydride produces the ester (509 X = OCOR) (79HC(25-3)l). 

Indoles and their quaternary salts are photochemically reduced to indolines in propan-2-ol, but irradiation in methanol produces the addition products (512) and (513) (62HCA1992). 

The use of RCM in the synthesis of 3,4-carbocyclic indoles was reported by Perez-Castells and co-workers as is exemplified in Scheme 29 <02T5407>. Vinyl indole 49 was quatemized with BnBr and quaternary salt underwent smooth addition of vinyl magnesium bromide to give the indole diene 50. RCM was accomplished with the MC2 in good yields. 

Pyrroles and 3//-indoles only exist as 2,2-disubstituted and 3,3-disubstituted examples. Both types are stronger bases than their aromatic analogues thus, each type readily undergoes N-alkylation to give quaternary salts (Scheme 107) and each forms stable protic salts. 

The derived quaternary salts (e.g., 246) give anhydro compounds (e.g., 247) on treatment with alkali. -Pentamethyl-pyrrolenine (2,3,3,4,5-pen tain ethyl-3//-pyrrole) undergoes quantitative conversion to the -isomer (2,2,3,4,5-penta-methyl-2//-pyrrole) either on heating (>200C) or in 1 M HC1 at room temperature. 3//-Indoles also undergo an acid-catalyzed rearrangement (e.g., 248 249), known as the Plancher rearrangement. 

The first method is perhaps the most common, and is exemplified by the condensation shown in Scheme 3 of a 2-alkyl heterocyclic quaternary salt or the corresponding methylene base with a 2-hydroxy unsaturated aldehyde grouping (which usually is part of an aromatic ring, as in salicylaldehyde). These intermediates have given a broad assortment of spiropyran classes. The ready availability of 1.2.3.3.-tetraalkyl-3/f-indoleninium salts and salicylaldehydes has led to a large number of spiro-(2i/-l-benzopyran-2,2 -indolines) [this name will be used in preference to the correct T,3 -dihydrospiro(2//-l-bcnzopyran-2,2 -(2 //(-indole)]. A common acronym for this class, BIPS, will be used in this chapter as both singular and plural. 

Reduction of isoquinamine gave the dihydro derivative, allodihydro-isoquinamine (XVI) which, in acid, unlike model dihydropseudoindoxyls, ring closed to the anhydro compound (XV) rather than rearranging to the indole (19). This tendency to cyclize was also evidenced when isoquinamine was heated with acids, the quaternary salt being produced (16, 22). 

Alkylation of phenols, alcohols, amides, and acids. N-Alkylation of indoles and pyrroles by means of solid KOH in DMSO was reported a few years ago. Actually this method is applicable to a number of substrates. The substrate and alkyl halide are added to powdered KOH and stirred in DMSO, usually at 20°. Methyl-ation of phenols, alcohols, and amides occurs in high yield in about 5-30 minutes. Esterification of acids is slower. Dehydrohalogenation is a competing or predominating reaction when secondary or tertiary halides are used. Another limitation is that amino groups are converted into quaternary salts under these conditions. The general method can be used for permethylation of peptides. 

Benzo[ ]quinolizinium 297 with a fused indole ring was synthesized (17%) by the cyclodehydration of the quaternary salt 296, obtained (95%) from 1-phenylpyridoindole 295 and bromoacetone (64JHC168). 

Coupling reactions. Quaternary salts of gramine couple with organoboronic acids to provide indoles with a 3-benzyl or a 3-allyl group. 

Aza-Henry reaction is rendered asymmetric by quaternary salts of Cinchona alkaloids. Addition reactions. Changing the 9-hydroxy group of Cinchona alkaloids to a 9-epiamino group not only is synthetically expedient, such products often show excellent catalytic activities in many asymmetric reactions. Those derived from dihydrocinchona alkaloids mediate Michael reactions to good results, including addition of indole to enones, and carbonyl compounds to nitroalkenes. Salt 4 has also been successfully employed in the alkenylation of t-butyl a-aryl-a-cyanoacetate. ... 

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