Indoles 1.3- dialkyl

Phosphorus trichloride in benzene is reported to effect mild and fast cydization. It has been used for synthesis of 2,3-dialkyl- and 2,3-diaryl-indoles[8-ll]. Table 7.2 presents some typical Fischer indolization reactions using both the traditional and more recently developed reaction conditions. 

Carbocations stabilized by functional groups can also effect 3-alkylalion of indoles. From a synthetic point of view the most important are jV.jV-dialkyl-methyleneiminium ions which can be generated under Mannich conditions from formaldehyde and secondary amines[13]. The products, 3-(A/,A-dialkyl-aminornethyl)indoles, are useful synthetic intermediates (see Chapter 12). 

A large number of pyridazines are synthetically available from [44-2] cycloaddition reactions. In one general method, azo or diazo compounds are used as dienophiles, and a second approach is based on the reaction between 1,2,4,5-tetrazines and various unsaturated compounds. The most useful azo dienophile is a dialkyl azodicarboxylate which reacts with appropriate dienes to give reduced pyridazines and cinnolines (Scheme 89). With highly substituted dienes the normal cycloaddition reaction is prevented, and, if the ethylenic group in styrenes is substituted with aryl groups, indoles are formed preferentially. The cycloadduct with 2,3-pentadienal acetal is a tetrahydropyridazine derivative which has been used for the preparation of 2,5-diamino-2,5-dideoxyribose (80LA1307). 

No systematic study of the mass spectra of pyridopyrazines has been noted, but those of 2,3-dialkyl and 2,3-diaryl derivatives have been recorded 750MS97), and mass spectrometry has been used in the elucidation of problems in the reactions of pyrido[2,3-f ]pyrazines with amide ion (including use of and derivatives) (79JHC305), and of pyrido[2,3-f ]pyrazinium salts with indoles (78ZOR431). The mass spectra of some 1-deazaflavins have been recorded (74JCS(P1)1965). 

Indole can be nitrated with benzoyl nitrate at low temperatures to give 3-nitroindole. More vigorous conditions can be used for the nitration of 2-methylindole because of its resistance to acid-catalyzed polymerization. In nitric acid alone it is converted into the 3-nitro derivative, but in a mixture of concentrated nitric and sulfuric acids 2-methyl-5-nitroindole (47) is formed. In sulfuric acid, 2-methylindole is completely protonated. Thus it is probable that it is the conjugate acid which is undergoing nitration. 3,3-Dialkyl-3H-indolium salts similarly nitrate at the 5-position. The para directing ability of the immonium group in a benzenoid context is illustrated by the para nitration of the conjugate acid of benzylideneaniline (48). 

The enamine-imine tautomerism of the indolenine system gives rise to rearrangement reactions of interest in indole alkaloid chemistry. Thus the synthesis of dihydroburnamicine (625) utilized the rearrangement of an acetoxyindolenine to an a-hydroxyalkyl indole, presumably through an intermediate enamine. Similarly 2,3-dialkyl indoles undergo oxidations to 2-acyl indoles (626-631). 

The Batcho indole synthesis involves the conversion of an o-nitrotolnene to a fi-dialkyl-amino-o-nitrostyrene v/ith dimethylformairude acetM, followed by redncdve cychzadon to indoles. This provides a nsefid strategy for synthesis of snbsdtuted indoles fEq. 10.49. ... 

Perhaps the advantage of the medicinal chemistry route lies in the flexibility of introducing different alkyl groups on the primary amine through reductive amination on 2-aminoethyl indole 10 and hence allows access to various N, N-dialkyl tryptamine derivatives for structure-activity relationship (SAR) studies. 

In terms of methodologies for the preparation of A-arylindoles 140, Buchwald reported improved conditions for the palladium-catalyzed coupling of aryl chlorides, bromides, iodides and triflates 138 with a variety of 2-, 7- and polysubstituted indoles 139 utilizing novel electron-rich biaryl(dialkyl)phosphine ligands in combination with Pd2(dba)3 <00OL1403>. Alternatively, Watanabe reports similar A-arylations of pyrrole, indole and carbazoles with aryl bromides and chlorides using Pd(OAc)2/P(f-Bu)3 in xylene at 120°C <00TL481>. 

Der Indol-Stickstoff der Lysergsaure- und Dihydro-lysergsaurederivate kann in mannigfacher Weise substituiert werden. So ist von Troxler und Hofmann 91) die Acetylierung, Hydroxymcthylierung und Dialkyl-aminometltylierung sowie die Alk lierung 92) beschricbcn worden. 

Dialkylated indolenines give mass spectra which are very similar to those of the isomeric 2,3-disubstituted indoles, and it is quite likely that both systems rearrange under electron impact to common ions (68T2227). 

With an excess of the lithiating agent, 1-benzenesulfonylindoles form dilithiated derivatives, which may be dialkylated or dideuterated (81JHC807). Reaction with carbonyl compounds, however, may result in the formation of the 2-substituted indole with cleavage of the protecting group (Scheme 37), although the reaction with benzoyl chloride yields the sultam (134). 

Pyrrole- and indole-carboxylic acid chlorides react with dialkyl- and diaryl-cadmium to yield the ketones and it is noteworthy that the reaction of the anhydride of indole-2,3-dicarboxylic acid with diphenylcadmium produces 3-benzoylindole-2-carboxylic acid and not its isomer (53JCS1889). The ability of l-methylindole-2-carboxylic acid to react with nucleophiles is enhanced by conversion into the mixed anhydride with methanesulfonic acid. The mixed anhydride reacts with carbanions derived from diethyl malonate and from methyl acetate to yield the indolyl (3- keto esters (80TL1957). 

The reaction of indole with pyrocatechol chlorophosphite (5), in which the electrophilicity of the phosphorus atom is higher than in dialkyl chlorophosphites, leading to an increase in the proportion of C(3)-phosphorylated compounds, was studied in order to explain the effect of the environment of the P(III) atom on the direction of phosphorylation [18]. In fact, according to the P NMR data, the reaction product 6 gives only one signal with a chemical shift of 128 ppm, indicating reaction at position 3 ... 

The synthesis of dialkyl 3-aryl-2-indolylphosphonates 171 by the Fischer indole synthesis by the cycloaddition of arylhydrazines with a-ketophosphonates in polyphosphoric acid or under the influence of zinc chloride was described [183] ... 

Several other examples of the utility of Pd-mediated reactions in synthesis of aryl and vinyl derivatives of pyrrole and indole were reported. Schmidt and coworkers examined arylation of 1-vinylpyrroles under Heck conditions. Reaction took place at the A-vinyl group. While the parent compound gave a mixture of -and -arylation, 2,3-dialkyl-1-vinylpyrroles preferred -substitution. <95RCB767> Grieb and Ketcha used Suzuki coupling conditions to prepare several 1-... 

Recently Liu and coworkers used (porphyrin)iron(III) chloride complex 96 to promote 1,5-hydrogen transfer/SHi reactions of aryl azides 95, which provided indolines or tetrahydroquinolines 97 in 72-82% yield (Fig. 24) [148]. The reaction starts probably with the formation of iron nitrenoids 95A from 95. These diradicaloids undergo a 1,5- or 1,6-hydrogen transfer from the benzylic position of the ortho-side chain. The resulting benzylic radicals 95B react subsequently with the iron(IV) amide unit in an Sni reaction, which liberates the products 97 and regenerates the catalyst. /V,/V-Dialkyl-w// o-azidobenzamides reacted similarly in 63-83% yield. For hydroxy- or methoxy-substituted indolines 97 (R2=OH or OMe) elimination of water or methanol occurred from the initial products 97 under the reaction conditions giving indoles 98 in 74—78% yield. 

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