Indoles by cyclization

Combes synthesis with pentan-2,4-dione that led to 157, was ascribed to unfavorable steric hindrance in the alternative orientation in the Combes synthesis. 2-Amino-l,4-dimethylcarbazole underwent the Skraup reaction in the only orientation available to it. Finally, the carbazol-1-yIhydrazone of ethyl pyruvate underwent normal Fischer indolization giving 158 its 3-isomer gave an indole by cyclization at C-4 producing 159. ... 

Cyclizations with nitrogen nucleophiles involving alkynes and allenes have received little attention until recently. The cyclizations of several a-aminoallenes to 3-pyrrolines with silver tetrafluoroborate was reported by Claesson and coworkers (equation 133).264 A similar cyclization to form A -carba-penems has been reported (equation 134).265 Diastereomeric allenes (R1 R2) were shown to cyclize with complete stereocontrol. Cyclization with palladium chloride in the presence of allyl bromide or electrophilic alkenes allowed for the intermediate vinylpalladium species to be trapped by the electrophile.2651 A related product was obtained by cyclization of an alkynic substrate (equation 13S).265 Other examples of 5-endo cyclization of p-aminoalkynes50 include the formation of indoles by cyclization of 2-alkynylanilines with mercury salts200 or palladium chloride,266a,266b,266c formation of 1-pyrrolines with catalytic palladium chloride (equation 136)198 and formation of pyrroles by cyclization of hydroxy-substituted p-aminoalkynes.198,2666... 

Starting with 2-ethynylaniline, Cacchi and co-workers have prepared 2-aryl and 2-(cycloalkenyl)indoles by coupling followed by cyelization[7]. The reagents for the coupling step are Pd(PPh3)3. Cul Et2NH. The cyclization is... 

Another category Ic indole synthesis involves cyclization of a-anilino aldehydes or ketones under the influence of protonic or Lewis acids. This corresponds to retro.synthetic path d in Scheme 4.1. Considerable work on such reactions was done in the early 1960s by Julia and co-workers. The most successful examples involved alkylation of anilines with y-haloacetoacetic esters or amides. For example, heating IV-substituted anilines with ethyl 4-bromoacetoacetate followed by cyclization w ith ZnClj gave indole-3-acetate esterfi]. Additional examples are given in Table 4.3. 

A -(2 2-Diethoxyethyl)anilines are potential precursors of 2,3-unsubstituted indoles. A fair yield of 1-methylindole was obtained by cyclization of N-inethyl-M-(2,2-diethoxyethyl)aniline with BFj, but the procedure failed for indole itself[2], Nordlander and co-workers alkylated anilines with bromo-acetaldehyde diethyl acetal and then converted the products to N-trifliioro-acetyl derivatives[3]. These could be cyclized to l-(trifluoroacetyl)indoles in a mixture of trifluoroacetic acid and trifluoroacetic anhydride. Sundberg and... 

Retrosynthesis a in Scheme 7,1 corresponds to the Fischer indole synthesis which is the most widely used of all indole syntheses. The Fischer cyclization converts arylhydrazones of aldehydes or ketones into indoles by a process which involves orf/io-substitution via a sigmatropic rearrangement. The rearrangement generates an imine of an o-aminobenzyl ketone which cyclizes and aromatizes by loss of ammonia. 

Transition-Metal Catalyzed Cyclizations. o-Halogenated anilines and anilides can serve as indole precursors in a group of reactions which are typically cataly2ed by transition metals. Several catalysts have been developed which convert o-haloanilines or anilides to indoles by reaction with acetylenes. An early procedure involved coupling to a copper acetyUde with o-iodoaniline. A more versatile procedure involves palladium catalysis of the reaction of an o-bromo- or o-trifluoromethylsulfonyloxyanihde with a triaLkylstaimylalkyne. The reaction is conducted in two stages, first with a Pd(0) and then a Pd(II) catalyst (29). 

In some instances, ring contraction is accompanied by cyclization to indole derivatives. For example, l-aryl-6-oxo-l,4,5,6-tetrahydropyridazines with a carboxyl or methyl group at position 3 give indoles when treated with an ethanolic solution saturated with hydrogen chloride or in the presence of BF3 etherate. 

There are reports of an increasing number of palladium-assisted reactions, in some of which the palladium has a catalytic function. Thus furan and thiophene undergo facile palladium-assisted alkenylation giving 2-substituted products. Benzo[6 Jfuran and TV- acetyl-indole yield cyclization products, dibenzofurans and carbazoles respectively, in addition to alkenylated products (8UOC851). The arylation of pyrroles can be effected by treatment with palladium acetate and an arene (Scheme 86) (81CC254). 

Previous efforts to prepare indoles by the cyclization of the corresponding 2-anihno acetals have been largely unsuccessful Flowever, N tnfluoroacetyl-2-amlino diethyl acetal and some derivatives can be converted to indoles in good yield [22] (equation 15)... 

Coe et al. reported an efficient modification for the preparation of /-substituted indole analogs for biology screening in good yield. The intermediate P-nitrostyrene 44, prepared from the condensation of 43 with DMFDMA, underwent methanolysis and reduction to provide the aniline acetal intermediate 45. Alkylation of amine 45 was carried out employing standard conditions of reductive alkylation to provide A-alkyl analogs represented by 46. The indole 47 was generated by formation of the oxonium ion (from 46) under acidic conditions, followed by cyclization, accompanied by loss of methanol. 

Because the nucleophiles can be introduced at the ortho-position of the nitro group, various heterocycles can be prepared via VNS and related reactions. Indoles and related compounds are prepared via the VNS reaction and subsequent cyclization. The VNS reaction of nitroarenes followed by cyclization with Et3N-Me3SiCl gives 1-hydroxyindoles (Eq. 9.53).86 Cyclization is also catalyzed on treatment with bases, in which nitroso intermediates are postulated. 

Similar to the Fisher indole synthesis, reductive cyclization of nitro aromatics offers a powerful means of forming indoles. Reductive cyclization of ortho, 2 -dinitrostyrenes has occurred in many ways, by TiCl3, NaBH4-Pd/C, H2-Pcl/C, and other reductive methods.89 Corey and coworkers have used the Borchardt modification (Fe-AcOFI, sihca gel, toluene at reflux for the reductive cyclization of o-ji-dinitrostyrenes) to prepare 6,7-dimethoxyindole (Eq. 10.65) in a total synthesis of aspidophytine (see Schemes 3.3 and 3.4 in Section 3.2.l).89d... 

Formylation of indole-2-carbohydrazides 644 gave the formylindole-2-carbohydrazide 645, which cyclized with phosphorus oxychloride to the corresponding 1,3,4-oxadiazolylindole 646. Treatment of the latter with hydrazine, followed by cyclization with formic or acetic acid gave [l,2,4]triazolo[3, 4 -/][l,2,4]triazino[4,5-fl]indoles 652 and 653, respectively [90IJC(B)372],... 

An improved procedure for the synthesis of octahydroindoloquinolizine (1) from 3-(2-piperidino-ethyl)indole by oxidative cyclization process has been reported (392). 

Derivatives of y-carbolines were also sucessfully obtained by cyclization of indole oxime derivatives. Refluxing of oximes 308 in xylene gave the y-carbolines 309 in 51-55% yields (equation 133). ... 

Dodd and co-workers (5) reported the first known synthesis of 11//-indolizino[8,7-h]indoles by the cycloaddition reaction of a nonstabilized ylide 21 and diethylacetylene dicarboxylate (DEAD). The azomethine ylide, formed by the alkylation of the 3,4-dihydro-p-carboline (22) with trimethylsilyl methyl triflate to the triflate salt, followed by in situ desilyation with cesium fluoride, underwent cycloaddition with DEAD at low temperature. The expected major cycloadduct 23 was isolated, along with quantities of a minor product 24, presumed to have been formed by initial reaction of the ylide with 1 equiv of DEAD and the intermediate undergoing reaction with a further equivalent of DEAD before cyclization. Dodd offers no explanation for the unexpected position of the double bond in the newly generated five-membered ring, although it is most likely due to post-reaction isomerization to the thermodynamically more stable p-amino acrylate system (Scheme 3.5). 

Kita has introduced a novel one-pot preparation of 5-methoxylated indoline 55 and indole 56 derivatives by intermolecular addition followed by cyclization between A-tosylaniline derivatives 53 and activated olefins 54 using phenyliodine(III) bis(trifluoroacetate) (FIFA) <99H511785>. In the reaction of 53 with phenyl vinyl sulfides, indoles were produced directly by the spontaneous elimination of thiophenol. 

Similarly, pyrrolo[3,4-A]indoles 394 and 395 were synthesized according to the method of Srinivasan <1995J(P1)2663, 1998SL1061, 2000T10133>. The pyrrolo[3,4-/ ]indole skeleton was obtained by cyclization of suitable precursors with bromo and carbonyl functions with benzylamine. The syntheses starting with an A -phenyl-sulfonyl-protected indole are depicted in Scheme 43. 

Fischer indole synthesis Cyclization of arylhydrazones by heating with an acid or Lewis acid catalyst yields an indole system. The most commonly used catalyst is ZnCl2- The disadvantage of this reaction is that unsymmetrical ketones give mixtures of indoles if R also has an a-methylene group. 

Indolo[ 1,2-a]quinazoline s (67) were prepared through the formation of their diazine rings, by cyclizing 2-acylamino-l-phenyl-indoles (66) with phosphoryl chloride (81KGS844). 

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