Cyclization indoline derivatives

The aryl radical cyclization has been successfully used for the preparation of substituted dihydrobenzo[Z)]indoline derivatives [59], An example is shown in Reaction (7.49). The diene 42 was preliminarly subjected to ring-closure metathesis using Grubbs catalyst and then treated with (TMS)3SiH and EtsB at -20 °C, in the presence of air, to provide the compound 43 with an excellent diastereoselectivity. 

The synthetic scheme for functionalized indolines shown in equation 83 assumes formation of a doubly metallated intermediate (335), derived from V,iV-diallyl-2,6-dibromo-p-toluidine, that may be quenched to the dehalogenated toluidine 336, or may undergo cyclization to 337. Quenching of 337 with trimethylchlorosilane in the presence of TMEDA leads to formation of indoline derivatives 338 and 339. Apparently a second cyclization of intermediate 337 to compound 340 is hard to accomplish . 

Cyclizations. ALDiphenyhnethylene derivatives of obromoarylethylamines form aryl radicals that add to the nitrogen atom to give indolines. ... 

Nitro groups adjacent to alkyl or other substituents containing abstractable hydrogen atoms can undergo intramolecular reactions leading to diradicals that can cyclize or follow other reaction paths. An example is the photoreaction of 2-(2-nitrophenyl)-ethanol to an indoline derivative (Bakke, 1970). 

This reaction involves the elelctrophilic attack of an aryldiazonium cation on the enol carbon atom of an active methinyl compound to give an azo intermediate, which then hydrolyzes to form an arylhydrazone. Tautomerization of aryl hydrazone yields the vinyl hydrazine, which undergoes [3,3] sigmatropic rearrangement and subsequently cyclizes to give an indoline derivative which, upon evolution of ammonium ion, yields the indole derivative, as shown below. 

The reaction of methane tricarboxylate with indoline 342 gave the tricyclic derivative 361 which can be transformed to the amide derivatives 362 (97JHC969). Alkylation of the iV-benzyl indoline 360 with pentafluor-oacetone gave 363 which upon debenzylation and subsequent acylation with diketene followed by cyclization gave 364. Other haloacetones were used to prepare different halogenated derivatives (79BEP872311) (Scheme 63). 

The unexpected formation of cyclopenta[b]indole 3-339 and cyclohepta[b]indole derivatives has been observed by Bennasar and coworkers when a mixture of 2-in-dolylselenoester 3-333 and different alkene acceptors (e. g., 3-335) was subjected to nonreductive radical conditions (hexabutylditin, benzene, irradiation or TTMSS, AIBN) [132]. The process can be explained by considering the initial formation of acyl radical 3-334, which carries out an intermolecular radical addition onto the alkene 3-335, generating intermediate 3-336 (Scheme 3.81). Subsequent 5-erafo-trig cyclization leads to the formation of indoline radical 3-337, which finally is oxidized via an unknown mechanism (the involvement of AIBN with 3-338 as intermediate is proposed) to give the indole derivative 3-339. 

In the course of our successful synthesis, we identified several limitations of our new method and associated strategy (1) the harsh conditions of the bicyclization reaction do not tolerate base-sensitive functionality such as vinyl halides (2) post-cyclization manipulations such as iododesilylation reactions are complicated by the sensitive/ reactive functionality of the products (a,p-unsaturated aldehyde, indoline, etc.) and (3) the incorporation of the required functionality into the Zincke aldehyde requires the synthesis of a complex tryptamine derivative, resulting in a lengthy, non-convergent route. In order to develop a concise route to strychnine, we would have to address each of these issues, and a straightforward solution to obviate all of these is described below. 

A novel procedure for the synthesis of an indole skeleton 81 was developed by Mori s group (Scheme 13).16e,16f Enantioselective allylic amination of 78 with A-sulfonated < r/ < -bromoaniline 79 followed by Heck cyclization of 80 provided chiral indoline 81. The treatment of a cyclohexenol derivative 78 with 79 in the presence of Pd2(dba)3-GHGl3 and ( )-BINAPO gave compound 80 with 84% ee in 75% yield. Total syntheses of (—)-tubifoline, (—)-dehydrotubifoline, and (—)-strychnine were achieved from compound 80. 

The combination of allylic amination, ring-closing metathesis, and a free radical cyclization provides a convenient approach to the dihydrobenzo[b]indoline skeleton, as illustrated in Scheme 10.10. The rhodium-catalyzed aUylic amination of 43 with the lithium anion of 2-iodo-(N-4-methoxybenzenesulfonyl)arrihne furnished the corresponding N-(arylsulfonyl)aniline 44. The diene 44 was then subjected to ring-closing metathesis and subsequently treated with tris(trimethylsilyl)silane and triethylborane to afford the dihydrobenzojhjindole derivative 46a in 85% yield [14, 43]. 

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. 

Iodophenethylamine derivatives were found to undergo palladium catalysed cyclization to indolines.45 Starting from the appropriate tetrahydro-isoquinoline derivative the reaction was extended by Buchwald to the preparation of tricyclic natural products (3.37.),46... 

The photochemically induced aryl-aryl coupling reaction of the diphenolic amide 28 was used as the key step in the synthesis of crassifolazonine (2). In this case, in addition to small amounts of the reduced derivative 29, indoline 30 was obtained as the result of N-attack (Scheme 6). Cyclization took place exclusively at the position para to the hydroxyl group to give a low yield of 31, which was transformed by the usual two-step procedure to crassifolazonine (2) (15). 

Another approach to the erythrinan skeleton has been developed (Scheme 3).11 The hexahydro-indolone (23), readily available from indoline (21) via the imino-enol ether (22), underwent cyclization [in very low yield (4%)] on treatment with phosphorus oxychloride to give the erythrinan derivative (24). Uncyclized compound (25) was identified as a by-product (16%) in this reaction. This latter compound was formed in 47% yield, with no product (24), when the cyclization was attempted in chloroform solution. Extensive variation of reaction conditions failed to give reasonable yields of the required compound (24). 

The indolines 95 or oxindoles 96 have been reported as products originating from the base-or fluoride-mediated exo-trig cyclization of the intermediates 97, derived from the precursors 98 by treatment with phenyliodine(III) diacetate (PIDA) <02JOC3425>. 

The Fischer indole synthesis. The Fischer acid-catalyzed conversion of an 7V-arylhydrazone 42 into an indole is one of the most powerful and versatile methods for the preparation of indoles . The mechanism involves a [3,3] sigmatropic Claisen-type rearrangement of a protonated enehydrazine tautomer 43 to give intermediate 44, which spontaneously cyclizes by loss of ammonia, probably via indoline 45, to an indole 46 (Scheme 27). For unsymmetrical ketones, two isomeric indoles are possible and the general result is that the indole derived from the more stable (usually the more highly substituted) enehydrazine is formed. 

The cascade sequence that affords bicyclic systems fails with the lithium derivatives of 2-bromo-iV,iV-diallylaniline. The methodology is useful for the synthesis of 3-substituted indolines and indoles, but the substrate undergoes only one anionic cyclization. Alkenyl vinyllithiums and alkenyl aryllithiums have also been employed in the preparation of alkylidenecyclopentanes and indanes. The intramolecular addition of vinyllithium reagents... 

The reaction of aromatic orf/zo-substituted imidoyllithiums 56 with carbon monoxide and methyl iodide afforded li/-isoindole derivatives 61 in moderate yields (Scheme 16)77. In this process the formation of an acyllithium 57 was proposed to occur which, after formation of intermediate 58, cyclized to give the compound 59. The rearrangement of the alkyl group giving the aromatic product 60, followed by quenching with methyl iodide at — 78 °C, gave indolines 61. 

In this context, it has been observed that dilithio derivative 333 cyclizes in the presence of TMEDA to give a dilithiated indoline that may be differentially functionalized by sequential addition of electrophiles, affording 1,3-disubstituted indolines 334 (Scheme 86)147. This cyclization reaction also proceeds in an enantioselective way when it is carried out in the presence of the pseudoephedrine ligand 332a. However, (—)-sparteine is in this case not able to promote the carbolithiation step, showing that the substrate structure may have a pronounced effect on the ability of a given ligand to facilitate the cyclization reaction. 

This method has been used for the synthesis of 1-aryl and polycyclic isatins derived from phenoxazine, phenothiazine and dibenzoazepine as well as indoline. In the case of dimethoxyanilines, spontaneous cyclization to yield dimethoxyisatins in the absence of a Lewis acid has been observed, as exemplified in the synthesis of melosatin A, albeit in very low yield (Scheme 8). 

In some cases an intramolecular arylation (Section A.l.i, f, equations 85 and 107) is problematic. Cyclic Af-(2-bromophenylethylenaminones instead of benzazepines with LiNEt2 yield indolines. Photolysis seems to be a good alternative method. A photolytic reaction of the same reagents leads to the desired benzazepines in high yield204-207 (equation 146). Carbazoles and phenanthridines can also be obtained by photocycliza-tion of brominated N-phenyl, N-benzyl derivatives of cyclic enaminones in yields similar to those in the base promoted cyclization (see equations 84, 106 and 107). 

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