2-haloaniline derivatives

Undoubted, 2-haloaniline derivatives still maintain most vored precursor status for the preparation of the indole nucleus. Larock now reports the frill details of his examination of the asymmetric addition of IV-tosyl-2-iodoaniline (63) to allenes 64 (e.g. 1,2-undecadadiene) in the presence of palladium catafysts and chiral bisoxazoline ligand to afford chiral indolines 65 in up to 88% ee <99JOC7312>. Cook has utilized the palladhjm-catafyzed heteroannulation of iodoanilines with alkynes derivatized with the Schollkopf chiral auxiliary as a reliable route to optically active ring-A substituted tryptophans <99TL657>. 

Cross-coupling carboamination reactions between allenes and 2-haloaniline derivatives or halogenated allylic amines have also been employed for the generation of substituted indolines, and use of an appropriate chiral catalyst for these transformations leads to formation of enantioenriched products [52]. For example, Larock has described the synthesis of indoline 56 via the Pd-catalyzed reaction of aryl iodide 54... 

Haloaniline derivatives are widely available from chemical suppliers and have been applied extensively in nitrogen-containing heterocycle synthesis. Additionally, 2-haloanilines can act as 1,2-dihaloarene precursors as well in the Sandmeyer reaction. As bully chemicals, anilines are usually applied as substrates for the synthesis of 2-haloanilines after halogenation. 

Due to the importance of 2-aminobenzothiazoles, Li and co-workers found a procedure by using 2-haloaniline derivatives and tetraalltylthiuram disulfides (TMTD) as substrates.In the presence of CuBr and CS2CO3, a variety of 2-haloanilines underwent the reaction with tetramethylthiuram disulfide efficiently to afford the corresponding 2-aminobenzothiazoles in... 

Indolylacetic acid derivatives were prepared by the ring closure of the appropriate N-(y-crotyl)-o-haloaniline derivative (3.11.).14 Although the reported yields of the original transformations15 were only mediocre, serious efforts were made to improve the method, due mainly to the value of the formed products in medicinal chemistry. 

When aniline or meta or / ara-substituted haloaniline derivatives were utilized, the isoquinuclidine derivatives (e.g., 97) were obtained nearly exclusively in high yield. Use of aniline derivatives containing an ort/zo-halogen, on the other hand, resulted in the formation of the unsaturated secondary amines (e.g., 98) in 70-80% yield, with the exception of o-fluoroaniline, which resulted in the formation of the isoquinuclidine. 

Yamanaka and co-workers studied Pd-catalyzed couplings of o-haloaniline derivatives with terminal alkynes, but cyclization to give indoles occurred upon treatment with mild base or Cul, often in one pot [213c, 216]. These workers also described the Pd-induced coupling of 1- and 2-substituted 2- and 3-iodomdoles with terminal alkynes to give the corresponding... 

Rearrangement of N-haloanilides or anilines to o- or p-haloaniline derivatives (see 1st edition). 

Mori and Ban then reported a novel synthesis of benzodiazepine derivatives by Pd-catalyzed carbonylation of o-haloaniline derivatives 10, which was prepared from o-haloanilines 8 (Scheme 4) and amino acid derivatives 9. They succeeded in the total synthesis of many benzodiazepine antitumor aulibiotics. A toluene solution of o-bromoani-line derivative 10a, which was prepared from 2-hromo-4-methoxy-5-tosyloxyaniline and 4-hydroxy-/-proline, Pd(OAc>2, PPhs, and BU3N, was heated at 110 °C for 48 h under carbon monoxide (5 atm) to produce benzodiazepiue derivative 11a. Compound 11a was converted into 12, which was a key intermediate for the synthesis of anthramycin (ISa). Using a similar procedure, they succeeded iu the total synthesis of tomaymycin (13b), prothracarcin (13c),t pretomaymycin (13d),t neothramycin (13e)t and SEN 215 (13f). ... 

The intramolecular trapping of benzyne intermediates with tethered nucleophiles is a powerful strategy for the synthesis of benzo-fused heterocycles. In this field, 7-functionalized benzoxazoles 59 and benzothiazoles 60 have been prepared by anionic cyclization of the corresponding lithiated benzyne (thio)amides and (thio)carbamates, which were generated from 3-haloaniline derivatives (Scheme 12.34) [55]. Related to this, substituted indolines 61 have also been accessed by benzyne-mediated cyclization-functionalization from Boc-protected (2-bromo-4-methoxy)phenetylamines using Mg(TMP)2 2LiCl as a base. This methodology has also been applied to the preparation of functionalized carbazoles (Scheme 12.34) [56]. 

The von Richter cinnoline process was further extended to solid-phase synthesis. The route began from benzylaminomethyl polystyrene and the required diverse o-haloaryl resins represented by 21 were prepared from substituted o-haloanilines. A Pd-mediated cross-coupling reaction with 21 and the alkynes provided the alkynylaryl derivatives represented by alkyne 22. The von Richter cyclization reaction with hydrobromic or hydrochloric acid in acetone/HaO and cleavage from the resin occurred in the same step to furnish the cinnoline derivatives 23 in 47-95% yield and 60-90% purity (no yield reported for each entry). 

See diazonium sulfides and derivatives (references 8,9) See other haloanilines... 

With conventional methods, the formation of indole derivatives from anilines proceeds at the expense of both unsubstituted ortho positions in the phenyl ring. This leads to undesirable by-products. Particularly, the formation of by-products takes place during Fischer s synthesis of benzohet-erocycles. In the previously described ion-radical variant of the synthesis, only one indole isomer is formed—the isomer that corresponds strictly to the structure of the starting haloaniline. 

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