2-haloanilines

The indole skeleton can also be constructed by Pd-mediated cyclization of A -propargyl-n-haloanilines. The vinylpalladium intermediates formed in the cyclization are sufficiently stable to permit further rcaction[4,5]. For example. 

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). 

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). 

Scheme 6 Indoles from o-haloanilines synthesis of tryptamines and tryptophols via re-gioselective hydroformylation of functionalized anilines...

See entry thermochemistry and exothermic decomposition (reference 2) See other HALOANILINES... 

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

A few additional Pd-catalyzed schemes have been employed for Ilac type cyclization chemistry. Palladium-phenanthroline complexes were used by the Ragaini group to prepare indoles via the intermolecular cyclization of nitroarenes and alkynes in the presence of carbon monoxide <06JOC3748>. Jia and Zhu employed Pd-catalysis for the annulation of o-haloanilines with aldehydes <06JOC7826>. A one-pot Ugi/Heck reaction was employed in the preparation of polysubstituted indoles from a four-component reaction system of acrylic aldehydes, bromoanilines, acids, and isocyanides <06TL4683>. 

Likewise, Sakamoto has synthesized the CC-1065/duocarmycin pharmacophore 284 via the cyclization of 282 [321]. Silver carbonate prevented unwanted isomerization of the exocyclic double bond in 283. Tietze and co-workers took full advantage of the power of these A-allyl-o-haloaniline Pd-catalyzed cyclizations in developing syntheses of the A-unit of CC-1065 and analogs [322-324]. 

The cyclization of IV-allyl-o-haloanilines was adapted to the solid phase for both indoles [332, 333] and oxindoles [334]. For example, as illustrated below, a library of l-acyl-3-aIkyl-6-hydroxyindoles is readily assembled from acid chlorides, allylic bromides, and 4-bromo-3-nitroanisole [332], Zhang and Maryanoff used the Rink amide resin to prepare Af-benzylindole-3-acetamides and related indoles via Heck cyclization [333], and Balasubramanian employed this technology to the synthesis of oxindoles via the palladium cyclization of o-iodo-N-acryloylanilines [334], This latter cyclization route to oxindoles is presented later in this section. 

Whereas Hegedus [335] and Danishefsky [336] were the first to discover a tandem Heck reaction from o-allyl-A -acryloylanilines leading to tricyclic pyrrolo[l,2-a]indoles or pyridino[l,2-a]indoles [336], it has been the fantastic work of Grigg to unleash the enormous potential of this chemistry. Grigg and his co-workers parlayed their Pd-catalyzed tandem polycyclization-anion capture sequence into a treasure trove of syntheses starting with IV-allyl-o-haloanilines [337-345], Diels-Alder and olefin metathesis reactions can be interwoven into the sequence or can serve as the culmination step, as can a wide variety of nucleophiles. An example of the transformation of 289 to 290 is shown below in which indole is the terminating nucleophile [340],... 

Grigg discovered that a 5-exo-dig Pd-catalyzed cyclization of IV-acetylenic-o-haloanilines 291 to give 3-exo-alkylidene indolines 292 occurs in the presence of a hydride source, such as formic acid [346]. The reaction is stereoselective and regiospecific. 

Larock and co-workers described the one-step Pd-catalyzed reaction of o-haloanilines with internal alkynes to give indoles [385, 386]. This excellent reaction, which is shown for the synthesis of indoles 303, involves oxidative addition of the aryl halide (usually iodide) to Pd(0),. vyw-insertion of the alkyne into the ArPd bond, nitrogen displacement of the Pd in the resulting vinyl-Pd intermediate, and final reductive elimination of Pd(0). 

Spiro-2-oxindoles, such as 331, are readily crafted from the Pd-catalyzed reactions of o-haloanilines with vinyl halides and triflates in the presence of CO [428]. The o-iodo enamide is presumed to form initially, followed by Heck cyclization. 

Needless to say, the Buchwald-Hartwig reaction can also be usefully employed in ways other than the efficient preparation of diphenylamines. Given the respective substitution, it should be possible to bring about the phenazine skeleton by Pd-catalyzed ring formation as well. There are two ways to proceed either the substituent pattern required by the intramolecular Buchwald-Hartwig reaction is elaborated after the formation of the diphenylamine (121 124), or the starting material already contains the substituents necessary for the two JV-arylations. A reasonable starting point is the intermolecular JV-arylation of an o-haloaniline... 

Even more attractive is the prospect of preparing phenazines in a single synthetic operation by sequential inter-Zintramolecular AT-arylation. This would require the transformation of either two o-haloanilines 122 and 135 or of an o-phenylenediamine 82 with an o-dihalobenzene 136. Until recently, not even a single example could be found for this one-step synthesis of heterocycles via double Pd-catalyzed AT-arylation. Numerous experiments conducted in a variety of different combinations of various Pd catalysts, bases, and phosphine ligands in our laboratory failed to realize this novel synthetic principle. 

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. 

In the second, >100 DBFs were identified in indoor chlorinated and brominated pools, including many nitrogenous DBFs (haloamides, halonitriles, haloanilines, haloamines, haloanisoles, and halonitro-compounds), likely due to the nitrogen-containing precursors from swimmers (urine, sweat, etc.) [143]. Trichloramine and THMs were also measured in the pool air [143]. Nitrosamines have been measured in chlorinated pools and hot tubs, up to a maximum of429 ng/L... 

Astatohalobenzenes have also been prepared from the corresponding haloaniline isomers by decomposition of their diazoniiun salts under conditions similarly described for astatotoluenes vide supra). Here again, relatively low radiochemical yields (10-26%) were obtained. Again, this has been attributed to the competing reaction of hydroxyl ions present in the aqueous solution in a much higher concentration than At , leading to the by-product formation of phenols 99,100,105). 

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