Anilines 2-haloanilines

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). 

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

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. 

The most frequent application of Larock s method is undoubtedly the conversion of o-haloanilines to indoles. The scope of this transformation covers a wide range of disubstituted acetylenes and anilines including both TV-substituted and unsubstituted derivatives. A schematic representation of... 

Amidine derivatives are effective dehalogenation inhibitors for the chemoselective hydrogenation of aromatic halonitro compounds with Raney nickel catalysts. The best modifiers are unsubstituted or N-alkyl substituted formamidine acetates and dicyandiamide which are able to prevent dehalogenation even of very sensitive substrates. Our results indicate that the dehalogenation occurs after the nitro group has been completely reduced i.e. as a consecutive reaction from the halogenated aniline. A possible explanation for these observations is the competitive adsorption between haloaniline, nitro compound, reaction intermediates and/or modifier. The measurement of the catalyst potential can be used to determine the endpoint of the desired nitro reduction very accurately. 

In this manner, a hydroformylation/condensation sequence of 0-vinyl-anilines give indoles directly. The starting o-vinylanilines are obtained by Heck reaction of the corresponding o-haloanilines. Hydroformylation of these styrene-type olefins proceeds preferably at the benzyl carbon. Intramolecular condensation gives pharmacologically interesting tryptophols and tryptamines in mediocre to good yields (Scheme 12, Table 1) [47]. 

The mechanism of 3-haloaniline phototransformation was investigated in more detail in a nanosecond flash photolysis and product analysis study in methanolic solution [52], Photosolvolysis, as witnessed by the formation of anisidine, was again the major pathway, in particular for 3-fluoroaniline. A photoreductive pathway yielding aniline was also observed, being most important for 3-bromoaniline transient absorption indicated the formation of anilino radicals by singlet state dehalogenation as an intermediate on this pathway. Homolytic C - Br cleavage was additionally evidenced. The possibility to observe the triplet-triplet absorption spectra of 3-fluoro- and 3-chloroaniline pointed to an unreactive triplet state [52]. 

There is one major difference between the phenol and aniline systems, however, related to the fact that the amino nitrogen is able to accommodate a positive charge in the 4-haloanilines the primary photolytic dehalogenation step generates an aminophenyl cation which can be seen as a tautomer of the protonated carbene (this renders the assignment of this species... 

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. 

Anilines themselves do not undergo photosubstitution reactions, but a few of their ring-substituted derivatives such as haloanilines undergo photoreactions that are not observed in the corresponding haloarenes179. Apparently, the electron-donating amino group plays an important role in these reactions. 

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

In the presence of potassium terf-butoxide, molecular oxygen converts certain substituted primary arylamines into azo compounds through radical intermediates 4,4 -dimethoxyazobenzene is obtained in 65% yield from p-anisidine in toluene at room temperature.319 Oxidation by oxygen is more effective with a pyridine solution of the arylamine containing copper(i) chloride an 81% yield of 4,4 -bis(dimethylamino)azobenzene was obtained in this way.320 Results are particularly good with potassium te/7-butoxide in dimethyl sulfoxide,321 giving, for instance, 87% of azobenzene from aniline and also being useful for various haloanilines. 

The Pd-catalyzed coupling of o-haloanilines and terminal alkynes tends to produce either the 2-(l-alkynyl)aniline or mixtures of the alkynylanilines and the corresponding indoles [17,18]. However, iV-benzyl-2-iodoaniline has recently been cross-coupled with terminal alkynes to afford the corresponding ben-zylindoles using a Pd zeolite catalyst (Eq. 14) [39]. One can also employ stoichiometric amounts of copper acetylides to effect this transformation [22-24]. 

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. 

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