A -Allylanilines

Methods for the enantioselective synthesis of 3-substituted indolines by means of the asymmetric intramolecular carbolithiation of 2-bromo-A,-allylanilines in the presence of (-)-sparteine were reported simultaneously by Bailey <00JA6787> and Groth <00JA6789>. Thus, addition of 89 to 2.2 equiv of /BuLi in the presence of the chiral ligand generates the lithium intermediate 90 which upon quenching with methanol affords the chiral indoline 91 in a process that is highly solvent dependent. 

The SnCU-catalysed Claisen and Cope rearrangements of A -allylanilines and N-allylenamines, and the effect of meffl-substituents in the aromatic ring on the Claisen aromatic amino rearrangement of a series of fluorinated anilines, have been investigated. 

Winterfeldt and co-workers67-69 have observed that A-allylmaleic ester derivatives (64) formed in the reaction of A-allylanilines with... 

Other means for generation and annulation of aryl radicals involve treatment of A -(t>-bromophenyl)propylamides with BusSnH/AIBN, which gives 3-alkylideneoxindoles <2(X)0J(P1)763>, or exposure of A -allyl(t>-iodoanilines) to fluorous tin hydride reagents, affording indolines <1999JA6607>. A set of indolines, for instance 239, have been obtained by radical cyclization of precursors such as 240, which were derived from A -allylanilines (Equation 76) <1999TL2533>. 

However, the most typical transformation of A-allylanilines is the [3,3]-sigmatropic rearrangement, known as the amino-Claisen rearrangement (46 - 47 48) that has been described in many reviews67-70 (equation 20). This process is sometimes also called the aza-Claisen rearrangement 71 as well as the aromatic aza-Cope rearrangement 72. 

Among early reported Pd-catalyzed reactions, the Mori-Ban indole synthesis has proven to be very useful for pyrrole annulation. In 1977, based on their success with the nickel-catalyzed synthesis of indole from 2-chloro-A -allylaniline, the group led by Mori and Ban disclosed Pd-catalyzed intramolecular reactions of aryl halides with pendant olefins [111]. Compound 117, easily prepared from 2-bromo-A-acetylaniline and methyl bromocrotonate, was adopted as a cyclization precursor. Treatment of 117 with PdiOAc), (2 mol%), PhjP (4 mol%), and NaHCOj in DMF provided indole 118 via an intramolecular Heck reaction followed by olefin isomerization to afford the fully aromatic product. Although yields fr om the initial report were moderate, they have been greatly improved over the last two decades [112]. 

Keywords A -allylaniline, 3-aza-Cope rearrangement, Zn " montmorillonite, microwave irradiation, 2-methylindoline... 

A -allylaniline (1.33 g, 10 mmol) was admixed with Zn " montmorillonite and subjected to microwave irradiation at 650 W (BPL, BMO-700T, operating at 2450 MHz) for 3 min. After cooling down to room temperature, the reaction mass was directly charged on a silica gel column (100-200 mesh) and eluted with ethyl acetate-n-hexane (3 7) to afford 2-methylindoline (1.06 g, 80% yield) as pale yellow liquid. 

Cyclizations. Indanes and indolines are readily formed by treatment of 3-butenylarenes and A-allylaniline derivatives with a stoichiometric amount of dilauroyl peroxide. Formation of a seven-membered ring adjoining an existing aromatic nucleus by radical cyclization of xanthate precursors has a useful scope. Several different functional groups inside the chain are tolerated. 

Aza-Cope rearrangement. The rearrangement of Af-alkyl-A-allylanilines is promoted by Lewis acids. In comparison with ZnCE, the catalytic effect of BFi OEti is superior. 

A series of reactions of nitroarenes with triallyl-, trimethallyl- and tricrotylborane have been studied. It has been established that the major process is reductive allylboration of nitro-groups accompanied by an allylic rearrangement. As a result, a new convenient method of the synthesis of A -allylanilines has been elaborated. 

The Mori-Ban indole synthesis is referred to the intramolecular version of the Heck reaction applied to synthesis indoles. The cyclization of o-halo-A-allylanilines to indoles is a general and efficient methodology. For... 

In synthesis of eletriptan (Relpax), Pfizer s triptan for the treatment of migraine, Macor again used the Mori—Ban indole synthesis as the key operation to assemble the indole ring. Jeffrey s conditions were once again employed to transform the o-bromo-A allylaniline into the indole core. 

On the other hand, for the preparation of an indole from o-halo A-allylaniline, the iodo aromatics usually give good yields of indole in the presence of Pd(OAc)2 and Et3N in CH3CN at 110°C for 72 h. However, due to the deactivation of the palladium catalyst, it is necessary to add fresh catalyst periodically. For instance, during 72 h of reaction, better results are obtained by adding one third of the catalyst each day than the reactions using same amount of catalyst in one portion. However, for the less reactive bromo aromatics, 2 equivalents of tris(o-tolyl)phosphine per Pd is necessary for an acceptable yield. ... 

This reaction has been extended to form 3-methylindole in higher yields and under milder conditions without using a phosphine ligand.In addition, the cyclization of o-halo-A-allylanilines has been performed in a homogeneous water/CHsCN medium in the presence of a water soluble tris(3-sulfonatophenyl)phosphine sodium salt (TPPTS) ligand, and in supercritical CO2 in the presence of Pd(OAc)2 and a fluorinated phosphine ligand, e.g., phenyl bis(2-perfluorohexyl)-ethylphosphine. ... 

The cyclization of o-halo A-allylaniline has been applied to the preparation of cycloprop[c]indol-5-ones, indole-3-acetic acids and hetero analogs, indole-3-pyruvic acid oxime ether, 5-(sulfamoylmethyl)indoles, the anti-migrsLinc agent CP-122,288, and the protected A-unit of CC-1065. In addition, the cyelization of -vinylaniline has been applied to 6>-vinyl-A-tosylanilines, o-vinylacetanilides, and vinyl-A-... 

A general mechanism for this reaction is displayed below, using o-bromo-A-allylaniline as the substrate and Pd(PPh3)4 as a catalyst. 

There are many variations and improvements on the application of Heck cyclization to the synthesis of indoles (the Mori-Ban indole synthesis) in the past three decades. The cyclization of o-halo-A -allylanilines to indoles is a general and efficient methodology that has been improved by Larock. These improvements include cyclozations of o-halo-A -allylanilines and o-halo-A -acryloylanilines into indoles and oxindoles. For example, the conversion of 16 to 17 can be performed at lower temperature, shorter reaction time, and with less catalyst to give 3-methylindole 17 in 87% yield. 

Microwave-assisted aza-Claisen rearrangements of A-allylanilines proceeded in very short reaction times in the presence of Zn -montmorillonite as a catalyst... 

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