O-Allylanilines

Hegedus et al. have thoroughly studied the homogeneous hydroamination of olefins in the presence of transition metal complexes. However, most of these reactions are either promoted or assisted, i.e. are stoichiometric reactions of an amine with a coordinated alkene [98-101] or, if catalytic, give rise to the oxidative hydroamination products, as for example in the cyclization of o-allylanilines to 2-alkylindoles [102, 103], i.e. are relevant to Wacker-type chemistry [104]. 

The specific ortho functionalization of arylamines is obviously important in quinoline synthesis (cf. the rc-allyl procedure devised for the preparation of o-allylanilines used as indole and quinoline precursors).76 Recently acetanilides have been subjected to orthopalladation and the ensuing complexes converted into useful precursors of 2-substituted quinoline derivatives (Scheme 143).215... 

The insertion of carbon monoxide into o-alkylpalladium(II) complexes followed by attack by either alcohols or amines is a powerful acylation method. This carbonylation reaction has been applied in several different ways to the reactions and syntheses of indoles. Hegedus and coworkers converted o-allylanilines to indoline esters 315 in yields up to 75% [293], In most of the examples in this section, CO at atmospheric pressure was employed. 

While the Mori-Ban indole synthesis is catalyzed by a Pd(0) species, the Hegedus indole synthesis is catalyzed by a Pd(II) complex. In addition, the Mori-Ban indole synthesis is accomplished via a Pd-catalyzed vinylation (a Heck recation), whereas the Hegedus indole synthesis established the pyrrole ring via a Pd(II)-catalyzed amination (a Wacker-type process). Hegedus conducted the Pd-induced amination of alkenes [430] to an intramolecular version leading to indoles from o-allylanilines and o-vinylanilines [291-293, 295, 250, 251]. Three of the original examples from the work of Hegedus are shown below. 

The Hegedus indole synthesis can be stoichiometric or catalytic and a range of indoles 340-342 was synthesized from the respective o-allylanilines in modest to very good yields (31-89%) [292],... 

In an analogous process o-allylanilines were converted into indole derivatives by Hegedus (3.66.). Since the process is initiated by a palladium(II) catalyst and produces palladium(O) as product, recycling of the catalyst had to be ensured by the addition of stoichiometric amounts of an oxidant (e g. benzoquinone).83... 

A related scheme can be applied to indole synthesis, with the aromatization being the result of elimination of Pd(0) and a proton (equation 27) (76JA2674). This scheme has been put into practice for AT-alkyl-o-allylanilines, a few aryl-substituted analogs and methyl-substituted allyl groups. The requisite o-allylanilines were obtained from o-bromoanilines and allylnickel. Provided the requisite starting materials can be constructed, the mild conditions of this cyclization would seem to recommend it for sensitive molecules. 

Recently, Inoue et al. have established the concept of multidimensional control of asymmetric photochemistry [58]. Applying this strategy, the product stereoselectivity can be inverted by environmental factors such as the temperature, pressure or solvent, and this control has been interpreted in terms of the contributions of both enthalpy (AH+) and entropy (AS+). Although originally designed for enantiodifferentiating photo sensitization of cycloalkenes [58], Miranda et al. were able to apply it to PET cyclizations of o-allylaniline derivatives [59]. In particular, irradiations at different temperatures revealed a significant entropy-controlled diastereoselectivity for compound 72 and the equipodal temperature was found at 292 K (Sch. 34). 

Cyclization of A -substituted-o-allylanilines in the presence of carbon monoxide, methanol and a palladium catalyst gives the dihydroindoleacetic acid ester (25) in 70% yield. ... 

In 1976, Hegedus et al. described the synthesis of indoles using a Pd-assisted intramolecular amination of olefins, which tolerated a range of functionalities [8a, 114]. For example, the requisite o-allylaniline 119 was prepared in high yield by the reaction of 5-methoxy-carbonyl-2-bromoaniline with n-ally I nickel bromide. Addition of 119 to a suspension of stoichiometric PdCl2(CH3CN)2 in THF produced a yellow precipitate (the putative intermediate 121), which upon treatment with Et, N gave rise to indole 120 and deposited metallic palladium. 

The intramolecular cyclization of o-allylaniline derivatives (42) and (43) have been studied. The irradiations were carried out in hexane or acetonitrile and irradiation has supplied evidence for the involvement of intramolecular CT complexes. Irradiation of (42) affords the products (44) in the yields shown. The reactivity of (43) was also studied and its cyclization gave the analogous products (45). The influence of substituents on the photochemical reactions of some aniline derivatives (46) has been studied. The unsubstituted derivatives (46) predominantly undergo cyclization. The yield of product is dependent upon the mode of irradiation. Two conditions are described as (a) benzene/air and (b) ben-zene/argon. Under the aerated conditions oxidation of the cyclized product (47) occurs to yield (48). Cyclization is suppressed when the nitrogen is acylated these compounds (46, R = COMe) predominantly undergo a photo-Fries process to yield a mixture of the ortho and para products (49). Detailed studies showed that cyclization occurs from a CT state. 

A new route to o-allylanilines consists of the silylmethylation of 3,4-dihydro-2,l-benzothiazin-2-ones at C-3 and fragmentation induced by TBAF. 

Intramolecular addition reactions of arenes and aryl olefins with secondary and primary amines have proven to be of broader scope than the analogous reactions with tertiary amines. The intramolecular addition of nonconjugated o-allylanilines 51 to yield the 2-methylindolines 52 was reported by Koch-Pomeranz et al. in 1977. Intramolecular electron transfer from the singlet aniline to the ground state alkene followed by N-H proton transfer to the alkene terminal carbon was proposed to account for the regioselective formation of indolines. Proton transfer to the internal carbon would yield tetrahydroquinolines, which were... 

Heck indole synthesis, and Hegedus-Mori-Heckreaction, in general contains at least two types of reactions for indole derivatives. They are the palladium (n) complex-catalyzed oxidative A -heterocyclization of o-allylaniline (developed in 1976) or o-aminostyrenes (reported in 1978) and the palladium-catalyzed intramolecular cyclization of o-halo N-allylaniline (reported in 1980) the latter preparation is also referred to as the Hegedus cyclization. ... 

The formation of indole from o-allylaniline with PdCl2 is believed to involve the formation of palladium complex in which both the amino group and the olefinic moiety are... 

One of the first applications of palladium to indole synthesis was due to Hegedus [12-17], who adapted the known Pd-mediated amination of alkenes [18] to the intramoleclar amination of o-vinyl- or o-allylanilines (Scheme 1, equations 1 and 2). This Wacker-like process involves Pd(II) and can be stoichiometric or catalytic. For an excellent review of the Hegedus indole synthesis, see Johnston [19]. Although it is rarely referred to as such, the Hegedus reaction has found several applications and extensions in indole synthesis (equations 3-5) [20, 21, 23]. The preparation of ethyl indole-2-carboxylates (equation 4) [21] has been improved by McNulty and Keskar [22], and Danheiser synthesized 6- -butyl-l,2-dimethyl-4-hydroxyindole via a... 

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