Palladium-catalyzed amination functional group tolerance

Halland et al. showed that the same o-alkynylhaloarene substrates used successfully by others to access indoles (Scheme 24.1, disconnection D-3) could be used to access 2//-indazole products (Scheme 24.19) [90]. The reaction proceeded via an initial regioselective intermolecular palladium-catalyzed amination using a mono-substituted hydrazine to generate an N,N -disubstituted hydrazine. Intramolecular hydroamination then forms a dihydroindazole intermediate such as 42. Isomerization to the aromatic 2//-indazole products occurred spontaneously under the reaction conditions. A variety of examples were reported, and good functional group tolerance was observed. 

Ma and coworkers reported the palladium-catalyzed direct amination of phenylalanine derivatives for the synthesis of dipeptides containing indoline-2-carboxylate via 2-methoxyiminoacyl (MIA) as a directing group and an fluorine source as the oxidant [22]. This method features high efficiency and wide functional group tolerance (Scheme 2.24). 

All of these processes are of limited synthetic utility because of the requirement of the use of stoi chiometric amounts of palladium complexes. However, by judicious choice of reactants and condition the above-mentioned impediments to catalysis can be overcome. For example, an efficient palladium(II) catalyzed cyclization of o-allyl- and o-vinyl-anilines to indoles has been developed (equation 14).28 Be cause arylamines are -106 less basic than aliphatic amines, and because the cyclized product in thi system gave an enamine (indole) stabilized by aromatization, the problems of catalyst poisoning by sub strate or product were circumvented, and catalysis was successfully achieved. The system was quit tolerant of a variety of functional groups and was used to prepare indoloquinones in excellent yieli... 

Another method that is widely used for C-C bond formation is the Heck coupling [3]. The arylation of olefinic double bonds is mostly catalyzed by palladium complexes in homogeneous solution. Important advantages of this reaction are the broad availability of arylbromides and chlorides and the tolerance of the reaction for a wide variety of functional groups. There were also developed heterogeneous Pd/C catalysts which exhibit high activity for the Heck reaction of aryl halides with olefins. The reaction conditions are 80 200 °C, solvents (NMP, DMF, tolueneAvater), base addition is necessary (NaOAc, amines, alkali carbonates). The reaction scheme can be described as follows (Eq. 8-22). 

Based on the ability of Pd(OAc)2 to accelerate the [2,3]-rearrangement of amine iV-oxide 114, we explored chiral palladium(ll) salts to catalyze the enantioselective rearrangement. When we treated amine iV-oxides 116 with Pd(OAc)2 and chiral phosphoramidite 118, chiral O-allylhydroxylamines 117 were isolated in 80-85% ee (Scheme 1S.28V Subsequent optimization revealed the beneficial effect of methanol and meta-chlorobenzoic acid (m-CBA) as additives, allowing the isolation of chiral nonracemic O-allylhydroxylamines 117 with greater than 90% enantioenrichment. This palladium-catalyzed enantioselective [2,31-rearrangement can tolerate a wide variety of functional groups in the amine N-oxide substrate. For example, we can synthesize chiral allylic hydrojq lamine products with reactive functional groups such as alcohols and aldehydes, which are inconpatible with many other methods for the synthesis of chiral alcohol derivatives. 

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