Ligands, Pd-catalyzed amination

The Pd-catalyzed amination of / -rm-butylphenyl bromide with pyrrole in the presence of Pd(OAc)2, dppf and one equivalent of NaOr-Bu led to the Af-arylation product 88. A simplified version of the mechanism commences with the oxidative addition of p-te/t-butylphenyl bromide to Pd(0), giving rise to the palladium complex 89. Ligand exchange with pyrrole followed by deprotonation by the base (NaOr-Bu) results in amido complex 90. Reductive elimination of 90 then gives the amination product 88 with concomitant regeneration of Pd(0) catalyst. If the amine had a (3-hydride in amido complex 90, a (3-hydride elimination would be a competing pathway, although reductive elimination is faster than P-hydride elimination in most cases. 

The coupling of chiral amines with aryl bromides proceeds without racemization by proper choice of ligands. Intermolecular animation of a chiral amine proceeds without loss of enantiomeric purity with Pd(0)-(o-Tol)3P. Synthesis of the optically pure indole 415, an intermediate for the synthesis of a potent ACE inhibitor, has been achieved by the Pd-catalyzed amination of 414, which is prepared by the Heck reaction of bromide 413 and Rh-catalyzed aymmetric hydrogenation [205],... 

Transition-metal-catalyzed synthesis of poly(arylene)s via carbon-carbon coupling reactions was started by Yamamoto et al. three decades ago [52,53] since then various carbon-carbon bond formation processes with transition-metal catalysts have been applied to polycondensation [54-57]. In recent years, Buchwald et al. and Hartwig et al. developed Pd-catalyzed amination and etherification of aromatic halides by using bulky, electron-rich phosphine ligands [58-60], and this chemistry has been applied to polycondensation for... 

Aromatic primary monoamine such as aniline serves as a difunctional monomer for Pd-catalyzed amination polycondensation to afford poly(triarylamine)s. For example, m-dibromobenzene [71] or 2,7-dibromo-fluorenes [72] reacted with aniline derivatives (Scheme 16). In these polymerizations, P(f-butyl)3 was an effective ligand of Pd2(dba)3 in a manner similar to the amination of aryl dibromides with secondary diamines. The Mw values were in the range of 9000-37 700. 

Di-tert,-butylphosphino)-biphenyl has been used by Buchwald [5] et al. as the most efficient ligand in the Pd-catalyzed amination of aryl chlorides. 2-Chloro-4-methyl-toluene can be aminated with pyrrolidine in 98% yield using sodium-tert.-butoxide [eq. (e)]. 

Furthermore, Pd-catalyzed aminations can be sequentially coupled with alkene insertion and amination. Wolfe and Lira [102] have established a transformation involving two different sequential metal-catalyzed reactions that lead to AT-aryl-2-benzylindolines 125 in moderate to excellent yields upon formation of two C - N bonds and one C - C bond in a one-pot process (Scheme 45). Interestingly, the selective installation of two different aryl groups in this sequence can be accomplished by in situ modification of the Pd catalyst system Pd-126 upon addition of the chelating ligand dpephos prior to addition of the second aryl bromide (Scheme 46). The selectively substituted indoline derivatives 127 were isolated in good to excellent yields. 

A Merck group reported an interesting kinetic resolution of a racemic di-bromocyclophane via Pd-catalyzed amination [91]. While BINAP was a poor ligand for the reaction in terms of selectivity, the C2-symmetric cyclophane-derived PHANEPHOS (17) proved to be optimal. Reaction of the cyclophane derivative with benzylamine afforded the unreacted dibromide in 45% ee after 37% conversion, corresponding to a selectivity factor of 12, Eq. (78). 

In most of the mechanistic schemes described below, the ligands on palladium have been omitted for the sake of clarity and simplicity. However, the nature of the ligands is often crucial for the reactivity and selectivity of palladium catalysts. For example, in many instances Pd-catalyzed amination reactions of aryl halides provide low yields with PPh,-ligated palladium complexes but proceed in excellent yields when catalysts bearing bulky electron-rich hgands are employed (see Section 1.7.1 below). Thus, the choice of the appropriate catalysVhgand is often crucial for success in these reactions. 

Amines are useful building blocks for biological or chemical applications, but were also a core element of polymers and materials for the electronics and xerographic industries. Watanabe et al. synthesized novel bis-(diarylamino)thiophene oligomers (92) and these amines showed intrinsic electronic properties [154]. The employment of the bulky and electron-rich ligand, P( -Bu)3, aided the Pd-catalyzed amination of 2,5-dibromothiophene to bisdiarylaminothiophene (92). 

Queiroz synthesized diarylamines in the benzothiophene series, where the ligand BINAP was used to achieve the Pd-catalyzed amination in medium to high yields [156]. The diarylamines 96 were used in materials with electronic or luminescent properties. These compounds were further cyclized to provide substituted thienocarbazoles, which are bioisosteres of natural antitumoral DNA intercalating compounds. The presence of fluorine atoms increased the solubility of these molecules [156]. 

Enanliopure tetrahydrobenzo-l,4-diazepin-3-(3//)-one 42 was obtained by intramolecular amination of the aryl iodide 41 using BINAP as a ligand without racemization [36], The chiral imidazole 47 was prepared by successive Pd-catalyzed amination of the chiral amine 43 with 1,2-dibromobenzene to give 44, which was iminated with benzophenone imine (45). Then deprotection gave 46, and acid-catalyzed ring closure yielded 47 [37], The reactions have been applied to the synthesis of various chiral imidazolium salts as precursors of chiral carbene ligands [38]. Amination of aryl bromides proceeds very rapidly by temperature-controlled microwave heating [39]. 

Conjugated enynes are very reactive and show interesting reactivity in the presence of Pd catalysts. Hydroamination of the conjugated enyne 71 in the presence of AcOH afforded 1,4-diamino-2-butene 72. In this reaction, Pd-catalyzed isomerization of the enyne to allene, followed by generation of the methylene-TT-allylpalladium 73 occurs, and amination yields the allenylamine 74. Further Pd-catalyzed amination of 74 affords the diamine 72. The reaction took place in the presence of AcOH using DPPF as a ligand [20]. A similar reaction occurred with carbon pronucleophiles [21]. 

A number of groups have investigated the Pd-catalyzed amination of aromatic electrophiles for a particular application or synthetic problem. These synthetic applications can be divided loosely into four categories synthesis of biologically active molecules, synthesis of materials for electronics or ion binding, amination in solid-phase organic synthesis, and synthesis of new ligands for transition metals. 

The overall mechanism for Pd-catalyzed amination of aryl halides is shown in Scheme 5. Initially, a Pd (0) complex is rapidly formed from Pd(OAc)2 and phosphine ligand in the presence of amine and base. If Pd(dba>2 is used, then either bisphosphine Pd(0) complexes are formed, as with P(t-Bu)3,t or mixed phosphine/dba Pd(0) complexes are formed as with arylphosphines.f In some cases, dba appears to be consumed under the reaction conditions, and simple bis-ligand Pd(0) complexes are formed. The mechanism for reduction of Pd(II) to Pd(0) has been studied," but the process occurs more rapidly in the presence of amine and base than in the absence of these reagents, even when the amine cannot undergo /3-hydrogen elimination. 

D.v.a. Formation of C—N Bonds. Though Pd-catalyzed amination— the Hartwig-Buchwald reaction—is normally performed in anhydrous media in the presence of strong bases, no steps of the mechanism of this reaction strictly require the absence of water. Moreover, it has been shown that amido complexes of Pd, the key intermediates of this reaction, can easily form by ligand exchange of water or hydroxyl (Scheme 56). ... 

The number of different ligands that can be used in amination chemistry is becoming bewildering. The intention of this review is to assist researchers wishing to conduct Pd-catalyzed aminations of aryl halides in their selection of a catalyst for a particular transformation. Although a synopsis of mechanistic data is provided in the final section, reviews with more detailed accounts of the mechanistic aspects of these reactions can be found elsewhere.Several reviews of catalyst development for Pd-catalyzed amination have been published, and a review of Pd-catalyzed carbon-heteroatom bond formation has been published. However, catalyst development for these processes has been rapid, and this review contains several new systems and synthetic applications. This development is likely to continue in the near future. Thus, some comments and predictions are made by the author about certain transformations that are likely to be developed based on known synthetic and mechanistic information. 

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