Pd-catalyzed amination

The Pd-catalyzed amination of aryl halides had rapidly become one of the most important methods to synthesize substituted aiylamines. Since its discovery in 1995, thanks to two independent studies by Buchwald and Hartwig, it has generated a... 

Table 13 Pd-catalyzed amination of 305 with n-octyl amine...

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. 

Buchwald parlayed the powerful Buchwald-Hartwig aryl amination technology [439-447] into a simple and versatile indoline synthesis [448-452], For example, indole 368, which has been employed in total syntheses of the marine alkaloids makaluvamine C and damirones A and B, was readily forged via the Pd-mediated cyclization shown below [448], This intramolecular amination is applicable to the synthesis of -substituted optically active indolines [450], and o-bromobenzylic bromides can be utilized in this methodology, as illustrated for the preparation of 369 [451]. Furthermore, this Pd-catalyzed amination reaction has been applied to the synthesis of arylhydrazones, which are substrates for the Fischer indole synthesis [453,454],... 

A synergistic combination of Pd-catalyzed amination and arylation was the central operation of Sakamoto s synthesis of carbolines [147]. Diarylamine 187 was first installed via the Buchwald-Hartwig amination protocol. Subsequent intramolecular Heck-like arylation of 187 provided a novel route to a-carboline 188. 

An extension of Buchwald s Pd-catalyzed amination led to animation of 2-chlorobenzothiazole with piperidine 112 to form 113 [62]. The marked reactivity enhancement of the chloride is attributed to the polarization at C(2). The methodology is also suitable for 2-chlorobenzoxazole and 2-chlorobenzoimidazole. 

In 2006 Maes and co-workers described the intramolecular Pd-catalyzed amination of A-(2-chloropyridin-3-yl)pyr-idazin-3-amine and A-(3-bromopyridin-2-yl)pyridazin-3-amine which involves intramolecular coordination of Pd(ll) to the N-2 nitrogen of the A-arylpyridazin-3-amine entity (Equation 8). A-(2-Chloropyridin-3-yl)pyridazin-3-amine and A-(3-bromopyridin-2-yl)pyridazin-3-amine are intermediates in the auto tandem amination of 2-chloro-3-iodo-pyridine and 2,3-dibromopyridine with pyridazin-3-amine, respectively <2004CC2466, 2006JOC260>. In the former case the ring closure proceeds partly via an SNAr process. 

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],... 

Paul, F. Influences on the relative rates for C-N bond-forming reductive elimination and /J-hydrogen elimination of amides. A case study on the origins of competing reduction in the Pd-catalyzed amination of aryl halides. 

J. Heterocyclic Chem. 1997, 34, 315-320. Beletskaya, I. P. Bessmertnykh, A. G. Guilard, R. Halo-substituted aminobenzenes prepared by Pd-catalyzed amination. Synlett 1999, 1459-1461. 

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)]. 

Yet, intramolecular sequences are often more viable than bimolecular processes. Therefore, the combination of Pd-catalyzed aminations with subsequent cyclization opens new perspectives in heterocycle synthesis. 

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. 

Intramolecular Pd-catalyzed amination of iV-allyl-anthranilamide 265 gave the quinazoline 266, as the main product (62%), and the benzodiazocine 267, as minor product (20%). The formation of 267 was explained by the formation of an 7]3-allyl-Pd complex, as outlined in Scheme 48 <2004JOC5627>. 

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). 

Several 2 -deoxyadenosine-amine adducts that have been implicated in carcinogenesis were prepared via the Pd-catalyzed amine arylation reaction as reported by Lakshman and co-coworkers [135]. For example, the coupling of the protected 6-bromoadenosine derivative below was achieved in good yield using the 4/Pd-catalyst, Eq. (168). 

Another substituted benzyl ether in occasional use is the /7-chlorobenzyl ether, mainly because of the high crystallinity and added stability of these derivatives. Recently, a methodology to remove p-chloro- and bromobenzyl ethers in the presence of both benzyl and /7-methoxybenzyl groups was reported [15]. It employed a two-stage deprotection scheme where thep-halobenzyl group was first converted to an arylamine by Pd-catalyzed amination. The arylamine was then selectively cleaved under very mild acidic conditions. 

---