Palladium-catalyzed amination phosphines

Tom and coworkers published three new types of phosphines derived from diarylsul-fones, tritylimidazole or 2-bromobenzophenone (Figure 13). Their activity in palladium-catalyzed amination of aryl bromides is not general, but they do catalyze the coupling of certain substrates. For example, the coupling of morpholine with l-bromo-4-nitrobenzene (97% with 47), 4-bromo-f-butylbenzene (81% with 48) and 4-bromoanisole (96% with 49) was achieved in high yields160. 

The overall mechanism for palladium-catalyzed amination of aryl halides is shown in Scheme 4. Initially, a palladium(O) 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(Bu-f)3170, or mixed phosphine/dba palladium(O) complexes are formed as with arylphosphines171. When the reactions are initiated with dba complexes, dba is 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 studied172, 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. 

The palladium-catalyzed amination of aryl halides has recently emerged as a powerful alternative to other methods for the synthesis of aryl amines.5 This method allows for the cross-coupling of aryl halides arrd triflates with amines in the presence of a stoichiometric amount of a base and catalytic amounts of palladium complexes bearing tertiary phosphine ligands. As shown in Tables I and II, the Pd/BlNAP catalyst is highly effective for reactions of aryl bromides and triflates with primary and cyclic... 

Transition metal catalyzed processes are useful tools for the synthesis of functionalized thiophenes. Thus for instance, a phosphine-free, palladium catalyzed coupling protocol for the synthesis of 2-arylbenzo[d]thiophenes from various 3-substituted benzo[6]thiophenes and aryl bromides or iodides has been reported <04T3221>. Likewise, 2,2 -bithiophenes have been 5,5 -diarylated directly with aryl bromides in the presence of Pd(OAc)2, bulky phosphine ligands and CS2CO3 <04T6757>. A series of electron-deficient and relatively electron-rich benzo[6]thienyl bromides have been shown to participate in palladium catalyzed amination reactions, as exemplified by the interesting conversion of 63 to the tetracyclic system 64 upon reaction with 2-aminopyridine 65 <04EJO3679>. 

The first paper that demonstrated the feasibility of a palladium-catalyzed amination was a report by T. Migita and co-workers.6 They demonstrated that a tri-ortho-tolyl phosphine palladium chloride catalyst will catalyze the cross-coupling of N,N-diethylamino-tributyltin with bromobenzene. The process can be thought of as an amino-Stille cross-coupling. 

Buchwald s XPhos ligand (L7) works well to catalyze the amination of 5-bromopyrimidine with anilines and secondary cyclic amines.67 Buchwald also found that ligands L20 and L21 were the best ligand for the palladium-catalyzed amination of benzothiazoles with secondary amines and anilines. Hartwig reports that (r-Bu)3P was excellent for the catalytic amination of 2-chloroheteroaryl compounds with secondary amines and anilines.35,68 As with other examples using bulky mono-dentate phosphines, primary aliphatic amines were not reported. 

The biarylphosphines 10 also reacted with the chloromethylated PS resin under basic conditions to give the PS-supported biarylphosphines 11 and 12 (Scheme 5) [38]. The resin-bound biaryl(dialkyl)phosphines 11 and 12 were the ligands designed for use in the palladium-catalyzed amination and Suzuki-Miyaura coupling of aryl halides, especially those of aryl chlorides. 

Very few examples of C2-lithiation reactions involving V-aryUndoles are known [258]. In the search for new indolyl phosphine ligands (e.g., 72) for palladium-catalyzed amination reactions, mono-lithiation and di-lithiation reactions involving V-arylindoles have been used (Scheme 15). Beller reported the synthesis of indolyl ligand 72a using a mono-lithiation of V-phenylindole (71a) [277], whereas Nifant ev used a dilithiation of 71b under much colder conditions to give bis (phosphine)indole 72b [278]. 

Ackermann HASPO Ligands Ackermann presented two new ligand families, named heteroatom-substituted secondary phosphine oxides (HASPO) and the corresponding phosphine chlorides. The development of the former ligand class is related to studies of Li (DuPont), who described the use of dialfeylphosphine oxides with electronically distinct properties as active and easily accessible ligands for palladium-catalyzed aminations (Figure 3.10) [107]. 

The sensitivity of palladium-catalyzed amination reactions towards air is heavily dependent on the properties of the phosphine Ugand. The degassing of solvents is of utmost importance when employing electron-rich phosphines, such as Pt-Bu3, although for some other Ugands the reactions can even be conducted under air, without any significant loss of efficacy. The presence of water is detrimental for only a few selected applications, as evidenced by several reports on C—N bond formation in aqueous media. 

Scheme 13.2 Catalytic cycle for the palladium-catalyzed amination with monodentate phosphines as supporting ligand [23].

The final step is desulfurization to form phosphines 2.155 either by a radical-mediated process initiated with AIBN (azoisobutironitrile) or by sulfur-lone pair exchange using tris(dimethylamino)phosphine. Dicyclohexyl(2,6-diphenylaryl)phosphine synthesized by this method was used as an effective ligand in the palladium-catalyzed amination of alkyl halides. 

Phosphine ligands based on the ferrocene backbone are very efficient in many palladium-catalyzed reactions, e.g., cross-coupling reactions,248 Heck reaction,249 amination reaction,250 and enantioselective synthesis.251 A particularly interesting example of an unusual coordination mode of the l,l -bis(diphenylphosphino)ferrocene (dppf) ligand has been reported. Dicationic palladium(II) complexes, such as [(dppf)Pd(PPh3)]2+[BF4 ]2, were shown to contain a palladium-iron bond.252,253 Palladium-iron bonds occur also in monocationic methyl and acylpalladium(II) complexes.254 A palladium-iron interaction is favored by bulky alkyl substituents on phosphorus and a lower electron density at palladium. 

Palladium-catalyzed aromatic C—O bond formation is less developed than palladium-catalyzed aryl amination. Except when the aryl halide is strongly electron deficient,107-110 catalysts ligated by the conventional aryl phosphines such as DPPF and BINAP are ineffective for coupling of... 

Fig. 10. Multiple derivatization of purines including palladium-catalyzed reaction at the poorly reactive C2 position, (a) NaBH(OAc)3, 1% HOAc, THF (b) 59 (0.5 equiv.), 2,6-dichloropurine (1 equiv.), DIEA (1.5 equiv.), BuOH 80° (c) R2OH, PPh3, DiAD (1.5 2 1.3) in excess, THF, RT (d) boronic acids (5 equiv.), 7% Pd2(dba)3, 14% carbene ligand, Cs2C03 (6 equiv.), 1,4-dioxane, 90°, 12 h (e) anilines (5 equiv.), 7% Pd2(dba)3, 14% carbene ligand, KO Bu (6 equiv.), 1,4-dioxane, 90°, 12 h (f) phenols (5 equiv.), 7% Pd2(dba)3, 28% phosphine ligand, K3P04 (7 equiv.), toluene, 90°, 12 h (g) primary or secondary amines (5 equiv.), 90°, 12 h.

The group of Van Leeuwen has reported the synthesis of a series of functionalized diphenylphosphines using carbosilane dendrimers as supports. These were applied as ligands for palladium-catalyzed allylic substitution and amination, as well as for rhodium-catalyzed hydroformylation reactions [20,21,44,45]. Carbosilane dendrimers containing two and three carbon atoms between the silicon branching points were used as models in order to investigate the effect of compactness and flexibility of the dendritic ligands on the catalytic performance of their metal complexes. Peripherally phosphine-functionalized carbosilane dendrimers (with both monodentate... 

The resulting peripheral phosphine-functionalized dendrimers were used as a ligand in the palladium-catalyzed allylic amination of crotyl acetate in a CFMR. The active catalysts were prepared by mixing all three components the dendrimer, the phosphine ligand and a suitable palladium precursor [(crotyl)PdCl]2. The catalytic activity and selectivity of 16 in a batch process... 

Fig. 6 Schematic representation of the Meijer-Reek noncovalently immobilized phosphine ligands applied in palladium-catalyzed allylic aminations...

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