Ligands DPEphos

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. 

Mechanistically, the latter sequence rationalizes as follows (Scheme 47). The Pd-catalyzed arylamination with the bulky monodentate phosphane stops at the stage of the N-aryl allyl benzene 128. Upon addition of the chelating ligand dpephos, a subsequent cycle is opened that commences with the oxidative addition of the aryl bromide to the Pd-dpephos chelate. After the complexation of 128 to the Pd complex, the insertion of the alkene takes place to furnish an alkyl aryl Pd species that, due to the chelating dpephos, undergoes reductive elimination rather than /1-hydride elimination to furnish the product 127. 

A palladium-catalyzed intramolecular cyclization of enolate O-aiylation and thio-enolate S-arylation was reported by Willis and co-workers in 2006. A catalyst generated from Pd2(dba)3 and the ligand DPEphos effects the key bond formation to deliver a variety of substituted products from both cyclic and acyclic precursors. The analogous thio-ketones undergo C-S bond formation using identical reaction conditions and were converted to ben-zothiophene products. A cascade sequence that produces the required a-atyl ketones in situ has also been developed (Scheme 2.6). 

The use of sometimes very low temperatures and highly flammable Li organyls explains the current considerable price of Xantphos and its relatives. Also, the con-formationally more flexible ligand DPEphos can be prepared via a related protocol (Scheme 2.15) [44, 48]. 

Bidentate ligands with very wide bite angles (like dpephos or xantphos, Scheme 4) are likely to form unstable chelates prone to dechelation at elevated temperatures, thus giving another route to monophosphine species. The application of such ligands to the crosscoupling of sterically hindered bromides and arylboronic acids under strictly anhydrous conditions enforced by the addition of molecular sieves has been shown to be advantageous (118).398... 

Amides and sulfonamides undergo intramolecular chemistry to form aryl amides and aryl sulfonamides (Equations (17)—(19)) in the presence of palladium catalysts ligated by arylphos-phines.35,89 Initially, complexes of P(furyl)3 and P(o-tol)3 were most effective catalysts, but complexes of Hayashi s MOP and van Leeuwen s DPEphos and xantphos have lately been shown to be more active.90 In the presence of catalysts containing one of these ligand systems, five-, six-, and seven-membered rings were formed from halogenated benzamides or from substrates containing an acetamide, an A-carbobenzyloxy, or a t-butylcarbamate substituent tethered to the aryl halide (Equations (18) and (19)) ... 

The previously problematic second substitution after the /ram-sclcclivc monoalkynylation can now be achieved selectively (>98% selective with retention) and in high yields. The use of alkylzincs and most critically alkylphosphines such as (f-Bu)3P, as ligands, was the key to the development of the satisfactory procedure (Scheme 47)85. Conventional arylphosphines, such as PPh3, I I P and DPEphos, as well as the use of Ni catalysts in conjunction with alkylmetals containing Mg106 and Zn led to low yields and/or extensive and synthetically unattractive stereoisomerization85. 

Lately, Willis and coworkers [97,98] have developed a cascade N-annu-lation route to 1-functionalized indoles. Amine, aniline, amide, carbamate, and sulfonamide functional groups can efficiently be introduced as coupling partners if 2-(2-bromo-phenyl)-cyclohex-l-enyl triflate 112 is reacted in the presence of [Pd2dba3] and dpephos or xantphos as ligands to give a variety of tetrahydrocarbazoles 113 in moderate to excellent yields (Scheme 41). 

Singer and Buchwald found that the catalyst derived from DPEphos (19) was optimal for the arylation of the triflate derived from BINOL shown below, Eq. (124) [107]. Several useful chiral ligand building blocks were prepared in good to excellent yield. 

Aryl triflates are also good substrates for the benzophenone imine coupling reaction. For example. Singer and Buchwald prepared the desired amino-BlNOL precursor in 87% yield after acidic hydrolysis the amination itself proceeded in 90% NMR yield when DPEphos (19) was used as the supporting ligand, Eq.(132) [107]. 

Buchwald has also shown that the easily synthesized DPEphos ligand is an ideal catalyst for the arylation of anilines with aryl bromides.24 Even di-ortho substituted aniline and aryl bromide can be efficiently coupled. Furthermore, Buchwald has reported that readily available, and cheaper, PdCl2 may serve as the Pd source rather than Pd(OAc)2. 

Weaker hydrazine derived nucleophiles may also participate in the amination reaction as has been reported by H. Katayama.105 They found that TV-acyl hydrazines 63 underwent a clean intramolecular cyclization to give the desired indol[l,2-A]indazole derivatives 64 using DPEphos as the ligand. 

In addition to amines, some derivatives of amines can be arylated. Weakly basic amides are arylated, and intermolecular reactions between aryl bromides and tri-flates 48 with benzamide can be carried out. Combined uses of xantphos (IX-IO) and CS2CO3 in THF or dioxane gave the most successful results. The cyclic urea 49 was diarylated [40]. Sulfonamides are also arylated [41]. Intramolecular reaction of the secondary amides such as 50 or carbamates offers convenient synthetic methods for five-, six-, and seven-membered lactams like 51. As ligands, MOP (VI-12), DPEphos (IX-9), xantphos (IX-IO), and BINAP are used depending on the size of the rings. As an example, ligand IX-9 is the most suitable for the preparation of the five-membered A-carbobenzyloxy derivative 52a from 52, but BINAP was not effective. 

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