Indole-phosphine ligands

In terms of methodologies for the preparation of A-arylindoles 140, Buchwald reported improved conditions for the palladium-catalyzed coupling of aryl chlorides, bromides, iodides and triflates 138 with a variety of 2-, 7- and polysubstituted indoles 139 utilizing novel electron-rich biaryl(dialkyl)phosphine ligands in combination with Pd2(dba)3 <00OL1403>. Alternatively, Watanabe reports similar A-arylations of pyrrole, indole and carbazoles with aryl bromides and chlorides using Pd(OAc)2/P(f-Bu)3 in xylene at 120°C <00TL481>. 

The usefulness of Pd-catalysed reactions is demonstrated amply in the total synthesis of clavicipitic acid [76]. The first step is intramolecular aminopalladation of the 2-vinyltosylamide 92 with Pd(II) to give the indole 93. Then stepwise Heck reactions of the iodide and bromide of 94 with two different alkenes 95 and 96 in the absence and presence of a phosphine ligand give 97. In the last step of the synthesis, the intramolecular aminopalladation of 97 with a catalytic amount of Pd(II) gives the cyclized product 99. It should be noted that the aminopalladation is a stoichiometric... 

An indole alkaloid synthesis employing a bona fide intramolecular Heck reaction was documented in Sundberg s preparation of 5,6-homoiboga derivatives [90]. Several attempts to construct S,6-homoiboga derivative 191 using inter- or intramolecular Heck reaction conditions with phosphine ligands led to poor yields. Application of Jeffery s ligand-free" phase-transfer... 

Sames discovery that phosphine ligands inhibited the reaction has lead to the development of a new phosphine-free arylation for N-H indoles and pyrroles (Scheme 13b) [28], Increased indole concentration makes possible the coupling of sterically demanding arene donors and indole motifs. 

A related example from He and co-workers demonstrated that phosphinous ligands on Pd(0) are also able affect an indole arylation reaction. A small selection of C3 arylated indoles can be realized using this method. Of particular note is the C3 selectivity observed in this reaction, when compared to the work of Sames who observed C2 selectivity (Scheme 15). 

M. Beller reports an improved phosphine ligand for aryl chloride amination based on //-phenyl indoles, L16 or L17. This class of ligands allows for the catalytic amination of aryl chlorides with primary aliphatic amines and anilines. Secondary cyclic amines also couple, but secondary acyclic amines were not reported. 

In 2005, Sames and co-workers reported the highly selective (>50 1) C2-arylation of NH-free indoles using a rhodium complex derived from an electron-deficient phosphine as the catalyst, CsOPiv as a base, and iodoar-enes as coupling partners (Scheme 37, 05JA4996). Mechanistic studies revealed that a highly electrophilic Ar-Rh(III) complex was formed in situ through the oxidative addition of aryl iodide to Rh(I) (Scheme 38). Then the displacement of the phosphine ligand by indoles takes place, followed by... 

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]. 

Although there is no report on rhodium-catalyzed selective Nl-arylation, Sames described a direct C2-arylation of indoles catalyzed by rhodium complexes [216]. When the rhodium catalyst was mixed with an electron-deficient phosphine ligand, a weak base, and an aryl iodide, a highly electrophilic and reactive Ar-Rh(lll) species was generated in situ. The catalyst then promotes the C-H bond activation at the C2 position and arylation would take place selectively at C2 as demonstrated by the transformation of 141 and 142. 

Rhodium-catalyzed selective C3-arylation of indoles was reported by Itami et al. in 2006 [217], Using a ihodium complex bearing a strong p-accepting phosphine ligand, they achieved a moderate selectivity of 2.4 1 for C3/C2 arylations as shown below. 

Reaction of o-iodoaniline (33) with internal alkynes offers a good synthetic method of substituted indoles [13], A practical synthesis of psilocin was carried out by utilizing the reaction of the iodoaniline derivative 34 with internal alkyne to form an indole derivative as a key reaction [14], The thieno[3.2- ]pyrrole 37 was obtained by the reaction of 2-iodo-3-aminothiophene (35) with the alkyne 36 [15], These reactions of aryl iodides proceed in the absence of phosphine ligands. The isocoumarin 39 was obtained by the reaction of methyl o-iodobenzoate (38). Poor yield was obtained when the free acid was used [11]. 

A-Arylhydrazones are useful agricultural materials. Moreover, they can be cleaved to form A-arylhydrazines for pyrazole synthesis, and the hydrazine portion can be transferred to ketones to serve as substrates for the Fischer indole synthesis.t The reactions of benzophenone hydrazone with aryl halides have been reported, and to date these reactions are best conducted with chelating phosphine ligands such as DPPF and BINAP, as shown in Eq. 22. These catalyst systans have been the only ones reported for hydra-zone arylation. The chemistry of hydrazonato complexes is similar to that of aniUdes and diarylamides.f Thus, the reactions of aryl chlorides with hydrazones should be accessible in the future using alkylphosphine ligands. 

Seller Adamantyl-, Arylpyrrole- and Arylindol-Based Phosphine Ligands The adamantly-, arylpyrrole-/imidazole- and indole-derived ligands [105] (Figure 3.8) presented by Beller are related to P(t-Bu)3 and Singer s heterocyclic ligands, respectively. They were applied to aminations of aryl chlorides under mild reaction conditions [105]. 

Subsequently, it was found that the use of [RhCl(coe)2]2, along with an electron-poor phosphine ligand and CsOPiv as base, allowed for the direct arylation of N—H free pyrroles when employing aryl iodides as electrophiles (Scheme 9.15) [27]. Interestingly, this protocol also proved appHcable to the direct arylation of (aza)indoles. 

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