Heck reaction ligand-free conditions

Heck reaction. Solvent-free conditions with microwave irradiation have been developed for the Heck reaction. Phosphites are excellent ligands such that even electron-deficient aryl chlorides can be used to couple with different alkenes. Isoquinolines are formed by using the more conventional procedure note the same 3-(o-iodobenzylamino)acrylic esters give dihydroisoindole derivatives when they are exposed to Bu,SnH-AIBN. A combination of BUjP and dppp together with /-Pr NEt constitutes support for Pd(OAc)2 in an intramolecular coupling which leads to benzophenanthridines. ... 

The intramolecular version of the Heck reaction has been extremely fruitful, enabling elegant synthesis of many complex molecules [68, 69]. The Mori-Ban indole synthesis (Section 1.10, vide infra) is a good example of such method. In addition, Rawal et al. carried out an intramolecular Heck cyclization of pentacyclic lactam 55 with a pendant vinyl iodide moiety [70]. Employing Jeffery s ligand-free conditions, 55 was converted to a hexacyclic strychnan alkaloid precursor 56 with complete stereochemical control... 

By taking advantage of the C(2) activation, 2-allyloxy-3-iodopyridine (173) was prepared by an SNAr displacement of 2-chloro-3-iodopyridine with sodium allyloxide [137]. 2-Chloro-3-iodopyridine was prepared by orrto-lithiation of 2-chloropyridine followed by iodine quench. The intramolecular Heck reaction of allyl ether 173 under Jeffery s ligand-free conditions resulted in 3-methylfuro[2,3-6]pyridine (174). 

In a synthetic route to the E-azaebumane series, an intramolecular heteroaryl Heck reaction was the major cyclization strategy [140], Under Jeffery s ligand-free conditions, E-azaebumane skeleton 182 was prepared from bromopyridine 181. The migratory insertion occurred at C(2) of the indole ring. 

An intramolecular Heck cyclization strategy was developed for the construction of indole and benzofuran rings on solid support [82], enabling rapid generation of small-molecular libraries by simultaneous parallel or combinatorial synthesis. Sn2 displacement of resin-bound y-bromocrotonyl amide 97 with o-iodophenol 96 afforded the cyclization precursor 98. A subsequent intramolecular Heck reaction using Jeffery s ligand-free conditions furnished, after double bond tautomerization, the resin-bound benzofurans, which were then cleaved with 30% TFA in CH2CI2 to deliver the desired benzofuran derivatives 99 in excellent yields and purity. 

Zhou P, Li Y, Sun P, Zhou J, Bao J (2007) A novel Heck reaction catalyzed by Co hollow nanospheres in ligand-free condition. Chem Commun 1418-1420... 

In 1984, Jeffery discovered that under ligand-free conditions, Pd-catalyzed vinylation of organic halides proceeds at or near room temperature, whereas normal Heck reactions require higher temperatuies [64]. Jeffery s hgand-free conditions have been broadly applied to a variety of Heck arylations that were not feasible using more standard reaction conditions. For example, efforts to use classical Heck-reaction conditions for the conversion of Al-allyl-Al-benzyl(3-bromoquinoxalin-2-yl)amine (64) to l-benzyl-3-methylpyrrolo[2,3-/ ]quinoxaline (65), resulted in slow reactions and low yields [65], which may be attributed to the poisoning of the palladium catalyst via complexation to the aminoquinoxalines. In contrast, the Jeffery conditions afforded the desired product in 83% yield. The enhanced reactivity and yield under Jeffery s ligand-free conditions may be due to the coordination/solvation of the palladium intermediates by bromide ions present in the reaction mixture, which presumably prevents the precipitation of Pd(0). 

An intramolecular heteroaryl Heck reaction was the pivotal step in the synthesis of 5-butyl-l -methyl- l//-imidazo[4,5-c]quinolin-4(5Z7)-one (77), a potent antiasthmatic agent [72]. The optimum yield was obtained under Jeffery s ligand-free conditions. 

Another often encountered substructure for intramolecular 5- xo-Mizoroki-Heck reactions is allyl side chain containing vinyl halide D (Figure 6.3) [73, 74], Based on this substrate structure, a series of 3-substituted pyrrolo[2,3-b]quinoxalines have been prepared via intramolecular Mizoroki-Heck reaction under Jeffery s ligand-free conditions in moderate to excellent yields (Scheme 6.25) [75]. 

Accordingly, catalytic and stoichiometric amounts of cuprous salts were employed for Mizoroki-Heck-type reactions of various conjugated alkenes [ 19]. Intermolecular catalytic arylations of methyl acrylate (1, not shown) and styrene (2) were accomplished under ligand-free conditions using CuBr (3) or Cul (4) as catalyst in A-methyl-2-pyrrolidinone (NMP) as solvent various aryl iodides could be employed (Scheme 10.2). On the contrary, aryl bromides and chlorides, as well as aliphatic halides, were found to be unsuitable substrates. The reactions employing an alkenyl bromide, methylmethacrolein or methyl methacrylate required stoichiometric amounts of copper salts. 

Palladium acetate immobilized on reversed-phase amorphous silica gel with the aid of an ionic liquid, [BMIm] PFs, was highly efficient in Mizoroki-Heck type reactions in water under ligand-free conditions. In several runs (up to the sixth reuse) a 95% average yield was obtained with a turnover number (TON, the number of converted substrate molecules per catalytically active centre, mol x mol ) of 1600000 and a turnover frequency (TOP, TON per time unit, mol x mol x h ) of 71000h [34]. 

Nanoparticles of palladium supported on resins were used in Mizoroki-Heck reactions of electron-poor olefins under ligand-free conditions. For instance, p-bromoanisole proceeded to j)-methoxy butylcinnamate in 94% yield when the power of microwave irradiation was increased to 375 W (Scheme 15.17) [209]. 

Another beneficial effect of water was observed for the synthesis of C-nucleosides, for example 104. Whereas the Heck reaction could not be achieved under standard conditions, the use of ligand-free conditions in aqueous ethanol (1 1, v/v) furnished the product in good yield. Interestingly suppression of double bond migration in the product was also observed (a common issue in these substrates). 

A Heck-type CDC reaction of indolizines with electron-deficient alkenes produces 3-alkenyl-substituted indolizines. The reaction took place selectively at the 3-position through palladium(II)-catalysed C-H activation, following a Heck-type cross-coupling reaction under mild and ligand-free conditions. The results of the H/D exchange experiments confirmed that the C-H activation was catalysed by palladium(II) acetate (Scheme 8). ... 

The Mizoroki-Heck reaction in liquid imidazolium salts as the solvent is a special case of an in situ system Under the reaction conditions NHC complexes of palladium are formed as the active catalyst from the solvent and the ligand-free palladium precursor. In general, ionic liquids are novel reaction media for homogeneous catalysis. They allow easy separation of product and catalyst after the reaction. ... 

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... 

---