Ligand-free conditions

Quite different from the original Sonogashira conditions, the following cross-coupling was achieved under the Jeffery s ligand-free conditions in the absence of cuprous iodide [63] [64]. 

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. 

An intramolecular heteroaryl Heck was the pivotal step in the synthesis of 5-butyl-1-methyl-l//-imidazo[4,5-c]quinolin-4(5//)-one (63), a potent antiasthmatic agent [46], The optimum yield was obtained under Jeffery s ligand-free conditions, echoing Ohta s observation for the intermolecular version. Once again, the Caryi—Caryi bond was constructed at the C(5) position of the imidazole ring. Another intramolecular heteroaryl Heck cyclization of pyrrole and imidazole derivatives was also reported to assemble annulated isoindoles [47]. 

Jeffery s ligand-free conditions, 17, 24, 217-8, 249, 285, 370 Jones oxidation, 306... 

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... 

It is believed that the accelerated reaction rates that are observed in ammonium salts are due to their ability to stabilise nanoparticles, and especially when simple palladium salts are employed under ligand-free conditions, formation of colloidal palladium is highly likely.[7 9] As carbon-carbon coupling reactions are frequently conducted at elevated temperatures, typically between 120-150°C, a wide range of low-melting salts may be... 

Frequently, formation of palladium black is observed during C-C coupling reactions and it appears to be likely that palladium nanoparticles account at least for some of catalytic activity observed.18 15 311 This is especially true when ligand-free conditions are employed and the stability and activity of... 

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). 

Finally, the Suzuki-Miyaura reaction, which has become one of the most versatile and important reactions for the construction of C-C bonds, could be performed in a continuous flow process under ligand-free conditions [43]. The PASSfiow reactor is suited for the coupling of 4-iodoacetophenone and other aryl halides with arylboronic acid to yield the corresponding diaryls within 3 h without formation of homocoupling by-products (Scheme 15). After collecting... 

Selective Nl-arylation via copper-catalyzed cross-coupling reaction may be achieved tmder ligand-free conditions or Hgand-promoted conditions. 

Also under ligand-free conditions, a series of 5-HT2 antagonists was synthesized using Cul as the catalyst, ZnO as the cocatalyst, and K2CO3 as the base [207, 208]. One example is shown below. A remarkable selectivity was achieved for the Nl-arylation for the indole NH versus the urea NH of the imidazolidin-2-one moiety. 

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. 

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