Heck Jeffery Conditions

Reaction conditions for C-H activation of thiophenes can be divided into three groups 1) Heck (Jeffery) conditions/ although these are used infrequently 2) with carboxylic acid additives 3) without carboxylic acid additives. The last two types of conditions have been used in polar and aprotic solvents and may be carried out with a phosphine ligand. 

Frejd and co-workers utilized a different tactic for aniline cyclization by first employing a Heck-Jeffery protocol under solvent-free conditions to prepare o-amino dehydrophenylalanine derivatives from o-aminoaryl iodides with the former undergoing a spontaneous la cyclization-elimination sequence to afford 2-methoxycarbonyl indoles <06S1183>. Dimethyl(methylthio)sulfonium trifluoromethanesulfonate (DMTST) was used by the Okuma group to promote the cyclization of o-vinyl-A-p-toluenesulfonylanilide to N-tosylindole <06CL1122>. 

Fourfold Heck coupling (twofold on each dibromobenzene moiety) and Jeffery conditions has been applied on the two easily accessible tetrabromo[2.2]paracyclophane isomers 21 and 23, respectively, to prepare new double-layered 1,2- and 1,4-distyrylbenzene chromophoric systems 22-R and 24-R respectively, to enable studies of intramolecular charge-transfer phenomena in such systems (Scheme... 

The natural polyenic lactone ( )-callystatin A, isolated in 1997 from the marine sponge Callyspongia truncata and exhibiting remarkable growth inhibition of cancer cells (IC50 10-20 pg/mL), was also prepared using this Heck-like reaction under Jeffery conditions (Scheme 10.31).53... 

While good yields in the multifold Heck reactions on the tetrabro-mide 159 were only achieved under Jeffery conditions with a solid base in the presence of a quaternary ammonium salt, classical Heck conditions using a tertiary amine proved to be superior in the case of simple... 

A major achievement was the discovery that Heck reactions are greatly accelerated in the presence of phase-transfer catalysts using quaternary ammonium salts and solid bases [ Jeffery conditions Pd(OAc)2, MHCO3 (M = K, Na), nBu4NX (X = Br, Cl), DMSO or DMF] [100]. Under these conditions, iodoarenes and iodoalkenes can be coupled to alkenes... 

Heck reactions are conducted in polar aprotic, cr-donor-type solvents such as acetonitrile, dimethyl sulfoxide, or dimethylacetamide. Reaction temperatures and times largely depend on the nature of the organic halide to be activated and on the catalyst s stability limit. lodo derivatives are much more reactive (<100 °C), so auxiliary (phosphine) ligands are not necessary here. Polar solvents such as DMF, DMAc, and A-methylpyrrolidone (NMP) in combination with NaOAc as base are specifically beneficial in all cases, and even mild phase-transfer conditions in a solid/solution system employing Pd(OAc)2 without phosphine co-ligands), [N(n-C4H9)4]X in DMF (X = Cl, Br), and K2CO3 as base ( Jeffery conditions ) [17, 18]. 

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 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... 

In addition, the Heck reaction of iodobenzene with butyl acrylate was studied in more detail [7]. In all experiments,butyl cinnamate was selectively produced. It was observed that the activity was only dependent on the pallaihum concentration in the hydrophihc Uquid,but neither on the total amount of complex applied nor on the quantity of the liquid used. In recycling ejqieriments, a short induction period occurred in the first runs. This was not observed in the following runs. Furthermore, repeated appUcation of the catalyst resulted in an increased reaction rate. Other investigators observed a decrease of activity during the recycling experiments [5]. The authors ejqilained their results with an accumulation of EtjNHI during consecutive runs. It was assumed that the accumulated ammonium salt had the same promotion effect as tetrabuty-lammonium halide additives in Heck reactions (Jeffery conditions) [8]. 

Furthermore, the combination of palladium(II) salts with tetrabutylammonium halide additives, called Jeffery conditions , is an efficient system for Heck-type reactions [7a], but the mechanistic implications are unknown. Also, nonionic phosphine ligands, such as triphenylphosphine which yields Pd(PPh3)4, are applied in water-miscible organic solvents, like DMF and acetonitrile. In these cases, the application of water is of crucial importance, but the role is often not well investigated. 

Fteproduced Irom Tullberg Schacher F, Peters D. Frejd T. Solvent-free Heck-Jeffery reactions under ball-milling conditions applied to the synthesis of unnatural amino acids precwsors and indoles. Synthesis 2006 1183-9. With permission from Thieme PubHshers. 

Heck reactions with aUyUc derivatives as substrates are presented in entries 27 and 28. In the absence of T1(I) or Ag(I) salts and under Jeffery conditions, arylation of allylic alcohols provides a useful highly regioselective direct route to arylethyl ketones. ... 

By far most the popular class of the allylic substrates in the Mizoroki-Heck reaction has been allylic alcohols, partly due to their ubiquitousness, but also due to the possibility of testing and developing catalytic systems for regiocontrol, as this coupling often results in mixtures of isomers. Reactions under Jeffery conditions are known to result in terminal insertions (Figure 3.24) [79], and similar reactions with vinylic triflates instead of halides are also well known (Figure 3.25) [80]. 

Besides the different mechanistic pathways mainly depending on the substrate types, the Mizoroki-Heck reaction can also be run under several conditions with diverse additives which affect the outcome. A major achievement in this field was the discovery of the so-called Jeffery conditions [25-28]. Mizoroki-Heck reactions are indeed greatly accelerated by the use of inorganic bases in combination with a phase-transfer agent which allows lowered reaction temperatures. In some cases, Jeffery conditions can even lead to the endo-cyclizod product, whereas standard conditions give the exo-cyclized compound [8]. 

Another way to prevent isomerization of the double bond to the thermodynamically more stable c do-cychc position is the use of the Jeffery conditions. Tietze and Grote [33] showed that, depending on the reaction conditions, either endo- or cxo-cychc double-bond formation can be favoured (Scheme 6.7). Under standard Mizoroki-Heck conditions using... 

Scheme 6.7 Standard Mizoroki-Heck versus Jeffery conditions...

An interesting case of 6-endo- versus 5- j o-cylization has been studied by Bombrun and Sageot [129], who investigated intramolecular Mizoroki-Heck cycUzation of enamides in a thiophene series (Scheme 6.50). If the reaction was carried out under Jeffery conditions, then it proceeded nearly exclusively via the 6- iio-cychzation mode however, when run under reductive Mizoroki-Heck conditions (e.g. in the presence of a hydride source), a 5-exo-cyclization is mostly achieved and the lack of a /3-hydrogen in this case leads to product 179. 

In the Mizoroki-Heck reaction of ethyl aciylate 1 and iodobenzene 2 (Scheme 1). under Jeffery conditions, Reetz et al. proved by in situ TEM analysis that Pd nanoparticles (l.3-1.6nm) persisted for the entirely of the reaction with almost complete (>95%) conversion observed by GC. 

Phase-tranter Conditions. The Heck conditions described above are not useful, however, for a large number of alkenic substrates. A sometimes serious drawback is the high temperature (ca. 100 °C) often required. Upon addition of tetrabutylammonium chloride ( phase-transfer conditions or Jeffery conditions ), aromatic halides or enol triflates react under mild conditions with vinylic substrates or allylic alcohols. Variations of these conditions include the optional or additional presence of silver or thallium salts. The effect of using different salts, bases, catalysts, solvents, and protecting groups in the coupling of aminoacrylates with iodobenzene has been studied. ... 

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