Bromides hetero aryl

PdCl2(PPh3)2 and Cul in a mixture of Et2NH and DMF at 120 °C for 5-25 min were found to be suitable as a general protocol. For less reactive (hetero)aryl bromides and 2-chloropyridine, extra triphenylphosphine was added to improve the stability of the palladium catalyst (Scheme 49). 

Leadbeater described the use of Ni(CN)2 for the microwave-assisted cyanation of (hetero)aryl bromides [81]. The use of 0.6equiv of Ni(CN)2 was found to be optimal. Unfortunately, the heteroaryl bromides reported in the study gave relatively low yields due to significant decomposition (Scheme 70). 

This is a problem that has been reported by several researchers in other cya-nation methods on heteroaromatic halides. (Hetero)aryl chlorides have also been tackled via in situ halogen exchange to (hetero)aryl bromides followed by sequential cyanation (Scheme 71). For this microwave-assisted process an equimolar amount of NiBr2 and a two-fold excess of NaCN were used. The only heteroaromatic chloride tested was 2-chloropyridine. Although the procedures described involve the use of significant amounts of nickel salts, a clear advantage is that the reactions can be performed in air. Moreover, the cyanat-ing reagents are easily removed since they are water soluble. 

Microwave-assisted Heck reaction of (hetero)aryl bromides with N,N-dimethyl-2-[(2-phenylvinyl)oxy]ethanamine, using Herrmann s palladacycle as a precatalyst, yielded the corresponding /3-(hetero)arylated Heck products in a good EjZ selectivity (Scheme 79) [90]. The a/yd-regioselectivity can be explained by the chelation control in the insertion step. This selectivity is better than 10/90 when no severe steric hindrance is introduced in the (hetero)aryl bromides. The process does not require an inert atmosphere. There is evidence that a Pd(0)/Pd(II)- and not Pd(II)/Pd(IV)-based catalytic cycle is involved. Similarly, other j6-amino-substituted vinyl ethers such as... 

More challenging are the (hetero)aryl chlorides, since they are cheaper and more widely available than the corresponding bromides and iodides. Maes et al. published the first examples of microwave-assisted Buchwald-Hartwig aminations on (hetero)aryl chlorides in a commimication in 2003 [99]. The substrates 2- and 3-chloropyridine as well as 2-chloroquinoline were smoothly coupled with N-methylaniline and p-toluidine within only 10 min using a catalyst loading of only 1 mol% (Schemes 96 and 97). The diazine... 

Hexamethylditin is a suitable reagent for Pd-catalyzed metallation of aryl-halides to furnish aryltin compounds that in turn can react in Stille couplings with aryl halides to form biaryl derivatives. Hitchcock and coworkers [ 126] have shown that 2-pyridyl triflate and (hetero)aryl bromides can be coupled to 2-(hetero)aryl pyridines 174 in moderate to good yields (Scheme 66). The underlying principle of this heterocoupling of two aryl (pseudo)hahdes is the selective stannylation of the triflate that is undergoing a faster oxidative addition to the Pd(0) complex than the bromide. 

Scheme 8 Palladium-catalyzed cross-coupling of (hetero)aryl bromides and chlorides with KOH employing XPhos-type biaryl monophosphines...

Extending reactivity to (hetero)aryl bromides and iodides... 

Lee et a/. subsequently reported the first examples of the palladium-catalyzed nucleophilic fluorination of (hetero)aryl bromides and iodides (Scheme 14). In seeking to achieve such transformations, they envisioned two required modifications to their previous catalytic protocols employed with (hetero)aryl triflates the use of a more... 

Fu et al. showed that a combination of NiCla and bis(oxazoline) 11 or 17 catalyses asymmetric Kumada coupling of racemic a-bromoketones with aryl Grignard reagents, giving a-arylketones in good yields and enantiomeric excess (Scheme 14.8). The reactions proceeded at low temperature, which enabled the asymmetric synthesis of racemisation-prone a-arylketones. The Pincer-nickel complex [(N2N)Ni-Cl] (18) catalyses Kumada reaction of primary allqrl bromides/iodides or secondary all l iodides with alkyl, (hetero)aryl or all nyl Grignard reagents (Scheme 14.9). The reactions... 

Buchwald developed a series of biarylphosphine ligands to enable a highly selective Pd-catalyzed Negishi reaction between (hetero)aryl halides 301 and turbo-like isopropylzinc bromide.This reaction worked well on a variety of heterocycles including 5-bromo-7-azaindole (140L4638). 

In 1975, three different protocols were available in the literature, each describing the synthesis of internal alkynes. Cassar described palladium- or nickel-mediated reactions between aryl or vinyl halides and alkynes complexes with phosphine as ligands in the presence of NaOMe [1]. As a second protocol, Heck pubhshed a variation of the Mizoroki-Heck couplings, in which the olefins were replaced by alkynes and coupled with (hetero)aryl, as weU as alkenyl bromides or iodides at 100 °C in the presence of a basic amine [2]. More than a decade earUer, Stephens and Castro had described the details of a palladium-free coupling of aryl iodides with cuprous acetylides in refluxing pyridine [3]. 

With the same reaction as that of alkoxycarbonylation, the first palladium-catalyzed amidation reaction of aryl-X compounds was again developed by Heck and his group. They demonstrated that by carbonylation reactions, secondary and tertiary amides are conveniently produced [118]. More specifically, (hetero)aryl bromides and vinyl iodides were reacted with primary or secondary amines under atmospheric CO pressure at 60-100 °C in the presence of 1.5 mol% PdX2(PPh3>2. Stoichiometric amounts of a tertiary amine were required to neutralize the formed acid if weakly basic amines were used as nucleophiles. 

Holzapfel and colleagues published an alternative methodology for pyridine and quinoline carboxaldehydes by the reductive carbonylation of (hetero)aryl bromides and triflates [32]. Synthesis gas was used as the formylation source as various hydrogen donors, e.g., BusSnH or polymethylhydrosiloxane (PMHS), which led to significant amounts of by-products resulting from reductive... 

Recently, Beller s group has developed the most general and efficient palladium-catalyzed formylation procedure for the synthesis of aromatic and heteroaromatic aldehydes (Scheme 3.6) [33-35]. Various (hetero)aryl bromides were successfully carbonylated with the cheap and environmentally benign formyl source, synthesis gas, in the presence of Pd(OAc)2/cataCXium A[36] and V,V,AT, -tetramethylethylenediamine (TMEDA) at 100 °C. Advantageously, the catalyst system was active at low concentrations (0.25 mol % Pd(OAc)2, 0.75 mol % cataCXium A) and at much lower pressures (5 bar) than those... 

Co(II)-mediated reduction in the presence of Zn(0) and Zn(II) salts also represents a valuable method for the preparation of (hetero)arylzinc halides from (hetero)aryl bromides [50] or chlorides [51]. 

P-Substituted vinylboronic esters were isolated in fair to high yields from the coupling under classical Heck conditions of vinylBhg with (hetero)aryl iodides and bromides (Table 3.1, entries 1-3). A dienyl boronic ester was obtained by coupling of vinylBhg with a vinyl iodide derived from phenylgly-cine (entry 4). The preparation of a styryl boronic ester with a sulfonamide moiety is described in a patent (entry 5) this product was later used in a Suzuki-Miyaura reaction. ... 

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