Halides hetero aryl

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. 

Our group has recently developed an alternative method for alkyl-(hetero)aryl- as well as aryl-heteroaryl cross coupling reactions catalyzed by iron salts.3 4 This methodology was inspired by early reports of Kochi et al.5>6 on iron-catalyzed cross coupling of vinyl halides and is distinguished by several notable advantages. 

The synthesis of (hetero)aryl cyanides from (hetero)aryl halides via transition-metal catalysis is a very valuable reaction since a nitrile can be easily transformed into several other functional groups. Not until 2000 were the first examples on microwave-assisted cyanation reported in the literature. Alter-man and Hallberg found that 3-bromopyridine and 3-bromothiophene were... 

A potentially interesting development is the microwave-assisted transition-metal-free Sonogashira-type coupling reaction (Eq. 4.10). The reactions were performed in water without the use of copper(I) or a transition metal-phosphine complex. A variety of different aryl and hetero-aryl halides were reactive in water.25a The amount of palladium or copper present in the reaction system was determined to be less than 1 ppm by AAS-MS technique. However, in view of the recent reassessment of a similarly claimed transition-metal-free Suzuki-type coupling reaction, the possibility of a sub-ppm level of palladium contaminants found in commercially available sodium carbonate needs to be ruled out by a more sensitive analytical method.25 ... 

Another solution is the use of formamide as the ammonia substitute.Thus, the Pd-catalyzed aminocarbonylation of (hetero)aryl halides with formamide as ammonia substitute as well as solvent under CO afforded the corresponding primary amides in moderate to excellent yields (Scheme 22). ... 

The aminocarbonylation of alkynes has been less explored as compared to that of alkenyl and (hetero)aryl halides. Nevertheless, several noteworthy applications of this reaction have been reported, including the syntheses of 2-ynamides, chiral 2-carbamoyl-7r-allylic tungsten complexes, angular triquinanes, 2-(carbamoylmethylene)tetrahydrofurans, alle-nyl amides, and others. ... 

Microwave irradiation was also successfully used to synthesize 26 different acyl sulfonamides through carbonylation of sulfonamides with (hetero)aryl halides in only 15 min, using Pd(OAc)2 as catalyst and Mo(CO)6 as source of... 

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. 

A couple of years ago we have disclosed a new mode of alkyne activation towards isomerization as a detouring outcome of the Sonogashira coupling. As a result of coupling electron deficient (hetero)aryl halides (or a,p-unsaturated p-halo carbonyl compounds) 11 and aryl propargyl alcohols 12 a new access to 1,3-di (hetero)aryl propenones 13, i.e., chalcones, was established (Scheme 9) [77, 78]. The scope for electron deficient (hetero)aromatic halides 11 is fairly broad and even organometallic complexes like 13c can be synthesized by this sequence. 

In comparison to conductive heating in an oil bath under comparable conditions, dielectric heating furnished higher yields in the model reaction at shorter reaction times. Whereas electron deficient (hetero)aryl halides are rapidly coupled and isomerized with triethylamine as a base, for electro neutral and electron rich aryl halides DBU has to be applied to achieve comparable reaction times and yields. Most remarkably the alkyl substituted propargyl alcohol 15 with R = "Pr can be successfully transformed giving rise to the enone 16f in moderate isolated yield. 

Scheme 11 Microwave-assisted CIR (MACIR) of (hetero)aryl halides 14 and propargyl alcohols 15 to give (hetero)aryl enones 16...

The mild reaction conditions (relatively weak amine bases, short reaction times) of the CIR of (hetero)aryl halides and l-(hetero)aryl propargyl alcohols opens a modular entry to chalcones, which are as Michael acceptors suitable starting points for consecutive multicomponent syntheses of heterocycles in a one-pot fashion [28, 86]. Both catalytic generations of ynones and enones have set stages for diversity-oriented multicomponent syntheses of heterocycles in a consecutive one-pot fashion. 

Pyrazoles by a Consecutive 3CR of (Hetero)aryl Halides, Propargyl Alcohols, and Hydrazines... 

Thus, upon CIR of electron-deficient (hetero)aryl halides 11 and phenyl propargyl alcohol 12a, and subsequent addition of a hydrazine (29b) (R = Me) 3,5-disubstituted... 

Likewise, upon CIR of electron-deficient (hetero)aryl halides 11 and (hetero)aryl propargyl alcohols 12, and subsequent addition of amidinium salts 32, 2,4,6-trisubstituted pyrimidines 89 can be obtained in a consecutive three-component reaction in good yields (Scheme 48) [241]. Interestingly, in all cases the aromatic products 89 are found and not the expected dihydropyrimidines, regardless whether the reaction has been performed under an anaerobic or an aerobic atmosphere. Therefore, it can be assumed that the presence of the transition metal catalysts is beneficial for a terminal aromatizing dehydrogenation. 

Interestingly, the mild reaction conditions of the CIR are fully compatible with the Stetter reaction. As a result a sequence of transition metal, base and organoca-talysis can be easily conceived. Upon CIR of electron-deficient (hetero)aryl halides 11 and (hetero)aryl propargyl alcohols 12, and after subsequent addition of aliphatic or aromatic aldehydes 92 and catalytic amounts of thiazolium salt 93 1,4-diketones 94 are obtained in moderate to excellent yields in a one-pot procedure (Scheme 50) [259, 260]. For aromatic aldehydes the catalyst precursor of choice is 3,4-dimethyl-5-(2-hydroxyethyl) thiazolium iodide (93a) (R = Me), and for aliphatic aldehydes 3-benzyl-4-methyl-5-(2-hydroxyethyl)-thiazolium chloride (93b) (R = CH2Ph) is applied. 

Thus, upon CIR of electron-deficient (hetero)aryl halides 11 and phenyl propargyl alcohol 12a, after subsequent Stetter reaction with aldehydes 92 in presence of catalytic amounts of thiazolium salt 93, and after addition of glacial acetic acid and concentrated HCl, the 2,3,5-trisubstituted furans 95 are obtained in moderate to good yields in a one-pot procedure (Scheme 51) [260]. 

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