Sonogashira reaction isomerization

Reddy and collaborators reported a new one-pot, three-component procedure toward the synthesis of novel 4-phenyl-2-[3-(alkynyl/alkenyl/aryl) phenyl] pyrimidine libraries starting with the Michael addition of enaminone 64 with 3-bromobenzimidamide hydrochloride (65) (Scheme 28) (13S75). This was followed by a cyclization, an isomerization, a dehydration, and a subsequent Sonogashira reaction with terminal alkynes or a Suzuki reaction with arylboronic acids or a Heck coupling reaction with alkenes. 

An unexpected isomerization was observed for several Sonogashira adducts of certain heteroaromatics [122]. Although the reaction between 3-bromopyridine and phenyl propargyl alcohol resulted in the normal adduct 150 [122, 123], 2-iodopyridine 151 produced the isomerized chalcone 152, presumably due to promotion by triethylamine, under the same conditions [122]. 

Several Sonogashira adducts of heteroaromatics including some pyridines (see Section 4.3) and pyrimidines underwent an unexpected isomerization [69]. This observed isomerization appeared to be idiosyncratic, and substrate-dependent. The normal Sonogashira adduct 100 was obtained when 2-methylthio-5-iodo-6-methylpyrimidine (99) was reacted with but-3-yn-ol, whereas chalcone 101, derived from isomerization of the normal Sonogashira adduct, was the major product when the reaction was carried out with l-phenylprop-2-yn-l-ol. 

Another option for Sonogashira coupling as an initiator of sequential catalysis is the coupling isomerization reaction (CIR) of electron-deficient halide and 1-aryl propargyl alcohols giving rise to the formation of chalcones [115, 116]. Based upon the CIR of electron-deficient halides 163 and l-(p-bromo phenyl) propyn-l-ol (164) Muller and Braun [117] presented a consecutive... 

Muller and coworkers have recently developed a coupling-isomerization reaction, initially identified as a side reaction which occurred under standard Sonogashira conditions [79]. As demonstrated below, the coupling reaction is followed by a shuffling of oxidation states via an alkyne-allene isomerization [80]. The product, a,P-unsaturated ketone 146, is reminiscent of a product which would be obtained from a Heck reaction. The utility of this reaction was further demonstrated when diamine 147 was added to the reaction pot. Following a conjugate addition reaction and imine formation, compound 148 resulted from the three-component, one-pot reaction sequence enabled by the coupling-isomerization reaction. 

The Sonogashira cross-coupling reaction, consisting of oxidative addition, cis-trans isomerization, transmetallation and reductive elimination has been modelled, using the DFT B3LYP/cc-pVDZ method, for Pd(diphosphane)-catalysed reaction between bro-mobenzene and phenylacetylene with CuBr as a co-catalyst and trimethylamine as a base. The reaction mechanism in both the gas phase and in CH2CI2 solution has been studied using the polarized continuum model (PCM) method. ... 

A reductive 1,8-didehydroxylation of l,2-dialkynyl-3,4-bis(diphenyl-methylene)-cyclobutenes 56, which themselves were prepared from 1,2-dibromocyclobut-l-ene 55 and the appropriate terminal alkyne by a Sonogashira coupling reaction, provided the deeply colored [4]radialenes 57a-d [50, 51]. A remarkable feature of 57 is the fast rotation around the cumulenic bonds at ambient temperature, with AG values of 13.7 (b, -20 °C), 14.9 (c, 0°C), and 17.8 (d, 27 °C) kcal mol" in chlorinated solvents. The bond rotation process was explained as proceeding through a diradical intermediate 58, that is, the geometrical isomerizations at the two cumulenic units occur independently (Scheme 4.13). 

Heck and Suzuki coupling reactions with bromo-oxepine 65 afforded 2-deoxy-2-alkyl/aryl septanosides. For example, Heck reaction of 65 with acrylates and styrene led to a high yield of coupled products groups as 86, whereas the use of a-methyl styrene furnished 87, in which the exo-cyc ic double bond isomerized to a terminal double bond. Suzuki coupling reaction with substituted phenylboronic acid led to 2-deoxy-2-C-aryl septanoside derivatives 88 in good yields. On the contrary, Sonogashira coupling reaction of 65 with acetylenes furnished 2-deoxy-2-C-alkenyl septanoside 89 (Scheme 13.24). 

There are several stereoisomers in disubstituted [2.2]paracyclophane, such as ortho-, meta-, para-, pstudo-ortho-, pseudo-m fa-, pseudo-para-, and pseudo-g mma/-disubstituted [2.2]paracyclophanes. Iron-catalyzed dibromination of commercially available [2.2]paracyclophane yields the mixtures of the dibromo[2.2]paracyclo-phane isomers, and pseudo-para-dibromo[2.2]paracyclophane 9 can be obtained by recrystallization as it has the poorest solubility in common organic solvents [76]. Thermal isomerization of 9 in triglyme afforded the psowdo-ortho isomer 38, as shown in Scheme 10. This transformation is an equilibrium reaction when the reaction was allowed to cool to room temperature, pseudo-para isomer 9 was precipitated as a result of its low solubility and was readily separated by simple filtration to obtain pseudo-arf/za isomer 38 in moderate isolated yield [76]. V ondo-ortho-dibromo[2.2]paracyclophane 38 was converted into pseudo-arf/ a-diethynyl[2.2] paracyclophane 40 via pseudo-arf/ a-diformyl[2.2]paracyclophane 39 (Scheme 10) [77]. Sonogashira-Hagihara coupling polymerization of 40 with 12 afforded the corresponding jc-stacked polymer 41 in 23 % isolated yield with the of 3,800 [78]. 

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