Cascade reactions alkynes, mechanisms

Scheme 7.25 Proposed mechanism for the Cu(I)-catalyzed cascade reaction of cyclic diaryliodo-niums, sodium azide, and alkynes...

In 2003, Zhu and Zhang reported a palladium-catalyzed cyclization/arylation cascade reactions of enynes with arylboronic acids leading to cyclic products with a stereodefined exocyclic double bond [44] (Scheme 6.26). Several types of enynes can be anployed carbon, oxygen, and nitrogen tethers [Y=C(COjMe)j, O, Ts], and alkyl- and arylalkynes are well tolerated. The author proposed a plausible mechanism, probably involving a Jt-allylpalladium complex which is formed from the aUyUc halide, followed by insertion of the alkynes and Suzuki coupling reactions. 

In 2001, Larock and Tian reported a palladium-catalyzed cascade reaction of aryl halides and 1-aryl-l-aIkynes to synthesize 9-aIkylidene-9/f-fluorenes 167 [66] (Scheme 6.44). Based on the active role of Pd(IV) in organopalladium chemistry, the authors proposed a mechanism involving the formation, transformation, and reductive elimination of Pd(IV) intermediates and aryl C—H bond activation. It is noteworthy that both carbocyclic and heterocyclic aryl iodides, such as pyridine and thiophene, could be introduced in this reaction. Later, Zhao and Larock reported an efficient palladium-catalyzed cascade reaction for the synthesis of substituted carbazoles 169 from A/-(3-iodophenyl)anilines 168 and alkynes [67] (Scheme 6.45). 

The proposed reaction mechanism is shown in Scheme 6.75. The nitroalkene moiety of bifunctional ortAo-alkyne-substituted nitrostyrenes 159 is activated through hydrogen bonding with catalyst 160 to incorporate the stereoehemieal information in the first AFC reaction. Then the alkyne is activated under gold catalysis to affect the seeond AFC/ring expansion cascade. 

In this section, only examples of Mizoroki-Heck reactions where a proper addition of the cr -aryl- or a -alkeny Ipalladium(II) complex to a double bond of an alkene or alkyne occurs are considered. As a consequence, an often-met deviation from the classic Mizoroki-Heck mechanism, the so-called cyclopalladation, will not be treated in further detail [12, 18]. However, as it is of some importance, especially in heterocycle formation and mainly because it will be encountered later during polycyclization cases, it shall be mentioned briefly below. Palladacycles are assumed to be intermediates in intramolecular Mizoroki-Heck reactions when j3-elimination of the formed intermediate cannot occur. These are frequently postulated as intermediates during intramolecular aryl-aryl Mizoroki-Heck reactions under dehydrohalogenation (Scheme 6.1). The reactivity of these palladacycles is strongly correlated to their size. Six-membered and larger palladacycles quickly undergo reductive elimination, whereas the five-membered species can, for example, lead to Mizoroki-Heck-type domino or cascade processes [18,19]. 

The potency of Danheiser s pericyclic cascade was further demonstrated in the construction of pyridine cores, disclosing presumably the first example in which an unactivated nitrile function participates in a [4+2]-cycloaddition. Two examples with established mechanisms are depicted in Scheme 6.33. If the required hydrogen for the anticipated ene reaction is present, pathway A dominates and follows the common domino reaction sequence to pyridine 181. If, however, the crucial position is substituted, for instance by an amide moiety, the system is able to overcome this hurdle and utilize its nitrile group for the preluding ene reaction (pathway B). This time, the alkyne group eventually terminates the cascade in a cycloaddition to give the tricyclic pyridine 184. Some efforts has been made to prove that pathway A is usually faster a gem-dialkyl effect in the substrates 179 as well as 182 was shown to play a role in order to facilitate the reaction progress. 

Yamamoto reported the Cu(I)-catalyzed synthesis of 2,4-di- and 2,3,4-tri-substi-tuted pyrroles 317 (Scheme 8.111) [309]. Target products were obtained in modest to good yields via a 3 + 2 cycloaddition reaction between isonitriles 315 and activated alkynes 316. Steric congestion around the triple bond of 316 decreases the reaction efficiency. It was also demonstrated that alkynes activated with electron-withdrawing groups other than carbalkoxy were somewhat inefficient in this cascade transformation. However, much better compatibility of electron-withdrawing substituents on isocyanide 315 was observed. The reaction mechanism is outlined in Scheme 8.112. 

An elegant example of the cascade processes involving rhodium-catalyzed C—H bond activation is the three-component reaction of benzaldehydes, amines, and alkynes, which led to the one-pot synthesis of isoquinoUnium salts 58 (Scheme 5.39) [39], The process involves generation of imine, C—H bond activation, and annula-tion. The mechanism proposed is strongly supported by the isolation of the five-membered rhodacycle A and an intermediate (Scheme 5.40). The significance of this cascade C—H activation/annulation reaction has been demonstrated by its application to the total synthesis of the isoquinohnone alkaloid oxychelerythrine 59 with excellent yield (Scheme 5.41). 

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