Cascade reactions nucleophiles

Keywords Absolute configuration, Amines, Amino acids, Carbenes, Cascade reactions, 2-chloro-2-cyclopropylideneacetates. Combinatorial libraries. Cycloadditions, Cyclobutenes, Cyclopropanes, Diels-Alder reactions. Heterocycles, Michael additions. Nitrones, Nucleophilic substitutions, Peptidomimetics, Palladium catalysis. Polycycles, Solid phase synthesis, Spiro compounds. Thiols... 

The successful utilization of nitrogen-based nucleophiles in the previously described cascade reactions has allowed for the synthesis of complex polycyclic structures from simple and readily available starting materials. The fact that carbamates can participate as nucleophiles has provided the opportunity for development of diastereoselective ring closures onto the halocyclopropane-derived allyl cation. 

Our interest in this chapter is in silver-catalyzed cycloisomerization reactions. Therefore, we shall present different silver-catalyzed cycloisomerization reactions as a function of the nucleophilic and electrophilic moiety. Cycloisomerization reactions including the classical ene-yne cycloisomerization (with X = CHR, Scheme 5.1), and the related heterocyclization reactions with heteroatoms embedded in unsaturated systems (X = NR, O Scheme 5.1) belong to the same reaction family. In addition, the alkynyl part can be exchanged for an allene unit. Internal or external nucleophiles (Nu) can then stabilize, through cascade reactions, the positive charge created.24... 

It is very well known that jr-allyl palladium complex 1, which is a key intermediate for the Tsuji-Trost type allylation, has an electrophilic character and reacts with nucleophiles to afford the corresponding allylation products. We discovered that bis 7r-allyl palladium complex 2 is nucleophilic and reacts with electophiles such as aldehydes [27] and imines [28-32] (Scheme 2, Structure 2). We have also shown that bis 7r-allyl palladium complex 2 can act as an amphiphilic catalytic allylating agent it reacts with both nucleophilic and electrophilic carbons at once to produce double allylation products [33]. These complexes incorporate two allyl moieties that can bind with different hapticity to palladium (Scheme 3). The different complexes may interconvert by ligand coordination. The complexes 2a, 2b and 2c are called as r]3,r]3-bisallypalladium complex (also called bis-jr-allylpalladium complex), r)l,r)3-bis(allyl)palladium complex, -bis(allyl)palladium complex, respectively. Bis zr-allyl palladium complex 2 can easily be generated by reaction of mono-allylpalladium complex 1 and allylmetal species 3 (Scheme 4) [33-36]. Because of the unique catalytic activities of the bis zr-allyl palladium complex 2, a number of interesting cascade reactions appeared in the literature. The subject of the present chapter is to review some recent synthetic and mechanistic aspects of the interesting palladium catalyzed cascade reactions which in-... 

A spectacular application allowed the synthesis of fenestranes by a three-step sequential action of cobalt nanoparticles and a palladium catalyst [131]. The cascade reaction started with a PKR of enyne 105, accomplished by the cobalt catalyst giving 106, followed by the formation of allyl-7r3 palladium complex 107 which reacted with a nucleophile derived from diethyl malonate, to give enyne 108. The final step was a second PKR that gave 109 in good yield. They used cobalt nanoparticles as with Co/charcoal the third step did not take place, apparently due to damage in this catalyst after the allylation step (Scheme 31). 

Despite that the regioselective cyclization of 5-hexenyllithiums could be synthetically useful, in those years there was no real development of this methodology9, probably due to the lack of a convenient and efficient procedure for the preparation of unsaturated alkyllithiums and to the conventional belief that simple alkenes are not thought of as sites of nucleophilic attack. Moreover, this was a period when radical cyclizations and radical cascade reactions came to the fore10, and 5-hexenyl substrates were used as probes for radical intermediates in reactions suspected of proceeding via single-electron transfer (SET). 

Some mechanistic aspects of the above cascade reaction deserve comment. Thus, after the intermolecular addition of the nucleophilic acyl radical to the alkene, the electrophilic radical adduct A, instead of undergoing reduction, reacts intramolecularly at the indole 3-position (formally a 5-endo cyclization) to give a new stabilized captodative radical B, which is oxidized to the fully aromatic system. (For a discussion of this oxidative step, see Section 1.5.)... 

Silyl allenes such as 48 and enol acetates such as 50 were particularly effective substrates for these reactions. The oxidative cascade reaction of trisubstituted alkene substrate 52 demonstrated a powerful application of ETIC chemistry to form bicycle 53 through consecutive carbon-carbon and carbon-oxygen bond construction. Highly diastereoselective reactions were observed when the nucleophile was... 

One of the themes to emerge from Bunce s research is the use of cascade reactions to produce an internal nucleophile that is subsequently intercepted by an enone to deliver heterocyclic architectures. Thus, nitro aromatics of type 387 undergo an iron-mediated reduction to furnish benzo-fused heterocycles 388 in 88-98% yield (Scheme 72) (OOJOC2847). Exposure of unsaturated esters like 389 to NaOEt... 

Domino or cascade reactions are particularly valuable for the construction of various carbo- and heterooligocyclic systems with three, four, or even more annelated rings. The Heck reaction has successfully been employed in various inter-inter-, intra-inter-, inter-intra-, as well as all-intramolecular reaction cascades. In this section, such processes with a termination by attack of various nucleophiles will be described. 

All-intermolecular cascade reactions involving nucleophilic attack at the end are at least three-component reactions. For a successful outcome the balance of reactivities of each component in the reaction mixture toward each other must be just right. 

Intramolecular termination by carbon nucleophiles has been achieved with dialkyl malonate moieties. These cascade reactions, developed essentially by Balme, Gore, and colleagues, open an avenue especially to variously substituted methylenecyclopentane derivatives (Scheme 19,and Sect. V.3.4). 

Termination by external nitrogen nucleophiles has been investigated for various systems (cf. Ref. [53]). AUenes, which are excellent relays for cascade reactions, give rise to the formation of Tr-aUylpaUadium complexes. The latter can be reacted in a straightforward manner with amines to yield highly functionalized allylamines (Scheme 30, Eqs. 1 and... 

Intra-intramolecular cascade reactions combined with termination by an external nucleophile provide access to various kinds of ring systems. 

Hong and Overman reported the intramolecular termination of cascade reactions by oxygen nucleophiles in their studies on a novel synthesis of morphine (Scheme Starting from an iodophenol derivative tethered with an iodophenol silyl ether, intramolecular carbopalladation provided a bicycUc Tr-allylpalladium intermediate, which in turn was attacked by the oxygen functionality (Scheme 37). 

A five-component cascade reaction in which the last step is the trapping of a Tr-allyl-palladium species with a nucleophile such as piperidine, pyrrolidine, morpholine, and NaBPh4 afforded benzocyclopentenone derivatives 68 (Scheme 25). ... 

The Pd(OAc)2/dppb-catalyzed cascade reaction of o-iodophenol with 1,2-nonadiene and CO starts with a CO insertion which is followed by carbopalladation of the allene and subsequently terminated by an intramolecular nucleophilic substitution to afford O-con-taining six-membered a-methylenebenzo-y-dihydropyrones (Scheme 34). ... 

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