Tandem addition-elimination products

Addition of hydroxylamines to Michael acceptors 44 possessing an ally lie leaving group results in formation of tandem addition-elimination products of type 45 (equation 30)". ... 

Theoretical calculations support a low-energy oxidative addition mechanism [26c], Reaction of the unsolvated cationic complex Cp Ir(PMe3)(CH3) with pentane, cyclohexane or benzene in the gas phase also gives Cp Ir(PMe3)(R) as the product. However, a mechanistic investigation of this process by electrospray tandem spectrometry has demonstrated that neither the oxidative addition-elimination mechanism nor the concerted a-bond metathesis mechanism is operative. Instead, the authors proposed a dissociative elimination-addition mechanism which proceeds through a series of 16-electron Ir(III) intermediates [26d]. 

Tang et al. reported an unexpected tetrahydrothiophene-catalyzed rearrangement/ annulation reaction via a tandem Michael addition/elimination/substitution for the synthesis of chromenes. The products are 27/-chromene- or 4f/-chromene-2-carboxylates, depending on the choice of the base. With K COj 2//-chromene is formed, with Cs COj, 47/-chromene is the major product (Scheme 7.40) [167]. 

A interesting and useful reaetion is the intramolecular polycyclization reaction of polyalkenes by tandem or domino insertions of alkenes to give polycyclic compounds[l 38]. In the tandem cyclization. an intermediate in many cases is a neopentylpalladium formed by the insertion of 1,1-disubstituted alkenes, which has no possibility of /3-elimination. The key step in the total synthesis of scopadulcic acid is the Pd-catalyzed construction of the tricyclic system 202 containing the bicyclo[3.2. Ijoctane substructure. The single tricyclic product 202 was obtained in 82% yield from 201 [20,164). The benzyl chloride 203 undergoes oxidative addition and alkene insertion. Formation of the spiro compound 204 by the intramolecular double insertion of alkenes is an exam-ple[165]. 

A tandem radical 5-exo cyclization/radical addition/allylic substitution reaction was subsequently described [292]. Allylic ot-bromo acetal 242b cyclized cobalt-catalyzed. Addition to diene 245 and subsequent coupling with coformed organocobalt(I) species generates an allylcobalt complex, which undergoes reductive elimination to cyclic product 246 in 93% yield (cf. Fig. 56). 

The indirect 3-alkylation of 2,5-dimethylfuran was achieved via a tandem Michael addition of a nitroalkane and elimination of nitrous acid starting from cis-3-hexene-2,5-dione, a ring opening product of 2,5-diraethylfuran. Hydrogenation of the carbon-carbon double bond and a subsequent Paal-Knorr reaction provided 3-substituted-2,5-dimethylfurans <01S2003>. Selective ring bromination of methyl 2-methyl-3-furoate with NBS was realized when DMF, an aprotic polar solvent, was used. If the same reaction was carried out in CCI,... 

The second exanple is a new synthetic approach to the synthesis of nakadomarin A 202 rscheme 20.. 38T To this end, Wnkler and coworkers developed a tandem Pummerer-Michael process.The generation of the activated thionium ion was performed by the elimination of ethanethiol from thioacetal 198. The intermediate 199 showed double reactivity, that is, a nucleophilic position on the furan to perform the Michael addition and the usual electrophilic thionium, which was in fact trapped by the enamine carbon generating tetracyclic product 200. Winkler presented the s)mthesis of a tetracyclic model system and suggested that this reaction sequence can also be applied to the synthesis of the natural product. 

A unique example of direct olefination of a cyclopropane was also disclosed by the Yu lab [21]. An electron-deficient arylamide was employed as directing group, as the previously employed oxazoline or hydroxamic acid was unreactive in the alkenylation. The proposed mechanism for the reaction involves an amide-directed C-H insertion of the Pd(II) catalyst into the cyclopropane methylene C-H bond of 9, followed by olefin carbopalladation and p-hydride elimination to provide intermediate 10 (Scheme 3a). Pd(0) is re-oxidized back to Pd(II) by Ag(I)/Cu(II), and a tandem 1,4-addition between the amide moiety of 10 and the acrylate provides the corresponding y-lactam 11 as the sole isolated product, fii the presence of an... 

The insertion of CO into Pd-carbon bonds has also been employed in several tandem/cascade reactions that afford five-membered nitrogen heterocycles [97]. A representative example of this approach to the construction of heterocydes involves synthesis of isoindolinones via the Pd-catalyzed coupling of 2-bromobenzaldehyde with two equivalents of a primary amine under an atmosphere of CO [97bj. As shown below (Eq. (1.57)), this method was used for the preparation of 144 in 64% yield. The mechanism of this reaction is likely via initial, reversible condensation of 2-bromobenzaldehyde with 2 equiv of the amine to form an aminal 145. Oxidative addition of the aryl bromide to Pd° followed by CO insertion provides the acylpalladium spedes 146, which is then captured by the pendant aminal to afford the observed product. An alternative mechanism involving intramolecular imine insertion into the Pd—C bond of a related acylpalladium species, followed by formation of a paUadium-amido complex and C—N bond-forming reductive elimination has also been proposed [97b],... 

Ogawa extended hydrocarbonylation to Pt(0) by demonstrating that catalytic amounts of aromatic thiols can promote the cyclization of alkynyl alcohols (Scheme 2.15). The authors propose a Pt sulfide intermediate in the catalytic cycle generated via S—H oxidative addition (i.e., carbopalladation see Scheme 2.12), followed by CO insertion, acylplatination and reductive elimination of the vinylic C—H bond. Cyclization of the pendant alcohol onto the thioester affords the lactone. It was observed that certain aromatic thiols could also undergo tandem conjugate addition with the lactone product [35]. 

Another tandem possibility is to use oxidative addition to generate the palladium(II) species that initiates cyclization (Scheme 6.44). The result is formation of both a C-C bond and a bond between an alkene carbon and a heteroatom. The C-C bond is formed by reductive elimination that generates a palladium(O) species. This is then returned to the palladium(II) state by oxidative addition, hence no added oxidant is required. The reaction has often been used in an intramolecular fashion to ensure regioselectivity. If the nucleophilic attack is slow, a by-product may occur, which is the Heck product arising from alkene insertion. Alkynes may also be used as substrates. 

The seven-memberedring product was obtained by tandem rhodium-catalyzed C-H bond activation/cycloisomerization of MCPs. Pyridine-directed C-H activation, intramolecular addition to the C=C bond, ring expansion by P-carbon elimination, and reductive elimination gave the 5-(2-pyridylmethylene)cycloheptene derivative 90 (Scheme 2.63) [102]. Analogous cycloisomerization employing an... 

In addition, it has been demonstrated that the reaction may take a different course depending on the nature of the dienophile [167b]. Thus, cyclopropene reacts as expected in the first step however, upon dinitrogen elimination, pyran 447 forms. Reaction with a deficiency of cyclooctyne produces furan 448 in 41% yield. However, when excess of cyclooctyne is used, the product of the tandem cycloaddition 449 forms in 74% yield (Scheme 16.90). 

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