Tandem reactions addition-alkylation

Carbocyclization of m-alkcnyl-z-methoxybcnzy I lithiums to form five- or six-membered rings has been studied 101 the five-membered ring is formed with a cis-stereochemical relationship between the methoxy substituent and the adjacent methyl group. Intramolecular carbolithiation of vinyl sulfides at — 105°C in THF has been found to occur non-stereospecifically with regard to the newly formed C—Li centre.102. The stereochemistry of selective tandem Michael addition alkylation reactions of vinylphosphonates has been explored.103... 

Among the most important of these tandem conjugate addition-alkylation reactions are those of cyclopentenones. With cyclopentenone itself, the trans diastereoisomer usually results because the alkylating agent approaches from the less hindered face of the enolate. 

We left compound 35 as the product of a tandem conjugate addition/alkylation and promised further chemistry later in the chapter. In fact, 35 was used in another more remarkable tandem sequence involving two pericyclic reactions and the creation of a polycyclic Daphniphyllum alkaloid. The first few steps are straightforward and give diol 173 in good yield.8... 

Examples of electrophilic addition of secondary phosphines to alkenes or alkynes were described. [114, 124, 125, 135]. Glueck [124-126] reported enantioselective tandem reaction of alkylated/arylation of primary phosphines catalyzed by platinum complex, proceeding with formation of chiral phosphaace-naphthenes. Palladium-catalyzed hydrophosphination of alkynes 219 tmder kinetic resolution conditions gave access to 1,1-disubstituted vinylphosphine boranes 220. However, despite screening several chiral ligands, temperatures, and solvents, the... 

Scheme 8.2. Tandem Reactions Involving Alkylation of Enolates Generated by Conjugate Addition of Organocopper Reagents...

Clerici and Porta reported that phenyl, acetyl and methyl radicals add to the Ca atom of the iminium ion, PhN+Me=CHMe, formed in situ by the titanium-catalyzed condensation of /V-methylanilinc with acetaldehyde to give PhNMeCHMePh, PhNMeCHMeAc, and PhNMeCHMe2 in 80% overall yield.83 Recently, Miyabe and co-workers studied the addition of various alkyl radicals to imine derivatives. Alkyl radicals generated from alkyl iodide and triethylborane were added to imine derivatives such as oxime ethers, hydrazones, and nitrones in an aqueous medium.84 The reaction also proceeds on solid support.85 A-sulfonylimines are also effective under such reaction conditions.86 Indium is also effective as the mediator (Eq. 11.49).87 A tandem radical addition-cyclization reaction of oxime ether and hydrazone was also developed (Eq. 11.50).88 Li and co-workers reported the synthesis of a-amino acid derivatives and amines via the addition of simple alkyl halides to imines and enamides mediated by zinc in water (Eq. 11.51).89 The zinc-mediated radical reaction of the hydrazone bearing a chiral camphorsultam provided the corresponding alkylated products with good diastereoselectivities that can be converted into enantiomerically pure a-amino acids (Eq. 11.52).90... 

When the conjugate addition is carried out under kinetic conditions with stoichiometric formation of the enolate, the adduct is also an enolate until the reaction mixture is quenched with a proton source. It should therefore be possible to effect a second reaction of the enolate if an electrophile is added prior to protonation of the enolate. This can be done by adding an alkyl halide to the solution of the adduct enolate, which results in an alkylation. Two or more successive reactions conducted in this way are referred to as tandem reactions. 

The Lee group originated rhodium alkenylidene-mediated catalysis by combining acetylide/alkenylidene interconversion with known metal vinylidene functionalization reactions [31], Thus, the first all-intramolecular three-component coupling between alkyl iodides, alkynes, and olefins was realized (Scheme 9.17). Prior to their work, such tandem reaction sequences required several distinct chemical operations. The optimized reaction conditions are identical to those of their original two-component cycloisomerization of enynes (see Section 9.2.2, Equation 9.1) except for the addition of an external base (Et3N). Various substituted [4.3.0]-bicyclononene derivatives were synthesized under mild conditions. Oxacycles and azacycles were also formed. The use of DMF as a solvent proved essential reactions in THF afforded only enyne cycloisomerization products, leaving the alkyl iodide moiety intact. 

Reaction at the C atom of nitronate salts is known with a variety of electrophiles, such as aldehydes (Henry reaction) and epoxides (191-193). Thus the incorporation of the nitro moiety and the cyclization event can be combined into a tandem sequence. Addition of the potassium salt of dinitromethane to an a-haloaldehyde affords a nitro aldol product that can then undergo intramolecular O-alkylation to provide the cyclic nitronate (208, Eq. 2.17) (59). This process also has been expanded to a-nitroacetates and unfunctionalized nitroalkanes. Other electrophiles include functionalized a-haloaldehydes (194,195), a-epoxyaldehydes (196), a-haloenones (60), and a-halosulfonium salts (197), (Chart 2.2). In the case of unsubstituted enones, it is reported that the intermediate nitronate salt can undergo formation of a hemiacetal, which can be acetylated in moderate yield (198). 

The ruthenium complex Cp Ru(bipyridyl)Cl has been developed as a catalyst for the first regioselective tandem Michael addition-allylic alkylation of activated Michael acceptors. The net outcome is the decarboxylative insertion of Michael acceptors into allyl /3-keto esters to produce (215). The reaction combines the generation of Ru-tt-allyl and enolate from (213) the enolate is first added to the Michael acceptor (214) and the resulting species is captured by the Ru-tt-allyl.254... 

Ishii and coworkers developed a Mn(OAc)2-catalyzed hydrophosphonation of alkenes 40 (Fig. 47) [271]. The active Mn(III) catalyst is generated by reaction of Mn(OAc)2 with oxygen. Hydrogen abstraction from diethyl phosphite 169 forms a phosphonyl radical, which adds to 40. The resulting alkyl radical is reduced by 169 to continue the chain reaction. Alkylphosphonates 170 were isolated in 51-84% yield. With (3-pinene a cyclobutylcarbinyl radical ring opening was observed in 32% yield, while 1,5-cyclooctadiene underwent a tandem radical addition/ transannular 5-exo cyclization (cf. Fig. 38). 

Reductive radical cyclization and tandem radical addition/cyclization reactions catalyzed by Ni(II) complexes, such as Ni(cyclam)(C104)2 98a, were studied starting in the 1990s by Ozaki s group [128]. The reaction conditions are applicable to alkyl and aryl halides bearing suitable positioned olefin units. Iodides and bromides can be used in some cases even aryl chlorides were successfully applied. The field was reviewed recently, and thus only more recent results are summarized here [19, 20]. 

Pyrrolidines are an important class of five-membered heterocycles with noteworthy biological properties [46]. In addition to pharmaceutical applications, the pyrrolidine moiety has also been widely used as a chiral auxiliary for asymmetric synthesis [47]. Although many elegant syntheses of chiral nonracemic pyrrolidines have been reported within the past decade or so [48-50], an alternative approach based on the intramolecular reaction of an azide and organoborane has been developed very recently [51-53], This approach utilizes the hydroboration-azide alkylation tandem reaction as a key sequence, taking advantage of the efficient stereocon-trolled steps. Scheme 20 shows an application of the synthesis of 3-substituted 5-(2-pyrrolidinyl)isoxazole which has been found to have nanomolar activity, comparable to (5)-nicotine, against whole rat brain [54]. 

The 5-alkyl cyclohexenone that we have chosen as our example gives the best results. The mechanism suggests that the enolate intermediate is protonated on the top face (axial addition again) though we cannot tell this. But, if we carry out a tandem reaction with the enolate trapped by a different electrophile, the product is again that of axial attack. 

The alkyllithium reagents to be used in tandem reactions can be prepared by direct alkylation or by an aldol reaction involving nucleophilic addition of the alkyllithium as the first step. Several complex heteroaromatic compounds, which can serve as pivotal intermediates in synthetic strategy of biologically active species, could be synthesized by this procedure. The preparation of polysubstituted pyridines has been an active research area for many years181. The synthesis of 2-alkyl- or 2-aryl-5-hydrazinopyridines 327 has never been performed directly from pyridine. The reported methods involve several steps... 

Tandem radical addition-aldol-type reaction of a,/3-unsaturated oxime ethers bearing an Oppolzer sultam auxiliary leads to stereoselective incorporation of alkyl groups in the 5- and 3-positions in tetrahydrofurans (Scheme 77) <2005AGE6190>. The observed /ra r,/ra r-stereoselectivity was explained by invoking a cyclic six-membered ring transition state. 

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