Tandem electrophilic/nucleophilic addition

Scheme 55. Tandem electrophile/nucleophile addition to the y -benzene ligand of TpRe(CO) (MeIm)(f/ -benzene) (MMTP = l-methoxy-2-methyl-l-(trimethylsiloxy)propene).

Dihydrooxazoles are also effective ortho directors for nucleophilic addition to naphthalene and some heteroaromatic derivatives. Tandem additions result if the reaction mixtures are quenched with electrophiles (Scheme 72). 

The two distinct bond-forming steps in tandem vicinal difunctionalization have been studied extensively. The first step consists of a nucleophilic addition to a ir-system the nucleophile is almost invariably an organometal. 1,4-Addition to an a, -unsaturated carbonyl substrate concomitantly generates a new cr-bond at the (3-carbon and an enolate ion. The second step constitutes C-functionalization of the enolate intermediate, forming a new o -bond between the nucleophilic a-carbon of the enolate and an electrophilic reagent. 

An alternative mode of reactivity is observed for [Os]-naphthalene when the nucleophile for the tandem addition is built into the electrophile. The normal mode of reactivity results in the formation of cis-l,4-dihydronaphthalenes (vide supra), but when a solution of the methyl vinyl ketone Michael addition product 24 in methanol (Table 6, entry 1) and a catalytic amount of triflic acid are allowed to react, the complexed hydrophenanthrenone 25 is isolated in 89 % yield [18]. This reactivity results from the pendant ketone undergoing a tauto-merization to form an enol, which can then attack the allyl cation at C2. The stereochemistry of the nucleophilic addition is still anti to the face involved in the metal coordination, but the... 

Hydroxylamino-4,5-dihydroimidazolium-<9-sulfonate 303 is prepared by reacting 2-chloro-4,5-dihydroimidazole with hydroxylamine-O-sulfonic acid. Reaction of 303 with carbon disulfide in the presence of triethylamine presumably proceeds via intermediate 304 to yield the 6,7-dihydro-5//-imidazo[2,l-c][l,2,4]thiadiazole-3-thione 305 by a tandem nucleophilic addition-electrophilic amination reaction <03JOC4791>. In an interesting photochemical reaction, irradiation of 5-phenyl-1,2,4-thiadiazole 306 results in the formation of benzonitrile 307 <03JOC4855>. 

Dihydrooxazoles are also effective ortho directors for nucleophilic addition to naphthalene and some heteroaromatic derivatives. Tandem additions result if the reaction mixtures are quenched with electrophiles (Scheme 54). When chiral oxazoles are used, asymmetric syntheses, such as that of scopadulcic acid, are achieved. Although most of the oxazoles employed have chelating groups to enhance stereoselectivity, the steric bias provided by valinol or t-leucinol derived oxazoles is often equivalent or superior. 

Among all tandem hydroformylation sequences the ones involving additional C,C-bond formations are the most synthetically valuable tandem hydroformylation sequences. These C,C-bonds can be formed by adding nucleophiles, which attack the carbonyl carbon, or by adding electrophiles, which attack the a-position. Furthermore, tandem reactions in which the aldehyde or an aldehyde derivative is involved in sigmatropic rearrangement are described. 

Electrophiles that have been used for the second alkylation of this tandem Michael addition -alkylation sequence are limited to primary iodoalkanes, (bromomethyl)benzenes and 3-bromo-propenes. Tables 9 and 10 provide details of the alkylations of enolate species prepared by 1,4-additions of -a,/j-unsaturated iron-acyl complexes by anionic carbon nucleophiles and anionic nitrogen nucleophiles, respectively. 

Derivatives of trifluoroethanethiol have limited though interesting chemistry. Unfortunately, metallated difluorothioenol chemistry has not been reported, because rapid nucleophilic attack occurs even by hindered bases such as LDA. Nakai et al. exploited this high electrophilicity in a tandem addition/elimina-tion-rearrangement sequence [146], but more recent applications have concerned free radical chemistry (Eq. 46). Chlorination of trifluoroethyl phenyl sulfide followed by exposure to tin hydride in the presence of an allylstannane resulted in C-C bond formation with a reasonable level of stereocontrol [147]. 

The general reaction sequence has been named more specifically as tandem vicinal dialkylation, nucleophilic-electrophilic carbacondensation,11 dicarbacondensation1213 or conjugate addition-enolate trapping,14 usually in reference to the fact that most of the reaction examples available create two new vicinal carbon-carbon bonds. Many noncarbon nucleophiles and electrophiles also are known, resulting... 

Racemic tandem additions Mild carbon nucleophiles add to the [Os]-anisolium complex 27 exclusively at C3 to afford substituted 1,3-cydohexadiene complexes 29-32 in moderate to high yields (Table 8) [21]. Nucleophiles that have been utilized in this manner include MMTP (29 and 30), N-methylpyrrole (31), and 2-trimethylsilyloxyfuran (32). As with other tandem additions to [Os] complexes, both the nucleophile and the electrophile add to the arene face opposite to that involved in metal coordination, such that the products are those of syn addition. 

The chiral anisole derivative 37 has been used in the synthesis of several asymmetric functionalized cyclohexenes (Table 9) [22]. In a reaction sequence similar to that employed with racemic anisole complexes, 37 adds an electrophile and a nucleophile across C4 and C3, respectively, to form the cyclohexadiene complex 38. The vinyl ether group of 38 can then be reduced by the tandem addition of a proton and hydride to C2 and Cl, respectively, affording the alkene complex 39. Direct oxidation of 39 liberates cydohexenes 40 and 41, in which the initial asymmetric auxiliary is still intact. Alternatively, the auxiliary may be cleaved under acidic conditions to afford /y3 -allyl complexes, which can be regioselectively attacked by another nucleophile at Cl. Oxidative decomplexation liberates the cyclohexenes 42-44. HPLC analysis revealed high ee values for the organic products isolated both with and without the initial asymmetric group. 

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