S 2 Substitution

Organocuprates react rapidly witli adylic balides for acetates), propargyl balides for acetates), and vinyloxiranes, frequently witli u2 regioselectivity. Tbe reaction ordinarily takes place witli oiui fwitli respect to tlie leaving group) steteoclieniistry. 

In an alternative syntliesis of panaatistaliti (S7) by Trost et al. [52], fSdieme 9.15) addilioti of tlie Grlgtiatd teagetil 63 [53] lo a mixture of tlie azide 62 and copper cyanide reprodudbly gave tlie desired adduct 64. Because of tlie difliciilties associated witli purification of adduct, tlie overall yield of tlie two steps ftlie next being diliydroxylation of tlie olefin) was 6 296. 

Wlien an allylic carbamate b syn substitution occurs [ 54], For diliydroxy-16-ene-vitaniin D 165 9.16) [55], In route A, tlie CD side cli S 2 syn substitution of allylic 

Hie advanlage of diis strategy is tlius die subsequenl irapping of tlie nietalale reanangenietil product lo provide a dean, efficient and biglily stereosdective roule to die trisubstitued alkenes. 

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For acyclic allylic substrates die situation is mote complex, since a larger number of reactive conformations, and betice corcesponding transition states, compete. Hius, mediyl ciimamyl derivatives 163 tX= O.Acj, upon treatment witli litliiiim dimetliylcuprate, mainly gave tlie S 2 substitution product 166 fentry 1, Tab. 6.6 and Sdieme 6.34) [80]. Hie preference for die S 2 product is expected, since de-conjugation of die alkene system is electronically imfavorable. 

Applications of orgatiocopper reagents and reactions to natural product syndiesis ate dassified by reaction type conjugate addition, S 2 substitution, S 2 substitution, 1,2-metalate teariangemenp and catboctiptadon. 

I Primary alkyl halides S 2 substitution occurs if a good nucleophile is used, 2 elimination occurs if a strong base is used, and ElcB elimination occurs if the leaving group is two carbons away from a carbonyl group. 

Aminoallenes constitute an important class of functionalized allenes with interesting chemical properties. They are known as attractive substrates for constructing three- to six-membered azacycles [78]. In 1999, Ohno and co-workers reported the stereoselective synthesis of chiral a-aminoallenes 179 and 181 by RCu(CN)M-medi-ated anti-SN2 substitution of chiral 2-ethynylaziridines 178 and 180 (Scheme 4.47) [79]. The X-ray data and specific rotations of the allenes were consistent with a net anti-S- 2 substitution reaction. 

As mentioned earlier, the Srn2 mechanism sketched in Scheme 11 has been suggested to explain the effect of a change of leaving group on product distribution in the reaction of 2-substituted 2-nitropropanes with enolate ions (Russell et al., 1981, 1982a,b). It has been proposed that the bimolecular substitution step (133) would involve, rather than S, 2 substitution at the... 

When the non-coordinating mesitoate system 156 was treated with lithium di-methylcuprate, formation of the anti-S 2 substitution product 157 was observed. Notably, the exclusive formation of the y-substitution product is the result of severe steric hindrance at the a-position, originating from the adjacent isopropyl group [78]. Conversely, the corresponding carbamate 158 was reported, on treatment with a higher order cuprate, to form the syn-SN2 product 159 exclusively [74]. The lithi-ated carbamate is assumed to coordinate the cuprate reagent (see 160), which forces the syn attack and gives trans-menthene (159). 

Nucleophilic displacement reactions One of the most common reactions in organic synthesis is the nucleophilic displacement reaction. The first attempt at a nucle-ophiHc substitution reaction in a molten salt was carried out by Ford and co-workers [47, 48, 49], Here, the rates of reaction between halide ion (in the form of its tri-ethylammonium salt) and methyl tosylate in the molten salt triethyUiexylammoni-um triethylhexylborate were studied (Scheme 5.1-20) and compared with similar reactions in dimethylformamide (DMF) and methanol. The reaction rates in the molten salt appeared to be intermediate in rate between methanol and DM F (a dipolar aprotic solvent known to accelerate S 2 substitution reactions). 

Increasing die effective nucleophilicity of an ion allows S 2 substitution reactions to occur under milder conditions. An anion will become a better nucleophile when it is less effectively solvated and when it is further separated from its counterion. Methods that can achieve these changes include selection of a tetraafldammomum counterion [see Eqs. (6) and (6)], addition of a crown ether or a cryptand [see Eq. (7)], and use of a solvent that effectively solvates cations [see Eqs. (1) and (2)]. 

Bicyclo[l. 1. l]pent-1 -yl anions (13) and radicals (14) carrying a suitable leaving group in position 3 undergo a 1,3-elimination reaction (path/, an intramolecular analog of Sw2 and S 2 substitution, respectively) and yield [l.l.ljpropellane (equations 6 and 7 Table 10). 

Comprehensive reviews of S 2 substitution can be found in (a) S. R. Hartshorn, Aliphatic Nucleophilic Substitution, Cambridge University Press, London, 1973 (b) A. Streitwieser, Solvolytic Displacement Reactions, McGraw-Hill, New York, 1962 (c) C. K. Ingold, Structure and Mechanism in Organic Chemistry, 2nd ed., Cornell University Press, Ithaca, N.Y., 1969. 

Predict which would be more reactive as a nucleophile in S 2 substitution ... 

Another application is to bimolecular SN2 and S 2 substitutions. Recall from Chapter 4 (pp. 174 and 205) that the nucleophilic reaction prefers backside attack by nucleophile on substrate whereas the electrophilic reaction prefers frontside attack. Figure 10.14 shows the appropriate frontier orbitals for frontside attack by a nucleophile. The nucleophile, symbolized by N, is the donor, and the C—X bond is the acceptor. The symmetries of the nucleophile HOMO and the C—X LUMO do not match (13) therefore only the filled-filled HOMO-... 

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