Reactions with Hard Nucleophiles

In contrast to soft carbanions or enol derivatives, organometallic reagents generally attack the metal of a 7t-allylmetal complex. As subsequent C-C bond formation occurs by reductive elimination, retention of configuration is observed for this last step of the reaction, giving overall inversion. Zn, B, Al, Sn, and Si compounds are the most widely used organometaUics for these cross-coupling reactions [2c, 

In general, transmetaUation is the rate-determining step, and sp carbons are transferred more easily than sp carbons. Therefore, arylations and vinylations are much more popular than alkylations. 

As described in the previous sections, electrophihc allylpalladium intermediates are well-established tools in synthetic organic chemistry. But the transformation of these electrophilic species into nucleophilic reactants is a relatively new method 

Allylic Alkylations with Other Transition Metals 

Although palladium is the most important transition metal for allylations, several others can be used, and they are discussed in alphabetical order. From a mechanistic point of view, they generally react as described for the palladium complexes, although they show different reactivities and selectivities. 

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Nitrogen-15 NMR has been used to study the course of acylation and carbamidization reactions of 3-amino-5-methylthio-1,2,4-thiadiazole (3). Using a N label in the 2-position of (3), its reaction with hard nucleophiles was found to proceed via initial reactioa on the 2-position followed by a Dimroth rearrangement to give the acylated product (4) with the N label in the exocyclic position. The reaction of (3) with soft nucleophiles, such as methyl isocyanate occurs directly on the exocyclic nitrogen to give the urea (5) (Scheme 1) <84CHEC-l(6)463 >. 

In several instances BTI has been used for the preparation of other hypervalent iodine compounds, such as iodonium salts and zwitterions. Of special interest is its reaction with hard nucleophiles which attack the carbonyl carbon rather than iodine, with eventual formation of a weso-compound [61] ... 

Under this heading only reactions with hard nucleophiles that result in reduced species that do not incorporate the nucleophilic reagent are considered. The additions of soft nucleophiles to HNCC are discussed in Section... 

An attempt has been made to predict the sites of nucleophilic attack on [M(CO)3(fl--hydrocarbon)] complexes using the perturbation theory of reactivity. For the model allyl substrate [Co(CO)3( j -C3H5)] the site preference CO > M > C3H5 was predicted for reaction with hard nucleophiles in polar solvents. On the other hand, with soft nucleophiles initial attack at the ir-allyl ligand was favored. Mechanistic studies have suggested only a small energy difference between attack by alkoxide ions on the allyl ligand and the metal in related ( Tr-allyl) palladium(II) complexes. ... 

TT-Aliylpalladium chloride reacts with a soft carbon nucleophile such as mal-onate and acetoacetate in DMSO as a coordinating solvent, and facile carbon-carbon bond formation takes place[l2,265], This reaction constitutes the basis of both stoichiometric and catalytic 7r-allylpalladium chemistry. Depending on the way in which 7r-allylpalladium complexes are prepared, the reaction becomes stoichiometric or catalytic. Preparation of the 7r-allylpalladium complexes 298 by the oxidative addition of Pd(0) to various allylic compounds (esters, carbonates etc.), and their reactions with nucleophiles, are catalytic, because Pd(0) is regenerated after the reaction with the nucleophile, and reacts again with allylic compounds. These catalytic reactions are treated in Chapter 4, Section 2. On the other hand, the preparation of the 7r-allyl complexes 299 from alkenes requires Pd(II) salts. The subsequent reaction with the nucleophile forms Pd(0). The whole process consumes Pd(ll), and ends as a stoichiometric process, because the in situ reoxidation of Pd(0) is hardly attainable. These stoichiometric reactions are treated in this section. 

Quinone methides are electron-deficient at C7, as readily understood via the resonance forms of QM1 shown in Fig. 12.7. They are therefore susceptible to nucleophilic attack at that position. Although reactions during high-temperature pulping demonstrate that 8-<9-4-aryl ether quinone methides QM1 are rearomatized by attack with hard nucleophiles such as HO- and HS, 81 these reactions do not readily occur at ambient temperatures.41,85 Thus, HO will not add to quinone methide QM1 under any conditions that we have tried (including with cosolvents, and using phase-transfer conditions). Of course water will add to quinone methides under acidic conditions... 

Alkyl halides normally undergo elimination reactions with hard (e.g., first-row) nucleophiles. If there is a choice of conformers from which anti elimination can take place, the stabler product is usually produced. The product is A-PhC(Me)=CHMe... 

Sn2 substitution reactions of alkyl halides with hard nucleophiles such as alkyl anions can be achieved most readily with the aid of organocopper chemistry [95]. Sn2 reactions with epoxides and aziridines are also synthetically useful [96]. The... 

Evans and Uraguchi also examined the rhodium-catalyzed allylic alkylation with hard nucleophiles [31]. Aryl organozinc halides proved optimal nucleophiles for the regio- and stereospecific allylic alkylation of enantiomerically enriched unsymmetrical allylic alcohol derivatives (Tab. 10.4). The reaction occurs with net inversion of absolute... 

Soft nucleophiles (X = CN", SCN-, I ) attack Ni(5-CtCH2- or 5-HOCH2-ODC) at C-10 to give Ni(5-Me-10-X-ODC), while SN2 reactions occur with hard nucleophiles (HO-, CF3CO ).25 ... 

The properties of dimethyl carbonate, (MeO)2CO, as an ambident electrophile have been investigated by analysis of the products of its reaction with various nucleophiles having different hard-soft character. Results were in good agreement with the Hard-Soft Acid-Base theory, hard nucleophiles attacking the hard C=0 group and soft nucleophiles the soft Me group (Scheme ll).37... 

Benzannulation (Figure 11) significantly influences both -electron distribution and reactivity of azoles. Compared to imidazole 51, benzimidazole 54 has an increased positive charge at position 2 and this is consistent with its tendency to undergo reaction at this position with hard nucleophiles. This behaviour is analogous to the chemistry of azines. Purine is also notable for its high -deficiency, 7/7-purine 56 being more -deficient than the 9//-tautomer 55. Possibly this is responsible for the natural occurrence of the less -deficient and therefore chemically more stable derivatives of 9/7-purine. 

Both of these centres were selectively carboxymetliylated (hard reaction, Scheme 13). Classical metal catalysts such as Pb(0Ac)2 or Sn[O2CCH(Et)Bu]2 effected N-2 activation under refluxing conditions (Table 10, entries 4-6) whilst potassium /-butoxide at room temperature activated N-1 (Table 10, entiy 1). It was reasoned that the reaction with a strong base was due to the deprotonation of N-1 creating an anion with hard nucleophilicity... 

In contrast to soft nucleophiles which attack the allyl face opposite the palladium complex, hard nucleophiles (e.g., organozinc reagents) first coordinate to the metal center and then are transferred intramolecularly to the allyl ligand (see, e.g.. Table 1 in [13]). Therefore, the reaction of allyl-palladium complexes with hard nucleophiles usually involves retention of configuration. However, the classification as soft and hard nucleophiles is not always unambiguous. With acetate as the nucleophile, e.g., the stereoselectivity depends on the reaction conditions and both overall inversion as well as retention have been observed [18]. 

Transition metal complexes are often very good nucleophiles and qualify as being supersoft under Pear son s HSAB classification for example, reaction with soft methyl iodide can be as much as 3 X 105 times faster than the reaction with hard methyl tosylate. Because soft nucleophiles are those with large a values in the Edwards equation, that rates for the transition metal nucleophiles are effectively correlated with oxidation potentials is not surprising. In the last chapter in this section, Chapter 16, Pearson uses recently obtained values of pKa for transition metal complexes to test the full Edwards... 

Bond-Cleavage Reactions with Hard Acid and Soft Nucleophile Systems... 

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