Soft carbanion

The interfacial mechanism provides an acceptable explanation for the effect of the more lipophilic quaternary ammonium salts, such as tetra-n-butylammonium salts, Aliquat 336 and Adogen 464, on the majority of base-initiated nucleophilic substitution reactions which require the initial deprotonation of the substrate. Subsequent to the interfacial deprotonation of the methylene system, for example the soft quaternary ammonium cation preferentially forms a stable ion-pair with the soft carbanion, rather than with the hard hydroxide anion (Scheme 1.8). Strong evidence for the competing interface mechanism comes from the observation that, even in the absence of a catalyst, phenylacetonitrile is alkylated under two-phase conditions using concentrated sodium hydroxide [51],... 

Soft carbanions, RCXY, as defined in Section 3.3.2.2.1, have been shown to add to ir-allylpalladium complexes directly on the allyl ligand, on the face opposite the Pd (inversion) (equations 150 and... 

Organolithiums have been shown to add to a variety of trithiocarbonate oxides exclusively in a thiophilic maimer, as a consequence of the electrophilic character of the sulfine sulfur, to give an intermediate carbanion stabilized by three sulfur atoms the soft carbanion, which forms trithioorthoester oxide on quenching with water, acts as the equivalent of the (alkylthio)carbonyl anion in Michael addition.98... 

Excellent nucleophiles in palladium(0)-eatalyzed allylic alkylations are soft carbanions, i.e.. metal salts of C — H acids with a pKa in the range of 10-20. These are activated methylene compounds which are substituted with at least two geminal electron-withdrawing groups [CO.R, S02R, — CN, —NC. COR, N02, (C6H5)2C = N]. As an exception, deprotonated simple nitroalkanes are sometimes also effective as nucleophiles. 

Usually, the reaction proceeds under mild conditions, but the rate and required temperature is strongly dependent on the steric demand of the substrate as well as the soft carbanion, on the electronic nature of the substituents on the allyl moiety (electron-rich alkenes are less reactive), on the ligands employed, and on the leaving group. 

The palladium-mediated substitution of allylic substrates proceeds in two independent steps. For stabilized carbanions both oxidative addition and the nucleophilic displacement occur with inversion of configuration. Thus, overall retention results, in contrast to the corresponding reactions of nonstabilized carbanions as nucleophiles (see Section D.l. 5.6.3.). The steric course of the reaction is proved by the absence of racemization in Lhe conversion of chiral substrates into chiral alkylated products. Furthermore, chiral n-allylpalladium complexes formed with inversion from stoichiometric reactions of palladium(O) with allyl substrates have been isolated. Coupling of these stereodefined complexes with soft carbanions yields the chiral alkylated products, again with inversion of configuration. 

An interesting method for the simultaneous formation of two C—C bonds is represented by the regio- and stereoselective arylation of 1,4-cyclohexadiene with iodobenzene and diethyl malonate. After oxidative insertion of palladium(O) into the aryl - iodine bond the arylpalladium species generated adds syn to a double bond and a subsequent syn palladium migration forms a ttK-woTt-allylpalladium intermediate. The palladium is displaced with inversion by the soft carbanion to produce the /ran.v-cy cl oh ex en e derivative 4 in high yield26, at the same time regenerating an active palladium(O) catalyst for the next catalytic cycle. 

Table 2. Stoichiometric Palladation of 4-Ene-3-keto Steroids and Subsequent C-6 -Alkylation with Soft Carbanions...

The solvent may determine the stereochemistry in the stoichiometric formation of 7r-allyl-palladium complexes from allyl halides. Strong donor solvents such as acetonitrile and dimethylsulfoxide lead to the expected m-ir-allyl complexes cis-16, whereas benzene, dichloro-methane or tetrahydrofuran give the. vva-addition product Irans-1639. Using soft carbanions in tetrahydrofuran. both complexes are converted to the corresponding alkylated products 17 with clean inversion of configuration. 

Table 5. Chemoselectivity with Palladium-Promoted Alkylation of Functionalized Cyclic Allyl Acetates with Soft Carbanions...

Bicyclic lactones8,60 are readily prepared from the corresponding cycloalkenyl acetic acids via iodolactonization and subsequent hydrogen iodide elimination. They are interesting starting materials for the stereoselective synthesis of civ-substituted cycloalkenes 25 and 26. The regiose-lectivity is determined by charge repulsion between the soft carbanion and the carboxylate anion. 

Table 7 summarizes several important aspects of substrate control of diastereoselectivity. Variation of either the relative configuration of the lactone or of the olefin geometry allows access to the opposite diastereochemical series (Table 7, entries 2-5)80. Since only the ( )-olefins are formed, a successful chirality transfer either requires ionization of the lactone from a single conformation B with nucleophilic attack being faster than stereorandomization or an involvement of solely the, mi,.n -7t-allyl complex generated via n-a-n rearrangement prior to C —C bond formation. The soft carbanion attacks the allyl complex charge directed distal to the carboxylate anion. 

By the isolation of nonracemic chiral it-allylpalladium complexes82,83, ss, it was unambiguously demonstrated that the oxidative addition step occurs with inversion of configuration. Loss of chirality is mainly due to anti attack of free palladium(O) species on the rr-allyl complex (sec Section 1.5.6.1.2.1.). When the chiral allyl complexes are subjected to nucleophilic addition with soft carbanions, inversion of configuration is observed and thus retention of configuration for the overall process results. 

In general, allyl ethers are less reactive than esters and therefore rarely used as substrates in the palladium-assisted alkylation with soft nucleophiles. Phenyl a- or )5-D-eor//jro-hex-2-enopyra-nosides react with a variety of soft carbanions under neutral conditions to give the a- or t -C -g]ycopyranosides, respectively in good to excellent yields both stereoselectively and with complete regioselectivity88. Since the liberated phenoxide ion deprotonates the active methylene compounds, no external base has to be added. 

Table 11. Palladium(0)-Catalyzed Neutral Alkylation of Vinyl Epoxides with Soft Carbanions...

Ionization of substrates 1 and 2 leading to the symmetrically 1,1-disubstituted diastereomeric Ti-allyl complexes 3 and 4 also allows complete conversion to one product enantiomer, provided that nucleophilic attack occurs at the carbon bearing substituent R2. High enantiomeric excess may be achieved if a rapid equilibration between the two intermediate re-allyl species is established and the soft carbanion preferentially attacks one of them. Interconversion of the reactive complexes is possible via epimerization by nucleophilic attack of free palladium(O) anti to the jr-allyl complex or by n-a-n rearrangement involving the formation of a Pd-C c-bond at the symmetrically substituted allyl terminus. This process is only fast for R1 = H, due to a low degree of steric congestion or for R1 = aryl because of rc-benzyl participation. 

Dialkylation in intermolecular substitutions with dimethyl malonate and 2-methyl-l,3-cyclo-hexadione as soft carbanions is minimized by the chiral ligand19. As expected, enantioselectiv-ity is not dependent on the choice of nucleophile. 

The influence of double stereodifferentiation on palladium(0)-assisted alkylation of soft car-banions has not yet been thoroughly investigated. Coupling of a chiral ally ligand, prepared from a- or //-phenyl-n-cn // ru-hcx-2-enopyranoside (see Section 1.5.6.1.2.1.)4 with a prostereogenic soft carbanion in the presence of Diop has not improved the simple diastereoselectivity. 

Whereas the vast majority of C —C bond forming nucleophilic additions to 7t-allylpalladium complexes are performed with soft carbanions stabilized by two electron-withdrawing groups (see Section 1.5.6.1.), certain enol derivatives of monocarbonyl compounds and aza-analogs can also be used. In view of the extraordinary importance of these nucleophiles for organic synthesis, their reactions with either stoichiometrically or catalytically generated 7r-allylpalladi-mn complexes are treated separately in this section. 

In contrast to soft carbanions (see Section 1.5.6.1.) and enol derivatives of monocarbonyl compounds or their aza-analogs (see Section 1.5.6.2.), organometallic compounds generally attack the metal of 7t-allylpalladium complexes1-33. Since subsequent C —C bond formation occurs by reductive elimination in these cases retention of configuration is observed in going from the re-allyl complex to the olefinic product. 

Whereas sodium indenide displays a stereoselectivity similar to phenylzinc chloride (see Table 26), sodium cyclopentadienide and 3-trimethylsilylindene act like soft carbanions. Both substrates 10 and 12 undergo allylic substitution with net retention of configuration to 1127 and 1328, respectively, via attack on the ally ligands of the intermediate 7t-allylpalladium complexes anti to the metal. Again, the ratio of the two possible diastereomers of structure 13 is unknown. 

Trimethylsilyl)oxazoles behave as soft carbanion equivalents and readily react with a wide variety of electrophiles to afford 2-substituted oxazoles. 

The other possibility that the soft carbanion transfers an electron completely to oxygen is ruled out by the cobalt precedent and also for energetic reasons (see Scheme 13). 

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