A-cyanoesters

Fig. 31 Bis-Pd(II)-catalyzed asymmetric Michael addition of a-cyanoesters 57 to enones...

Both overt carbanions and organometallic compounds, such as Grignard reagents, are powerful nucleophiles as we have seen in their addition reactions with C=0 (p. 221 et seq.) they tend therefore to promote an SN2 pathway in their displacement reactions. Particularly useful carbanions, in preparative terms, are those derived from CH2(C02Et)2, (3-ketoesters, l,3-( 3-)diketones, e.g. (55), a-cyanoesters, nitroalkanes, etc.—the so-called reactive methylenes ... 

Successful amination of chiral a-cyanoesters with 4a has been reported (Scheme 46) ". Appropriate reduction and removal of the chiral auxiliary give a,/3-diaminopropionic acids with good yield and enantiomeric excess. 

The use of nucleophiles, which can coordinate to a transition metal, provides an opportunity to control the orientation of a prochiral enolate (Eq. 8E, 19). With a-cyanoesters as substrate,... 

The Gewald Reaction is a synthesis of 2-aminothiophenes via a multi-component condensation between sulfur, an a-methylene carbonyl compound and an a-cyanoester. 

The reaction of 3-phenoxybenzaldehyde (351), sodium cyanide, and acyl halides 352 in the presence of DBU hydrochloride in aqueous heptane resulted in a-cyanoesters 353 in 99% yield (80MIP6222 81USP4254052 82USP4323685). 

In an alternative procedure, the ketones 10 can be cyclised to 2-aminofurans 1 under acidic conditions. For example, phenacylmalononitrile 10 (R1 = Ph, R2 = H, R3 = CN) cyclised in hot AcOH/concentrated HC1 (89JPC31) and further examples have been prepared by this method as synthetic intermediates (04BMCL3907). A similar cyclisation of a cyanoester has been achieved using AcOH/concentrated H2S04, but the 2-aminofuran was accompanied by some 2-hydroxyfuran (90JPC479). Phenacylmalononitrile has also been cyclised to 2-amino-3-cyano-5-phenylfuran (1 R1 = Ph, R2 = H, R3 = CN) by a primary alkylamine and a catalytic amount of concentrated HC1, but it should be noted that similar conditions using aromatic amines led to l-aryl-2-aminopyrroles (89LA1145). 

In a series of outstanding papers, Pinhey et al have shown that aryllead tricarboxylates react with soft nucleophiles to afford C-arylation products. These aryllead derivatives behave as aryl cation equivalents in reactions which involve a ligand coupling mechanism (see section 7.5).9 2 ju most cases, the reactions proceed in chloroform at 40-60 C in the presence of pyridine as a base with a ratio of substrate to organolead derivative to pyridine of 1 1 3. The substrates which easily undergo C-arylation include phenols, p-dicarbonyl compounds and their vinylogues, a-cyanoesters, a-hetero-substituted ketones, enamines and nitroalkanes. A very limited number of non-carbon nucleophiles has also been reported to react. 

Reduction of cyano groups under radical conditions is carried out employing tin hydrides such as /-IJu3SnH.286 Unfortunately, the reaction is so far restricted to malonitriles. Samarium iodide is a valid alternative to tin hydrides since in the presence of HMPA it promotes the reductive decyanation of malononitriles and a-cyanoesters in high yields (Eq. 165).287 -289... 

The Krapcho decarboxylation is the nucleophilic decarboxylation of malonate esters, p-ketoesters, a-cyanoesters, a-sulfonylesters, and related compounds. The reaction is done in dipolar aprotic solvents in the presence of salt and/or water at high temperatures.1... 

Several reviews have been written which cover the history of the Krapcho reaction through 1982.1,4 Further research in this area revealed the application of the decarboxylation method to compounds such as P-ketoesters, malonate esters, a-cyanoester, and a-sulfonylesters. The classical method for decarboxylation of these compounds usually involves acidic or basic hydrolysis, followed by thermal decarboxylation. Unfortunately, compounds containing acid or base sensitive functional groups are not compatible with these methods. Modem Krapcho conditions have replaced cyanide with less toxic halide anions. Additionally, several decarboxylations have occurred in the absence of salt.4... 

G) Under the influence of alkali, the ester will be hydrolyzed to a carboxylate salt. This in turn can be easily decarboxylated due to the fact that it is both an a-cyanoester and a vinylogous -ketoester. (The carbonyl group has its influence extended by the double bond.) Water then donates a proton to neutralize the negative charge. 

Recent applications of the dealkoxycarbonylation reactions of malonate esters, p-keto esters, a-cyanoesters, and related analogs including preparation and participation of heterocydes 07ARK(2)1,07ARK(2)54. 

The scope of Pd-catalyzed a-arylation of enolates has been further expanded so as to include amides,malononitrile, a-cyanoesters, ° a-cyanophosphates, and a-cyanosulfones. " The metal countercations in these reactions are mostly alkali metals, such as Li, Na, K, and Cs. Some representative examples of these reactions are shown in Scheme 13. The Pd-catalyzed reaction of 2-methyl-l-propenyl chloride with NaCH(COOMe)2 in the presence of 2 mol% of Me2Pd(dcypb), where dcypb is Cy2P(CH2)3PCy2, led to 2-methylallylationf i (Scheme 14). 

In the same paper, the Michael addition of a-aryl substituted a-cyanoesters to acrolein was also studied, also obtaining excellent yields and enantioselec-tivities for a variety of different Michael donors (Scheme 4.38). Remarkably, the structure of the catalyst needed additional optimization for achieving the best results, which were obtained by modifying the substituent at the secondary OH group of the central cinchonine framework from 9-phenanthryl to the more sterically demanding 6-chloro-2,5-diphenylpyrimidin-4-yl group. This new catalyst 83f showed a very good performance in this reaction. 

Scheme 4.38 Enantioselective Michael addition of a-alkyl a-cyanoesters to acrolein.

Nucleophilic decarboxylation of p-ketoesters, malonate esters, a-cyanoesters, or a-sulfonylesters. 

Other activated methylene-containing nucleophiles that have been successfully used in the conjugate addition to nitrooleflns are a-nitroesters [240], a-cyanoesters [240], a-isocyanoesters [259], 2-hydroxy-1,4-naphthoquinones [260], 3-substituted oxindoles [261], and anthrone [262]. For instance, cupreidine-derived catalysts 151 and 152 (see Fig. 2.15) afford very good yields, diastereo- and enantioselectivities... 

An interesting two-catalyst system has been developed for the highly enantioselective aUylation of a-cyanoesters. The allyl carbonate 143 reacts with the nucleophile 144 to give the substitution product 145 with up to a remarkable 99% ee (Scheme 31). The nucleophile 144 is activated to deprotonation by the rhodium catalyst, which also seems to be responsible for the control of enantioselectivity. However, in the absence of a palladium catalyst, the allyl carbonate 143 is inert. 

A variety of a, -unsaturated a-cyanoesters have been chemoselectively reduced with potassium formate in the presence of catalytic quantities of Pd(OAc)2. No reduction of cyano, car-boxylate and halogen groups is observed under these conditions (eq 129). 3 ... 

Scheme 34.36 Addition of a-cyanoesters to vinyl selenone 99 and postfiinctionalizations.

The second strategy to achieve the asymmetric protonation of double bonds through a conjugate addition is based on the use of a chiral proton source. This last strategy mainly focuses on the use of organocatalysts. This concept introduced by Pracejus et al. in 1977 in the course of thia-Michael addition to acceptor 98, mainly uses protic nucleophiles with low pKa such as thiol, a-ketoester, a-cyanoester, or secondary phosphine oxyde. ... 

---