Acyl anions cyanohydrin-derived

Acyl anion synthons derived from cyanohydrins may be generated catalytically by cyanide ion via the Stetter reaction " However, further reaction with electrophiles is confined to carbonyl compounds and Michael acceptors. 

Nucleophilic additions of inorganic anions to carbonyl groups also proceed efficiently under PTC conditions. Syntheses of acyl azides, acyl cyanides, cyanohydrin derivatives, and the Reissert compounds belong to this category of reactions ... 

Meyers, A. I. Heterocycles in Organic Synthesis Wiley-Interscience, 1974 (332 pages). DegITnnocenti, A. Pollicino, S. Capperucci, A. Synthesis and Stereoselective Functionalization of Silylated Heterocycles as a New Class of Formyl Anion Equivalents Chemical Communications 2006, 4881—4893. Yus, M. Najera, C. Foubelo, F. The Role of 1,3-Dithianes in Natural Product Synthesis Tetrahedron 2003, 59, 6147-6212. Albright, J. D. Reactions of Acyl Anion Equivalents Derived from Cyanohydrins, Protected Cyanohydrins and a-Dialkylaminonitriles Tetrahedron 1983, 39, 3207-3233. Seebach, D. Corey, E. J. Generation and Synthetic Applications of 2-Lithio-l,3-dithianes /. Orpi. Chem. 1975, 40, 231-237. 

Albright, J. D. Reactions of Acyl Anion Equivalents Derived from Cyanohydrins, Protected Cyanohydrins and a-Dialkylaminonitriles Tetrcthedron 1983, 59, 3207-3233. 

Cyanohydrin derivatives have also been widely used as acyl anion synthons. They are prepared from carbonyl compounds by addition of hydrogen cyanide. A very useful variant is to use trimethylsilyl cyanide with an aldehyde to produce a trimethylsilyloxy cyanide. The cyano group acidifies the a position (pKA 25) and the a proton can be removed by a strong base. Alkylation of the anion and unmasking of the hydroxy group cause elimination of cyanide and re-formation of the carbonyl group. 

In 1971 Stork and Maldonado214 showed that anions derived from 0-pro tec ted cyanohydrins of aldehydes could be efficiently metallated and the resultant anions could serve as synthetically useful acyl anion equivalents. Other develop-... 

Addition of acyl anion equivalents (propenal d reagents) to ketones provides general access to a -hy-droxy enones. In an application of this method to pentaimulation, the trimethylsilyl- or ethoxyethyl-pro-tected cyanohydrins of a, -enals were used." The derived tertiary acetates undergo elimination (p-TsOH/benzene) to the divinyl ketones which cyclize in the acidic reaction medium (equation 25)." In some cases the a -hydroxy or a -silyloxy enones underwent cyclization but in much lower yields. Substitution in the ring and on the double bonds is compatible. 

The mechanism of the benzoin condensation, as depicted in Scheme 1, suggested that anions derived from a protected aldehyde cyanohydrin should function as nucleophilic acylating reagents. The use of protected cyanohydrins as carbanion equivalents has been studied by Stork and by Hunig and has found wide applicability in chemical synthesis. Such species may serve as either acyl anion equivalents or homoenolate anions. ... 

Trimethylsiloxy cyanohydrins (9) derived from an a,3-unsaturatied aldehyde form ambident anions (9a) on deprotonation. The latter can react with electrophiles at the a-position as an acyl anion equivalent (at -78 C) or at the -y-position as a homoenolate equivalent (at 0 C). The lithium salt of (9) reacts exclusively at the a-position with aldehydes and ketones. The initial kinetic product (10) formed at -78 C undergoes an intramolecular 1,4-silyl rearrangement at higher temperature to give (11). Thus the initial kinetic product is trapped and only products resulting from a-attack are observed (see Scheme 11). The a-hydroxyenones (12), -y-lactones (13) and a-trimethylsiloxyenones (11) formed are useful precursors to cyclopentenones and the overall reaction sequence constitutes a three-carbon annelation procedure. 

Acid-catalyzed addition of aliphatic, aromatic or heteroaromatic cyanohydrins to ethyl vinyl ether, n-butyl vinyl ether or dihydro-4//-pyran provides base stable, protected cyanohydrin derivatives. Phase transfer catalyzed alkylation of aliphatic cyanohydrins with allylic bromides gave a-substituted a-allyl-oxyacetonitrile. Carbonyl compounds react wiA cyanide under phase transfer catalysis to give cyanohydrin anions, which are trapped by an acyl chloride or ethyl chloroformate to give acyl- or alkoxycarbonyl-protected cyanohydrins respectively. The reduction of the carbonyl group of an acyl cyanide by NaBH4 under phase transfer conditions followed by esterification serves as an alternative route to aldehyde-derived cyanohydrin esters. ... 

A system analogous to a cyanohydrin is a siloxyalkylphosphonate. Thus, the diethyl 1-phenyl-1-tri-methylsiloxymethylphosphonate carbanion derived from (61) on treatment with LDA acts as an effective acyl anion equivalent in the preparation of a-hydroxy ketones and ketones. The phosphonate (61) is formed from triethyl phosphite, benzaldehyde and TMS-Cl in excellent yield. 

Acyl Anions Derived from (9-Protected cyanohydrins contain a masked carbonyl group with inverted polarity. 

A number of methods for the generation of acyl anion equivalents from aldehydes have been developed. Related to the benzoin condensation, aldehyde cyanohydrins, protected as their ether derivatives, are readily transformed into anions by treatment with lithium diisopropylamide (LDA). Reaction with an alkyl halide gives the protected cyanohydrin of a ketone from which the ketone is liberated easily. Reaction with an aldehyde or ketone leads to the formation of an a-hydroxy ketone (1.109). ... 

Another modification of the cyanohydrin approach involves the use of anions derived from arylacetonitriles after alkylation the substituted nitriles can be oxidized to the cyanohydrin derivatives, which can be deprotected to give ketones. An example of the application of this approach for nucleophilic Michael-type acylation of a/3-unsaturated esters is shown in Scheme 3. ... 

Silyl ketene imines 21.126 (Scheme 21.18) developed by Denmark represent another group of useful nucleophilic reagents. These compounds are derived from protected cyanohydrins and thus can be viewed as acyl anion equivalents. They allow enantio- and diastereoselective construction of highly functionalised adducts 21.127, which can be further converted into useful synthetic intermediates, e.g. upon hydrolysis they produce crossbenzoin condensation products 21.128. ... 

Various versions of the acyl anion equivalent (32) are described by Stork etal. (use of Et2NCH2CN), Krief and co-workers (1,3-dithianes in regioselective Michael addition), Gokel et al. (use of sulphur heterocycles with thermal deblocking), Cohen and Weisenfeld" (conversion of acids into vinyl sulphides), Meyers and Campbell " (acetals derived from aryl aldehydes), and Hunig and co-workers (cyanohydrin derivatives of aryl aldehydes). 

An interesting extension of this method involves the reaction of Af-silyl oxyketene imines derived from cyanohydrins (Scheme 19) [81]. By judicious selection of the protecting group on the oxygen, highly functionalized (3-hydroxy cyanohydrins can be accessed with high levels of enantio- and diastereoselectivity. These products can then be transformed into a diversity of structural motifs (amines, aldehydes, imines, ketones) important for the synthesis of polyketide and other classes of natural products. In addition, the ethers can be easily converted to enantiomerically enriched unsymmetrical benzoins, thus revealing the synthetic equivalency of A-silyl oxyketene imines as acyl anions (Scheme 19). 

Furthermore, N-silyl oxyketene imines derived from protected cyanohydrins were found to serve as acyl anion equivalents in a similar reaction manifold, enabling the efficient preparation of cross-benzoin and glycolate-aldol products in an almost stereochemically pure form (Scheme 7.11) [18]. 

While the addition-oxidation and the addition-protonation procedures are successful with ester enol-ates as well as more reactive carbon nucleophiles, the addition-acylation procedure requires more reactive anions and the addition of a polar aptotic solvent (HMPA has been used) to disfavor reversal of anion addition. Under these conditions, cyano-stabilized anions and ester enolates fail (simple alkylation of the carbanion) but cyanohydrin acetal anions are successful. The addition of the cyanohydrin acetal anion (71) to [(l,4-dimethoxynaphthalene)Cr(CO)3] occurs by kinetic control at C-P in THF-HMPA and leads to the a,p-diacetyl derivative (72) after methyl iodide addition, and hydrolysis of the cyanohydrin acetal (equation 50).84,124-126... 

An interesting development in the lithiated cyanohydrin ether approach to acyl carbanion equivalents involves the [2,3] sigmatropic rearrangement of the anions derived from allyl- or propargyl-cyanohydrin ethers/ Scheme 2 shows an example of the application of this process in the synthesis of y-dicarbonyl compounds or their monoenol ethers. ... 

Protected cyanohydrin anions also behave as acyl carbanion equivalents, and this method can be extended to aj3-unsaturated derivatives (5). The reaction of yet another type of acyl carbanion equivalent (6) with esters gives products of type (7), which are useful for the synthesis of novel heterocyclic compounds. Species of type (8 Y = 0,S), are further modified acyl carbanion equivalents, and behave towards carbonyl compounds as synthetic equivalents of the Wittig reagents PhaP = C(YR)CHO. Compounds (9) are j8-acylvinyl anion equivalents. ... 

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