Alkylating and d-Synthons

Carbanions are negatively charged organic species with an even number of electrons and the charge mainly concentrated on a carbon atom. In alkyl, alkenyl, and alkynyl anions all of the 

A saturated alkyl group does not exhibit functionality. It is not a d -synthon, because the functional groups, e.g. halide or metal ions, are lost in the course of the reaction. It functions as an alkyl synthon. Alkenyl anions (R. West, 1961) on the other hand, constitute d -synthons, because the C = C group remains in the product and may be subject to further synthetic operations. 

Alkynyl anions are more stable = 22) than the more saturated alkyl or alkenyl anions (p/Tj = 40-45). They may be obtained directly from terminal acetylenes by treatment with strong base, e.g. sodium amide (pA, of NH 35). Frequently magnesium acetylides are made in proton-metal exchange reactions with more reactive Grignard reagents. Copper and mercury acetylides are formed directly from the corresponding metal acetates and acetylenes under neutral conditions (G.E. Coates, 1977 R.P. Houghton, 1979). 

Fieser, Reagents for Organic Synthesis, Vol 1, Wiley, N.Y., 1967 or standard textbooks. 

There exist a number of d -synthons, which are stabilized by the delocalization of the electron pair into orbitals of hetero atoms, although the nucleophilic centre remains at the carbon atom. From nitroalkanes anions may be formed in aqueous solutions (e.g. CHjNOj pK, = 10.2). Nitromethane and -ethane anions are particularly useful in synthesis. The cyanide anion is also a classical d -synthon (HCN pK = 9.1). 

More recent developments tire based on the finding, that the d-orbitals of silicon, sulfur, phosphorus and certain transition metals may also stabilize a negative charge on a carbon atom. This is probably caused by a partial transfer of electron density from the carbanion into empty low-energy d-orbitals of the hetero atom ( backbonding ) or by the formation of ylides , in which a positively charged onium centre is adjacent to the carbanion and stabilization occurs by ylene formation. 

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The metalation of vinyl ethers, the reaction of a-lithiated vinyl ethers obtained thereby with electrophiles and the subsequent hydrolysis represent a simple and efficient method for carbonyl umpolung. Thus, lithiated methyl vinyl ether 56 and ethyl vinyl ether 54, available by deprotonation with t- or n-butyllithium, readily react with aldehydes, ketones and alkyl halides. When the enol ether moiety of the adducts formed in this way is submitted to an acid hydrolysis, methyl ketones are obtained as shown in equations 72 and 73 . Thus, the lithiated ethers 56 and 54 function as an acetaldehyde d synthon 177. The reactivity of a-metalated vinyl ethers has been reviewed recently . 

A good equivalent for the ester enolate d synthon is a P-dicarbonyl compound, because it can easily be disconnected to diethyl malonate and an alkylating agent, thromboxane antagonist intermediate synthesis... 

Disconnections (a), (b), and (d) in Table 10.1 all require reagents for the carbanion synthon R. Simple carbanions are almost never formed in reactions so we shall need reagents in which carbon is joined to a more electropositive atom such as a metal. The most popular are Li and Mg. Bnty lithium (BuLi) is commercially available and other alkyl lithiums can be made from it by exchange (i). Otignard reagents (2) arc usually made directly from alkyl halides and magnesium metal (iii)—a method also available for RIJ (ii). These methods are available for aryl compounds too. Transformation of RHal into RIa or RNfgBr involves a formal inversion of polarity. 

Stoichiometric redox-umpolung becomes possible when the electron transfer process is faster than any coupling step, i.e., when the tendency of both the a- and the d-synthon for coupling is low. A classical example of such a situation is Grignard formation from alkyl or aryl halides, where the coupling product is generally formed only as a minor side product (Scheme 2.17). 

Alkyl-substituted allylmetals 1 usually cover the synthon A. Since oxidative cleavage of the C-C double bond in the products formed can be readily achieved, such reagents are often used as equivalents for the appropriate cnolatc synthons B and C or /1-hydroxycarbonyl anions D. Subsequent hydroboration extends their scope on y-hydroxyalkyl anions E. 

A sequence in which a carbonyl group has been masked as a sulfur derivative, alkylated with an electrophile, and then revealed again is a nucleophilic ac)4ation. These nucleophilic equivalents of carbonyl compoxmds are known as acyl anion equivalents. In the retrosynthetic terms of Chapter 30 they are d reagents corresponding to the acyl anion synthon. 

Furthermore, several syntheses of a,p-unsaturated carbonyl compounds have involved the alkylation of suitably functionalized sulfones, followed by the base-promoted elimination of the sulfenate moiety on related alkyl sulfones bearing an oxygen atom at the -y-position (Scheme 106, entries b-d Scheme 110, entry c Scheme 105, entry b). - 46i Particularly interesting is the synthesis of nuciferal (Scheme 106, entry d) which involves sequential alkylation of y,-y-dioxy sulfones, deblocking of the acetal moiety and sulfenate elimination. In this and related reactions y, y-dioxy-a-metalloalkyl sulfone has played the role of a masked p-metallo-a,p-unsaturated carbonyl compound (M(>aC—C—C=0), which is not a directly available synthon. 

Multifunctional carbohydrate derivatives have been used widely as chiral synthons [240], and they have more recently found application as chiral auxiliaries [241], In this chapter, examples of carbohydrates in which an alcohol functional group is the point of attachment to the reagent wall be presented. Alkylations of ester etiolates of the D-allofiiranose derivative 1.47 or of the diacetoneghicose... 

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