Alkyl synthons

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. 

It is beyond the scope of this review to describe in details the synthesis of the protected (o-functionalized alkyl synthons 29, 33, 37, 41, 44 (Schemes 18-22). For these details the reader should consult the original literature. 

Michael addition is one of the most efficient and effective routes to C-C bond formation[127]. This reaction is widely applied in organic synthesis and several new versions of it have been introduced recently. The commonly employed anionic alkyl synthons for Michael addition are those derived from nitroalkanes, ethyl cyanocarboxylates, and malonates, and their limitations have been largely overcome by newer methodologies. However, the newer approaches are by no means devoid of drawbacks such as long reaction times, modest product yields in many cases, and the requirement for excess nitroalkane. Michael addition reactions of Schiff s bases have long been known to constitute a convenient method for functionalizing a-amino esters at the a position and the ratio of Michael addition to cycloaddition product has been found to depend upon the metal ion employed to chelate the enolate produced upon deprotonation (see below). 

You can see how the alkyl-lithium acts as tlie synthon CH3CH2 since the carbon-lithium bond breaks so that the electrons go with the carbon atom. Suggest a disconnection for TM 16. 

The formation of the above anions ("enolate type) depend on equilibria between the carbon compounds, the base, and the solvent. To ensure a substantial concentration of the anionic synthons in solution the pA" of both the conjugated acid of the base and of the solvent must be higher than the pAT -value of the carbon compound. Alkali hydroxides in water (p/T, 16), alkoxides in the corresponding alcohols (pAT, 20), sodium amide in liquid ammonia (pATj 35), dimsyl sodium in dimethyl sulfoxide (pAT, = 35), sodium hydride, lithium amides, or lithium alkyls in ether or hydrocarbon solvents (pAT, > 40) are common combinations used in synthesis. Sometimes the bases (e.g. methoxides, amides, lithium alkyls) react as nucleophiles, in other words they do not abstract a proton, but their anion undergoes addition and substitution reactions with the carbon compound. If such is the case, sterically hindered bases are employed. A few examples are given below (H.O. House, 1972 I. Kuwajima, 1976). 

Alkyl halides and sulfonates are the most frequently used alkylating acceptor synthons. The carbonyl group is used as the classical a -synthon. O-Silylated hemithioacetals (T.H. Chan, 1976) and fomic acid orthoesters are examples for less common a -synthons. In most synthetic reactions carbon atoms with a partial positive charge (= positively polarized carbon) are involved. More reactive, "free carbocations as occurring in Friedel-Crafts type alkylations and acylations are of comparably limited synthetic value, because they tend to react non-selectively. 

If boranes (K. Utimoto, 1973 H.C. Brown, 1975, 1980 A. Pelter, 1979) are used as donor synthons for the alkylation of a, -unsatarated carbonyl compounds, no enolate anion is formed, and the, 8-position of the C=C bond is the only reaction site. 

The only common synthons for alkynes are acetylide anions, which react as good nucleophiles with alkyl bromides (D.E. Ames, 1968) or carbonyl compounds (p. 52, 62f.). 

In the synthesis of molecules without functional groups the application of the usual polar synthetic reactions may be cumbersome, since the final elimination of hetero atoms can be difficult. Two solutions for this problem have been given in the previous sections, namely alkylation with nucleophilic carbanions and alkenylation with ylides. Another direct approach is to combine radical synthons in a non-polar reaction. Carbon radicals are. however, inherently short-lived and tend to undergo complex secondary reactions. Escheirmoser s principle (p. 34f) again provides a way out. If one connects both carbon atoms via a metal atom which (i) forms and stabilizes the carbon radicals and (ii) can be easily eliminated, the intermolecular reaction is made intramolecular, and good yields may be obtained. 

The reactions described so far can be considered as alkylation, alkenylation, or alkynylation reactions. In principle all polar reactions in syntheses, which produce monofunctional carbon compounds, proceed in the same way a carbanion reacts with an electropositive carbon atom, and the activating groups (e.g. metals, boron, phosphorus) of the carbanion are lost in the work-up procedures. We now turn to reactions, in which the hetero atoms of both the acceptor and donor synthons are kept in a difunctional reaction produa. 

The 1,6-difunctional hydroxyketone given below contains an octyl chain at the keto group and two chiral centers at C-2 and C-3 (G. Magnusson, 1977). In the first step of the antithesis of this molecule it is best to disconnect the octyl chain and to transform the chiral residue into a cyclic synthon simultaneously. Since we know that ketones can be produced from add derivatives by alkylation (see p. 45ff,), an obvious precursor would be a seven-membered lactone ring, which is opened in synthesis by octyl anion at low temperature. The lactone in turn can be transformed into cis-2,3-dimethyicyclohexanone, which is available by FGI from (2,3-cis)-2,3-dimethylcyclohexanol. The latter can be separated from the commercial ds-trans mixture, e.g. by distillation or chromatography. 

An important method for construction of functionalized 3-alkyl substituents involves introduction of a nucleophilic carbon synthon by displacement of an a-substituent. This corresponds to formation of a benzylic bond but the ability of the indole ring to act as an electron donor strongly influences the reaction pattern. Under many conditions displacement takes place by an elimination-addition sequence[l]. Substituents that are normally poor leaving groups, e.g. alkoxy or dialkylamino, exhibit a convenient level of reactivity. Conversely, the 3-(halomethyl)indoles are too reactive to be synthetically useful unless stabilized by a ring EW substituent. 3-(Dimethylaminomethyl)indoles (gramine derivatives) prepared by Mannich reactions or the derived quaternary salts are often the preferred starting material for the nucleophilic substitution reactions. 

Reactions of carbon nucleophiles with organohalogen compounds have great diversity for the construction of now carbon-carbon bonds. The intriguing synthon, ethoxyethynylsodium, is generated and alkylated in 1-ETHOXY-1-BUTANE. Following an alkylation of propynylsodium, a vinyl halide is generated in a stereoselective manner... 

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