SN2-alkylation

The Sn2 alkylation reaction between an enolate ion and an alkyl halide is a powerful method for making C-C bonds, thereby building up larger molecules from smaller precursors. We ll study the alkylation of many kinds of carbonyl compounds in Chapter 22. 

Alpha hydrogen atoms of carbonyl compounds are weakly acidic and can be removed by strong bases, such as lithium diisopropylamide (LDA), to yield nucleophilic enolate ions. The most important reaction of enolate ions is their Sn2 alkylation with alkyl halides. The malonic ester synthesis converts an alkyl halide into a carboxylic acid with the addition of two carbon atoms. Similarly, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone. In addition, many carbonyl compounds, including ketones, esters, and nitriles, can be directly alkylated by treatment with LDA and an alkyl halide. 

Ammonia and other amines are good nucleophiles in SN2 reactions. As a result, the simplest method of alkylamine synthesis is by Sn2 alkylation of ammonia or an alkylamine with an alky) halide. If ammonia is used, a primary amine results if a primary amine is used, a secondary amine results and so on. Even tertiary amines react rapidly with alkyl halides to yield quaternary ammonium salts, R4N+ X-... 

While a large number of studies have been reported for conjugate addition and Sn2 alkylation reactions, the mechanisms of many important organocopper-promoted reactions have not been discussed. These include substitution on sp carbons, acylation with acyl halides [168], additions to carbonyl compounds, oxidative couplings [169], nucleophilic opening of electrophilic cyclopropanes [170], and the Kocienski reaction [171]. The chemistry of organocopper(II) species has rarely been studied experimentally [172-174], nor theoretically, save for some trapping experiments on the reaction of alkyl radicals with Cu(I) species in aqueous solution [175]. 

Although acetylene carbocupration and conjugate addition have previously been considered to be two separate reactions, they have been shown to share essentially the same reaction mechanism. The kinship of carbocupration, conjugate addition, Sn2 allylation, and Sn2 alkylation has now been established, through the theoretical studies of Nakamura, Mori, and Morokuma. 

A simple Sn2 alkylation reaction serves as example. As we have already seen, treating cyclohexanone with LDA gives the enolate anion, which can then be allowed to react with methyl iodide to give 2-methylcyclohexanone. 

The course of the alkylation was investigated in detail by Markl and Merz It was found that alkyl iodides attack by an SnI mechanism, primarily at the phosphorus, to form 144, while oxonium salts prefer the C—2 position. Nonpolar solvents favor SN2-alkylation at C—2 to 145. The X -phosphorins 144 are thermodynamically more stable than the isomeric 1,2-dihydro-X -phosphorins... 

Bicyclic keto esters can easily be prepared by a process called a,a -annulation.29 Thus, treatment of the enamine of cyclopentanone (64) with ethyl a-(bromomethyl)acrylate (98) affords, after work-up, the bicyclic keto ester (99) in 80% yield (equation IS).2911 The mechanism probably involves an initial Michael addition and elimination (or a simple Sn2 or Sn2 alkylation) followed by an intramolecular Michael addition of the less-substituted enamine on the acrylate unit. The use of the enamine of 4,4-bis(ethoxycarbonyl)cyclohexanone (100 equation 26) with (98) gives a 45% yield of the adaman-tanedione diester (101) (yield based on 100 70% when based on 98) via a,a -annulation followed by Dieckmann condensation.29 Enamines of heterocyclic ketones can also serve as the initial nucleophiles, e.g. (102) and (103) give (105) via (104), formed in situ, in 70% yield (Scheme 11 ).29>... 

Affinity Labels. Active site-directed, irreversible inhibitors or affinity labels are usually substrate analogues that contain a reactive electrophilic functional group. In the first step, they bind to the active site of the target enzyme in a reversible fashion. Subsequendy, an active site nucleophile in dose proximity reacts with the electrophilic group on the substrate to form a covalent bond between the enzyme and the inhibitor, typically via SN2 alkylation or acylation. Affinity labels do not require activation by the catalysis of the enzyme, as in the case of a mechanism-based inhibitor. 

Valsartan (Diovan, 13.35), a medication for high blood pressure, is a single enantiomer drug. The stereocenter in valsartan is derived from L-valine (13.33) and incorporated early in the synthesis by a simple SN2 alkylation (Scheme 13.5).15... 

Amines can be prepared by SN2 alkylation of ammonia or 1° and 2° amines. Aromatic amines are made by reduction of the corresponding nitro compounds. Amides, nitriles, and imines can also be reduced to amines. 

The simplest solvent-free method involves irradiation of neat reactants as interfacial reactions in an open container, either in a domestic oven or in a monomode reactor [34,55]. In the absence of reagents or supports, the scope for such processes appears to be limited to relatively straightforward condensations that can be conducted without added catalysts, to nucleophilic additions, Sn2 alkylations using neutral nucleophiles as amines or phosphines or to intramolecular thermolytic processes such as rearrangement or elimination. 

The thio-Claisen rearrangement can also be performed with secondary thioamides, providing allylation on the nitrogen atom rather than carbon atom. An elaborate example was reported by Fuchs and Smith [183]. They introduced an allyl ammonium salt to achieve SN2 alkylation of sulfur, and the product readily rearranged to furnish the expected thiolactam. However they finally preferred to employ in the first step an allyl mesylate, which was more easily synthesised. 

Thus Sn2 alkylation occurs on the carbon atom, whereas a-chloroethers, well known to react by an SnI mechanism, undergo O-alkylation as predicted by the SHAB principle. Both reactions are kinetically controlled, and bond formation is not far advanced in the transition state. Acylating agents (which have a hard electrophilic carbon atom) however, give the C-acylated product in the Claisen condensation. 

Similarly, the reactivity of phenolate ions as the tetra- -butylammonium salt has been shown to be 3 10" times higher than that of the corresponding potassium salt in the Sn2 alkylation reaction with 1-halobutanes, carried out in 1,4-dioxane [340], Whereas the rate of alkylation of the potassium salt increases by a factor of ca. 10 on going from 1,4-dioxane (fir = 2.2) to iV,iV-dimethylformamide (e, = 36.7), the alkylation rate of the quaternary phenolate is essentially insensitive to the same solvent change. Obviously, the phenolate ion combined with the larger ammonium ion is already very reactive because of the relatively weak cation-anion interaction in the ion pair. In such cases, dissociation to a truly free anion does not seem to be required in order to explain the high reactivity [340]. 

The effect of both podands and coronands on the Sn2 alkylation of potassium phenolate with 1-bromobutane in 1,4-dioxane s = 2.2) has been investigated by Ugel-... 

Only two examples will be mentioned here in more detail. The Sn2 alkylation reaction of ambident potassium 2-naphtholate (2-naphthol -I- KOH) with 1-bromobutane in [BMIM]+PF6 at room temperature proceeds at a similar rate as observed in dipolar aprotic solvents such as DMF or DMSO, to regioselectively afford 1-butyl 2-naphthyl ether in 98 cmol/mol isolated yield (0/C alkylation ratio > 99 1) [899]. In contrast to the reaction in dipolar aprotic solvents, which are difficult to remove from the product, the ether product can be simply extracted into an organic solvent such as toluene, leaving the ionic liquid behind. The by-product (potassium bromide) of the reaction can be extracted with water, and the ionic liquid can be used again. 

Fig. 7-1. Flammett correlation between ir-values and the logarithms of the relative rate constants of the Sn2 alkylation reaction of substituted pyridinium iV-phenolate betaines with iodomethane in trichloro-methane at 25 °C [16].

The attachment of a C5-side chain by SN2-alkylation at the intended benzylic position with the protected ketoester 139 as the nucleophile proceeded reliably and in good yield to form the alkylated ketoester 140 [86]. The second chain could also be coupled very efficiently by reacting the vinylic bromide 140 in a palladium-catalyzed Stille reaction [106] (review [107]) with the allyl tin compound 141 to afford the dialkylated naphthoquinone 142 (Scheme 36). Halonaphthoquinones have previously been coupled in a palladium/copper-catalyzed reaction by Echavarren et al. [108]. 

Monoalkylcopper complexes preferentially give Sn2 alkylation of allylic substrates [see Eq. (27)], whereas dialkylcuprates favor S s,2 with primary allylic substrates [47,48]. Consequently, if the Grignard reagent is added slowly or ki>k2, the monoalkylcopper species 92 will predominate, and the major compound will be the Sn2 product (higher temperature, more catalyst, and a substrate reacting rapidly with 92 will increase the 8 2 product). 

---