Alkyl halides silyl enol ethers

Enamines are among the most powerful neutral nucleophiles and react spontaneously with alkyl halides. Silyl enol ethers are less reactive and so require a more potent electrophile to initiate reaction. Carbocations will do, and they can be generated in situ by abstraction of a halide or other leaving group from a saturated carbon centre by a Lewis acid. 

Further refinements to the alkylation of silyl enol ethers have appeared. Ketones can be alkylated at the a-position by treatment of their silyl enol ethers with tertiary alkyl halides in the presence of Lewis acids such as titanium tetrachloride or tin tetrachloride.a-Cumylation of ketones is possible using catalytic quantities of mild Lewis acids such as zinc chloride. The method can be used to couple two tertiary centres. 

Activation of C-X Bonds. Even more important than carbonyl activation, ZnBr promotes substitution reactions with suitably active organic halides with a variety of nucleophiles. Alkylation of silyl enol ethers and silyl ketene acetals using benzyl and allyl halides proceeds smoothly (eq 13). Especially useful electrophiles are a-thio halides which afford products that may be desulfurized or oxidatively eliminated to result in a,p-unsaturated ketones, esters, and lactones (eq 14). Other electrophiles that have been used with these alkenic nucleophiles include Chloromethyl Methyl Ether, HC(OMe)3, and Acetyl Chloride... 

Silyl enol ethers and silyl ketene acetals also offer both enhanced reactivity and a favorable termination step. Electrophilic attack is followed by desilylation to give an a-substituted carbonyl compound. The carbocations can be generated from tertiary chlorides and a Lewis acid, such as TiCl4. This reaction provides a method for introducing tertiary alkyl groups a to a carbonyl, a transformation that cannot be achieved by base-catalyzed alkylation because of the strong tendency for tertiary halides to undergo elimination. 

All alkyl halides used in the couplings were primary, although some of them were branched or had an ester functionality. Some of the dialkylzincs had a functional group without affecting the outcome of the reaction. For example, organozinc derivative 302 with a silyl enol ether group reacted with alkyl iodide 303, affording the desired product 304 in 65% yield (Scheme 153). 

The best alkylating agents for silyl enol ethers are tertiary alkyl halides they form stable carbocations in the presence of Lewis acids such as TiCLj or SnCLj. Most fortunately, this is just the type of compounds that is unsuitable for reaction with lithium enolates or enamines, as elimination results rather than alkylation a nice piece of complementary selectivity. 

Silyl enol ethers of aldehydes or ketones can be used with 1 -reactive (tertiary, allylic or benzylic) alkyl halides... 

The copper-mediated 1,4-addition of alkyl groups to a,P-unsaturated ketones affords regiochemically pure enolate anions (see also Section 7.5) which may be trapped at oxygen with silyl halides, acyl halides, or dialkylcarbonates to provide silyl enol ethers, enol acetates, or enol carbonates, respectively. These can be unmasked at a later stage by reaction with MeLi to regenerate the enolate for further elaboration. ... 

Silyl enol ethers 64 need Lewis acid catalysis which generates at least a partial positive charge on the alkyl group so they react best with tertiary, allylic, and benzylic halides, and reasonably... 

Alkylation with tertiary halides is the special preserve of silyl enol ethers. Both the familiar isomers 22 and 25 give regiospecific alkylation in good yield with Lewis acid catalysis.23 The formation of 78 is remarkable as it puts two quaternary centres next to one another. 

It is more difficult to make alkylation reversible but Fleming and Paterson achieved this by using a PhS group to stabilise even a primary cation.21 An alkyl halide is converted into a sulfide 62 and then mto a chlorosulfide 63 with iV-chlorosuccinnimide (NCS) by the Pummerer reaction. These compounds 63 react with Fewis acids to give sulfur-stabilised cations that react in the y-position 64 with silyl enol ethers 65 to give 66. 

An indirect method for obtaining 1-dialkoxyphosphinyl-l-trimethylsilyoxyvinylphos-phonates is through the addition of dialkyl trimethylsilyl phosphite to a,jS-unsaturated aldehydes. When the initial j, 7-unsaturated phosphonates were treated with lithium diisopropylamide (Ida) followed by an electrophile such as an alkyl halide, acyl halide or aldehyde, the corresponding y-substituted silyl enol ethers resulted (equation 90) ... 

In addition to their use for the preparation of specific Uthium enolates, silyl enol ethers are also excellent substrates for actrf-catalysed alkylation. In the presence of a Lewis acid (e.g. TICU, SnCU, BF3 OEt2> they react readily with tertiary alkyl halides to give the alkylated product in high yield. This procedure thus complements the more-common base-catalysed alkylation of enolates which fails with tertiary haUdes. It is supposed that the Lewis acid promotes ionization of the electrophile, RX, to form the cation R+, which is trapped by the silyl enol ether to give the addition product with cleavage of the silicon-oxygen bond. 

In the presence of a Lewis acid, silyl enol ethers can be alkylated with reactive secondary halides, such as substituted benzyl halides, and with chloromethylphenyl sulfide (ClCH2SPh), an activated primary halide. Thus, reaction of the benzyl chloride 10 in the presence of zinc bromide with the trimethylsilyl enol ether derived from mesityl oxide allowed a short and efficient route to the sesquiterpene ( )-ar-turmerone (1.22). Reaction of ClCH2SPh with the trimethylsilyl enol ethers of lactones in the presence of zinc bromide, followed by 5-oxidation and pyrolytic ehmination of the resulting sulfoxide (see Section 2.2), provides a good route to the a-methylene lactone unit common in many cytotoxic sesquiterpenes (1.23). Desulfurization with Raney nickel, instead of oxidation and elimination, affords the a-methyl (or a-alkyl starting with RCH(Cl)SPh) derivatives. ... 

---