Reactive zinc aldehyde/ketone reactions

Indolyl A-Grignards, "" or even better their zinc analogues, undergo reaction predominantly at C-3 with a variety of carbon electrophiles such as aldehydes, ketones and acid halides, or reactive halo-hetero-cycles. Including aluminium chloride in the zinc reactions produces high yields of 3-acyl-indoles. The copper-catalysed reactions of indolyl-A-Grignards with A-t-butoxycarbonyl-aziridines also proceed well at C-3. ... 

Allylation of carbonyl compounds. The reaction of allyl bromide with carbonyl compounds in the presence of zinc iodide is mediated by germanium(II) iodide. Ketones are less reactive than aldehydes and require an excess of the reagent and longer reaction times. 

Rieke and Uhm have published more details concerning the preparation of a highly reactive zinc by reduction of anhydrous zinc chloride with potassium metal in refluxing THF (5, 753). The Reformatsky reaction of ethyl a-bromo-acetate with various aldehydes and ketones can be conducted in ether at 20° when this reactive form of zinc is used. Yields of hydroxy esters are usually greater than 95%. 

When a 1 1 mixture of ethyl a-bromoacetate and ketone was reacted with the active zinc at -5°C, followed by refluxing for various times, yields of the P hydroxy ester on the order of 70-85% were obtained. It was then discovered that a superior solvent system was diethyl ether. In this case, the highly reactive zinc was generated in THF by the usual procedure, then the THF was removed, and freshly distilled dry diethyl ether is added to the black powder. A one-to-one mixture of ketone or aldehydes and a-bromoester is then added dropwise at ice-bath temperatures. Finally, the reaction mixture is stirred at room temperature for 1 h followed by normal workup procedures. The ability to use diethyl ether at ice bath or room temperatures would appear to make the activated zinc procedure highly desirable. 

The reactivity of acylzirconocene chlorides towards carbon electrophiles is very low, and no reaction takes place with aldehydes at ambient temperature. In the reaction described in Scheme 5.12, addition of a silver salt gave the expected product, albeit in low yield (22—34%). The yield was improved to 79% by the use of a stoichiometric amount of boron trifluoride etherate (BF3OEt2) (1 equivalent with respect to the acylzirconocene chloride) at 0 °C. Other Lewis acids, such as chlorotitanium derivatives, zinc chloride, aluminum trichloride, etc., are less efficient. Neither ketones nor acid chlorides react with acylzirconocene chlorides. In Table 5.1, BF3 OEt2-mediated reactions of acylzirconocene chlorides with aldehydes in CH2C12 are listed. 

The role of titanium salt is to activate the carbonyl compounds as Lewis acid. As described above, bis(iodozincio)methane (3) is nucleophilic enough to attack the carbonyl group of aldehydes or ce-alkoxyketones. In the reaction with simple ketones or esters, however, the addition of titanium salt is necessary to facilitate the nucleophilic attack. Instead of this Lewis acid activator, simple heating may induce the nucleophilic attack. Treatment of 2-dodecanone with 3 without titanium salt at higher temperature, however, does not improve the yield of alkene (Scheme 13). The reason for the low reactivity of 3 at higher temperature comes from the structural change of 3 into the polymeric methylene zinc 4 through the Schlenk equilibrium shown in equation 740. 

By contrast, when the first electrophile was an aldehyde as illustrated for the reaction of 276 with benzaldehyde, the resulting alkenylmetal presumably became part of a six-membered ring alkoxide 279 and hence so poorly reactive that it did not even react with iodine. However, treatment with Me3SiCl resulted in the silylation of the secondary zinc alkoxide and allowed iodinolysis to subsequently proceed, affording the (Z)-alkenyl iodide 280 (equation 132)165. Unfortunately, this protocol was not efficient for tertiary alkoxides generated by initial reaction of 276 with ketones. 

The insight that zinc ester enolates can be prepared prior to the addition of the electrophile has largely expanded the scope of the Reformatsky reaction.1-3 Substrates such as azomethines that quaternize in the presence of a-halo-esters do react without incident under these two-step conditions.23 The same holds true for acyl halides which readily decompose on exposure to zinc dust, but react properly with preformed zinc ester enolates in the presence of catalytic amounts of Pd(0) complexes.24 Alkylations of Reformatsky reagents are usually difficult to achieve and proceed only with the most reactive agents such as methyl iodide or benzyl halides.25 However, zinc ester enolates can be cross-coupled with aryl- and alkenyl halides or -triflates, respectively, in the presence of transition metal catalysts in a Negishi-type reaction.26 Table 14.2 compiles a few selected examples of Reformatsky reactions with electrophiles other than aldehydes or ketones.27... 

The reactions of organometallic reagents such as organolithium [696], -zinc [697-700], -magnesium [701], and -aluminum species [702] are facilitated by the presence of TiCU [9] as exemplified in Eq. (308) [703]. Even addition of a titanium compound to aldehydes was promoted in the presence of an extra amount of a titanium salt (Eq. 309) [704,705]. Titanium Lewis acids increase the reactivity of the a-position of a ketone (Eq. 310) [706] and the /3-position of an a,/3-unsaturated carbonyl compound towards nucleophiles (Eq. 311) [608,707-709]. The positive role of TiCU in the photo-hydroxymethylation of ketones and aldimines is ascribed to activation of methanol by the titanium salt (Eq. 312) [710]. 

Although the selective reaction with electrophiles [7 11,29] constitutes an interesting reactivity pattern, the most useful synthetic application of 1,1-bimetallics are olefination reactions [30-32]. First investigations have shown that magnesium-zinc 1,1-bimetallics react with a range of aldehydes in the presence of stoichiometric amounts of boron trifluoride etherate, leading to (E)-disubstituted olefins [Eq. (21) 7]. Ketones do not undergo... 

---