Tertiary alcohols, nucleophilic additions

Additional evidence for carbocation intermediates in certain nucleophilic substitutions comes from observing rearrangements of the kind normally associated with such species For example hydrolysis of the secondary alkyl bromide 2 bromo 3 methylbutane yields the rearranged tertiary alcohol 2 methyl 2 butanol as the only substitution product... 

Acid halides are among the most reactive of carboxylic acid derivatives and can be converted into many other kinds of compounds by nucleophilic acyl substitution mechanisms. The halogen can be replaced by -OH to yield an acid, by —OCOR to yield an anhydride, by -OR to yield an ester, or by -NH2 to yield an amide. In addition, the reduction of an acid halide yields a primary alcohol, and reaction with a Grignard reagent yields a tertiary alcohol. Although the reactions we ll be discussing in this section are illustrated only for acid chlorides, similar processes take place with other acid halides. 

Step 2 of Figure 29.12 Isomerization Citrate, a prochiral tertiary alcohol, is next converted into its isomer, (2, 35)-isocitrate, a chiral secondary alcohol. The isomerization occurs in two steps, both of which are catalyzed by the same aconitase enzyme. The initial step is an ElcB dehydration of a /3-hydroxy acid to give cfs-aconitate, the same sort of reaction that occurs in step 9 of glycolysis (Figure 29.7). The second step is a conjugate nucleophilic addition of water to the C=C bond (Section 19.13). The dehydration of citrate takes place specifically on the pro-R arm—the one derived from oxaloacetate—rather than on the pro-S arm derived from acetyl CoA. 

As mentioned already, new methylidene-group IV metal complexes have been prepared and were subsequently used in nucleophilic additions to carbonyl electrophiles (Scheme 43).53 In contrast to titanium and zirconium, the reaction of methylidene hafnium dichloride 97 benzophenone stopped at the first stage (i.e., addition). The tertiary alcohol was obtained in 73% yield, while the corresponding alkene was formed only as minor product. 

These results support the /3-elimination from 220 to give 221, towards which KOtBu acts as a base and a nucleophile. As in the case of 215, the addition occurs at the central allene carbon atom leading the allyl anion 222, which is protonated to yield 223. On the other hand, the deprotonation of the methylene group brings about 224, whose major amount is converted to naphthalene, but a small proportion, behaving as a nucleophile, traps 221, giving rise to the allylanion 225, which in turn reacts with 221 and, by a hydride transfer, furnishes 228 and the allyl anion 229. By protonation, the latter is converted into 226. By conducting this experiment in the presence of benzophenone, this mechanistic model was confirmed as the tertiary alcohols 227 and 230 were obtained in addition to naphthalene, 223 and 228. Apparently, the anions 224 and 229 were intercepted in part or totally, respectively, by benzophenone (Scheme 6.52) [137]. 

The study above (Hanna et al., 1992) also addressed the problem of nucleophilic addition of alcohols to DMPO, using Fe111 as the oxidant in an aqueous-alcoholic solution (from 95% to 25% water). Only primary alcohols engaged in this reaction, whereas 2-propanol or 2-methyl-2-propanol did not react even when the alcohol concentration was increased to 70%. This may depend on either decreased reactivity of secondary and tertiary alcohols, perhaps for steric reasons, or lower stability of the corresponding spin adducts. 

The retrosynthesis involves the following transformations i) isomerisation of the endocyclic doble bond to the exo position ii) substitution of the terminal methylene group by a more stable carbonyl group (retro-Wittig reaction) iii) nucleophilic retro-Michael addition iv) reductive allylic rearrangement v) dealkylation of tertiary alcohol vi) homolytic cleavage and functionalisation vii) dehydroiodination viii) conversion of ethynyl ketone to carboxylic acid derivative ix) homolytic cleavage and functionalisation x) 3-bromo-debutylation xi) conversion of vinyl trimethylstannane to methyl 2-oxocyclopentanecarboxylate (67). 

With the alcohol protected, preparation of the Grignard reagent can proceed, and this can then react with the ketone carbonyl in a nucleophilic addition. The protecting group can then be removed by treatment with acid, to restore the hydroxyl function. This also involves a tertiary carbocation that is subsequently quenched with water. 

The TV-methoxy-jV-methylamide of tiglic acid (17) is used as an aeylating agent in a procedure developed by Weinreb.9 Lithiated aromatic species 18 attacks Weinreb amide 17 with formation of the chelate 19. which is hydrolyzed to ketone 5. Use of Weinreb amide 17 circumvents the primary threat here multiple addition and formation of a tertiary alcohol. Since complex 19 decomposes only in the course of workup, the ketone 5 itself is protected against further nucleophilic attack.10 "BuLi, LiCl. THF. 0 C->RT 17. 77%. 

Taddei has developed a soluble PEG supported scavenger 53 to capture a variety of nucleophilic functional groups (Scheme 13) [21]. This scavenger was based on an electrophilic dichlorotriazine core and relied on selective precipitation (by the addition of ether to acetonitrile) to remove it from the reaction mixture. This scavenger 53 is particularly versatile, and has been used to remove primary, secondary and tertiary alcohols, diols and thiols... 

Organolithium reagents reacts just like Grignard reagents. For example, reaction with aldehydes and ketones proceeds by nucleophilic addition to yield secondary and tertiary alcohols respectively. 

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