Disconnection of Alcohols

The forward reaction uses HC=CLi/THF/-78 °C, and the reaction is 97 % selective for the desired isomer. Attack is from the less hindered top face of the molecule. 

Propose a disconnection for each of the following tertiary alcohols  

FIGURE 19.8 Disconnection of primary alcohols to aldehydes or esters. 

Predict the product of each of the following reactions (a) 1 (1) LiC CH, HjNCHjCHjNHj, DMSO 

Show how each of the following alcohols could be prepared using a boron reagent  

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The best disconnection of alcohols to organometallic and carbonyl compound is normally the one that gives the most stable anion. 

Analysis The ester group is obviously just FGl, but immediate disconnection of the alcohol A doesn t get us very far so we do a bit more FGl. The double bond is the guide as it can be added as an aUyl group ... 

Disconnection of the ester removes alcohol (18) and leaves (19). The amipo group will have to be put in by nitration and we already know (p 34) that we need the free acid (16) for this. The ether must therefore be disconnected first. 

Answer Disconnection of the ether reveals a 1,2-diX compound (24) and an alcohol (25) easily made by reduction from a Friedel-Crafts adduct (26). 

Few carbanions are stable enough to be formed in solution as genuine intermediates by removal of a C-H proton by base CX (X = Cl, Br, I) are examples. The ester (1) is used as a rose perfume.Disconnection of the ester reveals alcohol (2) which can be disconnected to 3 and benzaldehyde. 

Grignard addition to COg must be the answer with this crowded acid and this leads us back to alcohol (20), Disconnection of any group now gives a simple ketone and an available alkyl halide. As we shall see in Chapter 11, it is best to divide the molecule into two nearly equal parts, so we shall use disconnection (a). 

Workers studying the eyelisation of acetylenic alcohols decided to make (30), Disconnection of the acetylene leaves a-hydroxy ketone (31), Since this ketone is blocked on one side by the aromatic ring it is reasonable to make (31) from (33) via bromoketone (32). Ana lysis... 

Ester disconnection gives easily made alcohol (39) and yclopropane acid (40), Disconnection of dlazoacetic trster leaves simple olefin (41),... 

An alternative disconnection of homopropargylic alcohols substrates for intramolecular hydrosilylation is the opening of an epoxide with an alkynyl anion. This strategy was employed in a total synthesis of the macrolide RK-397 (Scheme 20). Epoxide ring opening serves to establish homopropargylic alcohol C with the appropriate stereochemistry. A hydrosilylation/oxidation protocol affords the diol E after liberation of the terminal alkyne. The... 

Must belong to a nitroderivative 2 Must belong to an alcohol group Prevents disconnection of core bonds... 

SAMPLE SOLUTION (a) Because 2-hexanol is a secondary alcohol, we consider the reaction of a Grignard reagent with an aldehyde. Disconnection of bonds to the hydroxyl-bearing carbon generates two pairs of structural fragments ... 

The simplest route to aldehydes and ketones using the same strategy is oxidation of an alcohol. So the analysis involves FGI back to the alcohol and then a C-C disconnection of one of the bonds next to the OH group. Lythgoe4 wanted to make a series of ketones 34 with various R groups to demonstrate a new alkyne synthesis. Disconnection of the C-R bond of the alcohol 35 meant that they could all be made from aldehyde 36 which can be made by the same strategy. 

Acids can also be made by the oxidation of alcohols and acid derivatives are available from the acids via the acid chloride. Since acids can also be reduced to alcohols, there is a great deal of interdependence in all these methods. The synthesis of carbonyl compounds by one-group C-C disconnections is discussed more fully in chapter 13. 

The tertiary alcohol is an obvious place to disconnect. Rejecting the poor disconnection of one carbon atom 20a, we have a choice between 20b and 20c giving one of two ketones 23 or 24 and Grignard reagents made from one of two halides 22 or 25. We can easily make 22 and 24 by halogenation or Friedel-Crafts acylation of toluene. But what about 23 and 25 ... 

The keto-acetal 24 was needed for a prostaglandin synthesis.3 Disconnection of the acetal 24a reveals the symmetrical carbon skeleton 25 having 1,4- and 1,5-diCO relationships. There is another 1,4-diCO relationship between the two alcohols. 

An alternative disconnection of the alkoxide requires the addition of a silyllithium reagent to an enone. Addition of stoichiometric base to the alcohol 51 produces an alkoxide 52, but no evidence of Brook rearrangement to generate 53 was found on protonation of the product. However, alkoxide 52 must exist in equilibrium with some of the organolithium 53, since alkylation with a soft electrophile (Mel) produced 54.41 The equilibrium concentration of the organolithium 53 is lessened in this case by the impossibility of O-Li coordination. 

Analysis The normal FGI gives the alcohol, and disconnection of this in the usual way gives ... 

All of these disconnections relied on the reaction of a carbon electrophile with a nucleophilic functional group. The alternative, reaction of a carbon nucleophile (such as a Grignard reagent) with an electrophilic functional group, allows us to do C-C disconnections on alcohols, For example, this compound, which has a fragrance reminiscent of lilac, is a useful perfume for use in soap because (unlike many other perfumes that are aldehydes or ketones) it is stable to alkali. 

Our example is clobutinol—an antitussive (cough medicine). A preliminary 1,1 C-C disconnection of the tertiary alcohol is necessary to provide a 3-amino ketone that we can make by a Mannich reaction. 

Using guideline 5 (p. 787) we want to convert the halide to an oxygen-based group, and a sensible solution is to choose the ketone. 1,3-Disconnection of this compound corresponds to a Mannich reaction. This is another case where FGI of the amine to an alcohol is not desirable, because the Mannich reaction will produce the amine directly. 

This disconnection represents the retro-Grignard reaction. It leads almost automatically to organomagnesium or lithium compounds as equivalents of carbanions and aldehydes or ketones as equivalents to the carbocation in the synthesis of alcohols (Scheme 2.35), or carbon dioxide in the synthesis of carboxylic acids. 

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