Carbonyl reactions with bases

In some cases, a simple carbonyl reaction with the CH-acidic cyclopenta-dienes in the presence of a base gave a convenient entry to special types of azafulvalenes. Starting from the appropriate cyclic carbonylic and thiocar-bonylic systems respectively, or their acetals, the following azafulvalenes... 

Addition of thiamine. The conversion of pyruvate to acetyl CoA begins by reaction of pyruvate with thiamine pyrophosphate, a derivative of vitamin B, The hydrogen on the heterocyclic thiamine pyrophosphate is weakly acidic and can be removed by reaction with base to yield a nucleophilic ylide much like the phosphorus ylides u.sed in Wittig reactions /Section 19.12>. This nucleophilic yJide adds to the ketone carbonyl group of pyruvate to yield a tetrahedral intermediate. 

A second general reaction of aldehydes and ketones involves reaction at the a carbon. A C-H bond on the a carbon to a carbonyl group is more acidic than many other C-H bonds, because reaction with base forms a resonance-stabilized enolate anion. 

Reaction of a carbonyl compound with base forms an enolate. 

Reactions of carbonyl compounds with base invariabiy involve enolates because the a hydrogens of the carbonyl compound are easily removed. 

By far the most important activating group in synthesis is the carbonyl group. Removal of a proton from the a-carbon atom of a carbonyl compound with base gives the corresponding enolate anion. It is these enolate anions that are involved in many reactions of carbonyl compounds, such as the aldol eondensation, and in bimolecular nucleophilie displacements (alkylations, as depieted in Scheme 1.2). 

The reaction involves several steps (1) base-catalyzed generation of an enolate, (2) nucleophilic attack of this anion on a carbonyl carbon, and (3) protonation of the resulting anion to yield the initial aldol product, a p-hydroxy carbonyl compound. Note that each step in the sequence is in equilibrium and the entire reaction is, therefore, reversible. Treatment of the p-hydroxy carbonyl compound with base causes the reverse aldol (retro-aldol) reaction to occur. 

Oxidation of a Primary Alcohol to a Carboxylic Acid (Section 10.8A) A primary alcohol is oxidized to a carboxylic acid by chromic acid. The mechanism involves initial formation of an alkyl chromate intermediate, followed by reaction with base to remove a proton, generating the carbonyl group of an aldehyde and simultaneously reducing the chromium(VI) to chromium(IV). An initially formed aldehyde adds water, generating an aldehyde hydrate, which is oxidized according to the same mechanism to give the carboxylic acid. 

A particularly well documented example of systematic variation in Bronsted exponent for proton transfer involving carbon, and the curved Bronsted relation which results, is provided by the reaction of carbonyl compounds with bases (equation 6). The data, gathered over many years in a nuinber of laboratories, have recently been... 

Figure 1. Curved Bronsted plot for the reaction of carbonyl compounds with bases. [Reproduced by permission from The Proton in Chemistry (second edition), Cornell University Press, Ithaca,...

A second major approach to semi-synthetic cephamycin synthesis utilises carbanion formation a to the P-lactam carbonyl. Reaction with electrophiles then provides substrates suitable for the introduction of the methoxy group. Several papers have described how the anion generated from the SchifPs base (220 =60 ) reacts readily with methyl methan-... 

The phosphorus ylides of the Wittig reaction can be replaced by trimethylsilylmethyl-carbanions (Peterson reaction). These silylated carbanions add to carbonyl groups and can easily be eliminated with base to give olefins. The only by-products are volatile silanols. They are more easily removed than the phosphine oxides or phosphates of the more conventional Wittig or Homer reactions (D.J. Peterson, 1968). 

The Michael reaction is of central importance here. This reaction is a vinylogous aldol addition, and most facts, which have been discussed in section 1.10, also apply here the reaction is catalyzed by acids and by bases, and it may be made regioselective by the choice of appropriate enol derivatives. Stereoselectivity is also observed in reactions with cyclic educts. An important difference to the aldol addition is, that the Michael addition is usually less prone to sterical hindrance. This is evidenced by the two examples given below, in which cyclic 1,3-diketones add to o, -unsaturated carbonyl compounds (K. Hiroi, 1975 H, Smith, 1964). 

Intramolecular reactions between donor and acceptor centres in fused ring systems provide a general route to bridged polycyclic systems. The cts-decalone mesylate given below contains two d -centres adjacent to the carbonyl function and one a -centre. Treatment of this compound with base leads to reversible enolate formation, and the C-3 carbanion substitutes the mesylate on C-7 (J. Gauthier, 1967 A. Belanger, 1968). 

Alkynes undergo stoichiometric oxidative reactions with Pd(II). A useful reaction is oxidative carboiiyiation. Two types of the oxidative carbonyla-tion of alkynes are known. The first is a synthesis of the alkynic carbox-ylates 524 by oxidative carbonylation of terminal alkynes using PdCN and CuCh in the presence of a base[469], Dropwise addition of alkynes is recommended as a preparative-scale procedure of this reation in order to minimize the oxidative dimerization of alkynes as a competitive reaction[470]. Also efficient carbonylation of terminal alkynes using PdCU, CuCI and LiCi under CO-O2 (1 I) was reported[471]. The reaction has been applied to the synthesis of the carbapenem intermediate 525[472], The steroidal acetylenic ester 526 formed by this reaction undergoes the hydroarylalion of the triple bond (see Chapter 4, Section 1) with aryl iodide and formic acid to give the lactone 527(473],... 

---