Nucleophilic attack at the carbonyl group

All these facts—the observation of second order kinetics nucleophilic attack at the carbonyl group and the involvement of a tetrahedral intermediate—are accommodated by the reaction mechanism shown m Figure 20 5 Like the acid catalyzed mechanism it has two distinct stages namely formation of the tetrahedral intermediate and its subsequent dissociation All the steps are reversible except the last one The equilibrium constant for proton abstraction from the carboxylic acid by hydroxide is so large that step 4 is for all intents and purposes irreversible and this makes the overall reaction irreversible... 

The pharmaceutical interest in the tricyclic structure of dibenz[6,/]oxepins with various side chains in position 10(11) stimulated a search for a convenient method for the introduction of functional groups into this position. It has been shown that nucleophilic attack at the carbonyl group in the 10-position of the dibenzoxepin structure renders the system susceptible to water elimination. Formally, the hydroxy group in the enol form is replaced by nucleophiles such as amines or thiols. The Lewis acids boron trifluoride-diethyl ether complex and titanium(IV) chloride have been used as catalysts. 

Ultraviolet irradiation of oxadiazoline (38d) at 333.6 nm (or irradiation using benzophenone as a triplet sensitiser) gave 2-diazopropane and methyl acetate. A triplet biradical intermediate formed by cleavage of the C(OMe)—N bond was postulated <90TL863>. Oxadiazolinone (42) underwent nucleophilic attack at the carbonyl group by methyllithium to give acetate (41) after treatment of the product with acetyl chloride <89CJC1753>. 

Most reactions of oxadiazolinones (62) involve nucleophilic attack at the carbonyl group. This is typically followed by opening of the ring, often with subsequent rccyclization to a different heterocycle. Simple nucleophilic displacement occurred on conversion of oxadiazolinone (62a R = R) into chloro-oxadiazole (63) on treatment with a mixture of phosphorus oxychloride and phosphorus pentachloride <84JIC436) or with thionyl chloride <90AP(323)595>. 

The fluoro substituents proved to induce changes in the reactivities of the methyl- (X = H) and trifluoromethyl-substituted (X = F) pyrido[3, 2 4,5]furo[3,2- [l,3]oxazin-4(47r)-ones 105 with nucleophiles. When methyl-substituted compounds 105 (X = H) were reacted with piperidine in toluene, Wacetylamino carboxamides 106 were formed by nucleophilic attack at the carbonyl group of the l,3-oxazin-4-one ring (Scheme 16). However, the similar reactions of the trifluoromethyl-substituted analogs 105 (X = F) resulted in formation of amidino carboxylic acids 107 by attack at electron-poor position 2 <1995JFC(74)1>. 

Phenanthridine with DMAD in dry methanol yields 471, but if water is present related compounds are also formed.439 In benzene the expected quinolizine 472 and also the oxazine 473 are obtained.440,441 Nucleophilic attack at the carbonyl group of DMAD is uncommon. 

The most extensively studied reactions of coordinated amino acid derivatives are those involving nucleophilic attack at the carbonyl group. These aspects, as well as some of those already covered in the previous section, have been reviewed.335-337 Mechanistic aspects of these reactions have also been discussed in Chapter 7.4. The emphasis in this section will be on the synthetic value of stoichiometric reactions of this type. The two most important synthetic processes are peptide hydrolysis and peptide synthesis, both involving the same mechanism. 

For compounds such as 63, a more complex rearrangement replaces the decarbonyla-tion reaction [65]. This photoisomerization yields lactone 64 by a-cleavage at C-2, C-3 position (Norrish I) and hydrogen transfer from C-l to C-3 followed by a stereoselective nucleophilic attack at the carbonyl group by the terminal carbon of the electron-rich double bond and final ring closure (Scheme 34). 

Mithramycin shows a completely P-linked chain of D-conflgurated saccharides. This requires a totally different approach for the synthesis which is also done by application of the DBE method. The previously obtained disaccharide 180 is P-glycosylated with the monosaccharide precursor 176 to give the trisaccharide 185. After reductive debromination (Bu3SnH), an acid deformylation deblocked the C-3" position which is oxidized with pyridinium dichromate. Nucleophilic attack at the carbonyl group by methyl lithium affords a 1 1.2 mixture of 186 and 187 none of which is the desired compound [93]. Obviously, the methyl branch is formed exclusively in the axial way. 

Two comments on these pathways are required. First, since the reaction mixture could always yield the enolphosphate, aniline must participate in the reaction to form the Schiff base more rapidly than enolphosphate is formed. If the equations are correct, then the first step of the reaction is the same in both cases, that is, methyl metaphosphate attacks the carbonyl group of acetophenone to produce an intermediate that is activated both for nucleophilic attack at the carbonyl group and for removal of a proton from the methyl group of... 

LDA is bulky, so it does not take part in nucleophilic attack at the carbonyl group, and it is basic— the p.KTa of diisopropylamine is about 35—plenty basic enough to deprotonate next to any carbonyl group. The lithium enolate is stable at low temperature (-78 °C) but reactive enough to be useful. Lithium enolates are the most commonly used stable enolate equivalents in chemistry. 

Steric bulk means that f-butyl esters are resistant to nucleophilic attack at the carbonyl group, and that includes hydrolysis under basic conditions (nucleophilic attack by HO"). But they do hydrolyse relatively easily in acid, because the mechanism of hydrolysis of f-butyl esters in acid is quite different. It does not involve nucleophilic attack at the carbonyl group and is a favourable Sjsjl reaction at the f-butyl group (Chapter 17). 

The hydroxyl group eliminates upon deprotection and mesylation. The use of DBU as a particularly large, non-nucleophilic base is necessary for the elimination. It also prevents the formation of the thermodynamic, conjugated elimination product and a nucleophilic attack at the carbonyl group. 

It is somewhat surprising that the MTO/H2O2 system presents this activity since these oxidations involve nucleophilic attack at the carbonyl group which is in contrast to all the preceding examples where the substrates attacked the electrophilic... 

---