Three- carbon reagents esters

In several of the previously described methods the anion of the three-carbon fragments was added to an a-amino aldehyde to construct a C—C bond between the C3 and C4 atoms of the 1-hydroxyethylene isostere. However, Sakurai et al.[27l used an add chloride instead of an a-amino aldehyde. They synthesized 6-phthalimido-y-oxo esters by a palladium-catalyzed reaction between acid chlorides and organozinc reagents derived from p-iodo esters. Then, the oxo esters were converted into the y-lactone precursors. 

Examples of such three-carbon synthons are 2-nitro-2-propen-l-yl acetates and piva-lates, which have been developed by Seebach and coworkers57,58 as reagents for [3 + 3] cyclizations with cyclic and acyclic ketone enamines. After workup these reactions give 4-nitrocyclohexanones. With enamines from prolinol methyl ether and cyclic ketones, enantiomerically pure compounds were obtained58. An example of such a [3 + 3] cyclization is the synthesis of bicyclic nitroketone 99 from nitroallylic ester 97 and enamine 98 (equation 18). 

The presence of two negative charges in close proximity makes this new reagent 174 extremely reactive. Its carbanionic sites, at C-1 and C-3, however, differ sharply in their nucleophilicity and reactivity. The different surroundings of the carbanionic centers in this system makes the carbanion at C-3 better stabilized than at C-1. Therefore, electrophilic attack should be directed primarily at C-1. In fact, the addition of one equivalent of an electrophile to a solution of 174 leads to a highly selective attack at the terminal carbon atom. The product of this reaction, 175, still retains a carbanionic center and with the addition of another electrophile the formation of a second bond occurs selectively at C-2. In this manner, the dianion 174 is an excellent three-carbon building block for the synthesis of ketones of type 176 or four-carbon building block for the synthesis of esters of the type 177. 

The chain extension of carbanions by three carbon atoms by [1,4] addition to acrylate esters is attractive in theory, but beset with practical difficulties. It has now been shown that at low temperatures ( —40°C) Grignard reagents in the presence of CuCl give acceptable yields (40—80%) of Michael adducts with ethyl acrylate. Enol ethers can be directly oxidized to esters in high yield by pyridinium chloro-chromate. Thus, ethyl vinyl ether is converted into ethyl acetate and 2,3-dihydrofuran to butyrolactone. 

FIGURE 7.12 Preparation of activated esters of A-alkoxycarbonylamino acids by reaction of the hydroxy compound with a mixed anhydride (path A), obtained by leaving the three reagents (NMM = A-methylmorpholine) in CH2C12 at 23°C for 2 minutes.35 Mixed carbonate that is formed (path B) is readily eliminated by crystallization of the ester. 

Amino groups react very easily with aldehydes or ketones, and with aldehydes in the presence of amines, they can be acylated by the usual acylating agents, and they react with amidacetals, Vilsmeier reagents and nitroso compounds (Scheme 12). As mentioned earlier, alkylation leads mainly to AT(2)-alkylated products. The hydrazino group reacts in the same way as the amino group with aldehydes or ketones, with acyl chlorides or carboxylic anhydrides, with sulfonyl chlorides, ortho esters, carbon disulfide and with nitrous acid. The last three reactions have mainly been used for the synthesis of condensed 1,2,4-triazines. 

The Grignard reagent provides two of the three R groups attached to the hydroxylbearing carbon of the tertiary alcohol. The ester provides the third R group. So, from... 

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