Esters, from diazomethane

Charrette and Lebel [24] developed a catalytic enantioselective cyclopropa-nation of trans-cinnamate esters with diazomethane. Their procedure involves an argon-flow-mediated diazomethane addition, leading to high yields (up to 80%) in products with up to 80% ee, by using the bis(oxazoHne) arising from phenylglycinol (Scheme 10). 

The main drawback to this reaction is the toxicity of diazomethane and some of its precursors. Diazomethane is also potentially explosive. Trimethylsilyldia-zomethane is an alternative reagent,42 which is safer and frequently used in preparation of methyl esters from carboxylic acids.43 Trimethylsilyldiazomethane also O-methylates alcohols.44 The latter reactions occur in the presence of fluoroboric acid in dichloromethane. 

The reaction of diazomethane with a Ccirboxylic acid is an efficient way to produce a methyl ester however, the procedure is dangerous. Figure 12-25 illustrates the formation of a methyl ester from benzoic acid and diazomethane. 

Often, esters are homologated by one carbon using the diazomethane-based Amdt-Eistert procedure. Kowalski homologation, addition of the inexpensive dibromomethane followed by -elimination, is a more scalable alternative. Timothy Gallagher of the University of Bristol recently reported (J. Org. Chem. 2004, 69, 4849) the use of Kowalski homologation to prepare P-amino esters from a-amino esters, including the conversion of 3 to 4. Note that the transformation can be carried out without protection of the OH, and that it proceeds without loss of stereochemical integrity. 

The parent of the diazo compounds, diazomethane, CH2=N=N, has been mentioned before in connection with ylide reactions for ring enlargement (Section 16-4A) and the preparation of methyl esters from acids (Table 18-7). It is one of the most versatile and useful reagents in organic chemistry, despite the fact that it is highly toxic, dangerously explosive, and cannot be stored without decomposition. 

Fig. 2.32 Preparation of methyl esters from carboxylic acids and diazomethane.

The development of procedures for the identification of CW agents in biomedical samples is ongoing and existing procedures are continuously improved. Quantization is also an important factor, and an isotope dilution GC/MS/MS method was developed for the quantitative determination of five organophosphorus acids derived from the nerve agents VX, tabun, sarin, soman, and cyclohexyl sarin in urine samples. The acids were isolated and converted into their methyl esters by diazomethane. Detection limits in the low p,g I. 1 were obtained using CID of the protonated molecular ion peaks obtained with isobutane Cl(58). 

Whereas all the alkylations in Figure 2.26 take place in basic or neutral solutions, carboxylic acids can be methylated as such with diazomethane (Figure 2.27). The actual nucleophile (the carboxylate ion) and the actual methylating agent (H3C—N+=N) Fig. 2.27. Preparation of are then produced from the reaction partners by proton transfer, methyl esters from carboxylic acids and di azomethane. 

Diazomethane methylation is a good way of making methyl esters from carboxylic acids on a small scale because yields are excellent and the only by-product is nitrogen. However, there is a drawback diazomethane has a boiling point of-24°C, and it is a toxic and highly explosive gas. It therefore has to be used in solution, usually in ether the solution must be dilute, because concentrated solutions of diazomethane are also explosive. It is usually produced by reaction of N-methyl-N-nitrosourea or N-methyl-N-nitrosotoluenesulfonamide with base, and distilled out of that reaction mixture as an azeotrope with ether, straight into a solution of the carboxylic acid. 

One important application of this reaction is the chain extension of acyl chlorides to their homologous esters, known as the Amdt-Eistert reaction. Notice that the starting material for the Wolff rearrangement is easily made from RCO2H by reaction of the acyl chloride with diazomethane the product is RCH2CO2H—the carboxylic acid with one more carbon atom in the chain. A CH2 group, marked in black, comes from diazomethane and is inserted into the C-C bond between R and the carbonyl group. 

Palladium-catalyzed methylene transfer from diazomethane has proved effective for the cyclopropanation of 1-alkenylboronic acid esters allylic alcohols and amines 1-oxy-l,3-butadienes and allenes " Readily accessible iron complex (CO)2FeCH2S Me2 BF4 35 undergoes direct reaction with a range of alkenes to give cyclopropanes (equation 67) The salt is sensitive to steric effects and the reaction proceeds... 

Diazomethane is effective in esterifying free acids to their corresponding methyl esters under mild conditions and is fast. It will not produce methyl esters from acylglycerols, cholesterol esters, or phospholipids. Many researchers are concerned about the potential hazard of the diazomethane, its precursors, and the actual... 

The carbenoid generated from diiodomethane/diethylzinc is often found to be more reactive than the conventional Simmons-Smith reagent. Thus, in the case of 1-alkenylboronic acid esters, where diazomethane failed to cyclopropanate trisubstituted derivatives (Section 1.2.1.1.1.) diiodomethane/diethylzinc gave good yields of the required products 16. ... 

Urine. Urine samples collected from cows 821 and 59 in the 0-12 hour period after the administration of a 30 mg dose (injection 2) were utilized in the isolation and identification of metabolites. The isolation procedure involved ethyl acetate extraction of urine followed by solid phase extraction of the ethyl acetate extract on C-18 Bond Elut cartridges. The extract was derivatized into methyl esters with diazomethane and subjected to silica and alumina chromatography for further cleanup prior to analysis. The detailed procedure is described in flow diagram 1. 

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