Organic reactions with diazomethane

Vorbeck et al. [173] compared the yields of the esterification reaction of organic acids with diazomethane and two reaction mixtures methanol—hydrochloric acid and methanol—boron trifluoride. The best results were achieved when the diazomethane method was used. 

Short peptide chains in which one of the amino acid residues is replaced by a moiety related (or sometimes unrelated) to it appear with increased frequency in the literature. In the center of interest are enzyme inhibitors. Synthesis of these compounds is obviously determined by the reactivity of the unusual constituent and therefore it is hardly possible to set rules for such endeavours. We must confine the discussions therefore to generalities. For example chloromethylketones derived from certain amino acids are irreversible inhibitors which not merely interact but indeed react with the active site of an enzyme with the formation of a covalent bond. Chloromethyl ketones are synthesized by activation of the blocked amino acid followed by reaction with diazomethane to yield a diazoketone. This is transformed to the corresponding chloromethyl ketone by HCl in an organic solvent. From p-toluenesulfonyl-L-phenylalanine a chloromethyl ketone is obtained... 

In the light-induced reactions with diazoalkanes, methylene, the photolytic fragment from diazomethane, may be interposed between the halogen atom in the organic halide and the carbon atom to which it is attached,289 290 or may add to the double bonds in the aromatic ring.58 69... 

With a range of methods available for the formation of 1,3-dicarbonyl compounds, the dicarbonyl diazomethanes can be readily prepared via a simple diazo transfer reaction with sulfonyl azide. This has made a vast array of dicarbonyl diazomethanes available, which enhances the versatility in organic synthesis. A selection of examples from recent literature to illustrate the versatility of the cyclopropanation using dicarbonyl diazomethane in the construction of natural products as well as other biologically active compounds is described below. 

Olefinic double bonds substituted with one or more electron-withdrawing groups show significant dipolarophilic activity in cycloaddition reactions with organic azides,43,276-278 similar to the electron-rich double bonds of enamines and enol ethers the reactivity is less pronounced in azide additions compared to that observed in diazomethane reactions.7 The first triazolines reported resulted by the action of aryl azides on benzoquinones.1,279-281 As a rule, stereospecific cis additions occur,32 which are usually unidirectional except in the case of methacrylic derivatives67 and certain alkenes bearing... 

To a solution of 38.1 mmol of LDA ill 35 mL of THF and 24 mL of hexane at — 78 °C are added 2.74 g (17.34 mmol) of (Z)-2-butenyl 3-hydroxybutanoate in 7 mL of dry THF. After 30 min at — 78 C, the reaction mixture is allowed to stir for 6 h at r.t. and then warmed to 50 "C for an additional 6 h. The reaction mixture is then poured into 150mL of 5% aq NaOH. This aqueous layer is washed twice with 20-mL portions of EtzO, acidified with coned HC1 at 0CC, and extracted repeatedly with CH2C12. The combined organic phase is dried over Na,S04. filtered and concentrated under reduced pressure. An ethereal Solution of the crude carboxylic acid product is csterified with diazomethane. MPLC (hexane/EtOAc 1 1) gives an inseparable 81 19 mixture of rearranged -hydroxy esters 3a and b yield 1.31 g (44%). 

Methylation with diazomethane is rarely apphed as the only derivatization step to short-chain organic acids.It is, however, used in combination with o-(2,3,4,5,6-pentafluorobenzyl)-hydroxylamine (PFBHA) for ketoacids (see below). Once diazomethane has been generated, it is added to the extract which can then be injected in the GC, thus making this reagent rather convenient. Heating of the sample mixture is not required since the reaction takes place at low temperatures. The major disadvantages of diazomethane are its hazardous and explosive nature, and the necessity to generate it before it can be applied. ... 

There are very few exceptions. The most important are the methylation of alcoholic and carboxylic OH groups with diazomethane. This reaction is used for cases where high yields and mild conditions are required, e. g., for expensive hydroxy compounds like certain natural products. The methyl ester formation as well as the methylation of phenols does not need an acid catalyst as these substrates catalyze themselves the dediazoniation. For ether formation an acid catalyst, e. g., HBF4, is added (except from phenols). Typical is the methylation of 3)ff-hydroxycholestane, which proceeds in dichloromethane in 95 0 yield, as shown in the Organic Syntheses method of Neeman and Johnson (1973). Analogously, ethers can be transferred in dialkylmethyloxonium salts, as described in another Organic Syntheses procedure (Helmkamp and Pettitt, 1973) for the formation of a trimethyloxonium salt obtained... 

Esterification with diazomethane is employed for the profiling of carboxylic acids in body fluids [164, 165]. The mass spectra of organic acid methyl esters show a variety of structurally informative base peaks compared with the corresponding TMS esters. However, artefacts are produced on reaction of diazomethane with 2-keto acids and 2,3-unsaturated acids [166, 167]. The methyl esters also have the disadvantage of providing low molecular weight increments, especially for the low molecular weight volatile acids such as lactic acid. 

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