Hazardous diazomethane

This method for the preparation of cyclobutanone via oxaspiropentane is an adaptation of that described by Salaiin and Conia. The previously known large-scale preparations of cyclobutanone consist of the reaction of the hazardous diazomethane with ketene, the oxidative degradation or the ozonization in presence of pjrridine of methylenecyclobutane prepared from pentaerythritol, or the recently reported dithiane method of Corey and Seebach, which has the disadvantage of producing an aqueous solution of the highly water-soluble cyclobutanone. A procedure involving the solvolytic cyclization of 3-butyn-l-yl trifluoro-methanesulfonate is described in Org. Syn., 54, 84 (1974). 

Trimethylsilyldiazomethane, as a stable and safe substitute for hazardous diazomethane, is useful both as a reagent for introducing a Cj-unit and as a C-N-N synthon for the preparation of azoles. Many methods are described in the literature for the preparation of trimethylsilyldiazomethane, including the trimethylsilylation of diazomethane (7-74S), the alkaline decomposition of N-nitroso-N-(trimethylsilylmethyl)amides (25-61%) and the diazo group transfer reaction of trimethylsilylmethyllithium with p-toluenesulfonyl azide (38%). The present modified diazo group transfer method appears to be the most practical, high-yield, and large scale procedure for the preparation of... 

The use of trimethylsilyldiazomethane with methanol provides a less hazardous method for preparing methyl esters under mild conditions than ethereal diazomethane solution. Trimethylsilyldiazomethane is commercially available, obviating the need to synthesize diazomethane daily. It is a stable and safe substitute for either hazardous diazomethane or corrosive reagents containing boron trifluoride. 

A one-pot synthesis of furan 2-substituted-3-carboxylic and 2-substituted-3,4-dicarboxylic esters was reported. Thus, reaction of an acyl isocyanate with trimethylsilyldiazomethane, a safe replacement for hazardous diazomethane, gave 2-substituted oxazoles, which were treated with dimethyl acetylenedicarboxylate or ethyl propiolate to afford the corresponding di- and trisubstituted furans in good yields <04S1359>. 

In the case where liquid chromatography is not available, acidic herbicides need to be derivatized because they can dissociate in water and are not usually volatile to be analyzed by gas chromatography. The basic methods used for chlorophenoxy acid herbicides are esterification, silylation, and alkylation, as described in a recent exhaustive review.The derivatization step is performed after preconcentration and cleanup. The step consists of the formation of esters and ethers from the carboxyl and phenol groups of the acidic herbicides. A lot of reagents and chemical mechanisms can be used to perform derivatization reactions. The most employed derivatization reagents are diazomethane, methyliodide, trimethylsulfonium (or anilinium) hydroxide, bis (trimethylsilyl) trifluoroacetamide (BSTFA), pentafluorobenzyl bromide, and anhydride acetate. It should be noted that explosive and hazardous diazomethane was replaced by safer agents. Authors also underline that surface water generally contains humic substances, which can interfere with the derivatization reaction. ... 

Trimethylsilyldiazomethane is described as a safe, stable substitute for the hazardous diazomethane in the homologation of ketones [equation (12)]. ... 

The given examples represent nicely that synthesis and processing of the highly hazardous diazomethane is feasible on continuous microfluidic as well as on minifluidic scale. Due to the small inner dimensions, only little amounts of diazomethane are present in microstructured reactors. However, safety issues such as leakages still remain challenging for large-scale production in industry and academia. 

Trimethylsilyldiazomethane has been used in place of hazardous diazomethane in the Arndt-Eisfert synthesis for covering carboxylic acids to the next homo-logue. Ketones behave similarly. I.r. spectroscopy indicates that pyrolysing MeaSiCHN2 in an argon matrix gives the carbene, which isomerizes to the silene. ... 

Dream reactions can be performed using chemical micro process engineering, e.g., via direct routes from hazardous elements [18]. The direct fluorination starting from elemental fluorine was performed both on aromatics and aliphatics, avoiding the circuitous Anthraquinone process. While the direct fluorination needs hours in a laboratory bubble column, it is completed within seconds or even milliseconds when using a miniature bubble column. Conversions with the volatile and explosive diazomethane, commonly used for methylation, have been conducted safely as well with micro-reactors in a continuous mode. 

In the production of 4,4 -bipyridyl from pyridine, the reaction between pyridine and metallic. sodium in liquid ammonia is involved, followed by oxidation. By adopting a continuous reactor, the process has been made safer and yields have probably improved. For a hazardous chemical like diazomethane, even at a capacity of 60 tpa a continous plant has been adopted. 

Despite the higher selectivity of enzymatic methyl transfer over chemical methylation, where toxic or hazardous reagents are often employed, such as methyl sulfonate and diazomethane, the synthetic applications of these enzymes have been largely ignored primarily as a result of high costs associated with the cofactor SAM. Recent efforts have been directed to in vivo methylation, where SAM may be regenerated inside cells. For example, methyl benzoate production was engineered in recombinant Saccharomyces cerevisiae and in vivo... 

There is here also support from energetic considerations for a mechanism accounting for the formation of linear polymethylene from diazomethane. This subject had become popular, despite the hazards associated with that monomer, because of the almost frantic search in the 1950s for new methods of making that polymer. 

In addition to the methods sketched in Figure 4.2, diazoketones are frequently prepared from acyl halides and diazomethane. Because this methodology requires the use of distilled diazomethane, it is hazardous and not well suited to large-scale preparations. 

Dialkyltryptamines. JCS, 7175-79 (1965). First the tryptamine must be methylated as follows. Dissolve the tryptamine in ether (methanol also works and is cheaper), add 2.5 g of diazomethane (careful, this is nasty stuff see the making precursors chapter for synthesis and hazards) in ether and heat for 20 hours on oil bath. Evaporate in vacuo to get product. 

W-Methyl-A/ -nitroso-p-toluenesulfonamide (MNTS) is an important precursor for the production of diazomethane. Diazomethane is then further converted to a range of useful molecules in the pharmaceutical and fine chemical industry [69]. Production of MNTS is a highly exothermic process and includes the presence of the extremely toxic materials. Stark et al. [70] have explored the application of microreactor technology for the production of this industrially valuable material, assuming that due to the efficient heat exchange and the closed system, microflow conditions provide a safer environment for these hazards. 

The best large-scale preparation of cyclobutanone is the reaction of diazomethane with ketene.2 It requires a ketene generator and implies handling of large quantities of the potentially hazardous diazo compound. A more frequently used method for the preparation of cyclobutanone starts from pentaerythritol, the final step being the oxidative degradation of methylenecyclobutane,3,4 which can also be prepared from other precursors.5 A general survey of all methods used to obtain cyclobutanone has been published.6,7... 

Substitution of diazomethane by the less hazardous trimethylsilyl-substituted diazomethane (TMS-CHNj) is not possible, since YMS-CHNj is not acylated by mixed anhydrides. 

Both the toxicity and explosion hazards associated with diazomethane are discussed by Gutsche.4... 

Caution Diazotnelkane is hazardous. Follow the directions Jor safe handling of diazomethane given in earlier volumes. 3 All operations are carried out in a hood. 

In an early report on peptide hydroxamic acids as metalloprotease inhibitors, the peptide acid (Z-Gly-L-Leu-OH) was converted into the V-hydroxysuccinimide ester using DCC, which was subsequently reacted with hydroxylamineJ10 More reactive condensing reagents such as BOP can form the hydroxamic acid directly from the carboxylic acid and hydroxylamine via an intermediate HOBt ester. A number of hydroxamic acids has been synthesized by the treatment of the corresponding methyl esters with hydroxylamine in the presence of KOH 122 this reaction requires careful choice of reagent concentrations and ratios. In addition, the precursor carboxylic acid is treated with diazomethane to make the methyl ester. The use of diazomethane makes the procedure hazardous, but should be useful in special cases that require a better cost performance. 

CautionX All operations should be conducted in an efficient fume hood. Diazomethane is hazardous-, directions for safe handling are given in earlier volumes of Organic Syntheses.2-3 Diazoacetophenone is a skin irritant and direct contact should be avoided. 

Diazomethyldimethylarsine [59871-26-0] + 1 N-j As Preparative hazard See Diazomethane Dimethylaminodimethylarsine See other DIAZO COMPOUNDS C3H7AsN2... 

Finally, Wittig20 reported that treatment of zinc iodide with either one or two equivalents of diazomethane was an alternative method to prepare IZnCH2I (Table 13.1, entry 3a) or the analogous his(iodomethyl)zinc reagent [(Zn(CH2I)2] (Table 13.1, entry 3b). This method, however, has not attracted much attention from synthetic organic chemists due to the hazards involved when diazomethane is used on multigram scale.21... 

The method of preparing methyl esters is to treat carboxylic acids with diazomethane (Following fig.). In this method good yields are obtained because nitrogen is formed as one of the products and because it is lost from the reaction mixture, the reaction is driven to completion. However, diazomethane is a very hazardous chemical that can explode, and strict precautions are essential when using it. 

---