Diazonium intermediates

Attempts to intercept the diazonium intermediate 136 by addition of NOCl to 135 at -70° followed by a methanol solution of the sodium salt of i3-naphthol... 

A second group of aromatic substitution reactions involves aryl diazonium ions. As for electrophilic aromatic substitution, many of the reactions of aromatic diazonium ions date to the nineteenth century. There have continued to be methodological developments for substitution reactions of diazonium intermediates. These reactions provide routes to aryl halides, cyanides, and azides, phenols, and in some cases to alkenyl derivatives. 

Examples of the three mechanistic types are, respectively (a) hydrolysis of diazonium salts to phenols89 (b) reaction with azide ion to form aryl azides90 and (c) reaction with cuprous halides to form aryl chlorides or bromides.91 In the paragraphs that follow, these and other synthetically useful reactions of diazonium intermediates are considered. The reactions are organized on the basis of the group that is introduced, rather than on the mechanism involved. It will be seen that the reactions that are discussed fall into one of the three general mechanistic types. 

Introduction of Other Nucleophiles Using Diazonium Ion Intermediates. Cyano and azido groups are also readily introduced via diazonium intermediates. The former involves a copper-catalyzed reaction analogous to the Sandmeyer reaction. Reaction of diazonium salts with azide ion gives adducts that smoothly decompose to nitrogen and the aryl azide.56... 

The EfZ ratio of stilbenes obtained in the Rh2(OAc)4-catalyzed reaction was independent of catalyst concentration in the range given in Table 22 357). This fact differs from the copper-catalyzed decomposition of ethyl diazoacetate, where the ratio diethyl fumarate diethyl maleate was found to depend on the concentration of the catalyst, requiring two competing mechanistic pathways to be taken into account 365), The preference for the Z-stilbene upon C ClO -or rhodium-catalyzed decomposition of aryldiazomethanes may be explained by the mechanism given in Scheme 39. Nucleophilic attack of the diazoalkane at the presumed metal carbene leads to two epimeric diazonium intermediates 385, the sterically less encumbered of which yields the Z-stilbene after C/C rotation 357,358). Thus, steric effects, favoring 385a over 385 b, ultimately cause the preferred formation of the thermodynamically less stable cis-stilbene. 

These reactions involve addition of the diazoester to an adduct of the carbonyl compound and the Lewis acid. Elimination of nitrogen then triggers migration. Sections B and C of Scheme 10.2 give some additional examples of pinacol rearrangements involving diazo and diazonium intermediates. 

The diazonium intermediate releases molecular nitrogen (N2) to form reactive carbonium ions. If the R group is aromatic, the diazonium intermediates can be stabilized as a salt, and are widely used as intermediates in synthetic chemistry. The formation of a diazonium intermediate with sulfanilic acid by acidified nitrite, a source of nitrosonium ion, is the basis for measuring nitrite by the Griess reaction. 

Concept I in Scheme 4 represents a straightforward synthesis of ben-zoannelated heterocycles (e.g., cinnolines, benzotriazoles) via a diazonium intermediate and a nucleophilic ortho -substituent. While in the many examples, the diazonium group, upon cleavage from the resin, is lost as... 

The diazonium intermediate XXIV is unstable and is explosive under dry conditions. 

This is essentially where the project ended, but it is pertinent to outline some of our work on the preparation of temozolomide itself, especially our efforts to avoid preparation of the potentially explosive diazonium intermediate (XXIV in Scheme 14) and the use of methyl isocyanate. 

New Chemistry for the Preparation of Temozolomide. The three main disadvantages of the present synthesis (Scheme 14) were outlined earlier. Of these only the first two, the potential explosivity of the diazonium intermediate (XXIV) and the toxicity of methyl isocyanate, can be addressed. In the first, the handling of the potentially explosive intermediate is best accommodated by ensuring that this material remains wet at all times. Thus, avoiding the preparation and use of methyl isocyanate became the primary objective. 

Particularly useful is a synthetic approach utilizing the diazotization of 0-alkynylanilines 222 followed by cyclization of intermediate diazonium salts 223 (the Richter method) (Scheme 128) . In this reaction a nucleophile attacks the C(l) of the alkyne moiety in the diazonium intermediate 223, allowing substitution in the C(4) position of the cinnoline 224. Classically, water was used as the attacking species in the Richter reaction but more recently chloride and bromide nucleophiles have been successfully utilized <1995LA775, 2004T7983>. 

Many different variants of the thermal Balz-Schicmann reaction conditions, either in the preparation of the diazonium intermediate or in the thermal decomposition of this intermediate, have been repot ted. Thus, nitrites other than sodium nitrite have been used, e.g. isopcntyl nitrite in the preparation of fluorinated benzo[/j]- and benzo[ quinolines. Copper powder has been described as a catalyst in the preparation of a diazonium tetrafluoroborate from the corresponding amine with sodium nitrite/tetrafluoroboric acid, while fluoride salts, such as... 

Diazonium intermediates have also been employed in the synthesis of pyrazoles. A convenient one-pot procedure for the preparation of 3-phenyl- or 3-pyridylpyrazoles 27 from the 1,3-dipolar cycloadditions of phenylacetylene or 3-(pyridyl)acetylene with diazo compounds 26 generated in situ from aldehydes 25 has been reported <03JOC5381>. Cyclization of ortho-(arylethynyl)benzene diazonium salts 28 having substituents at the para-position of the aryl ring furnished indazoles 29 <03TL5453>. 

Mechanistically the reaction proceeds via a diazonium intermediate that undergoes cyclization by intramolecular nucleophilic attack, nitrogen being the leaving group. However, an alternative mechanism involving thiadiazole 5-oxide formation cannot be excluded80. 

Generation of a diazonium intermediate (619) from nitrosourea (618) gave products, which are derived from intermediate 620 (equation 161). Surprisingly, in this special case the C(l)-C(2)-bond of the cyclopropane was cleaved. In contrast, diazonium species of a 3-oxa-bicyclo[4.1.0]heptyl or 3,5-dioxabicyclo[5.1.0]octyl system decomposed via an... 

Examples of the chemical reaction method are the assay of sulfonamide by the Bratton-Marshall procedure. The drug in solution is reacted with sodium nitrite to form an unstable diazonium intermediate. This unstable salt couples with a reagent yielding a reaction product with an intense color. The dye-salt extraction method may also be exemplified by the assay of atropine. Atropine in solution reacts with bromthymol blue at an appropriate pH. After shaking, the color complex formed is extracted from the aqueous layer into the organic layer and measured quantitatively. 

The conversion of 3-deoxy-3-hydrazino-l,2 5,6-di-0-isopropylidene-n-allofuranose into the corresponding 3-deoxy-3-halo-D-glucose derivative by A-iodo-, A-bromo-, or A-chloro-succinimide may proceed by way of a diazonium intermediate formed by initial oxidation of the hydrazino derivative. The reaction is, however, probably more complex, as the oxidation by iodine in aqueous potassium iodide gave the gem di-iodo derivative. ... 

It became clear much later that diazoalkanes are obtained only if deprotonation of the metastable diazonium intermediate is faster than the dediazoniation or, in other words, if the C(a) —H bond is less stable than the C(a)—N(a) bond. This is the case for aliphatic amines containing a C(a)-atom substituted by an acidifying group. 

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