Introduction of a New Azidation Reagent
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Time :2022-12-16
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Organic azides are important intermediates for the synthesis of nitrogen-containing compounds. The azide group is stable in most cases, but it exhibits characteristic reactivity under special conditions. For example, organic azides are reacted with equivalents of primary amines and used in the Staudinger reaction. The photosensitivity of azides has also been widely used for photoaffinity labeling to study the structure of ligand-target receptors and their binding sites. Recently, Cu(I)-catalyzed reactions were found to be very reliable and widely used in click chemistry (link chemistry), whereby the 1,3-dipole reaction (Huisgen reaction) of organic azides and terminal alkynes re-enters organic Central stage in the field of chemical synthesis.

The synthesis methods of organic azides have been developing rapidly, and the nucleophilic substitution reactions with leaving groups in organic azides are more commonly used. Aryl halides and aryl diazonium salts are used as electrophiles, the former requires a strong electron-withdrawing group at the para or ortho position of the leaving group, while the latter is limited as a substrate because the aryl group is heavy Nitrogen salts are highly reactive intermediates. The transfer of diazonium to primary amines by trifluoromethanesulfonyl azide (TfN3) with the aid of catalyst Cu(II) is an alternative method for the synthesis of organic azides. The method is carried out under mild reaction conditions, only one step reaction is required for the conversion and the yield is high. However, TfN3 is explosive and needs to be handled with great care. Recently, it has been reported that imidazole-1-sulfonyl azide hydrochloride can be used as a diazonium transfer reagent. It is a crystalline solid, stable below 80 °C (decomposition temperature), and has almost the same reactivity as TfN3.

Mitsuru's group reported that 2-azido-1,3-dimethylimidazolium chloride (ADMC) is an effective diazo transfer reagent for 1,3-dicarbonyl compounds. In this reaction, the diazotization product is easily isolated because the only detectable by-product, 1,3-dimethyl-2-imidazolidinone (DMI), is readily soluble in water and can be removed by washing the reaction with water to give Higher purity diazo compounds.


figure 1

However, ADMC suffers from poor resolution during its synthesis due to its hygroscopicity. In contrast, the corresponding 2-azido-1,3-dimethylimidazolium hexafluorophosphate (ADMP) has a stable crystal structure with better resolution and a strong tendency to transfer to the primary amine diazo ability. The impact sensitivity test and friction sensitivity test show that the explosiveness of ADMP is within a controllable range, and Figure 2 shows that exothermic decomposition of ADMP is observed at around 200 °C. These results indicate that ADMP can be used safely below its decomposition temperature, preferably not exceeding 100°C, which is more safe and reliable.


figure 2

Select ADMP and para-substituted aniline to carry out the diazo transfer experiment. First, carry out the experiment with 4-methoxyaniline through triethylamine as the base. The reaction proceeds smoothly at room temperature to obtain the corresponding 4-methoxyphenyl azide compounds. In this reaction, the by-product DMI could be detected, similar to the diazotization reaction of 1,3-dicarbonyl compounds mentioned above (Table 1). Because DMI is very different from the target product in polarity, they are easily separated.


Table 1

Then there is the reaction experiment with p-acetanilide, a substrate that is not suitable for diazotization transfer with TfN3. When triethylamine is used as a base, only 8% of the azide is obtained, even if the reaction temperature is increased to 50°C for 7 hours, the effect is not good. Experiments have shown that strong bases or organic bases such as DBU are not suitable for this reaction, but it has been found that pyridine-type bases have a better effect. The yield of DMAP as the base reaches 83%, and the addition of copper sulfate pentahydrate has no significant effect. At the same time, experiments with aniline and ADMC were also done, and the result was that the yield was lower than that of ADMP.

To explore the scope of this reaction, various primary amines were reacted with ADMP using DMAP as base. In experiments 1–13 (Table 2), it was shown that unsubstituted anilines and anilines with electron-donating groups reacted with ADMP at room temperature, both giving the corresponding azides in high yields. Using a slight excess of ADMP to react with monohalogenated aniline at 50°C, the product yield is also very high. Anilines substituted with strong electron-withdrawing groups (such as acetyl, cyano, and nitro) also had good yields under the action of DMAP using excess ADMP. In the case of ortho-disubstituted anilines, the effect of the substituents is significant. Regardless of steric hindrance, anilines with dimethyl groups gave the corresponding azides in good yields, whereas dichloroanilines gave only 22% azides, probably due to low nucleophilicity. 1-Naphthylamine also reacts similarly with the corresponding aniline.

Next, the reaction of ADMP with primary alkylamines was investigated. In the reaction of DMAP with 2-phenylethylamine, only 21% yield was obtained, and 79% guanidine was formed. When using triethylamine as base, the yield increased to 74%. Similarly, in the diazotization of cyclohexylamine, triethylamine is better than DMAP as a base. While secondary alkylamines and tertiary alkylamines have a higher conversion rate when DMAP is used as a base.


Table 2

Studies have shown (Fig. 3) that the highly nucleophilic base in the reaction is more suitable for the highly nucleophilic primary amine, which has two functions: neutralizing the generated acid and activating ADMP. Based on this consideration, when the base is more nucleophilic than the primary amine, the base first reacts with ADMP to generate intermediate I, which is then substituted by the primary amine to generate intermediate II, hexafluorophosphate and base, and intermediate II occurs Intramolecular proton transfer results in the corresponding azides. In the case where the primary amine is more nucleophilic than the base, the primary amine attacks at the a and b positions of ADMP, generating guanidine and the corresponding azide, respectively.


image 3

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