Hydrazoic Acid Additions

Table 5. Synthesis of azides by hydrazoic acid additions to conjugated olehns...

Alkynes undergo 1,3-dipolar addition reactions with organic azides to form triazolesCommonly, hydrazoic acid additions to alkynes also give triazoles and this aspect of their chemistry has been... 

David s group have applied their diene approach to disaccharides to the synthesis of kasuganobiosamine (30). Cycloaddition of the dienyl ether (31) with menthyl glyoxylate gave a glycal which was converted to the glyceno-sidulose (32) which, in turn, led to (30) by sequential hydrazoic acid addition, oximation, reduction, and deblocking. ... 

The conjugate acid (II) may also be formed by the addition of hydrazoic acid to an acylium (carbonium) ion ... 

The intermediates in making amines are isocyanates (0==C==N) just like the Hofmann Rearrangement. The isocyanates are decomposed with water, just like the Hofmann. In fact, there is a lot of similarity between the Hofmann and the Schmidt reactions. Before I detail the synthesis steps, I should note that if you wish to generate the Hydrazoic Acid in the flask by adding Sodium Azide, you might need a powder addition funnel. This bit of equipment is quite pricey and it s likely you won t have one, so the first part of the synthesis details how to make the Hydrazoic Acid separately. 

Azides have been shown to react with itniniutn salts to give addition products. The same product is obtained if the iminium salt is treated with azide ion or if the enamine is treated with hydrazoic acid 14). The yields of the products were all very high (85-95 %). The interest in this reaction centers on the fact that the azides react with isonitriles to give substituted tetrazoles (83) 44). 

CAUTION All azides, particularly low molecular weight acyl and alkyl azides, are explosive, and great care should be taken while preparing and handling these materials. In addition, hydrazoic acid, which is liberated from unbuffered aqueous solutions of sodium azide, is highly toxic and all operations involving its use should be carried out in an efficient fume hood. 

In the formation of tert-butyl azidoformate by the addition of phosgene to alcohols followed by the addition of Na nitride or hydrazoic acid in the presence of pyridine, reaction of phosgene with the azide can cause the formation of expl carbazide (Ref 9)... 

There are actually three reactions called by the name Schmidt reaction, involving the addition of hydrazoic acid to carboxylic acids, aldehydes and ketones, and alcohols and alkenes. The most common is the reaction with carboxylic acids, illustrated above.Sulfuric acid is the most common catalyst, but Lewis acids have also been used. Good results are obtained for aliphatic R, especially for long chains. When R is aryl, the yields are variable, being best for sterically hindered compounds like mesi-toic acid. This method has the advantage over 18-13 and 18-14 that it is just one laboratory step from the acid to the amine, but conditions are more drastic. Under the acid conditions employed, the isocyanate is virtually never isolated. 

Addition of hydrazoic acid to carboxylic acids (Schmidt)... 

Fig. 36 Catalytic cycle for the Br0nsted-base catalyzed addition of phenols, hydrazoic acid, or 2-cyanopyirol to ketenes...

Fig. 37 Addition of phenols, 2-cyano-pyrrol, or hydrazoic acid to ketenes...

The addition products of hydrazoic acid and isocyanates have been used as intermediates in the synthesis of monophosphazenes ... 

Carboxylic acids and esters can also be converted to amines with loss of the carbonyl group by reaction with hydrazoic acid, HN3, which is known as the Schmidt reaction,278 The mechanism is related to that of the Curtius reaction. An azido intermediate is generated by addition of hydrazoic acid to the carbonyl group. The migrating group retains its stereochemical configuration. 

The addition of hydrazoic acid to carbon—nitrogen unsaturated bonds as in hydrogen cyanide, nitriles, and isonitriles leads to unsubstituted, 5-, or... 

Nitrilium salts, e.g., 66, prepared from the alkylation of nitriles, react with sodium azide to yield 1,5-disubstituted tetrazoles, e.g., 67 (Scheme 7).121 The Schmidt reaction,122 a versatile method for the preparation of 1,5-disubstituted tetrazoles from ketones and hydrazoic acid, can now be regarded as a special case of azide addition to nitrilium salts.123... 

Besides addition reactions, azides or hydrazoic acid can also yield tetrazoles through displacement reactions. Thus, halide displacement in imide chloride (78) yields 1,5-disubstituted tetrazoles (79), and in 2-chloro-pyridine (80), yields tetrazolopyridine (81) (Eq. 16a,b).141 143 Vinylogous... 

With a common intermediate from the Medicinal Chemistry synthesis now in hand in enantiomerically upgraded form, optimization of the conversion to the amine was addressed, with particular emphasis on safety evaluation of the azide displacement step (Scheme 9.7). Hence, alcohol 6 was reacted with methanesul-fonyl chloride in the presence of triethylamine to afford a 95% yield of the desired mesylate as an oil. Displacement of the mesylate using sodium azide in DMF afforded azide 7 in around 85% assay yield. However, a major by-product of the reaction was found to be alkene 17, formed from an elimination pathway with concomitant formation of the hazardous hydrazoic acid. To evaluate this potential safety hazard for process scale-up, online FTIR was used to monitor the presence of hydrazoic acid in the head-space, confirming that this was indeed formed during the reaction [7]. It was also observed that the amount of hydrazoic acid in the headspace could be completely suppressed by the addition of an organic base such as diisopropylethylamine to the reaction, with the use of inorganic bases such as... 

The addition of methanol or hydrazoic acid to ethenylidenecydopentadiene 3 demonstrates that 3 behaves like an acceptor-substituted allene (Scheme 7.27) [226, 227]. More examples of nudeophilic additions to alkyl-substituted derivatives of 3 were reported by Hafner [228]. Photoelectron spectroscopy of the spirocyclic compound 165b, easily accessible from azide 164b, shows that the lone-pair orbital n(N) of the 2H-azirine nitrogen atom interacts strongly with the Jt1-orbital of the cyclo-pentadiene ring [227]. 

A one-pot procedure for the conversion of alcohols into alkylamines is by treatment of the former with hydrazoic acid in the presence of triphenylphosphine and diisopropyl azodicarboxylate addition of triphenylphosphine to the resulting azide gives an hninophosphorane, which is hydrolysed to the alkylamine by water (equation 8)35. 

Elimination of HI, which in the presence of an excess of IN3 can form hydrazoic acid, followed by its addition to the vinyl azides can give an intermediate triazide 75. The same compound could arise directly by substitution of one iodine atom by an azido group. The intermediate 75 has been considered to undergo a transannular reaction with homolytic cleavage of the weak C—I bond to form the radical 76, which loses a nitrogen atom to a radical 77. Combination of the two radicals leads to the 2-tetrazene 74 (equation 77). 

Most of the important general methods of forming IZf-triazole derivatives involve azides several reviews discuss aspects of the formation of triazoles in this way. a-Diketones are also important precursors of both H- and 2 f-triazoles. Triazoles unsubstituted on nitrogen can be prepared by the direct addition of hydrazoic acid or of azide ion, but it is often more convenient to obtain these compounds by removal of a substituent from a H- or 2if-substituted triazole (Section IV, E). 

Kinetic studies using the water-soluble nitrile li revealed first-order dependence in both nitrile and azide and one-half order dependence for zinc bromide. The mechanism of the addition of hydrazoic acid/azide ion to a nitrile to give a tetrazole has been debated, with evidence supporting both a two-step mechanism (Scheme 1, eq 2) and a concerted [2 + 3] cycloaddition (Scheme 1, eq 3). Our mechanistic studies to date imply that the role of zinc is not simply that of a Lewis acid a number of other Lewis acids were tested and caused little to no acceleration of the reaction. In contrast, Zn exhibited a 10-fold rate acceleration at 0.03 M, which corresponds to a rate acceleration of approximately 300 at the concentrations typically used. The exact role of zinc is not yet clear. 

P25 Each of these [previous methods] involves one or more of the following drawbacks uses expensive and toxic metals, demonstrates severe water sensitivity, or produces hydrazoic acid, which is highly toxic and explosive as well as volatile. The few methods that seek to avoid hydrazoic acid liberation during the reaction, by avoiding acidic conditions, require a very large excess of sodium azide. In addition, ah of the known methods use organic solvents, in particular, dipolar aprotic solvents such as DMF. This is one of the solvent classes that process chemists would rather not use. (Adapted from Demko and Sharpless, 2001)... 

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