Hydrazoic acid, reaction with alkenes

The pattern of addition in polyenes in which the double bonds are neither contiguous nor conjugated does not require special comment. Compounds with conjugated double bonds are somewhat more susceptible to electrophilic addition than simple alkenes but nevertheless there appear to be no literature reports of such compounds undergoing addition reactions with hydrazoic acid in the absence of a catalyst. 

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. 

The Schmidt reactions refer to the acid-catalyzed reactions of hydrazoic acid with electrophiles, such as carbonyl compounds, tertiary alcohols and alkenes. These substrates undergo rearrangement and extrusion of nitrogen to furnish amines, nitriles, amides or imines. 

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... 

Hydrazoic acid is a reagent in the well-known Schmidt reactions in solution, but imidogen is probably not involved in these transformations. Systematic mechanistic studies of the photochemistry of HN3 in solution and the chemistry of NH with hydrocarbons, particularly cis- and trans- alkenes as per the detailed studies of CH2, have not been performed. 

Denson (Ref 9) on those a-azidoalkylidenimines which undergo cyclic isomerizations to tet-razoles and Boyer Canter (Ref 15) made a thorough survey of the available information on alkyl and aryl azides. Cirulis Straumanis (Ref 6) prepd a number of new azides of org bases bur none of these azides showed eiqjl props. Schaad (Ref 14) obtd a patent for the manuf of esters of hydrazoic acid based on the reaction of alkenes, cyclic olefins, ary 1-alkenes cycloalkylalkenes with HN3 in the presence of an acid catalyst... 

Related reactions of the substituted alkenes 176 and 178 with basic nucleophiles such as ammonia occur at C-3 and C-2, respectively, to give the thermodynamically favored gluco adducts 177200 and 179.201 Alternatively, the nitroalkene 178, under neutral or weakly acid conditions, adds nucleophiles such as hydrazoic acid, hydrogen cyanide-potassium cyanide, or purine bases at C-2 to give the a-manno products.201... 

The addition of hydrazoic acid to alkenes is generally catalyzed by Lewis acids and proceeds through the formation of intermediate carbocations1-4. The reaction can also be performed with alcohols, precursors of alkenes by dehydration, and enol ethers4. The addition is generally not stereoselective with simple alkenes, and only moderately stereoselective with substituted 1-phenylcyclohexenes and -cyclohexanols104-105, but a few examples of diastereoselective addition to steroidal alkenes have been reported. 

Hydrazoic acid is conveniently prepared in situ by hydrolysis of azidotrimethylsilane over silica gel. Only a catalytic amount of trifluoromethanesulfonic acid is required to achieve the hydroazidation of cyclic alkenes the completion of the reaction is preferentially controlled by gas-chromatographic analysis, as prolonged reaction time causes the partial decomposition of the organic azide by the acid catalyst. From norbornene the exo-azide 5 was exclusively produced, but no diastereoselectivity was observed with 1,2-dimethylcyclohexene106. 

The cycloaddition of hydrazoic acid and of organic azides to alkynes to give 1,2,3-triazoles is possible in almost all combinations. Ring opening reactions, in analogy to those of alkenes (see Scheme 2-67), are, in general, possible only with alkynes substituted by amino and alkoxy groups, i. e., with ynamines and ynyl ethers. 

The hydrohydrazination represented a general solution for the amination of alkenes, but the protected hydrazines obtained are sometimes difficult to transform to the free amines. At this point, we turned to sulfonyl azides as nitrogen sources, based on then-capacity to react both with enolates and carbon-centered radicals. Mechanistic investigations of the hydrohydrazination reaction had suggested a radical character for the formed organocobalt intermediate. " We were pleased to see that the Cobalt-catalyst 4 was able to promote the hydroazidation of 4-phenylbut-l-ene (3) with ethanesulfonyl azide (7), giving the product derived from the formal Markovnikov addition of hydrazoic acid onto the C-C double bond exclusively, albeit in moderate yields (50%). 

This method is unusually mild, using neutral conditions and low temperatures (20 °C and less). It tolerates a number of functional groups in the components (e.g. acetals, esters, alkenes, etc.)- The alcohol, the carboxylic acid and triphenylphosphine are treated dropwise in an inert solvent (dichloromethane, THF, ether) with diethyl azodicarboxylate (DEAD). The ester is formed rapidly. However, tedious chromatography is frequently required to remove the by-products, triphenylphosphane oxide and hydrazo ester. The main value of the reaction lies in the clean inversion of configuration at a secondary carbinol center and in its selectivity towards primary hydroxy groups (vide infra). Inversions are usually performed with benzoic or p-nitrobenzoic acid. The benzoates are purified and saponified with aqueous base to furnish the inverted alcohols in overall yields of ca. 50%. Elimination is the main side reaction. Thus, from (44) 75% of the desired Sn2 product (45) is formed, along with 25% of the elimination product (46) (equation 19). The mechanism of the reaction has been clarified to the point that betaine (47) is the pri-... 

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