Study On The Synthesis And Application Of Novel Asymmetric Azo Reagents In Mitsunobu Reaction

The Mitsunobu reaction has found a wide range of applications due to its stereoselectivity,versatility,effectiveness and mild reaction condition,especially in the field of pharmaceutical industry.So far,the most commonly used azo reagents for Mitsunobu reactions are diethyl azodicarboxylate(DEAD)and diisopropyl azodicarboxylate(DIAD).Although they are widely used in a variety of organic reactions,their disadvantages are significant,such as being sensitive to light,heat,impact,prone to explosion,needing to be stored under low temperature in dark and dry environment.In addition,their hydrazine by-products after Mitsunobu reaction are easily dissolved in common solvents like toluene,CH2Cl2,THF,which cause some difficulties in the separation.What's more,the hydrazine by-products are usually treated as waste,causing serious waste.Based on that,after carefully studying the related literatures on Mitsunobu reaction,we proposed a novel asymmetric azo reagent 1-(tert-butyl)-2-(4-substituted benzyl)azodicarboxylate,which to be expected to overcome the shortcomings of the traditional azo reagents.The main contents of this paper contain the exploration of new azo reagent synthesis route and the selecting of the azo reagents,the study on relevant properties of the selected 1-(tert-butyl)-2-(4-chlorobenzyl)azodicarboxylate(tBCAD),and the application of tBCAD in Mitsunobu reaction.First,the synthetic routes of azo reagents-the Triphosgene route and the CDI route were designed.Eventually,the Triphosgene route was discarded due to the unavoidable generation of a large amount of benzyl chloride by-product.However,the desired azo reagents can be successfully synthesized via the CDI route.The CDI route was that alcohol was first reacted with N,N'-carbonyldiimidazole(CDI)at room temperature to form imidazole-1-carboxylic acid-(4-substituted)benzyl ester.Then,imidazole-1-carboxylic acid-4-substituted benzyl ester was reacted with hydrazine hydrate under ice-water condition to produce hydrazinecarboxylic acid-4-substituted benzyl ester.Hydrazinecarboxylic acid-4-substituted benzyl ester was reacted with di-tert-butyl dicarbonate((Boc)2O)at 25? to give 1-(tert-butyl)-2-(4-substituted benzyl)hydrazide dicarboxylate.Finally,1-(tert-butyl)-2-(4-substituted benzyl)hydrazide dicarboxylate was oxidized to 1-(tert-butyl)-2-(4-substituted benzyl)azodicaboxylate by N-bromosuccinimide(NBS).The key products of each step were confirmed by melting point,1H NMR,13C NMR and elemental analysis.This synthetic route is safe,easy to operate and high yield(total yields of four steps were between 66.9%and 75.2%).After the desired azo reagents were successfully synthesized,an appropriate azo reagent 1-tert-butyl-2-(4-chlorobenzyl)azodiboxylate was selected by studying its stability at room temperature and reactivity in Mitsunobu reaction.DIAD and tBCAD were subjected to thermogravimetric analysis(TGA)and preservation experiments at 25?,40?,55? and 70?,respectively.The experimental results showed that tBCAD was stable at room temperature and had a wider applicable reaction temperature range than DIAD and exhibited better stability than DIAD.Then the solubility of tBCAD's precursor in toluene at 25? was studied by gravimetric method.The experimental results showed that it was 0.00442 g/mL.Finally,DIAD and tBCAD were applied to the Mitsunobu reaction to perform 12 sets of parallel control trials.The experimental results showed that the reactivity of tBCAD in Mitsunobu reaction was comparable to that of DIAD.Thus,tBCAD can be used instead of DIAD for Mitsunobu reactions.