Curtius rearrgment

Rearrangement

1. BY Dr . G.C.Wadhawa DEPARTMENT OF CHEMISTRY K. B. P . College,Vashi,Navimumbai Curtius Rearrangement Reaction

2. In 1857, Theodor Curtius was born in the Prussian Rhineland city of Duisburg, situated at the confluence of the Rhine and Ruhr rivers. Duisburg was then a major site of chemical industry in which the Curtius family held a large stake – Theodor’s grandfather Friedrich Wilhelm had founded a sulfuric acid factory in 1824, and his father Julius had established ultramarine pigment and alum works. After moving to Erlangen, Curtius began to follow a trail in which he discovered a remarkable series of new nitrogen-containing compounds, each following in a logical progression. He was the first to prepare hydrazine (H 2 N–NH 2 ) from diazoacetic acid ,  and filed patents for his production method in both Germany and the US. The availability of hydrazine salts then facilitated the earliest preparation of hydrazoic acid (HN 3 ) which he reported in 1890 using a cyclic structure to represent the azide group .

3. Curtius was the first person to make hydrazine, and then hydrazoic acid – which he represented as a cyclic structure Hydrazoic acid is highly explosive and Curtius declared himself lucky to have been saved from misfortune during its handling – one of his students was less fortunate, losing an eye while preparing the dried material. 5  This led Curtius to investigate the stability of hydrazoic acid salts as a safer alternative to direct synthesis of ‘free’ HN 3 . On the way he uncovered several extremely explosive examples, such as hydrazine azide (N 5 H 5 ) and lead azide ( Pb (N 3 ) 2 ) which was later used as a detonator during the first world war. Now the director of the Institute of Chemistry in Kiel, Curtius combined the strands of his discoveries to finally solve the problem of dangerous HN 3  synthesis. For a man whose earliest work had been in condensation chemistry and who had pioneered hydrazine synthesis, the first preparation of an acyl hydrazine (by condensing a carboxylic ester with H 2 N–NH 2 ) was a natural step (figure 1). Reaction with nitrous acid (HNO 2 ) led to the corresponding acyl azide , and substitution using sodium ethoxide then gave sodium azide (NaN 3 ). Curtius now had a stable precursor to HN 3  (by acidification) described as explosive ‘only by heating at a comparatively very high temperature’ (300°C). The reaction also produces a carboxylic ester that is recycled as the starting material for acyl hydrazine synthesis. Problem solved.

4. Curtius Rearrangement The Curtius Rearrangement is the thermal decomposition of carboxylic azides to produce an isocyanate . These intermediates may be isolated, or their corresponding reaction or hydrolysis products may be obtained. The reaction sequence - including subsequent reaction with water which leads to amines - is named the Curtius Reaction.

5. Mechanism of Reaction

6. Isocyate Reactions

7. Preparation of acyl azide The acyl azide is usually made from the reaction of acid chlorides or  anydrides with  sodium azide  or trimethylsilyl azide .   Acyl azides are also obtained from treating acylhydrazines with nitrous acid. Alternatively , the acyl azide can be formed by the direct reaction of a carboxylic acid with diphenylphosphoryl azide  (DPPA ).

8. Photochemical decomposition of the acyl azide is also possible .  However, photochemical rearrangement is not concerted and instead occurs by a nitrene intermediate, formed by the cleavage of the weak N–N bond and the loss of nitrogen gas. The highly reactive nitrene can undergo a variety of nitrene reactions, such as nitrene insertion and addition, giving unwanted side products .  In the example below, the nitrene intermediate inserts into one of the C–H bonds of the cyclohexane solvent to form N- cyclohexylbenzamide as a side product.

9. Darapsky degradation In one variation called the  Darapsky degradation ,or   Darapsky synthesis , a Curtius rearrangement takes place as one of the steps in the conversion of an α- cyanoester to an  amino acid . Hydrazine is used to convert the ester to an acylhydrazine, which is reacted with nitrous acid to give the acyl azide . Heating the azide in ethanol yields the ethyl carbamate via the Curtius rearrangement. Acid hydrolysis yields the amine from the carbamate and the carboxylic acid from the nitrile simultaneously, giving the product amino acid .

10. Harger reaction The photochemical Curtius-like migration and rearrangement of a phosphinic azide forms a metaphosphonimidate  in what is also known as the  Harger reaction  (named after Dr Martin Harger from University of Leicester ).This is followed by hydrolysis, in the example below with methanol, to give a phosphonamidate .

11. Unlike the Curtius rearrangement, there is a choice of R-groups on the phosphinic azide which can migrate. Harger has found that the alkyl groups migrate preferentially to aryl groups, and this preference increases in the order methyl < primary < secondary < tertiary. This is probably due to steric and conformational factors, as the bulkier the R-group, the less favorable the conformation for phenyl migration.

12. Triquinacene R. B. Woodward  et al. used the Curtius rearrangement as one of the steps in the total synthesis of the polyquinane  triquinacene in 1964. Following hydrolysis of the ester in the intermediate ( 1 ), a Curtius rearrangement was effected to convert the carboxylic acid groups in ( 2 ) to the methyl carbamate groups ( 3 ) with 84% yield. Further steps then gave triquinacene ( 4 ).

13. Oseltamivir In their synthesis of the antiviral drug oseltamivir, also known as Tamiflu , Ishikawa et al. used the Curtius rearrangement in one of the key steps in converting the acyl azide to the amide group in the target molecule. In this case, the isocyanate formed by the rearrangement is attacked by a carboxylic acid to form the amide. Subsequent reactions could all be carried out in the same reaction vessel to give the final product with 57% overall yield. An important benefit of the Curtius reaction highlighted by the authors was that it could be carried out at room temperature, minimizing the hazard from heating. The scheme overall was highly efficient, requiring only three “one-pot” operations to produce this important and valuable drug used for the treatment of avian influenza .

14. Dievodiamine Dievodiamine is a natural product from the plant Evodia rutaecarpa , which is widely used in traditional Chinese medicine. Unsworth et al.’s protecting group-free total synthesis of dievodiamine utilizes the Curtius rearrangement in the first step of the synthesis, catalyzed by boron trifluoride. The activated isocyanate then quickly reacts with the indole ring in an  electrophilic aromatic substitution reaction to give the amide in 94% yield, and subsequent steps give dievodamine .

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