Azides, hydrogenolysis

Functional groups that are stable to reduction during azide hydrogenolysis include benzyl ester, alkyl chloride, benzyl ether, epoxide, alkoxy imine, hydrazone, nitrile, aldehyde, and ketone (Scheme 33)P9H43]... 

The 2,6-dimethylbenzyl ether is considerably more stable to hydrogenolysis than is the benzyl ether. It has a half-life of 15 h at 1 atm of hydrogen in the presence of Pd-C whereas the benzyl ether has a half-life of —45 min. This added stability allows hydrogenation of azides, nitro groups, and olefins in the presence of a di-methylbenzyl group. ... 

The azidomethyl ether, used to protect phenols and prepared by the displacement of azide on the chloromethylene group, is cleaved reductively with LiAH4 or by hydrogenolysis (Pd-C, H2). It is stable to strong acids, permanganate, and free-radical brominations. ... 

Hydrogenolysis of the azide 9 furnished the amino derivative 10, which was subsequently coupled with W-tert-butyloxycarbonylaspartate (16) (11) in the presence of ethyl 2-ethoxy-1,2-dihydroquinoline-l-carboxylate (EEDQ) (17). 

Alternatively organic azides can easily be transformed into primary amines via a Staudinger reaction and subsequent hydrogenolysis (19HCA635 21HCA861 81T437 910PP1). 

Treatment of the alcohol ( ) with trifluoromethylsulfonic anhydride (triflic anhydride) at -78 C afforded the ester (1 ) which could be isolated and characterized. We knew from previous experience (2J that sulfonyl esters vicinal to an isopropylidene acetal are relatively stable. The triflate T,) reacted cleanly with potassium azide and 18-crown-6 in dichloromethane at room temperature. The crystalline product [68% overall from (1 )] was not the azide ( ) but the isomeric A -triazoline ( )- Clearly the initially formed azide (18) had undergone intramolecular 1,3-cyclo-addition to the double bond of the unsaturated ester (21- ). The stereochemistry of the triazoline (1 ), determined by proton nmr spectroscopy, showed that the reaction was stereospecific. There are several known examples of this reaction ( ), including one in the carbohydrate series ( ). When the triazoline was treated with sodium ethoxide ( ) the diazoester ( ) was rapidly formed by ring-opening and was isolated in 85% yield, Hydrogenolysis of the diazo group of (M) gave the required pyrrolidine ester ( ) (90%). 

The uniquely distinguished axial alcohol at C5 was activated by triflation and the resultant triflate was displaced by the action of tetra n-butylammonium azide in benzene at room temperature. Compound 25 was thus available in 86% yield from alcohol 24. Hydrogenolysis ((H24 d(OH)2C) followed by acetylation afforded compound 26 in 96% yield. TTie richly detailed NMR spectrum (490 MHz) of 26 was identical in every respect with that of the L-antipode derived from reaction of NeuSAc, first with acidic methanol and then with benzoyl chloride under the influence of DMAP. The infrared and mass spectra, as well as the chromatographic characteristics of the two materials, were identical. 

Semicarbazones of peptide aldehydes are stable to hydrogenolysis and various coupling procedures (azide and mixed anhydride). Deprotection of the Z-protected amino acid semicarbazones, such as Z-Phe-H semicarbazone, by catalytic dehydrogenation gives the deprotected derivatives in good yields,these can be coupled to peptide azides or peptide acids using the mixed anhydride procedure. The semicarbazone is readily deprotected with 37% formaldehyde/HCl to give the peptide aldehyde. 

---