Curtius rearrangement and Wolff homologation of functionalized peroxides

The Curtius and Wolff rearrangements of peroxide-containing alkanoyl azides and diazoketones provide an effi cient entry to peroxysubstituted amines, isocyanates, carbamates, and peroxyalkanoates. Scheme 2. Substrate preparation. Reagents and conditions: (a) tBuO2H, CsOH; (b) KMnO4; (c) m-CPBA; (d) t-BuO2H, BF3OEt2; (e) H2CrO4. 7456 DUSSAULT & XU IN TETRAHEDRON LETTERS 45 (2004) 2. Curtius rearrangements Conversion of the peroxyalkanoic acids to acyl azides was readily achieved via the mixed anhydrides, with the exception of the hindered acid 3a, which required activation as the acid chloride (Table 1).5 The azides were stable to extractive isolation but decomposed upon attempted purifi cation. Heating the crude azides with ethanol in refl uxing benzene directly furnished the ethyl carbamates 1b, 2b, and 4b as stable products. In the case of the hindered azide derived from 3a, thermolysis resulted in decomposition with loss of the peroxide functional group.6 We also briefl y investigated aprotic thermolysis of an azide as an approach to a peroxide-containing isocyanate. Refl uxing the acyl azide derived from 2a in dry benzene furnished a dioxolane isocyanate, which was not isolated but which could be observed by IR (Scheme 3). Hydrolysis of the isocyanate in aqueous acid furnished the aminomethyl dioxolane 5, which underwent coupling with CBZ-Phe to furnish a peroxide-containing amino acid 6. 3. Wolff rearrangement The success of the Curtius rearrangements described above led us to consider the potential of the Wolff rearrangement for preparation of peroxyalkanoates, a functional motif found in a number of marine natural products.7 As shown in Table 2, the peroxyalkanoic acids were easily converted, via the mixed anhydrides or the acid chlorides, to isolable diazomethyl ketones. Reaction of diazoketones 1c or 2c with silver benzoate and triethylamine in methanol furnished the homologated peroxyalkanoates 1d or 2d in excellent yield.8 Application of these conditions to substrate 4c resulted in a poor yield of homologated product, accompanied by signifi cant amounts of the oxodiazoketone, apparently derived from base-promoted decomposition of the starting material (Eq. 1).9 Photochemical Wolff rearrangement (254 nm, methanol) furnished a much better yield of the homologated peroxyalkanoate 4d, accompanied by small amounts of 2,3-epoxynonanoate, which presumably arises via intramolecular attack of a developing ester enolate on the peroxide. Performing the photochemical rearrangement in the presence of a trace amount of acetic acid resulted in an improved yield of peroxyalkanoate. The tertiary peroxide substrate 3c, which failed to give any homologation product in the presence of AgOBz/Et3N, underwent photochemical rearrangement to afford peroxyalkanoate 3d. In conclusion, we have demonstrated the ability to employ the Curtius and Wolff rearrangements for synthesis of peroxylamines or homologated peroxyalkanoates. The ability to homologate 2and 3-peroxyalkanoic acids holds particular promise for synthesis of peroxide natural products while the ability to perform the Curtius rearrangement opens new possibilities for the introduction of natural or unnatural peroxide-containing groups onto polymers and biomolecules. (a) EtOC(O)Cl then NaN3; (b) (ClCO)2 then NaN3; (c) EtOH, benzene, refl ux. Scheme 3. Synthesis of dioxolane isocyanate and aminomethyl dioxolane. Reagents and conditions: (a) EtOC(O)Cl then NaN3; (b) C6H6, refl ux; (c) aq HCl; (d) CBZ-Phe, DCC. Table 1. Curtius rearrangement of peroxylalkanoyl azides Table 2. Homologation via diazoketones (a) EtOC(O)Cl then CH2N2; (b) ClCOCOCl then CH2N2; (c) AgOBz (0.1 equiv), Et3N, MeOH; (d) hν, MeOH, HOAc. CURTIUS REARRANGEMENT AND WOLFF HOMOLOGATION 7457