R NH OH O R’’ R’ N OH R R [Ox] N O R R + - N O R R’ R’’ + - -H 2 O 1 2 3 4 5 R NH OH O R’’ R’ N OH R R [Ox] N O R R + - N O R R’ R’’ + - -H 2 O 1 3 4 5 TETRAHEDRON LETTERS Tetrahedron Letters 42 (2001) 6503–6505 Pergamon Manganese dioxide oxidation of hydroxylamines to nitrones Stefano Cicchi,* Marco Marradi, Andrea Goti and Alberto Brandi Dipartimento di Chimica Organica ‘Ugo Schiff’, Universita` degli Studi di Firenze and Centro di Studio CNR sulla Chimica e la Struttura dei Composti Eterociclici e loro Applica zioni (CSCEA), via G. Capponi 9, I -50121 Florence, Italy Received 29 June 2001; accepted 9 July 2001 Abstract—Several structurally differentiated N,N-dialkylhydroxylamines were oxidised to the corresponding nitrones using MnO 2 . Manganese dioxide revealed an efficient and mild reagent for oxidation of hydroxylamines, showing a level of regioselectivity comparable to HgO. Its non-toxicity makes MnO 2 the reagent of choice for replacing HgO in this oxidation. © 2001 Elsevier Science Ltd. All rights reserved. Nitrones are useful synthetic tools displaying a high reactivity, mainly as 1,3-dipoles in cycloaddition reactions 1 or as imines in nucleophilic additions, 2 that allows the straightforward synthesis of structurally complex molecules with a high degree of selectivity. Condensation of a N -alkylhydroxylamine with a car- bonyl compound and oxidation of a N,N -dialkylhy- droxylamine are the two commonest methods for the synthesis of nitrones (Scheme 1). 3 Recently, the second strategy was used to obtain a variety of enantiopure five membered cyclic nitrones. 4 Many methods have been employed for the oxidation of N,N -dialkylhydroxylamines into the corresponding nitrones. However, many of them lack generality and the most widely used oxidant for this transformation is yellow HgO. 3 Mercury oxide has proven a mild and selective oxidant for this class of compounds, but its high toxicity together with the large excess that is needed to ensure complete oxidation, raises severe con- cerns regarding its use and disposal. This issue prompted the development of alternative methods. Var- ious metal (copper, silver, lead and ruthenium) salts as well as organic oxidants and (salen)Mn(III) complexes proved useful for this oxidation. 3,5 Recently, we have reported an environmentally friendly oxidation method with bleach; 6 this method resulted valuable and general although it suffered from low yields for water soluble nitrones and low regioselectivity with non-symmetri- cally substituted dialkylhydroxylamines. In this com- munication we propose MnO 2 as a valid non-toxic substitute of HgO for the oxidation of N,N -dialkylhy- droxylamines. Manganese(IV) oxide is a well known oxidant for the dehydrogenation of activated alcohols and amines, as well as for the oxidative cleavage of 1,2-diols and has found broad application due to the mildness of the reagent. 7 A perusal of the literature showed that MnO 2 was used only occasionally for the oxidation of hydroxylamines with peculiar structures to the corresponding nitrones, 8 and has never reached the reputation of a first choice reagent for this reaction. The oxidation of several structurally differentiated hydroxylamines with commercial MnO 2 (‘activated’, 90% purity, Fluka catalogue no. 63548) gave nitrones in good to excellent yield (Table 1). Open-chain hydroxylamines 6–9 afforded the more sta- ble Z stereoisomers in over 90% yield, with 8 and 9 the oxidation took place only on the more reactive benzylic position. Substituted N -hydroxypyrrolidines, either at C -2 and C -3, allowed the evaluation of the regioselec- tivity of the reaction. Hydroxylamine 10 afforded a Scheme 1. Keywords : nitrones; hydroxylamines; manganese dioxide; oxidation; green chemistry. * Corresponding author. E-mail: stefano.cicchi@unifi.it 0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII:S0040-4039(01)01222-9