[185-80-8] · C6H11NO · 1-Oxa-2-azaspiro[2.5]octane · (MW 113.18)
(selective electrophilic aminating agent for N-, S-, C-, and O-nucleophiles;1 transfers either the NH function or the entire cyclohexylideneamino unit)
Alternate Name: 3,3-pentamethyleneoxaziridine.
Solubility: sol toluene, ether, chloroform, and other organic solvents; insol H2O.
Form Supplied in: freshly prepared solutions in organic solvents, preferably toluene, 0.2-0.5 M; main impurities are excess cyclohexanone from the preparation and N-chlorocyclohexylimine (5-10%), both in most applications without influence.
Preparative Methods: a mixture containing 125 mL of toluene, 25 mL of cyclohexanone, 25 mL of 2 N NH3 soln, and 100 g of finely crushed ice is shaken in a separatory funnel with 50 mmol NaOCl soln. (e.g. 31 mL of a 1.6 M soln.) for 30 s. The upper layer is washed with 0.1 N HCl and can be used directly for amination reactions or it can be dried with Na2SO4 or by removing of some solvent in vacuo.2 Solutions having less remaining cyclohexanone can be obtained from the reaction of hydroxylamine-O-sulfonic acid with cyclohexanone and NaOH.3
Analysis of Reagent Purity: redox titration:2 a 2 mL aliquot of the reagent soln. is added to 12 mL of acetic acid and 3 drops of a concentrated solution of KI in H2O; titration of the liberated iodine by 0.2 N thiosulfate soln. until decolorization (concn. in mol L-1 = 0.05 mL of S2O32- soln.).
Handling, Storage, and Precautions: solutions of the reagent are stable at 0-20 °C for 1-6 weeks without loss of more than 15% of the initial activity. Appropriate precautions should be taken for some evolution of gases during storage. With 0.2-0.4 M solutions, no problems have been encountered on a 0.1-2000 L scale. Use in a fume hood. Caution: no experience with solutions having reagent concentration of more than 0.5 mol L-1 has been acquired in the authors' laboratory or is reported in the literature.
Secondary amines are aminated by oxaziridine (1) at 20-30 °C within a few minutes, yielding cyclohexanone hydrazones which can be hydrolyzed to the free hydrazines or used for further transformations (eq 1),1 e.g. morpholine,2 tetrahydroisoquinolines.4 With 2,4-dibromo-6-(trans-4-hydroxycyclohexylaminomethyl)aniline, the amination takes place at the aliphatic amino group exclusively.1
Primary aliphatic amines are not aminated selectively or, if deactivated, they need higher temperatures (80-100 °C), e.g. amino acids,1 peptides,5 and 2-aminophosphonates.6 Aromatic and heteroaromatic amines can be aminated after acetylation and (partial) deprotonation (1,4-Diazabicyclo[2.2.2]octane). Thus even 3-hydrazinopyridines can be obtained, whereas other amination reagents exclusively attack the ring nitrogen.7
All (potential) thiols react exothermically with the reagent. Hydrolysis of the primary intermediate yields cyclohexanone and sulfenamides (eq 2). Elimination of water yields cyclohexanone thioximes (eq 3). Depending on the nature of the other functional groups in the starting material, the sulfenamides or thioximes can be stable or undergo further reactions to give a variety of heterocyclic products. A third possibility to be considered is the formation of sulfur-free final products.1
For example, the following heterocyclic compounds can be prepared using oxaziridine (1):
Hydrophilic cyanoacetic amides are converted into a-amino malondiamides by (1) in toluene/2 N NaOH (eq 4). Less hydrophilic cyanoacetic amides yield cyclic spirocyclohexane glycine amides with DABCO as base. Cyanoacetic amides, monosubstituted at the N-function, can give ring transformed amination products. Double amination often predominates, giving stable a,a-diamino acid derivatives (eq 5).11 All reactions are finished after few minutes at 0-20 °C, with complete hydration of the nitrile group. In some cases only 5 mol % of the base DABCO is necessary.11
Many other CH acidic compounds can be aminated by oxaziridine (1) if the generation of the carbanion can be realized under mild conditions.11 However, nitrobenzyl aryl sulfones are converted into aryl aldehydes or ketones.12 In contrast to other oxaziridines no direct hydroxylation reactions have been observed with (1).
Aziridines are obtained in 20-68% yield from substituted styrenes, acrylonitrile (41% 2-cyanoaziridine), and norbornene (20% exo-product). Cyclohexene gives the corresponding N-aminoaziridine by successive C- and N-amination.13
Possible conversions, e.g. water to hydroxylamine, methanol to cyclohexanone oxime O-methyl ether (40%),14 are not of preparative value.
Siegfried Andreae & Ernst Schmitz
Institut für Angewandte Chemie, Berlin-Adlershof, Germany