Synthesis of a Sterically Hindered Diazirine with a Satisfactory Yield: Optically Active 2-Azicamphane

Abstract

The optimized synthesis of 2-azicamphane (5), a sterically hindered 3,3-dialkyldiazirine, has finally made this interesting chiral diazirine available in useful quantities. The specific reaction conditions are discussed with regard to further general applications for future syntheses of diazirines that, until now, could not be prepared.The recent emergence of diazirines as popular carbene precursors can be attributed to their relative stabilities with regard to acids, bases and heat when compared with other sources. 1 That diazirines are easily photoactivated by long-wave UV light makes them not only suitable for mechanistic studies 1,2 but also as linkers for biochemical applications. 3 Consequently, efficient preparations of these compounds are in demand. Syntheses of sterically hindered 3,3-dialkyldiazirines generally afford very low yields, if anything at all. Just recently, 2-azicamphane (5), the diazirine derived from racemic camphor (1), was synthesized by a two-step approach, however, with a low yield. 4 A modification of the Schmitz diaziridine synthesis 5 starting from the corresponding isolated imine hydrochloride (3) 6 was employed, since all conventional methods failed. Thus, 3 was converted to diazirine 5 in 15% yield by the action of hydroxylamine-O-sulfonic acid (HOSA) followed by oxidation.Reaction sequence for the synthesis of 2-azicamphane (5) Scheme 1Optimization of this yield proved to be very difficult. Several parameters could be critical: (i) the temperature of addition of HOSA, (ii) temperature and waiting period before addition of base, (iii) the type and amount of base added, (iv) the temperature and standing period after addition of base, and (v) the work-up. Hence, a simple and accurate analytical method to monitor the reaction was needed to significantly improve the yield of title compound 5.The direct GC or GC-MS analysis of the reaction mixtures, unfortunately, gave neither reproducible nor definitive results. 2-Hydrazicamphane (4), the reaction product of 3 with HOSA, can be detected by GC. However, this diaziridine partially decomposes during injection to give peaks for other compounds, that may also be formed in the course of the normal reaction (e.g., the corresponding nitrile from Beckmann fragmentation and the azine). Moreover, the amount of decomposition varied substantially, depending on solvent composition and injector conditions that were not controllable. Yet, under the conditions employed, 2-azicamphane (5) gave a distinct GC peak accompanied by a small peak (2-3%) corresponding to the gas phase 1,3 C-H insertion product of the intermediate 2-camphanylidene (1,7,7-trimethyltricyclo[2.2.1.0 2,6 ]-heptane). 7 Thus, a simple oxidative work-up (in microscale) and subsequent GC analysis was employed to monitor the course of the reaction.From these studies, some critical points emerged: (i) Ammonia should be used as the base (tertiary amines gave no yield of the desired product) and the amount of base should be quite low. The best results were obtained when two equivalents of...

Carbene Rearrangements, 60.‡ Supramolecular Structure‐Reactivity Relationships: Photolysis of a Series of Aziadamantane@Cyclodextrin Inclusion Complexes in the Solid State

“…[4] The induced ellipticity of the achiral molecule 1 is strikingly similar to the CD of chiral azicamphane. [9] This close contact with the cyclodextrin obviously also favors the exclusive insertion of Ad: into the secondary hydroxy groups of 6-Cy and the redox reaction yielding adamantane (2) and oxidized 6-Cy derivatives. Apparently, these reactions do occur less within the complexes of hosts providing larger cavities.…”

Three‐Membered Heterocycles. Structure and Reactivity

“…However, diaziridine precursors can serve as suitable substrates for various one-pot procedures. Thus, the camphor-derived iminium salt 751 was converted into the sterically hindered chiral diaziridine 2-azicamphane 752 by treatment with hydroxylamine O-sulfonic acid in methanolic ammonia, followed by oxidation with iodine in the presence of triethylamine [743]. Ketones can also be used to advantage in this regard, as illustrated by the construction of the diaziridinyl cluster mannoside 754 from ketone 753 [744].…”