3,3-Dinitroazetidine (DNAZ) derivatives constitute an important class of energetic materials, with inherently high energies resulting from their strained ring systems and nitrogen contents. 1 In particular, 1,3,3-trinitroazetidine (TNAZ), with its higher nitrogen content, has received considerable attention as a potential high-performance melt-castable explosive in the defense and explosives industries.2 Recently, as an example of possible medical applications of energetic materials, 1-bromoacetyl-3,3-dinitroazetidine (ABDNAZ) was developed as a novel class of anticancer agent and is currently in Phase I clinical trial 3 (Figure 1). Because of this importance of DNAZ in the fields of both drug discovery and energetic materials, we planned to synthesize a variety of 2-substituted-3,3-dinitroazetidine derivatives to develop new pharmaceutical agents and high-energy materials. To the best of our knowledge, the asymmetric synthesis of 2-substituted-3,3-dinitroazetidine derivatives has never been reported despite their versatile applicability in medicinal chemistry. Therefore, we report the asymmetric synthesis of chiral 2-alkyl-3,3-dinitro-1-tosylazetidines 7 via the diastereoselective aza-Henry reaction of 2,2-dimethyl-5-nitro-1,3-dioxane (1) with chiral N-sulfinyl aldimines 2, followed by a Mitsunobu cyclization of dihydroxy sulfonamides 5 as the key steps (Scheme 1).To explore the feasibility of the diastereoselective azaHenry reaction, 4 we treated 1 with (S)-(E)-N-ethylidene-4-methylbenzenesulfinamide (2a) using potassium hydroxide (20 mol %) as the base at 25 C for 24 h in a variety of solvents (Table 1, entries 1-4). Among the solvents tested, CH 2 Cl 2 proved superior, providing the corresponding aza-Henry product 3a in 62% yield as a 12:1 mixture of diastereomers. However, when 2a was replaced with (S)-(E)-N-ethylidene-2-methylpropane-2-sulfinamide (2b) under otherwise identical conditions, the aza-Henry product 3b was obtained with a considerable increase in the diastereomeric ratio (dr, 24.7:1), but with a decrease in yield to 17% (Table 1, entry 5). Finally, increasing the reaction concentration to 0.2 M in CH 2 Cl 2 provided the corresponding aza-Henry product 3a in increased yield (86%) as an 11:1 mixture of diastereomers (Table 1, entry 6). Under the optimized conditions, the aza-Henry reaction with (S)-(E)-N-hexylidene-4-methylbenzenesulfinamide (2c) provided the desired product 3c in 63% yield as a 15.5:1 mixture of diastereomers (Scheme 2).Elaboration of the aza-Henry products 3a,c to the (S)-2-alkyl-3,3-dinitro-1-tosylazetidines 7a,c was achieved in four steps (Scheme 3). Oxidation of the major diastereomers of 3a,c with m-chloroperoxybenzoic acid in CH 2 Cl 2 afforded the sulfonamides 4a,c in excellent yields. The acetonide group in 4a,c was removed by hydrogen chloride in methanol to provide the dihydroxy sulfonamides 5a,c in excellent yields. The Mitsunobu cyclization 5 of 5a was performed with diisopropyl azodicarboxylate and triphenylphosphine in toluene at 50 C, providing the corresponding a...
Enantiopure 2-alkyl-1,3,3-trinitroazetidines 4 were efficiently synthesized by the nitrolysis of enantiopure 2-alkyl-3,3-dinitro-1-tosylazetidines 3 using an excess of fuming nitric acid in CHCl 3 at ambient temperature. In addition, elaboration of (S)-2-(2-methoxyethyl)-1,3,3-trinitroazetidine (4c) was successfully performed to synthesize a variety of enantiopure 2-alkyl-1,3,3-trinitroazetidines 5-7. The advantage of this strategy is that 2-alkyl-1,3,3-trinitroazetidines can be synthesized either asymmetrically or racemically depending on the presence or absence of chirality in N-sulfinyl aldimines 2 used as the starting material. Furthermore, the sensitivity measurement results of racemic 2-methyl-1,3,3-trinitroazetidine (racemic 4a) showed that the introduction of an alkyl substituent at the C2 position of 1,3,3-trinitroazetidine had a significant effect on the sensitivity of the resulting 2-alkyl-1,3,3-trinitroazetidine.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.