Reactivity of the 4‐Amino‐5H‐1,2‐Oxathiole‐2,2‐Dioxide Heterocyclic System: A Combined Experimental and Theoretical Study

Abstract

The reactivity of the 4-amino-5H-1,2-oxathiole-2,2-dioxide (or beta-amino-gamma-sultone) heterocyclic system has scarcely been studied. Here we describe the reactivity of this system towards electrophiles and amines on readily available model substrates differently substituted at the C-5 position. A variety of C-electrophiles, carbonyl electrophiles (such as acyl chlorides, isocyanates, or aldehydes) and halogen or nitrogen electrophiles have been explored. Both the C-3 and 4-amino positions of the beta-amino-gamma-sultone system are able to undergo electrophilic reactions, and the reaction products depend on the electrophile used and on the reaction conditions. On the other hand, nucleophilic attack of amines occurs at the C-4 position of the beta-amino-gamma-sultone system only in spiranic substrates bearing alicyclic substituents at the C-5 position. A comparative computational study between spiranic and non-spiranic substrates suggests that conformational changes, undergone on intermediate compounds, account for the observed reactivity differences. Moreover, these conformational changes seem to bring about an increase of electron density on the N-4 and C-3 atoms of the enaminic system, and a possible enhancement in the reactivity of spiranic substrates towards electrophiles in the presence of amines. Experimental data consistent with this predicted enhanced reactivity is also presented.

From β‐Amino‐γ‐sultone to Unusual Bicyclic Pyridine and Pyrazine Heterocyclic Systems: Synthesis and Cytostatic and Antiviral Activities

“…The required 4-(dimethylaminomethylene)amino sultone intermediates 14 a,b (Scheme 4) were easily prepared by condensation of 1 a,b with N,N-dimethylformamide dimethyl acetal (DMF-DMA) in excellent yields as previously described. [9] Reactions of 14 a,b with olefins such as methyl acrylate, methyl vinyl ketone, and methyl vinyl sulfone in the presence of palladium acetate in acetic acid under reflux resulted in the direct formation of the corresponding 6-substituted pyridosultones 15 a,b, 16, and 17 in moderate yields (34-51 %) (Scheme 4). However, an analogous treatment of 14 a,b with styrene or 4-chlorostyrene failed to give the desired 6-aryl derivatives 6 and 7; instead, complex mixtures of unidentified products were detected, in contrast to a previous report by Hirota and co-workers in which successful oxidative coupling and cyclization reactions with styrene-type olefins were described.…”

“…As shown in Scheme 6, formation of this novel bicyclic heterocyclic system was carried out in three steps: nitrosation, reduction of the nitroso group to the amine, and then ring closure with 1,2-dicarbonyl electrophiles as two-carbon source. Nitrosation of b-amino-g-sultones 1 a,b was carried out as previously described [9] with sodium nitrite in acetic acid to give the required 3-nitroso sultone derivatives 23 a,b [9] in good yields. Quantitative reduction of the nitroso group to the amine was achieved by catalytic hydrogenation of 23 a,b in the presence of 5 % Pd/ C in DMF at 30 8C.…”

“…The b-amino-g-sultones 1 a,b (Table 1), prepared from commercially available ketones as previously described, [9] were selected as simple and readily available substrates for our studies. In the beginning, we directed our efforts to the synthesis of the pyridosultone heterocyclic system I.…”

“…One of the interesting features of this system is its ambident nucleophilicity; nucleophilic reactions can take place either at the site of the enaminic carbon (C3) or at the primary amino nitrogen depending on the nature of the electrophile and the reaction conditions. [9] In our ongoing research on the chemistry and biological applications of this system, [4,5] we now explore for the first time the synthetic usefulness of this ambident nucleophile for the preparation of unusual fused nitrogen heterocyclic systems containing a g-sultone moiety, and evaluate these novel structures against HIV, HCMV, VZV, and a broad variety of other DNA/RNA viruses. In spite of the poor nucleophilicity of the amino group, which is considered to have an "amide-like" character, the b-amino-gsultone system (I, Figure 1) reacts with a variety of bis-electrophilic reagents to give 3H- [1,2]-oxathiole [4,3-b]pyridine and pyrazine 1,1-dioxide bicyclic systems (pyrido-and pyrazinosultones II and III, Figure 1).…”

“…[4] Even though several examples of chemical reactions on saturated g-sultones have been described, [6] there are fewer reported investigations on the chemistry of a,b-unsaturated g-sultones, [2a, 7] in particular the b-amino-substituted representatives of this family. [4,5,8] Recently, we reported [9] on the reactivity of the 4-amino-5H-1,2-oxathiole-2,2-dioxide (b-amino-g-sultone) heterocyclic system toward electrophiles and amines on readily available model substrates. One of the interesting features of this system is its ambident nucleophilicity; nucleophilic reactions can take place either at the site of the enaminic carbon (C3) or at the primary amino nitrogen depending on the nature of the electrophile and the reaction conditions.…”