Author: Rebecca Esther Norman
Norman, Rebecca Esther, 2015 Synthesis and Reactivity of Novel Pyrazolo-Thiatriazines and Thiadiazines, Flinders University, School of Chemical and Physical Sciences
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This research extends a body of work on the use of 1,3-dielectrophilic species: N,N-dialkyl N'-chlorosulfonyl chloroformamidines to generate novel, low molecular weight heterocyclic compounds. The versatility of the dichloride compounds was demonstrated by a series of reactions with readily available 3-aminopyrazoles. These selectively furnished representatives of the previously unreported pyrazolo[1,5 b][1,2,4,6]thiatriazine ring system. The dielectrophiles were also condensed with 1-substituted 5-aminopyrazoles to provide novel pyrazolo[3,4 e][1,2,4]thiadiazine dioxides as the sole isolated products. In some circumstances, the 4-ester substituted pyrazole gave rise to bis-adducts (or intermediate chlorides) by reaction at the ring nitrogen N1 instead. An unexpected sulfonamide product was isolated in one instance from a reaction between pyrazole and dichloride compound, which appeared to have formed via rearrangement of an intermediate similar to bis-adducts. Fused pyrazole compounds were shown to possess three nucleophilic NH sites which underwent a range of substitution reactions. Methylation of representative substrates of pyraolothiatraiznes occurred at both N4 and N7. Benzylation occurred preferentially at pyrazole nitrogen N7, but also at the pyrazole carbon C5 (when R1=H). Alkylation with α halo esters occurred at both N4 and N7, but the latter derivatives, under the reaction conditions, underwent a ring expansion to afford the first reported pyrimido[1,6 b][1,2,4,6]thiatriazine derivatives. The tautomeric NH moieties of compounds were reactive towards a selection of alkylating agents including benzylic halides, dimethyl sulfate and ethyl bromoacetate and alkylation occurred mostly at either thiadiazine ring nitrogens N2 or N4. A similar 'ring expansion' of the fused pyrazole ring gave the rare pyrimido[4,5-e][1,2,4]thiadiazine ring system. The tendency of some representative pyrazolo[1,5 b][1,2,4,6]thiatriazines to undergo ring cleavage at the sulfamide moiety was observed under a variety of conditions. Extrusion of the sulfur dioxide moiety was exploited for supplementary chemical transformations to produce pyrazolo[1,5-b][1,2,4]triazines by the formation of guanidines as intermediates. A range of cheap and commercially available electrophiles such as acid anhydrides and orthoesters were utilised to afford fused triazing rings. The pyrazolo[1,5-b][1,2,4,6]thaitraizine ring system underwent a nucleophilic addition of C5 to N acylpyridinium or N acylpyridazinium species; revealed by the attempted acylation with pyridine as acyl-transfer agent. Sulfonylation, thiolation and bromination was also achieved with selective reaction at C5. Bromination or tosylation of pyrazolo[1,5-b][1,2,4,6]thiatriazines afforded unstable 5 bromo or 5-tosyl derivatives, respectively, which were not synthetically useful due to insufficient stability. The susceptibility of the sulfamide moiety towards nucleophilic attack by a series of alcohols and amines was also established. An unusual rearrangement occurred upon heating fused pyrazolothiatriazine derivatives affording isomeric thiadiazine dioxides. These results provided insight into the relative thermal and chemical stabilities of both systems, and derivatives thereof, as well as general patterns of reactivity and selectivity of various substitution reactions.
Keywords: Heterocyclic chemistry,Organic Synthesis,X-ray crystallography,Synthetic Chemistry,NMR,Chemistry
Subject: Chemistry thesis
Thesis type: Doctor of Philosophy
School: School of Chemical and Physical Sciences
Supervisor: Associate Professor Michael Perkins