Synthesis of 4,4‐Disubstituted 1,2‐Thiazinane‐5‐one 1,1‐Dioxides via the CSIC^[≠]Reaction Strategy

Abstract

A series of sp3‐enriched 2,2‐disubstituted 1,2‐thiazinane‐5‐one 1,1‐dioxides (including spirocyclic derivatives) has been synthesized through the CSIC [Carbanion mediated Sulfonate (Sulfonamido) Intramolecular Cyclization] reaction strategy. In particular, 2,2‐disubstituted alkyl 3‐aminopropanoates were subsequently sulfonylated with mesyl chloride followed by alkylation with methyl iodide to give the key precursor 2,2‐disubstituted methyl 3‐(methylsulfonamido)propanoates. The latter were treated with sodium hydride and underwent the intramolecular sulfa‐Dieckmann cyclization yielding the target 4,4‐disubstituted 1,2‐thiazinane‐5‐one 1,1‐dioxides (so‐called β‐keto‐δ‐sultams). The structure of the target compounds was confirmed by an X‐ray diffraction study.

Updating the CSIC Reaction (2003–2020)

“…Specifically, the reaction of a,b with hydrazine hydrate gave sultamopyrazoles 19 a,b in high yield (90 % and 85 %), whereas the NaOMe-mediated treatment with a range of amidinium salts afforded appropriately substituted sultamopyrimidines 20-22 in 59-90 % yields (Scheme 7). [25] Continuing the study of the CSICr of sulfonylated α-aminonitriles founded by Marco-Contelles and co-workers, [11,28] the scope of the starting α-aminonitriles was extended with model 2,2-dimethylated (23 a) and 5-7-membered carbocyclic (23 b-d) compounds. These corresponding mesylated precursors 24 a-d, prepared in 20-83 % yield, were converted into the target βenamino-γ-sultams 25 a-d (56-84 %), following the general t-BuOK-mediated method except for additional heating up to 60°C (Scheme 8).…”

“…[24] The obtained results prompted further investigation of the substrate scope of the CSICr and gave rise to the synthesis of sp 3 -enriched 1,2-thiazinane-5-one 1,1-dioxides (β-keto-δ-sultams) starting from β-amino acid esters. [25] Thereby, a range of 2,2-disubstituted alkyl 3-aminopropanoates hydrochlorides 11 a-f • HCl were subjected to mesylation-alkylation-cyclization sequence, via intermediates 12 a-f and 13 a-f. The first two steps were carried out similarly to the procedures described for the synthesis of β-keto-γ-sultams 10 a-h (Scheme 2).…”

“…However, the best results on the cyclization step were obtained by using NaH dispersion in DMF -MeCN (1 : 1 v/v) media at rt that afforded 4,4-disubstituted and spirocyclic β-keto-δ-sultams 14 a-f in up to 55 % overall yield (Scheme 5). [25] Quite interesting results were obtained during attempts to synthesize the fused derivatives starting from β-keto-γ-sultams 7 and β-keto-δ-sultams 14.…”

“…However, the best results on the cyclization step were obtained by using NaH dispersion in DMF – MeCN (1 : 1 v/v) media at rt that afforded 4,4‐disubstituted and spirocyclic β‐keto‐δ‐sultams 14 a – f in up to 55 % overall yield (Scheme 5). [25] …”

“…Specifically, the reaction of 18 a , b with hydrazine hydrate gave sultamopyrazoles 19 a , b in high yield (90 % and 85 %), whereas the NaOMe‐mediated treatment with a range of amidinium salts afforded appropriately substituted sultamopyrimidines 20–22 in 59–90 % yields (Scheme 7). [25] …”