Properties and Reactions of Substituted 1,2‐Thiazetidine 1,1‐Dioxides: Methylation of β‐Sultams

Abstract

Methylation of N-substituted 1,2-thiazetidine 1,l-dioxides in the presence of lithium diisopropylamide (LDA) yields 4Adimethyl derivatives MonomeElgemhahen und Reaktfonen substituierter lf-Thlazetidin-l,l-Dioxide: Methylierung von f%-Sultamen thylation only occurs when one position at C-4 is blocked by a silyl group, which can be removed by treatment with tem,,,,tylmonium fluoride (TBAF). A silyl prowting group at the nimgen is easily re,,oved by cleavage w i t h TBAF on silica gel under mild conditions. In a forthcoming paper we shall describe the reaction of silylated 1 ,Zthiazetidine 1 ,I-dioxides with ketones and aldehydes yielding hydroxyalkyl-or substituted methylene derivatives I). Here, we wish to report about the methylation of the unsubstituted p-sultam 1 and some of its substituted derivatives.When 1 is treated at -78°C with an excess of base such as n-BuLi or LDA, a mixture of the mono-and the dianion is formed. Therefore, reaction with an electrophil results in a mixture of substitution products. Furthermore, with methyl iodide the overall yield is very poor. Therefore, we decided to study the methylation of N-substituted psultams, which can be easily prepared from 1. The dianion of 2 is formed with 2.5 eq. of LDA and quenched by an excess of methyl iodide yielding the dimethylated p-sultam 3. However, running the reaction with 1 eq. of LDA, and 1 eq. of methyl iodide, we did not obtain the monomethylated 4, but a mixture of 4 (8%) and 5 (31%)'). which was separated by CC. To establish the structure of 5, the N,4-bis-silylated psultam 3, 6 was deprotonated with 1.5 eq. of LDA, and methylated with methyl iodide yielding the identical product 5. The N-silylated compounds 3 and 4 were easily desilylated with TBAF on silica gel '). From 3, the 4,4-dimethyl-fh11-tam 7 (87%) was obtained, and from 4 resulted the monomethylated product 8 (83%). The identical product 8 is obtained from 5, but only with 17% yield, and only when 5 is refluxed in a solution of TBAF in THF to which were added some drops of glacial acetic acid, thus demonstrating that N-desilylation is much faster and easier than C-desilylation from a tetrasubstituted carbon atom. Furthermore, the removal of a rert-butyldimethylsilyl group is more difficult than the removal of a trimethylsilyl group 3! Synthesis of the dimethylated psultam 10 (5 1 %) was successful, when 9 in THF was slowly added at -78'C to 3 eq.of LDA in THF, followed by methyl iodide. The C-4 monomethylated products 13 became available when 9 was first O=S-N

A New Synthesis of α-Amino Acid Thioesters by Pummerer Reaction of 3-Substituted-4-sulfinyl-β-sultams

“…The cis -isomers 3 were obtained as inseparable mixtures with the starting materials 1 except for 3e . The use of 1 equiv of LDA generates a mixture of monoanion and dianion of the β-sultams which makes reactions complicated, and an excess amount of LDA is required for formation of the sole dianion and for clean reactions. It is necessary to quench reactions at −78 °C; for example, when the reaction of 1f was quenched at room temperature instead of at −78 °C, a ring-opened product 5 was obtained in 67% yield as a major product together with a trace amount of 2f (entry 7).…”