Eigenschaften und Reaktionen substituierter 1,2‐Thiazetidin‐1,1‐dioxide: 2‐und/oder 4‐silylierte 1,2‐Thiazetidin‐1,1‐dioxide

2004

Helvetica Chimica Acta

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The introduction of functional groups at the 4-position of the b-sultam ring was realized by the synthesis of mono-and disubstituted derivatives by reactions of N-silylated b-sultams with electrophiles in the presence of BuLi or LDA. As electrophiles, ketones, chlorosilanes, a b-sultam, CO 2 , chloroformiate, halogen, azodicarboxylate, phenyltriazoledione, tosyl azide, 1,3,5-triazine, propyl nitrate, and phenyl isocyanate were used. Furthermore, a number of derivatives of these substitution products were synthesized. All products were characterized by standard spectroscopic methods, and conformations were studied, supported by calculation.

Section: Experimental Partmentioning

confidence: 99%

“…The org. layer was again separated, dried (Na 2 SO 4 2-[(tert-Butyl)dimethylsilyl]-1,2-thiazetidine-4-carboxylic Acid 1,1-Dioxide (10). BuLi (9.4 ml, 15 mmol) was added to a soln.…”

Section: Experimental Partmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Properties and Reactions of Substituted 1,2‐Thiazetidine 1,1‐Dioxides: Functionalization and Reactions at C(4) of the β‐Sultam

Plagge

Manicone

2004

Helvetica Chimica Acta

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

Müller

1991

Archiv der Pharmazie

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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

Properties and Reactions of Substituted 1,2‐Thiazetidine 1,1‐Dioxides: Fluoride Catalyzed Reactions of Silylated β‐Sultams with Electrophiles

Müller

1991

Archiv der Pharmazie

N-Silylated 8-sultams 1 and 4 react with ketones and aldehydes in the presence of fluoride ions to 0-silylated carbinolsulfonamides 3. Under similar conditions, N-aminoalkylated 4-silylated p-sultams react to O-silylated C-4 aldol adducts 7, which are deprotected and desilylated to 8 and 10. The (a-hydroxyu-methylethyl)-substituted p-sultam 1 ,ZThiazetidine 1 ,I-dioxides (psultams) can be regarded as attractive sulfonyl analogues of the biological important P-lactams. Usually, they show much higher reactivity, as the rc-bond overlap which causes the stability of p-lactams is not available to psultams. Therefore, it is of great interest to know their chemistry, and eventually to synthesize sulfonyl analogues of p-lactam antibiotics '). In the preceding paper *) we have described the silylation of 1 ,Zthiazetidine 1,l-dioxides resulting in the preparation of all possible Nand/or C-4 substituted p-sultams. These silylated p-sultams enable us to introduce different types of substituents especially to the C-4 position. In some examples, a sub5titution at C-4 is possible without silylation, but deprotonation at C-4 usually results in dimerisaition and rearrangement 3, to dithiazine tetroxides 4). Here, we report about the fluoride catalyzed reactions of silylated p-sultams with ketones and aldehydes.When 1 reacts with an excess of 4-nitrobenzaldehyde in THF at room temp. in the presence of small amounts of caesium fluoride the aldehyde is inserted into the nitrogensilicon bond without substitution at C-4 yielding the O-silylated N-aldol 2. However, when the reactions occurs with tetrabutyl-ammonium fluoride (TBAF) on silica gel, both carbon-silicon bonds at C-4 are cleaved leading to the 0-silylated product 3a. Using 4-methoxybenzaldehyde, we isolated 3b. The 0-silylated N-aldols 3a-e were also obtained from 4 reacting with the appropriate carbonyl compound and TBAF on silica gel in THF at room temp. (Table 1). AsMeyle 5, has shown, 1,Zthiazetidine 1,l-dioxide reacts with n-BuLi and aldehydes to the N-aldol adducts (carbinolsulfonamides), which can be stabilized by 0-acylation (reaction with acyl halides). Therefore, it is not surprising that even structures 3 are stable compounds, which can be stored in vucuo for several months (3a-d). However, 3e exposed to air decomposes at room temp. within 1 h yielding acetaldehyde, unsubstituted psultam, and taurine.The IR-spectra of 3 do not show any unexpected absorptions. However, we highlight the characteristic absorption >3000 cm-', which is caused by the strained 4-membered ring ' ), and which is clearly detected in the spectra of 3d and 3e. In the spectra of 3a-c, this absorption is superposed by the absorption of the aromatic increments. In contrast to other N-substituted p-sultams 'I, the protons 3-H and 3'-H are diastereotop (except in 3d) as the N-substituent contains an asymmetriccally substituted carbon atom. The effect is seen in the 'H-NMR spectra of 3a-c, where the corresponding signals show differences in the shifts up to 0.43 ppm. The effect is much smaller in...