Chlorosulfonyl isocyanate activator

Compounds containing active hydrogens react with chlorosulfonyl isocyanate first at the isocyanate group to give N-sub-stituted sulfamyl chlorides which may react further with more active hydrogen compound at the sulfonyl chloride group.3,7 10... 

Graf [103] originally proposed a two-step mechanism for the cycloaddition of chlorosulfonyl isocyanate to alkenes. This leads to the 1,4-dipole shown in Eq. (5-35), which can then ring close to give a y9-lactam (and as by-product an unsaturated amide via a proton shift from R or R to N ). Moriconi [104], on the other hand, has proposed a nearly concerted, thermally allowed +, j2a] cycloaddition, probably initiated by a r-complex formation, and proceeding through the dipolar activated complex shown in the lower part of Eq. (5-35). 

Despite this they should be considered as possible alternatives in cases where more familiar methods fail. Amongst this group of activators are p-toluenesulfonyl chloride, tiifluoromethanesulfonic anhy-dride,silver tetrafluoroborate, molybdenum oxide, phosphorous pentoxide, trichloromethyl chloroformate, 2-fluoro-l-methylpyridiniumsulfonate, chlorosulfonyl isocyanate, antimony penta-chloride (for which an X-ray structure of the DMSO-SbCb conqilex was obtained) and phenyl dichlo-rophosphate. ... 

The reaction of chlorosulfonyl isocyanate with (7 )-l-isobutenylidene-2-phenylcyclopropane affords a mixture of optically active adducts 21-24, which possess the 1,2-dialkylidene structure and can be separated by column chromatography. The enantiomeric purity was determined by H-NMR techniques. In particular the adducts 21 and 22 contain a chiral, skewed diene system, and further addition of 4-phcnyl-3//-1,2,4-triazole-3,5(4W)-dionc produces a cycloadduct 25 or 26 with a stereogenic center, although with some loss of enantiomeric purity13. 

Activation of aliphatic and aromatic carboxylic acids with sulfuric acid derivatives yields amides (Table 3). Sulfuryl chloride fluoride and primary amines or chlorosulfonyl isocyanate and secondary amines are used as reaction partners. 

Chlorosulfonyl isocyanate is uniquely useful for the formation of hy-dantoins from sterically hindered acid- and base-labile amino nitriles, e.g., the synthesis of optically active spirohydantoins such as the biologically active (4S)-2,3-dihydro-6-fluorospiro(4H-1 -benzopyran-4,4 -imidazolidine)-2, 5 -dione.23... 

The formation of Burgess-type reagents (75) from chlorosulfonyl isocyanate (CSI) has recently been disclosed. The one-pot synthesis works well with primary, secondary, and tertiary alcohols and amines containing an active hydrogen.21... 

The sulfamoylated AZT analogue (25) has been prepared as a membrane permeable analogue of AZT triphosphate. The sulfonylating agent (26) was prepared from diethyl hydroxymethyl phosphonate and chlorosulfonyl isocyanate. Compound (25) was a poor inhibitor of HIV reverse transcriptase but exhibited some anticancer activity. 

The use of saccharin has been of particular interest and a number of compounds have been prepared that have a similar chemical structure and reactivity. The reaction of sulfuryldiisocyanate (LI) with acetic acid gives a disulfonamide that is an effective accelerator [53]. Similar reactions of p-toluenesulfonyl isocyanate (LII) and chlorosulfonyl isocyanate (LIII) can be used to prepare many different compounds which are active accelerators [54,55]. These methods allow the preparation of accelerators with improved solubility. 

The reaction between tri-O-acetyl-D-glucal 7 and chlorosulfonyl isocyanate has been studied in the past, but neither formation of a cycloadduct nor of a rearranged product has been observed. Isocyanate acted only as acid catalyst causing decomposition of sugar material. On the other hand, [2+2]cycloaddition of active isocyanates to dihydro-2H-pyran and to its derivatives has been widely investigated, under a variety of conditions. The reaction of tosyl isocyanate with dihydro-2H-pyran 1 at low temperature (0 ) led to the formation of bicyclic p-lactam 2. Elevation of the cyclization temperature resulted in the rearrangement of the four-membered ring to the open-chain amide 3 (Scheme 4). 

The Burgess reagent is a chlorine-free advancement of chlorosulfonyl isocyanate (see also Section 4.5.1), in which the two active sites are reacted with triethyl-amine and methanol, respectively, forming appropriate residues. This achieves the required level of reactivity and the right degree of selectivity, and thus enables consistent reaction mechanisms. 

The high reactivity of CSI is probably associated with the powerful electronwithdrawing character of the chlorosulfonyl moiety, which activates the adjacent isocyanate group with respect to nucleophilic addition. The [2 + 2] cycloadditions with alkenes may therefore be depicted as in Scheme 33. 

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