[97203-62-8] · C5H13ClO2SSi · b-Trimethylsilylethanesulfonyl Chloride · (MW 200.79)
(protection of primary and secondary amines as their sulfonamides, which are cleaved by fluoride ion1)
Alternate Name: SESCl.
Physical Data: bp 60 °C/0.1 mmHg; yellow oil.
Solubility: sol most common organic solvents.
Preparative Methods: can be most conveniently synthesized from commercially available Vinyltrimethylsilane (1) (eq 1).1 Radical addition of sodium bisulfite to the vinyl group catalyzed by t-butyl perbenzoate yields the sulfonate salt (2) which can be directly converted to SESCl (3) with Phosphorus(V) Chloride. The chloride (3) can then be purified by distillation. The intermediate sulfonate salt (2) is commercially available. The chloride (3) can also be prepared in 62% yield from the salt (2) using Sulfuryl Chloride and Triphenylphosphine (eq 2).2 A less convenient procedure to synthesize SESCl (3) using b-trimethylsilylethylmagnesium chloride (4) and sulfuryl chloride has also been developed (eq 3).1
Handling, Storage, and Precautions: stable liquid that can be stored at room temperature for weeks. Prone to hydrolysis.
Sulfonamides are among the most stable of amine protecting groups and it is this stability that detracts from their utility, since harsh reaction conditions are often needed for their removal. The advantage of using the b-trimethylsilylethanesulfonyl (SES) protecting group is that the sulfonamide (5) can be easily cleaved to regenerate the parent amine (eq 4)1 in good yields with either Cesium Fluoride (2-3 equiv) in DMF at 95 °C for 9-40 h, or Tetra-n-butylammonium Fluoride trihydrate (3 equiv) in refluxing MeCN. The main disadvantage of the latter procedure is an occasional difficulty in separating tetrabutylammonium salts from some amines.
The sulfonamides can be prepared from a wide variety of primary and secondary amines using sulfonyl chloride (3) in DMF containing Triethylamine. For aromatic and heterocyclic amines, Sodium Hydride is the preferred base. The sulfonamides are generally quite stable and are untouched by refluxing TFA, 6 M HCl in refluxing THF, 1 M TBAF in refluxing THF, LiBF4 in refluxing MeCN, BF3.OEt2, and 40% HF in ethanol. Table 1 lists a few examples of various amines and their protection as SES sulfonamides and cleavage with CsF in DMF at 95 °C.1
The SES group has been used successfully in the synthesis of glycosides (eq 5).4 Reaction of (6) with SES-sulfonamide and Iodonium Di-sym-collidine Perchlorate provides the iodo sulfonamide (7) in 82% yield. Treatment of (7) with (benzyloxy)tributylstannane in the presence of Silver(I) Trifluoromethanesulfonate provides the b-benzyl glycoside (8). Fluoride treatment of (8) removes both the silyl ether and the SES group, giving the amino alcohol (9).
The smooth removal of the SES protecting group from pyrrole and pyrrole-containing peptides demonstrates the synthetic potential of this protecting group in heterocyclic chemistry (eq 6).5 The SES group of (10) is removed with TBAF.3H2O in DMF at room temperature to yield (11). Other protecting groups (i.e. mesylate, triflate) cannot be removed without destruction of the substrates.
The N-SES group can be incorporated by treating an aldehyde with N-sulfinyl-b-trimethylsilylethanesulfonamide (SESNSO) (13), which can be made by treating the sulfonamide (12) with Thionyl Chloride and a catalytic amount of N,N-dichloro-p-toluenesulfonamide (eq 7) (see also N-Sulfinyl-p-toluenesulfonamide).6 The N-sulfonyl imine can be used in situ in a number of reactions. For example, the N-sulfonyl imine from aldehyde (14) reacts with 2,3-dimethylbutadiene (eq 8)7 to give the Diels-Alder adduct (15). Treatment of (15) with fluoride ion affords the bicyclic lactam (16). Also, the N-sulfonyl imine derived from isobutyraldehyde and (13) reacts with Vinylmagnesium Bromide to provide the allylic SES-sulfonamide (17) in 65% yield (eq 9).8
In a total synthesis of the antitumor antibiotic (-)-bactobolin (18), the choice of protecting group on the nitrogen was crucial (eq 10).6 Unlike other protecting groups, the SES group is compatible with a wide variety of transformations and reagents, and is easily removed at the end of the synthesis.
Steven M. Weinreb & Janet L. Ralbovsky
The Pennsylvania State University, University Park, PA, USA