Reductive cleavage with dimethyl sulfide

One of the most common reactions for the complete cleavage of an exocyclic C-C double bond is ozonolysis. The reaction is typically performed at low temperature in dichloromethane, methanol or a mixture of both, followed by the usual reduction of the ozonide with dimethyl sulfide 15 17 80 82 i48,337 or thiourea83 to give excellent yields of the corresponding cyclobu-tanone. 

Ozone, O3, is produced in the laboratory in an instrument called an ozonator, in which an arc discharge generates 3 % ozone in a dry oxygen stream. The gas mixture is passed through a solution of the alkene in methanol or dichloromethane. The first isolable intermediate is a species called an ozonide, which is reduced directly in a subsequent step by exposure to zinc in acetic acid or by reaction with dimethyl sulfide. The net result of the ozonolysis-reduction sequence is the cleavage of the molecule at the carbon-carbon double bond oxygen becomes attached to each of the carbons that had originally been doubly bonded. 

Both permanganate and ozonolysis break the carbon-carbon double bond and replace it with carbonyl (C=0) groups. In the permanganate cleavage, any aldehyde products are further oxidized to carboxylic acids. In the ozonolysis-reduction procedure, the aldehyde products are generated in the dimethyl sulfide reduction step (and not in the presence of ozone), and they are not oxidized. 

These amines can be deprotected under reduction conditions (Pd-C/R0H/HC02NH4 or Na/NH3). The allyl amines can be deprotected by oxidative cleavage with ozone (dimethyl-sulfide work up) or with KMn04 in acetone. 

Taking advantage of the experience gained with ammonium iodide/TFA for reduction of Met(O) residues, a new resin-cleavage-deprotection cocktail has been used that consists of TFA (81%), phenol (5%), thioanisole (5%), ethane-1,2-dithiol (2.5%), water (3%), dimethyl sulfide (2%), and ammonium iodide (1.5% w/w).P It was found to prevent oxidation of Met residues in the acid cleavage step that was observed to occur in considerable extents with other deprotection cocktails. 

Ozonides are rarely isolated [75, 76, 77, 78, 79], These substances tend to decompose, sometimes violently, on heating and must, therefore, be handled with utmost safety precautions (safety goggles or face shield, protective shield, and work in the hood). In most instances, ozonides are worked up in the same solutions in which they have been prepared. Depending on the desired final products, ozonide cleavage is done by reductive or oxidative methods. Reductions of ozonides to aldehydes are performed by catalytic hydrogenation over palladium on carbon or other supports [80, 81, 82, S3], platinum oxide [84], or Raney nickel [S5] and often by reduction with zinc in acetic acid [72, 81, 86, 87], Other reducing agents are tri-phenylphosphine [SS], trimethyl phosphite [89], dimethyl sulfide (DMS) [90, 91, 92], and sodium iodide [93], Lithium aluminum hydride [94, 95] and sodium borohydride [95, 96] convert ozonides into alcohols. 

Fig. 8.3 Ozonolysis allows the cleavage of alkene double bonds. According to the Criegee mechanism the primary ozonide (POZ) is rapidly transformed into the more stable secondary ozonide (SOZ). Depending on the work-up, different products may be isolated. Oxidative work-up with hydrogen peroxide leads to carboxylic acids/ketones, while reductive work-up with either dimethyl sulfide or sodium borohydride gives aldehydes/ketones or alcohols, respectively...

As a model study of methyl cobalamine (methyl transfer) in living bodies, a methyl radical, generated by the reduction of the /s(dimethylglyoximato)(pyridine)Co3+ complex to its Co1+ complex, reacts on the sulfur atom of thiolester via SH2 to generate an acyl radical and methyl sulfide. The formed methyl radical can be trapped by TEMPO or activated olefins [8-13]. As a radical character of real vitamin B12, the addition of zinc to a mixture of alkyl bromide (5) and dimethyl fumarate in the presence of real vitamin B12 at room temperature provides a C-C bonded product (6), through the initial reduction of Co3+ to Co1+ by zinc, reaction of Co1+ with alkyl bromide to form R-Co bond, its homolytic bond cleavage to form an alkyl radical, and finally the addition of the alkyl radical to diethyl fumarate, as shown in eq. 11.4 [14]. 

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