Isourea protonation

Scheme 6.9 Transition state of isourea protonation taking place in cwicert with C-O bond formation. Reprinted with permission from [74]. Copyright (2014) Springer...

A -substituted isourea, which is capable of protonation in the neutral and alkaline region. In the presence of primary amines and ammonia this linkage is unstable [98]. This is the primary flaw of this method when it is used for a single attachment. 

The original Pfittner-Moffatt procedure for alcohol oxidation by activated dimethyl sulfoxide utilized dicyclohexylcarbodiimide (DCC) and a source of protons such as polyphosphoric acid or pyridinium tri-fluoroacetate. The use of strong acids such as the common mineral acids must be avoided since, although acidic conditions are initially required, the reaction must readily become basic in the later stages of the process. Mechanistically it is reasonable to suggest that the activation follows the pattern whereby initial attack of the nucleophilic sulfinyl oxygen of dimethyl sulfoxide, with the protonated carbodiimide, forms a sulfonium isourea. This is followed by displacement of dicyclohexylurea by the alcohol to form an alkoxysulfonium salt. Base treatment of this salt forms an ylide, which collapses via the proven cyclic mechanism to the carbonyl compound and dimethyl sulfide (Scheme 4). 

The presence of a second nucleophile in the reaction mixture reduces the concentration of the O-acylisourea and thereby the extent of racemization. Also, HOBt, a weak acid, prevents proton abstraction from the chiral carbon atom and thus contributes to the conservation of chiral purity in a second manner as well. Last, but not least the availability of the auxiliary nucleophile (HOBt) efficiently shortens the lifetime of the overactivated O-acyl-isourea intermediate and thus diminishes the extent of O N acyl-migration leading to... 

Under those conditions, the highly reactive 0-acyl isourea in a first intermediate stage is formed, initiated with protonation of the diimide by the carboxylic component. 

B3LYP/6-311-I-I-G calculations reveal that 5 is 19.8 kcal mol more stable than 5, which is attributed to the formation of the double H-bond and also to the internal structural rearrangement of the protonated isourea moiety (Fig. 6.9). However, the data above clearly demonstrate that DCC is a promoter of the carboxylation of alcohols to dilakylcarbonates at room temperature, with a AG of ca. —38 kcal mol because of the formation of DCU. 

The (9-acyl isourea is activated by protonation at the imine nitrogen. This site is unusually basic because of resonance stabilization in the protonated species, not unlike the situation encountered in the case of the guanidino group (Section 26-1). The resulting protonated urea substituent is an excellent leaving group. We can then write an addition-elimination sequence for the attack of the amine on the carbonyl carbon to eventually furnish the amide. 

The same protonated (9-acyl isourea as above can also be attacked by carboxylate ion. Addition-elimination results in the carboxylic... 

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