Ureas bicyclic, formation

The Krebs bicycle involves interaction between components of the aspartate to urea formation. The amino group originates from a... 

The bicyclic adduct 133 was further functionalized by urea formation at N2 and reductive alkylation. 

Several syntheses of l,3-dioxoperhydropyrrolo[l,2-c]imidazoles have been developed using different strategies. a-Substituted bicyclic proline hydantoins were prepared by alkylation of aldimines 135 of resin-bound amino acids with a,tu-dihaloalkanes and intramolecular displacement of the halide to generate cr-substituted prolines 136 and homologs (Scheme 18). After formation of resin-bound ureas 137 by reaction of these sterically hindered secondary amines with isocyanates, base-catalyzed cyclization/cleavage yielded the desired hydantoin products <2005TL3131>. 

Interaction of 258 with anilines or five-membered nitrogen heterocycles produced 265 and 266 via an aminoalkylation . Bicyclic derivatives 267-271 with an aminal structure resulted from the interaction of 258 with amides, urethanes, imides, ureas, amines or hydrazines. Finally, 272 was formed with carbon acids and a reduction to 273 occurred with the sodium salt of formic acid " . It is not yet totally clear whether an iminium ion is involved in the formation of 259-273. The yields of isolated products varied from 45 to 95 %. 

The reaction has been shown to be of very broad scope with a multitude of nucleophiles Nu such as imides.23,24,29,32,33,36,37,42 amines,10,32 cyanide,25,32 hydroxide,10,32 alkox-ide,10,26,32 electron-rich isocyclic or heterocyclic aromatic compounds,28 carboxamides,31 lactams,31 ureas,31 sulfonamides,31 cyanate,31 formate (to give products with Nu = H),34 C-H acidic compounds,35 hydrazines and hydrazides,38 and sulfinates.38 The amino group NR R2 of cyclopropane-1,1-diamines and the nucleophile Nu in bicycles 8, 9 or 12, respectively, can be easily replaced with other nucleophiles Nu, such as water,10,32,33 alkoxide,10,32-34,42 Grignard compounds,27,42 amines,29,30,36,37,42,43 cyanide,29,33,42,44 hydride,34,42,44 and C-H acidic compounds39-41,43,44 (see Section 5.2.1.). Therefore, it is currently the most important method for the preparation of substituted bicyclic cyclopropylamines. The toxic and costly reagent methyl fluorosulfate can be avoided in a modified synthetic route, which instead of the fluorosulfate 5 proceeds via the corresponding tetraphenylborate, hexafluorophosphate, or (most conveniently) via the tosylate.23 The different steps of the method can often be combined in a one-pot procedure. Results are summarized in Table 3. 

Three different approaches to the synthesis of five-membered cyclic ureas have recently been described that involve Pd-catalyzed alkene diamination reactions. In a series of very interesting papers, Muniz has described the conversion of alkenes bearing pendant ureas to imidizolidin-2-one derivatives using catalytic amounts of Pd(OAc)2 in the presence of an oxidant such as PhI(OAc)2 or CuBr2 [61, 62]. For example, these conditions were used to effect the cyclization of 79 to 80 in 78% yield (Eq. (1.34)) [62aj. These reactions proceed via a mechanism similar to that shown above in Eq. (1.33), except that the heteropalladation may occur in a syn- rather than anti- fashion, and the reductive elimination occurs with intramolecular formation of a C—N bond rather than intermolecular formation of a C—O bond. The alkene diamination reactions have also been employed for the synthesis of bisindolines (Eq. (1.35)) [63] and bicyclic guanidines (Eq. (1-36)) [64]. 

AppUcation of the catalytic intramolecular C(sp )—H amination reaction to cycUc substrates has enabled the development of highly stereoselective processes. For example, as carbamates generaUy lead to the formation of oxazoUdinones, ds-bicyclic products are mostly isolated from cycloalkanol-derived substrates, an observation that also accounts for the reactions carried out from ureas or gyianidines (Scheme Such a... 

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