Mumm rearrangement

However, dicarboxylic acid dichlorides treated with iminophosphoranes (Scheme 116) show a substrate-dependent reaction. Thus, o-benzodiacetyl dichlorides (321) form chloroazepinones (322) only with A -arylimino-phosphoranes. N-Alkyliminophosphoranes, upon elimination of dichloro-triphenylphosphorane and subsequent Mumm rearrangement (71M168), give the cyclic imide (323) (90S149 91T53). 

Isocyanides, formal divalent carbon functionalities, are ideal candidates for the development of MCRs. Their reaction with carbonyls and imines, through an a-addition process, generates a zwitterionic intermediate, which is then trapped by a nucleophile. The resulting double a-addition adduct is unstable and rapidly undergoes the Mumm rearrangement to afford the final product (Scheme 12.32). The venerable three-component Passerini reaction is the first MCR based on this type of reaction process [116]. It addresses the formation of a-acyloxycarboxamides, which constitute a class of very versatile synthons in organic chemistry. In the present context, this reaction was utilized by Schmidt and collaborators for the elaboration of intermediate 234 [117], a key fragment for the synthesis of the prolyl endopeptidase inhibitor Eurystatin A 231 (Scheme 12.33) [118]. 

Acids or salts are utilized directly in Stephen s method 166 (iii) reaction with 3-chlorobenz[d]isothiazole-1,1-dioxide (6) (pseudosaccharin chloride3,166). The initial step is presumably formation of 29, followed by Mumm rearrangement. Frequently one obtains pseudosaccharin anhydride (32)25,162 as a by-product. From the reactions with silver acetate and below 3° only A-acetylsaccharin (33) besides 32 was isolated.167 In this context reexamination of the reported 3-O-benzene-sulfonylbenz[d] isothiazole-1,1-dioxide42 and the supposed 3-O-benzoyl... 

When tetraalkylammonium picrate was allowed to react with 6, i r-picrylsaccharin103 was isolated, among other products.96 The tendency toward a Mumm rearrangement is enhanced as the acid character of substituents R in 3 increases (cf. Section IV, D, 6). 

The Ugi four-component reaction (4CR) produced a-acetamidoamide by simply stirring a methanol solution of an aldehyde, an amine, a carboxylic acid and an isocyanide [57, 58]. The Mumm rearrangement (step 5, Scheme 5), being irreversible, drives the reaction towards the formation of the Ugi adduct in good to excellent yield under extremely mild conditions. 

The mechanism leading to adduct G presents clear analogies with that of the well established Ugi MCR, in which the isocyanide attacks the electrophilic carbon of an iminium ion for this reason, this process could be called the Ugi-Reissert reaction (Scheme 31). However, in this transformation, the adduct arises after a final hydration of the nitrilium ion, instead of undergoing the Mumm rearrangement as in the traditional Ugi reaction [188]. The novelty here lies in the use of M-acylazinium salts as a new source of reactive iminium ions for Ugi-type processes. 

Scheme 15.9 a-Addition of isonitrile and subsequent Mumm rearrangement. 

The protonation by the carboxylic acid moiety to give an imi-nium ion followed by a nucleophilic attack of the isonitrile leads to the formation of a nitrilium ion intermediate, which is subsequently intercepted by the corresponding carboxylate anion. The resulting imino anhydride typically undergoes an irreversible transacylation (Mumm rearrangement) to give a final Ugi product (Fig. Ic). For the construction of a 2D library array, only two of the four possible components involved in the Ugi reaction are varied. 

An accepted mechanism for this important reaction is depicted in the following Scheme 8.2, where the reaction proceeds through intermediate 6 before the final Mumm rearrangement [4] to allow a-acyloxyamides 4. However, the way how 6 is formed is still the focus of active debate [5]. 

Ugi multi-component reactions of an amine, aldehyde, carboxylic acid and isocyanide (or the three-component variant with preformed imines) involve a Mumm rearrangement of an imidate in the final step, often considered the stereoselective step. However, experimental and computational evidence for kinetic control has now been reported in Ugi reactions of a o-pentose-derived pyrroline (52). The selective step is the formation of the imidate by the addition of isocyanide to the intermediate iminium ion, with the conformation of the latter determined by its substitution pattern. 

Caprolactam scaffold represents a bioactive moiety in many drugs [99]. Fox and coworkers have described the synthesis of 3-(acylamino)azepan-2-one derivatives as stable broad-spectrum chemokine inhibitors resistant to metabolism in vivo [100]. Azepan-2-ones are also reported as valuable inhibitors of metallic proteinase [101]. The synthesis of N-alkyl-2-(2-oxoazepan-l-yl)-2-arylacetamide derivatives is carried out by a three-component Ugi reaction in water. The reaction of 6-aminohexanoic acid 133, aromatic aldehydes 51, and isocyanide derivatives 134 in water under reflux without any catalyst affords N-alkyl-2-(2-oxoazepan-l-yl)-2-arylacetamides 135 (Scheme 45) [102]. The first step of the reaction leads to the formation of imines 136 by the reaction of 6-aminohexanoic acid 133 and aldehydes 51 (Scheme 46). The nucleophilic attack of the isocyanide 134 on protonated imine 137 leads to the formation of nitrilium carboxylate intermediate 138, which xmdergoes cyclization through attack of carboxylate on nytrilium carbon to give an intermediate cyclic product 139. The latter product undergoes a Mumm rearrangement to yield the final product 135 via the intermediate 140. 

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