Intermediate, Nitrilium

As has been outlined for the Strecker synthesis, the Ugi reaction also proceeds via initial formation of a Schiff base from an aldehyde and an amine. The imine intermediate is attacked by the isocyanidc, a process which is supported by protonation of the imine by the carboxylic acid component. The resulting a-amino nitrilium intermediate is immediately trapped by the carboxylate to give an 6>-acyl imidiate. All steps up to this stage are reversible. Only the final oxygen to nitrogen acyl shift is irreversible and delivers the A-acyl-a-amino amide as the thermodynamically favored product which contains two amide groups. 

The mechanistic analogy to the Streckcr synthesis becomes obvious in the addition of the isocyanide to the imine to produce the a-amino nitrilium intermediate. Since all four components are involved in this step, it might be expected that every chiral component (chiral groups R1, R2, R3, R4) contributes to diastereofacial differentiation in the nucleophilic attack on the imine. However, in peptide syntheses by four-component condensation5, the chiral isocyanide or a chiral carboxylic acid component has only limited influence on the diastereoselectivity of the a-amino amide formation5. 

A mild and greener approach to the synthesis of 1,2,4-triazoles by the dipolar cycloaddition of nitrilimines with nitriles has been reported. The nitrilium intermediates were generated in situ from hydrazonyl chlorides 120 and reacted with the nitriles in a one-pot process. Yields of the 1,3,5-trisubstituted products 121a-o were good in the majority of cases (Equation 37 and Table 20) <2005H(65)1183>. 

Pathway 2 of Scheme 9 corresponds to one of the most interesting developments in the Beckmann rearrangement chemistry. By trapping of the electrophilic intermediate with a nucleophile (Nu ) other than water, an imine derivative 227 is produced that may be used for further transformations. Carbon or heteroatom nucleophiles have been used to trap the nitrilium intermediate. Reducing agents promote the amine formation. More than one nucleophile may be added (for example, two different Grignard reagents can be introduced at the electrophilic carbon atom). Some of the most used transformations are condensed in Scheme 11. 

I. Braccini, C. Derouet, J. Esnault, C. Hervd du Penhoat, J.-M. Mallet, V. Michon, and P. Sinay, Conformational analysis of nitrilium intermediates in glycosylation reactions, Carbohydr. Res. 246 23 (1993), and references therein. 

The preparation of amides by the addition of hydrogen cyanide or alkyl nitriles to alkenes in the presence of acids, known as the Ritter reaction, has been reviewed.229-232 The reaction may be considered simplistically as nucleophilic attack of a nitrile on a carbocation formed by the protonation of an alkene. Subsequent hydrolysis of the nitrilium intermediate gives the amide product (equation 164). The overall result is addition of a molecule of H—NHCOR to a C—C double bond. 

Hegarty and Chandler (17, 18) have found that secondary amines react with isonitriles 47 in the presence of AgCl at low temperature to give the iso-lable but thermodynamically unstable Z-amidines 50. This reaction is believed to occur via the formation of the metallated nitrilium intermediate... 

With Aralkyl- or Wacylpyridinium salts, the addition of isonitriles takes place efficiently when a carboxamido group is present in the 3-position. The outcome of the reaction involves the stabilization of the nitrilium intermediates by the amide, which suffers a mild dehydration providing 3-cyano-4-carbamoyl-l,4-dihydropyridines. This method also works with the corresponding Wacylquinolinium and Wacylisoquinolinium salts (Equation 58) <2006OL5789, 2004JOC3550>. 

It has been shown that different types of glycosyl donors (e.g. trichi oroacetimidates, fluorides, phosphates and pentenyl-, vinyl- and thio-glycosides) feature the ability to form highly reactive nitrilium intermediates in the presence of acetonitrile. The best (3 selectivities are... 

It is assumed86 that this reaction proceeds via the cationoid intermediates 251 and 252 which are analogous to those described by Zielinski95,96 (equations 48 and 50). The same type of nitrilium intermediates 258 and 259 are assumed to be formed by protonation of vinyl chlorides 255 by trifluoromethanesulfonic acid in the nitrile as a solvent (equation 7i)86133. The highly reactive vinyl cations 262 and 263 are generated from the vinyl triflates 261, obtained from corresponding ketones134. These cations react... 

On the basis of the same principle, we developed a three-component synthesis of macrocycles starting from azido amide (46), aldehyde (47) and a-isocyanoaceta-mide (48) (the cx-isocyanoacetamides are easily available, see [84—86]) bearing a terminal triple bond (Scheme 11) [87]. The sequence is initiated by a nucleophilic addition of isonitrile carbon to the in situ generated imine 50 led to the nitrilium intermediate 51, which was in turn trapped by the amide oxygen to afford oxazole 52 (selected examples [88-94]). The oxazole 52, although isolable, was in situ converted to macrocycle 51 by an intramolecular [3+2] cycloaddition upon addition of Cul and diisopropylethylamine (DIPEA). In this MCR, the azido and alkyne functions were not directly involved in the three-component construction of oxazole, but reacted intramolecularly leading to macrocycle once the oxazole (52) was built up. The reaction created five chemical bonds with concurrent formation of one macrocycle, one oxazole and one triazole (Scheme 15). 

Scheme 34 Internal trapping of the nitrilium intermediate by carboxamide groups...

A thiophilic electrophile (+SMe) from DMTST reacts with a lone parr on sulfur to afford a cationic sulfonium species, which is an excellent leaving group. Because of the participation of a lone pair on the ring oxygen, the C-S bond is cleaved, forming an oxocarbenium ion intermediate, with which MeCN reacts to form an axial-oriented nitrilium intermediate under kinetic control. This then undergoes Sn2 nucleophilic substitution with a hydroxyl of the glycosyl accepter to yield a-sialoside. 

Only specific ring sizes are available from these procedures since they are constrained by the configuration of the nitrilium intermediate (Section 1.9.4), in addition to the usual factors influencing intramolecular reactions. 

Intramolecular reaction of a nitrile group and a carbenium ion can produce a cyclic nitrilium intermediate leading to Ritter-type products after reaction with an external nucleophile (Scheme 15). Geome-... 

An improved and convenient preparation of pyrimidines and condensed pyrimidines from ketones and nitriles was reported. In the presence of acetonitrile, the cation generated from methyl ethyl ketone with trifluoromethanesulfonic anhydride is trapped by the nucleophile, whereby a resonance-stabilized nitrilium species is formed. A second molecule of nitrile reacts with nitrilium intermediate, and after elimination of triflic acid, cyclization, and loss of a proton, the pyrimidine product was obtained in a useful yield. The formation of pyrimidines is accompanied by a minimum... 

This consideration led us to perform the same reaction as described by Mat-sumoto but using a-isocyanoacetamide 23 [22] instead of the a-isocyanoacetate as a reaction partner. As shown in Scheme 15.10, the reaction indeed proceeded in a completely different way to afford 5-aminooxazole 24 in excellent yield [23]. We hypothesized that, under these mild conditions, the deprotonation of a-proton of amide 23 did not occur. Consequently, the sequence is initiated by a nucleophihc addition of the isocyano carbon to the in situ generated imine 19 and led to the nitrilium intermediate 25, which was in turn trapped by the amide oxygen to... 

A plausible reaction sequence that accounted for the formation of a-ketoamides is shown in Scheme 15.33. The condensation of an N-hydroxylmethylamine and an aldehyde gave the nitrone 112, which reacted with an isocyanide to afford the nitrilium intermediate 113. The classic Ugi reaction manifold would lead to the formation of a-acyloxyaminoamide 115 via the imidate intermediate 114. -Elimination of acetic acid under the optimized conditions would afford the a-iminoamide 116, which would then be hydrolyzed to 117. 

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