Amines with Additional Nucleophilic Groups

Studies have been made of the covalent amination of 3-nitro-l,X-naph-thyridines (X = 5,6, and 8).27 35 In contrast to the parent systems and their halogen and methyl derivatives, 3-nitronaphthyridines undergo covalent amination with weak nucleophilic liquid ammonia at — 45 C. The electrophilic character of the naphthyridine system is enhanced by the presence of the nitro group. 3-Nitro-l,8-naphthyridine (41a) undergoes addition at... 

The author envisioned that 1,3-diaminopropane would be an appropriate primary amine as it has an additional nucleophilic group that could sequentially form isoquinoline and pyrimidine rings (the reaction using 3-aminopropanol as the amine component 8 showed a promising result. However, the main product of this reaction was unstable and decomposed during purification). Thus, attempts to construct the pyrimido[2,l-a]isoquinoline framework was initiated with 2-ethynylbenzaldehyde la, paraformaldehyde 2, diisopropylamine 3a and 1,3-diaminopropane 8a (Table 1). Co-existence of two amines with two aldehydes in one-portion of the reaction would hamper the effective Mannich-type reaction of la, 2 and 3a and subsequent imine formation with 8a in the desired order. Therefore, the copper-catalyzed Mannich-type reaction of la, 2 (2 equiv) and 3a (2... 

The reaction of amines with the 4-phenylazo derivative (228) results in their rearrangement into triazolines. Depending on the basicity of the amines and the size of the alkoxy group, three different triazolines (229. 230, and 231) are obtained (Scheme 117) (454. 459, 472). In all cases, the first step involves nucleophilic addition of the amine to the carbonyl group followed by ring opening and further ring closure. 

A number of compounds of the general type H2NZ react with aldehydes and ketones m a manner analogous to that of primary amines The carbonyl group (C=0) IS converted to C=NZ and a molecule of water is formed Table 17 4 presents exam pies of some of these reactions The mechanism by which each proceeds is similar to the nucleophilic addition-elimination mechanism described for the reaction of primary amines with aldehydes and ketones... 

Reaction of primary amines with aldehydes and ketones (Section 17.10) Imines are formed by nucleophilic addition of a primary amine to the carbonyl group of an aldehyde or a ketone. The key step is formation of a carbinolamine intermediate, which then dehydrates to the imine. 

The reaction starts with the nucleophilic addition of a tertiary amine 4 to the alkene 2 bearing an electron-withdrawing group. The zwitterionic intermediate 5 thus formed, has an activated carbon center a to the carbonyl group, as represented by the resonance structure 5a. The activated a-carbon acts as a nucleophilic center in a reaction with the electrophilic carbonyl carbon of the aldehyde or ketone 1 ... 

If it is considered that at 150 °C water can be removed equally under both types of activation, the noticeable difference in yields is clearly indicative of an improvement in the nucleophilic addition of the amine to the carbonyl group when performed under the action of microwave irradiation, with important specific effects. 

Compound 874, as a representative of derivatives with an electron-withdrawing substituent at C-[1 of the vinyl group, is easily prepared by elimination of one benzotriazole from 2,2-/fo(benzotriazol-l-yl)ethyl methyl ketone 873. The stereoselective elimination catalyzed by NaOH gives exclusively the (E) isomer of derivative 874. Addition of nucleophiles to the double bond of vinyl ketone 874 followed by elimination of benzotriazole leads to a,P unsaturated ketones 875. Amines used as nucleophiles do not need any catalysis, but reactions with carbon and sulfur nucleophiles require addition of a base. The total effect is nucleophilic substitution of the benzotriazolyl group at the i-carbon of orji-iinsaturatcd ketone (Scheme 142) <1996SC3773>. 

By 1989 Mukaiyama had already explored the behaviour of phosphonium salts as Lewis acid catalysts. It was possible to show that the aldol-type reaction of aldehydes or acetals with several nucleophiles and the Michael reaction of a,j3-unsatu-rated ketones or acetals with silyl nucleophiles gave the products in good yields with a phosphonium salt catalyst [116]. In addition, the same group applied bisphosphonium salts as shown in Scheme 45 in the synthesis of ]3-aminoesters [117]. High yields up to 98% were obtained in the reaction of A-benzylideneaniline and the ketene silyl acetal of methyl isobutyrate. Various analogues of the reaction parteers gave similar results. The bisphosphonium salt was found to be superior to Lewis acids like TiCl and SnCl, which are deactivated by the resulting amines. 

As well as the Bingel reaction and its modifications some more reactions that involve the addition-elimination mechanism have been discovered. 1,2-Methano-[60]fullerenes are obtainable in good yields by reaction with phosphorus- [44] or sulfur-ylides [45,46] or by fluorine-ion-mediated reaction with silylated nucleophiles [47]. The reaction with ylides requires stabilized sulfur or phosphorus ylides (Scheme 3.9). As well as representing a new route to l,2-methano[60]fullerenes, the synthesis of methanofullerenes with a formyl group at the bridgehead-carbon is possible. This formyl-group can be easily transformed into imines with various aromatic amines. 

---