Electrophilic dehydrating agents

Generation of Organic Isocyanates from Amines, Carbon Dioxide, and Electrophilic Dehydrating Agents... 

In previous accounts the use of electrophilic dehydrating agents in the direct generation of isocyanates from amines and carbon dioxide has been discussed, equations 1-2 (1-3). 

Subsequently, the Monsanto researchers developed a variation of this activated carbon dioxide chemistry process whereby activated carbamate anions derived from primary amines could be reacted rapidly with electrophilic dehydrating agents, such as acid halides, to produce the corresponding isocyanates in excellent yields, according to the following reaction ... 

This has proven to be a very versatile reaction, which can start with a variety of electrophilic dehydrating agents and organic bases. Furthermore, the mild reaction conditions allow for the use of amine precursors, which can possess a number of different functional groups. Thus the Monsanto activated carbon dioxide process not only eliminates the use of phosgene as a starting material, but also provides additional benefits, including milder reaction conditions, urethane and isocyanate products in quantitative yields, reductions in problem impurities and by-products, and broader possibilities in choice of amine feedstock. 

A simpler non-phosgene process for the manufacture of isocyanates involves the reaction of amines with carbon dioxide (CO2) in the presence of an aprotic organic solvent and a nitrogenous base. The corresponding ammonium carbamate is treated with an electrophilic dehydrating agent [198, 282, 283]. This concept has been applied to the synthesis of several aromatic and ahphatic isocyanates. The process relies on the facile formation of amine<arbon dioxide salts using acid halides such as phosphoryl chloride and thionyl chloride [284, 285]. 

It has been recently reported that carbamate anions, obtained by reaction of primary amines, carbon dioxide, and an added base e.g. NEts), undergo rapid reaction with electrophilic dehydrating agents e.g. POCI3, P4O10) to afford the corresponding isocyanates in excellent yields (Scheme 1) [11]. 

Silicon presents an attractive option among eledrophilic activating and dehydrating agents of hemiacetals because of the wide commercial availability of eledrophilic silicon sources. The two main classes of silicon electrophiles used, namely silyl halides and silyl sulfonates, have been demonstrated to promote a variety of glycosylations including some examples of oligosaccharide synthesis. 

Reports from Kuhn and co-workers identified the reaction of stable car-benes with 1,2-dichloroethane to yield 2-chloro-l,3-disubstituted imidazo-lium chloride salts.58 The versatility of these salts has been demonstrated by Ishikawa and co-workers.59 Due to its strong electrophilicity, 2-chloro-l, 3-dimethylimidazolium chloride can be used in chlorination, oxidation, reduction and rearrangement reactions, in addition to being used as a dehydrating agent. 

Detailed mechanistic studies by Fodor revealed that the reaction is initiated by a nucleophilic attack of phenylethylamide to the dehydrating agent to afford intermediate imidoyl chlorides. Upon heating, these compounds are converted to nitrilium salts, which were cyclized through an intramolecular electrophilic aromatic substitution, providing the desired dihydroisoquinolines." Fodor prepared imidoyl chlorides using mild condition and promoted their cyclization to dihydroisoquinolines by using Lewis acids. His results supported the intermediacy of nitrilium salts as the key intermediates for the synthesis of dihydroisoquinolines. ... 

Another effective dehydrating agent is anhydrous acetic add. In addition to an electrophilic attack of the aromatic ring structure, radical mechanisms are also well known, involving a single electron-transfer reaction. A popular example is the nitration of phenol using nitric add [11]. 

A carbodiimide-related reagent is 2-chloro-l,3-dimethylimidazolinium chloride (CDC). It can act as a powerful dehydrating agent, equivalent to DCC. Nitriles 1379 can be prepared from primary amides 1377 or aldoximes 1380 on several structures at room temperature within reaction times of 4-72 h and in yields of 64-99% [1137]. As a strong electrophile, CDC reacts with 0-nucleophiles to form 1506,... 

Various PEKs were prepared via electrophilic substitution processes such as that exemplarily outlined in equation (54) [79]. The problems of this approach are in principle the same as in the case of PESs. An inert expensive solvent is needed, it is difficult to reach high conversions without side reactions and the number of useful monomers is lower than in the case of syntheses based on nucleophilic substitution reactions. The electrophilic polycondensations may be subdivided into two different methods. Firstly, acid chlorides are used as electrophilic monomers in combination with a Lewis acid. Secondly, free carboxylic acid served as monomers in combination with an acidic dehydrating agent. None of the polycondensation methods described in this section is new, and origin and early exploration of these methods has been reviewed in the 1st edition of this handbook (Chapter 9). 

The application of ethoxy(trimethylsilyl)acetylene as a dehydrating agent was also extended to polyanhydride synthesis (eq 5). In contrast to traditional methods, this was carried out at low temperature (20 0 °C) by the electrophilic addition-elimination reaction of ethoxy(trimethylsilyl)acetylene, avoiding decomposition due to heating of sensitive monomers and polymers. ... 

Lewis acid catalyst affects stereochemical course in cycloaddition and aldol reactions electrophilic substitutions powerful dehydrating agent when reduced to low-valent state, effects C-C bond formation by reductive coupling " reduction of functional groups )... 

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