Isocyanates, addition from isocyanic acid

Fusion of an all cyclic ring onto the piperidine so as to form a perhydroisoquinoline is apparently consistent with analgesic activity. Synthesis of this agent, ciprefadol (68), starts with the Michael addition of the anion from cyclohexanone 56 onto acrylonitrile (57). Saponification of the nitrile to the corresponding acid ( ) followed by Curtius rearrangement leads to isocyanate Acid... 

There are actually three reactions called by the name Schmidt reaction, involving the addition of hydrazoic acid to carboxylic acids, aldehydes and ketones, and alcohols and alkenes. The most common is the reaction with carboxylic acids, illustrated above.Sulfuric acid is the most common catalyst, but Lewis acids have also been used. Good results are obtained for aliphatic R, especially for long chains. When R is aryl, the yields are variable, being best for sterically hindered compounds like mesi-toic acid. This method has the advantage over 18-13 and 18-14 that it is just one laboratory step from the acid to the amine, but conditions are more drastic. Under the acid conditions employed, the isocyanate is virtually never isolated. 

A more detailed quantitative study of the water-o-tolyl isocyanate reaction by Shkapenko et al. 51) showed that at 80° in dioxane solution and in the presence of triethylamine or other catalysts the consumption of the isocyanate was complete within a short period when only approximately half of the theoretical amount of carbon dioxide was released. The evolution of carbon dioxide proceeded from this point on at a slow rate. It was also demonstrated that by heating the reaction mixture to 100°, 30-35% of theoretical CO2 was released, and that this portion of the CO2 was given off by the decomposition of the carbamic acid anhydride formed from the acid and a second molecule of isocyanate. Additional tests showed that 4-5% of the isocyanate formed o-tolyl ammonium-W-o-tolyl carbamate, 18.7% of the water added remained unreacted, and that a trace of the free o-tolyl amine was also present. In addition, the presence of di-o-tolyl urea was proven. 

Tertiary aliphatic isocyanates can be made by addition of isocyanic acid (a toxic material) to olefins (2.17). Cytec (formerly American Cyanamid) makes a diisocyanate this way.58 The reaction can be controlled to produce the monoadduct which can be used as a monomer. Tertiary isocyanates of this type react at lower rates than primary ones in addition reactions. The isocyanic acid can be produced by the pyrolysis of cyanuric acid which, in turn, can be prepared from the urea (reaction 2.18). 

Benzyne (from anthranilic acid) cycloadds to mesoionic pyrimidines 320 the adducts 321 were obtained in 42-62% yields. Examples include R = Ph or CH2Ph, R = Ph or CH3 and R = alkyl or CH2Ph. Thermal decomposition of 321 (70-210°C depending on substitution) gave near-quantitative yields of isoquinolones 322. If the initial benzyne addition is conducted at elevated temperatures and if phenyl isocyanate elimination from the initial adduct 321 occurs at relatively low temperatures, then benzyne cycloadducts of the isoquinolones may also be formed (cf additions to 312). 

Without additional reagents Isocyanates from hydroxamic acids via 1,3,2,4-dioxathiazole 2-oxides... 

Without additional reagents Isocyanates from carboxylic acid azides s. 21, 780... 

Reaction polymerization reactions of isocyanates with suitable monomers can he performed in an extruder or in a RIM machine. In the latter reaction thermosets (cross-hnked polymers) are produced. In an extruder usually linear polymers are manufactured. For example from methylene di-p-phenylene isocyanate (MDI), with some macroglycols and 1,4-hutanediol as extenders, segmented polyurethane elastomers are produced in an extruder (6). However, linear condensation polymers are also produced in a vented extruder. For example from MDI, with macrodicarboxylic acids and dicarboxyhc acids as extenders thermoplastic block copolyamide elastomers are produced. The by-product of the condensation reaction, carbon dioxide, is removed in the vented extruder. The polycondensation process can also be performed in solution. For example, MDI can be added to a solution of dicarboxyhc acids in tetramethylene sulfone, with simultaneous removal of the carbon dioxide. Tetramethylene sulfone is the solvent of choice for solution polymerization of isocyanates (7). In addition to dicarboxyhc acids trimellitic acid anhydride and benzophenonetetracarboxylic acid dianhydride (BTDA) are utilized as monomers for condensation polymers. With these monomers poly(amide imides) and poly(imides) are produced. The diisocyanate-derived commercial polycondensation products are listed in Table 1. 

The method was highly chemo- and stereoselective, and the products 58 could be easily prepared through one-pot reaction from accessible starting materials (Scheme 7.23). This transformation started from propiolic acid (57), an aldehyde, an amine, and an isocyanate followed by the addition of different amines. Different examples were described with yields ranging from 72 to 96%. 

Without additional reagents Urethans from carboxylic acids via carboxylic acid chlorides, carboxylic acid azides, and isocyanates Shortened Curtins degradation... 

Without additional reagents Isocyanates from hydroxyamic acids via aeetoacetyl hydroxamates... 

Ethyl carbamate in wine is formed (mostly at the end of fermentation) from urea. The intermediates of its degradation are probably cyanates and cyanic acid (HO-C=N), also known as hydrogen cyanate, which may isomerise to isocyanic acid (H-N=C=0). Iso-cyanic acid can also arise by protonation of the cyanate anion and nucleophilic addition of ethanol to isocyanic acid yields ethyl carbamate. Isocyanic acid also reacts with other nucleophilic reagents, such as water (with formation of ammonia and carbon dioxide), thiols and amino groups of proteins. By catalysis with ornithinecar-bamoyl transferase, citrulline is transformed into ornithine and carbamoyl phosphate, the ethanolysis of which yields ethyl carbamate (Figure 12.39). 

In 2005, Xi and coworkers reported that 1,1-cycloaddition of oxalyl chloride with l,4-dilithio-l,3-dienes 379 or zirconcyclopentadienes 397 afford CPDNs 399 in the presence of CuCl (Scheme 6.100a), in which the carbon-carbon bond of the 1,2-dicarbonyl component cleaves during nucleophilic addition [239]. They also found that no reaction is observed when 397 is treated with isocyanates. However, multiply substituted ICPDs 400 are formed from Lewis acid-promoted reactions (BF3-Et20) by a one-pot three-component coupling process (Scheme 6.100b) [240]. 

Adducts from various quaternary salts have been isolated, in reactions with aldehydes, a-ketoaldehydes, dialkylacylphosphonates and dialkyl-phosphonates, isocyanates, isothiocyanates, and so forth (Scheme 15) (36). The ylid (11) resulting from removal of a Cj proton from 3.4-dimethyl-S-p-hydroxyethylthiazolium iodide by NEtj in DMF gives with phenylisothiocyanate the stable dipolar adduct (12) that has been identified by its NMR spectrum and reactional product, such as acid addition and thiazolidine obtention via NaBH4 reduction (Scheme 16) (35). It must be mentioned that the adduct issued from di-p-tolylcarbodiimide is separated in its halohydrogenated form. An alkaline treatment occasions an easy ring expansion into a 1,4-thiazine derivative (Scheme 17) (35). 

Synthesis from OC-Amino Acids and Related Compounds. Addition of cyanates, isocyanates, and uiea derivatives to a-amino acids yields hydantoin piecuisois. This method is called the Read synthesis (2), and can be considered as the reverse of hydantoin hydrolysis. Thus the reaction of a-amino acids with alkaline cyanates affords hydantoic acids, which cyclize to hydantoins in an acidic medium. 

The addition of isocyanides and azide to aldehyde-derived enamines has led to tetrazoles (533,536). On the other hand the vinylogous amide of acetoacetic ester and related compounds reacted with aldehydes, isocyanides and acids to give a-acylaminoamides (534). Iminopyrrolidones and imino-thiopyrrolidones were obtained from the addition of cyclohexylisocyanide and isocyanates or isothiocyanates to enamines (535). An interesting method for the formation of organophosphorus compounds is found in the reactions of imonium salts with dialkylphosphites (536). 

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