Carbonate convertible isonitrile

Different novel resin-bound isonitriles have been prepared in order to perform Ugi multicomponent reactions on the solid phase. Thus, Kennedy et al. [346] prepared a novel resin-bound carbonate convertible isonitrile (CCI) that was applied in the preparation of constrained 2,5-diketopiperazine and l,4-benzodiazepine-2,5-dione libraries in parallel 80-well format The first step of the synthetic strategy was a Ugi reaction with a wide variety of amines, aldehydes, and carboxylic acids. Further manipulations of the Ugi MCR products were achieved after basic cleavage from the resin. 

Kennedy and cowoikers repOTted Ihe use of resin-bound isonitriles in the Ugi MCR to afford valuable 2,5-diketq)iperazines and l,4-benzodiazepine-2-5-diones [89]. They developed a resin-bound carbonate convertible isonitrile based on a hydroxymethyl polystyrene resin. As shown in Scheme 11.38, the Ugi reaction with these resin-bound convertible isonitiiles afforded, after several derivatizations, the desired 2,5-diketopiperazines in good yields 178. 

Note that carbon monoxide inserts into the Zr-H bond of 1 (2 equiv.) to afford an T -formaldehydo-type complex [(Cp2ZrCl)]2(g-CH20) [200-202]. Iminoacyl zir-conocene complexes are formed after addition of 1 to isonitriles [203]. Carbon dioxide [183, 202] is reduced to formaldehyde with 1 (2 equiv.). C02-like molecules such as isocyanates RNCO [204], isothiocyanates RNCS [205], and carbodiimides RNCNR [204] are readily converted to the corresponding bidentate form-amido ligands. 

The question of the constitution of hydrocyanic acid has already been considered (p. 139). Here it need only be remarked that the isonitriles are converted by hydrolysis into primary amines and formic acid no carbon monoxide is produced, although from the formula this might be expected. The reason for this is to be sought in the fact that the first stage in the reaction consists in the addition of water to the two free valencies of the carbon atom. The reaction must therefore be formulated thus ... 

In a dehydration reaction (Scheme 12.4), the IR band of the formamide carbonyl group at 1684 cm in (7) decreased and eventually converted to the isonitrile band at 2150 cm in (8) (Fig. 12.8). In a separate example (Scheme 12.5), the conversion of the IR band from the carbonate carbonyl group in (9) to the IR band of the carbamide carbonyl group in (10) can be monitored to assure the reaction completion (Fig. 12.9). Based on FTIR analysis, the reaction time course can be analyzed by integrating peak areas of the IR bands from the starting resin and the product. From the point of view of kinetics, the side reaction product formation can be excluded if the pseudo first order rates of the starting material consumption and the product formation are identical. 

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). 

In the aromatic series the direct conversion of acid amides into acid nitriles does not take place readily but the acid itself is made from the acid amide by the reverse process as indicated above, viz., by hydration to the ammonium salt of the acid, which then yields the acid. A related method, however, is used for preparing acids from anilides of formic acid. Aniline being an ammonia compound yields acid-amidelike products with aliphatic acids, e.g. acet anilide, CH3—CO—NH— CeHs (p. 556). Such a compound can not, however, lose water in the same way as the acid amide in the above reaction for the ammonia residue in an anilide contains only one hydrogen. Nevertheless anilides lose water but in a different way. In the case of the anilide of formic acid, i.e. formanilide, H—CO—NH—CeHs, the loss of water results in a compound in which the carbon and nitrogen remain linked to the benzene ring and an iso-cyanide or iso-nitrile is formed. The isonitrile is readily converted into the nitrile and the acid may then be obtained from that. 

Phosgene, as well as the easier to handle diphosgene (chloroformic acid trichloromethyl ester) or triphosgene (carbonic acid bis(trichloromethyl) ester) transform primary, secondary and tertiary amides and thioamides to chloromethyleneiminium chlorides (25 equation 15), whereby the reaction with thioamides is of broader scope and proceeds with fewer side reactions. The amide chlorides derived from primary and secondary amides can lose HCl, giving nitriles or imidoyl halides, respectively. /V-Sub-stituted formamides can be converted to isonitriles via amide halides. ... 

The third sesquiterpene isonitrile in Chart 5 has been isolated from the extracts of Acanthella acuta, which also yielded a number of minor compounds 138). The major component, acanthellin-1, proved to have a 4-epi-eudesmane structure (49). The carbon skeleton was deduced by lithium/ethylamine reduction, which afforded a saturated bycyclic hydrocarbon (60) converted into eudalene by drastic dehydrogenation. The i.r. 

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