Formamides isonitriles

Isonitriles are widespread metabolites in marine organisms, although little attention has been paid to their degradation. Pseudomonas putida strain N-19-2 can hydrolyze isonitriles to N-substituted formamides (Goda et al. 2001), and the enzyme is active toward cyclohexyl isonitrile and benzyl isonitrile. 

The first marine isocyano metabolite was appropriately named axisonitrile-1 (1) based on the trivial name isonitrile and the genus of the sponge, Axinella cannabina, which also furnished axisothiocyanate-1 (2) [1] and, subsequently, a minor constituent, axamide-1 (3) [5]. This observation that isonitriles are often accompanied by isothiocyanates (-N=C=S) and formamides (-NHCHO) was later duplicated by the Hawaiian researchers working with a Halichondria sp. In... 

A minor isonitrile named acanthellin-2 with a specific rotation of — 24.1° was reported with no further details except some IR and MS data [3]. Isothiocyanate 15 and formamide 16 were also isolated from Axinella cannabina in a later study, in which isonitrile 14 and isomers 17-19 were also secured [35]. That 17-19 are C4(14)-ene isomers of 14 was concluded after extensive double resonance H NMR experiments. Coupling constants and nOe effects between the affected protons and various substituents of 17 established the relative stereochemistry of this series. 

Several examples of the monocyclic isothiocyano sesquiterpenoids having the bisabolane (83) skeleton are known. Along with the hydrocarbon theonellin (84), isothiocyanate 86 and formamide 87 were obtained from the Okinawan sponge Theonella cf. swinhoei. It seems remarkable, but not unusual, that not only was the amide the major constituent, but the isonitrile 85 was the missing member of the triad [57], Relative stereostructures were indicated by NMR analysis of theonellin formamide (87) and its transformation products. 

The potential power of Fukuyama s method is illustrated by the synthesis of biindolyl 168 which was used in a synthesis of indolocarbazoles [176]. The isonitriles (e.g., 167) are generally prepared by dehydration of the corresponding formamides with POCI3. 

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. 

A similar cyclization can result from lithiation of an isonitrile lithiation of 553 requires two equivalents of LDA and the organolithium 554 can either be trapped with other electrophiles at low temperature or warmed to give an indole 555 (Scheme 219) . It is quite clear that isonitriles activate purely by conjugation, and indeed they promote deprotonation of methyl groups para to an isonitrile just as well as ortho. The ease with which isonitriles can be made from formamides suggests that these methods could be rather more widely used than they are. 

Tetramethylbutyl isonitrile, from N-( 1,1,3,3-tetramethylbutyl )-formamide and thionyl chloride, 51,31... 

The conversion of a Grignard or an organolithium reagent to an aldehyde has been accomplished by a variety of reagents. The methods include such reagents as N-ethoxymethyleneaniline ethyl ortho-formate a p-dimethylaminobenzaldehyde 26 dimethyl formamide 3 a dihydroquinazolinium salt, 4 and, more recently, a [Pg.44]

When labeled potassium cyanide reacted with the complex in an aqueous methanol solution, the bromide was rapidly replaced and the labeled cyanide ion entered slowly into the coordination complex. When the reaction was conducted at higher temperatures in ethylene glycol dimethyl ether as the solvent, the label was distributed among the benzyl isonitrile, benzyl formamide, and the polymer resulting from benzyl isonitrile and the iron isonitrile complexes. 

In a simple displacement of benzyl isonitrile by K14CN from II, all the labeled atoms should appear in the isonitrile complex and none in the benzyl isonitrile. But the label was present in all of the products isolated and in each to a different extent. For example, the benzyl isonitrile was more radioactive than the N-benzyl formamide which must have been formed by addition of water to benzyl isonitrile. The results indicate that the internal isomerization (III V, Equation 7), the generation of benzyl isonitrile and N-benzyl formamide, and the polymerization of benzyl isonitrile are concomitant reactions. 

The synthesised isonitriles were afterwards used in 3CC Ugi reactions performed under conventional heating. An alternative microwave-assisted synthesis of isonitriles has recently been reported by Prof. Bradley s group19. In order to reduce work-up they also employed a solid supported reagent strategy. Formamides, when treated with solid-supported sulphonyl chloride in pyridine (50 equiv in DCM) at 100°C for 10 min, provide the isonitriles in a quick and convenient fashion. As long as the formamides were not too heavily substituted, the isonitriles were obtained in high yields and purities, Fig. 5.2. 

Dehydration of formamides to isonitriles.3 This reaction can be effected in high yield at -78° with the combination of triflic anhydride and a tertiary amine. It is effective even in the case of vinyl formamides. 

The reaction of -halo carbonyl compounds with primary amides is appropriate for oxazoles containing one or more aryl groups . Ureas form 2-aminooxazoles. Formamide can be used resulting in a free 2-position in the oxazole. A convenient synthesis of 5-substituted-4-cyanooxazoles 223 is based on the condensation of -hydroxy—cyanoenamines 222 with trimethyl orthoformate (Scheme 109). The cyanoenamine intermediates 222 are derived from Lewis acid-catalyzed Passerini reactions between /-butyl isonitrile and aldehydes <2002S1969>. 

Finally, it should be remembered that isonitriles are not only obtained by substitution processes, but also by alternate routes, which may be of high value. In particular the various techniques for the dehydration of formamides, or the phase transfer version of the classical carbylamine reaction should be noted. ... 

Acidic hydrolysis of isonitriles proceeds in two steps to the N-formamide and subsequently to the amine derivatives in common with nitrilium ions produced in the Ritter reaction using hydrogen... 

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. ... 

Oxazoles. Oxazoles are formed using this building block on reaction with aldehydes and acid chlorides. The isonitrile is prepared from the corresponding formamide by dehydration with POClj-EtjN. 

Conversion of formamides into isonitrUes. In the course of a synthesis of dihydro-conessine from 3/3-acetoxy-A -bisnorcholenic ticid, Corey and Hertler treated the formamide (1) with tosyl chloride in pyridine in the expectation of merely tosylating the 3 8-hydroxyl group. The product, however, was not (3) but the tosylate isonitrile... 

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