Isocyanides convertible

Small molecules with novel combinations of functional groups sudi as N-(a-chlorobenzylidene)carbamoyl chloride S tosylmethyl isocyanide N-(chlorocarbonyl) isocyanate , or triphenyl(prop-2-ynyl)phosphonium bromide have each become the source of a variety of old and new compounds, mostly heterocyclics. By an anomalous reaction, tosylmethyl isocyanide converts adamantane into 2-cyanoadamantane in high yield . 

Isocyanide reaction. Since chloral hydrate is readily converted into chloroform by alkali, it will give the isocyanide reaction. To a few crystals of the solid add about 5 ml. of alcoholic NaOH solution and a few drops of aniline, and heat the disagreeable odour of phenyl isocyanide, C H(NC, is rapidly detected. 

The direct combination of selenium and acetylene provides the most convenient source of selenophene (76JHC1319). Lesser amounts of many other compounds are formed concurrently and include 2- and 3-alkylselenophenes, benzo[6]selenophene and isomeric selenoloselenophenes (76CS(10)159). The commercial availability of thiophene makes comparable reactions of little interest for the obtention of the parent heterocycle in the laboratory. However, the reaction of substituted acetylenes with morpholinyl disulfide is of some synthetic value. The process, which appears to entail the initial formation of thionitroxyl radicals, converts phenylacetylene into a 3 1 mixture of 2,4- and 2,5-diphenylthiophene, methyl propiolate into dimethyl thiophene-2,5-dicarboxylate, and ethyl phenylpropiolate into diethyl 3,4-diphenylthiophene-2,5-dicarboxylate (Scheme 83a) (77TL3413). Dimethyl thiophene-2,4-dicarboxylate is obtained from methyl propiolate by treatment with dimethyl sulfoxide and thionyl chloride (Scheme 83b) (66CB1558). The rhodium carbonyl catalyzed carbonylation of alkynes in alcohols provides 5-alkoxy-2(5//)-furanones (Scheme 83c) (81CL993). The inclusion of ethylene provides 5-ethyl-2(5//)-furanones instead (82NKK242). The nickel acetate catalyzed addition of r-butyl isocyanide to alkynes provides access to 2-aminopyrroles (Scheme 83d) (70S593). 

Van Leusen and co-workers also demonstrated the utility of dilithio-tosylmethyl isocyanide (dilithio-TosMIC) to extend the scope of the application. Dilithio-TosMIC is readily formed from TosMIC and two equivalents of n-butyllithium (BuLi) in THF at -70"C. Dilithio-TosMIC converts ethyl benzoate to oxazole 14 in 70% yield whereas TosMIC monoanion does not react. In addition, unsaturated, conjugated esters (15) react with dilithio-TosMIC exclusively through the ester carbonyl to provide oxazoles (16). On the other hand, use of the softer TosMIC-monoanion provides pyrroles through reaction of the carbon-carbon double bond in the Michael acceptor. 

When the reagent is the thiocyanate ion, S-alkylation is an important side reaction (10-43), but the cyanate ion practically always gives exclusive N-alkylation. ° Primary alkyl halides have been converted to isocyanates by treatment with sodium nitrocyanamide (NaNCNN02) and m-chloroperoxybenzoic acid, followed by heating of the initially produced RN(N02)CN. ° When alkyl halides are treated with NCO in the presence of ethanol, carbamates can be prepared directly (see 16-7). ° Acyl halides give the corresponding acyl isocyanates and isothiocyanates. For the formation of isocyanides, see 10-111. 

The cyanide ion is an ambident nucleophile and isocyanides may be side products. If the preparation of isocyanides is desired, they can be made the main products by the use of silver or copper(I) cyanide (p. 459). Vinylic bromides can be converted to vinylic cyanides with CuCN, with KCN, a crown ether, and a... 

In a related reaction, isocyanides can be converted to aromatic aldimines by treatment with an iron complex followed by irradiation in benzene solution RNC -I- CftHe PhCH=NR. ... 

Methyl 4-formylbenzoate, benzylamine, 2-nitrobenzoic acid, and cyclohexyl isocyanide were converted to the corresponding 4CC Ugi adduct [16],... 

Such a strategy follows the philosophy of resin capture, as introduced by Armstrong and Keating Keating TA, Armstrong RW. Postcondensation modifications of Ugi four-component condensation products 1-isocyano-cyclohexane as a convertible isocyanide. Mechanism of conversion, synthesis of diverse structures, and demonstration of resin capture. J Am Chem Soc 1996 118 2574-2583. See also Brown SD, Armstrong RW. Synthesis of tetrasubstituted ethylenes on solid support via resin capture. J Am Chem Soc 1996 118 6331-6332. 

Other ligands that have been successfully converted to coordinated carbynes include thiocarbonyls, isocyanides, and vinyl groups. The... 

A3-Pyrrolinones have also been obtained from metal-mediated cyclooligomerization processes in which concomitant hydrolytic or carbonyl insertion occurs. For example, tert-butyl isocyanide is converted in aqueous methanol by zerovalent nickel compounds e.g., Ni(t-BuNC)4, Ni(CO)4, into a di(alkylamino)-A3-pyrrolinone in moderate yield (Scheme 34). The reaction takes a different course in anhydrous methanol in which a di-tert-butylamino)ethylene derivative is formed, albeit in poor yield (Scheme 34).62... 

In a search for liquid crystalline phases, a series of (/>-alkoxy-phenyl)isocyanide complexes was prepared from (Me2S)AuCl and the corresponding ligands RNG, where R = C H2n + iO-C6H4 with n = 2-12 (in even numbers).206 The chlorides were converted into the bromides and iodides in metathesis reactions using KBr/KI. Mesogenic behavior was found for most of the new materials with transition temperatures in the range from ca. 95 to 160 °C. 

Regiospecific hydrocyanation of alkenes. Reaction of /-butyl isocyanide with the adducts of 1 with alkenes results in products (2) that are converted by iodine (excess) into hydrocyanides (3) and /-butyl iodide with release of ClCp2ZrI. (CH1).,SiN=C can be used in place of (CH,)3CN=C, but yields are generally lower.2... 

Aldehydes.1 This Wittig-Horner reagent (available from Fluka) converts aldehydes or ketones into a,fi-unsaturated isocyanides, which can be hydrolyzed to the one-carbon homologated aldehyde. 

Only at elevated temperatures is the isothiocyanate group also attacked by further addition of chlorine with simultaneous elimination of sulfur dichloride. It is thus converted into the isocyanide dichloride group, without isolation of an intermediate ... 

Isocyanides are converted, on addition of f-BuLi at the electrophilic carbon atom, to lithioimines—another class of anionic, nitrogen-containing functions which turn out to have good orf/zo-directing ability. The electrophile reacts at both lithium-bearing centres of 129 (Scheme 56). 

Benzodiazepinediones 15 have been synthesized starting from anthranilic derivatives 13 and Armstrong convertible isocyanides 1. When the amino group of 13 is secondary, it does not interfere too much with the Ugi reaction, and the acid... 

Diketopiperazines 17 and ketopiperazines 19, which are important privileged structures, have been obtained by using various convertible isocyanides and by introducing the additional amino function, respectively, on the carboxylic [39] or amine component [33]. 

The use of convertible isocyanides is not always necessary in particular cases, also normal alkyl [32,40] or aryl [30] isocyanides have been employed for this task. For example, microwave irradiation of the Ugi adduct 16 (R = uBu) at 120°C in the presence of 10% CF3CO2H gave the desired diketopiperazines 17 in good yield, without the need to use more complex convertible isocyanides. However, for the synthesis of ketopiperazines 19, butyl isocyanide was found to be unsuitable. 

While in most reported cases the nucleophiles were amines, there were few examples involving heterocyclic nitrogens [40], alcoholic oxygens [27] or carbon nucleophiles [42, 43] too. Figure 4 shows a recent example of tandem Ugi-Dieckmann protocol [42]. Ugi convertible isocyanide 2, which requires a basic activation, was used, allowing a domino activation-cyclization of the intermediate 20 to give pyrrolidinediones (tetramic acids) 22. 

Although diketo- and ketopiperazines can be formed by coupling the Ugi reaction with an intramolecular acylation using convertible isocyanides, as described earlier, the approach that involves Sn2 reactions enables the introduction of an additional substituent R avoiding the loss of the diversity carried by the isocyanide. 

Alternatively, the acidity of the aldehyde-derived CH or CH2 group can be enhanced by converting the isocyanide derived amide into an ester. According to this principle, tandem Ugi-Dieckmann was exploited in the context of carbapenem synthesis, where the first 4-membered ring was built through an intramolecular Ugi reaction of p-amino acid 66. Then, after a three-step manipulation of the carboxylic appendages, a Dieckmann cyclization afforded, stereoselectively, the desired carbapenem skeleton 67 [79]. 

We have previously seen how cyclic lactams can be synthesized by installing a protected amine in one of the Ugi or Passerini components, followed by cyclization onto the isocyanide-derived amide, taking advantage of the particular reactivity of convertible isocyanides. The same type of compounds can be accessed through nucleophilic attack of the amine onto an ester moiety, suitably installed as additional function into another component. This strategy has been widely used for the preparation of diketopiperazines 104 (Fig. 22), a typical privileged structure, starting with... 

Keating TA, Armstrong RW (1995) Molecular diversity via a convertible isocyanide in the Ugi four-component condensation. J Am Chem Soc 117 7842-7843... 

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