Isonitrile addition

Interaction of marine isonitriles derivatives with heme was shown to inhibit the transformation of heme into / -hematin and then hemozoin, a polymer produced by Plasmodium in order to neutralize the toxic (detergent-like) free heme produced in the food vacuole. In addition, isonitriles were shown to prevent both the peroxidative and glutathione-mediated destruction of heme under conditions that mimic the environment within the malaria parasite. In summary, isonitriles, similarly to quinoline antimalarials [38], exert their antiplasmodial activity by preventing heme detoxification. 

Perfluorinated isonitriles are of special interest as ligands in metallorganic chemistry [73]. Generally, W-perfluoroalkylated itmnes result from addition reactions A -Trifluoroniethylhalomethaneimines are obtained on reaction with HX (X = F, Cl, Br) [74] Via this route, the remarkably stable and distillable V-trifluo-romethylforraamide is obtained from trifluoromethyhsonitrile and trifluoroacetic acid [75] (equation 7)... 

Azides have been shown to react with itniniutn salts to give addition products. The same product is obtained if the iminium salt is treated with azide ion or if the enamine is treated with hydrazoic acid 14). The yields of the products were all very high (85-95 %). The interest in this reaction centers on the fact that the azides react with isonitriles to give substituted tetrazoles (83) 44). 

The only known representative of this type of compound, 91, was prepared by 1,3-dipolar addition of mesityl nitrile oxide to telluroketone 85 (93JA7019 94MI1). The reaction proceeds smoothly on heating equimolar amounts of the reactants at 80°C, giving rise to 91 in 70% yield. The heterocycle is a thermally unstable and light-sensitive compound. Thermolysis of a deuterochloroform solution of 91 at 60-90°C in a sealed ampule affords 1,1,3,3-tetramethylindanone and mesityl isonitrile (94MI1). 

Efficient stirring is required. A solution of 225 g. (5.6 moles) of sodium hydroxide in 225 ml. of water can be added to the stirred mixture of the organic substrates in dichloromethane if a more efficient mechanical stirrer is used. In the original procedure, the submitters noted an induction period of about 20 minutes which was stated to vary somewhat with the stirring rate, stirring-bar size, and relative amount of phase-transfer catalyst. Three moles of base are required for the reaction one to generate the carbene and two to react with the additional two moles of hydrochloric acid lost by the amine-carbene adduct in the isonitrile formation step. If less base is used, the excess hydrochloric acid reacts with the isonitrile by a-addition, and the yield is substantially reduced. 

The mechanism of the condensation in Part D probably involves thioformylation of the metallated isocyanoacetate followed by intramolecular 1,1-addition of the tautomeric enethiol to the isonitrile. This thi2izole synthesis is analogous to the formation of oxazoles from acylation of metallated isonitriles with acid chlorides or anhydrides. " Interestingly, ethyl formate does not react with isocyanoacetate under the conditions of this procedure. Ethyl and methyl isocyanoacetate have been prepared in a similar manner by dehydration of the corresponding N-formylglycine esters with phosgene and trichloromethyl chloroformate, respectively. The phosphoryl chloride method described here was provided to the submitters by Professor U. Schollkopf and is based on the procedure of Bohme and Fuchs. The preparation of O-ethyl thioformate in Part C was developed from a report by Ohno, Koi/.uma, and Tsuchihaski. " ... 

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 addition of hydrazoic acid to carbon—nitrogen unsaturated bonds as in hydrogen cyanide, nitriles, and isonitriles leads to unsubstituted, 5-, or... 

A very common combination in Pd-catalyzed domino reactions is the insertion of CO as the last step (this was discussed previously). However, there is also the possibility that CO is inserted as the first step after oxidative addition. This process, as well as the amidocarbonylation, the animation, the arylation of ketones, the isomerization of epoxides, and the reaction with isonitriles will be discussed in this section. 

In addition to genetic factors evidenced by sponge systematics, environmental parameters, such as time and site of collection, appear to play a part in the isonitrile inventory of a given taxon. Examples from the genera Ciocalypta and Acanthella will be discussed in the following sections. 

Reviews of the syntheses of marine natural products, including marine isonitriles, have appeared recently [72]. After the early synthetic challenges of the tricyclic 9-isocyanopupukeanane (76) [73, 74] and 2-isocyanopupukeanane (78) [75] were met in 1979, additional syntheses of marine isonitriles were reported during 1986-1991. These were ( )-7,20-diisocyanoadociane (95) [63], ( )-axisonitrile-1 (1) and ( )-axamide-l (3) [76], the axisonitrile-4 triad (7-9) [78], and ( )-8,15-diisocyano-ll(20)-amphilectene (96) [79], and theonellin isocyanide (85) [80],... 

Assuming that the metabolic pathways are similar in the biosynthesis of related isocyanoterpenes, these studies remain difficult, due in part to the competitive formation of other secondary metabolites. In addition to the common trio (-NC, NCS, -NHCHO) of the nitrogenous functions found attached to these skeletons, analogs such as -CN, -CNO, and -SCN foreshadow the complexity of identifying and selecting specific precursors to be targeted for incorporation into the family of marine isonitriles. 

The only examples dealing with [4 + 1] cycloadditions of alkylidenecyclo-propanes involve the additions of isonitriles to diacylmethylenecyclopropanes. 

A recent total synthesis of tubulysin U and V makes use of a one-pot, three-component reaction to form 2-acyloxymethylthiazoles <06AG(E)7235>. Treatment of isonitrile 25, Boc-protected Z-homovaline aldehyde 26, and thioacetic acid with boron trifluoride etherate gives a 3 1 mixture of two diastereomers 30. The reaction pathway involves transacylation of the initial adduct 27 to give thioamide 28. This amide is in equilibrium with its mercaptoimine tautomer 29, which undergoes intramolecular Michael addition followed by elimination of dimethylamine to afford thiazole 30. The major diastereomer serves as an intermediate in the synthesis of tubulysin U and V. 

Nucleophilic additions of titanium nucleophiles to nitriles or isonitriles are relatively rare. Eisch et al. recently reported the formation of three-membered ring titanacycles of type 84 and their reactions with benzonitrile and carbon dioxide, respectively (Scheme 34).119,120... 

This transformation proceeds through coordination of the isocyanide group to the ruthenium complex (structure 172), followed by insertion of the C-bound ruthenium into the benzylic C-H bond (intermediate 173). After ruthenium-mediated addition of the benzylic carbon to the isonitrile carbon and tautomerization, the desired product was obtained via elimination of the ruthenium complex. 

Rhodium-catalyzed reactions of diynes and an isonitrile give rise to iminocyclopentadienes (Equation (68)).421 Portionwise addition of the isonitrile (5 x0.2equiv.) was found to increase the yield. The reaction may proceed through formation of metallacyclopentadienes followed by insertion of an isonitrile molecule. 

The 2,3-substituted indols are formed via a palladium-catalyzed coupling reaction of aryl halide, o-alkenylphenyl isocyanide, and amine (Equation (122)).481 Oxidative addition of an aryl halide, insertion of both the isonitrile and alkene moieties of o-alkenylphenyl isocyanide, and 1,3-hydrogen migration may form a 7r-allylpalladium species, which is then attacked by an amine to afford an indol. 

The chalcogenolysis of the disilene 721 with N20, S, Se, and Te results in formation of the three- and four-membered heterocyles 748-752 (Scheme 98). The addition of the isonitrile /-BuNC to the disilene 721 affords... 

In many of its reactions hydrocyanic acid behaves as the nitrile of formic add H.CN. Many facts, in particular its great chemical and pharmacological similarity to the isonitriles >C = NR suggest another constitution, namely, that of carbimide >C =NH with bivalent carbon. The addition reactions of the nitriles (see above), which reactions are also characteristic of hydrocyanic acid, can equally well be explained on the basis of this second structural formula. In the nitrile form it is at the triple bond between carbon and nitrogen that addition takes place. In the methylene form this occurs at the two free valencies of the bivalent carbon atom, e.g. ... 

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 ... 

Besides the addition of non-carbon nucleophiles to carbonyl and isonitrile complexes (Tables 2.2, 2.4), heteroatom-disubstituted carbene complexes can be prepared by direct addition of stable or latent carbenes to suitable complexes. The synthetic routes sketched in Figure 2.12 are those commonly used for preparing imidazoline-2-ylidene or imidazolidine-2-ylidene complexes. 

The most important application of organolithium reagents is their nucleophilic addition to carbonyl compounds. One of the simplest cases would be the reaction with the molecule CO itself, whose products are stable at room temperature. Recently, it was shown that a variety of RLi species are able to react with CO or f-BuNC in a newly developed liquid xenon (LXe) cell . LXe was used as reaction medium because it suppresses electron-transfer reactions, which are known to complicate the reaction . In this way the carbonyllithium and acyllithium compounds, as well as the corresponding isolobal isonitrile products, could be characterised by IR spectroscopy for the first time. 

In addition, we should note that data of H, NMR spectroscopy, mass-spectra, and elemental analysis given in [138] did not contradict the structure of compound 98, being regioisomer of 97. The similar situation had already been shown in the synthesis of 3-aminoimidazo[l,2-a]pyrimidines [139]. Mandair et al. carried out the model MCRs of 2-aminopyrimidine with several aldehydes and isonitrile components in the methanol under the ambient temperamre with the various catalysts. As a result, 3-aminoimidazo[l,2-a]pyrimidine and position isomeric 2-aminoimidazo[l,2-a]pyrimidines were isolated from the reaction mixture in different ratio (Scheme 45). The stmctures of the isomers obtained in this case were confirmed by the X-ray diffraction analysis, as well as the structures of the side-products isolated. 

The first MCR involving the explicit use of a-acidic isonitriles was reported in 1998 by Sisko [131]. The reaction involves the cycloaddition of aTosMIC derivative (8) to an (in situ-generated) imine (10) followed by the elimination of p-toluenesulfinic acid (TsH) as described in 1977 by van Leusen for preformed imines (Fig. 5, scaffold P) [119]. Although several potential pitfalls for the conversion of the traditional van Leusen [3 + 2] cycloaddition to the so-called van Leusen three-component reaction (vL-3CR) of imidazoles were expected by the author, simply stirring the aldehyde and amine for 20 min followed by addition of the TosMIC derivative and base resulted in the isolation of the corresponding imidazole (9) in high yield [131]. 

Other (less acidic) ot-substituted isocyano acetates (1, R = H, Me, /Bu, /Pr) [159]. Silver(l) salts (AgOAc) were found to accelerate the reaction, probably by coordination of the terminal NC carbon atom to Ag which increases the a-acidity and NC electrophilicity (Fig. 22). Remarkably, unlike most other reactions reported with a-acidic isonitriles, no additional base or acid is required for the three-component coupling to 2//-2-imidazolines 65. Most likely, the intermediate imine is basic enough to deprotonate the isocyanide. 

The first application of NMR diffusion measurements to determine the aggregation state of a transition metal catalyst concerned the chiral, tetranuclear Cu(i) catalysts 130-132, used in the conjugate addition reactions of anions to a,p-unsatu-rated cyclic ketones. Compounds 130-132 react wdth isonitriles to form 133-135, and do not degrade to lower molecular weight species (see Eq. (20)) [109]. 

The mixture can be left stirring overnight since the isonitrile is stable to the reaction conditions. Alternatively, a hot water bath can be used, with very fast stirring, to heat the mixture quickly to 35°. The bath is then removed, and after 1 hour of additional stirring, the mixture is ready for the workup procedure. 

A. 1,1,3,3-Tetramethylbutyl isonitrile. A 3-1. three-necked round-bottomed flask is fitted with a Hershberg stirrer, a fiOO-ml. pressure-equalizing addition funnel, and a nitrogen gas... 

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