Isonitriles isocyano

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... 

In those cases where quantities of the test organisms are limited or non-aqueous conditions are preferred, blending of the lyophilized sponge with organic solvents is employed. The latter option is prudent, if one suspects the presence of reactive isocyano and isothiocyano functions. Although these isolation methods may not be unduly harsh, artifacts derived from isonitriles and isothiocyanates may arise. 

Naturally occurring marine isonitriles are either sesquiterpenes or diterpenes with one, two, or three isocyano (or isocyano-related) functions. As mentioned previously, it usually is the same carbon that bears the -NC, -NCS, or -NHCHO function. Commonly encountered in sesqui- and diterpenes are... 

The majority of marine isonitriles are sesquiterpenes with the molecular formula, C16H25N. Often cyclic, these are alkanes or alkenes possessing only a single isocyano-related functional group. In the mass spectrum, they exhibit a molecular ion at w/z 231, or an intense fragment ion at m/z 204, indicative of M+-HCN. Some are crystalline (see Table 2). With few exceptions most of the isothiocyano and formamido analogs are minor noncrystalline metabolites (see Table 3). 

In several related studies that involved Ciocalypta and Phyllidia spp., optically inactive isonitrile 85 was part of the mixture from a Sri Lankan Phyllidia sp. The mixture also contained a minor isothiocyanate which was not identified [55]. The observation that 7-isocyano-7,8-dihydrobisabolene 88 and isocyanato 89 were obtained from separate collections of Ciocalypta spp. was surprising... 

Attributed to seasonal variations was the noted absence of isocyano-related metabolites in one batch of C. luteomarginata [18]. Similarly, in previous studies on Acanthella acuta, aeanthellin-1 (14) was the major constituent of the isonitrile fraction [3], but a subsequent reinvestigation by a different group showed that 14 was only a minor constituent [32],... 

Although use of radio and stable isotope labels involving the trio of covalently-bonded nitrogenous functions in 3 and in 78, provided evidence that isocyano is the precursor of the isothiocyano and formamido groups [30, 81], it remains to be shown that a biosynthetic equivalent of the in vitro chemically-proven fusion process between isocyano and free sulfur (e.g., cf. Introduction) exists in the cells of sponges. In marine biota, various ionic forms of sulfur in a number of oxidation states, as well as organo-polysulfides are known. However, any association with the isonitrile group and a sulfated species has yet to be established. 

Before the discovery of the multifunctional kahilinols (cf. Sect. 4.2.2), ses-quiterpenoid isonitriles and related analogs were found distinctly void of other functions. Recent reports of isocyano analogs bearing hydroxy (46) [45], oxiran (10) [34], and chloro groups [86], for example, indicate the continued interest in the chemistry of marine isocyano compounds. 

Convertible isocyanide reagent 66 allows a mild and chemoselective in situ post-Ugi activation of the isonitrile bom amide with simultaneous deprotection of the nucleophilic amine, that is, liberation and activation of two Ugi-reactive groups, if desired also under subsequent lactam formation [33]. Another recently introduced convertible isocyanide, l-isocyano-2-(2,2-dimethoxyethyl)-benzene 73, was shown effective by Rhoden et al. In the course of this short sequence, a hydrolytically labile W-acylindole 78 is formed, which is displaced intramolecularly by the amine portion of the former Boc-protected amino acid 75 (Scheme 13). 

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. 

In 2006, our research group reported a novel MCR based on the reactivity of a-acidic isocyano esters (1) toward 1-azadienes (84) generated by the 3CR between phosphonates, nitriles, and aldehydes [169]. Remarkably, the dihydropyridone products (85) for this 4CR contained the intact isonitrile function at C3. The exceptional formation of the 3-isocyano dihydropyridone scaffold can be explained by the Michael-attack of the a-deprotonated isonitrile (1) to the (protonated) 1-azadiene (84), followed by lactamization via attack of the ester function by the intermediate enamine. Although in principle the isocyano functionality is not required for the formation of the dihydropyridone (85) scaffold, all attempts using differently functionalized esters (e.g., malonates, ot-nitro, and a-cyano esters) gave lower yields of the dihydropyridone analogs [170] (Fig. 26). 

For completeness, it was reported in the context of binary isonitrile complexes that the Re(III) precursor [Re2(OAc)4Cl2] reacted with 3-isocyano-l,2-dicarba-cZoso-dodecaboran to produce [Re(CN-R)6]+ in good yield. The X-ray structure of this complex was elucidated. Again, it remains to be shown that the same complex can be prepared with 99mTc to be useful in imaging [93]. Relevant complexes of this section are depicted in Scheme 21. 

SYNS BENZENE, 1-ISOCYANO-4-NITRO- p-NITROPHENYL ISOCYANIDE 4-NITROPHENYL ISOCYANIDE p-NITROPHENYL ISONITRILE PHENYL ISOCYANIDE, p-NITRO-... 

General procedure for Ugi reaction with support-bound isonitrile [346] A 1.2 m solution of 2-chlorobenzylamine (0.133 mL, 1.1 mmol) and 2-phenylpropio-naldehyde (0.146 mb, 1.1 mmol) in trimethylorthoformate (TMOF) was allowed to react for 30 min. (]3-Isocyano-ethyl)-alkyl-carbonate resin (126 mg, 110 pmol, 0.87 mmol g ) was suspended in 1,2-dichloroethane (1.75 mL) in a 5-mL Bohdan fritted reaction tube and allowed to stand for 15 min. The 1.2 M solution ofimine in trimethylorthoformate was added to the resin, and... 

In tMs approach, conjugate addition of the anion from an isocyano-acetate to an a,p-unsaturated nitrocompound with evenmal loss of nitrous acid, produces 5-unsubstituted pyrrole-2-esters. The example below shows a mechanistic sequence that can be seen to parallel that in the van Leusen synthesis. The most useful route to the a,P-unsaturated nitro-compound involves the base-catalysed condensation of an aldehyde with a nitroalkane giving an a-hydroxy-nitroalkane it can alternatively be generated in situ, in the presence of the isonitrile, using diazabicycloundecane (DBU) as base on the 0-acetate of the a-hydroxy-nitroalkane (for an example see 16.16.2.1). The process works even when the unsaturated nitro unit is a component of a polycyclic aromatic compound. ... 

Matsumoto and co-workers reported in 1978 that simply heating a solution of 4-chlorobenzaldehyde (6), methyl a-isocyanoacetate (7), and piperidine (8) in MeOH led to the formation of an amidine (9) in about 50% yield (Scheme 5.6) [19]. The reaction is suggested to be initiated by the Knoevenagel condensation followed by a formal a-addition of the secondary amine to the isocyano group. It is evident from this work that the a-proton of a-isocyanoacetate 7 is relatively acidic and is readily deprotonated under even weakly basic conditions [20]. The nucleophilicity of the a-carbanion of the enolate 12 produced is apparently higher than that of the terminal divalent carbon of the isonitrile, thus initiating the overall reaction sequence by the Knoevenagel condensation. 

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