Acylation metalated isocyanides

In the Schollkopf synthesis, a-metalated isocyanides 13 (from isocyanides and /z-butyllithium) react with acid chlorides to give 4,5-disubstituted oxazoles 14 via C-acylation and electrophilic C-O bond formation. 

The 2,5 -isomer (67) has not been reported, but the 2 -phenyl and 2 -heteroaryl derivatives have been synthesized by multistep procedures (86KGS826). Neither the parent 4,4 isomer (68) nor simple substituted derivatives have been reported. However, both the 4,5 and 5,5 isomers, 69 and 70, have been synthesized via the Schollkopf procedure that involves the acylation of a-metallated isocyanides. Thus, as shown in Scheme 26,... 

Six articles cover general aspects of heterocyclic chemistry 1,3-dipolar cycloreversions, syntheses with arylnitrenes and a-metallated isocyanides, and photo-oxygenation of nitrogen heterocycles,while others deal with more specialized subjects, i.e. preparation and use of halogeno-lactones, aspects of the chemistry of furan, 1-hydroxy-indoles, ring-opening of azoles by the action of amines, " the use of 2-chlorobenzoxazolium (1) and other heterocyclic onium salts for dehydration and condensation reactions," the synthesis of monosub-stituted tetrathiafulvalenes (2), cycloadditions of azoles containing three heteroatoms,sydnone imines (3), the conversion of acyl-benzofuroxans into nitro-indazoles (cf. p. 199), and advances in the chemistry of pyrrolizidine " and indolizine." ... 

This reaction was first reported by Schollkopf and Schroder in 1971 It is the formation of a 2-unsubstituted oxazole derivative by the condensation of an a-metalated isocyanide with an acylating reagent. Therefore, this reaction is known as the Schollkopf oxazole synthesis or Schollkopf reaction. ... 

The migratory insertion of alkyl and aryl isocyanides into metal alkyl bonds produces an iminoacyl function. The early transition metal iminoacyl, like its oxygen counterpart, has been shown to bond in a dihapto fashion.62 It has recently been shown that it is possible to couple either an acyl and art iminoacyl or two iminoacyls on the metals titanium or zirconium to produce enamidolate and enediamide ligands, respectively (equation 34).62,63... 

The -acyls, ) -iminoacryls and related complexes originate from the migratory insertion (see Migratory Insertion) of C=0 or isocyanides C=NR into a metal-alkyl bond. These complexes are of interest mainly because of their relevance to catalytic CO reduction and the C-C bond formation in Fischer-Tropsch (see Fischer- Tropsch Process) reactions. 

The preparation of 2-alkyl- and 2-acyl-l-methylimidazole-4-carboxylates from (Z)-y8-dimethylamino-o -isocyanoacrylate (21) with an alkyl or acyl halide bears similarities to the foregoing DAMN procedures (Scheme 2.1.8) 152, 53]. ITie isocyanoacrylates can be made quite readily by reaction of DMF diethylacetal with the carbanion generated when the isocyanide (22) is metallated f53J. 

Arylthioimidazoles can be made in high yields when thiophenates react with At-(l-cyanoalkyl) alkylidene A -oxides. Alkyl and aralkyl thiolates, however, react much less readily (see Section 2.1.1 and Scheme 2.1.10). Imidazole-4-thioethers can be made in a general reaction between nitriles and a range of isocyanides which are susceptible to o -metallation (see Section 4.2, Scheme 4.2.2 and Table 4.2.1). Oxoketene acetals bearing alkylthio substituents react with nitrosoaromatics to give 5-acyl-4-alkylthio-l-arylimidazoles in moderate to good yields (see Section 3.2 and Scheme 3.2.5). 

The nitrogen atom in a-ferrocenylalkylamines generally shows the same reaction pattern as that in other amines alkylation and acylation do not provide synthetic problems. Due to the high stability of the a-ferrocenylalkyl carbocations, ammonium salts readily lose amine and are, therefore, important synthetic intermediates. Acylation of primary amines with esters of formic acid gives the formamides, which can be dehydrated to isocyanides by the standard POClj/diisopropylamine technique (Fig. 4-16) [92]. Chiral isocyanides are obtained from chiral amines without any racemization during the reaction sequence. The isocyanides undergo normal a-addition at the isocyanide carbon, but could not be deprotonated at the a-carbon by even strong bases. This deviation from the normal reactivity of isocyanides prompted us to study the electrochemistry of these compounds, but no abnormal redox behaviour, compared with that of other ferrocene derivatives, was detected [93]. The isocyanides form chromium pentacarbonyl complexes on treatment with Cr(CO)s(THF) (Fig. 4-16) and electrochemistry demonstrated that there is no electronic interaction between the two metal centres. 

First, we will discuss reactions in which hydrogen or a metallic ion (or in one case phosphorus or sulfur) adds to the heteroatom and second reactions in which carbon adds to the heteroatom. Within each group, the reactions are classified by the nature of the nucleophile. Additions to isocyanides, which are different in character, follow. Acyl substitution reactions that proceed by the tetrahedral mechanism, which mostly involve derivatives of carboxylic acids, are treated at the end. 

Various unsaturated compounds can be inserted into the metal alkyl, aryl, and alkenyl complexes to give new organometallic complexes having various functional groups. The insertions of carbon monoxide (CO) and isocyanide (CNR) into transition metal-carbon a-bond are particularly important processes, since a carbon unit can be increased in the process and the acyl type complexes formed by the insertion processes can be subjected to further transformations to synthesize useful organic compounds. For example, the CO inserhon constitutes a fundamental step in industrially important processes such as hydroformylation of olefins, acetic acid synthesis from methanol and CO, Fischer-Tropsch process, amidocarbonylation, olefin and CO copolymerizahon processes as well as in a variety of laboratory syntheses of carbonyl containing compounds. 

Ohba and co-workers developed a general synthesis of chiral iV-protected 5-(aminomethyl)oxazoles from a-lithiated isocyanides and Af-protected amino acid esters (Scheme 1.101). Metalation of an alkyl or benzyl isocyanide with n-BuLi or LDA and acylation with an A-Boc-ot-amino acid methyl ester afforded an iV-Boc-a-amino acid acyl isocyanide 369, which cyclized to a chiral A-Boc-5-(aminomethyl) oxazole 370. The products were obtained in > 98% ee based on chiral HPLC analysis. The yields of 370 were somewhat variable, ranging from 45 to 91%. A-Boc-protected glycine, alanine, phenylalanine, proline, serine, and (9-benzyl serine were all compatible with these reaction conditions. 

Electrophilic addition to anionic molybdenum isocyanide derivatives [Na][Tp Mo(CNR)(CO)2] is dominated by direct attack at nitrogen to form alkylidyne products however, alkylation at the metal followed by isonitrile insertion can lead to j -iminoacyl complexes in some cases. The aminocarbyne products Tp Mo(=CNRMe)(CO)2 are formed in high yield for methyl and phenyl isocyanide reagents. However, the formation of the corresponding tcrt-butylamino-alkylidyne complex is accompanied by formation of f/ -acyl and / -iminoacyl complexes (Scheme 22). ... 

Generally, isocyanides can be attacked by proton bases HX (X = OR, RNH) in a nucleophilic reaction that leads to acylic heterocarbene complexes [27, 28] The use of functionalized isocyanides containing both the isocyanide group and the nucleophile in the same molecule gives access to complexes with heterocyclic carbene ligands via an 1,2-addition across the C=N triple bond [29]. A number of research groups have been active in the development of nucleophile-functionalized isocyanides, which could subsequently be cyclized in metal template-controlled reactions. 

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