Tert-Butyl isocyanide

Cyclization takes place when tert-butylisocyanide, benzaldehyde, anilinium chloride, and carbonyl(dicyano)cyclopentadienyl ferrate are reacted, the carbene complex 42 being the result (95JOM(491)135). /50-butyraldehyde, tert-butyl isocyanide, ammonium hexafluorophosphate, and [(T -Cp)Fe(CO)(CN)2] give the cationic bis-carbene 43. 

R)j 2S) is >100 1 when the reaction is carried out at — 78 C. f Phenyl isocyanide was used instead of tert-butyl isocyanide. 

A low stereoselection is also reported for an Ugi reaction which is the central step in the total synthesis of the antibiotic ( + )-furanomycin80. The carbohydrate-derived intermediate, formed from the following acetal and (+ )-a-methyIbenzylamine, reacts with benzoic acid and tert-butyl isocyanide to deliver the precursor 2 of the antibiotic and its diastcreomer 3 in equal amounts80. 

In the total synthesis of the protein kinase C inhibitors calphostins 146, the orf/zo-substituted intermediates, which are either obtained from photolysis or from reaction of the dienyl carbene complex 144 with tert-butyl isocyanide, were oxidised to yield the 1,2-benzoquinone 145 as a common product [81] (Scheme 61). 

Yields higher than about 70% for any of these isonitrile preparations generally indicate incomplete fractionation. The purity of the product may be conveniently checked by proton magnetic resonance spectroscopy. The characteristic 1 1 1 triplet for tert-butyl isocyanide appears at <5 1.45 (chloroform-d). A small upheld peak usually indicates the presence of unreacted amine. Other common contaminants are dichloromethane and chloroform The purity may be determined more accurately by gas chromatographic analysis on a 230 cm. by 0.6 cm. column packed with 10%SE30 on Chromosorb G, 60-80 mesh, at 80°. 

Other interesting multicomponent sequences utilizing isocyanides have been elaborated by Nair and coworkers. In a recent example, this group exploited the nucleophilic nature of the isocyanide carbon, which allows addition to the triple bond of dimethyl acetylenedicarboxylate (DMAD) (9-90) in a Michael-type reaction (Scheme 9.19) [59]. As a result, the 1,3-dipole 9-91 is formed, which reacts with N-tosylimines as 9-92 present in the reaction vessel to give the unstable iminolactam 9-93. Subsequently, this undergoes a [1,5] hydride shift to yield the isolable aminopyrroles 9-94. In addition to N-tosylimine 9-92 and cyclohexyl isocyanide (9-89), substituted phenyl tosylimines and tert-butyl isocyanide could also be used here. 

A more complex reaction is involved in the cooligomerization of acetylenes and tert-butyl isocyanide using nickel acetate as the catalyst (Scheme 20)43 the nature of intermediate complexes leading to the formation of 2-cyano-5-terf-butylaminopyrroles has not been established. Cocyclization of tert-butyl isocyanide with coordinated hexafluoro-2-butyne gives rise to coordinated cyclopentadienone anils for molybdenum systems,44 hence the nature of acetylene substitutents and of the organometallic catalyst play crucial roles in these processes. The pyrrole products from the former reaction can be decomposed by sulfuric acid and the overall sequence provides a simple synthesis of 5-amino-2-cyanopyrroles (Scheme 20). 

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... 

The silver cyanide-catalyzed reaction of difunctional nucleophiles with tert-butyl isocyanide has been described in earlier sections on azoles (see Scheme 105 in Section IV,D,6). An example of the use of this simple approach... 

The only carbene-like reaction reported so far is the low-temperature addition of tert-butyl isocyanide to carbenes 2d and 2u.78 From the P-hydrogenophosphonio carbene 2d, the heterocycle 89 was isolated in high yield. It is believed that the initial coupling product 87d rapidly inserts a further equivalent of isocyanide into the P-H bond, leading to the intermediate 88, which then undergoes rapid elimination of diisopropylamine. When the same reaction was performed with the P-chloro(phosphonio)car-bene 2u, a 1/1 mixture of keteneimine 90 and phosphinonitrile was obtained. This result can be explained by the cleavage of the carbene-isocyanide coupling product 87u by residual HCN, inherently present in the f-BuNC. 

Bassett, J.-M., Green, M., Howard, J.A.K. and Stone, F.G.A. (1978) Formation of nona(ethyl isocyanide)diiron from penta(ethyl isocyanide)iron and reaction of penta(tert-butyl isocyanide)iron with diphenylacetylene X-ray crystal structures of nona(ethyl isocyanide)diiron and tris(tert-butyl isocyanide) l,4-bis-(tert-butylimino)-2,3-diphenylbuta-l,3-diene ... 

Nikulnikov M, Tsirulnikov S, Kysil V, Ivachtchenko A, K-Rasavin M (2009) tert-Butyl isocyanide as a convertible reagent in Ugi reaction microwave-assisted preparation of 5,6-dihydropyrazolo[l,5-a]pyrazine-4,7-diones. Synlett 260-262... 

Dihydropyrazolo[l,5-a]pyrazine-4,7-diones 205 were synthesized by Nikulnikov et al. using tcrt-butyl isocyanide 209 as a convertible isocyanide [62]. The Ugi reaction of tert-butyl isocyanide and pyrazole-3-carboxylic acids 208 with various aldehydes 206 and amines 207 yields tert-butyl amides 210, which undergo cycli-zation into glacial acetic acid under microwave irradiation (Scheme 37). 

Scheme 6 DKP synthesis by UAC with tert-butyl isocyanide as convertible reagent The amide is activated by acid and microwave heating...

Polymerization of tert-butyl isocyanide using an optically active initiator gives an optically active product comprising helical polymer molecules with units of predominantly one chirality sense. 

Scheme 5). Whereas 5-substituted metallacycles 18 (R1 = Me, Ph) are quite unreactive, derivative 18 (R1 = H R2 = Ph), which is more efficiently prepared from the corresponding allyl amine 19 (R2 = Ph), allows insertion of tert-butyl isocyanide to furnish metallacycle 20 its metha-nolysis yielded a mixture of N- phenyl 21 and N-ferf-butylpyrrole 22. 

However, there will be a possibility of obtaining an optically active polymer when the polymerization proceeds by forming a tight helix of polymer chian and the helix is sufficiently stable in solution (26). This concept was first demonstrated with poly(tert-butyl isocyanide) [ = - ( ) ] (27). In this case, the polymer was resolved into two fractions of positive and negative optical rotations. This is not a vinyl polymer. The results of the copolymerization of (j3)-MBMA and TrMA prompted us to investigate the possibility of forming an optically active homopolymer of TrMA. 

Enantiopure acetal 237 and a-methyl benzylamine 238 were mixed in methanol in the presence of tert-butyl isocyanide and benzoic acid to afford a separable diastereomeric mixture of the Ugi reaction 4CR product 239. Debenzylation using... 

Fig. 31. A comparison of the 1H chemical shifts for the E11 valine 72-CH3 protons of the various isonitrile complexes of isolated a chains (o) and p chains (A) of Hb A, the o ( ) and p ( ) chains as identified within an intact Hb A molecule, and sperm whale myoglobin ( ). Ligands CO, carbon monoxide M, methyl isocyanide E, ethyl isocyanide P, n-propyl isocyanide B, n-butyl isocyanide iP, isopropyl isocyanide and tB, tert-butyl isocyanide. [From Mims et al. (1983a)].

Ring-current-shifted H NMR spectra for these heme proteins containing a series of C-l-substituted (or a-series) ligands, namely, methyl, ethyl, isopropyl, and tert-butyl isocyanide, are given in Fig. 32. The a-chain spectra show a marked downfield shift of the valine peak as methyl groups are added to ethyl isocyanide (Fig. 3IB). For the tert-butyl isocyanide complex, the valine resonance is indistinguishable... 

Fig. 32. Effects of alkyl isocyanides (a-series) on the 600-MHz ring-current-shifted proton resonances of isolated a chains and (3 chains of Hb A, Hb A, and sperm whale myoglobin (Mb) in 0.2 M phosphate in D20 at pH 6.6 and 21°C MNC, methyl isocyanide ENC, ethyl isocyanide iPNC, isopropyl isocyanide and tBNC, tert-butyl isocyanide. [Adapted from Mims et al. (1983a)].

In a three component one-pot reaction, tert-butyl isocyanide, dialkyl acetylenedicarboxylates and salicylaldehydes react to afford 3-carboxycoumarins in high yield (Scheme 169) <2004S679>. 

Woerpel and Nevarez demonstrated the synthetic potential of silaaziridines by selective insertion reactions (Scheme 7.52).123 Silver-catalyzed aldehyde insertion into the Si-N bond of 169b produced the N,0-cyclic acetal 180 as the cis isomer. In contrast to this process, insertion of tert-butyl isocyanide occurred into the weaker C-Si bond to afford imine 181. The authors rationalized the chemoselectivity for these two processes on the basis of Pearson s hard-soft acid-base theory 124-126 the more ionic Si-N bond reacted with harder benzaldehyde electrophile, whereas the more covalent Si-C bond reacted with the softer isocyanide. 

Butyl hypochlorite, warning, 44, 26 N-chlorination of amines with, 41, 82 M-Butyl isocyanide, 41,14 tert-Butyl isocyanide, 41,14 n-Butylmagnesium bromide, 41, 61 reaction with rec-butyl crotonate, 41, 61... 

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