A-Isocyano

Reaction of a-isocyano-a, / -unsaturated sulfones with primary aliphatic amines affords 1,5-disubstituted imidazoles 59 (equation 56)48. The reaction of aromatic amines such as aniline is too slow to be of practical use. Results of the preparation of 59 are listed in Table 5. 

For the dehydration of TV-formylamino compounds to give isocyanides the CDI is activated by protonation into its bisimidazolium form (CH3CN, room temperature, 4h). Thus, chiral a-isocyano esters and other base-sensitive isocyanides are obtained in high yield. CDI itself did not produce this dehydration. 

Aldol reactions of isocyanides with aldehydes are catalyzed by cationic platinum complexes having P-C-P or N-C-N ligands in the presence of a catalytic amount of an amine base to give 2-oxazolines (Equation (126)) 48S>485a>485b Platinum-coordinated a-isocyano carbanions presumably serve as nucleophiles toward aldehydes. Low to moderate enantioselectivities were obtained by using chiral platinum complexes.485 4853... 

The variety of educts and products of the higher MCRs is illustrated here. Product 72 (Scheme 1.18) is formed from the five functional groups of lysine, benzaldehyde, and tert-butylisocyanide. The synthesis of 73 is achieved with hydrazine, furanaldehyde, malonic acid, and the isocyano methylester of acetic acid, compound 74 results from the reaction of benzylamine, 5-methyl-2-furanaldehyde, maleic acid mono-ethylester, and benzylisocyanide. ° Zhu et al. prepared a variety of related products, such as, 75, from (9-amino-methyl cinnamate, heptanal, and a-isocyano a-benzyl acetamides. 

In 1979, Schollkopf et al. " formed a-isocyano- 3-dimethylamino-acryl methyl esters 86, and Bienayme prepared many similar isocyanides,which can undergo a variety of heterocycles, forming reactions like the synthesis of 88 from 84-87 (Scheme 1.20). 

Monoalkylation of a-isocyano esters by using tert-butyl isocyano acetate (R = fBu) has been reported by Schollkopf [28, 33]. Besides successful examples using primary halides, 2-iodopropane has been reported to produce the a-alkylated product (1) as well by this method (KOfBu in THF). In the years 1987-1991, Ito reported several methods for the monoalkylation of isocyano esters, including the Michael reaction under TBAF catalysis as described earlier [31], Claisen rearrangements [34], and asymmetric Pd-catalyzed allylation [35]. Finally, Zhu recently reported the first example of the introduction of an aromatic substituent by means of a nucleophilic aromatic substitution (Cs0H-H20, MeCN, 0°C) in the synthesis of methyl ot-isocyano p-nitrophenylacetate [36]. 

The synthesis of a-chiral isocyano amides has also been reported using various dehydration methods [47, 53-66]. Because of the lower acidity of the a-proton in a-isocyano amides, high stereoinductions can be obtained using relatively harsh dehydration methods (POCls/EtsN, —20°C) [62]. However, the triphosgene/NMM protocol remains the method of choice [53]. 

SCHEME 117. Asymmetric aldol-type reaction between aldehydes and a-isocyano-phosphonates. 

The possibility of obtaining scaffold diversity by the MCR strategy has been further demonstrated using the M-(cyanomethyl)amide 3CR [60] (discussed earlier) as the primary MCR [103]. By applying the primary a-isocyano amide derivative of 176, this MCR could be connected to the Passerini, the Ugi and the Ugi Smiles [106, 107] MCRs resulting in various new scaffolds. 

Optically active ferrocenylbisphosphines, (/J)-N,iV-dimethyl-l-[(5)-1, 2-bis(diphenylphosphino)ferrocenyIJethylamine [(/J)-(5)-BPPFA] and its derivatives, are efficient chiral bisphos-phine ligands for rhodium-catalyzed asymmetric hydrogenation, palladium-catalyzed asymmetric allylic substitution reactions, and gold-catalyzed asymmetric aldol-type reactions of a-isocyano carboxylates. ... 

Rearrangement of allylic a-isocyano esters Y. Ito, H. Higuchi and M. Murakami, Tetrahedron Lett., 1988, 29, 5151. 

The same group further developed the asymmetric aldol reaction of A -methoxy-A -methyl-a-isocyanoacetamide (a-isocyano Weinreb amide) with aldehydes (Sch. 25). The reaction of the Weinreb amide 96 with acetaldehyde in the presence of 86c Au(I) catalyst gives the optically active tram-oxazoline 98 (E = CON(Me)OMe R = Me) with high diastereo- and enantioselectivities similar to those of 95 [49], The oxazoline can be transformed into A,0-protected /3-hydroxy-a-amino aldehydes or ketones. 

The ferrocenylphosphine (R)-(S)-8a is also effective for the asymmetric allylation of several other active methine compounds, including 2-acetyl-1-tetralone, 6,6-dimethyl-2-acetylcyclohexanone, 2-acetylcyclooctanone, 1 -phenyl-2-methylbutane-1,3-dione, 2-phenylpropanal, and methyl a-isocyano(phenyl)acetate [43, 44], The allylation products and the values of enantiomeric excess are shown in Scheme 2-26. 

Bergemann, M., Neidlein, R. Studies on the reactivity of a-cyano a-isocyano alkanoates. Versatile synthons for the assembly of imidazoles. Helv. Chim. Acta 1999, 82, 909-918. 

Intramolecular heterocyclization in polyacrylonitrile 86UK62. a-Isocyano acetates, synthesis of N-heterocycles from 85YGK764. Isonitrosotosyl malonates in synthesis of N-heterocycles 80H(14)1581. Lactams, regioselective formation from bridged bicyclic ketones 81T1283. Malononitrile derivatives, synthesis of N-heterocycles condensed from ... 

Some multicomponent syntheses of trisubstituted oxazoles were described. a-Isocyano-a-alkyl(aryl)acetamides, as 131 <05S161>, was demonstrated to be a useful starting material for a three-component reaction involving isoquinoline 129 <05SL532>. A four-component synthesis was also published starting from an aldehyde, a silylamide, an acyl chloride and a terminal acetylene derivative. The overall process is a modification of a four-component synthesis of a propargylic amide 134 which can be eventually isolated <05T 11317>. 

Multicomponent reactions (MCR) were also highlighted in the literature. The reaction of dimethyl butynedioate 160 and benzyhdenemalononitrile 161 in anhydrous THF with isoquinoline at room temperature gave a mixture of two diastereomers 162 and 163 (2 1) in 81% yield (Scheme 46) <05TL5333>. Isoquinohne was also used in a MCR that included methyl chloroformate and morpholinyl-a-isocyano-P-phenylpropionamide resulting in the synthesis of (l,3-oxazol-2-yl)-l,2-dihydro(iso)quinoline derivatives in moderate yields <05SL532>. 

Synthesis of pyrroles form nitroolefins or p-acetoxy nitro compounds with a-isocyano esters in the presence of an organic base. 

The required a-isocyano derivatives (85) of a-amino acids are prepared from the corresponding a-formylamino acids. If (85) is a peptide derivative, no racemization is observed at the a-isocyanoacyl unit. - The preparation of chiral a-isocyanocarboxylate esters, however, is possible with phosgene or... 

Metal chelates that find use as aldol reaction catalysts are further exemplified hy the A1 complex of salen 60, which brings together a-isocyano amides and aldehyds to provide chiral 2-(a-hydroxyalkyl)-5-aminooxazoles. ... 

In 1968 Japanese workers79 filed a patent application in which was described the preparation of 4-methyl-5-alkoxyoxazolcs by thermal cyclization of lower alkyl esters of (a-isocyano)alkylcarboxylic acids (23). This application, followed by a detailed paper, claims a yield of 20-40% of the oxazole, accompanied by some other products such as the isomeric cyanide and its dimer. The mechanism of this reaction is uncertain, but... 

Smith and coworkersalso reported a novel synthesis of naphthochlorins. In their approach, reactions of 2-nitro-5, 10,15,20-tetraphenylporphyrin 77 with alkyl a-isocyano acetate afforded naphthochlorin 78 (in addition to the expected pyrroloporphyrin) which underwent free radical dimerization (Scheme 21). 

A one-pot synthesis of macrocycles by a domino three-component reaction and [3+2] cycloaddition was investigated by Zhu et aL [99]. By combining three appropriately designed simple substrates, a programmed sequence involving an a-isocyano acetamide-based three-component reaction followed by a copper-catalyzed cycloaddition of alkyne and azide took place to afford macrocycles 119 in moderate to good yields (Scheme 26). 

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