Isocyanoacetates, addition

The mechanism is presumed to involve a pathway related to those proposed for other base-catalyzed reactions of isocyanoacetates with Michael acceptors. Thus base-induced formation of enolate 9 is followed by Michael addition to the nitroalkene and cyclization of nitronate 10 to furnish 11 after protonation. Loss of nitrous acid and aromatization affords pyrrole ester 12. 

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. " ... 

Low-valent rhodium complexes are efficient catalysts for addition of isocyanoacetates to ketones or 1,3-dicarbonyl compounds (Equations (56) and (57)).405 The formation of isocyanoalkylrhodium species via a-G-H activation of... 

In addition, interest in combinatorial chemical applications led a team at AMGEN to the recognition of a related but different pathway which afforded tetrahydro tetrazolo[l,5-zz]pyrazine-6-ones 121 (Scheme 22) <2000TL8729>. In this procedure, three starting components, that is, the ketone, the primary amine, and trimethylsilyl azide, as in the previous method, were used, and the fourth component was methyl isocyanoacetate. This reaction also took place under relatively smooth conditions (methanolic solution at room temperature for 6h followed by reflux for 24 h) to yield the products 121 in good to high yields. The reaction obviously proceeds by the formation of intermediate 120. 

This unique pattern is represented in a rather special 2 1 condensation of alkyl isocyanoacetates with aldehydes (equation 129). Mechanistically, an initial conjugate addition followed by an anionic cyclization is likely. Yields of around 60% are obtained (74JOC1980). 

Recently it has been found that high stereoselectivity in the asymmetric aldol reaction of an isocyanoacetate is also obtainable with the silver catalyst containing ferrocenylphosphine ligands 2e, by keeping the isocyanoacetate concentration low throughout the reaction by the slow addition of 3a over a period of 1 h (Scheme 8B1.7, Table 8B1.8) [25]. 

Pyrrole synthesis. A new route to pyrroles1,2 is based on a base-catalyzed Michael addition of an alkyl isocyanoacetate to a nitroalkene to give an intermediate that cyclizes to a pyrrole. The nitroalkene is generally obtained from a P-acetoxy nitroalkane (1), prepared by a nitro aldol reaction of an aldehyde with a nitroalkane. The synthesis of ethyl 3,4-diethylpyrrole-2-carboxylate (2) is typical. 

Several 2-substituted 3,4-diarylpyrroles 3 have been prepared in a regioselective process employing the base induced addition of methyl isocyanoacetate to the a,f -unsaturated nitriles 4, and one of the pyrroles so obtained was used in a concise synthesis of the alkaloid ningalin B... 

A mixture consisting of 3-trifluoromethylaniline (1.15 equiv.) and 0.63 ml isobutyraldehyde dissolved in 15 ml methyl alcohol was stirred 15 minutes at 20°C, then treated with 0.46 ml of acetic acid, and stirred an additional 10 minutes at 20°C. The mixture was further treated with 0.8 ml 95% ethyl isocyanoacetate (1 equiv.), then... 

Silver(I)-Catalyzed Aldol Reaction. In 1991 the silver(I)-catalyzed aldol reaction of an aldehyde with an a-isocyanoacetate ester was reported, analogous to the above mentioned gold(I)-catalyzed reaction. The catalyst was prepared in situ from (2) and Silver(I) Perchlorate. The stereoselectivity of the silver(I)-catalyzed reaction was shown to be temperature dependent, which was attributed to the variation of the degree of metal coordination with temperature. Slow addition of the a-isocyanoacetate ester to a mixture of the aldehyde and catalyst, which favored the preferred tricoordinate Ag, gave high diastereo- and enantioselec-tivity (eq 3). 

Ito and coworkers found that chiral ferrocenylphosphine-silver(I) complexes also catalyze the asymmetric aldol reaction of isocyanoacetate with aldehydes (Sch. 26) [51]. It is essential to keep the isocyanoacetate at a low concentration to obtain a product with high optical purity. They performed IR studies on the structures of gold(I) and silver(I) complexes with chiral ferrocenylphosphine 86a in the presence of methyl isocyanoacetate (27) and found significant differences between the iso-cyanoacetate-to-metal coordination numbers of these metal complexes (Sch. 27). The gold(I) complex has the tricoordinated structure 100, which results in high ee, whereas for the silver(I) complex there is an equilibrium between the tricoordinated structure 101 and the tetracoordinated structure 102, which results in low enantioselectivity. Slow addition of isocyanoacetate 27 to a solution of the silver(I) catalyst and aldehyde is effective in reducing the undesirable tetracoordinated species and results in high enantioselectivity. 

Silver(i) complex coordinated with the ferrocenylbisphosphine ligand 8g is also effective as a catalyst for the asymmetric aldol reaction of isocyanoacetate when the isocyanoacetate is kept in low concentration in the reaction system (Scheme 2-58) [82], Thus, by the slow addition of isocyanoacetate over a period of 1 h to a solution of aldehyde and the silver catalyst, iranj-oxazolines are formed in 80—90% ee, the enantioselectivity being only a little lower than that observed in the gold(i)-catalyzed... 

Computational studies concerning theoretical approaches to the intrinsic basicity of neutral nitrogen bases have been reported, including those of phos-phoranimines. The non-ionic phosphazene bases BEMP (112), BTPP (113) and (114, R = Ph) appear to be excellent catalysts for the Michael addition reactions. Thus the yield of the coupling reaction of ethyl isocyanoacetate with l,2-bis(4-bromomethylphenyl)ethane is increased by the addition of the phosphazene base BEMP. Polymer-supported BEMP (P-BEMP) has been applied for the allylation of 2H-benzo[d]l,3-dioxolan-5-ol by allyl bromide. " Cyclodehydration of 1,2 diacylhydrazines by tosyl chloride in the presence of P-BEMP leads to excellent yields of 1,3,4,-oxadiazoles. Addition of P-BEMP also improves the yield of the Hofmann elimination step in the synthesis of tertiary mines using REM resin (polymer-bound acrylate ester). ... 

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. 

By introducing a substituent, especially an aryl group, into the a-position of an a-isocyanoacetate (e.g., 13) and using a primary amine as reaction partner of an aldehyde, a completely different product was obtained by Orru s group (Scheme 5.7) [21]. The reaction was also initiated by nucleophilic addition ofthe enolate anion of 13 to the imine (iminium) however, the lack of an additional acidic proton a to the ester group in the intermediate 14 (Mannich adduct) made P-elimination impossible. Therefore, the secondary amine would attack intramolecularly the divalent isocyano carbon leading,... 

The neuroexcitatory amino acid a-kainic acid, a popular testing ground for new pyrrolidine syntheses, has been prepared by a number of routes that involve free-radical cyclization reactions. Bachi has reported two approaches that involve iminoyl radical cyclizations. One enantioselective route is described in Scheme 6 [35]. Isonitrile 48 was prepared in 4 steps from 4-bromo-3-methyl-2-butenal dimethyl acetal, the key reaction being an enantioselective addition of tert-butyl oc-isocyanoacetate to an aldehyde mediated by Hiyashi s catalyst. Treatment of 48 with a catalytic... 

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