Isocyanoacetic ester

In 1985, in the course of their interest in nitroalkane chemistry, Barton and Zard reported the base-catalyzed reaction of nitroalkenes with a-isocyanoacetates leading to pyrrole esters having an ideal substitution pattern for the synthesis of porphyrins and bile... 

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. 

Thiol protection, 59, 190 Thiono esters, reaction with ethyl isocyanoacetate, 59,187 Thionyl chloride, 55, 27 Thiophenol, 55, 122 58, 144 Thorium dodecanedioate, 56,110 Toluene, 56, 86 58,125 p-Toluenesulfonates, reaction with organo-cuprates, 55,112 p-Toluenesulfonic acid, 58, 57, 63 p-Toluenesulfonic acid, monohydrate, 56,44... 

Thiazoles from Ethyl Isocyanoacetate and Thiono Esters Ethyl Thiazole-... 

THIAZOLES FROM ETHYL ISOCYANOACETATE AND THIONO ESTERS ETHYL THIAZOLE-4-CARBOXYLATE... 

The present procedure is illustrative of a mild and general method for preparing thiazoles substituted in the 4-position with electron-withdrawing substitutents such as carbethoxy, cyano, and p-toluenesulfonyl. Thus condensation of ethyl isocyanoacetate with various thiono esters affords the parent ethyl thiazole-4-carboxylate as well as a series of analogs bearing substituents in the... 

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. " ... 

Methyl formate Formic acid, methyl ester (8,9) (107-31-3) Ethyl isocyanoacetate Acetic acid, isocyano-, ethyl ester (8,9) (2999-46-4)... 

Solomon DM, Rizvi RK, Kaminski JJ (1987) Observations on the reactions of isocyanoacetate esters with isothiocyanates and isocyanates. Heterocycles 26(3) 651-674... 

The fusion of an additonal heterocyclic ring onto the above benzodiazepine restores at least partial agonistic activity. The benzodiazepine nucleus is built exactly as above using L-proline (20-2) instead of sarcosine to afford (20-3). The fused imidazole ring is again added by condensation with an isocyanoacetate, in this case the tert-butyl ester. This then affords bretazenil (20-4) [24], a compound that displays some antianxiety activity. 

Ito and Hayashi noticed that Au(I)-chiral fenocenylphosphine complexes are remarkably efficient in the Knoevenagel reaction between aldehydes and isocyanoacetic esters to form 5-alkyl-2-oxazoline-4-car-boxylates with high enantio- and diasteieoselectivity (Scheme 116)... 

Hebach and Kazmaier reported the synthesis of cyclic peptidomimetics containing an alkylated amino acid via Ugi-4CR of N-terminal-protected aloc-amino acids, allyl isocyanoacetate, and chiral amines in trifluoroethanol. Allylic esters of tripeptides 193 were obtained in high yields and good stereoselectivity. Metathesis with 5% of Grubbs first-generation catalyst gave 16-membered cyclic peptides 194 in 30-50% yield (Scheme 2.69) [101]. 

Several new examples of the Barton-Zard pyrrole synthesis from nitroalkenes and isocyanoacetate esters demonstrate the broad utility of this procedure. An excellent yield of ethyl 3-(9-anthryl)-4-ethylpyrrole-2-carboxylate was obtained starting with the nitroalkene from anthracene-9-carboxaldehyde and 1-nitropropane. <95TL8457> Bums et.al. reported an improved synthesis of benzyl isocyanoacetate which facilitates the synthesis of benzyl pyrrole-2-carboxylate esters by this method. <95SC379> 3-(l-Arylpyrrol-2-yl)pyrrole-2-carboxylates were prepared from l-aryl-2-(nitrovinyl)pyrroles. <95JHC 1703>... 

Wong and co-workers [22] also applied the methodology in the preparation of a library of neomycin B mimetics (Fig. 6). Two libraries were prepared by a multiple-component condensation of neamine derived aldehyde, f-butyl isocyanide or isocyanoacetic acid methyl ester, CBZ-N amino acids (xl3) and a glycine conjugated polyethylene glycol methyl ether. The products of the reaction were isolated by precipitation. 

Gold(I)-Catalyzed Aldol Reaction. In 1986 an elegant enantioselective and diastereoselective synthesis of dihydrooxazolines was reported, using the aldol reaction of an aldehyde with an a-isocyanoacetate ester (formally a Knoevenagel reaction) using a cationic gold(I) complex of (1) (eq 1). ... 

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). 

The gold(I) complex is prepared in situ by the reaction of (1) with bis(cyclohexyl isocyanide)gold(I) tetrafluoroborate (2), typically in anhydrous dichloromethane. The dihydrooxazolines obtained provide a ready access to enantiomerically pure p-hydroxy-a-amino acid derivatives. High diastereo- and enantios-electivity are generally maintained with a wide variety of substituted aldehydes, and a-isocyanoacetate esters. N,N-Dimethyl-a-isocyanoacetamides and a-keto esters have been substituted for the a-isocyanoacetate ester and aldehyde component, respectively, sometimes with improved stereoselectivity. The effect of both the central and planar chirality of (1) on the diastereo- and enantioselectivity of the gold(I)-catalyzed aldol reaction has been studied. The modification of the terminal di-alkylamino group of (1) can lead to improvements in the stereos-... 

This enantioselective aldol reaction employing isocyanoacetate 27 is quite effective for aromatic aldehydes or tertiary alkyl aldehydes, but not for sterically less hindered aliphatic aldehydes as described above. Ito and coworkers found that very high enantioselectivity is obtained even for acetaldehyde (R = Me) in the aldol reaction with Af,A -dimethyl-a-isocyanoacetamide (95) (Sch. 25) [47]. Use of a-keto esters in place of aldehydes also results in moderate to high enantioselectivity of up to 90 % ee [48]. 

Imidazole-4-carboxylates have been made from amidines derived from or-ainino acids (see Section 2.2.1 and Table 2.2.1), by Claisen rearrangement of the adduct formed when an arylamidoxime reacts with a propiolate ester (see Section 2.2.1 and Scheme 2.2.6), from a-aminocarbonyls with cyanates or thiocyanates (see Section 4.1 and Table 4.1.1), from a-oximino- 6-dicarbonyl compounds heated with an aUcylamine (see Section 4.1 and Scheme 4.1.7), and by anionic cycloaddition of an alkyl isocyanoacetate to diethoxyacetonitrile (see Section 4.2 and Scheme 4.2.11 see also Scheme 4.2.12). A further useful approach is to use an appropriate tricarbonyl compound with an aldehyde and a source of ammonia (see Chapter and Scheme 5.1.1). Irradiation of 1-alkenyltetrazoles bearing an ester substituent may have applications (see Section 6.1.2.3). 

Regiochemical synthesis of 1-substituted imidazole-4-carboxylates can be achieved by treatment of a (Z)-)3-dimethylamino-of-isocyanoacrylate with an alkyl or acyl halide (see Section 2.1.1 and Scheme 2.1.8), by cyclization of 3-alkylamino-2-aminopropanoic acids with triethyl orthoformate followed by dehydrogenation of the initially formed imidazoline (see Section 3.1.1 and Scheme 3.1.2), by condensation of 3-arylamino-2-nitro-2-enones with ortho esters in the presence of reducing agents (see Section 3.1.1 and Scheme 3.1.4), by reaction of an alkyl A -cyanoalkylimidate with a primary amine (see Section 3.2 and Scheme 3.2.1), the poor-yielding acid-catalysed cyclization of a 2-azabutadiene with a primary amine (see Section 3.2 and Scheme 3.2.3), the cyclocondensation of an isothiourea with the enolate form of ethyl isocyanoacetate (see Section 4.2 and Scheme 4.2.5), and from the interaction of of-aminonitrile, primary tunine and triethyl orthoformate (see Chapter 5, Scheme 5.1.5, and Tables 5.1.1 and 5.1.2). 

For the aldol reaction of small alkyl aldehydes such as acetaldehyde, the enantioselectivity is improved by the use of Ar,A -dialkyl-oe-isocyanoacetamides instead of isocyanoacetate esters (Scheme 2-54) [76]. For example, the reaction of acetaldehyde with AT,iV-dialkyl-a-isocyanoacetamides 64 in the presence of R)- S)-8g/gold catalyst gives the corresponding /ranj-oxazoline 65 of 99% ee, which is much higher than the enantioselectivity (85% ee) observed in the reaction with methyl isocyanoacetate under the same reaction conditions. 

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). ... 

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