A-isocyanoacetates

The Barton-Zard reaction refers to the base-induced reaction of nitroalkenes 1 with alkyl a-isocyanoacetates 2 to afford pyrroles 3. Solvents used are THF or alcohols (or mixtures) and the reaction often proceeds at room temperature. 

The Barton-Zard (BZ) pyrrole synthesis is similar both to the van Leusen pyrrole synthesis that uses Michael acceptors and TosMlC (Section 6.7) and the Montforts pyrrole synthesis using a,P-unsaturated sulfones and alkyl a-isocyanoacetates." An alternative to the use of the reactive nitroalkenes 1 is their in situ generation from P-acetoxy nitroalkanes, which are readily prepared via the Henry reaction between an aldehyde and a nitroalkane followed by acetylation. Examples are shown later. 

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... 

Base-induced reaction of nitroalkenes with alkyl a-isocyanoacetates to afford pyrroles. 

The use of an a-isocyanoacetamide instead of an a-isocyanoacetate is essential in order to obtain oxazoles when the latter compounds are employed, other condensations (Knoevenagel, Mannich), affording imidazolines or amidines, will take place [88]. This reaction has been explored for the preparation of a series of 2-imidazolines employing isocyanoacetates [91]. The reaction worked smoothly to give compounds 105a,b (Scheme 1.36) with the trans isomer prevailing, provided that a racemic isocyanide with an acidic a-proton and a sterically undemanding amine are used. 

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-... 

Alkyl- and arylisothiocyanates react with methyl a-isocyanoacetate (302) in the presence of potassium t-butoxide to give 5-amino-4-ethoxycarbonylthiazoles (303) (Equation (53)) <82S874>. 

Gold(I)/ferrocenylphosphine 2a-d complexes are applicable to asymmetric aldol reactions of a-alkyl substituted a-isocyanoacetates 12. Although the dependency of stereoselectivity on the structures of the substrates is fairly large, some combinations of 12 and aldehydes show high enantio- and diastereoselec-tivity (Scheme 3). The reaction with paraformaldehyde yields (S)-4-alkyl-2-ox-azoHne-4-carboxylates in 64 to 81% ee, which can be readily transformed to the... 

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. 

Scheme 5.6 Three-component synthesis of amidine from a-isocyanoacetate.

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,... 

It is conceivable that if one used a-isocyanoacetic acid derivatives having a less a-acidic proton and if the reaction conditions were sufficiently mild to prevent the a-deprotonation, then one could expect to have a reaction sequence initiated by the nucleophilicity of the isocyanide, consequently leading to a completely different product. 

Reaction of methyl a-(4-nitrophenyl) a-isocyanoacetate with an amine and an aldehyde afforded the 5-methoxyoxazole instead of imidazoline. In this case, the high acidity of the a-proton of substituted a-isocyanoacetate made the resulting enolate very stable, and hence inactive [24],... 

In a later study, Ito s group found that TBAF also effected aldol reactions of 1027 and aldehydes to produce oxazolines. Here, the authors proposed fluoride-catalyzed desilylation of 1027 generated an equilibrium mixture of the oxazol-2-yl carbanion 1031 and the isocyanovinyl enolate 1032 (Scheme 1.275). Condensation of 1032 with an aldehyde and cyclization then gave the oxazolines 1028 and 1029. Aromatic aldehydes gave predominately the cw-oxazoline 1029 in good yield. Interestingly, aliphatic aldehydes were unreactive. The authors also prepared 1028 and 1029 directly from an a-isocyanoacetate ester and an aldeyhde, but used only a catalytic amount of TBAF. 

By carefully tuning the structure of the starting materials, Orru et al. [21] developed an efficient synthesis of imidazoline 18 by using essentially the same reaction partners (Scheme 15.8). The key to substrate design is the use of a-aryl-substituted a-isocyanoacetate (17) and the primary amine instead of the secondary amine as reaction partner of the aldehyde. The reaction was initiated by nucleophihc addition of the enolate anion of 17 onto the imine 19, generated in situ. However, the lack of an additional acidic proton a to ester in the Mannich adduct 20 made the P-elimination impossible. On the other hand, the Mannich adduct having a secondary amine remained nucleophilic and could add intramolecularly to the divalent isocyano carbon, leading, after protonation, to the imidazoline 18 in... 

The divalent carbon of isocyanide has a pronounced nucleophilicity and undergoes readily a-addition to nucleophiles and electrophiles (Scheme 15.9). This chemical property is the basis of the Passerini three-component reaction (Eq. (1), Scheme 15.6) and the Ugi four-component reaction (Eq. (2), Scheme 15.6). However, the two aforementioned a-isocyanoacetate-based three-component reactions (cf. Scheme 15.7 and Scheme 15.8) were both initiated by the nucleophilicity of the a-carbon. The question one could ask is can we initiate the reaction sequence by taking advantage of the nucleophilicity of the isocyano function using similar substrates It is conceivable that, if the sequence can be initiated by the nucle-ophihcity of the isocyanide, a different reaction manifold wiU be induced leading to a different multicomponent adduct. 

The isocyanide is intrinsically nucleophilic, whereas the a-carbon of a-isocyanoacetate becomes a nucleophile only upon deprotonation. It is therefore... 

This consideration led us to perform the same reaction as described by Mat-sumoto but using a-isocyanoacetamide 23 [22] instead of the a-isocyanoacetate as a reaction partner. As shown in Scheme 15.10, the reaction indeed proceeded in a completely different way to afford 5-aminooxazole 24 in excellent yield [23]. We hypothesized that, under these mild conditions, the deprotonation of a-proton of amide 23 did not occur. Consequently, the sequence is initiated by a nucleophihc addition of the isocyano carbon to the in situ generated imine 19 and led to the nitrilium intermediate 25, which was in turn trapped by the amide oxygen to... 

A representative example is shown in Scheme 15.14. Simply stirring a toluene solution of sarcosine (42), 3-phenylpropanal (43), and potassium a-isocyanoacetate (37) in the presence of NH4CI at rt afforded the tetrapeptide 44 in 66% isolated... 

Scheme 15.13 Exploiting the reactivity of a-isocyanoacetic acids three-component synthesis of peptides.

On going from a-isocyanoacetates to a-isocyanoacetamides, the acidity of the a-CH decreases because of the diminished electron-withdrawing power of the amide group. This subtle structural change impacted significantly the reactivity profile of... 

We have shown in Scheme 15.27 that reaction of a-alkyl-substituted a-isocyanoacetic acids with amines (2.0equiv) and aldehydes afford the corresponding dipeptides. Further exploring the scope of the reaction, we synthesized a potassium salt of a-phenyl-a-isocyanoacetic acid 94a and submitted it to reaction with the hydrochloride salt of dimethyl amine (92), cyclohexanecarbaldehyde (93). While the expected dipeptide 38a was indeed formed in about 5% yield, the N-acyl-a-iminoamide 95 was isolated as a major product Compound 95 was isolable but could be directly converted into amide 97 and ketoamide 96a upon... 

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