Isocyanoacetates Aldol reactions

The asymmetric aldol reaction of a-ketoesters (RCOCOOMe R=Me, z-Bu, Ph) with methyl isocyanoacetate or A,A-dimethyl-isocyanoacetamide in the... 

Asymmetric aldol reaction. In the presence of a gold(I) complex (1) and a chiral ferrocenylphosphine (2), various aldehydes react with methyl isocyanoacetate... 

The gold catalyst has provided some very important achievements in chemistry in general, such as the asymmetric aldol reaction of aldehydes with isocyanoacetates reported by Ito, Sawamura and Hayashi [12,176]. The use of chiral ferrocenylpho-sphine gold (I) complexes allowed them to obtain enantiomerically-pure oxazo-lines. 

TABLE 8B1.1. Gold-Catalyzed Asymmetric Aldol Reaction of Isocyanoacetate 3a with Aldehydes (Scheme 8B1.1)"... 

TABLE 8B1.3. Asymmetric Aldol Reaction of Isocyanoacetate 3b with Functionalized Aldehydes in the Presence of Gold(I) Catalyst Containing Ligand 2a (Scheme 8B1.1) 1... 

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. 

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-... 

Organoaluminum and Sn(IV) Lewis acid-mediated [3 + 2] cycloadditions of oxa-zoles and aldehydes or diethyl ketomalonate have been observed [116]. The reactions are highly regioselective, with stereoselectivity highly dependent upon the Lewis acid used (Eq. 76). For example, the (BINOL)AlMe-promoted reaction between benzal-dehyde and the oxazole furnishes the oxazoline with a transicis ratio of 2 98. The selectivity is reversed with SnCU which results in a transicis ratio of 85 15. trans-5-Sub-stituted 4-alkoxycarbonyl-2-oxazolines are synthesized under thermodynamic conditions in the aldol reaction of isocyanoacetates with aldehydes [117]. 

Table 3. Diastereo- and enantioselective aldol reaction of methyl isocyanoacetate (27) with tildehydes catalyzed by chiral ferrocenylphosphine 86c gold(I) complex.

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]. 

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. 

Both /ranj-selectivity and enantioselectivity depend on the structure of the terminal amino group, six-membered ring amines represented by piperidino 8g and morpholino 8h generally being most selective [71]. Substituted aromatic aldehydes, a,i -unsaturated aldehydes, and secondary and tertiary alkyl aldehydes can be converted into the corresponding /ranj-oxazolines with high enantioselectivity. Enantiomeric purities and transjcis ratios obtained for the aldol reaction of several aldehydes in the presence of Au/(R)-(S)-8h are shown in Scheme 2-51. The gold-catalyzed aldol reaction of isocyanoacetate has been applied to the synthesis... 

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. 

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... 

Asymmetric Aldol Reaction of isocyanoacetates with Aidehydes... 

Use of isocyanoacetamide 5 instead of isocyanoacetate 3 improves the enan-tioselectivity of the aldol reaction with acetaldehyde and primary alkyl aldehydes (R=Me 99% ee, trans cis=9H9, R=Et 96% ee, trans cis=95 5, R=z-Bu ... 

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... 

---