Amides, vinylogous Mannich reaction

The enantioselective vinylogous Mannich reaction of siloxyfurans with ketimines catalyzed by a cinchona alkaloid amide/Cu(OAc)2 combination afforded furan-2(5fJ)-one containing contiguous tetra- and trisubstituted stereocenters with high selectivity (13AGE5557). 

More recently in 2001, Winkler and Kwak reported methodology designed to access the pyrrolidine core of the hetisine alkaloids via a photochemical [2+2], retro-Mannich, Mannich sequence (Scheme 1.3) [26]. In a representative example of the methodology, vinylogous amide 42 was photo-irradiated to give the [2+2] cycloaddition product 43. Heating cyclobutane 43 in ethanol provided enamine 44 via a retro-Mannich reaction. Exposure of enamine 44 to acidic conditions then effected a Mannich reaction, resulting in pyrrolidine 45. 

A novel intramolecular photocycloaddition involving vinylogous amides and allenes led to an interesting type lb entry to functionalized pyrroles <060L4031>. For example, photolysis of allene 11 provided fused pyrrole 12 via a [2+2] cycloaddition and retro-Mannich reaction. 

As reported by Thomas and Fritzen, a-diazo ketones react with preformed iminium salts with loss of N2 to a ord vinylogous amides. An example is shown in Scheme 6 involving an a-diazo ketone derivative (42) of spectinomycin, which upon treatment with salt (31) affords enamide (44) via the diazo-nium adduct (43). Triethylamine must be present in the reaction to prevent hydrolysis of the enamide. If the iodide salt (30) is used instead of the chloride salt (31), multiple products are obtained due to the higher reactivity of the counterion. This example elegandy portrays the degree of complex functionality which can be tolerated in Mannich reactions using preformed iminium salts. 

An intramolecular photocycloaddition of a vinylogous amide tethered at C-3 of a 1-acylindole has also been achieved in a stereospecific reaction, in which the cyclobutane adduct (332) undergoes a retro-Mannich reaction to give the imino ketone (333), a synthetic precursor of vindorosine (Scheme 104) <90JA8971>. 

The intramolecular photochemistry of the vinylogous amide 173 in terf-butyl alcohol yielded a retro-Mannich type reaction product 174 (equation 114)170. 

Using diene 288 and imine 289, the tandem Mannich/Michael reaction sequence afforded the vinylogous amide 290 in 66% yield (97TL2829). Imines derived from other aldehydes were also studied, providing derivatives of 290 in moderate yields... 

The appropriately substituted vinylogous amides can imdergo an intramolecular photocycloaddition-retro-Mannich-Mannich sequence. This sequence is analogous to the photocycloaddition-retro-aldol-aldol sequence shown in the formation of 19 from 15 (vide supra). Thus, irradiation of 110 leads to the formation of ketoimine 112, the product of photoaddition followed by rerra-Mannich fragmentation. Reaction of 112 with 1 equiv of trimethyloxonium tetrafluoroborate, followed by treatment of the resulting iminium ketone with aqueous hydrochloric acid, provides the photocycloaddition-re/ro-Mannich-Mannich product 113 in 50% yield from the acyclic photosubstrate 110. ... 

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