Penta-substituted pyrroles

A mixture of metals was utilized to promote a type Ilae synthesis of penta-substituted pyrroles <06OL2151>. Treatment of enyne 37 with a Ag(I) catalyst followed by BnNH2 and a Au(I) catalyst gave pyrrole 38 via a Claisen-type rearrangement and cyclocondensation. 

Scheme 4. Paal-Knorr synthesis of penta-substituted pyrrole 22.

Mori has reported a route to tetra- and penta-substituted pyrroles by a sequence involving reaction of the iminosilaacyl complex 5 with an alkyne in the presence of LiEt3BH to afford an initial azazirconacyclopentene intermediate <97CL825>. Addition of acyl halides and CuCl leads to the pentasubstituted pyrrole 6 or the desilylated product 7 in this one-pot reaction. 

After more than one year s exploration, the carefully controlled conditions were worked out to prepare penta-substituted pyrrole in 43% yield. The conditions entailed the condensation of the diketone with the diethyl acetal of 3-amino-propanal in the presence of 1 equivalent of pivalic acid. It was also significant that it was demonstrated that a totally convergent synthesis was possible. With this result in hand, it became possible to envision a route in which a fully elaborated side chain could be combined with the appropriate 1,4-diketone to assemble the entire molecule into one operation. 

Scheme 15 One-step synthesis of a penta-substituted pyrrole.

A number of 4-1-1 protocols for the synthesis of pyrrole cores featuring the Cu (I)primary amine derivatives as the key carbon-heteroatom bond forming reaction have been reported recently. Thus, Buchwald described an efficient Cu(I)-catalyzed synthesis of tri-, tetra-, and penta-substituted pyrroles 302 from 1,4-dihalo-l,3-dienes 300 and carbamates 281 (Scheme 8.107) [305]. This methodology displayed excellent functional group compatibility, providing good to... 

Beller and coworkers recently reported a new strategy for the synthesis of poly-substituted anilines based on a three-component-coupling reaction and a domino deprotec-tion/aromatization reaction (equation l)44. A mixture of O-benzyl carbamate, p-toluene-sulfonic acid, aldehyde, AC2O and dienophile in /V-rnclhy I pyrrol idone was allowed to react for 24 h at 120 °C, followed by Pd/C catalyzed dehydrogenation in triglyme at 140 °C. A variety of tri-, tetra- and penta-substituted anilines were efficiently created by this domino process. 

When the fully functionalized, stereochemically pure side chain and the fully substituted diketone were treated under very carefully defined conditions (1 equiv. pivalic acid, 1 4 1 toluene/heptanesyTHF), a 75% yield of the penta-substitued pyrrole was obtained.Deprotection and formation of the hemi-calcium salt produced stereochemically pure atorvastatin calcium in a convergent, high-yielding, and commercially viable manner. 

Dewar tetrakis(trifluoromethyl)thiophene, (59), has served as a dieneophile (dipolarophile) in several cycloadditions. Diels-Alder reaction of (59) with butadiene <8icci289> and pyrrole (82JA847) has served as the starting point for the synthesis of 1,2,3,8-tetrakis(trifluoromethyl)cyclooctatetraene (60) and tetrakis(trifluoromethyl)Dewar furan (61), respectively, as illustrated in Scheme 20. It is noteworthy that (61) was unattainable by direct photolysis of the substituted furan. Moreover, (59) served as a common precursor for the preparation of tetrakis- (80JA6633) and penta-<83JA3563> (trifluoromethyl)cyclopentadienides (64) and (65), respectively (Scheme 21). Accordingly, photolysis... 

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