Pyrroles with propiolic acid

Treatment of aziridinyl ketone 18 with propiolic acid ethyl ester 58 leads to two regioisomeric pyrroles 59 and 60 [76] (Scheme 1.15). The reaction of ketone... 

Acidic hydrolysis of the reactive enamide led to the corresponding carboxylic acids 14 whereas alcoholysis gave esters 16 and aminolysis amides 15. The mechanism of the hydrolysis was shown to proceed via miinchnone derivatives 20 which, instead of being opened with a nucleophile, reacted as a 1,3-dipole in [3+2] cycloaddition reactions with propiolic esters or acetylene dicarboxylic esters to give after elimination of carbon dioxide protected pyrroles 19 (Scheme 3.2.4)... 

FIGURE 8.20 Peptides activated at an IV-methylamino-acid residue are postulated to epimer-ize because of the formation of the oxazolonium ion. Evidence for the latter resides in spectroscopic studies,96 and the isolation of a substituted pyrrole that was formed when methyl propiolate was added to a solution of Z-Ala-MeLeu-OH in tetrahydrofuran 10 minutes after dicyclohexylcarbodiimide had been added.95 The acetylenic compound effected a 1,3-dipolar cycloaddition reaction (B), with release of carbon dioxide, with the zwitter-ion that was generated (A) by loss of a proton by the oxazolonium ion. 

Despite the uncertainties regarding regiochemistry, the reaction of propiolates with miinchnones has found use in synthesis. Kane and co-workers (84) synthesized the calcium channel activator FPL 64176 (161) using a mtinchnone cycloaddition protocol. Thus, reaction of amino acid 158 with acetic anhydride in the presence of acetylenic dipolarophUe 159 gave pyrrole 160 in 49% yield. Base-induced elimination of the 4-nitrophenethyl protecting group afforded FPL 64176 (161) in 85% yield. 

When the precursor is derived from malononitrile, reaction with maleimide leads to the expected a-cyano pyrrolidine adduct. However, methyl propiolate gives 3-carbomethoxy pyrrole, probably due to the acidity of hydrogen a- to the cyano group in the intermediate A3-pyrrolinic adduct first formed.171... 

Derivatives of other amino acids were also used for the preparation of pyrroles [54], Accordingly, the reaction of the unstable 122, generated in situ from A-phenylglycine 121, with ethyl propiolate gave an inseparable 9 1 mixture of 123 and 124 in 58 % yield. Similarly, the pyrroles 127 were synthesized from trifluoro-acetylated sarcosine 125 and the acetylenes 126 [55]. 

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