Reactions of β-alkoxyvinyl polyfluoroalkyl ketones with ethyl isocyanoacetate and its use for the synthesis of new polyfluoroalkyl pyrroles and pyrrolidines

Abstract

The hitherto unreported reactions of β-alkoxyvinyl polyfluoroalkyl ketones with ethyl isocyanoacetate and equimolar amounts of potassium-tert-butoxide proceeded mainly in the β-position of the α,β-unsaturated ketones in cases of α-nonsubstituted 1a–e and α-methyl substituted ketones 1g–j. Other α- or β-substituted ketones 1f,k–o gave mainly products 4 of initial attack at the carbonyl carbon. Depending on the solvent, the major products of β-attack do exist in different tautomeric forms. Generally the openchain enol tautomers 5 predominate in the polar DMSO-d(6), while the cyclic γ-hemiaminals 8 are the major tautomers in the less polar CDCl(3). Acid treatment of the latter compounds 8 led to the hitherto unknown ethyl 5-polyfluoroalkyl-pyrrole-2-carboxylates 11 by elimination of formic acid. Catalytic hydrogenation of pyrrole 11a was used for the synthesis of earlier unknown 5-trifluoromethyl proline 16.

Photochemical Perfluoroalkylation with Pyridine N -Oxides: Mechanistic Insights and Performance on a Kilogram Scale

“…The trifluoromethylated pyrrole 9a was subjected to an efficient, diastereoselective hydrogenation reaction to provide the trifluoromethylated proline derivative 17 (Scheme 2B), which has been proposed as a potential isostere of pyroglutamic acid. 67 …”

Comparative effects of trifluoromethyl- and methyl-group substitutions in proline

“…44,45 In 2006, the first synthesis of 2CF 3 Pro was reported, 46 and additional syntheses of this amino acid and its analogues were established later. [47][48][49][50] The synthesis of 5CF 3 Pro was first reported in 2012, 51 and since then additional synthetic approaches to this compound and its diastereomers have been reported. 52,53 Synthesis of 3CF 3 Pro has not yet been provided in the literature; nonetheless, this regioisomer is available from commercial sources.…”

Synthesis of complex unnatural fluorine-containing amino acids

“…The successful incorporation of CF 3 groups into α-prolines has been reported by various groups including Brigaud and co-workers [ 104 ] and Ulrich et al [ 105 ]. One particular example describes the synthesis of 5-trifluoromethyl proline 124 by Haufe and co-workers in 2012 according to Scheme 27 [ 106 ]. Starting from trifluoromethyl enone 120 , reaction with ethyl isocyanoacetate and potassium tert -butoxide enabled isolation of 121 as the major tautomer (85 %) in CDCl 3 (minor tautomers not shown in scheme).…”

“…Further catalytic hydrogenation to 123 was achieved through the employment of conditions already reported in the literature [ 107 , 108 ], followed by hydrolysis to acid 124 in the presence of 6 N HCl.

Scheme 27 Synthesis of 5-trifluoromethyl proline, Haufe and co-workers [ 106 ].

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