of bromoacetylene IV.160 (2.0 equiv) and base KHMDS (3.0 equiv). The protecting group was removed by the fluoride anione (TBAF) in almost quantitative yield 97 %. Compound IV.130d was isolated in 26 % overall yield over 3 steps starting from aniline IV.127. Scheme IV.94. Preparation of desired ynamide IV.130d through the N-alkynylation by Tam’s reaction conditions.75 In 2008, Skrydstrup described the second generation protocol. et al. Hsung’s (Scheme IV.95) Yields of ynamides were depended on the quality of K3PO4. The anhydrous K3PO4 provided higher ynamides yields (52 - 91 %) in comparison to K3PO4 contaminated with hydrates. Scheme IV.95. second generation protocol.145 Hsung’s The low yield of IV.164d obtained by protocol (28 %) encouraged us to test Tam’s also the Skrydstrup modified procedure. The use of mild conditions (K3PO4 as base and CuSO4 . 5 H2O as catalyst) was another motivation for testing this protocol. Finally, the reaction afforded an exceptional 97 % yield of (after purification on silica gel). IV.164d (Scheme IV.96) Cleavage of TIPS- protecting group afforded ynamide IV.130d in 88 % overall yield over 3 steps from aniline which represented a spectacular improvement IV.127, of the previous procedure (26 %). Scheme IV.96. IV.130d Preparation of ynamide through the direct N-alkynylation using the protocol of Skrydstrup et al. protecting group is generally cleaved under basic conditions. In order to N-COOMe have in hands also acidic sensitive protecting group, we decided to prepare protected N-Boc ynamide IV.130a. Boc- protection of aniline IV.127 was performed in 89 % yield with dicarbonate using the catalytic amount of 4-dimethylaminopyridine under reflux in THF overnight. (Scheme IV.97) Afterwards reaction protocol lead to accodring Skrydstrup’s
of bromoacetylene IV.160 (2.0 equiv) and base KHMDS (3.0 equiv). The protecting group was removed by the fluoride anione (TBAF) in almost quantitative yield 97 %. Compound IV.130d was isolated in 26 % overall yield over 3 steps starting from aniline IV.127. Scheme IV.94. Preparation of desired ynamide IV.130d through the N-alkynylation by Tam’s reaction conditions.75 In 2008, Skrydstrup et al. described the Hsung’s second generation protocol. (Scheme IV.95) Yields of ynamides were depended on the quality of K3PO4. The anhydrous K3PO4 provided higher ynamides yields (52 - 91 %) in comparison to K3PO4 contaminated with hydrates. Scheme IV.95. Hsung’s second generation protocol.145 The low yield of IV.164d obtained by Tam’s protocol (28 %) encouraged us to test also the Skrydstrup modified procedure. The use of mild conditions (K3PO4 as base and CuSO4 . 5 H2O as catalyst) was another motivation for testing this protocol. Finally, the reaction afforded an exceptional 97 % yield of IV.164d (after purification on silica gel). (Scheme IV.96) Cleavage of TIPS- protecting group afforded ynamide IV.130d in 88 % overall yield over 3 steps from aniline IV.127, which represented a spectacular improvement of the previous procedure (26 %). Scheme IV.96. Preparation of ynamide IV.130d through the direct N-alkynylation using the protocol of Skrydstrup et al. N-COOMe protecting group is generally cleaved under basic conditions. In order to have in hands also acidic sensitive protecting group, we decided to prepare N-Boc protected ynamide IV.130a. Boc- protection of aniline IV.127 was performed in 89 % yield with dicarbonate using the catalytic amount of 4-dimethylaminopyridine under reflux in THF overnight. (Scheme IV.97) Afterwards reaction accodring Skrydstrup’s protocol lead to
ab-11_mv-part-two_form-8.-bibliography.docx