was already reported by U. Jacquemard et al. Cleavage of tert-butyl carbamates using TBAB in THF has been also described.3 We suppose that bromide attacks the carboxyl group of Boc- to form a tetrahedric intermediate which can give intermediates A or B by two possible pathways as depicted in Scheme IV.67. N-arylformamide IV.133 was only isolated in our case confirming the first pathway of the mechanism. (Scheme IV.67) Scheme IV.67. Proposed Boc- group cleavage during the Corey-Fuchs reaction.120 4.2.1.1.2.2 Corey-Fuchs reaction with pivaloyl- protected formamide IV.131b As Boc- group deprotection occured during the Corey-Fuchs alkynylation, we prepared the more stable pivaloyl protected formamide IV.131b. (Scheme IV.68) Unfortunately, we observed also in this case the cleavage of pivaloyl group leading again to N-arylformamide IV.133. Scheme IV.68. Pivaloyl chloride protection of N-formamide IV.133 and unsuccessful dihalomethylation. 4.2.1.1.2.3 Corey-Fuchs reaction with p-toluensulfonyl protected formamide According to literature,, the selective cleavage of N-SO2 bond in the presence of aromatic-SO2R bond is described. Therefore we decided to use a p-toluensulfonyl as group. Such protecting group was also utilized in Brückner’s protocol.63,64 As depicted in Scheme IV.69, N-formamide IV.133 was protected with p-toluensulfonyl chloride and gave IV.131c in a good yield. (Scheme IV.69) Scheme IV.69. Preparation of N-tosylated formamide IV.131c. Reaction of IV.131c with CCl4 and PPh3 afforded dichloroenamide IV.135c at 60 °C in high yield. (Scheme IV.70) No detosylation reaction was observed in this case. It
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