Modification and Optimization of the Bis-picolylamide-Based Relay Protection for Carboxylic Acids to be Cleaved by Unusual Complexation with Cu²⁺ Salts

Abstract

A simple modification of our recently published protection scheme for carboxylic acids as amides resulted in a new protecting group with significantly improved properties. It requires shorter reaction times for deprotection and allows us to replace Cu(OTf)(2) by CuCl(2), indicating at the same time the importance of the nature of the anion of the Cu(2+) source. Since the new scheme fulfills all criteria required for an ideal protection group it should find widespread application in synthetic organic chemistry.

Efficient Transfer of Chelating Amides into Different Types of Esters and Lactones

“…With 2‐propanol as sterically more demanding secondary alcohol, the transformation into isopropyl ester 25a at room temp. was relatively slow but could be improved significantly by elevating the reaction temperature to 50 °C and/or by adding DIPEA so that it was also complete after approximately 3 h. Recently, we were able to demonstrate that the approach is not restricted to aromatic amides and that we also observed the formation of methyl esters when aliphatic amides were used 5,6. To demonstrate that it is possible to synthesise various esters from aliphatic amides, we prepared esters 18b – 25b by applying a range of alcohols.…”

“…Attempts to achieve the direct transfer of 2 into the free acid in aqueous systems was unsuccessful. We had demonstrated the principle for aromatic and aliphatic acids as well as for amino acids 5. The only disadvantages of the initially reported bpa‐based relay protection scheme were the relatively long reaction times and the use of the rather expensive Cu(OTf) 2 , which had to be applied in equimolar amounts.…”

Unusual metal complexes of N,N-bis(2-picolyl)amides – A comparative study of structure and reactivity

“…[15][16][17][18][19][20][21] In addition, the cleavage can proceed in an intramolecular fashion and give γ-, δ-and ε-lactones in moderate to high yields. [22] Figure 1: Parameters for the quantitative description of the (non-)/planarity of amides; a) twist angle τ, b) Winkler-Dunitzparameter χ N .…”

Unusual Orthogonality in the Cleavage Process of Closely Related Chelating Protecting Groups for Carboxylic Acids by Using Different Metal Ions

“…[8] Scheme 1. It can be easily obtained by reductive amination of pyridine-2-carboxaldehyde with N,N-dimethylethylenediamine and was used for the protection of carboxylic acids to yield amides of type 4.…”