Highly efficient one-pot amination of carboxylate-substituted nitrogen-containing heteroaryl chlorides via Staudinger reaction

Development of a Scalable Synthesis of the Small Molecule TGFβR1 Inhibitor BMS-986260

“…Our attempts to convert 18 to the corresponding amine 12 by treatment with an ammonia surrogate (such as benzophenone imine or LiHMDS) under Buchwald–Hartwig conditions provided very little conversion (<5%) to the desired product. This transformation has been reported in the literature using sodium azide at 120 °C followed by a Staudinger reduction using PPh 3 . While we were able to successfully reproduce these conditions on a laboratory scale, we were unable to accomplish this reaction under milder conditions. , Our inability to effect the amination under benign conditions, the hazards associated with handling azides especially at elevated temperatures, and the success we attained in our simultaneous efforts on route B (vide infra) prompted us to halt further work on route A.…”

Synthesis of 1,8-Diazaanthracenes as Building Blocks for Internally Functionalized Aromatic Oligoamide Foldamers

“…However, at the temperatures required for substitution to occur, the resulting azide decomposed, presumably to the nitrene, and gave a mixture of species, including the amine, in low yield (<30%) as well as an unstable species assigned to the 9-azido complex on the basis of a strong IR signal at 2116 cm −1 (KBr pellet), and several unidentified species attributed to decomposition products resulting from side reactions with the nitrene intermediate. By combining the displacement and reductive steps through the addition of PPh 3 to the reaction mixture, as described by Kandakar et al, 38 the yield could be greatly increased (61%) and the amine obtained as a bright red crystalline solid after workup.…”

Synthesis of Peptide Nucleic Acids Containing Pyridazine Derivatives As Cytosine and Thymine Analogs, and Their Duplexes with Complementary Oligodeoxynucleotides

“…The other difference was that aPz derivative 10a (Scheme 3) was directly synthesized from 8a via the intermediate 15 using a reaction in which sodium azide and P(n-Bu) 3 coexisted. 17 Stepwise synthesis via 9a failed because 9a was too stable toward the reduction by P(n-Bu) 3 . By using the PNA units 1a, 1b, 14a, 14b and commercially available PNA units and Fmoc-Lys-OH, 18 PNAs (Figure 3) were synthesized.…”

“…One of the differences between the routes to 14a and 14b was that, in 14a , the amino group was protected with a tert -butyl­oxy­carbonyl (tBoc) group instead of a Bhoc group (Scheme in the parentheses) because the Bhoc group introduced to the amino group of aPz was too labile under purification conditions. The other difference was that aPz derivative 10a (Scheme ) was directly synthesized from 8a via the intermediate 15 using a reaction in which sodium azide and P­( n -Bu) 3 coexisted . Stepwise synthesis via 9a failed because 9a was too stable toward the reduction by P­( n -Bu) 3 .…”