Development of a Telescoped Flow Process for the Safe and Effective Generation of Propargylic Amines

Abstract

Propargylic amines are important multifunctional building blocks that are frequently exploited in the synthesis of privileged heterocyclic entities. Herein we report on a novel flow process that achieves the safe and effective on-demand synthesis of propargylic amines in a telescoped manner. This process minimizes exposure to hazardous azide intermediates and renders a streamlined route into these building blocks. The value of this approach is demonstrated by the rapid generation of a small selection of drug-like thiazolines that result from a high-yielding reaction cascade between propargylic amines with different aryl isothiocyanates.

Continuous Flow Organophosphorus Chemistry

“…Recently, Baumann et al proposed a telescoped flow process involving a Staudinger reduction for the preparation of propargylic amines. [111] A first azidation of propargylic alcohol 161 was carried out using diphenylphosphoryl azide (DPPA) as an azidation agent (see section 3.6. for more information about DPPA) in presence of DBU at 60°C within 30 min of residence time (Figure 43). The generated azide (not shown) was next passed through a packed-bed containing a polymer-supported sulfonic acid (A15) and a polymer-supported tertiary amine base (A21) for scavenging unwanted by-products.…”

“…Telescoped process for the continuous flow azidation-Staudinger reduction sequence. [111] A recent report was proposed by researchers with UCB Biopharma concerning a continuous flow multistep synthesis towards a 1,3-substituted cyclobutyl derivative 167 through a sequential azidation followed by a Staudinger reduction allowing a stereospecific amination of the substrate 164. [113] The reactor effluent containing the azidation product was mixed with PMe 3 to avoid the isolation of potentially unstable alkyl azide intermediate 165.…”

Continuous-Flow Direct Azidation of Alcohols and Peroxides for the Synthesis of Quinoxalinone, Benzooxazinone, and Triazole Derivatives

“…Furthermore, azidation with azide exchange resin was a crucial step in the total synthesis of oxomaritidine . Moreover, a telescoped-flow process was also established to obtain propargyl amine using DPPA . However, these methods used NaN 3 or heating.…”

“…32 Moreover, a telescoped-flow process was also established to obtain propargyl amine using DPPA. 33 However, these methods used NaN 3 or heating. Henceforth, an efficient method for the broad substrates with mild and safer reaction conditions for the large-scale synthesis under continuous flow are still highly desirable.…”

Nickel-Catalyzed Domino Cross-Electrophile Coupling Dicarbofunctionalization Reaction To Afford Vinylcyclopropanes

“…Analytical data are consistent with literature values. 32 3-(3-Trifluoromethylphenyl)propiolaldehyde (SI-31) was prepared according to Method F. The following amounts of reagents were used: propargylic alcohol SI-30 (0.72 mg, 3.6 mmol, 1.0 equiv), MnO2 (4.7 g, 54 mmol, 15 equiv), CH2Cl2 (36 mL, 0.10 M). The compound was purified by flash column chromatography (0-10% EtOAc/hexanes) to afford the title compound as a yellow oil (0.45 g, 2.4 mmol, 66% yield).…”