TMSOTf mediated ‘5/6-endo-dig’ reductive hydroamination for the stereoselective synthesis of pyrrolidine and piperidine derivatives

Abstract

A TMSOTf mediated 5/6-endo-dig reductive hydroamination cascade on internal alkynylamines gave expedient, stereoselective access to pyrrolidine and piperidine derivatives. We also demonstrate that a protecting group on nitrogen has a profound effect on the reactivity as well as diastereoselectivity.

Synthesis of 3-Azabicyclo[m.2.0] Ring Systems via a Copper-Catalyzed Cascade Reaction of Diazo Compounds with 1,n-Allenynes

“…The title compound was synthesized from the corresponding 3-bromopropyne and aminoalkyne following GP-A, and obtained as a colorless oil in 69% yield (950.0 mg, 5 mmol scale): 1 H NMR (500 MHz, CDCl 3 ) δ 7.74 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 6.54 (t, J = 6.4 Hz, 1H), 5.24 (d, J = 6.4 Hz, 2H), 4.37–4.28 (m, 1H), 2.55–2.47 (m, 1H), 2.45–2.37 (m, 4H), 1.94 (d, J = 5.3 Hz, 1H), 1.21 (d, J = 6.9 Hz, 3H); 13 C­{ 1 H} NMR (125 MHz, CDCl 3 ) δ 203.9, 143.8, 137.2, 129.8, 127.3, 94.7, 85.6, 80.9, 70.6, 53.9, 24.2, 21.7, 17.1; HRMS (ESI) m / z [M + H] + calcd for C 15 H 18 NO 2 S 276.1053, found 276.1048.…”

“…The title compound was synthesized from the corresponding 3-bromopropyne and aminoalkyne following GP-A, and obtained as a colorless oil in 57% yield (961.6 mg, 5 mmol scale): 1 H NMR (500 MHz, CDCl 3 ) δ 7.65–7.61 (m, 2H), 7.32–7.21 (m, 7H), 6.35 (t, J = 6.3 Hz, 1H), 5.44 (dd, J = 8.6, 6.6 Hz, 1H), 5.09 (dd, J = 10.5, 6.3 Hz, 1H), 5.02 (dd, J = 10.5, 6.3 Hz, 1H), 3.05 (ddd, J = 17.0, 8.7, 2.7 Hz, 1H), 2.74 (ddd, J = 17.0, 6.6, 2.7 Hz, 1H), 2.41 (s, 3H), 1.92 (t, J = 2.7 Hz, 1H); 13 C­{ 1 H} NMR (125 MHz, CDCl 3 ) δ 204.6, 143.7, 137.2, 136.9, 129.6, 128.3, 128.1, 127.9, 127.4, 95.6, 85.7, 80.7, 71.3, 60.1, 22.2, 21.7; HRMS (ESI) m / z [M + Na] + calcd for C 20 H 19 NO 2 SNa 360.1029, found 360.1024.…”

“…The title compound was synthesized from the corresponding 3-bromopropyne and aminoalkyne following GP-A, and obtained as a white solid in 86% yield (1356.0 mg; 5 mmol scale; mixture of two inseparable diasteroisomers; dr ∼ 4:1): mp 63–66 °C; 1 H NMR (500 MHz, CDCl 3 ) δ 7.85–7.75 (m, 2H), 7.31–7.25 (m, 2H), 6.45 (t, J = 6.3 Hz, 1H), 5.24–5.17 (m, 2H), 3.98–3.72 (m, 1H), 2.83–2.44 (m, 1H), 2.43–2.40 (m, 3H), 1.85–1.78 (m, 1H), 1.75–1.60 (m, 4H), 1.54–1.01 (m, 4H); 13 C­{ 1 H} NMR (125 MHz, CDCl 3 ) δ 205.1, 144.0, 143.4, 137.8, 136.4, 129.5, 129.4, 127.9, 127.6, 85.0, 84.93, 84.88, 69.9, 69.8, 62.6, 62.5, 33.6, 33.3, 33.0, 32.7, 31.0, 30.2, 25.5, 25.0, 24.9, 24.6, 21.7, 21.6; HRMS (ESI) m / z [M + Na] + calcd for C 18 H 21 NO 2 SNa 338.1185, found 338.1178.…”

Acetal Substitution Reactions: Stereoelectronic Effects, Conformational Analysis, Reactivity vs Selectivity, and Neighboring-Group Participation

“…Acetal substitution reactions are common transformations used to prepare a variety of structures, as illustrated by syntheses of cyclic ethers [1][2][3] and amines, [4][5][6] and they are also used commonly in carbohydrate chemistry. 7,8 These reactions can follow different mechanisms, but, in acetals that do not have several nearby electron-withdrawing groups, these reactions likely proceed via oxocarbenium ion intermediates.…”

Harnessing Gold(I)-Catalyzed Hydroamination/1,3-Sulfonyl Migration Cascade for Divergent Synthesis of Isoxazolidine and Isoxazoline from O-Alkynyl Hydroxylamine

“…They are also valuable synthetic intermediates, which can be manipulated to a variety of compounds such as 1,3-amino alcohols and β-hydroxy ketones (aldol products) . While significant progress has been made on the synthesis of isoxazolidines/isoxazolines employing 1,3-dipolar cycloadditions as well as using olefins, usage of alkynes has received much less attention. , In continuation of our interest in the synthesis of N , O -containing heterocycles, herein we disclose the first example of gold-catalyzed 5- exo-dig hydroamination of the O -homopropargylic hydroxylamines 6/7 enabling access to isoxazolidines 8/10 . We further report that the higher gold catalyst loading results in a 5- exo-dig cyclization–intramolecular nitrogen to a carbon 1,3-sulfonyl migration cascade furnishing isoxazolines 9 .…”