A convenient route to 1-benzyl 3-aminopyrrolidine and 3-aminopiperidine

A Highly Divergent Synthesis of 3-Aminotetrahydropyridines

“…1 H NMR (CD 3 CN, 600 MHz): δ H 8.30 (d, 1H J = 2.0 Hz,), 8.00 (d, 1H, J = 2.0 Hz,), 7.84 (d, 1H, J = 2.0 Hz), 7.83 (d, 1H, J = 2.0 Hz), 7.75 (d, 1H, J = 2.0 Hz), 7.36 (d, 1H, J = 2.0 Hz), 6.35 (t, 1H, J = 2.0 Hz), 6.29 (t, 1H, J = 2.0 Hz), 6.26 (t, 1H, J = 2.0 Hz), 5.72 (dd, 1H, J = 7.5 Hz, 6.8 Hz), 3.86 (m, 1H), 3.78 (m, 1H), 3.74 (dd, 1H, J = 12.9 Hz, 5.8 Hz), 3.64 (dd, 1H, J = 6.1 Hz, 5.8 Hz), 3.15 (dd, 1H, J = 12.9 Hz, 6.1 Hz), 3.04 (dd, 1H, J = 13.8 Hz, 6.8 Hz), 2.89 (dd, 1H, J = 13.8 Hz, 7.5 Hz), 2.54 (s, 3H), 2.49 (ddd, 1H, J = 11.5 Hz, 11.2 Hz, 2.2 Hz), 1.96 (s, 3H), 1.20 (d, 9H, J = 8.4 Hz), 0.91 (d, 1H, J = 11.2 Hz), 0.87 (t, 3H, J = 7.1 Hz). 13 (10). Step 1.…”

“…Piperidines are abundant in natural products and FDA-approved small-molecule drugs. , Many of these molecules also feature exocyclic nitrogen functional groups, such as the 3-aminopiperidine structural motif found in drugs including troxipide, alogliptin, relebactam, the JAK3 inhibitors tasocitinib, and PF-06651600. − The amine functionality can be difficult to incorporate into the piperidine core, especially stereoselectively. For example, while the parent 3-piperidinamine is commercially available, approaches to the stereoselective synthesis of its derivatives have taken many different forms, ranging from cyclizations, ring expansion of pyrrolidines, , Curtius and Hofmann rearrangements, reductive amination of piperidin-3-ones, and hydrogenation of hydroxy- or aminopyridines (Figure ), often via Buchwald–Hartwig amination of a 3-halopyridine. , The latter approach would seem to be the most general, allowing for the greatest diversity, but two challenges emerge: the lack in availability of the corresponding substituted aminopyridine, and the ability to control the stereochemistry of the hydrogenation. , …”

Transition‐Metal‐Catalyzed Asymmetric Hydrogenation and Transfer Hydrogenation: Sustainable Chemistry to Access Bioactive Molecules

“…Chiral 3‐aminopiperidine derivatives are encountered in a plethora of pharmaceutically active agents encompassing a vast array of biological activities 33. Apart from chemical resolution, most of the traditional synthetic approaches are based on procedures employing chiral building blocks, auxiliaries, or reagents combined with long reaction sequences and multiple tedious purification steps 34. In 2016, we achieved the first enantioselective synthesis of both enantiomers of 3‐aminopiperidine derivatives through Rh‐catalyzed AH of easily accessible N ‐(1‐benzylpiperidin‐3‐yl)enamides (Table ) 35…”

Palladium-Mediated Arylation of 3-Aminopiperidines and 3-Aminopyrrolidines

“…The arylation of N -Boc-3-aminopyrrolidine 8 or N -Boc-3-aminopiperidine 10 , using the combination Pd(OAc) 2 /BINAP/Cs 2 CO 3 /toluene, afforded the desired compounds in low yields (11% and 2.5% after removal of the Boc protection). 3-Aminopyrrolidines 6 − 8 or 3-aminopiperidines 9 − 10 (Figure ) being easily available on a large scale, we have envisaged the use of a cross-coupling methodology to access rapidly to 3-( N -arylamino)pyrrolidines 11 − 13 and piperidines 14 and 15 (Scheme and Figure ). In this paper, we report that arylation of the secondary cyclic amine of unprotected 3-aminopyrrolidine 1 and 3-aminopiperidine 2 is highly selective whatever palladium ligand used.…”