Solution Phase Synthesis of Libraries of Variably Substituted Olefin Scaffolds:  A Library of Allylic Amines

Abstract

The synthesis of allylic amine libraries derived from olefin templates is described. The two-step, solution phase reaction sequence consists of amination of the template followed by Suzuki coupling and expedited purification via ion exchange chromatography. The methodology has been used to synthesize a 1344-member allylic amine library.

Controlling Chemoselectivity in Vinyl and Allylic C−X Bond Activation with Palladium Catalysis: A pKa-Based Electronic Switch

“…To illustrate a practical application of this reversed reactivity, consider the approach we devised recently to prepare a molecular library of approximately 1400 allylic amines for biological evaluation (Scheme 5). 13 Allylic amines are present as central motifs in molecules with diverse pharmacological properties such as Acrivastine (Semprex), 14 Flunarizine (Sibelium, Ca channel blocker), 15 and several GABA uptake inhibitors. 16 Despite the short synthetic approach, we struggled with this route for some time for a number of reasons.…”

“…Purification by flash chromatography (80:20 hexanes/ether) afforded 1.3 g of 2 as a colorless liquid (98% yield). 1 H NMR (CDCl3, 300 MHz) δ 5.66 (s, 1H), 5.58 (s, 1H), 3.74 (s, 6H), 3.16 (s, 2H), 1.50 (s, 3H); 13 C NMR [CDCl3, 75 MHz, APT pulse sequence, evens up (+), odds down (-)] δ 171.7 (+), 127.2 (+), 121.9 (+), 53.1 (+), 52.8 (-), 46.1 (+), 19.4 (-).…”

“…Purification by flash chromatography (95:5 hexanes/ether) afforded 1.51 g of 5 as a colorless liquid (98% yield). 1 H NMR (CDCl3, 300 MHz) δ 7.35 (d, J ) 8.0 Hz, 2H), 7.04 (t, J ) 7.5 Hz, 1H), 6.97 (d, J ) 8.0 Hz, 2H), 6.05 (s, 1H), 5.72 (s, 1H), 4.68 (s, 2H); 13 C NMR (CDCl3, 100 MHz) δ 157. 9, 129.6, 127.3, 121.7, 117.7, 115.0, 71.7; HRMS calcd for C18H19O6N -2H + (M -2H + ) 211.9865, found 211.9837.…”

Moderne Trennverfahren zur effizienten Aufarbeitung in der organischen Synthese

“…Die Methode wurde auf 8×6 Reaktionen parallel angewendet und lieferte Ausbeuten von bis zu 95 % und Reinheiten von bis zu 97 %. Kürzlich beschrieben Siegel und Organ et al die Synthese einer Bibliothek aus 1344 Allylaminen 251. Dazu wurde zunächst ein sekundäres Amin im Überschuss mit 2,3‐Dibrompropen 59 alkyliert (Schema ).…”

Further studies on vinamidinium salt amine exchange reactions, borohydride reductions, and subsequent transformations

“…Some examples involve the cross-linking of proteins10, rhodium catalyzed ylide formation11, directed metalation reactions12 and the preparation of GABA uptake inhibitors13. The quaternary salts derived from such amines can function as useful alkylating agents14,15 for a variety of nucleophilic species and when properly functionalized can undergo base mediated 2,3-sigmatropic rearrangement to give homoallylic amines16.…”