Asymmetric Synthesis. 39.¹ Synthesis of 2-(1-Aminoalkyl)piperidines via 2-Cyano-6-phenyl Oxazolopiperidine

Abstract

The asymmetric synthesis of a series of 2-(1-aminoalkyl) piperidines using (-)-2-cyano-6-phenyloxazolopiperidine 1 is described. LiAlH(4) reduction of 1 followed by hydrogenolysis led to the diamine 3. The same strategy applied to C-2-methylated compound 7 afforded [(2S)-2-methylpiperidin-2-yl]methanamine (9). Addition of lithium derivatives to the cyano group of 1 resulted in the formation of an intermediate imino bicyclic system (11a-c) which could be diastereoselectively reduced to substituted diamino alcohols 13a-c. The addition of an excess of PhLi to 1 in the presence of LiBr furnished disubstituted amine 19, the precursor of diphenyl[(2S)-piperidin-2-yl]methanamine (22).

Reactivity and stereoselectivity of oxazolopyridines with a ring‐junction nitrogen atom

“…Halogen/metal exchange of 269a and 269b each with butyl lithium led to the formation of the lithiated intermediate, which was transformed into the imines 270a and 270b (91% and 84% yields) (Scheme ) . The epimino‐chromenoazepines 270 were obtained through the intramolecular addition of the aryl‐lithium onto the cyano group and subsequent attack of imine salt on the angular C8a atom of the prospective iminium ion …”

A Selective and Rapid Access to Six‐ or Seven‐Membered Ring Iminosugars via 6,8‐Diazabicyclo[3.2.1]oct‐6‐ene Intermediates

“…[16] The relative configuration of the newly created stereogenic center (C-7) of 5b was determined directly from the NMR spectroscopic data and by comparison with the literature. [17] Indeed, the 2-H/7-H coupling constant of 4.5 Hz indicates a R/R configuration for the C-2/C-7 stereocenters.…”

Reductive and Oxidative Transformations of the N‐(Cyanomethyl)oxazolidine System to Expand the Chiral Pool of Piperidines

“…Further, these methods frequently result in competitive side reactions, notably in the presence of benzylamines and α-amino ethers, groups that are readily hydrogenolysable and reducible, respectively. Previous studies have shown, for example, that α-amino ether moieties are not tolerated by DI-BALH, LiAlH 4 , [13] or NaBH 4 . [14] Given the structural features of our compounds, it is necessary to find reaction conditions that are selective for the removal of the cyano group without opening of the oxazolidine ring and/or without cleavage of the chiral auxiliary.…”

“…Moreover, close similarities in the NMR spectra of 4a and 7a as well as those of 4b and 7b allowed us to assign the stereochemistry at C-6 in 7a and 7b. For example, the 13 C chemical shifts of C-6 for 7b (δ ϭ 87.4 ppm) and C-2 for 4b (δ ϭ 89.1 ppm) are both nearly identical and upfield with respect to those of the corresponding carbon atoms in 7a (δ ϭ 94.3 ppm) and 4a (δ ϭ 95.7 ppm). These comparisons and correspondences can be accounted for by an axial position for 6-H in 7a and an equatorial one in 7b.…”