Proton magnetic resonance studies of compounds with bridgehead nitrogen atoms—XX: The NMR spectra and stereochemistry of some hexahydropyrido[2, 1‐c] [1, 4] oxazin‐3(4H)‐ones and related compounds

Abstract

A series of substituted hexahydropyrido[2,1-c][l,4]oxazin-3(4H)-ones has been synthesised, and the configurations of these bicyclic lactones assigned utilising chemical and spectral data. All the compounds adopt frans-fused conformations and the conformation of the lactone ring is discussed with reference to the magnitude of the geminal coupling constant of the N-CH,-C(0)-0 protons, and the vicinal couplings between the angular proton and the methylene protons adjacent to the ring oxygen atom. The lactone ring conformation is shown to differ slightly from the half chair conformation described for some monocyclic 6-lactones. The synthesis and NMR spectra of some related compounds possessing the bridgehead N-CH,-C(0)-0 system are discussed and these compounds arc also shown to adopt a trans-fused ring conformation.A VALENCE-BOND approach to the calculation of adjacent n-electron effects on the geminal coupling constant (J,,,)? between methylene group protons has produced2 a relationship dependent upon the dihedral angle (#) between the z-bond and the C-H bond. This J -C $ relationship has been tested3 for a variety of cyclic compounds possessing a CH, adjacent to a keto-group or C=C and the results are generally in accord with the prediction^.^ to Most published applications of the Barfield-Grant J -# relationship to conformational analysis refer to cyclic and very little work has been described dealing with systems possessing a modified carbonyl group (e.g. COOR, CONH,). Accordingly, some substituted hexahydropyrido-[2,1-~][1,4]oxazin-3(4H)-ones (1) and related systems were chosen for study in order to provide data on the magnitude of Jgem for methylene grosp protons adjacent to lactone carbonyl. RESULTS A N D DISCUSSION Methyl substituted hexahydropyrido[2,1-c] [1,4]oxazin-3(4H)-onesThe presence of the conformationally mobile nitrogen atom in hexahydropyrido-[2,1-c] [ 1,4]oxazin-3(4H)-one (1) permits its existence as an equilibrium mixture of trans-fused and cis-fused ring conformations. In addition, various conformations of the perhydrooxazinone ring in these structures are possible (seen in a Dreiding model by movement of H4ax' and Hleq' towards or away from each other). NMR studies on some 6-methyItetrahydr0-1,4-oxazin-2-ones,~ some substituted valerolactones8 and some steroidal lactoness are consistent with a half chair conformation for the lactone ring, with the planar C-C(0)-0-C grouping demonstrated in jacobine bromodilactone and themonoterpenoid iridomyrmecin by crystal structureanalysis.loS1l * For Part XIX, see Ref. 1. t S, , , is assumed to be negative throughout this paper. 509

A series of hexahydro[1,4]oxazino[3,4-a]isoquinolines as potential neuroleptics

“…Recrystallization from ethanol gave an analytical sample, mp 168-183 °C. The NMR spectrum showed that the sample tra/is-TV,iV-Diethyl-1,3,4,6,7,1 lb-hexahydro-9,10-methylenedioxy [ 1,4]oxazino [3,4-a ]isoquinoline-3-carboxamide (31). The above mixture of cis and trans nitriles was refluxed with 0.5 N ethanolic potassium hydroxide (40 mL) and water (8 mL) for 4 h. The solvents were removed in vacuo (80 °C) to give a gummy residue which was dissolved in 2.5 N aqueous hydrochloric acid (15 mL) and allowed to crystallize on standing overnight.…”

“…Anal. (C16H20N2O4) C, , N. trans-l, 3,4,6,7, llb-Hexahydro-9,10,1 l-trimethoxy [ 1,4]oxazino [3,4-a]isoquinoline-3-carboxamide (34). A mixture of the above nitrile (3.7 g), 0.51 N potassium fert-butoxide in teri-butyl alcohol (25 mL), and teri-butyl alcohol (370 mL) was refluxed for 2 h and evaporated.…”

“…Chemistry. The [l,4]oxazino [3,4-a]isoquinoline ring system was novel when we began our synthesis (see Figure 2). More recently an aromatic analogue was described2 and a synthesis3 and NMR spectral analysis4 were reported for some 3-oxo analogues.…”

“…cis-and trans-1,3,4,6,7, llb-Hexahydro-9-methoxy[ 1,4]oxazino[3,4-a]isoquinolinecarbonitrile. Phosphorus oxychloride (26 ml,) was added to a solution of the above morpholinone (15.25 g)in 1,2-dichloroethane (175 mL), and the mixture was refluxed for 90 min.…”