Trevor A. Crabb

Conformational Equibria in Nitrogen-Containing Saturated Six-Membered Rings

Publisher Summary This chapter deals with conformational equilibria: (1) in piperidines, (2) in piperidine derivatives, in which ring methylenes are replaced by nitrogen, oxygen, and sulfur atoms, and (3) in systems incorporating these rings in fused ring structures, in which the additional rings are also six-membered. Fused-ring structures with other sizes of rings are generally not included, except for tropane. The chapter illustrates the principal methods available for the investigation of heterocyclic conformational analysis. Then follows a treatment of individual ring systems, in which the discussion centers on the conformational preferences of substituents on tertiary nitrogen and on ring carbon atoms, the energetics of nitrogen inversion, and phenomena arising from the presence of two or more heteroatoms in one ring. Emphasis is placed on simply the substituted free bases. The chapter deals with ring reversal equilibria and kinetics in the conformational analysis of six-membered rings. The problems of conformational equilibria in N-alkylpiperidinium salts and N-quaternization reactions, and the relationships of these to conformational equilibria in the free bases are not covered since this area is a large one requiring separate treatment.

Conformational analysis by carbon-13 nuclear magnetic resonance spectroscopy. Part I. Hexahydro-3H-oxazolo[3,4-a] pyridines

Compraison of the C(3), C(1), and C(8a) chemical shifts in hexahydro-3H-oxazolo [3,4-a] pyridine with those in methyl substituted derivatives suggests its existence in solution at n.m.r. probe temperature as a cis⇌trans equilibrium mixture containing 73–78% of the trans-fused conformation; 13C–H coupling constants involving the C(3) protons are dependent upon the orientation of adjacent heteroatom lone pairs.

Conformational analysis of hexahydro-3H-oxazolo[3,4-c]pyridines by carbon-13 fourier-transform nuclear magnetic resonance spectroscopy

Comparison of the C(3), C(1), and C(8a) chemical shifts in hexahydro-3H-oxazolo[3,4-c]pyridine with those in anancomeric derivatives suggests its existence in solution at n.m.r. probe temperature as a cis⇌trans equilibrium mixture containing ca. 76% of the trans-fused conformation; 13C–H coupling constants involving the C(3) protons are dependent upon the orientation of adjacent lone pairs.

Proton magnetic resonance studies on compounds with bridgehead nitrogen. Part XXXI. Reversible dimerisation of perhydropyrido [1,2-c][1,3]oxazepines; X-ray analysis of a fourteen-membered macrocyclic dimer; conformational analysis of perhydropyrido [1,2-c][1,3]oxazepines

Perhydropyrido(1,2-c)[1,3] oxazepine, cis(9-H, 5a-H)-9-methyl-, trans(8-H, 5a-H)-8-ethyl- and 8-methyl-, and cis(7-H, 5a-H)-7-methylperhydropyrido[1,2-c][1,3]oxazepine (6a, h, d, f, and c) undergo an unusual dimerisation from the liquid state; X-ray analysis shows that the crystalline dimer of the 8-ethyl compound contains a 14-membered heterocyclic ring. Epimers of the 8-ethyl and 8-methyl compounds together with cis(6-H, 5a-H)-6-methylperhydropyrido[1,2-c][1,3]oxazepine do not undergo the dimerisation and exist in solution predominantly in the cis-fused ring conformation. Compounds (6c, d, f, and h) prefer the trans-fused ring conformation.

The conformational analysis of perhydropyrido[1,2-c][1,3]oxazines, perhydropyrido[1,2-c][1,3]thiazines, and perhydropyrido[1,2-c] pyrimidines

Dipole moments of perhydropyrido[1,2-c][1,3]oxazine, 2-t-butylperhydropyrido[1,2-c]pyrimidine, and syn-perhydrodipyrido[1,2-c : 2′,l′-f] pyrimidine indicate their exclusive existence in the trans-fused conformation. Perhydropyrido[1,2-c][1,3]thiazine and 2-methylperhydropyrido[1.2-c]pyrimidine also exist to a significant extent in this conformation. The effects of cis(4a-H, 5-H)-5-methyl, cis(4a-H, 6-H)-6-methyl and cis and trans(4a-H, 7-H)-7-ethyl groups in the perhydropyrido[1,2-c][1,3] oxazine system are discussed, and the conformational behaviour of this series is rationalized. These results are compared with estimates of the positions of conformational equilibria based on n.m.r. data.

Synthesis of compounds related to endo-6,14-ethenotetrahydrothebaines

Diels–Alder adducts obtained from 6-methoxy-N-methyl-1,2,3,4,7,8-hexahydroisoquinoline and from 7-methoxy-N-methyl-1,2,3,4,5,6-hexahydroisoquinoline with ethyl acrylate, methyl vinyl ketone, and acrylonitrile are described.

Novel reversible dimerisation of perhydropyrido[1,2-c][1,3]oxazepines; X-ray analysis of a 14-membered macrocyclic dimer

trans-Isomers of the title oxazepines, e.g.(2) and (6), but not the cis-isomers, e.g.(5), undergo an unusual dimerisation from the liquid state; X-ray analysis shows that the crystalline dimer (7; R = Et) contains a 14-membered heterocyclic ring.