Effect of allylic strain on the conformations of diphenyl‐substituted tetrahydro‐1,3‐oxazin‐2‐ones and hexahydropyrimidin‐2‐ones

Abstract

The conformations of the cis and trans isomers of 4,6-diphenyl-, 4,5-diphenyl-and 5,6-&phenyltetrahydrro-1,3-oxazin-2-one and 4,5-diphenylhexahydropyrimidin-2-one, and of some of their N-substituted derivatives, have been studied by 'HNMR. Conformers with 4a, 6e-, 4a,5e-and Sa,se-phenyl groups are preferred in the respective isomers of the N-H oxazinones, confirming a half-chair conformation of the ring. Auylic strain caused by N-substituents shifts strongly the a,e =$ e,a equilibria in trans-4,6-diphenyl-and cis-4,s-diphenyloxazinones, but only moderately the e,e*a,a equilibria in the compounds with truns-vicinal phenyl groups. In the latter, the diaxial conformation is preferred only in the case of bulky N-substituents. The diaxial conformation is more favoured in the trans-4,5-diphenylpyrimidones.An important feature of six-membered rings containing double bonds is the allylic strain2 between substituents at an endocyclic or exocyclic double bond and an equatorial ring substituent, resulting in a preference for the axial conformation. The effect of N-substituents in saturated heterocycles with an endocyclic amide bond has received less attention, although cases of preferred axial conformation have been r e p~r t e d .~ A striking example4 was encountered in the case of the r-4, c-5, t-6-and r-4, t-5, t-6-isomers of 4,5,6-triphenyltetrahydro-1,3-oxazin-2-one. An N-substituent strongly shifted the e , e , a e a,a,e or e,a,a* a,e,e equilibria towards the conformer with an axial neighbouring phenyl group, irrespective of whether this involved two equatorial or two axial phenyl groups. It was of interest to assess the effect of allylic strain in similar systems where the axial conformation of the phenyl group can be attained with a varying degree of steric strain. We now report a 'HNMR study of the conformations of the compounds shown in Scheme 1.Thus, in the trans-4,6-diphenyl-and cis-4,5-diphenyltetrahydro-1,3-oxazin-2-ones (trans-1 and cis-2 respectively), allylic strain will affect a , e Z e,a equilibria, while in the trans-4,5-diphenyloxazinones (trans -2) and -hexahydropyrimidin-2-ones (truns-4), it will act against the strain of two axial phenyl groups. RESULTS AND DISCUSSIONThe coupling constant data are summarized in Table 1.Because of the biased diequatorial conformation of cis-4,6-diphenyloxazinone (cis-la, formula A, Scheme 2), the observed coupling constants J(4a5a) and * Author to whom correspondence should be addressed. J(5a6a) can be used as references in the estimates of conformational populations. The limitations of such estimates are well known, and one particular complication is discussed below. The following rounded off 'neat' values were assumed: J(4a5a) = 11.5 Hz; J(5a6a) = 12.0 Hz and J(4e5e) = J(5e6e) = 2 Hz. The J(4e5e) value is taken from data for strongly biased N-substituted triphenyloxa~inones;~ for J(5e6e) the choice is arbitrary.The form of the oxazinone ring approaches a halfchair,4 because of the greater double bond character of the N-CO bond than that of the 0-CO bond, and this e...

Tetrahydropyrimidin-2(1H)-ones with three neighbouring phenyl groups. Synthesis and allylic strain effects

“…A comparison of the results, described herein, with those obtained for the corresponding pyrimidinones with two neighbouring phenyl groups, 23 where the effects are not clearly revealed, demonstrates the crucial role of the third phenyl in the conformational distribution in these highly hindered heterocyclic systems. The latter and the relative symmetry of triphenylated pyrimidinones make them explicit models for conformational relationship studies, allylic strain of different groups in particular.…”

β-Ureido acids and dihydrouracils. Part 15. Effect of allylic strain on ring opening of 1,6-disubstituted dihydrouracils

“…The overall rate klk3/k-, is much smaller than that of dihydrouracil (l), the decrease being mainly contributed by k3/k-l. Although this could be attributed to an inductive effect on the doubly negatively charged transition state for k3, this is hardly the case as the changes brought about in the pK values by an Nmethyl group are very slight as can be seen in Table 1 for the pairs (1) and (2), (3) and (9, and (6) and (7). Rather this is most probably steric hindrance to ring opening.…”

“…With this compound however, the individual rate constants could not be obtained so that their contributions can only be estimated. The individual constants observed for the reference compounds (1)(2)(3)(4) would suggest that the main effect is due, as for the 6,6-dimethyl derivative, to a large decrease of k , because of the steric hindrance caused by the axial methyl group as depicted in structure (C). The addition step, k,, with 6,6-dimethyldihydrouracil (4) is 80 times slower than with 6methyldihydrouracil (3).…”

“…Because of the difference in ionic strength in the pKand rate measurements, the hydroxide ion concentrations used in the latter were converted into activities with a coefficient of 0.759 determined from pH measurements of the solutions used. The constants kl and k3/k,l were calculated from the upper curved portion of the plots by means of equation(3).…”

Erratum: Assisted hydrolysis of cis-2-(3-phenylthioureido)cyclopentane-carbonitrile in alkaline solution. Solvent dependent switch from hydrolysis to rearrangement of the iminothiooxopyrimidine intermediate

“…Isomerization most likely occurs by acid catalyzed enolization which requires prior protonation of the carbonyl or imino function. It has been previously shown (8) that upon cyclization of ureido acids to dihydrouracils, isomerization occurs with the more basic ring compounds. Under the conditions used for obtaining the amides 3 on a preparative scale (hydrolysis of the nitriles 1 in 60% sulfuric acid) the cis nitrile gave cis amide, shown by TLC to be free of the trans amide, while the trans nitrile hydrolyzed to a mixture of cis and trans isomers.…”