Conformational behaviour of medium-sized rings. part 11. dianthranilides and trianthranilides

Alireza Hoorfar, W. David Ollis*, Jennifer A. Price, Julia Stephanidou Stephanatou, J. Fraser Stoddart

*Corresponding author for this work

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29 Scopus citations

Abstract

Two approaches to the stepwise syntheses of N, N′-di- and N, N′, N˝-tri-substituted trianthranilide derivatives (5)-(20) are described. In the shorter synthetic route, the key acyclic intermediate, N-[2-(o-nitrobenzamido)benzoyl]anthranilic acid (26) is prepared in a stepwise manner from anthranilic acid, isatoic anhydride (23), followed by o-nitrobenzoyl chloride. Alkylations of the amide functions at nitrogen, reductions of the aromatic nitro-groups, and cyclisations of the acyclic amino-acid derivatives provide a direct route to N, N′-dimethyl-(5) and N, N′-dibenzyl-(14) trianthranilides. Further alkylations or acylations of either (5) or (14) afford (i)N, N′, N˝-trimethyltrianthranilide (7) and its trideuteriomethyl analogue (8), (ii)N, N′-dimethyl-N′-acetyl-(10), -N′-benzoyl-(11), and -N′-benzyl-(12) trianthranilides, (iii)N, N′, N˝-tribenzyltrianthranilide (15), and (iv)N, N′-dibenzyl-N′-methyltrianthranilide (16). In the longer synthetic route, the key acyclic intermediate, methyl N-methyl-N-[2-(o-nitrobenzamido)benzoyl]anthranilate (42) is prepared in a stepwise manner from anthranilic acid and two molar equivalents of o-nitrobenzoyl chloride. Alkylations of the unsubstituted amide functions at nitrogen, reductions of the aromatic nitro-groups, and cyclisations of the acyclic amino-acid derivatives provide, not only an alternative route to N, N′-dimethyltrianthranilide (5) but also, a general route to the N-methyl-N′-trideuteriomethyl-(6), N-methyl-N′-benzyl-(17), and N-methyl-N′-ethyl-(19) analogues. Further alkylations of these N, N′-disubstituted derivatives afford N-methyl-N′, N′-di(trideuteriomethyl)-(9), N-methyl-N′-trideuteriomethyl-N′-benzyl-(13), N-methyl-N′-benzyl-N′-ethyl-(18), and N-methyl-N′-ethyl-N′-benzyl-(20) trianthranilides. The constitutionally symmetrical N, N′, N˝-trimethyl-(7) and N, N′, N˝-tribenzyl-(15) trianthranilides exist in solution as an equilibrium mixture of propeller and helical conformations. In the case of the N, N′, N˝-trimethyl derivative (7), the predominant diastereoisomer with the helical conformation has been isolated as a pure compound. In the case of the N, N′, N˝-tribenzyl derivative (15), the propeller and helical conformational diastereoisomers have both been characterised as crystalline compounds. For both these compounds, the free-energy barriers to conformational inversion and interconversion processes in solution have been obtained from (i) direct equilibration experiments and (ii) dynamic 1H n.m.r. spectroscopy. Constitutionally unsymmetrical N, N′-di- and N, N′, N˝-tri-substituted trianthranilide derivatives can adopt three helical conformations in addition to a propeller conformation. Assignments have been made to conformations and conformational diastereoisomers of the N, N′-dimethyl-(5), N, N′-dimethyl-N′-benzyl-(12), N, N′-dibenzyl-(14), N, N′-dibenzyl-N′-methyl-(16), N-methyl-N′-benzyl-(17), N-methyl-N′-benzyl-N′-ethyl-(18), N-methyl-N′-ethyl-(19), and N-methyl-N′-ethyl-N′-b nzyl-(20) derivatives on the basis of (i) kinetically controlled trideuteriomethylations of N, N′-dimethyl-(5) and N-methyl-N′-trideuteriomethyl-(6) trianthranilides and (ii) a kinetically controlled benzylation of N, N′-dibenzyltrianthranilide (14). These experiments permit unambiguous site assignments to be made in the 1H n.m.r. spectra to (i) the homotopic N-methyl groups in the propeller conformation and the diastereotopic N-methyl groups in the helical conformation of N, N′, N˝-trimethyltrianthranilide (7) and (ii) the homotopic N-benzylic-methylene groups in the propeller conformation and the diastereotopic N-benzylic-methylene groups in the helical conformation of N, N′, N˝-tribenzyltr ianthranilide (15). Correlations between site assignments and chemical shifts, for these two 1H n.m.r. probes, lead to conformational assignments to other N, N′-di- and N, N′, N˝-tri-substituted derivatives. In most cases, free-energy barriers for conformational inversion and interconversion processes in solution could be obtained by dynamic, 1H n.m.r. spectroscopy. A satisfying complementary experimental approach is illustrated in the case of N, N′-dimethyltrianthranilide (5) where the occurrence of spontaneous resolution on crystallisation allows the barrier to racemisation to be measured by polarimetry. The temperature dependence of the 1H n.m.r. spectrum of 5,11,17-tribenzyl-6,6,12,12,18,18-hexadeuterio-5,6,11,12,17,18-hexahydrotribenzo[b, f, j][1,5,9]triazacyclododecine (22) can be interpreted in terms of ring inversion between enantiomeric helical conformations of this cyclic triamine. The barrier to conformational change is considerably lower than those for the N, N′, N˝-trisubstituted trianthranilide derivatives. Variable-temperature 1H n.m.r. spectroscopy on N, N′-dibenzyldianthranilide (4) indicates that its eight-membered ring exists in enantiomeric boat conformations where ring inversion is slow on the 1H n.m.r. time scale even at +180 °C. Inclusion compounds are formed on crystallisation between (i) ethanol and N, N′-dimethyl-N′-benzyltrianthranilide (12) as a mixture of its conformational diastereoisomers, (ii) toluene and a helical conformation of N, N′-dibenzyltrianthranilide (14), (iii) ethanol and the helical conformation of N, N′, N˝-tribenzyltrianthranilide (15), and (iv) ethanol and the helical conformation of 5,11,17-tribenzyl-6,6,12,12,18,18-hexadeuterio-5,6,11,12,17,18-hexahydrotribenzo[b, f, j][1,5,9]triazacyclodecine (22).

Original languageEnglish (US)
Pages (from-to)1649-1699
Number of pages51
JournalJournal of the Chemical Society, Perkin Transactions 1
DOIs
StatePublished - 1982

ASJC Scopus subject areas

  • Chemistry(all)

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