Julia Stephanidou Stephanatou

Synthesis and conformational behaviour of tri-3-methyltrianthranilides. A new example of spontaneous resolution and inclusion compound formation on crystallisation

Abstract The tri-3-methyltrianthranilide derivatives ( 7 )–( 9 ) have been synthesised. Dynamic 1H n.m.r. spectroscopy indicates that the N , N ′, N ″-trimethyl derivative ( 8 ) exists in solution as slowly ring inverting ( 16 ⇌ 16 *) enantiomeric helical conformations. X-Ray crystallography shows that the N , N ′-dimethyl- N ″-benzyl derivative ( 9 ) undergoes spontaneous resolution when it crystallises as a 1:1 adduct from toluene. The host molecules adopt a helical conformation (Figure 1) within a lattice structure that contains chiral channels (Figure 2) occupied by guest solvent molecules.

Conformational behaviour of medium-sized rings. Part 11. Dianthranilides and trianthranilides

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″-benzyl-(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″-tribenzyltrianthranilide (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).

Dithiosalicylides and trithiosalicylides. Their conformational behaviour in solution

Abstract The trithiosalicylide derivatives ( 11 ) - ( 14 ) have been synthesised and shown to exist in solution as ring inverting ( 15 ⇌ 15 *) enantiomeric helical conformations.

Conformational behaviour of medium-sized rings. Part 8. 6H,12H,18H-Tribenzo[b,f,j][1,5,9]trithiacyclododecin and its 5,5,11,11,17,17-hexaoxide

The temperature-dependences of the 1H n.m.r. spectra of 6H,12H,18H-tribenzo[b,f,j][1,5,9]trithiacyclodode (7) and its 5,5,11,11,17,17-hexaoxide (8) have been interpreted in terms of ring inversions between enantiomeric helical conformations. The free energy of activation for conformational inversion in the cyclic trisulphide (7) is compared with that previously obtained for the ring inversion of the enantiomeric C2 conformations of the parent hydrocarbon 5,6,11,12,17,18-hexahydrotribenzo[a,e,i]cyclododecene (1).

Conformational behaviour of medium-sized rings. Part 6. 5,6,11,12,17,18-Hexahydrotribenzo[a,e,i]cyclododecene and its 2,3,8,9,14,15- and 1,4,7,10,13,16-hexamethyl derivatives. 2,3,8,9- and 1,4,7,10-Tetramethyl-5,6,11,12-tetrahydrodibenzo[a,e]cyclo-octene

The temperature dependences of (i) the broad-band decoupled 13C n.m.r. spectrum of 5,6,11,12,17,18-hexahydrotribenzo[a,e,i]cyclododecene (1) and (ii) the 1H n.m.r. spectra of its 2,3,8,9,14,15-(2) and 1,4,7,10,13,16-(3) hexamethyl derivatives have been interpreted in terms of ring inversion between enantiomeric C2 conformations. Conformational analysis on these molecules has been carried out with the aid of strain energy calculations on selected conformations of the parent hydrocarbon (1) and its 1,4,7,10,13,16-hexamethyl derivative (3). Useful correlations between calculated and experimental thermodynamic parameters were found. The temperature dependences of the 1H n.m.r. spectra of the 2,3,8,9-(15) and 1,4,7,10-(16) tetramethyl derivatives of 5,6,11,12-tetrahydrodibenzo[a,e]cyclo-octene (14) have been interpreted in terms of interconversion of chair- and boat-like conformations. Strain energy calculations on selected conformations of the 1,4,7,10-tetramethyl derivative (14) have led to useful correlations between calculated and experimental thermodynamic parameters.

Conformational behaviour of medium-sized rings. Part 5. Transannular reactions of (16Z)-8,9-dihydro-8-methyl-7H-dinaphth-[1,8-cd:1′,8′-hi]azacycloundecine and (12Z)-6,7-dihydro-6-methyl-5H-dibenz[c,g]azonine. Two examples of ‘reverse Hofmann eliminations’

The olefinic double bonds in the cyclic ene-amines (5) and (8) have been shown to have the cis-configuration since two conformational diastereoisomers are formed in each case on quaternisation at nitrogen. The eleven-membered ring ene-amine (5), which is conformationally stable on the 1H n.m.r. time-scale up to +160 °C, undergoes transannular reactions involving the carbon–carbon double bond and the nitrogen atom in acidic, neutral, and basic media. Although the nine-membered ring ene-amine (8), which is conformationally mobile on the 1H n.m.r. time-scale at room temperature, also undergoes transannular reactions involving the carbon–carbon double bond and the nitrogen atom in acidic and neutral media, more vigorous reaction conditions are required.

Conformational behaviour of medium-sized rings. Part 10. Dithiosalicylides and trithiosalicylides

The trithiosalicylide derivatives (8)–(11) have been synthesised and shown by temperature-dependent 1H n.m.r. spectroscopy to exist in solution as ring inverting (35a)⇌(35b) enantiomeric helical conformations with trans-thioester linkages. The free energies of activation for these conformational changes are ca. 10 kcal mol–1 higher than those for the similar process in the corresponding trisalicylides. In contrast with the trisalicylides, the trithiosalicylides can only ring invert between enantiomeric helical conformations via intermediates containing a cis-thioester linkage. The dithiosalicylide derivatives (3)–(7) have been synthesised; the temperature dependence of the 1H n.m.r. spectrum of di-o-thiothymotide (7) has been interpreted in terms of ring inversion (40a)⇌(40b) between enantiomeric boat conformations. Comparison of the ΔG‡ value of 24.6 kcal mol–1 for this conformational change with that of 17.7 kcal mol–1 previously obtained for di-o-thymotide (41) suggests that cis-thioester linkages are subject to more resonance stabilisation than are cis-ester linkages.

Conformational behaviour of medium-sized rings. Part 12. Tri-3-methyltrianthranilide

The stepwise synthesis of the N,N′-di- and N,N′,N″-tri-substituted tri-3-methyltrianthranilides (13)–(19) are described. The amino-acid derivatives (34), (38), and (45), which are the key acyclic precursors in the synthesis of the tri-3-methyltrianthranilides, were all prepared from 2-amino-m-toluic acid (22) and 2-nitro-m-toluoyl chloride as starting materials.Tri-3-methyltrianthranilide derivatives with three equivalent N,N′,N″-substituents can exist in either propeller or helical conformations. The N,N′,N″-trimethyl derivative (14) adopts enantiomeric helical conformations in solution and the barrier to ring inversion is 26.8 kcal mol–1. The N,N′,N″-tribenzyl derivative (19) populates both propeller and helical conformations in solution: these two conformational diastereoisomers have been separated by chromatography and isolated as crystalline compounds.Tri-3-methyltrianthranilide derivatives with two or three non-equivalent N,N′,N″-substituents can, in principle, exist in either propeller or three different helical conformations. One of these three helical conformations is specifically populated in deuteriochloroform solution by compounds (13) and (15)–(17). The N,N′-dibenzyl derivative (18) populates the propeller and one helical conformation in solution: two conformational diastereoisomers have been isolated, one as an oil and the other as a crystalline compound.The N,N′-dimethyl-N″-benzyl derivative (15) undergoes spontaneous resolution when it crystallises as a 1 : 1 adduct from toluene. The N-methyl-N′-benzyl derivative (16) also forms a 1 : 1 inclusion compound on crystallisation from toluene. Although this derivative exists as only one conformational diastereoisomer of the helical type in deuteriochloroform solution, two different diastereoisomeric conformations undergo equilibration in hexadeuteriodimethyl sulphoxide with a barrier to interconversion of 16.1 kcal mol–1.

Conformational behaviour and inclusion compound forming properties of 5,18-disubstituted derivatives of 5, 11, 12, 18-tetrahydrotribenzo[b,f,j][1,4]diazacyclododecine-6, 17-dione

Abstract An X-ray structure analysis shows that the 5, 18-dimethyl derivative ( 5 ) of the title compound ( 4 ) crystallises from xylene as a 1:1 inclusion compound in which the host molecules adopt propeller-like conformations ( 7 and 7 *) with almost perfect C 2 symmetry. Dynamic 1 H n.m.r. spectroscopy shows that the 5, 18-dibenzyl derivative ( 6 ) of ( 4 ) forms a 1:1 inclusion compound with ethanol in the solid state and undergoes ring inversion ( 7 ⇌ 7 *) between enantiomeric propeller-like conformations in solution against a barrier of 21.1 kcal mol −1

Conformational behaviour of medium-sized rings. Part 9. Disalicylides and trisalicylides

The temperature dependences of the 1H n.m.r. spectra of di-o-thymotide (13) and di-o-carvacrotide (14) have been interpreted in terms of ring inversion (12a)⇌(12b) between enantiomeric boat conformations. Comparison of the ΔG‡ values (17.7 and 18.4 kcal mol–1, respectively) for this conformational change suggests that it takes place by a pseudorotational process involving folded boat conformations (17) in which the substituents (methyl and isopropyl, respectively) on C-3 enter into 1,5-interactions with the carbonyl oxygen atoms in the eight-membered rings at the rate-determining transition states. The temperature dependences of the 1H n.m.r. spectra of tri-o-cresotide (6) and tri-m-cresotide (7) provide further evidence that a mechanism involving pedalling of trans-ester linkages through the mean plane of the twelve-membered ring accounts for the conformational changes between enantiomeric propeller (4) and helical (5) conformations. The ΔG‡ values for interconversion and inversion processes of eight- and twelve-membered ring compounds show an informative dependence upon the steric demands of the ortho-substituents on the aromatic rings.