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 nitrogroups, 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 (1 4) afford (i) N,N',N"trimethyltrianthranilide (7) and its trideuteriomethyl analogue (8), (ii) N,N'-dimethyl-N"-acetyl-(1 0), -N"benzoyl-(1 1 ), and -N"-benzyl-(1 2) trianthranilides, (iii) N,N',N"-tribenzyltrianthranilide (1 5), and (iv) N,N'dibenzyl-N"-methyltrianthranilide (1 6). In the longer synthetic route, the key acyclic intermediate, methyl 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-(1 7 ) , and N-methyl-"-ethyl-(1 9) analogues. Further alkylations of these N,N'-disubstituted derivatives afford N-methyl-N',N"-di(trideuteriomethy1)-(9), N-methyl-N'-trideuteriomethyl-N"-benzyl-(1 3), N-methyl-N'-benzyl-"'-ethyl-(1 8), and N-methyl-N'-ethyl-N"-benzyl-(20) trianthrani tides.The constitutionally symmetrical N,N',N"-trimethyl-( 7) and N,N',N"-tribenzyl-(1 5) 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 (1 5), 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 H 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-1654 J. CHEM. SOC. PERKIN TRANS. I 1982 (46) X = NHMe (47) X = NMe, (48) ment to the corresponding N-acylurea intermediates. The N-acylurea derivative (48) undergoes cyclisation to N,N'-dimethyltrianthranilide (5) in refluxing ethanol.

The stepwise synthesis of the N, N'-di-and N,N',N"-tri-substituted tri-3-methyltrianthranilides (1 3)-(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 (1 4) adopts enantiomeric helical conformations in solution and the barrier to ring inversion is 26.8 kcal mol-l. The N,N',N"-tribenryl derivative (1 9) 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 (1 3) and (1 5)-(17). The N,N'-dibenzyl derivative (1 8) populatesthe propeller and one helicalconformation 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 (1 5) 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-l.PREVIOUSLY, we have demonstrated that the free energies of activation for ring inversion and interconversion processes 7 in solution for the trisalicylides (1)- (5) and trithiosalicylides (6)-(9) are raised dramatically by the introduction of alkyl substituents into the orthopositions of the aromatic rings. Subsequently, the conformational behaviour of a wide range of N,N'-diand N , N' ,N"-t ri-subs t it u t ed t riant hranilide derivatives l p 4 (10) in solution was studied by us in considerable detail. However, there was little or no incentive during our initial investigations reported in the preceding paper to incorporate alkyl substituents into the ortko-positions of the aromatic rings for two reasons: (i) the substituents associated with the nitrogen atoms of the trans-amide linkages provided the necessary n.m.r. probes with which to investigate the conformational behaviour of the trianthranilide derivatives in solution, and (ii) the barriers to ring inversions and interconversions involving enantiomeric pairs of diastereoisomeric propeller and helical conformations were generally in excess of 20 kcal mol-l. In some instanc...

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=9.3f0.2 kcal mol-') than for (5) (AG&,.=17.1 kcal mol-'). We believe there are two principal reasons for this difference: (i) the absence of methyl substituents in the ortho positions of the aromatic rings, and (ii) conjugative stabilization between the lone pairs on sulfur and the K system of the benzene rings in the inversion transition state.