In the Hems synthesis of diphenyl ethers, an ortho-carbonyl offered less obstruction when held in a lactone ring than when present as an ester. Side reactions interfered with the Hems synthesis of highly hindered diphenyl ethers, and the highly hindered, high1.y activated ethers produced in the synthesis were easily cleaved by nucleophilic reagents, often in a few minutes a t room temperature. The latter fact added a lively interest to the transformation of the ethers into other derivatives. Three of these were of special interest: ( a ) methyl 2-(6'-amino-4'-carbomethosy-2'-nitrophenosy)benzoate ( V l c ) which existed in remarltably stable dimorphic forms, ( b ) the dibenzosazepine V I I I , and ( c ) the quadruply orthosubstituted, asymmetrical 7-(4'-carbomethoxy-6'-laevo-menthosyacetamino -2'-nitrophenoxy)metameconine ( I X ) .
Sixteen steps from vanillin led to syntheses of ( a ) dimethyl 3-(4'-carbornethoxyphenoxy)-4,5-dimethoxyphthalate ( I c ) , a known degradation product of isochondrodendrine, and (b) the more hindered dimethyl 3-(4'-carbomethoxy-2'-methoxyphenoxp)-4,5-dimethoxyphthalate ( I a ) , which has not been derived from any alkaloid, though the usual concepts of biosynthesis do not rule out the occurrence of alkaloids which could lead to it. Diphenyl ethers related to l a would be expected to show the effects of steric hindrance, but even with the most hindered member of the group, 7-(41-carboxy-21-iodophenoxy)metameconine ( V A e ) , no evidence for a n appreciable half-life of rotational isomers could be obtained. Attempts to make diphenyl ethers through the condensation of phenols with dicyclohexylcarbodiimide led to other products.Diphenyl ethers of type I are of interest both because of their relationship to the bisbeilzylisoquii~oline alkaloids, and because of their place in the study of steric effects in diphenyl ethers. For example, the ester Ia would be expected to arise froin the hypothetical alkaloid IIa in the same reactions that actually gave Ic as the degradation product of the dimethyl ether of isochondrode~ldrine (IIb) (I). Indeed, our whole study of diphenyl -ethers arose from the efforts of Dr. J . A. McRae and his students to forin the ester Ia, the same biosynthetic argument3 that had succeeded for the structure of isochondrodendrine leading them to suppose IIa to be a probable structure for the alkaloid cularine (2, 3). The synthesis of Ia proved unexpectedly difficult, and the challenge presented by the difficulty maintained our interest even when it became apparent many years ago that Ia was not in fact closely related to cularine (111) (3).The early efforts of Dr. RllcRae and his students t o synthesize Ia had several practical results. Prolonged attempts to use the Ullmann reaction directly led t o the independent discovery of the transinethylation side reaction (5-7). Attempts to use the phthalide group as a guarded source of carboxyl groups led to two lines of attack continued in the present work: a study of the place of steric hindrance in the synthesis of diphenyl ethers (5, 9, 10, 13), and an extensive development of the chemistry of metameconine (IVa) (5,(8)(9)(10)(11)(12). Oxidation of the metameconines yielded phthalic acids. One of these (9) was related to pellotine (14) and to capaurine (15, 16), and another (11), an essential link in determining the structure of the bisbenzylisoquinoline alkaloids bebeerine and tubocurarine (17, 18), was synthesized by methods which added greatly to the security of its proof of structure.
Chlor~~iatcd derivatives of metameconine wcre formed for ihc first time. Partial demethylation of the derivatives with sulphuric acid occi~rred in highly selective fashion a t the 111ethoxyl ortho to the llalogen, without regard to the relative position of the carbonyl group which is Icno\vi~ to be highly directive for demethylatiolis in the absence of halogen. The phenolic products of the clemethylations are needed for the synthesis of sterically hindered cliphenyl ethers. They showed a type of intermolecular hydrogen bonding in the crystal which mas marlcedly subject to steric interference by thc halogen atoms.Our work with the cl~lorinated derivatives of metameconine (X) was first unc1c1-taken nlany years ago as a checlc upon the results we had obtained in the correspo~lding bromine series (1, 2, 3 ) ; these results had differed sharply fro111 those reported by others (4). The need for a check was emphasized when our inore recent worlc (5) led to solnewhat surprising conclusio~~s a s to the direction of brornination, nitration, and selective demethylation in the metameconi~les. This paper reports the independent characterization of the chlorine series of compounds, sllows that the chlorine series is an alnlost exact parallel to the bromine series, and therefore thoroughly verifies our previous results.TWO more reasons for proceeding with the chlorine series appeared later in our work.( a ) A subject of continuing interest to us is the study of steric hindrance in dipllenyl ethers (3, 6); obviously the ortho-chloro-and ortho-bro~no-phenols obtained in this work will alloxv the preparation of corresponding cliphenyl ethers with bloclcing groups of different sizes. (b) We hope to study the effect of crowding upon the quadrupole resonance frequency of the halogens; measurement of these frequencies is, of course, easier for chlorine compounds than for bromine or iodine compounds.The nlain novelty of the present worlc lies in the description of a n interesting steric. hindrance of hydrogen bonding in the solid phase. Synthesis a d S t r~l c t~l r eThe most easily available of the chlorine derivatives was 7-chloron~ctameconi~~c~ (XI I ) , made from metameconine (X) by nitration, reduction to the amine (XI) (1, 2, 4), diazotization of the amine, and the Sandrneyer reaction. No doubt the structure was obvious, since 7-bromomcta~~~econinc (1, 2, 4) and 7-iodometameco~li~le (1, 3), formed in corresponding ways, have had their structures tl~orouglily verified. Nevertheless the present I\-orl; offered a quite independent proof that the new substance was indeed 7-chlorornetameconine, its indirect formation from 2-chloroveratric acicl (XIV), as show11 in the chart, leaving no room for doubt as to its structure.The iso~lleric 4-chlorometameco~~i~~e (VII) was formed by the action of for~nalclel~ydc ilpon 5-chloroveratric acid (VI) in acid solution. The structure of the resulting phthaliclc
The reaction of 2-bromoveratric acid with acidified formaldehyde gave 5-methoxy-6-hydroxy-7-bromophthalide (IV) but no 7-bromometameconine (III). Some demethylation occurred during the reaction of 5-bromoveratric acid with formaldehyde. The investigation of these reactions led to the preparation of a series of hindered phenols needed in projected syntheses of highly hindered diphenyl ethers.Only two isomers (III and XI) can arise when a hydrogen atom attached to the benzene ring of metameconine (I) is replaced by a bromine atom.Three have been described. Previous papers4-6(1) Presented at the Meeting of the American Chemical Society in Cleveland, April 11, 1960. Most of the material is taken from the Thesis for the M.Sc. degree (Queen's University, September, 1951) of A. L. Promislow, and from the thesis for the Ph.D. of Mrs. Marjorie Allen (Queen's University, May, 1961).(2) Holders of Canadian Industries', Limited, Fellow-
Previous worlc had shown the somewhat unexpected course of nitration, bromination, and dernethylation reactions of rnetaineconine and its derivatives. The discovery that metarneconine could easily be dinitrated enabled us to bring t o light equally interesting results in the relative rates of reduction of the nitro groups, in the course of certain nucleophilic substitution reactions, in the activation of the methylene group, and in certain physical properties. i\/luch of the work, past and present, now holds as its main interest the somewhat special character of a nitro group in the 7-position.Metameconine (I), because its contrasting methylene and carbonyl groups are equivalently situated with respect to a pair of vacant positions and with respect to a pair of methoxyl groups, is beautifully adapted to the study of competing factors in aromatic reactions. RAy and Robinson (1) were the first to employ it in this way; we have followed their example, and the work of this paper, together with our previously reported experimental work, amounts to a qualitative survey of the possibilities of the system.In one of the earliest tests of the new "electronic" theory of reactions, RAy and Robinson (1) predicted that rnetalneconine should undergo nitration a t position 7 (because of the depression of the directing influence of the methoxyl a t position 5 by contributor I1 to the overall structure of metameconine) rather than a t position 4 (suggested by the simple summation of the effects of the separate groups). This predictioil was later verified (1-4). Ingold (5) generalized solnewhat similar situations as characteristic of systems having a +E group Ineta to a -I-iM group; his generalization has been applied to the present series by Blair and Newbold (6). Such systems often show differences between the directions of nitration and bromination, attributed by Ingold (5) to the greater steric requirements of bromination. Metameconine in particular is bromainated a t the 4-position (3), but Ingold's explanation is sufficiently less convincing for it than for the experimental examples cited by him to encourage consideration of other effects. Other differences between nitration and bromination are of course known; their importance is recognized and we hope to investigate them later, but in the absence of more quantitative data, only one is worth mentioning here because of its simplicity and because of its application in the quite different reaction of demethylation. Metameconine is much more likely to have its carbonyl protonated under the conditions of nitration than under those of
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