Unexpected course of a Williamson ether synthesis

The Williamson ether synthesis between the sodium salt of methyl mandelate and methyl α - bromophenylacetate was reinvestigated. In addition to the expected ether product cis -dimethyl 2,3-diphenyloxirane-2,3-dicarboxylate, methyl phenylacetate and methyl phenylglyoxylate were obtained. Their formation is explained by an initial α -elimination producing an α -oxo-carbene from the α -bromoester. This is followed by a hydride transfer from the sodium salt of methyl mandelate to the carbenic intermediate furnishing the enolate of methyl phenylacetate as reduction product and methyl phenylglyoxylate as oxidation product. Finally, the methyl phenylglyoxylate reacts with the enolate of the α -bromoester in a diastereospecific Darzens condensation to the cis -oxirane ( cis -conformation confirmed by single crystal structure analysis). In this series of parallel and sequential reactions, the sodium salt of methyl mandelate displays 3 modes of action: nucleophile (ether synthesis), base ( α -elimination) and hydride donor (redox process).


Introduction
3,5-Diphenyl-2,6-dioxo-1,4-dioxane (1) has been suspected as intermediate in the thermolysis of mandelic acid (2).To the best of our knowledge the literature gives only one reference for the synthesis of compound 1 published in the year 1933. 1 This synthesis comprises of 3 apparently simple steps: formation of the ether 5 by a Williamson synthesis (scheme 1), followed by saponification to the corresponding dicarboxylic acid and finally dehydration with formation of the cyclic anhydride 1, which should be obtained as a diastereomeric mixture of the meso-and racemic trans-product.In ref. 1 the stereochemistry of the product obtained was not investigated.When repeating the procedure for the synthesis of the ether 5 as described by Hurd and Raterink 1 a complex product mixture was obtained.In this communication the full range of competing and sequential reaction pathways is analyzed and discussed.

Results
When attempting the synthesis of the ether 5 by reaction of the sodium salt of racemic methyl mandelate with racemic methyl α-bromophenylacetate according to scheme 1, methyl phenylacetate (6), methyl phenylglyoxylate (7), cis-dimethyl 2,3-diphenyloxirane-2,3dicarboxylate (8), and meso-and racemic dimethyl 1,2-diphenylsuccinate (9) could be identified as additional reaction products.In table 1 the composition of the reaction mixture is compiled.The oxirane 8 could be precipitated in pure form from a solution of the reaction products in methanol at -23°C as a polycrystallinic material (m.p. 127-129°C).Recrystallization from dichloromethane/pentane furnishes a polymorphic modification of m.p. 131-132°C.Both polymorphic modifications show identical 1 H-, 13 C-NMR-, and mass spectra.The meso configuration is confirmed by the transformation of 8 to the bicyclic anhydride 11 via the route outlined in scheme 2 and by a X-ray structure analysis (see below).The residues from several runs, depleted of the oxirane 8 as much as possible by crystallization, were combined and subjected to distillation up to 100°C at 0.1 mbar.By this operation large amounts of volatile components (starting compounds and esters 6 and 7) could be removed and the diastereomeric ethers 5 were enriched in the remaining oil to over 44%.By subsequent column chromatography on silica gel with petroleum ether (40°C/60°C) and dichloromethane as eluent the diastereomeric mixture of 5 and small amounts of the diesters 9 could be isolated together with additional amounts of the oxirane 8 and the starting materials 3 and 4, which were incompletely removed by crystallization and distillation.Substantial total losses were noticed in the chromatographic separation.
After completion of the structural elucidation of 8 a literature search revealed that compounds 8, 10 and 11 have been synthesized before by a completely different route. 2 ARKAT USA, Inc.

Discussion
The oxirane 8, which has been formed in similar amounts as the ether 5, can be considered as a formal dehydrogenation product of the latter.This points to a redox process as parallel reaction to the Williamson ether synthesis (scheme 1) with the oxirane 8 as oxidation and methyl phenylacetate (6), also present in relatively large quantities in the reaction mixture, as reduction product.
The α-bromoester 4 is a CH-acidic compound and may therefore partly react with the alcoholate of methyl mandelate [3-H] -under proton abstraction.Subsequent loss of bromide from the bromoenolate 12 intermediately formed in the deprotonation step constitutes an αelimination process generating the α-oxocarbene 13 as reactive intermediate.Finally, interaction of the potential hydride donor [3-H] -with the electron deficient carbene 13 results in a redox process yielding the enolate of methyl phenylacetate [6-H] -as reduction and methyl phenylglyoxylate 7 as oxidation products.The complete sequence of α-elimination and redox reaction is summarized in scheme 3.
The α-oxoester 7 does not survive under the reaction conditions.It reacts immediately with the bromoenolate 12, undergoing a Darzens glycidic ester condensation.Both the threo (14) and the erythro (15) addition products are undoubtedly formed in the first step.However, only the thermodynamically less favorable cis-oxirane 8 is obtained as reaction product.The remarkable diastereospecificity of the Darzens reaction is well known 3,4 and can be rationalized in terms of an equilibrium between the two aldol addition products and kinetic control in the cyclization step by a favorable orbital overlap in the transition state of the oxirane formation from the threo diastereomer. 4RKAT USA, Inc.In order to test the suggested pathway leading to compound 8 a mixture of the α-oxoester 7 and the α-bromoester 4 were reacted in the presence of an equimolar amount of base.Indeed, in a smooth stereospecific reaction the cis-oxirane 8 was obtained.
It is worthwhile to consider the overall stoichiometry for the formation of the surprising product 8 from the starting compounds [3-H] -and 4.This can be obtained by combining the reaction sequences of schemes 3 and 4 and results in the overall reaction given in scheme 5. From this equation it follows that on the product side two equivalents of methyl mandelate (3) are concomitantly formed together with the cis-oxirane 8.In contrast to its deprotonation product [3-H] -methyl mandelate cannot react further, neither as nucleophile (scheme 1) nor as base and hydride donor (scheme 3).Therefore, it appears as final reaction product and explains the more than 60% of the recovered methyl mandelate in the reaction mixture.Furthermore, the overall stoichiometry (scheme 5) requires that the cis-oxirane 8 and methyl phenylacetate (6) should be present in a ratio of 1:1 after aqueous work-up.The experimental ratio is ~0.7:1 (table 1).This deviation is readily explained with the amount of methyl phenylglyoxylate (7) which survived in the reaction mixture.The sum of 7 and 8 (oxidation products) is within experimental error equal to the amount of 6 (reduction product).
In addition to the reaction products described so far trace amounts of the two diastereomers of dimethyl diphenylsuccinate (9) could be isolated and identified by comparison of their spectral data with literature values.Their formation may be rationalized by nucleophilic displacement of bromine in 4 by the enolate of methyl phenylacetate.As discussed in the previous sections, methyl phenylglyoxylate and the enolate of methyl αbromophenylacetate combine in a stereospecific fashion to cis-dimethyl 2,3-diphenyloxirane-2,3dicarboxylate.The stereochemical course of this C,C-bond formation according to the Darzens glycidic ester condensation follows from its transformation to the anhydride 11 and could be confirmed further by X-ray structure analysis.In the following the structural data are reported.Unequivocal confirmation for the cis arrangement of phenyl groups comes from the crystal structures of 8 and 11 (Fig. 1).The epoxide rings in 8 and 11 are typical when compared with the other 1863 epoxides that are available in the Cambridge Structural Database version 5.27 (November 2005): the bond angle at oxygen is slightly greater than 60°, while the angles at both carbon atoms are more acute (Tab.2).Formation of the five-membered anhydride ring causes the angle between the phenyl groups to widen: in 8 the angle between C(1)-C(5) and C(2)-C(11) is 60.7° but increases to 72.1° in 11.The interplanar angle between the benzene rings and the oxirane moiety are affected to a lesser extent when going from 8 to 11.They change from 57.48° (C(5)-C(10)) and 63.79°(C(11)-C( 16)) in 8 to 64.48° and 62.52° in 11.

Scheme 1 .
Scheme 1. Williamson ether synthesis of the diastereomeric bis(methoxycarbonylphenylmethyl)ethers 5.In ref. 1 the corresponding ethyl esters were used.To simplify 1 H-NMR analysis of the product mixture we applied the methyl esters.

Scheme 5 .
Scheme 5. Overall stoichiometry for the formation of the cis-oxirane 8.

Table 1 .
Composition of the mixture obtained by reaction of the sodium alcoholate of methyl mandelate and methyl α-bromophenylacetate after work-up with aqueous NH 4 Cl b ~1.14:1 mixture of two diastereomers.c 1:1 mixture of the meso and racemic diastereomers.