Tandem Claisen Condensation/Transesterification between Arylacetate Enolates and Arylmethylene-Substituted 2,2-Dimethyl-1,3-dioxolan-4-ones: An Improved Synthesis of Z-Configured Pulvinones

Abstract

Horner-Wadsworth-Emmons (HWE) alkenations of aromatic aldehydes with the novel phosphonate 24b led to E-configured arylmethylene-substituted 2,2-dimethyl-1,3-dioxolan-4-ones 25a-f (79-88% yield). The latter condensed with the lithium enolates of methyl arylacetates lithio-20b-d to give, after acid treatment and crystallization, isomerically pure (Z)-pulvinones 8d-s in 75-91% yield. We also showed that Horner-Wadsworth-Emmons reactions between phosphonate 24b and aliphatic aldehydes lead to E-configured alkylmethylene-substituted 2,2-dimethyl-1,3-dioxolan-4-ones 25g-i (82-96% yield).

Key words

crossed Claisen condensation - Horner-Wadsworth-Emmons alkenation - O-protected α-hydroxyacrylates - α-oxocarboxylates - stereoselective synthesis

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10

Type 7 compounds were obtained by the addition of substituted benzylmagnesium chlorides to the C≡N bond of the O-trimethylsilylated cyanohydrin of arylacetaldehydes, followed by hydrolysis. [11]

12

Method is given in ref. 9.

13

Ester 9 was prepared by the alkylation of potassium phenylacetate with ethyl 2-bromo-3-phenylpropionate. [9]

14

Tetronic ester 10a was obtained by the base-mediated condensation of (4-methoxyphenyl)acetonitrile with diethyl oxalate followed by O-methylation of the enol and anhydride formation: Knight, D. W.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1 1979, 62. Hydride reduction provided a separable mixture of 10a and hydroxy-10a which was once more reduced giving more 10a.

16

Tetronic ester 10b was obtained differently than tetronic ester 10a, namely by the Dieckmann condensation of (ethoxycarbonyl)methyl phenylacetate followed by O-methylation. [9]

22

Each of Ramage et al.’s three pulvinones emerged from a slightly different protocol: [21] (Z)-21a: Scheme [3] , steps (e₁) and (e₂) (there appeared to be no addition of acid other than in one of the two recrystallization procedures); (Z)-21b was obtained from PhCHO and lithio-20a in 71% yield analogously as described in (e₁); step (e₂) was replaced by no evaporation of THF, adding H₂O, refluxing (30 min), evaporating the solvents, adding Et₂O-H₂O (1:1), keeping the aqueous phase, adding HCl (to pH 1), isolating the resulting solid; (Z)-8b was obtained from PhCHO and the lithium enolate of methyl phenylacetate in 94% yield analogously as described in (e₁); step (e₂) was replaced by evaporating THF, adding Et₂O-H₂O (1:1), keeping the aqueous phase, adding HCl (to pH 1), isolating the resulting solid. We followed a blend of the three procedures, replacing Ramage’s step (e₂) by no evaporation of THF (i.e., like towards (Z)-21b), no refluxing with H₂O (i.e., unlike towards (Z)-21b), adding Et₂O-H₂O (1:1), etc.

33

In a related condensation using lithium diisopropylamide/ester 26/dioxolanone 25c, we ascertained that the yield of pulvinone 28 decreased from 60% to 40% upon changing the reactant ratio from 2.5:2.5:1 to 2.5:1.25:1 (Scheme 4). The analogous condensation using lithium diisopropylamide/carboxylic acid 27/dioxolanone 25c (2.2:1.1:1 ratio of the reactants) did not give pulvinone 28 under the conditions otherwise identical to those of Table 5 (Kaczybura, N. Dissertation; Universität Freiburg: Germany, 2005).

Scheme 4

36

We could not extend our approach to a synthesis of pulvinic acids 32 and 33. While dioxolanone 31 was accessible by a Horner-Wadsworth-Emmons reaction between phosphonate 24b and α-oxo ester 29 (79% yield), it did not react with the ester enolate 30 by Claisen condensation/transesterification (Scheme 5).

Scheme 5 Reagents and conditions: a) 24b (1.0 equiv), LDA (1.7 equiv), THF, -78 °C, 30 min; 29, 2.5 h; 79% (60:40 mixture of unassigned isomers); (b₁) 30 (2.5 equiv), THF, -78 °C, 2 h, to r.t., 0-2 h; (b₂) evaporation of THF; addition of Et₂O-H₂O (1:1), 60 °C, 1 h.