Nucleophilic Benzoylation Using a Mandelic Acid Dioxolanone as a Synthetic Equivalent of the Benzoyl Carbanion. Oxidative Decarboxylation of α-Hydroxyacids

Abstract

The synthesis of alkyl aryl ketones using a mandelic acid dioxolanone as a synthetic equivalent (Umpolung) of the benzoyl carbanion is reported. The methodology involves alkylation of the mandelic acid dioxolanone, hydrolysis of the dioxolanone moiety in the alkylated products and oxidative decarboxylation of the resulting α-hydroxyacids. The last step is carried out in a catalytic aerobic way using a Co (III) complex in the presence of pivalaldehyde under very mild conditions.

Introduction

We have recently reported the use of methyl mandelate as a masked d¹-synthon for nucleophilic benzoylation ("Umpolung") of the carbonyl group [1] in a synthesis of aryl alkyl ketones, which involves alkylation of methyl mandelate, hydrolysis of the ester group in the alkylated products and oxidative decarboxylation of the resulting α-hydroxyacids (Scheme 1). Because of the importance of the carbonyl group in organic chemistry, it is not surprising that several “Umpolung” methods for this group have been described, including the use of dithianes and dithiolanes [2], TosMIC [3], enol ethers [4], vinyl sulfides [5], α-aminonitriles [6], cyanohydrins [7], SAMP-hydrazones [8], or heterocycles [9] among other. In this paper, we wish to report a related procedure which uses a different mandelic acid derivative, namely 2,2-dimethyl-5-phenyl-1,3-dioxolan-4-one (3) as a new umpoled synthon of the benzoyl carbanion leading to alkyl aryl ketones.

Results and Discussion

In our earlier work [1] we carried out the alkylation of the dianion of methyl mandelate (2) using 2 equiv. of LDA and 1 equiv. of an alkyl halide as it had been described in the literature [10]. Now, we have carried out the alkylation of a mandelic acid dioxolanone, namely 2,2-dimethyl-5-phenyl-1,3-dioxolan-4-one (3), which has the advantage of requiring only one equivalent of strong base (Scheme 1).

Dioxolanone 3 was readily prepared by acid catalysed condensation of mandelic acid (1) with acetone. The lithium enolate derived from 3 was alkylated with several organic halides (Table 1). The use of alkyl, allyl or benzyl chlorides as alkylating reagents was unsuccessful as the starting materials were recovered unreacted in all of the cases. Nevertheless the introduction of benzylic or allylic groups could be successfully achieved using the corresponding bromides as alkylating reagents [11], while the introduction of an alkyl group required the use of the corresponding iodide and the addition of 20% HMPA as cosolvent. Following this methodology we were able to prepare in good yields several α-alkylated dioxolanones 5 bearing primary, allyl or benzyl groups, and other additional functional groups such as a bromide or a carboxyester.

Scheme 1.

Scheme 1.

Table 1. Alkylation of 2,2-dimethyl-5-phenyl-1,3-dioxolan-4-one (3) and oxidative decarboxylation of α-alkylated mandelic acids (6).

^a Entries a-c required RI as alkylating reagent and the use of 20% of HMPA as cosolvent.Entries d-h were carried out with RBr as alkylating reagent.^b Nearly quantitative yields of the hydrolysis products 6 were obtained in all cases.^c The reaction was carried out at room temperature; entries f-g at 0 °C and entry h at -47 °C.

Table 1. Alkylation of 2,2-dimethyl-5-phenyl-1,3-dioxolan-4-one (3) and oxidative decarboxylation of α-alkylated mandelic acids (6).

^a Entries a-c required RI as alkylating reagent and the use of 20% of HMPA as cosolvent.Entries d-h were carried out with RBr as alkylating reagent.^b Nearly quantitative yields of the hydrolysis products 6 were obtained in all cases.^c The reaction was carried out at room temperature; entries f-g at 0 °C and entry h at -47 °C.

Upon basic hydrolysis, the products 5 were transformed into the corresponding α-hydroxyacids 6 in almost quantitative yields. Finally, oxidative decarboxylation of 6 gave the corresponding alkyl aryl ketones 7. This transformation was achieved using a catalytic procedure developed in our laboratory which employs molecular oxygen as terminal oxidant in the presence of pivalaldehyde as co-reductant and a catalytic amount of the Co(III) ortho-phenylene-bis(N’-methyloxamidate) complex [Co(III)–Me₂opba] (Figure 1) [12].

Figure 1.

Figure 1.

Conclusions

In summary, we have presented in this paper a procedure for the use of a mandelic acid derivative, namely 2,2-dimethyl-5-phenyl-1,3-dioxolan-4-one (3) as a new masked d¹-synthon for the benzoyl group (Umpolung), in which the key step is the aerobic oxidative decarboxylation with oxygen in the presence of pivalaldehyde as co-reductant and the Co(III)-Me₂opba complex as catalysts. This reaction is carried out under very mild conditions and it is compatible with the presence in the molecule of other oxidisable groups.