Catalytic Hunsdiecker Reaction and One-Pot Catalytic Hunsdiecker–Heck Strategy: Synthesis of α,β-Unsaturated Aromatic Halides, α-(Dihalomethyl)benzenemethanols, 5-Aryl-2,4-pentadienoic acids, Dienoates and Dienamides

Abstract

The reaction of α,β-unsaturated aromatic (or heteroaromatic) carboxylic acids with N-halosuccinimides (1 equiv.) and catalytic tetrabutylammonium trifluoroacetate (0.2 equiv.) in dichloroethane results in facile halodecarboxylation affording the corresponding (E)-halides in good to excellent yields. A similar reaction, but with 2 equiv. of N-halosuccinimides in acetonitrile-water (1:1 v/v) results in the exclusive formation of the corresponding α-(dihalomethyl)benzenemethanols. Furthermore, a one-pot strategy has been developed combining catalytic Hunsdiecker reaction (using tetrabutylammonium trifluoroacetate in dichloroethane) and Heck coupling (using palladium acetate/triethylamine/triphenylantimony/dichloroethane) for the synthesis of 5-aryl-2,4-pentadienoic acids, esters and amides in moderate to good yields. The natural product piperine and pipergualamine has been synthesized via the above route. Mechanistic and theoretical studies (via AM1 calculations) provide a useful insight into the mechanism of the present halodecarboxylation reaction, suggesting an ionic pathway involving the attack of the halogenium ion across the carbon–carbon double bond, triggering the elimination of carbon dioxide.

Introduction

The halodecarboxylation of Ag(I), Hg(II), Tl(I) or Pb(IV) carboxylates with molecular halogen, trivially known as the Hunsdiecker reaction, is of proven utility for the synthesis of various organic halides notably alkyl (1°, 2°, 3°) and aryl halides.¹ When we viewed this classical reaction from a synthetic organic chemists perspective, the necessity to use stoichiometric metal carboxylate appeared against the dictum of atom-economy.² Other limitations include: (a) the necessity to use high temperature; (b) the toxicity/hazard related to molecular bromine and salts of Hg, Tl, Pb, Ag; and (c) very poor yields³ in cases of substrates such as α,β-unsaturated carboxylic acids.

We have recently invoked a novel protocol whereby a catalytic metal–salt pool is utilized in mediating a one-pot Hunsdiecker synthesis from in-situ generated metal carboxylates.⁴ The major question that warranted further investigation is: ‘What triggers the elimination of carbon dioxide?’ In the classical Hunsdiecker reaction, the elimination of carbon dioxide is believed to originate from hard–soft interaction between carboxylate oxygen as hard base and metal such as Ag, Tl, Hg, and Pb as soft acid. Such an interaction leads to homolytic cleavage of the M–O bond, thereby dictating the decarboxylation via a free-radical pathway. In the present study the interaction between carboxylate oxygen and group-1 metal ion is primarily a hard–hard interaction, leading to dominant ionic character. Therefore, it is necessary to find out whether the carboxylate anion of the α,β-unsaturated carboxylic acid is greatly involved in the catalytic Hunsdiecker reaction (CHR). In this direction, generating the carboxylate anion from the reaction of acid with an ‘all-organic’ catalyst appeared to be an interesting exercise. We delineate herein a study in this direction and our effort in coupling the halodecarboxylation reaction with the Heck reaction in one-pot. Both the strategies resulted in new routes to synthetically important intermediates namely α,β-unsaturated aromatic halides, α-(dihalomethyl)benzenemethanols, 5-aryl-2,4-pentadienoic acids, dienoates and dienamides.