Oxygen-containing heterocycles from α , α , ω , ω -alkane- tetracarboxylates and electro-generated formaldehyde

Tetramethyl α , α , ω , ω -alkanetetracarboxylates were transformed into 5-and 6-membered oxygen-containg heterocycles (65–90%) with electro-generated formaldehyde in an undivided cell.


Introduction
Recent advances in electrooxidation have provided organic chemists with a new versatile synthetic device of great promise. 1 Despite the long history of electroorganic chemistry most of the electroorganic reactions that could provide product selectivity have been developed within the last twenty years.Research on various applications has spread gradually to cover many areas of fundamental and industrial organic chemistry.Among them, reactions using mediators and electrochemically generated reagents occupy a special place in electroorganic synthesis. 2These methods use simple equipment and techniques that may be readily employed in both academic and industrial laboratories.During our studies on electrochemical dehydro-dimerization, 3 trimerization, 4 and cyclotrimerization 5 of dimethyl malonate and electrochemical cyclization of tetramethyl propane-1,1,3,3-tetracarboxylate into cyclopropane-1,1,2,2-tetracarboxylate 6 in methanol in the presence of alkali metal halides as mediators, we found that methanol underwent direct electrochemical oxidation to formaldehyde, if the reaction was carried out with alkali metal chlorides as mediators.Now we report our results of the synthesis of oxygen-containing heterocycles from tetramethyl alkane-α,α,ω,ω-tetracarboxylates and formaldehyde; the latter was generated in situ by anodic oxidation of methanol.

Results and Discussion
The first step of our research was the investigation of the electrochemical hydroxylation of substituted malonates by in situ generated formaldehyde.The electrochemical oxidation of methanol into formaldehyde was optimized in the case of the reactions of dimethyl benzylmalonate (1).

Scheme 1
Substrate 1 was electrolyzed and transformed into the hydroxymethylated ester 2 by electrolysis using 6 F/mol of electricity in an undivided cell in the presence of LiCl, LiNO 3 , NaClO 4 or NaOAc furnishing 2 in yields of 78, 82, 86, and 90%, respectively.In all other experiments NaOAc served as the electrolyte.The results are summarized in Table 1.In all cases, the first step was hydroxymethylation with electrochemically generated formaldehyde (CH 3 OH -2e --2H + → CH 2 O) at the α-carbon of the dimethyl malonate moiety.Where possible, this was followed by lactonization involving an additional remote ester group as shown for the conversion of 3 into 6 (Scheme 2).

Scheme 2
Ester 4 underwent bis(hydroxymethylation), and involving only one hydroxymethylene group a 6-ring lactone was formed under the electrolysis conditions employed (Scheme 3).

Scheme 3
Ester 5 underwent a more complex transformation during electrolysis in methanol.Formation of product 8 can be envisaged as follows (Scheme 4): Presumably, the initial step is bis(hydroxymethylation).Subsequent elimination of water and cyclization forms the tetrahydrofuran ring rather than a lactone.Hydrolysis of a methoxycarbonyl group followed by decarboxylation generates the final product, trimethyl tetrahydrofurantricarboxylate 8.

Scheme 4
Electrochemically generated formaldehyde may be employed in more complex reaction sequences including electrochemical reactions.For example, indirect electrochemical processes using alkali metal chlorides as mediators have been accomplished.In this case the potential of the anode is sufficient for the direct oxidation of methanol into formaldehyde as well as the oxidation of the chloride anion.Using this method, the following reactions have been carried out (Scheme 5).