One Pot O-alkylation/Wittig Olefination of Hydroxybenzaldehydes in DMSO †

: Hydroxybenzaldehydes are submitted to a one pot O-alkylation/Wittig olefination in dimethyl sulfoxide (DMSO) to give alkyl alkoxycinnamates. The reaction is carried out facilely and gives the products in high yield.


Introduction
In our endeavor to develop one-pot transformations involving Wittig olefination reactions with stabilized phosphoranes leading to substituted cinnamates [1,2] and cinnamic acids [3], we have recently turned to running etherification and Wittig olefination reactions with (carbomethoxymethylene)triphenylphosphorane (1a) (Figure 1) in one pot. The following contribution describes the scope of such procedures and gives experimental details.

General Remarks
Melting points were measured on a Stuart SMP 10 melting point apparatus and are uncorrected. Infrared spectra were measured with a Thermo/Nicolet Nexus 470 FT-IR ESP spectrometer and a Perkin Elmer Spectrum Two spectrometer. 1

Results and Discussion
Among other things, cinnamates are used as UV-B sunscreens and are present in over 90% of the commercial sunscreen products [5,6]. Cinnamates can be prepared by esterification of cinnamic acid and by Claisen reaction of benzaldehyde with alkyl acetates in the presence of Na. The Wittig reaction of benzaldehydes with the stabilized carbalkoxymethylenetriphenylphosphoranes have also been used in the synthesis of cinnamates. Carbalkoxymethylenetriphenylphosphoranes such as 1, as stabilized phosphoranes, are reactive enough to undergo Wittig olefination reactions with both aldehydes and ketones, but are not sensitive towards water (and oxygen/air) and tolerate a number of solvent systems that include THF, DMSO, DME, and CHCl3, aqueous systems [2], aqueous/organic solvent mixtures and even solventless conditions [1]. On the other hand, one of the best reaction systems for the alkylation of phenols by Williamson ether synthesis is the utilization of KOH in DMSO as initially forwarded by Johnstone and Rose [7]. Particularly with methyl halides, the alkylation of phenolates sometimes leads to ring alkyation, especially in ortho position of the phenolic function, but also in para position, however, the system KOH/DMSO, RX is known for its high O-alkylation versus C-alkylation selectivity [8].
When hydroxybenzaldehydes 6/9/11 are reacted with alkyl iodides/bromides in the presence of KOH as base in DMSO as a solvent with the subsequent addition of phosphorane 1, the alkoxycinnamates 8/10/12 are formed in high yields (Schemes 2-4). The workup is a simple aqueous extraction followed by a chromatographic separation of the reaction mixture, where the cinnamates can easily be purified from the accompanying triphenylphosphine oxide. Only, in the case of the preparation of the methylated products can small amounts of side products stemming from C-alkylation of the aromatic system be found. The Wittig-olefination is deemed to be a reaction of poor atom-economy as triphenylphosphine oxide is lost to the material yield of the product. This "deficiency" could be overcome by recycling of the triphenylphosphine oxide [9][10][11]. Studies on how such a recycling step can be incorporated in the above process are currently underway.

Conclusions
The reaction of hydroxybenzaldehydes with alkyl iodides/bromides in DMSO, in the presence of KOH as base, leads after addition of (carbomethoxymethylene)triphenylphosphorane to O-alkylated cinnamates in high yield.
Author Contributions: Conceptualization, supervision, synthetic investigation, writing-original draft preparation, T.T.; synthetic investigation, A.H.; analytical work, V.P. All authors have read and agreed to the published version of the manuscript.