Microwave-Assisted, Aqueous Wittig Reactions: Organic-Solvent- and Protecting-Group-Free Chemoselective Synthesis of Functionalized Alkenes (original) (raw)

2010, Chemistry - A European Journal

The Wittig olefination reaction [1] is regarded as one of the most strategic, widely applicable carbon-carbon doublebond-forming processes available in organic synthesis. [2-4] The reaction has had an enormous impact on the sophistication of the total synthesis of organic molecules. [5] Some drawbacks of the reaction are the lack of stereocontrol achieved in certain cases, for example, in the synthesis of stilbenes from semistabilised ylides, [6] and the practical issue of phosphane oxide side-product removal. Also, protecting groups are usually required on any acidic protons (OH, NH, etc.) on both the ylide and carbonyl components. Water is a desirable solvent for organic reactions for environmental, economical, safety and chemical processing reasons. [7, 8] It has been used as the reaction medium for Wittig reactions of stabilised ylides to give unsaturated esters. [9] Recently, we reported the first examples of aqueous Wittig reactions of semistabilised ylides derived from trialkylbenzyl and trialkylallyl phosphonium salts. [10a,b] Semistabilised tri-A C H T U N G T R E N N U N G ethylbenzylidenyl and triethylallylidenyl ylides were shown to be formed chemoselectively in water by using sodium or lithium hydroxide and to react with aromatic, unsaturated, aliphatic and even enolisable aliphatic aldehydes in water, yielding a wide array of olefinic products (Scheme 1). These reactions proceeded with high (E)-olefin selectivity. The triethylphosphane oxide side-product is readily removed from these processes due to its water solubility and, hence, the Wittig reactions of triethylphosphane-derived, semistabilised ylides encapsulate a single solution to two outstanding problems with Wittig olefinations leading to (E)-olefins. This method was applied to the synthesis of valuable transstilbenes, such as resveratrol and trans-3,4,5,4'-tetrameth-A C H T U N G T R E N N U N G oxystilbene (DMU-212). [11] High-purity trans-stilbenes are also the central component in light-emitting diodes (LEDs) [12] and organic-based photovoltaic solar cells. [13] In our original work, the phosphonium salts were prepared in the usual fashion, by direct substitution of benzylic or allylic halides with triethylphosphane. Triethylphosphane is a highly odoriferous lachrymator that undergoes rapid oxidation in air and is considered pyrophoric. Allyl and benzyl halides are also known lachrymators and are hydrolytically unstable, generally toxic, alkylating agents. We have now developed a direct alkylation strategy that circumvents these issues, allowing a safe, "off-the-shelf" approach to achieving the above Wittig chemistry. Triethylallyl and triethylbenzyl phosphonium salts are directly available from the reaction of a benzylic or allylic alcohol and air-stable triethylphosphane hydrobromide. We also uncovered a pronounced "microwave effect" in the aqueous olefination reaction, leading to successful Wittig reactions by using weak bases, such as potassium carbonate. The innate reactivity of these ylides in water drew our attention to chemoselectivity issues. We report the unprecedented protecting-group-free, aqueous Wittig reactions of phenols, indoles, pyrroles and ketones, including enolisable substrates. The chemistry employed in the direct synthesis of trieth-A C H T U N G T R E N N U N G ylallyl and triethylbenzyl phosphonium salts is outlined in Scheme 2. The synthesis of allylic triphenylphosphonium salts from allylic alcohols and acidic Ph 3 P-HBr was first re-[a] Dr.