Prenylcoumarins in One or Two Steps by a Microwave-Promoted Tandem Claisen Rearrangement/Wittig Olefination/Cyclization Sequence

Abstract

The one-pot synthesis of 8-prenylcoumarins from 1,1-dimethylallylated salicylaldehydes and the stabilized ylide [(ethoxycarbonyl)methylene]triphenylphosphorane under microwave conditions was found to have a limited scope. The sequence suffers from a difficult and sometimes low-yielding synthesis of the precursors and from a competing deprenylation upon microwave irradiation. This side reaction occurs in particular with electron rich arenes with two or more alkoxy groups at adjacent positions, a prominent substitution pattern in naturally occurring 8-prenylcoumarins. Both limitations of this one-step sequence were overcome by a two-step synthesis consisting of a microwave-promoted tandem allyl ether Claisen rearrangement/Wittig olefination and a subsequent olefin cross metathesis with 2-methyl-2-butene. The cross metathesis step proceeds with a high selectivity and yields exclusively the desired prenyl, rather than the alternative crotyl substituent. Several naturally occurring 8-prenylcoumarins that were previously inaccessible have been synthesized in good overall yields along this route.

Assembling the prenylneoflavone system through a Pechmann condensation/Mitsunobu reaction/Claisen rearrangement/olefin cross-metathesis sequence

“…Two approaches towards the prenylcoumarin motif are distinguished: (1) starting from salicylic aldehydes and cinnamates through the tandem Claisen rearrangement/Wittig olefination/cyclization sequence [9] and (2) using preformed coumarin skeleton via the Mitsunobu reaction/Claisen rearrangement/olefin cross-metathesis reaction sequence [10]. The latter was used by Tischer and Metz for the synthesis of the naturally occurring 8-prenylnaringenin (1), 6-prenylnaringenin (4), 6-prenylgenistein (5), and 6-prenylquercetin (6) ( Fig.…”

Ring-closing-metathesis-based synthesis of annellated coumarins from 8-allylcoumarins

“…To study the heteroannellation reactions, a set of four 8-allyl-7-hydroxycoumarins 8 were synthesized starting from the MOM-protected precursors 5a – d using the conditions of the microwave-promoted tandem sequence [29]. The intermediate MOM-protected coumarins were not isolated but immediately deprotected by treatment with aq HCl in methanol.…”

“…The intermediate MOM-protected coumarins were not isolated but immediately deprotected by treatment with aq HCl in methanol. Isolation of the MOM-protected coumarins 7 [29] and deprotection in a separate step resulted in virtually identical overall yields of coumarins 8 and did therefore not offer any advantage (Table 1).…”

“…Sparked by our interest in the development and application of sequential one-pot transformations and motivated by the relevance of prenylated and other substituted coumarins in natural products and medicinal chemistry, we [27–29] and others [30] have investigated a microwave-promoted tandem reaction for the synthesis of 8-substituted coumarins over the past few years. Starting materials are allyl ethers of salicylic aldehydes or ketones 5 and the stable ylide ethyl (triphosphoranylidene)acetate ( 6 ), which upon microwave irradiation undergo a tandem Claisen rearrangement/Wittig olefination/cyclization sequence.…”

Functionalized Benzofurans via Microwave‐Promoted Tandem Claisen‐Rearrangement/5‐endo‐dig Cyclization

“…Along these lines, straightforward syntheses of pyranocoumarins , prenylcoumarins , furanocoumarins , chroman‐4‐ones , and chromene‐4‐ones were developed and implemented in the total synthesis of several natural products. In the above‐mentioned examples, the cyclization step proceeds through a nucleophilic acyl substitution (for the synthesis of coumarins) or through an addition across an electronically biased C─C‐multiple bond (for the synthesis of chroman‐4‐ones and chromene‐4‐ones).…”