Cross-coupling of dissimilar ketone enolates via enolonium species to afford non-symmetrical 1,4-diketones.

Keshaba N Parida,Gulab K Pathe,Alex M Szpilman,Shimon Maksymenko

doi:10.3762/bjoc.14.84

Abstract

Due to their closely matched reactivity, the coupling of two dissimilar ketone enolates to form a 1,4-diketone remains a challenge in organic synthesis. We herein report that umpolung of a ketone trimethylsilyl enol ether (1 equiv) to form a discrete enolonium species, followed by addition of as little as 1.2–1.4 equivalents of a second trimethylsilyl enol ether, provides an attractive solution to this problem. A wide array of enolates may be used to form the 1,4-diketone products in 38 to 74% yield. Due to the use of two TMS enol ethers as precursors, an optimization of the cross-coupling should include investigating the order of addition.

Highlights

Substituted 1,4-dicarbonyl compounds are key intermediates for the preparation of numerous natural products and active pharmaceutical ingredients (APIs) with important biological activities
We have shown that the enolonium species 4 (R1 = Ph, R2 = H) can be produced from the corresponding TMS enol ether 1 (R1 = Ph, R2 = H) and subsequently coupled with a second molecule of enol ether 1/5 (R1/3 = Ph, R2/4 = H) to afford the 1,4-diketone 7 in 71% yield (Scheme 2) [31]
We focused on identifying the minimum amount of the second enolate that would lead to optimal yields and found that as little as 1.2–1.4 equiv provided the desired 1,4-diketones in acceptable yields without the need for a large excess of the second coupling partner (Scheme 2)

Summary

Introduction

Substituted 1,4-dicarbonyl compounds are key intermediates for the preparation of numerous natural products and active pharmaceutical ingredients (APIs) with important biological activities. We have shown that the enolonium species 4 (R1 = Ph, R2 = H) can be produced from the corresponding TMS enol ether 1 (R1 = Ph, R2 = H) and subsequently coupled with a second molecule of enol ether 1/5 (R1/3 = Ph, R2/4 = H) to afford the 1,4-diketone 7 in 71% yield (Scheme 2) [31].

Results

Conclusion