Synthesis of α-Allyloxy-Substituted α,β-Unsaturated Esters via Aldol Condensation. Convenient Access of Highly Substituted Allyl Vinyl Ethers

Abstract

a-Allyloxy-substituted a,b-unsaturated esters 1a-r have been prepared in 5 steps from commercially available starting materials. The key sequence of the synthesis is an aldol addition between an a-allyloxy-substituted ester 2a-i and an aldehyde R 1 CHO followed by mesylation and DBU mediated elimination to afford the 2-alkoxycarbonyl-substituted allyl vinyl ethers 1a-r. The E/Z ratio of the newly generated vinyl ether double bond is apparently determined by the steric bulk of the vinyl ether double bond substituent R 1 . Z:E ratios from 3:2-9:1 were obtained.Without doubt, sigmatropic rearrangements create one of the most important classes of synthetic transformations.Several striking examples have proven the utility of sigmatropic rearrangements for the stereoselective synthesis of organic compounds. 1 In an ongoing effort to further increase the synthetic efficiency, much work is devoted to extend the scope of classical sigmatropic rearrangements. 2 In this regard, we are engaged in a research program which focuses on the development of metal catalyzed Claisen rearrangements and pericyclic domino reactions which are triggered by a dienolate [2,3]-Wittig rearrangement. The starting materials for both processes are a-allyloxy-substituted a,b-unsaturated esters 1.Particularly, we were able to show that the 2-alkoxycarbonyl-substituted allyl vinyl ether 1f can be transformed to an a-keto ester diastereoselectively employing a combination of Pd(II)-catalysis and thermal reaction conditions (Scheme 1). 3 Scheme 1Furthermore, when treated with an appropriate base a-allyloxy-substituted a,b-unsaturated esters 1 can be transformed to the corresponding dienolates which undergo a dienolate [2,3]-Wittig rearrangement to 3-alkoxycarbonyl-3-hydroxy-substituted 1,5-hexadienes. 4 These compounds are substrates for a domino 3-oxy-Cope rearrangement/type II carbonyl ene reaction affording substituted carbocycles (Scheme 2). 5 Scheme 2Finally, we have recently established first examples for a domino ester dienolate [2,3]-Wittig/anionic 3-oxy Cope rearrangement to afford the corresponding a-keto esters (Scheme 3). 6 Scheme 3Obviously, it was indispensable to develop a reliable, flexible and efficient synthetic access to a-allyloxy-subEt CO 2 R O n-Pr Et n-Pr CO 2 R O 5 % PdCl 2 (PhCN) 2 toluene 60 °C, 3 h 150 °C 3 h 90 % anti:syn 95:5 1f, R= CH 2 CH 2 OCH 3 Z:E= 67:33 OH CO 2 i-Pr OH CO 2 i-Pr Ph Ph O Ph CO 2 i-Pr O Ph O Oi-Pr Li O CO 2 i-Pr Ph LDA, THF -78 °C to 25 °C 89 % toluene 200 °C, 19 h sealed tube 85 % [3,3] ene [2,3] O O Oi-Pr CO 2 i-Pr O LDA, THF -78 °C to 25 °C 84 % 1h Downloaded by: University of Pittsburgh. Copyrighted material. 1280 M. Hiersemann PAPER Synthesis 2000, No. 9, 1279-1290 ISSN 0039-7881 © Thieme Stuttgart · New Yorkstituted a,b-unsaturated esters 1 to be in the position to study the scope and limitations of the newly developed synthetic processes. At the outset, an aldol condensation strategy seemed to be an ideal approach with respect to synthetic convergence and substrate availability (Scheme 4). Sche...

Catalysis of the Claisen Rearrangement of Aliphatic Allyl Vinyl Ethers

“…The application of this class of allyl vinyl ethers offers advantages in terms of synthesis, stability, and reactivity. [28] We performed a variety of different studies to determine the best Lewis acid in terms of reactivity and chemoselectivity. All the commercially available lanthanide(III) triflates and also Ce(OTf) 4 were tested as catalysts for the Claisen rearrangement of the 1-isopropyl-6-propyl-substituted allyl vinyl ether 3c (Scheme 15, Table 1), used in our screening program as a (Z)/(E) ϭ 9:1 mixture of vinyl ether doublebond isomers.…”

Triphenyl(prop-2-yn-1-yl)silane

“…For background to silane chemistry, see: Abraham et al (2001Abraham et al ( , 2003; Helmboldt & Hiersemann (2003); Hiersemann (1999Hiersemann ( , 2000; Nelson et al (2011). Data collection: CrysAlis CCD (Oxford Diffraction, 2008); cell refinement: CrysAlis CCD; data reduction: CrysAlis RED (Oxford Diffraction, 2008); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: SHELXTL-Plus (Sheldrick, 2008); software used to prepare material for publication: SHELXL97 and PLATON (Spek, 2009 …”

“…Silane acts as an intermediate en route to alkoxy-carbonyl substituted allyl vinyl ethers (Hiersemann, 2000), which exhibit a wide range of reactivity for further synthetic transformation (Hiersemann, 1999;Abraham et al, 2001;Abraham et al, 2003;Helmboldt et al, 2003;Nelson et al, 2011) developed in our laboratory.…”

The Ester Dienolate [2,3]-WittigRearrangement - Development, Opportunities, andLimitations

“…13 The appropriate allylic alcohol 13 was etherificated with either the in situ generated sodium salt of bromo acetic acid or the commercially available sodium salt of iodo acetic acid. The latter method is now established as the method of choice due to a convenient experimental procedure along with a reliable reproducibility.…”