@Waylander's cogent Comment to the query of @Random Guy inspired me to post a problem in synthesis to test a question I have pondered for some time. The activation energy (AE) for the Cope rearrangement of 1 is higher than that for the rearrangement of oxy-Cope precursor 2, whose AE is higher than that of the alkoxy-Cope precursor 3. The AE for the Claisen rearrangement of 4 is lower than that for the Cope rearrangement of 1. Can the analogs 5 (R = alkyl, silyl) and 6 be prepared to test whether or not a Claisen rearrangement occurs? The observant reader will recognize 6 as the 1,2-addition product of the enolate of acetaldehyde (or similar enolate) to methyl vinyl ketone (MVK). Does a Michael addition occur by cleavage of 6 with subsequent 1,4-addition or does a Claisen rearrangement intercede? The stereochemistry of the rearrangement of 7 may prove insightful. Would the rearrangement of 9, enolate stereochemistry notwithstanding, be the same or different from that of a Michael addition?

Design a synthesis of 5 or a precursor to 6 taking any liberties with substitution patterns. If you are truly ambitious, go for 7 or a precusor to 9. Feel free to utilize (Z)-and/or (E)-double bonds in 7 and 9.

I am looking for an enterprising young chemist to solve this problem.


Having had no responses to this post, I thought I would offer a scheme in an effort to answer the question about the existence of the oxy Claisen rearrangement. α-Diketone 1[1] was chosen as a starting material owing to the equivalency of the two carbonyls. Selective monoketalization of α-diketone 1 with β-bromoethanol affords cyclohexanone 2. Over ketalization is unlikely owing to steric considerations. Wittig reactions of the type 2 $\rightarrow$ 3 have been conducted successfully.[2]
The elimination of HBr from 3-(2-bromoethoxy)prop-1-ene with powdered KOH to form 3-(vinyloxy)prop-1-ene (allyl vinyl ether) was conducted by Hurd and Pollack.[3] Ideally, allyl vinyl ether 4 would be a more suitable precursor for an alkoxy Claisen rearrangement than divinyl ether 5, given the competing resonance stabilization introduced into the structure by the additional vinyl ether group. Nonetheless, vinyl ethers 4 and 5 may lead to rearrangement products 8 and 6, respectively. Acidic hydrolysis of either of these aldehydes under equilibrating conditions would afford keto aldehyde 7. While the attainment of keto aldehyde 7 would be an achievement, its realization does not determine whether the product is obtained by a concerted rearrangement, or by dissociation into an acetaldehyde enolate/oxyallylcarbocation pair of ions followed by recombination. Barring an intimate ion pair, a crossover experiment is required.
A crossover experiment requires isotopic labeling in both residues involved in the transformation. Deuterium may be incorporated judiciously in both moieties through the use of 2-bromoethan-1,1-d2-1-ol[4] and (methylene-d2)triphenyl-λ5-phosphane leading to substrate 10. If rearrangement is concerted, then keto aldehyde 14 will contain three non-exchangeable deuteria.

In the event that a dissociative mechanism applies, then a near statistical mixture of keto aldehydes 16-d2 and 17-d1 is expected when an equal mixture of 3-d0 and 10-d6 undergo the rearrangement process. Both 1H NMR and mass spectrometry would be critical in an analysis of labeling patterns. The presence of the methyl groups in the deuterated products provides an internal standard for NMR integration. These keto aldehydes will likely lend themselves to McLafferty rearrangements.

  1. R. Lenz, S. V. Ley, D. R. Owen, S. L. Warriner, Tetrahedron: Asymmetry, 1998, 8, 2471.
  2. M. Pellet, F. Huet, J. M. Conia, Tetrahedron Lett., 1977, 39, 1979.
  3. C. D. Hurd, M. A Pollack, J. Am. Chem. Soc., 1938, 60, 1905.
  4. I. Bird, P. B. Farmer, J. Labelled Compounds and Radiopharmaceuticals, 1989, 27, 199.

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