Synthesis of 17-disubstituted steroids by the Claisen rearrangement

Mercuric trifluoracetate (0.2-0.6 equiv) is shown to be an effective catalyst for equilibrating , -dimethylcarbamic esters of allylic alcohols at room temperature. Acyclic, cyclic, terpene, and steroid examples are reported. Yields are uniformly high (Tables I-III), and side reactions typically encountered in acid-catalyzed isomerizations are not observed. This method for allylically transposing oxygen functionality would appear to be the method of choice in cases where "classical" acid-catalyzed methods fail. When an excess of mercuric trifluoroacetate (1.1-3.0 equiv) is employed, a significant amount of the allylic carbamates is bound as covalent adducts. This observation forms the basis of a method for achieving contrathermodynamic allylic isomerizations (eq 3). The method is limited in scope and preparatively significant contrathermodynamic isomer enrichments were obtained only with the 2-alken-l-yl carbamates 3 and 18. Future applications of this methodology are discussed in terms of the semiquantitative model of Scheme I. The mechanism of the mercury (Il)-catalyzed allylic rearrangement is considered in detail. An ionization-recombination mechanism is ruled out by (a) the inability to detect allyl cation intermediates, (b) the formation of rearranged carbamates rather than amines, and (c) the inversion of the allyl fragment which is observed in the catalyzed rearrangement of thionocarbamate 27. The experimental observations are most consistent with a mechanism (eq 8) in which the mercuric catalyst interacts with the carbon-carbon bond to promote an intramolecular cyclization to yield a 1,3-dioxanium ion intermediate. We suggest the name cyclization-induced rearrangement for this catalysis mechanism (eq 6). More general implications of the cyclization-induced rearrangement mechanism are also considered.Besides being one of the focal points for the evolution of mechanistic organic chemistry, the allylic rearrangement of allylic alcohols and their derivatives occupies a position of some importance in synthetic organic chemistry.3 Often the more readily accessible allylic isomer is not the desired one. If in such cases, the desired isomer predominates at equilibrium, or is favored under kinetically controlled conditions, a synthetic strategy involving an allylic rearrangement may be utilized.

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“…3-Methyl-2-buten-l-yl , -Dimethylcarbamate (15). Purified by preparative GLC:71 >98% pure by GLC;72 t-max (film) 1712 (C=0)…”

Section: Methodsmentioning

confidence: 99%

Mild procedures for interconverting allylic oxygen functionality. Cyclization-induced [3,3] sigmatropic rearrangement of allylic carbamates

Overman¹,

Campbell²,

Knoll³

1978

J. Am. Chem. Soc.

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“…The classical method for equilibrating an allylic alcohol or ester is with a strong protic or Lewis acid catalyst. ,− In favorable cases, this method succeeds splendidly and near quantitative yields have been obtained . More typically, however, the yields are only moderate, the allyl cation intermediates being diverted in part along other reaction pathways .…”

Section: Introductionmentioning

confidence: 99%

“…More typically, however, the yields are only moderate, the allyl cation intermediates being diverted in part along other reaction pathways . Side reactions typically encountered are elimination to yield dienes, skeletal rearrangements, cyclization, and the formation of resinous materials. , Herein, we report the use of the Lewis acid methyltrioxorhenium (CH 3 ReO 3 , abbreviated as MTO) to effect allylic transpositions in a single step.…”

Section: Introductionmentioning

confidence: 99%

1,3-Transposition of Allylic Alcohols Catalyzed by Methyltrioxorhenium

et al. 1998

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Methyltrioxorhenium (MTO) catalyzes the 1,3-transposition of allylic alcohols to generate the more stable isomer at equilibrium. The direction of the equilibrium is largely decided by the nature of the OH group, i.e., whether it is primary, secondary, or tertiary. In the case of aliphatic allylic alcohols, tertiary is preferred to secondary which is preferred to primary. For aromatic allyl alcohols, the more conjugated isomer predominates largely at equilibrium. Oxygen-18 labeling showed that the OH groups of the parent and product are the same. The reaction is first order with respect to both allyl alcohol and MTO but strongly inhibited by traces of water. Theoretical calculations suggest the same results in the case of aliphatic allyl alcohols, although aromatic allyl alcohols do not follow the predictions. Studies of deuterium-labeled substrates show a large equilibrium isotope effect (K = 1.20 ± 0.02). For isomeric allyl alcohols differing in the position of deuterium only, the isomer with the deuterium at the sp3center predominates at equilibrium. The effect of conjugation from a phenyl group appears to be less important since calculations suggest that the phenyl group is forced out of plane of the allylic π system. Disciplines Chemistry CommentsReprinted (adapted) Methyltrioxorhenium (MTO) catalyzes the 1,3-transposition of allylic alcohols to generate the more stable isomer at equilibrium. The direction of the equilibrium is largely decided by the nature of the OH group, i.e., whether it is primary, secondary, or tertiary. In the case of aliphatic allylic alcohols, tertiary is preferred to secondary which is preferred to primary. For aromatic allyl alcohols, the more conjugated isomer predominates largely at equilibrium. Oxygen-18 labeling showed that the OH groups of the parent and product are the same. The reaction is first order with respect to both allyl alcohol and MTO but strongly inhibited by traces of water. Theoretical calculations suggest the same results in the case of aliphatic allyl alcohols, although aromatic allyl alcohols do not follow the predictions. Studies of deuterium-labeled substrates show a large equilibrium isotope effect (K ) 1.20 ( 0.02). For isomeric allyl alcohols differing in the position of deuterium only, the isomer with the deuterium at the sp 3 center predominates at equilibrium. The effect of conjugation from a phenyl group appears to be less important since calculations suggest that the phenyl group is forced out of plane of the allylic π system.

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TheClaisen andCope Rearrangements

Rhoads

Raulins

2011

Organic Reactions

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Since the first observation of a thermal rearrangement vinyl allyl ether to the corresponding homoallylcyclic carbonyl compound by Claisen in 1912, rearrangements of vinyl and aryl allylic ethers have been extensively studied and exploited for their synthetic value. The corresponding rearrangement of substituted 1,5‐hexadiene was first recognized by Cope in 1940 as the carbon analog of the Claisen rearrangement. Today it is recognized that such transformations fall within the general category of a [3,3] sigamtropic reaction and that considerable variation may be accommodated in the basic requirement of a system of six atoms with terminal unsaturated linkage. This chapter attempts to survey the vas t accumulation of Claisen and Cope rearrangements recorded since the first coverage in 1944.

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Synthesis of 17-disubstituted steroids by the Claisen rearrangement

Cited by 13 publications

References 4 publications

Mild procedures for interconverting allylic oxygen functionality. Cyclization-induced [3,3] sigmatropic rearrangement of allylic carbamates

Mild procedures for interconverting allylic oxygen functionality. Cyclization-induced [3,3] sigmatropic rearrangement of allylic carbamates

1,3-Transposition of Allylic Alcohols Catalyzed by Methyltrioxorhenium

TheClaisen andCope Rearrangements

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