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The Ramberg-Bäcklund Reaction The Ramberg-Bäcklund Reaction Richard J. K. Taylor, University of York, Heslington, York, UK Guy Casy, Cambridge, UK 1. Introduction The base-mediated conversion of -halosulfones into regio-defined alkenes was first described by Ludwig Ramberg and Birger Bäcklund. (1) This transformation, generalized in Eq. 1, has proved to be of wide synthetic value and is now known as the Ramberg-Bäcklund reaction. (Also referred to as the Ramberg-Bäcklund rearrangement, and abbreviated herein as RBR). (1) The facile nature of the RBR is surprising given the difficulties encountered when attempting to carry out nucleophilic substitution reactions on -halosulfones. (2) In contrast to halogens adjacent to carbonyls and related electron-withdrawing groups, (3) polar, steric, and field effects appear to combine leading to the marked deactivation of -halosulfones. The stereochemical outcome of the reaction was also unexpected: a predominance of Z-alkenes is often observed with relatively weak bases (e.g. sodium hydroxide) whereas stronger bases [e.g. potassium tert-butoxide] tend to favor E-alkenes. The mechanism of the RBR was therefore the subject of intense interest, particularly in the 1950's and 1960's; mechanistic aspects are reviewed in the next section. From the synthetic viewpoint, the RBR is attractive for a number of reasons: i. The accessibility of the precursor sulfides and sulfones, ii. The conjunctive nature of the process, iii. The unambiguous location of the resulting double bond, iv. The absence of alkene rearrangement processes due to the alkaline reaction conditions, v. The applicability of the procedure to all alkene substitution patterns including tetra-substituted variants, vi. The efficiency with which strained alkenes such as cyclobutenes and cyclophanes can be prepared, vii. The availability of polyenes via the RBR, viii. The availability of deuterated alkenes by carrying out the RBR in deuterated solvents, ix. The applicability of the procedure to complex, multifunctional molecules, provided certain base-sensitive groups are absent or protected. Organic sulfones are readily available but the preparation of -halosulfones can be problematic. In view of this, perhaps the most significant synthetic advance concerning the RBR has been the development of Meyers' modification, (4) which involves an in situ halogenation-RBR sequence and enables sulfones to be converted directly into alkenes. This procedure therefore avoids the need to prepare -halogenated sulfones in advance. Eq. 2 shows one of the first examples of this type: first, the -sulfonyl anion undergoes halogenation by the solvent; the product then undergoes cyclization and subsequent olefin formation in the normal manner. (2) The following sections discuss the mechanism of the RBR, its scope and limitations, applications of the reaction in natural product synthesis, and comparison of the RBR with related procedures. Representative experimental procedures are also given. The RBR has been well reviewed over the years, (5-7) the seminal contribution being the Organic Reactions chapter by Paquette. (5) The aim of the current chapter is to update the Paquette review with minimal duplication. Particular emphasis is therefore given to major developments in the reaction since 1977 as well as to the isolation and synthetic utility of thiirane dioxides. The Tabular Survey covers all publications since the previous review in Organic Reactions. For a comprehensive listing of published RBR processes, therefore, both Chapters should be consulted. To conclude this introductory section, two examples are included to illustrate the utility of the RBR. Eq. 3 shows the key RBR of a pre-formed -halosulfone during a synthesis of the antitumor natural product eremantholide A, (8) and Eq. 4 shows the use of the Meyers modification, en route to methyl C-gentiobioside. (9) (3) (4) 2. Mechanism and Stereochemistry Extensive studies have been carried out to elucidate the mechanism of the RBR and these investigations have been well reviewed. (5, 10-13) Thus, only an overview will be presented here, with emphasis on advances reported after 1977. The intermediacy of thiirane dioxides (episulfones) was first proposed in 1951. (2) Later studies confirmed this hypothesis and produced the generally accepted anionic mechanism for the RBR shown in Eq. 5. Other proposals, such as carbenoid and dipolar mechanisms, were considered but dismissed after experimentation. (12, 14) (5) Thus, rapid and reversible formation of the -sulfonyl anion (which is in equilibrium with the ˘-anion if the substrate can form one) is followed by the rate-determining step, the loss of halide in a 1,3-cyclization process (with kI > kBr > kCI), generating the thiirane dioxide intermediate. The intramolecular nature of this process ensures that the carbanionic center is remote from the polar sulfonyl oxygens (15) and therefore avoids the unfavorable electronic factors present in the intermolecular displacements of -halosulfones. (2) There is a stereoelectronic preference for the so-called “W-plan” co-planar arrangement of the proton and leaving group adjacent to the sulfonyl group. This is nicely shown in Eqs. 6 and 7. (16) The cis-fused system 1, which possesses the W-plan arrangement, undergoes facile RBR giving alkene 2, whereas with the trans-fused isomer 3 the major product 4 results from 1,2-elimination. It should be noted that inversion of configuration at both reacting centers is required to convert 1 into the corresponding thiirane dioxide. (6) (7) Indirect support for the intermediacy of thiirane dioxides was obtained by first preparing them by other procedures, and then showing that they are converted into alkenes under the conditions of the RBR. (17-19) However, in 1989 it was shown that treatment of -iodothiane dioxides with bases at low temperature gives thiirane dioxides as the major products (Eq. 8). (20, 21) Heating thiirane dioxide 5, or treating it with potassium tert-butoxide, converts 5 into the expected RBR alkene product 6. Further aspects of the formation and reactivity of thiirane dioxides are discussed later. (8) The conversion of thiirane dioxides into alkenes has been well studied and reviewed. (22) In general, on heating (usually in the range between room temperature and 110°) thiirane dioxides lose sulfur dioxide to give the corresponding alkenes in a stereospecific process. There have been a number of mechanistic proposals for this thermal desulfonylation reaction. (12, 19, 23, 24) Concerted, linear cheleotropic loss is symmetry forbidden and therefore dipolar and diradical stepwise mechanisms were initially considered, with the proviso that loss of sulfur dioxide must occur at a faster rate than rotation around the carbon-carbon bond in order to accommodate the observed stereospecificity. The intermediacy of 1,3-diradicals possessing significant rotational barriers is consistent with experimental evidence, (19) and this mechanism was advocated by Bordwell et al. (19) However, Woodward and Hoffman subsequently stated that “the available evidence is also consistent with the view that the elimination follows the concerted symmetry-allowed non-linear cheleotropic pathway” (23) and more recent theoretical studies are in accord with this statement. (25) The rate of thiirane dioxide decomposition is increased by base (19) and in general the reactions are stereospecific when hydroxide ion is employed. Again, there have been numerous mechanistic proposals; (12, 19, 24, 26, 27) Bordwell's mechanism is shown in Eq. 9. (19) The initial step, involving addition to the sulfone group, now seems to be generally accepted. (26, 27) Whether the subsequent decomposition occurs via a rotationally restricted diradical anionic intermediate as shown, or via a non-linear cheleotropic extrusion from the initially formed hypervalent intermediate, (23) still has to be confirmed. (9) 2.1. Stereoselectivity The original publication made the surprising claim that Z-alkenes predominate from the treatment of -bromoethyl and -bromopropyl ethyl sulfone. These observations were later confirmed and extended to other sulfones. In the same study, it was established that the E:Z ratio is remarkably consistent over a range of solvents and bases. However, when the strong base potassium tert-butoxide in tert-butanol (or toluene) is employed there is a dramatic change and the E-isomer predominates, as shown in Eq. 10. (17) (10) A second anomaly is that -chlorobenzyl benzyl sulfone was reported to give only (E)-stilbene on treatment with hydroxide as shown in Eq. 11. (2) (11) In order to solve this stereochemical conundrum, experiments were carried out on isolated thiirane dioxides. (17-19) Thus, with cis-1,2-dimethylthiirane dioxide, thermolysis or treatment with hydroxide gives only (Z)-but-2-ene, whereas treatment with tert-butoxide gives predominantly the E-alkene (Eq. 12). (17) With cis-1,2-diphenylthiirane dioxide, thermal decomposition is again stereospecific but treatment with hydroxide or methoxide yields predominantly (E)-stilbene. (19, 24) (12) These results have been rationalized as shown in Eq. 13. In most reactions, the ratio of the trans- and cis-disubstituted thiirane dioxide established in the intramolecular cyclization step is reflected in the final E:Z-alkene ratio since the thermal or base-mediated loss of sulfur dioxide from the thiirane dioxide intermediates occurs in a stereospecific manner. However, when a stronger base such as tert-butoxide is employed, or when there are additional acidifying substituents (e.g.
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