Scope and Mechanism of the (4+3) Cycloaddition Reaction of Furfuryl Cations (2011)

It all adds up: Furfuryl alcohols are revealed as direct reaction partners for a wide range of conjugated dienes in a (4+3) cycloaddition motif (see scheme). This novel Lewis acid promoted process gives straightforward access to various polycyclic skeletons containing a seven-membered ring. A plausible cationic stepwise mechanism was confirmed by DFT calculations. Whereas reactions of vinyloxocarbenium species are believed to proceed by a concerted (4+2) cycloaddition followed by a Wagner–Meerwein-type ring expansion,5 allylic cations with a Z group at the 2-position have been suggested to undergo “true” (4+3) cycloaddition reactions, either through a concerted or a stepwise process.7 The synthetic utility of these cycloadditions is limited however by issues concerning the generation of the allylic cation reaction partner. The precursors required for allylic cations can be synthetically challenging, and the carbocationic species themselves are generally quite unstable, thus giving rise to various by-products. We surmised that the mechanism of this intriguing cycloaddition reaction involves the initial formation of a furfuryl cation intermediate,9 which then undergoes an intramolecular (4+3)-type cycloaddition with the appended diene (cf. Scheme 1). The initially formed bicyclic oxocarbenium ion can then be converted into the observed product through straightforward loss of a proton and regeneration of the furan ring. The cationic reaction partner in this sequence can thus be regarded as an allylic cation with a stabilizing oxygen substituent at the 2-position [cf. Eq. (1)], and moreover, if the oxonium ion resonance structure is considered (Scheme 1, bottom), it can be viewed as a vinylogous vinyloxocarbenium ion [cf. Eq. (2)]. If it is concerted, the observed cycloaddition can then be regarded as a rare example of a “higher order” pericyclic reaction, that is, a [6π+4π] cycloaddition with an unprecedented 2-oxafulvene-type 6π reactant.10 Proposed mechanism of cycloaddition via a furfuryl cation intermediate. As the prospect of an efficient (4+3) cycloaddition method using simple furfuryl alcohol starting materials is highly attractive from a synthetic point of view, we decided to investigate the scope and mechanism of this unprecedented reaction by a joint experimental and theoretical approach. Although the efficiency of the cycloaddition reaction in [Eq. 3] is impressive (the polycycle is obtained as a single diastereomer in quantitative yield), it is definitely helped by the intramolecular nature of the reaction and possibly by the quite specific substitution patterns of the reactants. Thus, we have examined corresponding intermolecular cycloadditions of some simple furfuryl cations with 1,3-cyclohexadiene (CHD) as a model substrate. Our initial results are summarized in Table 1. Entry[a] Starting material Product Yield [%][b] 1 polymers – 2[c] 17 3[c] 82 (4:1)[d] 4[c] 89 (4:1)[d] 5[c] 72 (10:1)[d] 6 96 7 97 Using a number of cation-generating conditions (TFA, TiCl4, or TMSOTf), we were not able to achieve a cycloaddition reaction with furfuryl alcohol itself (Table 1; entry 1). Instead, we invariably observed a swift polymerization reaction to give a black tar. However, when the homologue 1, in which the highly nucleophilic 5-position of the furan is blocked by a methyl substituent, was used (entry 2) we could isolate the expected adduct 2, albeit in poor yield. Best results were obtained using a stoichiometric amount of TiCl4, as a Lewis acid. However, poly- and oligomerization reactions still seemed to be the prevalent reaction pathways for compound 1. By employing an excess of CHD (2 equiv) and by increasing substitution at the carbinol position (entries 3–5), we were able to suppress furfuryl oligomerization and obtained good to excellent yields of cycloadducts 4, 6, and 8. Moreover, these reactions showed moderate to good selectivity for the diastereomer that corresponds to an exo (or “extended”) mode of addition of the diene to the furfuryl cation (i.e. with the furan oxygen and the diene are at opposite sides of the plane of the forming bonds). Finally, almost quantitative yields of cycloadducts were achieved using the tertiary furfuryl alcohols 9 and 11, even without resorting to using an excess of diene (entries 6 and 7). Given the general efficiency of the formation of cycloadducts with CHD, we next examined alternative diene substrates (Scheme 2). The reaction between furfuryl alcohol 9 and cyclopentadiene smoothly gave the expected cycloadduct 13. The corresponding reaction with the acyclic diene isoprene proved somewhat less efficient. However, the cyclohepta[b]furan 14 was obtained as a single regioisomer in reasonable yield when an excess of isoprene was used. Surprisingly, reactions with furan, which is one of the most widely used dienes in (4+3) cycloadditions, were quite problematic. The only observed cycloaddition product was the unusual bisadduct 15, which was isolated as a single diastereomer. To further explore the scope and synthetic potential of this reaction, cycloadditions with some the more challenging dienes 16, 18, and 21 were tested. Thus, the tricyclic furan 17, which incorporates the widdrane sesquiterpene carbon skeleton,11 was obtained in a single step from the commercially available diene 16. Reactions with the bicyclic diene 18 gave access to C-homo-D-oxasteroids 19 and 20,12 with interesting substrate-dependant regioselectivities. Finally, the novel terpene-like homochiral polycyclic compound 22 was efficiently obtained from a reaction with (+)-nopadiene 21. Cycloaddition reactions with alternative dienes. These intriguing cycloaddition reactions almost certainly take place by the formation of a furfuryl cation, and we have modelled their reactions with CHD at the DFT level of theory.13 The phenyl-substituted furfuryl alcohol 7 (see Table 1, entry 5) was chosen for this purpose, as this substrate gives mostly exo-selective cycloaddition. Several competing pathways have been investigated in an effort to deduce a plausible mechanism (Scheme 3). Both a stepwise and a concerted process were identified as viable routes for the formation of the observed reaction products, although calculated energies were shown to consistently favor the stepwise pathway at different levels of theory (See the Supporting Information, Tables 1–3). Possible pathways for the reaction of CHD and furfuryl cation by either a stepwise electrophilic addition (AdE) pathway or a concerted (conc.) pathway. In the stepwise pathway, a highly reactive allylic cation intermediate II is formed, and this intermediate can undergo several very low barrier intramolecular electrophilic additions (Scheme 3). Reactions at the 2-position of the furan—by either a 6-exo-trig or a 4-exo-trig cyclization process—lead to six- and four-membered ring intermediates III and IV, respectively. These intermediates are unable to undergo a proton elimination to regain a stable furan ring. Moreover, transition states for low-barrier ring expansions of these intermediates to seven- or five-membered ring intermediates (V and VI, respectively) could not be located, instead intermediates III and IV were found to be more likely to re-form intermediate II. Low-barrier reactions at the 3-position of the furan lead either to intermediates V or VI (formation of a seven- or five-membered ring, respectively). The 7-endo-trig cyclization was shown to be favored over the 5-endo-trig cyclization (see the Supporting Information, Table 1–3), in accordance with Baldwin’s rules. Simple deprotonation of this cation (V) then leads to the final product 8. The observed isomers, exo-8 and endo-8, are derived from the diastereomeric allylic cation intermediates exo-II and endo-II (Figure 1). The calculated energy profiles for the formation of the allylic cation (exo-II/endo-II) and the subsequent ring closure favor the formation of the experimentally verified major adduct, exo-V (see Figure 2 and the Supporting Information). Observed diastereomers for 8 and optimized geometries (BMK/6-311+G(d,p)//B3LYP/6-31+G(d,p)) for the corresponding diastereomeric intermediate allylic cations II. Free-energy profile for the stepwise (4+3) cycloaddition leading to endo and exo adducts. Free energies in kcal mol−1 at the BMK/6-311+G(d,p)//B3LYP/6-31+G(d,p) level of theory, CPCM (ε=8.93, dichloromethane) results in parentheses, distances in Å. In the pericyclic pathway, the seven-membered-ring intermediate cation V is formed directly through a concerted [6π+4π] cycloaddition. The calculated energies for the pericyclic TS’s were found to be at least 3.0 kcal mol−1 higher than for the corresponding stepwise pathways and favor the formation of the exo-adduct (Figure 3 and the Supporting Information). The evolution of furanyl bond distances throughout the reaction suggests that all 6π-electrons of the furfuryl cation are involved in the process (see the Supporting Information). Transition-state geometries and Gibb’s free energies of activation for the pericyclic [6π+4π] cycloaddition leading to exo- and endo-adducts. Free energies in kcal mol−1 at the BMK/6-311+G(d,p)//B3LYP/6-31+G(d,p) level of theory, CPCM (ε=8.93, dichloromethane) results in parenthesis, distances are in Å. In conclusion, the reactions reported here uncover a readily available and versatile class of starting materials for the (4+3) cycloaddition reaction between a diene and an allylic cation. The synthetic usefulness of the novel cycloaddition has been shown by a number of illustrative examples and its mechanism has been investigated at the DFT level of theory. The theoretical results point to an efficient and stereoselective two-step cationic cyclization process and are in good qualitative agreement with the experimental results. Further investigations into substrate tolerance and applications in total synthesis, as well as further refinement of the reaction mechanism are now under way and will be reported in due course. Detailed facts of importance to specialist readers are published as ”Supporting Information”. 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