Diversion from Bicyclo[4.2.0]octanol Formation Through the Use of Vinyl Electrophiles

Abstract

Bicyclo[4.2.0]octanols can be obtained from the reaction of phenyl vinyl sulfoxide and the lithium enolate of cyclohexanone under controlled conditions. Diversion to alkylation or MichaelMichael-ring closure was observed when alternative vinyl electrophiles were used. Novel bicyclic disulfones and hydroxyhexahydronaphthalenes were isolated. The use of a vinyl sulfoxide electrophile is crucial to the formation of bicyclo[4.2.0]octanols from simple ketones.Previously, the efficient assembly of bicyclo[n.2.0]alkan-1-ols was achieved by reaction of the lithium enolate of (simple) ketones and phenyl (or tolyl) vinyl sulfoxide (for example 1, Scheme 1). 1-4 Controlled reaction conditions are required to favour bicyclo[n.2.0]alkanol formation over alkylation products such as 2. 1 Notably alternate electrophiles have not been tested under the specific conditions required for bicyclo[n.2.0]alkanol formation. Now selected a,b-unsaturated electrophiles were considered in order to explore whether other novel functionality could be introduced to produce functionalized bicyclo[4.2.0]octan-1-ols in this process. Scheme 1Presently, the role of oxidation state and geometry at sulfur, and the polarity of the sulfur-oxygen bond in the electrophile were probed, using cyclohexanone as a representative ketone. Phenyl vinyl sulfide (3), phenyl vinyl sulfone (5), ethyl acrylate (6) and diphenylvinylphosphine oxide (7), were selected as electrophiles (Figure 1). Acrylonitrile was not considered due to its propensity to polymerise. Figure 1 a,b-Unsaturated electrophiles used in this workIn this study, the lithium enolate of cyclohexanone was generated from cyclohexanone or TMS cyclohexyl ether, either method giving similar results with phenyl vinyl sulfoxide (4) as previously described. 2 To allow for comparison, the lithium enolate of cyclohexanone was treated with electrophiles 3, 5-7 under conditions that had previously given moderate to good yields of bicyclo[4.2.0]octan-1-ols with 4 (-30°C, 5 min or -10°C, 10 min). 1

Structural Analysis of the Michael-Michael Ring Closure (MIMIRC) Reaction Products

“…Contrary to this, the relative stereochemistry at C-1 and C-8a is uniformly maintained as cis. This behavior was also systematically observed in the literature [17][18][19][20]. It should be noted that C-4a defines the cis or trans fusion of the newly formed cycle; however, discerning between these geometries is often not so trivial in some cases.…”

“…After analyzing its 1 H NMR spectrum (see Supplementary Materials), it was found that its relative stereochemistry at C-1, C-3, C-4a and C-8a is β, α, α and β, respectively, as was obtained by the scalar couplings of H-1/H-2ax, H-2eq (J H-1,H-2ax = 13.0, J H-1/H-2eq = 4.0 Hz), H-2ax,H-2eq/ H-3 (J H-3,H-2ax = 5.0, J H-3/H-2eq = 2.1 Hz) and H-3/H-4ax,H-4eq (J H-3,H-4ax = 5.0, J H-3/H-4eq = 2.0 Hz). In contrast with this finding, different diastereomers have been described [17,20] as the major product for the same MIMIRC reaction under similar conditions (Figure 3). It can be observed that the stereochemical outcome is consistent at C-1 and C-8a, while configurations at C-3 and C-4a change in a seemingly random event.…”

Phenylsulfinylethylene

“…32 After extensive studies, the Loughlin group found optimal conditions that provided exclusively the bicyclic alcohol (eq 23). 33 Bicyclooctanol formation is favored at short reaction times (less then 15 min). Potassium enolates of nitriles generated catalytically using t-BuOK in DMSO undergo conjugate addition to a variety of Michael acceptors, including phenylsulfinylethylene (eq 24).…”