(Scheme 3) [9]. We tested methyl vinyl ketone (8) as a cross-metathesis partner, along with the recently described Umicore M51 initiator (A) [20,33,34], as well asBeilstein J. Org. Chem. 2013, 9, 2544?555.Scheme 2: Synthetic plan for stagonolide E.Scheme 3: Synthesis of RCM/ring opening precursor 14.Beilstein J. Org. Chem. 2013, 9, 2544?555.Grubbs’ second generation carbene complex B [35] as precatalysts (Table 1). Phosphine-free precatalysts using a hemilabile alkoxy ligand are supposed to become well-suited for cross metathesis reactions [36,37]. Having a moderate catalyst loading of two.0 mol of A, we isolated the anticipated cross metathesis product 11 in an acceptable yield of 76 (Table 1, entry 1). Surprisingly, the yield decreased significantly to 51 with an elevated catalyst loading of 5.0 mol , and formation of a byproduct with an Rf value pretty related to that from the cross metathesis solution 11 was observed by TLC (Table 1, entry two). Inspection of your 1H NMR spectrum of the crude reaction mixture revealed that two singlets at 2.35 ppm and 6.75 ppm inside a 1:3 ratio were present, which matches the NMR data previously reported for (E)-hex-3-ene-2,5-dione [38]. Obviously, catalyst A is sufficiently active to initiate the self metathesis of methyl vinyl ketone (8) to a considerable extent at a catalyst loading of five.0 mol , and consequently reduced amounts of catalyst have been tested inside the following experiments. With 0.five mol , the isolated yield was 67 under otherwise identical situations (Table 1, entry 3), and 85 of 11 were obtained with 1.0 mol of A (Table 1, entry four). With these catalyst loadings self metathesis of 8 is largely suppressed plus the chromatographic isolation of 11 is facilitated, which could clarify the enhanced yields below these circumstances. With second generation Grubbs’ catalyst B, the self metathesis on the supposedly less reactive CM companion occurs only to a minor extent, even at elevated temperatures and catalyst loadings.Price of 1-(5-Bromo-2-nitrophenyl)ethanone When we used 2 mol of B (Table 1, entry 5) the yield was 61 , but might be improvedto 78 by adding phenol (Table 1, entry 6). The valuable impact of phenol in cross metathesis reactions is recognized and has been attributed to a stabilization of the reactive 14-electron species [39].tert-Butyl 4-bromopicolinate site A really high yield of 93 was eventually obtained by utilizing 5 mol of B in refluxing dichloromethane (Table 1, entry 7). In the subsequent step, the remaining hydroxy group was protected as a MOM ether 12, which was then selectively reduced at the electron-deficient double bond, utilizing polymethylhydrosiloxane (PMHS) [40] as a minimizing agent and a BDP u hydride catalyst.PMID:26760947 This variant of Stryker’s reagent [41] has far more not too long ago been described by Lipshutz et al. [42] and was identified to furnish ketone 13 in 74 yield. Desilylation of 13 may very well be accomplished quantitatively applying TBAF at elevated temperature. On the other hand, an unidentified byproduct presumably a sixmembered lacol was formed, which couldn’t be separated by chromatography. For that reason the mixture was subjected to the second step, a Steglich esterification [43] with vinylacetic acid, to provide the preferred precursor 14 in pure type in 71 yield. To avoid the formation on the inseparable byproduct, we investigated a reversed order of actions. To this finish, 12 was very first desilylated to allyl alcohol 15, which was then converted to butenoate 16, again by means of Steglich esterification. For the selective reduction from the enoate 16, the Stryker ipshutz protocol was again the process of choice and optimi.