Gold-Catalyzed Highly Regioselective Oxidation of C−C Triple Bonds without Acid Additives: Propargyl Moieties as Masked α,β-Unsaturated Carbonyls

Abstract

Gold-catalyzed intermolecular oxidations of internal alkynes have been achieved with high regioselectivities using 8-alkylqinoline N-oxides as oxidants and in the absence of acid additives. Synthetically versatile α,β-unsaturated carbonyls are obtained in good to excellent yields and with excellent E-selectivities. A range of functional groups such as THP, MOMO, N 3 , OTBS, and NBoc are tolerated. This reaction allows to mask α,β-unsaturated carbonyls as propargyl moieties, thus offering a practical solution to issues of functional group compatibility with α,β-unsaturated carbonyls, likely encountered in syntheses of complex structures.Although alkene epoxidation is a classic and versatile reaction in organic synthesis, epoxidation of C-C triple bonds1 with DMDO or peracids has little synthetic utility except with electronically biased ynamide substrates2 as often multiple products including α,β-unsaturated ketones were formed with little chemoselectivity and regioselectivity. Many of the product formations could be rationalized via an initial rearrangement of oxirene A3 into highly reactive α-oxocarbene B (Scheme 1A). In the cases of alternative metal-mediated/ catalyzed intermolecular alkynes oxidation, further oxidation is unavoidable,4 leading to α,β-epoxy ketones,5 1,2-dicarbonyl, or carboxylic products;6 hence, regioselectivity has not been studied nor achieved. Herein, we report a rare highly regioselective single oxidation of internal alkynes via gold catalysis under exceedingly mild conditions, and synthetically versatile α,β-unsaturated carbonyls are directly formed from propargyl moieties for the first time in good yields and with high to excellent regioselectivities.We have recently reported that terminal alkynes or alkynoates can be oxidized intermolecularly into α-oxo gold carbene C,7 which could be trapped efficiently by tethered OH groups.8 We envisioned such a gold carbene intermediate, if generated from internal alkynes, might undergo facile 1,2-C-H insertions, thus avoiding further oxidation and forming highly valuable α,β-unsaturated carbonyls (Scheme 1B). This gold catalysis would make a propargyl moiety a masked α,β-unsaturated carbonyl;9 however, the challenge is how to achieve high regioselectivities10 without much structural bias in the substrate.To our delight, the oxidation of symmetric 6-dodecyne indeed afforded α,β-unsaturated ketone 2a in 77% yield albeit sluggish reaction (Eq. 1). In contrast to cis-C-C double bonds formed in zhang@chem.ucsb.edu. Supporting Information Available: Experimental procedures, compound characterization data. This material is available free of charge via the Internet at http://pubs.acs.org. Rh-catalyzed decomposition of α-diazo carbonyl compounds,11 only trans-2a was observed, reflecting a unique aspect of gold carbene reactivities. NIH Public AccessWith this encouraging result, we then chose non-symmetric aliphatic alkyne 1b to study regioselectivity by tuning the steric and electronic properties of gold catalysts and N-oxides. Table 1 shows some...

Modern Methods for Total Synthesis of Important Oxindole Alkaloids

“…According to a method reported by Lu et al, the gold-promoted oxidation of alkyne 212 using 2-bromopyridine N-oxide gave the enone 214. 31 Finally, diastereoselective epoxidation of enone 214 to deliver a mixture (5:1) of epoxides (-)-citrinadin A 216 and …”

A Flexible and Stereoselective Synthesis of Azetidin‐3‐ones through Gold‐Catalyzed Intermolecular Oxidation of Alkynes

“…Early in 2010 our research group showed for the first time [8] that reactive a-oxo gold carbenes [9] could be readily accessed by simple intermolecular oxidation [10] of terminal alkynes, [11] therefore allowing substitution of toxic a-diazo ketones with benign and readily available alkynes (Scheme 1). This approach was later applied to the preparation of oxetan-3-ones from easily available propargyl alcohols.…”

“…[20] To our delight, this new cationic gold(I) complex offered a significant improvement (Table 1, entry 12). Inspired by our recent work that did not use acid additives, [11] the reaction was attempted without MsOH. Pleasingly, azetidin-3-one 2 was formed in an 85 % (82 % isolated) yield, and the reaction rate did not decrease to a significant extent (Table 1, With the optimal reaction conditions secured, the reaction scope was then studied.…”

Mechanistic insights and functionalization of alkynes in homogeneous gold catalysis.

“…4,7,28,[51][52][53][54][55][56][57][58] In particular, the gold-catalyzed oxygen transfer of a nucleophilic oxygen atom to an alkyne group is synthetically useful. [59][60][61][62][63][64][65] To further explore the reactivity of Au catalysts towards oxygen-atom transfer reactions, we investigated the gold-catalyzed addition of O-nucleophiles to alkynes to produce synthetically important vinyl ether products in excellent yields and regioselectivities at room temperature. Although these vinyl ethers are generally not stable enough to be isolated with standard silica gel chromatography, they were stable in our hands.…”

“…[59][60][61][62][63][64][65][178][179][180] In 2009, Asensio and co-workers applied the oxygen transfer concept in their intermolecular gold-catalyzed sulfoxide addition to alkynes that allowed the preparation of sulfur containing arenes (Scheme 16b).…”