Alkynyl Thioethers in Gold‐Catalyzed Annulations To Form Oxazoles

Abstract

Non-oxidative,regioselective,and convergent access to densely functionalized oxazoles is realized in af unctionalgroup tolerant manner using alkynyl thioethers.S ulfur-terminated alkynes provideaccess to reactivity previously requiring strong donor-substituted alkynes such as ynamides.Sulfur does not act in an analogous donor fashion in this gold-catalyzed reaction, thus leading to complementary regioselective outcomes and addressing the limitations of using ynamides.Compared to other heteroatom-substituted alkynes,alkynyl thioethers are remarkably little explored in intermolecular late-transition-metal catalysis,d espite being readily accessed and robust. [1,2] Ynamides,i nc ontrast, are privileged substrates:i np-acid catalysis their donor nature aids metalalkyne coordination and affords highly polarized electrophiles,t hus providing the high chemo-and regioselectivity required for the discovery of efficient intermolecular reactions (Scheme 1a). [3,4] As the resulting inclusion of ad onornitrogen atom limits the utility of the products,r etaining the reactivity profile of these transformations whilst accessing more flexible and readily elaborated substitution patterns would be desirable.T he value of sulfur-substituted compounds [5] coupled with progress in C À Ca nd C-heteroatom bond formation from CÀSbonds, [6] renders alkynyl thioethers appealing alternatives to ynamides.I ndeed the ketenethionium pathway (Scheme 1a)f rom alkynyl thioethers has recently been invoked in proton-catalyzed reactions with nitriles [2g,h] and gold-catalyzed reactions with sulfides.[2i]Ynamides enabled the discovery of formal [3+ +2] dipolar cycloadditions with nucleophilic nitrenoids, [7] thus allowing intermolecular access to a-imino gold carbene-type reactivity for heterocycle synthesis (Scheme 1b). [8, 9] Such reactions, which do not depend on ynamides,a re scarce.[8b,h] As trong donor alkyne substituent proved critical in the formation of oxazoles using N-acyl pyridinium N-aminides,aselectron-rich alkynes such as anisole derivatives did not react (Scheme 1b, inset). [8a,b] Oxazoles are valuable synthetic intermediates [10,11] and structural components in bioactive natural products, [12] agrochemicals, [13] ligands, [14] and functional materials.[15]Despite recent advances,asingle modular and convergent route to trisubstituted oxazoles,which provides the structural and functional-group diversity needed across the 2-, 4-, and 5-positions,r emains unrealized. [16] Following our interest in the use of gold catalysis with sulfides [17] we report here on the reactivity of alkynyl thioethers with nucleophilic nitrenoids to prepare oxazoles. Importantly,t he regioselectivity is not consistent with ac ontrolling ketenethionium species.T he sulfur group plays an alternative role in enabling reactivity,t hus proving complementary to donor-enabled approaches.Ther eaction of the alkynyl thioether 1a and aminide 2a (Table 1) showed that conversion into the oxazole 3 was possible at 125 8 8Ci n1 ,2-dichlorobenzene (1,2-DCB;s ee...

CsF-Mediated in Situ Desilylation of TMS-Alkynes for Sonogashira Reaction

“…Column chromatography (silica gel, eluting with 0−100% dichloromethane/heptane gradient) afforded the desired product as a colorless oil (644 mg, 82%). Characterization data obtained agree with the literature data: 16 1 H NMR (300 MHz, chloroform-d) δ 7.34 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 3.78 (s, 3H), 2.04 (s, 3H); 13 C{ 1 H} NMR (75 MHz, chloroform-d) δ 159.1, 132.9, 116.3, 113.9, 84.2, 79.5, 55.2, 4.3.…”

Recent advances in thiolation via sulfur electrophiles

“…In this strategy, the thiosulfonates 48 were commonly used as the electrophiles (Scheme 44). 58 Both the aliphatic and aromatic thio group could be well incorporated to form the C-S bond.…”

DFT Rationalization of Gold(I)-Catalyzed Couplings between Alkynyl Thioether and Nitrenoid Derivatives: Mechanism, Selectivity Patterns, and Effects of Substituents

“…7 For example, Davies and coworkers showed that the use of N-acylpyridinium amine with a Au(III) precatalyst results in selective attack on the β-position of alkynyl sulfide. 8 A zinc(II)-catalyzed coupling of alkynyl thioether and isoxazole derivatives was also described by Ye's group, featuring selective α-addition and 1,2-S migration with the formation of sulfur-bearing β-keto enamide products. 9 Davies and coworkers recently reported a compelling Aucatalyzed reaction between alkynyl thioethers and isoxazole or anthranil derivatives (Scheme 1).…”

“…However, only a few specific examples of systems can show efficient conversions when using other types of alkynes . For example, Davies and coworkers showed that the use of N -acylpyridinium amine with a Au­(III) precatalyst results in selective attack on the β-position of alkynyl sulfide . A zinc­(II)-catalyzed coupling of alkynyl thioether and isoxazole derivatives was also described by Ye’s group, featuring selective α-addition and 1,2-S migration with the formation of sulfur-bearing β-keto enamide products …”