Selectivity Reversal during Thia-Michael Additions Using Tetrabutylammonium Hydroxide: Operationally Simple and Extremely High Turnover

Abstract

The use of tetrabutylammonium hydroxide as a novel and exceedingly efficient thia-Michael addition catalyst is herein described. This extremely simple methodology allows for the conjugate addition of a wide variety of mercaptan nucleophiles, and functions remarkably well with a very wide range of both classical and non-classical Michael acceptors. Contradistinctive to current literature reports, the use of this catalyst more efficiently promotes the addition of more basic thiols. This methodology is especially attractive and operationally simple, as it generally proceeds with only 1 mol% catalytic loading and without excess reagent, and the produced products typically require no purification.

Sequential Ytterbium(III) Triflate Catalyzed One‐Pot Three‐Component Thia‐Michael Addition

“…3‐[(2‐Hydroxyethyl)thio]cyclopentan‐1‐one (3 j) : Employing general procedure I with 2‐bromoethanol (100 mg, 0.80 mmol) and cyclopent‐2‐enone (131 mg, 1.60 mmol) gave the crude product, which was purified by column chromatography (hexane/EtOAc=2:1) to give 3 j (68 mg, 53 % yield) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ): δ =3.78 (q, J= 5.4 Hz, 2 H), 3.54–3.48 (m, 1 H), 2.85–2.74 (m, 2 H), 2.66–2.60 (m, 1 H), 2.51–2.35 (m, 2 H), 2.26–2.18 (m, 2 H), 2.05 (t, J= 5.2 Hz, 1 H), 2.01–1.93 ppm (m, 1 H); 13 C NMR (100 MHz, CDCl 3 ): δ =216.5, 60.9, 45.8, 40.2, 37.1, 34.3, 30.2 ppm.…”

“…Conventional methods for thia‐Michael reactions involve the addition of a free thiol to a Michael acceptor in the presence of a strong base as the catalyst . More recently, numerous reagents and catalysts, including Brønsted acids [e.g., NH 4 Cl, B(OH) 3 , and Tf 2 NH (Tf=trifluoromethanesulfonyl)], Lewis acids [e.g., BF 3 ⋅ OEt 2 , ZrCl 4 , Hf(OTf) 4 , Cu(BF 4 ) 2 ⋅ x H 2 O, Zn(ClO 4 ) 2 ⋅ 6H 2 O, InBr 3 , Bi(NO 3 ) 3 , FeCl 3 , VO(OTf) 2 , and Ln(OTf) 3 (Ln=lanthanide)], heterogeneous catalysts [e.g., HBF 4 ‐SiO 2 , HClO 4 ‐SiO 2 , silica nanoparticles, and zeolite], ionic liquids, and other reagents [e.g., I 2 , H 2 O, N‐heterocyclic carbenes, ceric ammonium nitrate (CAN), and tetrabutylammonium hydroxide (TBA‐OH)], have been developed for carbon‐sulfur bond formation reactions (Scheme a). Although numerous methods exist to efficiently perform thia‐Michael additions, one disadvantage is that the thiol group has a propensity toward slow oxidation towards disulfide formation under ambient conditions.…”

Synthesis of Steroidal Thioethers via [HDBU][OAc]‐Mediated Michael Addition of Thiols to 16‐Dehydropregnenolone

“…A wide range of ionic liquids with OAc − or OH − anions were shown to accelerate the thiol‐Michael reaction efficiently, such as [BMIM]OH, [31] Bu 4 NOH, [32] [BMIM][OAc], [33] [HMIM][OAc] (HMIM: 1‐hexyl‐3‐methylimidazolium), [34] triethylammonium acetate [35] or 2‐hydroxyethylammonium formate (2‐HEAF) [36] . At the same time, instability of imidazolium‐ and quaternary ammonium ionic liquids under basic conditions might lead to the formation of undesirable side products [37] .…”

Reactivity, Selectivity, and Stability in Sulfenic Acid Detection: A Comparative Study of Nucleophilic and Electrophilic Probes

“…53–55 Moreover, the product of the reaction of Cys-SOH and strained cycloalkyne 6 is an activated vinylic sulfoxide which is a Michael-acceptor and may readily react with biological thiols as well. 56 As a consequence of the promiscuous reactivity of strained cycloalkynes and the resultant sulfoxide adduct, an additional thiol-blocking step is required to increase the selectivity for sulfenic acid. As mentioned above, even though over the past decade several nucleophilic and electrophilic probes for sulfenic acid detection have been developed and commercialized, the issue of modest reactivity of such probes is well documented.…”

“…Currently reported examples of electrophilic probes are commercially available compounds such as (i) low reactivity NBD-Cl ( 4 ) which also lacks the chemoselectivity and reacts with several biological nucleophiles including sulfenic acid (but the resulting adducts are distinguishable due to difference in their spectroscopic properties); ,, (ii) arylboronates ( 5 ) which react with Cys-SOH in a reversible manner and thus have limited utility in proteomic-based sulfenic acid detection; and (iii) strained cycloalkynes ( 6 ) which were recently reported as new, highly reactive sulfenic acid traps ( k obs = 13.3–16.7 M –1 s –1 ) with >100-fold higher reactivity than 1,3-dicarbonyls . Not surprisingly, over the years strained cycloalkynes have been shown to react with other sulfur species such as protein and small molecule thiols (present in millimolar concentration inside the cells) and persulfides. − Moreover, the product of the reaction of Cys-SOH and strained cycloalkyne 6 is an activated vinylic sulfoxide which is a Michael-acceptor and may readily react with biological thiols as well . As a consequence of the promiscuous reactivity of strained cycloalkynes and the resultant sulfoxide adduct, an additional thiol-blocking step is required to increase the selectivity for sulfenic acid.…”