Mechanistic Insights into the Decarboxylative Electrophilic Trifluoromethylthiolation of β‐Ketocarboxylic Acids

Abstract

A metal‐free protocol for the domino trifluoromethylthiolation/decarboxylation of β‐ketocarboxylic acids is described. The catalytic reactions take place in acetonitrile in the presence of aqueous ammonium hydroxide and N‐trifluoromethylthiosaccharin. The sequence of events and reaction mechanism were established experimentally and using density functional theory calculations. This synthetic method offers a convenient alternative to known routes for the synthesis of α‐trifluoromethylthio‐substituted ketones.

β‐Keto Acids in Organic Synthesis

“…Alkenyl substrates 28.2 were well tolerated. During the same year, as reported by Han and co‐workers,[14b] tandem reactions between β ‐keto acids, N ‐bromosuccinimide (NBS) and sodium sulfinates 28.3 have shown their power in the decarboxylative sulfonylation (Equation 28–2). A bromination intermediate formed during the process (Scheme ).…”

“…The construction of S‐containing compounds through the direct introduction of the SCF 3 [14a] or sulfonyl[14b] motif could come from electrophilic[14a] or nucleophilic[14b] reagents. In 2018, the Cahard group[14a] utilized 28.1 as electrophilic SCF 3 source in the metal‐free trifluoromethylthiolation/decarboxylation (Equation 28–1). Alkenyl substrates 28.2 were well tolerated.…”

Ag(I)-Mediated Oxidative Radical Trifluoromethylthiolation of Alkenes

“…19 F NMR (376 MHz, CDCl3) δ -41.38 (s, 3F). [4] Light yellow oil, 0.085 g, 73%. 1 H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 9.7 Hz, 2H), 7.47 (d, J = 7.5 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 4.53 (s, 2H), 2.45 (s, 3H).…”

“…19 F NMR (376 MHz, CDCl3) δ -41.44 (s, 3F). [4] Colorless oil, 0.080 g, 67%. 1 H NMR (400 MHz, CDCl3) δ 8.09-7.92 (m, 2H), 7.26-7.15 (m, 2H), 4.51 (s, 2H).…”

“…1 H NMR (400 MHz, CDCl3) δ 3.83 (s, 2H), 2.59 (t, J = 7.4 Hz, 2H), 1.30 (s, 11H), 0.90 (t, J = 6.9 Hz, 4H). 13 C NMR (101 MHz, 1-phenyl-2-((trifluoromethyl)thio)propanone (3g): [4] Light yellow oil, 0.068 g, 58%. 1 H NMR (400 MHz, CDCl3) δ 8.03-7.95 (m, 2H), 7.76-7.62 (m, 1H), 7.54 (dd, J = 10.6, 4.7 Hz, 2H), 5.01 (q, J = 7.1 Hz, 1H), 1.75 (d, J = 7.1 Hz, 3 H).…”