Organophotocatalytic selective deuterodehalogenation of aryl or alkyl chlorides

Abstract

Development of practical deuteration reactions is highly valuable for organic synthesis, analytic chemistry and pharmaceutic chemistry. Deuterodehalogenation of organic chlorides tends to be an attractive strategy but remains a challenging task. We here develop a photocatalytic system consisting of an aryl-amine photocatalyst and a disulfide co-catalyst in the presence of sodium formate as an electron and hydrogen donor. Accordingly, many aryl chlorides, alkyl chlorides, and other halides are converted to deuterated products at room temperature in air (>90 examples, up to 99% D-incorporation). The mechanistic studies reveal that the aryl amine serves as reducing photoredox catalyst to initiate cleavage of the C-Cl bond, at the same time as energy transfer catalyst to induce homolysis of the disulfide for consequent deuterium transfer process. This economic and environmentally-friendly method can be used for site-selective D-labeling of a number of bioactive molecules and direct H/D exchange of some drug molecules.

Radical deuteration

“…The photoredox catalytic cleavage of unactivated C–Cl bonds is an attractive but challenging task because of the highly negative reduction potential. Accordingly, Gong and co-workers 25 developed strongly reductive aryl amine-based photocatalysts by modifying the structure of conjugated aryl amines. The measured photophysical and electrochemical properties, such as excited-state lifetimes (2–24 ns) and oxidation potentials (* E 1/2 = −1.61 to −2.71 V vs. SCE in DMSO), have demonstrated the significant photocatalytic ability of these catalysts.…”

Visible-light mediated catalytic asymmetric radical deuteration at non-benzylic positions

“…Motivated by the growing interest in merging asymmetric organocatalysis with photocatalysis [25][26][27][28][29][30][31][32] and in view of the paucity of practical methods for asymmetric radical deuterations, we recently questioned whether a photocatalytic radical deuteration could be achieved in a highly enantioselective and cost-effective fashion. In particular, we hypothesized that a combination of chiral thiols with deuterium oxide (D 2 O) might be a potential solution, given the widespread use of achiral thiols as a catalyst for non-asymmetric radical deuteration 4,[33][34][35][36] and the encouraging stereocontrol that chiral thiol catalysts exerted in a handful of prior work [37][38][39][40] . Additionally, the following features make this strategy promising: 1) uncatalyzed background deuteration-a common issue when carbon anions are involved-would be inhibited as prochiral carbon radicals are virtually unreactive towards D 2 O due to the high bond dissociation energy (BDE) of the O-D bond (119 kcal/mol for HO-H bond) 24,41 , 2) deuterium atom would be covalently bonded to the chiral thiol catalyst through facile in-situ hydrogen/deuterium exchange 4 , thereby enhancing enantiofacial discrimination for the deuteration event.…”

Arylboronic Acid Deborylation Deuteration via Synergistic Thiol, Lewis Base, and Photoredox Catalysis

“…Photocatalytic radical chemistry has been rapidly developed recently. 14 In fact, the visible-light-mediated deuteration of arenes from aryl halides, 15 redox-active carboxylic ester, 16 aryl diazonium salts, 17 and arylazosulfones 18 can be tedious to synthesize, which limits the ability to use these protocols for complex molecules. We speculated that arylboronic acids, which are readily available reagents, might serve as alternative radical precursors.…”

“…The radical trapping product 4-(4-(benzyloxy)benzyl)-2,6-di-tert-butylphenol (13) was observed by mass spectrometry when 2,6-di-tert-butyl-4-methylphenol (BHT) was used as the radical scavenger. The radical trapping products (2-(4-(benzyloxy)phenyl)ethene-1,1-diyl)dibenzene (14) and tert-butyl(2,2-diphenylvinyl)sulfane (15) were observed by mass spectrometry when 1,1-diphenylethylene was used as the radical scavenger. The radical trapping product benzyl 3-(4-(benzyloxy)phenyl)propanoate (17) was observed by mass spectrometry when benzyl acrylate (16) was used as a radical scavenger.…”

“…Photocatalytic radical chemistry has been rapidly developed recently . In fact, the visible-light-mediated deuteration of arenes from aryl halides, redox-active carboxylic ester, aryl diazonium salts, and arylazosulfones as aryl radical precursors has been reported. However, aryl radical precursors can be tedious to synthesize, which limits the ability to use these protocols for complex molecules.…”