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Photoredox Mediated Nickel Catalyzed Cross-Coupling of Thiols With Aryl and Heteroaryl Iodides Via Thiyl Radicals Martins Sunday Oderinde, Mathieu Frenette, Daniel W. Robbins, Brian Aquila, and Jeffrey W. Johannes J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b11244 • Publication Date (Web): 21 Jan 2016 Downloaded from on January 24, 2016

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Journal of the American Chemical Society

Photoredox Mediated Nickel Catalyzed Cross-Coupling of Thiols With Aryl and Heteroaryl Iodides Via Thiyl Radicals Martins S. Oderinde,*† Mathieu Frenette,‡ Daniel W. Robbins,† Brian Aquila,† Jeffrey W. Johannes*† †

Chemistry Department (Oncology), AstraZeneca Pharmaceuticals LP, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States ‡ Département de Chimie, Université du Québec à Montréal, Montreal, Quebec, Canada, H2X 2J6 Supporting Information Placeholder ABSTRACT: Ni-catalyzed cross-couplings of aryl, benzyl and alkyl thiols with aryl and heteroaryl iodides were accomplished in the presence of an Ir-photoredox catalyst. Highly chemoselective C-S cross-coupling was achieved versus competitive C-O and CN cross-couplings. This C-S cross-coupling method exhibits remarkable functional group tolerance and the reactions can be carried out in the presence of molecular oxygen. Mechanistic investigations indicated that the reaction proceeded through transient Ni(I)-species and thiyl radicals. Distinct from nickel-catalyzed cross-coupling reactions involving carbon-centred radicals, control experiments and spectroscopic studies suggest that this C-S cross-coupling reaction does not involve a Ni(0)-species.

Scheme 1. Metal-catalyzed C-O and C-S cross-couplings a. Conventional methods utilizing thiolates R-SH

strong base


"Pd"/ "Cu"/ "Ni"


S R1

up to 200 C

b. This work: New strategy utilizing thiyl radicals R-SH

Ir(III) Light






S R1

weak base, 23 C

c. MacMillan's C-O coupling enabled by Ir/ Ni dual-catalysis X R-OH +

Nature employs thiyl radicals in a broad range of enzymatic processes including the deoxygenation of ribonucleotides.1 The ease in formation of thiyl radicals from thiols and their exceptional reactivity make them extremely attractive for efficient and useful radical reactions in organic synthesis.2 Some notable synthetic applications of thiyl radicals include addition to unsaturated systems,3 thiol-ene reactions,4 thiol-yne reactions,5 radical cyclization reactions,6 reduction processes,7 addition-fragmentation reactions,8a and hydrogen atom abstraction processes.8b However, engaging thiyl radicals in a transition-metal catalyzed crosscoupling reactions with aryl halides to construct C-S bonds remains an elusive reaction in organic chemistry.2 The high frequency of C-S bonds in drug-molecules across many disease types such as cancer, HIV, and Alzheimer’s disease necessitates the continued development of C-S bond-forming reactions.9 Transition-metal catalyzed C-S cross-coupling reactions of thiols with aryl halides generally rely on the conversion of the thiols to their corresponding thiolates (Scheme 1a).10,11 The strong coordination of thiolates to transition-metal catalysts often leads to catalyst deactivation, thus requiring high catalyst loading, specially designed ligands and/or high temperature to facilitate the desired reaction.10,11 Furthermore, the high temperature and strong base required for these reactions limit functional group tolerance. Strategically, we reasoned that the utilization of thiyl radicals,12a in lieu of thiolates may eliminate the problem of catalyst deactivation and deliver a more efficient C-S cross-coupling reaction with the use of simple ancillary ligands. We also envisioned that employing thiyl radicals could provide a highly chemoselective reaction that operates at room temperature with broad functional group tolerance. The combination of a photoredox catalytic cycle with an organometallic cycle has emerged as a powerful tool for crosscoupling reactions.13 The ability of the photoredox catalyst to modulate transition-metal oxidation states, which allows easy




Ir(III)/ Ni weak base, 23 C Light


O R1

access to elusive reactivity makes the dual-catalytic platform very attractive.13 We recently undertook a mechanistic investigation into the effect of oxygen on the Ir/Ni dual-catalytic reactions developed by the laboratories of Molander, Doyle, and MacMillan involving carbon-centered radicals.13a,b,14 Our investigations of these systems prompted us to consider whether the photoredox mediated dual-catalysis could be used as a tool to form thiyl radicals and promote their cross-coupling with aryl halides to form carbon-sulfur bonds (Scheme 1b). MacMillan and colleagues recently demonstrated that the Ir/Ni dual-catalytic platform can be extended to carbon-heteroatom cross-coupling by elegantly developing a new C-O cross-coupling method (Scheme 1c).13d Herein, we demonstrate that photogenerated thiyl radicals from various thiols can engage in Ni-catalyzed cross-couplings with aryl and heteroaryl iodides to afford C-S bonds in a highly chemoselective fashion under an Ir/Ni dual-catalytic system. From the outset, a principle concern in the development of such a cross-coupling method was identifying conditions wherein the thiyl radicals can react selectively with a Ni-species. In addition, unlike the Ni-catalyzed cross-couplings involving carboncentered radicals,13a,b,14 the oxidation state of Ni that would promote the cross-coupling involving heteroatom radicals was unknown. With these challenges in mind, we evaluated a number of potential Ir-photoredox and Ni catalysts under various conditions in the cross-coupling of 4-methoxybenzyl thiol (1a) (pKa = 15.4, for benzyl thiol)15a and 4-iodotoluene (2a). The irradiation of a reaction mixture containing 4-methoxybenzyl thiol (1a), 4iodotoluene (2a), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (Ir-B), NiCl2·glyme, dtbbpy (4,4’-di-tert-butyl-2,2’-dipyridyl) and pyridine (pKa = 5.2)16 in MeCN with blue-LEDs for 24 hours at room temperature in the presence of O2 gave the C-S cross-coupled product 3a in excellent conversion (Table 1, entry 1).

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Table 1. Ir-photoredox/Ni dual-catalyzed C-S cross-coupling: Effect of reaction parameters SH I + O

1a 1.5 equiv.

2a 1.0 equiv.

Ir[dF(CF3)ppy]2(bpy)PF6 (Ir-A)

Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Ir-B (2 mol%), NiCl2•glyme (10 mol%), dtbbpy (15 mol%), pyridine (2 equiv.), MeCN, 34 W blue-LED, 24 h, Not degassed




Ir[dF(CF3)ppy]2(dtbbpy)PF6 (Ir-B)

Variation from the standard conditionsa none no light (dark) no Ir(III)-catalyst no NiCl2•glyme and no dtbbpy no pyridine 4-bromotoluene instead of 4-iodotoluene Ir-A instead of Ir-B 26 W CF-lamp instead of 34 W blue-LEDs Ir-B with 34 W green-LEDs degassed NiCl2•bpy instead of NiCl2•dtbbpy NiCl2•dppe instead of NiCl2•dtbbpy Ni(COD)2 instead of NiCl2•glyme Ni(COD)2 and degassed

Yield (%)b >95 NRc NR NR 95 70

Photoredox Mediated Nickel Catalyzed Cross-Coupling of Thiols With Aryl and Heteroaryl Iodides via Thiyl Radicals.

Ni-catalyzed cross-couplings of aryl, benzyl, and alkyl thiols with aryl and heteroaryl iodides were accomplished in the presence of an Ir-photoredox ...
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