Pyridine sulfinates as general nucleophilic coupling partners in palladium-catalyzed cross-coupling reactions with aryl halides

Markovic, Tim; Rocke, Benjamin N.; Blakemore, David C.; Mascitti, Vincent; Willis, Michael C.

doi:10.1039/c7sc00675f

Cited by 85 publications

(50 citation statements)

References 36 publications

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“…A minimum of three steps are required, and there are challenges in the coupling step, such as catalyst poisoning and decomposition of starting materials (16). Furthermore, drug-like molecules and intermediates often have multiple reactive sites and a high proportion of polar functional groups, such as basic amines, that interfere with catalytic processes and cause a considerable number of them to fail (15, 17). Another serious problem arises from the lack of methods to prepare the cross-coupling precursors.…”

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confidence: 99%

Heterobiaryl synthesis by contractive C–C coupling via P(V) intermediates

Hilton

Zhang

Boyle

et al. 2018

Science

163

112

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Heterobiaryls composed of pyridine and diazine rings are key components of pharmaceuticals and are often central to pharmacological function. We present an alternative approach to metal-catalyzed cross-coupling to make heterobiaryls using contractive phosphorus C–C couplings, also termed phosphorus ligand coupling reactions. The process starts by regioselective phosphorus substitution of the C–H bonds para to nitrogen in two successive heterocycles; ligand coupling is then triggered via acidic alcohol solutions to form the heterobiaryl bond. Mechanistic studies imply that ligand coupling is an asynchronous process involving migration of one heterocycle to the ipso position of the other around a central pentacoordinate P(V) atom. The strategy can be applied to complex drug-like molecules containing multiple reactive sites and polar functional groups, and also enables convergent coupling of drug fragments and late-stage heteroarylation of pharmaceuticals.

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confidence: 99%

Heterobiaryl synthesis by contractive C–C coupling via P(V) intermediates

Hilton

Zhang

Boyle

et al. 2018

Science

163

112

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“…GC-MS (EI, 70 eV): m / z = 221 (33), 220 (44), 218 (100), 191 (18), 190 (55), 189 (29), 188 (18), 154 (30), 140 (10), 127 (16), 114 (16), 75 (10), 63 (14). 2-Methoxy-5-(3-methoxyphenyl)pyridine [ 62 ] ( 5 ): The crude product purified by column chromatography (SiO 2 , n -hexane: ethyl acetate 15:1), gave colorless oil in 91% yield. 1 H NMR (400.1 MHz, CDCl 3 ): δ 3.85 (s, 3H, OCH 3 ), 3.98 (s, 3H, OMe), 6.80 (dd, J = 8.6, 0.8 Hz,1H, CH-3), 6.89 (ddd, J = 8.2, 2.6, 1.0 Hz, 1H, C 6 H 4 ), 7.05 (dd, J = 2.6, 1.7 Hz, 1H, C 6 H 4 ), 7.10 (dt, J = 7.7, 1.3 Hz, 1H, C 6 H 4 ), 7.35 (dd, J = 8.2, 7.7 Hz, 1H, C 6 H 4 ), 7.77 (dd, J = 8.6, 2.6 Hz, 1H, CH-4), 8.39 (dd, J = 2.6, 0.8 1H, CH-6).…”

Section: Appendix A1 Synthesis Of Precursors Of Compounds mentioning

confidence: 99%

Synthesis and Anticancer Activity of Mitotic-Specific 3,4-Dihydropyridine-2(1H)-thiones

Perużyńska

Borzyszkowska-Ledwig

Sośnicki

et al. 2021

IJMS

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Most anticancer drugs target mitosis as the most crucial and fragile period of rapidly dividing cancer cells. However the limitations of classical chemotherapeutics drive the search for new more effective and selective compounds. For this purpose structural modifications of the previously characterized pyridine aalog (S1) were incorporated aiming to obtain an antimitotic inhibitor of satisfactory and specific anticancer activity. Structure-activity relationship analysis of the compounds against a panel of cancer cell lines allowed to select a compound with a thiophene ring at C5 of a 3,4-dihydropyridine-2(1H)-thione (S22) with promising antiproliferative activity (IC50 equal 1.71 ± 0.58 µM) and selectivity (SI = 21.09) against melanoma A375 cells. Moreover, all three of the most active compounds from the antiproliferative study, namely S1, S19 and S22 showed better selectivity against A375 cells than reference drug, suggesting their possible lower toxicity and wider therapeutic index. As further study revealed, selected compounds inhibited tubulin polymerization via colchicine binding site in dose dependent manner, leading to aberrant mitotic spindle formation, cell cycle arrest and apoptosis. Summarizing, the current study showed that among obtained mitotic-specific inhibitors analogue with thiophene ring showed the highest antiproliferative activity and selectivity against cancer cells.

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“…Pyridine and its derivatives are important structural motifs, are vital reacting partners in synthesis of heterobyaryls required in pharmaceuticals, [1–4] agrochemicals and optoelectronic materials, and serve as a versatile ligand in catalysis [5–12] . As such, the development of efficient methods to install substituents/aryls directly and regioselectively into a pyridine has become a topic of high scientific and technological importance [13–18] . In spite of extensive efforts, however, the regioselective functionalization of pyridine still remains a significant challenge due to their low reactivity and presence of Lewis‐basic sp 2 nitrogen.…”

Section: Introductionmentioning

confidence: 99%

Hydrogen‐Bonding as a Factor to Determine the Regioselectivity for Pd‐mediated C−H Activation of Pyridine

Haines

Musaev

2020

ChemCatChem

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Direct and regioselective functionalization of pyridine is a topic of high scientific and technological importance. In spite of extensive efforts, the regioselective functionalization of pyridine still remains a significant challenge due to their low reactivity and presence of Lewis‐basic sp2 nitrogen. Here, we studied the effect of hydrogen bonding interactions on the regiochemical outcome of Pd‐mediated C−H activation of pyridine by utilizing DFT calculations. We demonstrated that hydrogen bonding can act as a second independent factor to override the inherent regioselectivity of pyridine. This novel approach complements previously reported strategies, such as: (a) coordination of pyridine to transition metal center via its N‐center, (b) installation of directing group (DG) and then coordination of pyridine to the transition metal center via this DG (i. e. chelation assistant strategy), (c) protection of its nitrogen lone pair with N‐oxide or N‐imino groups or with Lewis acids, (d) the inherent positional reactivity of C−H bonds based on the electronic or steric properties of the substituents, and (e) by the identity of the oxidant used. We have also demonstrated that the oxidation state of the Pd catalyst has impact on the regiochemical outcome of the C−H activation step in pyridine. The implications of our study for regioselective C−H functionalization catalyst design of heteroarenes are twofold: It demonstrates (1) hydrogen bonding as a viable design principle, and (2) Pd(IV) as a catalyst for C−H functionalization.

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Pyridine sulfinates as general nucleophilic coupling partners in palladium-catalyzed cross-coupling reactions with aryl halides

Cited by 85 publications

References 36 publications

Heterobiaryl synthesis by contractive C–C coupling via P(V) intermediates

Heterobiaryl synthesis by contractive C–C coupling via P(V) intermediates

Synthesis and Anticancer Activity of Mitotic-Specific 3,4-Dihydropyridine-2(1H)-thiones

Hydrogen‐Bonding as a Factor to Determine the Regioselectivity for Pd‐mediated C−H Activation of Pyridine

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