Polyarylated Thiazoles via a Combined Halogen Dance – Cross‐Coupling Strategy

Schnürch, Michael; Khan, Ather Farooq; Mihovilovic, Marko D.; Stanetty, Peter

doi:10.1002/ejoc.200900092

Cited by 22 publications

(4 citation statements)

References 46 publications

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“…However, it has been difficult to introduce two or more different alkynyl groups to (hetero)arenes by conventional Sonogashira coupling because of the low chemo- and regioselectivities of the reaction of polyhalogenated (hetero)arenes, such as dihaloarenes (Scheme , upper). For selective reactions, arenes bearing bromine and iodine atoms have usually been used as substrates, but a multistep synthesis is needed to obtain these substrates. , To obtain such bisalkynylated compounds, the direct C–H coupling of monoalkynylated products and haloalkynes is a promising approach (Scheme , middle), but commercially available haloalkynes are still limited. The direct dehydrogenative coupling (oxidative coupling) of terminal alkynes and monoalkynylated (hetero)arenes is an alternative route to such dialkynylated compounds (Scheme , lower) .…”

Section: Introductionmentioning

confidence: 99%

Palladium-Catalyzed C–H Bond Direct Alkynylation of 5-Membered Heteroarenes: A Well-Defined Synthetic Route to Azole Derivatives Containing Two Different Alkynyl Groups

2012

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A widely applicable oxidative coupling of 5-membered heteroarenes and terminal alkynes that uses a combination of palladium and silver salts was developed. Under suitable conditions, imidazole and benzimidazole, which are sluggish under similar previously reported oxidative coupling conditions, as well as imidazo[1,5-a]pyridines, oxazole, benzoxazole, thiazole, and benzothiazole could be alkynylated. In addition, the bromine atom on the substrates was intact under the reaction conditions, and conventional Sonogashira coupling did not occur at all. With these reactivities in hand, a well-defined synthetic route to imidazo[1,5-a]pyridines and thiazole containing two different alkynyl groups was achieved in a simple manner. In addition, linear correlations were observed between the fluorescence wavelength and the Hammett substituent constants of aryl groups, not only on the C1- but also on the C3-alkynyl group of the obtained 1,3-bis(arylethynyl)imidazo [1,5-a]pyridines.

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Section: Introductionmentioning

confidence: 99%

Palladium-Catalyzed C–H Bond Direct Alkynylation of 5-Membered Heteroarenes: A Well-Defined Synthetic Route to Azole Derivatives Containing Two Different Alkynyl Groups

2012

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“…Thiazole ring formation followed by bromination at 5-position using NBS gave k , 25 which subsequently afforded l under halogen-dance conditions. 26 A Suzuki cross-coupling reaction between l and the substituted trifluoroborates produced analogues of formula m , which upon iodination and Stille cross-coupling reactions furnished n and o , respectively. A Buchwald cross-coupling 24 between o and 4-amino-2-methylpyridine or 4-aminopyrimidine followed by Boc-deprotection under acidic conditions finally led to the final products 58–60 .…”

Section: Resultsmentioning

confidence: 99%

“…Regarding the synthesis of analogues 58–60 (Scheme ), the 4-bromo-2-(4-piperidinyl)thiazole analogue l was initially built from N -Boc-piperidinethioamide. Thiazole ring formation followed by bromination at 5-position using NBS gave k , which subsequently afforded l under halogen-dance conditions . A Suzuki cross-coupling reaction between l and the substituted trifluoroborates produced analogues of formula m , which upon iodination and Stille cross-coupling reactions furnished n and o , respectively.…”

Section: Resultsmentioning

confidence: 99%

Development of Chemical Entities Endowed with Potent Fast-Killing Properties against Plasmodium falciparum Malaria Parasites

et al. 2019

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One of the attractive properties of artemisinins is their extremely fast-killing capability, quickly relieving malaria symptoms. Nevertheless, the unique benefits of these medicines are now compromised by the prolonged parasite clearance times and the increasing frequency of treatment failures, attributed to the increased tolerance of Plasmodium falciparum to artemisinin. This emerging artemisinin resistance threatens to undermine the effectiveness of antimalarial combination therapies. Herein, we describe the medicinal chemistry efforts focused on a cGMP-dependent protein kinase (PKG) inhibitor scaffold, leading to the identification of novel chemical entities with very potent, similar to artemisinins, fast-killing potency against asexual blood stages that cause disease, and activity against gametocyte activation that is required for transmission. Furthermore, we confirm that selective PKG inhibitors have a slow speed of kill, while chemoproteomic analysis suggests for the first time serine/arginine protein kinase 2 (SRPK2) targeting as a novel strategy for developing antimalarial compounds with extremely fast-killing properties.

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“…When C2C12 cells were treated with compounds of type 21, the differentiation to skeletal muscle cells was significantly accelerated (for details see reference 43). Even though we have gained significant experience in Stille and Suzuki-Miyaura cross-coupling of thiazoles over the years, [46][47][48][49][50] we decided to use a palladium catalyzed direct arylation reaction in the final step of the synthesis since we could avoid pre-functionalization of the thiazole system. Hence, we envisioned an overall synthetic sequence as depicted in Scheme 7.…”

Section: Methodsmentioning

confidence: 99%

Exploiting the C-H bond in metal catalyzed C-C bond forming reactions

Schnürch¹

2015

Arkivoc

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This account summarizes our work in the field of direct C-H bond functionalization. We have explored methods in the area of directing group assisted C(sp 2 )-H and C(sp 3 )-H activation and investigated arylation as well as deuteration reactions. In these transformations either ruthenium or palladium catalysts were applied. In case of C(sp 2 )-H activation, we developed a protocol for the synthesis of ortho arylated anilines and disclosed the first method for a direct arylation in a continuous flow reactor. Additionally, we applied a direct arylation in the synthesis of compounds which can accelerate cell differentiation. In the field of C(sp 3 )-H activation we developed a protocol for the selective mono-arylation of piperidine and three different arylation protocols for acyclic amines employing either aryl chlorides, aryl bromides, aryl iodides, or arylboronic acid esters as the aryl donor.

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Polyarylated Thiazoles via a Combined Halogen Dance – Cross‐Coupling Strategy

Abstract: The application of the halogen dance reaction for the synthesis of starting materials for cross-coupling reactions is reported. The obtained compounds were then successfully applied in sequential Stille and Suzuki-Miyaura cross-coupling reactions to obtain novel thiazole derivatives.

Cited by 22 publications

References 46 publications

Palladium-Catalyzed C–H Bond Direct Alkynylation of 5-Membered Heteroarenes: A Well-Defined Synthetic Route to Azole Derivatives Containing Two Different Alkynyl Groups

Palladium-Catalyzed C–H Bond Direct Alkynylation of 5-Membered Heteroarenes: A Well-Defined Synthetic Route to Azole Derivatives Containing Two Different Alkynyl Groups

Development of Chemical Entities Endowed with Potent Fast-Killing Properties against Plasmodium falciparum Malaria Parasites

Exploiting the C-H bond in metal catalyzed C-C bond forming reactions

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