Pd-catalyzed C–C and C–N cross-coupling reactions in 2-aminothieno[3,2-<i>d</i>]pyrimidin-4(3<i>H</i>)-one series for antiplasmodial pharmacomodulation

Mustière, Romain; Lagardère, Prisca; Hutter, Sébastien; Deraeve, Céline; Schwalen, Florian; Amrane, Dyhia; Masurier, Nicolas; Azas, Nadine; Lisowski, Vincent; Verhaeghe, Pierre; Mazier, Dominique; Vanelle, Patrice; Primas, Nicolas

doi:10.1039/d2ra01687g

Cited by 7 publications

(4 citation statements)

References 16 publications

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“…[ 25 ] It is notable that the coupling completed within 1.5 h. In 2022, Primas presented the synthesis of 6‐alkynyl‐2‐ aminothieno[3,2‐ d ]pyrimidin4(3 H )‐ones by Sonogashira coupling using 4 mol% Pd(PPh 3 )Cl 2 and 16 mol% CuI, yielding the corresponding alkynes in moderate yield due to volatile behavior of some alkynes and purification difficulties. [ 26 ] Apart from heteroaryl halides, heterocyclic phosphonium salts were also feasible substrates for Sonogashira coupling using 10 mol% Pd(PPh 3 ) 2 Cl 2 and 10 mol% CuI catalyst system. [ 27 ]…”

Section: Classical Sonogashira Coupling Reactionsmentioning

confidence: 99%

Recent Expedition inPd‐CatalyzedSonogashira Coupling and Related Processes^†

2023

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Sonogashira cross-coupling protocol, typically showing the reaction between aryl/vinyl halide and terminal alkyne, has been a widely used protocol for constructing C(sp 2 )-C(sp) bond. The resulting internal alkynes are highly versatile for reaching differently functionalized alkyne-containing scaffolds or serving as valuable synthetic synthons to many other functional groups. It is worth noting that products originated from this coupling reaction are mostly applicable to be transformed into corresponding Z-alkene, alkane, or heterocyclic moieties in natural product syntheses. The reaction conditions and catalyst systems are able to be tweaked in order to facilitate the activation of steric hindered and/or electron-rich electrophiles. Pd-catalyzed copper-free Sonogashira coupling reaction has caught increasing attention as the improved method can be more environmentally friendly. What is more, the conditions of the coupling reaction can be readily amended to allow the fusion of other carbonylation or decarboxylation step in the catalytic cycle, and thus allow more complex yet versatile convergent synthesis to proceed in an operationally simple one-pot manner.

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Section: Classical Sonogashira Coupling Reactionsmentioning

confidence: 99%

Recent Expedition inPd‐CatalyzedSonogashira Coupling and Related Processes^†

2023

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“…The thienopyrimidinone framework is widely documented in many biologically active compounds such as anti-tumor [ 33 ], anti-malarial [ 34 , 35 ], anti-microbial and anti-fungal [ 36 ], anti-inflammatory [ 37 ] and anti-tubercular [ 38 ] agents.…”

Section: Introductionmentioning

confidence: 99%

Dihydroxyphenyl- and Heteroaromatic-Based Thienopyrimidinones to Tackle HIV-1 LEDGF/p75-Dependent IN Activity

Tocco,

Canton,

Laus

et al. 2023

Molecules

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The spread of Human Immunodeficiency Virus (HIV) still represents a global public health issue of major concern, and would benefit from unveiling unique viral features as targets for drug design. In this respect, HIV-1 integrase (IN), due to the absence of homologs in human cells, is a popular target for the synthesis of novel selective compounds. Moreover, as drug-resistant viral strains are rapidly evolving, the development of novel allosteric inhibitors is acutely required. Recently, we have observed that Kuwanon-L, quinazolinones and thienopyrimidinones containing at least one polyphenol unit, effectively inhibited HIV-1 IN activity. Thus, in the present research, novel dihydroxyphenyl-based thienopyrimidinone derivatives were investigated for their LEDGF/p75-dependent IN inhibitory activity. Our findings indicated a close correlation between the position of the OH group on the phenyl moiety and IN inhibitory activity of these compounds. As catechol may be involved in cytotoxicity, its replacement by other aromatic scaffolds was also exploited. As a result, compounds 21–23, 25 and 26 with enhanced IN inhibitory activity provided good lead candidates, with 25 being the most selective for IN. Lastly, UV spectrometric experiments suggested a plausible allosteric mode of action, as none of the thienopirimidinones showed Mg2+ chelation properties otherwise typical of IN strand transfer inhibitors (INSTIs).

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“…Встановлено, що в результаті алкілування бромистим алілом 5,6-диметил-2-(тіофен-2-іл)тієно [2,3-d] Тієно [2,3-d]піримидинони є важливими гетероциклічними сполуками які володіють цілим рядом фармакологічних та фармацевтичних властивостей. Зокрема, в ряді робіт доведено їх противірусну [1], протипухлинну [2][3][4], протималярійну [5][6][7], протимікробну [8], протигрибкову [8], протизапальну [9] та протитуберкульозну активності [10].…”

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Kaliendina S., Brynzei M., Kut M., Sukharev S.M., Ostapchuk Е., Onysko M. REGIOSELECTIVITY OF ALKYLATION OF 2-(THIOPHENE-2-IL)THIENO[2,3 d]PYRIMIDINE-4(3H)-ONE

Kaliendina,

Brynzei,

Kut

et al. 2024

Наук. вісник Ужг

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Thieno[2,3-d]pyrimidines are an important class of heterocyclic compounds with a wide range of biological activities. The thieno[2,3-d]pyrimidin-4-one system is of the greatest interest to scientists, as it is one of a large number of possible thienopyrimidine derivatives. The presence of an amide fragment in these molecules allows for the introduction of various substituents via alkylation reactions. On the other hand, the presence of N- and O-nucleophilic centres makes it possible to form different types of alkylation products. In the present work, the alkylation reaction of 5,6-dimethyl-2-(thiophen-2-yl)thieno[2,3-d]pyrimidin-4(3H)-one, which contains N(3)- and O-nucleophilic centres for attacking alkylating reagents, was investigated. Allyl bromide was used as an alkylating reagent. It was found that the alkylation of 5,6-dimethyl-2-(thiophen-2-yl)thieno[2,3-d]pyrimidin-4(3H)-one with allyl bromide in DMF resulted in the regioselective preparation of 4-(allyloxy)-5,6-dimethyl-2-(thiophen-2-yl)thieno[2,3-d]pyrimidine, which can be used in the future to study the process of electrophilic intramolecular cyclisation. An increase in the reaction time of the starting reagents leads to an increase in the yield of the target ester. Keywords: 5,6-dimethyl-2-(thiophen-2-yl)thieno[2,3-d]pyrimidin-4(3H)-one; alkylation; regioselectivity; ether; 4-allyloxypyrimidine.

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Pd-catalyzed C–C and C–N cross-coupling reactions in 2-aminothieno[3,2-d]pyrimidin-4(3H)-one series for antiplasmodial pharmacomodulation

Abstract: Pharmacomodulation at position 6 of a thienopyrimidinone antiplasmodial hit using palladium-catalyzed cross-coupling reactions afforded 33 new compounds, among which a new hit was found with enhanced metabolic stability.

Cited by 7 publications

References 16 publications

Recent Expedition inPd‐CatalyzedSonogashira Coupling and Related Processes^†

Recent Expedition inPd‐CatalyzedSonogashira Coupling and Related Processes^†

Dihydroxyphenyl- and Heteroaromatic-Based Thienopyrimidinones to Tackle HIV-1 LEDGF/p75-Dependent IN Activity

Kaliendina S., Brynzei M., Kut M., Sukharev S.M., Ostapchuk Е., Onysko M. REGIOSELECTIVITY OF ALKYLATION OF 2-(THIOPHENE-2-IL)THIENO[2,3 d]PYRIMIDINE-4(3H)-ONE

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Pd-catalyzed C–C and C–N cross-coupling reactions in 2-aminothieno[3,2-d]pyrimidin-4(3H)-one series for antiplasmodial pharmacomodulation

Abstract: Pharmacomodulation at position 6 of a thienopyrimidinone antiplasmodial hit using palladium-catalyzed cross-coupling reactions afforded 33 new compounds, among which a new hit was found with enhanced metabolic stability.

Cited by 7 publications

References 16 publications

Recent Expedition inPd‐CatalyzedSonogashira Coupling and Related Processes†

Recent Expedition inPd‐CatalyzedSonogashira Coupling and Related Processes†

Dihydroxyphenyl- and Heteroaromatic-Based Thienopyrimidinones to Tackle HIV-1 LEDGF/p75-Dependent IN Activity

Kaliendina S., Brynzei M., Kut M., Sukharev S.M., Ostapchuk Е., Onysko M. REGIOSELECTIVITY OF ALKYLATION OF 2-(THIOPHENE-2-IL)THIENO[2,3 d]PYRIMIDINE-4(3H)-ONE

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Recent Expedition inPd‐CatalyzedSonogashira Coupling and Related Processes^†

Recent Expedition inPd‐CatalyzedSonogashira Coupling and Related Processes^†