Toolbox for Distal C–H Bond Functionalizations in Organic Molecules

Chemical Reviews, Год журнала: 2021, Номер 122(6), С. 5682 - 5841

Опубликована: Окт. 18, 2021

Transition-metal-catalyzed C–H activation has developed a contemporary approach to the omnipresent area of retrosynthetic disconnection. Scientific researchers have been tempted take help this methodology plan their synthetic discourses. This paradigm shift helped in development industrial units as well, making synthesis natural products and pharmaceutical drugs step-economical. In vast zone bond activation, functionalization proximal bonds gained utmost popularity. Unlike bonds, distal is more strenuous requires distinctly specialized techniques. review, we compiled various methods adopted functionalize mechanistic insights within each these procedures, scope methodology. With give complete overview expeditious progress made field organic chemistry while also highlighting its pitfalls, thus leaving open for further modifications.

Язык: Английский

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HFIP in Organic Synthesis

Chemical Reviews, Год журнала: 2022, Номер 122(15), С. 12544 - 12747

Опубликована: Июль 17, 2022

1,1,1,3,3,3-Hexafluoroisopropanol (HFIP) is a polar, strongly hydrogen bond-donating solvent that has found numerous uses in organic synthesis due to its ability stabilize ionic species, transfer protons, and engage range of other intermolecular interactions. The use this exponentially increased the past decade become choice some areas, such as C–H functionalization chemistry. In review, following brief history HFIP an overview physical properties, literature examples reactions using or additive are presented, emphasizing effect each reaction.

Язык: Английский

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Transition-Metal-Catalyzed C–H Bond Activation for the Formation of C–C Bonds in Complex Molecules

Chemical Reviews, Год журнала: 2023, Номер 123(12), С. 7692 - 7760

Опубликована: Май 10, 2023

Site-predictable and chemoselective C–H bond functionalization reactions offer synthetically powerful strategies for the step-economic diversification of both feedstock fine chemicals. Many transition-metal-catalyzed methods have emerged selective activation bonds. However, challenges regio- chemoselectivity with application to highly complex molecules bearing significant functional group density diversity. As molecular complexity increases within structures risks catalyst intolerance limited applicability grow number groups potentially Lewis basic heteroatoms. Given abundance bonds already diversified such as pharmaceuticals, natural products, materials, design selection reaction conditions tolerant catalysts has proved critical successful direct functionalization. such, innovations formation carbon–carbon been discovered developed overcome these limitations. This review highlights progress made metal-catalyzed C–C forming including alkylation, methylation, arylation, olefination targets.

Язык: Английский

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Photoinduced Regioselective Olefination of Arenes at Proximal and Distal Sites

Journal of the American Chemical Society, Год журнала: 2022, Номер 144(4), С. 1929 - 1940

Опубликована: Янв. 20, 2022

The Fujiwara–Moritani reaction has had a profound contribution in the emergence of contemporary C–H activation protocols. Despite applicability traditional approach different fields, associated reactivity and regioselectivity issues rendered it redundant. revival this exemplary requires development mechanistic paradigm that would have simultaneous control on both regioselectivity. Often, high thermal energy required to promote olefination leads multiple site functionalizations. To aim, we established photoredox catalytic system constituting merger palladium/organo-photocatalyst (PC) forges oxidative an explicit regioselective fashion with diverse arenes heteroarenes. Visible light plays significant role executing "regioresolved" reactions without requirement silver salts energy. is also amenable toward proximal distal aided by respective directing groups (DGs), which entails versatility protocol engaging entire spectrum C(sp2)–H olefination. Furthermore, streamlining synthesis natural products, chiral molecules, drugs, diversification through late-stage functionalizations underscore importance sustainable protocol. photoinduced attainment transformation mechanistically kinetic studies.

Язык: Английский

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Palladium-Catalyzed Nondirected Late-Stage C–H Deuteration of Arenes

Journal of the American Chemical Society, Год журнала: 2021, Номер 143(40), С. 16370 - 16376

Опубликована: Сен. 28, 2021

We describe a palladium-catalyzed nondirected late-stage deuteration of arenes. Key aspects include the use D2O as convenient and easily available deuterium source discovery highly active N,N-bidentate ligands containing an N-acylsulfonamide group. The reported protocol enables high degrees incorporation via reversible C–H activation step features extraordinary functional group tolerance, allowing for complex substrates. This is exemplified by isotopic labeling various pharmaceutically relevant motifs related scaffolds. expect that this method, among other applications, will prove useful tool in drug development processes mechanistic studies.

Язык: Английский

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Dual Ligand Enabled Nondirected C–H Chalcogenation of Arenes and Heteroarenes

Journal of the American Chemical Society, Год журнала: 2022, Номер 144(27), С. 12032 - 12042

Опубликована: Июнь 27, 2022

Chalcogenide motifs are present as principal moieties in a vast array of natural products and complex molecules. Till date, the construction these chalcogen has been restricted to either use directing groups or employment large excess electronically activated arenes, typically employed cosolvent. Despite being highly effective, methods have their own limitations step economy deployment an amount arenes. Herein, we report evolution catalytic system employing arene-limited, nondirected thioarylation arenes heteroarenes using complimentary dual-ligand approach. The reaction is controlled by combination steric electronic factors, utilization suitable ligand enables generation on spectrum that generated classical methods. ligands remains imperative protocol with theoretical calculations pointing towards monoprotected amino acid crucial concerted metalation deprotonation (CMD) mechanism characteristic [5,6]-palladacyclic transition state, while pyridine moiety assists active catalyst species formation product release. Combined experimental computational mechanistic investigations point toward C–H activation both regio- rate-determining. Interestingly, oxidative addition diphenyl disulfide substrate found be unlikely, alternative transmetalation-like involving Pd–Ag heterometallic proposed operative.

Язык: Английский

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Synthesis of Arynes via Formal Dehydrogenation of Arenes

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(6), С. 3306 - 3311

Опубликована: Фев. 2, 2023

Arynes offer immense potential for diversification of benzenoid rings, which occur in pharmaceuticals, agrochemicals, and liquid crystals. However, accessing these high-energy intermediates requires synthetic precursors, involve either harsh conditions or multistep syntheses. The development alternative methods to access arynes using simpler substrates milder is necessary a more streamlined approach. Here, we describe two-step formal dehydrogenation simple arenes generate at remote position relative traditionally reactive groups, e.g., halides. This approach enabled by regioselective installation ejection an "onium" leaving group, demonstrate the compatibility (20 examples) arynophiles (8 examples). Moreover, through direct comparison, show that our method both functional group tolerant efficient generating than current state-of-the-art aryne precursors. Finally, opportunities C-H amination are distinct from other methods.

Язык: Английский

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Dual-Ligand Catalyst for the Nondirected C–H Olefination of Heteroarenes

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(14), С. 8198 - 8208

Опубликована: Март 28, 2023

Pd(II)-catalyzed nondirected C-H functionalization of heteroarenes is a significant challenge for the following reasons: poor reactivity electron-deficient heterocycles and unproductive coordination Lewis basic nitrogen atoms. Existing methodologies using palladium catalysis often employ large excess heterocycle substrates to overcome these hurdles. Despite recent advances in arenes that allow them be used as limiting reagents, reaction conditions are incompatible with heteroarenes. Herein we report dual-ligand catalyst enables olefination without substrate. In general, use 1-2 equiv was sufficient obtain synthetically useful yields. The rationalized by synergy between two types ligands: bidentate pyridine-pyridone ligand promotes cleavage; monodentate substrate acts second form cationic Pd(II) complex has high affinity arenes. proposed cooperation supported combination X-ray, kinetics, control experiments.

Язык: Английский

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Controlling Reactivity and Selectivity in the Nondirected C–H Activation of Arenes with Palladium

Accounts of Chemical Research, Год журнала: 2023, Номер 56(18), С. 2459 - 2472

Опубликована: Авг. 24, 2023

ConspectusAromatic structures are widespread motifs throughout organic chemistry, and C-H activation has been recognized as a major tool for enabling their sustainable efficient functionalization. Through activation, arenes can be modified without the need prefunctionalization, leading to inherent atom- step-economic advantages over traditional methods. However, development of synthetically useful methods, several hurdles have overcome. The strength bonds necessitates sufficiently reactive catalysts, while presence multiple within substrate poses challenges in terms site-selectivity. Traditionally these addressed by control. By attaching different directing groups (DGs), reactivity respective arene was significantly enhanced DG guided metal close proximity specific bonds, resulting high introduction removal add additional steps synthetic sequence, scope reaction is limited class. complementary nondirected methods that applied broad range necessity carry functional group coordinates Pd (referred simple arenes) therefore highly desirable. intrinsically lower such substrates absence selectivity-determining pose significant solved only catalysts. Consequently, field especially with respect Pd-catalyzed remained comparatively underdeveloped when we initiated our research program 2017. At time, state-of-the-art required used large excess, precluding its use late-stage Since organopalladium species among most versatile intermediates, realized developing system, which effectively selectively activate limiting reagent, would powerful chemistry. This account summarizes groups' toward application catalytic systems offering this desired focuses explicitly on functionalization reactions arenes, where employed reagent. After an state before 2017 associated challenges, experimental mechanistic details about first arene-limited, palladium will discussed. enabled identification combination two ligands, N-heterocycle amino acid-derived ligand. Afterward discuss expansion dual-ligand approach further arene-limited transformations. Finally, describe methodologies originated from observations made during studies, namely, deuteration selective olefination method uses noncovalent interactions induce meta selectivity.

Язык: Английский

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Diversification of pharmaceutical molecules via late-stage C(sp2)–H functionalization

Green Synthesis and Catalysis, Год журнала: 2023, Номер 4(2), С. 104 - 123

Опубликована: Янв. 2, 2023

C–H late-stage functionalization has gradually become a powerful approach for the rapid optimization of lead compounds' bioactivity. Significant advances in this field have been achieved past few years, mainly, system (hetero)aryl activation owing to importance moiety pharmaceutical. In review, we described selected recent examples how developed intermolecular C(sp2)–H methodologies involving diverse techniques diversify pharmaceutical molecules late stage.

Язык: Английский

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