Toolbox for Distal C–H Bond Functionalizations in Organic Molecules

Chemical Reviews, Journal Year: 2021, Volume and Issue: 122(6), P. 5682 - 5841

Published: Oct. 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.

Language: Английский

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HFIP in Organic Synthesis

Chemical Reviews, Journal Year: 2022, Volume and Issue: 122(15), P. 12544 - 12747

Published: July 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.

Language: Английский

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

Chemical Reviews, Journal Year: 2023, Volume and Issue: 123(12), P. 7692 - 7760

Published: May 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.

Language: Английский

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Photoinduced Regioselective Olefination of Arenes at Proximal and Distal Sites

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(4), P. 1929 - 1940

Published: Jan. 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.

Language: Английский

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

Journal of the American Chemical Society, Journal Year: 2021, Volume and Issue: 143(40), P. 16370 - 16376

Published: Sept. 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.

Language: Английский

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

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(27), P. 12032 - 12042

Published: June 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.

Language: Английский

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Synthesis of Arynes via Formal Dehydrogenation of Arenes

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(6), P. 3306 - 3311

Published: Feb. 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.

Language: Английский

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

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(14), P. 8198 - 8208

Published: March 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.

Language: Английский

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

Green Synthesis and Catalysis, Journal Year: 2023, Volume and Issue: 4(2), P. 104 - 123

Published: Jan. 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.

Language: Английский

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Synthesis of 1,3-Dienes via Ligand-Enabled Sequential Dehydrogenation of Aliphatic Acids

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(24), P. 13003 - 13007

Published: June 7, 2023

1,3-Dienes are common scaffolds in biologically active natural products as well building blocks for chemical synthesis. Developing efficient methods the synthesis of diverse 1,3-dienes from simple starting materials is therefore highly desirable. Herein, we report a Pd(II)-catalyzed sequential dehydrogenation reaction free aliphatic acids via β-methylene C–H activation, which enables one-step E,E-1,3-dienes. Free varying complexities, including antiasthmatic drug seratrodast, were found to be compatible with reported protocol. Considering high lability and lack protecting strategies, reveal at late stage offers an appealing strategy complex molecules containing such motifs.

Language: Английский

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