Copper(II)-Catalyzed Regioselective H/D Exchange Based on Reversible C-H Activation.

Despite the increasing use of copper in C-H functionalizations, the Cu-catalyzed direct deuteration of C-H bonds remains a significant challenge due to its inherent low reactivity in inverse C-H bond reconstruction. In this paper, a novel strategy had been developed to reverse the copper-catalyzed concerted metalation-deprotonation process by inhibiting the unexpected disproportionation of Cu(II) to Cu(III). Picolinic acid was identified as a powerful ligand for facilitating this H/D exchange with D2O as deuterium source, and its inhibition activity was supported by preliminary control experiments and DFT studies.

H/D Exchange of Aromatic Sulfones via Base Promotion and Silver Catalysis.

Aromatic sulfones are the prevailing scaffolds in pharmaceutical and material sciences. However, compared to their widespread application, the selective deuterium labeling of these structures is restricted due to their electron-deficient properties. This study presents two comprehensive strategies for the deuteration of aromatic sulfones. The base-promoted deuteration uses DMSO-d6 as the deuterium source, resulting in a rapid H/D exchange within 2 h. Meanwhile, a silver-catalyzed protocol offers a much milder option by using economical D2O to furnish the labeled sulfones.

Pd-Catalyzed Regioselective Deuteration of Indole's C4-Position with Transient Directing Groups.

As a representative scaffold of alkaloids, indoles have been extensively subjected to deuteration, but the regioselective C4 labeling has not been achieved due to its low reactivity. In this work, a Pd-catalyzed deuterium labeling at the indole's C4 position has been developed under the strategy of transient directing, using D2O as a deuterium source. The substituent effect is found to be crucial in facilitating this H/D exchange process, where the reversing C-D bond formation favors an electron-enriched ligation contrary to its C-H halogenation counterpart.

Multideuteration of Nitroaromatics by Silver-Catalyzed Hydrogen-Isotope Exchange.

Silver-catalyzed deuteration of nitroaromatics has been achieved using D2O as the deuterium source. Distinct from the well-established directing group-guided hydrogen-isotope exchange, this protocol showed an interesting deuteration pattern, where considerable deuterium accumulation was observed around the aromatic rings. Controlling experiments suggested that the deuteration was initiated by a silver-promoted C-H activation. Therefore, a tentative two-stage deuteration mechanism involving aryl-silver species was proposed to explain the deuteration on meta- and para-positions.

Ortho-Deuteration of Aromatic Aldehydes via a Transient Directing Group-Enabled Pd-Catalyzed Hydrogen Isotope Exchange.

A practical and scalable ortho-selective deuteration of aromatic aldehydes was accomplished by Pd-catalyzed hydrogen isotope exchange with deuterium oxide as an inexpensive deuterium source. The use of tert-leucine as a transient directing group facilitates the exchange, affording a wide range of ortho-deuterated aromatic aldehydes with deuterium incorporation up to 97%. The control experiments suggest that the addition of silver trifluoroacetate resists the unexpected reduction of Pd(II), while the theoretical study indicates a rapid reversible concerted metalation-deprotonation process.

One-Pot Cascade Heterocyclization of γ- and ß-Ketomalononitriles to 2,4-Dichloro-Substituted Pyrano[2,3- d]pyrimidines and Furo[2,3- d]pyrimidines Mediated by Triphosgene and Triphenylphosphine Oxide.

A one-pot cascade heterocyclization strategy has been developed for the synthesis of 2,4-dichloro-substituted pyrano[2,3- d]pyrimidines and furo[2,3- d]pyrimidines from linear γ- and ß-ketomalononitriles using triphosgene and triphenylphosphine oxide. The reaction afforded synthetic useful products with moderate to good yields, bypassing the conventional harsh conditions of chlorination. The mechanistic study revealed that the reaction proceeded with a non-isocyanate route, and the second step may conduct in a triphenylphosphine oxide-catalyzed manner.

Liquid-Assisted Grinding Accelerating: Suzuki-Miyaura Reaction of Aryl Chlorides under High-Speed Ball-Milling Conditions.

The effect of liquid-assisted grinding has been studied using mechanical Suzuki-Miyaura reaction of aryl chlorides as the model reaction. Catalytic systems of Davephos and PCy3 are tested respectively showing strong influences from different liquids. Unexpected improvement of yield over 55% is observed using alcohols as additives, which is explained by in situ formed alkoxides and their participation in oxidative addition. Further expansion of substrates using Pd(OAc)2/PCy3/MeOH system gives desired products in good to high yields.

Mechanically Induced Fe(III) Catalysis at Room Temperature: Solvent-Free Cross-Dehydrogenative Coupling of 3-Benzylic Indoles with Methylenes/Indoles.

An Fe(III)-catalyzed solvent-free cross-dehydrogenative coupling of 3-benzylic indoles and compounds with acidic methylene groups has been achieved under high-speed ball-milling (HSBM) conditions at room temperature. The reactions afford desired 3-arylmethylindole derivatives in moderate to high yields within 21 min of grinding. Besides, both N-substituted and N-free indoles can take part in this mechanochemical reaction as efficient nucleophiles to give bisindoles with satisfactory results. Remarkably, this protocol displays the possibility to induce high activity when using iron catalysts under HSBM conditions.

Mechanochemically Activated Oxidative Coupling of Indoles with Acrylates through C-H Activation: Synthesis of 3-Vinylindoles and ß,ß-Diindolyl Propionates and Study of the Mechanism.

Construction of 3-vinylindoles (3) and ß,ß-diindolyl propionates (4) through solvent-free C-H functionalization has been explored under high-speed ball-milling conditions. The reaction selectivity is influenced by the catalyst dramatically: Pd(OAc)2 provides 3 in moderate to good yields, whereas PdX2 (X = Cl, I) affords 4 as the major products. The reaction mechanism has been further studied by using electrospray ionization mass spectrometry, implicating the dimeric palladium complex A as the key intermediate in an explanation of the selectivity.

Nickel-catalyzed regioselective hydrogen isotope exchange accelerated by 2-pyridones.

A nickel-catalyzed hydrogen isotope exchange has been developed with acetone-d6 as the deuterium source. The reaction showed an improved kinetic feature of H/D exchange under the assistance of 2-pyridones, efficiently affording regioselective labeled aryl and alkyl carboxamides.

Geometric constraints regulated regioselectivity: Pd-catalyzed α-deuteration of pyridines with secondary phosphine oxide.

A Pd-catalyzed regioselective H/D exchange at the α-position of pyridines was achieved by employing secondary phosphine oxide as an internal base. The proposed five-membered structure enabled the reaction to overcome its conventional ortho-directing feature, allowing the efficient deuteration of pyridines and quinolines at adjacent sites of N-atoms.

Site-Selective Deuteration of α-Amino Esters with 2-Hydroxynicotinaldehyde as a Catalyst.

An efficient method has been developed for the synthesis of α-deuterated α-amino esters via hydrogen isotope exchange of α-amino esters in D2O with 2-hydroxynicotinaldehyde as a catalyst under mild conditions. This methodology exhibits a wide range of substrate scopes, remarkable functional group tolerance, and affording the desired products in good yields with excellent deuterium incorporation. Notably, the ortho-hydroxyl group and the pyridine ring of the catalyst play a crucial role in the catalytic activity, which not only stabilizes the carbon-anion intermediates but also enhances the acidity of the amino esters' α-C-H bond.

B(C6F5)3-Catalyzed Intramolecular Hydroalkoxylation Deuteration Reactions of Unactivated Alkynyl Alcohols.

Using D2O as a deuterium source, a method for the deuteration of intra- and extra-cyclic methylene has been developed for cyclic ethers with moderate yield and excellent deuterium incorporation. This transformation features superb functional group tolerance in a wide range of alkynols. Notably, the critical factor to achieve high deuterium incorporation is determined by the hydrogen isotope exchange reaction of an unstable oxonium ion. This novel methodology provides an efficient and concise synthetic route to a number of valuable deuterated cyclic ethers that are often difficult to prepare with other methods.

Regioselective Cycloaddition and Substitution Reaction of Tertiary Propargylic Alcohols and Heteroareneboronic Acids via Acid Catalysis.

We report an acid-catalyzed formal cycloaddition and dehydrative substitution reaction of tertiary propargylic alcohols and heteroareneboronic acids. The properties of the substituents on the alkynyl moiety determines the regioselectivity of the reaction, which could selectively construct fused heterocycles, tetrasubstituted allenes, or 1,3-dienes. This reaction proceeds efficiently with a wide array of substrate scope in up to 89% yield. A significant advantage of this protocol is the transition-metal-free and mild conditions needed.

Potassium tert-butoxide promoted regioselective deuteration of pyridines.

A regioselective deuteration at the ß- and γ-position of pyridines is reported. Efficient deuteration occurred with a combination of KOtBu and DMSO-d6, replenishing the prevailing α-deuteration of the pyridine systems. Preliminary mechanistic studies suggested that the dimsyl carbanion acts as one of the key intermediates.

Selective hydrogenation of nitroaromatics to N-arylhydroxylamines in a micropacked bed reactor with passivated catalyst.

In this contribution, a protocol was established for the selective catalytic hydrogenation of nitroarenes to the corresponding N-arylhydroxylamines. The reduction of 1-(4-chlorophenyl)-3-((2-nitrobenzyl)oxy)-1H-pyrazole, an intermediate in the synthesis of the antifungal reagent pyraclostrobin that includes carbon-chlorine bonds, benzyl groups, carbon-carbon double bonds and other structures that are easily reduced, was chosen as the model reaction for catalyst evaluation and condition optimization. Extensive passivant evaluation showed that RANEY®-nickel treated with ammonia/DMSO (1 : 10, v/v) afforded the optimal result, especially with a particle size of 400-500 mesh. To combine the modified catalyst with continuous-flow reaction technology, the reaction was conducted at room temperature, rendering the desired product with a conversion rate of 99.4% and a selectivity of 99.8%. The regeneration of catalytic activity was also studied, and an in-column strategy was developed by pumping the passivate liquid overnight. Finally, the generality of the method was explored, and 7 substrates were developed, most of which showed a good conversion rate and selectivity, indicating that the method has a certain degree of generality.