Boronyl-Group-Assisted Decatungstate-Catalyzed Benzylic C(sp3)-H Alkylation.

Boronic acid synthesis primarily involves the introduction of boronyl groups. However, an alternative route that involves the functionalization of boronic acids has not received much attention. This study describes the catalytic C(sp3)-H alkylation of ortho-tolylboronic acids utilizing the interaction between a free boronyl group [-B(OH)2] and a decatungstate photocatalyst [W10O32]4-. The boronyl groups of the alkylated products could be converted without isolation of the alkylated product.

Decatungstate-Catalyzed C(sp3)-H Alkylation of a Val Residue Proximal to the N-Terminus Controlled by an Electrostatic Interaction.

The decatungstate photocatalyst [W10O32]4- efficiently promoted the C(sp3)-H alkylation of the trifluoroacetic acid salt of valine methyl ester (H-Val-OMe·TFA) with electron-deficient alkenes under UV irradiation. The electrostatic interaction between the cationic ammonium group (+NH3) of the main chain and anionic [W10O32]4- played an important role in this reaction. The influence of various protected amino acids in the C(sp3)-H alkylation was investigated as the model reaction for the alkylation of Val-containing peptides. The introduction of an alkyne moiety into Val through this alkylation was successful, and successive copper-catalyzed azide-alkyne cycloaddition (CuAAC) was demonstrated. The C(sp3)-H bond of a Val residue located at the second from the N-terminus was also successfully converted. C(sp3)-H alkylation of oligopeptides containing two Val residues selectively proceeded proximally to the N-terminus.

3-Position-Selective C-H Trifluoromethylation of Pyridine Rings Based on Nucleophilic Activation.

The first example of the 3-position-selective C(sp2)-H trifluoromethylation of pyridine rings was established. 3-Position-selective trifluoromethylation was achieved by the nucleophilic activation of pyridine and quinoline derivatives through hydrosilylation and successive electrophilic trifluoromethylation of the enamine intermediate. This reaction was applicable to perfluoroalkylation at the 3 position of the pyridine rings and late-stage trifluoromethylation of a bioactive molecule. Mechanistic studies indicated that the reaction proceeds via the formation of N-silyl enamine and trifluoromethylated enamine intermediates.

Iridium-Catalyzed C(sp3 )-H Borylation Using Silyl-Bipyridine Pincer Ligands.

New ligands for the iridium-catalyzed C(sp3 )-H borylation of aliphatic compounds were established. In sharp contrast to 6-methyl-2,2'-bipyridine and 6-isobutyl-2,2'-bipyridine, 2,2'-bipyridine and 1,10-phenanthroline derivatives bearing a hydrosilylmethyl group (which would give a thermally stable NNSi pincer complex) served as suitable ligands for the reaction. Among them, a phenanthroline-based NNSi pincer ligand was shown to be an excellent ligand, and various aliphatic compounds were efficiently converted to the corresponding borylated products using the Ir/NNSi pincer catalyst system. The NNSi pincer ligand showed unique selectivity and enabled the iridium-catalyzed C(sp3 )-H borylation using pinacolborane [H-B(pin)] instead of B2 (pin)2 . The formation of an iridium complex bearing a quinoline-based NNSi pincer ligand from [IrCl(cod)]2 was observed, and the catalytic activity of the complex was demonstrated.

Manganese/bipyridine-catalyzed non-directed C(sp3)-H bromination using NBS and TMSN3.

A Mn(II)/bipyridine-catalyzed bromination reaction of unactivated aliphatic C(sp3)-H bonds has been developed using N-bromosuccinimide (NBS) as the brominating reagent. The reaction proceeded in moderate-to-good yield, even on a gram scale. The introduced bromine atom can be converted into fluorine and allyl groups.

Regioselective C-H Trifluoromethylation of Aromatic Compounds by Inclusion in Cyclodextrins.

A regioselective radical C-H trifluoromethylation of aromatic compounds was developed using cyclodextrins (CDs) as additives. The C-H trifluoromethylation proceeded with high regioselectivity to afford the product in good yield, even on the gram scale. In the presence of CDs, some substrates underwent a single trifluoromethylation selectively, whereas mixtures of single- and double-trifluoromethylated products were formed in the absence of the CD. 1H NMR experiments indicated that the regioselectivity was controlled by the inclusion of a substrate inside the CD cavity.

Regioselective C(sp3)-H alkylation of a fructopyranose derivative by 1,6-HAT.

Regioselective C(sp3)-H alkylation of a fructopyranose derivative using electron-deficient alkenes as alkylation reagents was achieved. The reaction proceeded via 1,6-hydrogen atom transfer under photoredox iridium catalysis. Several functional groups were introduced into the fructopyranose derivative.

Recent progress of transition metal-catalysed regioselective C-H transformations based on noncovalent interactions.

Transition metal-catalysed C-H transformations are powerful methods to obtain functionalised organic molecules from simple starting materials. Controlling regioselectivity is one of the most important issues in C-H transformations. Since the remarkable work by Murai and co-workers in 1993, many groups have reported ortho-selective C(sp2)-H transformations using directing group methods, in which interactions exist between substrates and catalytically active metal centres. In this review, new methodologies to achieve regioselective C-H transformations are described. In these methhodologies, noncovalent interactions between substrates and reagents or ligands of catalysts play important roles. In these cases, selective functionalization of remote C-H bonds, such as meta- and para-C-H bonds, can also be realized.

Iridium-Catalyzed ortho-C-H Borylation of Thioanisole Derivatives Using Bipyridine-Type Ligand.

A simple iridium catalytic system was developed that allows for a variety of 2-borylthioanisoles to be easily synthesized via ortho-selective C-H borylation of thioanisole derivatives. Once introduced, boryl and methylthio groups were converted by palladium-catalyzed transformations. Density functional theory calculations revealed that weak interactions, such as hydrogen bonding between the C-H bond of the SCH3 group and the oxygen atom of the boryl ligand, control the ortho-selectivity.

Copper-Catalyzed Tertiary Alkylative Cyanation for the Synthesis of Cyanated Peptide Building Blocks.

In this paper, we report efficient cyanation of various peptides containing the α-bromocarbonyl moiety using a Cu-catalyzed radical-based methodology employing zinc cyanide as the cyanide source. Mechanistic studies revealed that in situ formed CuCN was a key intermediate during the catalytic cycle. Our method could be useful for the synthesis of modified peptides containing quaternary carbons.

2-Position-Selective Trifluoromethylthiolation of Six-Membered Heteroaromatic Compounds.

The regioselective C-H trifluoromethylthiolation of six-membered heteroaromatic compounds via nucleophilic attack of a CF3S source on the electrophilically activated six-membered heteroaromatic ring was developed. The reaction proceeds in good yield with good functional group tolerance, even on a gram-scale. The key to the successful regioselective transformation is the presence of an additive (2,4-dinitrobenzenesulfonyl chloride). The regioselective trifluoromethylthiolation of quinidine derivative is also demonstrated. Trifluoromethylthiolation, followed by S-oxidation, affords the corresponding sulfones.

Hydrogen-Bond-Controlled Formal Meta-Selective C-H Transformations and Regioselective Synthesis of Multisubstituted Aromatic Compounds.

The meta-selective introduction of functional groups into aromatic substrates was successfully achieved by hydrogen-bond-controlled meta-selective C-H borylation and successive conversion of the boryl group to other functional groups. By this method a wide range of functional groups could be introduced without isolation of the borylated intermediates. The desired meta-functionalized aromatic products were obtained in a one-pot manner even on a gram scale. Regioselective synthesis of multisubstituted aromatic compounds was also achieved.

Asymmetric Cycloisomerization of o-Alkenyl-N-Methylanilines to Indolines by Iridium-Catalyzed C(sp3 )-H Addition to Carbon-Carbon Double Bonds.

Highly enantioselective cycloisomerization of N-methylanilines, bearing o-alkenyl groups, into indolines is established. An iridium catalyst bearing a bidentate chiral diphosphine effectively promotes the intramolecular addition of the C(sp3 )-H bond across a carbon-carbon double bond in a highly enantioselective fashion. The reaction gives indolines bearing a quaternary stereogenic carbon center at the 3-position. The reaction mechanism involves rate-determining oxidative addition of the N-methyl C-H bond, followed by intramolecular carboiridation and subsequent reductive elimination.

Utilization of a Trimethylsilyl Group as a Synthetic Equivalent of a Hydroxyl Group via Chemoselective C(sp3)-H Borylation at the Methyl Group on Silicon.

A conversion of trimethylsilylalkanes into the corresponding alcohols is established based on an iridium-catalyzed, chemoselective C(sp3)-H borylation of the methyl group on silicon. The (borylmethyl)silyl group formed by C(sp3)-H borylation is treated with H2O2/NaOH, and the resulting (hydroxymethyl)silyl group is converted into a hydroxyl group by Brook rearrangement, followed by oxidation of the resulting methoxysilyl group under Tamao conditions. An alternative route proceeding through the formylsilyl group formed from a (hydroxymethyl)silyl group by Swern oxidation is also established. The method is applicable to substituted trimethylsilylcycloalkanes and 1,1-dimethyl-1-silacyclopentane for conversion into the corresponding stereodefined cycloalkyl alcohols and 1,4-butanediol.

Iridium-Catalyzed Intramolecular Methoxy C-H Addition to Carbon-Carbon Triple Bonds: Direct Synthesis of 3-Substituted Benzofurans from o-Methoxyphenylalkynes.

Catalytic hydroalkylation of an alkyne with methyl ether was accomplished. Intramolecular addition of the C-H bond of a methoxy group in 1-methoxy-2-(arylethynyl)benzenes across a carbon-carbon triple bond took place efficiently either in toluene at 110 °C or in p-xylene at 135 °C in the presence of an iridium catalyst. The initial 5-exo cyclization products underwent double-bond migration during the reaction to give 3-(arylmethyl)benzofurans in high yields.

Iridium-catalysed borylation of sterically hindered C(sp³)-H bonds: remarkable rate acceleration by a catalytic amount of potassium tert-butoxide.

The C(sp(3))-H bonds located on the methyl groups of an isopropyl group participate in iridium-catalysed C-H borylation with bis(pinacolato)diboron via a significant rate acceleration caused by a catalytic amount of t-BuOK.

Catalytic functionalization of methyl group on silicon: iridium-catalyzed C(sp3)-H borylation of methylchlorosilanes.

A methyl group of methylchlorosilanes undergoes C-H borylation in an iridium-catalyzed reaction with bis(pinacolato)diboron in cyclohexane at 80 °C, giving (borylmethyl)chlorosilanes selectively.