Byeong-Seon Kim

Nickel-catalyzed arylation of heteroaryl-containing diarylmethanes: exceptional reactivity of the Ni(NIXANTPHOS)-based catalyst

Nickel(0)-catalyzed cross-coupling of heteroaryl-containing diarylmethanes with both aryl bromides and chlorides has been achieved.

Palladium-Catalyzed Selective α-Alkenylation of Pyridylmethyl Ethers with Vinyl Bromides

An efficient palladium-catalyzed α-alkenylation of pyridylmethyl ethers with vinyl bromides is presented. A Pd/NIXANTPHOS-based catalyst system enables a mild and chemoselective coupling between a variety of pyridylmethyl ethers and vinyl bromides in good to excellent yields. Under the mild conditions, β,γ-unsaturated products are obtained without isomerization or Heck byproducts observed.

Chemoselective palladium-catalyzed deprotonative arylation/[1,2]-Wittig rearrangement of pyridylmethyl ethers

Control of chemoselectivity is one of the most challenging problems facing chemists and is particularly important in the synthesis of bioactive compounds and medications.

Palladium‐Catalyzed C(sp3)H Arylation of N‐Boc Benzylalkylamines via a Deprotonative Cross‐Coupling Process

Diarylmethylamines are key intermediates and products in the pharmaceutical industry. Herein we disclose a novel method toward the synthesis of these important compounds via CH functionalization. Presented is a reversible deprotonation of N-Boc benzylalkylamines at the benzylic CH with in situ arylation by a NiXantPhos-based palladium catalyst (50-93 % yield, 29 examples). The method is also successful with N-Boc-tetrahydroisoquinolines. The advantages of this method are it avoids strong bases, low temperatures, and the need to transmetallate to main group metals for the coupling.

Breaking Conjugation: Unusual Regioselectivity with 2-Substituted Allylic Substrates in the Tsuji-Trost Reaction

η3-Allyl palladium complexes are key intermediates in Tsuji-Trost allylic substitution reactions. It is well known that (η3-1-aryl-3-alkyl substituted allyl)Pd intermediates result in nucleophilic attack at the alkyl substituted terminus. In contrast, the chemistry of (η3-1,2,3-trisubstituted allyl)Pd intermediates is relatively unexplored. Herein we probe the regioselectivity with 1,2,3-trisubstituted allylic substrates in Tsuji-Trost allylic substitution reactions. DFT investigation of cationic (η3-1-Ph-2-B(pin)-3-alkyl-allyl)Pd(PPh3)2 intermediates predict that nucleophilic attack should occur preferentially on anti-allyls rather than the syn-isomers to generate benzylic substitution products under Curtin-Hammett conditions. Experimentally, systematic studies with 1,2,3-trisubstituted allylic substrates revealed that a Linear Free Energy Relationship (LFER) is observed when Charton steric parameters of the C-2 substituents are plotted against the log of the ratio of regioisomers. Bulkier C-2 substituents in 1,2,3-trisubstituted η3-allyl palladium intermediates provide stronger preference for nucleophilic attack at anti-oriented benzylic termini. Additionally, the geometry of 1,4-elimination products supports the presence of anti-allyl palladium intermediates.

Palladium-catalysed synthesis of triaryl(heteroaryl)methanes

Tetraarylmethane derivatives are desirable for a variety of applications, but difficult to access with modern C–C bond-forming reactions. Here we report a straightforward method for palladium-catalysed arylation of aryl(heteroaryl)methanes and diaryl(heteroaryl)methanes with aryl chlorides. This reaction enables introduction of various aryl groups to construct triaryl(heteroaryl)methanes via a C–H functionalization in good to excellent yield, and represents the first step towards a general transition metal catalysed synthesis of tetraarylmethanes.

Synthesis of Diarylated 4-Pyridylmethyl Ethers via Palladium-Catalyzed Cross-Coupling Reactions

The direct arylation of weakly acidic sp3-hybridized C-H bonds via deprotonated cross-coupling processes (DCCP) is a challenge. Herein, a Pd(NIXANTPHOS)-based catalyst for the mono arylation of 4-pyridylmethyl 2-aryl ethers to generate diarylated 4-pyridyl methyl ethers is introduced. Furthermore, under similar conditions, the diarylation of 4-pyridylmethyl ethers with aryl bromides has been developed. These methods enable the synthesis of new pyridine derivatives, which are common in medicinally active compounds and in application in materials science.

Palladium-Catalyzed Benzylic Arylation of Pyridylmethyl Silyl Ethers: One-Pot Synthesis of Aryl(pyridyl)methanols

An efficient palladium-catalyzed direct arylation of pyridylmethyl silyl ethers with aryl bromides is described. A Pd(OAc)2/NIXANTPHOS-based catalyst provides aryl(pyridyl)methyl alcohol derivatives in good to excellent yields (33 examples, 57-100% yield). This protocol is compatible with different silyl ether protecting groups, affording either the protected or the free alcohols in an effective one-pot process. The scalability of the reaction is demonstrated.

Palladium-Catalyzed Chemoselective Allylic Substitution, Suzuki–Miyaura Cross-Coupling, and Allene Formation of Bifunctional 2-B(pin)-Substituted Allylic Acetate Derivatives†

A formidable challenge at the forefront of organic synthesis is the control of chemoselectivity to enable the selective formation of diverse structural motifs from a readily available substrate class. Presented herein is a detailed study of chemoselectivity with palladium-based phosphane catalysts and readily available 2-B(pin)-substituted allylic acetates, benzoates, and carbonates. Depending on the choice of reagents, catalysts, and reaction conditions, 2-B(pin)-substituted allylic acetates and derivatives can be steered into one of three reaction manifolds: allylic substitution, Suzuki-Miyaura cross-coupling, or elimination to form allenes, all with excellent chemoselectivity. Studies on the chemoselectivity of Pd catalysts in their reactivity with boron-bearing allylic acetate derivatives led to the development of diverse and practical reactions with potential utility in synthetic organic chemistry.

Tandem C(sp3)−H Arylation/Oxidation and Arylation/Allylic Substitution of Isoindolinones

Isoindolinones comprise an important class of medicinally active compounds. Herein we report a straightforward functionalization of the isoindolinones with aryl bromides (22 examples) using a Pd(OAc)2/NIXANTPHOS-based catalyst system. Additionally 3-aryl 3-hydroxy isoindolinone derivatives, which exhibit anti-tumor activity, can be accessed via a tandem reaction. Thus, when the arylation product is exposed to air under basic conditions, in situ oxidation takes place to install the 3-hydroxyl group. Furthermore, a tandem arylation/allylic substitution reaction is advanced in which both the arylation and allylic substitution are catalyzed by the same palladium catalyst. Finally, a tandem arylation/alkylation procedure is presented. These tandem reactions enable the synthesis of a variety of structurally diverse isoindolinone derivatives from common starting materials.