Anant R. Kapdi

Kumada-Corriu cross-couplings with 2-pyridyl Grignard reagents.

Substituted heterobiaryls constitute privileged scaffolds of compounds with activities of relevance to various research areas, ranging from medicinal chemistry and catalysis to material sciences. Their regioselective syntheses rely strongly on transition-metal-catalyzed cross-coupling reactions, which have matured to being indispensable tools in modern organic syntheses. Since organomagnesium reagents are more readily available than are alternative organometallic nucleophiles, catalytic cross-couplings of Grignard reagents have proven particularly useful for streamlining heterobiaryl synthesis. Therefore, catalysts derived from various transition metals, such as nickel, palladium, iron, 12] cobalt, or manganese, were developed for Kumada–Corriu-type coupling reactions. 19] While this research significantly expanded the pool of viable electrophiles, cross-coupling reactions of electron-deficient N-heterocyclic nucleophiles continue to be challenging because of their reduced nucleophilicities. Hence, a generally applicable protocol for metal-catalyzed arylations of less nucleophilic 2-azine Grignard reagents has, to the best of our knowledge, proven elusive. As part of our program directed towards the use of air-stable secondary phosphine oxides (SPO) as preligands in transition-metal catalysis, we noted that efficient cross-couplings with 2-pyridyl organomagnesium compounds could be accomplished, provided that palladium catalysts derived from airand moisturestable SPOs were employed as preligands. Herein, we report on these findings, which highlight the unique reactivity profile of SPO preligands. At the outset of our studies, we probed various transitionmetal complexes and ligands in the cross-coupling of challenging 2-pyridyl Grignard 1 a with aryl bromide 2 a (Table 1). Unfortunately, monodentate phosphines 4 a–4 d provided unsatisfactory results (Table 1, entries 2–5), as did bidentate ligands 4 e–4 g or phosphite 5 (Table 1, entries 6– 9). Further, in situ generated (Table 1, entries 10 and 11) or preformed, well-defined palladium N-heterocyclic carbene complexes (Table 1, entries 12 and 13) did not deliver the desired product 3 a.

C–H Bond Arylations and Benzylations on Oxazol(in)es with a Palladium Catalyst of a Secondary Phosphine Oxide

An air-stable, well-defined palladium complex derived from secondary phosphine oxide (SPO) (1-Ad)(2)P(O)H enabled efficient C-H bond functionalizations with ample scope, which set the stage for direct arylations and benzylations of (benz)oxazoles, as well as unprecedented palladium-catalyzed C-H bond arylations on nonaromatic oxazolines.

Air-stable secondary phosphine oxide or chloride (Pre)ligands for cross-couplings of unactivated alkyl chlorides.

In situ generated and crystallographically well-defined, isolated palladium complexes derived from seven novel air-stable secondary phosphine oxides or chlorides enabled challenging Kumada-Corriu cross-couplings of unactivated alkyl chlorides bearing beta-hydrogens and proved applicable to transformations of alkyl-substituted organometallics.

Well‐Defined Air‐Stable Palladium HASPO Complexes for Efficient Kumada–Corriu Cross‐Couplings of (Hetero)Aryl or Alkenyl Tosylates

Palladium complexes of representative heteroatom-substituted secondary phosphine oxide (HASPO) preligands were synthesized and fully characterized, including X-ray crystal structure analysis. Importantly, these well-defined complexes served as highly efficient catalysts for Kumada-Corriu cross-coupling reactions of aryl, alkenyl, and even heteroaryl tosylates. Particularly, an air-stable catalyst derived from inexpensive PinP(O)H displayed a remarkably high catalytic efficacy, which resulted in cross-couplings at low catalyst loadings under exceedingly mild reaction conditions with ample scope.

A new precatalyst for the Suzuki reaction—a pyridyl-bridged dinuclear palladium complex as a source of mono-ligated palladium(0)

A dinuclear pyridyl-bridged palladium complex, trans-(P,N)-[PdBr(μ-C5H4N-C2,N)(PPh3)]21, was obtained from material isolated from the Suzuki cross-coupling reaction of 2-bromopyridine with 2,4-difluorophenylboronic acid in the presence of catalytic (PPh3)4Pd. Complex 1 is an effective precatalyst for the Suzuki cross-coupling reactions of a variety organoboronic acids and aryl bromides, and represents a useful source of mono-ligated palladium(0), “(Ph3P)Pd(0)”.

The Elusive Structure of Pd2(dba)3. Examination by Isotopic Labeling, NMR Spectroscopy, and X-ray Diffraction Analysis: Synthesis and Characterization of Pd2(dba-Z)3 Complexes

Pd(0)2(dba)3 (dba = E,E-dibenzylidene acetone) is the most widely used Pd(0) source in Pd-mediated transformations. Pd(0)2(dba-Z)3 (Z = dba aryl substituents) complexes exhibit remarkable and differential catalytic performance in an eclectic array of cross-coupling reactions. The precise structure of these types of complexes has been confounding, since early studies in 1970s to the present day. In this study the solution and solid-state structures of Pd(0)2(dba)3 and Pd(0)2(dba-Z)3 have been determined. Isotopic labeling ((2)H and (13)C) has allowed the solution structures of the freely exchanging major and minor isomers of Pd(0)2(dba)3 to be determined at high field (700 MHz). DFT calculations support the experimentally determined major and minor isomeric structures, which show that the major isomer of Pd(0)2(dba)3 possesses bridging dba ligands found exclusively in a s-cis,s-trans conformation. For the minor isomer one of the dba ligands is found exclusively in a s-trans,s-trans conformation. Single crystal X-ray diffraction analysis of Pd(0)2(dba)3·CHCl3 (high-quality data) shows that all three dba ligands are found over two positions. NMR spectroscopic analysis of Pd(0)2(dba-Z)3 reveals that the aryl substituent has a profound effect on the rate of Pd-olefin exchange and the global stability of the complexes in solution. Complexes containing the aryl substituents, 4-CF3, 4-F, 4-t-Bu, 4-hexoxy, 4-OMe, exhibit well-resolved (1)H NMR spectra at 298 K, whereas those containing 3,5-OMe and 3,4,5-OMe exhibit broad spectra. The solid-state structures of three Pd(0)2(dba-Z)3 complexes (4-F, 4-OMe, 3,5-OMe) have been determined by single crystal X-ray diffraction methods, which have been compared with Goodsons X-ray structure of Pd(0)2(dba-4-OH)3.

Regioselective palladium-catalysed cross-coupling reactions: a powerful synthetic tool

The purpose of this review is to highlight the powerful nature of palladium-catalysed regioselective (site-selective) cross-coupling reactions for facilitating the synthesis of biologically important natural products as well as certain industrially relevant drugs. A total of 28 natural products have been included to highlight the potential of this methodology.

New water soluble Pd-imidate complexes as highly efficient catalysts for the synthesis of C5-arylated pyrimidine nucleosides

The direct reactions between the precursors trans-[Pd(imidate)2(SMe2)2] and 1,3,5-triaza-7-phosphaadamantane (PTA) yield new water-soluble palladium(II) complexes trans-[Pd(imidate)2(PTA)2](imidate = succinimidate (suc) 1, maleimidate (mal) 2, phthalimidate (phthal) 3 or saccharinate (sacc) 4. The new complexes were revealed as excellent catalysts for environmentally friendly, efficient Suzuki–Miyaura cross-coupling of synthetically challenging substrates like the antiviral nucleoside analogue 5-iodo-2′-deoxyuridine in water as solvent.

New phospha-palladacycles: efficient catalysts in the formylation of aryl chlorides

The direct reaction between [{Pd(μ-AcO)(CˆP)}2] 1 and cyclic imides to yield new dinuclear cyclometallated palladium(II) complexes containing –NCO– bridging imidates of general formula [{Pd(μ-NCO)(CˆP)}2] (CˆP = CH2C6H4P(o-tolyl)2; –NCO– = succinimidate (suc) 2, maleimidate (mal) 3, phthalimidate (phthal) 4 or saccharinate (sacc) 5 is described. Spectroscopic techniques and structural characterisation by X-ray diffraction of complex 2 confirmed the proposed formulae. The new dimeric complexes are shown to be excellent catalysts for the selective formylation of aryl halides under CO-free conditions to obtain synthetically important aromatic aldehydes. Yields are diminished by steric hindrance around the aryl halides.

Water-Soluble Pd–Imidate Complexes: Broadly Applicable Catalysts for the Synthesis of Chemically Modified Nucleosides via Pd-Catalyzed Cross-Coupling

A broadly applicable catalyst system consisting of water-soluble Pd--imidate complexes has been enployed for the Suzuki-Miyaura cross-coupling of four different nucleosides in water under mild conditions. The efficient nature of the catalyst system also allowed its application in developing a microwave-assisted protocol with the purpose of expediting the catalytic reaction. Preliminary mechanistic studies, assisted by catalyst poison tests and stoichiometric tests performed using an electrospray ionization spectrometer, revealed the possible presence of a homotopic catalyst system.