Recent progress in the C-H coupling reactions of heteroaromatic compounds in our group is summarized. Coupling of thiophene derivatives occurs in the presence of a nickel or palladium catalyst with a base as an additive. Lithium t-butoxide and several magnesium amides are effective for the coupling reaction of aryl chlorides, bromides, and iodides. Coupling at the C-H bond of thiophene with thienyl halides also occurs smoothly forming a thiophene-thiophene bond. The reaction is successfully applied to the polymerization of 2-halo-3-substituted thiophenes leading to highly regioregular head-to-tail-type poly(3-substituted thiophene)s. The reaction of thiazole at the C-H bond (2-position) with several secondary amines induces C-H, N-H coupling with a copper catalyst.
Recent progress in the preparation of organoboron reagents for cross-coupling reactions is described. Organoboron reagents are versatile synthons in Suzuki-Miyaura coupling. A common method for the synthesis of organoboron reagents is the borylation of aryl or vinyl magnesium (or lithium) intermediates that are produced from aryl or vinyl halides. In addition to these traditional methods, the direct borylation of aromatic and heteroaromatic compounds has also been recently reported as a more atom-economical method. We describe our new homogeneous and heterogeneous catalysts for aromatic C-H borylation. Regarding the heterogeneous catalyst, the recovered catalyst could be reused without a loss of activity. We developed this heterogeneous batch reaction system into a continuous-flow reaction system using a column field with our heterogeneous catalyst.
Tetraorganosilanes having a 2-(hydroxymethyl)phenyl group are found to undergo the silicon-based cross-coupling reaction. The proximal hydroxy group allows transmetalation of alkyl, alkenyl, and aryl groups on silicon to palladium(II), nickel(II), or copper(I or II) to occur, and hence participation in the cross-coupling reaction under mild conditions with excellent chemoselectivity. The high stability of the tetraorganosilicon structure is demonstrated by functionalization under various acidic, basic, and oxidative conditions which leave the silyl group completely intact. Moreover, highly efficient synthesis of functional molecules such as oligoarenes has been achieved through iterative cross-coupling/O-deprotection sequences by simply switching reactivity with orthogonal O-protection/deprotection.
A new series of phosphine ligands, the 2,2-diphenylvinylphosphines (vBRIDPs) 1 and 2,2-diphenylcyclopropylphosphines (cBRIDPs) 2, were designed and synthesized. Despite their high electron density on phosphorus, BRIDPs are air stable because of their unique structures that prevent their oxidation to the phosphine oxides. A catalyst system consisting of BRIDPs and palladium species effectively catalyzes coupling reactions of a wide range of aryl halides with arylboronic acids, amines, and aryl ketones. In this article, typical preliminary examples of coupling reactions, such as the Suzuki-Miyaura coupling and the Buchwald-Hartwig amination, are described along with two concepts of ligand design, which are based on the electron richness and steric hindrance of vBRIDPs 1a and 1b and their structural hybrids, cBRIDPs 2a and 2b. In addition, we also compare the characteristics of Pd/BRIDP complexes with different substituent groups on the phosphorus atom, such as tert-butyl and cyclohexyl groups, and give some examples of successful applications of these ligands to industrial processes.
Hypervalent iodine reagents, such as phenyliodine diacetate (PIDA) and phenyliodine bis(trifluoroacetate) (PIFA), are promising alternatives to metal-based oxidants for developing environmentally benign oxidation reactions, due to their low toxicities, mild reactivities, ready availability, high stabilities, and easy handling. During the study on the hypervalent iodine chemistry, we first determined in the 1990’s the single-electron-transfer (SET) oxidation ability of the hypervalent iodine(III) reagent toward electron-rich aromatic rings, such as the phenyl ether compounds, affording the corresponding aromatic cation radicals. This discovery led us to develop a series of metal-free carbon-hydrogen (C-H) bond functionalizations of aromatic compounds using the hypervalent iodine oxidants. We have extended the strategy to the carbon-carbon bond formation of biaryls based on the double aromatic C-H bond couplings, which can now provide a novel technology to the synthetic area of metal-free cross couplings for producing mixed biaryls from two molecules of unfunctionalized aromatic compounds. These achievements found by us during the development of hypervalent iodine-induced metal-free C-H cross couplings are now summarized in detail.
The ladder-shaped polycyclic ether marine natural products present formidable and challenging synthetic targets due to their structural complexity, and exceptionally potent biological activities. Over the past decade, however, the limited availability of these substances from natural sources has precluded detailed biological studies. There has been an urgent need for means to supply useful quantities of these natural products and their analogues by total synthesis. We have developed a highly convergent strategy for the rapid and efficient assembly of polycyclic ether arrays, which relies on the palladium-catalyzed Suzuki-Miyaura cross-coupling reaction of cyclic enol triflates or phosphates. The utility of this strategy has been demonstrated by its application to the convergent total synthesis of the polycyclic ether class of natural products.
This account describes our recent work on catalytic cross-coupling reactions using carboxylate and carbonate leaving groups in the electrophilic substrate. Some bisphosphine-chelated palladium(0) complexes are effective for the cleavage of benzylic C-O bonds in benzyl carbonates and acetates. This C-O bond cleavage was utilized in catalytic reactions of these benzylic esters; the nucleophilic benzylic substitutions and the cross-coupling reactions with organometallic compounds. Furthermore, vinyl acetate was proved to work as the coupling partner of arylboronates in the presence of [RhCl(cod)]2-DPPB. Interestingly, the organoborons react selectively at the position β to the leaving group in the alkenyl ester when the rhodium-catalyzed reaction is conducted in the absence of the bisphosphine.
Transition metal catalyzed alkylation reactions resulting in cross-coupling and multicomponent-coupling are described. These reactions proceed efficiently under mild conditions using a combination of transition metal catalysts and alkyl (pseudo)halides in the presence of Grignard reagents and represent the practical routes to the alkylation of sp3-, sp2-, and sp-carbons. Anionic transition metal complexes play important roles as active catalytic species for SN2 and electron transfer processes in reactions with alkyl halides. The carbometalation of C-C unsaturated bonds with alkylmetal species is also a promising tool for the introduction of alkyl groups.
New cross-coupling reactions catalyzed by iron or iron group metals (IGMs), consisting of Fe, Co, and Ni with N-heterocyclic carbenes (NHCs), are described in this report. Highly selective biaryl cross-coupling reactions between aryl halides and aryl Grignard reagents were achieved by using a combination of fluoride salts of IGMs and NHCs. In the course of the study, an unexpected alkenylative cross-coupling between alkyl aryl sulfides and aryl Grignard reagents was found, in which a typical Ni/NHC catalyst displayed unprecedented reactivity toward sulfide substrates. Theoretical studies suggest that the biaryl coupling and the alkenylative coupling reactions proceed via two nonconventional mechanisms, which are substantially different from the widely-accepted cross-coupling mechanism: In the biaryl cross-coupling, treatment of the catalyst mixtures of IGM fluorides and NHCs with an excess amount of the aryl Grignard reagent results in the generation of organometalate complexes, [Ar1MIIF2]MgBr (M=Fe, Co, and Ni). These organometalate species undergo oxidative addition of aryl halide substrates to form intermediates in a high oxidation state (most likely a+IV state) possessing two different aryl groups, Ar1Ar2MIVF2. The heteroleptic diaryl organometallic intermediates collapse easily to afford unsymmetrical biaryls in a highly selective manner. On the other hand, the alkenylative coupling reaction using a Ni/NHC catalyst involves formation of a low-oxidation-state Ni(0)-thioaldehyde complex, which is transformed to an alkenylnickel species via α-deprotonation of the thioaldehyde and subsequent C-S bond cleavage of the resulting enethiolate intermediate. The alkenylnickel species undergoes transmetalation with an aryl Grignard reagent to form alkenyl/aryl coupling products via reductive elimination. The present cross-coupling reactions catalyzed by IGMs with NHC ligands provide highly selective Csp2-Csp2 coupling methods for the synthesis of unsymmetrical biaryls and styrene derivatives, offering an opportunity to gain new mechanistic insights into IGM-catalyzed cross-coupling reactions.