RESUMEN
The myriad nickel-catalyzed cross-coupling reactions rely on the formation of an organonickel intermediate, but limitations in forming monoalkylnickel species have limited options for C(sp3) cross-coupling. The formation of monoalkylnickel(II) species from abundant carboxylic acid esters would be valuable, but carboxylic acid derivatives are primarily decarboxylated to form alkyl radicals that lack the correct reactivity. In this work, we disclose a facile oxidative addition and decarbonylation sequence that forms monoalkylnickel(II) intermediates through a nonradical process. The key ligand, bis(4-methylpyrazole)pyridine, accelerates decarbonylation, stabilizes the alkylnickel(II) intermediate, and destabilizes off-cycle nickel(0) carbonyl species. The utility of this new reactivity in C(sp3)-C(sp3) bond formation is demonstrated in a reaction that is challenging by purely radical methods-the selective cross-coupling of primary carboxylic acid esters with primary alkyl iodides.
RESUMEN
Carbon-heteroatom bonds, most often amide and ester bonds, are the standard method to link together two complex fragments because carboxylic acids, amines, and alcohols are ubiquitous and the reactions are reliable. However, C-N and C-O linkages are often a metabolic liability because they are prone to hydrolysis. While C(sp2)-C(sp3) linkages are preferable in many cases, methods to make them require different starting materials or are less functional-group-compatible. We show here a new, decarbonylative reaction that forms C(sp2)-C(sp3) bonds from the reaction of activated carboxylic acids (via 2-pyridyl esters) with activated alkyl groups derived from amines (via N-alkyl pyridinium salts) and alcohols (via alkyl halides). Key to this process is a remarkably fast, reversible oxidative addition/decarbonylation sequence enabled by pyridone and bipyridine ligands that, under reaction conditions that purge CO(g), lead to a selective reaction. The conditions are mild enough to allow coupling of more complex fragments, such as those used in drug development, and this is demonstrated in the coupling of a typical Proteolysis Targeting Chimera (PROTAC) anchor with common linkers via C-C linkages.
RESUMEN
A deeply ingrained assumption in the conventional understanding and practice of organometallic chemistry is that an unactivated aliphatic C(sp3)-H bond is less reactive than an aromatic C(sp2)-H bond within the same molecule given that they are at positions unbiasedly accessible for activation. Herein, we demonstrate that a pincer-ligated iridium complex catalyzes intramolecular dehydrogenative silylation of the unactivated δ-C(sp3)-H (δ to the Si atom) with exclusive site selectivity over typically more reactive ortho δ-C(sp2)-H bonds. A variety of tertiary hydrosilanes undergo δ-C(sp3)-H silylation to form 5-membered silolanes, including chiral silolanes, which can undergo further oxidation to produce enantiopure ß-aryl-substituted 1,4-diols. Combined computational and experimental studies reveal that the silylation occurs via the Si-H addition to a 14-electron Ir(I) fragment to give an Ir(III) silyl hydride complex, which then activates the C(sp3)-H bond to form a 7-coordinate, 18-electron Ir(V) dihydride silyl intermediate, followed by sequential reductive elimination of H2 and silolane. The unprecedented site selectivity is governed by the distortion energy difference between the rate-determining δ-C(sp3)-H and δ-C(sp2)-H activation, although the activation at sp2 sites is much more favorable than sp3 sites by the interaction energy.
Asunto(s)
Alcoholes , Iridio , Catálisis , Iridio/química , Alcoholes/química , Electrones , Oxidación-ReducciónRESUMEN
A trans-semihydrogenation of 1,3-enynes with ethanol as the hydrogen source was developed using a new (PCN)Ir complex as the precatalyst and tBuNH2 as the cocatalyst. This catalyst system provides an efficient and atom-economical access to unsymmetrical (E,E)-1,4-diarylbutadienes with high yields and stereoselectivities. Monitoring the process revealed that a sequence of cis-semihydrogenation of the triple bond of 1,3-enynes (to form (E,Z)-butadienes) and (E,Z)-to-(E,E) isomerization occurs to form (E,E)-butadienes.
Asunto(s)
Etanol , Iridio , Butadienos , Catálisis , Iridio/química , Estructura MolecularRESUMEN
The discovery and development of organometallic catalysts is of paramount importance in modern organic synthesis, among which the ligand scaffolds play a crucial role in controlling the activity and selectivity. Over the past several decades, d8 transition-metal complexes of pincer ligands have been developed extensively thanks to their easy structural modification, versatile reactivities, and high stability. One paradigm is the bis(phosphine)-based pincer iridium complexes PCP-Ir, which are highly active for alkane dehydrogenation, partly due to their high thermostability. However, except for alkane dehydrogenation and related transformations, few applications of pincer iridium catalysis have been seen in organic synthesis. This mainly arises from the low functional-group compatibility and poor substrate scope and the limited catalytic chemistry that invariably involves Ir(I/III) redox processes initiated by oxidative addition of substrates to 14-electron (PCP)Ir fragments (the proposed catalytically active intermediates). In this Account, we describe our endeavor on the development of a new family of PCN-Ir complexes with initial intention on creating more efficient alkane dehydrogenation catalysts. The replacement of a soft, σ-donor phosphine arm in the PCP ligands by a harder, π-acceptor N-heteroarene (pyridine or oxazoline) not only provides an additional platform to modify the structural properties but also offers new modes of bond activation and novel reactivities and catalysis. One uniqueness of the PCN-Ir system lies in the formation, via ortho-C(sp2)-H cyclometalation of the pyridine unit in the PCNPy ligand, of the neutral monohydride (PCC)IrIIIHL (L = neutral ligand), which catalyzes positional and stereoselective 1-alkene-to-(E)-2-alkene isomerization. Moreover, the PCN-Ir catalysts effect ethanol dehydrogenation without decarbonylation, allowing for transfer hydrogenation of unactivated alkenes and trans-selective semihydrogenation of internal alkynes with user-friendly ethanol as the H-donor. Another feature originates from the ability of the pentacoordinate hydrido chloride complex (PCN)IrIIIHCl to undergo reversible solvent-coordination-induced-ionization (SCII), furnishing a cationic monohydride [(PCN)IrIIIH(Sol)]+Cl- bearing an uncoordinated Cl anion that effects selective hydrometalation of internal alkynes over the corresponding (Z)-alkenes; the resulting (PCN)IrIII(vinyl)Cl complex undergoes amine-assisted formal alcoholysis involving the protonation of the Cl anion by the activated IrIII-bound EtOH, again via the SCII pathway. Together these elementary reactions lay the foundation for cis-selective semihydrogenation of alkynes with EtOH. Further, the design of the oxazoline-containing chiral complexes (PCNOxa)IrIIIHCl enables asymmetric transfer hydrogenation of alkenes/ketones with ethanol. The efficient catalytic α-alkylation of unactivated esters/amides with alcohols is another case showing the benefit that the PCN-Ir catalyst can offer. These examples illustrate the profound impact of the pincer ligands on the reactivities and catalysis. We hope this Account will provide an in-depth view into the fundamentals of pincer iridium chemistry and ultimately broaden its applications in organic synthesis.
Asunto(s)
Iridio , Alcanos , Alquenos/química , Alquinos , Catálisis , Etanol , Hidrogenación , Iridio/química , Ligandos , PiridinasRESUMEN
Chiral iridium complexes ligated by anionic oxazoline-bearing NCP-type pincer ligands were developed and applied to the asymmetric transfer hydrogenation (ATH) of diarylethenes using environmentally benign ethanol as the hydrogen donor. High enantioselectivities could be achieved for substrates bearing ortho-Me, ortho-Cl, or ortho-Br substituents on one of the aryl groups. The ATH of ortho-Br-substituted diarylethenes is particularly attractive due to the propensity of the C(aryl)-Br bond to undergo various new bond-forming events.
RESUMEN
The selective synthesis of Z-alkenes in alkyne semihydrogenation relies on the reactivity difference of the catalysts toward the starting materials and the products. Here we report Z-selective semihydrogenation of alkynes with ethanol via a coordination-induced ionic monohydride mechanism. The EtOH-coordination-driven Cl- dissociation in a pincer Ir(III) hydridochloride complex (NCP)IrHCl (1) forms a cationic monohydride, [(NCP)IrH(EtOH)]+Cl-, that reacts selectively with alkynes over the corresponding Z-alkenes, thereby overcoming competing thermodynamically dominant alkene Z-E isomerization and overreduction. The challenge for establishing a catalytic cycle, however, lies in the alcoholysis step; the reaction of the alkyne insertion product (NCP)IrCl(vinyl) with EtOH does occur, but very slowly. Surprisingly, the alcoholysis does not proceed via direct protonolysis of the Ir-C(vinyl) bond. Instead, mechanistic data are consistent with an anion-involved alcoholysis pathway involving ionization of (NCP)IrCl(vinyl) via EtOH-for-Cl substitution and reversible protonation of Cl- ion with an Ir(III)-bound EtOH, followed by ß-H elimination of the ethoxy ligand and C(vinyl)-H reductive elimination. The use of an amine is key to the monohydride mechanism by promoting the alcoholysis. The 1-amine-EtOH catalytic system exhibits an unprecedented level of substrate scope, generality, and compatibility, as demonstrated by Z-selective reduction of all alkyne classes, including challenging enynes and complex polyfunctionalized molecules. Comparison with a cationic monohydride complex bearing a noncoordinating BArF- ion elucidates the beneficial role of the Cl- ion in controlling the stereoselectivity, and comparison between 1-amine-EtOH and 1-NaOtBu-EtOH underscores the fact that this base variable, albeit in catalytic amounts, leads to different mechanisms and consequently different stereoselectivity.
RESUMEN
The first general catalytic approach to effecting transfer hydrogenation (TH) of unactivated alkenes using ethanol as the hydrogen source is described. A new NCP-type pincer iridium complex (BQ-NCOP)IrHCl containing a rigid benzoquinoline backbone has been developed for efficient, mild TH of unactivated C-C multiple bonds with ethanol, forming ethyl acetate as the sole byproduct. A wide variety of alkenes, including multisubstituted alkyl alkenes, aryl alkenes, and heteroatom-substituted alkenes, as well as O- or N-containing heteroarenes and internal alkynes, are suitable substrates. Importantly, the (BQ-NCOP)Ir/EtOH system exhibits high chemoselectivity for alkene hydrogenation in the presence of reactive functional groups, such as ketones and carboxylic acids. Furthermore, the reaction with C2D5OD provides a convenient route to deuterium-labeled compounds. Detailed kinetic and mechanistic studies have revealed that monosubstituted alkenes (e.g., 1-octene, styrene) and multisubstituted alkenes (e.g., cyclooctene (COE)) exhibit fundamental mechanistic difference. The OH group of ethanol displays a normal kinetic isotope effect (KIE) in the reaction of styrene, but a substantial inverse KIE in the case of COE. The catalysis of styrene or 1-octene with relatively strong binding affinity to the Ir(I) center has (BQ-NCOP)IrI(alkene) adduct as an off-cycle catalyst resting state, and the rate law shows a positive order in EtOH, inverse first-order in styrene, and first-order in the catalyst. In contrast, the catalysis of COE has an off-cycle catalyst resting state of (BQ-NCOP)IrIII(H)[O(Et)···HO(Et)···HOEt] that features a six-membered iridacycle consisting of two hydrogen-bonds between one EtO ligand and two EtOH molecules, one of which is coordinated to the Ir(III) center. The rate law shows a negative order in EtOH, zeroth-order in COE, and first-order in the catalyst. The observed inverse KIE corresponds to an inverse equilibrium isotope effect for the pre-equilibrium formation of (BQ-NCOP)IrIII(H)(OEt) from the catalyst resting state via ethanol dissociation. Regardless of the substrate, ethanol dehydrogenation is the slow segment of the catalytic cycle, while alkene hydrogenation occurs readily following the rate-determining step, that is, ß-hydride elimination of (BQ-NCOP)Ir(H)(OEt) to form (BQ-NCOP)Ir(H)2 and acetaldehyde. The latter is effectively converted to innocent ethyl acetate under the catalytic conditions, thus avoiding the catalyst poisoning via iridium-mediated decarbonylation of acetaldehyde.
RESUMEN
Palladium-catalyzed intermolecular alkylation of enamides with α-bromo carbonyls was developed. Under mild reaction conditions, various cyclic and acyclic enamides reacted well with α-bromo carbonyls to afford the corresponding multi-substituted alkene products in good yields. The coupling products could be converted into very useful γ-amino acid, δ-amino alcohol, 1,4-dicarbonyl and γ-lactam derivatives.
RESUMEN
An efficient Pd-catalyzed silylation reaction of benzylic halides with silylboronate is reported. In this reaction, primary and secondary benzylic halides could react well with silylboronates to afford benzylic silanes. This reaction accommodates a broad substrate scope and proceeds smoothly under very mild reaction conditions. The corresponding products could be obtained in moderate to high yields and with stereospecificity.