Joseph Moran

Iridium-catalysed direct C–C coupling of methanol and allenes

Methanol is an abundant (35 million metric tons per year), renewable chemical feedstock, yet its use as a one-carbon building block in fine chemical synthesis is highly underdeveloped. Using a homogeneous iridium catalyst developed in our laboratory, methanol engages in a direct C–C coupling with allenes to furnish higher alcohols that incorporate all-carbon quaternary centres, free of stoichiometric by-products. A catalytic mechanism that involves turnover-limiting methanol oxidation, a consequence of the high energetic demand of methanol dehydrogenation, is corroborated through a series of competition kinetics experiments. This process represents the first catalytic C–C coupling of methanol to provide discrete products of hydrohydroxymethylation. Methanol is an abundant, renewable chemical feedstock. Here, a homogenous iridium catalyst enables a byproduct-free C–C coupling of methanol and allenes, producing higher alcohols that incorporate all-carbon quaternary centres. This process represents the first catalytic C–C coupling of methanol to provide discrete products of hydrohydroxymethylation.

Formation of C-C bonds via ruthenium-catalyzed transfer hydrogenation().

Ruthenium-catalyzed transfer hydrogenation of diverse π-unsaturated reactants in the presence of aldehydes provides products of carbonyl addition. Dehydrogenation of primary alcohols in the presence of the same π-unsaturated reactants provides identical products of carbonyl addition. In this way, carbonyl addition is achieved from the alcohol or aldehyde oxidation level in the absence of stoichiometric organometallic reagents or metallic reductants. In this account, the discovery of ruthenium-catalyzed C–C bond-forming transfer hydrogenations and the recent development of diastereo- and enantioselective variants are discussed.

Diastereo- and Enantioselective Ruthenium Catalyzed Hydrohydroxyalkylation of 2-Silyl-Butadienes: Carbonyl syn- Crotylation from the Alcohol Oxidation Level

Exposure of alcohols 2a-2j to 2-silyl-butadienes in the presence of ruthenium complexes modified by (R)-SEGPHOS or (R)-DM-SEGPHOS results in redox-triggered generation of allylruthenium-aldehyde pairs, which combine to form products of carbonyl crotylation 4a-4j in the absence of stoichiometric byproducts and with high levels of syn-diastereo- and enantioselectivity. In the presence of isopropanol under otherwise identical conditions, aldehydes 3a-3j are converted to an equivalent set of adducts 4a-4j. Whereas reactions conducted using conventional heating require 48 h, microwave irradiation enables full conversion in only 4 h. Finally, as illustrated in the conversion of adduct 4a to compounds 6a and 6b, diastereoselective hydroboration-Suzuki cross-coupling with aryl and vinyl halides followed by Fleming-Tamao oxidation enables generation of anti,syn-stereotriads found in numerous polyketide natural products.

Intermolecular Cope-Type Hydroamination of Alkenes and Alkynes†

Nitrogen-containing functional groups are ubiquitous in natural products and pharmaceuticals. The hydroamination of unactivated alkenes and alkynes is an attractive approach for the synthesis of such molecules, but it is underdeveloped and remains challenging, especially for intermolecular reactions. Most recent progress has been accomplished using transition-metal catalysis, or strong acids with less basic nitrogen nucleophiles, but often procedures are limited to specific substrate classes and functional-group compatibility is either limited or yet undefined. A conceptually different approach to the functionalization of alkenes and alkynes in intramolecular reactions is the Cope-type hydroamination (also referred to as reverse-Cope cyclization). 6] While this strategy has received some attention (particularly in the formation of fiveand six-membered heterocycles), fundamental limitations have precluded its application in synthesis and in more challenging intermolecular reactions. Notably, the nitrogen atom is usually substituted to increase reactivity, but this severely limits the reaction scope, leading to the formation of amine oxides, which are less versatile synthetic intermediates and less stable products. Consequently, the intermolecular process is energetically unfavorable (Scheme 1). To expand the use of this concerted hydroamination strategy, we sought a solution to this requirement for nitrogen substitution (R’, R’’= alkyl). Herein, we report that heating (unsubstituted) aqueous hydroxylamine with alkynes and alkenes affords the intermolecular hydroamination products under mild conditions and in the absence of a metal catalyst. We also present experimental and theoretical evidence which suggest that the reduced reactivity of less substituted hydroxylamines is associated with a difficult intramolecular proton-transfer step rather than a difficult hydroamination step (Scheme 2). Thus, the presence of alcohols or water in our reaction conditions is crucial to mediate a facile, bimolecular proton transfer of the amine oxide intermediate.

A catalytic tethering strategy: simple aldehydes catalyze intermolecular alkene hydroaminations.

Herein we describe a catalytic tethering strategy in which simple aldehyde precatalysts enable, through temporary intramolecularity, room-temperature intermolecular hydroamination reactivity and the synthesis of vicinal diamines. The catalyst allows the formation of a mixed aminal from an allylic amine and a hydroxylamine, resulting in a facile intramolecular hydroamination event. The promising enantioselectivities obtained with a chiral aldehyde also highlight the potential of this catalytic tethering approach in asymmetric catalysis and demonstrate that efficient enantioinduction relying only on temporary intramolecularity is possible.

Intermolecular cope-type hydroamination of alkenes and alkynes using hydroxylamines.

The development of the Cope-type hydroamination as a method for the metal- and acid-free intermolecular hydroamination of hydroxylamines with alkenes and alkynes is described. Aqueous hydroxylamine reacts efficiently with alkynes in a Markovnikov fashion to give oximes and with strained alkenes to give N-alkylhydroxylamines, while unstrained alkenes are more challenging. N-Alkylhydroxylamines also display similar reactivity with strained alkenes and give modest to good yields with vinylarenes. Electron-rich vinylarenes lead to branched products while electron-deficient vinylarenes give linear products. A beneficial additive effect is observed with sodium cyanoborohydride, the extent of which is dependent on the structure of the hydroxylamine. The reaction conditions are found to be compatible with common protecting groups, free OH and NH bonds, as well as bromoarenes. Both experimental and theoretical results suggest the proton transfer step of the N-oxide intermediate is of vital importance in the intermolecular reactions of alkenes. Details are disclosed concerning optimization, reaction scope, limitations, and theoretical analysis by DFT, which includes a detailed molecular orbital description for the concerted hydroamination process and an exhaustive set of calculated potential energy surfaces for the reactions of various alkenes, alkynes, and hydroxylamines.

Polarity Inversion of Donor–Acceptor Cyclopropanes: Disubstituted δ-Lactones via Enantioselective Iridium Catalysis

The coupling of carbonyl electrophiles at the donor position of donor-acceptor cyclopropanes is described, representing an inversion of polarity with respect to conventional reactivity modes displayed by these reagents. Specifically, upon exposure of donor-acceptor cyclopropanes to alcohols in the presence of a cyclometalated iridium catalyst modified by (S)-BINAP, catalytic C-C coupling occurs, providing enantiomerically enriched products of carbonyl allylation. Identical products are obtained upon isopropanol-mediated transfer hydrogenation of donor-acceptor cyclopropanes in the presence of aldehydes. The reaction products are directly transformed to cis-4,5-disubstituted δ-lactones.

Ligand Control of E/Z Selectivity in Nickel-Catalyzed Transfer Hydrogenative Alkyne Semireduction.

A nickel-catalyzed transfer hydrogenative alkyne semireduction protocol that can be applied to both internal and terminal alkynes using formic acid and Zn as the terminal reductants has been developed. In the case of internal alkynes, the (E)- or (Z)-olefin isomer can be accessed selectively under the same reaction conditions by judicious inclusion of a triphos ligand.

Ground-State Chemical Reactivity under Vibrational Coupling to the Vacuum Electromagnetic Field.

Abstract The ground‐state deprotection of a simple alkynylsilane is studied under vibrational strong coupling to the zero‐point fluctuations, or vacuum electromagnetic field, of a resonant IR microfluidic cavity. The reaction rate decreased by a factor of up to 5.5 when the Si−C vibrational stretching modes of the reactant were strongly coupled. The relative change in the reaction rate under strong coupling depends on the Rabi splitting energy. Product analysis by GC‐MS confirmed the kinetic results. Temperature dependence shows that the activation enthalpy and entropy change significantly, suggesting that the transition state is modified from an associative to a dissociative type. These findings show that vibrational strong coupling provides a powerful approach for modifying and controlling chemical landscapes and for understanding reaction mechanisms.

Ketonitrones via Cope-type hydroamination of allenes.

The synthesis of ketonitrones from N-alkylhydroxylamines and monosubstituted allenes is accomplished via a Cope-type hydroamination reaction in moderate to good yields. Allenes also undergo a similar reaction with aqueous hydroxylamine to give oximes in excellent yield. DFT calculations support a proposed concerted, five-membered hydroamination process, and calculated transition state energies are in excellent agreement with experimental observations.