Streamlined Alkylation via Nickel-Hydride-Catalyzed Hydrocarbonation of Alkenes

Srikrishna Bera, Chao Fan, Xile Hu, Zhikun Zhang
AMER CHEMICAL SOC, 2022
Article

Résumé

Compounds rich in sp(3)-hybridized carbons are desirable in drug discovery. Nickel-catalyzed hydrocarbonation of alkenes is a potentially efficient method to synthesize these compounds. By using abundant, readily available, and stable alkenes as pro-nucleophiles, these reactions can have broad scope and high functional group tolerance. However, this methodology is still in an early stage of development, as the first efficient examples were reported only in 2016. Herein, we summarize the progress of this emerging field, with an emphasis on enantioselective reactions. We highlight major developments, critically discuss a wide range of possible mechanisms, and offer our perspective of the state and challenges of the field. We hope this Perspective will stimulate future works in this area, making the methodology widely applicable in organic synthesis.

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Palladium Catalysed Intramolecular Carbo-oxygenation of Propargylic Amines to Access 1,2-Amino Alcohols and alpha-Amino Ketones via in situ Tether Formation

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a-Amino ketones and 1,2-amino alcohols are important structural motifs in organic chemistry, that can be observed in natural products, pharmaceutically and bioactive compounds. For these reasons, they constitute privileged targets for the development of new and effective synthetic methods. The dual-functionalisation of unsaturated carbon-carbon bonds is a powerful approach to access these crucial motifs. In this context, Pd catalysis has been comprehensively investigated and has consistently demonstrated its capability. Methods enabling the concomitant formation of a carbonâ heteroatom and a carbonâcarbon bond are highly valuable, but the challenges of intermolecular reactions have led to the development of tether systems that require additional steps for their introduction and removal. In situ tethering strategies have previously been explored within the Waser group to circumvent these limitations. This approach relies on a one-pot, three component, Pd catalysed carboetherification or amination reaction, leading to rapidly increase in complexity of simple substrates. So far, the in situ methodologies developed by the Waser group have focused on the functionalisation of alkenes from allylic amines and alcohols. In this regard, the goal of my PhD was to expand the in situ tethering methodologies established within the Waser group, to the synthesis of a-amino ketones and 1,2-amino alcohols. Specifically, my focus was on the formation a trifluoromethyl hemiaminal with a propargylic amine and using the resulting aminal to direct the oxyalkynylation and oxyarylation of the alkyne substrate via a Pd catalysed transformation. Upon optimisation, the reaction of a protected terminal propargylamine, trifluoroacetaldehyde ethyl hemiacetal and silylbromoacetylene using a Pd0 complex with DPEPhos as the catalytic system and Cs2CO3 as the base gave the desired oxazolidine alkenes in high yields and E:Z selectivity. Substrates with substitution on the terminal position and at the propargylic required a change of ligand and base. The transformation was broadly tolerant towards substitution on the nitrogen and the alkyne. An oxyarylative variant was also developed, using Ruphos as ligand, and worked well with a range of iodoarene partners. The obtained oxazolidines could be conveniently orthogonally deprotected to access the a-amino ketone and terminal alkyne; the hydrogenation of the unsaturated oxazolidines has allowed access to 1,2-amino alcohol scaffolds and the application of gold catalysis converted the enyne-oxazolidine system into trisubstituted silyl furans. The identification of a sideproduct of the oxyalkynylation process led to the development of a carboxy-alkynylation reaction using a "CO2" unit derived from the carbonate base. Optimisation established CsHCO3 to the best base/"CO2" source, using DPEPhos as ligand. This transformation gave convenient access to diverse library of cyclic carbamates. Work is ongoing to achieve an enantioselective oxyarylation using chiral phosphine ligands. The asymmetric synthesis of oxazolidines, followed by the diastereoselective alkene hydrogenation and subsequent tether removal would allow the stereodivergent access to interesting diarylalkyl-1,2- amino alcohols. Most recently, the product was synthesised in 66% yield, with 66%ee using commercially available Trost ligand.

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Alkene functionality can be found in the majority of natural products, drugs, catalysts and organic materials. Therefore, methods of C-C double bond formation constitute a cornerstone of organic synthesis. Selective formation of either (Z)- or (E)-isomer is especially desirable. 1,2-Addition to alkynes unites a large arsenal of methods of C-C double bond formation, among which the addition of carbon-centered species is the most interesting, since it offers a possibility of construction of the carbon skeleton. The first part of the present dissertation is devoted to the development of methods of selective addition of carbon reagents to alkynes. Chapter 1 reviews the existing methods of addition of carbon-centered species, generated from organometallic reagents, organic halides or carbonyl compounds to C-C triple bond with the accent on their stereoselectivity. Carbometalative mechanisms lay in the background of the majority of the reactions in this chemistry. The Z/E selectivity of 1,2-addition to triple bond can be controlled via predominance of either syn- or anti-addition or via Z/E isomerization of the addition intermediates. In Chapter 2 a novel method of disubstituted alkene synthesis via reductive addition of alkyl halides to terminal arylalkynes is described. The remarkable feature of this method is highly selective formation of (Z)-alkenes (generally Z/E > 10:1). Minor modifications of the reducing agent allowed the extension of the substrate scope to the primary alkyl iodides. Mechanistic studies revealed that this reaction proceeds as a formal anti-carbozincation. The resulting organozinc species form disubstituted (Z)-alkenes upon aqueous work-up. On the other hand, it would be interesting to utilize these species in cross-coupling reactions to allow the selective synthesis of trisubstituted alkenes. In Chapter 3 a catalytic system for highly regioselective copper-catalyzed allylation of these reagents is described. In Chapter 4 the results on stereoselective intermolecular addition of aldehydes and ketones to alkynes in the presence of zinc and trimethylchlorosilane are summarized. This reaction gives 1-chloro-1,3-dienes as products. The activation of small molecules has become an increasingly attractive area of research over the last years. In Chapter 5 an outline is given of the literature examples of small-molecule activation, namely activation of carbon dioxide and hydrogen peroxide, by iron complexes. In Chapter 6 the studies on small-molecule activation by iron-sulfur cubane clusters are presented. Electrochemical reduction of carbon dioxide and hydrogenation of alkenes were studied. As an additional result, synthesis and characterization of an unprecedented organic iron(I) ate-complex is reported. Structural modification of a non-heme iron complex with hydrogen-bond-donating substituents is described in Chapter 7. The deep impact of these modifications on the structure and reactivity of the resulting complex is discussed.

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Carbon-carbon bond forming reactions are among the most important and useful methods for organic synthesis. During the last years, significant progress has been made in this field. Whereas many catalysts were developed for the coupling of aryl, alkenyl, and alkynyl halides, non-activated alkyl halides remain challenging substrates, mainly due to unproductive β-hydride elimination and difficulty in oxidative addition of alkyl halides. This dissertation is devoted to the development of a well-defined nickel catalyst for cross coupling of non-activated alkyl halides and direct alkylation of C–H bonds. Chapter 2 describes the synthesis of a new pincer MeN2N ligand and its Ni complexes. This ligand can be obtained by Pd-catalyzed C–N coupling of 2-amino-N,N-dimethylaniline and 2-bromo-N,N-dimethylaniline. Reaction of its Li salt with Ni(dme)Cl2 gives [(MeN2N)Ni-Cl] (1). Complex 1 can be akylated with Grignard reagents to give [(MeN2N)Ni-Alkyl] species. Stability of the alkyl complexes against β-hydride elimination inspired us to use the [(MeN2N)Ni-Cl] complex as a catalyst for cross coupling of carbon nucleophiles with alkyl halides. After investigating different experimental conditions, we found that complex 1 is an active catalyst for cross coupling of non-activated alkyl polyhalides (Chapter 3) and alkyl monohalides (Chapter 4) with alkyl Grignard reagents. The reaction with alkyl monohalides can be done at -35 °C in DMA and only 30min is required to accomplish the formation of the desired products. The high activity of the catalyst resulted in a high group tolerance. Ester, ketone, amide, nitrile, heterocyclic, and acetal groups didn't pose problems. In Chapter 5, the catalysis was extended to include aryl and heteroaryl Grignard reagents as nucleophiles. The best results were obtained with primary alkyl bromides and iodides and cyclic secondary alkyl iodides in THF and at room temperature. Addition of an additive such as TMEDA or bis[2-(N,N-dimethylaminoethyl)]ether (O-TMEDA) was necessary to prevent the formation of undesired homocoupling products. Functionalized Grignard reagents could be readily coupled. The [(MeN2N)Ni-Cl] catalyst was then used for the Sonogashira coupling of alkyl halides with alkynes (Chapter 6). A wide range of functionalized alkyl halides could be used for this reaction. Not only alkyl iodides and bromides but also alkyl chlorides can be used. Moreover, by changing reaction conditions (additive and temperature), selective coupling of C–Br bond in the presence of C–Cl bond, and of C–I bond in the presence of both C–Br and C–Cl bonds can be achieved. This feature allowed us to carry out multiple and selective Sonogashira coupling of the substrates containing different alkyl halide bonds. We could combine Sonogashira coupling with Kumada-Corriu-Tamao coupling. Utilization of these two methods leads to a simple and rapid synthesis of organic molecules. Similar conditions were then applied for the direct alkylation of aromatic heterocycles in Chapter 7. Aromatic heterocyclic compounds are widely used as bio-active molecules, pharmaceuticals, and organic materials. Direct C–H functionalization represents the most straightforward way for the derivatization of these compounds. Despite of the developments during the last years, direct alkylation of C–H bond with alkyl halides is still challenging. Utilization of our [(MeN2N)Ni-Cl] catalyst gives the desired products in high yields and a wide range of aromatic heterocyclic compounds can be used for the reaction. The well-defined nature and a high stability of [(MeN2N)Ni-Cl] complex and its derivatives enabled us to perform detailed mechanistic investigations of the catalytic transformations. Presumed intermediates of catalytic cycles were determined and some of them were synthesized or separated from the reaction mixture. The resting states of the catalysts were also defined in most of the cases, giving important information for the mechanistic elucidation. In the last part (Chapter 8) we developed a direct C–H carboxylation chemistry for aromatic heterocycles. The carboxylation can be done under catalyst-free conditions and with a mild base Cs2CO3. The unstable carboxylic acids were converted to the more stable esters by a one-pot reaction with MeI. A wide substrate scope was achieved.

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