New Acetylene Chemistry

Davinia Fernández González
EPFL, 2011
EPFL thesis

Abstract

This thesis is divided in seven main chapters including an introduction about the state of the art in the field, four main chapters describing the main part of the work, a short insight on the implications of the presented results for other research projects and a conclusion. The experimental procedures as well as spectroscopic data are grouped in a special section at the end of the thesis. Acetylenes are versatile intermediates in chemistry, biochemistry and material sciences. The functionalization of alkynes by addition reactions to carbonyl compounds, cycloaddition or coupling reactions using metal catalysis for example make them excellent building blocks for the construction of organic molecules. Furthermore, there are several examples of natural products and drugs containing an acetylene group. Usually, they are synthesized by addition of an acetylide anion to an electrophile. However, the reverse approach (Umpolung of the reactivity) via an electrophilic acetylene synthon has been more rarely used. This constitutes a serious limitation, in particular when considering that "classical" C-C bond formation is not adequate for the synthesis of quaternary centers containing an acetylene. The subject of this thesis is the development of a new class of alkynylation reactions to access propargylic quaternary centers by using hypervalent iodine reagents for the Umpolung of the normal reactivity of alkynes. We started our studies examining the alkynylation reaction with different β-keto esters using the hypervalent iodine reagent TMS-Ethynyl BenziodoXone (TMS-EBX). The excellent reactivity of this cyclic iodine reagent as alkynylation reagent led to the formation of free acetylene products even in the presence of sterically hindered ester groups. The ethynylation reaction proceeded in good yield using TBAF both as a base and fluoride source with TMS-EBX as alkynylation reagent for cyclic and non-cyclic keto esters. Different hypervalent iodine compounds have been tested for the alkynylation of cyclic keto esters. EBX reagents have shown to be generally more efficient than the established iodonium salts. Based on these first results, we next examined the alkynylation of nitro and cyano esters as well as β-keto amides, which have never been used in the past. We were pleased to see that the developed method was also applicable for these classes of compounds affording the corresponding ethynylated products in good yield. The synthetic potential of propargylic nitro compounds bearing free acetylenes was demonstrated by their transformation into propargylic triazoles, hydroxylamines and protected amines, as well as into allyl amines in good yield. We have investigated next, the asymmetric version of the alkynylation reaction under organocatalytic phase-transfer conditions. An enantiomeric excess of 40% has been obtained for cyclic keto esters using cinchona-derived catalysts. Phosphonium catalysts gave an improved enantiomeric excess (51% ee). Higher asymmetric induction has been obtained using the binaphthyl-derived catalysts developed by Maruoka, which has been tested for different substrates to give 12-79% ee. Finally, we have conducted preliminary mechanistic investigations. In situ NMR experiments, isotope labeling and structure-activity relationship studies have allowed us to propose a first crude picture of the catalytic cycle for the alkynylation reaction. In summary, we have reported the first truly general approach for the alkynylation of soft nucleophiles using hypervalent iodine reagents. The developed reaction conditions led to high yields of unprotected acetylenes with cyclic, nitro and linear keto esters as well as keto amides. Furthermore, asymmetric induction was observed using cinchona or binaphthyl derived phase-transfer catalysts (up to 79% ee). This allows a new direct access to chiral acetylene compound in high yields under operationally simple reaction conditions. Future work will be dedicated to the improvement of the enantiomeric excess as well as the scope of the reaction.

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Davinia Fernández González
EPFL, 2011
EPFL thesis

Abstract

Official source

https://infoscience.epfl.ch/record/168988?ln=en

About this result

Related concepts (37)

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Related publications (82)

Related publications

Synthetic methodologies for C-C and C-N bond formation involving alkyl radicals

Guido Barzanò

C-C and C-N bonds are some of the most common structures in molecules ranging from drugs to catalysts and to food additives. Many coupling reactions were developed to form these types of bonds with excellent selectivity and good performance. Still, the synthesis of some of those species either depends on traditional methods or requires expensive and rare reagents and catalysts. The use of precious metals in chemistry, and particularly in the industry, can make molecular synthesis expensive and energy-intensive since the extraction of those materials is costly. Moreover, in homogeneous catalysis, the recovery of metal-based catalysts is almost impossible, making these processes unsustainable for the future. Thus, the discovery of chemical reactions that donât involve precious materials is indispensable. This thesis concentrates on the development of two chemical transformations, one performing an sp2-sp3 radical reductive coupling, one performing a photocatalyzed alkyl amination, involving inexpensive reagents and catalysts. The first chapter reviews the existing methodologies which use alkyl radicals to form carbon-carbon and carbon-nitrogen bonds. Alkyl radicals are formed from alkyl halides and pseudo-halides (Acids, esters, tosylates, etc.) via oxidation or reduction performed by metal or photoredox catalyst. The wide variety of available methodologies was illustrated, highlighting the advantages and weaknesses of each reaction. The second chapter of this dissertation is devoted to the development of a new iron-based catalytic method to form stereoselectively Z-alkene boron species from the corresponding boron-alkyne. This novel stereoselective method opens a new way to obtain these types of molecules with cheap reagents, in high yields, with excellent stereoselectivity (Z:E ratio >10:1), and with good tolerance of functional group. The reaction is radical based, avoiding the problem of beta-hydride elimination, which usually occurs in ionic reactions involving metal centers. In order to prove the versatility of this method, the vinyl boron compound formed from this reaction was used for further functionalizations. The formal total synthesis of a 5-HT2c receptor agonist was successfully performed, improving the overall yield of the process, and avoiding the use of expensive and polluting chemicals. The third chapter of this thesis is concentrated on the development of a tandem photoredox/metal base catalyzed functionalization of anilines and imines with alkyl carboxylic esters. In this reaction, no late transition metal is used, and the traditional metal-based photocatalyst is substituted with an inexpensive and more efficient organic dye. The alkylation of amines is a challenging topic in organic chemistry and classical nucleophilic substitution lacks selectivity and scope. Harvesting visible light with a photoredox catalyst opens the possibility to a radical pathway, making this coupling easy and with high tolerance for functional groups. In order to understand the catalytic cycle of the reaction, additional mechanistic studies were conducted, leading to some insight on how this reaction works.

EPFL2020

The goal of this thesis is to develop new carbon-carbon bond forming reactions using inexpensive and simple coupling partners like aryl halides (pseudohalides), sulfonyl derivatives, Grignard reagents, alkenes and alkynes with metal catalysis, preferably under environmental friendly conditions. A brief review of different cross-coupling reactions is presented applying noble metal catalysts like palladium and nickel. The importance of sustainability and hence the development of alternative iron-catalysis is discussed. The history of iron-catalyzed cross-coupling reactions and their applications to the synthesis of natural products, significant new developments in the field are visited. On our side, we have shown that 2-methylpropene-, prop-2-ene-, 1-methylprop-2-ene- and but-2-enesulfonyl chlorides can be used as electrophilic partners in palladium-catalyzed desulfinylative C-C cross-coupling reactions with both hard and soft nucleophiles. Alk-2-enesulfonate esters can also be used as electrophilic partners in allylic arylations and allylic alkylations. The regioselectivity of the reaction depends on the nature of the catalyst. With PdCl2(PhCN)2, (E)-crotylderivatives are formed with high regioselectivity using either 1-methylprop-2-ene- or but-2-enesulfonyl chlorides. We found also the alk-2-enesulfonyl chlorides that are electrophilic partners in palladium-catalyzed C-C coupling reactions can also be used as nucleophilic partners towards carbonyl compounds by Umpolung. In the presence of a catalytic amount of palladium and a transmetallating agent such as diethylzinc, sulfonyl chlorides can be coupled both with aldehydes and ketones to form homoallylic alcohols in good yields. In the case of unsymmetrical sulfonyl chlorides, regioselectivity depends on the polarity of the solvent and generates selectively products of γ-addition. Most useful is our discovery of conditions permitting the desulfinylative C-C cross-coupling of inexpensive alkanesulfonyl chlorides and Grignard reagents. Above 65 °C, the iron-catalyzed reaction generates products of C-C coupling rather than sulfones. It does not require any expensive and/or toxic ligand. This procedure was also applied to the ligand free iron-catalyzed couplings of alk-2-enesulfonyl chlorides with aromatic and aliphatic Grignard reagents. We have also discovered the synergic effect of iron and copper salts in palladium-free Sonogashira-Hagihara cross-coupling reaction of a wide range of aryl iodides, aromatic and aliphatic alkynes. Together with Dr. R. Loska we have studied the iron-catalyzed Mizoroki-Heck cross-coupling reaction with styrenes. In the presence of iron(II) chloride and potassium tert-butoxide in dimethyl sulfoxide, aryl and heteroaryl iodides undergo stereoselective Mizoroki–Heck C-C cross-coupling reactions with electron-rich alkenes at 60 °C giving the corresponding (E)-alkenes. The best yields were obtained upon addition of a ligand such as proline or picolinic acid. Aryl bromides and pyridinyl bromides are also coupled with styrenes but in lower yields. Finally, we have explored iron-catalyzed C-H activation. Ligand and solvent free-conditions have been developed for the iron-catalyzed oxidative C-C cross-coupling of tertiary amines and terminal alkynes. FeCl2 catalyzes the coupling to generate propargylamines using tert-butylperoxide as oxidant. High chemoselectivity was observed for the aminomethyl group and was attributed to a steric factor.

EPFL2009

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.

EPFL2011

Synthetic methodologies for C-C and C-N bond formation involving alkyl radicals

Guido Barzanò

EPFL2020

EPFL2009

EPFL2011