Alkynyl triazenes enable divergent syntheses of 2-pyrones

The 2-pyrone motif occurs frequently in bioactive natural products and is appreciated as synthetic intermediates. However, only few methods allow for diversifying functional group modifications on this relevant heterocycle. The distinct properties of 1-alkynyl triazenes promote a smooth addition of propiolic acids across the triple bond. Addition of catalytic amounts of silver salt induces cyclization to 2-pyrones. Depending on the reaction temperature, either 6-triazenyl or 5-triazenyl 2-pyrones are selectively formed. The triazenyl unit is subsequently replaced by a variety of valuable groups in a one-pot process yielding for instance 2-fluoro pyrones. The substitution occurs with an intriguing 1,5-carbonyl transposition. Moreover, the triazenyl group serves as traceless activating group for subsequent Diels–Alder cycloadditions and as a constituting unit for rare fused aminopyrazole pyrone heterocycles.

New developments in iron-catalyzed carbon-carbon bond forming reactions

Chandra Mouleeswara Rao Volla

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

Novel Applications of Nitrous Oxide and Transition Metals for C-C and C-N Bond Formation

Gregor Kiefer

This thesis describes novel methods for and investigations into C–C and C–N bond formation reactions. Chapter 1 gives a very brief overview of established strategies for the formation of new C–C bonds in organic synthesis. In chapter 2, a multi‐step one‐pot synthesis is described. Arylalkynes and ethylene are converted to 2‐arylbutadienes by ruthenium catalyzed enyne metathesis. Upon addition of polyhalogenated substrates, the butadienes react in a 1,4‐atom transfer radical addition (ATRA) to yield 1,5‐dichloropen‐2‐enes. These form substituted vinylcyclopropanes via reductive 1,5 dechlorination with magnesium or manganese. Chapter 3 describes a study about two complex organometallic structures that form by reaction of rhodium(III) chloride with tert‐butylacetylene. The reaction products demonstrate the ability of rhodium to mediate various reactions of alkynes such as [2+2+1] cycloadditions, oxidative cleavages and others. Cobalt‐catalyzed reactions for C–C bond formation are reported in chapter 4. In the first part, the focus lies on the putative pre‐catalysts [CoX2(dppe)] (X = Cl, Br, I; dppe = diphenylphosphinoethane), which are used together with a reducing agent (e. g. zinc) in a wide range of C–C bond formation reactions. It is shown that they are, in reality, complex salts of the formula [CoX(dppe)2]2[X3Co(dppe)CoX3]. The second part describes the synthesis and characterization of the complexes [CoX(dppe)(PPh3)] and [CoX(dppe)(η4‐isoprene)]. Without addition of a reducing agent, these cobalt(I) complexes catalyze reactions that are usually accomplished with the catalyst system Co(II)/dppe/Zn. These results provide evidence that the active species in these reactions are indeed Co(I) complexes as supposed. In the fifth chapter, two methods for the use of nitrous oxide (N2O, laughing gas) in organic reactions are described. The challenge of using N2O in synthetic chemistry is to overcome its kinetic inertness. In the oxidative homo‐ and cross‐coupling of Grignard reagents, N2O takes the role of an oxidizing agent. The reactions proceed under mild conditions with copper, iron and cobalt salts as catalysts and exhibit high turnover numbers. The utilization of N2O has advantages compared to established methods with other oxidation agents such as oxygen. Furthermore, a procedure for the synthesis of triazenes from lithium dialkylamides, N2O and Grignard reagents is described. This method enables the synthesis of aryl and alkyl triazenes, but also alkenyl and alkynyl triazenes that are difficult to access via established procedures. Some alkynyl triazenes are selectively cytotoxic against certain cancer cell lines.

EPFL2015

Stereoselective synthesis of alkenes via base-metal-catalyzed addition reactions to alkynes and activation of hydrogen peroxide and carbon dioxide by iron complexes

Fedor Zhurkin

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.

EPFL2017