Helga Krause

Preparation, Structure, and Reactivity of Nonstabilized Organoiron Compounds. Implications for Iron-Catalyzed Cross Coupling Reactions

A series of unprecedented organoiron complexes of the formal oxidation states -2, 0, +1, +2, and +3 is presented, which are largely devoid of stabilizing ligands and, in part, also electronically unsaturated (14-, 16-, 17- and 18-electron counts). Specifically, it is shown that nucleophiles unable to undergo beta-hydride elimination, such as MeLi, PhLi, or PhMgBr, rapidly reduce Fe(3+) to Fe(2+) and then exhaustively alkylate the metal center. The resulting homoleptic organoferrate complexes [(Me 4Fe)(MeLi)][Li(OEt 2)] 2 ( 3) and [Ph 4Fe][Li(Et 2O) 2][Li(1,4-dioxane)] ( 5) could be characterized by X-ray crystal structure analysis. However, these exceptionally sensitive compounds turned out to be only moderately nucleophilic, transferring their organic ligands to activated electrophiles only, while being unable to alkylate (hetero)aryl halides unless they are very electron deficient. In striking contrast, Grignard reagents bearing alkyl residues amenable to beta-hydride elimination reduce FeX n ( n = 2, 3) to clusters of the formal composition [Fe(MgX) 2] n . The behavior of these intermetallic species can be emulated by structurally well-defined lithium ferrate complexes of the type [Fe(C 2H 4) 4][Li(tmeda)] 2 ( 8), [Fe(cod) 2][Li(dme)] 2 ( 9), [CpFe(C 2H 4) 2][Li(tmeda)] ( 7), [CpFe(cod)][Li(dme)] ( 11), or [Cp*Fe(C 2H 4) 2][Li(tmeda)] ( 14). Such electron-rich complexes, which are distinguished by short intermetallic Fe-Li bonds, were shown to react with aryl chlorides and allyl halides; the structures and reactivity patterns of the resulting organoiron compounds provide first insights into the elementary steps of low valent iron-catalyzed cross coupling reactions of aryl, alkyl, allyl, benzyl, and propargyl halides with organomagnesium reagents. However, the acquired data suggest that such C-C bond formations can occur, a priori, along different catalytic cycles shuttling between metal centers of the formal oxidation states Fe(+1)/Fe(+3), Fe(0)/Fe(+2), and Fe(-2)/Fe(0). Since these different manifolds are likely interconnected, an unambiguous decision as to which redox cycle dominates in solution remains difficult, even though iron complexes of the lowest accessible formal oxidation states promote the reactions most effectively.

A Cheap Metal for a “Noble” Task: Preparative and Mechanistic Aspects of Cycloisomerization and Cycloaddition Reactions Catalyzed by Low-Valent Iron Complexes

Reaction of ferrocene with lithium in the presence of either ethylene or COD allows the Fe(0)-ate complexes 1 and 4 to be prepared on a large scale, which turned out to be excellent catalysts for a variety of Alder-ene, [4+2], [5+2], and [2+2+2] cycloadditon and cycloisomerization reactions of polyunsaturated substrates. The structures of ferrates 1 and 4 in the solid-state reveal the capacity of the reduced iron center to share electron density with the ligand sphere. This feature, coupled with the kinetic lability of the bound olefins, is thought to be responsible for the ease with which different enyne or diyne substrates undergo oxidative cyclization as the triggering event of the observed skeletal reorganizations. This mechanistic proposal is corroborated by highly indicative deuterium labeling experiments. Moreover, it was possible to intercept two different products of an oxidative cyclization manifold with the aid of the Fe(+1) complex 6, which, despite its 17-electron count, also turned out to be catalytically competent in certain cases. The unusual cyclobutadiene complex 38 derived from 6 and tolane was characterized by X-ray crystallography.

Total synthesis of the turrianes and evaluation of their DNA- cleaving properties

The first total synthesis of three naturally occurring cyclophane derivatives belonging to the turriane family of natural products is described. Their sterically hindered biaryl entity is formed by reaction of the Grignard reagent derived from aryl bromide 10 with the oxazoline derivative 18, and the macrocyclic tether of the targets is efficiently forged by ring closing metathesis. While conventional RCM catalyzed by the ruthenium-carbene complexes 33 or 34 invariably leads to the formation of mixtures of both stereoisomers with the undesirable (E)-alkene prevailing, ring closing alkyne metathesis (RCAM) followed by Lindlar reduction of the resulting cycloalkynes 37 and 38 opens a convenient and stereoselective entry into this class of compounds. RCAM can either be accomplished by using the tungsten alkylidyne complex [(tBuO)3 [triple bond] WCCMe3] or by means of a catalyst formed in situ from [Mo(CO)6] and para-trifluoromethylphenol. The latter method is significantly accelerated when carried out under microwave heating. Furthermore, the judicious choice of the protecting groups for the phenolic -OH functions turned out to be crucial. PMB-ethers were found to be compatible with the diverse reaction conditions en route to 3-5; their cleavage, however, had to be carried out under carefully optimized conditions to minimize competing O-C PMB migration. Turrianes 3-5 are shown to be potent DNA cleaving agents under oxidative conditions when administered in the presence of copper ions.

Efficient relay syntheses and assessment of the DNA-cleaving properties of the pyrrole alkaloid derivatives permethyl storniamide A, lycogalic acid A dimethyl ester, and the halitulin core

Palladium catalyzed Suzuki- and Negishi cross coupling reactions are used to convert the now readily available 3,4-dibromopyrrole derivatives 13 and 26 into the core structures of different pyrrole alkaloids. Several compounds of this series exhibit respectable cytotoxicity and resensitize multidrug resistant (MDR) cancer cell lines at non-toxic concentrations. Cytotoxicity and MDR reversal can be efficiently uncoupled by per-O-methylation of the peripheral hydroxyl groups. For the storniamide core structure 9 it is demonstrated that this chemical modification goes hand in hand with a complete loss of the DNA-cleaving capacity of the alkaloid.

Low-valent titanium induced indole formation: Syntheses of secofascaplysin, indolopyridocoline and an endothelin-receptor-antagonist

Abstract The versatility of a titanium-induced reductive oxo-amide coupling reaction is illustrated by the syntheses of the alkaloids secofascaplysin 8 and indolopyridocoline 14 as well as by an efficient and flexible approach to the arylated indole-2-carboxylic acid 4 , which has recently been disclosed as a promising endothelin-receptor-antagonist. Depending on the particular substitution pattern in the substrates, either pre-formed titanium on graphite or low-valent titanium formed in situ (“instant conditions”) are the preferred coupling agents for reductive heterocycle syntheses of this type.

Elementary steps of iron catalysis: exploring the links between iron alkyl and iron olefin complexes for their relevance in C-H activation and C-C bond formation.

The alkylation of complexes 2 and 7 with Grignard reagents containing β-hydrogen atoms is a process of considerable relevance for the understanding of C-H activation as well as C-C bond formation mediated by low-valent iron species. Specifically, reaction of 2 with EtMgBr under an ethylene atmosphere affords the bis-ethylene complex 1 which is an active precatalyst for prototype [2+2+2] cycloaddition reactions and a valuable probe for mechanistic studies. This aspect is illustrated by its conversion into the bis-alkyne complex 6 as an unprecedented representation of a cycloaddition catalyst loaded with two substrates molecules. On the other hand, alkylation of 2 with 1 equivalent of cyclohexylmagnesium bromide furnished the unique iron alkyl species 11 with a 14-electron count, which has no less than four β-H atoms but is nevertheless stable at low temperature against β-hydride elimination. In contrast, the exhaustive alkylation of 1 with cyclohexylmagnesium bromide triggers two consecutive C-H activation reactions mediated by a single iron center. The resulting complex has a diene dihydride character in solution (15), whereas its structure in the solid state is more consistent with an η(3) -allyl iron hydride rendition featuring an additional agostic interaction (14). Finally, the preparation of the cyclopentadienyl iron complex 25 illustrates how an iron-mediated C-H activation cascade can be coaxed to induce a stereoselective CC bond formation. The structures of all relevant new iron complexes in the solid state are presented.

Preparation, structure and catalytic properties of a binuclear Pd(0) complex with bridging silylene ligands

In contrast to the N-heterocyclic carbene (NHC) 1, the homologous N-heterocyclic silylene (NHS) 4 acts as a bridging ligand to Pd(0), giving rise to the dinuclear complex 5 which is catalytically active in Suzuki reactions.

N-Heterocyclic carbenes can coexist with alkenes and C–H acidic sites

The isolation of compounds 3 and 7a,b proves that a singlet carbene center can coexist with alkenes or C-H acidic sites in proximity without spontaneous annihilation.