Alkyl Transfer Research Articles

Reactions of Aromatic N-Heterocycles with d0fn-Metal Alkyl Complexes Supported by Chelating Diamide Ligands

Aromatic heterocycles are a prominent feature within natural products and pharmaceuticals and considerable efforts are directed toward their synthesis and functionalization. These molecules also appear as unwanted impurities in carbon-based fuels, and processes that fragment them are of increasing interest. Early transition metal-carbon bonds show diverse reactivity toward aromatic heterocycles: researchers have reported both functionalization, relevant to synthetic efforts, and ring opening, relevant to their removal from fuels. In particular, chelating ferrocene-diamides possess unique electronic characteristics as ancillary ligands that enable a wide range of reactivity behaviors for the resulting metal complexes. In this Account, we describe our efforts to understand the reactivity of group 3 metal and uranium alkyl complexes supported by these organometallic ligands toward aromatic N-heterocycles. Two geometrically related ancillary ligands were investigated: 1,1'-ferrocenylene-diamides and pincer-type pyridine-diamides. A substrate-dependent behavior was observed. For example, all the benzyl metal complexes cleaved 1-methylimidazole. In the case of pyridines, differences in reactivity were identified: C-H activation and C-C coupling occurred with substituted pyridines, while alkyl transfer predominated with isoquinoline and chelating pyridines. The products of the C-C coupling or the alkyl-transfer reactions underwent subsequent hydrogen transfer: within the same ring for the substituted pyridines and between two different heterocycles for isoquinoline and chelating pyridines. The comparison between yttrium and lutetium benzyl complexes supported by ferrocene- or pyridine-diamide ligands indicated that similar reactions occurred for specific substrates (1-methylimidazole, 2-picoline, and isoquinoline). A broader range of reaction types and a larger substrate scope were identified, however, for the ferrocene than for the pyridine-type complexes. Based on the reactions discussed in this Account and on isolated examples drawn from the literature, we conclude that the ferrocene-diamides represent a versatile ligand framework. We propose that iron's ability to accommodate changes in the electronic density at the metal center more readily than classical supporting ligands leads to the privileged status of these organometallic ancillary ligands.

Reactions of Aromatic Heterocycles with Uranium Alkyl Complexes

The reactivity of a uranium dibenzyl complex supported by a ferrocenediamide ligand toward aromatic N-heterocycles was investigated. The uranium dibenzyl complex reacted with 1 equiv of pyridine or picoline to give the respective ortho-metalated product. In turn, the eta(2)-N,C-pyridyl complexes reacted with benzoxazole or benzothiazole, leading to a cascade of transformations that involves C-C coupling of the two heterocyclic rings, ring opening, and alkyl transfer. A similar cascade was previously reported for 1-methylimidazole. The present results provide support for the mechanism proposed earlier and attest to the generality of the reaction cascade described.

ChemInform Abstract: High Yield Phase Transfer N-Alkylation of Some Benzodiazepines by Esters of ω-Halo Acids.

Abstract Different i, 4-benzodiazepinyl acetic and propionic acids were prepared by hydrogenolysis of benzyl or hydrolysis of the corresponding ethyl esters which were obtained by phase transfer alkylation of respective amides with benzyl bromoacetate and benzyl or ethyl 2-bromopropionate.

Cross‐Coupling Reactions through the Intramolecular Activation of Alkyl(triorgano)silanes

A palladium/copper-catalyzed transfer of both primary or secondary alkyl groups from [2-(2-hydroxyprop-2-yl)phenyl]-substituted trialkylsilanes to aryl and alkenyl bromides or chlorides in the presence of K3PO4 as mild activator is reported to give a variety of alkylated arenes.

ChemInform Abstract: Organolithium Addition to Styrene and Styrene Derivatives: Scope and Limitations.

Styrene and a range of aryl-substituted styrene derivatives are shown to undergo efficient carbolithiation–trapping reactions in diethyl ether at −78 to −25 °C. The reactivities of different types of organolithium reagents were found to be: tertiary, secondary > primary; ≫ alkenyl, methyl, phenyl. Electron donating groups (e.g. methoxy and dialkylamino) at the ortho- or para- positions of the benzene ring deactivate the double bond towards organolithium addition, but their reactions with butyllithium can be facilitated by using TMEDA as co-solvent. 2-Benzyloxystyrene and 2-allyloxystyrene undergo efficient carbolithiation at −78 °C, but at room temperature alkyl transfer occurs, generating the corresponding alkylated phenol. 2-Vinylnaphthalene also undergoes carbolithiation–carboxylation in reasonable yield.

Trihaloacetaldehyde N, O-acetals: useful building blocks for dihalomethylene compounds

The reaction of trifluoroacetaldehyde N, O-acetals with more than 2 equiv of alkyllithiums at −78 °C resulted in regiospecific defluorinative alkylation with unusual regioselectivity to give α,α-difluoroketone N, O-acetals in excellent yield. In contrast, under similar conditions, trichloroacetaldehyde N, O-acetals gave simple mono-dechlorinated product without the alkyl transfer reaction from alkyllithiums to the generated intermediates.

ChemInform Abstract: Potassium Trifluoroborate Salts as Convenient, Stable Reagents for Difficult Alkyl Transfers

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Reactions of Aromatic N-Heterocycles with Yttrium and Lutetium Benzyl Complexes Supported by a Pyridine-Diamide Ligand

A comparison between the reactivity behavior of yttrium and lutetium benzyl complexes supported by a pyridine diamide, on one hand, and by a ferrocene diamide, on the other hand, toward aromatic N-heterocycles, such as 1-methylimidazole, isoquinoline, acridine, and 2-picoline, is presented. The ring opening of 1-methylimidazole by the pyridine-diamide complexes was observed, analogously to the ring opening of the same substrate by group 3 benzyl complexes supported by the ferrocene-diamide ligand. Also, analogous products were observed in the reactions with 2-picoline and isoquinoline. However, when acridine was employed, different products were obtained for the two metal centers: alkyl transfer for yttrium and ortho-metalation for lutetium.

Si−H Bond Activation of Alkynylsilanes by Group 4 Metallocene Complexes

The reactivity of variously substituted alkynylsilanes toward selected group 4 metallocene complexes was investigated. Reactions of the alkynylsilanes R(1)C(2)SiR(2)(2)H (R(1) = SiMe(3), R(2) = Me, 1; R(1) = SiMe(3), R(2) = Ph, 2; R(1) = SiMe(2)H, R(2) = Me, 5) with Cp(2)TiMe(2) (Cp = eta(5)-cyclopentadienyl) resulted, upon methyl group transfer to the silyl group, in the previously described titanocene alkyne complexes Cp(2)Ti(R(1)C(2)SiR(2)(2)R(3)) (R(1) = Me(3)Si, R(2) = R(3) = Me, 3; R(1) = HMe(2)Si, R(2) = R(3) = Me, 6) or the unreported complex 4 (R(1) = Me(3)Si, R(2) = Ph, R(3) = Me). The Cp(2)TiCl(2)/n-BuLi system yielded alkyne complexes 6 and 7 (R(1) = HMe(2)Si, R(2) = Me, R(3) = H); no alkyl group transfer was detected. On the other hand, reactions utilizing the Cp(2)ZrCl(2)/n-BuLi system afforded inseparable mixtures; however, complexes of the type Cp(2)Zr[R(1)C(2)SiMe(2)(n-Bu)] (R(1) = Me(3)Si, 8; R(1) = HMe(2)Si, 9) were detected. Cp(2)Hf(n-Bu)(2) reacted with the alkynylsilanes in a diverse way, depending on the substituents of the alkyne substrate. The reaction with an excess of alkyne 1 (R(1) = Me(3)Si, R(2) = Me) afforded only an intractable mixture, which contained Me(3)SiC(2)SiMe(2)(n-Bu) (10). Hafnacyclopentadienes 13-15 as precedented product types were obtained when alkyne 12 (R(1) = Ph, R(2) = Me) was used. In sharp contrast, the symmetrically substituted alkynes 5 (R(1) = HMe(2)Si, R(2) = Me) and H(2)PhSiC(2)SiPhH(2) (18) yielded the hitherto unknown Si-containing metallacycles 16 and 19. A reaction mechanism leading to these products was proposed and subsequently supported by DFT calculations. In addition, the reduction of Cp(2)HfCl(2) with magnesium in THF in the presence of alkynylsilanes was shown to be an alternative route to compounds 14-16 and 19. Presumably due to steric reasons, alkyne 1 could not form any of the product types described above. Nevertheless, it was utilized for the preparation of the PMe(3)-stabilized hafnocene alkyne complex 11.

Hybrid Scorpionate/Cyclopentadienyl Magnesium and Zinc Complexes: Synthesis, Coordination Chemistry, and Ring-Opening Polymerization Studies on Cyclic Esters

The reaction of the hybrid scorpionate/cyclopentadienyl lithium salt [Li(bpzcp)(THF)] [bpzcp = 2,2-bis(3,5-dimethylpyrazol-1-yl)-1,1-diphenylethylcyclopentadienyl] with 1 equiv of RMgCl proceeds cleanly to give very high yields of the corresponding monoalkyl kappa(2)-NN-eta(5)-C(5)H(4) magnesium complexes [Mg(R)(kappa(2)-eta(5)-bpzcp)] (R = Me 1, Et 2, (n)Bu 3, (t)Bu 4, CH(2)SiMe(3) 5, CH(2)Ph 6). Hydrolysis of the hybrid lithium salt [Li(bpzcp)(THF)] with NH(4)Cl/H(2)O in ether cleanly affords the two previously described regioisomers: (bpzcpH) 1-[2,2-bis(3,5-dimethylpyrazol-1-yl)-1,1-diphenylethyl]-1,3-cyclopentadiene (a) and 2-[2,2-bis(3,5-dimethylpyrazol-1-yl)-1,1-diphenylethyl]-1,3-cyclopentadiene (b). Subsequent reaction of the bpzcpH hybrid ligand with ZnR(2) quantitatively yields the monoalkyl kappa(2)-NN-eta(1)(pi)-C(5)H(4) zinc complexes [Zn(R){kappa(2)-eta(1)(pi)-bpzcp}] (R = Me 7, Et 8, (t)Bu 9, CH(2)SiMe(3) 10). Additionally, magnesium alkyls 1, 2, 4, and 5 can act as excellent cyclopentadienyl and alkyl transfers to the zinc metal center and yield zinc alkyls 7-10 in good yields. The single-crystal X-ray structures of the derivatives 4, 5, 7, and 10 confirm a 4-coordinative structure with the metal center in a distorted tetrahedral geometry. Interestingly, whereas alkyl magnesium derivatives 4 and 5 present a eta(5) coordination mode for the cyclopentadienyl fragment, zinc derivatives 7 and 10 feature a peripheral eta(1)(pi) arrangement in the solid state. Furthermore, the reaction of the hybrid lithium salt [Li(bpzcp)(THF)] with 1 equiv of ZnCl(2) in tetrahydrofuran (THF) affords very high yields of the chloride complex [ZnCl{kappa(2)-eta(1)(pi)-bpzcp}] (11). Compound 11 was used as a convenient starting material for the synthesis of the aromatic amide zinc compound [Zn(NH-4-MeC(6)H(4)){kappa(2)-eta(1)(pi)-bpzcp}] (12), by reaction with the corresponding aromatic primary amide lithium salt. Alternatively, aliphatic amide and alkoxide derivatives were only accessible by protonolysis of the bis(amide) complexes [M{N(SiMe(3))(2)}(2)] (M = Mg, Zn) and the mixed ligand complex [EtZnOAr)] with the hybrid ligand bpzcpH to afford [Zn(R){kappa(2)-eta(1)(pi)-bpzcp}] (R = N(SiMe(3))(2) 13, R = 2,4,6-Me(3)C(6)H(2)O 14) and [Mg{N(SiMe(3))(2)}(kappa(2)-eta(5)-bpzcp)] (15). Finally, alkyl and alkoxide-containing complexes 1-10 and 14 can act as highly effective single-component living initiators for the ring-opening polymerization of epsilon-caprolactone and lactides over a wide range of temperatures. Epsilon-caprolactone is polymerized within minutes to give high molecular weight polymers with medium-broad polydispersities (M(n) > 10(5), M(w)/M(n) = 1.45). Lactide afforded poly(lactide) materials with medium molecular weights and polydispersities as narrow as M(w)/M(n) = 1.02. Additionally, polymerization of L-lactide occurred without racemization in the propagation process and offered highly crystalline, isotactic poly(L-lactides) with very high melting temperatures (T(m) = 165 degrees C). Microstructural analysis of poly(rac-lactide) by (1)H NMR spectroscopy revealed that propagations occur without appreciable levels of stereoselectivity. Polymer end group analysis showed that the polymerization process is initiated by alkyl transfer to the monomer.

Preparation of MCM-41 supported phosphoric acid catalyst for thiophenic compounds alkylation in FCC gasoline

Abstract The alkylation of thiophenic sulfur compounds with olefins in FCC gasoline followed by distillation of heavy compounds is a good alternative to classical desulfurization technologies. In this study, the preparation condition of MCM-41 supported phosphoric acid catalyst was optimized and the activity tests in real gasoline proved that the optimal catalyst was promising to be applied in the alkylation transfer process of thiophenic sulfurs compared to the HY zeolite previously studied. Moreover, characterization results obtained by XRD and NH3-TPD revealed that the factors affecting on catalytic activity such as surface acid properties and crystallinity were greatly influenced by preparation conditions.

New achiral and chiral NNE heteroscorpionate ligands. Synthesis of homoleptic lithium complexes as well as halide and alkyl scandium and yttrium complexes

The reaction of bis(3,5-dimethylpyrazol-1-yl)methane (bdmpzm) with Bu(n)Li and alkyl- or aryl-containing isocyanates or isothiocyanates, some of which were chiral reagents, and subsequent treatment with saturated aqueous ammonium chloride or HCl in diethyl ether gave (i) new heteroscorpionate ligands in the form of the acetamide or thioacetamide compounds [pbpamH (1), tbpamH (2), sbpamH (3) as racemic mixtures, (S)-mbpamH (4) as an enantiopure compound, pbptamH (5) and tbptamH (6)] and (ii) stabilization of new homoleptic lithium complexes containing fac-coordinating NNE-donor ligands [Li{NNE(H)}(2)]Cl (E = O, S) (7-10). A series of scandium and yttrium complexes have been prepared by the reaction of MCl(3)(THF)(3) (M = Sc, Y) with the amide or thioamide compounds. Under the appropriate experimental conditions mononuclear complexes, namely [MCl(3){kappa(3)-NNE(H)}] (E = O, S) (11-18) have been prepared. A family of alkyl-containing complexes of general formulae [M(CH(2)SiMe(3))(2)(kappa(3)-pbptam)] [M = Sc (19), Y (20)] and [M(CH(2)SiMe(3))(2)(kappa(3)-tbptam)] [M = Sc (21), Y (22)] was also prepared. Preliminary results show that compounds and can act as single-component living initiators for ring-opening polymerization. Polymerization of epsilon-caprolactone occurred within minutes to give medium molecular weight polymers (Mn up to 2 x 10(5)) and narrow polydispersities (Mw/Mn < 1.6). Polymer end group analysis showed that the polymerization process is initiated by alkyl transfer to the monomer. The structures of these complexes have been determined by spectroscopic methods and the X-ray crystal structures of 5, 6 and 8 were also established.

Stabilization and Activation: New Alkyl Complexes of Zinc, Magnesium and Cationic Aluminium Featuring Chelating Bisguanidine Ligands

AbstractIn this work we report on the synthesis of new zinc, magnesium and cationic aluminium alkyl as well as Mg aryl complexes featuring chelating bisguanidine ligands [2,8‐bis(tetramethylguanidino)naphthalene (btmgn) and 1,2‐bis(tetramethylguanidino)benzene (btmgb)]. The bond properties in the complexes are analyzed with a combination of experiments and quantum chemical calculations. VT NMR studies shed light on the fluxional processes within the complexes and their activation barriers. The compounds are stable against alkylation of the C=N imine bonds of the guanidino groups and might represent interesting alkyl transfer reagents and (co‐)catalysts. (© Wiley‐VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2009)

Cytosine Methylation Effects on the Repair of O6-Methylguanines within CG Dinucleotides

O(6)-alkyldeoxyguanine adducts induced by tobacco-specific nitrosamines are repaired by O(6)-alkylguanine DNA alkyltransferase (AGT), which transfers the O(6)-alkyl group from the damaged base to a cysteine residue within the protein. In the present study, a mass spectrometry-based approach was used to analyze the effects of cytosine methylation on the kinetics of AGT repair of O(6)-methyldeoxyguanosine (O(6)-Me-dG) adducts placed within frequently mutated 5'-CG-3' dinucleotides of the p53 tumor suppressor gene. O(6)-Me-dG-containing DNA duplexes were incubated with human recombinant AGT protein, followed by rapid quenching, acid hydrolysis, and isotope dilution high pressure liquid chromatography-electrospray ionization tandem mass spectrometry analysis of unrepaired O(6)-methylguanine. Second-order rate constants were calculated in the absence or presence of the C-5 methyl group at neighboring cytosine residues. We found that the kinetics of AGT-mediated repair of O(6)-Me-dG were affected by neighboring 5-methylcytosine ((Me)C) in a sequence-dependent manner. AGT repair of O(6)-Me-dG adducts placed within 5'-CG-3' dinucleotides of p53 codons 245 and 248 was hindered when (Me)C was present in both DNA strands. In contrast, cytosine methylation within p53 codon 158 slightly increased the rate of O(6)-Me-dG repair by AGT. The effects of (Me)C located immediately 5' and in the base paired position to O(6)-Me-dG were not additive as revealed by experiments with hypomethylated sequences. Furthermore, differences in dealkylation rates did not correlate with AGT protein affinity for cytosine-methylated and unmethylated DNA duplexes or with the rates of AGT-mediated nucleotide flipping, suggesting that (Me)C influences other kinetic steps involved in repair, e.g. the rate of alkyl transfer from DNA to AGT.

Carbon−Carbon Coupling of C(sp3)−F Bonds Using Alumenium Catalysis

Dialkylalumenium cation equivalents coupled with the hexabromocarborane anion function as efficient and long-lived catalysts for alkylation of aliphatic C-F bonds (alkylative defluorination or AlkDF) by alkylaluminum compounds. Only C(sp(3))-F bonds undergo AlkDF; C(sp(2))-F bonds are unaffected. Examples of compounds undergoing AlkDF include monofluoroalkanes, gem-difluorocyclopentane, and compounds containing a CF(3) group attached to either an aryl or an alkyl substituent. Conversion of C-F bonds to C-Me bonds is accomplished with high fidelity using Me(3)Al as the stoichiometric reagent. In reactions with Et(3)Al, hydrodefluorination of the C-F bonds is competitive with alkylation, indicative presumably of competitive hydride vs alkyl transfer from Et(3)Al. In a trialkylaluminum reagent, 1.1-1.4 alkyl groups per Al can be used to replace C-F bonds. Organoaluminum compounds efficiently remove water from the reaction mixture, obviating the need for rigorously dry solvents. Some organoaluminum compounds, especially methylaluminoxane, are capable of AlkDF with more reactive substrates, but catalysis by alumenium offers an advantage over the uncatalyzed C-F activation in terms of both increased rate and, in some cases, a dramatically increased selectivity.

A New Reaction for Organoselenium Compounds: Alkyl Transfer from Diorganoselenium(IV) Dibromides to Alkenoic Acids To Give γ- and δ-Lactones

Various 1-[[bis(1-methylethyl)amino]carbonyl]-2-(dibromo-n-alkylseleno)ferrocene derivatives reacted with 2 equiv of 4-pentenoic acid or 5-hexenoic acid to give the corresponding γ- or δ-lactones, respectively, from transfer of the alkyl group bound to selenium to the terminal alkene carbon. In the lactone cyclization, 1-[[bis(1-methylethyl)amino]carbonyl]-2-(bromoselenenyl)ferrocene (25) is formed and reacts with a second equivalent of the alkenoic acid to give either 5-[1-[[bis(1-methylethyl)amino]carbonyl]ferrocene-2-selenenylmethyl]tetrahydro-2-furanone (23) or 6-[1-[[bis(1-methylethyl)amino]carbonyl]ferrocene-2-selenenylmethyl]tetrahydro-2H-pyran-2-one (26) as a mixture of diastereomers in yields comparable to the corresponding γ- or δ-lactone. The addition of 1-[[bis(1-methylethyl)amino]carbonyl]-2-(dibromo-n-butylseleno)ferrocene to 3-butenoic acid gave alkyl transfer to the internal alkene carbon and formation of the γ-lactone. Density functional theory (DFT) geometry optimizations were performed on several idealized n-alkyldibromselenoferrocene structures to examine the role of iron in the alkyl transfer and the role of various structural features on the alkyl carbon−selenium bond length. The results of the computations suggested that the ferrocenyl iron was not involved in the alkyl transfer reactions.

Palladium catalysis in reductive alkyl group transfer from trialkylamines to nitroarenes followed by cyclization

Abstract Nitroarenes having electron donating and withdrawing substituents are reductively cyclized with an array of trialkylamines in the presence of a catalytic amount of Pd/C along with tin(II) chloride at 120 °C in a toluene/H2O medium to afford quinolines in moderate to good yields. The product yield depends on the position of the substituent of nitroarenes and the chain length of trialkylamines. The addition of tin(II) chloride is essential for the formation of quinolines and toluene/H2O is the solvent of choice.

Direct intramolecular gas‐phase transfer reactions during fragmentation of sildenafil and thiosildenafil analogs in electrospray ionization mass spectrometry

A study is made of the mass spectral fragmentation pathways of sildenafil, thiosildenafil, and analogous compounds. A prominent gas-phase reaction that occurs during collision-induced dissociation (CID) of thiosildenafil compounds is the transfer of an alkyl group from the piperazine nitrogen atom to the sulfur atom of the thiocarbonyl group. This phenomenon is clearly demonstrated through a comparison of electrospray ionization mass spectral fragmentation patterns of four sildenafil-type compounds and three related thiosildenafil derivatives. Molecular modeling and fragmentation patterns support a direct intramolecular alkyl transfer mechanism rather than an ion-neutral complex mechanism. CID of thiohydroxyhomosildenafil results in a facile hydroxyethyl migration to the sulfur atom followed by a second intramolecular reaction to form a spiro-1,3-oxathiolane ring, which fragments in two directions to generate both carbonyl and thiocarbonyl product ions from this thiocarbonyl compound. While methyl migration to the thiocarbonyl sulfur atom of thiosildenafil is dominant, methyl migration to the carbonyl oxygen atom of sildenafil may occur to a small extent.

Novel defluorinative alkylation of trifluoroacetaldehyde N,O-acetal derivatives and its application to multi-component reaction

The reaction of trifluoroacetaldehyde N,O-acetal derivatives with 2 molar equivalents of alkyllithium reagents proceeded viabeta-elimination of fluoride followed by alkyl transfer from excess alkyllithium to the generated ketene N,O-acetal intermediate at the beta-carbon of fluorine groups.

Ruthenium-Catalyzed Synthesis of Benzimidazoles from N-Alkyl-1,2-diaminobenzenes via Alkyl Group Transfer

Conventional benzimi-dazole synthesis can be achieved by condensation between1,2-phenylenediamines and carboxylic acids or derivatives.Besides such a conventional route, transition metal-cata-lyzed reactions for benzimidazole skeletons have also beenattempted as alternative synthetic methods because of thefacility and efficiency of reaction and the wide availabilityof substrates. It was reported that primary alcohols areoxidatively cyclized with 1,2-phenylenediamines in thepresence of RuCl